Inhibiting the transient receptor potential A1 ion channel (2025)

U.S. patent number 10,221,177 [Application Number 15/512,213] was granted by the patent office on 2019-03-05 for inhibiting the transient receptor potential a1 ion channel. This patent grant is currently assigned to Hydra Biosciences, Inc.. The grantee listed for this patent is HYDRA BIOSCIENCES, INC.. Invention is credited to Bertrand L. Chenard, Xinyuan Wu.

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Inhibiting the transient receptor potential A1 ion channel

Abstract

The present invention relates to pharmaceutical compounds of theFormula (I), or a pharmaceutically acceptable salt or compositionthereof, and methods of their use for the treatment of pain,respiratory conditions, as well as inhibiting the TransientReceptor Potential A1 ion channel (TRPA1).

Prior Publication Data

Related U.S. Patent Documents

References Cited [Referenced By]

U.S. Patent Documents

Foreign Patent Documents

Other References

Primary Examiner: Rao; Deepak R
Assistant Examiner: Daniel; Laura M
Attorney, Agent or Firm: Goodwin Procter LLP

Parent Case Text

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a U.S. National Phase Application under 35U.S.C. .sctn. 371 of International Application No.PCT/US2015/051063, filed Sep. 18, 2015, which claims the benefit ofU.S. Provisional Application 62/052,678 filed on Sep. 19, 2014. Theentire contents of these applications are incorporated herein byreference in their entirety.

Claims

The invention claimed is:

1. A compound of Formula (I): ##STR00806## or a pharmaceuticallyacceptable salt thereof, wherein: R.sup.1 is hydroxypropyl,hydroxylethyl, hydroxymethyl, --C.sub.1-C.sub.6alkyl-O--C.sub.0-C.sub.6 alkyl, --C.sub.0-C.sub.6alkyl-O--C.sub.1-C.sub.6 alkyl, --C.sub.1-C.sub.6alkyl-C(O)--C.sub.0-C.sub.6 alkyl, --C.sub.0-C.sub.6alkyl-C(O)--C.sub.1-C.sub.6 alkyl, --C.sub.1-C.sub.6alkyl-C(O)N(R.sup.8).sub.2, --C.sub.1-C.sub.6 alkyl-CN,--C.sub.1-C.sub.6 haloalkyl, aryl, heteroaryl, heterocyclyl,heteroarylalkyl, or heterocyclylalkyl, each of which is substitutedwith (R.sup.7).sub.1-7; R.sup.2 is H or C.sub.1-C.sub.6 alkyl;R.sup.3 is a 3 to 8-membered cycloalkyl, aryl, heterocyclyl, orheteroaryl, each of which is substituted with (R.sup.4).sub.1-2 inaddition to the R.sup.4 shown in Formula (I); R.sup.4 isindependently H, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 alkoxy,C.sub.1-C.sub.3 haloalkyl, --C.sub.1-C.sub.6alkyl-O--C.sub.0-C.sub.6 alkyl, --C.sub.0-C.sub.6alkyl-O--C.sub.1-C.sub.6 alkyl, --N(R.sup.8).sub.2, 3 to 8-memberedcycloalkyl, aryl, heterocyclyl, heterocyclylalkyl, heteroaryl,cyano, or halo, or two R.sup.4 together with the atoms to whichthey are attached may form an optionally substituted 3 to7-membered ring each of which is optionally substituted with(R.sup.5).sub.1-3; R.sup.5 is independently H, C.sub.3-C.sub.10heterocyclyl, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 alkoxy,--C.sub.1-C.sub.6 alkyl-O--C.sub.0-C.sub.6 alkyl, --C.sub.0-C.sub.6alkyl-O--C.sub.1-C.sub.6 alkyl, --N(C.sub.1-C.sub.3 alkyl).sub.2,C.sub.1-C.sub.6 haloalkyl, --C.sub.1-C.sub.3alkyl-N(R.sup.8).sub.2, heterocyclylalkyl, halo, cyano, or keto,each of which is optionally substituted with (R.sup.7).sub.1-3;R.sup.6 is H or C.sub.1-C.sub.6 alkyl; R.sup.7 is independently H,C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 haloalkyl,hydroxy, aryl, heteroaryl, heterocyclyl, arylalkyl, aryloxy,heteroaryloxy, arylalkoxy, heteroarylalkoxy, heterarylalkyl,haloalkyl, keto, cyano, or halo, or two R.sup.6 together with theatoms to which they are attached may form an optionally substituted3 to 7-membered ring; and R.sup.8 is H, C.sub.1-C.sub.6 alkyl, orC.sub.1-C.sub.6 haloalkyl.

2. The compound of claim 1, wherein R.sup.1 is, hydroxypropyl,hydroxylethyl, hydroxymethyl, --C.sub.1-C.sub.4alkyl-O--C.sub.0-C.sub.4 alkyl, --C.sub.0-C.sub.4alkyl-O--C.sub.1-C.sub.4 alkyl, --C.sub.0-C.sub.4alkyl-C(O)--C.sub.1-C.sub.5 alkyl-, --C.sub.1-C.sub.4alkyl-C(O)--C.sub.0-C.sub.5 alkyl, C.sub.1-C.sub.2alkyl-C(O)N(R.sup.8).sub.2, --C.sub.1-C.sub.6 alkyl-CF.sub.3,--C.sub.2-C.sub.4 alkyl-CN, heteroarylalkyl, or heterocyclylalkyl,each of which is optionally substituted with (R.sup.7).sub.1-4.

3. The compound of claim 1, wherein R.sup.1 is hydroxypropyl,hydroxylethyl, ketopentyl, hydroxymethyl, pyridinylmethyl,oxazolylmethyl, methylisoxazolylmethyl, oxetanylmethyl,oxadiazolylmethyl, methyloxadiazolylmethyl, methoxyethyl,hydroxymethoxypropyl, methoxyketopropyl, ketomethylbutyl,ketopropyl, ketobutyl, acetamido, cyanomethyl, methylacetamido,trifluoroethyl, or trifluoropropyl.

4. The compound of claim 1, wherein R.sup.1 is ##STR00807####STR00808##

5. The compound of claim 1, wherein R.sup.2 is methyl.

6. The compound of claim 1, wherein R.sup.2 is H.

7. The compound of claim 1, wherein R.sup.3 is aryl or heteroaryl,each of which is substituted with (R.sup.4).sub.1-2, in addition tothe R.sup.4 shown in Formula (I).

8. The compound of claim 1, wherein R.sup.3 is phenyl, pyridyl,pyrimidinyl, pyrazinyl, or thiazolyl, each of which is substitutedwith (R.sup.4).sub.1-2, in addition to the R.sup.4 shown in Formula(I).

9. The compound of claim 1, wherein R.sup.3 is ##STR00809##

10. The compound of claim 1, wherein R.sup.4 is H, C.sub.1-C.sub.3alkyl, C.sub.1-C.sub.3 alkoxy, C.sub.1-C.sub.3 haloalkyl,--N(R.sup.8).sub.2, 3 to 8-membered cycloalkyl, aryl, heterocyclyl,heteroaryl, cyano, or halo, or two R.sup.4 together with the atomsto which they are attached may form an optionally substituted 3 to7-membered ring each of which is optionally substituted with(R.sup.5).sub.1-3.

11. The compound of claim 1, wherein R.sup.4 is independently H,methyl, ethyl, propyl, --N(R.sup.8).sub.2, phenyl, halo, cyano,haloalkyl, methoxy, pyridinyl, pyrimidinyl, oxadiazolyl,piperdinyl, azetidinyl, pyrazinyl, azabicyclohexyl, piperazinyl, orpyrrolidinyl, each of which is substituted with(R.sup.5).sub.1-2.

12. The compound of claim 1, wherein R.sup.4 is independently H,methyl, ethyl, propyl, cyano, methoxy, chlorine, fluorine, bromine,--CF.sub.3, --CF.sub.2, ##STR00810##

13. The compound of claim 1, wherein R.sup.5 is independently H,pyrrolidinyl, trifluoromethyl, trifluoroethyl, halo, methyl,isopropyl, cyano, propyl, ethyl, azabicyclohexyl,difluoroazabicyclohexyl, keto, methoxy, methoxyethyl, dialkylamino,or ethoxy, each of which is optionally substituted with(R.sup.6).sub.1-3.

14. The compound of claim 1, wherein R.sup.5 is independently H,--CF.sub.3, cyanomethyl, bromine, chlorine, fluorine, methyl,ethyl, isopropyl, cyano, keto, ##STR00811##

15. The compound of claim 1, wherein R.sup.6 is H.

16. The compound of claim 1, wherein R.sup.6 is methyl.

17. The compound of claim 1, wherein R.sup.8 is H, methyl, ethyl,or CF.sub.3.

18. The compound of claim 1, wherein R.sup.1 is ##STR00812##R.sup.2 is H or methyl; R.sup.3 is ##STR00813## R.sup.4 isindependently H, methyl, ethyl, propyl, cyano, methoxy, chlorine,fluorine, bromine, --CF.sub.3, --CF.sub.2, ##STR00814## R.sup.5 isindependently H, --CF.sub.3, cyanomethyl, bromine, chlorine,fluorine, methyl, ethyl, isopropyl, cyano, keto, ##STR00815##R.sup.6 is H or methyl; and R.sup.8 is H, methyl, ethyl, orCF.sub.3.

19. The compound claim 1, wherein the compound is selected from thegroup consisting of: ##STR00816## ##STR00817## ##STR00818####STR00819## ##STR00820## ##STR00821## ##STR00822## ##STR00823####STR00824## ##STR00825## ##STR00826## ##STR00827## ##STR00828####STR00829## ##STR00830## ##STR00831## ##STR00832## ##STR00833####STR00834## ##STR00835## ##STR00836## ##STR00837## ##STR00838####STR00839## ##STR00840## ##STR00841## ##STR00842## ##STR00843####STR00844## ##STR00845## ##STR00846## ##STR00847## ##STR00848####STR00849## ##STR00850## ##STR00851## ##STR00852## ##STR00853####STR00854## ##STR00855## ##STR00856## ##STR00857## ##STR00858####STR00859## ##STR00860## ##STR00861## ##STR00862##

20. A pharmaceutical composition comprising at least one compoundaccording to claim 1 or a pharmaceutically acceptable salt thereofin a mixture with a pharmaceutically acceptable excipient, diluentor carrier.

21. A compound according to claim 1 for use as a medicament.

22. A compound according to claim 1 or a pharmaceuticallyacceptable salt thereof for use in the treatment of a disorderselected from the group consisting of: pain, atopic dermatitis,acute pruritis, psoriasis, hives, eczema, mouth ulcers, diaperrash, cough, chronic obstructive pulmonary disease and asthma.

Description

TECHNICAL FIELD

The present invention relates to pharmaceutical compounds,compositions, and methods for the treatment of pain, respiratoryconditions, as well as inhibiting the Transient Receptor PotentialA1 ion channel (TRPA1).

BACKGROUND

Transient Receptor Potential A1 (herein, "TRPA1") is anon-selective cation channel related to pain sensation in humans.TRPA1 is found in sensory neurons and functions as a detector thathelps link detection of noxious chemicals, tissue damage, andinflammation to pain. Activation of TRPA1 is believed to cause painby inducing firing of nociceptive neurons and driving centralsensitization in the spinal cord. TRPA1 stimulation can alsoincrease firing of sensory neurons, leading to the release ofpro-inflammatory neuropeptides such as NK-A, substance P and CGRP(which induce vasodilation and help recruit immune cells). Avariety of endogenous reactive compounds produced duringinflammation activate TRPA1 (including 4-hydroxynonenal releasedduring liposome peroxidation; cyclopentane prostaglandinssynthesized by COX enzymes; hydrogen peroxide produced by oxidativestress). Activation of TRPA1 also sensitizes TRPA1 to cold.Furthermore, a gain-of-function mutation in TRPA1 causes familialepisodic pain syndrome; patients suffering from this condition haveepisodic pain that may be triggered by cold. Thus, TRPA1 isconsidered to play a role in pain related to nerve damage, coldallodynia, and inflammatory pain.

Compounds that inhibit the TRPA1 ion channel can be useful, forexample, in treating conditions ameliorated, eliminated orprevented by inhibition of the TRPA1 ion channel. For example,pharmaceutical compositions that inhibit TRPA1 can be used to treatpain. Inhibition of TRPA1 (e.g., by genetic ablation and chemicalantagonism) has been shown to result in reduced pain behavior inmice and rats. Knockout mice lacking functional TRPA1 havediminished nociceptive responses to TRPA1 activators (includingAITC, formalin, acrolein, 4-hydroxynonenal) and, in addition, havegreatly reduced thermal and mechanical hypersensitivity in responseto the inflammatory mediator bradykinin (e.g., Kwan, K. Y. et al.Neuron 2006, 50, 277-289; Bautista, D. M. et al. Cell 2006, 124,1269-1282). In animal pain models, down regulation of TRPA1expression by gene specific antisenses prevented and reversed coldhyperalgesia induced by inflammation and nerve injury (See, e.g.,Obata, K. et al., Journal of Clinical Investigation 2005, 115,2393-2401; Jordt, S. E. et al., Nature 2004, 427, 260-265; Katsura,H. et al., Exploratory Neurology 2006, 200, 112-123). TRPA1inhibitor compounds are effective in a variety of rodent painmodels. TRPA1 inhibitors have been shown to reduce mechanicalhypersensitivity and cold allodynia following inflammation inducedby Complete Freund's Adjuvant (without altering normal coldsensation in naive animals) and also to improve function in the ratmono-iodoacetate osteoarthritis model. Materazzi, S et al.,European Journal of Physiology 2012, 463(4):561-9; Wei H et al.,Anesthesiology 2012, 117(1):137-48; Koivisto, A et al., PharmacolRes. 2012, 65(1):149-58. TRPA1 inhibitor compounds havedemonstrated reduced pain behavior in rodents injected with AITC(mustard oil), formalin, cinnamaldehyde, acrolein, and other TRPA1activators. TRPA1 inhibitor compounds have also demonstratedefficacy in rodent models for postoperative pain, see, for example,Wei et al., Anesthesiology 2012, 117(1):137-48; chemotherapyinduced peripheral neuropathy, see, for example, Trevisan, et al.,Cancer Res. 2013 May 15; 73(10):3120-31 Online Mar. 11, 2013; andpainful diabetic neuropathy, see, for example, Koivisto et al.,Pharmacol Res (2011).

SUMMARY OF THE INVENTION

The present invention provides compounds of the Formula (I) andpharmaceutically acceptable salts thereof:

##STR00001## wherein each of the variables above are as describedherein, for example, in the detailed description below.

The present invention further provides compositions comprising acompound of Formula (I) and a pharmaceutically acceptableexcipient, diluent or carrier.

The compounds and compositions described herein can be used totreat various disorders in a subject. For example, described hereinare methods of treatment such as a method of treating a TRPA1mediated disorder in a subject, the method comprising administeringan effective amount of a compound of Formula (I), or apharmaceutically acceptable salt thereof. Methods of treating painin a subject, the method comprising administering an effectiveamount of a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof are also described herein. Exemplary typesof pain include neuropathic pain, e.g., painful diabeticneuropathy, chemotherapy-induced peripheral neuropathy, lower backpain, trigeminal neuralgia, post-herpetic neuralgia, sciatica, andcomplex regional pain syndrome; inflammatory pain, e.g., fromrheumatoid arthritis, osteoarthritis, temperomandibular disorder;PDN or CIPN; visceral pain, e.g., from pancreatitis, inflammatorybowel disease, colitis, Crohn's disease, endometriosis, pelvicpain, and angina; pain selected from the group: cancer pain, burnpain, oral pain, crush and injury-induced pain, incisional pain,bone pain, sickle cell disease pain, fibromyalgia andmusculoskeletal pain; or pain from hyperalgesia or allodynia.

DETAILED DESCRIPTION

The present invention provides compounds of Formula I:

##STR00002## or a pharmaceutically acceptable salt thereof,wherein:

R.sup.1 is C.sub.2-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,C.sub.2-C.sub.6 alkynyl, --C.sub.1-C.sub.6 alkyl-O--C.sub.0-C.sub.6alkyl, --C.sub.0-C.sub.6 alkyl-O--C.sub.1-C.sub.6 alkyl,--C.sub.1-C.sub.6 alkyl-C(O)--C.sub.0-C.sub.6 alkyl,--C.sub.0-C.sub.6 alkyl-C(O)--C.sub.1-C.sub.6 alkyl,--C.sub.1-C.sub.6 alkyl-C(O)N(R.sup.8).sub.2, --C.sub.1-C.sub.6alkyl-CN, --C.sub.1-C.sub.6 haloalkyl, aryl, heteroaryl,heterocyclyl, heteroarylalkyl, or heterocyclylalkyl, each of whichis substituted with (R.sup.7).sub.1-7;

R.sup.2 is H or C.sub.1-C.sub.6 alkyl;

R.sup.3 is a 3 to 8-membered cycloalkyl, aryl, heterocyclyl, orheteroaryl, each of which is substituted with(R.sup.4).sub.1-2;

R.sup.4 is independently H, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3alkoxy, C.sub.1-C.sub.3 haloalkyl, --C.sub.1-C.sub.6alkyl-O--C.sub.0-C.sub.6 alkyl, --C.sub.0-C.sub.6alkyl-O--C.sub.1-C.sub.6 alkyl, --N(R.sup.8).sub.2, 3 to 8-memberedcycloalkyl, aryl, heterocyclyl, heterocyclylalkyl, heteroaryl,cyano, or halo, or two R.sup.4 together with the atoms to whichthey are attached may form an optionally substituted 3 to7-membered ring each of which is optionally substituted with(R.sup.5).sub.1-3;

R.sup.5 is independently H, C.sub.3-C.sub.10 heterocyclyl,C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 alkoxy, --C.sub.1-C.sub.6alkyl-O--C.sub.0-C.sub.6 alkyl, --C.sub.0-C.sub.6alkyl-O--C.sub.1-C.sub.6 alkyl, --N(C.sub.1-C.sub.3 alkyl).sub.2,C.sub.1-C.sub.6 haloalkyl, --C.sub.1-C.sub.3alkyl-N(R.sup.8).sub.2, heterocyclylalkyl, halo, cyano, or keto,each of which is optionally substituted with (R.sup.7).sub.1-3;

R.sup.6 is H or C.sub.1-C.sub.6 alkyl;

R.sup.7 is independently H, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 alkoxy,C.sub.1-C.sub.6 haloalkyl, hydroxy, aryl, heteroaryl, heterocyclyl,arylalkyl, aryloxy, heteroaryloxy, arylalkoxy, heteroarylalkoxy,heterarylalkyl, haloalkyl, keto, cyano, or halo, or two R.sup.6together with the atoms to which they are attached may form anoptionally substituted 3 to 7-membered ring; and

R.sup.8 is H, C.sub.1-C.sub.6 alkyl, or C.sub.1-C.sub.6haloalkyl.

In a second embodiment, in the general Formula I, R.sup.2, R.sup.3,R.sup.4, R.sup.5, R.sup.6, R.sup.7, and R.sup.8 have the meaning asdefined in the preceding embodiments and R.sup.1 is C.sub.2-C.sub.5alkyl, C.sub.2-C.sub.4 alkynyl, --C.sub.1-C.sub.4alkyl-O--C.sub.0-C.sub.4 alkyl, --C.sub.0-C.sub.4alkyl-O--C.sub.1-C.sub.4 alkyl, --C.sub.0-C.sub.4alkyl-C(O)--C.sub.1-C.sub.5 alkyl-, --C.sub.1-C.sub.4alkyl-C(O)--C.sub.0-C.sub.5 alkyl, C.sub.1-C.sub.2alkyl-C(O)N(R.sup.8).sub.2, --C.sub.1-C.sub.6 haloalkyl-CF.sub.3,--C.sub.2-C.sub.4 alkyl-CN, heteroarylalkyl, or heterocyclylalkyl,each of which is optionally substituted with (R.sup.7).sub.1-4.

In another embodiment, in the general Formula I, R.sup.2, R.sup.3,R.sup.4, R.sup.5, R.sup.6, R.sup.7, and R.sup.8 have the meaning asdefined in any of the preceding embodiments, and R.sup.1 ishydroxypropyl, hydroxyethyl, ketopentyl, hydroxymethyl,pyridinylmethyl, oxazolylmethyl, oxetanylmethyl,methylisooxazolylmethyl, oxadiazolylmethyl, methoxyethyl,hydroxymethoxypropyl, methyloxadiazolylmethyl, methoxyketopropyl,ketomethylbutyl, ketopropyl, ketobutyl, acetamido, cyanomethyl,methylacetamido, trifluoroethyl, trifluoropropyl, or butynyl.

In another embodiment, in the general Formula I, R.sup.2, R.sup.3,R.sup.4, R.sup.5, R.sup.6, R.sup.7, and R.sup.8 have the meaning asdefined in any of the preceding embodiments, and R.sup.1 is

##STR00003##

In another embodiment, in the general Formula I, R.sup.1, R.sup.3,R.sup.4, R.sup.5, R.sup.6, R.sup.7, and R.sup.8 have the meaning asdefined in any of the preceding embodiments, and R.sup.2 ismethyl.

In another embodiment, in the general Formula I, R.sup.1, R.sup.3,R.sup.4, R.sup.5, R.sup.6, R.sup.7, and R.sup.8 have the meaning asdefined in any of the preceding embodiments, and R.sup.2 is H.

In another embodiment, in the general Formula I, R.sup.1, R.sup.2,R.sup.4, R.sup.5, R.sup.6, R.sup.7, and R.sup.8 have the meaning asdefined in any of the preceding embodiments, and R.sup.3 is aryl orheteroaryl, each of which is substituted with(R.sup.4).sub.1-2.

In another embodiment, in the general Formula I, R.sup.1, R.sup.2,R.sup.4, R.sup.5, R.sup.6, R.sup.7, and R.sup.8 have the meaning asdefined in any of the preceding embodiments, and R.sup.3 is phenyl,pyridyl, pyrimidinyl, pyrazinyl, or thiazolyl, each of which issubstituted with (R.sup.4).sub.1-2.

In another embodiment, in the general Formula I, R.sup.1, R.sup.2,R.sup.4, R.sup.5, R.sup.6, R.sup.7, and R.sup.8 have the meaning asdefined in any of the preceding embodiments, and R.sup.3 is

##STR00004##

In another embodiment, in the general Formula I, R.sup.1, R.sup.2,R.sup.3, R.sup.5, R.sup.6, R.sup.7, and R.sup.8 have the meaning asdefined in any of the preceding embodiments, and R.sup.4 isindependently H, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 alkoxy,C.sub.1-C.sub.3 haloalkyl, --N(R.sup.8).sub.2, 3 to 8-memberedcycloalkyl, aryl, heterocyclyl, heteroaryl, cyano, or halo, or twoR.sup.4 together with the atoms to which they are attached may forman optionally substituted 3 to 7-membered ring each of which isoptionally substituted with (R.sup.5).sub.1-3.

In another embodiment, in the general Formula I, R.sup.1, R.sup.2,R.sup.3, R.sup.5, R.sup.6, R.sup.7, and R.sup.8 have the meaning asdefined in any of the preceding embodiments, and R.sup.4 isindependently H, methyl, ethyl, propyl, --N(R.sup.8).sub.2, phenyl,halo, cyano, haloalkyl, methoxy, pyridinyl, pyrimidinyl,oxadiazolyl, piperdinyl, azetidinyl, pyrazinyl, azabicyclohexyl,piperazinyl, or pyrrolidinyl, each of which is substituted with(R.sup.5).sub.1-2.

In another embodiment, in the general Formula I, R.sup.1, R.sup.2,R.sup.3, R.sup.5, R.sup.6, R.sup.7, and R.sup.8 have the meaning asdefined in any of the preceding embodiments, and R.sup.4 isindependently H, methyl, ethyl, propyl, cyano, methoxy, chlorine,fluorine, bromine, --CF.sub.3, --CF.sub.2,

##STR00005##

In another embodiment, in the general Formula I, R.sup.1, R.sup.2,R.sup.3, R.sup.4, R.sup.6, R.sup.7, and R.sup.8 have the meaning asdefined in any of the preceding embodiments, and R.sup.5 isindependently H, pyrrolidinyl, trifluoroethyl, halo, haloalkyl,methyl, isopropyl, cyano, propyl, ethyl, trifluoromethyl,azabicyclohexyl, difluoroazabicyclohexyl, keto, methoxy,methoxyethyl, dialkylamino, or ethoxy, each of which is optionallysubstituted with (R.sup.6).sub.1-3.

In another embodiment, in the general Formula I, R.sup.1, R.sup.2,R.sup.3, R.sup.4, R.sup.6, R.sup.7, and R.sup.8 have the meaning asdefined in any of the preceding embodiments, and R.sup.5 isindependently H, --CF.sub.3, cyanomethyl, bromine, chlorine,fluorine, methyl, ethyl, isopropyl, cyano, keto,

##STR00006##

In another embodiment, in the general Formula I, R.sup.1, R.sup.2,R.sup.3, R.sup.4, R.sup.5, R.sup.7, and R.sup.8 have the meaning asdefined in any of the preceding embodiments, and R.sup.6 is H.

In another embodiment, in the general Formula I, R.sup.1, R.sup.2,R.sup.3, R.sup.4, R.sup.5, R.sup.7, and R.sup.8 have the meaning asdefined in any of the preceding embodiments, and R.sup.6 ismethyl.

In another embodiment, in the general Formula I, R.sup.1, R.sup.2,R.sup.3, R.sup.4, R.sup.5, R.sup.6, and R.sup.7 have the meaning asdefined in any of the preceding embodiments, and R.sup.8 is H,methyl, ethyl, or CF.sub.3.

A further embodiment of the present invention comprises compoundsof formula I in which

R.sup.1 is

##STR00007## ##STR00008## R.sup.2 is H or methyl; R.sup.3 is

##STR00009## R.sup.4 is independently H, methyl, ethyl, propyl,cyano, methoxy, chlorine, fluorine, bromine, --CF.sub.3,--CF.sub.2,

##STR00010## R.sup.5 is independently H, --CF.sub.3, cyanomethyl,bromine, chlorine, fluorine, methyl, ethyl, isopropyl, cyano,keto,

##STR00011## R.sup.6 is H or methyl; and R.sup.8 is H, methyl,ethyl, or CF.sub.3.

In an embodiment, R.sup.4 is independently C.sub.1-C.sub.3 alkyl,C.sub.1-C.sub.3 alkoxy, C.sub.1-C.sub.3 haloalkyl,--C.sub.1-C.sub.6 alkyl-O--C.sub.0-C.sub.6 alkyl, --C.sub.0-C.sub.6alkyl-O--C.sub.1-C.sub.6 alkyl, --N(R.sup.8).sub.2, 3 to 8-memberedcycloalkyl, aryl, heterocyclyl, heterocyclylalkyl, heteroaryl,cyano, or halo, or two R.sup.4 together with the atoms to whichthey are attached may form an optionally substituted 3 to7-membered ring each of which is optionally substituted with(R.sup.5).sub.1-3.

In an embodiment, R.sup.5 is independently C.sub.3-C.sub.10heterocyclyl, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 alkoxy,--C.sub.1-C.sub.6 alkyl-O--C.sub.0-C.sub.6 alkyl, --C.sub.0-C.sub.6alkyl-O--C.sub.1-C.sub.6 alkyl, --N(C.sub.1-C.sub.3 alkyl).sub.2,--C.sub.1-C.sub.6 haloalkyl, --C.sub.1-C.sub.3alkyl-N(R.sup.8).sub.2, heterocyclylalkyl, halo, or cyano, each ofwhich is optionally substituted with (R.sup.7).sub.1-3.

In an embodiment, R.sup.7 is independently H, C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl,C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 hydroxy, aryl, heteroaryl,heterocyclyl, arylalkyl, aryloxy, heteroaryloxy, arylalkoxy,heteroarylalkoxy, heterarylalkyl, haloalkyl, keto, cyano, or halo,or two R.sup.6 together with the atoms to which they are attachedmay form an optionally substituted 3 to 7-membered ring.

In an embodiment, R.sup.8 is H, methyl, ethyl, or CF.sub.3.

In another aspect, the present invention provides compounds ofFormula I:

##STR00012## or a pharmaceutically acceptable salt thereof,wherein:

R.sup.1 is C.sub.2-C.sub.6 alkyl, C.sub.1-C.sub.6 alkenyl,C.sub.1-C.sub.6 alkynyl, --C.sub.1-C.sub.6 alkyl-O--C.sub.0-C.sub.6alkyl, --C.sub.0-C.sub.6 alkyl-O--C.sub.1-C.sub.6 alkyl,--C.sub.1-C.sub.6 alkyl-C(O)--C.sub.0-C.sub.6 alkyl,--C.sub.0-C.sub.6 alkyl-C(O)--C.sub.1-C.sub.6 alkyl,--C.sub.1-C.sub.6 alkyl-C(O)N(R.sup.8).sub.2, --C.sub.1-C.sub.6alkyl-CN, --C.sub.1-C.sub.6 haloalkyl, aryl, heteroaryl,heterocyclyl, heteroarylalkyl, heterocyclylalkyl, each of which issubstituted with (R.sup.7).sub.1-7;

R.sup.2 is H or C.sub.1-C.sub.6 alkyl;

R.sup.3 is a 3 to 8-member cycloalkyl, aryl, heterocyclyl, orheteroaryl, each of which is substituted with(R.sup.4).sub.1-2;

R.sup.4 is independently H, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3alkoxy, C.sub.1-C.sub.3 haloalkyl, --C.sub.1-C.sub.6alkyl-O--C.sub.0-C.sub.6 alkyl, --C.sub.0-C.sub.6alkyl-O--C.sub.1-C.sub.6 alkyl, --N(R.sup.8).sub.2, 3 to 8-membercycloalkyl, aryl, heterocyclyl, heterocyclylalkyl, heteroaryl,cyano, halo, or two R.sup.4 together with the atoms to which theyare attached may form an optionally substituted 3 to 7-member ringeach of which is optionally substituted with (R.sup.5).sub.1-3;

R.sup.5 is independently H, C.sub.3-C.sub.10 heterocyclyl,C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 alkoxy, --C.sub.1-C.sub.6alkyl-O--C.sub.0-C.sub.6 alkyl, --C.sub.0-C.sub.6alkyl-O--C.sub.1-C.sub.6 alkyl, --N(C.sub.1-C.sub.3 alkyl).sub.2,--C.sub.1-C.sub.6 haloalkyl, --C.sub.1-C.sub.3alkyl-N(R.sup.8).sub.2, heterocyclylalkyl, halo, cyano, each ofwhich is optionally substituted with (R.sup.7).sub.1-3;

R.sup.6 is H or C.sub.1-C.sub.6 alkyl;

R.sup.7 is independently H, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6alkenyl, C.sub.1-C.sub.6 alkynyl, C.sub.1-C.sub.6 alkoxy,C.sub.1-C.sub.6 hydroxy, aryl, heteroaryl, heterocyclyl, arylalkyl,aryloxy, heteroaryloxy, arylalkoxy, heteroarylalkoxy,heterarylalkyl, haloalkyl, keto, cyano, halo, or two R.sup.6together with the atoms to which they are attached may form anoptionally substituted 3 to 7-member ring; and

R.sup.8 is H or C.sub.1-C.sub.6 alkyl.

In a embodiment, in the general Formula I, R.sup.2, R.sup.3,R.sup.4, R.sup.5, R.sup.6, and R.sup.7 have the meaning as definedin the preceding embodiments and R.sup.1 is C.sub.2-C.sub.5 alkyl,C.sub.2-C.sub.4 alkynyl, --C.sub.1-C.sub.4 alkyl-O--C.sub.0-C.sub.4alkyl, --C.sub.0-C.sub.4 alkyl-O--C.sub.1-C.sub.4 alkyl,--C.sub.0-C.sub.4 alkyl-C(O)--C.sub.1-C.sub.5 alkyl-,--C.sub.1-C.sub.4 alkyl-C(O)--C.sub.0-C.sub.5 alkyl,C.sub.1-C.sub.2 alkyl-C(O)N(R.sup.8).sub.2, --C.sub.1-C.sub.6alkyl-CF.sub.3, --C.sub.2-C.sub.4 alkyl-CN, heteroarylalkyl,heterocyclylalkyl, each of which is optionally substituted with(R.sup.7).sub.1-4.

In another embodiment, in the general Formula I, R.sup.2, R.sup.3,R.sup.4, R.sup.5, R.sup.6, and R.sup.7 have the meaning as definedin any of the preceding embodiments, and R.sup.1 is ishydroxypropyl, ketopentyl, hydroxymethyl, pyridinylmethyl,oxazolylmethyl, oxetanylmethyl, oxadiazolylmethyl, methoxyethyl,hydroxymethoxypropyl, methoxyketopropyl, ketomethylbutyl,ketopropyl, ketobutyl, acetamido, cyanomethyl, methylacetamido,trifluoroethyl, trifluoropropyl, or butynyl.

In another embodiment, in the general Formula I, R.sup.2, R.sup.3,R.sup.4, R.sup.5, R.sup.6, and R.sup.7 have the meaning as definedin any of the preceding embodiments, and R.sup.1 is

##STR00013## ##STR00014##

In another embodiment, in the general Formula I, R.sup.1, R.sup.3,R.sup.4, R.sup.5, R.sup.6, and R.sup.7 have the meaning as definedin any of the preceding embodiments, and R.sup.2 is methyl.

In another embodiment, in the general Formula I, R.sup.1, R.sup.3,R.sup.4, R.sup.5, R.sup.6, and R.sup.7 have the meaning as definedin any of the preceding embodiments, and R.sup.2 is H.

In another embodiment, in the general Formula I, R.sup.1, R.sup.2,R.sup.4, R.sup.5, R.sup.6, and R.sup.7 have the meaning as definedin any of the preceding embodiments, and R.sup.3 is aryl orheteroaryl, each of which is substituted with(R.sup.4).sub.1-2.

In another embodiment, in the general Formula I, R.sup.1, R.sup.2,R.sup.4, R.sup.5, R.sup.6, and R.sup.7 have the meaning as definedin any of the preceding embodiments, and R.sup.3 is phenyl,pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, or thiazolyl each ofwhich is substituted with (R.sup.4).sub.1-2.

In another embodiment, in the general Formula I, R.sup.1, R.sup.2,R.sup.4, R.sup.5, R.sup.6, and R.sup.7 have the meaning as definedin any of the preceding embodiments, and R.sup.3 is

##STR00015##

In another embodiment, in the general Formula I, R.sup.1, R.sup.2,R.sup.3, R.sup.5, R.sup.6, and R.sup.7 have the meaning as definedin any of the preceding embodiments, and R.sup.4 is independentlyH, methyl, ethyl, propyl, --N(R.sup.8).sub.2, phenyl, halo, cyano,haloalkyl, methoxy, pyridinyl, pyrimidinyl, oxadiazolyl,piperdinyl, azetidinyl, pyrazinyl, azabicyclohexyl, piperazinyl, orpyrrolidinyl, each of which is substituted with(R.sup.5).sub.1-2.

In another embodiment, in the general Formula I, R.sup.1, R.sup.2,R.sup.3, R.sup.5, R.sup.6, and R.sup.7 have the meaning as definedin any of the preceding embodiments, and R.sup.4 is independentlyH, methyl, ethyl, propyl, cyano, methoxy, chlorine, fluorine,bromine, --CF.sub.3, --C.sub.2F,

##STR00016##

In another embodiment, in the general Formula I, R.sup.1, R.sup.2,R.sup.3, R.sup.4, R.sup.6, and R.sup.7 have the meaning as definedin any of the preceding embodiments, and R.sup.5 is independentlyH, pyrrolidinyl, trifluoroethyl, halo, haloalkyl, methyl,isopropyl, cyano, propyl, ethyl, trifluoromethyl, azabicyclohexyl,difluoroazabicyclohexyl, ketone, methanol, methoxy, ormethoxyethyl, dialkylamino, ethoxy, each of which is optionallysubstituted with (R.sup.6).sub.1-3.

In another embodiment, in the general Formula I, R.sup.1, R.sup.2,R.sup.3, R.sup.4, R.sup.6, and R.sup.7 have the meaning as definedin any of the preceding embodiments, and R.sup.5 is independentlyH, --CF.sub.3, cyanomethyl, bromine, chlorine, fluorine, methyl,ethyl, isopropyl, cyano, ketone,

##STR00017##

In another embodiment, in the general Formula I, R.sup.1, R.sup.2,R.sup.3, R.sup.4, R.sup.5, and R.sup.7 have the meaning as definedin any of the preceding embodiments, and R.sup.6 is H.

In another embodiment, in the general Formula I, R.sup.1, R.sup.2,R.sup.3, R.sup.4, R.sup.5 and R.sup.7 have the meaning as definedin any of the preceding embodiments, and R.sup.6 is methyl.

A further embodiment of the present invention comprises compoundsof formula I in which

R.sup.1 is

##STR00018## R.sup.2 is H or methyl; R.sup.3 is

##STR00019## R.sup.4 is independently H, methyl, ethyl, propyl,cyano, methoxy, chlorine, fluorine, bromine, --CF.sub.3,--C.sub.2F,

##STR00020## R.sup.5 is independently H, --CF.sub.3, cyanomethyl,bromine, chlorine, fluorine, methyl, ethyl, isopropyl, cyano,ketone,

##STR00021## and R.sup.6 is H or methyl.

In an embodiment, R.sup.4 is independently C.sub.1-C.sub.3 alkyl,C.sub.1-C.sub.3 alkoxy, C.sub.1-C.sub.3 haloalkyl,--C.sub.1-C.sub.6 alkyl-O--C.sub.0-C.sub.6 alkyl, --C.sub.0-C.sub.6alkyl-O--C.sub.1-C.sub.6 alkyl, --N(R.sup.8).sub.2, 3 to 8-membercycloalkyl, aryl, heterocyclyl, heterocyclylalkyl, heteroaryl,cyano, halo, or two R.sup.4 together with the atoms to which theyare attached may form an optionally substituted 3 to 7-member ringeach of which is optionally substituted with (R.sup.5).sub.1-3.

In an embodiment, R.sup.5 is independently C.sub.3-C.sub.10heterocyclyl, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 alkoxy,--C.sub.1-C.sub.6 alkyl-O--C.sub.0-C.sub.6 alkyl, --C.sub.0-C.sub.6alkyl-O--C.sub.1-C.sub.6 alkyl, --N(C.sub.1-C.sub.3 alkyl).sub.2,--C.sub.1-C.sub.6 haloalkyl, --C.sub.1-C.sub.3alkyl-N(R.sup.8).sub.2, heterocyclylalkyl, halo, cyano, each ofwhich is optionally substituted with (R.sup.7).sub.1-3.

In an embodiment, R.sup.7 is independently H, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6 alkenyl, C.sub.1-C.sub.6 alkynyl,C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 hydroxy, aryl, heteroaryl,heterocyclyl, arylalkyl, aryloxy, heteroaryloxy, arylalkoxy,heteroarylalkoxy, heterarylalkyl, haloalkyl, keto, cyano, halo, ortwo R.sup.6 together with the atoms to which they are attached mayform an optionally substituted 3 to 7-member ring.

In certain embodiments, exemplary compounds of Formula (I) includethe compounds described in Table 1 and in the Examples.

TABLE-US-00001 TABLE 1 Compound # Structure 1 ##STR00022## 2##STR00023## 3 ##STR00024## 4 ##STR00025## 5 ##STR00026## 6##STR00027## 7 ##STR00028## 8 ##STR00029## 9 ##STR00030## 10##STR00031## 11 ##STR00032## 12 ##STR00033## 13 ##STR00034## 14##STR00035## 15 ##STR00036## 16 ##STR00037## 17 ##STR00038## 18##STR00039## 19 ##STR00040## 20 ##STR00041## 21 ##STR00042## 22##STR00043## 23 ##STR00044## 24 ##STR00045## 25 ##STR00046## 26##STR00047## 27 ##STR00048## 28 ##STR00049## 29 ##STR00050## 30##STR00051## 31 ##STR00052## 32 ##STR00053## 33 ##STR00054## 34##STR00055## 35 ##STR00056## 36 ##STR00057## 37 ##STR00058## 38##STR00059## 39 ##STR00060## 40 ##STR00061## 41 ##STR00062## 42##STR00063## 43 ##STR00064## 44 ##STR00065## 45 ##STR00066## 46##STR00067## 47 ##STR00068## 48 ##STR00069## 49 ##STR00070## 50##STR00071## 51 ##STR00072## 52 ##STR00073## 53 ##STR00074## 54##STR00075## 55 ##STR00076## 56 ##STR00077## 57 ##STR00078## 58##STR00079## 59 ##STR00080## 60 ##STR00081## 61 ##STR00082## 62##STR00083## 63 ##STR00084## 64 ##STR00085## 65 ##STR00086## 66##STR00087## 67 ##STR00088## 68 ##STR00089## 69 ##STR00090## 70##STR00091## 71 ##STR00092## 72 ##STR00093## 73 ##STR00094## 74##STR00095## 75 ##STR00096## 76 ##STR00097## 77 ##STR00098## 78##STR00099## 79 ##STR00100## 80 ##STR00101## 81 ##STR00102## 82##STR00103## 83 ##STR00104## 84 ##STR00105## 85 ##STR00106## 86##STR00107## 87 ##STR00108## 88 ##STR00109## 89 ##STR00110## 90##STR00111## 91 ##STR00112## 92 ##STR00113## 93 ##STR00114## 94##STR00115## 95 ##STR00116## 96 ##STR00117## 97 ##STR00118## 98##STR00119## 99 ##STR00120## 100 ##STR00121## 101 ##STR00122## 102##STR00123## 103 ##STR00124## 104 ##STR00125## 105 ##STR00126## 106##STR00127## 107 ##STR00128## 108 ##STR00129## 109 ##STR00130## 110##STR00131## 111 ##STR00132## 112 ##STR00133## 113 ##STR00134## 114##STR00135## 115 ##STR00136## 116 ##STR00137## 117 ##STR00138## 118##STR00139## 119 ##STR00140## 120 ##STR00141## 121 ##STR00142## 122##STR00143## 123 ##STR00144##

124 ##STR00145## 125 ##STR00146## 126 ##STR00147## 127 ##STR00148##128 ##STR00149## 129 ##STR00150## 130 ##STR00151## 131 ##STR00152##132 ##STR00153## 133 ##STR00154## 134 ##STR00155## 135 ##STR00156##136 ##STR00157## 137 ##STR00158## 139 ##STR00159## 140 ##STR00160##141 ##STR00161## 142 ##STR00162## 143 ##STR00163## 144 ##STR00164##145 ##STR00165## 146 ##STR00166## 147 ##STR00167## 148 ##STR00168##149 ##STR00169## 150 ##STR00170## 151 ##STR00171## 152 ##STR00172##153 ##STR00173## 154 ##STR00174## 155 ##STR00175## 156 ##STR00176##157 ##STR00177## 158 ##STR00178## 159 ##STR00179## 160 ##STR00180##161 ##STR00181## 162 ##STR00182## 163 ##STR00183## 164 ##STR00184##165 ##STR00185## 166 ##STR00186## 167 ##STR00187## 168 ##STR00188##169 ##STR00189## 170 ##STR00190## 171 ##STR00191## 172 ##STR00192##173 ##STR00193## 174 ##STR00194## 175 ##STR00195## 176 ##STR00196##177 ##STR00197## 178 ##STR00198## 181 ##STR00199## 182 ##STR00200##183 ##STR00201## 184 ##STR00202## 185 ##STR00203## 186 ##STR00204##187 ##STR00205## 188 ##STR00206## 189 ##STR00207## 190 ##STR00208##191 ##STR00209## 192 ##STR00210## 193 ##STR00211## 194 ##STR00212##195 ##STR00213## 196 ##STR00214## 197 ##STR00215## 198 ##STR00216##199 ##STR00217## 200 ##STR00218## 201 ##STR00219## 202 ##STR00220##203 ##STR00221## 204 ##STR00222## 211 ##STR00223## 212 ##STR00224##213 ##STR00225## 214 ##STR00226## 215 ##STR00227## 216 ##STR00228##217 ##STR00229## 218 ##STR00230## 219 ##STR00231## 220 ##STR00232##221 ##STR00233## 222 ##STR00234## 223 ##STR00235## 224 ##STR00236##225 ##STR00237## 226 ##STR00238## 227 ##STR00239## 228 ##STR00240##229 ##STR00241## 230 ##STR00242## 231 ##STR00243## 232 ##STR00244##233 ##STR00245## 234 ##STR00246## 235 ##STR00247## 236 ##STR00248##237 ##STR00249## 238 ##STR00250## 239 ##STR00251## 240 ##STR00252##241 ##STR00253## 242 ##STR00254## 243 ##STR00255## 245 ##STR00256##246 ##STR00257## 247 ##STR00258## 248 ##STR00259## 249 ##STR00260##250 ##STR00261## 251 ##STR00262## 252 ##STR00263## 253 ##STR00264##254 ##STR00265## 255 ##STR00266## 256 ##STR00267## 257 ##STR00268##258 ##STR00269##

259 ##STR00270## 260 ##STR00271## 261 ##STR00272## 262 ##STR00273##263 ##STR00274## 264 ##STR00275## 265 ##STR00276## 266 ##STR00277##267 ##STR00278## 268 ##STR00279## 269 ##STR00280## 270 ##STR00281##271 ##STR00282## 272 ##STR00283##

This disclosure is not limited in its application to the details ofthe methods and compositions described herein. Also, thephraseology and terminology used herein is for the purpose ofdescription and should not be regarded as limiting.

Chemical Definitions

At various places in the present specification, substituents ofcompounds of the invention are disclosed in groups or in ranges. Itis specifically intended that the invention include each and everyindividual subcombination of the members of such groups and ranges.For example, the term "C.sub.1-6 alkyl" is specifically intended toindividually disclose methyl, ethyl, propyl, butyl, and pentyl.

For compounds of the invention in which a variable appears morethan once, each variable can be a different moiety selected fromthe Markush group defining the variable. For example, where astructure is described having two R groups that are simultaneouslypresent on the same compound; the two R groups can representdifferent moieties selected from the Markush group defined forR.

It is further appreciated that certain features of the invention,which are, for clarity, described in the context of separateembodiments, can also be provided in combination in a singleembodiment. Conversely, various features of the invention whichare, for brevity, described in the context of a single embodiment,can also be provided separately or in any suitablesubcombination.

In case a compound of the present invention is depicted in form ofa chemical name and as a formula in case of any discrepancy theformula shall prevail.

An asterisk may be used in sub-formulas to indicate the bond whichis connected to the core molecule as defined.

As used herein, "alkyl," by itself or as part of anothersubstituent, means, unless otherwise stated, a straight or branchedchain, and can have a number of carbon atoms optionally designated(i.e., C.sub.1-C.sub.6 means one to six carbons). Examples ofsaturated hydrocarbon groups include, but are not limited to,groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl,t-butyl, isobutyl, sec-butyl, n-pentyl, isopentyl, homologs andisomers of, for example, n-pentyl, n-hexyl, and the like.

As used herein, "alkenyl" can be a straight or branched hydrocarbonchain, containing at least one double bond, and having from two tosix carbon atoms (i.e. C.sub.2-C.sub.6 alkenyl). Examples ofalkenyl groups, include, but are not limited to, groups such asethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl,pent-1-enyl, penta-1,4-dienyl, and the like.

As used herein, "alkoxy" can be a straight chain or branched alkoxygroup (e.g. C1-C6 alkyl-O--) having from one to six carbon atoms(i.e., C.sub.1-C.sub.6 alkoxy). Examples of alkoxy groups, include,but are not limited to, groups such as methoxy, ethoxy, propyloxy,isopropyloxy, butyloxy, isobutyloxy, tert-butyloxy, pentyloxy, orhexyloxy, and the like.

As used herein, "alkynyl" can be a straight or branched hydrocarbonchain, containing at least one triple bond, having from two to sixcarbon atoms (i.e. C.sub.2-C.sub.6 alkynyl). Examples of alkynylgroups, include, but are not limited to, groups such as ethynyl,propynyl, butynyl, pentynyl, hexynyl, and the like.

As used herein, "amide" or "amido" refers to a chemical moiety withthe formula --C(O)NR.sup.a-- or --NR.sup.aC(O)-- wherein R.sup.a isH or C.sub.1-C.sub.6 alkyl.

As used herein, "amino" or "amine" refers to a --NH.sub.2 radicalgroup.

As used herein, "aryl" refers to a polyunsaturated, aromatic,hydrocarbon moiety which can be a single ring or multiple rings(e.g., 1 to 2 rings) which are fused together or linked covalently,having from six to twelve carbon atoms (i.e. C.sub.6-C.sub.12aryl). Non-limiting examples of aryl groups include phenyl,1-naphthyl, 2-naphthyl, and 4-biphenyl and the like.

As used herein, "arylalkyl" refers to an (aryl)alkyl- radicalwherein aryl and alkyl moieties are as disclosed herein.

As used herein, "aryloxy" refers to --O-(aryl), wherein the arylmoiety is as defined herein.

As used herein, "arylalkoxy" refers to --O-(arylalkyl), wherein thearylalkyl moiety is as defined herein.

As used herein, "cyano" refers to a --CN radical.

As used herein, "cycloalkyl" refers to a monocyclic or polycyclicradical that contains only carbon and hydrogen, and may besaturated, or partially unsaturated. Cycloalkyl groups includegroups having from 3 to 10 ring atoms (i.e. C.sub.3-C.sub.10cycloalkyl). Examples of cycloalkyl groups include, but are notlimited to, groups such as cyclopropyl, cyclobutyl, cyclopentyl,cyclopentenyl, cyclohexyl, cyclohexenyl, cycloseptyl, cyclooctyl,cyclononyl, cyclodecyl, norbornyl, and the like.

As used herein, "halo" or "halogen," independently or as part ofanother substituent, mean, unless otherwise stated, a fluorine,chlorine, bromine, or iodine atom. The term "halide" by itself oras part of another substituent, refers to a fluoride, chloride,bromide, or iodide atom.

As used herein, "haloalkyl" and "haloalkoxy" can include alkyl andalkoxy structures that are substituted with one or more halo groupsor with combinations thereof. For example, the terms "fluoroalkyl"and "fluoroalkoxy" include haloalkyl and haloalkoxy groups,respectively, in which the halo is fluorine (e.g.,--C.sub.1-C.sub.6 alkyl-CF.sub.3, --C.sub.1-C.sub.6alkyl-C.sub.2F). Non-limiting examples of haloalkyl includetrifluoroethyl, trifluoropropyl, trifluoromethyl, fluoromethyl,difluromethyl, and fluroisopropyl.

As used herein, "heteroaryl" refers to a 5- to 14-membered aromaticradical (e.g., C.sub.2-C.sub.13 heteroaryl) that includes one ormore ring heteroatoms selected from nitrogen, oxygen and sulfur,and which may be a monocyclic or bicyclic ring system. Thepolycyclic heteroaryl group may be fused or non-fused. Theheteroatom(s) in the heteroaryl radical is optionally oxidized. Oneor more nitrogen atoms, if present, are optionally quaternized. Theheteroaryl is attached to the rest of the molecule through any atomof the ring(s). The term "heteroaryl" is intended to include allthe possible isomeric forms. Examples of heteroaryl groups includewithout limitation, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl,triazinyl, furyl (furanyl), quinolyl, isoquinolyl, thienyl,imidazolyl, thiazolyl, indolyl, pyrryl, oxazolyl, oxadiazolyl,benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl,triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl, isothiazolyl,benzothienyl, purinyl, carbazolyl, benzimidazolyl, indolinyl, andthe like.

As used herein, "heterocyclyl" can be a stable 3- to 18-memberednon-aromatic mono, di, or tricyclic ring radical that comprises twoto twelve carbon atoms and from one to six heteroatoms selectedfrom nitrogen, oxygen and sulfur. Examples of heterocycloalkylgroups include, but are not limited to, groups such as dioxolanyl,thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl,imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl,octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl,piperazinyl, 4-piperidonyl, azetidinyl, azabicyclohexyl,pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl,tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl,thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl,and the like.

As used herein, "heteroarylalkyl" refers to refers to an(heteroaryl)alkyl- radical wherein the heteroaryl and alkylmoieties are as disclosed herein.

As used herein, "heteraryloxy" refers to --O-(heteroaryl), whereinthe heteroaryl moiety is as defined herein.

As used herein, "heterocycloalkyl" refers to an(heterocyclyl)alkyl-moiety and can be a stable 3- to 18-memberednon-aromatic ring moiety that comprises two to twelve carbon atomsand from one to six heteroatoms selected from nitrogen, oxygen andsulfur. Examples of heterocycloalkyl groups include, but are notlimited to, groups such as dioxolanyl, thienyl[1,3]dithianyl,decahydroisoquinolyl, imidazolinyl, imidazolidinyl,isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl,octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl,2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl,4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl,thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl,thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl,1,1-dioxo-thiomorpholinyl, and the like covalently bonded to one ormore alkyl moieties as defined herein.

As used herein, "hydroxy" or "hydroxyl" refers to --OH.

As used herein, "nitro" refers to --NO.sub.2.

As used herein, "keto" refers to --C.dbd.O.

Many of the terms given above may be used repeatedly in thedefinition of a formula or group and in each case have one of themeanings given above, independently of one another.

As used herein, the term "substituted" is contemplated to includeall permissible substituents of organic compounds. In a broadaspect, the permissible substituents include acyclic and cyclic,branched and unbranched, carbocyclic and heterocyclic, aromatic andnonaromatic substituents of organic compounds (e.g., alkyl,alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, orheteroaryl, any of which may itself be further substituted), aswell as halogen, carbonyl (e.g., aldehyde, ketone, ester, carboxyl,or formyl), thiocarbonyl (e.g., thioester, thiocarboxylate, orthioformate), amino, --N(R.sup.b)(R.sup.c), wherein each R.sup.band R.sup.c is independently H or C.sub.1-C.sub.6 alkyl, cyano,nitro, --SO.sub.2N(R.sup.b)(R.sup.c), --SOR.sup.d, andS(O).sub.2R.sup.d, wherein each R.sup.b, R.sup.c, and R.sup.d isindependently H or C.sub.1-C.sub.6 alkyl. Illustrative substituentsinclude, for example, those described herein above. The permissiblesubstituents can be one or more and the same or different forappropriate organic compounds. For purposes of this invention, theheteroatoms such as nitrogen may have hydrogen substituents and/orany permissible substituents of organic compounds described hereinwhich satisfy the valences of the heteroatoms. This invention isnot intended to be limited in any manner by the permissiblesubstituents of organic compounds.

It will be understood that "substitution" or "substituted with"includes the implicit proviso that such substitution is inaccordance with permitted valence of the substituted atom and thesubstituent, and that the substitution results in a stablecompound, e.g., which does not spontaneously undergo transformationsuch as by rearrangement, cyclization, elimination, etc.

The abbreviations Me, Et, Ph, Tf, Nf, Ts, Ms represent methyl,ethyl, phenyl, trifluoromethanesulfonyl, nonafluorobutanesulfonyl,p-toluenesulfonyl and methanesulfonyl, respectively. A morecomprehensive list of the abbreviations utilized by organicchemists of ordinary skill in the art appears in the first issue ofeach volume of the Journal of Organic Chemistry; this list istypically presented in a table entitled Standard List ofAbbreviations. The abbreviations contained in said list, and allabbreviations utilized by organic chemists of ordinary skill in theart are hereby incorporated by reference.

Contemplated equivalents of the compounds described above includecompounds which otherwise correspond thereto, and which have thesame general properties thereof (e.g., the ability to inhibit TRPA1activity), wherein one or more simple variations of substituentsare made which do not adversely affect the efficacy of thecompound. In general, the compounds of the present invention may beprepared by the methods illustrated in the general reaction schemesas, for example, described below, or by modifications thereof,using readily available starting materials, reagents andconventional synthesis procedures. In these reactions, it is alsopossible to make use of variants which are in themselves known, butare not mentioned here.

For purposes of this invention, the chemical elements areidentified in accordance with the Periodic Table of the Elements,CAS version, Handbook of Chemistry and Physics, 67th Ed., 1986-87,inside cover. Also for purposes of this invention, the term"hydrocarbon" is contemplated to include all permissible compoundshaving at least one hydrogen and one carbon atom. In a broadaspect, the permissible hydrocarbons include acyclic and cyclic,branched and unbranched, carbocyclic and heterocyclic, aromatic andnonaromatic organic compounds which can be substituted orunsubstituted.

Definitions

As used herein, the articles "a" and "an" refer to one or to morethan one (e.g., to at least one) of the grammatical object of thearticle.

"About" and "approximately" shall generally mean an acceptabledegree of error for the quantity measured given the nature orprecision of the measurements. Exemplary degrees of error arewithin 20 percent (%), typically, within 10%, and more typically,within 5% of a given value or range of values.

As used herein, an amount of a compound or combination effective totreat a disorder (e.g., a disorder as described herein),"therapeutically effective amount", "effective amount" or"effective course" refers to an amount of the compound orcombination which is effective, upon single or multiple doseadministration(s) to a subject, in treating a subject, or incuring, alleviating, relieving or improving a subject with adisorder (e.g., a disorder as described herein) beyond thatexpected in the absence of such treatment.

As set out above, certain embodiments of the present compounds maycontain a basic functional group, such as amino or alkylamino, andare, thus, capable of forming pharmaceutically acceptable saltswith pharmaceutically acceptable acids. The term "pharmaceuticallyacceptable salts" in this respect, refers to the relativelynon-toxic, inorganic and organic acid addition salts of compoundsdisclosed herein. These salts can be prepared in situ during thefinal isolation and purification of the compounds of the invention,or by separately reacting a purified compound of the invention inits free base form with a suitable organic or inorganic acid, andisolating the salt thus formed. Representative salts include thehydrobromide, hydrochloride, sulfate, bisulfate, phosphate,nitrate, acetate, valerate, oleate, palmitate, stearate, laurate,benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate,succinate, tartrate, napthylate, mesylate, glucoheptonate,lactobionate, and laurylsulphonate salts and the like (see, forexample, Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci.66:1-19.)

In other cases, the compounds disclosed herein may contain one ormore acidic functional groups and, thus, are capable of formingpharmaceutically acceptable salts with pharmaceutically acceptablebases. The term "pharmaceutically acceptable salts" in theseinstances refers to the relatively non-toxic, inorganic and organicbase addition salts of compounds disclosed herein. These salts canlikewise be prepared in situ during the final isolation andpurification of the compounds, or by separately reacting thepurified compound in its free acid form with a suitable base, suchas the hydroxide, carbonate or bicarbonate of a pharmaceuticallyacceptable metal cation, with ammonia, or with a pharmaceuticallyacceptable organic primary, secondary or tertiary amine.Representative alkali or alkaline earth salts include the lithium,sodium, potassium, calcium, magnesium, and aluminum salts and thelike. Representative organic amines useful for the formation ofbase addition salts include ethylamine, diethylamine,ethylenediamine, ethanolamine, diethanolamine, piperazine and thelike.

The term, "treat" or "treatment," as used herein, refers to theapplication or administration of a compound, alone or incombination with, an additional agent to a subject, e.g., a subjectwho has a disorder (e.g., a disorder as described herein), asymptom of a disorder, or a predisposition toward a disorder, withthe purpose to cure, heal, alleviate, relieve, alter, remedy,ameliorate, improve or affect the disorder.

As used herein, the term "subject" is intended to include human andnon-human animals. Exemplary human subjects include a human subjecthaving a disorder, e.g., a disorder described herein. The term"non-human animals" of the invention includes all vertebrates,e.g., non-mammals (such as chickens, amphibians, reptiles) andmammals, such as non-human primates, domesticated and/oragriculturally useful animals, e.g., sheep, dog, cat, cow, pig,etc.

The terms "antagonist" and "inhibitor" are used interchangeably torefer to an agent that decreases or suppresses a biologicalactivity, such as to repress an activity of an ion channel, such asTRPA1. TRPA1 inhibitors include inhibitors having any combinationof the structural and/or functional properties disclosedherein.

An "effective amount" of, e.g., a TRPA1 antagonist, with respect tothe subject methods of inhibition or treatment, refers to an amountof the antagonist in a preparation which, when applied as part of adesired dosage regimen brings about a desired clinical orfunctional result. Without being bound by theory, an effectiveamount of a TRPA1 antagonist for use in the methods of the presentinvention, includes an amount of a TRPA1 antagonist effective todecrease one or more in vitro or in vivo functions of a TRPA1channel. Exemplary functions include, but are not limited to,membrane polarization (e.g., an antagonist may preventdepolarization of a cell), ion flux, ion concentration in a cell,outward current, and inward current. Compounds that antagonizeTRPA1 function include compounds that antagonize an in vitro or invivo functional activity of TRPA1. When a particular functionalactivity is only readily observable in an in vitro assay, theability of a compound to inhibit TRPA1 function in that in vitroassay serves as a reasonable proxy for the activity of thatcompound. In certain embodiments, an effective amount is an amountsufficient to inhibit a TRPA1-mediated current and/or the amountsufficient to inhibit TRPA1 mediated ion flux.

The term "hydrate" as used herein, refers to a compound formed bythe union of water with the parent compound.

The term "preventing," when used in relation to a condition, suchas a local recurrence (e.g., pain), a disease such as cancer, asyndrome complex such as heart failure or any other medicalcondition, is well understood in the art, and includesadministration of a composition which reduces the frequency of, ordelays the onset of, symptoms of a medical condition in a subjectrelative to a subject which does not receive the composition. Thus,prevention of cancer includes, for example, reducing the number ofdetectable cancerous growths in a population of patients receivinga prophylactic treatment relative to an untreated controlpopulation, and/or delaying the appearance of detectable cancerousgrowths in a treated population versus an untreated controlpopulation, e.g., by a statistically and/or clinically significantamount. Prevention of an infection includes, for example, reducingthe number of diagnoses of the infection in a treated populationversus an untreated control population, and/or delaying the onsetof symptoms of the infection in a treated population versus anuntreated control population. Prevention of pain includes, forexample, reducing the magnitude of, or alternatively delaying, painsensations experienced by subjects in a treated population versusan untreated control population.

The term "solvate" as used herein, refers to a compound formed bysolvation (e.g., a compound formed by the combination of solventmolecules with molecules or ions of the solute).

The terms "TRPA1", "TRPA1 protein", and "TRPA1 channel" are usedinterchangeably throughout the application. These terms refer to anion channel (e.g., a polypeptide) comprising the amino acidsequence set forth in SEQ ID NO: 1, SEQ ID NO:3, or SEQ ID NO: 5 ofWO 2007/073505, or an equivalent polypeptide, or a functionalbioactive fragment thereof. In certain embodiments, the term refersto a polypeptide comprising, consisting of, or consistingessentially of, the amino acid sequence set forth in SEQ ID NO: 1,SEQ ID NO:3, or SEQ ID NO: 5. TRPA1 includes polypeptides thatretain a function of TRPA1 and comprise (i) all or a portion of theamino acid sequence set forth in SEQ ID NO: 1, SEQ ID NO:3 or SEQID NO: 5; (ii) the amino acid sequence set forth in SEQ ID NO: 1,SEQ ID NO:3 or SEQ ID NO: 5 with 1 to about 2, 3, 5, 7, 10, 15, 20,30, 50, 75 or more conservative amino acid substitutions; (iii) anamino acid sequence that is at least 70%, 75%, 80%, 90%, 95%, 96%,97%, 98%, or 99% identical to SEQ ID NO: 1, SEQ ID NO:3 or SEQ IDNO: 5; and (iv) functional fragments thereof. Polypeptides of theinvention also include homologs, e.g., orthologs and paralogs, ofSEQ ID NO: 1, SEQ ID NO: 3 or SEQ ID NO: 5.

In some embodiments the methods include treating inflammatorydisease in a subject, the method comprising administering aneffective amount of a compound of Formula (I), or apharmaceutically acceptable salt thereof.

In some embodiments the methods include treating neuropathy in asubject, the method comprising administering an effective amount ofa compound of Formula (I), or a pharmaceutically acceptable saltthereof. In some embodiments, the neuropathy is from diabetes,chemical injury, chemotherapy, and or trauma.

In some embodiments the methods include treating a dermatogologicaldisorder in a subject, the method comprising administering aneffective amount of a compound of Formula (I), or apharmaceutically acceptable salt thereof. Exemplarydermatogological disorders include atopic dermatitis, acutepruritus, psoriasis, hives, eczema, dyshidrotic eczema, mouthulcers, and diaper rash.

In some embodiments the methods include treating a respiratorycondition in a subject, the method comprising administering aneffective amount of a compound of Formula (I), or apharmaceutically acceptable salt thereof. Exemplary respiratoryconditions include obstructive diseases such as chronic obstructivepulmonary disease. Additional exemplary respiratory conditionsinclude asthma and cough.

Another aspect of the invention features a pharmaceuticalpreparation suitable for use in a human patient, or for veterinaryuse, comprising an effective amount of a compound of Formula (I)(or a salt thereof, or a solvate, hydrate, oxidative metabolite orprodrug of the compound or its salt), and one or morepharmaceutically acceptable excipients. The invention furthercontemplates the use of compounds of Formula (I) in the manufactureof a medicament or pharmaceutical preparation to treat or reducethe symptoms of any of the diseases or conditions provided in thespecification. The compounds of of Formula (I) for use in treatinga particular disease or condition can be formulated foradministration via a route appropriate for the particular diseaseor condition.

Compounds of Formula (I) can be administered alone or incombination with another therapeutic agent. For instance, thecompounds of Formula (I) can be administered conjointly with one ormore of an anti-inflammatory agent, anti-acne agent, anti-wrinkleagent, anti-scarring agent, anti-psoriatic agent,anti-proliferative agent, anti-fungal agent, anti-viral agent,anti-septic agent, anti-migraine agent, keratolytic agent, or ahair growth inhibitor. Compounds of Formula (I) can be administeredtopically, orally, transdermally, rectally, vaginally, parentally,intranasally, intrapulmonary, intraocularly, intravenously,intramuscularly, intraarterially, intrathecally, intracapsularly,intraorbitally, intracardiacly, intradermally, intraperitoneally,transtracheally, subcutaneously, subcuticularly, intraarticularly,subcapsularly, subarachnoidly, intraspinally, intrasternally,sublingually, or by inhalation. In some embodiments, compounds ofFormula (I) can be administered topically. In some embodiments,compounds of Formula (I) can be administered orally.

In some embodiments, compounds of Formula (I) can be administeredparentally.

Compounds of Formula (I) include molecules having an aqueoussolubility suitable for oral or parenteral (e.g., intravenous)administration leading to or resulting in the treatment of adisorder described herein, for example the treatment of pain. Insome embodiments, the compound is formulated into a compositionsuitable for oral administration. The potency in inhibiting theTRPA1 ion channel of compounds of Formula (I) described herein wasmeasured using the method of Example 1. Table 2 discloses the TRPA1inhibition in vitro potency of exemplary compounds (measured by themethod of Example 1).

Preferred compounds of Formula (I) include compounds that inhibitthe TRPA1 ion channel with a IC.sub.50 value obtained by the methodof Example 1 of less than about 100 nM (preferably, less than about75 nM, more preferably less than about 25 nM).

Compounds of Formula (I) can inhibit the TRPA1 ion channel. In someembodiments, a compound of Formula (I) can be administered as partof an oral or parenteral (e.g., intravenous) pharmaceuticalcomposition to treat a disorder described herein (e.g., pain) in atherapeutically effective manner.

Certain compounds disclosed herein may exist in particulargeometric or stereoisomeric forms. The present inventioncontemplates all such compounds, including cis- and trans-isomers,R- and S-enantiomers, diastereomers, (d)-isomers, (l)-isomers, theracemic mixtures thereof, and other mixtures thereof, as fallingwithin the scope of the invention. For example, if one chiralcenter is present in a molecule, the invention includes racemicmixtures, enantiomerically enriched mixtures, and substantiallyenantiomerically or diastereomerically pure compounds. Thecomposition can contain, e.g., more than 50%, more than 60%, morethan 70%, more than 80%, more than 90%, more than 95%, or more than99% of a single enantiomer or diastereomer. Additional asymmetriccarbon atoms may be present in a substituent such as an alkylgroup. All such isomers, as well as mixtures thereof, are intendedto be included in this invention.

The "enantiomeric excess" or "% enantiomeric excess" of acomposition can be calculated using the equation shown below. Inthe example shown below a composition contains 90% of oneenantiomer, e.g., the S enantiomer, and 10% of the otherenantiomer, i.e., the R enantiomer. ee=(90-10)/100=80%. Thus, acomposition containing 90% of one enantiomer and 10% of the otherenantiomer is said to have an enantiomeric excess of 80%.

The "diastereomeric excess" or "% diastereomeric excess" of acomposition can be calculated using the equation shown below. Inthe example shown below a composition contains 90% of onediastereomer, and 10% of another enantiomer. ee=(90-10)/100=80%.Thus, a composition containing 90% of one diastereomer and 10% ofthe other diastereomer is said to have an diastereomeric excess of80%.

In addition, compounds of Formula (I) can include one or moreisotopes of the atoms present in Formula (I). For example,compounds of Formula (I) can include: those in which H (orhydrogen) is replaced with any isotopic form of hydrogen including.sup.1H, .sup.2H or D (Deuterium), and .sup.3H (Tritium); those inwhich C is replaced with any isotopic form of carbon including.sup.12C, .sup.13C, and .sup.14C; those in which O is replaced withany isotopic form of oxygen including .sup.16O, .sup.17O and.sup.18O; those in which N is replaced with any isotopic form ofnitrogen including .sup.13N, .sup.14N and .sup.15N; those in whichP is replaced with any isotopic form of phosphorous including.sup.31P and .sup.32P; those in which S is replaced with anyisotopic form of sulfur including .sup.32S and .sup.35S; those inwhich F is replaced with any isotopic form of fluorine including.sup.19F and .sup.18F; and the like. In an embodiment, compoundsrepresented by Formula (I) comprise isomers of the atoms therein intheir naturally occurring abundance.

Certain compounds disclosed herein can exist in unsolvated forms aswell as solvated forms, including hydrated forms. In general, thesolvated forms are equivalent to unsolvated forms and areencompassed within the scope of the present invention. Certaincompounds disclosed herein may exist in multiple crystalline oramorphous forms. In general, all physical forms are equivalent forthe uses contemplated by the present invention and are intended tobe within the scope of the present invention.

Pharmaceutical Compositions

Pharmaceutical compositions containing compounds described hereinsuch as a compound of Formula (I) or pharmaceutically acceptablesalt thereof can be used to treat or ameliorate a disorderdescribed herein, for example, a disorder responsive to theinhibition of the TRPA1 ion channel in subjects (e.g., humans andanimals).

The amount and concentration of compounds of Formula (I) in thepharmaceutical compositions, as well as the quantity of thepharmaceutical composition administered to a subject, can beselected based on clinically relevant factors, such as medicallyrelevant characteristics of the subject (e.g., age, weight, gender,other medical conditions, and the like), the solubility ofcompounds in the pharmaceutical compositions, the potency andactivity of the compounds, and the manner of administration of thepharmaceutical compositions. For further information on Routes ofAdministration and Dosage Regimes the reader is referred to Chapter25.3 in Volume 5 of Comprehensive Medicinal Chemistry (CorwinHansch; Chairman of Editorial Board), Pergamon Press 1990.

While it is possible for a compound disclosed herein to beadministered alone, it is preferable to administer the compound asa pharmaceutical formulation, where the compound is combined withone or more pharmaceutically acceptable diluents, excipients orcarriers. The compounds disclosed herein may be formulated foradministration in any convenient way for use in human or veterinarymedicine. In certain embodiments, the compound included in thepharmaceutical preparation may be active itself, or may be aprodrug, e.g., capable of being converted to an active compound ina physiological setting.

The phrase "pharmaceutically acceptable" is employed herein torefer to those compounds, materials, compositions, and/or dosageforms which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of human beings andanimals without excessive toxicity, irritation, allergic response,or other problem or complication, commensurate with a reasonablebenefit/risk ratio.

Examples of pharmaceutically acceptable carriers include: (1)sugars, such as lactose, glucose and sucrose; (2) starches, such ascorn starch and potato starch; (3) cellulose, and its derivatives,such as sodium carboxymethyl cellulose, ethyl cellulose andcellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin;(7) talc; (8) excipients, such as cocoa butter and suppositorywaxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil,sesame oil, olive oil, corn oil and soybean oil; (10) glycols, suchas propylene glycol; (11) polyols, such as glycerin, sorbitol,mannitol and polyethylene glycol; (12) esters, such as ethyl oleateand ethyl laurate; (13) agar; (14) buffering agents, such asmagnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16)pyrogen-free water; (17) isotonic saline; (18) Ringer's solution;(19) ethyl alcohol; (20) phosphate buffer solutions; (21)cyclodextrins such as Captisol.RTM.; and (22) other non-toxiccompatible substances employed in pharmaceutical formulations.

Examples of pharmaceutically acceptable antioxidants include: (1)water soluble antioxidants, such as ascorbic acid, cysteinehydrochloride, sodium bisulfate, sodium metabisulfite, sodiumsulfite and the like; (2) oil-soluble antioxidants, such asascorbyl palmitate, butylated hydroxyanisole (BHA), butylatedhydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol,and the like; and (3) metal chelating agents, such as citric acid,ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid,phosphoric acid, and the like.

Solid dosage forms (e.g., capsules, tablets, pills, dragees,powders, granules and the like) can include one or morepharmaceutically acceptable carriers, such as sodium citrate ordicalcium phosphate, and/or any of the following: (1) fillers orextenders, such as starches, lactose, sucrose, glucose, mannitol,and/or silicic acid; (2) binders, such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone,sucrose and/or acacia; (3) humectants, such as glycerol; (4)disintegrating agents, such as agar-agar, calcium carbonate, potatoor tapioca starch, alginic acid, certain silicates, and sodiumcarbonate; (5) solution retarding agents, such as paraffin; (6)absorption accelerators, such as quaternary ammonium compounds; (7)wetting agents, such as, for example, cetyl alcohol and glycerolmonostearate; (8) absorbents, such as kaolin and bentonite clay;(9) lubricants, such a talc, calcium stearate, magnesium stearate,solid polyethylene glycols, sodium lauryl sulfate, and mixturesthereof; and (10) coloring agents.

Liquid dosage forms can include pharmaceutically acceptableemulsions, microemulsions, solutions, suspensions, syrups andelixirs. In addition to the active ingredient, the liquid dosageforms may contain inert diluents commonly used in the art, such as,for example, water or other solvents, solubilizing agents andemulsifiers, such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate,propylene glycol, 1,3-butylene glycol, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor and sesame oils),glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, and mixtures thereof.

Suspensions, in addition to the active compounds, may containsuspending agents as, for example, ethoxylated isostearyl alcohols,polyoxyethylene sorbitol and sorbitan esters, microcrystallinecellulose, aluminum metahydroxide, bentonite, agar-agar andtragacanth, and mixtures thereof.

Ointments, pastes, creams and gels may contain, in addition to anactive compound, excipients, such as animal and vegetable fats,oils, waxes, paraffins, starch, tragacanth, cellulose derivatives,polyethylene glycols, silicones, bentonites, silicic acid, talc andzinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to an active compound,excipients such as lactose, talc, silicic acid, aluminum hydroxide,calcium silicates and polyamide powder, or mixtures of thesesubstances. Sprays can additionally contain customary propellants,such as chlorofluorohydrocarbons and volatile unsubstitutedhydrocarbons, such as butane and propane.

The formulations may conveniently be presented in unit dosage formand may be prepared by any methods well known in the art ofpharmacy. The amount of active ingredient which can be combinedwith a carrier material to produce a single dosage form will varydepending upon the host being treated, the particular mode ofadministration. The amount of active ingredient that can becombined with a carrier material to produce a single dosage formwill generally be that amount of the compound which produces atherapeutic effect. Generally, out of one hundred percent, thisamount will range from about 1 percent to about ninety-nine percentof active ingredient, preferably from about 5 percent to about 70percent, most preferably from about 10 percent to about 30percent.

The tablets, and other solid dosage forms of the pharmaceuticalcompositions disclosed herein, such as dragees, capsules, pills andgranules, may optionally be scored or prepared with coatings andshells, such as enteric coatings and other coatings well known inthe pharmaceutical-formulating art. They may also be formulated soas to provide slow or controlled release of the active ingredienttherein using, for example, hydroxypropylmethyl cellulose invarying proportions to provide the desired release profile, otherpolymer matrices, liposomes and/or microspheres. They may besterilized by, for example, filtration through a bacteria-retainingfilter, or by incorporating sterilizing agents in the form ofsterile solid compositions that can be dissolved in sterile water,or some other sterile injectable medium immediately before use.These compositions may also optionally contain opacifying agentsand may be of a composition that they release the activeingredient(s) only, or preferentially, in a certain portion of thegastrointestinal tract, optionally, in a delayed manner. Examplesof embedding compositions that can be used include polymericsubstances and waxes. The active ingredient can also be inmicro-encapsulated form, if appropriate, with one or more of theabove-described excipients.

Dosage forms for the topical or transdermal administration of acompound of this invention include powders, sprays, ointments,pastes, creams, lotions, gels, solutions, patches and inhalants.The active compound may be mixed under sterile conditions with apharmaceutically acceptable carrier, and with any preservatives,buffers, or propellants that may be required.

The formulations disclosed herein can be delivered via a device.Exemplary devices include, but are not limited to, a catheter,wire, stent, or other intraluminal device. Further exemplarydelivery devices also include a patch, bandage, mouthguard, ordental apparatus. Transdermal patches have the added advantage ofproviding controlled delivery of a compound disclosed herein to thebody. Such dosage forms can be made by dissolving or dispersing thecompound in the proper medium. Absorption enhancers can also beused to increase the flux of the compound across the skin. The rateof such flux can be controlled by either providing a ratecontrolling membrane or dispersing the compound in a polymer matrixor gel.

Ophthalmic formulations, eye ointments, drops, solutions and thelike, are also contemplated as being within the scope of thisinvention.

In some cases, in order to prolong the effect of a drug, it isdesirable to slow the absorption of the drug from subcutaneous orintramuscular injection. This may be accomplished by the use of aliquid suspension of crystalline or amorphous material having poorwater solubility. The rate of absorption of the drug then dependsupon its rate of dissolution, which, in turn, may depend uponcrystal size and crystalline form. Alternatively, delayedabsorption of a parenterally administered drug form is accomplishedby dissolving or suspending the drug in an oil vehicle.

Injectable depot forms are made by forming microencapsule matricesof the subject compounds in biodegradable polymers such aspolylactide-polyglycolide. Depending on the ratio of drug topolymer, and the nature of the particular polymer employed, therate of drug release can be controlled. Examples of otherbiodegradable polymers include poly(orthoesters) andpoly(anhydrides). Depot injectable formulations are also preparedby entrapping the drug in liposomes or microemulsions that arecompatible with body tissue.

When the compounds disclosed herein are administered aspharmaceuticals, to humans and animals, they can be given per se oras a pharmaceutical composition containing, for example, 0.1 to99.5% (more preferably, 0.5 to 90%) of active ingredient incombination with a pharmaceutically acceptable carrier.

The formulations can be administered topically, orally,transdermally, rectally, vaginally, parenterally, intranasally,intrapulmonary, intraocularly, intravenously, intramuscularly,intraarterially, intrathecally, intracapsularly, intraorbitally,intracardiacly, intradermally, intraperitoneally, transtracheally,subcutaneously, subcuticularly, intraarticularly, subcapsularly,subarachnoidly, intraspinally, intrasternally or by inhalation.

One specific embodiment is an antitussive composition for peroraladministration comprising an agent that inhibits both aTRPA1-mediated current with an IC.sub.50 of 1 micromolar or less,and an orally-acceptable pharmaceutical carrier in the form of anaqueous-based liquid, or solid dissolvable in the mouth, selectedfrom the group consisting of syrup, elixer, suspension, spray,lozenge, chewable lozenge, powder, and chewable tablet. Suchantitussive compositions can include one or more additional agentsfor treating cough, allergy or asthma symptom selected from thegroup consisting of: antihistamines, 5-lipoxygenase inhibitors,leukotriene inhibitors, H3 inhibitors, .beta.-adrenergic receptoragonists, xanthine derivatives, .alpha.-adrenergic receptoragonists, mast cell stabilizers, expectorants, and NK1, NK2 and NK3tachykinin receptor antagonists.

Still another embodiment is a metered dose aerosol dispensercontaining an aerosol pharmaceutical composition for pulmonary ornasal delivery comprising an agent that inhibits a TRPA1-mediatedcurrent with an IC.sub.50 of 1 micromolar or less. For instance, itcan be a metered dose inhaler, a dry powder inhaler or an air-jetnebulizer.

Dosages

Actual dosage levels of the active ingredients in thepharmaceutical compositions of this invention may be varied so asto obtain an amount of the active ingredient that is effective toachieve the desired therapeutic response for a particular patient,composition, and mode of administration, without being toxic to thepatient.

The selected dosage level will depend upon a variety of factorsincluding the activity of the particular compound disclosed hereinemployed, or the ester, salt or amide thereof, the route ofadministration, the time of administration, the rate of excretionof the particular compound being employed, the duration of thetreatment, other drugs, compounds and/or materials used incombination with the particular compound employed, the age, sex,weight, condition, general health and prior medical history of thepatient being treated, and like factors well known in the medicalarts.

A physician or veterinarian having ordinary skill in the art canreadily determine and prescribe the effective amount of thepharmaceutical composition required. For example, the physician orveterinarian could start doses of the compounds of the inventionemployed in the pharmaceutical composition at levels lower thanthat required in order to achieve the desired therapeutic effectand gradually increase the dosage until the desired effect isachieved.

In general, a suitable daily dose of a compound of the inventionwill be that amount of the compound that is the lowest doseeffective to produce a therapeutic effect. Such an effective dosewill generally depend upon the factors described above. Generally,intravenous, intracerebroventricular, intrathecal and subcutaneousdoses of the compounds of this invention for a patient will rangefrom about 0.0001 to about 100 mg per kilogram of body weight perday. For example, the dose can be 1-50, 1-25, or 5-10 mg/kg.

If desired, the effective daily dose of the active compound may beadministered as two, three, four, five, six or more sub-dosesadministered separately at appropriate intervals throughout theday, optionally, in unit dosage forms.

Methods of Treatment

The compounds described herein can be used to treat or prevent adisorder described herein. For example, compounds with TRPA1inhibitory activity are provided herein for the prevention,treatment, or alleviating symptoms of a disease or conditionassociated with TRPA1. Compounds of Formula (I), or pharmaceuticalcompositions containing one or more compounds of Formula (I), canbe administered to treat disorders, conditions, or diseasesdescribed herein such as those treatable by the inhibition ofTRPA1. For example, the pharmaceutical compositions comprisingcompounds of Formula (I), or pharmaceutically acceptable saltsthereof, are useful as a perioperative analgesic, for example inthe management of mild to moderate acute post-operative pain andmanagement of moderate to severe acute pain as an adjunct to opioidanalgesics. The pharmaceutical compositions comprising atherapeutically-effective dose of compounds of Formula (I), can beadministered to a patient for treatment of pain in a clinicallysafe and effective manner, including one or more separateadministrations of the pharmaceutical compositions comprisingcompounds of Formula (I). Additional exemplary methods include thetreatment of peripheral diabetic neuropathy (PDN) and chemotherapyinduced peripheral neuropathy (CIPN). For example, a pharmaceuticalcomposition comprising a therapeutically effective dose ofcompounds of Formula (I), or pharmaceutically acceptable saltsthereof can be administered (e.g., intravenously) to a subject inneed thereof multiple times per day (e.g., BID) over a course oftreatment of one or more days to treat pain in the subject.Pharmaceutical compositions comprising compounds of Formula (I) canalso be used to treat or ameliorate respiratory conditions, such asobstructive diseases, e.g., chronic obstructive pulmonary disease(COPD), asthma (e.g., cold induced asthma, exercise-induced asthma,allergy-induced asthma, and occupational asthma), and cough.

