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Title:
PYRROLIDINYL UREA, THIOUREA, GUANIDINE AND CYANOGUANIDINE COMPOUNDS AS TRKA KINASE INHIBITORS
Document Type and Number:
WIPO Patent Application WO/2014/078378
Kind Code:
A1
Abstract:
Compounds of Formula (I): or stereoisomers, tautomers, or pharmaceutically acceptable salts, or solvates or prodrugs thereof, where R1, R2, Ra, Rb, Rc, Rd, X, Ring B, and Ring C are as defined herein, and wherein Ring B moiety and the NH-C(=X)-NH moiety are in the trans configuration, are inhibitors of TrkA kinase and are useful in the treatment of diseases which can be treated with a TrkA kinase inhibitor such as pain, cancer, inflammation/inflammatory diseases, neurodegenerative diseases, certain infectious diseases, Sjogren's syndrome, endometriosis, diabetic peripheral neuropathy, prostatitis and pelvic pain syndrome.

Inventors:
ALLEN SHELLEY (US)
ANDREWS STEVEN WADE (US)
BLAKE JAMES F (US)
BRANDHUBER BARBARA J (US)
CONDROSKI KEVIN RONALD (US)
HAAS JULIA (US)
JIANG YUTONG (US)
KERCHER TIMOTHY (US)
KOLAKOWSKI GABRIELLE R (US)
WINSKI SHANNON L (US)
Application Number:
PCT/US2013/069838
Publication Date:
May 22, 2014
Filing Date:
November 13, 2013
Export Citation:
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Assignee:
ARRAY BIOPHARMA INC (US)
ALLEN SHELLEY (US)
ANDREWS STEVEN WADE (US)
BLAKE JAMES F (US)
BRANDHUBER BARBARA J (US)
CONDROSKI KEVIN RONALD (US)
HAAS JULIA (US)
JIANG YUTONG (US)
KERCHER TIMOTHY (US)
KOLAKOWSKI GABRIELLE R (US)
WINSKI SHANNON L (US)
International Classes:
C07D403/12; A61K31/4025; A61P13/06; A61P13/08; A61P25/28; A61P27/02; A61P29/00; A61P35/00; C07D401/12; C07D401/14; C07D413/12; C07D417/12; C07D417/14
Domestic Patent References:
WO2010033941A12010-03-25
WO2012158413A22012-11-22
Foreign References:
EP2336105A12011-06-22
Other References:
WANG T ET AL: "Trk kinase inhibitors as new treatments for cancer and pain", EXPERT OPINION ON THERAPEUTIC PATENTS, INFORMA HEALTHCARE, GB, vol. 19, no. 3, 1 March 2009 (2009-03-01), pages 305 - 319, XP002557234, ISSN: 1354-3776, DOI: 10.1517/13543770902721261
Attorney, Agent or Firm:
HARRIS, Robert, J. et al. (7900 International DriveSuite 67, Bloomington MN, US)
Download PDF:
Claims:
What is claimed is:

1. A compound of Formula I:

I

or stereoisomers, tautomers, or pharmaceutically acceptable salts, solvates or prodrugs thereof, wherein:

Ring B and the NH-C(=X)-NH moiety are in the trans configuration;

Ra, Rb, Rc and Rd are independently selected from H and (l-3C)alkyl,

or Rc and Rd are independently selected from H and (l-3C)alkyl, and Ra and Rb together with the atom to which they are attached form a cyclopropyl ring;

X is O, S, NH or N-CN;

R1 is (1-3C alkoxy)(l-6C)alkyl, (trifluoromethoxy)(l-6C)alkyl, (1-3C sulfanyl)(l- 6C)alkyl, monofluoro(l-6C)alkyl, difluoro(l-6C)alkyl, trifluoro(l-6C)alkyl, tetrafluoro(2- 6C)alkyl, pentafluro(2-6C)alkyl, cyano(l-6C)alkyl, aminocarbonyl(l-6C)alkyl, hydroxy(l- 6C)alkyl, dihydroxy(2-6C)alkyl, (l-6C)alkyl, (l-3Calkylamino)(l-3C)alkyl, (1-4C alkoxycarbonyl)(l-6C)alkyl, amino(l-6C)alkyl, hydroxy(l-3C alkoxy)(l-6C)alkyl, di(l-3C alkoxy)(l-6C)alkyl, (1-3C alkoxy)trifluoro(l-6C)alkyl, hydroxytrifluoro(l-6C)alkyl, (1-4C alkoxycarbonyl)(l-3C alkoxy)(l-6C)alkyl, or hydroxycarbonyl(l-3C alkoxy)(l-6C)alkyl;

R2 is H, F, or OH;

Ring B is Ar1 or hetAr1;

Ar1 is phenyl optionally substituted with one or more substituents independently selected from halogen, CF3, CF30-, (l-4C)alkoxy, hydroxy(l-4C)alkyl, (l-6C)alkyl and CN; hetAr1 is a 5-6 membered heteroaryl having 1-3 ring heteroatoms independently selected from N, S and O, and optionally substituted with one or more groups independently selected from (l-6C)alkyl, halogen, OH, CF3, NH2 and hydroxy(l-2C)alkyl;

Ring C is selected from formulas C-l through C-13:

C-13

R is H, NH2, CN, halogen, (l-3C)alkyl [optionally substituted with 1 to 3 fluoros],

H2NC(=0)-, (l-3Calkyl)NHC(=0)-, di(l-3Calkyl)NHC(=OK hydroxy(l-3C)alkyl, CH3OCH2CH2, (3-4C)cycloalkyl or (l-3C)alkoxy;

R3a is H, (l-3C)alkyl, CF3CH2CH2, HCF2CH2CH2, H2FCCH2CH2, CF3CH2, HOCH2CH2, MeOCH2CH2, or (3-4C)cycloalkyl;

R4 is H, OH, (l-6C)alkyl [optionally substituted with 1-5 fluoros], cyano(l-6C)alkyl, hydroxy(l-6C)alkyl, dihydroxy(2-6C)alkyl, (1-3C alkoxy)(l-6C)alkyl, amino(l-6C)alkyl, aminocarbonyl( 1 -6C)alkyl, ( 1 -3C)alkylsulfonamido( 1 -6C)alkyl, sulfamido( 1 -6C)alkyl, hydroxycarbonyl(l-6C)alkyl, hetAr3(l-6C)alkyl, Ar3(l-6C)alkyl, (l-6C)alkoxy [optionally substituted with 1-5 fluoros], cyano(l-6C)alkoxy, hydroxy(l-6C)alkoxy, dihydroxy(2- 6C)alkoxy, amino(2-6C)alkoxy, hydroxyl-carbonyl(l-6C)alkoxy, hetCyc (l-6C)alkoxy, hetAr3(l-6C)alkoxy, Ar3(l-6C)alkoxy, (1-4C alkoxy)(l-6C)alkoxy, (1-3C alkylsulfonyl)(l- 6C)alkoxy, (3-6C)cycloalkyl [optionally substituted with F, OH, (1-6C alkyl), (1-6C) alkoxy, or (1-3C alkoxy)(l-6C)alkyl], hetAr4, hetAr4-0-, Ar4, hetCyc2(0)CH2-, (1-4C alkoxycarbonyl)( 1 -6C)alkoxy, hydroxycarbonyl( 1 -6C)alkoxy, aminocarbonyl( 1 -6C)alkoxy, hetCyc2C(=0)( 1 -6C)alkoxy, hydroxy( 1 -3 C alkoxy)( 1 -6C)alkoxy, hydroxytrifluoro( 1 - 6C)alkoxy, (l-3C)alkylsulfonamido(l-6C)alkoxy, (l-3C)alkylamido(l-6C)alkoxy, di(l-3C alkyl)amino-carboxy, hetCyc C(=0)0-, hydroxydifluoro(l-6C)alkyl, (1-4C alkylcarboxy)(l- 6C)alkyl, (l-6C)alkoxycarbonyl, hydroxylcarbonyl, aminocarbonyl, (1-3C alkoxy)aminocarbonyl, hetCyc , halogen, CN, trifluoromethylsulfonyl, N-(1-3C alkyl)oxadiazolonyl, or hetAr5;