Those of skill in the treatment of diseases linked to the mediationof the TRPA1 receptor will be able to determine the therapeuticallyeffective amount of a compound of Formula (I) from the test resultspresented hereinafter. In general, a suitable daily dose of acompound of the invention will be that amount of the compound thatis the lowest dose able to produce a therapeutic effect. Such aneffective dose will generally depend upon various factors.Generally, oral, sublingual, rectal, intravenous, topical,transdermal, inhaled and intracerebroventricular doses of thecompounds of this invention for a patient will range from about0.0001 to about 100 mg per kilogram of body weight per day. Forexample, the dose can be 1-50, 1-25, or 5-10 mg/kg. It iscontemplated, for instance, that a therapeutically effective dosewill be from about 0.001 mg/kg to about 50 mg/kg per kg of bodyweight, more preferably from about 0.01 mg/kg to about 10 mg/kg perkg of body weight of the patient to be treated. It may beappropriate to administer the therapeutically effective dose in theform of two or more sub-doses at appropriate intervals throughoutthe day. Said sub-doses may be formulated as unit dosage forms, forexample each containing from about 0.1 mg to about 1000 mg, moreparticularly from about 1 to about 500 mg, of the active ingredientper unit dosage form.

The exact dosage and frequency of administration depends on theparticular compound of formula (I) used, the particular conditionbeing treated, the severity of the condition being treated, theage, weight and general physical condition of the particularpatient as well as the other medication the patient may be taking,as is well known to those skilled in the art. Furthermore, said"therapeutically effective amount" may be lowered or increaseddepending on the response of the treated patient and/or dependingon the evaluation of the physician prescribing the compounds of theinstant invention. The effective daily amount ranges mentionedhereinabove are therefore only guidelines. A physician orveterinarian having ordinary skill in the art can readily determineand prescribe the effective amount of the pharmaceuticalcomposition required.

Exemplary disorders suitable for treatment with a compound orcomposition described herein are provided below.

Pain

The compounds of Formula (I) that are useful in the modulation ofTRPA1 can be used in the formulation of analgesic pharmaceuticalssuitable for the treatment and/or prophylaxis of pain in mammals,especially in humans. Endogenous activators of TRPA1 are producedduring many pathological conditions including tissue injury,inflammation, and metabolic stress. Compounds and pharmaceuticalcompositions of the present invention can be administered to treatpain resulting from activation of TRPA1 including neuropathic pain.Relevant neuropathic pain conditions include, but are not limitedto, painful diabetic neuropathy, chemotherapy-induced peripheralneuropathy, lower back pain, trigeminal neuralgia, post-herpeticneuralgia, sciatica, and complex regional pain syndrome

Compositions and methods provided herein may also be used inconnection with treatment of in the treatment of inflammation andinflammatory pain. Such disorders include rheumatoid arthritis,osteoarthritis, temperomandibular disorder. In some embodiments,the compositions and methods provided herein may be used to treatheadache pain, e.g., migraine.

Disclosed compounds also may be useful in the treatment of visceralpain and inflammation. Relevant diseases include pancreatitis,inflammatory bowel disease, colitis, Crohn's disease,endometriosis, pelvic pain, and angina.

Additional exemplary pain indications for which compounds disclosedherein can be used include temperomandibular disorder, cancer pain(resulting either from the underlying disease or from thetreatments), burn pain, oral pain, oral pain due to cancertreatment, crush and injury induced pain, incisional pain, bonepain, sickle cell disease pain, fibromyalgia and musculoskeletalpain. TRPA1 has been show to play a role in cancer related pain(See, e.g., Trevisan et al., Cancer Res Mar. 11, 2013);postoperative pain (See, e.g., Wei et al, Anasthesiology, V 117,No. 1 (2012); pathological pain (See, e.g., Chen et al, Pain(2011).); and pain related to chemical injury (See, e.g.,Macpherson et al, The Journal of Neuroscience, Oct. 17, 200727(42):11412-11415).

Hyperalgesia (e.g., mechanical hyperalegsia, cold hyperalegsia) orincreased sensitivity to pain (e.g., acute, chronic). MultipleChemical Sensitivity is a disorder linked to chemical exposure withmulti-organ symptoms including respiratory symptoms andheadache.

Allodynia (e.g., cutaneous allodynia, e.g., cephalic,extracephalic) is a pain due to a stimulus which does not normallyprovoke pain, e.g., temperature or physical stimuli, and differsfrom hyperalgesia, which generally refers to an extreme,exaggerated reaction to a stimulus which is normally painful.

Migraine

The compounds of Formula (I) that are useful in the modulation ofTRPA1 can be used in the formulation of pharmaceuticals suitablefor the treatment and/or prophylaxis of migraine in mammals,especially in humans. Exposure to TRPA1 activators has been shownto trigger migraine in susceptible populations. Such activatorsinclude but are not limited to umbellulone, nitroglycerin,cigarette smoke, and formaldehyde. Accordingly, TRPA1 antagonistsof the invention represent a significant possible therapeutic forthe treatment of both chronic and acute migraine.

Inflammatory Diseases and Disorders

Compositions and methods provided herein may also be used inconnection with treatment of inflammatory diseases. These diseasesinclude but are not limited to asthma, chronic obstructivepulmonary disease, rheumatoid arthritis, osteoarthritis,inflammatory bowel disease, glomerulonephritis, neuroinflammatorydiseases such as multiple sclerosis, and disorders of the immunesystem. TRPA1 has been show to play a role in pancreatic pain andinflammation (See, e.g., Schwartz et al., Gastroenterology. 2011April; 140(4): 1283-1291.).

Peripheral neuropathy, for example diabetic neuropathy, is aparticular condition that involves both a neuronal and aninflammatory component. Without being bound by a mechanistictheory, the TRPA1 antagonists of the invention may be useful intreating peripheral neuropathies including, but not limited to,diabetic neuropathy. In addition to their use in the treatment ofperipheral neuropathies (e.g., reducing inflammation), the subjectinhibitors may also be useful in reducing the pain associated withperipheral neuropathy. TRPA1 has been show to play a role inneuropathy and neuropathic pain (See, e.g., Wei et al,Anesthesiology 2009; 111:147-54; and Koivisto et al.,Pharmacological Research 2011.).

Neurogenic inflammation often occurs when neuronalhyperexcitability leads to the release of peptides that triggerinflammation. These peptides include substance P and CGRP. BlockingTRPA1 would reduce neuronal activity and thus could blockneurogenic inflammation. For example, neurogenic inflammation inthe respiratory tract, can result in asthma and allergic rhinitissymptoms, and neurogenic inflammation in the dura may also mediatemigraine pain.

Pancreatitis

Pancreatitis is an inflammation of the pancreas. The pancreas is alarge gland behind the stomach and close to the duodenum. Normally,digestive enzymes do not become active until they reach the smallintestine, where they begin digesting food. But if these enzymesbecome active inside the pancreas, they start "digesting" thepancreas itself. TRPA1 has been show to play a role in pancreaticpain and inflammation (See, e.g., Schwartz et al.,Gastroenterology. 2011 April; 140(4): 1283-1291.).

Acute pancreatitis is usually, although not exclusively, caused bygallstones or by alcohol abuse. Acute pancreatitis usually beginswith pain in the upper abdomen that may last for a few days. Thepain may be severe and may become constant. The pain may beisolated to the abdomen or it may reach to the back and otherareas. Sometimes, and for some patients, the pain is sudden andintense. Other times, or for other patients, the pain begins as amild pain that worsens after eating. Someone with acutepancreatitis often looks and feels very sick. Other symptoms mayinclude swollen and tender abdomen, nausea, vomiting, fever, andrapid pulse. Severe cases of acute pancreatitis may causedehydration and low blood pressure, and may even lead to organfailure, internal bleeding, or death.

During acute pancreatitis attacks, the blood levels of amylase andlipase are often increased by at least 3-fold. Changes may alsooccur in blood levels of glucose, calcium, magnesium, sodium,potassium, and bicarbonate.

The current treatment depends on the severity of the attack.Treatment, in general, is designed to support vital bodilyfunctions, manage pain, and prevent complications. Although acutepancreatitis typically resolved in a few days, pain managementduring an attack is often required. The compounds disclosed hereincan be used to relieve the pain associated with acutepancreatitis.

Chronic pancreatitis may develop if injury to the pancreascontinues. Chronic pancreatitis occurs when digestive enzymesattack and destroy the pancreas and nearby tissues, causingscarring and pain. Chronic pancreatitis may be caused byalcoholism, or by blocked, damaged, or narrowed pancreatic ducts.Additionally, hereditary factors appear to influence the disease,and in certain cases, there is no identifiable cause (so calledidiopathic pancreatitis).

Most people with chronic pancreatitis have abdominal pain. The painmay get worse when eating or drinking, spread to the back, orbecome constant and disabling. Other symptoms include nausea,vomiting, weight loss, and fatty stools.

Relieving pain is the first step in treating chronic pancreatitis.Once the pain has been managed, a high carbohydrate and low fatdietary plan is put in place. Pancreatic enzymes may be used tohelp compensate for decrease enzyme production from the injuredpancreas. Sometimes insulin or other drugs are needed to controlblood glucose.

Although pain is typically managed using drug therapy, surgery maybe necessary to relieve pain. Surgery may be necessary to drain anenlarged pancreatic duct or even to 10 removing a portion of aseriously injured pancreas.

Pain is frequently present with chronic pancreatitis. For example,pain is present for approximately 75% of patients with alcoholicchronic pancreatitis, 50% of patients with lateonset idiopathicchronic pancreatitis, and 100% of patients with early-onsetidiopathic chronic pancreatitis (DiMagno, 1999, Gastroenterology116(5): 1252-1257).

A minority of patients with pain have readily identifiable lesionswhich are relatively easy to treat surgically or endoscopically. Inother patients, pain is often thought to result from a variety ofcauses, including elevated intrapancreatic pressure, ischemia, andfibrosis. Without being bound by theory, however, these phenomenaare not likely the underlying cause of the pain. Rather, pain mayresult from a background of neuronal sensitization induced bydamage to the perineurium and subsequent exposure of the nerves tomediators and products of inflammation.

Given the importance of effective pain management in patients withchronic pancreatitis, additional therapies for treating painfulsymptoms are important and useful. The compounds disclosed hereincan be used to manage the pain associated with chronicpancreatitis; they can be used alone or as part of an overalltherapeutic treatment plan to manage patients with chronicpancreatitis. For example, the compounds can be administered withpancreatic enzymes and/or insulin as part of a therapeutic regimendesigned to manage patients with chronic pancreatitis.

Cancer treatments are not only painful, but they may even be toxicto healthy tissue. Some chemotherapeutic agents can cause painfulneuropathy. Accordingly, the compounds disclosed herein couldrepresent a significant possible therapeutic for the treatment ofthe pain and/or inflammation associated with cancer treatments thatcause neuropathy.

A major function of prostaglandins is to protect the gastricmucosa. Included in this function is the modulation ofintracellular calcium level in human gastric cells which plays acritical role in cell proliferation. Consequently, inhibition ofprostaglandins by nonsteroidal anti-inflammatory drugs (NSAIDs) caninhibit calcium influx in gastric cells (Kokoska et al. (1998)Surgery (St Louis) 124 (2):429-437). The NSAIDs that relieveinflammation most effectively also produce the greatestgastrointestinal damage (Canadian Family Physician, 5 Jan. 1998, p.101). Thus, the ability to independently modulate calcium channelsin specific cell types may help to alleviate such side effect ofanti-inflammatory therapy. Additionally or alternatively,administration of TRPA1 inhibitory compounds disclosed herein maybe used in combination with NSAIDs, thus promoting pain reliefusing reduced dosage of NSAIDs.

TRPA1 may mediate ongoing nociception in chronic pancreatitis; andmay be involved in transforming acute into chronic inflammation andhyperalgesia in pancreatitis. TRPA1 may also mediate irritation andburning in the e.g., nasal and oral mucosa and respiratorylining.

Neuropathy

Because TRPA1 overactivity can lead to a toxic calcium overload,TRPA1 antagonists also have utility in the prevention of neuropathyassociated with diabetes, chemical injury, chemotherapy, medicinessuch as statins, HIV/AIDS, Fabry's disease, vitamin deficiency,inherited polyneuropathy such as Marie-Charcot Tooth disease, andtrauma. Peripheral neurodegenerative diseases such as AmyotrophicLateral Sclerosis may also be amenable to treatment with a TRPA1antagonist.

Pulmonary Disease and Cough

Compositions and methods provided herein may also be used inconnection with the treatment of pulmonary diseases, including, butnot limited to, asthma (including exercise-induced asthma, atopicasthma, allergic asthma), Chronic Obstructive Pulmonary disease(COPD, emphysema) cystic fibrosis, bronchiectasis, bronchiolitis,allergic bronchopulmonary aspergillosis, bronchiolitis obliterans(popcorn worker lung), diseases due to chemical exposure includingexposures to diacetyl, formaldehyde, and other irritants. Theseconditions also include tuberculosis, restrictive lung diseaseincluding asbestosis, radiation fibrosis, hypersensitivitypneumonitis, infant respiratory distress syndrome, idiopathicpulmonary fibrosis, idiopathic interstial pneumonia sarcoidosis,eosinophilic pneumonia, lymphangioleiomyomatosis, pulmonaryLangerhan's cell histiocytosis, and pulmonary alveolar proteinosis;respiratory tract infections including upper respiratory tractinfections (e.g., common cold, sinusitis, tonsillitis, pharyngitisand laryngitis) and lower respiratory tract infections (e.g.,pneumonia); respiratory tumors whether malignant (e.g., small celllung cancer, non-small cell lung cancer, adenocarcinoma, squamouscell carcinoma, large cell undifferentiated carcinoma, carcinoid,mesothelioma, metastatic cancer of the lung, metastatic germ cellcancer, metastatic renal cell carcinoma) or benign (e.g., pulmonaryhamartoma, congenital malformations such as pulmonary sequestrationand congenital cystic adenomatoid malformation (CCAM)); pleuralcavity diseases (e.g., empyema and mesothelioma); and pulmonaryvascular diseases, e.g, pulmonary embolism such as thromboembolism,and air embolism (iatrogenic), pulmonary arterial hypertension,pulmonary edema, pulmonary hemorrhage, inflammation and damage tocapillaries in the lung resulting in blood leaking into thealveoli. Other conditions that may be treated include disordersthat affect breathing mechanics (e.g., obstructive sleep apnea,central sleep apnea, Guillan-Barre syndrome, and myastheniagravis).

The present compounds can also be useful for treating, reducing, orpreventing cough (with or without the production of sputum), coughassociated with asthma, cough associated with influenza, coughingblood (haemoptysis), cough of unknown etiology, and cough due tochemical exposures.

Dermatological Disorders

A number of agents that cause itch activate TRPA1 directly or viaactivation of receptors which couple to TRPA1 downstream.Compositions and methods provided herein may also be used inconnection with the treatment of itch. Indications include, but arenot limited to, conditions triggered by exposure to exogenouschemicals such as contact dermatitis, poison ivy, itch due tocancer including lymphomas, itch caused by medications such aschloroquine, itch due to reactive drug metabolites or itch due todry skin.

Additional exemplary indications include atopic dermatitis,psoriasis, hives, eczema, dyshidrotic eczema, mouth ulcers, diaperrash.

Itch

Itch, or acute pruritus, while serving an important protectivefunction by e.g., warning against harmful agents in theenvironment, it can also be a debilitating condition that e.g.,accompanies numerous skin, systemic and nervous system disorders.Some forms of itch are mediated by histamine signaling as such aresusceptible to treatment with e.g., antihistamines. However, mostpathophysiological itch conditions are insensitive to antihistaminetreatment. Compounds and pharmaceutical compositions of the presentinvention can be administered to treat itch.

Atopic dermatitis (AD) is a chronic itch and inflammatory disorderof the skin. Patients with severe AD can develop asthma andallergic rhinitis, also known as atopic march. Skin rash andpruritus may be associated with atopic disease. Chronic itch, e.g.,in AD and psoriasis; includes pathophysiological hallmarks such asrobust scratching, extensive epidermal hyperplasia from e.g.,eczema, kidney failure, cirrhosis, nervous system disorders, somecancers.

Allergic contact dermatitis is a common skin disease associatedwith inflammation and persistent pruritus.

Methods as disclosed herein may inhibit skin edema, keratinocytehyperplasia, nerve growth, leukocyte infiltration, andantihistamine-resistant scratching behavior. Methods as disclosedherein may inhibit allergic response to e.g., exogenous stimulants,e.g., haptens, oxazolone, urushiol (e.g., from poison ivy).

Disease and Injury Models

Compounds that antagonize TRPA1 function may be useful in theprophylaxis and treatment of any of the foregoing injuries,diseases, disorders, or conditions. In addition to in vitro assaysof the activity of these compounds, their efficacy can be readilytested in one or more animal models. There are numerous animalmodels for studying pain. The various models use various agents orprocedures to simulate pain resulting from injuries, diseases, orother conditions (Blackburn-Munro (2004) Trends in PharmacologicalSciences 25: 299-305 (see, for example, Tables 1, 3, or 4)).Behavioral characteristics of challenged animals can then beobserved. Compounds or procedures that may reduce pain in theanimals can be readily tested by observing behavioralcharacteristics of challenged animals in the presence versus theabsence of the test compound(s) or procedure.

Exemplary behavioral tests used to study chronic pain include testsof spontaneous pain, allodynia, and hyperalgesia. To assessspontaneous pain, posture, gait, nocifensive signs (e.g., pawlicking, excessive grooming, excessive exploratory behavior,guarding of the injured body part, and self-mutilation) can beobserved. To measure evoked pain, behavioral responses can beexamined following exposure to heat (e.g., thermal injurymodel).

Exemplary animal models of pain include, but are not limited to,the models described in the Trevisan model, and the Koivistoreferences including Streptozotocin induced painful diabeticneuropathy, bortezomib induced peripheral neuropathy andoxaliplatin induced peripheral neuropathy; the Chung model, thespared nerve injury model, the carageenan induced hyperalgesiamodel, the complete Freund's adjuvant induced hyperalgesia model,the thermal injury model, the formalin model and the BennettModel.

In the Trevisan reference, chemotherapy-induced peripheralneuropathy model involves the induction if a CIPN phenotype in miceby treatment with bortezomib or oxaliplatin (Trevisan et al, Cancerresearch 73, 3120-3131, 2013). Treatment of an animal with aninhibitor of TRPA1 can be evaluated using any of a variety ofnociceptive tests such as the Von Frey hair test, the hot platetest, cold simulation, chemical hyperalgesia, or the rotarodtest.

The model of peripheral diabetic neuropathy (PDN) in the Koivistoreference involves induction of diabetes mellitus (DM) in rats withstreptozotocin, and assessing axon reflex induced by intraplantarinjection of a TRPA1 agonist. (Pharmacological Research 2011)Treatment with a compound that inhibits TRPA1 can be evaluated forthe reduction in DM-induced attenuation of the cutaneous axonreflex.

The Chung model of neuropathic pain (without inflammation) involvesligating one or more spinal nerves (Chung et al. (2004) Methods MolMed 99: 35-45; Kim and Chung (1992) Pain 50: 355-363). Ligation ofthe spinal nerves results in a variety of behavioral changes in theanimals including heat hyperalgesia, cold allodynia, and ongoingpain. Compounds that antagonize TRPA1 can be administered toligated animals to assess whether they diminish theseligation-induced behavioral changes in comparison to that observedin the absence of compound.

Carageenan induced hyperalgesia and complete Freund's adjuvant(CFA) induced hyperalgesia are models of inflammatory pain (Walkeret al. (2003) Journal of Pharmacol Exp Ther 304: 56-62; McGaraughtyet al. (2003) Br J Pharmacol 140: 1381-1388; Honore et al. (2005) JPharmacol Exp Ther). Compounds that antagonize TRPA1 can beadministered to carrageenan or CFA challenged animals to assesswhether they diminish cold, mechanical or heat hypersensitivity incomparison to that observed in the absence of compound. Inaddition, the ability of compounds that antagonize TRPA1 functionto diminish cold and/or mechanical hypersensitivity can also beassessed in these models. Typically, the carrageenan inducedhyperalgesia model is believed to mimic acute inflammatory pain andthe CFA model is believed to mimic chronic pain and chronicinflammatory pain.

Exemplary models of inflammatory pain include the rat model ofintraplantar bradykinin injection. Briefly, the baseline thermalsensitivity of the animals is assessed on a Hargreave's apparatus.TRPA1 blockers are then administered systemically. Bradykinin issubsequently injected into the paw and a hyperalgesia is allowed todevelop. Thermal escape latency is then measured at multiple timepoints over the next few hours (Chuang et al., 2001; Vale et al.,2004).

Inflammation is often an important contributing factor to pain. Assuch, it is useful to identify compounds that act asanti-inflammatories. Many compounds that reduce neural activityalso prevent neurogenic inflammation. To measure inflammationdirectly, the volume of a rat paw can be assessed using aplethysmometer. After baseline measurement is taken, carrageenancan be injected into the paw and the volume can be monitored overthe course of hours in animals that have been treated with vehicleor drug. Drugs that reduce the paw swelling are considered to beanti-inflammatory.

Migraines are associated with significant pain and inability tocomplete normal tasks. Several models of migraine exist includingthe rat neurogenic inflammation model, (see Buzzi et al (1990) Br JPharmacol; 99:202-206), and the Burstein Model (see Strassman etal., (1996) Nature 384: 560-564).

The Bennett model uses prolonged ischemia of the paw to mirrorchronic pain (Xanthos et al. (2004) J Pain 5: S1). This provides ananimal model for chronic pain including post-operative pain,complex regional pain syndrome, and reflex sympathetic dystrophy.Prolonged ischemia induces behavioral changes in the animalsincluding hyperalgesia to mechanical stimuli, sensitivity to cold,pain behaviors (e.g., paw shaking, licking, and/or favoring), andhyperpathia. Compounds that antagonize TRPA1 can be administered tochallenged animals to assess whether they diminish any or all ofthese behaviors in comparison to that observed in the absence ofcompound. Similar experiments can be conducted in a thermal injuryor UV-burn model which can be used to mimic post-operativepain.

Additional models of neuropathic pain include central pain modelsbased on spinal cord injury. Chronic pain is generated by inducinga spinal cord injury, for example, by dropping a weight on asurgically exposed area of spinal cord (e.g., weight-drop model).Spinal cord injury can additionally be induced by crushing orcompressing the spinal cord, by delivering neurotoxin, usingphotochemicals, or by hemisecting the spinal cord.

Additional models of neuropathic pain include peripheral nerveinjury models. Exemplary models include, but are not limited to,the neuroma model, the Bennett model, the Seltzer model, the Chungmodel (ligation at either L5 or L5/L6), the sciatic cryoneurolysismodel, the inferior caudal trunk resection model, and the sciaticinflammatory neuritis model. Id.

Exemplary models of neuropathic pain associated with particulardiseases are also available. Diabetes and shingles are two diseasesoften accompanied by neuropathic pain. Even following an acuteshingles episodes, some patients continue to suffer frompostherpetic neuralgia and experience persistent pain lastingyears. Neuropathic pain caused by shingles and/or postherpeticneuralgia can be studied in the postherpetic neuralgia model (PHN).Diabetic neuropathy can be studied in diabetic mouse models, aswell as chemically induced models of diabetic neuropathy.

As outlined above, cancer pain may have any of a number of causes,and numerous animal models exist to examine cancer pain related to,for example, chemotherapeutics or tumor infiltration. Exemplarymodels of toxin-related cancer pain include the vincristine-inducedperipheral neuropathy model, the taxol-induced peripheralneuropathy model, and the cisplatin-induced peripheral neuropathymodel. An exemplary model of cancer pain caused by tumorinfiltration is the cancer invasion pain model (CIP).

Primary and metastatic bone cancers are associated with tremendouspain. Several models of bone cancer pain exist including the mousefemur bone cancer pain model (FBC), the mouse calcaneus bone cancerpain model (CBC), and the rat tibia bone cancer model (TBC).Id.

An additional model of pain is the formalin model Like thecarrageenan and CFA models, the formalin model involves injectionof an irritant intradermally or intraperitoneally into an animal.Injection of formalin, a 37-40% percent solution of formaldehyde,is the most commonly used agent for intradermal paw injection (theformalin test). Injection of a 0.5 to 15 percent solution offormalin (usually about 3.5%) into the dorsal or plantar surface ofthe fore- or hindpaw produces a biphasic painful response ofincreasing and decreasing intensity for about 60 minutes after theinjection. Typical responses include the paw being lifted, licked,nibbled, or shaken. These responses are considered nociceptive. Theinitial phase of the response (also known as the Early Phase),which lasts 3 to 5 minutes, is probably due to direct chemicalstimulation of nociceptors. This is followed by 10 to 15 minutesduring which animals display little behavior suggestive ofnociception. The second phase of this response (also known as theLate Phase) starts about 15 to 20 minutes after the formalininjection and lasts 20 to 40 minutes, initially rising with bothnumber and frequency of nociceptive behaviors, reaching a peak,then falling off. The intensities of these nociceptive behaviorsare dependent on the concentration of formalin used. The secondphase involves a period of sensitization during which inflammatoryphenomena occur. The two phases of responsiveness to formalininjection makes the formalin model an appropriate model forstudying nociceptive and acute inflammatory pain. It may alsomodel, in some respects, neuropathic pain.

In addition to any of the foregoing models of chronic pain,compounds that antagonize TRPA1 function can be tested in one ormore models of acute pain. Valenzano et al. (2005)Neuropharmacology 48: 658-672. Regardless of whether compounds aretested in models of chronic pain, acute pain, or both, thesestudies are typically (though not exclusively) conducted, forexample, in mice, rats, or guinea pigs. Additionally, compounds canbe tested in various cell lines that provide in vitro assays ofpain.

Many individuals seeking treatment for pain suffer from visceralpain. Animal models of visceral pain include the rat model ofinflammatory uterine pain (Wesselmann et al., (1997) Pain73:309-317), injection of mustard oil into the gastrointestinaltract to mimic irritable bowel syndrome (Kimball et al., (2005) AmJ Physiol Gastrointest Liver Physiol, 288(6):G1266-73), injectionof mustard oil into the bladder to mimic overactive bladder orbladder cystitis (Riazimand (2004), BJU 94: 158-163). Theeffectiveness of a TRPA1 compound can be assessed by a decrease inwrithing, gastrointestinal inflammation or bladderexcitability.

For testing the efficacy of TRPA1 antagonists for the treatment ofcough, experiments using the conscious guinea pig model of coughcan be readily conducted (Tanaka and Maruyama (2003) JournalPharmacol Sci 93: 465-470; McLeod et al. (2001) Br J Pharmacol 132:1175-1178). Briefly, guinea pigs serve as a useful animal model forcough because, unlike other rodents such as mice and rats, guineapigs actually cough. Furthermore, guinea pig coughing appears tomimic human coughing in terms of the posture, behavior, andappearance of the coughing animal.

To induce cough, conscious guinea pigs are exposed to an inducingagent such as citric acid or capsaicin. The response of the animalis measured by counting the number of coughs. The effectiveness ofa cough suppressing agent, for example a compound that inhibitsTRPA1, can be measured by administering the agent and assessing theability of the agent to decrease the number of coughs elicited byexposure to citric acid, capsaicin, or other similar cough-inducingagent. In this way, TRPA1 inhibitors for use in the treatment ofcough can be readily evaluated and identified.

Additional models of cough may also include the unconscious guineapig model (Rouget et al. (2004) Br J Pharmacol 141: 1077-1083).Either of the foregoing models can be adapted for use with otheranimals capable of coughing. Exemplary additional animals capableof coughing include cats and dogs.

Compounds of the invention may be tested in multiple models ofasthma. One example is the murine ovalbumin model of asthma(Caceres A I et al., Proc Natl Acad Sci USA. 2009 Jun. 2;106(22):9099-104; Epub 2009 May 19). In this model, ovalbumin isinjected into the intraperitoneal cavity several times over 2weeks. Sometime in the third week, animals are challenged withintranasal ovalbumin an airway hyperresponsiveness, inflammationand inflammatory cytokine production may be measured. Compounds aredosed during the challenge phase of the model. TRPA1 knock-out micemay be substituted into the above models as reported by Caceres etal.

An example of a large animal model of asthma the conscious allergicsheep model as described in Abraham, W. M. et al. may be used toassess effects of compounds on the antigen-induced late stageresponse of asthma (Abraham W M., Am J Respir Crit Care Med. 2000August; 162(2 Pt 1):603-11). Briefly, baseline airwayresponsiveness is measured by plethysmograph in conscious sheepprior to a nebulized administration of Ascaris suum extract toinduce asthma. After baseline readings are captured, animals arechallenged with a nebulized dose of Ascaris suum. Antigensensitivity is determined by decrease in pulmonary flow resistancefrom baseline. Once animals demonstrate antigen-sensitivity, testcompounds may be administered and additional pulmonary flowresistance readings captured to assess changes airwayresponsiveness. Models in the horse and beagle dog are sometimesalso used.

Additional models may include the Brown Norway rat model and theC57BL/6J mouse model of asthma as described in Raemdonck et al.(Raemdonck K et al., Thorax. 2012 January; 67(1):19-25; Epub 2011Aug. 13). Briefly Brown Norway rats and C57BL/6J mice may besensitized and challenged with aerosol delivered ovalbumin. Oncesensitivity is confirmed by a decrease in lung function as measuredby whole body plethysmograph readings, compounds of the inventionmay be administered. Visual and audible signs of respiratorydistress including wheezing may also be present.

Dermatitis

Multiple mouse models of dermatological disease currently exist.For example, Liu et al. describe multiple oxazolone andurushiol-induced contact dermatis models (Liu B et al., FASEB J.2013 September; 27(9):3549-63; Epub 2013 May 30). Briefly, Trpalknock-out mice receive topical administrations of oxazolone orurushiol to induce dermatitis and itch responses. Epidermisthickness may also be measured by taking ear punches andmeasurements of challenged areas compared with untreated ears. Invivo treatment compounds may be determined by administeringcompounds to the animals prior to or after ozazolone or urushioltreatments. Scratching behaviors are recorded by video cameraspositioned above observation chambers. Observers blind to treatmentgroups record the time animals spend scratching over the course ofthirty minutes.

An alternative mouse model of dry-skin evoking itch involvesadministration of acetone, ether, and water to the mouse asreported by Wilson et al. (Wilson S R et al., J Neurosci. 2013 May29; 33(22):9283-94) In this model, the area to be treated is shavedand mice receive topical administration of acetone and ether twicedaily on the area to be observed, e.g. cheek or caudal back. Invivo efficacy of treatment compounds may be determined byadministering compounds to the animals prior to or after acetoneand ether administration. Scratching behavior is recorded by camerafor a period of 20 minutes and quantified by observers blind totreatment groups.

In addition, pruritus may be induced by direct injection of anagent that causes itch. Examples of these agents may be found inAkayimo and Carstens, 2013. Some examples are: chloroquine (Wilsonet al., 2011), bile acids, TSLP (Wilson et al., 2013), and IL-31(Cevikbas et al., 2014). Typically scratching bouts in a definedperiod are recorded by an observed blinded to treatment group.

Numerous rodent models of incontinence exist. These include modelsof incontinence induced by nerve damage, urethral impingement andinflammation. Models of urethral impingement include the ratbladder outflow obstruction model. (Pandita, R K, and Andersson KE. Effects of intravesical administration of the K+ channel opener,Z.D6169, in conscious rats with and without bladder outflowobstruction. J Urol 162: 943-948, 1999). Inflammatory modelsinclude injection of mustard oil into the bladder.

To test the effectiveness of a TRPA1 inhibitor compound in treatingincontinence, varying concentrations of compound (e.g., low,medium, and high concentration) can be administered to ratsfollowing surgical partial bladder outlet obstruction (BOO).Efficacy of the varying doses of TRPA1 inhibitory compound can becompared to controls administered excipients alone (sham control).Efficacy can further be compared to rats administered a positivecontrol, such as atropine. Atropine is expected to decrease bladderover-activity following partial bladder outlet obstruction in theBOO model. Note that when testing compounds in the BOO model,compounds can be administered directly to the bladder or urethra(e.g., by catheter) or compounds can be administered systemically(e.g., orally, intraveneously, intraperitoneally, etc).

Several rat models of pancreatitic pain have recently beendescribed (Lu, 2003, Anesthesiology 98(3): 734-740; Winston et al.,2003, Journal of Pain 4(6): 329-337). Lu et al. inducedpancreatitis by systemic delivery of dibutylin dichloride in rats.Rats showed an increase in withdrawal events after von Freyfilament stimulation of the abdomen and decreased withdrawallatency after thermal stimulation during a period of 7 days. Thepain state induced in these animals was also characterized byincreased levels of substance P in spinal cords (Lu, et al., 2003).To test the efficacy of a TRPA1 inhibitor in this model, a TRPA1inhibitor can be administered following or concurrently withdelivery of dibutylin dichloride. Control animals can beadministered a carrier or a known pain reliever. Indicia of paincan be measured. Efficacy of a TRPA1 inhibitor can be evaluated bycomparing the indicia of pain observed in animals receiving a TRPA1inhibitor to that of animals that did not receive a TRPA1inhibitor. Additionally, efficacy of a TRPA1 inhibitor can becompared to that of known pain medicaments.

The efficacy of von Frey filament testing as a means to measurenociceptive behavior was also shown by inducing pancreatitis bysystemic L-arginine administration (Winston et al, 2003). Theefficacy of a TRPA1 inhibitor can similarly be tested followingpancreatitis induced by systemic L-arginine administration.

Lu et al. also described direct behavioral assays for pancreaticpain using acute noxious stimulation of the pancreas via anindwelling ductal cannula in awake and freely moving rats. Theseassays included cage crossing, rearing, and hind limb extension inresponse to intrapancreatic bradykinin infusion. Intrathecaladministration of either D-APV (NMDA receptor antagonist) ormorphine alone partially reduced visceral pain behaviors in thismodel. Combinations of both reduced pain behaviors to baseline. Theefficacy of a TRPA1 inhibitor can similarly be tested in thissystem.

Any of the foregoing animal models may be used to evaluate theefficacy of a TRPA1 inhibitor in treating pain associated withpancreatitis. The efficacy can be compared to a no treatment orplacebo control. Additionally or alternatively, efficacy can beevaluated in comparison to one or more known pain relievingmedicaments.

EXAMPLES

In Vitro Characterization of Exemplary Compounds of theInvention

Example 1 Method for Measuring Inhibition of the TRPA1 IonChannel

Compounds of Formula (I) inhibit the TRPA1 channel, as shown bymeasuring the in vitro inhibition of human TRPA1, provided in datatables shown in Table 2, using the procedure outlined in del Caminoet al., The Journal of Neuroscience, 30(45):15165-15174 (Nov. 10,2010), incorporated herein by reference and summarized below. Datafor TRPA1 inhibition was obtained by this method for the indicatedcompounds of Formula (I), with the relevant data included in Table2 below. All currents were recorded in whole-cell configurationusing EPC-9 and EPC-10 amplifiers and Patchmaster software (HEKA)or similar. Patch pipettes had a resistance of 1.5-3 M.sub.-- andup to 75% of the series resistance was compensated. The standardpipette solution consisted of 140 mM CsAsp, 10 mM EGTA, 10 mMHEPES, 2.27 mM, 20 MgCl.sub.2, 1.91 mM CaCl.sub.2, and up to 0.3 mMNa.sub.2GTP, with pH adjusted to 7.2 with CsOH. In addition, asolution containing 145 mM CsCl, 10 mM HEPES, 10 mM EGTA, and up to0.3 mM Na.sub.2GTP and 1 mM MgCl.sub.2 (pH 7.2 adjusted with CsOH)can be used. The standard bath solution contained 150 mM NaCl, 10mM HEPES, 10 mM glucose, 4.5 mM KCl, 1 mM EGTA, 3 mM MgCl.sub.2,with pH adjusted to 7.4 with NaOH. In some instances, 2 mMCaCl.sub.2 was added in place of EGTA and the concentration ofMgCl.sub.2 was reduced to 1 mM.

Data were collected either by continuous recordings at -60 mV or byapplying voltage ramps from a holding potential of -40 mV every 4s. Continuous recordings were collected at 400 Hz and digitallyfiltered off-line at 10 Hz for presentation. Voltage ramps wereapplied from -100 mV or -80 mV to +100 mV or +80 mV over the courseof 400 ms, and data were collected at 10 kHz and filtered at 2.9kHz. Inward and outward currents were analyzed from the ramps at-80 and 80 mV, respectively. Liquid junction potential correctionwas not used.

Solutions were switched using a gravity-fed continuous focalperfusion system. To achieve rapid temperature changes, twotemperature control, and perfusion systems were employedsimultaneously. For temperatures greater than or equal to22.degree. C., a Warner Instruments bipolar temperature controller(TC-344B) and inline heater (SHM-8) were used. For temperaturesbelow 22.degree. C. a Warner Instruments temperature controller(CL-100) and thermal cooling module (TCM-1) were used. Temperatureswere confirmed using a thermistor (Warner Instruments, TA-29), withtemperatures at the recorded cell estimated to be within+/-2.degree. C. of those reported.

Table 2 shows data obtained from the in vitro assay describedabove. The antagonist effects of compounds of Formula (I) againsthuman TRPA1 ("hTRPA1") in a whole cell patch configuration wereevaluated using the in vitro assay described above. The currentactivation tested was 10 .mu.M AITC, and the tested concentrationsranged from 320 pM to 3.2 .mu.M.

TABLE-US-00002 TABLE 2 Antagonist effects of Compounds of Formula(I) against human TRPA1 hTRPA1 IC50 Compound # (nM) 1 28 2 21 3 494 25 5 39 6 39 7 5 8 44 9 59 10 24 11 5 12 7 13 8 14 1 15 4 16 2 178 18 1 19 1 20 2 21 19 22 203 23 5 24 10 25 4 26 1 27 2 28 1 29 130 3 31 16 32 3 33 1 34 1 35 6 36 2 37 3 38 3 39 3 40 8 41 12 42 443 8 44 14 45 4 46 22 47 4 48 7 49 7 50 4 51 >3200 52 23 53 1454 7 55 5 56 3 57 2 58 2 59 45 60 7 61 8 62 5 63 2 64 2 65 8 66 267 7 68 5 69 7 70 5 71 44 72 95 73 93 74 6 75 3 76 10 77 2 78 86 793 80 1 81 10 82 5 83 2 84 4 85 3 86 267 87 258 88 894 89 11 90 3 912 92 33 93 >3200 94 3 95 9 96 2 97 5 98 3 99 1 100 8 101 12 10230 103 370 104 15 105 6 106 639 107 1 108 1 109 8 110 1 111 3 112 1113 2 114 2 115 1 116 >3200 117 18 118 17 119 28 120 26 121 1122 1 123 2 124 1 125 1 126 1 127 25 128 4 129 2 130 8 131 6 132 9133 9 134 3 135 4 136 3 137 13 139 11 140 32 141 80 142 7 143 20144 6 145 2 146 3 147 6 149 2 150 4 151 16 152 7 153 2 154 >3200155 5 156 3 157 1 158 6 159 6 160 20 161 219 162 22 163 2 164 21165 7 166 6 167 4 168 12 169 10 170 27 171 23 172 2 173 6 174 24175 54 176 10 177 42 178 14 181 19 182 42 183 3 184 310 185 45 18674 187 74 188 33 189 2 190 17 191 51 192 33 193 45 194 62 195 3 196122 197 294 198 11 199 404 200 34 201 309 202 26 203 1610 204 3250211 >1000 212 62 213 141 214 92 215 25 216 16 217 3 218 4 219 23220 72 221 5 222 5 223 25 224 19 225 49 226 8 227 22 228 17 229 9230 14 231 16 232 56 233 10 234 4 235 2 236 711 237 236 238 4 239 3240 7 241 1 242 290 243 6 245 8 246 1 247 2 248 4 249 6 250 6 251219 252 1 253 20 254 14 255 13

256 5 257 11 258 7 259 17 260 17 261 5 262 1 263 4 264 31 265 3 2667 267 2 268 1 269 4 270 3 271 5 272 7

In Vivo Efficacy of Exemplary Compounds of the Invention

Example 2 Formalin Model

Exemplary compounds of the invention were tested in theformalin-induced pain test reported by Dubuisson et al., Pain 1977December; 4(2):161-74 (incorporated herein by reference in itsentirety). Briefly, dilute formalin (50 .mu.L of 3% formalin) wasinjected into the plantar surface of the hind paw of a rat. Theanimal was promptly returned to an observation arena (standardPlexiglass rat cage), at which point a trained observer recordedthe time the animal exhibited pain behaviors (flinching, licking,biting of the injected paw/leg) in two distinct phases. Theindividual responsible for counting the pain behaviors in aparticular study was blinded to the treatment groups.

The initial phase (Phase I: 0-5 min) is thought to have asignificant component that is dependent upon direct activation ofafferent fibers by formalin and functional TRPA1 (McNamara et al.,2007).

Investigators studied oral administration of compounds of theinvention at the doses presented in Table 3 on pain behaviors inthe formalin model in the rat. Compounds were formulated assolutions in water with various solvents and excipients includingdimethyl sulfoxide (DMSO), polyethylene glycol (15)-hydroxystearate(Solutol.RTM., Sigma-Aldrich), caprylocaproyl macrogol-8 glyceride(Labrasol.RTM., Sigma-Aldrich), polysorbate-80 (Tween.RTM.-80,Sigma-Aldrich), and polyoxyl 35 castor oil (Cremophor.RTM. EL, BASFCorp.); or suspensions in methylcellulose as indicated in Table 3.Animals were dosed orally with the vehicle, or compounds of theinvention one hour prior to intraplantar formalin. Table 3 showsthe duration of pain behaviors observed in the first two minutes orthe duration of pain behaviors during the entire study period; fiveminutes. A decrease over Vehicle indicates a positive result. Pvalues, when indicated, indicate significance compared Vehicle.Results without p values did not achieve statisticalsignificance.

Oral administration of the compounds of the invention reduced thenociceptive responses in Phase 1 of the formalin model as seen fromthe data presented in Table 3.

TABLE-US-00003 TABLE 3 Duration (0-2 Minutes) Duration (0-5 Averagep Minutes) p (Seconds) value Average (Seconds) value n Study ACompound 7 formulated as solution in 4% DMSO, 10% Solutol, 86%water Vehicle PO: 4% DMSO, 10% 81.88 194.50 8 Solutol, 86% waterCompound 7@ 1 mpk PO 82.38 200.38 8 Compound 7@ 3 mpk PO 78.25173.75 8 Compound 7@ 10 mpk PO 67.00 170.50 8 Study B Compound 15formulated as solution in 8% DMSO; 92% Labrasol Vehicle PO: 8%DMSO; 92% 97.75 222.50 8 Labrasol Compound 15@ 30 mpk PO 76.00190.20 5 Study C Compound 18 formulated as solution in 4% DMSO; 5%Tween-80; 20% Cremophor EL; 71% water Vehicle, PO: 4% DMSO; 5% 91.6207.0 8 Tween-80; 20% Cremophor EL; 71% water Compound 18@1 mg/kg,PO 78.0 183.3 8 Compound 18@3 mg/kg, PO 58.0 157.1 8 Compound 18@10 mg/kg, PO 35.3 <0.01 181.6 8 Study D Compound 25 formulatedas solution in 4% DMSO; 5% Tween-80; 20% Cremophor EL; 71% waterVehicle, PO: 4% DMSO; 5% 97.4 228.4 8 Tween-80; 20% Cremophor EL;71% water Compound 25@ 1 mg/kg, PO 87.8 190.1 8 Compound 25@ 3mg/kg, PO 22.8 <0.01 98.3 <0.01 8 Compound 25@ 10 mg/kg, PO29.1 <0.01 146.0 8 Study E Compounds formulated as solution in4% DMSO; 5% Tween-80; 20% Cremophor EL; 71% water Vehicle, PO: 4%DMSO; 5% 103.4 226.0 8 Tween-80; 20% Cremophor EL; 71% waterCompound 144@ 10 mg/kg, PO 64.6 181.3 8 Compound 34@ 10 mg/kg, PO34.9 <0.01 154.6 8 Compound 155@ 10 mg/kg, PO 59.4 <0.05182.5 8 Compound 149@ 30 mg/kg, PO 41.9 <0.01 153.0 8 Study FCompound 74 formulated as solution in 4% DMSO; 5% Tween-80; 20%Cremophor EL; 71% water Vehicle, PO: 4% DMSO; 5% 103.6 186.9 8Tween-80; 20% Cremophor EL; 71% water Compound 74@ 1 mg/kg, PO 94.8169.0 8 Compound 74@ 3 mg/kg, PO 78.3 172.9 8 Compound 74@ 10mg/kg, PO 62.3 <0.01 152.6 8 Study G Compound 97 formulated assolution in 4% DMSO; 5% Tween-80; 20% Cremophor EL; 71% waterVehicle, PO: 4% DMSO; 5% 102.9 213.7 7 Tween-80; 20% Cremophor EL;71% water Compound 97@ 1 mg/kg, PO 69.3 <0.05 162.4 8 Compound97@ 3 mg/kg, PO 78.5 175.3 8 Compound 97@ 10 mg/kg, PO 56.8<0.01 185.4 8 Study H Compound 105 formulated as solution in 4%DMSO; 5% Tween-80; 20% Cremophor EL; 71% water Vehicle, PO: 4%DMSO; 5% 98.5 183.9 8 Tween-80; 20% Cremophor EL; 71% waterCompound 105@ 1 mg/kg, PO 97.9 162.6 8 Compound 105@ 3 mg/kg, PO86.0 154.0 8 Compound 105@ 10 mg/kg, PO 70.1 <0.05 137.3<0.01 8 Study I Compound 160 formulated as solution in 4% DMSO;5% Tween-80; 20% Cremophor EL; 71% water Vehicle, PO: 4% DMSO; 5%91.0 192.1 8 Tween-80; 20% Cremophor EL; 71% water Compound 160@ 1mg/kg, PO 68.6 167.3 8 Compound 160@ 3 mg/kg, PO 78.1 232.0 8Compound 160@ 10 mg/kg, PO 42.5 <0.01 150.4 8 Study J Compound135 formulated as solution in 4% DMSO; 5% Tween-80; 20% CremophorEL; 71% water Vehicle, PO: 4% DMSO; 5% 91.4 184.9 8 Tween-80; 20%Cremophor EL; 71% water Compound 135@ 1 mg/kg, PO 91.1 153.3 7Compound 135@ 3 mg/kg, PO 80.3 120.3 <0.01 7 Compound 135@ 10mg/kg, PO 74.3 139.0 <0.05 7 Study K Compound 61 formulated assolution in 4% DMSO; 5% Tween-80; 20% Cremophor EL; 71% waterVehicle, PO: 4% DMSO; 5% 86.9 177.9 8 Tween-80; 20% Cremophor EL;71% water Compound 61@ 1 mg/kg, PO 89.4 149.3 7 Compound 61@ 3mg/kg, PO 90.3 152.3 8 Compound 61@ 10 mg/kg, PO 52.8 <0.01120.0 <0.01 8 Study L: 406 Compound 79 formulated as suspensionin 0.5% methylcellulose Vehicle, PO: 0.5% methylcellulose 95.1184.1 8 Compound 79: '180 1 mg/kg, PO 86.1 169.8 8 Compound 79:'180 3 mg/kg, PO 86.5 151.1 8 Compound 79: '180 10 mg/kg, PO 77.3142.5 <0.05 8 Study M Compound 104 formulated as solution in 4%DMSO; 5% Tween-80; 20% Cremophor EL; 71% water Vehicle, PO: 4%DMSO; 5% 104.3 176.9 8 Tween-80; 20% Cremophor EL; 71% waterCompound 104@ 1 mg/kg, PO 98.5 167.9 8 Compound 104@ 3 mg/kg, PO70.9 <0.01 140.0 7 Compound 104@ 10 mg/kg, PO 56.6 <0.01128.9 <0.01 8 Study N Compound 172 formulated as solution in 4%DMSO; 5% Tween-80; 20% Cremophor EL; 71% water Vehicle, PO: 4%DMSO; 5% 92.0 187.9 8 Tween-80; 20% Cremophor EL; 71% waterCompound 172@ 1 mg/kg, PO 88.6 151.0 8 Compound 172@ 3 mg/kg, PO91.1 149.0 8 Compound 172@ 10 mg/kg, PO 83.1 151.6 8 Study OCompound 61 formulated as solution in 4% DMSO; 5% Tween-80; 20%Cremophor EL; 71% water Vehicle, PO: 4% DMSO; 5% 92.3 160.3 8Tween-80; 20% Cremophor EL; 71% water Compound 253@ 1 mg/kg, PO79.3 126.4 <0.05 8 Compound 253@ 3 mg/kg, PO 78.8 119.6 <0.018 Compound 253@ 10 mg/kg, PO 76.4 116.0 <0.01 8 Study PCompounds formulated as solution in 8% DMSO and 92% LabrasolVehicle, PO: 8% DMSO and 92% 76.0 194.0 8 Labrasol Compound 153@ 30mg/kg, PO 31.9 <0.05 173.1 7 Compound 14@ 30 mg/kg, PO 34.3<0.05 123.4 7 Study Q Compound 153 formulated as solution in 8%DMSO and 92% Labrasol Vehicle, PO: 8% DMSO and 92% 100.3 231.1 8Labrasol Compound 153@ 1 mg/kg, PO 84.5 172.5 8 Compound 153@ 3mg/kg, PO 86.4 198.8 8 Compound 153@ 10 mg/kg, PO 87.9 214.6 8Study R Compounds formulated as solution in 8% DMSO and 92%Labrasol Vehicle, PO: 8% DMSO and 92% 98.6 227.9 9 LabrasolCompound 153@ 30 mg/kg, PO 52.8 <0.01 173.4 8 Compound 14@ 30mg/kg, PO 39.6 <0.01 160.6 <0.05 8 Study S Compound 153formulated as solution in 4% DMSO; 5% Tween-80; 25% Cremophor EL;66% water Vehicle, PO: 4% DMSO; 5% 83.5 199.9 8 Tween-80; 25%Cremophor EL; 66% water Compound 153@ 1 mg/kg, PO 71.4 164.6 8Compound 153@ 3 mg/kg, PO 81.5 216.9 8 Compound 153@ 10 mg/kg, PO50.1 160.3 8 Study T Compound 21 formulated as solution in 4% DMSO;5% Tween-80; 20% Cremophor EL; 71% water Vehicle, PO: 4% DMSO; 5%97.8 196.9 8 Tween-80; 20% Cremophor EL; 71% water Compound 21@ 1mg/kg, PO 99.6 206.9 8 Compound 21@ 3 mg/kg, PO 97.5 186.9 8Compound 21@ 10 mg/kg, PO 71.8 <0.05 116.5 <0.01 8 Study UCompound 21 formulated as suspension in 0.5% methylcelluloseVehicle, PO: 0.5% methylcellulose 88.3 200.8 8 Compound 21@ 1mg/kg, PO 80.5 202.5 8 Compound 21@ 3 mg/kg, PO 86.5 190.1 8Compound 21@ 10 mg/kg, PO 78.0 202.8 8 Study V Compound 21formulated as suspension in 0.5% methylcellulose Vehicle, PO: 0.5%methylcellulose 100.1 192.3 8 Compound 21@ 10 mg/kg, PO 92.3 163.18 Compound 21@ 30 mg/kg, PO 100.5 165.4 8

Example 3 Effect on Cold Hypersensitivity

Embodiments of the invention may be efficacious in the treatment ofinflammatory pain. Compounds of the invention were tested by theCFA-induced pain test method. Compounds were formulated assolutions in water with various solvents and excipients includingdimethyl sulfoxide (DMSO), polyethylene glycol (15)-hydroxystearate(Solutol.RTM., Sigma-Aldrich), caprylocaproyl macrogol-8 glyceride(Labrasol.RTM., Sigma-Aldrich), polysorbate-80 (Tween.RTM.-80,Sigma-Aldrich), and polyoxyl 35 castor oil (Cremophor.RTM. EL, BASFCorp.); or suspensions in methylcellulose as indicated in Table 3for oral delivery.

Briefly, the hind paw was sensitized to cold temperature(allodynic) by administering 0.1 mL of Complete Freund's Adjuvant(CFA) to the right hind paw. Three days later, the time taken forthe animal to lift its CFA-injected paw was recorded compared toits un-injected normal left hind paw. Animals were placed on thesurface of the cold plate (1.degree. C.) and the operator stoppedtesting at the instant when the animal displayed discomfort byflinching or lifting its paw from the plate (paw withdrawallatency, or PWL). To avoid tissue damage the maximum cut-off timewas 5 minutes. Animals that were allodynic (average PWL to thefirst three pain behaviors <150 seconds for the CFA-injectedhind paw: .about..gtoreq.50% difference between the normal andCFA-injected paw) were included in the study and subsequentlyrandomized across treatment groups. The following day, the animalswere dosed orally under blinded conditions. Following the 1-2 hourpre-treatment time, the post-dose PWL readings were again taken.The efficacy of the drug treatment was assessed by comparing thePWL in the drug treatment animals to those animals that receive thevehicle. P values, when indicated, indicate significance comparedVehicle. Results without p values did not achieve statisticalsignificance.

Compounds of the invention were tested at the doses presented inTable 4 below.

TABLE-US-00004 TABLE 4 Average Average PWL PWL Post- PWL Post-Treat- Change P CFA ment (s) Value n Study AA Compound 18formulated as solution in 4% DMSO; 5% Tween-80; 20% Cremophor EL;and 71% water Vehicle, PO: 4% DMSO; 5% 96.5 128.3 31.7 10 Tween-80;20% Cremophor EL; and 71% water Compound 18@ 1 mg/kg, PO 97.1 246.8149.7 <0.01 11 Compound 18@ 3 mg/kg, PO 97.0 233.5 136.4<0.01 11 Compound 18@ 10 mg/kg, PO 97.0 256.1 159.1 <0.01 11Study BB Compound 25 formulated as solution in 4% DMSO; 5%Tween-80; 20% Cremophor EL; and 71% water Vehicle, PO: 4% DMSO; 5%103.0 99.5 -3.5 10 Tween-80; 20% Cremophor EL; and 71% waterCompound 25@ 0.3 mg/kg, PO 105.0 170.2 65.2 <0.05 10 Compound25@ 1 mg/kg, PO 105.1 224.8 119.7 <0.01 10 Compound 25@ 3 mg/kg,PO 105.1 259.9 154.9 <0.01 10 Study CC Compound 34 formulated assolution in 4% DMSO; 5% Tween-80; 20% Cremophor EL; and 71% waterVehicle, PO: 4% DMSO; 5% 103.9 105.3 1.4 10 Tween-80; 20% CremophorEL; and 71% water Compound 34@ 0.3 mg/kg, PO 104.9 185.6 80.7 9Compound 34@ 1 mg/kg, PO 98.0 205.4 107.4 <0.05 10 Compound 34@3 mg/kg, PO 103.6 272.6 169.0 <0.01 10 Study DD Compound 74formulated as solution in 4% DMSO; 5% Tween-80; 20% Cremophor EL;and 71% water Vehicle, PO: 4% DMSO; 5% 90.1 89.2 -0.9 10 Tween-80;20% Cremophor EL; and 71% water Compound 74@ 0.3 mg/kg, PO 91.1160.9 69.9 <0.05 10 Compound 74@ 1 mg/kg, PO 90.4 271.3 181.0<0.01 10 Compound 74@ 3 mg/kg, PO 90.9 273.2 182.3 <0.01 10Study EE Compound 97 formulated as solution in 4% DMSO; 5%Tween-80; 20% Cremophor EL; and 71% water Vehicle, PO: 4% DMSO; 5%111.9 108.7 -3.2 9 Tween-80; 20% Cremophor EL; and 71% waterCompound 97@ 0.3 mg/kg, PO 117.3 194.7 77.3 <0.05 10 Compound97@ 1 mg/kg, PO 112.9 262.7 149.8 <0.01 10 Compound 97@ 3 mg/kg,PO 103.5 260.8 157.3 <0.01 8 Study FF Compound 105 formulated assolution in 4% DMSO; 5% Tween-80; 20% Cremophor EL; and 71% waterVehicle, PO: 4% DMSO; 5% 102.3 126.1 23.8 10 Tween-80; 20%Cremophor EL; and 71% water Compound 105@ 0.3 mg/kg, 102.4 137.334.9 10 PO Compound 105@ 1 mg/kg, PO 102.3 215.2 112.8 <0.01 10Compound 105@ 3 mg/kg, PO 102.7 226.3 123.6 <0.01 10 Study GGCompound 160 formulated as solution in 4% DMSO; 5% Tween-80; 20%Cremophor EL; and 71% water Vehicle, PO: 4% DMSO; 5% 107.6 105.5-2.1 10 Tween-80; 20% Cremophor EL; and 71% water Compound 160@ 0.3mg/kg, 108.2 173.0 64.7 <0.05 10 PO Compound 160@ 1 mg/kg, PO108.1 269.6 161.5 <0.01 10 Compound 160@ 3 mg/kg, PO 107.5 253.6146.2 <0.01 10 Study HH Compound 61 formulated as solution in 4%DMSO; 5% Tween-80; 20% Cremophor EL; and 71% water Vehicle, PO: 4%DMSO; 5% 96.0 99.2 3.3 10 Tween-80; 20% Cremophor EL; and 71% waterCompound 61@ 0.3 mg/kg, PO 96.2 157.1 60.9 10 Compound 61@ 1 mg/kg,PO 96.0 235.4 139.4 <0.01 10 Compound 61@ 3 mg/kg, PO 95.8 278.5182.7 <0.01 10 Study II Compound 79 formulated as a suspensionin 0.5% methylcellulose Vehicle, PO: 0.5% 101.8 122.0 20.2 10methylcellulose Compound 79@ 1 mg/kg, PO 102.2 140.2 38.0 10Compound 79@ 3 mg/kg, PO 102.2 201.8 99.6 <0.05 10 Compound 79@10 mg/kg, PO 102.3 231.5 129.3 <0.01 10 Study JJ Compound 104formulated as solution in 4% DMSO; 5% Tween-80; 20% Cremophor EL;and 71% water Vehicle, PO: 4% DMSO; 5% 104.1 108.6 4.5 10 Tween-80;20% Cremophor EL; and 71% water Compound 104@ 0.3 mg/kg, 105.1190.0 84.9 <0.01 10 PO Compound 104@ 1 mg/kg, PO 104.2 295.1190.9 <0.01 10 Compound 104@ 3 mg/kg, PO 104.9 281.7 176.8<0.01 10 Study KK Compound 14 formulated as solution in 4% DMSO;5% Tween-80; 25% Cremophor EL; and 66% water Vehicle, PO: 4% DMSO;5% 90.8 109.7 19.2 10 Tween-80; 25% Cremophor EL; and 66% waterCompound 14@ 1 mg/kg, PO 90.3 194.8 104.2 <0.01 10 Compound 14@3 mg/kg, PO 92.3 180.0 87.6 <0.01 10 Compound 14@ 10 mg/kg, PO90.9 237.4 146.3 <0.01 10 Study LL Compound 153 formulated assolution in 4% DMSO; 5% Tween-80; 25% Cremophor EL; and 66% waterVehicle, PO: 4% DMSO; 5% 92.6 101.7 9.1 9 Tween-80; 25% CremophorEL; and 66% water Compound 153@ 1 mg/kg, PO 92.5 178.1 85.6<0.01 10 Compound 153@ 3 mg/kg, PO 92.8 223.6 130.8 <0.01 10Compound 153@ 10 mg/kg, 92.7 247.1 154.3 <0.01 10 PO Study MMCompound 21 formulated as solution in 4% DMSO; 5% Tween-80; 20%Cremophor EL; and 71% water Vehicle, PO: 4% DMSO; 5% 110.4 96.5-13.9 10 Tween-80; 20% Cremophor EL; and 71% water Compound 21@ 0.3mg/kg, PO 109.6 159.2 49.6 10 Compound 21@ 1 mg/kg, PO 114.3 208.594.2 <0.01 10 Compound 21@ 3 mg/kg, PO 110.1 258.9 148.8<0.01 10 Study NN Compound 21 formulated as a suspension in 0.5%methylcellulose Vehicle, PO: 0.5% 95.3 93.5 -1.7 11 methylcelluloseCompound 21@ 0.3 mg/kg, PO 94.5 106.4 11.9 11 Compound 21@ 1 mg/kg,PO 95.4 155.2 59.8 <0.01 10 Compound 21@ 3 mg/kg, PO 94.3 236.7142.4 <0.01 10

In summary, these studies suggest that compounds of the inventionhave the potential to be efficacious in the treatment ofinflammatory pain following oral administration.

Example 4 General Experimental Procedures

General Procedures

All reactions were run under an inert atmosphere, generallynitrogen. All non-aqueous reactions were run using solvents. Allreactions were stirred either with a magnetic stir bar or withoverhead mechanical stirring. All saturated extraction solutionsare assumed to be aqueous (saturated NH.sub.4Cl for example).Drying organic solutions with a drying agent implies that thedrying agent was removed from the organic solution by filtration.Chromatography refers to column chromatography on silica gel.Preparative thin layer chromatography (TLC) was run plates.Concentration of reaction mixtures implies concentration underreduced pressure and the use of a rotary evaporation instrument.Drying of final products implies drying under high vacuumconditions. Sonication implies the use of an ultrasonic bath. All.sup.1H-NMR data were obtained at 400 MHz. Mass spectra wereobtained in positive ion mode and are reported as the protonatedspecies MH.sup.+. LCMS were performed on a SHIMADZU LCMS-2010EVinstrument (Chromolith SdeedROP, RP-18e column. 50.times.4.6 mm.mobile phase: Solvent A: CH.sub.3CN/H.sub.2O/HCOOH=10/90/0.05.Solvent B: CH.sub.3CN/H.sub.2O/HCOOH.dbd.90/10/0.05. 0.8 min@10% B.2.7 min gradient (10-95% B), then 0.8 min@95% B. Flow rate: 3mL/min. temperature: 40.degree. C.). Preparative HPLC was performedeither on a SHIMADZU LC-8A instrument. (Column: YMC Pack ODS-A(150*30 mm 10 um)) or LC-6AD (column: Shim=Pack PREP-ODS-H (250*20mm, 10 um)) with UV detection which was controlled by LC solutionChemstation software, with H.sub.2O (0.1% HCOOH) and MeOH(CH.sub.3CN) as mobile phase at the indicated flow rate. ChiralHPLC was performed using a CHIRALPAK IB column (150*4.6 mm, 5 um)with the mobile phase comprised of hexanes/EtOH (65/35, 0.8 mL/min,25 minute run time) at 30.degree. C., using a 15 uL sampleinjection volume (1 mg/mL in MeOH) and UV detector set at 220/254nm.

Abbreviations

DCM dichloromethane DIC N,N'-diisopropylcarbodiimide DMAP4-dimethylaminopyridine DMF N,N-dimethylformamide EDC1-ethyl-3-(3-dimethylaminopropyl)carbodiimide EA ethyl acetateEther diethyl ether h hours HOAc acetic acid HOAT1-hydroxy-7-azabenzotriazole LAH lithium aluminum hydride MeOHmethanol min minutes n-BuLi .sup.nbutyllithium Pd/C palladium onactivated carbon, generally 10% palladium load PE petroleum etherRT room temperature S. aq. Saturated aqueous TBAItetrabutylammonium iodide TEA triethylamine TFA trifluoroaceticacid TLC thin layer chromatography THF tetrahydrofuran

PREPARATIONS

Preparation 1 (S)-methyl2-(3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)propanoate

##STR00284##

Step 1 (R)-methyl 2-(methylsulfonyloxy)propanoate

##STR00285##

A solution of (R)-methyl 2-hydroxypropanoate (30 g, 0.28 mol) andTEA (80 mL, 0.56 mol) in DCM (300 mL) was chilled to 0.degree. C.and methanesulfonyl chloride (33.6 mL, 0.42 mol) was added dropwiseat 0.degree. C. over 1 h. The mixture was stirred at 10-20.degree.C. for 1.5 h. The reaction mixture was quenched with ice-water (100mL). The organic layer was separated, washed with water (2.times.50mL) and brine, dried over Na.sub.2SO.sub.4 and concentrated toafford the crude product (R)-methyl 2-(methylsulfonyloxy)propanoate(50 g, 95.2%) as brick red oil which was used withoutpurification.

Step 2 (S)-methyl2-(3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)propanoate

##STR00286##

To a mixture of 3-methyl-xanthine (5.858 g, 35.3 mmol) and(R)-methyl 2-(methylsulfonyloxy)propanoate (6.417 g, 35.3 mmol) inDMF (100 mL) was added potassium carbonate (7.298 g, 53 mmol). Thereaction mixture was stirred at 50.degree. C. for 20 h. Thereaction mixture was poured into water (10 mL) and extracted withEA (2.times.10 mL). LCMS showed product in the aqueous phase, sothe aqueous phase was acidified to pH 0 and extracted with DCM.Combined organic layers were dried over Na.sub.2SO.sub.4 andconcentrated. The residue was purified by chromatography (elutedwith MeOH/DCM 0-3%) to afford (S)-methyl2-(3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)propanoate(4.5843 g, 52% yield) as a white solid. MH.sup.+ 253.

Preparation 2(S)-2-(2-(2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidin-5-yl)pyrimidin-4-a-mine

##STR00287##

Step 1(S)-5-bromo-2-(2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidine

##STR00288##

A mixture of (S)-2-(trifluoromethyl)pyrrolidine hydrochloride (40g, 0.23 mol), POTASSIUM CARBONATE (94.6 g, 0.68 mol) and5-bromo-2-chloropyrimidine (48 g, 0.25 mol) in DMF (200 mL) wasstirred at 100.degree. C. for 24 hr, thenN.sub.1,N.sub.2-dimethylethane-1,2-diamine (4 mL) was added and thereaction was stirred for another 2 h to consume unreacted5-bromo-2-chloropyrimidine. The reaction was quenched with water(400 mL), and extracted with EA (3.times.500 mL). The combinedorganic phase was washed with 10% aqueous LiCl, dried overNa.sub.2SO.sub.4 and concentrated. The residue was purified bychromatography eluting with PE:EA (50:1) to afford(S)-5-bromo-2-(2-(trifluoromethyl) pyrrolidin-1-yl)pyrimidine (50g, 74%) as a white solid. .sup.1H NMR (DMSO-d.sub.6) .delta. 8.54(s, 2H), 4.90-4.94 (m, 2H), 3.56-3.58 (m, 2H), 2.02-2.16 (m, 4H).MH.sup.+ 296.

Step 2(S)-2-(2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidin-5-ylboronicAcid

##STR00289##

A solution of(S)-5-bromo-2-(2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidine (50 g,0.17 mol) and triisopropyl borate (44.4 g, 0.23 mol) in THF (400mL) was cooled to -78.degree. C. and n-BuLi (105 mL, 2.4 M inhexane) was added dropwise. The reaction was stirred 2 h at-78.degree. C. The reaction was quenched with water (150 mL) andallowed to warm to RT. The reaction was concentrated to leave theaqueous phase. The aqueous phase was extracted with ether(2.times.50 mL) to remove impurities (product in aqueous layer).The pH was adjusted to 5 with 6 N HCl and then it was extractedwith EA (3.times.100 mL). The combined organic phase was dried overNa.sub.2SO.sub.4 and concentrated to afford(S)-2-(2-(trifluoromethyl)pyrrolidin-1-yl) pyrimidin-5-ylboronicacid (45 g, quantitative yield) as an off-white solid. MH.sup.+262.

Step 3(S)-2-(2-(2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidin-5-yl)pyrimid-in-4-amine

##STR00290##

To a mixture of(S)-2-(2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidin-5-ylboronicacid (9.5 g, 36.4 mmol), 2-chloropyrimidin-4-amine (4.3 g, 33.1mmol) and Na.sub.2CO.sub.3 (7.0 g, 66.2 mmol) in dioxane (105 mL)and water (35 mL) was added Pd(PPh.sub.3).sub.4 (3.8 mg, 3.31mmol). The mixture was degassed with nitrogen and then stirred at110.degree. C. for 3 h. The reaction was cooled and filteredthrough Celite. The filtrate was partitioned with EA (300 mL) andwater (150 mL). The organic phase was washed with brine (100 mL),dried over Na.sub.2SO.sub.4 and concentrated. The residue waspurified by chromatography eluting with DCM/MeOH (100:1 to 80:1 to70:1) to give(S)-2-(2-(2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidin-5-yl)pyrimidin-4-a-mine (8 g, 78%) as a white solid. .sup.1H-NMR (CDCl.sub.3) .delta.9.16 (s, 2H), 8.13-8.14 (d, J=10 Hz, 1H), 6.97 (s, 2H), 6.34-6.35(d, J=6 Hz, 1H), 5.09-5.13 (m, 1H), 3.67-3.72 (m, 2H), 2.06-2.21(m, 4H). MH.sup.+ 311.

Preparation 3(R)-2-(2-(2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidin-5-yl)pyrimidin-4-a-mine

##STR00291##

The title compound was prepared using the method of preparation 2.MH.sup.+ 311

Preparation 4 3-azabicyclo[3.1.0]hexane Hydrochloride

##STR00292##

Step 1 3-benzyl-3-azabicyclo[3.1.0]hexane-2,4-dione

##STR00293##

To a mixture of 3-oxabicyclo[3.1.0]hexane-2,4-dione (2.3 g, 20.5mmol) in AcOH (30 mL) was added DMAP (150 mg) and benzylamine (2.2mL, 20.5 mmol). The mixture was stirred at 100.degree. C. for 40 h;then it was cooled to RT. The reaction was concentrated and theresidue was dissolved in EA. The organic phase was washed withwater and brine, dried over Na.sub.2SO.sub.4 and concentrated. Theresidue was purified via chromatography eluting with PE:EA (8:1 to5:1) to afford 3-benzyl-3-azabicyclo[3.1.0]hexane-2,4-dione (3.7 g,89.6%) as a white solid. MH.sup.+ 202.

Step 2 3-benzyl-3-azabicyclo[3.1.0]hexane

##STR00294##

To a solution of 3-benzyl-3-azabicyclo[3.1.0]hexane-2,4-dione (2.0g, 10.0 mmol) in THF (30 mL) was added LAH (1.5 g, 40.0 mmol). Thereaction mixture was heated at reflux 4 h and then it was cooled to0.degree. C. The cold reaction mixture was carefully quenched withsaturated NH.sub.4Cl and then it was filtered. The filtrate wasconcentrated to afford the title compound (1.5 g, 86.7%) as clearoil. MH.sup.+ 174.

Step 3 3-azabicyclo[3.1.0]hexane Hydrochloride

##STR00295##

A mixture of 3-benzyl-3-azabicyclo[3.1.0]hexane (1.3 g, 7.5 mmol),10% Pd/C (130 mg) and conc. HCl (0.63 mL, 7.5 mmol) in MeOH (20 mL)was stirred at RT under an of hydrogen (balloon) for 18 h. Thereaction was filtered through Celite and the filtrate wasconcentrated to give the title compound (850 mg, 95%) as a whitesolid. MH.sup.+ 84

Preparation 52'-(3-azabicyclo[3.1.0]hexan-3-yl)-[2,5'-bipyrimidin]-4-amine

##STR00296##

Step 1 3-(5-bromopyrimidin-2-yl)-3-azabicyclo[3.1.0]hexane

##STR00297##

A sealed tube was charged with 5-bromo-2-chloropyrimidine (671.7mg, 3.5 mmol), 3-azabicyclo[3.1.0]hexane hydrochloride (416.7 mg,3.5 mmol), potassium carbonate (967.5 mg, 7.0 mmol) and DMF (4 mL).The tube was sealed and stirred at 130.degree. C. for 2 h. Thereaction was cooled to RT and poured into cold water (4 mL). Thesolid that formed was collected and dried to give3-(5-bromopyrimidin-2-yl)-3-azabicyclo[3.1.0]hexane (480 mg, 57.4%)as a white solid. MH.sup.+ 240.

Step 2 (2-(3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)boronicacid

##STR00298##

To a solution of3-(5-bromopyrimidin-2-yl)-3-azabicyclo[3.1.0]hexane (480 mg, 2.0mmol) and triisopropyl borate (0.7 mL, 3.0 mmol) in THF (6 mL) wasadded n-BuLi (1.1 mL, 2.4 M in hexane, 2.6 mmol) dropwise at-78.degree. C. The reaction was stirred at -78.degree. C. for 2 hand then it was quenched with water and warmed to RT. The reactionwas concentrated and the aqueous residue was extracted with ether(2.times.20 mL). The aqueous layer was separated, adjusted to pH 6with 1N HCl and extracted with EA (3.times.20 mL). The combinedorganic phase was washed with brine, dried over Na.sub.2SO.sub.4,and concentrated to give the title product (200 mg, 48.5%) as awhite solid. MH.sup.+ 206.

Step 32'(3-azabicyclo[3.1.0]hexan-3-yl)-[2,5'-bipyrimidin]-4-amine

##STR00299##

A mixture of(2-(3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)boronic acid(150.0 mg, 1.2 mmol), 2-chloropyrimidin-4-amine (237.9 mg, 1.2mmol), Pd(PPh.sub.3).sub.2Cl.sub.2 (86.0 mg, 0.1 mmol) andNa.sub.2CO.sub.3 (245.9 mg, 2.3 mmol) in 1,4-dioxane (5 mL) andwater (1 mL) was degassed with nitrogen and stirred at 80.degree.C. overnight. The reaction was cooled to RT and poured into EA. Theorganic phase was separated, washed with water and brine, driedover Na.sub.2SO.sub.4 and concentrated. The residue was dissolvedin ether. An insoluble residue was removed by filtration and thefiltrate was concentrated to give2'-(3-azabicyclo[3.1.0]hexan-3-yl)-[2,5'-bipyrimidin]-4-amine (100mg, 33.8%) as a white solid. MH.sup.+ 255.

Preparation 63-methyl-1-((5-methylisoxazol-3-yl)methyl)-1H-purine-2,6(3H,7H)-dione

##STR00300##

Step 13-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)--dione

##STR00301##

To a stirred solution of 3-methyl-1H-purine-2,6(3H,7H)-dione (5 g,30.10 mmol) and potassium carbonate (6.24 g, 45.14 mmol) in DMF (50mL) at 0.degree. C. was added(2-(chloromethoxy)ethyl)trimethylsilane (5.33 mL, 30.1 mml). Afterthe addition, the mixture was warmed to RT and stirred overnight.The reaction mixture was diluted with DCM, and washed with s. aq.LiCl. The organic layer was separated, dried over Na2SO4, andconcentrated to afford3-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione(3.78 g, 42.4% yield) as yellow solid. Retention time (LC-MS):1.160 min. MH.sup.+ 297.

Step 23-methyl-1-((5-methylisoxazol-3-yl)methyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione

##STR00302##

To a mixture of3-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione(1.0 g, 3.37 mmol) and 3-(chloromethyl)-5-methylisoxazolehydrochloride (665.8 mg, 5.06 mmol) in DMF (20 mL) was addedpotassium carbonate (1.17 g, 8.43 mmol) and TBAI (61.84 mg,0.17mmol). The mixture was stirred at 50.degree. C. for 2 h. Thereaction mixture was diluted with DCM and washed with S. aq. LiCl.The organic layer was separated, dried over Na2SO4, andconcentrated and the residue was purified by chromatography (elutedwith PE:EA=5:1) to afford3-methyl-1-((5-methylisoxazol-3-yl)methyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione (750 mg, 56.8% yield) asyellow solid. Retention time (LC-MS): 1.476 min. MH.sup.+ 392.

Step 33-methyl-1-((5-methylisoxazol-3-yl)methyl)-1H-purine-2,6(3H,7H)-dio-ne

##STR00303##

To a stirred solution of3-methyl-1-((5-methylisoxazol-3-yl)methyl)-7-((2-(trimethylsilyl)ethoxy)m-ethyl)-1H-purine-2,6(3H,7H)-dione (750 mg, 1.92 mmol) in EtOH (5mL) was added conc. HCl (1 mL). After the addition, the mixture washeated to reflux for 2 h and then cooled to RT. The mixture wasconcentrated to dryness to give a crude product of3-methyl-1-((5-methylisoxazol-3-yl)methyl)-1H-purine-2,6(3H,7H)-dione(415 mg, 82.9% yield) as yellow solid which was used in the nextstep without any further purification. Retention time (LC-MS):0.544 min. MH.sup.+ 262.

Preparation 7 (S)-methyl2-(3-methyl-2,6-dioxo-1-(pyridin-2-ylmethyl)-1,2,3,6-tetra-hydropurin-7-y-l)propanoate

##STR00304##

Step 13-methyl-1-(pyridin-2-ylmethyl)-7-((2-(trimethylsilyl)ethoxy)methyl-)-1H-purine-2,6(3H,7H)-dione

##STR00305##

To a solution of3-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione(500 mg, 1.69 mmol) in DMF (10 mL) were added cesium carbonate (1.1g, 3.37 mmol), 2-(bromomethyl)pyridine (509 mg, 2.02 mmol) andtetrabutyl ammonium iodide (62 mg, 0.17 mmol). After the addition,the mixture was stirred at 100.degree. C. for 2 h and cooled to RT.The mixture was diluted with EA and washed with S. aq. LiCl. Theorganic layer was separated, dried over Na2SO4, and concentratedand the residue was purified by chromatography to afford3-methyl-1-(pyridin-2-ylmethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-1H-p-urine-2,6(3H,7H)-dione (370 mg, 56.4% yield) as a white solid.Retention time (LC-MS): 1.373 min. MH.sup.+ 388

Step 23-methyl-1-(pyridin-2-ylmethyl)-1H-purine-2,6(3H,7H)-dione

##STR00306##

To a stirred solution of3-methyl-1-(pyridin-2-ylmethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione (370 mg, 0.95 mmol) in EtOH (8mL) was added conc. HCl (4 mL). After the addition, the mixture washeated to reflux for 2 h and cooled to RT. The solvent was removedunder vacuum, then the residue was adjusted pH to 7 with aqueousNa.sub.2CO.sub.3 and filtered. The filter cake dried under vacuumto afford 3-methyl-1-(pyridin-2-ylmethyl)-1H-purine-2,6(3H,7H)-dione (170 mg, 69.1% yield) as an off-white solid.Retention time (LC-MS): 0.452 min. MH.sup.+ 258

Step 3 (S)-methyl2-(3-methyl-2,6-dioxo-1-(pyridin-2-ylmethyl)-1,2,3,6-tetrahydropurin-7-yl)propanoate

##STR00307##

To a mixture of3-methyl-1-(pyridin-2-ylmethyl)-1H-purine-2,6(3H,7H)-dione (100 mg,0.39 mmol) and potassium carbonate (53 mg, 0.39 mmol) in DMF (2 mL)was added (R)-methyl 2-(methylsulfonyloxy)propanoate (142 mg, 0.78mmol). After the addition, the mixture was stirred at RT for 3 h.The mixture was cooled to 0.degree. C., diluted with water (4 mL)and extracted with EA (3.times.2 mL). The combined organic layerswere dried over Na.sub.2SO.sub.4 and filtered. The filtrate wasconcentrated under reduced pressure and the residue was purified bychromatography (eluted with DCM/MeOH=40/1) to afford (S)-methyl2-(3-methyl-2,6-dioxo-1-(pyridin-2-ylmethyl)-1,2,3,6-tetrahydropurin-7-yl-)propanoate (50 mg, 37.5% yield) as a white solid. Retention time(LC-MS): 0.348 min. MH.sup.+ 344

Preparation 8 6'-(trifluoromethyl)-[2,3'-bipyridin]-6-amine

##STR00308##

Step 1 (2-(3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)boronic

##STR00309##

To a solution of 5-bromo-2-(trifluoromethyl)pyridine (1.6 g, 7.2mmol) and (.sup.iPrO).sub.3B (2.5 mL, 10.8 mmol) in THF (6 mL) wasadded dropwise n-BuLi (4.5 mL, 2.4 M in hexane, 10.8 mmol) at-78.degree. C. The reaction mixture was stirred at the sametemperature for 2 h and quenched with water. The solvent wasremoved under reduced pressure and the residue was extracted withEther (2.times.60 mL). The aqueous layer was separated, adjusted topH 6 with 1N HCl and extracted with EA (3.times.60 mL). Combinedorganic layers were washed with brine, dried over Na2SO4, andconcentrated to give the title product (1.3 g, 95.7% yield) as awhite solid.

Step 2 6'-(trifluoromethyl)-[2,3'-bipyridin]-6-amine

##STR00310##

A mixture of (6-(trifluoromethyl)pyridin-3-yl)boronic acid (382.1mg, 2.0 mmol), 6-chloropyridin-2-amine (343.9 mg, 2.0 mmol),Pd(PPh.sub.3).sub.2Cl.sub.2 (140.4 mg,0.2 mmol) andNa.sub.2CO.sub.3 (424.0 mg, 4.0 mmol) in 1,4-dioxane (10 mL) andH.sub.2O (2 mL) was degassed and stirred at 80.degree. C. underN.sub.2 overnight. The reaction mixture was cooled down and pouredinto EA. The organic phase was separated, washed with water andbrine, dried over Na.sub.2SO.sub.4 and filtered. The filtrate wasconcentrated under reduced pressure and the residue was trituratedwith Ether. The mixture was filtered and the filtrate wasconcentrated to give the title compound (190 mg, 39.7% yield) as awhite solid. Retention time (LC-MS): 0.42 min. MH.sup.+ 255.

Preparation 96-(2-(trifluoromethyl)pyrimidin-5-yl)pyrazin-2-amine

##STR00311##

Step 1 (2-(trifluoromethyl)pyrimidin-5-yl)boronic Acid

##STR00312##

To a solution of 5-bromo-2-(trifluoromethyl)pyrimidine (700.6 mg,3.1 mmol) and (.sup.iPrO).sub.3B (1.1 mL, 4.7 mmol) in THF (10 mL)was added dropwise n-BuLi (1.7 mL, 2.4M in hexane, 4.0 mmol) at-78.degree. C. The mixture was stirred at the same temperature for2 h and quenched with water. The solvent was removed under reducedpressure and the residue was extracted with Ether (2.times.40 mL).The aqueous layer was separated, then adjusted to pH 6 with 1N HCland extracted with EA (3.times.40 mL). Combined organic layers werewashed with brine, dried over Na2SO4, and concentrated to give thetitle product (400 mg, 67.2% yield) as a white solid. Retentiontime (LC-MS): 0.66 min. MH.sup.+ 193

Step 2 6-(2-(trifluoromethyl)pyrimidin-5-yl)pyrazin-2-amine

##STR00313##

A mixture of (2-(trifluoromethyl)pyrimidin-5-yl)boronic acid (420.0mg, 2.2 mmol), 6-chloropyrazin-2-amine (378.3 mg, 2.2 mmol),Pd(PPh.sub.3).sub.4 (252.7 mg, 0.2 mmol) and potassium carbonate(604.6 mg, 4.4 mmol) in 1,4-dioxane (5 mL) and H.sub.2O (1 mL) wasdegassed and stirred at 90.degree. C. under N.sub.2 overnight. Thereaction mixture was cooled down and poured into EA. The organicphase was separated, washed with water and brine, dried overNa.sub.2SO.sub.4 and filtered. The filtrate was concentrated underreduced pressure and the residue was dissolved in Ether. Themixture was filtered and the filtrate was concentrated to give thetitle product (200 mg, 52.6% yield) as a white solid.