R4a is H, (l-6C)alkyl, CF3CH2CH2, HCF2CH2CH2, H2FCCH2CH2, CF3CH2„ cyano(l- 6C)alkyl, hydroxy(l-6C)alkyl, dihydroxy(2-6C)alkyl, (1-3C alkoxy)(l-6C)alkyl, amino(l- 6C)alkyl, aminocarbonyl(l-6C)alkyl, (l-3C)alkylsulfonamido(l-6C)alkyl, sulfamido(l- 6C)alkyl, hydroxycarbonyl(l-6C)alkyl, hetAr3(l-6C)alkyl, Ar3(l-6C)alkyl, (3-6C)cycloalkyl [optionally substituted with F, OH, (1-6C alkyl), (1-6C) alkoxy, or (1-3 C alkoxy)(l-6C)alkyl], hetAr4, Ar4, hydroxydifluoro(l-6C)alkyl, (1-4C alkylcarboxy)(l-6C)alkyl, hetCyc3, N-(1-3C alkyl)oxadiazolonyl, or hetAr5;

hetCyc is a 4-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O and optionally substituted with 1-2 groups independently selected from (l-6C)alkyl, (1-4C alkylcarboxy)(l-6C)alkyl, and (l-6C)acyl;

hetCyc is a 4-7 membered heterocycle having 1-2 ring heteroatoms independently selected from N and O and optionally substituted with one or more substituents independently selected from F, CN, (l-6C)alkyl, trifluoro(l-6C)alkyl, hydroxy(l-6C)alkyl, (1-3C alkoxy)(l- 6C)alkyl, (l-6C)acyl-, (l-6C)alkylsulfonyl, trifluoromethylsulfonyl and (1-4C alkoxy)carbonyl;

hetAr is a 5-membered heteroaryl ring having 1-3 ring atoms independently selected from N, O and S and optionally substituted with (l-6C)alkyl;

Ar is phenyl optionally substituted with (l-4C)alkoxy;

hetAr4 is independently a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, S and O and optionally substituted with one or more substituents independently selected from (l-6C)alkyl [optionally substituted with 1-3 fluoros], halogen, CN, hydroxy(l-6C)alkyl, (3-6C)cycloalkyl, (3-6C cycloalkyl)CH2- (3-6C cycloalkyl)C(=0)-, (1-3C alkoxy)(l-6C)alkyl, (l-6C)alkoxy, (l-6C)alkylsulfonyl, NH2, (1-6C alkyl)amino, di(l-6C alkyl)amino, (1-3C trifluoroalkoxy), fluoro(l-6C alkyl)amino, difluoro(l-6C alkyl)amino, trifluoro(l-6C alkyl)amino, and (3-4C cycloalkyl)amino;

hetAr5 is a group selected from the structures:

where Rz is (3-4C)cycloalkyl or (l-3C)alkyl (optionally substituted with 1-3 fluoros), wherein each of said hetAr5 groups is optionally further substituted with one or more groups independently selected from F and (l-3C)alkyl optionally substituted with 1-3 fluoros;

Ar4 is phenyl optionally substituted with one or more groups independently selected from (l-6C)alkyl, halogen, CN, CF3, CF30-, (l-6C)alkoxy, (l-6Calkyl)OC(=0)-, aminocarbonyl, (l-6C)alkylthio, hydroxy(l-6C)alkyl, (1-6C alkyl)S02-, HOC(=0)- and (1-3C alkoxy)(l-3C alkyl)OC(=0)-;

R5 is H, (l-6C)alkyl [optionally substituted with 1-5 fluoros], halogen, CN, (1- 4C)alkoxy, hydroxy(l-4C)alkyl, (1-3C alkoxy)(l-4C)alkyl, (1-4C alkyl)OC(=0)-, (1- 6C)alkylthio, (3-4C)cycloalkyl, amino, aminocarbonyl, trifluoro(l-3C alkyl)amido, or phenyl [optionally substituted with one or more groups independently selected from halogen, (1- 6C)alkyl and (l-6C)alkoxy];

R5a is H, (l-6C)alkyl, CF3CH2CH2, HCF2CH2CH2, H2FCCH2CH2, CF3CH2, hydroxy(l-4C)alkyl, (1-3C alkoxy)(l-4C)alkyl, (3-4C)cycloalkyl, or phenyl [optionally substituted with one or more groups independently selected from halogen, (l-6C)alkyl and (1- 6C)alkoxy];

R is (l-6C)alkyl, (3-6C)cycloalkyl, or phenyl [optionally substituted with one or more groups independently selected from halogen, (l-6C)alkyl, (l-6C)alkoxy, (3- 4C)cycloalkyl, amino, aminocarbonyl, and trifluoro(l-3C)alkylamido];

R8a and R8b are independently H, halogen, CN, NH2, (l-6C)alkyl [optionally substituted with 1-5 fluoros], (l-6C)alkoxy, (1-3C alkoxy)(l-6C)alkyl, (1-3C alkoxy)(l-6C)alkoxy, (1-6C alkyl)sulfonyl, (3-6C cycloalkyl)sulfonyl, (3-4C)cycloalkyl, amino, (l-6Calkyl)NH-, phenyl [optionally substituted with (1-6C alkyl)S02-] or hetAr4, wherein only one of R8a and R8b can be phenyl [optionally substituted with (1-6C alkyl)S02-] or hetAr4;

R9 is H, (l-6C)alkyl, CF3CH2-, CF3CH2CH2-, (l-3Calkoxy)(l-6C)alkyl or (3- 4C)cycloalkyl; and

R10 is (3-6C)cycloalkyl or phenyl [optionally substituted with one or more substituents independently selected from halogen, (l-6C)alkyl, (l-6C)alkoxy, (3-4C)cycloalkyl, amino, aminocarbonyl and trifluoro(l-3C alkyl)amido].

2. A compound according to claim 1 , wherein X is O.

3. A compound according to claim 1 , wherein X is S.

4. A compound according to any one of claims 1-3, wherein R1 is selected from (1-3C alkoxy)(l-6C)alkyl, difluoro(l-6C)alkyl, and trifluoro(l-6C)alkyl.

5. A compound according to claim 4, wherein R1 is (1-3C alkoxy)(l-6C)alkyl.

6. A compound according to any one of claims 1-5, wherein Ring B is Ar1.

7. The compound of claim 6, wherein Ar1 is phenyl optionally substituted with one or more halogens.

8. A compound according to any one of claims 1-5, wherein Ring B is hetAr1.

9. A compound according to claim 8, wherein Ring B is pyridyl optionally substituted with 1-2 groups independently selected from (l-6C)alkyl and halogen.

10. A compound according to any one of claims 1-9, wherein Ring C is formula C- 1, C-2, C-3, C-4, C-5, C-6 or C-13.

11. A compound according to claim 10, wherein Ring C is formula C-l or C-2.

12. A compound according to claim 11 , wherein

R3 is (l-3C)alkyl [optionally substituted with 1 to 3 fluoros] or H2NC(=0)-; and R5 is phenyl [optionally substituted with one or more groups independently selected from halogen, (l-6C)alkyl and (l-6C)alkoxy].

13. A compound according to claim 10, wherein Ring C is formula C-3, C-4, C-5, C-6 or C-13.

14. A compound according to claim 13, wherein:

R3a is (l-3C)alkyl;

R4 is selected from ( 1 -6C)alkyl, hydroxy( 1 -6C)alkyl, ( 1 -6C)alkoxycarbonyl, aminocarbonyl, hetAr4, Ar4, and hetAr5;

R4a is selected from (l-6C)alkyl, hydroxy(l-6C)alkyl, hetAr4, Ar4, and hetAr5;

R5 is halogen or (l-6C)alkyl [optionally substituted with 1-5 fluoros] or phenyl [optionally substituted with one or more groups independently selected from halogen, (1- 6C)alkyl and (l-6C)alkoxy]; and

R5a is (l-6C)alkyl, CF3CH2CH2, HCF2CH2CH2, H2FCCH2CH2, CF3CH2, or phenyl [optionally substituted with one or more groups independently selected from halogen, (l-6C)alkyl and (l-6C)alkoxy].

15. A compound according to claim 14, wherein R4 or R4a is (l-6C)alkyl, hydroxy(l-6C)alkyl or phenyl.

16. A compound according to any one of claims 1-9, wherein Ring C is formula C-

7.

17. A compound according to claim 16, wherein: R3a is (l-3C)alkyl, CF3CH2CH2, HCF2CH2CH2, H2FCCH2CH2 or CF3CH2; R4a is (l-6C)alkyl; and

R5 is phenyl optionally substituted with one or more groups independently selected from halogen, (l-6C)alkyl and (l-6C)alkoxy.

18. A compound according to any one of claims 1-9, wherein Ring C is formula C- 8 or C-9.

19. A compound according to claim 18, wherein R7 is (l-6C)alkyl or phenyl [optionally substituted with one or more groups independently selected from F, CI, methoxy, ethoxy, cyclopropyl, NH2, NH2C(=0)- and CF3C(=0)NH-].

20. A compound according to claim 19, wherein:

R8a is H, halogen, CN, NH2, (l-6C)alkyl [optionally substituted with 1-5 fluoros], (l-6C)alkoxy, (1-3C alkoxy)(l-6C)alkyl, (1-3C alkoxy)(l-6C)alkoxy, (1-6C alkyl)sulfonyl, (3-6C cycloalkyl)sulfonyl, (3-4C)cycloalkyl, amino, (l-6Calkyl)NH-, phenyl [optionally substituted with (1-6C alkyl)S02-] or hetAr4; and

R8b is H.

21. A compound according to claim 20, wherein:

R8a is H, halogen, (l-6C)alkyl [optionally substituted with 1-5 fluoros], (1- 6C)alkoxy, (1-3C alkoxy)(l-6C)alkoxy, (1-6C alkyl)sulfonyl, (3-6C cycloalkyl)sulfonyl, phenyl or hetAr4; and

hetAr4 is a 6-membered heteroaryl having 1-2 ring nitrogen atoms and optionally substituted with one or more groups independently selected from (l-6C)alkyl [optionally substituted with 1-3 fluoros], halogen, (1-6C alkyl)amino, fluoro(l-6C alkyl)amino, difluoro(l-6C alkyl)amino, trifluoro(l-6C alkyl)amino, and (3-4C cycloalkyl)amino.

22. A compound according to claim 21, wherein R8a is H, CI, Br, methyl, ethyl, isopropyl, methoxy, ethoxy, CH30CH2CH2O, cyclopropylsulfonyl, MeS02, phenyl or pyridyl.

23. A compound according to claim 19, wherein:

R8b is H, halogen, CN, NH2, (l-6C)alkyl [optionally substituted with 1-5 fluoros], (l-6C)alkoxy, (1-3C alkoxy)(l-6C)alkyl, (1-3C alkoxy)(l-6C)alkoxy, (1-6C alkyl)sulfonyl, (3-6C cycloalkyl)sulfonyl, (3-4C)cycloalkyl, amino, (l-6Calkyl)NH-, phenyl [optionally substituted with (1-6C alkyl)S02-] or hetAr4; and

R8a is H.

24. A compound according to claim 23, wherein: R is H, halogen, (l-6C)alkyl [optionally substituted with 1-5 fluoros], (1- 6C)alkoxy, (1-3C alkoxy)(l-6C)alkoxy, (1-6C alkyl)sulfonyl, (3-6C cycloalkyl)sulfonyl, phenyl or hetAr4; and

hetAr4 is a 6-membered heteroaryl having 1-2 ring nitrogen atoms and optionally substituted with one or more groups independently selected from (l-6C)alkyl [optionally substituted with 1-3 fluoros], halogen, (1-6C alkyl)amino, fiuoro(l-6C alkyl)amino, difluoro(l-6C alkyl)amino, trifluoro(l-6C alkyl)amino, and (3-4C cycloalkyl)amino.

25. A compound according to claim 24, wherein R8b is H, CI, Br, methyl, ethyl, isopropyl, methoxy, ethoxy, CH3OCH2CH20-, cyclopropylsulfonyl, MeS02, phenyl or pyridyl.

26. A compound according to any one of claims 1-9, wherein Ring C is formula C- 10, C-l l or C-12.

27. A compound according to claim 26, wherein R10 is phenyl optionally substituted with one or more substituents independently selected from halogen, (l-6C)alkyl, (l-6C)alkoxy, and amino.

28. A compound according to any one of claims 1-27, wherein R2 is H.

29. A compound according to any one of claims 1-28, wherein Ra, Rb, Rc and Rd are

H.

30. A compound according to any one of claims 1-29, wherein Ring B and the - NH-C(=X)-NH- moiety of Formula I are trans in the absolute configuration shown in structure C:

31. A compound according to any one of claims 1 -29, wherein ring B and the -NH- C(=X)-NH- moiety of Formula I are trans in the absolute configuration shown in structure D:

32. A compound of claim 1, selected from a compound of Examples 1-56 or a pharmaceutically acceptable salt thereof.

33. A pharmaceutical composition, which comprises a compound of Formula I as defined in any one of claims 1 to 32 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.

34. A method for treating a disease or disorder selected from pain, cancer, inflammation/inflammatory diseases, neurodegenerative diseases, certain infectious diseases, Sjogren's syndrome, endometriosis, diabetic peripheral neuropathy, prostatitis and pelvic pain syndrome in a mammal, which comprises administering to said mammal a therapeutically effective amount of a compound of Formula I as defined in any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof.

35. The method of claim 34, wherein the method is a method for treating pain.

36. The method of claim 34, wherein the cancer is a cancer having a dysregulation ofTrkA.

37. The method of claim 36, wherein the cancer is selected from non-small cell lung cancer, papillary thyroid carcinoma, glioblastoma multiforme, acute myeloid leukemia, acute myeloid leukemia, colorectal carcinoma, large cell neuroendocrine carcinoma, prostate cancer, neuroblastoma, pancreatic carcinoma, melanoma, head and neck squamous cell carcinoma and gastric carcinoma.

38. A compound of Formula I as defined in any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, for use in the treatment of pain, cancer, inflanimation/inflammatory diseases, neurodegenerative diseases, certain infectious diseases, Sjogren's syndrome, endometriosis, diabetic peripheral neuropathy, prostatitis and pelvic pain syndrome.

39. Use of a compound of Formula I as defined in any one of claims 1 to 32, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating pain, cancer, inflammation/inflammatory diseases, neurodegenerative diseases, certain infectious diseases, Sjogren's syndrome, endometriosis, diabetic peripheral neuropathy, prostatitis and pelvic pain syndrome.

40. A process for the preparation of a compound of claim 1 , which comprises:

(a) for a compound of Formula I where X is O, coupling a corresponding compound having the formula II

II

with a corresponding compound having the formula III

ΠΙ

in the presence carbonyldiimidazole or triphosgene and a base; or

(b) for a compound of Formula I where X is S, coupling a corresponding compound having the formula II

II

with a corresponding compound having the formula III

III

in the presence di(lH-imidazol-2-yl)methanethione and a base; or

(c) for a compound of Formula I where X is O, coupling a corresponding compound having the formula II

II

with a corresponding compound having the formula IV

IV

where L1 is a leaving group, in the presence of a base; or

(d) for a compound of Formula I where X is O, coupling a corresponding compound having the formula V

V

where L is a leaving group, with a corresponding compound having the formula III

III

in the presence of a base; or

(e) for a compound of Formula I where X is O, activating a corresponding compound having the formula VI

VI

with diphenylphosphoryl azide followed by coupling the activated intermediate with a corresponding compound having the formula III

III

in the presence a base; or (f) for a compound of Formula I where X is O, coupling a corresponding compound having the formula II

with a corresponding compound having the formula VII

vn

in the presence of a base; or

(g) for a compound of Formula I where X is O, coupling a corresponding compound having the formula VIII

VIII

with a corresponding compound having the formula III

III

in the presence of a base; and

optionally removing protecting groups and optionally preparing a pharmaceutically acceptable salt thereof,

wherein in any of the above methods (a), (b), (c), (d), (e), (f), or (g), the ring A is

where R1, R2, Ring B, Ra, Rb, R° and Rd are as defined in claim 1.