Preparation 10(S)-2-(3-methyl-2,6-dioxo-1-(2-oxopropyl)-2,3-dihydro-1H-purin-7(6H)-yl)p-ropanoic Acid

##STR00314##

Step 1 (S)-methyl2-(3-methyl-2,6-dioxo-1-(2-oxopropyl)-2,3-dihydro-1H-purin-7(6H)-yl)propa-noate

##STR00315##

To a mixture of 3-methyl-1-(2-oxopropyl)-1H-purine-2,6(3H,7H)-dione(4.3 g, 19.35 mmol) and (R)-methyl 2-(methylsulfonyloxy)propanoate(6.5 g, 38.70 mmol) in DMF (30 mL) was added potassium carbonate(2.67 g, 19.35 mmol). The reaction mixture was stirred at r.t. for3 h. The reaction mixture was poured into water (50 mL) andextracted with EA (2.times.50 mL). Combined organic layers weredried over Na.sub.2SO.sub.4 and filtered. The filtrate wasconcentrated under reduced pressure and the residue was purified bychromatography (eluted with PE:EA=2:1) to afford3-methyl-1-(2-oxopropyl)-1H-purine-2,6 (3H,7H)-dione (850 mg, 14.3%yield) as yellow solid. Retention time (LC-MS): 0.556 min. MH.sup.+309.

Step 2(S)-2-(3-methyl-2,6-dioxo-1-(2-oxopropyl)-2,3-dihydro-1H-purin-7(6H-)-yl)propanoic Acid

##STR00316##

A mixture of (S)-methyl2-(3-methyl-2,6-dioxo-1-(2-oxopropyl)-2,3-dihydro-1H-purin-7(6H)-yl)propa-noate (850 mg, 2.74 mmol) and HCl (1M, 2.5 mL) in dioxane (5 mL)was stirred at 110.degree. C. for 2 h. The reaction mixture waspoured into water (50 mL) and extracted with EA (2.times.50 mL).The combined organic layers were dried over Na.sub.2SO.sub.4 andfiltered. The filtrate was concentrated under reduced pressure andthe residue was purified by chromatography (DCM:MeOH=20:1) toafford(S)-2-(3-methyl-2,6-dioxo-1-(2-oxopropyl)-2,3-dihydro-1H-purin-7(6H)-yl)p-ropanoic acid (540 mg, 67.0% yield) as yellow oil. Retention time(LC-MS): 0.424 min. MH.sup.+ 295.

Preparation 11(S)-2-(2-(2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidin-5-yl)thiazol-4-ami-ne

##STR00317##

Step 1(S)-2,2,2-trifluoro-N-(2-(2-(2-(trifluoromethyl)pyrrolidin-1-yl)pyr-imidin-5-yl)thiazol-4-yl)acetamide

##STR00318##

A mixture of(S)-2-(2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidin-5-ylboronicacid (573 mg, 2.19 mmol),N-(2-bromothiazol-4-yl)-2,2,2-trifluoroacetamide (500 mg, 1.82mmol), Pd(PPh.sub.3).sub.4 (105 mg, 0.09 mmol) and Cs.sub.2CO.sub.3(1.8 g, 5.46 mmol) in 1,4-dioxane (10 mL) and H.sub.2O (2 mL) wasdegassed and stirred at 110.degree. C. under N.sub.2 for 3 h. Thereaction mixture was cooled down and poured into EA. The organicphase was separated, washed with water and brine, dried overNa.sub.2SO.sub.4 and filtered. The filtrate was concentrated underreduced pressure and the residue was purified via chromatography(eluted with PE:EA=10:1) to give(S)-2,2,2-trifluoro-N-(2-(2-(2-(trifluoromethyl)pyrrolidin-1-yl)pyri-midin-5-yl)thiazol-4-yl)acetamide (247 mg, 32.9% yield) as yellowsolid. Retention time (LC-MS): 1.822 min. MH.sup.+ 412.

Step 2(S)-2-(2-(2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidin-5-yl)thiazol--4-amine

##STR00319##

To a stirred solution of(S)-2,2,2-trifluoro-N-(2-(2-(2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidin--5-yl)thiazol-4-yl)acetamide (200 mg, 0.48 mmol) in MeOH (4 mL) wasadded 50% NaOH (2 mL). After addition, the mixture was heated toreflux for 2 hr, cooled to r.t., and concentrated under reducedpressure. The residue was diluted with water (4 mL) and extractedwith DCM (3.times.2 mL). Combined organic layers were dried overNa.sub.2SO.sub.4 and filtered. The filtrate was concentrated underreduced pressure to afford(S)-2-(2-(2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidin-5-yl)thiazol-4-ami-ne (110 mg, 71.9% yield) as yellow solid. Retention time (LC-MS):0.785 min. MH.sup.+ 316.

Preparation 122-(3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)acetonitrile

##STR00320##

Step 12-(3-methyl-2,6-dioxo-7-((2-(trimethylsilyl)ethoxy)methyl)-2,3,6,7--tetrahydro-1H-purin-1-yl)acetonitrile

##STR00321##

To a solution of3-methyl-7-(2-trimethylsilanyl-ethoxymethyl)-3,7-dihydro-purine-2,6-dione(450 mg, 1.52 mmol) in DMF (7 mL) was added potassium carbonate(420 mg, 3.04 mmol), TBAI (56 mg, 0.15 mmol) followed by dropwiseaddition of 2-bromoacetonitrile (0.13 mL, 1.82 mmol). The reactionmixture was stirred at 50.degree. C. under N.sub.2 overnight. Thereaction mixture was quenched by water (30 mL), and then extractedwith EA (3.times.5 mL). The combined organic layers were washedwith saturated aqueous LiCl solution (15 mL) and brine (15 mL),dried over Na.sub.2SO.sub.4 and filtered. The filtrate wasconcentrated to give a residue, which was purified with columnchromatography (eluted with DCM:MeOH=70:1) to afford2-(3-methyl-2,6-dioxo-7-((2-(trimethylsilyl)ethoxy)methyl)-2,3,6,7-tetrah-ydro-1H-purin-1-yl)acetonitrile (490 mg, 80% yield) as a brown oil.Retention time (LC-MS): 1.486 min. MH.sup.+ 336.

Step 22-(3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)acetonitrile

##STR00322##

To a solution of2-(3-methyl-2,6-dioxo-7-((2-(trimethylsilyl)ethoxy)methyl)-2,3,6,7-tetrah-ydro-1H-purin-1-yl)acetonitrile (400 mg, 1.19 mmol) in THF (10 mL)was added TBAF (933 mg, 3.57 mmol), then the mixture was stirred at75.degree. C. overnight. The mixture was cooled to RT andconcentrated. The residue was diluted with water and extracted withchloroform/isopropanol (3:1) (3.times.5 mL). Then the organiclayers were dried over Na.sub.2SO.sub.4 and filtered. The filtratewas concentrated and the residue was purified with columnchromatography (eluted with DCM:MeOH=70:1) to afford2-(3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)acetonitrile(210 mg yield 86%) as a brown solid. Retention time (LC-MS): 0.372min. MH.sup.+ 206.

Preparation 132-chloro-N-(6-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-2-yl)propanamide

##STR00323##

Step 1 6-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-2-amine

##STR00324##

A mixture of 5-bromo-2-(trifluoromethyl)pyrimidine (1 g, 4.42mmol),4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2--dioxaborolane (1.35 g, 5.31 mmol), KOAc (1.30 g, 13.27 mmol) in adioxane (10 mL) was added Pd(dppf)Cl.sub.2 (161.8 mg, 0.22 mmol).After the mixture was degassed and purged with N.sub.2 for threetimes, it was stirred at 100.degree. C. for 2 hrs under N.sub.2atmosphere. The mixture was cooled to RT 6-bromopyridin-2-amine(633.5 mg, 3.68 mmol), aqueous Na.sub.2CO.sub.3 solution (5 mL, 2M) and Pd(dppf)Cl.sub.2 (161.8 mg 0.22 mmol) were added to theabove mixture under N.sub.2 atmosphere. The mixture was stirred at100.degree. C. under N.sub.2 for 2 hrs. The reaction mixture wasextracted with DCM (2.times.10 mL). Combined organic layers werewashed with brine, dried over Na2SO4, and concentrated and theresidue was purified with column chromatography (eluted withPE:EA=5:1) to afford6-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-2-amine (670 mg, 64%yield) as a white solid. Retention time (LC-MS): 1.029 min.MH.sup.+ 241.

Step 22-chloro-N-(6-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-2-yl)propa-namide

##STR00325##

To a mixture of6-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-2-amine (100 mg, 0.42mmol) in pyridine (2 mL) was added 3-chloro-butan-2-one (0.06 mL,0.63 mmol) at 0.degree. C. Then the mixture was stirred at RT for 2hrs. The reaction mixture was quenched by water (20 mL), and thenextracted with EA (3.times.5 mL). The combined organic layers werewashed by the saturated aqueous LiCl and brine, dried overNa.sub.2SO.sub.4 and filtered. The filtrate was concentrated andthe residue was purified with column chromatography (eluted withPE:EA=3:1) to afford2-chloro-N-(6-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-2-yl)propanamide(80 mg, 58% yield) as a white solid. Retention time (LC-MS): 1.560min. MH.sup.+ 331.

Preparation 14 (S)-methyl2-(1-(cyanomethyl)-3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)propa-noate

##STR00326##

To solution of2-(3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)acetonitrile(300 mg, 1.46 mmol) in DMF (7 mL) was added (R)-methyl2-(methylsulfonyloxy)propanoate (533 mg, 2.93 mmol), and potassiumcarbonate (202 mg 1.46 mmol). The reaction mixture was stirred at50.degree. C. under N.sub.2 overnight. The reaction mixture wasquenched by water (50 mL), and then extracted with EA (3.times.10mL). The combined organic layers were washed by the saturatedaqueous LiCl and brine, dried over Na.sub.2SO.sub.4 and filtered.The filtrate was concentrated and the residue was purified withcolumn chromatography (eluted with DCM:MeOH=100:1) to afford(S)-methyl2-(1-(cyanomethyl)-3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)propa-noate (250 mg, 59% yield) as a brown oil. Retention time (LC-MS):0.622 min. MH.sup.+ 292.

Preparation 152'-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-[2,5'-bipyrimidin]-4-amin-e

##STR00327##

Step 13-(5-bromopyrimidin-2-yl)-6,6-difluoro-3-azabicyclo[3.1.0]hexane

##STR00328##

A sealed tube was charged with 5-bromo-2-chloropyrimidine (748.5mg, 3.9 mmol), 6,6-difluoro-3-azabicyclo[3.1.0]hexane hydrochloride(604.6 mg, 3.9 mmol), potassium carbonate (1.1 g, 7.8 mmol) and NMP(3 mL). After the mixture was stirred at 130.degree. C. for 3 hrs,it was poured into water (4 mL). The solid was collected byfiltration and dried under vacuum to give the title product (1.0 g,93.2% yield) as a white solid. Retention time (LC-MS): 1.65 min.M.sup.+ 276.

Step 2(2-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)boron-ic Acid

##STR00329##

To a solution of3-(5-bromopyrimidin-2-yl)-6,6-difluoro-3-azabicyclo[3.1.0]hexane(1.1 g, 4.1 mmol) and (i-PrO).sub.3B (1.4 mL, 6.2 mmol) in THF (20mL) was added n-BuLi (3.9 mL, 1.6 M in hexane, 6.2 mmol) dropwiseat -78.degree. C. After the mixture was stirred at -78.degree. C.for 2 hrs, it was quenched with water. The solvent was removedunder reduced pressure and the aqueous layer was washed with Ether(2.times.50 mL). The aqueous layer was then adjusted to pH 6 with1N HCl and extracted with EA (3.times.50 mL). The combined organiclayers were washed with brine, dried over Na2SO4, and concentratedto give2-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)boronicacid (700 mg, 72.6% yield) as a white solid.

Step 32'-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-[2,5'-bipyrimidin]--4-amine

##STR00330##

A mixture of(2-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)boronicacid (241.0 mg, 1.0 mmol), 2-chloropyrimidin-4-amine (129.0 mg, 1.0mmol), Pd(PPh.sub.3).sub.4 (57.8 mg, 0.05 mmol) and potassiumcarbonate (276.4 mg, 2.0 mmol) in 1,4-dioxane (5 mL) and H.sub.2O(1 mL) was degassed and purged with N.sub.2 for three times andstirred at 90.degree. C. under N.sub.2 for 3 hrs. The reactionmixture was cooled down and poured into EA. The organic phase wasseparated, washed with water and brine, dried over Na.sub.2SO.sub.4and filtered. The filtrate was concentrated under reduced pressureand the residue was purified with column chromatography (elutedwith DCM:MeOH=50:1) to afford2'-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-[2,5'-bipyrimidin]-4-amin-e (210 mg, 72.3% yield) as a white solid. Retention time (LC-MS):0.37 min. MH.sup.+ 291.

Preparation 166-(2-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)pyrazin-2--amine

##STR00331##

A mixture of(2-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)boronicacid (192.9 mg, 0.8 mmol), 6-chloropyrazin-2-amine (103.2 mg, 0.8mmol), Pd(PPh.sub.3).sub.4 (46.2 mg, 0.04 mmol) and potassiumcarbonate (221.1 mg, 1.6 mmol) in 1,4-dioxane (5 mL) and H.sub.2O(1 mL) was degassed and stirred at 90.degree. C. under N.sub.2 for3 hrs. The reaction mixture was cooled down and diluted with EA.The organic phase was separated, washed with water and brine, driedover Na.sub.2SO.sub.4 and filtered. The filtrate was concentratedunder reduced pressure and the residue was purified with columnchromatography (eluted with DCM:MeOH=50:1) to afford6-(2-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)pyrazin-2--amine (180 mg, 77.5% yield) as a white solid. Retention time(LC-MS): 0.37 min. MH.sup.+ 291.

Preparation 17 (S)-methyl2-(3-methyl-1-((5-methylisoxazol-3-yl)methyl)-2,6-dioxo-2,3-dihydro-1H-pu-rin-7(6H)-yl)propanoate

##STR00332##

To a solution of3-methyl-1-((5-methylisoxazol-3-yl)methyl)-1H-purine-2,6(3H,7H)-dione(600 mg, 2.30 mmol) and potassium carbonate (836.78 mg, 4.60 mmol).The mixture was stirred at 50.degree. C. overnight. The mixture wasdiluted with EA, washed with water, brine, dried overNa.sub.2SO.sub.4 and filtered. The filtrate was evaporated to givethe crude product. The crude product was purified with columnchromatography (PE:EA=4:1 to 1:3) to give the (S)-methyl2-(3-methyl-1-((5-methylisoxazol-3-yl)methyl)-2,6-dioxo-2,3-dihydro-1H-pu-rin-7(6H)-yl)propanoate (640 mg, 80.2% yield) as a white solid.Retention time (LC-MS): 0.735 min. MH.sup.+ 347.

Preparation 186-(2-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)pyridin-2--amine

##STR00333##

A mixture of2-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-ylboronicacid (200 mg, 0.83 mmol), 6-bromopyridin-2-amine (128 mg, 1.0mmol), Pd(PPh.sub.3).sub.4 (57.8 mg, 0.05 mmol) and potassiumcarbonate (229 mg, 1.66 mmol) in 1,4-dioxane (5 mL) and H.sub.2O (1mL) was degassed and stirred at 90.degree. C. under N.sub.2 for 3hrs. The reaction mixture was cooled to RT and poured into EA. Theorganic phase was separated, washed with water and brine, driedover Na.sub.2SO.sub.4 and filtered. The filtrate was concentratedunder reduced pressure and the residue was purified with columnchromatography (eluted with DCM:MeOH=50:1) to afford6-(2-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)pyridin-2--amine (180 mg, 75.0% yield) as a white solid. Retention time(LC-MS): 0.499 min. MH.sup.+ 290.

The procedure set forth above was used to produce the followingcompounds using the appropriate starting materials.

##STR00334##

Retention time (LC-MS): 0.723 min. MH.sup.+ 254.

Preparation 19(R)-2-(2-(2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidin-5-yl)thiazol-4-ami-ne

##STR00335##

A mixture of N-(2-bromothiazol-4-yl)-2,2,2-trifluoroacetamide (200mg, 0.73 mmol),(R)-2-(2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidin-5-ylboronicacid (228 mg, 0.87 mmol), Pd(PPh.sub.3).sub.4 (57.8 mg, 0.05 mmol)and Cs.sub.2CO.sub.3 (710 mg, 2.18 mmol) in 1,4-dioxane (5 mL) andH.sub.2O (1 mL) was degassed and stirred at 110.degree. C. underN.sub.2 for 3 hrs. The reaction mixture was cooled down and pouredinto EA. The organic phase was separated, washed with water andbrine, dried over Na.sub.2SO.sub.4 and filtered. The filtrate wasconcentrated under reduced pressure and the residue was purifiedwith column chromatography (eluted with DCM:MeOH=10:1) to afford(R)-2-(2-(2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidin-5-yl)thiazol-4-ami-ne (55 mg, 24.0% yield) as a white solid. Retention time (LC-MS):1.417 min. MH.sup.+ 316.

Preparation 20N-(2'-(3-azabicyclo[3.1.0]hexan-3-yl)-2,5'-bipyrimidin-4-yl)-2-chloroprop-anamide (3, ZY-000461-133)

##STR00336##

To a solution of2'-(3-azabicyclo[3.1.0]hexan-3-yl)-2,5'-bipyrimidin-4-amine (100mg, 0.39 mmol) in pyridine (3 mL) was added drop-wise2-chloropropanoyl chloride (0.56 mL, 0.59 mmol) at 0.degree. C.After the mixture was stirred at RT for 1 h and it was poured intoEA. The organic layer was separated, washed with water and brine,dried over Na2SO4, and concentrated to give the title product (120mg, 88.5% yield) as a yellow solid. Retention time (LC-MS): 1.571min. MH.sup.+ 345.

Preparation 216-(2-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)pyridin-2--amine

##STR00337##

A mixture of2-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-ylboronicacid (200 mg, 0.83 mmol), 6-bromopyridin-2-amine (128 mg, 1.0mmol), Pd(PPh.sub.3).sub.4 (57.8 mg, 0.05 mmol) and potassiumcarbonate (229 mg, 1.66 mmol) in 1,4-dioxane (5 mL) and H.sub.2O (1mL) was degassed and stirred at 90.degree. C. under N.sub.2 for 3hrs. The reaction mixture was cooled to RT and poured into EA. Theorganic phase was separated, washed with water and brine, driedover Na.sub.2SO.sub.4 and filtered. The filtrate was concentratedunder reduced pressure and the residue was purified with columnchromatography (eluted with DCM:MeOH=50:1) to afford6-(2-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)pyridin-2--amine (180 mg, 75.0% yield) as a white solid. Retention time(LC-MS): 0.499 min. MH.sup.+ 290.

The procedure set forth above was used to produce the followingcompounds using the appropriate starting materials.

##STR00338##

Retention time (LC-MS): 0.449 min. MH.sup.+ 205.

##STR00339##

Retention time (LC-MS): 0.723 min. MH.sup.+ 254.

Preparation 22 6-(3,4-dichlorophenyl)pyridin-2-amine

##STR00340##

To a mixture of 3,4-dichlorophenylboronic acid (200 mg, 1.05 mmol),6-bromopyridin-2-amine (218 mg, 1.26 mmol) in 1,4-dioxane (5 mL)and H.sub.2O (1 mL) was added potassium carbonate 290 mg, 2.10mmol). After the mixture was degassed with N.sub.2 for 3 times,Pd(PPh.sub.3).sub.4 (57.8 mg, 0.05 mmol) was added under N.sub.2and the mixture was stirred at 100.degree. C. for 3 hrs. Thereaction mixture was cooled down and poured into EA. The organicphase was separated, washed with water and brine, dried overNa.sub.2SO.sub.4 and filtered. The filtrate was concentrated underreduced pressure and the residue was purified by chromatography(eluted with DCM:MeOH=50:1) to afford6-(3,4-dichlorophenyl)pyridin-2-amine (200 mg, 79.8% yield) as awhite solid. Retention time (LC-MS): Retention 1.546 min. MH.sup.+240.

Preparation 23 2-(3,4-dichlorophenyl)thiazol-4-amine

##STR00341##

To a mixture of 3,4-dichlorophenylboronic acid (600 mg, 2.18 mmol),N-(2-bromothiazol-4-yl)-2,2,2-trifluoroacetamide (416 mg, 2.18mmol) in 1,4-dioxane (15 mL) and H.sub.2O (3 mL) was addedCs.sub.2CO.sub.3 (2.13 g, 6.54 mmol) and the mixture was degassedwith N.sub.2 for three times. Pd(PPh.sub.3).sub.4 (75 mg, 0.06mmol) was added and the reaction mixture was stirred at 100.degree.C. under N.sub.2 overnight. The mixture was cooled down and pouredinto EA. The organic phase was separated, washed with water andbrine, dried over Na.sub.2SO.sub.4 and filtered. The filtrate wasconcentrated under reduced pressure. The filtrate was concentratedand the residue was purified by chromatography (eluted withDCM:MeOH=100:1) to afford 2-(3,4-dichlorophenyl)thiazol-4-amine(200 mg, 26.88% yield) as a yellow solid. Retention time (LC-MS):1.651 min. MH.sup.+ 245.

Preparation 24N-(2'-(3-azabicyclo[3.1.0]hexan-3-yl)-2,5'-bipyrimidin-4-yl)-2-chloroprop-anamide

##STR00342##

To a solution of2'-(3-azabicyclo[3.1.0]hexan-3-yl)-2,5'-bipyrimidin-4-amine (80 mg,0.31 mmol) in pyridine (2 mL) was added drop-wise 2-chloropropanoylchloride (0.04 mL, 0.45 mmol) at 0.degree. C. The mixture wasstirred at RT for 2 hrs and poured into EA. The organic layer wasseparated, washed with water and brine, dried over Na.sub.2SO.sub.4and filtered. The filtrate was concentrated and the residue waspurified by chromatography (eluted with DCM:MeOH=70:1) to affordN-(2'-(3-azabicyclo[3.1.0]hexan-3-yl)-2,5'-bipyrimidin-4-yl)-2-chloroprop-anamide (130 mg, 120% yield) as a white solid. Retention time(LC-MS): 1.525 min. MH.sup.+ 345.

Preparation 252-(2-(diethylamino)pyrimidin-5-yl)thiazol-4-amine

##STR00343##

Step 1 5-bromo-N,N-diethylpyrimidin-2-amine

##STR00344##

A solution of 5-bromo-2-chloropyrimidine (1.0 g, 5.17 mmol) anddiethylamine (2.13 mL, 20.68 mmol) in THF (5 mL) was stirred at80.degree. C. for 3 hrs. The mixture was cooled and concentrated todryness to give the crude product, which was purified bychromatography (eluted with PE:EA=100:1) to give5-bromo-N,N-diethylpyrimidin-2-amine (1.14 g, 95.8% yield) as ayellow solid. Retention time (LC-MS): 1.827 min. MH.sup.+ 231.

Step 2 2-(diethylamino)pyrimidin-5-ylboronic acid

##STR00345##

To a solution of 5-bromo-N,N-diethylpyrimidin-2-amine (1.14 g, 4.95mmol) and triisopropyl borate (2.29 mL, 9.91 mmol) in THF (20 mL)was added drop-wise n-BuLi (5.95 mL, 1M in THF, 5.95 mmol) at-78.degree. C. and the mixture was stirred at this temperature for3 hrs. The mixture was poured into ice-water (15 mL) and washedwith Ether (5 mL.times.2). The aqueous layer was adjusted to pH 5with diluted aq. HCl and the mixture was extracted with EA (20mL.times.2). The combined organic layer was separated, washed withwater and brine, dried over Na.sub.2SO.sub.4, and filtered. Thefiltrate was concentrated and under reduced pressure to give2-(diethylamino)pyrimidin-5-ylboronic acid (450 mg, 65.3% yield) asa white solid. Retention time (LC-MS): 0.398 min. MH.sup.+ 196.

Step 3 2-(2-(diethylamino)pyrimidin-5-yl)thiazol-4-amine

##STR00346##

To a mixture of 2-(diethylamino)pyrimidin-5-ylboronic acid (100 mg,0.51 mmol), 6-bromopyridin-2-amine (106 mg, 0.62 mmol) in1,4-dioxane (5 mL) and H.sub.2O (1 mL) was added potassiumcarbonate (142 mg, 1.03 mmol). After the mixture was degassed withN.sub.2 for 3 times, Pd(PPh.sub.3).sub.4 (57.8 mg, 0.05 mmol) wasadded under N.sub.2 and the mixture was stirred at 100.degree. C.for 3 hrs. The reaction mixture was cooled down and poured into EA.The organic phase was separated, washed with water and brine, driedover Na.sub.2SO.sub.4 and filtered. The filtrate was concentratedunder reduced pressure and the residue was purified bychromatography (eluted with DCM:MeOH=100:1) to afford5-(6-aminopyridin-2-yl)-N,N-diethylpyrimidin-2-amine (100 mg, 80.2%yield) as a white solid. Retention time (LC-MS): Retention 0.399min. MH.sup.+ 244.

Preparation 26(R)-2-(6-(2-(trifluoromethyl)pyrrolidin-1-yl)pyridin-3-yl)thiazol-4-amine

##STR00347##

Step 1(R)-2,2,2-trifluoro-N-(2-(2-(2-(trifluoromethyl)pyrrolidin-1-yl)pyr-imidin-5-yl)thiazol-4-yl)acetamide

##STR00348##

To a mixture of(R)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2-(trifluoromethyl-)pyrrolidin-1-yl)pyrimidine (246.5 mg, 0.9 mmol),N-(2-bromothiazol-4-yl)-2,2,2-trifluoroacetamide (309.0 mg, 0.9mmol) in 1,4-dioxane (5 mL) and H.sub.2O (1 mL) was addedCs.sub.2CO.sub.3 (880.2 mg, 2.7 mmol). After the mixture wasdegassed with N.sub.2 for 3 times, Pd(PPh.sub.3).sub.4 (52.0 mg,0.05 mmol) was added under N.sub.2 and the mixture was stirred at100.degree. C. for 4 hrs. The reaction mixture was cooled down andpoured into EA. The organic phase was separated, washed with waterand brine, dried over Na.sub.2SO.sub.4 and filtered. The filtratewas concentrated under reduced pressure and the residue waspurified by chromatography (eluted with PE:EA=10:1) to afford thetitle product (140 mg, 37.8% yield) as a white solid. Retentiontime (LC-MS): Retention 1.769 min. MH.sup.+ 411.

Step 2(R)-2-(6-(2-(trifluoromethyl)pyrrolidin-1-yl)pyridin-3-yl)thiazol-4--amine

##STR00349##

A mixture of(R)-2,2,2-trifluoro-N-(2-(2-(2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidin--5-yl)thiazol-4-yl)acetamide (140.0 mg, 0.34 mmol) in MeOH (5 mL)and 50% NaOH (1 mL) was stirred at 60.degree. C. overnight. Thesolvent was removed. The residue was purified by columnchromatography (eluted with PE:EA=1:1) to afford the title product(70 mg, 65.2% yield) as a white solid. Retention time (LC-MS):1.426 min. MH.sup.+ 316.

Preparation 272-(2-(trifluoromethyl)pyrimidin-5-yl)thiazol-4-amine

##STR00350##

Step 1 N-(2-bromothiazol-4-yl)acetamide (ZSL-000466-082)

##STR00351##

To a suspension of 2-bromothiazol-4-amine hydrogen bromide (1 g,3.87 mmol) in DCM (5 mL) was added dropwise TEA (2.1 mL, 15.48mmol) at 0.degree. C. After the addition, the reaction mixture wasstirred at r.t for 15 min. then acetyl chloride (450 mg, 5.81 mmol)was added. The reaction mixture was stirred at r.t overnight. Thereaction mixture was quenched with water (10 mL). The mixture wasneutralized with saturated aq. NaHCO.sub.3 solution and extractedwith EA. Combined organic layers were washed with water and brine,dried over Na.sub.2SO.sub.4 and filtered. The filtrate wasconcentrated under reduced pressure and the residue was purified bychromatography (eluted with PE:EA=10:1 to 3:1) to affordN-(2-bromothiazol-4-yl)acetamide (250 mg, 29.4% yield) as a whitesolid. Retention time (LC-MS): 1.930 min. MH.sup.+ 221.

Step 2 N-(2-(2-(trifluoromethyl)pyrimidin-5-yl)thiazol-4-yl)

##STR00352##

To a mixture of 2-(trifluoromethyl)pyrimidin-5-ylboronic acid (173mg, 0.90 mmol), N-(2-bromothiazol-4-yl)acetamide (200 mg, 0.90mmol) in 1,4-dioxane (4 mL) and H.sub.2O (0.8 mL) was addedCs.sub.2CO.sub.3 (880 mg, 2.70 mmol). The mixture was degassed withN.sub.2 for three times. Pd(PPh.sub.3).sub.4 (52 mg, 0.045 mmol)was added and the reaction mixture was stirred at 100.degree. C.under N.sub.2 overnight. The mixture was cooled down and pouredinto EA. The organic phase was separated, washed with water andbrine, dried over Na.sub.2SO.sub.4 and filtered. The filtrate wasconcentrated under reduced pressure. The residue was purified bychromatography (eluted with DCM:MeOH=100:1) to affordN-(2-(2-(trifluoromethyl)pyrimidin-5-yl)thiazol-4-yl)acetamide (90mg, 34.6% yield) as a white solid. Retention time (LC-MS): 1.663min. MH.sup.+ 289.

Step 3 2-(2-(trifluoromethyl)pyrimidin-5-yl)thiazol-4-amine

##STR00353##

To a solution ofN-(2-(2-(trifluoromethyl)pyrimidin-5-yl)thiazol-4-yl)acetamide (3,90 mg, 0.31 mmol) in MeOH (2 mL) was added con.HCl (0.4 mL). Thereaction mixture was heated to reflux for 2 hrs. The solvent wasremoved under reduced pressure to afford the product2-(2-(trifluoromethyl)pyrimidin-5-yl)thiazol-4-amine (77 mg, 99.1%yield) as a yellow solid without further purification. Retentiontime (LC-MS): 0.758 min. MH.sup.+ 247.

Preparation 282-(6-(3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)thiazol-4-amine

##STR00354##

Step 1 3-(5-bromopyridin-2-yl)-3-azabicyclo[3.1.0]hexane

##STR00355##

In a microwave reaction tube containing 3-azabicyclo[3.1.0]hexanehydrochloride (892.9 mg, 7.5 mmol) and 5-bromo-2-fluoropyridine(1.3 g, 7.5 mmol) was added MeCN (4 mL) and potassium carbonate(2.1 g, 15.0 mmol). The mixture was heated in a Biotage MicrowaveInitiator device at 90.degree. C. for 45 min. The mixture waspoured into EA. The organic phase was washed with water and brine,dried over Na.sub.2SO.sub.4 and filtered. The filtrate wasconcentrated under reduced pressure. The crude product was purifiedby chromatography (eluted with PE:EA=8:1) to afford3-(5-bromopyridin-2-yl)-3-azabicyclo[3.1.0]hexane (550 mg, 30.8%yield) as a white solid. Retention time (LC-MS): 1.295 min.MH.sup.+ 239.

Step 2 (6-(3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)boronicacid

##STR00356##

To a solution of 3-(5-bromopyridin-2-yl)-3-azabicyclo[3.1.0]hexane(119.0 mg, 0.5 mmol) and (.sup.iPrO).sub.3B (0.17 mL, 0.75 mmol) inTHF (4 mL) was added n-BuLi (0.47 mL, 1.6 M in hexane, 0.75 mmol)dropwise at -78.degree. C. The mixture was stirred at the sametemperature for 2 h. The reaction was quenched with water. Thesolvent was removed under reduced pressure and the aqueous layerwas extracted with Ether (2.times.5 mL). The aqueous layer was thenadjusted to pH 6 with 1N HCl and extracted with EA (3.times.10 mL).Combined organic layers were washed with brine, dried over Na2SO4,and concentrated to give the title product (80 mg, 78.4% yield) asa white solid. Retention time (LC-MS): 0.384 min. MH.sup.+ 205.

Step 3N-(2-(6-(3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)thiazol-4-yl)-2-,2,2-trifluoroacetamide

##STR00357##

To a mixture of(6-(3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)boronic acid (80.0mg, 0.4 mmol), N-(2-bromothiazol-4-yl)-2,2,2-trifluoroacetamide(107.4 mg, 0.4 mmol) in 1,4-dioxane (5 mL) and H.sub.2O (1 mL) wasadded Cs.sub.2CO.sub.3 (260.6 mg, 0.8 mmol). After the mixture wasdegassed with N.sub.2 for 3 times, Pd(PPh.sub.3).sub.4 (23.0 mg,0.02 mmol) was added under N.sub.2 and the mixture was stirred at100.degree. C. for 4 hrs. The reaction mixture was cooled down andpoured into EA. The organic phase was separated, washed with waterand brine, dried over Na.sub.2SO.sub.4 and filtered. The filtratewas concentrated under reduced pressure and the residue waspurified by chromatography (eluted with PE/EA=10:1) to afford thetitle product (50 mg, 36.0% yield) as a white solid. Retention time(LC-MS): 1.978 min. MH.sup.+ 355.

Step 42-(6-(3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)thiazol-4-amine

##STR00358##

A mixture ofN-(2-(6-(3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)thiazol-4-yl)-2,2,2-t-rifluoroacetamide (50.0 mg, 0.14 mmol) in MeOH (2 mL) and 50% NaOH(0.3 mL) was stirred at 60.degree. C. overnight. The solvent wasremoved. The residue was purified by column chromatography (elutedwith PE:EA=1:1) to afford the title product (30 mg, 82.0% yield) asa white solid. Retention time (LC-MS): 0.629 min. MH.sup.+ 259.

Preparation 296'-(3-azabicyclo[3.1.0]hexan-3-yl)-2,3'-bipyridin-6-amine

##STR00359##

To a mixture of6-(3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-ylboronic acid (300 mg,1.47 mmol) and 6-bromopyridin-2-amine (305 mg, 1.76 mmol) in1,4-dioxane (5 mL) and H.sub.2O (1 mL) was added potassiumcarbonate (610 mg, 4.41 mmol). After the mixture was degassed withN.sub.2 for 3 times, Pd(PPh.sub.3).sub.4 (80.9 mg, 0.07 mmol) wasadded under N.sub.2 and the mixture was stirred at 100.degree. C.for 3 hrs. The reaction mixture was cooled down and poured into EA.The organic phase was separated, washed with water and brine, driedover Na.sub.2SO.sub.4 and filtered. The filtrate was concentratedunder reduced pressure and the residue was purified bychromatography (eluted with DCM:MeOH=50:1) to afford6'-(3-azabicyclo[3.1.0]hexan-3-yl)-2,3'-bipyridin-6-amine (200 mg,54.0% yield) as a white solid. Retention time (LC-MS): Retention0.445 min. MH.sup.+ 253.

Preparation 302-(2-(diethylamino)pyrimidin-5-yl)thiazol-4-amine

##STR00360##

A mixture of 2-(diethylamino)pyrimidin-5-ylboronic acid (600 mg,3.08 mmol), N-(2-bromothiazol-4-yl)-2,2,2-trifluoroacetamide (864mg, 3.08 mmol), Pd(PPh.sub.3).sub.4 (75 mg, 0.06 mmol) andCs.sub.2CO.sub.3 (3.01 g, 9.23 mmol) in 1,4-dioxane (15 mL) andH.sub.2O (3 mL) was degassed and stirred at 110.degree. C. underN.sub.2 overnight. The reaction mixture was cooled down and pouredinto EA. The organic phase was separated, washed with water andbrine, dried over Na.sub.2SO.sub.4 and filtered. The filtrate wasconcentrated under reduced pressure and the residue was purified bychromatography (eluted with DCM:MeOH=80:1) to afford2-(2-(diethylamino)pyrimidin-5-yl)thiazol-4-amine (245 mg, yield31.94%) as a brown solid. Retention time (LC-MS): 1.310 min.MH.sup.+ 250.

Preparation 31(R)-6-(2-(2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidin-5-yl)pyridin-2-ami-ne

##STR00361##

A mixture of(R)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2-(trifluoromethyl-)pyrrolidin-1-yl)pyrimidine (129 mg, 0.375 mmol),6-bromopyridin-2-amine (65 mg, 0.375 mmol), Pd(PPh.sub.3).sub.4 (6mg, 0.003 mmol) and Na.sub.2CO.sub.3 (119 mg, 1.13 mmol) in1,4-dioxane (5 mL) and H.sub.2O (1 mL) was degassed and stirred at110.degree. C. under N2 overnight. The reaction mixture was cooleddown and poured into EA. The organic phase was separated, washedwith water and brine, dried over Na.sub.2SO.sub.4 and filtered. Thefiltrate was concentrated under reduced pressure and the residuewas purified by chromatography (eluted with DCM:MeOH=50:1) toafford(R)-6-(2-(2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidin-5-yl)pyridi-n-2-amine (70 mg, yield 60.24%) as a yellow solid. Retention time(LC-MS): 0.536 min. MH.sup.+ 310.

Preparation 32(R)-6-(2-(2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidin-5-yl)pyrazin-2-ami-ne

##STR00362##

A mixture of(R)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2-(trifluoromethyl-)pyrrolidin-1-yl)pyrimidine (132 mg, 0.385 mmol),6-chloropyrazin-2-amine (50 mg, 0.385 mmol), Pd(PPh.sub.3).sub.4 (6mg, 0.003 mmol) and potassium carbonate (132 mg, 0.9 mmol) in1,4-dioxane (5 mL) and H.sub.2O (1 mL) was degassed and stirred at110.degree. C. under N.sub.2 overnight. The reaction mixture wascooled down and poured into EA. The organic phase was separated,washed with water and brine, dried over Na.sub.2SO.sub.4 andfiltered. The filtrate was concentrated under reduced pressure andthe residue was purified by chromatography (eluted withDCM/MeOH=50:1) to afford(R)-6-(2-(2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidin-5-yl)pyrazi-n-2-amine (70 mg, yield 60%) as a yellow solid. Retention time(LC-MS): 1.198 min. MH.sup.+ 311.

Preparation 336-(6-(3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)pyrazin-2-amine

##STR00363##

To a mixture of(6-(3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)boronic acid (163.2mg, 0.8 mmol), 6-chloropyrazin-2-amine (103.2 mg, 0.8 mmol) in1,4-dioxane (5 mL) and H.sub.2O (1 mL) was added potassiumcarbonate (221.1 mg, 1.6 mmol). After the mixture was degassed withN.sub.2 for 3 times, Pd(PPh.sub.3).sub.4 (46.2 mg, 0.04 mmol) wasadded under N.sub.2 and the mixture was stirred at 100.degree. C.for 2 hrs. The reaction mixture was cooled down and poured into EA.The organic phase was separated, washed with water and brine, driedover Na.sub.2SO.sub.4 and filtered. The filtrate was concentratedunder reduced pressure and the residue was purified bychromatography (eluted with PE:EA=1:1) to afford the title product(140 mg, 69.2% yield) as a white solid. Retention time (LC-MS):0.353 min. MH.sup.+ 254.

Preparation 34(S)-6-(2-(2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidin-5-yl)pyridin-2-ami-ne

##STR00364##

To a mixture of(S)-2-(2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidin-5-ylboronicacid (731 mg, 2.79 mmol), 6-bromopyridin-2-amine (400 mg, 2.32mmol) in 1,4-dioxane (8 mL) and H.sub.2O (1.6 mL) was addedpotassium carbonate (641 mg, 4.65 mmol). After the mixture wasdegassed with N.sub.2 for three times, Pd(PPh.sub.3).sub.4 (133 mg,0.12 mmol) was added under N.sub.2 and the mixture was stirred at100.degree. C. for 3 hrs. The reaction mixture was cooled down andpoured into EA. The organic phase was separated, washed with waterand brine, dried over Na.sub.2SO.sub.4 and filtered. The filtratewas concentrated under reduced pressure and the residue waspurified by chromatography (eluted with PE:EA=3:1) to afford(S)-6-(2-(2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidin-5-yl)pyridin-2-ami-ne (550 mg, 76.6% yield) as a white solid. Retention time (LC-MS):Retention 1.556 min. MH.sup.+ 310.

Preparation 352-(6-(3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)pyrimidin-4-amine

##STR00365##

To a mixture of6-(3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-ylboronic acid (400 mg,1.96 mmol), potassium carbonate (542.00 mg, 3.92 mmol) and2-chloropyrimidine (254.90 mg, 1.96 mmol) in 1,4-dioxane (15 mL)and H.sub.2O (3 mL) was added Pd(PPh.sub.3).sub.4 (226.47 mg, 0.20mmol). The reaction mixture was stirred at 100.degree. C. underN.sub.2 for 2 h. The mixture was cooled and filtered throughCelite, and the filtrate was extracted with EA (3.times.50 mL). Thecombined organic layers were dried over Na.sub.2SO.sub.4 andfiltered. The filtrate was concentrated under reduced pressure andthe residue was purified with column chromatography (PE:EA=20:1 to=1:1) to afford2-(6-(3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)pyrimidin-4-amine(150 mg, 30.2% yield) as a yellow solid. Retention time (LC-MS):0.449 min. MH.sup.+ 254.

Preparation 36((R)-2'-(2-(trifluoromethyl)pyrrolidin-1-yl)-2,5'-bipyrimidin-4-amine

##STR00366##

To a mixture of(R)-2-(2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidin-5-ylboronicacid (200 mg, 0.766 mmol), 2-chloropyrimidin-4-amine (88 mg, 0.689mmol) in 1,4-dioxane (2.3 mL) and H.sub.2O (0.75 mL) was addedNa.sub.2CO.sub.3 (162 mg, 1.52 mmol). After the mixture wasdegassed with N.sub.2 for 3 times, Pd(PPh.sub.3).sub.4 (28 mg,0.029 mmol) was added under N.sub.2 and the mixture was stirred at100.degree. C. for 3 hrs. The reaction mixture was cooled down andpoured into EA. The organic phase was separated, washed with waterand brine, dried over Na.sub.2SO.sub.4 and filtered. The filtratewas concentrated under reduced pressure and the residue waspurified with column chromatography (eluted with PE:acetone=4:1) toafford(R)-2'-(2-(trifluoromethyl)pyrrolidin-1-yl)-2,5'-bipyrimidin-4-amine(200 mg,84% yield) as a white solid. Retention time (LC-MS):Retention 0.361 min. MH.sup.+ 311.

Preparation 37(R)-2-(2-(2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidin-5-yl)thiazol-4-ami-ne

##STR00367##

To a mixture of(R)-2-(2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidin-5-ylboronicacid (229 mg, 0.87 mmol),N-(2-bromothiazol-4-yl)-2,2,2-trifluoroacetamide (200 mg, 0.73mmol) in 1,4-dioxane (4 mL) and H.sub.2O (0.8 mL) was addedCs.sub.2CO.sub.3 (731 mg, 2.19 mmol). After the mixture wasdegassed with N.sub.2 for three times, Pd(PPh.sub.3).sub.4 (42 mg,0.04 mmol) was added and the reaction mixture was stirred at100.degree. C. under N.sub.2 overnight. The mixture was cooled downand poured into EA. The organic phase was separated, washed withwater and brine, dried over Na.sub.2SO.sub.4 and filtered. Thefiltrate was concentrated under reduced pressure. The filtrate wasconcentrated and the residue was purified with columnchromatography (eluted with DCM:MeOH=100:1) to afford(R)-2-(2-(2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidin-5-yl)thiazo-l-4-amine (60 mg, 26.02% yield) as a yellow solid. Retention time(LC-MS): 1.651 min. MH.sup.+ 316.

Preparation 38(S)-2-(3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)-N-(6-(2-(trifluo-romethyl)pyrimidin-5-yl)pyridin-2-yl)propanamide

##STR00368##

To a solution of6-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-2-amine (200 mg, 0.83mmol) in DCM (5 mL) was added drop-wise trimethylaluminum (2.90 mL,1M in n-hexane, 2.90 mmol) at 0.degree. C. After the addition, themixture was warmed to RT and stirred for 0.5 h. Then a solution of(S)-methyl2-(3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)propanoate (210mg, 0.83 mmol) in DCM (2 mL) was added drop-wise and the reactionmixture was stirred at 30.degree. C. overnight. The reaction wasquenched by addition of several drops of MeOH. The mixture wasconcentrated under reduced pressure and the residue was purified bychromatography (PE/EA=1:2) to afford a crude product, which wasfurther purified via preparative HPLC to afford(S)-2-(3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)-N-(6-(2-(trifluo-romethyl)pyrimidin-5-yl)pyridin-2-yl)propanamide (250 mg, 55.1%yield) as a white solid. Retention time (LC-MS): 0.573 min.MH.sup.+ 461.

Preparation 39 Oxetan-3-ylmethyl Methanesulfonate

##STR00369##

To a solution of oxetan-3-ylMeOH (300 mg, 3.40 mmol) and TEA (0.95mL, 6.80 mmol) in DCM (4 mL) was added dropwise methanesulfonylchloride (0.4 mL, 5.11 mmol) at 0.degree. C. over 10 min. After theaddition, the mixture was stirred at 10.degree. C. to 20.degree. C.for 1.5 h. TLC (PE/EA=3/1, R.sub.f (TM)=0.6, R.sub.f (SM)=0.5,developed by potassium permanganate) showed the starting materialwas completely consumed. The reaction was quenched by addition ofice-water (5 mL). The organic layer was separated, washed withwater (2.times.3 mL) and brine, dried over Na.sub.2SO.sub.4 andfiltered. The filtrate was concentrated to afford the crude productoxetan-3-ylmethyl methanesulfonate (500 mg, 88.3% yield) as a brickred oil which was used directly in the next step without furtherpurification.

Preparation 40 N-(2-(4-(trifluoromethyl)phenyl)thiazol-4-yl)

##STR00370##

To a solution of pentan-2-one (4 g, 46.5 mmol) in MeOH (45 mL)cooled to -30.degree. C. under a nitrogen atmosphere, Br.sub.2(2.32 mL, 46.5 mmol) was added drop-wise. The reaction mixture wasallowed to warm to RT and stirred for 2 hrs, then concentrated invacuo, diluted with ether and washed with aqueous saturatedNaHCO.sub.3 solution followed by brine. The organic layer was driedover Na.sub.2SO.sub.4, filtered and concentrated under reducedpressure. The residue was purified by chromatography (eluted withPE:EA=100:1) to afford 1-bromopentan-2-one (5 g, 65.79% yield) as abrown oil.

Preparation 412-(2-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)thiazol-4--amine

##STR00371##

Step 1N-(2-(2-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)-thiazol-4-yl)-2,2,2-trifluoroacetamide

##STR00372##

To a solution of2-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-ylboronicacid (300 mg, 1.24 mmol), Cs.sub.2CO.sub.3 (811.17 mg, 2.49 mmol)and N-(2-bromothiazol-4-yl)-2,2,2-trifluoroacetamide (376.62 mg,1.37 mmol) in 1,4-dioxane (10 mL) and H.sub.2O (1.24 mL) was addedPd(PPh.sub.3).sub.4 (143.78 mg, 0.12 mmol). After degassed threetimes under N.sub.2, the reaction mixture was stirred at110.degree. C. under N.sub.2 for 2 hrs. The mixture was cooled andfiltered through Celite, and the filtrate was extracted with EA(3.times.50 mL). Combined organic layers were dried overNa.sub.2SO.sub.4 and filtered. The filtrate was concentrated underreduced pressure and the residue was purified by chromatography(PE/EA=10:1 to =1:1) to affordN-(2-(2-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)thiazo-l-4-yl)-2,2,2-trifluoroacetamide (240 mg, 65.1% yield) as a yellowsolid. Retention time (LC-MS): 1.402 min. MH.sup.+ 392.

Step 22-(2-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)thi-azol-4-amine

##STR00373##

To a solution ofN-(2-(2-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)thiazo-l-4-yl)-2,2,2-trifluoroacetamide (240 mg, 0.61 mmol) in MeOH (10mL) was added NaOH (2 mL, 50% wt) at RT. The reaction mixture wasstirred at 80.degree. C. overnight. The mixture was concentrated todryness and ethanol (4 mL) was added. The slurry was filtered. Thesolids were washed with water (10 mL.times.4) and dried undervacuum to afford2-(2-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)thiazol-4--amine (140 mg, 77.3% yield) as a gray solid. Retention time(LC-MS): 0.856 min. MH.sup.+ 296.

Preparation 42 (S)-methyl2-(1-(3-methoxy-2-oxopropyl)-3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H-)-yl)propanoate

##STR00374##

Step 11-(2-hydroxy-3-methoxypropyl)-3-methyl-7-((2-(trimethylsilyl)ethox-y)methyl)-1H-purine-2,6(3H,7H)-dione

##STR00375##

To a solution of3-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione(500 mg, 1.689 mmol) in DMF (10 mL) was added1-chloro-3-methoxypropan-2-ol (252 mg, 2.02 mmol) followed bypotassium carbonate (466 mg 3.37 mmol) and TBAI (59 mg 0.16 mmol).The mixture was stirred at RT under N.sub.2 overnight. The reactionmixture was quenched by water (20 mL), and then extracted with EA(3.times.10 mL). The combined organic layers were washed by thesaturated aqueous lithium chloride solution (15 mL) and brine (15mL), dried over Na.sub.2SO.sub.4 and filtered. The filtrate wasconcentrated and the residue was purified by chromatography (elutedwith DCM:MeOH=80:1) to afford1-(2-hydroxy-3-methoxypropyl)-3-methyl-7-((2-(trimethylsilyl)ethoxy)methy-l)-1H-purine-2,6(3H,7H)-dione (420 mg, 64.75% yield) as a whitesolid. Retention time (LC-MS): 1.005 min. MH.sup.+ 385.

Step 21-(3-methoxy-2-oxopropyl)-3-methyl-7-((2-(trimethylsilyl)ethoxy)met-hyl)-1H-purine-2,6(3H,7H)-dione

##STR00376##

To mixture of1-(2-hydroxy-3-methoxypropyl)-3-methyl-7-((2-(trimethylsilyl)ethoxy)methy-l)-1H-purine-2,6(3H,7H)-dione (350 mg, 0.91 mmol) in DCM (10 mL)was added Dess-Martin periodinane (578 mg, 1.365 mmol) in portionsat 0.degree. C. The mixture was stirred at RT overnight. Thereaction mixture was quenched by water (8 mL), and then extractedwith DCM (3.times.10 mL). Combined organic layers were washed bythe saturated aqueous lithium chloride solution (15 mL) and brine(15 mL), dried over Na.sub.2SO.sub.4 and filtered. The filtrate wasconcentrated and the residue was purified by chromatography (elutedwith DCM:MeOH=100:1) to afford1-(3-methoxy-2-oxopropyl)-3-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-1-H-purine-2,6(3H,7H)-dione (340 mg, 97.65% yield) as a white solid.Retention time (LC-MS): 1.127 min. MH.sup.+ 383.

Step 31-(3-methoxy-2-oxopropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione

##STR00377##

To a solution of1-(3-methoxy-2-oxopropyl)-3-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-1-H-purine-2,6(3H,7H)-dione (340 mg, 0.88 mmol) in EtOH (6 mL) wasadded concentrated hydrochloride acid (3 mL), and the mixture wasstirred at 90.degree. C. for 2 hrs. The mixture was concentrated todryness and the residue was dissolved in water (10 mL) andextracted with chloroform/iso-propanol (2/1, 15 mL.times.2). Thecombined organic layers were concentrated to dryness to give crudeproduct, which was purified by chromatography (eluted withDCM:MeOH=20:1) to afford1-(3-methoxy-2-oxopropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (140mg, 62.44% yield) as a yellow solid. Retention time (LC-MS): 0.326min. MH.sup.+ 253.

Step 4 (S)-methyl2-(1-(3-methoxy-2-oxopropyl)-3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H-)-yl)propanoate

##STR00378##

To a solution of1-(3-methoxy-2-oxopropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (140mg, 0.555 mmol) in DMF (10 mL) was added (R)-methyl2-((methylsulfonyl)oxy)propanoate (202 mg, 1.11 mmol) and potassiumcarbonate (76.7 mg 0.555). The mixture was stirred at 50.degree. C.overnight. The reaction mixture was quenched by water (10 mL), andthen extracted with EA (3.times.10 mL). The combined organic layerswere washed by the saturated aqueous lithium chloride solution (10mL) and brine (10 mL), dried over Na.sub.2SO.sub.4 and filtered.The filtrate was concentrated and the residue was purified bychromatography (eluted with DCM:MeOH=100:1) to afford (S)-methyl2-(1-(3-methoxy-2-oxopropyl)-3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H-)-yl)propanoate (140 mg, 74.55% yield) as a yellow oil. Retentiontime (LC-MS): 0.417 min. MH.sup.+ 339.

Preparation 436-(2-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)pyrazin-2--amine

##STR00379##

To a mixture of2-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-ylboronicacid (250 mg, 1.04 mmol), 6-chloropyrazin-2-amine (160 mg, 1.24mmol) in 1,4-dioxane (5 mL) and H.sub.2O (1 mL) was added potassiumcarbonate (287 mg, 2.07 mmol). After the mixture was degassed withN.sub.2 for 3 times, Pd(PPh.sub.3).sub.4 (25 mg, 0.02 mmol) wasadded under N.sub.2 and the mixture was stirred at 100.degree. C.for 3 hrs. The reaction mixture was cooled down and poured into EA.The organic phase was separated, washed with water and brine, driedover Na.sub.2SO.sub.4 and filtered. The filtrate was concentratedunder reduced pressure and the residue was purified bychromatography (eluted with DCM:MeOH=50:1) to afford6-(2-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)pyrazin-2--amine (160 mg, 53.1% yield) as a yellow solid. Retention time(LC-MS): Retention 0.623 min. MH.sup.+ 290.

Preparation 442'-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-[2,5'-bipyrimidin]-4-amin-e

##STR00380##

To a mixture of(2-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)boronicacid (250.0 mg, 1.0 mmol), 2-chloropyrimidin-4-amine (133.8 mg, 1.0mmol) in 1,4-dioxane (6 mL) and H.sub.2O (1.5 mL) was addedpotassium carbonate (286.6 mg, 2.1 mmol). After the mixture wasdegassed with N.sub.2 for 3 times, Pd(PPh.sub.3).sub.4 (59.9 mg,0.05 mmol) was added under N.sub.2 and the mixture was stirred at90.degree. C. overnight. The reaction mixture was cooled down andpoured into EA. The organic phase was separated, washed with waterand brine, dried over Na.sub.2SO.sub.4 and filtered. The filtratewas concentrated under reduced pressure and the residue waspurified by chromatography (eluted with PE:acetone=2:1) to affordthe title product (210 mg, 69.8% yield) as a white solid. Retentiontime (LC-MS): 0.422 min. MH.sup.+ 291.

Preparation 456'-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-[2,3'-bipyridin]-6-amine

##STR00381##

Step 13-(5-bromopyridin-2-yl)-6,6-difluoro-3-azabicyclo[3.1.0]hexane

##STR00382##

A sealed tube was charged with6,6-difluoro-3-azabicyclo[3.1.0]hexane hydrochloride (620 mg, 4.0mmol), 5-bromo-2-fluoropyridine (835.2 g, 4.8 mmol), NMP (5 mL) andpotassium carbonate (1.38 g, 10.0 mmol). The mixture was stirred at100.degree. C. overnight. The mixture was poured into EA. Theorganic phase was washed with water and brine, dried overNa.sub.2SO.sub.4 and filtered. The filtrate was concentrated underreduced pressure. The crude product was purified by chromatography(eluted with PE:EA=10:1) to afford3-(5-bromopyridin-2-yl)-6,6-difluoro-3-azabicyclo[3.1.0]hexane (680mg, 62.0% yield) as a white solid. Retention time (LC-MS): 1.249min. MH.sup.+ 275.

Step 2(6-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)boronicAcid

##STR00383##

To a solution of3-(5-bromopyridin-2-yl)-6,6-difluoro-3-azabicyclo[3.1.0]hexane(900.0 mg, 3.3 mmol) and (.sup.iPrO).sub.3B (1.14 mL, 4.9 mmol) inTHF (10 mL) was added n-BuLi (2.67 mL, 1.6 M in hexane, 6.6 mmol)drop-wise at -78.degree. C. The mixture was stirred at the sametemperature for 1 h. The reaction was quenched with water. Thesolvent was removed under reduced pressure and the aqueous layerwas extracted with Ether (2.times.5 mL). The aqueous layer was thenadjusted to pH 8 with 1N HCl and extracted with EA (3.times.30 mL).Combined organic layers were washed with brine, dried overNa.sub.2SO.sub.4, and concentrated to give the title product (780mg, 98.9% yield) as a white solid. Retention time (LC-MS): 0.347min. MH.sup.+ 241.

Step 36'-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-[2,3'-bipyridin]-6--amine

##STR00384##

To a mixture of(6-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)boronicacid (300.0 mg, 1.25 mmol), 6-bromopyridin-2-amine (215.0 mg, 1.25mmol) in 1,4-dioxane (5 mL) and H.sub.2O (1 mL) was added potassiumcarbonate (345.5 mg, 2.5 mmol). After the mixture was degassed withN.sub.2 for 3 times, Pd(PPh.sub.3).sub.4 (72.2 mg, 0.06 mmol) wasadded under N.sub.2 and the mixture was stirred at 90.degree. C.for 2 hrs. The reaction mixture was cooled down and poured into EA.The organic phase was separated, washed with water and brine, driedover Na.sub.2SO.sub.4 and filtered. The filtrate was concentratedunder reduced pressure and the residue was purified bychromatography (eluted with PE:EA=1:1) to afford the title product(280 mg, 77.8% yield) as a white solid. Retention time (LC-MS):0.321 min. MH.sup.+ 289.

Preparation 462-(6-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)pyrimidin-4--amine

##STR00385##

To a mixture of(6-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)boronicacid (240.0 mg, 1.0 mmol), 2-chloropyrimidin-4-amine (129.0 mg, 1.0mmol) in 1,4-dioxane (5 mL) and H.sub.2O (1 mL) was added potassiumcarbonate (276.4 mg, 2.0 mmol). After the mixture was degassed withN.sub.2 for 3 times, Pd(PPh.sub.3).sub.4 (57.8 mg, 0.05 mmol) wasadded under N.sub.2 and the mixture was stirred at 90.degree. C.for 3 hrs. The reaction mixture was cooled down and poured into EA.The organic phase was separated, washed with water and brine, driedover Na.sub.2SO.sub.4 and filtered. The filtrate was concentratedunder reduced pressure and the residue was purified bychromatography (eluted with PE:EA=1:1) to afford the title product(140 mg, 58.1% yield) as a white solid. Retention time (LC-MS):0.365 min. MH.sup.+ 290.

Preparation 47(S)-2-(3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)-N-(6-(2-(trifluo-romethyl)pyrimidin-5-yl)pyridin-2-yl)propanamide

##STR00386##

To a mixture of6-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-2-amine (200 mg, 0.83mmol) in DCM (10 mL) was added trimethylaluminium (3.32 mL, 3.32mmol) at 0.degree. C. The mixture was stirred at 0.degree. C. for30 min, followed by (S)-methyl2-(3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)propanoate (210mg, 0.83 mmol) was added. The final mixture was stirred at30.degree. C. overnight. The mixture was concentrated under reducedpressure directly and the residue was purified by chromatography(DCM:MeOH=20:1) to afford(S)-2-(3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)-N-(6-(2-(trifluo-romethyl)pyrimidin-5-yl)pyridin-2-yl)propanamide (150 mg, 39%yield, ee: 99%) as a white solid. Retention time (LC-MS): 1.796min. MH.sup.+ 460. 1H NMR (400 MHz, DMSO) .delta. 11.25 (s, 1H),9.68 (s, 2H), 8.33 (s, 1H), 8.18-7.87 (m, 3H), 5.78 (d, J=10.4 Hz,1H), 3.39 (s, 3H), 1.86 (d, J=7.3 Hz, 3H), 1.24 (s, 1H).

Preparation 48(2S)--N-(2-(2-(3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)thiazol-4-yl)--2-(3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)propanamide

##STR00387##

To a solution of(S)-2-(3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)propanoicacid (275 mg, 1.16 mmol) and2-(2-(3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)thiazol-4-amine(300 mg, 1.16 mmol) in DCM (20 mL) was added HOAt (157 mg, 1.16mmol) at RT. The reaction mixture was cooled under ice-water bathto 0.degree. C., and pyridine (0.19 mL, 2.31 mmol) was addeddrop-wise followed by drop-wise addition of DIC (0.27 mL, 1.74mmol) under N.sub.2 protection. The ice-water bath was removedafter the addition and the mixture was stirred at 30.degree. C.overnight. The reaction mixture was washed with water (20 mL). TheDCM layer was separated, and the aqueous layer was extracted withDCM (20 mL.times.2). The combined organic layers were dried overNa.sub.2SO.sub.4, filtered, concentrated under reduced pressuredirectly and the residue was purified by chromatography(DCM:MeOH=20:1) to afford(2S)--N-(2-(2-(3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)thiazol-4-yl)--2-(3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)propanamide(500 mg, 90% yield, ee>98%) as a white solid. Retention time(LC-MS): 4.217 min. MH.sup.+ 479.

Preparation 496-(2-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)pyrazin-2--amine

##STR00388##

To a mixture of2-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-ylboronicacid (300 mg, 1.5 mmol) and 6-bromopyrazin-2-amine (238 mg, 1.37mmol) in toluene/ethanol (4 mL/2 mL) was added aqueousNa.sub.2CO.sub.3 solution (1 mL, 2M) and the mixture was degassedunder N.sub.2 for three times. To the above mixture,6-tetrakis(triphenylphosphine)palladium (30 mg, 0.04 mmol) wereadded under N.sub.2 and the reaction mixture was stirred at100.degree. C. under N.sub.2 for 2 h. The mixture was diluted withDCM, washed with brine, dried over Na.sub.2SO.sub.4, concentratedand purified by chromatography (eluted with PE:EA=2:1) to give6-(2-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)pyrazin-2--amine (210 mg, 58.1% yield) as a white solid. Retention time(LC-MS): 1.359 min. MH.sup.+ 291.

Preparation 506-(6-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)pyrazin-2-a-mine

##STR00389##

To a mixture of6-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-ylboronicacid (220 mg, 0.9 mmol), 6-chloropyrazin-2-amine (190 mg, 1.1 mmol)in 1,4-dioxane (5 mL) and H.sub.2O (1 mL) was added potassiumcarbonate (380 mg, 2.8 mmol). After the mixture was degassed withN.sub.2 for three times, Pd(PPh.sub.3).sub.4 (23.0 mg, 0.02 mmol)was added under N.sub.2 and the mixture was stirred at 100.degree.C. for 4 hrs. The reaction mixture was cooled down and diluted EA(15 mL). The mixture was washed with water and brine, dried overNa.sub.2SO.sub.4 and filtered. The filtrate was concentrated underreduced pressure and the residue was purified by chromatography(eluted with PE:EA=5:1) to afford6-(6-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)pyrazin-2-a-mine (160 mg, 60.3% yield) as a light yellow solid. Retention time(LC-MS): 0.509 min. MH.sup.+ 290.

Preparation 516-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-amine

##STR00390##

Step 1 6-aminopicolinonitrile

##STR00391##

In a microwave reaction tube containing 6-bromopyridin-2-amine (1g, 5.8 mmol), Zn(CN).sub.2 (1.4 g, 11.6 mmol) and NMP (10 mL) wasadded Pd(PPh.sub.3).sub.4 (0.67 g, 0.58 mmol). The mixture washeated in a Biotage Microwave Initiator device at 150.degree. C.for 30 min. The mixture was poured into EA. The organic phase waswashed with water and brine, dried over Na.sub.2SO.sub.4 andfiltered. The filtrate was concentrated under reduced pressure. Thecrude product was purified by chromatography (eluted withPE:EA=5:1) to afford 6-aminopicolinonitrile (600 mg, 86.96% yield)as a white solid. Retention time (LC-MS): 0.378 min. MH.sup.+120.

Step 2 6-amino-N-hydroxypicolinimidamide

##STR00392##

To a solution of 6-aminopicolinonitrile (600 mg, 5.1 mmol) inethanol (6 mL) and water (3 mL) was added hydroxylaminehydrochloride (711 mg, 10.2 mmol) and sodium carbonate (1.6 g, 15.3mmol) and the mixture was stirred at 85.degree. C. for 1 h. Themixture was concentrated under reduced pressure, the residue waswashed with water and extracted with chloroform/isopropanol (3:1).The organic layer was dried over Na.sub.2SO.sub.4, and evaporatedto afford 6-amino-N-hydroxypicolinimidamide (500 mg, 72.67% yield)as a yellow solid. Retention time (LC-MS): 0.348 min. MH.sup.+153.

Step 36-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-amine

##STR00393##

To a solution of 6-amino-N-hydroxypicolinimidamide (250 mg, 1.85mmol) in THF (5 mL) was added drop-wise trifluoroacetic anhydride(0.05 mL, 3.70 mmol) at 0.degree. C. and the mixture was heated at60.degree. C. overnight. The reaction mixture was concentrated,diluted with water, extracted with EA (3.times.10 mL). The organiclayers were washed with brine, dried over sodium sulfate andconcentrated. The crude product obtained was purified bychromatography (eluted with PE:EA=5:1) to afford6-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)pyridin-2-amine (80 mg,18.82% yield) as a white solid. Retention time (LC-MS): 0.953 min.MH.sup.+ 231.

Preparation 522-(6-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)thiazol-4-a-mine

##STR00394##

Step 1N-(2-(6-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)th-iazol-4-yl)-2,2,2-trifluoroacetamide

##STR00395##

To a mixture of(6-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)boronicacid (240.0 mg, 1.0 mmol),N-(2-bromothiazol-4-yl)-2,2,2-trifluoroacetamide (273.9 mg, 1.0mmol) in 1,4-dioxane (8 mL) and H.sub.2O (2 mL) was addedCs.sub.2CO.sub.3 (978.0 mg, 3.0 mmol). After the mixture wasdegassed with N.sub.2 for 3 times, Pd(PPh.sub.3).sub.4 (57.8 mg,0.05 mmol) was added under N.sub.2 and the mixture was stirred at90.degree. C. for 2 hrs. The reaction mixture was cooled down andpoured into EA. The organic phase was separated, washed with waterand brine, dried over Na.sub.2SO.sub.4 and filtered. The filtratewas concentrated under reduced pressure and the residue waspurified by chromatography (eluted with PE:EA=10:1) to affordN-(2-(6-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)thiazol--4-yl)-2,2,2-trifluoroacetamide (150 mg, 46.1% yield) as a whitesolid. Retention time (LC-MS): 1.447 min. MH.sup.+ 391.

Step 22-(6-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)thiaz-ol-4-amine

##STR00396##

A mixture ofN-(2-(6-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)thiazol--4-yl)-2,2,2-trifluoroacetamide (150.0 mg, 0.38 mmol) in MeOH (5 mL)and 50% aqueous NaOH solution (0.5 mL) was stirred at 60.degree. C.overnight. The solvent was removed. The residue was purified bycolumn chromatography (eluted with PE:EA=1:1) to afford2-(6-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)thiazol-4-a-mine (100 mg, 88.4% yield) as light yellow solid. Retention time(LC-MS): 0.844 min. MH.sup.+ 295.

Preparation 532-(5-methyl-6-(trifluoromethyl)pyridin-3-yl)thiazol-4-amine

##STR00397##

Step 1N-(2-(5-methyl-6-(trifluoromethyl)pyridin-3-yl)thiazol-4-yl)

##STR00398##

To a mixture of (5-methyl-6-(trifluoromethyl)pyridin-3-yl)boronicacid (451.0 mg, 2.2 mmol), N-(2-bromothiazol-4-yl)acetamide (483.8mg, 2.2 mmol) in 1,4-dioxane (12 mL) and H.sub.2O (3 mL) was addedCs.sub.2CO.sub.3 (1.8 g, 5.5 mmol). After the mixture was degassedwith N.sub.2 for 3 times, Pd(PPh.sub.3).sub.4 (127.1 mg, 0.11 mmol)was added under N.sub.2 and the mixture was stirred at 90.degree.C. for 3 hrs. The reaction mixture was cooled down and poured intoEA. The organic phase was separated, washed with water and brine,dried over Na.sub.2SO.sub.4 and filtered. The filtrate wasconcentrated under reduced pressure and the residue was purified bychromatography (eluted with PE:EA=3:1) to afford the title product(500 mg, 75.7% yield) as light yellow solid. Retention time(LC-MS): 1.331 min. MH.sup.+ 302.

Step 22-(5-methyl-6-(trifluoromethyl)pyridin-3-yl)thiazol-4-amine

##STR00399##

A mixture ofN-(2-(5-methyl-6-(trifluoromethyl)pyridin-3-yl)thiazol-4-yl)acetamide(500.0 mg, 1.7 mmol) in MeOH (10 mL) and 50% NaOH (0.8 mL) wasstirred at 85.degree. C. overnight. The solvent was removed. Theresidue was purified by column chromatography (eluted withPE:EA=1:1) to afford the title product (360 mg, 83.6% yield) as awhite solid. Retention time (LC-MS): 1.243 min. MH.sup.+ 260.

Preparation 542-(5-methyl-6-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-amine

##STR00400##

To a mixture of 5-methyl-6-(trifluoromethyl)pyridin-3-ylboronicacid (50 mg, 0.24 mmol), 2-chloropyrimidin-4-amine (35 mg, 0.27mmol) in 1,4-dioxane (5 mL) and H.sub.2O (1 mL) was addedNa.sub.2CO.sub.3 (78 mg, 0.73 mmol). After the mixture was degassedwith N.sub.2 for 3 times, Pd(PPh.sub.3).sub.4 (5.0 mg, 0.01 mmol)was added under N.sub.2 and the mixture was stirred at 100.degree.C. overnight. The reaction mixture was cooled down and poured intoEA. The organic phase was separated, washed with water and brine,dried over Na.sub.2SO.sub.4 and filtered. The filtrate wasconcentrated under reduced pressure and the residue was purified bychromatography (eluted with PE:EA=5:1) to afford2-(5-methyl-6-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-amine (58mg, 93.5% yield) as light yellow solid. Retention time (LC-MS):0.522 min. MH.sup.+ 255.

Preparation 555'-(3-azabicyclo[3.1.0]hexan-3-yl)-2,2'-bipyrazin-6-amine

##STR00401##

Step 1 3-(5-bromopyrazin-2-yl)-3-azabicyclo[3.1.0]hexane

##STR00402##

To a solution of 2,5-dibromopyrazine (1 g, 4.2 mmol) in DMSO (20mL) was added 3-azabicyclo[3.1.0]hexane hydrochloride (0.6 g, 5.04mmol) followed by Cs.sub.2CO.sub.3 and the mixture was stirred at100.degree. C. in an sealed tube for 2 hrs. The mixture was cooledand diluted with EA (50 mL) and washed with water, brinesuccessively, dried and concentrated to give crude product, whichwas purified by chromatography (PE/EA=5:1) to give3-(5-bromopyrazin-2-yl)-3-azabicyclo[3.1.0]hexane (560 mg, 55.5%yield) as yellow solid. Retention time (LC-MS): 1.468 min. MH.sup.+240.

Step 25'-(3-azabicyclo[3.1.0]hexan-3-yl)-2,2'-bipyrazin-6-amine

##STR00403##

A mixture of 3-(5-bromopyrazin-2-yl)-3-azabicyclo[3.1.0]hexane (400mg, 1.66 mmol), 6-chloropyrazin-2-amine (1.08 g, 8.33 mmol), LiCl(84.35 mg, 1.99 mmol) and 2,6-di-tert-butyl-4-methylphenol (36.6mg, 0.166 mmol) in 1,4-dioxane (25 mL) was degassed under N.sub.2for three times and terakis(triphenylphosphine)palladium (153 mg,0.133 mmol) was added under N.sub.2 atmosphere. The mixture wasdegassed again and Hexa-n-butyldizinn (1.15 g, 1.99 mmol) wasadded, the reaction mixture was stirred under N.sub.2 at110.degree. C. overnight. The mixture was concentrated to drynessand the crude product was purified column chromatography(DCM/MeOH=50:1 to 20:1) to give5'-(3-azabicyclo[3.1.0]hexan-3-yl)-2,2'-bipyrazin-6-amine (140 mg.33.2% yield) as brown solid. Retention time (LC-MS): 1.023 min.MH.sup.+ 255.

Preparation 566-(5-(3-azabicyclo[3.1.0]hexan-3-yl)pyrazin-2-yl)pyridin-2-amine

##STR00404##

Step 1 2-bromo-6-(2,5-dimethyl-1H-pyrrol-1-yl)pyridine

##STR00405##

To a mixture of 6-bromopyridin-2-amine (5 g, 28.7 mmol) andacetonylacetone (4.1 mL, 34.7 mmol) in toluene (30 mL) was addedp-toluenesulfonic acid (50 mg, 0.28 mmol) and the mixture washeated in a Dean-Stark apparatus for 2 hrs. The mixture was cooledto r.t. and diluted with EA (50 mL), washed with saturated aq.NaHCO3, brine successively, dried and concentrated to give crudeproduct, which was purified by chromatography (PE/EA=20:1) to give2-bromo-6-(2,5-dimethyl-1H-pyrrol-1-yl)pyridine (6.8 g, 94.1%yield) as yellow solid. Retention time (LC-MS): 1.575 min. MH.sup.+251.

Step 23-(5-(6-(2,5-dimethyl-1H-pyrrol-1-yl)pyridin-2-yl)pyrazin-2-yl)-3-a-zabicyclo[3.1.0]hexane

##STR00406##

A mixture of 3-(5-bromopyrazin-2-yl)-3-azabicyclo[3.1.0]hexane (240mg, 1 mmol), 2-bromo-6-(2,5-dimethyl-1H-pyrrol-1-yl)pyridine (250mg, 1 mmol), LiCl (42.2 mg, 1 mmol) and2,6-di-tert-butyl-4-methylphenol (50 mg, 0.227 mmol) in 1,4-dioxane(10 mL) was degassed under N.sub.2 for three times andterakis(triphenylphosphine)palladium (92.4 mg, 0.08 mmol) was addedunder N.sub.2 atmosphere. The mixture was degassed again andHexa-n-butyldizinn (696 mg, 1.2 mmol) was added, the reactionmixture was stirred under N.sub.2 at 110.degree. C. overnight. Themixture was concentrated to dryness and the crude product waspurified column chromatography (DCM/MeOH=80:1 to 50:1) to give3-(5-(6-(2,5-dimethyl-1H-pyrrol-1-yl)pyridin-2-yl)pyrazin-2-yl)-3-azabicy-clo[3.1.0]hexane (130 mg. 39.2% yield) as brown solid. Retentiontime (LC-MS): 1.905 min. MH.sup.+ 332.

Step 36-(5-(3-azabicyclo[3.1.0]hexan-3-yl)pyrazin-2-yl)pyridin-2-amine

##STR00407##

To a solution of3-(5-(6-(2,5-dimethyl-1H-pyrrol-1-yl)pyridin-2-yl)pyrazin-2-yl)-3-azabicy-clo[3.1.0]hexane (130 mg, 0.392 mmol) in EtOH (5 mL) was addedconcentrated aq. HCl (1 mL) and the mixture was heated to refluxfor 2 hrs. The mixture was concentrated to dryness and dissolved inDCM (10 mL), washed with saturated aq. NaHCO.sub.3, brinesuccessively, dried and concentrated to give crude product, whichwas purified column chromatography (DCM/MeOH=20:1) to give6-(5-(3-azabicyclo[3.1.0]hexan-3-yl)pyrazin-2-yl)pyridin-2-amine(56 mg, 59.4 yield) as dark brown solid. Retention time (LC-MS):0.890 min. MH.sup.+ 254.

Preparation 57 2-(5-chloro-6-methylpyridin-3-yl)thiazol-4-amine

##STR00408##

Step 1 5-chloro-6-methylpyridin-3-ylboronic Acid

##STR00409##

To a solution of 5-bromo-3-chloro-2-methylpyridine (1.03 g, 5 mmol)and (i-PrO).sub.3B (2.24 mL, 10 mmol) in THF (10 mL) was addedn-BuLi (3.75 mL, 1.6 M in hexane, 6 mmol) drop-wise at -78.degree.C. After the mixture was stirred at -78.degree. C. for 1 hr, it wasquenched with water. The solvent was removed under reduced pressureand the aqueous layer was washed with Ether (2.times.10 mL). Theaqueous layer was then adjusted to pH.about.8 with 1N aqueous HClsolution and extracted with EA (3.times.50 mL). The combinedorganic layers were dried over Na2SO4, and concentrated to give5-chloro-6-methylpyridin-3-ylboronic acid (650 mg, 76% yield) as awhite solid. Retention time (LC-MS): Retention 0.458 min. MH.sup.+172

Step 2 2-(5-chloro-6-methylpyridin-3-yl)thiazol-4-amine

##STR00410##

To a mixture of 5-chloro-6-methylpyridin-3-ylboronic acid (600 mg,3.5 mmol), N-(2-bromothiazol-4-yl)-2,2,2-trifluoroacetamide (1.06g, 3.85 mmol) in EtOH (18 mL), H.sub.2O (9 mL) and toluene (36 mL)was added Na.sub.2CO.sub.3 (1.16 g, 10.5 mmol). After the mixturewas degassed with N.sub.2 for 3 times, Pd(PPh.sub.3).sub.4 (203 mg,1.75 mmol) was added under N.sub.2 and the mixture was stirred at90.degree. C. overnight. The reaction mixture was cooled down andpoured into EA. The organic phase was separated, washed with waterand brine, dried over Na.sub.2SO.sub.4 and filtered. The filtratewas concentrated under reduced pressure and the residue waspurified by chromatography (eluted with PE:Acetone=10:1) to afford2-(5-chloro-6-methylpyridin-3-yl)thiazol-4-amine (120 mg, 15%yield) as yellow solid. Retention time (LC-MS): Retention 1.225min. MH.sup.+ 226.

Preparation 58 2-(5-fluoro-6-methylpyridin-3-yl)thiazol-4-amine

##STR00411##

Step 1 (6-chloro-5-fluoropyridin-3-yl)boronic Acid

##STR00412##

To a solution of 5-bromo-2-chloro-3-fluoropyridine (1 g, 4.78 mmol)and triisopropyl borate (2.2 mL, 9.56 mmol) in THF (10 mL) wasadded drop-wise n-butyllithium (3.6 mL, 1.6 M, 5.95 mmol) at-78.degree. C. and stirred for 3 hrs. Then the mixture was pouredinto H.sub.2O and THF was evaporated. The H.sub.2O layer wasadjusted to pH 14 with NaOH (1 M) and extracted with Ether. Thenthe H.sub.2O layer was adjusted to pH 5 with HCl (6 M) andextracted with EA. The organic layer was separated, washed withwater and brine, dried over Na2SO4, and concentrated to give(6-chloro-5-fluoropyridin-3-yl)boronic acid (600 mg, 71.8% yield)as a white solid. Retention time (LC-MS): 0.635 min. MH.sup.+178.

Step 2N-(2-(6-chloro-5-fluoropyridin-3-yl)thiazol-4-yl)acetamide

##STR00413##

To a solution of N-(2-bromothiazol-4-yl)acetamide (750 mg, 3.41mmol) (6-chloro-5-fluoropyridin-3-yl)boronic acid (600 mg, 3.41mmol) in 1,4-dioxane (10 mL) and H.sub.2O (2.5 mL) was addedCs.sub.2CO.sub.3 (2.2 g, 6.80 mmol) and the mixture was degassedwith N.sub.2 for three times Pd(PPh.sub.3).sub.4 (345 mg, 0.34mmol) was added and the reaction mixture was stirred at 100.degree.C. under N.sub.2 overnight. The mixture was cooled down and pouredinto EA. The organic phase was separated, washed with water andbrine, dried over Na.sub.2SO.sub.4 and filtered. The filtrate wasconcentrated under reduced pressure. The filtrate was concentratedand the residue was purified by chromatography (eluted withPE:EA=8:1) to affordN-(2-(6-chloro-5-fluoropyridin-3-yl)thiazol-4-yl)acetamide (800 mg,86.6% yield) as yellow solid. Retention time (LC-MS): 1.194 min.MH.sup.+ 272.

Step 3N-(2-(5-fluoro-6-methylpyridin-3-yl)thiazol-4-yl)acetamide

##STR00414##

To a solution ofN-(2-(6-chloro-5-fluoropyridin-3-yl)thiazol-4-yl)acetamide (700 mg,2.58 mmol), trimethylboroxine (0.40 mL, 2.84 mmol) in 1,4-dioxane(10 mL) and H.sub.2O (1 mL) was added potassium carbonate (712 mg,5.16 mmol) and the mixture was degassed with N.sub.2 for threetimes Pd(PPh.sub.3).sub.4 (300 mg, 0.26 mmol) was added and thereaction mixture was stirred at 100.degree. C. under N.sub.2 for 4hrs. The mixture was cooled down and poured into EA. The organicphase was separated, washed with water and brine, dried overNa.sub.2SO.sub.4 and filtered. The filtrate was concentrated underreduced pressure. The filtrate was concentrated and the residue waspurified by chromatography (eluted with PE:EA=3:1) to affordN-(2-(5-fluoro-6-methylpyridin-3-yl)thiazol-4-yl)acetamide (370 mg,57.18% yield) as a white solid. Retention time (LC-MS): 1.252 min.MH.sup.+ 252.

Step 4 2-(5-fluoro-6-methylpyridin-3-yl)thiazol-4-amine

##STR00415##

To a solution ofN-(2-(5-fluoro-6-methylpyridin-3-yl)thiazol-4-yl)acetamide (370 mg,1.47 mmol) in MeOH (10 mL) was added 50% NaOH (2 mL). The mixturewas stirred at 80.degree. C. for 2 hrs. The reaction mixture wasconcentrated and extracted with DCM. The organic phase wasseparated, washed with brine, dried over Na.sub.2SO.sub.4 andfiltered. The filtrate was concentrated under reduced pressure toafford 2-(5-fluoro-6-methylpyridin-3-yl)thiazol-4-amine (40 mg,yield 58.82%) as a yellow solid. Retention time (LC-MS): 1.068 min.MH.sup.+ 210.

Preparation 59 (S)-methyl3-(6-aminopyridin-2-yl)-1,2,4-oxadiazol-5(2H)-one

##STR00416##

To a solution of 6-amino-N-hydroxypicolinimidamide (300 mg, 1.97mmol) in THF (10 mL) was added CDI (447.60 mg, 2.76 mmol) at RT.The reaction was stirred at RT for 2 h, then the mixture was cooledto 0.degree. C. and DBU (0.41 mL, 2.76 mmol) was added. After thereaction was stirred at RT overnight and water was added. The solidwas filtered off and washed with aq. HCl (0.5M), the aqueous wasextracted with EA (3.times.50 mL). Combined organic layers weredried over Na.sub.2SO.sub.4 and filtered. The filtrate wasconcentrated under reduced pressure to afford3-(6-aminopyridin-2-yl)-1,2,4-oxadiazol-5(2H)-one (300 mg, 85.4%yield) as a a yellow solid. Retention time (LC-MS): 0.694 min.MH.sup.+ 179.

Preparation 606'-methyl-5'-(trifluoromethyl)-[2,3'-bipyridin]-6-amine

##STR00417##

To a mixture of (6-methyl-5-(trifluoromethyl)pyridin-3-yl)boronicacid (205.0 mg, 1.0 mmol), 6-bromopyridin-2-amine (172.0 mg, 1.0mmol) in 1,4-dioxane (4 mL) and H.sub.2O (1 mL) was added potassiumcarbonate (276.4 mg, 2.0 mmol). After the mixture was degassed withN.sub.2 for 3 times, Pd(PPh.sub.3).sub.4 (57.8 mg, 0.05 mmol) wasadded under N.sub.2 and the mixture was stirred at 90.degree. C.for 2 hrs. The reaction mixture was cooled down and diluted withEA, washed with water and brine, dried over Na.sub.2SO.sub.4 andfiltered. The filtrate was concentrated under reduced pressure andthe residue was purified by chromatography (eluted with PE:EA=1:1)to afford 6'-methyl-5'-(trifluoromethyl)-[2,3'-bipyridin]-6-amine(180 mg, 71.1% yield) as a white solid. Retention time (LC-MS):0.499 min. MH.sup.+ 254.

Preparation 612-(6-methyl-5-(trifluoromethyl)pyridin-3-yl)thiazol-4-amine

##STR00418##

Step 1N-(2-(6-methyl-5-(trifluoromethyl)pyridin-3-yl)thiazol-4-yl)acetami-de

##STR00419##

To a mixture of (6-methyl-5-(trifluoromethyl)pyridin-3-yl)boronicacid (451.0 mg, 2.2 mmol), N-(2-bromothiazol-4-yl)acetamide (483.8mg, 2.2 mmol) in 1,4-dioxane (4 mL) and H.sub.2O (1 mL) was addedCs.sub.2CO.sub.3 (1.79 g, 5.5 mmol). After the mixture was degassedwith N.sub.2 for 3 times, Pd(PPh.sub.3).sub.4 (127.1 mg, 0.11 mmol)was added under N.sub.2 and the mixture was stirred at 100.degree.C. for 2 hrs. The reaction mixture was cooled down and poured intoEA. The organic phase was separated, washed with water and brine,dried over Na.sub.2SO.sub.4 and filtered. The filtrate wasconcentrated under reduced pressure and the residue was purified bychromatography (eluted with PE:EA=4:1) to affordN-(2-(6-methyl-5-(trifluoromethyl)pyridin-3-yl)thiazol-4-yl)acetamide(550 mg, 83.0% yield) as a white solid. Retention time (LC-MS):1.458 min. MH.sup.+ 302.

Step 22-(6-methyl-5-(trifluoromethyl)pyridin-3-yl)thiazol-4-amine

##STR00420##

A mixture ofN-(2-(6-methyl-5-(trifluoromethyl)pyridin-3-yl)thiazol-4-yl)acetamide(550.0 mg, 1.8 mmol) in MeOH (8 mL) and 50% aqueous NaOH solution(1.0 mL) was stirred at 80.degree. C. for 4 hrs. The solvent wasremoved. The residue was purified by column chromatography (elutedwith PE:EA=1:1) to afford2-(6-methyl-5-(trifluoromethyl)pyridin-3-yl)thiazol-4-amine (420mg, 88.4% yield) as a white solid. Retention time (LC-MS): 1.343min. MH.sup.+ 260.

Preparation 62(S)-2-(1-(3-methoxy-2-oxopropyl)-3-methyl-2,6-dioxo-2,3-dihydro-1H-purin--7(6H)-yl)propanoic Acid

##STR00421##

To a solution of (S)-methyl2-(1-(3-methoxy-2-oxopropyl)-3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H-)-yl)propanoate (300 mg, 0.887 mmol) in dioxane (5 mL) was addedconcentrated aq. HCl (6 M, 5 mL) and the mixture was heated toreflux for 2 hrs. The mixture was concentrated to dryness anddissolved in DCM (10 mL), washed with saturated aq. NaHCO.sub.3,brine successively, dried and concentrated to give crude product,which was purified column chromatography (PE/EA=1:2) to give(S)-2-(1-(3-methoxy-2-oxopropyl)-3-methyl-2,6-dioxo-2,3-dihydro-1H-purin--7(6H)-yl)propanoic acid (260 mg, 93% yield) as a yellow solid.Retention time (LC-MS): 0.385 min, MH.sup.+ 324.

Preparation 63(S)-2-(3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)-N-(2-(5-methyl-6--(trifluoromethyl)pyridin-3-yl)thiazol-4-yl)propanamide

##STR00422##

To a solution of(S)-2-(3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)propanoicacid (73 mg, 0.308 mmol) and2-(5-methyl-6-(trifluoromethyl)pyridin-3-yl)thiazol-4-amine (80 mg,0.308 mmol) in DCM (2 mL) was added HOAt (42 mg, 0.308 mmol) at RT.The reaction mixture was cooled under ice-water bath to 0.degree.C., and pyridine (0.07 mL, 0.925 mmol) was added drop-wise followedby drop-wise addition of DIC (0.07 mL, 0.462 mmol) under N.sub.2protection. The ice-water bath was removed after the addition andthe mixture was stirred at 30.degree. C. overnight. The reactionmixture was washed with water (2 mL). The organic layer wasseparated, and the aqueous layer was extracted with DCM (2mL.times.2). The combined organic layers were dried overNa.sub.2SO.sub.4, filtered and concentrated to dryness to givecrude product, which was purified by chromatography (DCM:MeOH=20:1)to afford(S)-2-(3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)-N-(2-(5-methyl-6--(trifluoromethyl)pyridin-3-yl)thiazol-4-yl)propanamide (130 mg,91% yield) as a white solid. Retention time (LC-MS): 3.042 min,MH.sup.+ 465.

Preparation 646-(6-methyl-5-(trifluoromethyl)pyridin-3-yl)pyrazin-2-amine

##STR00423##

To a mixture of 6-methyl-5-(trifluoromethyl)pyridin-3-ylboronicacid (200.0 mg, 1.0 mmol), 6-chloropyrazin-2-amine (130.0 mg, 1.0mmol) in 1,4-dioxane (8 mL) and H.sub.2O (2 mL) was added potassiumcarbonate (346.0 mg, 2.5 mmol). After the mixture was degassed withN.sub.2 for 3 times, Pd(PPh.sub.3).sub.4 (11.5 mg, 0.01 mmol) wasadded under N.sub.2 and the mixture was stirred at 100.degree. C.for 3 hrs. The reaction mixture was cooled down and poured into EA.The organic phase was separated, washed with water and brine, driedover Na.sub.2SO.sub.4 and filtered. The filtrate was concentratedunder reduced pressure and the residue was purified bychromatography (eluted with PE:EA=5:1) to afford6-(6-methyl-5-(trifluoromethyl)pyridin-3-yl)pyrazin-2-amine (178mg, 69.78% yield) as a yellow solid. Retention time (LC-MS): 1.058min. MH.sup.+ 255.

Preparation 656-(6-methyl-5-(trifluoromethyl)pyridin-3-yl)pyrazin-2-amine

##STR00424##

To a mixture of 6-methyl-5-(trifluoromethyl)pyridin-3-ylboronicacid (359.0 mg, 1.93 mmol), 2-chloropyrimidin-4-amine (250.0 mg,1.93 mmol) in 1,4-dioxane (8 mL) and H.sub.2O (2 mL) was addedNa.sub.2CO.sub.3 (465.0 mg, 4.4 mmol). After the mixture wasdegassed with N.sub.2 for 3 times, Pd(PPh.sub.3).sub.4 (21.5 mg,0.019 mmol) was added under N.sub.2 and the mixture was stirred at100.degree. C. for 3 hrs. The reaction mixture was cooled down andpoured into EA. The organic phase was separated, washed with waterand brine, dried over Na.sub.2SO.sub.4 and filtered. The filtratewas concentrated under reduced pressure and the residue waspurified by chromatography (eluted with PE:EA=5:1) to afford2-(6-methyl-5-(trifluoromethyl)pyridin-3-yl)pyrimidin-4-amine (330mg, 73.99% yield) as a yellow solid. Retention time (LC-MS): 0.812min. MH.sup.+ 255.

Preparation 662-(8-((tert-butyldimethylsilyloxy)methyl)-3-methyl-2,6-dioxo-1-(2-oxobuty-l)-2,3-dihydro-1H-purin-7(6H)-yl)-N-(6'-(trifluoromethyl)-2,3'-bipyridin-6--yl)propanamide

##STR00425##

Step 18-(hydroxymethyl)-3-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-1H--purine-2,6(3H,7H)-dione

##STR00426##

To a mixture of8-(hydroxymethyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (2.0 g, 10.2mmol), potassium carbonate (4.23 g, 30.59 mmol) in DMF (40 mL) wasadded 2-(trimethylsilyl)ethoxymethyl chloride (1.8 mL, 10.2 mmol)dropwise at 0.degree. C. The mixture was stirred at 0.degree. C.for 10 min and RT overnight. The reaction mixture was quenched bywater (20 mL), and then extracted with EA (3.times.20 mL). Thecombined organic layers were washed with saturated aqueous LiClsolution (15 mL) and brine (15 mL), dried over Na.sub.2SO.sub.4 andfiltered. The filtrate was concentrated to get8-(hydroxymethyl)-3-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine--2,6(3H,7H)-dione (1.6 g, yield 48%) as a yellow solid. Retentiontime (LC-MS): 1.210 min. MH.sup.+ 327.

Step 28-(hydroxymethyl)-3-methyl-1-(2-oxobutyl)-7-((2-(trimethylsilyl)eth-oxy)methyl)-1H-purine-2,6(3H,7H)-dione

##STR00427##

To a solution of8-(hydroxymethyl)-3-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine--2,6(3H,7H)-dione (300 mg, 0.919 mmol) in DMF (300 mL) was addedpotassium carbonate (254 mg 1.84 mmol), TBAI (30 mg 0.081 mmol)followed by dropwise addition of 1-bromobutan-2-one (166 mg, 1.1mmol), the mixture was stirred at RT for 2 hrs. The reactionmixture was quenched by water (20 mL), and then extracted with EA(3.times.5 mL). The combined organic layers were washed withsaturated aqueous LiCl solution (15 mL) and brine (15 mL), driedover Na.sub.2SO.sub.4 and filtered. The filtrate was concentratedto give a residue, which was purified with column chromatography(eluted with DCM:MeOH=40:1) to afford8-(hydroxymethyl)-3-methyl-1-(2-oxobutyl)-7-((2-(trimethylsilyl)ethoxy)me-thyl)-1H-purine-2,6(3H,7H)-dione (350 mg, yield 96%) as a brownsolid. Retention time (LC-MS): 1.477 min. MH.sup.+ 396.

Step 38-(hydroxymethyl)-3-methyl-1-(2-oxobutyl)-1H-purine-2,6(3H,7H)-dion-e

##STR00428##

To a solution of8-(hydroxymethyl)-3-methyl-1-(2-oxobutyl)-7-((2-(trimethylsilyl)ethoxy)me-thyl)-1H-purine-2,6(3H,7H)-dione (300 mg, 2.3 mmol) in EtOH (5 mL)was added conc. hydrochloride acid (2 mL) and the mixture wasstirred at 90.degree. C. for 2 hrs. The mixture was cooled to RTand concentrated to one third volume. The mixture was neutralizedwith 1N aqueous NaOH solution at 0.degree. C. and extracted with EA(3.times.5 mL). The combined organic layers were dried overNa.sub.2SO.sub.4 and concentrated to afford8-(hydroxymethyl)-3-methyl-1-(2-oxopropyl)-1H-purine-2,6(3H,7H)--dione (160 mg, 79% yield) as a white solid. Retention time(LC-MS): 0.384 min. MH.sup.+ 267.

Step 48-((tert-butyldimethylsilyloxy)methyl)-3-methyl-1-(2-oxobutyl)-1H-p-urine-2,6(3H,7H)-dione

##STR00429##

To mixture of8-(hydroxymethyl)-3-methyl-1-(2-oxobutyl)-1H-purine-2,6(3H,7H)-dione(100 mg, 0.375 mmol) in pyridine (3 mL) was added TBSCl (339 mg,2.25 mmol) in portions. The mixture was stirred at RT overnight.The reaction mixture was quenched by water (8 mL), and thenextracted with EA (3.times.10 mL). The combined organic layers werewashed saturated aqueous LiCl solution (5 mL) and brine (5 mL),dried over Na.sub.2SO.sub.4 and filtered. The filtrate wasconcentrated to get8-((tert-butyldimethylsilyloxy)methyl)-3-methyl-1-(2-oxobutyl)-1H-purine--2,6(3H,7H)-dione (140 mg, 97% yield) as a brown solid. Retentiontime (LC-MS): 1.577 min. MH.sup.+ 381.

Step 52-(8-((tert-butyldimethylsilyloxy)methyl)-3-methyl-2,6-dioxo-1-(2-o-xobutyl)-2,3-dihydro-1H-purin-7(6H)-yl)-N-(6'-(trifluoromethyl)-2,3'-bipyr-idin-6-yl)propanamide

##STR00430##

To a mixture of8-((tert-butyldimethylsilyloxy)methyl)-3-methyl-1-(2-oxobutyl)-1H-purine--2,6(3H,7H)-dione (60 mg, 0.157 mmol),2-chloro-N-(6'-(trifluoromethyl)-2,3'-bipyridin-6-yl)propanamide(52 mg, 0.157 mmol) in DMSO (2 mL) was added Cs.sub.2CO.sub.3 (92mg, 0.394 mmol) and TBAI (6 mg 0.02 mmol) and the mixture wasstirred at 50.degree. C. under N.sub.2 for 6 hrs. The reactionmixture was quenched by water (10 mL), and then extracted with EA(3.times.8 mL). The combined organic layers were washed withsaturated aqueous LiCl solution (5 mL) and brine (5 mL), dried overNa.sub.2SO.sub.4 and filtered. The filtrate was concentrated togive a crude product, which was purified with column chromatography(eluted with DCM:MeOH=30:1) to afford2-(8-((tert-butyldimethylsilyloxy)methyl)-3-methyl-2,6-dioxo-1-(2-oxobuty-l)-2,3-dihydro-1H-purin-7(6H)-yl)-N-(6'-(trifluoromethyl)-2,3'-bipyridin-6--yl)propanamide (12 mg, 11% yield) as a white solid. Retention time(LC-MS): 2.042 min. MH.sup.+ 674.

Preparation 67 6-(5-chloro-6-methylpyridin-3-yl)pyrazin-2-amine

##STR00431##

To a solution of 6-chloropyrazin-2-amine (413 mg, 2.96 mmol) indioxane (12 mL) in a sealed tube was added3-chloro-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(750 mg, 2.96 mmol) and aq. potassium carbonate (2M, 4.44 mL, 8.88mmol). The reaction was degassed with argon for 5 min andPd(PPh.sub.3).sub.4 (171 mg, 0.148 mmol) was added. The reactionwas heated at 90.degree. C. for 18 h, cooled to RT, diluted withwater (100 mL) and extracted with EA (3.times.75 mL). The combinedorganic layers were dried with MgSO.sub.4 and concentrated to aresidue which was purified by chromatography eluted with EA/Hep(20:80 to 100:0) to give6-(5-chloro-6-methylpyridin-3-yl)pyrazin-2-amine (346 mg, 53%yield) as a pale yellow solid. LCMS: MH.sup.+ 221 and T.sub.R=2.162min.

Preparation 686'-methyl-5'-(trifluoromethyl)-[2,3'-bipyridin]-6-amine

##STR00432##

Step 12-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluo-romethyl)pyridine

##STR00433##

To a solution of 5-bromo-2-methyl-3-(trifluoromethyl)pyridine (1.0g, 4.17 mmol) in dioxane (20 mL) in a sealed tube was added4,4,4',5,5,5'5'-octamethyl-2-2'-bi(1,3,2-dioxaborolane) (1.59 g,6.25 mmol) and KOAc (819 mg, 8.34 mmol). The reaction was degassedwith argon for 5 minutes then Pd(PPH.sub.3).sub.2Cl.sub.2 (0.0147mg, 0.021 mmol) was added. The reaction was heated at 105.degree.C. for 18 h, cooled to RT, diluted with water (100 mL) andextracted with EA (3.times.75 mL). The combined organic layer weredried with MgSO.sub.4 and concentrated to a residue which waspurified by chromatography eluted with EA/HEP (5:95 to 30:70) togive2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluorometh-yl)pyridine (1.2 g, 100% yield) as a white solid. LCMS: MH.sup.+206 (converts to boronic acid on LCMS) and T.sub.R=1.804 min.

Step 2 6'-methyl-5'-(trifluoromethyl)-[2,3'-bipyridin]-6-amine

##STR00434##

To a solution of 6-chloropyridin-2-amine (723 mg, 4.18 mmol) indioxane (18 mL) in a sealed tube was added2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluorometh-yl)pyridine (1.20 g, 4.18 mmol) and aq. potassium carbonate (2M,6.27 mL, 12.54 mmol). The reaction was degassed with argon for 5min then Pd(PPh.sub.3).sub.4 (242 mg, 0.209 mmol) was added. Thereaction was heated at 90.degree. C. for 4 h, cooled to RT, dilutedwith water (100 mL) and extracted with EA (3.times.75 mL). Thecombined organic layers were dried with MgSO.sub.4 and concentratedto a residue which was purified by chromatography eluted withEA/Hep (5:95 to 30:70) to give6'-methyl-5'-(trifluoromethyl)-[2,3'-bipyridin]-6-amine (1.02 g,96% yield) as a pale yellow solid. LCMS: MH.sup.+ 254 andR.sub.t=1.814 min.

Preparation 696-(6-methyl-5-(trifluoromethyl)pyridin-3-yl)pyrazin-2-amine

##STR00435##

To a solution of 6-chloropyrazin-2-amine (465 mg, 3.59 mmol) indioxane (15 mL) in a sealed tube was added2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluorometh-yl)pyridine (1.03 g, 3.59 mmol) and aq. potassium carbonate (2M,5.39 mL, 12.54 mmol). The reaction was degassed with argon for 5min, Pd(PPh.sub.3).sub.4 (207 mg, 0.180 mmol) was added and thenheated at 90.degree. C. for 4 h. The reaction was cooled to RT,diluted with water (100 mL) and extracted with EA (3.times.75 mL).The combined organic layers were dried with MgSO.sub.4 andconcentrated to a residue which was purified by chromatographyeluted with EA/Hep (10:90 to 30:70) to give6-(6-methyl-5-(trifluoromethyl)pyridin-3-yl)pyrazin-2-amine (707mg, 96% yield) as a pale yellow solid. LCMS: MH.sup.+ 255 andR.sub.t=2.507 min.

Preparation 706-(5-(3-azabicyclo[3.1.0]hexan-3-yl)pyrazin-2-yl)pyridin-2-amine

##STR00436##

Step 1 3-(5-bromopyrazin-2-yl)-3-azabicyclo[3.1.0]hexane

##STR00437##

To a solution of 2,5-dibromopyrazine (4.65 g, 19.57 mmol) in DMSO(100 mL) was added 3-azabicyclo[3.1.0]hexane hydrochloride (1.8 g,15.05 mmol) followed by Cs.sub.2CO.sub.3 (12.26 g, 37.63 mmol) andthe mixture was stirred at 100.degree. C. in a sealed tube for 4hrs. The mixture was cooled and diluted with EA (150 mL) and washedwith water, brine successively, dried and concentrated to give acrude product, which was purified by chromatography (PE/EA=5:1) togive 3-(5-bromopyrazin-2-yl)-3-azabicyclo[3.1.0]hexane (3.3 g,91.32% yield) as a yellow solid. Retention time (LC-MS): 1.468 min.MH.sup.+240.

Step 26-(5-(3-azabicyclo[3.1.0]hexan-3-yl)pyrazin-2-yl)pyridin-2-amine

##STR00438##

A mixture of 3-(5-bromopyrazin-2-yl)-3-azabicyclo[3.1.0]hexane (1.3g, 5.4 mmol), 6-bromopyridin-2-amine (1.12 g, 6.5 mmol), LiCl (229mg, 5.4 mmol) and 2,6-di-tert-butyl-4-methylphenol (220 mg, 1 mmol)in 1,4-dioxane (30 mL) was degassed with N.sub.2 for three timesand terakis(triphenylphosphine)palladium (499 mg, 0.43 mmol) wasadded under N.sub.2 atmosphere. The mixture was degassed again andhexa-n-butylditin (6.26 g, 10.8 mmol) was added, the reactionmixture was stirred under N.sub.2 at 110.degree. C. for 40 hrs. Themixture was diluted with EA (200 mL) and washed with aq. KFsolution, brine successively, dried and concentrated to dryness andthe crude product was purified with column chromatography(DCM/MeOH=60:1 to 30:1) to give6-(5-(3-azabicyclo[3.1.0]hexan-3-yl)pyrazin-2-yl)pyridin-2-amine(750 mg. 54.8% yield) as brown solid. Retention time (LC-MS): 0.456min. MH.sup.+ 254.

Preparation 715'-(3-azabicyclo[3.1.0]hexan-3-yl)-2,2'-bipyrazin-6-amine

##STR00439##

Step 1 2-chloro-6-(2,5-dimethyl-1H-pyrrol-1-yl)pyrazine

##STR00440##

To a mixture of 6-chloropyrazin-2-amine (5 g, 38.6 mmol) andacetonylacetone (6.6 g, 57.9 mmol) in toluene (50 mL) was addedp-toluenesulfonic acid (100 mg, 0.56 mmol) and the mixture washeated in a Dean-Stark apparatus for 2 hrs. The mixture was cooledto r.t. and diluted with EA (50 mL), washed with saturated aq.NaHCO.sub.3, brine successively, dried and concentrated to give acrude product, which was purified by chromatography (PE/EA=20:1) togive 2-chloro-6-(2,5-dimethyl-1H-pyrrol-1-yl)pyrazine (6.1 g, 77.3%yield) as a yellow solid. Retention time (LC-MS): 1.503 min.MH.sup.+ 208.

Step 23-(6'-(2,5-dimethyl-1H-pyrrol-1-yl)-2,2'-bipyrazin-5-yl)-3-azabicyc-lo[3.1.0]hexane

##STR00441##

A mixture of 3-(5-bromopyrazin-2-yl)-3-azabicyclo[3.1.0]hexane (2.6g, 10.8 mmol), 2-chloro-6-(2,5-dimethyl-1H-pyrrol-1-yl)pyrazine(2.6 g, 12.52 mmol), LiCl (530 mg, 12.52 mmol) and2,6-di-tert-butyl-4-methylphenol (220 mg, 1 mmol) in 1,4-dioxane(60 mL) was degassed with N.sub.2 for three times andtetrakis(triphenylphosphine)palladium (1.1 g, 1 mmol) was addedunder N.sub.2 atmosphere. The mixture was degassed again andhexa-n-butylditin (14.5 g, 25.64 mmol) was added, the reactionmixture was stirred under N.sub.2 at 110.degree. C. for 40 hrs. Themixture was diluted with EA (200 mL) and washed with aq. KFsolution, brine successively, dried and concentrated to dryness togive a crude product, which was purified by chromatography(PE/EA=5:1 to 1:1) to give5'-(3-azabicyclo[3.1.0]hexan-3-yl)-2,2'-bipyrazin-6-amine (1.4 g.33.6% yield) as a pale yellow solid. Retention time (LC-MS): 1.964min. MH.sup.+ 333.

Step 35'-(3-azabicyclo[3.1.0]hexan-3-yl)-2,2'-bipyrazin-6-amine

##STR00442##

To a solution of5'-(3-azabicyclo[3.1.0]hexan-3-yl)-2,2'-bipyrazin-6-amine (850 mg,2.56 mmol) in EtOH/H.sub.2O (20 mL/5 mL) was added hydroxylaminehydrochloride (1.77 g, 25.57 mmol) and the mixture was heated toreflux for 40 hrs. The mixture was concentrated to one third volumeand basified by adding 2 N aq. NaOH solution at 0.degree. C. Themixture was extracted with DCM twice and then combined organiclayers were washed with brine, dried and concentrated to give acrude product, which was purified by chromatography (DCM/MeOH=60:1to 30:1) to give5'-(3-azabicyclo[3.1.0]hexan-3-yl)-2,2'-bipyrazin-6-amine (410 mg,21.0 mg, 63% yield) as brown solid. Retention time (LC-MS): 0.832min. MH.sup.+ 255.

The procedure set forth above was used to produce the followingcompounds using the appropriate starting materials.

##STR00443##

Retention time (LC-MS): 0.521 min. MH.sup.+290.

##STR00444##

Retention time (LC-MS): 0.652 min. MH.sup.+291.

Preparation 722-(5-(3-azabicyclo[3.1.0]hexan-3-yl)pyrazin-2-yl)thiazol-4-amine

##STR00445##

Step 1 tert-butyl2-(5-(3-azabicyclo[3.1.0]hexan-3-yl)pyrazin-2-yl)thiazole-4-carboxylate

##STR00446##

To a mixture of tert-butyl thiazole-4-carboxylate (928 mg, 5.02mmol), 3-(5-bromopyrazin-2-yl)-3-azabicyclo[3.1.0]hexane (1 g, 4.18mmol) in DMF (20 mL) was added Cs.sub.2CO.sub.3 (2.7 g, 8.36 mmol).After the mixture was degassed with N.sub.2 for three times,Pd(OAc).sub.2 (94 mg, 0.42 mmol) and John-phos (146 mg, 0.42 mmol)were added under N.sub.2 and the mixture was stirred at 100.degree.C. overnight. The reaction mixture was cooled down and poured intoEA. The organic phase was separated, washed with water and brine,dried over Na.sub.2SO.sub.4 and filtered. The filtrate wasconcentrated under reduced pressure and the residue was purified bychromatography (eluted with PE:EA=4:1) to afford tert-butyl2-(5-(3-azabicyclo[3.1.0]hexan-3-yl)pyrazin-2-yl)thiazole-4-carboxylate(800 mg, 55.5% yield) as yellow solid. Retention time (LC-MS):1.347 min. MH.sup.+ 345.

Step 22-(5-(3-azabicyclo[3.1.0]hexan-3-yl)pyrazin-2-yl)thiazole-4-carboxy-lic Acid

##STR00447##

To a solution of tert-butyl2-(5-(3-azabicyclo[3.1.0]hexan-3-yl)pyrazin-2-yl)thiazole-4-carboxylate(800 mg, 2.31 mmol) in DCM (10 mL) was added TFA (2 mL) at0.degree. C. After the addition, the mixture was stirred at RTovernight. The mixture was concentrated to dryness. The crude waswashed with ether to give2-(5-(3-azabicyclo[3.1.0]hexan-3-yl)pyrazin-2-yl)thiazole-4-carboxylicacid (500 mg, 74.9% yield) as a white solid. Retention time(LC-MS): 0.790 min. MH.sup.+ 289.

Step 3 Tert-butyl2-(5-(3-azabicyclo[3.1.0]hexan-3-yl)pyrazin-2-yl)thiazol-4-ylcarbamate

##STR00448##

Diphenylphosphonic azide (0.45 mL, 2.12 mmol) was added drop-wiseto a mixture of2-(5-(3-azabicyclo[3.1.0]hexan-3-yl)pyrazin-2-yl)thiazole-4-carboxylicacid (500 mg, 1.73 mmol) and Et.sub.3N (0.35 mL, 2.60 mmol) int-BuOH (10 mL). The mixture was heated to 80.degree. C. overnight.The reaction mixture was quenched with water and extracted with EA(2.times.5 mL). The combined organic layers were dried overNa.sub.2SO.sub.4 and filtered. The filtrate was concentrated andthe residue was purified by chromatography (eluted with PE:EA=10:1)to afford tert-butyl(2-(5-(3-azabicyclo[3.1.0]hexan-3-yl)pyrazin-2-yl)thiazol-4-yl)carbamate(5, 130 mg, 20.8% yield) as a white solid. Retention time (LC-MS):1.543 min. MH.sup.+ 360.

Step 42-(5-(3-azabicyclo[3.1.0]hexan-3-yl)pyrazin-2-yl)thiazol-4-amine

##STR00449##

To a solution of tert-butyl(2-(5-(3-azabicyclo[3.1.0]hexan-3-yl)pyrazin-2-yl)thiazol-4-yl)carbamate(130 mg, 0.36 mmol) in DCM (4 mL) was added TFA (2 mL) at 0.degree.C. After the addition, the mixture was stirred at RT for 2 hrs. Thereaction mixture was diluted with DCM and quenched with sat.potassium carbonate. The organic layer was separated, dried overNa.sub.2SO.sub.4 and filtered. The filtrate was concentrated underreduced pressure to give2-(5-(3-azabicyclo[3.1.0]hexan-3-yl)pyrazin-2-yl)thiazol-4-amine(80 mg, 85.2% yield) as yellow solid. Retention time (LC-MS): 0.790min. MH.sup.+ 260.

Preparation 73N-(6-bromopyridin-2-yl)-2-(3,8-dimethyl-2,6-dioxo-1-(pyridin-2-ylmethyl)--2,3-dihydro-1H-purin-7(6H)-yl)acetamide

##STR00450##

Step 18-bromo-3-methyl-1-(pyridin-2-ylmethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione

##STR00451##

To a mixture of8-bromo-3-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H-)-dione (2.9 g, 9.78 mmol) and 2-(bromomethyl)pyridine hydrobromide(3.0 g, 11.74 mmol) in DMF (50 mL) was added cesium carbonate (6.5g, 19.57 mmol) and TBAI (142.7 mg, 0.39 mmol). The reaction mixturewas stirred at 100.degree. C. for 2 h. The mixture was cooled downto RT and diluted with DCM. The resulting solution was washed withS. aq. LiCl, dried over Na2SO4, and concentrated and the residuewas purified by chromatography (eluted with PE:EA=5:1) to afford8-bromo-3-methyl-1-(pyridin-2-ylmethyl)-7-((2-(trimethylsilyl)ethoxy)meth-yl)-1H-purine-2,6(3H,7H)-dione (2.5 g, 66.0% yield) as yellow oil.Retention time (LC-MS): 1.534 min. MH.sup.+ 468.

Step 23,8-dimethyl-1-(pyridin-2-ylmethyl)-7-((2-(trimethylsilyl)ethoxy)me-thyl)-1H-purine-2,6(3H,7H)-dione

##STR00452##

To a mixture of8-bromo-3-methyl-1-(pyridin-2-ylmethyl)-7-((2-(trimethylsilyl)ethoxy)meth-yl)-1H-purine-2,6(3H,7H)-dione (2, 1 g, 2.14 mmol),2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (404 mg, 3.22 mmol)and potassium carbonate (593 mg, 4.29 mmol) in dioxane (50 mL) wasadded Pd(dppf)Cl.sub.2 (80 mg, 0.11 mmol) after degassed threetimes under N.sub.2 atmosphere. The mixture was then heated to110.degree. C. for 2 h. The reaction mixture was cooled andfiltered through Celite. The filtrate was extracted with EA(3.times.200 mL). Combined organic layers were dried overNa.sub.2SO.sub.4 and filtered. The filtrate was concentrated underreduced pressure and the residue was purified by chromatography(eluted with PE/EA=1/1) to afford3,8-dimethyl-1-(pyridin-2-ylmethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione (800 mg, 93.1% yield) asa white solid. Retention time (LC-MS): 1.232 min. MH.sup.+ 403.

Step 33,8-dimethyl-1-(pyridin-2-ylmethyl)-1H-purine-2,6(3H,7H)-dione

##STR00453##

To a stirred solution of3,8-dimethyl-1-(pyridin-2-ylmethyl)-7-((2-(trimethylsilyl)ethoxy)methyl)--1H-purine-2,6(3H,7H)-dione (800 mg, 1.99 mmol) in EtOH (5 mL) wasadded conc. HCl (1 mL). After the addition, the mixture was heatedto reflux for 2 h and then cooled to RT. The mixture wasconcentrated to dryness to give crud3,8-dimethyl-1-(pyridin-2-ylmethyl)-1H-purine-2,6(3H,7H)-dione (490mg, 98.0% yield) as an off-white solid which was used directlywithout any further purification. Retention time (LC-MS): 0.386min. MH.sup.+ 272.

Step 4N-(6-bromopyridin-2-yl)-2-(3,8-dimethyl-2,6-dioxo-1-(pyridin-2-ylme-thyl)-2,3-dihydro-1H-purin-7(6H)-yl)acetamide

##STR00454##

A mixture of3,8-dimethyl-1-(pyridin-2-ylmethyl)-1H-purine-2,6(3H,7H)-dione (490mg, 1.81 mmol), TBAI (68 mg, 0.018 mmol),N-(6-bromopyridin-2-yl)-2-chloroacetamide (541 mg, 2.17 mmol) andpotassium carbonate (499 mg, 3.61 mmol) in DMF (5 mL) was stirredat 50.degree. C. for 2 h. The reaction mixture was quenched bywater (40 mL), and then extracted with EA (3.times.50 mL). Combinedorganic layers were dried over Na.sub.2SO.sub.4 and filtered. Thefiltrate was concentrated and the residue was purified bychromatography (eluted with DCM:MeOH=60:1) to affordN-(6-bromopyridin-2-yl)-2-(3,8-dimethyl-2,6-dioxo-1-(pyridin-2-ylmethyl)--2,3-dihydro-1H-purin-7(6H)-yl)acetamide (740 mg, 84.6% yield) as awhite solid. Retention time (LC-MS): 1.081 min. MH.sup.+ 486.

Preparation 74N-(6-bromopyridin-2-yl)-2-(8-(hydroxymethyl)-3-methyl-2,6-dioxo-1-(2-oxop-ropyl)-2,3-dihydro-1H-purin-7(6H)-yl)acetamide

##STR00455##

A mixture ofN-[6-(3,4-Difluoro-phenyl)-pyridin-2-yl]-2-[8-hydroxymethyl-3-methyl-2,6--dimethylene-1-(2-oxo-propyl)-1,2,3,6-tetrahydro-purin-7-yl]-acetamide(370 mg, 0.94 mmol), potassium carbonate (260 mg, 1.88 mmol), TBAI(58 mg, 0.09 mmol) in DMF (2 ml) was stirred at 50.degree. C. underN.sub.2 overnight. The reaction mixture was quenched by water (10mL), and then extracted with EA (3.times.5 mL). Combined organiclayers were dried over Na.sub.2SO.sub.4 and filtered. The filtratewas concentrated and the residue was purified by chromatography(eluted with DCM:MeOH=15:1) to affordN-(6-bromopyridin-2-yl)-2-(8-(hydroxymethyl)-3-methyl-2,6-dioxo-1--(2-oxopropyl)-2,3-dihydro-1H-purin-7(6H)-yl)acetamide (136 mg, 32%yield) as a yellow solid. Retention time (LC-MS): 0.815 min.MH.sup.+ 465.

Preparation 75N-(6-bromopyridin-2-yl)-2-(3-methyl-2,6-dioxo-1-(2-oxopropyl)-1,2,3,6-tet-rahydropurin-7-yl)acetamide

##STR00456##

Step 1 N-(6-bromopyridin-2-yl)-2-chloroacetamide

##STR00457##

To a solution of 6-bromopyridin-2-amine (5 g, 28.90 mmol) and TEA(10.0 ml, 43.35 mmol) in DCM (50 mL) was added dropwise2-chloroacetyl chloride (3.45 mL, 72.25 mmol) at RT under N.sub.2atmosphere. After addition, the mixture was stirred at RTovernight. The reaction was quenched by addition of water, and thereaction mixture was extracted with DCM (2.times.50 mL). Combinedorganic layers were dried over Na.sub.2SO.sub.4 and filtered. Thefiltrate was concentrated under reduced pressure and the residuewas purified by chromatography (eluted with PE:EA=20:1) to affordN-(6-bromopyridin-2-yl)-2-chloroacetamide (3.0 g, 41.6% yield) as awhite solid. Retention time (LC-MS): 1.276 min. MH.sup.+ 251.

Step 2N-(6-bromopyridin-2-yl)-2-(3-methyl-2,6-dioxo-1,2,3,6-tetrahydro-pu-rin-7-yl)acetamide

##STR00458##

To a mixture of N-(6-bromopyridin-2-yl)-2-chloroacetamide (3.0 g,12.04 mmol) and 3-methyl-1H-purine-2,6(3H,7H)-dione (2.2 g, 13.24mmol) in DMF (60 mL) was added potassium carbonate (2.16 g, 15.65mmol). The reaction mixture was stirred at RT overnight. Themixture was poured into water (200 mL) and filtered. The solid wascollected and dried under vacuum to giveN-(6-bromopyridin-2-yl)-2-(3-methyl-2,6-dioxo-1,2,3,6-tetrahydropuri-n-7-yl)acetamide (4.2 g, 83.7% yield) as a white solid. Retentiontime (LC-MS): 0.658 min. MH.sup.+ 379.

Step 3N-(6-bromopyridin-2-yl)-2-(3-methyl-2,6-dioxo-1-(2-oxopropyl)-1,2,3-,6-tetrahydropurin-7-yl)acetamide

##STR00459##

A mixture ofN-(6-bromopyridin-2-yl)-2-(3-methyl-2,6-dioxo-1,2,3,6-tetrahydropurin-7-y-l)acetamide (5, 1.5 g, 3.96 mmol), 1-chloropropan-2-one (0.47 mL,5.93 mmol), potassium carbonate (1.37 g, 9.89 mmol) and a catalyticamount of TBAI in N, N-dimethyl formamide (50 mL) was stirred at50.degree. C. for 2 h. The reaction mixture was poured into waterand filtered. The solid was washed with water twice, collected,dried under vacuum and then re-crystallized from ethanol to giveN-(6-bromopyridin-2-yl)-2-(3-methyl-2,6-dioxo-1-(2-oxopropyl)-1,2,3,6-tet-rahydropurin-7-yl)acetamide (835 mg, 48.5% yield) as a white solid.Retention time (LC-MS): 1.100 min. MH.sup.+ 435.

Preparation 76N-(6-bromopyridin-2-yl)-2-(3-methyl-2,6-dioxo-1-(pyridin-2-ylmethyl)-2,3--dihydro-1H-purin-7(6H)-yl)acetamide

##STR00460##

To a solution ofN-(6-bromopyridin-2-yl)-2-(3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)--yl)acetamide (1.5 g, 3.97 mmol) in DMF (15 mL) were added potassiumcarbonate (1.6 g, 12 mmol), 2-(bromomethyl)pyridine (1.2 g, 4.76mmol) and tetrabutyl ammonium iodide (30 mg, 0.081 mmol). After theaddition, the mixture was stirred at 100.degree. C. for 2 h andcooled to RT. The mixture was diluted with EA and washed with S.aqueous LiCl. The organic layer was separated, dried over Na2SO4,and concentrated and the residue was purified by chromatography toaffordN-(6-bromopyridin-2-yl)-2-(3-methyl-2,6-dioxo-1-(pyridin-2-ylmethyl)-2,3--dihydro-1H-purin-7(6H)-yl)acetamide (450 mg, 24.2% yield) as greysolid. Retention time (LC-MS): 0.473 min. MH.sup.+ 470.

Preparation 77N-(2-bromothiazol-4-yl)-2-(3-methyl-2,6-dioxo-1-(pyridin-2-ylmethyl)-2,3--dihydro-1H-purin-7(6H)-yl)acetamide

##STR00461##

Step 1 N-(2-bromothiazol-4-yl)-2-chloroacetamide

##STR00462##

To a solution of 2-bromothiazol-4-amine hydrobromide (1 g, 3.85mol) in methylene chloride (10 mL) was added slowly TEA (1.5 g,15.4 mol) at 0.degree. C. The solution was stirred for 15 min atthe same temperature and then 2-chloroacetyl chloride (651 mg, 5.77mmol) was added. The mixture was stirred overnight at RT. Thesolvent was removed under reduced pressure and the residue waspurified via chromatography (eluted with PE:EA=2:1) to affordN-(2-bromothiazol-4-yl)-2-chloroacetamide (650 mg, 66.1% yield) aslight yellow oil.

Step 2N-(2-bromothiazol-4-yl)-2-(3-methyl-2,6-dioxo-1-(pyridin-2-ylmethyl-)-2,3-dihydro-1H-purin-7(6H)-yl)acetamide

##STR00463##

To a mixture of3-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione(250 mg, 1.50 mmol), N-(2-bromothiazol-4-yl)-2-chloroacetamide (346mg, 1.35 mmol) in DMF (10 mL) was added potassium carbonate (250mg, 1.81 mmol), and the mixture was stirred at RT for 2 h. Then2-(bromomethyl)pyridine (400 mg, 2.25 mmol), potassium carbonate(200 mg, 3.76 mmol) and TBAI (10 mg) were added into the mixture.The mixture was stirred at 100.degree. C. for 2 h and cooled to RT.The mixture was extracted with DCM (3.times.10 mL). Combinedorganic layers were washed with S. aqueous ammonium chloride, driedover Na.sub.2SO.sub.4, and filtered. The filtrate was concentratedand the residue was purified by chromatography (eluted withDCM:MeOH=20:1) to giveN-(2-bromothiazol-4-yl)-2-(3-methyl-2,6-dioxo-1-(pyridin-2-ylmethyl)-2,3--dihydro-1H-purin-7(6H)-yl)acetamide (270 mg, 54.0% yield) as brownoil. Retention time (LC-MS): 1.874 min. MH.sup.+ 477.

Preparation 78N-(6-bromopyridin-2-yl)-2-(3,8-dimethyl-2,6-dioxo-1-(2-oxopropyl)-1,2,3,6--tetrahydropurin-7-yl)acetamide

##STR00464##

Step 18-bromo-3-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6-(3H,7H)-dione

##STR00465##

To a mixture of 8-bromo-3-methyl-1H-purine-2,6(3H,7H)-dione (3 g,0.012 mol) and potassium carbonate (3.4 g, 0.024 mol) in DMF (30mL) was added SEM-Cl (2.45 g, 0.014 mol) at 0.degree. C. After theaddition, the mixture was stirred at RT for 2 h. The mixture wasthen diluted with EA and washed with water, 10% aqueous LiClsuccessively, dried and concentrated to give crude product, whichwas washed with EtOH to afford8-bromo-3-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H-)-dione (3.5 g, 74% yield) as a white solid. Retention time(LC-MS): 1.364. MH.sup.+--CO 347.

Step 2 8-bromo-3-methyl-1-(2-oxopropyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione

##STR00466##

To a mixture of8-bromo-3-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H-)-dione (1.5 g, 4.01 mmol), TBAI (148 mg, 0.4 mmol) and potassiumcarbonate (3.4 g, 0.024 mol) in DMF (30 mL) was added1-chloropropan-2-one (422 mg, 4-81 mmol) at 0.degree. C. After theaddition, the mixture was stirred at 50.degree. C. for 2 h. Themixture was cooled to RT, diluted with water (60 mL) and filtered.The filter cake was washed with EtOH and dried under vacuum toafford8-bromo-3-methyl-1-(2-oxopropyl)-74(2-(trimethylsilyl)ethoxy)methyl)-1H-p-urine-2,6(3H,7H)-dione (1.6 g, 93% yield) as a white solid.Retention time (LC-MS): 1.639 min. (MH.sup.+--CO) 403.

Step 3 3,8-dimethyl-1-(2-oxopropyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione

##STR00467##

To a mixture of8-bromo-3-methyl-1-(2-oxopropyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-1H--purine-2,6(3H,7H)-dione (1.5 g, 3.48 mmol),2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (526 mg, 4.17 mmol)and potassium carbonate (960 mg, 6.96 mmol) in dioxane (400 mL) wasadded Pd(dppf)Cl.sub.2 (254 mg, 0.348 mmol) after degassed threetimes under N.sub.2 atmosphere, then the mixture was heated to110.degree. C. for 2 h. The mixture was cooled and filtered throughCelite. The filtrate was extracted with EA (3.times.500 mL).Combined organic layers were dried over Na.sub.2SO.sub.4 andfiltered. The filtrate was concentrated under reduced pressure andthe residue was purified by chromatography (eluted with PE/EA=1/1)to afford3,8-dimethyl-1-(2-oxopropyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-1H-puri-ne-2,6(3H,7H)-dione (650 mg, 50.2% yield) as a white solid.Retention time (LC-MS): 1.454 min. MH.sup.+ 339.

Step 4 3,8-dimethyl-1-(2-oxopropyl)-1H-purine-2,6(3H,7H)-dione

##STR00468##

To a stirred solution of3,8-dimethyl-1-(2-oxopropyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-1H-puri-ne-2,6(3H,7H)-dione (650 mg, 1.77 mmol) in EtOH (15 mL) was addedconc. HCl (3 mL). After the addition, the mixture was heated toreflux for 2 h and cooled to RT. The mixture was concentrated todryness to give3,8-dimethyl-1-(2-oxopropyl)-1H-purine-2,6(3H,7H)-dione (410 mg,85% yield) as an off-white solid. Retention time (LC-MS): 0.405min. MH.sup.+ 237.

Step 5N-(6-bromopyridin-2-yl)-2-(3,8-dimethyl-2,6-dioxo-1-(2-oxopropyl)-1-,2,3,6-tetrahydropurin-7-yl)acetamide

##STR00469##

A mixture of3,8-dimethyl-1-(2-oxopropyl)-1H-purine-2,6(3H,7H)-dione (410 mg,1.73 mmol), TBAI (64 mg, 0.017 mmol),N-(6-bromopyridin-2-yl)-2-chloroacetamide (514 mg, 2.07 mmol) andpotassium carbonate (477 mg, 3.46 mmol) in DMF (8 mL) was stirredat 50.degree. C. for 2 h. The reaction mixture was quenched bywater (60 mL), and then extracted with EA. Combined organic layerswere dried over Na.sub.2SO.sub.4 and filtered. The filtrate wasconcentrated and the residue was purified by chromatography (elutedwith DCM/MeOH=80/1) to affordN-(6-bromopyridin-2-yl)-2-(3,8-dimethyl-2,6-dioxo-1-(2-oxopropyl)--1,2,3,6-tetrahydropurin-7-yl)acetamide (550 mg, 65.1% yield) as awhite solid. Retention time (LC-MS): 1.024 min. MH.sup.+ 449.

Preparation 793-methyl-1-((5-methylisoxazol-3-yl)methyl)-1H-purine-2,6(3H,7H)-dione

##STR00470##

Step 13-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)--dione

##STR00471##

To a stirred solution of 3-methyl-1H-purine-2,6(3H,7H)-dione (5 g,30.10 mmol) and potassium carbonate (6.24 g, 45.14 mmol) in DMF (5mL) at 0.degree. C. was added(2-(chloromethoxy)ethyl)trimethylsilane (5.33 mL, 30.10 mml). Afterthe addition, the mixture was warmed to RT and stirred over night.The reaction mixture was diluted with DCM, and washed with s. aq.LiCl. The organic layer was separated, dried over Na2SO4, andconcentrated to afford 3-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione (3.78 g, 42.4% yield) asyellow solid. Retention time (LC-MS): 1.160 min. MH.sup.+ 297.

Step 23-methyl-1-((5-methylisoxazol-3-yl)methyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione

##STR00472##

To a mixture of3-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione(1.0 g, 3.37 mmol) and 3-(chloromethyl)-5-methylisoxazolehydrochloride (665.80 mg, 5.06 mmol) in DMF (20 mL) was addedpotassium carbonate (1.17 g, 8.43 mmol) and TBAI (61.84 mg, 0.17mmol). The mixture was stirred at 50.degree. C. for 2 h. Thereaction mixture was diluted with DCM and washed with S. aq. LiCl.The organic layer was separated, dried over Na2SO4, andconcentrated and the residue was purified by chromatography (elutedwith PE:EA=5:1) to afford3-methyl-1-((5-methylisoxazol-3-yl)methyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione (750 mg, 56.8% yield) asyellow solid. Retention time (LC-MS): 1.476 min. MH.sup.+ 392.

Step 33-methyl-1-((5-methylisoxazol-3-yl)methyl)-1H-purine-2,6(3H,7H)-dio-ne

##STR00473##

To a stirred solution of3-methyl-1-((5-methylisoxazol-3-yl)methyl)-7-((2-(trimethylsilyl)ethoxy)m-ethyl)-1H-purine-2,6(3H,7H)-dione (750 mg, 1.92 mmol) in EtOH (5mL) was added conc. HCl (1 mL). After the addition, the mixture washeated to reflux for 2 h and then cooled to RT. The mixture wasconcentrated to dryness to give a crude product of3-methyl-1-((5-methylisoxazol-3-yl)methyl)-1H-purine-2,6(3H,7H)-dione(415 mg, 82.9% yield) as yellow solid which was used in the nextstep without any further purification. Retention time (LC-MS):0.544 min. MH.sup.+ 262.

Preparation 80N-(5-bromo-6-(trifluoromethyl)pyridin-2-yl)-2-chloroacetamide

##STR00474##

Step 1 5-bromo-6-(trifluoromethyl)pyridin-2-amine

##STR00475##

To a mixture of 6-(trifluoromethyl)pyridin-2-amine (600 mg, 3.7mmol) in MeOH (10 mL) was added NBS (659 mg, 3.7 mmol) in portionsat 0.degree. C. The reaction mixture was stirred at r.t. overnight.The reaction mixture was concentrated under reduced pressure andthe residue was purified by chromatography (eluted with PE:EA=4:1)to afford the title compound (650 mg, 73.1% yield) as a whitesolid. Retention time (LC-MS): 1.33 min. MH.sup.+ 241.

Step 2N-(5-bromo-6-(trifluoromethyl)pyridin-2-yl)-2-chloroacetamide

##STR00476##

To a solution of 5-bromo-6-(trifluoromethyl)pyridin-2-amine (72 mg,0.3 mmol) in DMF (2 mL) was added dropwise 2-chloroacetyl chloride(0.05 mL, 0.6 mmol) at 0.degree. C. The reaction mixture wasstirred at r.t. for 2 h and poured into EA. The mixture was washedwith water and brine, dried over Na2SO4, and concentrated to givethe title compound (85 mg, 89.7% yield) as yellow solid. Retentiontime (LC-MS): 1.64 min. MH.sup.+ 319.

Preparation 81N-(3,4-dimethoxybenzyl)-N-(4-ethyl-6-(trifluoromethyl)pyridin-2-yl)-2-(1--(isoxazol-3-ylmethyl)-3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)ace-tamide

##STR00477##

Step 1 2-chloro-3-iodo-6-(trifluoromethyl)pyridine

##STR00478##

To a solution of 2-chloro-6-(trifluoromethyl)pyridine (10.0 g,55.25 mmol) in THF (200 mL) was added dropwise LDA (30.39 mL, 2 M)at -78.degree. C. via funnel under N.sub.2 atmosphere. The reactionmixture was stirred at that temperature for 1 hr, followed bydropwise addition of I.sub.2 (16.84 g, 66.30 mmol). The mixture wasstirred at that temperature for 1 hr, then warmed to r.t. andstirred for another 2 h. The reaction mixture was quenched withwater (40 mL), and concentrated under reduced pressure. The aqueouslayer was separated, and extracted with EA (2.times.100 mL).Combined organic layers were washed with water and brine, driedover Na.sub.2SO.sub.4 and filtered. The filtrate was concentratedand the residue was purified by column chromatography (eluted withPE) to give the 2-chloro-3-iodo-6-(trifluoromethyl)pyridine (14.3g, 84% yield) as a white solid. .sup.1HNMR (400 MHz, DMSO-d.sub.6).delta. 8.64 (d, J=8.0 Hz, 1H), 7.61 (d, J=8.0 Hz, 1H).

Step 2 2-chloro-4-iodo-6-(trifluoromethyl)pyridine

##STR00479##

To a mixture of 2-chloro-3-iodo-6-(trifluoromethyl)pyridine (3.07g, 10.0 mmol) in THF (35 mL) was added dropwise LDA (5.5 mL, 2M) at-78.degree. C. via syringe under N.sub.2 atmosphere. The reactionmixture was stirred at that temperature for 1 h. The reactionmixture was quenched with aqueous HCl (15 mL, 1 M) at -78.degree.C. and stirred for 0.5 h. The mixture was warmed to r.t., stirredfor another 0.5 hr, and then concentrated under reduced pressure.The aqueous layer was separated and extracted with EA (2.times.100mL). Combined organic layers were washed with water and brine,dried over Na.sub.2SO.sub.4 and filtered. The filtrate wasconcentrated and the residue was purified by column chromatography(eluted with PE) to give the2-chloro-4-iodo-6-(trifluoromethyl)pyridine (2.5 g, 81% yield) as awhite solid. .sup.1HNMR (400 MHz, DMSO-d.sub.6) .delta. 8.39 (s,1H), 8.34 (s, 1H).

Step 3N-(3,4-dimethoxybenzyl)-4-iodo-6-(trifluoromethyl)pyridin-2-amine

##STR00480##

To a solution of 2-chloro-4-iodo-6-(trifluoromethyl)pyridine (1.0g, 3.26 mmol) in NMP (5 mL) was added(3,4-dimethoxyphenyl)methanamine (2.45 mL, 16.29 mmol) andEt.sub.3N (2.26 mL, 16.29 mmol). The mixture was heated in amicrowave at 100.degree. C. for 20 min. The reaction mixture wasdiluted with EA, washed with water and brine, dried overNa.sub.2SO.sub.4 and filtered. The filtrate was concentrated underreduced pressure and the residue was purified by columnchromatography (eluted with PE:EA=15:1 to 10:1) to give theN-(3,4-dimethoxybenzyl)-4-iodo-6-(trifluoromethyl)pyridin-2-amine(400 mg, 28% yield) as a white solid. Retention time (LC-MS): 1.923min. MH.sup.+ 439.

Step 4N-(3,4-dimethoxybenzyl)-6-(trifluoromethyl)-4-vinylpyridin-2-amine

##STR00481##

To a solution ofN-(3,4-dimethoxybenzyl)-4-iodo-6-(trifluoromethyl)pyridin-2-amine(320 mg, 0.73 mmol), potassium carbonate (201.64 mg, 1.46 mmol) and2,4,6-triviny 1-1,3,5,2,4,6-trioxatriborinane (141.65 mg, 0.88mmol) in 1,4-dioxane (5 mL) and H.sub.2O (1 mL) was addedPd(dppf)Cl.sub.2 (53.46 mg, 0.073 mmol) after degassed three timesunder N.sub.2 atmosphere. The reaction mixture was stirred at80.degree. C. under N.sub.2 overnight. The reaction mixture wascooled and filtered through Celite. The filtrate was extracted withEA (3.times.50 mL). Combined organic layers were dried overNa.sub.2SO.sub.4 and filtered. The filtrate was concentrated underreduced pressure and the residue was purified by chromatography(eluted with DCM:MeOH=100:1 to 80:1) to affordN-(3,4-dimethoxybenzyl)-6-(trifluoromethyl)-4-vinylpyridin-2-amine(210 mg, 85% yield) as a white solid. Retention time (LC-MS): 1.776min. MH.sup.+ 339.

Step 5N-(3,4-dimethoxybenzyl)-4-ethyl-6-(trifluoromethyl)pyridin-2-amine

##STR00482##

To a solution ofN-(3,4-dimethoxybenzyl)-6-(trifluoromethyl)-4-vinylpyridin-2-amine(210 mg, 0.62 mmol) in ethanol (5 mL) was added Pd/C (50 mg) afterdegassed three times under H.sub.2 atmosphere. The reaction mixturewas stirred at r.t. under H.sub.2 for 1.5 h. The reaction mixturewas filtered through Celite. The filtrate was concentrated underreduced pressure and the residue was purified by chromatography(PE:EA=10:1 to 3:1) to affordN-(3,4-dimethoxybenzyl)-6-(trifluoromethyl)-4-vinylpyridin-2-amine(210 mg, 99% yield) as a white solid. Retention time (LC-MS): 1.786min. MH.sup.+ 341.

Step 62-chloro-N-(3,4-dimethoxybenzyl)-N-(4-ethyl-6-(trifluoromethyl)pyri-dine-2-yl)acetamide

##STR00483##

To a solution ofN-(3,4-dimethoxybenzyl)-4-ethyl-6-(trifluoromethyl)pyridin-2-amine(50 mg, 0.15 mmol) and DIPEA (0.05 mL, 0.29 mmol) in DCM (5 mL) wasadded dropwise 2-chloroacetyl chloride (0.02 mL, 0.22 mmol) at0.degree. C. The reaction mixture was warmed to r.t. and stirredfor 5 h. The reaction mixture was quenched with water (10 mL). Themixture was neutralized with S. aq. NaHCO.sub.3 and extracted withEA. Combined organic layers were washed with water and brine, driedover Na.sub.2SO.sub.4 and filtered. The filtrate was concentratedunder reduced pressure and the residue was purified bychromatography (eluted with PE:EA=10:1 to 3:1) to afford2-chloro-N-(3,4-dimethoxybenzyl)-N-(4-ethyl-6-(trifluoromethyl)pyridin-2--yl)acetamide (50 mg, 81% yield) as a white solid. Retention time(LC-MS): 1.730 min. MH.sup.+ 417.

Step 7N-(3,4-dimethoxybenzyl)-N-(4-ethyl-6-(trifluoromethyl)pyridin-2-yl)--2-(1-(isoxazol-3-ylmethyl)-3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)--yl)acetamide

##STR00484##

A mixture of2-chloro-N-(3,4-dimethoxybenzyl)-N-(4-ethyl-6-(trifluoromethyl)pyridin-2-yl)acetamide (50 mg, 0.12 mmol), potassium carbonate(33.17 mg, 0.24 mmol),3-methyl-1-((5-methylisoxazol-3-yl)methyl)-1H-purine-2,6(3H,7H)-dione(25.96 mg, 0.192 mmol) and TBAI (4.44 mg, 0.012 mmol) in DMF (5 mL)was stirred at 50.degree. C. for 2 h. The reaction mixture wasdiluted with EA, washed with water, brine, dried overNa.sub.2SO.sub.4 and filtered. The filtrate was purified bychromatography (eluted with DCM:MeOH=100:1 to 50:1) to affordN-(3,4-dimethoxybenzyl)-N-(4-ethyl-6-(trifluoromethyl)pyridin-2-yl)-2-(1--(isoxazol-3-ylmethyl)-3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)ace-tamide (50 mg, 64% yield) as yellow solid. Retention time (LC-MS):1.703 min. MH.sup.+ 642.

Preparation 82 6-(4,4-difluoropiperidin-1-yl)pyridin-2-amine

##STR00485##

To a mixture of 2-bromo-6-(4,4-difluoropiperidin-1-yl)pyridine (400mg, 1.44 mmol), Pd.sub.2(dba).sub.3 (53 mg, 57.74 .mu.mol) andbiphenyl-2-yldicyclohexylphosphine (41 mg, 115.48 .mu.mol) indioxane (5 mL) was added LiHMDS (483 mg, 2.89 mmol) after degassedthree times under N.sub.2 atmosphere. The mixture was then heatedto 60.degree. C. for 2 h. The reaction mixture was concentratedunder reduced pressure and the residue was purified bychromatography (eluted with DCM:MeOH=50:1) to afford6-(4,4-difluoropiperidin-1-yl)pyridin-2-amine (165 mg, 53.6% yield)as a white solid. Retention time (LC-MS): 0.527 min. MH.sup.+214.

Preparation 83N-(6-(4-chlorophenyl)pyridin-2-yl)-2-(8-(hydroxymethyl)-3-methyl-2,6-diox-o-2,3-dihydro-1H-purin-7(6H)-yl)acetamide

##STR00486##

Step 18-(hydroxymethyl)-1-(4-methoxybenzyl)-3-methyl-1H-purine-2,6(3H,7H)--dione

##STR00487##

A mixture of5,6-diamino-3-(4-methoxybenzyl)-1-methylpyrimidine-2,4(1H,3H)-dione(2 g, 7.2 mmol) and 2-hydroxyHOAc (1.104 g, 18.1 mmol) was heatedto 100.degree. C. under stirring. The mixture was melted andsolidified. EtOH (10 mL) was then added in and the reaction mixturewas stirred at 100.degree. C. for another 2 h till completion. NaOH(2M, 20 mL) was added to a stirred solution of the above mixture inEtOH (10 mL). The mixture was heated at 80.degree. C. for 3 hr,then cooled to 0.degree. C. and neutralized with acetic acid. Thereaction mixture was pooled into water (10 mL), and then extractedwith EA (3.times.5 mL). Combined organic layers were dried overNa.sub.2SO.sub.4 and filtered. The filtrate was concentrated underreduced pressure to afford8-(hydroxymethyl)-1-(4-methoxybenzyl)-3-methyl-1H-purine-2,6(3H,7H)-dione(800 mg 42% yield) as orange solid. Retention time (LC-MS): 0.643min. MH.sup.+ 317.

Step 2N-(6-bromopyridin-2-yl)-2-(8-(hydroxymethyl)-1-(4-methoxybenzyl)-3--methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)acetamide

##STR00488##

A mixture of8-(hydroxymethyl)-1-(4-methoxybenzyl)-3-methyl-1H-purine-2,6(3H,7H)-dione(650 mg, 2.05 mmol), N-(6-bromopyridin-2-yl)-2-chloroacetamide (612mg, 2.46 mmol), potassium carbonate (568 mg 4.11 mmol), TBAI (76 mg0.21 mmol) and DMF (20 mL) was stirred at 50.degree. C. underN.sub.2 for 2 h. The reaction mixture was quenched by water (20mL), and then extracted with EA (3.times.5 mL). Combined organiclayers were washed with S. aq. LiCl (15 mL) and S. aq. NaCl (15mL), dried over Na.sub.2SO.sub.4 and filtered. The filtrate wasconcentrated and the residue was purified by chromatography (elutedwith DCM:MeOH=50:1) to affordN-(6-bromopyridin-2-yl)-2-(8-(hydroxymethyl)-1-(4-methoxybenzyl)-3-methyl--2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)acetamide (670 mg 61%yield) as a yellow solid. Retention time (LC-MS): 1.329 min.MH.sup.+ 529.

Step 3N-(6-(4-chlorophenyl)pyridin-2-yl)-2-(8-(hydroxymethyl)-1-(4-methox-y benzyl)-3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)

##STR00489##

To a mixture ofN-(6-bromopyridin-2-yl)-2-(8-(hydroxymethyl)-1-(4-methoxybenzyl)-3-methyl--2,6-dioxo-2,3-dihydro-1H-purin-7(6H,8H,9H)-yl)acetamide (200 mg,0.38 mmol) and 4-chlorophenylboronic acid (118 mg, 0.14 mmol) intoluene/EtOH/2N aq. Na.sub.2CO.sub.3 (6 mL/3 mL/1.5 mL) was addedPd(PPh.sub.3).sub.4 (44 mg, 0.04 mmol) after degassed three timesunder N.sub.2 atmosphere. The mixture was then heated to100.degree. C. for 2 h. The reaction mixture was cooled to r.t. andfiltered. The filtrate was extracted with EA (3.times.5 mL).Combined organic layers were dried over Na.sub.2SO.sub.4 andfiltered. The filtrate was concentrated and the residue waspurified by chromatography (eluted with DCM:MeOH=50:1) to affordN-(6-(4-chlorophenyl)pyridin-2-yl)-2-(8-(hydroxymethyl)-1-(4-metho-xybenzyl)-3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)acetamide(150 mg 57% yield) as brown solid. Retention time (LC-MS): 1.579min. MH.sup.+ 561.

Step 4N-(6-(4-chlorophenyl)pyridin-2-yl)-2-(8-(hydroxymethyl)-3-methyl-2,-6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)acetamide

##STR00490##

To a mixture ofN-(6-(4-chlorophenyl)pyridin-2-yl)-2-(8-(hydroxymethyl)-1-(4-methoxybenzy-l)-3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)acetamide (120mg, 0.303 mmol) in PhOMe (10 mL) was added AlCl.sub.3 (162 mg,1.212 mmol) at 0.degree. C. The mixture was stirred at 0.degree. C.for 10 min and at r.t. overnight. The reaction mixture was quenchedby conc. HCl (10 mL), and then extracted with EA (3.times.5 mL).Combined organic layers were washed with the S. aq. NaCl (15 mL),dried over Na.sub.2SO.sub.4 and filtered. The filtrate wasconcentrated under reduced pressure and the residue was purified bychromatography (eluted with DCM:MeOH=50:1) to affordN-(6-(4-chlorophenyl)pyridin-2-yl)-2-(8-(hydroxymethyl)-3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)acetamide(60 mg 51% yield) as a yellow solid. Retention time (LC-MS): 1.382min. MH.sup.+ 441.

Preparation 83N-(6-Bromo-pyridin-2-yl)-2-(8-hydroxymethyl-3-methyl-2,6-dioxo-1-pyridin--2-ylmethyl-1,2,3,6-tetrahydro-purin-7-yl)-acetamide

##STR00491##

Step 18-Hydroxymethyl-3-methyl-7-(2-trimethylsilanyl-ethoxymethyl)-3,7-di-hydro-purine-2,6-dione

##STR00492##

To mixture of 8-hydroxymethyl-3-methyl-3,7-dihydro-purine-2,6-dione(500 mg, 2.5 mmol), potassium carbonate (706 mg, 5 mmol) in DMF (5mL) was added SEMCl (0.5 mL, 3.0 mmol) at 0.degree. C. The mixturewas stirred at 0.degree. C. for 10 min and at r.t. overnight. Thereaction mixture was quenched with water (20 mL), and thenextracted with EA (3.times.5 mL). Combined organic layers werewashed with S. aq. LiCl (15 mL) and brine (15 mL), dried overNa.sub.2SO.sub.4 and filtered. The filtrate was concentrated underreduced pressure to give8-Hydroxymethyl-3-methyl-7-(2-trimethylsilanyl-ethoxymethyl)-3,7-dihydro--purine-2,6-dione (380 mg, yield 38%) as a white solid. Retentiontime (LC-MS): 1.165 min. MH.sup.+ 327.

Step 28-Hydroxymethyl-3-methyl-1-pyridin-2-ylmethyl-7-(2-trimethylsilanyl--ethoxymethyl)-3,7-dihydro-purine-2,6-dione

##STR00493##

A mixture of8-hydroxymethyl-3-methyl-7-(2-trimethylsilanyl-ethoxymethyl)-3,7-dihydro--purine-2,6-dione (380 mg, 0.96 mmol), 2-bromomethyl-pyridine (292mg, 1.15 mmol), Cs.sub.2CO.sub.3 (629 mg 1.92 mmol), TBAI (89 mg0.10 mmol) and DMF (5 mL) was stirred at 100.degree. C. underN.sub.2 for 2 h. The reaction mixture was quenched with water (20mL), and then extracted with EA (3.times.5 mL). Combined organiclayers were washed with s. aq. LiCl (15 mL) and brine (15 mL),dried over Na.sub.2SO.sub.4 and filtered. The filtrate wasconcentrated under reduced pressure and the residue was purified bychromatography (eluted with DCM:MeOH=50:1) to afford8-Hydroxymethyl-3-methyl-1-pyridin-2-ylmethyl-7-(2-trimethylsilanyl-ethox-ymethyl)-3,7-dihydro-purine-2,6-dione (300 mg, yield 62%) as awhite solid. Retention time (LC-MS): 1.059 min. MH.sup.+ 418.

Step 38-Hydroxymethyl-3-methyl-1-pyridin-2-ylmethyl-3,7-dihydro-purine-2,-6-dione

##STR00494##

A mixture of8-hydroxymethyl-3-methyl-1-pyridin-2-ylmethyl-7-(2-trimethylsilanyl-ethox-ymethyl)-3,7-dihydro-purine-2,6-dione (300 mg, 0.72 mmol) in 12 Naq. HCl/EtOH (3 mL/6 mL) was stirred at 90.degree. C. for 2 h. Themixture was cooled to r.t. and concentrated. The residue wasneutralized with 1N aq. NaOH at 0.degree. C. and concentrated toafford8-hydroxymethyl-3-methyl-1-pyridin-2-ylmethyl-3,7-dihydro-purine-2,6-dion-e (200 mg yield 97%) as a white solid. Retention time (LC-MS):0.366 min. MH.sup.+ 288.

Step 4N-(6-Bromo-pyridin-2-yl)-2-(8-hydroxymethyl-3-methyl-2,6-dioxo-1-py-ridin-2-ylmethyl-1,2,3,6-tetrahydro-purin-7-yl)-acetamide

##STR00495##

A mixture of8-hydroxymethyl-3-methyl-1-pyridin-2-ylmethyl-3,7-dihydro-purine-2,6-dion-e (200 mg, 0.70 mmol), N-(6-bromopyridin-2-yl)-2-chloroacetamide(208 mg, 0.84 mmol), potassium carbonate (192 mg 1.40 mmol), TBAI(26 mg 0.07 mmol) and DMF (3 mL) was stirred at 50.degree. C. underN.sub.2 for 2 h. The reaction mixture was quenched with water (20mL), and then extracted with EA (3.times.5 mL). Combined organiclayers were washed by the S. aq. LiCl (15 mL) and brine (15 mL).Then the organic layers were dried over Na.sub.2SO.sub.4 andfiltered. The filtrate was concentrated and the residue waspurified by chromatography (eluted with DCM:MeOH=30:1) to affordN-(6-bromo-pyridin-2-yl)-2-(8-hydroxymethyl-3-methyl-2,6-dioxo-1-p-yridin-2-ylmethyl-1,2,3,6-tetrahydro-purin-7-yl)-acetamide (300 mg,yield 87%) as a yellow solid. Retention time (LC-MS): 0.803 min.MH.sup.+ 500.

Preparation 84 N1-ethyl-N1-(trifluoromethyl)benzene-1,4-diamine

##STR00496##

Step 1 N-ethyl-4-nitroaniline

##STR00497##

A solution of 1-fluoro-4-nitrobenzene (2 g, 14.17 mmol) inEtNH.sub.2/THF solution (30 mL, 2 mmol/L) was stirred at 50.degree.C. in a sealed tube for 16 h. The mixture was concentrated todryness to give crude product which was purified by chromatography(eluted with PE:EA=5:1) to afford N-ethyl-4-nitroaniline (1.7 g,72.2% yield) as yellow solid. Retention time (LC-MS): 1.347 min.MH.sup.+ 167.

Step 2 Methyl ethyl(4-nitrophenyl)carbamodithioate

##STR00498##

To a solution of N-ethyl-4-nitroaniline (1 g, 6.01 mmol) in THF (30mL) was added dropwise n-BuLi (3 mL, 7.2 mmol) at -10.degree. C.After addition, the mixture was stirred at 0.degree. C. for 1 h.Carbon disulphide (0.91 g, 12.03 mmol) was added dropwise to theabove mixture and the reaction mixture was stirred at r.t. for 16h. Iodomethane (1.7 g, 12.03 mmol) was added to the mixture at0.degree. C. and the mixture was stirred at r.t. for 5 h. Themixture was quenched with saturated aqueous sodium bicarbonate (50mL) and extracted with EA (3.times.50 mL). Combined organic layerwere dried over Na.sub.2SO.sub.4 and concentrated under reducedpressure. The residue was purified by chromatography (eluted withPE:EA=3:1) to give methyl ethyl(4-nitrophenyl)carbamodithioate (350mg, 22.72% yield) as yellow syrup. .sup.1H-NMR (400 MHz,CDCl.sub.3) .delta. 8.33-8.35 (d, J=6.8 Hz, 2H), 7.43-7.45 (d,J=7.2 Hz, 2H), 4.32-4.36 (q, 2H), 2.52 (s, 3H), 1.26-1.30 (t,3H).

Step 3 N-ethyl-4-nitro-N-(trifluoromethyl)aniline

##STR00499##

To a solution of methyl ethyl(4-nitrophenyl)carbamodithioate (250mg, 0.975 mmol) in DCM (10 mL) was added tetrabutylammoniumdihydrogentrifluoride (1.47 g, 4.875 mmol). The mixture was stirredat RT for 10 min, followed by addition of1,3-dibromo-5,5-dimethylhydantoin (1.11 g, 3.9 mmol) in oneportion. The reaction mixture was stirred at r.t. for 3 hr, thenpoured into a mixture of aqueous NaHCO.sub.3/NaHSO.sub.3/NaOHsolution (10 mL, 1M:1M:1M) and extracted with EA (3.times.10 mL).Combined organic layer were washed with brine, dried overNa.sub.2SO.sub.4 and concentrated under reduced pressure. Theresidue was purified by chromatography (eluted with PE:EA=3:1) togive N-ethyl-4-nitro-N-(trifluoromethyl)aniline (140 mg, 61.7%yield) as yellow solid. .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.8.28-8.30 (d, J=8.8 Hz, 2H), 7.43-7.45 (br, 2H), 3.80-3.86 (q, 2H),2.52 (s, 3H), 1.25-1.31 (t, 3H).

Step 4 N1-ethyl-N1-(trifluoromethyl)benzene-1,4-diamine

##STR00500##

To a solution of N-ethyl-4-nitro-N-(trifluoromethyl)aniline (140mg, 0.598 mmol) in MeOH (3 mL) was added Pd/C (30 mg, 10%) underN.sub.2 atmosphere. The mixture was degassed under N.sub.2 forthree times and stirred under H.sub.2 balloon at r.t. for 16 h. Themixture was filtered and the filtrate was concentrated to giveN1-ethyl-N1-(trifluoromethyl)benzene-1,4-diamine (110 mg, 90%yield) as yellow oil, which was directly used to the next reactionwithout purification. Retention time (LC-MS): 0.602 min.

Preparation 85N-(6-(3-azabicyclo[3.1.0]hexan-3-yl)pyridin-2-yl)-2-chloroacetamide

##STR00501##

Step 1 3-(6-bromopyridin-2-yl)-3-azabicyclo[3.1.0]hexane

##STR00502##

To a solution of 3-azabicyclo[3.1.0]hexane hydrochloride (300 mg,2.51 mmol) in NMP (3 mL) was added 2,6-dibromopyridine (594.53 mg,12.51 mmol) and POTASSIUM CARBONATE (693.42 mg, 5.02 mmol). Themixture was heated in a sealed tube at 130.degree. C. for 6 hrs.The mixture was diluted with EA and water, and the organic layerwas washed with brine, dried over Na.sub.2SO.sub.4 and filtered.The filtrate was evaporated and the crude product obtained waspurified with column chromatography (PE:EA=100:1) to give3-(6-bromopyridin-2-yl)-3-azabicyclo[3.1.0]hexane (500 mg, 83.7%yield) as a white solid. Retention time (LC-MS): 1.798 min,MH.sup.+ 238.

Step 26-(3-azabicyclo[3.1.0]hexan-3-yl)-N-(diphenylmethylene)pyridin-2-am-ine

##STR00503##

To a solution of 3-(6-bromopyridin-2-yl)-3-azabicyclo[3.1.0]hexane(350 mg, 1.47 mmol), diphenylmethanimine (0.5 mL, 2.94 mmol), BINAP(91.62 mg, 0.15 mmol) and t-BuONa (282.65 mg, 2.49 mmol) in1,4-dioxane (10 mL) was added Pd.sub.2(dba) .sub.3 (134.71 mg, 0.15mmol). After the mixture was degassed and purged with N.sub.2 threetimes, it was stirred at 100.degree. C. under N.sub.2 for 1 h and.The mixture was cooled, filtered through Celite and the solids werewashed with EA. The filtrate was concentrated under reducedpressure to afford6-(3-azabicyclo[3.1.0]hexan-3-yl)-N-(diphenylmethylene)pyridin-2-amine(350 mg, 70.1% yield) as a brown oil, which was used for next stepwithout purification. Retention time (LC-MS): 1.541 min. MH.sup.+339.

Step 3 6-(3-azabicyclo[3.1.0]hexan-3-yl)pyridin-2-amine

##STR00504##

To a solution of6-(3-azabicyclo[3.1.0]hexan-3-yl)-N-(diphenylmethylene)pyridin-2-amine(400 mg, 1.18 mmol) in EtOH (20 mL) was added aqueous HCl (2 mL, 12M). The mixture was stirred at RT for 30 min. The mixture wasneutralized with saturated aqueous NaHCO.sub.3 to pH=7-8 andextracted with EA (3.times.50 mL). The combined organic layers werewashed with water and brine, dried over Na.sub.2SO.sub.4 andfiltered. The filtrate was evaporated to give the crude product,which was purified with column chromatography (PE:EA=50:1 to 10:1)to give the 6-(3-azabicyclo[3.1.0]hexan-3-yl)pyridin-2-amine (160mg, 77.4% yield) as a brown oil. Retention time (LC-MS): 0.364 min.MH.sup.+ 175.

Step 4N-(6-(3-azabicyclo[3.1.0]hexan-3-yl)pyridin-2-yl)-2-chloroacetamide

##STR00505##

To a solution of 6-(3-azabicyclo[3.1.0]hexan-3-yl)pyridin-2-amine(50 mg, 0.15 mmol) in pyridine (5 mL) was added dropwise2-chloroacetyl chloride (0.05 mL, 0.57 mmol) at 0.degree. C. Afteraddition, the mixture was warmed to RT and stirred for 3 hrs. Thereaction mixture was diluted with water (10 mL) and EA (15 mL). Theorganic layer was washed with brine, dried over Na.sub.2SO.sub.4and filtered. The filtrate was concentrated under reduced pressureand the residue was purified with column chromatography (PE:EA=20:1to 5:1) to affordN-(6-(3-azabicyclo[3.1.0]hexan-3-yl)pyridin-2-yl)-2-chloroacetamide(30 mg, 46.1% yield) as a white solid. Retention time (LC-MS):1.229 min. MH.sup.+ 252.

Preparation 862-chloro-N-(6-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyridine-2-yl)a-cetamide

##STR00506##

Step 13-(6-bromopyridin-2-yl)-6,6-difluoro-3-azabicyclo[3.1.0]hexane

##STR00507##

In a microwave reaction tube containing6,6-difluoro-3-azabicyclo[3.1.0]hexane hydrochloride (1, 190.0 mg,1.2 mmol), 2,6-dibromopyridine (287.8 mg, 1.2 mmol) was added NMP(4 mL) and TEA (248.0 mg, 2.5 mmol). The mixture was heated in aBiotage Microwave Initiator device at 150.degree. C. for 45 min.The mixture was poured into EA. The organic phase was washed withwater and brine, dried over Na.sub.2SO.sub.4 and filtered. Thefiltrate was concentrated under reduced pressure. The crude productwas purified by chromatography (eluted with PE:EA=8:1) to afford3-(6-bromopyridin-2-yl)-6,6-difluoro-3-azabicyclo[3.1.0]hexane (300mg, 89.3% yield) as a white solid. Retention time (LC-MS): 1.70min. MH.sup.+ 275.

Step 26-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-N-(diphenylmethylene--)pyridin-2-amine

##STR00508##

A solution of3-(6-bromopyridin-2-yl)-6,6-difluoro-3-azabicyclo[3.1.0]hexane (320mg, 1.2 mmol), diphenylmethanimine (0.4 mL, 2.3 mmol), BINAP (72.7mg, 0.1 mmol), Pd.sub.2(dba).sub.3 (107.0 mg, 0.1 mmol) and t-BuONa(224.5 mg, 2.3 mmol) in 1,4-dioxane (6 mL) was degassed withN.sub.2 and stirred at 100.degree. C. under nitrogen for 1 h. LCMSshowed the starting materials was consumed. The mixture wasextracted with EA. The organic layer was washed with brine, driedover Na.sub.2SO.sub.4 and concentrated to give6-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-N-(diphenylmethylene)188yr-idine-2-amine (350 mg, 85.2% yield) as a yellow solid. Retentiontime (LC-MS): 1.83 min. MH.sup.+ 376.

Step 36-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyridine-2-amine

##STR00509##

To a solution of6-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-N-(diphenylmethylene)pyrid-ine-2-amine (350 mg, 1.0 mmol) in EtOH (5 mL) was added conc.hydrochloride acid (12 M, 1 mL). The mixture was stirred at RT for1 h. Then mixture was neutralized with 1M aq. NaHCO.sub.3 solution.The mixture was extracted with EA, washed with brine, dried overNa.sub.2SO.sub.4 and concentrated. The residue was purified bychromatography (eluted with PE:EA=4:1) to afford6-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyridine-2-amine (300mg, 89.3% yield) as a white solid. Retention time (LC-MS): 0.35min. MH.sup.+ 212.

Step 42-chloro-N-(6-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyridine--2-yl)acetamide

##STR00510##

To a solution of6-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyridine-2-amine(160.0 mg, 0.8 mmol) in pyridine (3 mL) was added dropwise2-chloroacetyl chloride (0.09 mL, 1.1 mmol) at 0.degree. C. Themixture was stirred at RT for 1 hr and poured into EA. The organiclayer was separated, washed with water and brine, dried overNa2SO4, and concentrated to give2-chloro-N-(6-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyridine-2-yl)a-cetamide (200 mg, 91.9% yield) as a yellow solid. Retention time(LC-MS): 1.47 min. MH.sup.+ 288.

Preparation 872-chloro-N-(6-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)pyridin-2-yl)acetam-ide

##STR00511##

Step 1 1-(6-bromopyridin-2-yl)piperazine

##STR00512##

To a solution of 2,6-dibromopyridine (1.0 g, 4.22 mmol) in MeCN (20mL) was added piperazine (1.09 g, 12.66 mmol) and potassiumcarbonate (583.44 mg, 4.22 mmol). The mixture was stirred at85.degree. C. overnight. The mixture was concentrated and dilutedwith EA, washed with water, brine, dried over Na.sub.2SO.sub.4 andfiltered. The filtrate was evaporated to give the crude product.The crude product was purified by column chromatography(DCM/MeOH=100:1 to 50:1) to give the product. MeOH/HCl (5 mL) wasadded and concentrated to give 1-(6-bromopyridin-2-yl)piperazinehydrochloride (1.03 g, 87.5% yield) as a white solid. Retentiontime (LC-MS): 0.369 min. MH.sup.+ 242.

Step 21-(6-bromopyridin-2-yl)-4-(2,2,2-trifluoroethyl)piperazine

##STR00513##

To a mixture of 1-(6-bromopyridin-2-yl)piperazine hydrochloride(300 mg, 1.08 mmol) in DMF (10 mL) was added 2,2,2-trifluoroethyltrifluoromethanesulfonate (0.31 mL, 2.15 mmol) and potassiumcarbonate (446.51 mg, 3.23 mmol). The mixture was stirred at70.degree. C. for 3 h. The mixture was diluted with EA, washed withwater, brine, dried over Na.sub.2SO.sub.4 and filtered. Thefiltrate was evaporated to give the crude product. The crudeproduct was purified by column chromatography (PE/EA=10:1 to 1:2)to give 1-(6-bromopyridin-2-yl)-4-(2,2,2-trifluoroethyl)piperazine(320 mg, 91.7% yield) as a brown oil. Retention time (LC-MS): 1.826min. MH.sup.+ 325.

Step 3N-(diphenylmethylene)-6-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)pyr-idin-2-amine

##STR00514##

To a solution of1-(6-bromopyridin-2-yl)-4-(2,2,2-trifluoroethyl)piperazine (200 mg,0.62 mmol), diphenylmethanimine (0.21 mL, 1.23 mmol), BINAP (38.46mg, 0.062 mmol) and t-BuONa (118.64 mg, 1.23 mmol) in 1,4-dioxane(15 mL) was added Pd.sub.2(dba).sub.3 (56.54 mg, 0.062 mmol) underN.sub.2 atmosphere. The reaction mixture was stirred at 130.degree.C. under N.sub.2 for 2 h. The mixture was cooled and filteredthrough Celite, and the filtrate was extracted with EA (3.times.50mL). The combined organic layers were dried over Na.sub.2SO.sub.4and filtered. The filtrate was concentrated under reduced pressureand the residue was used to next step without purification toaffordN-(diphenylmethylene)-6-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)pyridin-2--amine (200 mg, 76.4% yield) as a brown oil. Retention time(LC-MS): 1.951 min. MH.sup.+ 425.