Description:
PYRROLIDINYL UREA, THIOUREA, GUANIDINE AND CYANOGUANIDINE

COMPOUNDS AS TRKA KINASE INHIBITORS

BACKGROUND OF THE INVENTION

[0001] The present invention relates to novel compounds, to pharmaceutical compositions comprising the compounds, to processes for making the compounds and to the use of the compounds in therapy. More particularly, it relates to pyrrolidinyl urea, thiourea, guanidine and cyanoguanidine compounds which exhibit TrkA kinase inhibition, and which are useful in the treatment of pain, cancer, inflammation/inflammatory diseases, neurodegenerative diseases, certain infectious diseases, Sjogren's syndrome, endometriosis, diabetic peripheral neuropathy, prostatitis and pelvic pain syndrome.

[0002] The current treatment regimens for pain conditions utilize several classes of compounds. The opioids (such as morphine) have several drawbacks including emetic, constipatory and negative respiratory effects, as well as the potential for addictions. Nonsteroidal anti-inflammatory analgesics (NSAIDs, such as COX-1 or COX-2 types) also have drawbacks including insufficient efficacy in treating severe pain. In addition, COX-1 inhibitors can cause ulcers of the mucosa. Accordingly, there is a continuing need for new and more effective treatments for the relief of pain, especially chronic pain.

[0003] Trk's are the high affinity receptor tyrosine kinases activated by a group of soluble growth factors called neurotrophins (NT). The Trk receptor family has three members: TrkA, TrkB and TrkC. Among the neurotrophins are (i) nerve growth factor (NGF) which activates TrkA, (ii) brain-derived neurotrophic factor (BDNF) and NT-4/5 which activate TrkB and (iii) NT3 which activates TrkC. Trk's are widely expressed in neuronal tissue and are implicated in the maintenance, signaling and survival of neuronal cells (Patapoutian, A. et al., Current Opinion in Neurobiology, 2001, 11, 272-280).

[0004] Inhibitors of the Trk/neurotrophin pathway have been demonstrated to be effective in numerous pre-clinical animal models of pain. For example, antagonistic NGF and TrkA antibodies such as RN-624 have been shown to be efficacious in inflammatory and neuropathic pain animal models (Woolf, C.J. et al. (1994) Neuroscience 62, 327-331 ; Zahn, P.K. et al. (2004) J. Pain 5, 157-163; McMahon, S.B. et al., (1995) Nat. Med. 1, 774-780; Ma, Q. P. and Woolf, C. J. (1997) NeuroReport 8, 807-810; Shelton, D. L. et al. (2005) Pain 116, 8-16; Delafoy, L. et al. (2003) Pain 105, 489-497; Lamb, K. et al. (2003) Neurogastroenterol. Motil. 15, 355-361 ; Jaggar, S. I. et al. (1999) Br. J. Anaesth. 83, 442^48) and neuropathic pain animal models (Ramer, M. S. and Bisby, M. A. (1999) Eur. J. Neurosci. 11, 837-846; Ro, L. S. et al. (1999); Herzberg, U. et al., Pain 79, 265-274 (1997) Neuroreport 8, 1613-1618; Theodosiou, M. et al. (1999) Pain 81, 245-255; Li, L. et al. (2003) Mol. Cell. Neurosci. 23, 232-250; Gwak, Y. S. et al. (2003) Neurosci. Lett. 336, 117-120).

[0005] It has also been shown that NGF secreted by tumor cells and tumor invading macrophages directly stimulates TrkA located on peripheral pain fibers. Using various tumor models in both mice and rats, it was demonstrated that neutralizing NGF with a monoclonal antibody inhibits cancer related pain to a degree similar or superior to the highest tolerated dose of morphine. Because TrkA kinase may serve as a mediator of NGF driven biological responses, inhibitors of TrkA and/or other Trk kinases may provide an effective treatment for chronic pain states.

[0006] Recent literature has also shown that overexpression, activation, amplification and/or mutation of Trk kinases are associated with many cancers including neuroblastoma (Brodeur, G. M, Nat. Rev. Cancer 2003, 3, 203-216), ovarian (Davidson. B., et al., Clin. Cancer Res. 2003, 9, 2248-2259), colorectal cancer (Bardelli, A., Science 2003, 300, 949), melanoma (Truzzi, F., et al., Dermato-Endocrinology 2008, 3 (1), pp. 32-36), head and neck cancer (Yilmaz, T., et al., Cancer Biology and Therapy 2010, 10 (6), pp. 644-653), gastric carcinoma (Du, J. et al., World Journal of Gastroenterology 2003, 9 (7), pp. 1431-1434), lung carcinoma (Ricci A., et al., American Journal of Respiratory Cell and Molecular Biology 25 (4), pp. 439-446), breast cancer (Jin, W., et al., Carcinogenesis 2010, 31 (11), pp. 1939-1947), Glioblastoma (Wadhwa, S., et al., Journal of Biosciences 2003, 28 (2), pp. 181-188), medulloblastoma (Gruber-Olipitz, M., et al., Journal of Proteome Research 2008, 7 (5), pp. 1932-1944), secratory breast cancer (Euthus, D.M., et al., Cancer Cell 2002, 2 (5), pp. 347- 348), salivary gland cancer (Li, Y.-G., et al., Chinese Journal of Cancer Prevention and Treatment 2009, 16 (6), pp. 428-430), papillary thyroid carcinoma (Greco, A., et al., Molecular and Cellular Endocrinology 2010, 321 (1), pp. 44-49) and adult myeloid leukemia (Eguchi, M, et al., Blood 1999, 93 (4), pp. 1355-1363). In preclinical models of cancer, non-selective small molecule inhibitors of TrkA, B and C were efficacious in both inhibiting tumor growth and stopping tumor metastasis (Nakagawara, A. (2001) Cancer Letters 169:107-114; Meyer, J. et al. (2007) Leukemia, 1-10; Pierottia, M.A. and Greco A., (2006) Cancer Letters 232:90-98; Eric Adriaenssens, E., et al. Cancer Res (2008) 68:(2) 346-351).

[0007] In addition, inhibition of the neurotrophin/Trk pathway has been shown to be effective in treatment of pre-clinical models of inflammatory diseases with NGF antibodies or nonselective small molecule inhibitors of TrkA. For example, inhibition of the neurotrophin/Trk pathway has been implicated in preclinical models of inflammatory lung diseases including asthma (Freund-Michel, V; Frossard, N., Pharmacology & Therapeutics (2008) 117(1), 52- 76), interstitial cystitis (Hu Vivian Y; et. al. The Journal of Urology (2005), 173(3), 1016- 21), bladder pain syndrome (Liu, H.-T., et al., (2010) BJU International, 106 (11), pp. 1681- 1685), inflammatory bowel diseases including ulcerative colitis and Crohn's disease (Di Mola, F. F, et. al., Gut (2000) 46(5), 670-678) and inflammatory skin diseases such as atopic dermatitis (Dou, Y.-C, et. al. Archives of Dermatological Research (2006) 298(1), 31-37), eczema and psoriasis (Raychaudhuri, S. P., et al., J. Investigative Dermatology (2004) 122(3), 812-819).

[0008] The TrkA receptor is also thought to be critical to the disease process of the parasitic infection of Trypanosoma cruzi (Chagas disease) in human hosts (de Melo- Jorge, M. et al., Cell Host & Microbe (2007) 1(4), 251-261).

[0009] Trk inhibitors may also find use in treating disease related to an imbalance of the regulation of bone remodeling, such as osteoporosis, rheumatoid arthritis, and bone metastases. Bone metastases are a frequent complication of cancer, occurring in up to 70 percent of patients with advanced breast or prostate cancer and in approximately 15 to 30 percent of patients with carcinoma of the lung, colon, stomach, bladder, uterus, rectum, thyroid, or kidney. Osteolytic metastases can cause severe pain, pathologic fractures, life- threatening hypercalcemia, spinal cord compression, and other nerve-compression syndromes. For these reasons, bone metastasis is a serious and costly complication of cancer. Therefore, agents that can induce apoptosis of proliferating osteoblasts would be highly advantageous. Expression of TrkA receptors has been observed in the bone-forming area in mouse models of bone fracture (K. Asaumi, et al., Bone (2000) 26(6) 625-633). In addition, localization of NGF was observed in almost all bone-forming cells (K. Asaumi, et al.). Recently, it was demonstrated that a Trk inhibitor inhibits the signaling activated by neurotrophins binding to all three of the Trk receptors in human hFOB osteoblasts (J. Pinski, et al., (2002) 62, 986- 989). These data support the rationale for the use of Trk inhibitors for the treatment of bone remodeling diseases, such as bone metastases in cancer patients.

[0010] Trk inhibitors may also find use in treating diseases and disorders such as

Sjogren's syndrome (Fauchais, A.L., et al., (2009) Scandinavian Journal of Rheumatology, 38(1), pp. 50-57), endometriosis (Barcena De Arellano, M.L., et al., (2011) Reproductive Sciences, 18(12), pp. 1202-1210; Barcena De Arellano, et al., (2011) Fertility and Sterility, 95(3), pp. 1123-1126; Cattaneo, A., (2010) Current Opinion in Molecular Therapeutics, 12(1), pp. 94-106), diabetic peripheral neuropathy (Kim, H.C., et al., (2009) Diabetic Medicine, 26 (12), pp. 1228-1234; Siniscalco, D., et al., (2011) Current Neuropharmacology, 9(4), pp. 523- 529; Ossipov, M.H., (2011) Current Pain and Headache Reports, 15(3), pp. 185-192), and prostatitis and pelvic pain syndrome (Watanabe, T., et al., (2011) BJU International, 108(2), pp. 248-251; and Miller, L.J., et al., (2002) Urology, 59(4), pp. 603-608).

[0011] Several classes of small molecule inhibitors of Trk kinases said to be useful for treating pain or cancer are known {Expert Opin. Ther. Patents (2009) 19(3), 305-319).

[0012] International application publication WO 2010/032856 describes compounds represented by the formula

[0013] wherein ring B is an aromatic ring, ring D is an aromatic ring, and L is NR ,

NR 3 C(R 4a R 4b ), O or OC(R 4a R 4b ), which are asserted to be tachykinin receptor antagonists.

SUMMARY OF THE INVENTION

[0014] It has now been found that pyrrolidinyl urea, thiourea, guanidine and cyanoguanidine compounds are inhibitors of TrkA, and useful for treating disorders and diseases such as pain, including chronic and acute pain. Compounds of the invention useful in the treatment of multiple types of pain including inflammatory pain, neuropathic pain, and pain associated with cancer, surgery, or bone fracture. In addition, compounds of the invention are useful for treating cancer, inflammation or inflammatory diseases, neurodegenerative diseases, certain infectious diseases, Sjogren's syndrome, endometriosis, diabetic peripheral neuropathy, prostatitis or pelvic pain syndrome, and diseases related to an imbalance of the regulation of bone remodeling, such as osteoporosis, rheumatoid arthritis, and bone metastases.

[0015] More specifically, provided herein are compounds of Formula I:

I

[0016] or stereoisomers, tautomers, or pharmaceutically acceptable salts, solvates or prodrugs thereof, wherein Ring B and the NH-C(=X)-NH moiety are in the trans configuration and R 1 , R 2 , R a , R b , R c , R d , X, Ring B and Ring C are as defined herein. [0017] Another aspect of the present invention provides methods of treating a disease or disorder modulated by TrkA, comprising administering to a mammal in need of such treatment an effective amount of a compound of this invention or a stereoisomer, solvate or pharmaceutically acceptable salt thereof. In one embodiment, the disease and disorders include chronic and acute pain, including but not limited to inflammatory pain, neuropathic pain, and pain associated with cancer, surgery, or bone fracture. In another embodiment, the disease and disorders include, but are not limited to, cancer, inflammation or inflammatory diseases, neurodegenerative diseases, certain infectious diseases, Sjogren's syndrome, endometriosis, diabetic peripheral neuropathy, prostatitis or pelvic pain syndrome, and diseases related to an imbalance of the regulation of bone remodeling, such as osteoporosis, rheumatoid arthritis, and bone metastases. In one embodiment, the treatment includes treating the mammal with a compound of this invention in combination with an additional therapeutic agent.

[0018] Another aspect of the present invention provides a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof.

[0019] Another aspect of the present invention provides the compounds of the present invention for use in therapy.

[0020] Another aspect of the present invention provides the compounds of the present invention for use in the treatment of disease and disorders such as chronic and acute pain, including but not limited to inflammatory pain, neuropathic pain, and pain associated with cancer, surgery, or bone fracture. Another aspect of the present invention provides the compounds of the present invention for use in the treatment of disease and disorders selected from cancer, inflammation or inflammatory diseases, neurodegenerative diseases, certain infectious diseases, Sjogren's syndrome, endometriosis, diabetic peripheral neuropathy, prostatitis or pelvic pain syndrome, and diseases related to an imbalance of the regulation of bone remodeling, such as osteoporosis, rheumatoid arthritis, and bone metastases.

[0021] Another aspect of the present invention provides the use of a compound of this invention in the manufacture of a medicament for the treatment of disease and disorders such as chronic and acute pain including, but not limited to, inflammatory pain, neuropathic pain, and pain associated with cancer, surgery, or bone fracture.

[0022] Another aspect of the present invention provides the use of a compound of this invention in the manufacture of a medicament for the treatment of disease and disorders selected from cancer, inflammation or inflammatory diseases, neurodegenerative diseases, certain infectious diseases, Sjogren's syndrome, endometriosis, diabetic peripheral neuropathy, prostatitis or pelvic pain syndrome, and diseases related to an imbalance of the regulation of bone remodeling, such as osteoporosis, rheumatoid arthritis, and bone metastases.

[0023] Another aspect of the present invention provides intermediates for preparing compounds of Formula I.

[0024] Another aspect of the present invention includes methods of preparing, methods of separation, and methods of purification of the compounds of this invention.

DETAILED DESCRIPTION OF THE INVENTION

[0025] Provided herein are compounds, and pharmaceutical formulations thereof, that are useful in the treatment of diseases, conditions and/or disorders modulated by TrkA.

[0026] A representative compound of the invention (See Table B below), was found to be highly selective for TrkA over a panel of about 230 other kinases at 10 μΜ concentration. In addition, compounds of the invention such as those shown in Table A below, were found to be at least 1000 fold more selective for TrkA versus p38a.

[0027] One embodiment provides a com ound of Formula I:

I

[0028] or stereoisomers, tautomers, or pharmaceutically acceptable salts, solvates or prodrugs thereof, wherein:

[0029] Ring B and the NH-C(=X)-NH moiety are in the trans configuration;

[0030] R a , R b , R c and R d are independently selected from H and ( 1 -3C)alkyl,

[0031] or R c and R d are independently selected from H and (l-3C)alkyl, and R a and R b together with the atom to which they are attached form a cyclopropyl ring;

[0032] X is O, S, NH or N-CN;

[0033] R 1 is (1-3C alkoxy)(l-6C)alkyl, (trifluoromethoxy)(l-6C)alkyl, (1-3C sulfanyl)(l-6C)alkyl, monofluoro(l-6C)alkyl, difluoro(l-6C)alkyl, trifluoro(l-6C)alkyl, tetrafluoro(2-6C)alkyl, pentafluro(2-6C)alkyl, cyano(l-6C)alkyl, aminocarbonyl(l-6C)alkyl, hydroxy(l-6C)alkyl, dihydroxy(2-6C)alkyl, (l-6C)alkyl, (l-3Calkylamino)(l-3C)alkyl, (1-4C alkoxycarbonyl)(l-6C)alkyl, amino(l-6C)alkyl, hydroxy(l-3C alkoxy)(l-6C)alkyl, di(l-3C alkoxy)(l-6C)alkyl, (1-3C alkoxy)trifluoro(l-6C)alkyl, hydroxytrifluoro(l-6C)alkyl, (1-4C alkoxycarbonyl)(l-3C alkoxy)(l-6C)alkyl, or hydroxy carbonyl( 1-3 C alkoxy)(l-6C)alkyl;

[0034] R 2 is H, F, or OH;

[0035] Ring B is Ar 1 or hetAr 1 ;

[0036] Ar 1 is phenyl optionally substituted with one or more substituents independently selected from halogen, CF 3 , CF 3 0-, (l-4C)alkoxy, hydroxy(l-4C)alkyl, (l-6C)alkyl and CN;