Step 46-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)pyridin-2-amine

##STR00515##

To a solution ofN-(diphenylmethylene)-6-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)pyridin-2--amine (200 mg, 0.47 mmol) in EtOH (10 mL) was added HC (1 mL, 12M). After stirred at rt for 3 h, the mixture was neutralized withaq. NaHCO.sub.3 to pH 7-8 and evaporated. The mixture was extractedwith EA (3.times.50 mL), washed with water, brine, dried overNa.sub.2SO.sub.4 and filtered. The filtrate was evaporated to givethe crude product. The crude product was purified by columnchromatography (PE/EA=10:1 to 1:1) to give6-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)pyridin-2-amine (100 mg,81.5% yield) as a brown oil. Retention time (LC-MS): 0.493 min.MH.sup.+ 261.

Step 52-chloro-N-(6-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)pyridin-2-yl)-acetamide

##STR00516##

To a solution of6-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)pyridin-2-amine (100 mg,0.38 mmol) in pyridine (3 mL) was added dropwise 2-chloroacetylchloride (0.06 mL, 0.77 mmol) at 0.degree. C. After addition, themixture was warmed to RT and stirred for 3 h. The reaction mixturewas quenched with water (10 mL). The mixture was neutralized withsaturated aqueous NH.sub.4Cl and extracted with EA. The organiclayer was washed with water, brine, dried over Na.sub.2SO.sub.4 andfiltered. The filtrate was concentrated under reduced pressure andthe residue was purified by chromatography (PE/EA=20:1 to 8:1) toafford2-chloro-N-(6-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)pyridin-2-yl)acetam-ide (15 mg, 11.5% yield) as a brown solid. Retention time (LC-MS):1.510 min. MH.sup.+ 337.

Preparation 882-chloro-N-(6'-(trifluoromethyl)-2,3'-bipyridin-6-yl)acetamide

##STR00517##

To a mixture of 6'-(trifluoromethyl)-2,3'-bipyridin-6-amine (60 mg,0.25 mmol) and DMF (3 mL) was added dropwise 2-chloroacetylchloride (34.1 mg, 0.301 mmol) at 0.degree. C. The mixture wasstirred at RT overnight and poured into EA. The organic phase wasseparated, washed with water and brine, dried over Na2SO4, andconcentrated and the residue was purified by chromatography to give2-chloro-N-(6'-(trifluoromethyl)-2,3'-bipyridin-6-yl)acetamide. (75mg, 94.7% yield) as a white solid. Retention time (LC-MS): 1.440min. MH.sup.+ 316.

Preparation 892-chloro-N-(2-(5-methyl-6-(trifluoromethyl)pyridin-3-yl)thiazol-4-yl)acet-amide

##STR00518##

To a solution of2-(5-methyl-6-(trifluoromethyl)pyridin-3-yl)thiazol-4-amine (60 mg,0.23 mmol) in DMF (2 mL) was added 2-chloroacetyl chloride (0.04mL, 0.46 mmol) at 0.degree. C. After the addition, the mixture wasstirred at RT for 1 h. The reaction mixture was quenched by water(10 mL) and diluted with EA (15 mL). The organic layer wasseparated, washed with saturated aq. NH.sub.4Cl (10 mL) and brine(10 mL), dried over Na.sub.2SO.sub.4 and filtered. The filtrate wasconcentrated and the residue was purified by chromatography (elutedwith PE:EA=15:1) to afford2-chloro-N-(2-(5-methyl-6-(trifluoromethyl)pyridin-3-yl)thiazol-4-yl)acet-amide (70 mg, 90.1% yield) as a white solid. Retention time(LC-MS): 1.519 min. MH.sup.+ 336.

Preparation 902-chloro-N-(2-(6-methyl-5-(trifluoromethyl)pyridin-3-yl)thiazol-4-yl)acet-amide

##STR00519##

To a solution of2-(6-methyl-5-(trifluoromethyl)pyridin-3-yl)thiazol-4-amine (170mg, 0.656 mmol) in DMF (5 mL) was added 2-chloroacetyl chloride(105 mg, 925.74 mmol) drop-wise at 0.degree. C. The mixture wasstirred at RT for 1 h. The mixture was diluted with EA and washedwith water and brine, dried over Na.sub.2SO.sub.4 and filtered. Thefiltrate was concentrated under reduced pressure. The filtrate wasconcentrated and the residue was purified by chromatography(PE/EA=5:1) to afford2-chloro-N-(2-(6-methyl-5-(trifluoromethyl)pyridin-3-yl)thiazol-4-yl)acet-amide (200 mg, 91% yield) as a yellow solid. Retention time(LC-MS): 1.494 min. MH.sup.+ 335.

Preparation 912-(3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)-N-(6'-methyl-5'-(tri-fluoromethyl-[2,3'-bipyridin]-6-yl)acetamide

##STR00520##

Step 1 ethyl2-(3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)acetate

##STR00521##

To a suspension of 3-methyl-1H-purine-2,6(3H,7H)-dione (10 g, 60.19mmol) in DMF (160 mL) was added potassium carbonate (16.64 g,120.38 mmol). The reaction was stirred by a mechanical stirrer,heated at 90.degree. C. for 3 h, cooled to RT then ethyl2-bromoacetate (6.66 mL, 60.19 mmol) dissolved in DMF (40 mL) wasadded drop wise over 1 h. The heterogeneous white reaction wasrapidly stirred for 18 h, cooled in an ice bath, water (240 ml) wasadded, stirred for 15 min then filtered the insoluble solid. Thesolid was washed with water (100 ml) and MeOH (4.times.50 mL) thendried to give ethyl2-(3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)acetate (8.30g, 55% yield) as a white solid. LCMS: MH.sup.+ 253 andR.sub.t=1.454 min.

Step 2 2-(3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)aceticAcid

##STR00522##

Ethyl 2-(3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)acetate(8.20 g, 32.51 mmol) was slurried in aq. HCl (3M, 162.6 mL, 487.66mmol). The reaction was heated at reflux for 30 min, cooled to RTand filtered the insoluble solid. The solid was washed with water(2.times.20 mL), MeOH (2.times.20 mL) and Ether (50 mL) thenazeotroped with toluene (2.times.25 mL) and dried to give2-(3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)acetic acid(7.29 g, 100% yield) as a white solid. LCMS: MH.sup.+225 andR.sub.t=0.40 min.

Step 32-(3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)-N-(6'-methyl-5-'-(trifluoromethyl)-[2,3-bipyridin]-6-yl)acetamide

##STR00523##

2-(3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)acetic acid(0.531 g, 2.37 mmol),6'-methyl-5'-(trifluoromethyl)-[2,3'-bipyridin]-6-amine (0.40 g,1.58 mmol) and EDCI (1.21 g, 6.32 mmol) were combined in pyridine(24 mL). The reaction was heated at 100.degree. C. for 18 h, cooledto RT and EA (100 mL) was added. The insoluble solid was filteredoff, washed with water (2.times.15 mL), EA (30 mL) and dried togive2-(3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)-N-(6'-methyl-5'-(tri-fluoromethyl)-[2,3-bipyridin]-6-yl)acetamide (0.72 g, 100% yield)as a tan solid. LCMS MH.sup.+460 and R.sub.t=2.615. Used withoutfurther purification.

Preparation 922-(3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)-N-6-(6-methyl-5-(tri-fluoromethyl) pyridin-3-yl)pyrazin-2-yl)acetamide

##STR00524##

2-(3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)acetic acid(0.661 g, 2.95 mmol),6-(6-methyl-5-(trifluoromethyl)pyridin-3-yl)pyrazin-2-amine (0.50g, 1.58 mmol) and EDCI (1.51 g, 7.88 mmol) were combined inpyridine (30 mL). The reaction was heated at 100.degree. C. for 18h, cooled to RT and aq. NH.sub.4Cl (100 mL) was added. The mixturewas stirred for 20 min an insoluble solid formed and was filteredoff. The solid was washed with EA (2.times.20 mL), dried to give2-(3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)-N-6-(6-methyl-5-(tri-fluoromethyl)pyridin-3-yl)pyrazin-2-yl)acetamide (494 mg, 54.4%yield) as a tan solid. LCMS MH.sup.+461 and R.sub.t=2.341. Usedwithout further purification.

Preparation 933-methyl-1-(2-oxopropyl)-8-(pyridine-4-yl)-1H-purine-2,6(3H,7H)-dione

##STR00525##

Step 18-Bromo-3-methyl-7-((2-trimethylsilyl)ethoxy)methyl-1H-purine-2,6(3-H,7H)-dione

##STR00526##

8-bromo-3-methyl-1H-purine-2,6(3H,7H)-dione (5 g, 20.41 mmol) andpotassium carbonate (8.46 g, 61.23 mmol) were combined in DMF (50mL), cooled to 0.degree. C. and 2-(trimethylsilyl)ethoxymethylchloride (3.61 mL, 20.41 mmol) was added drop wise. The reactionwas stirred at RT for 3 h, diluted with water (300 mL) andextracted with EA (3.times.100 mL). Pooled organic layers werewashed with aq. 1N LiCl (2.times.150 mL), dried with MgSO.sub.4 andconcentrated to give8-bromo-3-methyl-7-((2-trimethylsilyl)ethoxy)methyl-1H-purine-2,6(3H,7H)--dione (7.0 g, 91.3% yield) as a white solid. Used without furtherpurification.

Step 28-Bromo-3-methyl-1-(2-oxopropyl)-7-((2-(trimethylsilyl)ethoxy)methy-l)-1H-purine-2,6(3H,7H)-dione

##STR00527##

8-bromo-3-methyl-7-((2-trimethylsilyl)ethoxy)methyl-1H-purine-2,6(3H,7H)--dione (2.0 g, 5.33 mmol), potassium carbonate (1.47 g, 10.66 mmol)and 1-chloropropane (0.64 mL, 7.99 mmol) were combined in DMF (20mL). The reaction was heated at 70.degree. C. for 3 h, cooled toRT, diluted with water (100 mL) and extracted with EA (3.times.75mL). Combined organic layers were washed with aq. 1N LiCl(2.times.100 mL), dried with MgSO.sub.4 and concentrated to aresidue which was purified by chromatography eluted with EA/Hep(10:90 to 25:75) to give8-bromo-3-methyl-1-(2-oxopropyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-1H--purine-2,6(3H,7H)-dione (1.48 g, 64.35 yield) as a white solid.

Step 33-Methyl-1-(2-oxopropyl)-8-(pyridine-4-yl)-7-((2-(trimethylsilyl)et-hoxy)-methyl)-1H-purine-2,6(3H,7H)-dione

##STR00528##

8-bromo-3-methyl-1-(2-oxopropyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-1H--purine-2,6(3H,7H)-dione (250 mg, 0.580 mmol), potassium carbonate(192 mg, 1.392 mmol) and pyridine-4-ylboronic acid (71 mg, 0.580mmol) were combined in EtOH (4 mL), water (0.6 mL) and toluene (0.6mL). The mixture was degassed with Argon then Pd(Ph.sub.3).sub.4(67 mg, 0.058 mmol) was added. The reaction was heated at70.degree. C. for 18 h then concentrated to a residue which waspurified by chromatography eluted with EA/Hep (20:80 to 100:0) togive3-methyl-1-(2-oxopropyl)-8-(pyridine-4-yl)-7-((2-(trimethylsilyl)ethoxy)m-ethyl)-1H-purine-2,6(3H,7H)-dione (210 mg, 84.3% yield) as a whitesolid. .sup.1H NMR (CDCl.sub.3) .delta.: 8.84 (d, J=8 Hz), 8.43 (d,J=8 Hz, 2H),5.95 (s, 2H), 4.88 (s, 2H), 3.89 (t, J=12 Hz, 2H), 3.62(s, 2H), 2.30 (s, 3H), 1.01 (t, J=8 Hz, 2H), 0.01 (s, 9H). LCMSMH.sup.+ 430 and R.sub.t=3.178 min.

Step 43-Methyl-1-(2-oxopropyl)-8-(pyridine-4-yl)-1H-purine-2,6(3H,7H)-dio-ne

##STR00529##

3-methyl-1-(2-oxopropyl)-8-(pyridine-4-yl)-7-((2-(trimethylsilyl)ethoxy)m-ethyl)-1H-purine-2,6(3H,7H)-dione (210 mg, 0.489 mmol) wasdissolved in EtOH (5 mL) and concentrated HCl (1 mL). The reactionwas heated at reflux for 1 h, cooled to RT and filtered theinsoluble solid. The solid was washed with EtOH (2.times.5 mL) anddried to give3-methyl-1-(2-oxopropyl)-8-(pyridine-4-yl)-1H-purine-2,6(3H,7H)-dione(82 mg, 56.2% yield) as a yellow solid. .sup.1H NMR (DMSO-d6).delta.: 8.88 D, J=8 Hz, 2H), 8.33 (d, J=8 Hz, 2H), 4.79 (s, 2H),3.52 (s, 3H), 2.22 (s, 3H). LCMS: MH.sup.+ 300 and R.sub.t=1.414min.

Preparation 94 (S)-methyl2-(3-methyl-2,6-dioxo-1-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-purin-7(6H)--yl)propanoate

##STR00530##

A mixture of (S)-methyl2-(3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)propanoate (200mg, 0.792 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate(184 mg, 0.792 mmol), potassium carbonate (109 mg, 0.792 mmol) anda catalytic amount of TBAI in N, N-dimethyl formamide (5 mL) wasstirred at 50.degree. C. for 2 hrs. The mixture was cooled down andpoured into EA. The organic phase was separated, washed with waterand brine, dried over Na.sub.2SO.sub.4 and filtered. The filtratewas concentrated under reduced pressure. The filtrate wasconcentrated and the residue was purified by chromatography(PE/EA=1:1) to afford (S)-methyl2-(3-methyl-2,6-dioxo-1-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-purin-7(6H)--yl)propanoate (250 mg, 94% yield) as a white solid. Retention time(LC-MS): 0.905 min. MH.sup.+334.

Preparation 952-(3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)-N-(2-(6-methyl-5-(tr-ifluoromethyl)pyridin-3-yl)thiazol-4-yl)acetamide

##STR00531##

A mixture of2-chloro-N-(2-(6-methyl-5-(trifluoromethyl)pyridin-3-yl)thiazol-4-yl)acet-amide (120 mg, 0.302 mmol), 3-methyl-1H-purine-2,6(3H,7H)-dione (60mg, 0.302 mmol), potassium carbonate (42.5 mg, 0.302 mmol) and acatalytic amount of TBAI in N, N-dimethylformamide (10 mL) wasstirred at 50.degree. C. for 2 hrs. The mixture was cooled down andpoured into EA. The organic phase was separated, washed with waterand brine, dried over Na.sub.2SO.sub.4 and filtered. The filtratewas concentrated under reduced pressure. The filtrate wasconcentrated and the residue was purified by chromatography(DCM/MeOH=20:1) to afford2-(3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)-N-(2-(6-methyl-5-(tr-ifluoromethyl)pyridin-3-yl)thiazol-4-yl)acetamide (140 mg, 83%yield) as a white solid. R.sub.t (LC-MS): 1.340 min.MH.sup.+465.

Preparation 96(2S)--N-(6-(2-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)-pyrazin-2-yl)-2-(3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)propanam-ide

##STR00532##

To a solution of(2S)--N-(6-(2-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)-pyrazin-2-yl)-2-(3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)propanam-ide (115.1 mg, 0.40 mmol) in DCM (2 mL) was added drop-wisetrimethylaluminum (1.60 mL, 1.60 mmol) at 0.degree. C. After theaddition, the mixture was warmed to RT and stirred for 0.5 h. Thena solution of (S)-methyl2-(3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)propanoate(100.0 mg, 0.40 mmol) in DCM (2 mL) was added drop-wise and thereaction mixture was stirred at 30.degree. C. overnight. Thereaction was quenched by addition of several drops of MeOH. Themixture was concentrated under reduced pressure and the residue waspurified by chromatography (DCM:MeOH=100:1) to afford a crudeproduct, which was further purified via preparative TLC(DCM:MeOH=20:1) to give(2S)--N-(6-(2-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)-pyrazin-2-yl)-2-(3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)propanam-ide (6 mg, 3.0% yield) as a white solid. R.sub.t (LC-MS): 1.274min. LC-MS: m/z: 511. .sup.1H NMR (400 MHz, DMSO) .delta. 11.34 (s,1H), 11.17 (s, 1H), 9.13 (s, 1H), 9.07 (s, 2H), 8.93 (s, 1H), 8.32(s, 1H), 5.81 (s, 1H), 4.00 (d, J=12.2 Hz, 2H), 3.86 (d, J=11.0 Hz,2H), 3.38 (s, 3H), 2.72 (d, J=11.2 Hz, 2H), 1.86 (d, J=7.3 Hz,3H).

Preparation 97(S)-2-(3-methyl-1-((5-methyl-1,2,4-oxadiazol-3-yl)methyl)-2,6-dioxo-2,3-d-ihydro-1H-purin-7(6H)-yl)-N-(6'-methyl-5'-(trifluoromethyl)-2,3'-bipyridin--6-yl)propanamide

##STR00533##

Step 1 (5-methyl-1,2,4-oxadiazol-3-yl)MeOH

##STR00534##

To a solution of ethyl 5-methyl-1,2,4-oxadiazole-3-carboxylate (2.0g, 12.8 mmol) in EtOH (20 mL) was added NaBH.sub.4 (0.97 g, 25.6mmol) at RT. The reaction was stirred at RT for overnight. Thereaction mixture was concentrated under reduced pressure and theresidue was purified by chromatography (DCM/MeOH=100:1 to 40:1) togive (5-methyl-1,2,4-oxadiazol-3-yl)MeOH (500 mg, 34.2% yield) as acolorless oil. Retention time (LC-MS): 0.385 min. .sup.MH+ 115.

Step 2 (5-methyl-1,2,4-oxadiazol-3-yl)methyl methanesulfonate

##STR00535##

To a solution of (5-methyl-1,2,4-oxadiazol-3-yl)MeOH (100.0 mg,0.88 mmol) and TEA (0.14 mL, 0.96 mmol) in DCM (3 mL) was cooledunder ice-water bath to 0.degree. C., followed by drop-wiseaddition of methanesulfonyl chloride (0.08 mL, 0.96 mmol). Theice-water bath was removed after the addition and the mixture wasstirred at RT overnight. The reaction mixture was washed with water(5 mL). The organic layer was separated, dried overNa.sub.2SO.sub.4 and filtered. The filtrate was concentrated underreduced pressure and the residue was purified by chromatography(DCM/MeOH=50:1) to give (5-methyl-1,2,4-oxadiazol-3-yl)methylmethanesulfonate (100 mg, 86.08% yield) as a colorless oil.Retention time (LC-MS): 0.324 min. .sup.MH+ 193.

Step 3 (S)-methyl2-(3-methyl-1-((5-methyl-1,2,4-oxadiazol-3-yl)methyl)-2,6-dioxo-2,3-dihyd-ro-1H-purin-7(6H)-yl)propanoate

##STR00536##

A mixture of (5-methyl-1,2,4-oxadiazol-3-yl)methyl methanesulfonate(100.0 mg, 0.52 mmol), (S)-methyl2-(3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)propanoate(130.0 mg, 0.52 mmol), potassium carbonate (143.0 mg, 1.03 mmol)and a catalytic amount of TBAI in N, N-dimethylformamide (1 mL) wasstirred at 50.degree. C. overnight. The mixture was diluted with EAand washed with water, brine successively, dried and concentratedto give crude product, which was purified by chromatography(DCM/MeOH=50:1) to give (S)-methyl2-(3-methyl-1-((5-methyl-1,2,4-oxadiazol-3-yl)methyl)-2,6-dioxo-2,3-dihyd-ro-1H-purin-7(6H)-yl)propanoate (150 mg, 63.7% yield) as acolorless oil. Retention time (LC-MS): 0.537 min. LC-MS: m/z:349.

Preparation 98(2-(3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)-N-(2-(5-methyl-6-(t-rifluoromethyl)pyridin-3-yl)thiazol-4-yl)acetamide

##STR00537##

To a solution of2-chloro-N-(2-(5-methyl-6-(trifluoromethyl)pyridin-3-yl)thiazol-4-yl)acet-amide (130 mg, 0.39 mmol) and 3-methyl-1H-purine-2,6(3H,7H)-dione(64.33 mg, 0.39 mmol) in DMF (5 mL) was added TBAI (14.30 mg, 0.039mmol) and POTASSIUM CARBONATE (107.03 mg, 0.77 mmol) under N.sub.2protection. The mixture was stirred at 50.degree. C. for 2 hrs. Thereaction was quenched by water (15 mL) and extracted with EA(2.times.15 mL). The combined organic layer was washed withsaturated brine (2.times.15 mL), dried over Na.sub.2SO.sub.4 andfiltered. The filtrate was concentrated. The crude product waspurified by chromatography (DCM:MeOH=100:1 to 40:1) to afford2-(3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)-N-(2-(5-methyl-6-(tr-ifluoromethyl)pyridin-3-yl)thiazol-4-yl)acetamide (70 mg, 38.9%yield) as a yellow solid. Retention time (LC-MS): 1.156 min.MH.sup.+ 466.

Preparation 996-(5-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyrazin-2-yl)pyridin-2-a-mine

##STR00538##

A mixture of3-(5-bromopyrazin-2-yl)-6,6-difluoro-3-azabicyclo[3.1.0]hexane (500mg, 1.81 mmol), 6-bromopyridin-2-amine (374 mg, 2.17 mmol), LiCl(76.0 mg, 1.81 mmol) and 2,6-di-tert-butyl-4-methylphenol (39.6 mg,0.18 mmol) in 1,4-dioxane (10 mL) was degassed with N.sub.2 forthree times and tetrakis(triphenylphosphine)palladium (104 mg, 0.09mmol) was added under N.sub.2 atmosphere. The mixture was degassedagain and hexa-n-butylditin (2.09 g, 3.62 mmol) was added, thereaction mixture was stirred under N.sub.2 at 110.degree. C. overtwo nights. The mixture was concentrated to dryness and the crudeproduct was purified column chromatography (DCM/MeOH=50:1 to 20:1)to give6-(5-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyrazin-2-yl)pyridin-2-a-mine (140 mg. 26.7% yield) as a yellow solid. Retention time(LC-MS): 1.038 min. MH.sup.+ 290.

Preparation 1002'-(3-azabicyclo[3.1.0]hexan-3-yl)-2,5'-bipyrimidin-4-amine

##STR00539##

To a mixture of 2-chloropyrimidin-4-amine (100.0 mg, 0.772 mmol),2-(3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-ylboronic acid (158.0mg, 0.772 mmol) in 1,4-dioxane (5 mL) and H.sub.2O (1 mL) was addedNa.sub.2CO.sub.3 (204.5 mg, 1.93 mmol). After the mixture wasdegassed with N.sub.2 for 3 times, Pd(PPh.sub.3).sub.4 (11.5 mg,0.01 mmol) was added under N.sub.2 and the mixture was stirred at90.degree. C. for 2 hrs. The reaction mixture was cooled down anddiluted with EA, washed with water and brine, dried overNa.sub.2SO.sub.4 and filtered. The filtrate was concentrated underreduced pressure and the residue was purified by chromatography(eluted with PE:EA=1:1) to afford2'-(3-azabicyclo[3.1.0]hexan-3-yl)-2,5'-bipyrimidin-4-amine (124mg, 63.17% yield) as a yellow solid. Retention time (LC-MS): 0.573min. MH.sup.+ 255.

Preparation 1016-(2-(3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)pyrazin-2-amine

##STR00540##

To a mixture of 6-chloropyrazin-2-amine (100.0 mg, 0.772 mmol),2-(3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-ylboronic acid (158.0mg, 0.772 mmol) in 1,4-dioxane (5 mL) and H.sub.2O (1 mL) was addedpotassium carbonate (266.0 mg, 1.93 mmol). After the mixture wasdegassed with N.sub.2 for 3 times, Pd(PPh.sub.3).sub.4 (11.5 mg,0.01 mmol) was added under N.sub.2 and the mixture was stirred at90.degree. C. for 2 hrs. The reaction mixture was cooled down anddiluted with EA, washed with water and brine, dried overNa.sub.2SO.sub.4 and filtered. The filtrate was concentrated underreduced pressure and the residue was purified by chromatography(eluted with PE:EA=1:1) to afford6-(2-(3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)pyrazin-2-amine(160 mg, 81.51% yield) as a yellow solid. Retention time (LC-MS):1.071 min. MH.sup.+255.

Preparation 102(S)-2-(3-methyl-2,6-dioxo-1-(2-oxobutyl)-2,3-dihydro-1H-purin-7(6H)-yl)pr-opanoic Acid

##STR00541##

Step 1 (S)-methyl2-(3-methyl-2,6-dioxo-1-(2-oxobutyl)-2,3-dihydro-1H-purin-7(6H)-yl)propan-oate

##STR00542##

A mixture of 1-bromobutan-2-one (407 mg, 2.69 mmol), (S)-methyl2-(3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)propanoate (523mg, 2.07 mmol) and potassium carbonate (429 mg, 3.11 mmol) in DMF(15 mL) was stirred at rt overnight. The mixture was diluted withEA and washed with water and brine successively, dried, andconcentrated, and the resulting residue was purified bychromatography (EA:heptane 0-100%) to give (S)-methyl2-(3-methyl-2,6-dioxo-1-(2-oxobutyl)-2,3-dihydro-1H-purin-7(6H)-yl)propan-oate (449 mg, 67% yield) as a colorless oil. MH+ 323.

Step 2(S)-2-(3-methyl-2,6-dioxo-1-(2-oxobutyl)-2,3-dihydro-1H-purin-7(6H)--yl)propanoic Acid

##STR00543##

A mixture of (S)-methyl2-(3-methyl-2,6-dioxo-1-(2-oxobutyl)-2,3-dihydro-1H-purin-7(6H)-yl)propan-oate (390 mg, 1.21 mmol) and HCl (1M, 2.5 mL) in dioxane (5 mL) wasstirred at 110.degree. C. for 2 h. The reaction mixture was pouredinto water (50 mL) and extracted with EA (2.times.50 mL). Thecombined organic layers were dried over Na.sub.2SO.sub.4 andfiltered. The filtrate was concentrated under reduced pressure andthe residue was purified by chromatography (DCM:MeOH=20:1) toafford(S)-2-(3-methyl-2,6-dioxo-1-(2-oxobutyl)-2,3-dihydro-1H-purin-7(6H)-yl)pr-opanoic acid (224 mg, 60% yield) as a yellow oil. MH.sup.+ 309.

Compound 1.(2S)-2-(3-methyl-2,6-dioxo-1-(pyridin-2-ylmethyl)-1,2,3,6-tetrahydropurin-7-yl)-N-(6-(6-(trifluoromethyl)pyridin-3-yl)pyridin-2-yl)propanamid-e

##STR00544##

To a solution of (S)-methyl6-(6-(trifluoromethyl)pyridin-3-yl)pyridin-2-amine (20 mg, 0.084mmol) in DCM (1 mL) was added dropwise trimethylaluminium (0.06 mL,2.0 M) at 0.degree. C. via syringe under N.sub.2 atmosphere. Afterthe addition, the mixture was stirred at RT for 20 min, then asolution of (S)-methyl2-(3-methyl-2,6-dioxo-1-(pyridin-2-ylmethyl)-1,2,3,6-tetrahydropurin-7-yl-)propanoate (28 mg, 0.084 mmol) in dry DCM was added. The reactionsolution was stirred for 3 hr, and then quenched with water (5 mL).The reaction mixture was extracted with DCM (3.times.3 mL).Combined organic layers were dried over Na.sub.2SO.sub.4 andfiltered. The filtrate concentrated under reduced pressure and theresidue was purified by pre-TLC to afford(2S)-2-(3-methyl-2,6-dioxo-1-(pyridin-2-ylmethyl)-1,2,3,6-tetrahydropurin--7-yl)-N-(6-(6-(trifluoromethyl)pyridin-3-yl)pyridin-2-yl)propanamide(20 mg, 43.4% yield) as a white solid. 1H-NMR (400 MHz,DMSO-d.sub.6) .delta. 11.17 (s, 1H), 9.40 (s, 1H), 8.68 (t, J=1.2Hz, 1H), 8.38 (s, 2H), 8.02 (d, J=8.4 Hz, 2H), 7.95 (t, J=7.6 Hz,1H), 7.88 (d, J=7.6 Hz, 1H), 7.68 (t, J=6.4 Hz, 1H), 7.18 (s, 1H),5.80 (d, J=5.6 Hz, 1H), 5.11 (s, 2H), 3.57 (s, 3H), 1.85 (d, J=7.6Hz, 3H). Retention time (LC-MS): 1.441 min. MH.sup.+ 551.

Compound 2.(S)-2-(3-methyl-2,6-dioxo-1-(2-oxopropyl)-2,3-dihydro-1H-purin-7(6H)-yl)--N-(6'-(trifluoromethyl)-[2,3'-bipyridin]-6-yl)propanamide

##STR00545##

To a solution of 6'-(trifluoromethyl)-[2,3'-bipyridin]-6-amine(59.8 mg, 0.25 mmol) and(S)-2-(3-methyl-2,6-dioxo-1-(2-oxopropyl)-2,3-dihydro-1H-purin-7(6H)-yl)p-ropanoic acid (73.5 mg, 0.25 mmol) in DCM (3 mL) was added HOAt(40.8 mg, 0.3 mmol) at r.t. The reaction mixture was cooled underice-water bath to 0.degree. C., followed by slow dropwise additionof pyridine (39.5 mg, 0.5 mmol) and DIC (47.2 mg, 0.4 mmol) underN.sub.2 protection. The ice-water bath was removed after theaddition and the mixture was stirred at r.t. for 18 h. The reactionmixture was washed with water (5 mL), and S. aq. NH.sub.4Cl (5 mL).The organic layer was separated, dried over Na.sub.2SO.sub.4 andfiltered. The filtrate was concentrated under reduced pressure andthe residue was purified via prep-TLC (eluted with PE:EA=1:1) toafford the title product (80 mg, 62.1% yield) as a white solid..sup.1HNMR (400 MHz, DMSO-d.sub.6) .delta. 11.20 (s, 1H), 9.45 (s,1H), 8.71 (d, J=8.1 Hz, 1H), 8.39 (s, 1H), 8.07 (t, J=8.1 Hz, 2H),7.98 (t, J=7.9 Hz, 1H), 7.92 (d, J=7.7 Hz, 1H), 5.79 (s, 1H), 4.70(d, J=2.5 Hz, 2H), 3.46 (s, 3H), 2.16 (s, 3H), 1.88 (d, J=7.3 Hz,3H). Retention time (LC-MS): 2.28 min. MH.sup.+ 516.

Compound 3.(S)-2-(3-methyl-2,6-dioxo-1-(2-oxopropyl)-2,3-dihydro-1H-purin-7(6H)-yl)--N-(6-(6-(trifluoromethyl)pyridin-3-yl)pyrazin-2-yl)propanamide

##STR00546##

This compound was prepared using the method described for compound2 with appropriate starting materials. .sup.1HNMR (400 Hz,DMSO-d.sub.6) .delta. 11.57 (s, 1H), 9.48 (s, 1H), 9.30 (s, 1H),9.18 (s, 1H), 8.76 (d, J=8.0 Hz, 1H), 8.42 (s, 1H), 8.14 (d, J=8.3Hz, 1H), 5.80 (d, J=6.9 Hz, 1H), 4.78-4.59 (m, 2H), 3.47 (s, 3H),2.16 (s, 3H), 1.91 (d, J=7.2 Hz, 3H). Retention time (LC-MS): 2.055min. MH.sup.+ 517.1.

Compound 4.(S)-2-(3-methyl-2,6-dioxo-1-(2-oxopropyl)-2,3-dihydro-1H-purin-7(6H)-yl)--N-(6-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-2-yl)propanamide

##STR00547##

This example was prepared using the similar method described inExample 2 with appropriate starting materials. .sup.1HNMR (400 MHz,DMSO-d.sub.6) .delta. 10.70 (s, 1H), 9.66 (s, 1H), 8.40 (s, 1H),8.10-8.12 (d, J=7.6 Hz, 1H), 7.98-8.01 (m, 2H), 5.78-5.79 (m, 1H),4.70 (s, 2H), 3.64 (s, 3H), 2.16 (s, 3H), 1.87-1.89 (d, J=7.2 Hz,3H). Retention time (LC-MS): 2.217 min. MH.sup.+ 517.1.

Compound 5.(S)-2-(3-methyl-2,6-dioxo-1-(pyridin-2-ylmethyl)-2,3-dihydro-1H-purin-7(6-H)-yl)-N-(6-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-2-yl)propanamide

##STR00548##

This compound was prepared using the method described for Compound2 with appropriate starting materials. .sup.1H NMR (400 Hz,DMSO-d.sub.6) .delta. 11.26 (s, 1H), 9.65 (s, 2H), 8.40 (d, J=7.1Hz, 2H), 8.10 (d, J=7.8 Hz, 1H), 8.06-7.94 (m, 2H), 7.69 (td,J=7.7, 1.7 Hz, 1H), 7.25-7.16 (m, 2H), 5.90-5.73 (m, 1H), 5.20-5.07(m, 2H), 3.48 (s, 3H), 1.88 (d, J=7.3 Hz, 3H). Retention time(LC-MS): 2.128 min. MH.sup.+ 552.

Compound 6.(S)-2-(3-methyl-2,6-dioxo-1-(2-oxopropyl)-2,3-dihydro-1H-purin-7(6H)-yl)--N-(6-(2-(trifluoromethyl)pyrimidin-5-yl)pyrazin-2-yl)propanamide

##STR00549##

This compound was prepared using the method described for Compound2 with appropriate starting materials. 1H NMR (400 MHz,DMSO-d.sub.6) .delta. 11.64 (s, 1H), 9.71 (s, 2H), 9.35 (s, 1H),9.23 (s, 1H), 8.42 (s, 1H), 5.80 (d, J=7.2 Hz, 1H), 4.70 (s, 2H),3.47 (s, 3H), 2.16 (s, 3H), 1.90 (d, J=7.3 Hz, 3H). Retention time(LC-MS): 2.21 min. MH.sup.+ 518.

Compound 7.(S)-2-(3-methyl-1-((5-methylisoxazol-3-yl)methyl)-2,6-dioxo-2,3-dihydro-1-H-purin-7(6H)-yl)-N-(6'-(trifluoromethyl)-[2,3'-bipyridin]-6-yl)propanamid-e

##STR00550##

To a solution of(S)-2-(3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)-N-(6'-(trifluoro-methyl)-[2,3'-bipyridin]-6-yl)propanamide (27 mg, 0.059 mmol) andpotassium carbonate (8.1 mg, 0.059 mmol) in DMF (1 mL) was added3-(bromomethyl)-5-methylisoxazole (10 mg, 0.059 mmol). The mixturewas stirred at rt overnight. The mixture was diluted with EA andwashed with water, saturated aqueous NH.sub.4Cl solution and brine,dried over Na.sub.2SO.sub.4, and evaporated. The residue waspurified by silica gel column chromatography (0-2% MeOH/DCM) togive the product(S)-2-(3-methyl-1-((5-methylisoxazol-3-yl)methyl)-2,6-dioxo-2,3-dihydro-1-H-purin-7(6H)-yl)-N-(6'-(trifluoromethyl)-[2,3'-bipyridin]-6-yl)propanamid-e (30.1 mg, 92% yield) as a white solid. .sup.1H NMR (400 MHz,DMSO-D6) .delta. 11.20 (s, 1H), 9.94 (d, J=1.5 Hz, 1H), 8.69 (m,1H), 8.39 (s, 1H), 7.90-8.24 (m, 4H), 6.07 (s, 1H), 5.81 (m, 1H),5.02 (m, 2H), 3.46 (s, 3H), 2.29 (m, 3H), 1.87 (m, 3H). MH.sup.+555.

Compound 8.(S)-2-(3-methyl-2,6-dioxo-1-(pyridin-2-ylmethyl)-2,3-dihydro-1H-purin-7(6-H)-yl)-N-(6-(2-(trifluoromethyl)pyrimidin-5-yl)pyrazin-2-yl)propanamide

##STR00551##

This compound was prepared using the method described for compound2 with appropriate starting materials. .sup.1H NMR (400 MHz,DMSO-d.sub.6) .delta. 11.63 (s, 1H), 9.68 (s, 2H), 9.34 (s, 1H),9.22 (s, 1H), 8.46-8.37 (m, 2H), 7.69 (t, J=6.9 Hz, 1H), 7.21 (t,J=8.4 Hz, 2H), 5.84 (d, J=7.0 Hz, 1H), 5.13 (s, 2H), 3.48 (s, 3H),1.90 (d, J=7.3 Hz, 3H). Retention time (LC-MS): 1.92 min. MH.sup.+553.

Compound 9.(2S)-2-(3-methyl-2,6-dioxo-1-(pyridin-2-ylmethyl)-1,2,3,6-tetrahydropurin--7-yl)-N-(6-(6-(trifluoromethyl)pyridin-3-yl)pyrazin-2-yl)propanamide

##STR00552##

This compound was prepared using the method described for compound2 with appropriate starting materials. .sup.1H-NMR (400 MHz,DMSO-d.sub.6) .delta. 11.09 (s, 1H), 8.12 (s, 1H), 7.94-7.95 (d,J=1.6 Hz, 1H), 7.87-7.91 (t, J=14.6 Hz, 1H), 7.72-7.74 (d, J=8.0Hz, 1H), 7.58-7.60 (d, J=8.4 Hz, 1H), 5.30 (s, 2H), 4.49 (s, 2H),3.42 (s, 3H), 2.50 (s, 3H), 2.17 (s, 3H). Retention time (LC-MS):1.211 min. MH.sup.+ 552.

Compound 10.2-(1-(cyanomethyl)-3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)-N-(6--(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-2-yl)propanamide

##STR00553##

To a solution of2-(3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)acetonitrile(42 mg, 0.20 mmol) in DMF (1 mL) was added2-chloro-N-(6-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-2-yl)propanamide(7, 80 mg, 0.24 mmol), followed by potassium carbonate (56 mg, 0.40mmol) and TBAI (8 mg, 0.02 mmol). The mixture was stirred at50.degree. C. under N.sub.2 overnight. The reaction mixture wasquenched by water (20 mL), and then extracted with EA (3.times.5mL). The combined organic layers were washed with saturated aqueousLiCl solution and brine, dried over Na.sub.2SO.sub.4 and filtered.The filtrate was concentrated to dryness and purified withpreparative HPLC to afford2-(1-(cyanomethyl)-3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)-N-(6--(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-2-yl)propanamide (6.1mg, 5% yield) as a white solid. .sup.1H NMR (400 MHz, DMSO-D6).delta. 11.33 (s, 1H), 9.68 (s, 2H), 8.45 (s, 1H), 8.12 (d, J=7.0Hz, 1H), 8.02 (q, J=7.7 Hz, 2H), 5.81 (s, 1H), 4.85 (s, 2H), 3.49(s, 3H), 1.89 (d, J=7.2 Hz, 3H). Retention time (LC-MS): 2.289 min.MH.sup.+ 500.

Compound 11.(2S)--N-(6-(2-(3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)pyridin-2-yl)--2-(1-(cyanomethyl)-3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)propa-namide

##STR00554##

This compound was prepared using the method described for compound1 with appropriate starting materials. .sup.1H NMR (400 MHz,DMSO-D6) .delta. 11.05 (s, 1H), 9.00 (s, 2H), 8.43 (s, 1H), 7.83(dd, J=18.9, 11.2 Hz, 2H), 7.61 (d, J=8.2 Hz, 1H), 5.76 (s, 1H),4.84 (s, 2H), 3.85 (d, J=11.2 Hz, 2H), 3.55 (d, J=11.2 Hz, 2H),3.49 (s, 3H), 1.87 (d, J=7.3 Hz, 3H), 1.70 (s, 2H), 0.78 (s, 1H),0.18 (s, 1H). Retention time (LC-MS): 3.161 min. MH.sup.+ 513.

Compound 12.(2S)--N-(6-(2-(3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)pyrazin-2-yl)--2-(1-(cyanomethyl)-3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)propa-namide

##STR00555##

This compound was prepared using the method described for compound1 with appropriate starting materials. .sup.1H NMR (400 MHz,DMSO-D6) .delta. 11.40 (s, 1H), 9.11 (s, 1H), 9.04 (s, 2H), 8.91(s, 1H), 8.44 (s, 1H), 5.82 (s, 1H), 4.84 (s, 2H), 3.86 (d, J=11.4Hz, 2H), 3.56 (d, J=11.5 Hz, 2H), 3.49 (s, 3H), 1.89 (d, J=7.2 Hz,3H), 1.70 (s, 2H), 0.78 (d, J=4.6 Hz, 1H), 0.17 (d, J=4.3 Hz, 1H).Retention time (LC-MS): 2.074 min. MH.sup.+ 514.

Compound 13.(2S)--N-(6-(2-(3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)pyrazin-2-yl)--2-(3-methyl-2,6-dioxo-1-(2-oxobutyl)-2,3-dihydro-1H-purin-7(6H)-yl)propan-amide

##STR00556##

This compound was prepared using the method described for Compound2 with appropriate starting materials. .sup.1H NMR (400 MHz,DMSO-D6) .delta. 11.33 (s, 1H), 9.09 (s, 1H), 9.02 (s, 2H), 8.90(s, 1H), 8.40 (s, 1H), 5.80 (s, 1H), 4.69 (d, J=2.1 Hz, 2H), 3.85(d, J=11.4 Hz, 2H), 3.56 (d, J=10.9 Hz, 2H), 3.46 (s, 3H), 2.54 (d,J=7.3 Hz, 2H), 1.88 (d, J=7.3 Hz, 3H), 1.73-1.67 (m, 2H), 0.93 (t,J=7.3 Hz, 3H), 0.77 (d, J=4.7 Hz, 1H), 0.16 (d, J=4.3 Hz, 1H).Retention time (LC-MS): 2.24 min. MH.sup.+ 545.

Compound 14.((2S)--N-(2-(2-(3-azabicyclo[3.1.0]hexan-3-yl)pyramidin-5-yl)thiazol-4-yl-)-2-(3-methyl-2,6-dioxo-1-(2-oxobutyl)-2,3-dihydro-1H-purin-7(6H)-yl)propa-namide

##STR00557##

This compound was prepared using the method described for compound1 with appropriate starting materials and was purified withpreparative TLC. .sup.1H NMR (400 MHz, DMSO-D6) .delta. 11.58 (s,1H), 8.80 (s, 2H), 8.37 (s, 1H), 7.46 (s, 1H), 5.70 (d, J=7.3 Hz,1H), 4.69 (d, J=2.4 Hz, 2H), 3.83 (d, J=11.4 Hz, 2H), 3.55 (d,J=11.3 Hz, 2H), 3.45 (s, 3H), 2.57-2.51 (m, 2H), 1.83 (d, J=7.3 Hz,3H), 1.73-1.67 (m, 2H), 0.94 (t, J=7.3 Hz, 3H), 0.77 (d, J=4.8 Hz,1H), 0.16 (d, J=4.2 Hz, 1H). Retention time (LC-MS): 2.41 min.MH.sup.+ 550.

Compound 15.(S)-2-(3-methyl-1-((5-methylisoxazol-3-yl)methyl)-2,6-dioxo-2,3-dihydro-1-H-purin-7(6H)-yl)-N-(6-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-2-yl)pro-panamide

##STR00558##

This compound was prepared using the method described for compound1 with appropriate starting materials. 1H NMR (400 MHz, DMSO-D6).delta. 11.28 (s, 1H), 9.67 (s, 2H), 8.41 (s, 1H), 8.12 (d, J=7.6Hz, 1H), 8.07-7.80 (m, 2H), 6.09 (s, 1H), 5.83 (d, J=6.7 Hz, 1H),5.02 (s, 2H), 3.48 (s, 3H), 2.30 (s, 3H), 1.88 (d, J=7.3 Hz, 3H).Retention time (LC-MS): 2.523 min. MH.sup.+ 555.

Compound 16.(S)-2-(3-methyl-2,6-dioxo-1-(2-oxopropyl)-2,3-dihydro-1H-purin-7(6H)-yl)--N-(2-(2-((S)-2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidin-5-yl)thiazol-4-y-l)propanamide

##STR00559##

This compound was prepared using the method described for Compound1 with appropriate starting materials. .sup.1H NMR (400 MHz,DMSO-D6) .delta. 11.64 (s, 1H), 8.94 (s, 2H), 8.41 (d, J=14.0 Hz,1H), 7.54 (s, 1H), 5.71 (q, J=7.2 Hz, 1H), 5.10 (p, J=7.8 Hz, 1H),4.76-4.63 (m, 2H), 3.78-3.62 (m, 2H), 3.46 (s, 3H), 2.21 (d, J=9.0Hz, 1H), 2.17 (s, 4H), 2.09 (d, J=14.0 Hz, 2H), 1.84 (d, J=7.3 Hz,3H). Retention time (LC-MS): 2.570 min. MH.sup.+ 592.

Compound 17.N-(2'-(3-azabicyclo[3.1.0]hexan-3-yl)-2,5'-bipyrimidin-4-yl)-2-(3-methyl--2,6-dioxo-1-(2-oxobutyl)-2,3-dihydro-1H-purin-7(6H)-yl)propanamide

##STR00560##

This compound was prepared using the method described for compound10 with appropriate starting materials and was purified withpreparative TLC. .sup.1H NMR (400 MHz, DMSO-D6) .delta. 11.41 (s,1H), 9.15 (s, 2H), 8.67 (d, J=6 Hz, 2H), 8.40 (s, 1H), 7.79 (d,J=5.6 Hz, 1H), 5.78 (d, J=7.2 Hz, 1H), 4.69 (d, J=2.4 Hz, 2H), 3.86(d, J=11.2 Hz, 2H), 3.57 (d, J=11.2 Hz, 2H), 3.33 (s, 3H),2.55-2.49 (m, 2H), 1.87 (d, J=7.2 Hz, 3H), 1.70 (t, J=3.6 Hz, 2H),0.93 (t, J=7.2 Hz, 3H), 0.77 (d, J=4.8 Hz, 1H), 0.17 (q, J=4.0 Hz,1H). Retention time (LC-MS): 2.246 min. MH.sup.+ 545.

Compound 18.(S)-2-(3-methyl-2,6-dioxo-1-(2-oxobutyl)-2,3-dihydro-1H-purin-7(6H)-yl)-N--(2-(2-((S)-2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidin-5-yl)thiazol-4-yl-)propanamide

##STR00561##

This compound was prepared using the method described for compound2 with appropriate starting materials. .sup.1H NMR (400 MHz,DMSO-D6) .delta. 11.65 (s, 1H), 8.94 (s, 2H), 8.41 (d, J=11.7 Hz,1H), 7.54 (s, 1H), 5.72 (d, J=7.3 Hz, 1H), 5.21-5.00 (m, 1H), 4.69(d, J=2.4 Hz, 2H), 3.71 (t, J=6.6 Hz, 2H), 3.46 (s, 3H), 2.58-2.52(m, 2H), 2.28-2.01 (m, 4H), 1.84 (d, J=7.3 Hz, 3H), 0.94 (t, J=7.3Hz, 3H). Retention time (LC-MS): 2.675 min. MH.sup.+ 605.

Compound 19.(S)--N-(2-(3,4-dichlorophenyl)thiazol-4-yl)-2-(3-methyl-2,6-dioxo-1-(2-ox-obutyl)-2,3-dihydro-1H-purin-7(6H)-yl)propanamide

##STR00562##

This compound was prepared using the method described for compound2 with appropriate starting materials. .sup.1H NMR (400 MHz,DMSO-D6) .delta. 11.65 (s, 1H), 8.39 (s, 1H), 8.13 (d, J=1.9 Hz,1H), 7.89 (dd, J=8.4, 2.0 Hz, 1H), 7.79 (d, J=8.4 Hz, 1H), 7.66 (s,1H), 5.71 (q, J=7.3 Hz, 1H), 4.78-4.60 (m, 2H), 3.46 (s, 3H),2.59-2.52 (m, 2H), 1.85 (d, J=7.3 Hz, 3H), 0.94 (t, J=7.3 Hz, 3H).Retention time (LC-MS): 2.869 min. MH.sup.+ 534.

Compound 20.(S)--N-(2-(3,4-dichlorophenyl)thiazol-4-yl)-2-(3-methyl-2,6-dioxo-1-(2-ox-opropyl)-2,3-dihydro-1H-purin-7(6H)-yl)propanamide

##STR00563##

This compound was prepared using the method described for compound2 with appropriate starting materials. .sup.1H NMR (400 MHz,DMSO-D6) .delta. 11.65 (s, 1H), 8.39 (s, 1H), 8.13 (d, J=2.1 Hz,1H), 7.89 (dd, J=8.4, 2.1 Hz, 1H), 7.79 (d, J=8.4 Hz, 1H), 7.66 (s,1H), 5.71 (q, J=7.2 Hz, 1H), 4.70 (d, J=1.3 Hz, 2H), 3.46 (s, 3H),2.17 (s, 3H), 1.85 (d, J=7.3 Hz, 3H). Retention time (LC-MS): 2.750min. MH.sup.+ 521.

Compound 21. Preparation of(S)-2-(3-methyl-1-((5-methylisoxazol-3-yl)methyl)-2,6-dioxo-2,3-dihydro-1-H-purin-7(6H)-yl)-N-(6-(2-(trifluoromethyl)pyrimidin-5-yl)pyrazin-2-yl)pro-panamide

##STR00564##

This compound was prepared using the method described for compound1 with appropriate starting materials. .sup.1H NMR (400 MHz,DMSO-D6) .delta. 11.65 (s, 1H), 9.70 (s, 2H), 9.35 (s, 1H), 9.23(s, 1H), 8.43 (s, 1H), 6.09 (s, 1H), 5.84 (d, J=7.0 Hz, 1H), 5.02(s, 2H), 3.48 (s, 3H), 2.32 (d, J=12.0 Hz, 3H), 1.90 (d, J=7.3 Hz,3H). Retention time (LC-MS): 2.241 min. MH.sup.+ 557.

Compound 22.(S)-2-(1-(cyanomethyl)-3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)--N-(6-(2-(trifluoromethyl)pyrimidin-5-yl)pyrazin-2-yl)propanamide

##STR00565##

This compound was prepared using the method described for compound2 with appropriate starting materials. .sup.1H NMR (400 MHz,DMSO-D6) .delta. 11.76 (s, 1H), 9.78 (s, 2H), 9.42 (s, 1H), 9.29(s, 1H), 8.52 (s, 1H), 5.89 (d, J=7.1 Hz, 1H), 4.91 (s, 2H), 3.55(s, 3H), 1.98 (d, J=7.3 Hz, 3H). Retention time (LC-MS): 2.091 min.MH.sup.+ 501.

Compound 23.(S)-2-(1,3-dimethyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)-N-(6-(4-(tri-fluoromethyl)phenyl)pyridin-2-yl)propanamide

##STR00566##

This compound was prepared using the method described for compound2 with appropriate starting materials. .sup.1H NMR (400 MHz,DMSO-D6) .delta. 11.18 (s, 1H), 11.18 (s, 1H), 8.41 (s, 1H), 8.41(s, 1H), 8.32 (d, J=8.3 Hz, 2H), 8.32 (d, J=8.3 Hz, 2H), 8.01 (s,1H), 8.01 (s, 1H), 7.94 (t, J=7.9 Hz, 1H), 7.99-7.79 (m, 4H), 7.89(d, J=8.3 Hz, 2H), 7.83 (d, J=7.6 Hz, 1H), 6.09 (s, 1H), 6.09 (s,1H), 5.82 (s, 1H), 5.82 (s, 1H), 5.02 (s, 2H), 5.02 (s, 2H), 3.47(s, 3H), 3.47 (s, 3H), 3.34 (s, 33H), 2.54-2.46 (m, 27H), 2.30 (s,3H), 2.30 (s, 3H), 1.87 (d, J=7.3 Hz, 3H), 1.87 (d, J=7.3 Hz, 3H),-0.00 (s, 6H). Retention time (LC-MS): 2.718 min. MH.sup.+ 554.

Compound 24.N-(2'-(3-azabicyclo[3.1.0]hexan-3-yl)-2,5'-bipyrimidin-4-yl)-2-(1-(cyanom-ethyl)-3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)propanamide

##STR00567##

This compound was prepared using the method described for compound10 with appropriate starting materials. .sup.1H NMR (400 MHz,DMSO-D6) .delta. 11.46 (s, 1H), 9.14 (s, 2H), 8.66 (d, J=5.7 Hz,1H), 8.41 (s, 1H), 7.78 (d, J=5.6 Hz, 1H), 5.77 (s, 1H), 4.82 (s,2H), 3.85 (d, J=11.5 Hz, 2H), 3.56 (d, J=11.3 Hz, 2H), 3.46 (s,3H), 1.86 (d, J=7.3 Hz, 3H), 1.68 (s, 2H), 0.76 (s, 1H), 0.16 (d,J=4.2 Hz, 1H). Retention time (LC-MS): 2.147 min. MH.sup.+ 514.

Compound 25.(2S)--N-(6-(2-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)-pyridin-2-yl)-2-(3-methyl-2,6-dioxo-1-(2-oxopropyl)-2,3-dihydro-1H-purin-7-(6H)-yl)propanamide

##STR00568##

This compound was prepared using the method described for compound2 with appropriate starting materials. .sup.1H NMR (400 MHz,DMSO-D6) .delta. 11.02 (s, 1H), 9.03 (s, 2H), 8.40 (s, 1H), 7.89(d, J=7.7 Hz, 1H), 7.83 (t, J=7.9 Hz, 1H), 7.63 (d, J=8.0 Hz, 1H),5.79 (s, 1H), 4.75-4.64 (m, 2H), 3.99 (d, J=11.9 Hz, 2H), 3.84 (d,J=10.5 Hz, 2H), 3.46 (s, 3H), 2.70 (d, J=10.8 Hz, 2H), 2.16 (s,3H), 1.86 (d, J=7.3 Hz, 3H). Retention time (LC-MS): 2.311 min.MH.sup.+ 566.

Compound 26.(2S)--N-(6-(2-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)-pyridin-2-yl)-2-(3-methyl-2,6-dioxo-1-(2-oxobutyl)-2,3-dihydro-1H-purin-7(-6H)-yl)propanamide

##STR00569##

This compound was prepared using the method described for compound2 with appropriate starting materials. .sup.1H NMR (400 MHz,DMSO-D6) .delta. 11.02 (s, 1H), 9.03 (s, 2H), 8.40 (s, 1H), 7.89(d, J=8.4 Hz, 1H), 7.83 (t, J=7.9 Hz, 1H), 7.63 (d, J=7.6 Hz, 1H),5.79 (s, 1H), 4.79-4.62 (m, 2H), 3.99 (d, J=11.9 Hz, 2H), 3.84 (d,J=10.7 Hz, 2H), 3.46 (s, 3H), 2.71 (d, J=11.2 Hz, 2H), 2.61-2.51(m, 2H), 1.86 (d, J=7.2 Hz, 3H), 0.93 (t, J=7.2 Hz, 3H). Retentiontime (LC-MS): 2.364 min. MH.sup.+ 580.

Compound 27.(S)--N-(6-(2-(diethylamino)pyrimidin-5-yl)pyridin-2-yl)-2-(3-methyl-1-((5--methylisoxazol-3-yl)methyl)-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)propa-namide

##STR00570##

This compound was prepared using the method described for compound1 with appropriate starting materials. .sup.1H NMR (400 MHz,DMSO-D6) .delta. 10.99 (s, 1H), 8.97 (s, 2H), 8.37 (s, 1H), 7.85(d, J=7.4 Hz, 1H), 7.79 (t, J=7.9 Hz, 1H), 7.58 (d, J=7.9 Hz, 1H),6.06 (s, 1H), 5.77 (d, J=25.7 Hz, 1H), 5.00 (s, 2H), 3.63 (q, J=7.0Hz, 4H), 3.45 (s, 3H), 2.28 (s, 3H), 1.84 (d, J=7.3 Hz, 3H), 1.13(t, J=7.0 Hz, 6H). Retention time (LC-MS): 2.563 min. MH.sup.+559.

Compound 28.(S)-2-(1-(cyanomethyl)-3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)--N-(2-(2-((S)-2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidin-5-yl)thiazol-4-y-l)propanamide

##STR00571##

This compound was prepared using the method described for compound2 with appropriate starting materials and was purified viapreparative HPLC, 19.7% yield as a light yellow solid. .sup.1H NMR(400 MHz, DMSO-D6) .delta. 11.73 (s, 1H), 8.98 (s, 2H), 8.46 (s,1H), 7.58 (s, 1H), 5.76 (q, J=7.4 Hz, 1H), 5.19-5.08 (m, 1H), 4.88(s, 2H), 3.73 (dd, J=12.3, 6.6 Hz, 2H), 3.51 (s, 3H), 2.30-2.09 (m,4H), 1.89 (d, J=7.3 Hz, 3H). Retention time (LC-MS): 2.607 min.MH.sup.+ 575.

Compound 29.(S)-2-(1-(cyanomethyl)-3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)--N-(2-(3,4-dichlorophenyl)thiazol-4-yl)propanamide

##STR00572##

This compound was prepared using the method described for compound2 with appropriate starting materials and was purified viapreparative HPLC to provide a yellow solid (10.5% yield). .sup.1HNMR (400 MHz, DMSO-D6) .delta. 11.71 (s, 1H), 8.43 (s, 1H), 8.14(d, J=2.0 Hz, 1H), 7.90 (dd, J=8.4, 2.1 Hz, 1H), 7.80 (d, J=8.4 Hz,1H), 7.67 (s, 1H), 5.73 (q, J=7.3 Hz, 1H), 4.85 (s, 2H), 3.49 (s,3H), 1.86 (d, J=7.3 Hz, 3H). Retention time (LC-MS): 2.819 min.MH.sup.+ 504.

Compound 30.(2S)-2-(1-(cyanomethyl)-3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)--N-(6-(2-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)pyridi-n-2-yl)propanamide

##STR00573##

This compound was prepared using the method described for compound2 with appropriate starting materials to provide a white solid (14%yield). .sup.1H NMR (400 MHz, DMSO-D6) .delta. 11.08 (s, 1H), 9.04(s, 2H), 8.43 (s, 1H), 7.90 (d, J=7.9 Hz, 1H), 7.83 (t, J=7.9 Hz,1H), 7.64 (d, J=7.9 Hz, 1H), 5.81 (s, 1H), 4.84 (s, 2H), 3.99 (d,J=11.9 Hz, 2H), 3.85 (d, J=10.5 Hz, 2H), 3.48 (s, 3H), 2.70 (d,J=10.6 Hz, 2H), 1.87 (d, J=7.3 Hz, 3H). Retention time (LC-MS):2.309 min. MH.sup.+ 549.

Compound 31.(S)-2-(3-methyl-2,6-dioxo-1-(2-oxopropyl)-2,3-dihydro-1H-purin-7(6H)-yl)--N-(2-(2-(trifluoromethyl)pyrimidin-5-yl)thiazol-4-yl)propanamide

##STR00574##

This was prepared using the method described for compound 2 withappropriate starting materials and purified via preparative HPLC toprovide a yellow solid (23.5% yield). .sup.1H NMR (400 MHz,DMSO-D6) .delta. 11.84 (s, 1H), 9.53 (s, 2H), 8.40 (s, 1H), 7.86(s, 1H), 5.72 (d, J=7.4 Hz, 1H), 4.70 (s, 2H), 3.46 (s, 3H), 2.17(s, 3H), 1.86 (d, J=7.3 Hz, 3H). Retention time (LC-MS): 2.286 min.MH.sup.+ 523.

Compound 32.(S)-2-(3-methyl-1-((5-methylisoxazol-3-yl)methyl)-2,6-dioxo-2,3-dihydro-1-H-purin-7(6H)-yl)-N-(2-(2-(trifluoromethyl)pyrimidin-5-yl)thiazol-4-yl)pro-panamide

##STR00575##

This compound was prepared using the method described for compound1 with appropriate starting materials to provide a white solid(29.8% yield). .sup.1H NMR (400 MHz, DMSO-D6) .delta. 11.86 (s,1H), 9.53 (s, 2H), 8.41 (s, 1H), 7.87 (s, 1H), 6.09 (s, 1H),5.75-5.77 (m, 1H), 5.02 (s, 2H), 3.47 (s, 3H), 2.31 (s, 3H), 1.86(d, J=7.2 Hz, 3H). Retention time (LC-MS): 2.241 min. MH.sup.+562.

Compound 33.(2S)--N-(2-(6-(3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)thiazol-4-yl)-2--(1-(cyanomethyl)-3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)propana-mide

##STR00576##

This compound was prepared using the method described for compound2 with appropriate starting materials to provide a white solid(5.5% yield). .sup.1H NMR (400 MHz, DMSO-D6) .delta. 11.54 (s, 1H),8.61 (d, J=2.4 Hz, 1H), 8.38 (s, 1H), 7.92 (dd, J=8.8, 2.5 Hz, 1H),7.40 (s, 1H), 6.56 (d, J=8.7 Hz, 1H), 5.70 (d, J=7.4 Hz, 1H), 4.70(d, J=2.6 Hz, 2H), 3.70 (d, J=10.4 Hz, 2H), 3.46 (s, 3H), 2.05-1.95(m, 2H), 1.84 (d, J=7.3 Hz, 3H), 1.72 (s, 2H), 0.94 (t, J=7.3 Hz,3H), 0.81 (dd, J=30.4, 5.8 Hz, 3H), 0.18 (d, J=4.1 Hz, 1H).Retention time (LC-MS): 2.045 min. MH.sup.+ 549.

Compound 34.(2S)--N-(2-(2-(3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)thiazol-4-yl)--2-(1-(cyanomethyl)-3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)propa-namide

##STR00577##

This compound was prepared using the method described for compound1 with appropriate starting materials as a white solid. .sup.1H NMR(400 MHz, DMSO-D6) .delta. 11.67 (s, 1H), 8.81 (s, 2H), 8.42 (s,1H), 7.47 (s, 1H), 5.72 (d, J=7.2 Hz, 1H), 4.84 (s, 2H), 3.84 (d,J=11.4 Hz, 2H), 3.55 (d, J=11.0 Hz, 2H), 3.48 (s, 3H), 1.84 (d,J=7.2 Hz, 3H), 1.70 (s, 2H), 0.77 (d, J=4.6 Hz, 1H), 0.17 (d, J=4.0Hz, 1H). Retention time (LC-MS): 2.249 min. MH.sup.+ 519.

Compound 35.(2S)--N-(6'-(3-azabicyclo[3.1.0]hexan-3-yl)-2,3'-bipyridin-6-yl)-2-(1-(cy-anomethyl)-3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)

##STR00578##

This compound was prepared using the method described for Compound1 with appropriate starting materials in 36.5% yield as a whitesolid. .sup.1H NMR (400 MHz, DMSO-D6) .delta. 11.01 (s, 1H), 8.80(d, J=2.2 Hz, 1H), 8.43 (s, 1H), 8.18 (dd, J=8.9, 2.4 Hz, 1H), 7.83(d, J=8.2 Hz, 1H), 7.77 (t, J=7.9 Hz, 1H), 7.58 (d, J=8.1 Hz, 1H),6.57 (d, J=8.9 Hz, 1H), 5.81 (d, J=6.8 Hz, 1H), 4.85 (s, 2H), 3.72(d, J=10.4 Hz, 2H), 3.49 (s, 3H), 3.44 (d, J=10.0 Hz, 2H), 1.87 (d,J=7.3 Hz, 3H), 1.74-1.68 (m, 2H), 0.76 (dd, J=12.2, 7.7 Hz, 1H),0.24-0.17 (m, 1H). Retention time (LC-MS): 1.400 min. MH.sup.+512.

Compound 36.(S)--N-(2-(2-(diethylamino)pyrimidin-5-yl)thiazol-4-yl)-2-(3-methyl-1-((5--methylisoxazol-3-yl)methyl)-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)propa-namide

##STR00579##

This compound was prepared using the method described for Compound1 with appropriate starting materials .sup.1H NMR (400 MHz,DMSO-D6) .delta. 11.73 (s, 1H), 8.93 (s, 2H), 8.50 (s, 1H), 7.58(s, 1H), 6.20 (s, 1H), 5.86 (q, J=7.1 Hz, 1H), 5.13 (s, 2H), 3.76(q, J=7.0 Hz, 4H), 3.58 (s, 3H), 2.43 (s, 3H), 1.95 (d, J=7.3 Hz,3H), 1.27 (t, J=7.0 Hz, 6H). Retention time (LC-MS): 2.641 min.MH.sup.+ 565.

Compound 37.(2S)--N-(6'-(3-azabicyclo[3.1.0]hexan-3-yl)-2,3'-bipyridin-6-yl)-2-(3-met-hyl-2,6-dioxo-1-(2-oxobutyl)-2,3-dihydro-1H-purin-7(6H)-yl)propanamide

##STR00580##

This compound was prepared using the method described for Compound2 with appropriate starting materials in 44.6% yield as a whitesolid. .sup.1H NMR (400 MHz, DMSO-D6) .delta. 10.96 (s, 1H), 8.79(d, J=2.2 Hz, 1H), 8.40 (s, 1H), 8.16 (s, 1H), 7.82 (d, J=7.7 Hz,1H), 7.77 (t, J=7.9 Hz, 1H), 7.58 (d, J=7.9 Hz, 1H), 6.56 (d, J=8.9Hz, 1H), 5.78 (d, J=6.7 Hz, 1H), 4.77-4.62 (m, 2H), 3.71 (d, J=10.4Hz, 2H), 3.46 (s, 3H), 3.42 (s, 2H), 2.57-2.52 (m, 2H), 2.09 (s,1H), 1.86 (d, J=7.3 Hz, 3H), 1.74-1.67 (m, 2H), 0.93 (t, J=7.3 Hz,3H), 0.76 (dd, J=12.2, 7.7 Hz, 1H), 0.20 (d, J=4.1 Hz, 1H).Retention time (LC-MS): 1.428 min. MH.sup.+ 543.

Compound 38.(S)--N-(2-(2-(diethylamino)pyrimidin-5-yl)thiazol-4-yl)-2-(3-methyl-2,6-d-ioxo-1-(2-oxobutyl)-2,3-dihydro-1H-purin-7(6H)-yl)propanamide

##STR00581##

This compound was prepared using the method described for compound2 with appropriate starting materials in 28.57% yield as a whitesolid. .sup.1H NMR (400 MHz, DMSO-D6) .delta. 11.60 (s, 1H), 8.82(s, 2H), 8.39 (s, 1H), 7.46 (s, 1H), 5.71 (d, J=7.1 Hz, 1H),4.75-4.63 (m, 2H), 3.65 (d, J=6.9 Hz, 4H), 3.46 (s, 3H), 2.53 (d,J=7.6 Hz, 2H), 1.84 (d, J=7.1 Hz, 3H), 1.15 (t, J=6.8 Hz, 6H), 0.94(t, J=7.2 Hz, 3H). Retention time (LC-MS): 2.587 min. MH.sup.+540.

Compound 39.(S)-2-(1-(cyanomethyl)-3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)--N-(6-(2-((R)-2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidin-5-yl)pyridin-2-y-l)propanamide

##STR00582##

This compound was prepared using the method described for compound1 with appropriate starting materials in 10% yield as a whitesolid. .sup.1H NMR (400 MHz, DMSO-D6) .delta. 11.10 (s, 1H), 9.12(s, 2H), 8.44 (s, 1H), 7.87 (dd, J=19.5, 11.8 Hz, 2H), 7.69 (d,J=7.6 Hz, 1H), 5.82 (s, 1H), 5.15-5.06 (m, 1H), 4.85 (s, 2H), 3.72(t, J=6.8 Hz, 2H), 3.49 (s, 3H), 2.23-2.11 (m, 2H), 2.09 (s, 2H),1.88 (d, J=7.2 Hz, 3H). Retention time (LC-MS): 2.517 min. MH.sup.+569.

Compound 40.(S)-2-(1-(cyanomethyl)-3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)--N-(6-(2-((R)-2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidin-5-yl)pyrazin-2-y-l)propanamide

##STR00583##

This compound was prepared using the method described for compound1 with appropriate starting materials in 12% yield as a whitesolid. .sup.1H NMR (400 MHz, DMSO-D6) .delta. 11.45 (s, 1H), 9.17(s, 1H), 9.15 (s, 2H), 8.98 (s, 1H), 8.45 (s, 1H), 5.82 (d, J=7.5Hz, 1H), 5.18-5.08 (m, 1H), 4.85 (s, 2H), 3.72 (dd, J=13.6, 6.9 Hz,2H), 3.49 (s, 3H), 2.18 (dd, J=32.5, 12.2 Hz, 2H), 2.08 (s, 2H),1.90 (d, J=7.3 Hz, 3H). Retention time (LC-MS): 3.073 min. MH.sup.+570.

Compound 41.(2S)--N-(6-(6-(3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)pyrazin-2-yl)-2--(3-methyl-2,6-dioxo-1-(2-oxopropyl)-2,3-dihydro-1H-purin-7(6H)-yl)propana-mide

##STR00584##

This compound was prepared using the method described for compound2 with appropriate starting materials in 32% yield as a whitesolid. .sup.1H NMR (400 MHz, DMSO-D6) .delta. 11.29 (s, 1H), 9.04(s, 1H), 8.89 (s, 1H), 8.85 (d, J=2.3 Hz, 1H), 8.41 (s, 1H), 8.19(dd, J=8.9, 2.4 Hz, 1H), 6.61 (d, J=9.0 Hz, 1H), 5.79 (s, 1H), 4.70(s, 2H), 3.73 (d, J=10.4 Hz, 2H), 3.46 (s, 3H), 3.45 (s, 2H), 2.16(s, 3H), 1.88 (d, J=7.3 Hz, 3H), 1.74-1.69 (m, 2H), 0.77 (d, J=4.6Hz, 1H), 0.19 (d, J=4.2 Hz, 1H). Retention time (LC-MS): 2.460 min.MH.sup.+ 530.

Compound 42.(2S)--N-(6-(6-(3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)pyrazin-2-yl)-2--(3-methyl-2,6-dioxo-1-(2-oxobutyl)-2,3-dihydro-1H-purin-7(6H)-yl)propanam-ide

##STR00585##

This compound was prepared using the method described for compound2 with appropriate starting materials in 23.9% yield. Retentiontime (LC-MS): 2.581 min. MH.sup.+ 544. .sup.1H NMR (400 MHz,DMSO-D6) .delta. 11.28 (s, 1H), 9.04 (s, 1H), 8.89 (s, 1H), 8.85(d, J=2.2 Hz, 1H), 8.41 (s, 1H), 8.19 (dd, J=8.9, 2.4 Hz, 1H), 6.60(d, J=9.0 Hz, 1H), 5.79 (d, J=6.8 Hz, 1H), 4.70 (t, J=4.1 Hz, 2H),3.73 (d, J=10.5 Hz, 2H), 3.46 (s, 3H), 3.45 (s, 2H), 2.55 (d, J=7.3Hz, 2H), 1.88 (d, J=7.3 Hz, 3H), 1.74-1.70 (m, 2H), 0.93 (t, J=7.3Hz, 3H), 0.77 (dd, J=12.3, 7.8 Hz, 1H), 0.19 (d, J=4.2 Hz, 1H).

Compound 43.(2S)--N-(6-(6-(3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)pyrazin-2-yl)-2--(1-(cyanomethyl)-3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)propana-mide

##STR00586##

This compound was prepared using the method described for compound1 with appropriate starting materials in 24.7% yield as a whitesolid. .sup.1H NMR (400 MHz, DMSO-D6) .delta. 11.35 (s, 1H), 9.06(s, 1H), 8.90 (s, 1H), 8.86 (d, J=2.3 Hz, 1H), 8.45 (s, 1H), 8.20(dd, J=8.9, 2.4 Hz, 1H), 6.61 (d, J=9.0 Hz, 1H), 5.83 (s, 1H), 4.85(s, 2H), 3.73 (d, J=10.5 Hz, 2H), 3.49 (s, 3H), 3.45 (s, 2H), 1.89(d, J=7.3 Hz, 3H), 1.72 (s, 2H), 0.77 (d, J=4.6 Hz, 1H), 0.20 (d,J=4.1 Hz, 1H). Retention time (LC-MS): 2.528 min. MH.sup.+ 513.

Compound 44.(2S)--N-(6'-(3-azabicyclo[3.1.0]hexan-3-yl)-2,3'-bipyridin-6-yl)-2-(3-met-hyl-2,6-dioxo-1-(2-oxopropyl)-2,3-dihydro-1H-purin-7(6H)-yl)propanamide

##STR00587##

This compound was prepared using the method described for compound2 with appropriate starting materials in 36.5% yield as a whitesolid. .sup.1H NMR (400 MHz, DMSO-D6) .delta. 10.95 (s, 1H), 8.78(d, J=2.2 Hz, 1H), 8.39 (s, 1H), 8.17 (dd, J=8.9, 2.4 Hz, 1H), 7.82(d, J=8.1 Hz, 1H), 7.76 (t, J=7.8 Hz, 1H), 7.57 (d, J=8.0 Hz, 1H),6.56 (d, J=8.9 Hz, 1H), 5.77 (d, J=8.1 Hz, 1H), 4.76-4.63 (m, 2H),3.71 (d, J=10.3 Hz, 2H), 3.45 (s, 3H), 3.41 (s, 2H), 2.16 (s, 3H),1.86 (d, J=7.2 Hz, 3H), 1.74-1.65 (m, 2H), 0.76 (dd, J=12.3, 7.7Hz, 1H), 0.19 (d, J=4.1 Hz, 1H). Retention time (LC-MS): 2.556 min.MH.sup.+ 529.

Compound 45.(S)-2-(1-(cyanomethyl)-3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)--N-(6-(2-((S)-2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidin-5-yl)pyridin-2-y-l)propanamide

##STR00588##

This compound was prepared using the method described for compound1 with appropriate starting materials in 6.5% yield as a whitesolid. .sup.1H NMR (400 MHz, DMSO-D6) .delta. 11.09 (s, 1H), 9.12(s, 2H), 8.44 (s, 1H), 7.83-7.93 (m, 2H), 7.68 (d, J=7.2 Hz, 1H),5.79-5.82 (m, 1H), 5.11 (t, J=8.8 Hz, 1H), 4.85 (s, 2H), 3.68-3.74(m, 2H), 3.49 (s, 3H), 2.09-2.32 (m, 4H), 1.87 (d, J=7.6 Hz, 3H).Retention time (LC-MS): 2.341 min. MH.sup.+ 569.

Compound 46.(2S)--N-(2-(6-(3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)pyrimidin-4-yl)--2-(3-methyl-2,6-dioxo-1-(2-oxopropyl)-2,3-dihydro-1H-purin-7(6H)-yl)propa-namide

##STR00589##

This compound was prepared using the method described for compound2 with appropriate starting materials in 9.5% yield as a yellowsolid. .sup.1H NMR (400 MHz, DMSO-D6) .delta. 11.36 (s, 1H), 9.04(d, J=2.2 Hz, 1H), 8.65 (d, J=5.7 Hz, 1H), 8.40 (s, 1H), 8.35 (dd,J=8.9, 2.3 Hz, 1H), 7.73 (d, J=5.6 Hz, 1H), 6.58 (d, J=9.0 Hz, 1H),5.78 (d, J=6.9 Hz, 1H), 4.76-4.52 (m, 2H), 3.73 (d, J=10.6 Hz, 2H),3.47 (d, J=6.1 Hz, 2H), 3.46 (s, 3H), 2.16 (s, 3H), 1.88 (d, J=7.3Hz, 3H), 1.77-1.67 (m, 2H), 0.77 (dd, J=12.3, 7.7 Hz, 1H),0.25-0.13 (m, 1H). Retention time (LC-MS): 2.568 min. MH.sup.+530.

Compound 47.(2S)--N-(2-(6-(3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)pyrimidin-4-yl)--2-(3-methyl-2,6-dioxo-1-(2-oxobutyl)-2,3-dihydro-1H-purin-7(6H)-yl)propan-amide

##STR00590##

This compound was prepared using the method described for compound2 with appropriate starting materials in 13.9% yield as a yellowsolid. .sup.1H NMR (400 MHz, DMSO-D6) .delta. 11.35 (s, 1H), 9.04(s, 1H), 8.65 (d, J=5.6 Hz, 1H), 8.40 (s, 1H), 8.35 (d, J=8.8 Hz,1H), 7.74 (d, J=5.4 Hz, 1H), 6.58 (d, J=9.0 Hz, 1H), 5.79 (s, 1H),4.67 (d, J=19.8 Hz, 2H), 3.73 (d, J=10.4 Hz, 2H), 3.47 (d, J=4.7Hz, 2H), 3.42 (d, J=30.5 Hz, 3H), 1.88 (d, J=7.2 Hz, 3H), 1.72 (s,2H), 1.24 (s, 2H), 0.94 (t, J=7.2 Hz, 3H), 0.78 (s, 1H), 0.20 (d,J=3.8 Hz, 1H). Retention time (LC-MS): 1.504 min. MH.sup.+ 544.

Compound 48.(S)-2-(1-(cyanomethyl)-3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)--N-(6-(2-((S)-2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidin-5-yl)pyrazin-2-y-l)propanamide

##STR00591##

This compound was prepared using the method described for compound1 with appropriate starting materials in 21.3% yield as a whitesolid. .sup.1H NMR (400 MHz, DMSO-D6) .delta. 11.54 (s, 1H), 9.22(s, 1H), 9.22 (s, 2H), 9.04 (s, 1H), 8.52 (s, 1H), 5.88 (d, J=6.8Hz, 1H), 5.23-5.15 (m, 1H), 4.91 (s, 2H), 3.78 (d, J=6.1 Hz, 2H),3.55 (s, 3H), 2.34-2.20 (m, 2H), 2.14 (s, 2H), 1.96 (d, J=7.2 Hz,3H). Retention time (LC-MS): 1.939 min. MH.sup.+ 570.

Compound 49.(S)-2-(1-(cyanomethyl)-3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)--N-(2'-((R)-2-(trifluoromethyl)pyrrolidin-1-yl)-2,5'-bipyrimidin-4-yl)propa-namide

##STR00592##

This compound was prepared using the method described for compound1 with appropriate starting materials in 16.9% yield. .sup.1H NMR(400 MHz, DMSO-D6) .delta. 11.53 (s, 1H), 9.26 (s, 2H), 8.73 (d,J=5.6 Hz, 1H), 8.45 (s, 1H), 7.85 (d, J=5.2 Hz, 1H), 5.80 (d J=6.8Hz, 1H), 5.17-5.13 (m, 1H), 4.84 (s, 2H), 3.76-3.71 (m, 2H), 3.49(s, 3H), 2.36-2.00 (m, 4H), 1.89 (d, J=7.6 Hz, 3H). Retention time(LC-MS): 2.016 min. MH.sup.+: 570.

Compound 50.(R)-2-(2-(2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidin-5-yl)thiazol-4-ami-ne

##STR00593##

This compound was prepared using the method described for compound1 with appropriate starting materials in 28.3% yield as a whitesolid. .sup.1H NMR (400 MHz, DMSO-D6) .delta. 11.77 (s, 1H), 9.01(s, 2H), 8.50 (s, 1H), 7.61 (s, 1H), 5.79-5.81 (m, 1H), 5.15-5.19(m, 1H), 4.91 (s, 2H), 3.74-3.80 (m, 2H), 3.55 (s, 3H), 2.14-2.29(m, 4H), 1.91 (d, J=7.2 Hz, 3H). Retention time (LC-MS): 2.441 min.MH.sup.+ 575.

Compound 51.(S)-2-(3-methyl-1-(oxetan-3-ylmethyl)-2,6-dioxo-2,3-dihydro-1H-purin-7(6H-)-yl)-N-(6-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-2-yl)

##STR00594##

To a solution of(S)-2-(3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)-N-(6-(2-(trifluo-romethyl)pyrimidin-5-yl)pyridin-2-yl)propanamide (80 mg, 0.17 mmol)and potassium carbonate (48 mg, 0.35 mmol) in DMF (2 mL) was addedoxetan-3-ylmethyl methanesulfonate (69 mg, 0.42 mmol). The mixturewas stirred at 50.degree. C. overnight. The mixture was dilutedwith EA and washed with water, saturated aqueous NH.sub.4Clsolution and brine, dried over Na.sub.2SO.sub.4, and evaporated.The residue was purified by preparative TLC to give the product(S)-2-(3-methyl-1-(oxetan-3-ylmethyl)-2,6-dioxo-2,3-dihydro-1H-purin-7(6H-)-yl)-N-(6-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-2-yl)propanamide(20 mg, 21.7% yield) as a white solid. .sup.1H NMR (400 MHz,DMSO-D6) .delta. 11.28 (s, 1H), 9.68 (s, 2H), 8.43 (s, 1H),7.99-8.12 (m, 3H), 5.82-5.84 (m, 1H), 4.51-4.55 (m, 2H), 4.33-4.39(m, 2H), 4.07-4.18 (m, 2H), 3.45 (s, 3H), 3.19-3.27 (m, 1H), 1.87(d, J=6.8 Hz, 3H). Retention time (LC-MS): 2.656 min. MH.sup.+531.

Compound 52.(S)-2-(3-methyl-2,6-dioxo-1-(2-oxopentyl)-2,3-dihydro-1H-purin-7(6H)-yl)--N-(6-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-2-yl)propanamide

##STR00595##

To a mixture of(S)-2-(3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)-N-(6-(2-(trifluo-romethyl)pyrimidin-5-yl)pyridin-2-yl)propanamide (80 mg, 0.17 mmol)and potassium carbonate (48 mg, 0.34 mmol) in DMF (2 mL) was addeddrop-wise 1-bromopentan-2-one (68 mg, 0.42 mmol). The reactionmixture was stirred at 50.degree. C. for 1 h and poured into EA.The organic phase was separated, washed with water and brine, driedover Na2SO4, and concentrated and the residue was purified byprep-HPLC to afford(S)-2-(3-methyl-2,6-dioxo-1-(2-oxopentyl)-2,3-dihydro-1H-purin-7(6H)-yl)--N-(6-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-2-yl)propanamide(25 mg, 27.17% yield) as a white solid. .sup.1H NMR (400 MHz,DMSO-D6) .delta. 11.27 (s, 1H), 9.67 (s, 2H), 8.41 (s, 1H), 8.11(d, J=6.7 Hz, 1H), 8.02 (q, J=7.6 Hz, 2H), 5.81 (s, 1H), 4.69 (s,2H), 3.46 (s, 3H), 2.47 (d, J=7.2 Hz, 2H), 1.88 (d, J=7.3 Hz, 3H),1.48 (m, 2H), 0.84 (t, J=7.4 Hz, 3H). Retention time (LC-MS): 2.181min. MH.sup.+ 545.