[0037] hetAr 1 is a 5-6 membered heteroaryl having 1-3 ring heteroatoms independently selected from N, S and O, and optionally substituted with one or more groups independently selected from (l-6C)alkyl, halogen, OH, CF 3 , NH 2 and hydroxy(l-2C)alkyl;

[0038] Ring C is selected from formulas C-l through C-13:

-5 C-6 C-7 C-8

C-13

[0039] R 3 is H, NH 2 , CN, halogen, (l-3C)alkyl [optionally substituted with 1 to 3 fluoros], H 2 NC(=0)-, (l-3Calkyl)NHC(=0)-, di(l-3Calkyl)NHC(=0)-, hydroxy(l-3C)alkyl, CH 3 OCH 2 CH 2 , (3-4C)cycloalkyl or (l-3C)alkoxy;

[0040] R 3a is H, (l-3C)alkyl, CF 3 CH 2 CH 2 , HCF 2 CH 2 CH 2 , H 2 FCCH 2 CH 2 , CF 3 CH 2 ,

HOCH 2 CH 2 , MeOCH 2 CH 2 or (3-4C)cycloalkyl;

[0041] R 4 is H, OH, (l-6C)alkyl [optionally substituted with 1-5 fluoros], cyano(l-

6C)alkyl, hydroxy(l-6C)alkyl, dihydroxy(2-6C)alkyl, (1-3C alkoxy)(l-6C)alkyl, amino(l- 6C)alkyl, aminocarbonyl(l-6C)alkyl, (l-3C)alkylsulfonamido(l-6C)alkyl, sulfamido(l- 6C)alkyl, hydroxycarbonyl(l-6C)alkyl, hetAr 3 (l-6C)alkyl, Ar 3 (l-6C)alkyl, (l-6C)alkoxy [optionally substituted with 1-5 fluoros], cyano(l-6C)alkoxy, hydroxy(l-6C)alkoxy, dihydroxy(2-6C)alkoxy, amino(2-6C)alkoxy, hydroxyl-carbonyl(l-6C)alkoxy, hetCyc (1- 6C)alkoxy, hetAr 3 (l-6C)alkoxy, Ar 3 (l-6C)alkoxy, (1-4C alkoxy)(l-6C)alkoxy, (1-3C alkylsulfonyl)(l-6C)alkoxy, (3-6C)cycloalkyl [optionally substituted with F, OH, (1-6C alkyl), (1-6C) alkoxy, or (1-3C alkoxy)(l-6C)alk l], hetAr 4 , hetV-O-, Ar 4 , hetCyc 2 (0)CH 2 -, (1-4C alkoxycarbonyl)( 1 -6C)alkoxy, hydroxycarbonyl( 1 -6C)alkoxy, aminocarbonyl( 1 -6C)alkoxy, hetCyc 2 C(=0)(l-6C)alkoxy, hydroxy(l-3C alkoxy)(l-6C)alkoxy, hydroxytrifluoro(l- 6C)alkoxy, (l-3C)alkylsulfonamido(l-6C)alkoxy, (l-3C)alkylamido(l-6C)alkoxy, di(l-3C alkyl)amino-carboxy, hetCyc C(=0)0-, hydroxydifluoro(l-6C)alkyl, (1-4C alkylcarboxy)(l- 6C)alkyl, (l-6C)alkoxycarbonyl, hydroxylcarbonyl, aminocarbonyl, (1-3C

•a

alkoxy)aminocarbonyl, hetCyc , halogen, CN, trifluoromethylsulfonyl, N-(1-3C alkyl)oxadiazolonyl, or hetAr 5 ;

[0042] R 4a is H, (l-6C)alkyl, CF 3 CH 2 CH 2 , HCF 2 CH 2 CH 2 , H 2 FCCH 2 CH 2 , CF 3 CH 2 „ cyano(l-6C)alkyl, hydroxy(l-6C)alkyl, dihydroxy(2-6C)alkyl, (1-3C alkoxy)(l-6C)alkyl, amino( 1 -6C)alkyl, aminocarbonyl( 1 -6C)alkyl, ( 1 -3C)alkylsulfonamido( 1 -6C)alkyl, sulfamido(l-6C)alkyl, hydroxycarbonyl(l-6C)alkyl, hetAr 3 (l-6C)alkyl, Ar 3 (l-6C)alkyl, (3- 6C)cycloalkyl [optionally substituted with F, OH, (1-6C alkyl), (1-6C) alkoxy, or (1-3C alkoxy)(l-6C)alkyl], hetAr 4 , Ar 4 , hydroxydifluoro(l-6C)alkyl, (1-4C alkylcarboxy)(l- 6C)alkyl, hetCyc 3 , N-(1-3C alkyl)oxadiazolonyl, or hetAr 5 ;

[0043] hetCyc is a 4-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O and optionally substituted with 1 -2 groups independently selected from (l-6C)alkyl, (1-4C alkylcarboxy)(l-6C)alkyl, and (l-6C)acyl;

[0044] hetCyc is a 4-7 membered heterocycle having 1-2 ring heteroatoms independently selected from N and O and optionally substituted with one or more substituents independently selected from F, CN, (l-6C)alkyl, trifluoro(l-6C)alkyl, hydroxy(l-6C)alkyl, (1- 3C alkoxy)(l-6C)alkyl, (l-6C)acyl-, (l-6C)alkylsulfonyl, trifluoromethylsulfonyl and (1-4C alkoxy)carbonyl;

[0045] hetAr 3 is a 5-membered heteroaryl ring having 1-3 ring atoms independently selected from N, O and S and optionally substituted with (l-6C)alkyl;

[0046] Ar 3 is phenyl optionally substituted with (l-4C)alkoxy;

[0047] hetAr 4 is independently a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, S and O and optionally substituted with one or more substituents independently selected from (l-6C)alkyl [optionally substituted with 1-3 fluoros], halogen, CN, hydroxy(l-6C)alkyl, (3-6C)cycloalkyl, (3-6C cycloalkyl)CH 2 - (3-6C cycloalkyl)C(=0)-, (1-3C alkoxy)(l-6C)alkyl, (l-6C)alkoxy, (l-6C)alkylsulfonyl, NH 2 , (1-6C alkyl)amino, di(l-6C alkyl)amino, (1-3C trifluoroalkoxy), fluoro(l-6C alkyl)amino, difluoro(l-6C alkyl)amino, trifluoro(l-6C alkyl)amino, and (3-4C cycloalkyl)amino;

[0048]

[0049] where R z is (3-4C)cycloalkyl or (l-3C)alkyl (optionally substituted with 1-3 fluoros), wherein each of said hetAr 5 groups is optionally further substituted with one or more groups independently selected from F and (l-3C)alkyl optionally substituted with 1-3 fluoros;

[0050] Ar 4 is phenyl optionally substituted with one or more groups independently selected from (l-6C)alkyl, halogen, CN, CF 3 , CF 3 0-, (l-6C)alkoxy, (l-6Calkyl)OC(=0)-, aminocarbonyl, (l-6C)alkylthio, hydroxy(l-6C)alkyl, (1-6C alkyl)S0 2 -, HOC(=0)- and (1-3C alkoxy)(l-3C alkyl)OC(=0)-;

[0051] R 5 is H, (l-6C)alkyl [optionally substituted with 1-5 fluoros], halogen, CN, (1-

4C)alkoxy, hydroxy(l-4C)alkyl, (1-3C alkoxy)(l-4C)alkyl, (1-4C alkyl)OC(=0)-, (1- 6C)alkylthio, (3-4C)cycloalkyl, amino, aminocarbonyl, trifluoro(l-3C alkyl)amido, or phenyl [optionally substituted with one or more groups independently selected from halogen, (1- 6C)alkyl and (l-6C)alkoxy];

[0052] R 5a is H, (l-6C)alkyl, CF 3 CH 2 CH 2 , HCF 2 CH 2 CH 2 , H 2 FCCH 2 CH 2 , CF 3 CH 2 , hydroxy(l-4C)alkyl, (1-3C alkoxy)(l-4C)alkyl, (3-4C)cycloalkyl, or phenyl [optionally substituted with one or more groups independently selected from halogen, (l-6C)alkyl and (1- 6C)alkoxy];

[0053] R is (l-6C)alkyl, (3-6C)cycloalkyl, or phenyl [optionally substituted with one or more groups independently selected from halogen, (l-6C)alkyl, (l-6C)alkoxy, (3- 4C)cycloalkyl, amino, aminocarbonyl, and trifluoro(l-3C)alkylamido];

[0054] R 8a and R 8b are independently H, halogen, CN, NH 2 , (l-6C)alkyl [optionally substituted with 1-5 fluoros], (l-6C)alkoxy, (1-3C alkoxy)(l-6C)alkyl, (1-3C alkoxy)(l- 6C)alkoxy, (1-6C alkyl)sulfonyl, (3-6C cycloalkyl)sulfonyl, (3-4C)cycloalkyl, amino, (1- 6Calkyl)NH-, phenyl [optionally substituted with (1-6C alkyl)S0 2 -] or hetAr 4 , wherein only one of R 8a and R 8b can be phenyl [optionally substituted with (1-6C alkyl)S0 2 -] or hetAr 4 ;

[0055] R 9 is H, (l-6C)alkyl, CF 3 CH 2 -, CF 3 CH 2 CH 2 -, (l-3Calkoxy)(l-6C)alkyl or (3-

4C)cycloalkyl; and

[0056] R 10 is (3-6C)cycloalkyl or phenyl [optionally substituted with one or more substituents independently selected from halogen, (l-6C)alkyl, (l-6C)alkoxy, (3- 4C)cycloalkyl, amino, aminocarbonyl and trifluoro(l-3C alkyl)amido].

[0057] It is to be understood that in instances where two or more radicals are used in succession to define a substituent attached to a structure, the first named radical is considered to be terminal and the last named radical is considered to be attached to the structure in question. Thus, for example, the radical "alkoxyalkyl" is attached to the structure in question by the alkyl group.

[0058] The terms *'(l-6C)alkyl", "(l-4C)alkyl" and "(l-3C)alkyl" as used herein refer to saturated linear monovalent hydrocarbon radicals of one to six carbon atoms, one to four carbon atoms, and one to three carbon atoms, respectively, or a branched saturated monovalent hydrocarbon radical of three to six carbon atoms, three to four carbon atoms, or three carbon atoms, respectively. Examples include, but are not limited to, methyl, ethyl, 1 -propyl, 2- propyl, 1 -butyl, 2 -methyl- 1 -propyl, 2-butyl, 2-methyl-2 -propyl, 2,2-dimethylpropyl, 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3 -methyl- 1 -butyl, 2-methyl-l -butyl, 1- hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3- pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, and 3,3-dimethyl-2 -butyl.

[0059] "(l-4C)Alkoxy", "(l-3C)alkoxy", "(l-6C)alkoxy" and "(2-6C)alkoxy" refer to an -OR radical where R is (l-4C)alkyl, (l-3C)alkyl, (l-6C)alkyl, or (2-6C)alkyl, respectively, as defined above. Examples include methoxy, ethoxy, and the like.

[0060] "(l-6C)Acyl" means a RC(=0)- radical where R is a linear saturated monovalent hydrocarbon radical of one to five carbon atoms or a branched saturated monovalent hydrocarbon radical of three to five carbon atoms, e.g., methylcarbonyl, and the like.

[0061] "(1-3C Alkoxy)(l-6C)alkyl" and "(1-3C alkoxy)(l-4C)alkyl" mean a linear saturated monovalent hydrocarbon radical of one to six carbon atoms or one to four carbon atoms, or a branched saturated monovalent hydrocarbon radical of three to six carbon atoms or three to four carbon atoms, respectively, wherein one of the carbon atoms is substituted with one (l-3C)alkoxy group as defined herein. [0062] "(1-3C Alkoxy)(l-6C)alkoxy" means a (l-6C)alkoxy group as defined herein, wherein one of the carbon atoms is substituted with a (l-3C)alkoxy group as defined herein. Examples include methoxymethoxy, methoxyethoxy, and the like.

[0063] "(1-3C Alkoxy)aminocarbonyl" means a (1-3C alkyl)-O-NH-C(-O)- group.

[0064] "(l-6C)Alkoxycarbonyl" and "(l-4C)alkoxycarbonyl" mean a (l-6C)-0-

C(=0)- and (l-4C)-0-C(=0)- group, respectively.

[0065] (1-4C Alkoxycarbonyl)(l-6C)alkyl means a (l-6C)alkyl group as defined herein, wherein one of the carbons is substituted with a (1-4C alkoxy)carbonyl group as defined herein.

[0066] "(1-3C Alkoxy)trifluoro(l-6C)alkyl" means a (l-6C)alkyl group as defined herein, wherein one of the carbons is substituted with three fluoros, and another carbon is substituted with a (l-3C)alkoxy group as defined herein.

[0067] "(1-4C Alkoxycarbonyl)(l-6C alkoxy)" means a (1-6C) alkoxy group as defined herein wherein one of the carbon atoms is substituted with one (1-4C alkoxy)carbonyl group, i.e., an alkyl-0-C(=0)- group.

[0068] "(1-4C Alkoxycarbonyl)(l-3C alkoxy)(l-6C)alkyl" means a (1-3C alkoxy)(l-

6C)alkyl group as defined herein wherein one of the carbon atoms is substituted with one (1- 4C alkoxycarbonyl group, i.e., an alkyl-0-C(=0)- group.

[0069] "(1-3C Alkoxy )hydroxycarbonylalkyl" means a hydroxycarbonylalkyl group as defined herein wherein one of the carbon atoms is substituted with one (1-3C alkoxy) group.

[0070] "Amino" means a -NRR' group where R and R' are independently selected from hydrogen or (l-3C)alkyl as defined herein. Examples include ¾N-, CH 3 NH-, (C¾) 2 N, and the like.

[0071] "Amino(l-6C)alkyl" means a linear saturated monovalent hydrocarbon radical of one to six carbon atoms or a branched saturated monovalent hydrocarbon radical of three to six carbon atoms, wherein one of the carbon atoms is substituted with one -NRR' group where R and R' are independently selected from hydrogen or (l-3C)alkyl as defined herein. Examples include aminomethyl, methylaminoethyl, 2-ethylamino-2-methylethyl, and the like.

[0072] "Amino(2-6C)alkoxy" means a (2-6C)alkoxy group as defined herein, wherein one of the carbon atoms is substituted with one -NRR' group where R and R' are independently selected from hydrogen or (l-3C)alkyl as defined herein.

[0073] "Aminocarbonyl" means a RRTSiCO- radical where R and R' are independently hydrogen or (l-6C)alkyl as defined herein. Examples include H 2 NCO-, dimethylaminocarbonyl, and the like. [0074] "Aminocarbonyl(l-6C)alkyl" means a linear saturated hydrocarbon radical of one to six carbon atoms or a branched saturated monovalent hydrocarbon radical of three to six carbons wherein one of the carbon atoms is substituted with one aminocarbonyl group as defined herein, e.g., 2-aminocarbonylethyl, 1-, 2-, or 3-dimethylaminocarbonylpropyl, and the like.

[0075] "Aminocarbonyl(l-6C)alkoxy" means a (l-6C)alkoxy as defined herein, wherein one of the carbon atoms is substituted with one aminocarbonyl group as defined herein.

[0076] "(l-3C)Alkylamido(l-6C)alkoxy" means a (l-6C)alkoxy as defined herein, wherein one of the carbon atoms is substituted with one alkylamido group, i.e., substituted with a (l-3C)C(=0)NH- group.

[0077] "( 1 -4C alkyl)carboxy" means a R'-C(=0)0- group where R' is ( 1 -4C)alkyl.

[0078] "(1-4C alkylsiloxy)(l-6C)alkoxy" means a (l-6C)alkoxy group as defined herein wherein one of the carbon atoms is substituted with one (1-4C alkyl)siloxy group, e.g., a (1-4C alkyl)Si-0- group such as a tert-butylsiloxy group.

[0079] "(l-3C)Alkylsulfonamido" means a (l-3C)alkylS0 2 NH- radical where (1-

3C)alkyl is as defined herein.