Compound 53.(2S)--N-(2-(6-(3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)pyrimidin-4-yl)--2-(1-(cyanomethyl)-3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)propa-namide

##STR00596##

To a solution of2-(6-(3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)pyrimidin-4-amine(50 mg, 0.20 mmol) in 1,4-dioxane (3 mL) was added drop-wisetrimethylaluminum (0.79 mL, 0.79 mmol) at 0.degree. C. After theaddition, the mixture was warmed to RT and stirred for 0.5 h. Thena solution of (S)-methyl2-(1-(cyanomethyl)-3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)propa-noate (57.49 mg, 0.20 mmol) in 1,4-dioxane (2 mL) was addeddrop-wise and the reaction mixture was stirred at 100.degree. C.overnight. The reaction was quenched by addition of several dropsof MeOH. The mixture was concentrated under reduced pressure andthe residue was purified by chromatography (DCM:MeOH=100:1 to 50:1)to afford a crude product, which was further purified viapreparative TLC (DCM:MeOH=15:1) to afford(2S)--N-(2-(6-(3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)pyrimidin-4-yl)--2-(1-(cyanomethyl)-3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)propa-namide (15 mg, 14.8% yield) as a yellow solid. 1H NMR (400 MHz,DMSO-D6) .delta. 11.41 (s, 1H), 9.04 (d, J=2.1 Hz, 1H), 8.64 (d,J=5.7 Hz, 1H), 8.43 (s, 1H), 8.34 (m, J=8.9, 2.3 Hz, 1H), 7.73 (d,J=5.7 Hz, 1H), 6.57 (d, J=9.0 Hz, 1H), 5.77 (d, J=17.5 Hz, 1H),4.83 (s, 2H), 3.72 (d, J=10.8 Hz, 2H), 3.46 (d, J=10.6 Hz, 5H),1.87 (d, J=7.3 Hz, 3H), 1.70 (s, 2H), 0.76 (d, J=4.6 Hz, 1H), 0.18(d, J=3.9 Hz, 1H). Retention time (LC-MS): 2.282 min. MH.sup.+513.

Compound 54.(S)-2-(1-(cyanomethyl)-3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)--N-(2'-((S)-2-(trifluoromethyl)pyrrolidin-1-yl)-2,5'-bipyrimidin-4-yl)propa-namide

##STR00597##

This compound was prepared using the method described for compound53 with appropriate starting materials in 5.4% yield as a yellowsolid. .sup.1H NMR (400 MHz, DMSO-D6) .delta. 11.54 (s, 1H), 9.26(s, 2H), 8.73 (d, J=5.7 Hz, 1H), 8.45 (s, 1H), 7.85 (d, J=5.7 Hz,1H), 5.80 (d, J=7.0 Hz, 1H), 5.23-5.08 (m, 1H), 4.84 (s, 2H),3.80-3.64 (m, 2H), 3.49 (s, 3H), 2.25-2.01 (m, 4H), 1.89 (d, J=7.3Hz, 3H). Retention time (LC-MS): 2.097 min. MH.sup.+ 570.

Compound 55.(S)-2-(3-methyl-1-((5-methylisoxazol-3-yl)methyl)-2,6-dioxo-2,3-dihydro-1-H-purin-7(6H)-yl)-N-(6-(5-(trifluoromethyl)pyridin-3-yl)pyrazin-2-yl)propa-namide

##STR00598##

This compound was prepared using the method described for compound1 with appropriate starting materials in 7.6% yield as a whitesolid. .sup.1H NMR (400 MHz, DMSO-D6) .delta. 11.57 (s, 1H), 9.64(s, 1H), 9.31 (s, 1H), 9.24 (s, 1H), 9.13 (s, 1H), 8.84 (s, 1H),8.43 (s, 1H), 6.09 (s, 1H), 5.83 (d, J=7.1 Hz, 1H), 5.02 (s, 2H),3.48 (s, 3H), 2.31 (s, 3H), 1.90 (d, J=7.3 Hz, 3H). Retention time(LC-MS): 1.834 min. MH.sup.+ 556.

Compound 56.(2S)--N-(2-(2-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)-thiazol-4-yl)-2-(3-methyl-2,6-dioxo-1-(2-oxopropyl)-2,3-dihydro-1H-purin-7-(6H)-yl)propanamide

##STR00599##

This compound was prepared using the method described for Compound2 with appropriate starting materials in 38.7% yield as a yellowsolid. .sup.1H NMR (400 MHz, DMSO-d6) .delta. 11.62 (s, 1H), 8.85(s, 2H), 8.39 (s, 1H), 7.49 (s, 1H), 5.70 (d, J=7.1 Hz, 1H), 4.70(s, 2H), 3.98 (d, J=12.1 Hz, 2H), 3.85 (d, J=11.4 Hz, 2H), 3.45 (s,3H), 2.72 (d, J=11.5 Hz, 2H), 2.17 (s, 3H), 1.84 (d, J=7.1 Hz, 3H).Retention time (LC-MS): 1.846 min. MH.sup.+ 572.

Compound 57.(2S)--N-(2-(2-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)-thiazol-4-yl)-2-(3-methyl-2,6-dioxo-1-(2-oxobutyl)-2,3-dihydro-1H-purin-7(-6H)-yl)propanamide

##STR00600##

This compound was prepared using the method described for Compound2 with appropriate starting materials in 40.2% yield as a lightyellow solid. .sup.1H NMR (400 MHz, DMSO-d6) .delta. 11.62 (s, 1H),8.85 (s, 2H), 8.39 (s, 1H), 7.49 (s, 1H), 5.80-5.64 (m, 1H),4.78-4.60 (m, 2H), 3.98 (d, J=12.0 Hz, 2H), 3.85 (d, J=10.9 Hz,2H), 3.45 (s, 3H), 2.72 (d, J=10.7 Hz, 2H), 2.58-2.52 (m, 2H), 1.84(d, J=7.2 Hz, 3H), 0.94 (t, J=7.3 Hz, 3H). Retention time (LC-MS):1.999 min. MH.sup.+ 586.

Compound 58.(2S)-2-(1-(cyanomethyl)-3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)--N-(2-(2-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)thiazo-l-4-yl)propanamide

##STR00601##

This compound was prepared using the method described for Compound1 with appropriate starting materials in 17.7% yield as a yellowsolid. .sup.1H NMR (400 MHz, DMSO-d6) .delta. 11.68 (s, 1H), 8.87(s, 2H), 8.43 (s, 1H), 7.51 (s, 1H), 5.73 (q, J=7.0 Hz, 1H), 4.85(s, 2H), 3.99 (d, J=12.1 Hz, 2H), 3.86 (d, J=11.0 Hz, 2H), 3.49 (s,3H), 2.72 (d, J=10.6 Hz, 2H), 1.85 (d, J=7.3 Hz, 3H). Retentiontime (LC-MS): 1.945 min. MH.sup.+ 555.

Compound 59.(S)-2-(1-(3-methoxy-2-oxopropyl)-3-methyl-2,6-dioxo-2,3-dihydro-1H-purin--7(6H)-yl)-N-(6-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-2-yl)propanamide

##STR00602##

This compound was prepared using the method described for compound1 with appropriate starting materials and purified via preparativeHPLC to afford(S)-2-(1-(cyanomethyl)-3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6-H)-yl)-N-(6-(2-((R)-2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidin-5-yl)pyra-zin-2-yl)propanamide in 3% yield as a white solid. .sup.1H NMR (400MHz, DMSO-D6) .delta. 9.62 (s, 2H), 8.31 (s, 1H), 8.18 (s, 1H),7.95 (t, 1H), 7.88 (d, J=7.6 Hz, 1H), 7.53 (s, 1H), 5.87 (d, J=7.1Hz, 1H), 4.92 (s, 2H), 4.22 (s, 2H), 3.60 (d, J=8.9 Hz, 3H), 3.43(s, 3H), 1.98 (d, J=7.3 Hz, 3H). Retention time (LC-MS): 1.799 min.MH.sup.+ 547.

Compound 60.(2S)-2-(1-(cyanomethyl)-3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)--N-(6-(2-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)pyrazi-n-2-yl)propanamide

##STR00603##

This compound was prepared using the method described for compound1 with appropriate starting materials in 27.7% yield as a whitesolid. .sup.1H NMR (400 MHz, DMSO-D6) .delta. 11.39 (s, 1H), 9.14(s, 1H), 9.08 (s, 2H), 8.93 (s, 1H), 8.45 (s, 1H), 5.83 (d, J=6.8Hz, 1H), 4.85 (s, 2H), 4.01 (d, J=12.0 Hz, 2H), 3.87 (d, J=10.5 Hz,2H), 3.50 (s, 3H), 2.72 (d, J=12.1 Hz, 2H), 1.90 (d, J=7.3 Hz, 3H).Retention time (LC-MS): 2.013 min. MH.sup.+ 550.

Compound 61.(2S)--N-(2'-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-[2,5'-bipyrimidi-n]-4-yl)-2-(3-methyl-2,6-dioxo-1-(2-oxopropyl)-2,3-dihydro-1H-purin-7(6H)--yl)propanamide

##STR00604##

This compound was prepared using the method described for compound2 with appropriate starting materials in 5.0% yield as a whitesolid. .sup.1H NMR (400 MHz, DMSO-D6) .delta. 11.44 (s, 1H), 9.19(s, 2H), 8.69 (d, J=5.7 Hz, 1H), 8.40 (s, 1H), 7.81 (d, J=5.7 Hz,1H), 5.77 (d, J=7.4 Hz, 1H), 4.70 (s, 2H), 4.01 (d, J=12.1 Hz, 2H),3.87 (d, J=11.3 Hz, 2H), 3.46 (s, 3H), 2.72 (d, J=10.9 Hz, 2H),2.16 (s, 3H), 1.88 (d, J=7.3 Hz, 3H). Retention time (LC-MS): 1.598min. MH.sup.+ 567.

Compound 62.(2S)--N-(2'-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-[2,5'-bipyrimidi-n]-4-yl)-2-(3-methyl-2,6-dioxo-1-(2-oxobutyl)-2,3-dihydro-1H-purin-7(6H)-y-l)propanamide

##STR00605##

This compound was prepared using the method described for compound2 with appropriate starting materials in 5.0% yield. .sup.1H NMR(400 MHz, DMSO-D6) .delta. 11.41 (s, 1H), 9.19 (s, 2H), 8.69 (d,J=5.7 Hz, 1H), 8.40 (s, 1H), 7.81 (d, J=5.7 Hz, 1H), 5.78 (d, J=6.8Hz, 1H), 4.69 (d, J=2.1 Hz, 2H), 4.01 (d, J=12.1 Hz, 2H), 3.87 (d,J=10.7 Hz, 2H), 3.46 (s, 3H), 2.72 (d, J=11.2 Hz, 2H), 2.54 (d,J=7.3 Hz, 2H), 1.87 (d, J=7.3 Hz, 3H), 0.93 (t, J=7.3 Hz, 3H).Retention time (LC-MS): 1.819 min. MH.sup.+ 581.

Compound 63.(2S)--N-(2-(6-(3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)thiazol-4-yl)-2--(3-methyl-2,6-dioxo-1-(2-oxopropyl)-2,3-dihydro-1H-purin-7(6H)-yl)propana-mide

##STR00606##

This compound was prepared using the method described for compound2 with appropriate starting materials in 14.5% yield. .sup.1H NMR(400 MHz, DMSO-D6) .delta. 11.54 (s, 1H), 8.61 (d, J=2.2 Hz, 1H),8.38 (s, 1H), 7.92 (dd, J=8.8, 2.3 Hz, 1H), 7.39 (s, 1H), 6.56 (d,J=8.9 Hz, 1H), 5.70 (d, J=7.3 Hz, 1H), 4.70 (s, 2H), 3.70 (d,J=10.5 Hz, 2H), 3.45 (s, 3H), 3.44 (s, 2H), 2.17 (s, 3H), 1.84 (d,J=7.3 Hz, 3H), 1.71 (s, 2H), 0.77 (d, J=4.7 Hz, 1H), 0.18 (d, J=4.0Hz, 1H). Retention time (LC-MS): 0.739 min. MH.sup.+ 535.

Compound 64.(2S)--N-(2-(6-(3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)thiazol-4-yl)-2--(1-(cyanomethyl)-3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)propana-mide

##STR00607##

This compound was prepared using the method described for compound1 with appropriate starting materials in 4.8% yield (ee: 92%) as awhite solid. .sup.1H NMR (400 MHz, DMSO-D6) .delta. 11.59 (s, 1H),8.61 (d, J=2.3 Hz, 1H), 8.42 (s, 1H), 7.92 (dd, J=8.9, 2.4 Hz, 1H),7.40 (s, 1H), 6.56 (d, J=9.0 Hz, 1H), 5.72 (d, J=7.2 Hz, 1H), 4.84(s, 2H), 3.70 (d, J=10.1 Hz, 2H), 3.48 (s, 3H), 3.45 (d, J=10.7 Hz,2H), 1.84 (d, J=7.3 Hz, 3H), 1.71 (s, 2H), 0.77 (d, J=4.4 Hz, 1H),0.18 (d, J=4.2 Hz, 1H). Retention time (LC-MS): 0.853 min. MH.sup.+518.

Compound 65.((2S)--N-(6'-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-[2,3'-bipyridin-]-6-yl)-2-(3-methyl-2,6-dioxo-1-(2-oxopropyl)-2,3-dihydro-1H-purin-7(6H)-y-l)propanamide

##STR00608##

This compound was prepared using the method described for compound2 with appropriate starting materials in 17.9% yield (ee: 94%) as awhite solid. .sup.1H NMR (400 MHz, DMSO-D6) .delta. 10.96 (s, 1H),8.82 (d, J=2.2 Hz, 1H), 8.39 (s, 1H), 8.21 (dd, J=8.9, 2.4 Hz, 1H),7.84 (d, J=7.9 Hz, 1H), 7.78 (t, J=7.9 Hz, 1H), 7.60 (d, J=8.1 Hz,1H), 6.60 (d, J=8.9 Hz, 1H), 5.79 (s, 1H), 4.70 (d, J=2.5 Hz, 2H),3.86 (m, 2H), 3.76 (d, J=9.5 Hz, 2H), 3.46 (s, 3H), 2.72 (d, J=10.9Hz, 2H), 2.16 (s, 3H), 1.86 (d, J=7.3 Hz, 3H). Retention time(LC-MS): 0.600 min. MH.sup.+ 565.

Compound 66.(2S)--N-(2-(6-(3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)thiazol-4-yl)-2--(1-(cyanomethyl)-3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)propana-mide

##STR00609##

This compound was prepared using the method described for compound1 with appropriate starting materials in 4.3% yield (ee: 99.5%)..sup.1H NMR (400 MHz, DMSO-D6) .delta. 11.01 (s, 1H), 8.83 (d,J=2.2 Hz, 1H), 8.43 (s, 1H), 8.23 (dd, J=8.8, 2.4 Hz, 1H), 7.85 (d,J=7.1 Hz, 1H), 7.79 (t, J=7.9 Hz, 1H), 7.60 (d, J=7.9 Hz, 1H), 6.61(d, J=8.9 Hz, 1H), 5.82 (s, 1H), 4.85 (s, 2H), 3.86 (d, J=11.0 Hz,2H), 3.77 (d, J=9.5 Hz, 2H), 3.49 (s, 3H), 2.72 (d, J=10.5 Hz, 2H),1.88 (d, J=7.3 Hz, 3H). Retention time (LC-MS): 2.608 min. MH.sup.+545.

Compound 67.(2S)-2-(1-(cyanomethyl)-3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)--N-(2'-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-[2,5'-bipyrimidin]-4-y-l)propanamide

##STR00610##

This compound was prepared using the method described for compound53 with appropriate starting materials in 10.6% yield (ee: 61.2%)..sup.1H NMR (400 MHz, DMSO-D6) .delta. 11.49 (s, 1H), 9.23 (d,J=20.1 Hz, 2H), 8.69 (d, J=5.7 Hz, 1H), 8.43 (s, 1H), 7.82 (d,J=5.6 Hz, 1H), 5.80 (d, J=7.5 Hz, 1H), 4.84 (s, 2H), 4.02 (d,J=12.2 Hz, 2H), 3.88 (d, J=11.2 Hz, 2H), 3.49 (s, 3H), 2.71 (d,J=11.4 Hz, 2H), 1.89 (d, J=7.2 Hz, 3H). Retention time (LC-MS):2.082 min. MH.sup.+ 550.

Compound 68.(2S)--N-(6'-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-[2,3'-bipyridin]--6-yl)-2-(3-methyl-2,6-dioxo-1-(2-oxobutyl)-2,3-dihydro-1H-purin-7(6H)-yl)-propanamide

##STR00611##

This compound was prepared using the method described for compound2 with appropriate starting materials in 14.7% yield (ee: 98.6%),.sup.1H NMR (400 MHz, DMSO-D6) .delta. 10.97 (s, 1H), 8.82 (d,J=2.2 Hz, 1H), 8.40 (s, 1H), 8.22 (dd, J=8.8, 2.4 Hz, 1H),7.90-7.75 (m, 2H), 7.60 (d, J=7.9 Hz, 1H), 6.61 (d, J=8.9 Hz, 1H),5.79 (d, J=6.4 Hz, 1H), 4.70 (d, J=3.6 Hz, 2H), 3.86 (d, J=11.1 Hz,2H), 3.76 (d, J=9.4 Hz, 2H), 3.46 (s, 3H), 2.72 (d, J=10.8 Hz, 2H),2.55 (d, J=7.2 Hz, 2H), 1.87 (d, J=7.3 Hz, 3H), 0.94 (t, J=7.3 Hz,3H). Retention time (LC-MS): 1.731 min. MH.sup.+ 579.

Compound 69.(2S)--N-(2-(6-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)py-rimidin-4-yl)-2-(3-methyl-2,6-dioxo-1-(2-oxopropyl)-2,3-dihydro-1H-purin-7-(6H)-yl)propanamide

##STR00612##

This compound was prepared using the method described for compound2 with appropriate starting materials in 26.5% yield (ee: 86.7%)..sup.1H NMR (400 MHz, DMSO-D6) .delta. 11.42 (s, 1H), 9.02 (d,J=2.0 Hz, 1H), 8.68 (d, J=5.7 Hz, 1H), 8.44 (dd, J=9.0, 2.2 Hz,1H), 8.40 (s, 1H), 7.78 (d, J=5.6 Hz, 1H), 6.73 (d, J=9.0 Hz, 1H),5.77 (d, J=7.2 Hz, 1H), 4.69 (d, J=1.4 Hz, 2H), 3.91 (d, J=11.3 Hz,2H), 3.83 (d, J=9.7 Hz, 2H), 3.46 (s, 3H), 2.76 (d, J=10.3 Hz, 2H),2.16 (s, 3H), 1.88 (d, J=7.3 Hz, 3H). Retention time (LC-MS): 1.773min. MH.sup.+ 566.

Compound 70.(2S)--N-(2-(6-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)py-rimidin-4-yl)-2-(3-methyl-2,6-dioxo-1-(2-oxobutyl)-2,3-dihydro-1H-purin-7(-6H)-yl)propanamide

##STR00613##

This compound was prepared using the method described for compound2 with appropriate starting materials in 6.9% yield (ee: 85.4%)..sup.1H NMR (400 MHz, DMSO-D6) .delta. 11.42 (s, 1H), 9.02 (d,J=2.0 Hz, 1H), 8.68 (d, J=5.7 Hz, 1H), 8.45 (dd, J=9.1, 2.1 Hz,1H), 8.41 (s, 1H), 7.78 (d, J=5.7 Hz, 1H), 6.74 (d, J=9.1 Hz, 1H),5.78 (d, J=7.5 Hz, 1H), 4.69 (d, J=2.5 Hz, 2H), 3.91 (d, J=11.3 Hz,2H), 3.83 (d, J=9.6 Hz, 2H), 3.46 (s, 3H), 2.77 (d, J=10.5 Hz, 2H),2.55 (d, J=7.3 Hz, 2H), 1.88 (d, J=7.3 Hz, 3H), 0.94 (t, J=7.3 Hz,3H). Retention time (LC-MS): 2.046 min. MH.sup.+ 580.

Compound 71.(2S)--N-(2-(2-(3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)thiazol-4-yl)--2-(3-methyl-1-(2-(methylamino)-2-oxoethyl)-2,6-dioxo-2,3-dihydro-1H-purin--7(6H)-yl)propanamide

##STR00614##

A mixture of(2S)--N-(2-(2-(3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)thiazol-4-yl)--2-(3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)propanamide(50 mg, 0.104 mmol), 2-chloro-N-methylacetamide (11.2 mg, 0.104mmol), potassium carbonate (14 mg, 0.104 mmol) and a catalyticamount of TBAI in N, N-dimethyl formamide (1 ml) was stirred at50.degree. C. for 2 hrs. The mixture was poured into water,filtered and the solid was washed with water twice, dried undervacuum and recrystallized from ethanol to give(2S)--N-(2-(2-(3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)thiazol-4-yl)--2-(3-methyl-1-(2-(methylamino)-2-oxoethyl)-2,6-dioxo-2,3-dihydro-1H-purin--7(6H)-yl)propanamide (10.5 mg, ee: 93%) as a white solid. .sup.1HNMR (400 MHz, DMSO-D6) .delta. 11.58 (s, 1H), 8.75 (s, 2H), 8.32(s, 1H), 7.90 (s, 1H), 7.42 (s, 1H), 5.69 (q, J=7.6 Hz, 1H), 4.31(d, J=4.4 Hz, 2H), 3.79 (d, J=11.6 Hz, 2H), 3.50 (d, J=11.2 Hz,2H), 3.39 (s, 3H), 2.49 (d, J=4.8 Hz, 3H), 1.78 (d, J=7.2 Hz, 3H),1.64 (m, 2H), 0.72 (m, 1H), 0.11 (m, 1H). Retention time (LC-MS):1.881 min. MH.sup.+: 551.

Compound 72.(2S)--N-(2-(2-(3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)thiazol-4-yl)--2-(1-(2-amino-2-oxoethyl)-3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-y-l)propanamide

##STR00615##

A mixture of(2S)--N-(2-(2-(3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)thiazol-4-yl)--2-(3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)propanamide(50 mg, 0.104 mmol), 2-bromoacetamide (14 mg, 0.104 mmol),potassium carbonate (14 mg, 0.104 mmol) and a catalytic amount ofTBAI in N, N-dimethyl formamide (1 ml) was stirred at 50.degree. C.for 2 hrs. The mixture was poured into water, filtered and thesolid was washed with water twice, dried under vacuum andrecrystallized from ethanol to give(2S)--N-(2-(2-(3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)thiazol-4-yl)--2-(1-(2-amino-2-oxoethyl)-3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-y-l)propanamide (23.1 mg, ee: 93%) as a white solid. 1H NMR (400 MHz,DMSO-D6) .delta. 11.47 (s, 1H), 8.65 (s, 2H), 8.21 (s, 1H), 7.34(d, J=20.9 Hz, 2H), 6.91 (s, 1H), 5.58 (d, J=7.3 Hz, 1H), 4.20 (s,2H), 3.67 (d, J=11.4 Hz, 2H), 3.39 (d, J=11.3 Hz, 2H), 3.28 (s,3H), 1.67 (d, J=7.3 Hz, 3H), 1.59 (m, 2H), 0.61 (d, J=4.7 Hz, 1H),0.01 (d, J=4.2 Hz, 1H). Retention time (LC-MS): 1.830 min. MH.sup.+536.

Compound 73.(2S)--N-(2-(2-(3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)thiazol-4-yl)--2-(3-methyl-1-(oxetan-2-ylmethyl)-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl-)propanamide

##STR00616##

A mixture of(2S)--N-(2-(2-(3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)thiazol-4-yl)--2-(3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)propanamide(50 mg, 0.104 mmol), oxetan-2-ylmethyl 4-methylbenzenesulfonate (25mg, 0.104 mmol), potassium carbonate (14 mg, 0.104 mmol) and acatalytic amount of TBAI in N, N-dimethylformamide (1 ml) wasstirred at 50.degree. C. for 2 hrs. The mixture was poured intowater, filtered and the solid was washed with water twice, driedunder vacuum and recrystallized from ethanol to give(2S)--N-(2-(2-(3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)thiazol--4-yl)-2-(3-methyl-1-(oxetan-2-ylmethyl)-2,6-dioxo-2,3-dihydro-1H-purin-7(6-H)-yl)propanamide (3.3 mg, ee: 21.7%) as a white solid. 1H NMR (400MHz, DMSO-D6) .delta. 11.61 (s, 1H), 8.81 (s, 2H), 8.34 (s, 1H),7.46 (s, 1H), 5.73 (d, J=7.2 Hz, 1H), 4.94 (m, 1H), 4.42 (dd,J=14.2, 6.7 Hz, 2H), 4.27 (m, 2H), 3.83 (d, J=11.4 Hz, 2H), 3.57(s, 2H), 3.44 (s, 3H), 2.57 (d, J=7.7 Hz, 1H), 2.43 (d, J=10.1 Hz,1H), 1.82 (d, J=7.2 Hz, 3H), 1.70 (s, 2H), 0.77 (d, J=4.9 Hz, 1H),0.16 (d, J=4.3 Hz, 1H). Retention time (LC-MS): 2.347 min. MH.sup.+549.

Compound 74.(2S)--N-(6-(2-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)-pyrazin-2-yl)-2-(3-methyl-2,6-dioxo-1-(2-oxopropyl)-2,3-dihydro-1H-purin-7-(6H)-yl)propanamide (ZY-000530-052)

##STR00617##

This compound was prepared using the method described for compound2 with appropriate starting materials in 7.8% yield (ee: 59.7%) asa white solid. .sup.1H NMR (400 MHz, DMSO-D6) .delta. 11.37 (s,1H), 9.12 (s, 1H), 9.07 (s, 2H), 8.93 (s, 1H), 8.41 (s, 1H), 5.80(d, J=7.5 Hz, 1H), 4.76-4.64 (m, 2H), 4.01 (d, J=12.0 Hz, 2H), 3.87(d, J=10.5 Hz, 2H), 3.47 (s, 3H), 2.72 (d, J=10.5 Hz, 2H), 2.17 (s,3H), 1.89 (d, J=7.3 Hz, 3H). Retention time (LC-MS): 0.937 min.MH.sup.+ 567.

Compound 75.(2S)--N-(6-(2-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)-pyrazin-2-yl)-2-(3-methyl-2,6-dioxo-1-(2-oxobutyl)-2,3-dihydro-1H-purin-7(-6H)-yl)propanamide

##STR00618##

This compound was prepared using the method described for compound2 with appropriate starting materials. .sup.1H NMR (400 MHz,DMSO-D6) .delta. 9.12 (s, 1H), 9.07 (s, 2H), 8.93 (s, 1H), 8.41 (s,1H), 5.80 (d, J=7.4 Hz, 1H), 4.70 (d, J=2.1 Hz, 2H), 4.00 (d,J=12.1 Hz, 2H), 3.86 (d, J=10.5 Hz, 2H), 3.46 (s, 3H), 2.72 (d,J=10.7 Hz, 2H), 2.54 (d, J=3.8 Hz, 2H), 1.89 (d, J=7.3 Hz, 3H),0.93 (t, J=7.3 Hz, 3H). Retention time (LC-MS): 2.283 min. MH.sup.+581. ee: 74.8%

Compound 76.(2S)--N-(6-(6-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)py-razin-2-yl)-2-(3-methyl-2,6-dioxo-1-(2-oxopropyl)-2,3-dihydro-1H-purin-7(6-H)-yl)propanamide

##STR00619##

This compound was prepared using the method described for compound2 with appropriate starting materials in 7.7% yield (ee: 82.7%) asa white solid. .sup.1H NMR (400 MHz, DMSO-D6) .delta. 11.28 (s,1H), 9.06 (s, 1H), 8.93-8.85 (m, 2H), 8.40 (s, 1H), 8.25 (dd,J=8.9, 2.4 Hz, 1H), 6.67 (d, J=9.0 Hz, 1H), 5.80 (d, J=6.9 Hz, 1H),4.70 (s, 2H), 3.88 (d, J=11.2 Hz, 2H), 3.79 (d, J=9.2 Hz, 2H), 3.47(s, 3H), 2.73 (d, J=9.9 Hz, 2H), 2.16 (s, 3H), 1.89 (d, J=7.3 Hz,3H). Retention time (LC-MS): 1.466 min. MH.sup.+ 566.

Compound 77.(2S)--N-(6-(6-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)py-razin-2-yl)-2-(3-methyl-2,6-dioxo-1-(2-oxopropyl)-2,3-dihydro-1H-purin-7(6-H)-yl)propanamide

##STR00620##

This compound was prepared using the method described for compound1 with appropriate starting materials in 17.6% yield (ee: 95.5%) asa white solid. .sup.1H NMR (400 MHz, DMSO-D6) .delta. 11.34 (s,1H), 9.07 (s, 1H), 8.95-8.84 (m, 2H), 8.44 (s, 1H), 8.25 (dd,J=8.9, 2.4 Hz, 1H), 6.66 (d, J=8.9 Hz, 1H), 5.83 (d, J=7.1 Hz, 1H),4.85 (s, 2H), 3.88 (d, J=11.3 Hz, 2H), 3.79 (d, J=9.6 Hz, 2H), 3.50(s, 3H), 2.73 (d, J=10.8 Hz, 2H), 1.90 (d, J=7.3 Hz, 3H). Retentiontime (LC-MS): 1.558 min. MH.sup.+ 549.

Compound 78.(S)-2-(3-methyl-2,6-dioxo-1-(2-oxopentyl)-2,3-dihydro-1H-purin-7(6H)-yl)--N-(6-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-2-yl)propanamide

##STR00621##

This compound was prepared using the method described for compound2 with appropriate starting materials in 6.5% yield (ee: 69.3%) asa white solid. .sup.1H NMR (400 MHz, DMSO-D6) .delta. 11.54 (s,1H), 8.40 (s, 1H), 8.25 (d, J=8.8 Hz, 1H), 8.12-8.02 (m, 1H), 7.92(d, J=7.6 Hz, 1H), 6.08 (s, 1H), 5.83 (d, J=7.2 Hz, 1H), 5.02 (s,2H), 3.47 (s, 3H), 2.31 (s, 3H), 1.87 (d, J=7.2 Hz, 3H). Retentiontime (LC-MS): 2.445 min. MH.sup.+ 546.

Compound 79.(2S)--N-(2-(6-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)th-iazol-4-yl)-2-(3-methyl-2,6-dioxo-1-(2-oxopropyl)-2,3-dihydro-1H-purin-7(6-H)-yl)propanamide

##STR00622##

This compound was prepared using the method described for compound2 with appropriate starting materials in 68.8% yield as a yellowsolid. .sup.1H NMR (400 MHz, DMSO-D6) .delta. 11.56 (s, 1H), 8.64(d, J=2.1 Hz, 1H), 8.39 (s, 1H), 7.97 (dd, J=8.9, 2.3 Hz, 1H), 7.42(s, 1H), 6.61 (d, J=8.9 Hz, 1H), 5.70 (d, J=7.3 Hz, 1H), 4.70 (s,2H), 3.85 (d, J=11.3 Hz, 2H), 3.76 (d, J=10.4 Hz, 2H), 3.46 (s,3H), 2.73 (d, J=11.2 Hz, 2H), 2.17 (s, 3H), 1.84 (d, J=7.2 Hz, 3H).Retention time (LC-MS): 1.591 min. MH.sup.+ 571.

Compound 80.(2S)--N-(2-(6-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)th-iazol-4-yl)-2-(3-methyl-2,6-dioxo-1-(2-oxobutyl)-2,3-dihydro-1H-purin-7(6H-)-yl)propanamide

##STR00623##

This compound was prepared using the method described in Compound 2with appropriate starting materials in 59.1% yield as yellow solid..sup.1H NMR (400 MHz, DMSO-D6) .delta. 11.55 (s, 1H), 8.64 (d,J=2.3 Hz, 1H), 8.38 (s, 1H), 7.96 (dd, J=8.9, 2.4 Hz, 1H), 7.42 (s,1H), 6.60 (d, J=8.9 Hz, 1H), 5.70 (d, J=7.3 Hz, 1H), 4.69 (d, J=2.4Hz, 2H), 3.85 (d, J=11.4 Hz, 2H), 3.76 (d, J=9.6 Hz, 2H), 3.45 (s,3H), 2.72 (d, J=10.9 Hz, 2H), 2.53 (d, J=7.4 Hz, 2H), 1.83 (d,J=7.3 Hz, 3H), 0.94 (t, J=7.3 Hz, 3H). Retention time (LC-MS):1.813 min. MH.sup.+ 585.

Compound 81.(S)--N-(2-(5-chloro-6-methylpyridin-3-yl)thiazol-4-yl)-2-(3-methyl-2,6-di-oxo-1-(2-oxopropyl)-2,3-dihydro-1H-purin-7(6H)-yl)propanamide

##STR00624##

This compound was prepared using the method described for compound2 with appropriate starting materials in 18.7% yield as lightyellow solid. .sup.1H NMR (400 MHz, DMSO-D6) .delta. 11.69 (s, 1H),8.95 (d, J=1.9 Hz, 1H), 8.40 (s, 1H), 8.30 (d, J=1.9 Hz, 1H), 7.68(s, 1H), 5.71 (d, J=7.3 Hz, 1H), 4.70 (d, J=1.2 Hz, 2H), 3.46 (s,3H), 2.61 (s, 3H), 2.17 (s, 3H), 1.85 (d, J=7.3 Hz, 3H). Retentiontime (LC-MS): 1.737 min. MH.sup.+ 502.

Compound 82.(S)-2-(3-methyl-2,6-dioxo-1-(2-oxopropyl)-2,3-dihydro-1H-purin-7(6H)-yl)--N-(2-(5-methyl-6-(trifluoromethyl)pyridin-3-yl)thiazol-4-yl)propanamide

##STR00625##

This compound was prepared using the method described for compound2 with appropriate starting materials in 56.2% yield as yellowsolid. .sup.1H NMR (400 MHz, DMSO-D6) .delta. 11.76 (s, 1H), 9.07(s, 1H), 8.39 (s, 2H), 7.76 (s, 1H), 5.72 (d, J=7.3 Hz, 1H), 4.70(s, 2H), 3.46 (s, 3H), 2.55 (d, J=1.5 Hz, 3H), 2.16 (s, 3H), 1.86(d, J=7.3 Hz, 3H). Retention time (LC-MS): 2.286 min. MH.sup.+536.

Compound 83.(S)-2-(3-methyl-2,6-dioxo-1-(2-oxobutyl)-2,3-dihydro-1H-purin-7(6H)-yl)-N--(2-(5-methyl-6-(trifluoromethyl)pyridin-3-yl)thiazol-4-yl)propanamide

##STR00626##

This compound was prepared using the method described for compound2 with appropriate starting materials in 45.5% yield as lightyellow solid. .sup.1H NMR (400 MHz, DMSO-D6) .delta. 11.76 (s, 1H),9.06 (s, 1H), 8.39 (s, 2H), 7.76 (s, 1H), 5.72 (d, J=7.3 Hz, 1H),4.69 (d, J=2.4 Hz, 2H), 3.46 (s, 3H), 2.55 (d, J=1.6 Hz, 3H), 2.53(d, J=7.6 Hz, 2H), 1.86 (d, J=7.3 Hz, 3H), 0.94 (t, J=7.3 Hz, 3H).Retention time (LC-MS): 2.488 min. MH.sup.+ 550.

Compound 84.(2S)--N-(6-(6-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)py-razin-2-yl)-2-(3-methyl-2,6-dioxo-1-(2-oxobutyl)-2,3-dihydro-1H-purin-7(6H-)-yl)propanamide

##STR00627##

This compound was prepared using the method described for compound2 with appropriate starting materials in 15.0% yield as a whitesolid. .sup.1H NMR (400 MHz, DMSO-D6) .delta. 11.31 (s, 1H), 9.06(s, 1H), 8.93-8.86 (m, 2H), 8.41 (s, 1H), 8.24 (dd, J=8.9, 2.4 Hz,1H), 6.65 (d, J=8.9 Hz, 1H), 5.79 (d, J=6.6 Hz, 1H), 4.70 (d, J=2.1Hz, 2H), 3.88 (d, J=11.2 Hz, 2H), 3.78 (d, J=9.7 Hz, 2H), 3.47 (s,3H), 2.73 (d, J=10.9 Hz, 2H), 2.58-2.52 (m, 2H), 1.89 (d, J=7.3 Hz,3H), 0.94 (t, J=7.3 Hz, 3H). Retention time (LC-MS): 0.837 min.MH.sup.+ 580.

Compound 85.(S)-2-(3-methyl-1-((5-methylisoxazol-3-yl)methyl)-2,6-dioxo-2,3-dihydro-1-H-purin-7(6H)-yl)-N-(2-(5-methyl-6-(trifluoromethyl)pyridin-3-yl)pyrimidin--4-yl)propanamide

##STR00628##

This compound was prepared using the method described for compound2 with appropriate starting materials in 17.6% yield as a whitesolid. .sup.1H NMR (400 MHz, DMSO-D6) .delta. 9.39 (s, 1H), 8.86(d, J=5.8 Hz, 1H), 8.74 (s, 1H), 8.42 (s, 1H), 8.00 (d, J=5.7 Hz,1H), 6.08 (s, 1H), 5.82 (d, J=7.3 Hz, 1H), 5.01 (s, 2H), 3.48 (s,3H), 2.58 (s, 3H), 2.30 (s, 3H), 1.89 (d, J=7.3 Hz, 3H). Retentiontime (LC-MS): 2.482 min. MH.sup.+ 570.

Compound 86.(2S)--N-(2-(2-(3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)thiazol-4-yl)--2-(1-(2-methoxyethyl)-3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)pr-opanamide

##STR00629##

A mixture of(2S)--N-(2-(2-(3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)thiazol-4-yl)--2-(3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)propanamide(50 mg, 0.104 mmol), 1-chloro-2-methoxyethane (14 mg, 0.104 mmol),potassium carbonate (14 mg, 0.104 mmol) and a catalytic amount ofTBAI in N, N-dimethyl formamide (1 mL) was stirred at 50.degree. C.for 2 hrs. The mixture was diluted with EA and washed with water,brine successively, dried and concentrated to give crude product,which was purified via preparative HPLC to give(2S)--N-(2-(2-(3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)thiazol-4-yl)--2-(1-(2-methoxyethyl)-3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)pr-opanamide (5.1 mg, 9.1% yield) as a white solid. .sup.1H NMR (400MHz, DMSO-D6) .delta. 11.62 (s, 1H), 8.82 (s, 2H), 8.35 (s, 1H),7.48 (s, 1H), 5.75 (m, J=7.3 Hz, 1H), 4.01 (m, J=6.0 Hz, 2H), 3.84(m, J=11.4 Hz, 2H), 3.57 (s, 2H), 3.43 (m, 5H), 3.20 (s, 3H), 1.83(m, J=7.3 Hz, 3H), 1.72 (m, 2H), 0.76 (m, 1H), 0.16 (m, 1H).Retention time (LC-MS): 1.897 min. MH.sup.+ 537.

Compound 87.(S)-2-(3-methyl-1-(2-(methylamino)-2-oxoethyl)-2,6-dioxo-2,3-dihydro-1H-p-urin-7(6H)-yl)-N-(6-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-2-yl)propan-amide

##STR00630##

A mixture of(S)-2-(3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)-N-(6-(2-(trifluo-romethyl)pyrimidin-5-yl)pyridin-2-yl)propanamide (50 mg, 0.108mmol), 2-chloro-N-methylacetamide (12 mg, 0.108 mmol), potassiumcarbonate (15 mg, 0.108 mmol) and a catalytic amount of TBAI in N,N-dimethyl formamide (1 mL) was stirred at 50.degree. C. for 2 hrs.The mixture was diluted with EA and washed with water, brinesuccessively, dried and concentrated to give crude product, whichwas purified via preparative HPLC to give(S)-2-(3-methyl-1-(2-(methylamino)-2-oxoethyl)-2,6-dioxo-2,3-dihydro-1H-p-urin-7(6H)-yl)-N-(6-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-2-yl)propan-amide (2.8 mg, 5% yield) as a white solid. .sup.1H NMR (400 MHz,DMSO-D6) .delta. 11.30 (s, 1H), 9.68 (s, 2H), 8.41 (s, 1H), 8.12(m, J=6.9 Hz, 1H), 8.12 (m, 3H), 5.83 (s, 1H), 4.37 (m, J=7.5 Hz,2H), 3.46 (s, 3H), 2.54 (m, J=4.5 Hz, 3H), 1.88 (m, J=7.3 Hz, 3H).Retention time (LC-MS): 1.383 min. MH.sup.+ 531.

Compound 88.(2S)-2-(3-methyl-1-(oxetan-2-ylmethyl)-2,6-dioxo-2,3-dihydro-1H-purin-7(6-H)-yl)-N-(6-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-2-yl)propanamide

##STR00631##

A mixture of(S)-2-(3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)-N-(6-(2-(trifluo-romethyl)pyrimidin-5-yl)pyridin-2-yl)propanamide (50 mg, 0.108mmol), oxetan-2-ylmethyl 4-methylbenzenesulfonate (26 mg, 0.108mmol), potassium carbonate (15 mg, 0.108 mmol) and a catalyticamount of TBAI in N, N-dimethyl formamide (1 mL) was stirred at50.degree. C. for 2 hrs. The mixture was diluted with EA and washedwith water, brine successively, dried and concentrated to givecrude product, which was purified via preparative HPLC to give(2S)-2-(3-methyl-1-(oxetan-2-ylmethyl)-2,6-dioxo-2,3-dihydro-1H-purin-7(6-H)-yl)-N-(6-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-2-yl)propanamide(7.2 mg, 12.6% yield) as a white solid. .sup.1H NMR (400 MHz,DMSO-D6) .delta. 11.28 (s, 1H), 9.68 (s, 2H), 8.37 (m, J=1.2 Hz,1H), 8.11 (m, J=7.1 Hz, 1H), 8.01 (m, J=8.2 Hz, 2H), 5.83 (s, 1H),4.83 (m, 1H), 4.41 (m, 2H), 4.11 (m, 2H), 3.45 (s, 3H), 2.59 (m,1H), 2.42 (m, J=8.5 Hz, 1H), 1.87 (m, J=7.3 Hz, 3H). Retention time(LC-MS): 1.841 min. MH.sup.+ 530.

Compound 89.(S)-2-(3-methyl-1-(3-methyl-2-oxobutyl)-2,6-dioxo-2,3-dihydro-1H-purin-7(-6H)-yl)-N-(6-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-2-yl)propanamide

##STR00632##

A mixture of(S)-2-(3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)-N-(6-(2-(trifluo-romethyl)pyrimidin-5-yl)pyridin-2-yl)propanamide (50 mg, 0.108mmol), 1-bromo-3-methylbutan-2-one (17 mg, 0.108 mmol), potassiumcarbonate (15 mg, 0.108 mmol) and a catalytic amount of TBAI in N,N-dimethyl formamide (1 ml) was stirred at 50.degree. C. for 2 hrs.The mixture was diluted with EA and washed with water, brinesuccessively, dried and concentrated to give crude product, whichwas purified via preparative HPLC to give(S)-2-(3-methyl-1-(3-methyl-2-oxobutyl)-2,6-dioxo-2,3-dihydro-1H-purin-7(-6H)-yl)-N-(6-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-2-yl)propanamide(20.7 mg, 35.1% yield) as a white solid. 1H NMR (400 MHz, DMSO-D6).delta. 11.28 (s, 1H), 9.68 (s, 2H), 8.42 (s, 1H), 8.12 (m, J=7.4Hz, 1H), 7.99 (m, 2H), 5.82 (s, 1H), 4.79 (s, 2H), 3.47 (s, 3H),2.79 (m, 1H), 1.89 (m, J=7.3 Hz, 3H), 1.05 (m, 6H). Retention time(LC-MS): 2.519 min. MH.sup.+ 544.

Compound 90.(S)--N-(2-(5-chloro-6-methylpyridin-3-yl)thiazol-4-yl)-2-(1,3-dimethyl-2,-6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)propanamide

##STR00633##

This compound was prepared using the method described for compound2 with appropriate starting materials and purified via preparativeHPLC in 50% yield as a white solid. .sup.1H NMR (400 MHz, DMSO-D6).delta. 11.69 (s, 1H), 8.95 (d, J=2.0 Hz, 1H), 8.34 (s, 1H), 8.29(d, J=2.4 Hz, 1H), 7.68 (s, 1H), 5.71 (d, J=7.2 Hz, 1H), 4.69 (d,J=2.4 Hz, 2H), 2.53 (q, J=7.2 Hz, 2H),3.46 (s, 3H), 2.61 (s, 3H),1.85 (d, J=7.2 Hz, 3H), 0.94 (t, J=7.2 Hz, 3H). Retention time(LC-MS): 2.098 min. MH.sup.+ 516.

Compound 91.(S)--N-(2-(5-chloro-6-methylpyridin-3-yl)thiazol-4-yl)-2-(1,3-dimethyl-2,-6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)propanamide

##STR00634##

This compound was prepared using the method described for compound2 with appropriate starting materials in 20% yield as a whitesolid. .sup.1H-NMR (400 MHz, DMSO-D6) .delta. 11.72 (s, 1H), 11.72(s, 1H), 8.95 (d, J=1.6 Hz, 1H), 8.40 (s, 1H), 8.30 (s, 1H), 7.68(s, 1H), 6.09 (s, 1H), 5.75 (d, J=7.2 Hz, 1H), 5.02 (s, 2H), 3.55(s, 1H), 2.61 (s, 3H), 2.31 (s, 3H), 1.85 (d, J=7.2 Hz, 3H).Retention time (LC-MS): 2.088 min. MH.sup.+ 541.

Compound 92.(S)--N-(2-(5-fluoro-6-methylpyridin-3-yl)thiazol-4-yl)-2-(3-methyl-2,6-di-oxo-1-(2-oxopropyl)-2,3-dihydro-1H-purin-7(6H)-yl)propanamide

##STR00635##

This compound was prepared using the method described for compound2 with appropriate starting materials in 2.6% yield as a whitesolid. .sup.1H NMR (400 MHz, DMSO-D6) .delta. 11.69 (s, 1H), 8.87(s, 1H), 8.39 (s, 1H), 8.09 (d, J=10.4 Hz, 1H), 7.68 (s, 1H), 5.72(d, J=7.2 Hz, 1H), 4.70 (s, 2H), 3.46 (s, 3H), 2.52 (m, 3H), 2.17(s, 3H), 1.85 (d, J=7.2 Hz, 3H). Retention time (LC-MS): 1.544 min.MH.sup.+ 486.

Compound 93.(S)-2-(3-methyl-1-((5-methylisoxazol-3-yl)methyl)-2,6-dioxo-2,3-dihydro-1-H-purin-7(6H)-yl)-N-(6-(5-oxo-2,5-dihydro-1,2,4-oxadiazol-3-yl)pyridin-2-y-l)propanamide

##STR00636##

This compound was prepared using the method described for compound2 with appropriate starting materials in 7.7% yield as a whitesolid. 1H NMR (400 MHz, DMSO-D6) .delta. 11.25 (s, 1H), 8.39 (s,1H), 8.15 (s, 1H), 8.05 (d, J=7.9 Hz, 1H), 7.91 (t, J=7.9 Hz, 1H),7.61 (d, J=7.5 Hz, 1H), 6.08 (s, 1H), 5.82 (d, J=6.7 Hz, 1H),5.09-4.92 (m, 2H), 3.47 (s, 3H), 2.31 (s, 3H), 1.85 (d, J=7.2 Hz,3H). Retention time (LC-MS): 3.437 min. MH.sup.+ 494.

Compound 94.(S)-2-(3-methyl-1-((5-methylisoxazol-3-yl)methyl)-2,6-dioxo-2,3-dihydro-1-H-purin-7(6H)-yl)-N-(2-(5-methyl-6-(trifluoromethyl)pyridin-3-yl)thiazol-4--yl)propanamide

##STR00637##

This compound was prepared using the method described for compound2 with appropriate starting materials in 54.1% yield as a yellowsolid. 1H NMR (400 MHz, DMSO-D6) .delta. 11.79 (s, 1H), 9.07 (s,1H), 8.41 (s, 2H), 7.78 (s, 1H), 6.10 (s, 1H), 5.77 (d, J=7.1 Hz,1H), 5.03 (s, 2H), 3.48 (s, 3H), 2.56 (s, 3H), 2.32 (s, 3H), 1.87(d, J=7.1 Hz, 3H). Retention time (LC-MS): 2.044 min. MH.sup.+575.

Compound 95.(S)-2-(1-(isoxazol-3-ylmethyl)-3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(-6H)-yl)-N-(6'-(trifluoromethyl)-[2,3'-bipyridin]-6-yl)propanamide

##STR00638##

To a solution of(S)-2-(3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)-N-(6'-(trifluoro-methyl)-[2,3'-bipyridin]-6-yl)propanamide (15 mg, 0.033 mmol) andPOTASSIUM CARBONATE (9 mg, 0.065 mmol) in DMF (1 mL) was added3-(chloromethyl)isoxazole (3.7 mg, 0.049 mmol). The mixture wasstirred at rt overnight. The mixture was diluted with EA and washedwith water, saturated aqueous NH.sub.4Cl solution and brine, driedover Na.sub.2SO.sub.4, and evaporated. The residue was purified bysilica gel column chromatography (0-2% MeOH/DCM) to give theproduct(S)-2-(1-(isoxazol-3-ylmethyl)-3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(-6H)-yl)-N-(6'-(trifluoromethyl)-[2,3'-bipyridin]-6-yl)propanamide(16.5 mg, 92% yield) as a white solid. .sup.1H NMR (400 MHz,DMSO-D6) .delta. 11.20 (s, 1H), 9.43 (s, 1H), 8.78 (s, 1H), 8.68(d, J=1.8 Hz, 1H), 8.39 (s, 1H), 7.89-8.05 (m, 4H), 6.45 (s, 1H),5.82 (m, 1H), 5.09 (s, 2H), 3.47 (s, 3H), 1.87 (d, J=7.3 Hz, 3H).MH.sup.+ 541.

Compound 96.(S)-2-(3-methyl-1-((5-methylisoxazol-3-yl)methyl)-2,6-dioxo-2,3-dihydro-1-H-purin-7(6H)-yl)-N-(6-(2-((S)-2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidi-n-5-yl)pyrazin-2-yl)propanamide

##STR00639##

This compound was prepared using the method described for compound1 with appropriate starting materials in 28% yield as a whitesolid. 1H NMR (400 MHz, DMSO-D6) .delta. 11.37 (s, 1H), 9.13 (m,3H), 8.95 (s, 1H), 8.39 (s, 1H), 6.07 (s, 1H), 5.82 (d, J=7.1 Hz,1H), 5.10 (m, 1H), 5.01 (s, 2H), 3.70 (m, 2H), 3.46 (s, 3H), 2.29(s, 3H), 1.98-2.20 (m, 4H), 1.87 (d, J=7.1 Hz, 3H). MH.sup.+626.

Compound 97(S)-2-(3-methyl-2,6-dioxo-1-(2-oxopropyl)-2,3-dihydro-1H-purin-7(6H)-yl)--N-(6'-methyl-5'-(trifluoromethyl)-[2,3'-bipyridin]-6-yl)propanamide

##STR00640##

This compound was prepared using the method described for compound2 with appropriate starting materials in 23.6% yield (ee: 90%) as agrey solid. .sup.1H NMR (400 MHz, DMSO-d6) .delta. 11.14 (s, 1H),9.41 (s, 1H), 8.70 (s, 1H), 8.39 (s, 1H), 8.02 (s, 1H), 7.98-7.90(m, 2H), 5.79 (d, J=7.2 Hz, 1H), 4.74-4.64 (m, 2H), 3.46 (s, 3H),2.71 (s, 3H), 2.15 (s, 3H), 1.87 (d, J=7.3 Hz, 3H). Retention time(LC-MS): 2.149 min. MH.sup.+ 530.

Compound 98.(S)-2-(3-methyl-2,6-dioxo-1-(2-oxopropyl)-2,3-dihydro-1H-purin-7(6H)-yl)--N-(2-(6-methyl-5-(trifluoromethyl)pyridin-3-yl)thiazol-4-yl)propanamide

##STR00641##

This compound was prepared using the method described for compound2 with appropriate starting materials in 56.1% yield as a lightyellow solid. .sup.1H NMR (400 MHz, DMSO-d6) .delta. 11.70 (s, 1H),9.22 (d, J=1.8 Hz, 1H), 8.46 (d, J=1.9 Hz, 1H), 8.38 (s, 1H), 7.70(s, 1H), 5.71 (d, J=7.3 Hz, 1H), 4.69 (s, 2H), 3.46 (s, 3H), 2.70(d, J=1.1 Hz, 3H), 2.16 (s, 3H), 1.85 (d, J=7.3 Hz, 3H). Retentiontime (LC-MS): 2.023 min. MH.sup.+ 536.

Compound 99.(S)-2-(3-methyl-2,6-dioxo-1-(2-oxobutyl)-2,3-dihydro-1H-purin-7(6H)-yl)-N--(2-(6-methyl-5-(trifluoromethyl)pyridin-3-yl)thiazol-4-yl)propanamide

##STR00642##

This compound was prepared using the method described for compound2 with appropriate starting materials and purified via preparativeHPLC, 54.7% yield as a light yellow solid. .sup.1H NMR (400 MHz,DMSO-d6) .delta. 11.70 (s, 1H), 9.21 (s, 1H), 8.45 (s, 1H), 8.38(s, 1H), 7.70 (s, 1H), 5.72 (q, J=7.1 Hz, 1H), 4.69 (d, J=2.2 Hz,2H), 3.45 (s, 3H), 2.70 (s, 3H), 2.56-2.51 (m, 2H), 1.85 (d, J=7.3Hz, 3H), 0.94 (t, J=7.3 Hz, 3H). Retention time (LC-MS): 2.195 min.MH.sup.+ 550.

Compound 100.(S)--N-(2-(5-fluoro-6-methylpyridin-3-yl)thiazol-4-yl)-2-(3-methyl-1-((5--methylisoxazol-3-yl)methyl)-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)propan-amide

##STR00643##

This compound was prepared using the method described for compound2 with appropriate starting materials in 13.9% yield as a whitesolid. .sup.1H NMR (400 MHz, DMSO-d6) .delta. 11.71 (s, 1H), 8.86(s, 1H), 8.40 (s, 1H), 8.12-8.05 (m, 1H), 7.68 (s, 1H), 6.09 (s,1H), 5.75 (q, J=7.6 Hz, 1H), 5.02 (s, 2H), 3.47 (s, 3H), 2.51 (s,3H), 2.31 (s, 3H), 1.85 (d, J=7.2 Hz, 3H). Retention time (LC-MS):1.306 min. MH.sup.+ 525.

Compound 101.(S)--N-(2-(5-fluoro-6-methylpyridin-3-yl)thiazol-4-yl)-2-(3-methyl-2,6-di-oxo-1-(2-oxobutyl)-2,3-dihydro-1H-purin-7(6H)-yl)propanamide

##STR00644##

This compound was prepared using the method described for compound2 with appropriate starting materials in 16.7% yield as a whitesolid. .sup.1H NMR (400 MHz, DMSO-d6) .delta. 11.70 (s, 1H), 8.87(s, 1H), 8.40 (s, 1H), 8.08 (dd, J=10.0, 1.8 Hz, 1H), 7.68 (s, 1H),5.72 (d, J=7.2 Hz, 1H), 4.79-4.61 (m, 2H), 3.46 (s, 3H), 2.52 (m,5H), 1.85 (d, J=7.2 Hz, 3H), 0.94 (t, J=7.2 Hz, 3H). Retention time(LC-MS): 1.807 min. MH.sup.+ 500.

Compound 102.(2S)--N-(2-(2-(3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)thiazol-4-yl)--2-(3-methyl-2,6-dioxo-1-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-purin-7(6H)--yl)propanamide

##STR00645##

A mixture of(2S)--N-(2-(2-(3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)thiazol-4-yl)--2-(3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)propanamide(50 mg, 0.104 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate(24 mg, 0.104 mmol), potassium carbonate (14 mg, 0.104 mmol) and acatalytic amount of TBAI in DMF (1 mL) was stirred at 50.degree. C.for 2 hrs. The mixture was diluted with EA and washed with water,brine successively, dried and concentrated to give crude product,which was purified via preparative HPLC to give(2S)--N-(2-(2-(3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)thiazol-4-yl)--2-(3-methyl-2,6-dioxo-1-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-purin-7(6H)--yl)propanamide (8.7 mg, 14.9% yield) as a white solid. .sup.1H NMR(400 MHz, DMSO-d6) .delta. 11.63 (s, 1H), 8.80 (s, 2H), 8.38 (m,1H), 7.45 (s, 1H), 5.70 (m, J=7.3 Hz, 1H), 4.62 (m, 2H), 3.82 (m,J=11.4 Hz, 2H), 3.54 (m, J=10.1 Hz, 2H), 3.47 (s, 3H), 1.83 (m,J=7.3 Hz, 3H), 1.68 (m, 2H), 0.77 (m, J=12.4, 7.9 Hz, 1H), 0.15 (m,1H). Retention time (LC-MS): 2.335 min. MH.sup.+ 561.

Compound 103.(2S)--N-(2-(2-(3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)thiazol-4-yl)--2-(3-methyl-2,6-dioxo-1-(3,3,3-trifluoropropyl)-2,3-dihydro-1H-purin-7(6H-)-yl)propanamide

##STR00646##

A mixture of(2S)--N-(2-(2-(3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)thiazol-4-yl)--2-(3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)propanamide(50 mg, 0.104 mmol), 1,1,1-trifluoro-3-iodopropane (23 mg, 0.104mmol), potassium carbonate (14 mg, 0.104 mmol) and a catalyticamount of TBAI in DMF (1 mL) was stirred at 50.degree. C. for 2hrs. The mixture was diluted with EA and washed with water, brinesuccessively, dried and concentrated to give crude product, whichwas purified via preparative HPLC to give(2S)--N-(2-(2-(3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)thiazol-4-yl)--2-(3-methyl-2,6-dioxo-1-(3,3,3-trifluoropropyl)-2,3-dihydro-1H-purin-7(6H-)-yl)propanamide (12.1 mg, 20% yield) as a white solid. 1H NMR (400MHz, DMSO-d6) .delta. 11.62 (s, 1H), 8.81 (s, 2H), 8.36 (s, 1H),7.46 (s, 1H), 5.75 (m, J=7.3 Hz, 1H), 4.06 (m, 2H), 3.83 (m, J=11.4Hz, 2H), 3.55 (m, J=11.0 Hz, 2H), 3.45 (s, 3H), 2.55 (m, 2H), 1.83(m, J=7.3 Hz, 3H), 1.68 (m, 2H), 0.77 (m, 1H), 0.16 (m, 1H).Retention time (LC-MS): 2.427 min. MH.sup.+ 575.

Compound 104(S)-2-(3-methyl-1-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)-2,6-dioxo-2,3-d-ihydro-1H-purin-7(6H)-yl)-N-(6-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin--2-yl)propanamide

##STR00647##

This compound was prepared using the method described for Compound2 with appropriate starting materials in 18% yield as a whitesolid. .sup.1H NMR (400 MHz, DMSO) .delta. 11.29 (s, 1H), 9.66 (s,2H), 8.46 (s, 1H), 8.11 (d, J=7.5 Hz, 1H), 8.06-7.97 (m, 2H), 5.82(s, 1H), 5.33-5.21 (m, 2H), 3.49 (s, 3H), 2.26 (s, 3H), 1.89 (d,J=7.3 Hz, 3H). Retention time (LC-MS): 2.333 min. MH.sup.+ 557.

Compound 105.(2S)--N-(2-(2-(3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)thiazol-4-yl)--2-(1-(3-methoxy-2-oxopropyl)-3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H-)-yl)propanamide

##STR00648##

This compound was prepared using the method described for compound2 with appropriate starting materials in 11.6% yield as a yellowsolid. .sup.1H NMR (400 MHz, DMSO-d6) .delta. 11.58 (s, 1H), 8.81(s, 2H), 8.38 (s, 1H), 7.47 (s, 1H), 5.71 (m, J=7.3 Hz, 1H), 4.74(s, 2H), 4.21 (s, 2H), 3.84 (m, J=11.4 Hz, 2H), 3.56 (m, J=11.6 Hz,2H), 3.46 (s, 3H), 3.32 (s, 3H), 1.84 (m, J=7.2 Hz, 3H), 1.71 (s,2H), 0.78 (m, J=4.5 Hz, 1H), 0.16 (m, J=4.3 Hz, 1H). Retention time(LC-MS): 1.918 min. MH.sup.+ 565.

Compound 106.(2S)--N-(2-(2-(3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)thiazol-4-yl)--2-(1-(2-hydroxy-3-methoxypropyl)-3-methyl-2,6-dioxo-2,3-dihydro-1H-purin--7(6H)-yl)propanamide

##STR00649##

To a solution of(2S)--N-(2-(2-(3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)thiazol-4-yl)--2-(1-(3-methoxy-2-oxopropyl)-3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H-)-yl)propanamide (50 mg, 0.088 mmol) in MeOH (1 mL) was addedsodium borohydride (334 mg, 0.088 mmol) at 0.degree. C. and themixture was stirred at -10.degree. C. for 2 hrs. The mixture wasquenched with diluted hydrochloride acid (0.2 mL, 1N) and themixture was concentrated to dryness to give a residue, which waspurified via preparative HPLC to afford(2S)--N-(2-(2-(3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)thiazo-l-4-yl)-2-(1-(2-hydroxy-3-methoxypropyl)-3-methyl-2,6-dioxo-2,3-dihydro-1H--purin-7(6H)-yl)propanamide (28.3 mg, 56.6% yield) as a whitesolid. .sup.1H-NMR (400 MHz, DMSO-d6) .delta. 11.60 (s, 1H), 8.81(s, 2H), 8.32 (s, 1H), 7.46 (m, J=1.1 Hz, 1H), 5.75 (m, J=7.0 Hz,1H), 4.87 (m, J=4.7 Hz, 1H), 3.92 (m, 2H), 3.83 (m, J=11.4 Hz, 2H),3.75 (m, J=7.2 Hz, 1H), 3.55 (m, J=11.1 Hz, 2H), 3.44 (s, 3H), 3.21(m, J=5.3 Hz, 2H), 3.16 (m, 3H), 1.82 (m, J=7.3 Hz, 3H), 1.67 (m,2H), 0.77 (m, J=12.6, 7.8 Hz, 1H), 0.15 (m, 1H). Retention time(LC-MS): 1.773 min. MH.sup.+ 567.

Compound 107.(S)-2-(3-methyl-1-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)-2,6-dioxo-2,3-d-ihydro-1H-purin-7(6H)-yl)-N-(2-(5-methyl-6-(trifluoromethyl)pyridin-3-yl)t-hiazol-4-yl)propanamide

##STR00650##

A mixture of(S)-2-(3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)-N-(2-(5-methyl-6--(trifluoromethyl)pyridin-3-yl)thiazol-4-yl)propanamide (50 mg,0.104 mmol), 5-(chloromethyl)-3-methyl-1,2,4-oxadiazole (14 mg,0.104 mmol), potassium carbonate (14 mg, 0.104 mmol) and acatalytic amount of TBAI in N, N-dimethyl formamide (1 mL) wasstirred at 50.degree. C. for 2 hrs. The mixture was concentrated todryness and purified via preparative HPLC to afford(S)-2-(3-methyl-1-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)-2,6-d-ioxo-2,3-dihydro-1H-purin-7(6H)-yl)-N-(2-(5-methyl-6-(trifluoromethyl)pyri-din-3-yl)thiazol-4-yl)propanamide (12.1 mg, 20.2% yield) as a whitesolid. 1H NMR (400 MHz, DMSO-d6) .delta. 11.81 (s, 1H), 9.07 (s,1H), 8.43 (m, 2H), 7.78 (s, 1H), 5.75 (m, J=7.1 Hz, 1H), 5.21 (m,2H), 3.49 (s, 3H), 2.56 (s, 3H), 2.27 (s, 3H), 1.87 (m, J=7.3 Hz,3H). Retention time (LC-MS): 2.321 min. MH.sup.+ 575.

Compound 108.(S)-2-(3-methyl-1-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)-2,6-dioxo-2,3-d-ihydro-1H-purin-7(6H)-yl)-N-(2-(6-methyl-5-(trifluoromethyl)pyridin-3-yl)t-hiazol-4-yl)propanamide

##STR00651##

This compound was prepared using the method described for compound1 with appropriate starting materials in 9.2% yield as a whitesolid. 1H NMR (400 MHz, DMSO-d6) .delta. 11.76 (s, 1H), 9.24 (m,J=1.8 Hz, 1H), 8.45 (m, 2H), 7.72 (s, 1H), 5.74 (m, J=7.1 Hz, 1H),5.27 (m, 2H), 3.49 (s, 3H), 2.71 (m, J=1.2 Hz, 3H), 2.27 (s, 3H),1.87 (m, J=7.3 Hz, 3H). Retention time (LC-MS): 2.183 min. MH.sup.+575.

Compound 109.(S)-2-(3-methyl-2,6-dioxo-1-(2-oxopropyl)-2,3-dihydro-1H-purin-7(6H)-yl)--N-(6-(6-methyl-5-(trifluoromethyl)pyridin-3-yl)pyrazin-2-yl)propanamide

##STR00652##

This compound was prepared using the method described for compound2 with appropriate starting materials in 11% yield as a whitesolid. .sup.1H NMR (400 MHz, DMSO-d6) .delta. 11.53 (s, 1H), 9.48(s, 1H), 9.28 (s, 1H), 9.21 (s, 1H), 8.74 (s, 1H), 8.43 (s, 1H),5.81 (s, 1H), 4.70 (s, 2H), 3.47 (s, 3H), 2.74 (s, 3H), 2.16 (s,3H), 1.90 (d, J=7.2 Hz, 3H). Retention time (LC-MS): 1.440 min.MH.sup.+ 531.

Compound 110.(S)-2-(3-methyl-1-((5-methylisoxazol-3-yl)methyl)-2,6-dioxo-2,3-dihydro-1-H-purin-7(6H)-yl)-N-(2-(6-methyl-5-(trifluoromethyl)pyridin-3-yl)pyrimidin--4-yl)propanamide

##STR00653##

This compound was prepared using the method described for compound2 with appropriate starting materials in 9.36% yield as a whitesolid. .sup.1H NMR (400 MHz, DMSO-d6) .delta. 11.62 (s, 1H), 9.59(s, 1H), 8.88-8.80 (m, 2H), 8.40 (s, 1H), 7.98 (d, J=5.7 Hz, 1H),6.08 (s, 1H), 5.82 (d, J=7.3 Hz, 1H), 5.02 (s, 2H), 3.48 (s, 3H),2.74 (s, 3H), 2.30 (s, 3H), 1.89 (d, J=7.2 Hz, 3H). Retention time(LC-MS): 1.975 min. MH.sup.+ 570.

Compound 111.(S)--N-(2-(5-chloro-6-methylpyridin-3-yl)thiazol-4-yl)-2-(3-methyl-2,6-di-oxo-1-(2-oxopropyl)-2,3-dihydro-1H-purin-7(6H)-yl)propanamide

##STR00654##

This compound was prepared using the method described for compound2 with appropriate starting materials in 7.5% yield as a whitesolid. .sup.1H NMR (400 MHz, DMSO-d6) .delta. 11.63 (s, 1H), 9.59(s, 1H), 8.85 (d, 2H), 8.42 (s, 1H), 7.97 (d, J=5.8 Hz, 1H), 5.77(d, J=7.3 Hz, 1H), 4.67 (d, 2H), 3.46 (s, 3H), 2.75 (s, 3H), 2.16(s, 3H), 1.89 (d, J=7.2 Hz, 3H). Retention time (LC-MS): 2.022 min.MH.sup.+ 531.

Compound 112.(S)-2-(3-methyl-1-((5-methylisoxazol-3-yl)methyl)-2,6-dioxo-2,3-dihydro-1-H-purin-7(6H)-yl)-N-(2-(6-methyl-5-(trifluoromethyl)pyridin-3-yl)thiazol-4--yl)propanamide

##STR00655##

This compound was prepared using the method described for compound2 with appropriate starting materials in 31.6% yield as a yellowsolid. .sup.1H NMR (400 MHz, DMSO-D6) .delta. 11.76 (s, 1H), 9.23(s, 1H), 8.47 (s, 1H), 8.40 (s, 1H), 7.72 (s, 1H), 6.09 (s, 1H),5.76 (d, J=7.4 Hz, 1H), 5.02 (s, 2H), 3.48 (s, 3H), 2.71 (s, 3H),2.31 (s, 3H), 1.86 (d, J=7.2 Hz, 3H). Retention time (LC-MS): 2.254min. MH.sup.+ 575.

Compound 113.(2S)--N-(6-(5-(3-azabicyclo[3.1.0]hexan-3-yl)pyrazin-2-yl)pyridin-2-yl)-2--(3-methyl-2,6-dioxo-1-(2-oxobutyl)-2,3-dihydro-1H-purin-7(6H)-yl)propanam-ide

##STR00656##

To a solution of(S)-2-(3-methyl-2,6-dioxo-1-(2-oxobutyl)-2,3-dihydro-1H-purin-7(6H)-yl)pr-opanoic acid (61 mg, 0.2 mmol) and6-(5-(3-azabicyclo[3.1.0]hexan-3-yl)pyrazin-2-yl)pyridin-2-amine(50 mg, 0.20 mmol) in dichloromethane (4 mL) was added HOAt (30 mg,0.22 mmol) at room temperature. The reaction mixture was cooled inan ice-water bath to 0.degree. C., and pyridine (0.03 mL, 0.30mmol) was added drop-wise followed by drop-wise addition of DIC(0.04 mL, 0.40 mmol) under N.sub.2 protection. The ice-water bathwas removed after the addition and the mixture was stirred at30.degree. C. overnight. The resulting mixture was washed withwater (5 mL) and saturated aq. NH.sub.4Cl (5 mL), dried overanhydrous Na.sub.2SO.sub.4 and filtered. The filtrate wasconcentrated under reduced pressure and the residue was purifiedvia preparative HPLC to afford(2S)--N-(6-(5-(3-azabicyclo[3.1.0]hexan-3-yl)pyrazin-2-yl)pyrid-in-2-yl)-2-(3-methyl-2,6-dioxo-1-(2-oxobutyl)-2,3-dihydro-1H-purin-7(6H)-y-l)propanamide (5 mg, 5% yield) as a white solid. Retention time(LC-MS): 1.409 min. MH.sup.+ 544. .sup.1H NMR (400 MHz, DMSO-D6).delta. 10.99 (s, 1H), 8.93 (d, J=1.2 Hz, 1H), 8.39 (s, 1H), 8.03(s, J=1.2 Hz, 1H), 7.95 (s, 1H), 7.83 (m, 2H) 5.79 (q, J=6.4 Hz1H), 4.70 (s, 2H), 3.78 (d, J=11.2 Hz, 2H), 3.52 (d, J=10.4 Hz,3H), 3.46 (s, 3H), 2.55 (m, 2H) 1.86 (d, J=6.4 Hz, 3H), 1.74 (m,2H), 0.93 (m, 3H), 0.77 (m, 1H), 0.20 (m, 1H).

Compound 114.(S)-2-(3-methyl-1-((5-methylisoxazol-3-yl)methyl)-2,6-dioxo-2,3-dihydro-1-H-purin-7(6H)-yl)-N-(2'-((S)-2-(trifluoromethyl)pyrrolidin-1-yl)-[2,5'-bip-yrimidin]-4-yl)propanamide

##STR00657##

This compound was prepared using the method described for compound1 with appropriate starting materials in 77% yield as a whitesolid. .sup.1H NMR (400 MHz, DMSO-D6) .delta. 11.46 (s, 1H), 9.23(s, 2H), 8.70 (d, J=5.7 Hz, 1H), 8.39 (s, 1H), 7.83 (d, J=5.7 Hz,1H) 6.06 (s, 1H), 5.81 (d, J=7.1 Hz, 1H), 5.13 (m, 1H), 5.00 (s,2H), 3.69 (m, 2H), 3.46 (s, 3H), 2.29 (s, 3H), 2.08-2.20 (m, 4H),1.87 (d, J=7.2 Hz, 3H). MH.sup.+ 626.

Compound 115.(S)-2-(3-methyl-1-((5-methylisoxazol-3-yl)methyl)-2,6-dioxo-2,3-dihydro-1-H-purin-7(6H)-yl)-N-(6-(2-((S)-2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidi-n-5-yl)pyridin-2-yl)propanamide

##STR00658##

This compound was prepared using the method described for compound1 with appropriate starting materials in 55% yield as a whitesolid. .sup.1H NMR (400 MHz, DMSO-D6) .delta. 11.02 (s, 1H), 9.09(s, 2H), 8.38 (s, 1H), 7.82-7.92 (m, 2H), 7.76 (m, 1H), 6.06 (s,1H), 5.81 (d, J=7.1 Hz, 1H), 5.10 (m, 1H), 5.01 (s, 2H), 3.68 (m,2H), 3.46 (s, 3H), 2.29 (s, 3H), 2.08-2.20 (m, 4H), 1.85 (d, J=7.2Hz, 3H). MH.sup.+ 625.

Compound 116(S)-2-(3-methyl-2,6-dioxo-1-(2-oxobutyl)-2,3-dihydro-1H-purin-7(6H)-yl)-N--(6'-(trifluoromethyl)-[2,3'-bipyridin]-6-yl)propanamide

##STR00659##

This compound was prepared using the method described for compound1 with appropriate starting materials in 29% yield as a whitesolid. .sup.1H NMR (400 MHz, DMSO-D6) .delta. 11.18 (s, 1H), 9.43(s, 1H), 8.69 (d, J=7.3 Hz, 1H), 8.39 (s, 1H), 7.90-8.01 (m, 3H),5.78 (m, 1H), 5.54 (m, 1H), 4.69 (m, 2H), 3.46 (s, 3H), 1.87 (d,J=7.3 Hz, 3H), 1.73 (d, J=7.3 Hz, 1H), 0.84 (m, 3H). MH.sup.+530.

Compound 117.(S)-2-(1-(isoxazol-3-ylmethyl)-3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(-6H)-yl)-N-(6-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-2-yl)propanamide

##STR00660##

This compound was prepared using the method described for compound1 with appropriate starting materials as a white solid. .sup.1HNMR(400 MHz, DMSO-d.sub.6) .delta. 11.26 (s, 1H), 9.66 (s, 2H), 8.79(s, 1H), 8.40 (s, 1H), 7.98-8.02 (m, 3H), 6.45 (s, 1H), 5.83 (m,1H), 5.10 (s, 2H), 3.48 (s, 3H), 1.88 (d, J=7.2 Hz, 3H). MH.sup.+542.

Compound 118.(S)-2-(3-methyl-1-((5-methylisoxazol-3-yl)methyl)-2,6-dioxo-2,3-dihydro-1-H-purin-7(6H)-yl)-N-(6-(6-(trifluoromethyl)pyridin-3-yl)pyrazin-2-yl)propa-namide

##STR00661##

This compound was prepared using the method described for compound1 with appropriate starting materials as a white solid. .sup.1HNMR(400 MHz, DMSO-d.sub.6) .delta. 11.57 (s, 1H), 9.48 (s, 1H), 9.31(s, H), 9.17 (s, 1H), 8.76 (d, J=8.0 Hz, 1H), 8.41 (s, 1H), 8.13(d, J=8.2 Hz, 1H), 6.08 (s, 1H), 5.84 (m, 1H), 5.02 (s, 2H), 3.48(s, 3H), 2.30 (s, 3H), 1.90 (d, J=7.3 Hz, 3H). MH.sup.+ 556.

Compound 119.(S)-2-(1-(isoxazol-3-ylmethyl)-3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(-6H)-yl)-N-(6-(6-(trifluoromethyl)pyridin-3-yl)pyrazin-2-yl)propanamide

##STR00662##

This compound was prepared using the method described for compound1 with appropriate starting materials as a white solid. .sup.1HNMR(400 MHz, DMSO-d.sub.6) .delta. 11.57 (s, 1H), 9.48 (s, 1H), 9.31(s, H), 9.18 (s, 1H), 8.76 (m, 2H), 8.42 (s, 1H), 8.13 (d, J=8.3Hz, 1H), 6.46 (s, 1H), 5.84 (m, 1H), 5.10 (s, 2H), 3.48 (s, 3H),1.90 (d, J=7.3 Hz, 3H). MH.sup.+ 542.

Compound 120.(S)-2-(1-(isoxazol-3-ylmethyl)-3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(-6H)-yl)-N-(6-(2-(trifluoromethyl)pyrimidin-5-yl)pyrazin-2-yl)propanamide

##STR00663##

This compound was prepared using the method described for compound1 with appropriate starting materials as a white solid. .sup.1HNMR(400 MHz, DMSO-d.sub.6) .delta. 11.61 (s, 1H), 9.68 (s, 2H), 9.33(s, 1H), 9.19 (s, 1H), 8.78 (s, 1H), 8.41 (s, 1H), 6.44 (s, 1H),5.82 (m, 1H), 5.09 (s, 2H), 3.47 (s, 3H), 1.89 (d, J=7.2 Hz, 3H).MH.sup.+ 543.

Compound 121.(S)--N-(6'-methoxy-5'-(trifluoromethyl)-[2,3'-bipyridin]-6-yl)-2-(3-methy-l-1-((5-methylisoxazol-3-yl)methyl)-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-y-l)propanamide

##STR00664##

This compound was prepared using the method described for compound1 with appropriate starting materials as a white solid. .sup.1HNMR(400 MHz, DMSO-d.sub.6) .delta. 11.09 (s, 1H), 9.13 (s, 1H), 8.71(s, 1H), 8.39 (s, 1H), 7.83-7.99 (m, 3H), 6.07 (s, 1H), 5.81 (m,1H), 5.01 (s, 2H), 4.06 (s, 3H), 3.46 (s, 3H), 2.29 (s, 3H), 1.86(d, J=7.3 Hz, 3H). MH.sup.+ 585.

Compound 122.(S)--N-(6'-ethoxy-5'-(trifluoromethyl)-[2,3'-bipyridin]-6-yl)-2-(3-methyl--1-((5-methylisoxazol-3-yl)methyl)-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl-)propanamide

##STR00665##

This compound was prepared using the method described for compound1 with appropriate starting materials as a white solid. .sup.1HNMR(400 MHz, DMSO-d.sub.6) .delta. 11.08 (s, 1H), 9.11 (s, 1H), 8.70(s, 1H), 8.38 (s, 1H), 7.82-7.96 (m, 3H), 6.06 (s, 1H), 5.82 (m,1H), 5.01 (s, 2H), 4.52 (m, 2H), 3.46 (s, 3H), 2.28 (s, 3H), 1.86(d, J=7.3 Hz, 3H), 1.35 (t, 3H). MH.sup.+ 599.

Compound 123.(S)--N-(6'-chloro-5'-(trifluoromethyl)-[2,3'-bipyridin]-6-yl)-2-(3-methyl--1-((5-methylisoxazol-3-yl)methyl)-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl-)propanamide

##STR00666##

This compound was prepared using the method described for compound1 with appropriate starting materials as a white solid. .sup.1HNMR(400 MHz, DMSO-d.sub.6) .delta. 11.19 (s, 1H), 9.38 (s, 1H), 8.89(s, 1H), 8.39 (s, 1H), 7.85-8.06 (m, 3H), 6.07 (s, 1H), 5.82 (m,1H), 5.01 (s, 2H), 3.46 (s, 3H), 2.29 (s, 3H), 1.86 (d, J=7.3 Hz,3H), 1.35 (t, 3H). MH.sup.+ 589.

Compound 124.(S)--N-(6'-methoxy-5'-(trifluoromethyl)-[2,3'-bipyridin]-6-yl)-2-(3-methy-l-2,6-dioxo-1-(2-oxobutyl)-2,3-dihydro-1H-purin-7(6H)-yl)propanamide

##STR00667##

This compound was prepared using the method described for compound1 with appropriate starting materials as a white solid. .sup.1HNMR(400 MHz, DMSO-d.sub.6) .delta. 11.07 (s, 1H), 9.15 (s, 1H), 8.72(s, 1H), 8.39 (s, 1H), 7.83-7.99 (m, 3H), 5.81 (m, 1H), 4.69 (t,2H), 4.06 (s, 3H), 3.45 (s, 3H), 2.50 (m, 2H), 1.86 (d, J=7.3 Hz,3H), 0.93 (t, 3H). MH.sup.+ 560.

Compound 125.(S)--N-(6'-ethoxy-5'-(trifluoromethyl)-[2,3'-bipyridin]-6-yl)-2-(3-methyl--2,6-dioxo-1-(2-oxobutyl)-2,3-dihydro-1H-purin-7(6H)-yl)propanamide

##STR00668##

This compound was prepared using the method described for compound1 with appropriate starting materials as a white solid. .sup.1HNMR(400 MHz, DMSO-d.sub.6) .delta. 11.07 (s, 1H), 9.12 (s, 1H), 8.71(s, 1H), 8.38 (s, 1H), 7.83-7.99 (m, 3H), 5.78 (m, 1H), 4.69 (t,2H), 4.52 (q, 2H), 3.45 (s, 3H), 2.50 (m, 2H), 1.86 (d, J=7.3 Hz,3H), 1.36 (t, 3H), 0.93 (t, 3H). MH.sup.+ 574.

Compound 126.(S)-2-(3-methyl-1-((5-methylisoxazol-3-yl)methyl)-2,6-dioxo-2,3-dihydro-1-H-purin-7(6H)-yl)-N-(6'-methyl-5'-(trifluoromethyl)-[2,3'-bipyridin]-6-yl)-propanamide

##STR00669##

This compound was prepared using the method described for compound1 with appropriate starting materials as a white solid. .sup.1HNMR(400 MHz, DMSO-d.sub.6) .delta. 11.15 (s, 1H), 9.40 (s, 1H), 8.70(s, 1H), 8.26 (s, 1H), 7.90-8.03 (m, 3H), 6.07 (s, 1H), 5.82 (m,1H), 5.01 (s, 2H), 3.46 (s, 3H), 2.70 (s, 3H), 2.29 (s, 3H), 1.86(d, J=7.3 Hz, 3H). MH.sup.+ 569.

Compound 127.(S)--N-(5',6'-dimethyl-[2,3'-bipyridin]-6-yl)-2-(3-methyl-1-((5-methyliso-xazol-3-yl)methyl)-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)propanamide

##STR00670##

This compound was prepared using the method described for compound1 with appropriate starting materials as a white solid. .sup.1HNMR(400 MHz, DMSO-d.sub.6) .delta. 11.08 (s, 1H), 8.94 (s, 1H), 8.38(s, 1H), 8.17 (s, 1H), 7.72-7.96 (m, 3H), 6.07 (s, 1H), 5.82 (m,1H), 5.01 (s, 2H), 3.46 (s, 3H), 2.33 (s, 3H), 2.29 (s, 3H), 1.86(d, J=7.3 Hz, 3H). MH.sup.+ 515.

Compound 128.(S)-2-(3-methyl-1-((5-methylisoxazol-3-yl)methyl)-2,6-dioxo-2,3-dihydro-1-H-purin-7(6H)-yl)-N-(6-(6-methyl-5-(trifluoromethyl)pyridin-3-yl)pyrazin-2--yl)propanamide

##STR00671##

This compound was prepared using the method described for compound1 with appropriate starting materials as a white solid. .sup.1HNMR(400 MHz, DMSO-d.sub.6) .delta. 11.49 (s, 1H), 9.46 (s, 1H), 9.27(s, 1H), 9.19 (s, 1H), 8.72 (s, 1H), 8.40 (s, 1H), 6.07 (s, 1H),5.82 (m, 1H), 5.01 (s, 2H), 3.47 (s, 3H), 2.72 (s, 3H), 2.29 (s,3H), 1.89 (d, J=7.3 Hz, 3H). MH.sup.+ 570.

Compound 129.(S)-2-(3-methyl-1-((5-methylisoxazol-3-yl)methyl)-2,6-dioxo-2,3-dihydro-1-H-purin-7(6H)-yl)-N-(5'-methyl-6'-(trifluoromethyl)-[2,3'-bipyridin]-6-yl)-propanamide

##STR00672##

This compound was prepared using the method described for compound1 with appropriate starting materials as a white solid. .sup.1HNMR(400 MHz, DMSO-d.sub.6) .delta. 11.19 (s, 1H), 9.20 (s, 1H), 8.55(s, 1H), 8.39 (s, 1H), 7.86-8.07 (m, 3H), 6.07 (s, 1H), 5.82 (m,1H), 5.01 (s, 2H), 3.46 (s, 3H), 2.55 (s, 3H), 2.29 (s, 3H), 1.87(d, J=7.3 Hz, 3H). MH.sup.+ 569.

Compound 130.(S)-2-(3-methyl-1-((5-methylisoxazol-3-yl)methyl)-2,6-dioxo-2,3-dihydro-1-H-purin-7(6H)-yl)-N-(6-(5-methyl-6-(trifluoromethyl)pyridin-3-yl)pyrazin-2--yl)propanamide

##STR00673##

This compound was prepared using the method described for compound1 with appropriate starting materials as a white solid. .sup.1HNMR(400 MHz, DMSO-d.sub.6) .delta. 11.55 (s, 1H), 9.29 (s, 1H), 9.24(s, 1H), 9.14 (s, 1H), 8.61 (s, 1H), 8.40 (s, 1H), 6.07 (s, 1H),5.82 (m, 1H), 5.01 (s, 2H), 3.47 (s, 3H), 2.56 (s, 3H), 2.29 (s,3H), 1.89 (d, J=7.3 Hz, 3H). MH.sup.+ 570.

Compound 131.(S)-2-(3-methyl-1-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)-2,6-dioxo-2,3-d-ihydro-1H-purin-7(6H)-yl)-N-(5'-methyl-6'-(trifluoromethyl)-[2,3'-bipyridi-n]-6-yl)propanamide

##STR00674##

This compound was prepared using the method described for compound1 with appropriate starting materials as a white solid. .sup.1HNMR(400 MHz, DMSO-d.sub.6) .delta. 11.20 (s, 1H), 9.19 (s, 1H), 8.55(s, 1H), 8.44 (s, 1H), 7.86-8.07 (m, 3H), 5.81 (m, 1H), 5.26 (q,2H), 3.48 (s, 3H), 2.55 (s, 3H), 2.25 (s, 3H), 1.88 (d, J=7.3 Hz,3H). MH.sup.+ 570.

Compound 132.(S)-2-(3-methyl-1-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)-2,6-dioxo-2,3-d-ihydro-1H-purin-7(6H)-yl)-N-(6-(6-methyl-5-(trifluoromethyl)pyridin-3-yl)p-yrazin-2-yl)propanamide

##STR00675##

This compound was prepared using the method described for compound1 with appropriate starting materials as a white solid. .sup.1HNMR(400 MHz, DMSO-d.sub.6) .delta. 11.51 (s, 1H), 9.45 (s, 1H), 9.26(s, 1H), 9.19 (s, 1H), 8.71 (s, 1H), 8.45 (s, 1H), 5.82 (m, 1H),5.25 (q, 2H), 3.48 (s, 3H), 2.72 (s, 3H), 2.25 (s, 3H), 1.89 (d,J=7.3 Hz, 3H). MH.sup.+ 571.

Compound 133.(S)-2-(3-methyl-1-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)-2,6-dioxo-2,3-d-ihydro-1H-purin-7(6H)-yl)-N-(6-(5-methyl-6-(trifluoromethyl)pyridin-3-yl)p-yrazin-2-yl)propanamide

##STR00676##

This compound was prepared using the method described for compound1 with appropriate starting materials as a white solid. .sup.1HNMR(400 MHz, DMSO-d.sub.6) .delta. 11.57 (s, 1H), 9.09-9.28 (m, 3H),8.60 (s, 1H), 8.45 (s, 1H), 5.82 (m, 1H), 5.25 (q, 2H), 3.48 (s,3H), 2.56 (s, 3H), 2.25 (s, 3H), 1.90 (d, J=7.3 Hz, 3H). MH.sup.+571.

Compound 134.(S)-2-(3-methyl-1-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)-2,6-dioxo-2,3-d-ihydro-1H-purin-7(6H)-yl)-N-(5'-methyl-6'-(trifluoromethyl)-[2,3'-bipyridi-n]-6-yl)propanamide

##STR00677##

This compound was prepared using the method described for compound1 with appropriate starting materials as a white solid. .sup.1HNMR(400 MHz, DMSO-d.sub.6) .delta. 11.16 (s, 1H), 9.40 (s, 1H), 8.69(s, 1H), 8.44 (s, 1H), 7.92-8.01 (m, 3H), 5.80 (m, 1H), 5.25 (q,2H), 3.48 (s, 3H), 2.70 (s, 3H), 2.24 (s, 3H), 1.87 (d, J=7.3 Hz,3H). MH.sup.+ 570.

Compound 135.(S)-2-(3-methyl-2,6-dioxo-1-(2-oxobutyl)-2,3-dihydro-1H-purin-7(6H)-yl)-N--(6'-methyl-5'-(trifluoromethyl)-[2,3'-bipyridin]-6-yl)propanamide

##STR00678##

This compound was prepared using the method described for compound1 with appropriate starting materials as a white solid. .sup.1HNMR(400 MHz, DMSO-d.sub.6) .delta. 11.13 (s, 1H), 9.40 (s, 1H), 8.70(s, 1H), 8.39 (s, 1H), 7.93-8.02 (m, 3H), 5.79 (m, 1H), 4.69 (t,2H), 3.45 (s, 3H), 2.71 (s, 3H), 2.50 (m, 2H), 1.86 (d, J=7.3 Hz,3H), 0.93 (t, 3H). MH.sup.+ 544.

Compound 136.(S)-2-(1-(isoxazol-3-ylmethyl)-3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(-6H)-yl)-N-(6'-methyl-5'-(trifluoromethyl)-[2,3'-bipyridin]-6-yl)propanamid-e

##STR00679##

This compound was prepared using the method described for compound1 with appropriate starting materials as a white solid. .sup.1HNMR(400 MHz, DMSO-d.sub.6) .delta. 11.14 (s, 1H), 9.40 (s, 1H), 8.78(s, 1H), 8.69 (s, 1H), 8.39 (s, 1H), 7.92-8.01 (m, 3H), 6.45 (s,1H), 5.82 (m, 1H), 5.09 (s, 2H), 3.47 (s, 3H), 2.70 (s, 3H), 1.86(d, J=7.3 Hz, 3H). MH.sup.+ 555.

Compound 137.(S)-2-(1-(isoxazol-3-ylmethyl)-3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(-6H)-yl)-N-(6-(5-methyl-6-(trifluoromethyl)pyridin-3-yl)pyrazin-2-yl)propan-amide

##STR00680##

This compound was prepared using the method described for compound1 with appropriate starting materials as a white solid. .sup.1HNMR(400 MHz, DMSO-d.sub.6) .delta. 11.56 (s, 1H), 9.29 (s, 1H), 9.24(s, 1H), 9.14 (s, 1H), 8.78 (s, 1H), 8.60 (s, 1H), 8.41 (s, 1H),6.45 (s, 1H), 5.83 (m, 1H), 5.09 (s, 2H), 3.47 (s, 3H), 2.56 (s,3H), 1.89 (d, J=7.3 Hz, 3H). MH.sup.+ 556.

Compound 139(S)--N-(6-(5-chloro-6-methylpyridin-3-yl)pyrazin-2-yl)-2-(3-methyl-1-((5--methylisoxazol-3-yl)methyl)-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)propan-amide

##STR00681##

To a suspension of(S)-2-(3-methyl-1-((5-methylisoxazol-3-yl)methyl)-2,6-dioxo-2,3-dihydro-1-H-purin-7(6H)-yl)propanoic acid (58 mg, 0.172 mmol) in DCM (2 mL)was added oxalyl chloride (0.035 mL, 0.413 mmol). The reaction wascooled to 0.degree. C. then DMF (1 drop) was added. The mixture wasstirred at 0.degree. C. for 5 min, warmed to RT for 1 h, evaporatedto dryness then diluted with THF (2 mL) and cooled to 0.degree. C.Next 6-(5-chloro-6-methylpyridin-3-yl)pyrazin-2-amine (38 mg, 0.172mmol) was added and the reaction was stirred at 0.degree. C. for 1h, diluted with 0.2N HCl (10 mL) and water (30 ml) then extractedwith EA (3.times.25 mL). The combined organic layers were driedwith MgSO.sub.4 and concentrated to a residue which was purified bychromatography eluted with MeOH/DCM (2:98 to 3:97) to give(S)--N-(6-(5-chloro-6-methylpyridin-3-yl)pyrazin-2-yl)-2-(3-methyl-1-((5--methylisoxazol-3-yl)methyl)-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)propan-amide (37 mg, 40% yield) as an off-white solid. .sup.1H NMR(CDCl.sub.3) .delta.: 9.92 (s, 1H), 9.22 (s, 1H), 8.84 (s, 1H),8.72 (s, 1H), 8.10 (s, 1H), 7.93 (s, 1H), 5.95 (s, 1H), 5.88 (q,J=4 and 8 Hz, 1H), 5.28 (d, J=4 Hz, 2H), 3.63 (s, 3H), 2.69 (s,3H), 2.15 (s, 3H), 1.98 (d, J=8 Hz, 3H). LCMS: MH.sup.+ 536 andT.sub.R=2.837 min.

Compound 140(S)--N-(6-(5-chloro-6-methylpyridin-3-yl)pyrazin-2-yl)-2-(3-methyl-1-((5--methylisoxazol-3-yl)methyl)-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)propan-amide

##STR00682##

To a suspension of(S)-2-(3-methyl-2,6-dioxo-1(2-oxopropyl)-2,3-dihydro-1H-purin-7(6H)-yl)pr-opanoic acid (0.067 mg, 0.227 mmol) in DCM (3 mL) was added oxalylchloride (0.046 mL, 0.545 mmol). The reaction was cooled to0.degree. C. then DMF (2 drops) was added. The mixture was stirredat 0.degree. C. for 5 min, stirred at RT for 1 h, evaporated todryness then diluted with THF (3 mL) and cooled to 0.degree. C.Next 6-(5-chloro-6-methylpyridin-3-yl)pyrazin-2-amine (50 mg, 0.227mmol) was added and the reaction was stirred at 0.degree. C. for 1h, diluted with water (30 ml) then extracted with EA (3.times.25mL). The combined organic layers were dried with MgSO.sub.4 andconcentrated to a residue which was purified by Prep TLC elutedwith EA to give(S)--N-(6-(5-chloro-6-methylpyridin-3-yl)pyrazin-2-yl)-2-(3-methyl-2,6-di-oxo-1(2-oxopropyl)-2,3-dihydro-1H-purin-7(6H)-yl)propanamide (30mg, 26.5% yield) as an off-white solid. .sup.1H NMR (CDCl.sub.3).delta.: 9.80 (s, 1H), 9.40 (s, 1H), 8.97 (s, 1H), 8.79 (s, 1H),8.24 (s, 1H), 7.91 (s, 1H), 5.70 (q, J=8 and 16 Hz, 1H), 4.90 (d,J=4 Hz, 2H), 3.59 (s, 3H), 2.70 (s, 3H), 2.32 (s, 3H), 1.93 (d, J=4Hz, 3H). LCMS: MH.sup.+ 497 and T.sub.R=2.560 min.

Compound 1412-(3-methyl-2,6-dioxo-1-(pyridin-2-ylmethyl)-2,3-dihydro-1H-purin-7(6H)-y-l)-N-(2'(trifluoromethyl)-2,5'-bipyrimidin-4-yl)propanamide

##STR00683##

This compound was prepared using the method described for compound10 with appropriate starting materials as a white solid. .sup.1HNMR (400 MHz, DMSO-d.sub.6) .delta. 11.74 (s, 1H), 9.76 (s, 2H),8.89 (d, J=5.6 Hz, 1H), 8.42-8.36 (m, 2H), 8.04 (d, J=5.6 Hz, 1H),7.69 (t, J=7.6 Hz, 1H), 7.20 (t, J=6.8 Hz, 2H), 5.81 (d, J=7.2 Hz,1H), 5.12 (s, 2H), 3.48 (s, 3H), 1.89 (d, J=7.2 Hz, 3H). Retentiontime (LC-MS): 2.190 min. MH.sup.+ 553.

Compound 142(2S)--N-(6-(2-(3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)pyridin-2-yl)--2-(3-methyl-2,6-dioxo-1-(2-oxopropyl)-2,3-dihydro-1H-purin-7(6H)-yl)propa-namide

##STR00684##

This Compound was prepared using the similar method described inCompound 2 with appropriate starting materials as a white solid..sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 10.82 (s, 1H), 8.82 (s,2H), 8.21 (s, 1H), 7.65 (m, 2H), 7.43 (d, J=7.6 Hz, 1H), 5.58 (s,1H), 4.53 (s, 2H), 3.67 (d, J=11.2 Hz, 2H), 3.37 (d, J=10.8 Hz,2H), 3.28 (s, 3H), 1.99 (s, 3H), 1.69 (d, J=7.2 Hz, 3H), 1.52 (s,2H), 0.60 (d, J=4.8 Hz, 1H), 0.00 (d, J=4.0 Hz, 1H). Retention time(LC-MS): 2.273 min. MH.sup.+ 530.

Compound 143(2S)--N-(2'-(3-azabicyclo[3.1.0]hexan-3-yl)-2,5'-bipyrimidin-4-yl)-2-(3-m-ethyl-2,6-dioxo-1-(2-oxopropyl)-2,3-dihydro-1H-purin-7(6H)-yl)propanamide

##STR00685##

This compound was prepared using the method described for compound2 with appropriate starting materials as a white solid. .sup.1H NMR(400 MHz, DMSO-d.sub.6) .delta. 11.24 (s, 1H), 8.99 (s, 2H), 8.51(d, J=5.6 Hz, 1H), 8.22 (s, 1H), 7.62 (d, J=5.6 Hz, 1H), 5.60 (d,J=7.2 Hz, 1H), 4.53 (s, 2H), 3.70 (d, J=11.2 Hz, 2H), 3.40 (d,J=10.4 Hz, 2H), 3.29 (s, 3H), 1.99 (s, 3H), 1.70 (d, J=7.2 Hz, 3H),1.53 (s, 2H), 0.61 (d, J=4.4 Hz, 1H), 0.00 (d, J=4.4 Hz, 1H).Retention time (LC-MS): 2.167 min. MH.sup.+ 531.

Compound 144(2S)--N-(2'-(3-azabicyclo[3.1.0]hexan-3-yl)-2,5'-bipyrimidin-4-yl)-2-(3-m-ethyl-2,6-dioxo-1-(2-oxopropyl)-2,3-dihydro-1H-purin-7(6H)-yl)propanamide

##STR00686##

This compound was prepared using the method described for compound10 with appropriate starting materials and separated viapreparative Chiral HPLC in 33.94% yield to form a white solid..sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 11.40 (s, 1H), 9.11 (s,1H), 9.04 (s, 2H), 8.91 (s, 1H), 8.44 (s, 1H), 5.82 (s, 1H), 4.84(s, 2H), 3.86 (d, J=11.2 Hz, 2H), 3.56 (d, J=11.6 Hz, 2H), 3.49 (s,3H), 1.89 (d, J=7.2 Hz, 3H), 1.70 (s, 2H), 0.78 (d, J=4.6 Hz, 1H),0.17 (d, J=4.2 Hz, 1H). Retention time (LC-MS): 1.567 min. MH.sup.+514.

Compound 145(2S)--N-(2-(2-(3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)thiazol-4-yl)--2-(1-(but-2-ynyl)-3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)propan-amide

##STR00687##

This compound was prepared using the method described for compound1 with appropriate starting materials in 22.64% yield as a yellowsolid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 11.64 (s, 1H),8.82 (s, 2H), 8.36 (s, 1H), 7.48 (s, 1H), 5.83-5.63 (m, 1H), 4.52(s, 2H), 3.84 (d, J=11.2 Hz, 2H), 3.56 (d, J=10.8 Hz, 2H), 3.46 (s,3H), 1.84 (d, J=7.2 Hz, 3H), 1.70 (m, 5H), 0.78 (d, J=4.8 Hz, 1H),0.17 (d, J=4.4 Hz, 1H). Retention time (LC-MS): 2.260 min. MH.sup.+532.

Compound 146(2S)--N-(6-(2-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)-pyridin-2-yl)-2-(1-(3-methoxy-2-oxopropyl)-3-methyl-2,6-dioxo-2,3-dihydro--1H-purin-7(6H)-yl)propanamide

##STR00688##

This compound was prepared using the method described for compound2 with appropriate starting materials in 6.7% yield. White solid..sup.1H-NMR (400 MHz, DMSO-d6) .delta. 11.01 (s, 1H), 9.03 (s, 2H),8.40 (s, 1H), 7.84 (m, 2H), 7.63 (d, J=7.6 Hz, 1H), 5.79 (s, 1H),4.89-4.64 (m, 2H), 4.21 (s, 2H), 3.99 (d, J=12.0 Hz, 2H), 3.84 (d,J=10.4 Hz, 2H), 3.46 (s, 3H), 3.31 (s, 3H), 2.70 (d, J=10.4 Hz,2H), 1.86 (d, J=7.2 Hz, 3H). Retention time (LC-MS): 1.510 min.MH.sup.+ 596.

Compound 147(2S)--N-(6-(2-(3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)pyridin-2-yl)--2-(3-methyl-2,6-dioxo-1-(2-oxobutyl)-2,3-dihydro-1H-purin-7(6H)-yl)propan-amide

##STR00689##

This compound was prepared using the method described for compound2 with appropriate starting materials in 49.6% yield. White solid..sup.1HNMR (400 MHz, DMSO-d.sub.6) .delta.. 10.98 (s, 1H), 8.97 (s,2H), 8.37 (s, 1H), 7.85 (d, J=8.2 Hz, 1H), 7.79 (t, J=7.9 Hz, 1H),7.59 (d, J=7.8 Hz, 1H), 5.78 (s, 1H), 4.75-4.61 (m, 2H), 3.83 (d,J=11.3 Hz, 2H), 3.52 (d, J=11.0 Hz, 2H), 3.44 (s, 3H), 2.55-2.50(m, 2H), 1.85 (d, J=7.3 Hz, 3H), 1.71-1.64 (m, 2H), 0.92 (t, J=7.3Hz, 3H), 0.75 (dd, J=12.4, 7.6 Hz, 1H), 0.19-0.10 (m, 1H).Retention time (LC-MS): 2.43 min. MH.sup.+ 544.

Compound 148(2R)--N-(6-(2-(3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)pyridin-2-yl)--2-(1-(cyanomethyl)-3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)propa-namide

##STR00690##

This compound was prepared using the method described for compound10 with appropriate starting materials and separated viapreparative Chiral HPLC in 22.9% yield as a white solid. .sup.1HNMR (400 MHz, DMSO-d.sub.6) .delta. 11.03 (s, 1H), 9.00 (s, 2H),8.43 (s, 1H), 7.88 (d, J=7.7 Hz, 1H), 7.82 (t, J=7.9 Hz, 1H), 7.61(d, J=8.1 Hz, 1H), 5.83 (s, 1H), 4.85 (s, 2H), 3.86 (d, J=11.3 Hz,2H), 3.55 (d, J=11.1 Hz, 2H), 3.49 (s, 3H), 1.88 (d, J=7.3 Hz, 3H),1.73-1.66 (m, 2H), 0.78 (dt, J=12.3, 6.2 Hz, 1H), 0.18 (dd, J=8.4,4.2 Hz, 1H). Retention time (LC-MS): 1.89 min. MH.sup.+ 513.

Compound 149(2S)--N-(6-(2-(3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)pyridin-2-yl)--2-(1-(cyanomethyl)-3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)propa-namide

##STR00691##

This compound was prepared using the method described for compound10 with appropriate starting materials and separated viapreparative Chiral HPLC in 34.2% yield as a white solid. .sup.1HNMR (400 MHz, DMSO-d.sub.6) .delta. 11.06 (s, 1H), 9.00 (s, 2H),8.43 (s, 1H), 7.88 (d, J=8.0 Hz, 1H), 7.81 (t, J=7.9 Hz, 1H), 7.61(d, J=7.6 Hz, 1H), 5.81 (s, 1H), 4.84 (s, 2H), 3.85 (d, J=11.2 Hz,2H), 3.54 (d, J=10.6 Hz, 2H), 3.48 (s, 3H), 1.87 (d, J=7.2 Hz, 3H),1.69 (s, 2H), 0.77 (d, J=4.8 Hz, 1H), 0.17 (d, J=4.0 Hz, 1H).Retention time (LC-MS): 1.89 min. MH.sup.+ 513.

Compound 150(S)-2-(3-methyl-1-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)-2,6-dioxo-2,3-d-ihydro-1H-purin-7(6H)-yl)-N-(2-(5-methyl-6-(trifluoromethyl)pyridin-3-yl)p-yrimidin-4-yl)propanamide

##STR00692##

This compound was prepared using the method described for compound2 with appropriate starting materials and separated via preparativeHPLC as a white solid. .sup.1H NMR (400 MHz, DMSO-d6) .delta. 11.70(s, 1H), 9.38 (s, 1H), 8.86 (d, J=5.7 Hz, 1H), 8.73 (s, 1H), 8.46(s, 1H), 7.99 (d, J=5.7 Hz, 1H), 5.80 (d, J=7.0 Hz, 1H), 5.32-5.21(m, 2H), 3.49 (s, 3H), 2.58 (d, J=1.6 Hz, 3H), 2.26 (s, 3H), 1.90(d, J=7.3 Hz, 3H). Retention time (LC-MS): 2.147 min. MH.sup.+571.

Compound 151(S)-2-(3-methyl-1-((5-methyl-1,2,4-oxadiazol-3-yl)methyl)-2,6-dioxo-2,3-d-ihydro-1H-purin-7(6H)-yl)-N-(6'-methyl-5'-(trifluoromethyl)-2,3'-bipyridin--6-yl)propanamide

##STR00693##

This compound was prepared using the method described for compound1 with appropriate starting materials in 24.5% yield as a whitesolid. .sup.1HNMR (400 MHz, DMSO-d.sub.6) .delta. 11.16 (s, 1H),9.41 (s, 1H), 8.70 (d, J=1.8 Hz, 1H), 8.43 (s, 1H), 8.03 (s, 1H),7.99-7.91 (m, 2H), 5.83 (d, J=6.6 Hz, 1H), 5.17-5.05 (m, 2H), 3.48(s, 3H), 2.72 (d, J=1.3 Hz, 3H), 1.89 (d, J=7.3 Hz, 3H). Retentiontime (LC-MS): 2.411 min. MH.sup.+ 570.

Compound 152(2S)--N-(6-(2-(3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)pyrazin-2-yl)--2-(3-methyl-2,6-dioxo-1-(2-oxopropyl)-2,3-dihydro-1H-purin-7(6H)-yl)propa-namide

##STR00694##

This compound was prepared using the method described for compound2 with appropriate starting materials in 22.1% yield. White solid..sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 11.33 (s, 1H), 9.10 (s,1H), 9.02 (s, 2H), 8.90 (s, 1H), 8.40 (s, 1H), 5.78 (d, J=6.9 Hz,1H), 4.69 (s, 2H), 3.85 (d, J=11.4 Hz, 2H), 3.56 (d, J=11.0 Hz,2H), 3.46 (s, 3H), 2.16 (s, 3H), 1.88 (d, J=7.2 Hz, 3H), 1.70 (s,2H), 0.77 (d, J=4.8 Hz, 1H), 0.16 (d, J=4.3 Hz, 1H). Retention time(LC-MS): 2.072 min. MH.sup.+ 531.

Compound 153(2S)--N-(2-(2-(3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)thiazol-4-yl)--2-(3-methyl-2,6-dioxo-1-(2-oxopropyl)-2,3-dihydro-1H-purin-7(6H)-yl)propa-namide

##STR00695##

This compound was prepared using the method described for compound2 with appropriate starting materials in 54.5% yield as a yellowsolid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 11.60 (s, 1H),8.81 (s, 2H), 8.39 (s, 1H), 7.47 (s, 1H), 5.70 (d, J=7.3 Hz, 1H),4.70 (d, J=1.2 Hz, 2H), 3.84 (d, J=11.4 Hz, 2H), 3.56 (d, J=11.2Hz, 2H), 3.46 (s, 3H), 2.17 (s, 3H), 1.84 (d, J=7.3 Hz, 3H),1.73-1.67 (m, 2H), 0.78 (d, J=4.7 Hz, 1H), 0.17 (d, J=4.3 Hz, 1H).Retention time (LC-MS): 2.303 min. MH.sup.+ 536.

Compound 154(S)-2-(3-methyl-2,6-dioxo-1-(2-oxopropyl)-2,3-dihydro-1H-purin-7(6H)-yl)--N-(5-(2-(trifluoromethyl)pyrimidin-5-yl)thiazol-4-yl)propanamide

##STR00696##

This compound was prepared using the method described for compound2 with appropriate starting materials in 45.0% yield as a yellowsolid. .sup.1H NMR (DMSO-d.sub.6) .delta. 11.18 (s, 1H), 9.26 (s,1H), 9.05 (s, 2H), 8.27 (s, 1H), 5.58-5.61 (m, 1H), 4.69-4.84 (m,2H), 3.49 (s, 3H), 2.20 (s, 3H), 1.81 (d, J=7.20 Hz, 3H). Retentiontime (LC-MS): 1.658 min. MH.sup.+ 523.

Compound 155(2S)--N-(2'-(3-azabicyclo[3.1.0]hexan-3-yl)-2,5'-bipyrimidin-4-yl)-2-(1-(-cyanomethyl)-3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)propanamide

##STR00697##

This compound was prepared using the method described for compound10 with appropriate starting materials and separated viapreparative Chiral HPLC in 40.3% yield as a white solid. .sup.1HNMR (DMSO-d.sub.6) .delta. 11.49 (s, 1H), 9.17 (s, 2H), 8.68 (d,J=5.6 Hz, 1H), 8.44 (s, 1H), 7.80 (d, J=6.0 Hz, 1H), 5.79-5.82 (m,1H), 4.85 (s, 2H), 3.87 (d, J=11.2 Hz, 2H), 3.57 (d, J=11.2 Hz,2H), 3.49 (s, 3H), 1.88 (d, J=7.2 Hz, 3H), 1.69-1.72 (m, 2H),0.76-0.81 (m, 1H), 0.16-0.20 (m, 1H). Retention time (LC-MS): 1.739min. MH.sup.+ 514.

Compound 156(S)-2-(3-methyl-1-((5-methylisoxazol-3-yl)methyl)-2,6-dioxo-2,3-dihydro-1-H-purin-7(6H)-yl)-N-(5'-(trifluoromethyl)-2,3'-bipyridin-6-yl)propanamide

##STR00698##

This compound was prepared using the method described for compound2 with appropriate starting materials in 18.1% yield as a whitesolid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 11.20 (s, 1H),9.59 (s, 1H), 9.07 (s, 1H), 8.81 (s, 1H), 8.41 (s, 1H), 8.07 (d,J=6.7 Hz, 1H), 8.03-7.94 (m, 2H), 6.08 (s, 1H), 5.82 (d, J=7.0 Hz,1H), 5.02 (s, 2H), 3.47 (s, 3H), 2.30 (s, 3H), 1.88 (d, J=7.3 Hz,3H). Retention time (LC-MS): 2.406 min. MH.sup.+ 555.

Compound 157(S)-2-(1-(but-2-ynyl)-3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)-N--(2-(2-((R)-2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidin-5-yl)thiazol-4-yl-)propanamide

##STR00699##

This compound was prepared using the method described for compound2 with appropriate starting materials in 30% yield as a yellowsolid. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. 11.68 (s, 1H),8.95 (s, 2H), 8.37 (s, 1H), 7.55 (s, 1H), 5.74 (d, J=7.2 Hz, 1H),5.10 (t, J=8.0 Hz, 1H), 4.51 (m, 2H), 3.71 (m, 2H), 3.47 (s, 3H),2.17 (m, 4H), 1.83 (m, 3H), 1.71 (d, J=7.2 Hz, 3H). Retention time(LC-MS): 2.066 min. MH.sup.+ 588.

Compound 158(2S)--N-(5'-(3-azabicyclo[3.1.0]hexan-3-yl)-[2,2'-bipyrazin]-6-yl)-2-(3-m-ethyl-2,6-dioxo-1-(2-oxobutyl)-2,3-dihydro-1H-purin-7(6H)-yl)propanamide

##STR00700##

This compound was prepared using the method described for compound2 with appropriate starting materials in 20.3% yield as a yellowsolid. 1H NMR (400 MHz, DMSO-d6) .delta. 11.34 (s, 1H), 9.13 (s,1H), 9.01 (s, 1H), 8.87 (d, J=1.2 Hz, 1H), 8.41 (s, 1H), 8.09 (d,J=1.2 Hz, 1H), 5.82 (d, J=7.0 Hz, 1H), 4.79-4.60 (m, 2H), 3.80 (d,J=10.8 Hz, 2H), 3.55 (d, J=10.7 Hz, 2H), 3.47 (s, 3H), 2.57-2.52(m, 2H), 1.89 (d, J=7.3 Hz, 3H), 1.80-1.67 (m, 2H), 0.94 (t, J=7.3Hz, 3H), 0.80 (m, 1H), 0.21 (m, 1H). Retention time (LC-MS): 1.873min. MH.sup.+ 545.

Compound 159(2S)--N-(5'-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-[2,2'-bipyrazin]--6-yl)-2-(3-methyl-2,6-dioxo-1-(2-oxobutyl)-2,3-dihydro-1H-purin-7(6H)-yl)-propanamide

##STR00701##

This compound was prepared using the method described for compound2 with appropriate starting materials in 25.0% yield as a yellowsolid. .sup.1H NMR (400 MHz, DMSO-d6) .delta. 9.15 (s, 1H), 9.02(s, 1H), 8.90 (d, J=1.1 Hz, 1H), 8.41 (s, 1H), 8.30 (s, 1H), 8.14(s, 1H), 5.82 (s, 1H), 4.70 (s, 2H), 3.96 (d, J=11.4 Hz, 2H), 3.86(d, J=9.9 Hz, 2H), 3.46 (s, 3H), 2.78 (d, J=10.7 Hz, 2H), 2.58-2.52(m, 2H), 1.89 (d, J=7.3 Hz, 3H), 0.93 (m, 3H). Retention time(LC-MS): 1.845 min. MH.sup.+ 581.

Compound 160(S)-2-(3-methyl-1-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)-2,6-dioxo-2,3-d-ihydro-1H-purin-7(6H)-yl)-N-(6-(2-(trifluoromethyl)pyrimidin-5-yl)pyrazin--2-yl)propanamide

##STR00702##

This compound was prepared using the method described for compound1 with appropriate starting materials in 12.9% yield as a whitesolid. .sup.1H NMR (400 Hz, DMSO-d.sub.6) .delta. 11.66 (s, 1H),9.70 (s, 2H), 9.35 (s, 1H), 9.23 (s, 1H), 8.47 (s, 1H), 5.82 (m,1H), 5.29 (m, 2H), 3.49 (s, 3H), 2.26 (s, 3H), 1.91 (d, J=7.3 Hz,3H). Retention time (LC-MS): 1.707 min. MH.sup.+ 558.

Compound 161(S)-2-(3-methyl-2,6-dioxo-1-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-purin-7-(6H)-yl)-N-(2-(5-methyl-6-(trifluoromethyl)pyridin-3-yl)thiazol-4-yl)propa-namide

##STR00703##

This compound was prepared using the method described for compound102 with appropriate starting materials in 35.4% yield as a whitesolid. .sup.1H NMR (400 Hz, DMSO-d.sub.6) .delta. 11.81 (s, 1H),9.08 (s, 1H), 8.44 (s, 1H), 8.41 (s, 1H), 7.77 (s, 1H), 5.74 (m,1H), 4.64 (m, 2H), 3.49 (s, 3H), 2.56 (s, 3H), 1.87 (d, J=7.2 Hz,3H). Retention time (LC-MS): 2.473 min. MH.sup.+ 562.

Compound 162(S)-2-(3-methyl-2,6-dioxo-1-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-purin-7-(6H)-yl)-N-(2-(6-methyl-5-(trifluoromethyl)pyridin-3-yl)thiazol-4-yl)propa-namide

##STR00704##

This compound was prepared using the method described for compound1 with appropriate starting materials in 14.8% yield as a whitesolid. .sup.1H NMR (400 Hz, DMSO-d.sub.6) .delta. 11.75 (s, 1H),9.24 (s, 1H), 8.47 (s, 1H), 8.42 (s, 1H), 7.71 (s, 1H), 5.74 (m,1H), 4.71-4.59 (m, 2H), 3.49 (s, 3H), 2.71 (s, 3H), 1.86 (d, J=7.6Hz, 3H). Retention time (LC-MS): 2.676 min. MH.sup.+ 562.

Compound 163(S)-2-(3-methyl-1-((5-methyl-1,2,4-oxadiazol-3-yl)methyl)-2,6-dioxo-2,3-d-ihydro-1H-purin-7(6H)-yl)-N-(2-(6-methyl-5-(trifluoromethyl)pyridin-3-yl)t-hiazol-4-yl)propanamide

##STR00705##

This compound was prepared using the method described for compound1 with appropriate starting materials in 17.6% yield as a whitesolid. .sup.1H NMR (400 Hz, DMSO-d.sub.6) .delta. 11.75 (s, 1H),9.23 (d, J=1.7 Hz, 1H), 8.46 (d, J=1.7 Hz, 1H), 8.42 (s, 1H), 7.71(s, 1H), 5.75 (q, J=7.3 Hz, 1H), 5.11 (s, 2H), 3.47 (s, 3H), 2.70(s, 3H), 2.53 (s, 3H), 1.86 (d, J=7.3 Hz, 3H). Retention time(LC-MS): 2.309 min. MH.sup.+ 576.

Compound 164(2S)--N-(5'-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-[2,2'-bipyrazin]--6-yl)-2-(3-methyl-2,6-dioxo-1-(2-oxopropyl)-2,3-dihydro-1H-purin-7(6H)-yl-)propanamide

##STR00706##

This compound was prepared using the method described for compound2 with appropriate starting materials in 14.3% yield as a yellowsolid. .sup.1H NMR (400 MHz, DMSO-d6) .delta. 11.37 (s, 1H), 9.15(s, 1H), 9.02 (s, 1H), 8.91 (d, J=1.2 Hz, 1H), 8.41 (s, 1H), 8.14(d, J=1.6 Hz, 1H), 5.80 (m, 1H), 4.70 (s, 2H), 3.96 (d, J=11.6 Hz,2H), 3.86 (d, J=9.4 Hz, 2H), 3.46 (s, 3H), 2.78 (d, J=10.6 Hz, 2H),2.16 (s, 3H), 1.89 (d, J=7.3 Hz, 3H). Retention time (LC-MS): 1.663min. MH.sup.+ 567.

Compound 165(2S)--N-(6-(2-(3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)pyridin-2-yl)--2-(1-(3-methoxy-2-oxopropyl)-3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H-)-yl)propanamide

##STR00707##

This compound was prepared using the method described for compound2 with appropriate starting materials in 19.1% yield as a yellowsolid. .sup.1H NMR (400 MHz, DMSO-d6) .delta. 11.01 (s, 1H), 8.99(s, 2H), 8.39 (d, J=6.9 Hz, 1H), 7.88-7.78 (m, 2H), 7.60 (d, J=7.8Hz, 1H), 5.79 (s, 1H), 4.74 (d, J=3.7 Hz, 2H), 4.21 (s, 2H), 3.85(d, J=11.2 Hz, 2H), 3.55 (s, 3H), 3.46 (s, 3H), 3.31 (s, 3H), 1.86(d, J=7.3 Hz, 3H), 1.68 (m, 2H), 0.77 (m, 1H), 0.17 (m, 1H).Retention time (LC-MS): 1.975 min. MH.sup.+ 560.

Compound 166(2S)--N-(2-(2-(3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)thiazol-4-yl)--2-(3-methyl-1-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)-2,6-dioxo-2,3-dihyd-ro-1H-purin-7(6H)-yl)propanamide

##STR00708##

This compound was prepared using the method described for compound107 with appropriate starting materials in 12.2% yield as a whitesolid. .sup.1H NMR (400 MHz, DMSO-d6) .delta. 11.63 (s, 1H), 8.81(s, 2H), 8.43 (s, 1H), 7.47 (s, 1H), 5.72 (d, J=7.3 Hz, 1H), 5.25(m, 2H), 3.83 (d, J=11.4 Hz, 2H), 3.55 (d, J=10.9 Hz, 2H), 3.48 (s,3H), 2.26 (s, 3H), 1.84 (d, J=7.3 Hz, 3H), 1.67 (m, 2H), 0.76 (m,1H), 0.17 (d, J=4.3 Hz, 1H). Retention time (LC-MS): 2.361 min.MH.sup.+ 576.

Compound 167(2S)--N-(6-(2-(3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)pyridin-2-yl)--2-(3-methyl-1-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)-2,6-dioxo-2,3-dihyd-ro-1H-purin-7(6H)-yl)propanamide

##STR00709##

This compound was prepared using the method described for compound1 with appropriate starting materials in 10.4% yield as a whitesolid. .sup.1H NMR (400 MHz, DMSO-d6) .delta. 11.02 (s, 1H), 8.99(s, 2H), 8.44 (s, 1H), 7.82 (m, 2H), 7.61 (d, J=8.2 Hz, 1H), 5.80(s, 1H), 5.27 (m, 2H), 3.84 (d, J=11.3 Hz, 2H), 3.54 (d, J=11.2 Hz,2H), 3.48 (s, 3H), 2.26 (s, 3H), 1.87 (d, J=7.6 Hz, 3H), 1.69 (m,2H), 0.752 (m, 1H), 0.16 (m, 1H). Retention time (LC-MS): 2.298min. MH.sup.+ 570.

Compound 168(2S)--N-(6-(2-(3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)pyridin-2-yl)--2-(1-(but-2-yn-1-yl)-3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)pro-panamide

##STR00710##

This compound was prepared using the method described for compound1 with appropriate starting materials in 7.6% yield as a whitesolid. .sup.1H NMR (400 MHz, DMSO-d6) .delta. 11.04 (s, 1H), 9.00(s, 2H), 8.37 (s, 1H), 7.81 (m, 2H), 7.61 (d, J=8.3 Hz, 1H), 5.83(s, 1H), 4.52 (m, 2H), 3.85 (d, J=11.6 Hz, 2H), 3.55 (d, J=11.1 Hz,2H), 3.46 (d, J=4.7 Hz, 3H), 1.86 (d, J=7.3 Hz, 3H), 1.70 (m, 5H),0.76 (m, 1H), 0.17 (m, 1H). Retention time (LC-MS): 2.312 min.MH.sup.+ 526.

Compound 169(2S)-2-(1-(but-2-yn-1-yl)-3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-y-l)-N-(6-(2-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)pyri-din-2-yl)propanamide

##STR00711##

This compound was prepared using the method described for compound1 with appropriate starting materials and separated via preparativeHPLC in 3.9% yield as a white solid. .sup.1H NMR (400 MHz, DMSO-d6).delta. 11.05 (s, 1H), 9.04 (s, 2H), 8.37 (s, 1H), 7.84 (m, 2H),7.64 (d, J=8.4 Hz, 1H), 5.83 (s, 1H), 4.52 (m, 2H), 3.99 (d, J=12Hz, 2H), 3.87 (d, J=10.4 Hz, 2H), 3.46 (s, 3H), 2.70 (d, J=10.4 Hz,2H), 1.86 (d, J=7.6 Hz, 3H), 1.69 (m, 3H). Retention time (LC-MS):2.379 min. MH.sup.+ 562.

Compound 170(S)-2-(3-methyl-1-((5-methyl-1,2,4-oxadiazol-3-yl)methyl)-2,6-dioxo-2,3-d-ihydro-1H-purin-7(6H)-yl)-N-(6-(6-methyl-5-(trifluoromethyl)pyridin-3-yl)p-yrazin-2-yl)propanamide

##STR00712##

This compound was prepared using the method described for compound1 with appropriate starting materials in 13.4% yield as a whitesolid. .sup.1H NMR (400 MHz, DMSO-d6) .delta. 11.54 (s, 1H), 9.47(s, 1H), 9.27 (s, 1H), 9.21 (s, 1H), 8.73 (s, 1H), 8.45 (s, 1H),5.86-5.78 (m, 1H), 5.11 (s, 2H), 3.48 (s, 3H), 2.73 (s, 3H), 2.52(s, 3H), 1.90 (d, J=7.3 Hz, 3H). Retention time (LC-MS): 1.817 min.MH.sup.+ 571.

Compound 171(S)-2-(3-methyl-1-((5-methyl-1,2,4-oxadiazol-3-yl)methyl)-2,6-dioxo-2,3-d-ihydro-1H-purin-7(6H)-yl)-N-(6-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin--2-yl)propanamide

##STR00713##

This compound was prepared using the method described for compound1 with appropriate starting materials in 20.4% yield as a whitesolid. .sup.1H NMR (400 MHz, DMSO-d6) .delta. 11.29 (s, 1H), 9.66(s, 2H), 8.43 (s, 1H), 8.11 (d, J=7.5 Hz, 1H), 8.06-7.96 (m, 2H),5.83 (s, 1H), 5.16-5.05 (m, 2H), 3.48 (s, 3H), 2.51 (s, 3H), 1.89(d, J=7.3 Hz, 3H). Retention time (LC-MS): 1.876 min. MH.sup.+557.

Compound 172(S)-2-(3-methyl-1-((5-methyl-1,2,4-oxadiazol-3-yl)methyl)-2,6-dioxo-2,3-d-ihydro-1H-purin-7(6H)-yl)-N-(2-(6-methyl-5-(trifluoromethyl)pyridin-3-yl)p-yrimidin-4-yl)propanamide

##STR00714##

This compound was prepared using the method described for compound1 with appropriate starting materials in 15.0% yield as a whitesolid. .sup.1H NMR (400 MHz, DMSO-d6) .delta. 11.60 (s, 1H), 9.59(s, 1H), 8.88-8.81 (m, 2H), 8.44 (s, 1H), 7.97 (d, J=5.6 Hz, 1H),5.81 (s, 1H), 5.10 (s, 2H), 3.48 (s, 3H), 2.74 (s, 3H), 2.52 (s,3H), 1.90 (d, J=7.3 Hz, 3H). Retention time (LC-MS): 1.305 min.MH.sup.+ 571.

Compound 173(2S)--N-(2'-(3-azabicyclo[3.1.0]hexan-3-yl)-[2,5'-bipyrimidin]-4-yl)-2-(1--(but-2-yn-1-yl)-3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)propanam-ide

##STR00715##

This compound was prepared using the method described for compound1 with appropriate starting materials and separated via preparativeHPLC in 13.8% yield as a white solid. .sup.1H NMR (400 MHz,DMSO-d6) .delta. 11.46 (s, 1H), 9.17 (s, 2H), 8.68 (d, J=6 Hz, 1H),8.37 (s, 1H), 7.80 (d, J=5.6 Hz, 1H), 5.81 (s, 1H), 4.51 (m, 2H),3.87 (d, J=11.2 Hz, 2H), 3.59 (d, J=12 Hz, 2H), 3.46 (s, 3H), 1.88(d, J=7.2 Hz, 3H), 1.70 (m, 5H), 0.78 (m, 1H), 0.17 (m, 1H).Retention time (LC-MS): 2.225 min. MH.sup.+ 527.

Compound 174N-(6-(4-chlorophenyl)pyridin-2-yl)-2-(3,8-dimethyl-2,6-dioxo-1-(pyridin-2--ylmethyl)-2,3-dihydro-1H-purin-7(6H)-yl)acetamide

##STR00716##

To a mixture ofN-(6-bromopyridin-2-yl)-2-(3,8-dimethyl-2,6-dioxo-1-(pyridin-2-ylmethyl)--2,3-dihydro-1H-purin-7(6H)-yl)acetamide (140 mg, 0.29 mmol) and4-chlorophenylboronic acid (68 mg, 0.43 mmol) in toluene/ethanol/2Naq. Na.sub.2CO.sub.3 (2 mL/1 mL/0.5 mL) was addedPd(PPh.sub.3).sub.4 (48 mg, 0.04 mmol) after degassed three timesunder N.sub.2 atmosphere. The mixture was then heated to100.degree. C. for 2 h. The reaction mixture was cooled to RT andfiltered through Celite. The filtrate was extracted with EA(3.times.20 mL). Combined organic layers were dried overNa.sub.2SO.sub.4 and filtered. The filtrate was concentrated andthe residue was purified via prep-HPLC to giveN-(6-(4-chlorophenyl)pyridin-2-yl)-2-(3,8-dimethyl-2,6-dioxo-1-(pyridin-2--ylmethyl)-2,3-dihydro-1H-purin-7(6H)-yl)acetamide (100 mg, 67.1%yield) as a white solid. H-NMR (400 MHz, DMSO-d.sub.6) .delta.11.09 (s, 1H), 8.42 (dd, J=5.1, 1.7 Hz, 1H), 8.12 (t, J=8.7 Hz,2H), 7.95 (s, 1H), 7.89 (t, J=7.9 Hz, 1H), 7.76-7.65 (m, 2H), 7.57(d, J=8.6 Hz, 2H), 7.22 (d, J=9.7 Hz, 2H), 5.33 (s, 2H), 5.13 (s,2H), 3.45 (s, 3H), 2.45 (s, 3H). Retention time (LC-MS): 2.160 min.MH.sup.+ 516.

Compound 175N-(6-(3,4-difluorophenyl)pyridin-2-yl)-2-(3,8-dimethyl-2,6-dioxo-1-(pyrid-in-2-ylmethyl)-2,3-dihydro-1H-purin-7(6H)-yl)acetamide

##STR00717##

This compound was prepared using the method described for compound174 with appropriate starting materials. .sup.1H-NMR (400 MHz,DMSO-d.sub.6) .delta. 11.08 (s, 1H), 8.42 (d, J=3.5 Hz, 1H),8.22-8.08 (m, 1H), 7.96 (s, 2H), 7.90 (t, J=7.9 Hz, 1H), 7.72 (m,2H), 7.58 (m, 1H), 7.22 (d, J=7.9 Hz, 2H), 5.33 (s, 2H), 5.13 (s,2H), 3.44 (d, J=7.1 Hz, 3H), 2.45 (s, 3H). Retention time (LC-MS):2.040 min. MH.sup.+ 518.

Compound 176(S)-2-(3,8-dimethyl-2,6-dioxo-1-(pyridin-2-ylmethyl)-2,3-dihydro-1H-purin--7(6H)-yl)-N-(6-(2-(2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidin-5-yl)pyri-din-2-yl)acetamide

##STR00718##

This compound was prepared using the method described for compound1 with appropriate starting materials. .sup.1H-NMR (400 MHz,DMSO-d.sub.6) .delta. 11.03 (s, 1H), 9.10 (s, 2H), 8.42 (dd, J=5.1,1.7 Hz, 1H), 7.91 (s, 1H), 7.86 (t, J=7.9 Hz, 1H), 7.74-7.63 (m,2H), 7.22 (d, J=9.9 Hz, 2H), 5.33 (s, 2H), 5.16-5.05 (m, 3H),3.77-3.63 (m, 2H), 3.45 (s, 3H), 2.45 (s, 3H), 2.23-2.02 (m, 4H).Retention time (LC-MS): 2.247 min. MH.sup.+ 419.2.

Compound 1772-(3,8-dimethyl-2,6-dioxo-1-(pyridin-2-ylmethyl)-2,3-dihydro-1H-purin-7(6-H)-yl)-N-(6-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-2-yl)acetamide

##STR00719##

A mixture of 5-bromo-2-(trifluoromethyl)pyrimidine (113 mg, 0.50mmol),4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2--dioxaborolane (153 mg, 0.60 mmol), potassium acetate (148 mg, 1.51mmol) and[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (15 mg)in a dioxane (5 mL) was degassed under N.sub.2 for three times andstirred at 100.degree. C. for 2 h under N.sub.2 atmosphere. Themixture was cooled to RT.N-(6-bromopyridin-2-yl)-2-(3,8-dimethyl-2,6-dioxo-1-(pyridin-2-ylmethyl)--2,3-dihydro-1H-purin-7(6H)-yl)acetamide (140 mg, 0.29 mmol),aqueous Na.sub.2CO.sub.3 solution (1 mL, 2 M) and[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (15 mg)were added to the above mixture under N.sub.2 atmosphere. Themixture was stirred at 100.degree. C. under N.sub.2 for 2 h andcooled to RT. The reaction mixture was extracted with DCM(2.times.30 mL). Combined organic layers were washed with brine,dried over Na2SO4, and concentrated and the residue was purifiedprep-HPLC to give2-(3,8-dimethyl-2,6-dioxo-1-(pyridin-2-ylmethyl)-2,3-dihydro-1H-purin-7(6-H)-yl)-N-(6-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-2-yl)acetamide(40 mg, 25.1% yield) as a white solid. .sup.1H NMR (400 MHz,DMSO-d.sub.6) .delta. 11.26 (s, 1H), 9.66 (s, 2H), 8.42 (d, J=3.6Hz, 1H), 8.10 (s, 1H), 8.07-7.96 (m, 2H), 7.70 (td, J=7.7, 1.6 Hz,1H), 7.22 (d, J=7.7 Hz, 2H), 5.35 (s, 2H), 5.13 (s, 2H), 3.45 (s,3H), 2.46 (s, 3H). Retention time (LC-MS): 1.640 min. MH.sup.+552.

Compound 178N-(2-(3,4-difluorophenyl)thiazol-4-yl)-2-(3-methyl-2,6-dioxo-1-(pyridin-2--ylmethyl)-2,3-dihydro-1H-purin-7(6H)-yl)acetamide

##STR00720##

A mixture ofN-(2-bromothiazol-4-yl)-2-(3-methyl-2,6-dioxo-1-(pyridin-2-ylmethyl)-2,3--dihydro-1H-purin-7(6H)-yl)acetamide (70 mg, 0.15 mmol),4-chlorophenylboronic acid (35 mg, 0.22 mmol) in a mixed solution(toluene:ethanol:aq Na.sub.2CO.sub.3 (2 M)=4:2:1, 7 mL) wasdegassed under N.sub.2 atmosphere, followed by addition oftetrakis(triphenylphosphine)palladium (10 mg). The mixture wasstirred under N.sub.2 at 100.degree. C. for 2 h and cooled to RT.The mixture was extracted with DCM (3.times.10 mL). Combinedorganic layers were washed with brine, dried over Na2SO4, andconcentrated and the residue was purified prep-HPLC to giveN-(2-(3,4-difluorophenyl)thiazol-4-yl)-2-(3-methyl-2,6-dioxo-1-(pyridin-2--ylmethyl)-2,3-dihydro-1H-purin-7(6H)-yl)acetamide (20 mg, 27.8%yield) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6).delta. 11.60 (s, 1H), 8.42 (d, J=4.1 Hz, 1H), 8.14 (s, 1H), 7.94(d, J=9.1 Hz, 1H), 7.82-7.68 (m, 2H), 7.64-7.54 (m, 2H), 7.26-7.19(m, 2H), 5.27 (s, 2H), 5.13 (s, 2H), 3.48 (s, 3H). Retention time(LC-MS): 2.160 min. MH.sup.+ 510.

Compound 181N-(6-(4-chlorophenyl)pyridin-2-yl)-2-(3-methyl-2,6-dioxo-1-(2-oxopropyl)--1,2,3,6-tetrahydropurin-7-yl)acetamide

##STR00721##

To a solution ofN-(6-bromopyridin-2-yl)-2-(3-methyl-2,6-dioxo-1-(2-oxopropyl)-1,2,3,6-tet-rahydropurin-7-yl)acetamide (150 mg, 0.34 mmol) in toluene/ethanol(4 mL/2 mL) was added aqueous Na.sub.2CO.sub.3 solution and themixture was degassed under N.sub.2 for three times. To the abovemixture, 4-chlorophenylboronic acid (80 mg, 0.52 mmol) andtetrakis(triphenylphosphine)palladium (19.6 mg, 0.017 mmol) wereadded under N.sub.2 atmosphere. The resulting mixture was stirredat 100.degree. C. under N.sub.2 for 2 h. The mixture was dilutedwith DCM, washed with brine, dried over Na2SO4, and concentratedand the residue was purified via prep-HPLC to giveN-(6-(4-chlorophenyl)pyridin-2-yl)-2-(3-methyl-2,6-dioxo-1-(2-oxopropyl)--1,2,3,6-tetrahydropurin-7-yl)acetamide (30 mg, 20.0% yield) as awhite solid. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. 11.08 (s,1H), 8.13 (d, J=10.4 Hz, 3H), 7.95 (s, 1H), 7.89 (t, J=7.9 Hz, 1H),7.73 (d, J=7.8 Hz, 1H), 7.59 (d, J=8.5 Hz, 2H), 5.30 (s, 2H), 4.70(s, 2H), 3.46 (s, 4H), 2.17 (s, 3H). Retention time (LC-MS): 1.375min. MH.sup.+ 467.

Compound 182N-(6-(3,4-difluorophenyl)pyridin-2-yl)-2-(3-methyl-2,6-dioxo-1-(2-oxoprop-yl)-1,2,3,6-tetrahydropurin-7-yl)acetamide

##STR00722##

This compound was prepared using the method described for compound181 with appropriate starting materials. .sup.1H-NMR (400 MHz,DMSO-d.sub.6) .delta. 11.04 (s, 1H), 8.13 (s, 1H), 7.93 (d, J=29.1Hz, 2H), 7.76 (s, 1H), 7.57 (s, 1H), 5.31 (s, 1H), 4.69 (s, 1H),3.46 (s, 2H), 2.50 (s, 2H), 2.16 (s, 2H), 2.07 (s, 1H). Retentiontime (LC-MS): 2.141 min. MH.sup.+ 469.

Compound 183(S)-2-(3-methyl-2,6-dioxo-1-(2-oxopropyl)-1,2,3,6-tetrahydropurin-7-yl)-N--(6-(2-(2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidin-5-yl)pyridin-2-yl)ace-tamide

##STR00723##

This compound was prepared using the method described for compound181 with appropriate starting materials. .sup.1H NMR (400 MHz,DMSO-d.sub.6) .delta. 11.01 (s, 1H), 9.11 (s, 2H), 8.14 (s, 1H),7.87 (dd, J=16.4, 8.8 Hz, 2H), 7.68 (d, J=8.0 Hz, 1H), 5.30 (s,2H), 5.20-5.01 (m, 1H), 4.70 (s, 2H), 3.71 (t, J=6.7 Hz, 2H), 3.46(s, 3H), 2.21 (d, J=9.3 Hz, 1H), 2.16-2.13 (m, 1H), 2.09 (d, J=13.6Hz, 2H). Retention time (LC-MS): 2.405 min. MH.sup.+ 572.

Compound 1842-(1-(2-hydroxypropyl)-3-methyl-2,6-dioxo-1,2,3,6-tetrahydropurin-7-yl)-N-(6-(2-((S)-2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidin-5-y-l)pyridin-2-yl)acetamide

##STR00724##

To a solution of(S)-2-(3-methyl-2,6-dioxo-1-(2-oxopropyl)-1,2,3,6-tetrahydropurin-7-yl)-N--(6-(2-(2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidin-5-yl)pyridin-2-yl)ace-tamide (25 mg, 43.90 .mu.mol) in MeOH (2 mL) was added sodiumborohydride (3 mg, 65.84 .mu.mol) and the mixture was stirred at RTfor 2 h. The reaction was poured into ice water, and extracted withEA. Combined organic layers were dried over Na.sub.2SO.sub.4 andfiltered. The filtrate was concentrated under reduced pressure andthe residue was purified via prep-HPLC to give2-(1-(2-hydroxypropyl)-3-methyl-2,6-dioxo-1,2,3,6-tetrahydropurin-7-yl)-N--(6-(2-((S)-2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidin-5-yl)pyridin-2-yl-)acetamide (20 mg, 79.7% yield) as a white solid. .sup.1H NMR (400MHz, DMSO-d.sub.6) .delta. 11.01 (s, 1H), 9.12 (s, 2H), 8.08 (s,1H), 7.88 (dd, J=17.2, 9.5 Hz, 2H), 7.68 (d, J=8.0 Hz, 1H), 5.31(s, 2H), 5.18-5.03 (m, 1H), 4.67 (d, J=4.4 Hz, 1H), 3.97-3.85 (m,2H), 3.69 (dt, J=12.1, 7.4 Hz, 3H), 3.45 (s, 4H), 2.29-2.01 (m,4H), 1.00 (d, J=5.8 Hz, 3H). Retention time (LC-MS): 2.090 min.MH.sup.+ 574.

Compound 1852-(3-methyl-2,6-dioxo-1-(2-oxopropyl)-2,3-dihydro-1H-purin-7(6H)-yl)-N-(6--(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-2-yl)acetamide

##STR00725##

A mixture of 5-bromo-2-(trifluoromethyl)pyrimidine (113 mg, 0.50mmol),4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2--dioxaborolane (153 mg, 0.60 mmol), potassium acetate (148 mg, 1.51mmol) and[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (15 mg)in a dioxane (5 mL) was degassed under N.sub.2 for three times andstirred at 100.degree. C. for 2 h under N.sub.2 atmosphere. Themixture was cooled to RT.N-(6-bromopyridin-2-yl)-2-(3-methyl-2,6-dioxo-1-(2-oxopropyl)-1,2,3,6-tet-rahydropurin-7-yl)acetamide (150 mg, 0.34 mmol), aqueousNa.sub.2CO.sub.3 solution (1 mL, 2 M) and[1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (15 mg)were added to the above mixture under N.sub.2 atmosphere. Themixture was stirred at 100.degree. C. under N.sub.2 for 2 h andcooled to RT. The reaction mixture was extracted with DCM(2.times.10 mL). Combined organic layers were washed with brine,dried over Na2SO4, and concentrated and the residue was purifiedprep-HPLC to give2-(3-methyl-2,6-dioxo-1-(2-oxopropyl)-1,2,3,6-tetrahydropurin-7-yl)-N-(6--(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-2-yl)acetamide (10 mg,10.0% yield) as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6).delta. 11.23 (s, 4H), 9.67 (s, 9H), 8.15 (s, 5H), 8.05 (d, J=7.5Hz, 6H), 8.01 (t, J=5.8 Hz, 6H), 5.33 (s, 8H), 4.70 (s, 9H), 3.47(s, 14H), 2.17 (s, 14H). Retention time (LC-MS): 1.968 min.MH.sup.+ 503.

Compound 1862-(3-methyl-2,6-dioxo-1-(pyridin-2-ylmethyl)-2,3-dihydro-1H-purin-7(6H)-y-l)-N-(6-(2-(trifluoromethyl)pyrimidin-5-yl)pyridin-2-yl)acetamide

##STR00726##

This compound was prepared using the method described for compound185 with appropriate starting materials. .sup.1H NMR (400 MHz,DMSO-d.sub.6) .delta. 11.22 (s, 1H) 9.66 (s, 2H), 8.42-8.41 (d,1H), 8.15 (s, 1H), 7.98-8.05 (m, 3H), 7.68-7.72 (m, 2H), 7.20-7.23(t, 2H), 5.34 (s, 2H), 5.13 (s, 2H) 3.717-3.644 (m, 2H), 3.49 (s,3H). Retention time (LC-MS): 1.938 min. MH.sup.+ 538.

Compound 187N-(6-(3,4-difluorophenyl)pyridin-2-yl)-2-(3-methyl-2,6-dioxo-1-(pyridin-2--ylmethyl)-2,3-dihydro-1H-purin-7(6H)-yl)acetamide

##STR00727##

To a mixture ofN-(6-bromopyridin-2-yl)-2-(3-methyl-2,6-dioxo-1-(pyridin-2-ylmethyl)-2,3--dihydro-1H-purin-7(6H)-yl)acetamide (150 mg, 0.32 mmol) in toluene(2 mL) was added 3,4-difluorophenylboronic acid (75.64 mg, 0.479mmol), ethanol (1 mL), aq. sodium carbonate (0.5 mL, 2 N solution)and tetrakis(triphenylphosphine)palladium under N.sub.2 atmosphere.After the addition, the mixture was stirred at 100.degree. C. for16 h. The reaction was quenched by water and extracted with EA(3.times.5 mL). Combined organic layers were washed with brine,dried over Na2SO4, and concentrated to give the crude product whichwas purified via prep-TLC to giveN-(6-(3,4-difluorophenyl)pyridin-2-yl)-2-(3-methyl-2,6-dioxo-1-(pyri-din-2-ylmethyl)-2,3-dihydro-1H-purin-7(6H)-yl)acetamide (26.8 mg,16.65% yield) as a white solid. .sup.1H NMR (MeOH-d.sub.4) .delta.11.05 (s, 1H), 8.42-8.41 (d, 1H), 8.16-8.11 (m, 2H), 7.96-7.87 (m,3H), 7.76-7.68 (m, 2H), 7.61-7.54 (m, 1H), 7.23-7.20 (m, 2H), 5.31(s, 2H), 5.13 (s, 2H), 3.47 (s, 3H). Retention time (LC-MS): 2.379min. MH.sup.+ 504.

The procedure set forth above was used to produce the followingcompounds using the appropriate starting materials.

Compound 188N-(6-(4-chlorophenyl)pyridin-2-yl)-2-(3-methyl-2,6-dioxo-1-(pyridin-2-ylm-ethyl)-2,3-dihydro-1H-purin-7(6H)-yl)acetamide

##STR00728##

This compound was prepared using the method described for compound187 with appropriate starting materials. .sup.1H NMR (MeOH-d.sub.4).delta. 11.060 (m, 1H) 8.426-8.415 (d, 1H), 8.142-8.098 (m, 3H),7.947-7.866 (m, 2H), 7.628-7.683 (m, 2H), 7.583-7.561 (d, 2H),7.236-7.204 (m, 2H), 5.317 (s, 2H), 5.134 (s, 2H), 3.476 (s, 3H).Retention time (LC-MS): 2.490 min. MH.sup.+ 502.

Compound 189(S)-2-(3-methyl-2,6-dioxo-1-(pyridin-2-ylmethyl)-2,3-dihydro-1H-purin-7(6-H)-yl)-N-(6-(2-(2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidin-5-yl)pyridin--2-yl)acetamide

##STR00729##

This compound was prepared using the method described for compound187 with appropriate starting materials. .sup.1H NMR (MeOH-d.sub.4).delta. 11.010 (s, 1H) 9.095 (s, 2H), 8.423-8.412 (d, 1H), 8.143(s, 1H), 7.904-7.838 (m, 2H), 7.729-7.661 (m, 2H), 7.239-7.208 (m,2H), 5.314 (s, 2H), 5.135-5.081 (m, 3H) 3.717-3.644 (m, 2H),3.597-3.518 (m, 3H),2.216-2.069 (m, 4H). Retention time (LC-MS):2.258 min. MH.sup.+ 607.

Compound 190(S)-2-(3-methyl-2,6-dioxo-1-(pyridin-2-ylmethyl)-1,2,3,6-tetrahydropurin-7-yl)-N-(2-(2-(2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidin-5--yl)thiazol-4-yl)acetamide

##STR00730##

A mixture ofN-(2-bromothiazol-4-yl)-2-(3-methyl-2,6-dioxo-1-(pyridin-2-ylmethyl)-2,3--dihydro-1H-purin-7(6H)-yl)acetamide (70 mg, 0.15 mmol),4-chlorophenylboronic acid (35 mg, 0.22 mmol) in a mixed solution(toluene:ethanol:aq Na.sub.2CO.sub.3 (2 M)=4:2:1, 7 mL) wasdegassed under N.sub.2 and tetrakis(triphenylphosphine)palladium(10 mg) was added. The mixture was stirred under N.sub.2 at100.degree. C. for 2 h and cooled to RT. The mixture was extractedwith DCM (3.times.10 mL). Combined organic layers were washed withbrine, dried over Na2SO4, and concentrated and the residue waspurified prep-HPLC to giveN-(2-(4-chlorophenyl)thiazol-4-yl)-2-(3-methyl-2,6-dioxo-1-(pyridin-2-ylm-ethyl)-2,3-dihydro-1H-purin-7(6H)-yl)acetamide (20 mg, 28.0% yield)as a white solid. .sup.1H NMR (400 MHz, DMSO-d.sub.6) .delta. 11.60(s, 1H), 8.42 (d, J=4.3 Hz, 1H), 8.14 (s, 1H), 7.92 (d, J=8.5 Hz,2H), 7.71 (t, J=7.7 Hz, 1H), 7.63-7.54 (m, 3H), 7.29-7.16 (m, 2H),5.27 (s, 2H), 5.13 (s, 2H), 3.47 (s, 3H). Retention time (LC-MS):2.117 min. MH.sup.+ 508.

Compound 1912-(3-methyl-2,6-dioxo-1-(pyridin-2-ylmethyl)-2,3-dihydro-1H-purin-7(6H)-y-l)-N-(2-(2-(trifluoromethyl)pyrimidin-5-yl)thiazol-4-yl)acetamide

##STR00731##

This compound was prepared using the method described for compound190 with appropriate starting materials. .sup.1H NMR (400 MHz,DMSO-d.sub.6) .delta. 11.80 (s, 1H), 9.51 (s, 2H), 8.42 (d, J=4.2Hz, 1H), 8.15 (s, 1H), 7.85 (s, 1H), 7.72 (dd, J=10.7, 4.6 Hz, 1H),7.32-7.15 (m, 2H), 5.29 (s, 2H), 5.14 (d, J=7.2 Hz, 2H), 3.47 (d,J=6.1 Hz, 4H). Retention time (LC-MS): 1.808 min. MH.sup.+ 544.

Compound 192N-(6-(4-chlorophenyl)pyridin-2-yl)-2-(3,8-dimethyl-2,6-dioxo-1-(2-oxoprop-yl)-1,2,3,6-tetrahydropurin-7-yl)acetamide

##STR00732##

To a mixture ofN-(6-bromopyridin-2-yl)-2-(3,8-dimethyl-2,6-dioxo-1-(2-oxopropyl)-1,2,3,6--tetrahydropurin-7-yl)acetamide (7, 150 mg, 0.334 mmol) and4-chlorophenylboronic acid (62 mg, 0.4 mmol) in toluene/EtOH/2N aq.Na.sub.2CO.sub.3 (1.6 mL/0.8 mL/0.4 mL) was addedPd(PPh.sub.3).sub.4 (38 mg, 0.034 mmol) after degassed three timesunder N.sub.2 atmosphere, then the mixture was heated to100.degree. C. for 2 h. The mixture was cooled to RT and filteredthrough Celite. The filtrate was extracted with EA (3.times.5 mL).Combined organic layers were dried over Na.sub.2SO.sub.4 andfiltered. The filtrate was concentrated and the residue waspurified by chromatography (eluted with PE/acetone=3/1) to giveN-(6-(4-chlorophenyl)pyridin-2-yl)-2-(3,8-dimethyl-2,6-dioxo-1-(2-oxoprop-yl)-1,2,3,6-tetrahydropurin-7-yl)acetamide (100 mg, 62.5% yield) asa white solid. 1H-NMR (400 MHz, DMSO-d.sub.6) .delta. 11.09 (s,1H), 8.12-8.14 (d, J=8.8 Hz, 2H), 7.94-7.95 (d, J=1.6 Hz, 1H),7.87-7.91 (t, J=14.6 Hz, 1H), 7.72-7.74 (d, J=8.0 Hz, 1H),7.58-7.60 (d, J=8.4 Hz, 1H), 5.30 (s, 2H), 4.49 (s, 2H), 3.42 (s,3H), 2.50 (s, 3H), 2.17 (s, 3H). Retention time (LC-MS): 1.551 min.MH.sup.+ 481.

Compound 193N-(6-(3,4-difluorophenyl)pyridin-2-yl)-2-(3,8-dimethyl-2,6-dioxo-1-(2-oxo-propyl)-1,2,3,6-tetrahydropurin-7-yl)acetamide

##STR00733##

This compound was prepared using the method described for compound192 with appropriate starting materials. .sup.1H-NMR (400 MHz,DMSO-d.sub.6) .delta. 11.09 (s, 1H), 8.16-8.18 (m, 1H), 8.13-8.15(m, 2H), 7.92-7.99 (m, 1H), 7.76-7.78 (d, J=8.4 Hz, 1H), 7.56-7.63(m, 1H), 5.31 (s, 2H), 4.69 (s, 2H), 3.46 (s, 3H), 2.50 (s, 3H),2.17 (s, 3H). Retention time (LC-MS): 1.414 min. MH.sup.+ 483.

Compound 1942-(3,8-dimethyl-2,6-dioxo-1-(2-oxopropyl)-1,2,3,6-tetrahydropurin-7-yl)-N--(6-(2-(trifluo-romethyl)pyrimidin-5-yl)pyridin-2-yl)acetamide

##STR00734##

This compound was prepared using the method described for compound192 with appropriate starting materials. .sup.1H-NMR (400 MHz,DMSO-d.sub.6) .delta. 11.26 (s, 1H), 9.68 (s, 2H), 8.13-8.16 (d,J=12.4 Hz, 1H), 8.01-8.04 (t, J=10.0 Hz, 2H), 5.33 (s, 2H), 4.69(s, 2H), 3.42 (s, 3H), 2.50 (s, 3H), 2.17 (s, 3H). Retention time(LC-MS): 1.431 min. MH.sup.+ 517.

Compound 1952-(3,8-dimethyl-2,6-dioxo-1-(2-oxopropyl)-1,2,3,6-tetrahydropurin-7-yl)-N--(6-(2-(trifluoro methyl)pyrimidin-5-yl)pyridin-2-yl)acetamide

##STR00735##

This compound was prepared using the method described for compound192 with appropriate starting materials. .sup.1H-NMR (400 MHz,DMSO-d.sub.6) .delta. 11.02 (s, 1H), 9.11 (s, 2H), 7.84-7.88 (m,2H), 7.67-7.69 (d, J=8.0 Hz, 1H), 5.30 (s, 2H), 5.09-5.13 (m, 1H),4.69 (s, 2H), 3.68-3.72 (m, 2H), 3.43 (s, 3H), 2.43 (s, 3H), 2.30(s, 5H), 2.02-2.08 (m, 2H). Retention time (LC-MS): 1.501 min.MH.sup.+ 586.

Compound 196N-(6-(4,4-difluoropiperidin-1-yl)pyridin-2-yl)-2-(3-methyl-1-((5-methylisoxazol-3-yl)methyl)-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)acetamide

##STR00736##

A mixture of3-methyl-1-((5-methylisoxazol-3-yl)methyl)-1H-purine-2,6(3H,7H)-dione (80 mg, 306.24 .mu.mol),2-chloro-N-(6-(4,4-difluoropiperidin-1-yl)pyridin-2-yl)acetamide(133 mg, 459.35 TBAI (68 mg, 18 .mu.mol) and POTASSIUM CARBONATE(106 mg, 765.59 .mu.mol) in DMF (5 mL) was stirred at 50.degree. C.for 2 h. The reaction mixture was quenched by water (40 mL), andthen extracted with EA (3.times.10 mL). Combined organic layerswere dried over Na.sub.2SO.sub.4 and filtered. The filtrate wasconcentrated and the residue was purified by chromatography (elutedwith PE:EA=1:1) to affordN-(6-(4,4-difluoropiperidin-1-yl)pyridin-2-yl)-2-(3-methyl-1-((5-methylisoxazol-3-yl)methyl)-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)acetamide (40 mg,25.4% yield) as a white solid. .sup.1H-NMR (400 MHz, DMSO-d.sub.6).delta. 10.52 (s, 1H), 8.10 (s, 1H), 7.53 (t, J=8.1 Hz, 1H), 7.27(s, 1H), 6.65 (d, J=8.3 Hz, 1H), 6.09 (s, 1H), 5.28 (m, 2H), 5.01(s, 2H), 3.74-3.64 (m, 4H), 3.46 (s, 3H), 2.32 (s, 3H), 2.06-1.89(m, 4H). Retention time (LC-MS): 2.363 min. MH.sup.+ 515.2.

Compound 197N-(6-(3,3-difluoroazetidin-1-yl)pyridin-2-yl)-2-(3-methyl-1-((5-methyliso-xazol-3-yl)methyl)-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)acetamide

##STR00737##

This compound was prepared using the method described for compound196 with appropriate starting materials. .sup.1H NMR (400 MHz,CDCl.sub.3) .delta. 9.93 (s, 1H), 8.00 (d, J=8.5 Hz, 1H), 7.84 (d,J=8.8 Hz, 1H), 7.77 (s, 1H), 5.99 (s, 1H), 5.28 (d, J=8.8 Hz, 4H),3.65 (s, 3H), 2.23 (s, 3H). Retention time (LC-MS): 2.19 min.MH.sup.+ 487.

Compound 198N-(5-(4-isopropylpiperidin-1-yl)pyridin-2-yl)-2-(3-methyl-1-((5-methyliso-xazol-3-yl)methyl)-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)acetamide

##STR00738##

This compound was prepared using the method described for compound196 with appropriate starting materials. .sup.1H-NMR (400 MHz,DMSO-d.sub.6) .delta. 10.70 (s, 1H), 8.09 (s, 1H), 8.00 (d, J=2.8Hz, 1H), 7.80 (d, J=9.1 Hz, 1H), 7.36 (dd, J=9.1, 2.7 Hz, 1H), 6.08(s, 1H), 5.20 (s, 2H), 5.00 (s, 2H), 3.68 (m, 2H), 3.45 (s, 3H),2.56 (t, J=11.4 Hz, 2H), 2.31 (s, 3H), 1.69 (m, 2H), 1.42 (m, 1H),1.26 (m, 2H), 1.14 (d, J=11.5 Hz, 1H), 0.86 (d, J=6.7 Hz, 6H).Retention time (LC-MS): 2.506 min. MH.sup.+ 519.2.

Compound 1992-(3-Methyl-1-((5-methylisoxazol-3-yl)methyl)-2,6-dioxo-2,3-dihydro-1H-pu-rin-7(6H)-yl)-N-(quinolin-2-yl)acetamide

##STR00739##

This compound was prepared using the method described for compound196 with appropriate starting materials. .sup.1H NMR (400 MHz,DMSO-d.sub.6) .delta. 11.34 (s, 1H), 8.37 (d, J=8.9 Hz, 1H), 8.15(s, 2H), 7.93 (d, J=7.8 Hz, 1H), 7.85 (d, J=8.5 Hz, 1H), 7.74 (t,J=7.7 Hz, 1H), 7.52 (t, J=7.5 Hz, 1H), 6.10 (s, 1H), 5.35 (s, 2H),5.02 (s, 2H), 3.48 (s, 3H), 2.32 (s, 3H). Retention time (LC-MS):1.992 min. MH.sup.+ 446.

Compound 200N-(5-bromo-6-(trifluoromethyl)pyridin-2-yl)-2-(3-methyl-1-((5-methyl-isox-azol-3-yl)methyl)-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)acetamide

##STR00740##

A mixture ofN-(5-bromo-6-(trifluoromethyl)pyridin-2-yl)-2-chloroacetamide (70.5mg, 0.27 mmol), potassium carbonate (74.6 mg, 0.54 mmol), TBAI(10.0 mg, 0.03 mmol) and3-methyl-1-((5-methylisoxazol-3-yl)methyl)-1H-purine-2,6(3H,7H)--dione (85.0 mg, 0.27 mmol) in DMF (3 mL) was stirred at 80.degree.C. overnight. The reaction mixture was diluted with EA, washed insequence with water, aq. NH.sub.4Cl and brine, dried overNa.sub.2SO.sub.4, and concentrated under reduced pressure. Theresidue was purified by chromatography (eluted with PE:EA=1:1) togive the title compound (100.0 mg, 68.7% yield) as a white solid..sup.1HNMR (400 MHz, CDCl.sub.3) .delta. 9.93 (s, 1H), 7.99 (d,J=8.5 Hz, 1H), 7.84 (d, J=8.8 Hz, 1H), 7.77 (s, 1H), 5.99 (s, 1H),5.29 (t, J=6.9 Hz, 4H), 3.65 (s, 3H), 2.23 (s, 3H). Retention time(LC-MS): 2.59 min. MH.sup.+ 542.

Compound 201N-(5-cyano-6-(trifluoromethyl)pyridin-2-yl)-2-(3-methyl-1-((5-methylisoxazol-3-yl)methyl)-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)acetamide

##STR00741##

N-(5-bromo-6-(trifluoromethyl)pyridin-2-yl)-2-(3-methyl-1-((5-methylisoxa-zol-3-yl) methyl)-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)acetamide(27.1 mg, 0.05 mmol) and Zn(CN).sub.2(5.9 mg, 0.05 mmol) wasdissolved in NMP in a microwave oven vessel, followed by additionof Pd(PPh.sub.3).sub.4 (5.8 mg, 0.005 mmol). The reaction mixturewas heated under nitrogen in a Biotage Initiator device at180.degree. C. and high absorbance for 30 min. The reaction mixturewas poured into EA. The mixture was washed with water and brine,dried over Na.sub.2SO.sub.4 and filtered. The filtrate wasconcentrated under reduced pressure. The residue was purifiedprep-TLC to afford the title compound (15 mg, 61.4% yield) as awhite solid. .sup.1HNMR (400 MHz, DMSO-d.sub.6) .delta. 12.01 (s,1H), 8.62 (d, J=8.8 Hz, 1H), 8.42 (d, J=8.8 Hz, 1H), 8.19 (s, 1H),6.17 (s, 1H), 5.41 (s, 2H), 5.08 (s, 2H), 3.54 (s, 3H), 2.39 (s,3H). Retention time (LC-MS): 2.18 min. MH.sup.+ 489.

Compound 2022-(3-methyl-1-((5-methylisoxazol-3-yl)methyl)-2,6-dioxo-2,3-dihydro-1H-pu-rin-7(6H)-yl)-N-(6-(4-(trifluoromethyl)piperidin-1-yl)pyridin-2-yl)acetami-de

##STR00742##

This compound was prepared using the method described for compound196 with appropriate starting materials. .sup.1HNMR (400 Hz,DMSO-d.sub.6) .delta. 10.49 (s, 1H), 8.11 (s, 1H), 7.51 (t, J=8.1Hz, 1H), 7.24 (d, J=6.7 Hz, 1H), 6.58 (d, J=8.4 Hz, 1H), 6.10 (s,1H), 5.23 (s, 2H), 5.02 (s, 2H), 4.41 (dd, J=12.1, 7.1 Hz, 2H),3.46 (d, J=4.1 Hz, 3H), 2.84 (t, J=12.1 Hz, 2H), 2.61 (d, J=8.6 Hz,1H), 2.32 (s, 3H), 1.87 (d, J=11.0 Hz, 2H), 1.48-1.34 (m, 2H).Retention time (LC-MS): 2.457 min. MH.sup.+ 547.3.

Compound 203N-(4-ethyl-6-(trifluoromethyl)pyridin-2-yl)-2-(3-methyl-1-((5-methylisoxa-zol-3-yl)methyl)-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)acetamide

##STR00743##

To a solution ofN-(3,4-dimethoxybenzyl)-N-(4-ethyl-6-(trifluoromethyl)pyridin-2-yl)-2-(1--(isoxazol-3-ylmethyl)-3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)ace-tamide (50 mg, 0.078 mmol) in MeCN (3 mL) and H.sub.2O (3 mL) wasadded portionwise CAN (128.29 mg, 0.23 mmol) at 0.degree. C. Afterthe addition, the mixture was warmed to r.t. and stirred for 3 h.The reaction mixture was diluted with EA, washed with water, brine,dried over Na.sub.2SO.sub.4 and filtered. The filtrate was purifiedvia prep-TLC twice (eluted with PE:EA=1:2 and then DCM:MeOH=10:1)to affordN-(4-ethyl-6-(trifluoromethyl)pyridin-2-yl)-2-(3-methyl-1-((5-methylisoxa-zol-3-yl)methyl)-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)acetamide(5 mg, 13% yield) as a white solid. .sup.1HNMR (400 MHz,DMSO-d.sub.6) .delta. 11.41 (s, 1H), 8.13 (d, J=11.9 Hz, 2H), 7.53(s, 1H), 6.10 (s, 1H), 5.29 (s, 2H), 5.01 (s, 2H), 3.47 (s, 3H),2.76-2.67 (m, 2H), 2.32 (s, 3H), 1.18 (t, J=7.6 Hz, 3H). MH.sup.+492.

Compound 204N-(4-methoxy-6-(trifluoromethyl)pyridin-2-yl)-2-(3-methyl-1-((5-methyliso-xazol-3-yl)methyl)-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)acetamide

##STR00744##

This compound was prepared using the method described for compound203 with appropriate starting materials. .sup.1HNMR (400 MHz,DMSO-d.sub.6) .delta. 11.42 (s, 1H), 8.11 (s, 1H), 7.82 (s, 1H),7.21 (d, J=2.0 Hz, 1H), 6.10 (s, 1H), 5.29 (s, 2H), 5.02 (s, 2H),3.88 (s, 3H), 3.47 (s, 3H), 2.32 (s, 3H). MH.sup.+ 494.

Compound 211N-(4-(ethyl(trifluoromethyl)amino)phenyl)-2-(3-methyl-1-((5-methylisoxazo-l-3-yl)methyl)-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)acetamide

##STR00745##

To a solution of N1-ethyl-N1-(trifluoromethyl)benzene-1,4-diamine(35.2 mg, 0.156 mmol) in DMF (1 mL) was added drop-wisechloroacetyl chloride (35 mg, 0.31 mmol) at 0.degree. C. Themixture was stirred at r.t. for 1 hr, then poured into aqueousNaHCO.sub.3 solution and extracted with EA twice. Combined organiclayers were concentrated under reduced pressure. The residue wasdissolved in DMF (2 mL), followed by addition of3-methyl-1-((5-methylisoxazol-3-yl)methyl)-1H-purine-2,6(3H,7H)-dione(50 mg, 0.156 mmol) and POTASSIUM CARBONATE (43.2 mg, 0.313 mmol).The mixture was then stirred at 60.degree. C. for 4 h and dilutedwith EA (10 mL) and brine (10 mL). The organic layers wasseparated, washed with S. aq. NH.sub.4C1, dried overNa.sub.2SO.sub.4 and concentrated under reduced pressure. Theresidue was purified via preparative TLC (DCM:MeOH=30:1) to giveN-(4-(ethyl(trifluoromethyl)amino)phenyl)-2-(3-methyl-1-((5-methylisoxazol-3-yl)methyl)-2,6-dioxo-2,3--dihydro-1H-purin-7(6H)-yl)acetamide (11.2 mg, 14.2% yield) as awhite solid. .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. 11.61 (s,1H), 8.13 (s, 1H), 7.61-7.63 (d, J=8.8 Hz, 2H), 7.31-7.33 (d, J=8.8Hz, 2H), 6.09 (s, 1H), 5.21 (s, 2H), 5.02 (s, 2H), 3.61-3.63 (m,2H), 3.47 (s, 3H), 2.32 (s, 3H), 1.06-1.09 (t, 3H). Retention time(LC-MS): 2.028 min. MH.sup.+ 506.

Compound 212N-(6-(3-azabicyclo[3.1.0]hexan-3-yl)pyridin-2-yl)-2-(3-methyl-1-((5-methy-lisoxazol-3-yl)methyl)-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)acetamide

##STR00746##

A solution ofN-(6-(3-azabicyclo[3.1.0]hexan-3-yl)pyridin-2-yl)-2-chloroacetamide(30 mg, 0.12 mmol), POTASSIUM CARBONATE (32.95 mg, 0.24 mmol),3-methyl-1-((5-methylisoxazol-3-yl)methyl)-1H-purine-2,6(3H,7H)-dione(31.14 mg, 0.12 mmol) and TBAI (4.40 mg, 0.012 mmol) in DMF (3 mL)was stirred at 50.degree. C. for 3 hrs. The mixture was dilutedwith EA, washed with water, brine, dried over Na.sub.2SO.sub.4 andfiltered. The filtrate was concentrated and purified withpreparative TLC (DCM/MeOH=20:1) to affordN-(6-(3-azabicyclo[3.1.0]hexan-3-yl)pyridin-2-yl)-2-(3-methyl-1-((5-methy-lisoxazol-3-yl)methyl)-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)acetamide(15 mg, 26.3% yield) as a white solid. .sup.1H NMR (400 MHz, DMSO).delta. 10.40 (s, 1H), 8.10 (s, 1H), 7.42 (t, J=8.0 Hz, 1H), 7.19(s, 1H), 6.16 (d, J=8.2 Hz, 1H), 6.09 (s, 1H), 5.23 (s, 2H), 5.01(s, 2H), 3.64 (d, J=10.2 Hz, 2H), 3.46 (s, 3H), 3.34-3.30 (m, 2H),2.32 (s, 3H), 1.74-1.55 (m, 2H), 0.72 (d, J=4.4 Hz, 1H), 0.17 (d,J=4.0 Hz, 1H). Retention time (LC-MS): 1.965 min. MH.sup.+ 477.

Compound 213N-(6-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-2-yl)-2-(3-methy-l-1-((5-methylisoxazol-3-yl)methyl)-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-y-l)acetamide

##STR00747##

A mixture of2-chloro-N-(6-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-2-yl)ac-etamide (6, 200.0 mg, 0.7 mmol), potassium carbonate (145.1 mg, 1.1mmol),3-methyl-1-((5-methylisoxazol-3-yl)methyl)-1H-purine-2,6(3H,7H)-dione(7, 182.8 mg, 0.7 mmol) and TBAI (25.9 mg, 0.07 mmol) in DMF (5 mL)was stirred at 80.degree. C. overnight. The mixture was dilutedwith EA and washed with water, saturated aqueous NH.sub.4Clsolution and brine, dried over Na.sub.2SO.sub.4, and evaporated.The residue was purified by preparative TLC to giveN-(6-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-2-yl)-2-(3-methy-l-1-((5-methylisoxazol-3-yl)methyl)-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-y-l)acetamide (15.0 mg, 4.2% yield) as a white solid. .sup.1H NMR(400 MHz, DMSO) .delta. 10.46 (s, 1H), 8.11 (s, 1H), 7.48 (t, J=7.9Hz, 1H), 7.24 (s, 1H), 6.19 (d, J=8.1 Hz, 1H), 6.10 (s, 1H), 5.24(s, 2H), 5.02 (s, 2H), 3.78 (d, J=10.8 Hz, 2H), 3.67 (d, J=9.7 Hz,2H), 3.47 (s, 3H), 2.68 (d, J=10.8 Hz, 2H), 2.32 (s, 3H). Retentiontime (LC-MS): 2.26 min. MH.sup.+ 513.

Compound 2142-(3-methyl-1-((5-methylisoxazol-3-yl)methyl)-2,6-dioxo-2,3-dihydro-1H-pu-rin-7(6H)-yl)-N-(6-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)pyridin-2-yl)ac-etamide

##STR00748##

A mixture of2-chloro-N-(6-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)pyridin-2-yl)acetam-ide (15 mg, 0.045 mmol), potassium carbonate (12.30 mg, 0.089mmol),3-methyl-1-((5-methylisoxazol-3-yl)methyl)-1H-purine-2,6(3H,7H)-dione(11.62 mg, 0.045 mmol) and TBAI (1.64 mg, 0.0045 mmol) in DMF (3mL) was stirred at 70.degree. C. for 3 h. The mixture was dilutedwith EA, washed with water, brine, dried over Na.sub.2SO.sub.4 andfiltered. The filtrate was purified via prep HPLC to afford2-(3-methyl-1-((5-methylisoxazol-3-yl)methyl)-2,6-dioxo-2,3-dihydro-1H-pu-rin-7(6H)-yl)-N-(6-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)pyridin-2-yl)ac-etamide (10 mg, 40% yield) as a white solid. 1H NMR (400 MHz, DMSO).delta. 10.55 (s, 1H), 8.17 (s, 1H), 7.57 (t, J=7.9 Hz, 1H), 7.32(s, 1H), 6.61 (d, J=8.4 Hz, 1H), 6.16 (s, 1H), 5.29 (s, 2H), 5.08(s, 2H), 3.57 (s, 4H), 3.53 (s, 3H), 3.30 (d, J=10.5 Hz, 2H), 2.77(s, 4H), 2.39 (s, 3H). Retention time (LC-MS): 2.362 min. MH.sup.+562.

Compound 2152-(3-methyl-1-((5-methylisoxazol-3-yl)methyl)-2,6-dioxo-2,3-dihydro-1H-pu-rin-7(6H)-yl)-N-(6'-(trifluoromethyl)-2,3'-bipyridin-6-yl)acetamide

##STR00749##

A mixture of3-methyl-1-((5-methylisoxazol-3-yl)methyl)-1H-purine-2,6(3H,7H)-dione(33 mg, 0.126 mmol),2-chloro-N-(6'-(trifluoromethyl)-2,3'-bipyridin-6-yl)acetamide (40mg, 0.126 mmol), POTASSIUM CARBONATE (34 mg, 0.252 mmol), and TBAI(4.5 mg, 0.012 mmol) in DMF (5 mL) was stirred at 50.degree. C. for3 hrs. The reaction mixture was then diluted with EA. The reactionmixture was washed in sequence with water, saturated NH.sub.4Clsolution and brine, dried over Na.sub.2SO.sub.4 and filtered. Thefiltrate was concentrated under reduced pressure and the residuewas purified prep-HPLC to give2-(3-methyl-14(5-methylisoxazol-3-yl)methyl)-2,6-dioxo-2,3-dihydro-1H-pur-in-7(6H)-yl)-N-(6'-(trifluoromethyl)-2,3'-bipyridin-6-yl)acetamide(14 mg, 20.4% yield) as a white solid. Retention time (LC-MS):2.347 min. MH.sup.+ 541. .sup.1H NMR (400 MHz, DMSO) .delta. 11.21(s, 1H), 9.45 (s, 1H), 8.72 (d, J=7.6 Hz, 1H), 8.15 (s, 1H), 8.04(m, 3H), 7.93 (d, J=8.0 Hz, 1H), 6.10 (s, 1H), 5.34 (s, 2H), 5.02(s, 2H), 3.48 (s, 3H), 2.32 (s, 3H).

Compound 2162-(3-methyl-2,6-dioxo-1-(2-oxopropyl)-2,3-dihydro-1H-purin-7(6H)-yl)-N-(2--(5-methyl-6-(trifluoromethyl)pyridin-3-yl)thiazol-4-yl)acetamide

##STR00750##

To a solution of2-chloro-N-(2-(5-methyl-6-(trifluoromethyl)pyridin-3-yl)thiazol-4-yl)acet-amide (35 mg, 0.1 mmol) and8-isopropyl-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione (23.2 mg, 0.1mmol) in DMF (3 mL) was added TBAI (3.8 mg, 0.01 mmol) andPOTASSIUM CARBONATE (28.9 mg, 0.2 mmol) under N.sub.2 protection.The mixture was stirred at 60.degree. C. for 2 hrs. The reactionwas quenched by water (5 mL) and extracted with EA (2*5 mL). Thecombined organic layer was washed with saturated aq. LiCl (2*5 mL),dried over Na.sub.2SO.sub.4 and filtered. The filtrate wasconcentrated. The crude product was purified via Prep-HPLC toafford2-(3-methyl-1-((5-methylisoxazol-3-yl)methyl)-2,6-dioxo-2,3-dihydro-1H-pu-rin-7(6H)-yl)-N-(2-(5-methyl-6-(trifluoromethyl)pyridin-3-yl)thiazol-4-yl)-acetamide (30 mg, 55.1% yield) as a white solid. Retention time(LC-MS): 1.931 min. MH.sup.+ 522. .sup.1H NMR (400 MHz, DMSO-d6).delta. 11.74 (s, 1H), 9.07 (s, 1H), 8.40 (s, 1H), 8.14 (s, 1H),7.76 (s, 1H), 5.26 (s, 2H), 4.70 (s, 2H), 3.46 (s, 3H), 2.56 (d,J=1.8 Hz, 3H), 2.17 (s, 3H).

Compound 2172-(3-methyl-1-((5-methylisoxazol-3-yl)methyl)-2,6-dioxo-2,3-dihydro-1H-pu-rin-7(6H)-yl)-N-(2-(5-methyl-6-(trifluoromethyl)pyridin-3-yl)thiazol-4-yl)-acetamide

##STR00751##

This compound was prepared using the method described for compound43 with appropriate starting materials and purified via preparativeHPLC, 73.4% yield as a light yellow solid. Retention time (LC-MS):2.202 min. MH.sup.+ 561. .sup.1H NMR (400 MHz, DMSO-d6) .delta.11.72 (s, 1H), 9.06 (s, 1H), 8.39 (s, 1H), 8.14 (s, 1H), 7.76 (s,1H), 6.10 (s, 1H), 5.28 (s, 2H), 5.02 (s, 2H), 3.48 (s, 3H), 2.55(d, J=1.6 Hz, 3H), 2.32 (s, 3H).

Compound 2182-(3-methyl-2,6-dioxo-1-(2-oxopropyl)-2,3-dihydro-1H-purin-7(6H)-yl)-N-(2--(6-methyl-5-(trifluoromethyl)pyridin-3-yl)thiazol-4-yl)acetamide

##STR00752##

A mixture of(2-chloro-N-(2-(6-methyl-5-(trifluoromethyl)pyridin-3-yl)thiazol-4-yl)ace-tamide (3, 45 mg, 0.135 mmol),3-methyl-1-(2-oxopropyl)-1H-purine-2,6(3H,7H)-dione (30 mg, 0.135mmol), potassium carbonate (18 mg, 0.135 mmol) and a catalyticamount of TBAI in DMF (1 mL) was stirred at 50.degree. C. for 2hrs. The mixture was diluted with EA and washed with water, brinesuccessively, dried and concentrated to give crude product, whichwas purified via preparative HPLC to give2-(3-methyl-2,6-dioxo-1-(2-oxopropyl)-2,3-dihydro-1H-purin-7(6H)-yl)-N-(2--(6-methyl-5-(trifluoromethyl)pyridin-3-yl)thiazol-4-yl)acetamide(17.6 mg, 25.5% yield) as a white solid. Retention time (LC-MS):1.910 min. MH.sup.+ 521. .sup.1H-NMR (400 MHz, DMSO-d6) .delta.11.71 (s, 1H), 9.24 (s, 1H), 8.44 (m, 1H), 8.14 (s, 1H), 7.70 (s,1H), 5.25 (s, 2H), 4.70 (s, 2H), 3.46 (s, 3H), 2.71 (s, 3H), 2.17(s, 3H).

Compound 219N-(6-(4-(2-fluoropropan-2-yl)piperidin-1-yl)pyridin-2-yl)-2-(3-methyl-1-(-(5-methylisoxazol-3-yl)methyl)-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)ace-tamide

##STR00753##

This compound was prepared using the method described for compound196 with appropriate starting materials. .sup.1HNMR (400 Hz,DMSO-d.sub.6) .delta. 10.42 (s, 1H), 8.76 (d, J=3.1 Hz, 1H), 8.51(d, J=8.4 Hz, 1H), 8.09 (s, 1H), 7.44-7.48 (m, 2H), 7.19 (bs, 1H),6.52 (d, J=6.4 Hz, 1H), 6.08 (s, 1H), 5.22 (s, 2H), 5.01 (s, 2H),4.39 (d, J=12.8 Hz, 2H), 3.45 (s, 3H), 2.71 (t, J=12.1 Hz, 3H),2.31 (s, 3H), 1.73 (d, J=11.5 Hz, 2H), 1.29 (s, 3H), 1.24 (s, 3H).MH.sup.+ 539.

Compound 220N-(5-(4-(2-fluoropropan-2-yl)piperidin-1-yl)pyridin-2-yl)-2-(3-methyl-1-(-(5-methylisoxazol-3-yl)methyl)-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)ace-tamide

##STR00754##

This compound was prepared using the method described for compound196 with appropriate starting materials. .sup.1HNMR (400 Hz,DMSO-d.sub.6) .delta. 10.73 (s, 1H), 8.11 (s, 1H), 8.04 (s, 1H),7.82 (d, J=8.1 Hz, 1H), 7.40 (d, J=6.7 Hz, 1H), 6.10 (s, 1H), 5.22(s, 2H), 5.02 (s, 2H), 3.76 (d, J=4.1 Hz, 2H), 3.47 (s, 3H), 2.60(t, J=12.1 Hz, 3H), 2.32 (s, 3H), 1.75 (d, J=11.0 Hz, 2H), 1.64 (m,2H), 1.26-1.43 (m, 8H). MH.sup.+ 539.

Compound 2212-(3-methyl-1-((5-methylisoxazol-3-yl)methyl)-2,6-dioxo-2,3-dihydro-1H-pu-rin-7(6H)-yl)-N-(5'-methyl-6'-(trifluoromethyl)-[2,3'-bipyridin]-6-yl)acet-amide

##STR00755##

3-(Chloromethyl)-5-methylisoxazole (6.5 mg, 0.05 mmol) andpotassium carbonate (8.5 mg, 0.06 mmol) were added to2-(3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)-N-(5'-methyl-6'-(tri-fluoromethyl)-[2,3'-bipyridin]-6-yl)acetamide (19 mg, 0.041 mmol)in DMF (4 mL). The mixture was stirred at RT overnight. The mixturewas diluted with water and extracted with EA twice. The combinedorganic phases were concentrated and purified by silica gel columnchromatography (0-3% MeOH/DCM) to afford title compound (13.4 mg,59% yield) as a white solid. .sup.1H-NMR (400 MHz, DMSO-d.sub.6).delta. 11.15 (s, 1H), 9.20 (s, 1H), 8.55 (s, 1H), 7.87-8.13 (m,4H), 6.09 (s, 1H), 5.33 (s, 2H), 5.01 (s, 2H), 3.46 (s, 3H), 2.55(s, 3H), 2.31 (s, 3H). MH.sup.+ 555.

Compound 2222-(3-methyl-1-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)-2,6-dioxo-2,3-dihyd-ro-1H-purin-7(6H)-yl)-N-(5'-methyl-6'-(trifluoromethyl)-[2,3'-bipyridin]-6--yl)acetamide

##STR00756##

This compound was prepared using the method described for compound221 with appropriate starting materials as a white solid..sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. 11.16 (s, 1H), 9.20 (s,1H), 8.55 (s, 1H), 8.17 (s, 1H) 7.87-8.06 (m, 3H), 5.33 (s, 2H),5.26 (s, 2H), 3.48 (s, 3H), 2.54 (s, 3H), 2.26 (s, 3H). MH.sup.+556.

Compound 2232-(3-methyl-1-((5-methyl-1,2,4-oxadiazol-3-yl)methyl)-2,6-dioxo-2,3-dihyd-ro-1H-purin-7(6H)-yl)-N-(5'-methyl-6'-(trifluoromethyl)-[2,3'-bipyridin]-6--yl)acetamide

##STR00757##

This compound was prepared using the method described for compound221 with appropriate starting materials as a white solid..sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. 11.16 (s, 1H), 9.20 (s,1H), 8.55 (s, 1H), 8.15 (s, 1H) 7.87-8.06 (m, 3H), 5.33 (s, 2H),5.10 (s, 2H), 3.47 (s, 3H), 2.54 (m, 6H). MH.sup.+ 556.

Compound 2242-(1-(isoxazol-3-ylmethyl)-3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)--yl)-N-(5'-methyl-6'-(trifluoromethyl)-[2,3'-bipyridin]-6-yl)acetamide

##STR00758##

This compound was prepared using the method described for compound221 with appropriate starting materials as a white solid..sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. 11.15 (s, 1H), 9.20 (s,1H), 8.80 (s, 1H), 8.55 (s, 1H), 8.14 (s, 1H) 7.87-8.06 (m, 3H),6.46 (s, 1H), 5.33 (s, 2H), 5.10 (s, 2H), 3.47 (s, 3H), 2.55 (m,6H). MH.sup.+ 541.

Compound 2252-(3-methyl-1-((3-methylisoxazol-5-yl)methyl)-2,6-dioxo-2,3-dihydro-1H-pu-rin-7(6H)-yl)-N-(5'-methyl-6'-(trifluoromethyl)-[2,3'-bipyridin]-6-yl)acet-amide

##STR00759##

This compound was prepared using the method described for compound221 with appropriate starting materials as a white solid..sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. 11.15 (s, 1H), 9.20 (s,1H), 8.55 (s, 1H), 8.14 (s, 1H), 7.87-8.06 (m, 3H), 6.19 (s, 1H),5.33 (s, 2H), 5.09 (s, 2H), 3.47 (s, 3H), 2.55 (s, 3H), 2.14 (s,3H). MH.sup.+ 555.

Compound 2262-(3-methyl-2,6-dioxo-1-(2-oxobutyl)-2,3-dihydro-1H-purin-7(6H)-yl)-N-(5'--methyl-6'-(trifluoromethyl)-[2,3'-bipyridin]-6-yl)acetamide

##STR00760##

This compound was prepared using the method described for compound221 with appropriate starting materials as a white solid..sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. 11.14 (s, 1H), 9.20 (s,1H), 8.55 (s, 1H), 8.13 (s, 1H), 7.87-8.06 (m, 3H), 5.31 (s, 2H),4.68 (s, 2H), 3.45 (s, 3H), 2.51 (m, 5H), 0.93 (t, 3H). MH.sup.+530.

Compound 2272-(3-methyl-2,6-dioxo-1-(2-oxopropyl)-2,3-dihydro-1H-purin-7(6H)-yl)-N-(5-'-methyl-6'-(trifluoromethyl)-[2,3'-bipyridin]-6-yl)acetamide

##STR00761##

This compound was prepared using the method described for compound221 with appropriate starting materials as a white solid..sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. 11.14 (s, 1H), 9.20 (s,1H), 8.55 (s, 1H), 8.13 (s, 1H), 7.87-8.04 (m, 3H), 5.31 (s, 2H),4.69 (s, 2H), 3.45 (s, 3H), 2.55 (s, 3H), 2.16 (s, 3H). MH.sup.+516.

Compound 228N-(5'-fluoro-6'-methyl-[2,3'-bipyridin]-6-yl)-2-(3-methyl-1-((5-methyliso-xazol-3-yl)methyl)-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)acetamide

##STR00762##

This compound was prepared using the method described for compound221 with appropriate starting materials as a white solid..sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. 11.08 (s, 1H), 9.04 (s,1H), 8.25 (d, J=10.9 Hz, 1H), 8.13 (s, 1H), 7.80-8.04 (m, 3H), 6.09(s, 1H), 5.32 (s, 2H), 5.01 (s, 2H), 3.47 (s, 3H), 2.50 (s, 3H),2.31 (s, 3H). MH.sup.+ 505.

Compound 2292-(3-methyl-1-((5-methylisoxazol-3-yl)methyl)-2,6-dioxo-2,3-dihydro-1H-pu-rin-7(6H)-yl)-N-(6-(5-methyl-6-(trifluoromethyl)pyridin-3-yl)pyrazin-2-yl)-acetamide

##STR00763##

This compound was prepared using the method described for compound221 with appropriate starting materials as a white solid..sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. 11.53 (s, 1H), 9.28(bs, 1H), 9.24 (s, 1H), 9.15 (s, 1H), 8.61 (s, 1H), 8.14 (s, 1H),6.09 (s, 1H), 5.37 (s, 2H), 5.01 (s, 2H), 3.47 (s, 3H), 2.56 (s,3H), 2.31 (s, 3H). MH.sup.+ 556.

Compound 2302-(3-methyl-1-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)-2,6-dioxo-2,3-dihyd-ro-1H-purin-7(6H)-yl)-N-(6-(5-methyl-6-(trifluoromethyl)pyridin-3-yl)pyraz-in-2-yl)acetamide

##STR00764##

This compound was prepared using the method described for compound221 with appropriate starting materials as a white solid..sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. 11.53 (s, 1H), 9.28(bs, 1H), 9.24 (s, 1H), 9.15 (s, 1H), 8.61 (s, 1H), 8.19 (s, 1H),5.38 (s, 2H), 5.26 (s, 2H), 3.48 (s, 3H), 2.56 (s, 3H), 2.27 (s,3H). MH.sup.+ 557.

Compound 231N-(5'-fluoro-6'-methyl-[2,3'-bipyridin]-6-yl)-2-(3-methyl-1-((3-methyl-1,-2,4-oxadiazol-5-yl)methyl)-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)acetami-de

##STR00765##

This compound was prepared using the method described for compound221 with appropriate starting materials as a white solid..sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. 11.08 (s, 1H), 9.04 (s,1H), 8.24 (d, J=10.9 Hz, 1H), 8.17 (s, 1H), 7.80-8.00 (m, 3H), 5.32(s, 2H), 5.26 (s, 2H), 3.48 (s, 3H), 2.51 (s, 3H), 2.26 (s, 3H).MH.sup.+ 506.

Compound 2322-(3-methyl-2,6-dioxo-1-(2-oxopropyl)-2,3-dihydro-1H-purin-7(6H)-yl)-N-(6--(5-methyl-6-(trifluoromethyl)pyridin-3-yl)pyrazin-2-yl)acetamide

##STR00766##

This compound was prepared using the method described for compound221 with appropriate starting materials as a white solid..sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. 11.51 (s, 1H), 9.28 (s,1H), 9.24 (s, 1H), 9.15 (s, 1H), 8.61 (s, 1H), 8.14 (s, 1H), 5.35(s, 2H), 4.67 (s, 2H), 3.46 (s, 3H), 2.56 (s, 3H), 2.16 (s, 3H).MH.sup.+ 517.

Compound 2332-(3-methyl-2,6-dioxo-1-(2-oxobutyl)-2,3-dihydro-1H-purin-7(6H)-yl)-N-(6--(5-methyl-6-(trifluoromethyl)pyridin-3-yl)pyrazin-2-yl)acetamide

##STR00767##

This compound was prepared using the method described for compound221 with appropriate starting materials as a white solid..sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. 11.51 (s, 1H), 9.28 (s,1H), 9.24 (s, 1H), 9.15 (s, 1H), 8.61 (s, 1H), 8.14 (s, 1H), 5.36(s, 2H), 4.69 (s, 2H), 3.46 (s, 3H), 2.56 (m, 5H), 0.93 (t, 3H).MH.sup.+ 531.

Compound 2342-(3-methyl-2,6-dioxo-1-(2-oxopropyl)2,3-dihydro-1H-purin-7(6H)-yl)-N-(6'--methyl-5'-(trifluoromethyl)-[2,3'-bipyridin]-6-yl)acetamide

##STR00768##

2-(3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)-N-(6'-methyl-5'-(tri-fluoromethyl)-[2,3-bipyridin]-6-yl)acetamide (50 mg, 0.109 mmol)and potassium carbonate (23 mg, 0.164 mmol) were combined in DMF (4mL) then chloroacetone (0.010 mL, 0.120 mmol) was added drop wise.The reaction was stirred at RT for 18 h, diluted with water (10 mL)and extracted with EA (3.times.10 ml). The combined organic layerswere washed with aq. 1 N LiCl (2.times.10 ml), dried withMgSO.sub.4 and concentrated to a residue which was purified bychromatography eluted with MeOH/DCM (1:99 to 1:97) to give2-(3-methyl-2,6-dioxo-1-(2-oxopropyl)2,3-dihydro-1H-purin-7(6H)-y-l)-N-(6'-methyl-5'-(trifluoromethyl)-[2,3'-bipyridin]-6-yl)acetamide(19 mg, 33.9% yield) as an off-white solid. .sup.1H NMR(CDCl.sub.3) .delta.: 9.44 (brd s, 1H), 9.18 (s, 1H), 8.51 (s, 1H),8.11 (s, 1H), 7.82 (s, 1H), 7.79 (s, 1H), 7.55 (d, 1H, J=8 Hz),5.10 (s, 2H), 4.88 (s, 2H), 3.60 (s, 3H), 2.78 (s, 3H), 2.29 (s,3H). LCMS: MH.sup.+ 516 and T.sub.R=2.897 min.

Compound 2352-(3-methyl-2,6-dioxo-1-(2-oxobutyl)-2,3-dihydro-1H-purin-7(6H)-yl)-N-(6'--methyl-5'-(trifluoromethyl)-[2,3'-bipyridin]-6-yl)acetamide

##STR00769##

2-(3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)-N-(6'-methyl-5'-(tri-fluoromethyl)-[2,3-bipyridin]-6-yl)acetamide (50 mg, 0.109 mmol)and potassium carbonate (23 mg, 0.164 mmol) were combined in DMF (4mL) then 1-bromobutan-2-one (0.012 mL, 0.120 mmol) was added dropwise. The reaction was heated at 55.degree. C. for 18 h thenconcentrated to a residue which was purified by chromatographyeluted with MeOH/DCM (1:99 to 1:97) to give2-(3-methyl-2,6-dioxo-1-(2-oxobutyl)-2,3-dihydro-1H-purin-7(6H)-yl)-N-(6'--methyl-5'-(trifluoromethyl)-[2,3'-bipyridin]-6-yl)acetamide (18mg, 31.2% yield) as a white solid. .sup.1H NMR (CDCl.sub.3).delta.: 9.44 (brd s, 1H), 9.21 (s, 1H), 8.55 (s, 1H), 8.13 (d, J=4Hz, 1H), 7.87-7.81 (m, 2H), 7.58 (d, 1H, J=8 Hz), 5.13 (s, 2H),4.89 (s, 2H), 3.62 (s, 3H), 2.81 (s, 3H), 2.61 (q, J=8 Hz and 12Hz, 2H), 1.14 (t, J=8 Hz, 3H). LCMS: MH.sup.+ 530 and T.sub.R=3.091min.

Compound 2362-(1-(3-hydroxypropyl)-3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)--N-(6'-methyl-5'-(trifluoromethyl)-[2,3'-bipyridin]-6-yl)acetamide

##STR00770##

2-(3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)-N-(6'-methyl-5'-(tri-fluoromethyl)-[2,3-bipyridin]-6-yl)acetamide (50 mg, 0.109 mmol)and potassium carbonate (23 mg, 0.164 mmol) were combined in DMF (4mL) then (3-bromopropoxy)(tert-butyl)dimethylsilane (30 mg, 0.120mmol) was added. The reaction was heated at 80.degree. C. for 18 h,cooled to RT then enough aq. 6N HCl was added until PH=1. Thereaction was stirred at RT for 1 h, diluted with water (20 mL) andextracted with EA (3.times.20 mL). The combined organic layers weredried with MgSO.sub.4 and concentrated to a residue which waspurified by Prep TLC eluted with MeOH/DCM (1:9) to give2-(1-(3-hydroxypropyl)-3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)--N-(6'-methyl-5'-(trifluoromethyl)-[2,3'-bipyridin]-6-yl)acetamide(15 mg, 26.8% yield) as a white solid. .sup.1H NMR (CDCl.sub.3).delta.: 9.80 (brd s, 1H), 9.30 (s, 1H), 8.45 (s, 1H), 7.82 (t, J=8Hz, 1H), 7.78 (s, 1H), 7.55 (d, J=8 Hz, 1H), 5.13 (s, 2H), 5.12 (s,2H), 4.24 (t, J=8 Hz, 2H), 3.91-3.84 (m, 1H), 3.66-3.56 (m, 5H),2.78 (s, 3H), 2.00-1.90 (m, 2H). LCMS: MH.sup.+ 518 andT.sub.R=2.682 min.

Compound 2372-(1-(3-hydroxyethoxy)-3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)--N-(6'-methyl-5'-(trifluoromethyl)-[2,3'-bipyridin]-6-yl)acetamide

##STR00771##

2-(3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)-N-(6'-methyl-5'-(tri-fluoromethyl)-[2,3-bipyridin]-6-yl)acetamide (100 mg, 0.218 mmol)and potassium carbonate (45 mg, 0.327 mmol) were combined in DMF (5mL) then (3-bromoethoxy)(tert-butyl)dimethylsilane (57 mg, 0.240mmol) was added. The reaction was heated at 80.degree. C. for 18 h,cooled to RT then enough aq. 6N HCl was added until PH=1. Thereaction was stirred at RT for 1 h and concentrated to a residuewhich was purified by chromatography eluted with MeOH/DCM (2:98 to8:92) to give2-(1-(3-hydroxyethoxy)-3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)--N-(6'-methyl-5'-(trifluoromethyl)-[2,3'-bipyridin]-6-yl)acetamide(28 mg, 25.5% yield) as a white solid. .sup.1H NMR (CDCl.sub.3).delta.: 9.66 (brd s, 1H), 9.24 (s, 1H), 8.54 (s, 1H), 7.87-7.80(m, 2H), 7.58 (d, J=8 Hz, 1H), 5.15 (s, 2H), 4.37 (t, J=8 Hz, 2H),3.93 (t, J=4 Hz, 1H), 3.64 (s, 3H), 2.81 (s, 3H). LCMS: MH.sup.+504 and T.sub.R=2.607 min.

Compound 2382-(3-methyl-1-((5-methylisoxazol-3-yl)methyl)-2,6-dioxo-2,3-dihydro-1H-pu-rin-7(6H)-yl)-N-(6'-methyl-5'-(trifluoromethyl)-[2,3'-bipyridin]-6-yl)acet-amide

##STR00772##

2-(3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)-N-(6'-methyl-5'-(tri-fluoromethyl)-[2,3-bipyridin]-6-yl)acetamide (50 mg, 0.109 mmol)and potassium carbonate (25 mg, 0.327 mmol) were combined in DMF (3mL) then 3-(chloromethyl)-5-methylisoxazole (16 mg, 0.120 mmol) wasadded. The reaction was heated at 55.degree. C. for 18 h, cooled toRT then concentrated to a residue which was purified bychromatography eluted with MeOH/DCM (1:99 to 3:97) to give2-(3-methyl-1-((5-methylisoxazol-3-yl)methyl)-2,6-dioxo-2,3-dihydro-1H-pu-rin-7(6H)-yl)-N-(6'-methyl-5'-(trifluoromethyl)-[2,3'-bipyridin]-6-yl)acet-amide (19 mg, 31.7% yield) as a white solid. .sup.1H NMR(CDCl.sub.3) .delta.: 9.53 (brd s, 1H), 9.17 (s, 1H), 8.51 (s, 1H),8.08 (brd s, 1H), 7.84-7.75 (m, 2H), 7.55 (d, J=8 Hz, 1H), 6.02 (s,1H), 5.30 (s, 2H), 5.20 (s, 2H) 3.64 (s, 3H), 2.80 (s, 3H), 2.28(s, 3H). LCMS: MH.sup.+ 555 and T.sub.R=3.108 min.

Compound 2392-(1-(isoxazol-3-ylmethyl)-3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)--yl)-N-(6'-methyl-5'-(trifluoromethyl)-[2,3'-bipyridin]-6-yl)acetamide

##STR00773##

2-(3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)-N-(6'-methyl-5'-(tri-fluoromethyl)-[2,3-bipyridin]-6-yl)acetamide (50 mg, 0.109 mmol)and potassium carbonate (25 mg, 0.327 mmol) were combined in DMF (3mL) then 3-(chloromethyl)isoxazole (16 mg, 0.120 mmol) was added.The reaction was heated at 55.degree. C. for 18 h, cooled to RTthen concentrated to a residue which was purified by chromatographyeluted with MeOH/DCM (1:99 to 3:97) to give2-(1-(isoxazol-3-ylmethyl)-3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)--yl)-N-(6'-methyl-5'-(trifluoromethyl)-[2,3'-bipyridin]-6-yl)acetamide(29 mg, 49.2% yield) as a white solid. .sup.1H NMR (CDCl.sub.3).delta.: 9.45 (brd s, 1H), 9.14 (s, 1H), 8.48 (s, 1H), 8.23 (s,1H), 8.07 (brd s, 1H), 7.82-7.73 (m, 2H), 7.53 (d, J=8 Hz, 1H),6.40 (s, 1H), 5.35 (s, 2H), 5.17 (s, 2H) 3.61 (s, 3H), 2.77 (s,3H). LCMS: MH.sup.+ 541 and T.sub.R=3.005 min.

Compound 2402-(3-methyl-1-((5-methyl-1,2,4-oxadiazol-3-yl)methyl-2,6-dioxo-2,3-dihydr-o-1H-purin-7(6H)-yl)-N-(6'-methyl-5'-(trifluoromethyl)-[2,3'-bipyridin]-6--yl)acetamide

##STR00774##

2-(3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)-N-(6'-methyl-5'-(tri-fluoromethyl)-[2,3-bipyridin]-6-yl)acetamide (50 mg, 0.109 mmol)and potassium carbonate (25 mg, 0.327 mmol) were combined in DMF (3mL) then 3-(chloromethyl)-5-methyl-1,2,4-oxadiazole (16 mg, 0.120mmol) was added. The reaction was heated at 55.degree. C. for 18 h,cooled to RT then concentrated to a residue which was purified bychromatography eluted with MeOH/DCM (1:99 to 3:97) to give2-(3-methyl-1-((5-methyl-1,2,4-oxadiazol-3-yl)methyl-2,6-dioxo-2,3-dihydr-o-1H-purin-7(6H)-yl)-N-(6'-methyl-5'-(trifluoromethyl)-[2,3'-bipyridin]-6--yl)acetamide (18 mg, 29.5% yield) as a light tan solid. .sup.1H NMR(CDCl.sub.3) .delta.: 9.26 (brd s, 1H), 9.14 (s, 1H), 8.47 (s, 1H),8.08 (brd s, 1H), 7.84-7.75 (m, 2H), 7.54 (d, J=8 Hz, 1H), 5.35 (s,2H), 5.16 (s, 2H) 3.62 (s, 3H), 2.77 (s, 3H), 2.47 (s, 3H). LCMS:MH.sup.+ 556 and T.sub.R=2.962 min.

Compound 2412-(3-methyl-1-((3-methyl-1,2,4-oxadiazol-5-yl)methyl-2,6-dioxo-2,3-dihydr-o-1H-purin-7(6H)-yl)-N-(6'-methyl-5'-(trifluoromethyl)-[2,3'-bipyridin]-6--yl)acetamide

##STR00775##

2-(3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)-N-(6'-methyl-5'-(tri-fluoromethyl)-[2,3-bipyridin]-6-yl)acetamide (50 mg, 0.109 mmol)and potassium carbonate (25 mg, 0.327 mmol) were combined in DMF (3mL) then 5-(chloromethyl)-3-methyl-1,2,4-oxadiazole (16 mg, 0.120mmol) was added. The reaction was heated at 55.degree. C. for 18 h,cooled to RT then concentrated to a residue which was purified bychromatography eluted with MeOH/DCM (1:99 to 3:97) to give2-(3-methyl-1-((3-methyl-1,2,4-oxadiazol-5-yl)methyl-2,6-dioxo-2,3-dihydr-o-1H-purin-7(6H)-yl)-N-(6'-methyl-5'-(trifluoromethyl)-[2,3'-bipyridin]-6--yl)acetamide (28 mg, 45.9% yield) as a white solid. .sup.1H NMR(CDCl.sub.3) .delta.: 9.14 (s, 2H), 8.47 (s, 1H), 8.08 (brd s, 1H),7.88-7.77 (m, 2H), 7.55 (d, J=8 Hz, 1H), 5.42 (s, 2H), 5.15 (s, 2H)3.53 (s, 3H), 2.77 (s, 3H), 2.27 (s, 3H). LCMS: MH.sup.+ 556 andT.sub.R=3.032 min.

Compound 2422-(3-methyl-2,6-dioxo-1-(3-oxobutyl)-2,3-dihydro-1H-purin-7(6H)-yl)-N-(6'--methyl-5'-(trifluoromethyl)-[2,3'-bipyridin]-6-yl)acetamide

##STR00776##

2-(3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)-N-(6'-methyl-5'-(tri-fluoromethyl)-[2,3-bipyridin]-6-yl)acetamide (50 mg, 0.109 mmol)and potassium carbonate (23 mg, 0.164 mmol) were combined in DMF (3mL) then 4-chlorobutane-2-one (12 mg, 0.109 mmol) was added. Thereaction was stirred at RT for 18 h and concentrated to a residuewhich was purified by chromatography eluted with MeOH/DCM (1:99 to3:97) to give2-(3-methyl-2,6-dioxo-1-(3-oxobutyl)-2,3-dihydro-1H-purin-7(6H)-yl)-N-(6'--methyl-5'-(trifluoromethyl)-[2,3'-bipyridin]-6-yl)acetamide (11mg) as a white solid. .sup.1H NMR (CDCl.sub.3) .delta.: 9.69 (brds, 1H), 9.30 (s, 1H), 8.68 (s, 1H), 8.14 (d, J=8 Hz, 1H), 7.83 (t,J=8 Hz, 1H), 7.76 (s, 1H), 7.55 (d, J=4 Hz, 1H), 5.22 (brd s, 2H),4.27 (t, J=8 Hz, 2H), 3.59 (s, 3H), 2.92 (s, 3H), 2.80 (t, J=8 Hz,2H), 2.12 (s, 3H), 2.12 (s, 3H). LCMS: MH.sup.+ 530 andT.sub.R=2.906 min.

Compound 2432-(3-methyl-2,6-dioxo-1-(2-oxobutyl)-2,3-dihydro-1H-purin-7(6H)-yl)-N-(6--(6-methyl-5-(trifluoromethyl)pyridin-3-yl)pyrazin-2-yl)acetamide

##STR00777##

2-(3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)-N-(6-(6-methyl-5-(tr-ifluoromethyl) pyridin-3-yl)pyrazin-2-yl)acetamide (50 mg, 0.109mmol) and potassium carbonate (23 mg, 0.164 mmol) were combined inDMF (4 mL) then 1-bromobutan-2-one (0.012 mL, 0.120 mmol) was addeddrop wise. The reaction was stirred at RT for 18 h thenconcentrated to a residue which was purified by chromatographyeluted with MeOH/DCM (1:99 to 1:97) to give2-(3-methyl-2,6-dioxo-1-(2-oxobutyl)-2,3-dihydro-1H-purin-7(6H)-yl)--N-(6-(6-methyl-5-(trifluoromethyl)pyridin-3-yl)pyrazin-2-yl)acetamide(14 mg, 24.1% yield) as a white solid. .sup.1H NMR (CDCl.sub.3).delta.: 9.93 (brd s, 1H), 9.43 (s, 1H), 9.29 (s, 1H), 8.87 (s,1H), 8.58 (s, 1H), 7.82 (s, 1H), 5.17 (s, 2H), 4.95 (s, 2H), 3.59(s, 3H), 2.87 (s, 3H), 2.59 (q, J=8 Hz and 12 Hz, 2H), 1.09 (t, J=8Hz, 3H). LCMS: MH.sup.+ 531 and T.sub.R=2.821 min.

Compound 2452-(3-methyl-2,6-dioxo-1-(2-oxopropyl)-2,3-dihydro-1H-purin-7(6H)-yl)-N-(6--(6-methyl-5-(trifluoromethyl)pyridin-3-yl)pyrazin-2-yl)acetamide

##STR00778##

2-(3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)-N-(6-(6-methyl-5-(tr-ifluoromethyl) pyridin-3-yl)pyrazin-2-yl)acetamide (100 mg, 0.217mmol) and potassium carbonate (45 mg, 0.326 mmol) were combined inDMF (5 mL) then 1-chloropropan-2-one (0.017 mL, 0.217 mmol) wasadded drop wise. The reaction was stirred at RT for 18 h thenconcentrated to a residue which was purified by chromatographyeluted with MeOH/DCM (1:99 to 1:97) to give2-(3-methyl-2,6-dioxo-1-(2-oxopropyl)-2,3-dihydro-1H-purin-7(6H)-yl)--N-(6-(6-methyl-5-(trifluoromethyl)pyridin-3-yl)pyrazin-2-yl)acetamide(16 mg, 14.3% yield) as a white solid. .sup.1H NMR (CDCl.sub.3).delta.: 9.91 (brd s, 1H), 9.45 (s, 1H), 9.29 (s, 1H), 8.88 (s,1H), 8.60 (s, 1H), 7.81 (s, 1H), 5.14 (s, 2H), 4.88 (s, 2H), 3.60(s, 3H), 2.88 (s, 3H), 2.30 (s, 3H). LCMS: MH.sup.+ 517 andT.sub.R=2.635 min.

Compound 2462-(3-methyl-1-((5-methylisoxazol-3-yl)methyl)-2,6-dioxo-2,3-dihydro-1H-pu-rin-7(6H)-yl)-N-(2-(6-methyl-5-(trifluoromethyl)pyridin-3-yl)thiazol-4-yl)-acetamide

##STR00779##

A mixture of3-methyl-1-((5-methylisoxazol-3-yl)methyl)-1H-purine-2,6(3H,7H)-dione(31 mg, 0.12 mmol),2-chloro-N-(2-(6-methyl-5-(trifluoromethyl)pyridin-3-yl)thiazol-4-yl)acet-amide (40 mg, 0.12 mmol), potassium carbonate (33 mg, 0.24 mmol)and a catalytic amount of TBAI in N, N-dimethylformamide (1 mL) wasstirred at 50.degree. C. overnight. The mixture was diluted with EAand washed with water, brine successively, dried and concentratedto give a crude product, which was purified via preparative HPLC togive2-(3-methyl-1-((5-methylisoxazol-3-yl)methyl)-2,6-dioxo-2,3-dihydro-1H-pu-rin-7(6H)-yl)-N-(2-(6-methyl-5-(trifluoromethyl)pyridin-3-yl)thiazol-4-yl)-acetamide (25 mg, 37.3% yield) as a white solid. .sup.1H NMR (400MHz, DMSO) .delta. 11.71 (s, 1H), 9.24 (s, 1H), 8.46 (s, 1H), 8.14(s, 1H), 7.71 (s, 1H), 6.10 (s, 1H), 5.27 (s, 2H), 5.02 (s, 2H),3.47 (s, 3H), 2.71 (s, 3H), 2.32 (s, 3H). Retention time (LC-MS):1.415 min. MH.sup.+ 561.

Compound 2472-(3-methyl-2,6-dioxo-1-(2-oxobutyl)-2,3-dihydro-1H-purin-7(6H)-yl)-N-(2--(6-methyl-5-(trifluoromethyl)pyridin-3-yl)thiazol-4-yl)acetamide

##STR00780##

This compound was prepared using the method described for compound246 with appropriate starting materials in 29.7% yield as a whitesolid. 1H NMR (400 MHz, DMSO-d6) .delta. 11.69 (s, 1H), 9.24 (s,1H), 8.46 (s, 1H), 8.14 (s, 1H), 7.70 (s, 1H), 5.26 (s, 2H), 4.69(s, 2H), 3.46 (s, 3H), 2.71 (s, 3H), 2.54 (s, 2H), 0.95 (t, J=6 Hz,3H). Retention time (LC-MS): 2.069 min. MH.sup.+ 536.

Compound 2482-(3-methyl-1-((5-methyl-1,2,4-oxadiazol-3-yl)methyl)-2,6-dioxo-2,3-dihyd-ro-1H-purin-7(6H)-yl)-N-(2-(6-methyl-5-(trifluoromethyl)pyridin-3-yl)thiaz-ol-4-yl)acetamide

##STR00781##

This compound was prepared using the method described for compound246 with appropriate starting materials in 18.4% yield as a whitesolid. .sup.1H NMR (400 MHz, DMSO-d6) .delta. 11.72 (s, 1H), 9.23(d, J=4 Hz, 1H), 8.46 (d, J=4 Hz, 1H), 8.16 (s, 1H), 7.70 (s, 1H),5.28 (s, 2H), 5.11 (s, 2H), 3.48 (s, 3H), 2.71 (s, 3H), 2.53 (s,3H). Retention time (LC-MS): 2.280 min. MH.sup.+ 562.

Compound 2492-(3-methyl-2,6-dioxo-1-(2-oxobutyl)-2,3-dihydro-1H-purin-7(6H)-yl)-N-(2--(5-methyl-6-(trifluoromethyl)pyridin-3-yl)thiazol-4-yl)acetamide

##STR00782##

This compound was prepared using the method described for compound246 with appropriate starting materials in 39.2% yield as a whitesolid. .sup.1H NMR (400 MHz, DMSO-d6) .delta.11.74 (s, 1H), 9.07(s, 1H), 8.39 (s, 1H), 8.15 (s, 1H), 7.76 (s, 1H), 5.27 (s, 2H),4.70 (s, 2H), 3.46 (s, 3H), 2.51 (s, 5H), 0.95 (t, J=6.4 Hz, 3H).Retention time (LC-MS): 2.424 min. MH.sup.+ 536.

Compound 2502-(3-methyl-1-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)-2,6-dioxo-2,3-dihyd-ro-1H-purin-7(6H)-yl)-N-(2-(5-methyl-6-(trifluoromethyl)pyridin-3-yl)thiaz-ol-4-yl)acetamide

##STR00783##

To a solution of2-(3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)-N-(2-(5-methyl-6-(tr-ifluoromethyl)pyridin-3-yl)thiazol-4-yl)acetamide (20 mg, 0.043mmol) and 5-(chloromethyl)-3-methyl-1,2,4-oxadiazole (6.27 mg,0.047 mmol) in DMF (1 mL) was added TBAI (1.59 mg, 0.0043 mmol) andpotassium carbonate (11.88 mg, 0.086 mmol) under N.sub.2protection. The mixture was stirred at 40.degree. C. for 1 hrs. Thereaction was quenched by water (5 mL) and extracted with EA(2.times.5 mL). The combined organic layer was washed withsaturated brine (2.times.5 mL), dried over Na.sub.2SO.sub.4 andfiltered. The filtrate was concentrated. The crude product waspurified via Preparative-TLC (DCM:MeOH=20:1) to afford2-(3-methyl-1-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)-2,6-dioxo-2,3-dihyd-ro-1H-purin-7(6H)-yl)-N-(2-(5-methyl-6-(trifluoromethyl)pyridin-3-yl)thiaz-ol-4-yl)acetamide (10 mg, 41.4% yield) as a white solid. .sup.1HNMR (400 MHz, DMSO-d6) .delta. 11.76 (s, 1H), 9.07 (s, 1H), 8.40(s, 1H), 8.19 (s, 1H), 7.76 (s, 1H), 5.28 (d, J=6.2 Hz, 4H), 3.49(s, 3H), 2.55 (s, 3H), 2.28 (s, 3H). Retention time (LC-MS): 2.104min. MH.sup.+ 562.

Compound 2512-(3-methyl-2,6-dioxo-1-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-purin-7(6H)--yl)-N-(2-(5-methyl-6-(trifluoromethyl)pyridin-3-yl)thiazol-4-yl)acetamide

##STR00784##

This compound was prepared using the method described for compound250 with appropriate starting materials and separated viapreparative-TLC in 42.5% yield as a white solid. .sup.1H NMR (400MHz, DMSO-d6) .delta. 11.76 (s, 1H), 9.07 (s, 1H), 8.40 (s, 1H),8.18 (s, 1H), 7.76 (s, 1H), 5.29 (s, 2H), 4.65 (q, J=9.1 Hz, 2H),3.49 (s, 3H), 2.56 (d, J=1.5 Hz, 3H). Retention time (LC-MS): 2.355min. MH.sup.+ 548.

Compound 2522-(3-methyl-1-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)-2,6-dioxo-2,3-dihyd-ro-1H-purin-7(6H)-yl)-N-(2-(6-methyl-5-(trifluoromethyl)pyridin-3-yl)thiaz-ol-4-yl)acetamide

##STR00785##

This compound was prepared using the method described for compound250 with appropriate starting materials and separated viapreparative-HPLC in 16.3% yield as a white solid. .sup.1H NMR (400MHz, DMSO-d6) .delta. 11.71 (s, 1H), 9.23 (d, J=1.6 Hz, 1H), 8.45(d, 1H), 8.18 (s, 1H), 7.70 (s, 1H), 5.27 (s, 4H), 3.48 (s, 3H),2.70 (d, J=1.2 Hz, 3H), 2.27 (s, 3H). Retention time (LC-MS): 2.252min. MH.sup.+ 562.

Compound 2532-(3-methyl-1-((5-methyl-1,2,4-oxadiazol-3-yl)methyl)-2,6-dioxo-2,3-dihyd-ro-1H-purin-7(6H)-yl)-N-(2-(5-methyl-6-(trifluoromethyl)pyridin-3-yl)thiaz-ol-4-yl)acetamide

##STR00786##

This compound was prepared using the method described for compound250 with appropriate starting materials and separated viapreparative-TLC in 49.7% yield as a white solid. .sup.1H NMR (400MHz, DMSO-d6) .delta. 11.75 (s, 1H), 9.07 (s, 1H), 8.40 (s, 1H),8.17 (s, 1H), 7.76 (s, 1H), 5.29 (s, 2H), 5.11 (s, 2H), 3.48 (s,3H), 2.55 (d, J=1.4 Hz, 3H), 2.53 (s, 3H). Retention time (LC-MS):2.286 min. MH.sup.+ 562.

Compound 2542-(1-(3-methoxy-2-oxopropyl)-3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H-)-yl)-N-(2-(6-methyl-5-(trifluoromethyl)pyridin-3-yl)thiazol-4-yl)acetamid-e

##STR00787##

This compound was prepared using the method described for compound246 with appropriate starting materials and separated viapreparative-HPLC in 8.9% yield as a white solid. .sup.1H NMR (400MHz, DMSO-d6) .delta. 11.71 (s, 1H), 9.24 (s, 1H), 8.46 (s, 1H),8.15 (s, 1H), 7.70 (s, 1H), 5.26 (s, 2H), 4.75 (s, 2H), 4.22 (s,2H), 3.46 (s, 3H), 3.32 (s, 3H), 2.71 (s, 3H). Retention time(LC-MS): 1.990 min. MH.sup.+ 552.

Compound 2552-(1-(3-methoxy-2-oxopropyl)-3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H-)-yl)-N-(2-(5-methyl-6-(trifluoromethyl)pyridin-3-yl)thiazol-4-yl)acetamid-e

##STR00788##

This compound was prepared using the method described for compound246 with appropriate starting materials in 30.4% yield. Whitesolid. .sup.1H NMR (400 MHz, DMSO-d6) .delta. 11.72 (s, 1H), 9.07(s, 1H), 8.40 (s, 1H), 8.15 (s, 1H), 7.75 (s, 1H), 5.26 (s, 2H),4.74 (s, 2H), 4.22 (s, 2H), 3.46 (s, 3H), 3.32 (s, 3H), 2.55 (s,3H). Retention time (LC-MS): 2.065 min. MH.sup.+ 552.

Compound 256(2S)--N-(6-(5-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyrazin-2-yl)py-ridin-2-yl)-2-(3-methyl-2,6-dioxo-1-(2-oxobutyl)-2,3-dihydro-1H-purin-7(6H-)-yl)propanamide

##STR00789##

To a solution of6-(5-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyrazin-2-yl)pyridin-2-a-mine (40 mg, 0.138 mmol) and(S)-2-(3-methyl-2,6-dioxo-1-(2-oxobutyl)-2,3-dihydro-1H-purin-7(6H)-yl)pr-opanoic acid (47 mg, 0.151 mmol) in DCM (4 mL) was added HOAt (19mg, 0.138 mmol) at RT. The reaction mixture was cooled underice-water bath to 0.degree. C., followed by drop-wise addition ofpyridine (0.02 mL, 0.27 mmol) and DIC (0.03 mL, 0.21 mmol) underN.sub.2 protection. The ice-water bath was removed after theaddition and the mixture was stirred at RT overnight. The reactionmixture was washed with brine. The organic layer was separated,dried over Na.sub.2SO.sub.4 and filtered. The filtrate wasconcentrated under reduced pressure and the residue was purifiedvia preparative HPLC to give(2S)--N-(6-(5-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyrazin-2-yl)py-ridin-2-yl)-2-(3-methyl-2,6-dioxo-1-(2-oxobutyl)-2,3-dihydro-1H-purin-7(6H-)-yl)propanamide (16 mg, 20.1% yield) as a white solid. Retentiontime (LC-MS): 1.842 min. MH.sup.+ 580. .sup.1H NMR (400 MHz, DMSO).delta. 11.00 (s, 1H), 8.96 (s, 1H), 8.39 (s, 1H), 8.08 (s, 1H),7.92 (s, 1H), 7.83-7.87 (m, 2H), 5.79-5.81 (m, 1H), 4.69 (s, 2H),3.94 (d, J=11.2 Hz, 2H), 3.83 (d, J=9.2 Hz, 2H), 3.46 (s, 3H), 2.76(d, J=11.2 Hz, 2H), 2.50-2.55 (m, 2H), 1.87 (d, J=7.2 Hz, 3H), 0.93(t, J=7.2 Hz, 3H).

Compound 257(2S)--N-(6-(5-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyrazin-2-yl)py-ridin-2-yl)-2-(3-methyl-2,6-dioxo-1-(2-oxopropyl)-2,3-dihydro-1H-purin-7(6-H)-yl)propanamide

##STR00790##

The title compound was prepared as described for Compound 256 in15.3% yield as a white solid. Retention time (LC-MS): 1.844 min.MH.sup.+ 566. .sup.1H NMR (400 MHz, DMSO) .delta. 11.01 (s, 1H),8.96 (s, 1H), 8.40 (s, 1H), 8.08 (s, 1H), 7.91 (s, 1H), 7.84-7.87(m, 2H), 5.79-5.81 (m, 1H), 4.69 (s, 2H), 3.93 (d, J=11.2 Hz, 2H),3.83 (d, J=9.2 Hz, 2H), 3.46 (s, 3H), 2.76 (d, J=10.8 Hz, 2H), 2.16(s, 3H), 1.87 (d, J=7.2 Hz, 3H).

Compound 258(2S)--N-(6'-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-[2,3'-bipyridin]--6-yl)-2-(1-(3-methoxy-2-oxopropyl)-3-methyl-2,6-dioxo-2,3-dihydro-1H-puri-n-7(6H)-yl)propanamide

##STR00791##

To a mixture of6'-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-[2,3'-bipyridin]-6-amine(45 mg, 0.156 mmol) and(S)-2-(1-(3-methoxy-2-oxopropyl)-3-methyl-2,6-dioxo-2,3-dihydro-1H-purin--7(6H)-yl)propanoic acid (55.7 mg, 0.172 mmol) in dichloromethane (4mL) was added HOAt (21.2 mg, 0.156 mmol) at room temperature. Thereaction mixture was cooled under ice-water bath to 0.degree. C.,and pyridine (0.025 mL, 0.312 mmol) was added drop-wise followed bydrop-wise addition of DIC (0.036 mL, 0.234 mmol) under N.sub.2protection. The ice-water bath was removed after the addition andthe mixture was stirred at room temperature overnight. Theresulting mixture was poured into ice water (5 mL) and extractedwith ethyl acetate. The organic layer was separated, dried overanhydrous Na.sub.2SO.sub.4 and filtered. The filtrate wasconcentrated under reduced pressure and the residue was purifiedvia preparative HPLC to afford(2S)--N-(6'-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)-[2,3'-bipyridin]--6-yl)-2-(1-(3-methoxy-2-oxopropyl)-3-methyl-2,6-dioxo-2,3-dihydro-1H-puri-n-7(6H)-yl)propanamide (27.9 mg, 30.0% yield) as a white solid.Retention time (LC-MS): 0.994 min. MH.sup.+ 595. .sup.1H NMR (400MHz, DMSO-d6) .delta. 10.96 (s, 1H), 8.81 (d, J=2.0 Hz, 1H), 8.40(s, 1H), 8.23-8.17 (m, 1H), 7.85-7.76 (m, 2H), 7.60 (d, J=8.4 Hz,1H), 6.60 (d, J=9.2 Hz, 1H), 5.79-5.78 (m, 1H), 4.79-4.69 (m, 2H),4.21 (s, 2H), 3.86 (d, J=10.8 Hz, 2H), 3.76 (d, J=9.2 Hz, 2H),3.46-3.44 (m, 3H), 3.29 (d, J=14.8 Hz, 3H), 2.72 (d, J=10.8 Hz,2H), 1.86 (d, J=6.8 Hz, 3H).

Compound 2592-(3-methyl-1-((5-methylisoxazol-3-yl)methyl)-2,6-dioxo-2,3-dihydro-1H-pu-rin-7(6H)-yl)-N-(2-(2-(trifluoromethyl)pyrimidin-5-yl)thiazol-4-yl)acetami-de

##STR00792##

To a solution of2-(2-(trifluoromethyl)pyrimidin-5-yl)thiazol-4-amine (40 mg, 0.16mmol) in DCM (3 mL) was added drop-wise trimethylaluminum (0.48 mL,0.48 mmol) at 0.degree. C. After the addition, the mixture waswarmed to RT and stirred for 0.5 h. Then a solution of (S)-methylethyl2-(3-methyl-1-((5-methylisoxazol-3-yl)methyl)-2,6-dioxo-2,3-dihydro-1H-pu-rin-7(6H)-yl)acetate (56 mg, 0.16 mmol) in DCM (1 mL) was addeddrop-wise and the reaction mixture was stirred at 30.degree. C.overnight. The reaction was quenched by addition of several dropsof MeOH. The mixture was concentrated under reduced pressure andthe residue was purified by chromatography (DCM:MeOH=100:1 to 40:1)to afford a crude product, which was further purified viapreparative HPLC to afford2-(3-methyl-1-((5-methylisoxazol-3-yl)methyl)-2,6-dioxo-2,3-dihydro-1H-pu-rin-7(6H)-yl)-N-(2-(2-(trifluoromethyl)pyrimidin-5-yl)thiazol-4-yl)acetami-de (25 mg, 28.4% yield) as a yellow solid. Retention time (LC-MS):1.679 min. MH.sup.+ 548. .sup.1H NMR (400 MHz, DMSO) .delta. 11.82(s, 1H), 9.52 (s, 2H), 8.14 (s, 1H), 7.85 (s, 1H), 6.10 (s, 1H),5.29 (s, 2H), 5.02 (s, 2H), 3.47 (s, 3H), 2.32 (s, 3H).

Compound 2602-(3-methyl-1-((3-methyl-1,2,4-oxadiazol-5-yl)methyl)-2,6-dioxo-2,3-dihyd-ro-1H-purin-7(6H)-yl)-N-(2-(2-(trifluoromethyl)pyrimidin-5-yl)thiazol-4-yl-)acetamide

##STR00793##

The title compound was prepared as described for Compound 259 in20.2% yield as a yellow solid. Retention time (LC-MS): 1.528 min.MH.sup.+549. .sup.1H NMR (400 MHz, DMSO) .delta. 11.83 (s, 1H),9.52 (s, 2H), 8.19 (s, 1H), 7.85 (s, 1H), 5.28 (d, J=8.8 Hz, 4H),3.48 (s, 3H), 2.29 (s, 3H).

Compound 261((2S)--N-(2'-(3-azabicyclo[3.1.0]hexan-3-yl)-2,5'-bipyrimidin-4-yl)-2-(1--(but-2-ynyl)-3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)propanamide

##STR00794##

To a solution of6-(2-(3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)pyrazin-2-amine(42.0 mg, 0.164 mmol) in DCM (4 mL) was added drop-wisetrimethylaluminum (0.66 mL, 0.657 mmol) at 0.degree. C. After theaddition, the mixture was warmed to RT and stirred for 0.5 h. Thena solution of (S)-methyl2-(1-(but-2-ynyl)-3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)propan-oate (50 mg, 0.164 mmol) in DCM (1 mL) was added drop-wise and thereaction mixture was stirred at 30.degree. C. overnight. Thereaction was quenched by addition of several drops of MeOH. Themixture was concentrated under reduced pressure and the residue waspurified by chromatography (DCM:MeOH=100:1 to 40:1) to afford acrude product, which was further purified via preparative HPLC toafford(2S)--N-(6-(2-(3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)pyrazin-2-yl)--2-(1-(but-2-ynyl)-3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)propan-amide (30 mg, 34.67% yield) as a white solid. Retention time(LC-MS): 1.534 min. MH.sup.+ 527. .sup.1H NMR (400 MHz, DMSO).delta. 11.38 (s, 1H), 9.11 (s, 1H), 9.04 (s, 2H), 8.91 (s, 1H),8.39 (s, 1H), 5.82 (m, 1H), 4.53-4.50 (m, 2H), 3.86 (d, J=11.2 Hz,2H), 3.56 (d, J=11.2 Hz, 2H), 3.47 (s, 3H), 1.88 (d, J=7.6 Hz, 3H),1.71-1.69 (m, 5H), 0.78-0.77 (m, 1H), 0.18-0.17 (m, 1H).

Compound 262(2S)-2-(1-(but-2-yn-1-yl)-3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-y-l)-N-(2-(6-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)thiazo-l-4-yl)propanamide

##STR00795##

To a solution of2-(6-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)thiazol-4-a-mine (70 mg, 0.238 mmol) in dry DCM (3 mL) was added drop-wisetrimethylaluminum (0.95 mL, 0.952 mmol) at 0.degree. C. After theaddition, the mixture was warmed to RT and stirred for 0.5 h. Thena solution of (S)-methyl2-(1-(but-2-yn-1-yl)-3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)pro-panoate (5, 72 mg, 0.238 mmol) in dry DCM (0.5 mL) was addeddrop-wise and the reaction mixture was stirred at RT overnight. Thereaction was quenched by addition of several drops of MeOH. Themixture was concentrated under reduced pressure and the residue waspurified by chromatography (DCM:MeOH=80:1) to afford a crudeproduct, which was further purified via preparative HPLC to afford(2S)-2-(1-(but-2-yn-1-yl)-3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-y-l)-N-(2-(6-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)thiazo-l-4-yl)propanamide (5.6 mg, 3.73% yield) as a white solid.Retention time (LC-MS): 1.333 min. MH.sup.+ 567. 1H NMR (400 MHz,DMSO-d6) .delta. 11.59 (s, 1H), 8.65 (s, 1H), 8.37 (s, 1H),7.99-7.96 (m, 1H), 7.43 (s, 1H), 6.61 (d, J=8.8 Hz, 1H), 5.77-5.73(m, 1H), 4.52 (d, J=2.4 Hz, 2H), 3.86 (d, J=11.2 Hz, 2H), 3.77 (d,J=10.0 Hz, 2H), 3.46 (s, 3H), 2.73 (d, J=10.8 Hz, 2H), 1.84 (d,J=7.6 Hz, 3H), 1.70 (s, 3H).

Compound 263(2S)--N-(2-(6-(3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)thiazol-4-yl)-2--(1-(but-2-yn-1-yl)-3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)propa-namide

##STR00796##

To a solution of2-(6-(3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)thiazol-4-amine(70 mg, 0.238 mmol) in dry DCM (3 mL) was added drop-wisetrimethylaluminum (1.1 mL, 1.084 mmol) at 0.degree. C. After theaddition, the mixture was warmed to RT and stirred for 0.5 h. Thena solution of (S)-methyl2-(1-(but-2-yn-1-yl)-3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)pro-panoate (82 mg, 0.271 mmol) in dry DCM (0.5 mL) was added drop-wiseand the reaction mixture was stirred at RT overnight. The reactionwas quenched by addition of several drops of MeOH. The mixture wasconcentrated under reduced pressure and the residue was purified bychromatography (DCM:MeOH=80:1) to afford a crude product, which wasfurther purified via preparative HPLC to afford(2S)--N-(2-(6-(3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)thiazol-4-yl)-2--(1-(but-2-yn-1-yl)-3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)propa-namide (3.3 mg, 2% yield) as a pale yellow solid. Retention time(LC-MS): 1.273 min. MH.sup.+ 531. .sup.1H NMR (400 MHz, DMSO-d6).delta. 11.58 (s, 1H), 8.62 (s, 1H), 8.36 (s, 1H), 7.94-7.91 (m,1H), 7.40 (s, 1H), 6.56 (d, J=8.8 Hz, 1H), 5.75-5.73 (m, 1H),4.53-4.51 (m, 2H), 3.70 (d, J=10.8 Hz, 2H), 3.45 (d, J=10.0 Hz,5H), 1.84 (d, J=7.2 Hz, 3H), 1.72-1.70 (m, 5H), 0.78-0.76 (m, 1H),0.20-0.17 (m, 1H).

Compound 264(2S)--N-(2-(5-(3-azabicyclo[3.1.0]hexan-3-yl)pyrazin-2-yl)thiazol-4-yl)-2--(1-(3-methoxy-2-oxopropyl)-3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)--yl)propanamide

##STR00797##

To a mixture of2-(5-(3-azabicyclo[3.1.0]hexan-3-yl)pyrazin-2-yl)thiazol-4-amine(40 mg, 0.155 mmol) and(S)-2-(1-(3-methoxy-2-oxopropyl)-3-methyl-2,6-dioxo-2,3-dihydro-1H-purin--7(6H)-yl)propanoic acid (2, 56 mg, 0.171 mmol) in DCM (3 mL) wasadded HOAt (21 mg, 0.155 mmol) at RT. The reaction mixture wascooled under ice-water bath to 0.degree. C., and pyridine (0.025mL, 0.310 mmol) was added drop-wise followed by drop-wise additionof DIC (0.036 mL, 0.233 mmol) under N.sub.2 protection. Theice-water bath was removed after the addition and the mixture wasstirred at RT overnight. The reaction mixture was poured into icewater (5 mL) and extracted with DCM. The organic layer wasseparated, dried over Na.sub.2SO.sub.4 and filtered. The filtratewas concentrated under reduced pressure and the residue waspurified via preparative HPLC to afford(2S)--N-(2-(5-(3-azabicyclo[3.1.0]hexan-3-yl)pyrazin-2-yl)thiazol-4-yl)-2--(1-(3-methoxy-2-oxopropyl)-3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)--yl)propanamide (6.5 mg, 7.4% yield) as a yellow solid. Retentiontime (LC-MS): 1.485 min. MH.sup.+ 566. .sup.1H NMR (400 MHz,DMSO-d6) .delta. 11.58 (s, 1H), 8.66 (s, 1H), 8.39 (s, 1H), 8.01(s, 1H), 7.47 (s, 1H), 5.76-5.70 (m, 1H), 4.74 (s, 2H), 4.21 (s,2H), 3.77 (d, J=10.8 Hz, 2H), 3.53 (d, J=10.4 Hz, 2H), 3.50-3.48(m, 3H), 3.31 (s, 3H), 1.84 (d, J=7.6 Hz, 3H), 1.75 (d, J=4.4 Hz,2H), 0.85-0.78 (m, 1H), 0.20 (d, J=4.0 Hz, 1H)

Compound 265(2S)--N-(2-(2-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)-thiazol-4-yl)-2-(1-(3-methoxy-2-oxopropyl)-3-methyl-2,6-dioxo-2,3-dihydro--1H-purin-7(6H)-yl)propanamide

##STR00798##

To a mixture of2-(2-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)thiazol-4--amine (50 mg, 0.169 mmol) and(S)-2-(1-(3-methoxy-2-oxopropyl)-3-methyl-2,6-dioxo-2,3-dihydro-1H-purin--7(6H)-yl)propanoic acid (2, 60.3 mg, 0.186 mmol) in DCM (3 mL) wasadded HOAt (23 mg, 0.169 mmol) at RT. The reaction mixture wascooled under ice-water bath to 0.degree. C., and pyridine (0.027mL, 0.338 mmol) was added drop-wise followed by drop-wise additionof DIC (0.039 mL, 0.254 mmol) under N.sub.2 protection. Theice-water bath was removed after the addition and the mixture wasstirred at RT overnight. The reaction mixture was poured into icewater (5 mL) and extracted with DCM. The organic layer wasseparated, dried over Na.sub.2SO.sub.4 and filtered. The filtratewas concentrated under reduced pressure and the residue waspurified via preparative HPLC to afford(2S)--N-(2-(2-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)-thiazol-4-yl)-2-(1-(3-methoxy-2-oxopropyl)-3-methyl-2,6-dioxo-2,3-dihydro--1H-purin-7(6H)-yl)propanamide (28.7 mg, 28.2% yield) as a whitesolid. Retention time (LC-MS): 1.979 min. MH.sup.+ 602. .sup.1H NMR(400 MHz, DMSO-d6) .delta. 11.62 (s, 1H), 8.85 (s, 2H), 8.39 (s,1H), 7.49 (s, 1H), 5.71-5.69 (m, 1H), 4.74 (s, 2H), 4.22 (s, 2H),3.98 (d, J=12.0 Hz, 2H), 3.85 (d, J=10.4 Hz, 2H), 3.51 (s, 3H),3.33 (d, J=13.2, 3H), 2.71 (d, J=10.8, 2H), 1.84 (d, J=7.2,3H).

Compound 266(2S)--N-(6-(5-(3-azabicyclo[3.1.0]hexan-3-yl)pyrazin-2-yl)pyridin-2-yl)-2--(1-(3-methoxy-2-oxopropyl)-3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)--yl)propanamide

##STR00799##

To a solution ofS)-2-(1-(3-methoxy-2-oxopropyl)-3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7-(6H)-yl)propanoic acid (61 mg, 0.2 mmol) and6-(5-(3-azabicyclo[3.1.0]hexan-3-yl)pyrazin-2-yl)pyridin-2-amine(50 mg, 0.20 mmol) in DCM (4 mL) was added HOAt (30 mg, 0.22 mmol)at RT. The reaction mixture was cooled under ice-water bath to0.degree. C., and pyridine (0.03 mL, 0.40 mmol) was added drop-wisefollowed by drop-wise addition of DIC (0.04 mL, 0.30 mmol) underN.sub.2 protection. The ice-water bath was removed after theaddition and the mixture was stirred at 30.degree. C. overnight.The reaction mixture was washed with water (5 mL) and saturated aq.NH.sub.4Cl (5 mL), dried over Na.sub.2SO.sub.4 and filtered. Thefiltrate was concentrated under reduced pressure and the residuewas purified via preparative HPLC to afford(2S)--N-(6-(5-(3-azabicyclo[3.1.0]hexan-3-yl)pyrazin-2-yl)pyridin-2-yl)-2--(1-(3-methoxy-2-oxopropyl)-3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)--yl)propanamide (18.3 mg, 15.2% yield) as a white solid. Retentiontime (LC-MS): Retention 1.539 min. MH.sup.+ 560. .sup.1H NMR.delta. 10.99 (s, 1H), 8.93 (d, J=0.8 Hz, 1H),8.40 (s, 1H), 8.03(s, J=0.8 Hz, 1H), 7.83 (m, 3H), 5.80 (d, J=6.0 Hz, 1H), 4.75 (s,J=3.2 Hz, 2H), 4.21 (s, 2H), 3.78 (d, J=10.4 Hz, 2H), 3.52 (s, 2H),3.46 (s, 3H), 3.32 (s, 3H), 1.87 (d, J=7.2 Hz, 3H), 1.74 (t, J=3.6Hz, 2H), 0.77 (m, 1H),0.20 (m, 1H).

Compound 267(2S)-2-(1-(but-2-ynyl)-3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)--N-(2-(2-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)thiazol--4-yl)propanamide

##STR00800##

To a solution of2-(2-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)thiazol-4--amine (50 mg, 0.17 mmol) in DCM (8 mL) was added drop-wisetrimethylaluminum (0.68 mL, 0.68 mmol) at 0.degree. C. After theaddition, the mixture was warmed to RT and stirred for 0.5 h. Thena solution of (S)-methyl2-(1-(but-2-ynyl)-3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)propan-oate (51.52 mg, 0.17 mmol) in DCM (2 mL) was added drop-wise andthe reaction mixture was stirred at RT overnight. The reaction wasquenched by addition of several drops of MeOH. The mixture wasconcentrated under reduced pressure and the residue was purifiedvia Pre.HPLC to give(2S)-2-(1-(but-2-ynyl)-3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)--N-(2-(2-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-5-yl)thiazol--4-yl)propanamide (5 mg, 5.2% yield) as a yellow solid. Retentiontime (LC-MS): 2.285 min. MH.sup.+ 568. .sup.1H NMR (400 MHz, DMSO).delta. 11.66 (s, 1H), 8.86 (s, 2H), 8.37 (s, 1H), 7.50 (s, 1H),5.74 (q, J=6.8 Hz, 1H), 4.53-4.52 (m, 2H), 4.00-3.97 (m, 2H),3.87-3.84 (d, J=11.6 Hz, 2H), 3.46 (s, 3H), 2.73-2.71 (m, J=10.8Hz, 2H), 1.85-1.83 (d, J=7.6 Hz, 3H), 1.71 (s, 3H).

Compound 268(S)-2-(1-(but-2-ynyl)-3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)-N--(2-(2-((S)-2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidin-5-yl)thiazol-4-yl-)propanamide

##STR00801##

To a solution of(S)-2-(2-(2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidin-5-yl)thiazol-4-ami-ne (50 mg, 0.16 mmol) in DCM (8 mL) was added drop-wisetrimethylaluminum (0.63 mL, 0.63 mmol) at 0.degree. C. After theaddition, the mixture was warmed to RT and stirred for 0.5 h. Thena solution of (S)-methyl2-(1-(but-2-ynyl)-3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)propan-oate (48.25 mg, 0.16 mmol) in DCM (2 mL) was added drop-wise andthe reaction mixture was stirred at RT overnight. The reaction wasquenched by addition of several drops of MeOH. The mixture wasconcentrated under reduced pressure and the residue was purifiedvia Prep HPLC to give(S)-2-(1-(but-2-ynyl)-3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)-yl)-N--(2-(2-((S)-2-(trifluoromethyl)pyrrolidin-1-yl)pyrimidin-5-yl)thiazol-4-yl-)propanamide (10 mg, 10.7% yield) as a yellow solid. Retention time(LC-MS): 2.034 min. MH.sup.+588. .sup.1H NMR (400 MHz, DMSO).delta. 11.67 (s, 1H), 8.95 (s, 1H), 8.37 (s, 1H), 7.55 (s, 1H),5.75 (s, 1H), 5.12-5.08 (m, 1H), 4.51 (m, 2H), 3.71 (m, 2H), 3.47(s, 3H), 2.25-2.04 (m, 4H), 1.85 (d, J=7.2 Hz, 3H), 1.71 (s,3H).

Compound 269(2S)--N-(2-(6-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)th-iazol-4-yl)-2-(1-(3-methoxy-2-oxopropyl)-3-methyl-2,6-dioxo-2,3-dihydro-1H--purin-7(6H)-yl)propanamide

##STR00802##

To a solution of2-(6-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)thiazol-4-a-mine (25 mg, 0.085 mmol) and(S)-2-(1-(3-methoxy-2-oxopropyl)-3-methyl-2,6-dioxo-2,3-dihydro-1H-purin--7(6H)-yl)propanoic acid (30.31 mg, 0.094 mmol) in DCM (10 mL) wasadded HOAT (13.89 mg, 0.10 mmol) at RT. The reaction mixture wascooled under ice-water bath to 0.degree. C., followed by slowdropwise addition of pyridine (0.01 mL, 0.17 mmol) and DIC (0.02mL, 0.13 mmol) under N.sub.2 protection. The ice-water bath wasremoved after the addition and the mixture was stirred at RT.overnight. The reaction mixture was washed with water (10 mL), and.aq. HCl (10 mL, 0.5M). The organic layer was separated, dried overNa.sub.2SO.sub.4 and filtered. The filtrate was concentrated underreduced pressure and the residue was purified via Prep-HPLC to give(2S)--N-(2-(6-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)th-iazol-4-yl)-2-(1-(3-methoxy-2-oxopropyl)-3-methyl-2,6-dioxo-2,3-dihydro-1H--purin-7(6H)-yl)propanamide (20 mg, 39.1% yield) as a yellow solid.Retention time (LC-MS): 2.050 min. MH.sup.+ 601. .sup.1H NMR (400MHz, DMSO) .delta. 11.55 (s, 1H), 8.64 (d, J=2.4 Hz, 1H), 8.39 (s,1H), 7.97 (m, 1H), 7.42 (s, 1H), 6.60 (d, J=9.2 Hz, 1H), 5.71 (m,1H), 4.74 (m, 2H), 4.21 (s, 2H), 3.85 (d, J=10.8 Hz, 2H), 3.76 (d,J=9.2 Hz, 2H), 3.46 (s, 3H), 3.31 (s, 3H), 2.72 (m, 2H), 1.84 (d,J=7.2 Hz, 3H).

Compound 270(2S)--N-(2-(5-(3-azabicyclo[3.1.0]hexan-3-yl)pyrazin-2-yl)thiazol-4-yl)-2--(3-methyl-2,6-dioxo-1-(2-oxobutyl)-2,3-dihydro-1H-purin-7(6H)-yl)propanam-ide

##STR00803##

To a solution of2-(5-(3-azabicyclo[3.1.0]hexan-3-yl)pyrazin-2-yl)thiazol-4-amine(40 mg, 0.15 mmol) and(S)-2-(3-methyl-2,6-dioxo-1-(2-oxobutyl)-2,3-dihydro-1H-purin-7(6H)-yl)pr-opanoic acid (47.5 mg, 0.15 mmol) in dichloromethane (4 mL) wasadded HOAt (20.9 mg, 0.15 mmol) at room temperature. The reactionmixture was cooled under ice-water bath to 0.degree. C., andpyridine (24.3 mg, 0.32 mmol) was added drop-wise followed bydrop-wise addition of DIC (29.0 mg, 0.23 mmol) under N.sub.2protection. The ice-water bath was removed after the addition andthe mixture was stirred at 30.degree. C. overnight. The resultingmixture was washed with water (3 mL) and saturated aq. NH.sub.4Cl(3 mL). The organic layer was separated, dried over anhydrousNa.sub.2SO.sub.4 and filtered. The filtrate was concentrated underreduced pressure and the residue was purified via preparative HPLCto afford(2S)--N-(2-(5-(3-azabicyclo[3.1.0]hexan-3-yl)pyrazin-2-yl)thiazol--4-yl)-2-(3-methyl-2,6-dioxo-1-(2-oxobutyl)-2,3-dihydro-1H-purin-7(6H)-yl)p-ropanamide (25.1 mg, 29.5% yield) as yellow solid. Retention time(LC-MS): 1.637 min. MH.sup.+ 550. .sup.1H NMR (400 MHz, DMSO).delta. 11.57 (s, 1H), 8.66 (s, 1H), 8.38 (s, 1H), 8.01 (s, 1H),7.47 (s, 1H), 5.69-5.71 (m, 1H), 4.69 (s, 2H), 3.76 (d, J=10.8 Hz,2H),3.53 (d, J=10.4 Hz, 2H), 3.45 (s, 3H), 2.52-2.56 (m, 2H), 1.84(d, J=7.2 Hz, 3H), 1.71-1.76 (m, 2H), 0.94 (t, J=7.2 Hz, 3H),0.77-0.80 (m, 1H), 0.18-0.21 (m, 1H).

Compound 271(2S)--N-(6-(6-(3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)pyrazin-2-yl)-2--(1-(3-methoxy-2-oxopropyl)-3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)--yl)propanamide

##STR00804##

To a solution of6-(6-(3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)pyrazin-2-amine(50 mg, 0.197 mmol) and(S)-2-(1-(3-methoxy-2-oxopropyl)-3-methyl-2,6-dioxo-2,3-dihydro-1H-purin--7(6H)-yl)propanoic acid (64 mg, 0.197 mmol) in dichloromethane (4mL) was added HOAt (26.8 mg, 0.197 mmol) at room temperature. Thereaction mixture was cooled under ice-water bath to 0.degree. C.,and pyridine (31 mg, 0.394 mmol) was added drop-wise followed bydrop-wise addition of DIC (37 mg, 0.296 mmol) under N.sub.2protection. The ice-water bath was removed after the addition andthe mixture was stirred at 30.degree. C. overnight. The resultingmixture was washed with water (3 mL) and saturated aq. NH.sub.4Cl(3 mL). The organic layer was separated, dried over anhydrousNa.sub.2SO.sub.4 and filtered. The filtrate was concentrated underreduced pressure and the residue was purified via preparative HPLCto afford(2S)--N-(6-(6-(3-azabicyclo[3.1.0]hexan-3-yl)pyridin-3-yl)pyrazin-2-yl)-2--(1-(3-methoxy-2-oxopropyl)-3-methyl-2,6-dioxo-2,3-dihydro-1H-purin-7(6H)--yl)propanamide (27.8 mg, 25.2% yield) as light yellow solid.Retention time (LC-MS): 0.735 min. MH.sup.+ 560. .sup.1H NMR (400MHz, DMSO) .delta. 11.31 (s, 1H), 9.04 (s, 1H), 8.88 (s, 1H),8.84-8.85 (d, J=2.4 Hz, 1H), 8.41 (s, 1H), 8.17-8.20 (dd, J=8.8 Hz,2.4 Hz, 1H), 6.59-6.61 (d, J=8.8 Hz, 1H), 5.78-5.80 (m, 1H),4.73-4.74 (d, J=2 Hz, 2H), 4.20 (s, 2H), 3.71-3.73 (d, J=10.4 Hz,2H), 3.46 (s, 3H), 3.44-3.46 (d, J=10.4 Hz, 2H), 3.30 (s, 3H),1.87-1.89 (d, J=7.2 Hz, 2H), 1.70-1.72 (m, 2H), 0.74-0.79 (m, 2H),0.17-0.20 (m, 1H).

Compound 272(2S)--N-(6-(5-(6,6-difluoro-3-azabicyclo[3.1.0]hexan-3-yl)pyrazin-2-yl)py-ridin-2-yl)-2-(3-methyl-2,6-dioxo-1-(2-oxopropyl)-2,3-dihydro-1H-purin-7(6-H)-yl)propanamide

##STR00805##

The title compound was prepared as Compound 256, 30.4% yield as awhite solid. Retention time (LC-MS): 1.555 min. MH.sup.+ 596..sup.1H NMR (400 MHz, DMSO) .delta. 11.02 (s, 1H), 8.96 (s, 1H),8.41 (s, 1H), 8.08 (s, 1H), 7.92 (s, 1H), 7.83-7.87 (m, 2H),5.79-5.81 (m, 1H), 4.74 (s, 2H), 4.21 (s, 2H), 3.93 (d, J=10.8 Hz,2H), 3.83 (d, J=9.2 Hz, 2H), 3.46 (s, 3H), 3.31 (s, 3H), 2.76 (d,J=10.4 Hz, 2H), 1.87 (d, J=7.2 Hz, 3H).

EQUIVALENTS

The disclosures of each and every patent, patent application, andpublication cited herein are hereby incorporated herein byreference in their entirety. While this invention has beendisclosed with reference to specific aspects, it is apparent thatother aspects and variations of this invention may be devised byothers skilled in the art without departing from the true spiritand scope of the invention. The appended claims are intended to beconstrued to include all such aspects and equivalentvariations.

Any patent, publication, or other disclosure material, in whole orin part, that is said to be incorporated by reference herein isincorporated herein only to the extent that the incorporatedmaterial does not conflict with existing definitions, statements,or other disclosure material set forth in this disclosure. As such,and to the extent necessary, the disclosure as explicitly set forthherein supersedes any conflicting material incorporated herein byreference.

While this invention has been particularly shown and described withreferences to preferred embodiments thereof, it will be understoodby those skilled in the art that various changes in form anddetails may be made therein without departing from the scope of theinvention encompassed by the appended claims.

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References

• webmd.com/arthritis/about-inflammation#2