[0080] "(1-3C Alkylsulfonamido)(l-6C)alkyl" means a linear saturated hydrocarbon radical of one to six carbon atoms or a branched saturated monovalent hydrocarbon radical of three to six carbons substituted with one (l-3C)alkylsulfonamido group as defined herein.

[0081] "(l-3C)Alkylsulfonamido(l-6C)alkoxy" means a (l-6C)alkoxy group as defined herein wherein one of the carbon atoms is substituted with one (l-3C)alkylsulfonamido group as defined herein.

[0082] "(l-3C)Alkylsulfonyl" means a -S0 2 R radical where R is (l-3C)alkyl as defined above, e.g., methylsulfonyl, and the like.

[0083] "(1-3C Alkylsulfonyl)(l-6C)alkoxy" means a (l-6C)alkoxy group as defined herein, wherein one of the carbon atoms is substituted with a (l-3C)alkylsulfonyl group.

[0084] "Hydroxycarbonyl" means HOC(=0)-.

[0085] "(1-4C alkyl)carboxy(l-6C)alkyl" means a (l-6C)alkyl group as defined herein wherein one of the carbon atoms is substituted with a (1-4C alkyl)carboxy group as defined herein.

[0086] "Cyano(l-6C)alkyl" means a linear saturated hydrocarbon radical of one to six carbon atoms or a branched saturated monovalent hydrocarbon radical of three to six carbons substituted with a cyano (CN) group. [0087] "(3-6C)Cycloalkyl" means a cyclic saturated monovalent hydrocarbon radical of three to six carbon atoms, e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0088] "Di(l-3C alkoxy)(l-6C)alkyl" means a (l-6C)alkyl group as defined herein, wherein two carbons are each substituted with one (l-3C)alkoxy group as defined herein.

[0089] "Dihydroxy(2-6C)alkyl" means a linear saturated hydrocarbon radical of two to six carbon atoms or a branched saturated monovalent hydrocarbon radical of three to six carbons substituted with two hydroxy (OH) groups, provided that two hydroxy groups are not both on the same carbon atom.

[0090] "Dihydroxy(2-6C)alkoxy" means a (2-6C)alkoxy group as defined herein, wherein two of the carbon atoms are substituted with a hydroxy group.

[0091] "Halogen" as used herein means F, CI, Br or I.

[0092] "Heterocycle" refers to a saturated or partially unsaturated ring system having one or more ring heteroatoms as recited for the specific heterocyclic group, wherein the heterocycle is optionally substituted with substituents as defined for that particular heterocyclic group.

[0093] "Heteroaryl" refers to a 5-6 membered unsaturated ring system having one or more ring heteroatoms as recited for the specific heteroaryl group, wherein the heteroaryl is optionally substituted with substituents as defined for that particular heteroaryl group.

[0094] "hetCyc 2 C(=0)( 1 -6C)alkoxy " means a ( 1 -6C)alkoxy as defined herein, wherein one of the carbon atoms is substituted with a hetCyc C(=0) group, wherein hetCyc is as defined herein.

[0095] "Hydroxy(l-6C)alkyl" and "hydroxy(l-4C)alkyl" means a linear saturated hydrocarbon radical of one to six carbon atoms or one to four carbon atoms, respectively, or a branched saturated monovalent hydrocarbon radical of three to six carbon atoms or three to four carbon atoms, respectively, wherein one of the carbon atoms is substituted with a hydroxy (OH) group.

[0096] "Hydroxy(l-6C)alkoxy" means a (l-6C)alkoxy group as defined herein, wherein one of the carbon atoms is substituted with a hydroxy group.

[0097] "Hydroxy(l-3C alkoxy)(l-6C)alkyl" means a (1-3C alkoxy)(l-6C)alkyl group as defined herein, wherein one of the carbons is substituted with a hydroxy group.

[0098] "Hydroxy(l-3C alkoxy)(l-6C)alkoxy" means a (1-3C alkoxy)(l-6C)alkoxy as defined herein, wherein one of the carbon atoms is substituted with a hydroxy group.

[0099] "Hydroxydifluoro(l-6C)alkyl" means a difluoro(l-6C)alkyl group as defined herein, wherein one of the carbon atoms is substituted with a hydroxy group. [00100] "Hydroxytrifluoro(l-6C)alkoxy" means a trifluoro(l-6C)alkoxy group as defined herein, wherein one of the carbon atoms is substituted with a hydroxy group.

[00101] "Hydroxycarbonylalkyl" means a linear saturated hydrocarbon radical of one to six carbon atoms or a branched saturated monovalent hydrocarbon radical of three to six carbons substituted with one -COOH group. Examples include 2-hydroxycarbonylethyl, 1 -, 2-, or 3-hydroxycarbonylpropyl, and the like.

[00102] "Isoindoline-l,3-dionyl(l-6C)alkoxy" means a (l-6C)alkoxy group as defined herein, wherein one of the carbon atoms is substituted with an isoindoline-l,3-dionyl group.

[00103] "(Trifluoromethoxy)(l-6C)alkyl" means a linear saturated hydrocarbon radical of one to six carbon atoms or a branched saturated monovalent hydrocarbon radical of three to six carbons substituted with one CF3O- group.

[00104] "Trifluoro(l-3C alkyl)amido" means a (1-3C alkyl)C(=0)NH- group wherein one of the carbons is substituted with three fluoros.

[00105] "Trifluoro(l-6C)alkoxy" means a (l-6C)alkoxy group as defined herein, wherein one of the carbon atoms is substituted with three fluoros.

[00106] "Sulfamido(l-6C)alkyl" means a linear saturated hydrocarbon radical of one to six carbon atoms or a branched saturated monovalent hydrocarbon radical of three to six carbons substituted with one sulfamido (H 2 NSO 2 NH-) group.

[00107] It should be noted that compounds of the invention may contain groups that may exist in tautomeric forms, such as heteroatom substituted heteroaryl or heterocyclic groups and the like, which are illustrated in the following general and specific examples:

[00108] where Y' = O, S, or NR, and though one form is named, described, displayed and/or claimed herein, all the tautomeric forms are intended to be inherently included in such name, description, display and/or claim. [00109] In one embodiment of Formula I, R a , R b , R c and R d are independently selected from H and methyl. In one embodiment, R a , R b , R c and R d are hydrogen. In one embodiment, R a is methyl and R b , R c and R d are hydrogen. In one embodiment, R a and R b are methyl and R c and R d are hydrogen. In one embodiment, R a , R b and R c are hydrogen and R d is methyl. In one embodiment, R a and R b are hydrogen and R c and R d are methyl.

[00110] In one embodiment, R c and R d are independently selected from H and (1- 3C)alkyl, and R a and R b together with the atom to which they are attached form a cyclopropyl ring. In one embodiment, R c and R d are H, and R a and R b together with the atom to which they are attached form a cyclopropyl ring.

[00111] In one embodiment, X is O.

[00112] In one embodiment, X is S.

[00113] In one embodiment, X is NH.

[00114] In one embodiment, X is N-CN.

[00115] In one embodiment, R 1 is (1-3C alkoxy)(l-6C)alkyl, for example, methoxyethyl, methoxypropyl, ethoxyethyl and 2-methoxypropyl. Particular examples include 2-methox eth l and 2-methoxypropyl having the structures:

[00116] In one embodiment, R 1 is 2-methoxyethyl.

[00117] In one embodiment, R 1 is (trifluoromethoxy)(l-6C)alkyl, for example, trifluoromethoxyethyl, trifluoromethoxypropyl, and the like. A particular example is trifluoromethoxyethyl .

[00118] In one embodiment, R 1 is (1-3C sulfanyl)(l-6C)alkyl, for example methylsulfanylethyl, ethylsulfanylethyl, and the like. A particular example is methylsulfanylethyl.

[00119] In one embodiment, R 1 is monofluoro(l-6C)alkyl, difluoro(l-6C)alkyl or trifluoro(l-6C)alkyl. Particular examples include l,3-difluoroprop-2-yl, 2,2-difluoroethyl, 4,4,4-trifluorobutyl and 2,2,2-trifluoroethyl having the structures:

[00120] In one embodiment, R 1 is tetrafluoro(2-6C)alkyl or pentafluoro(2-6C)alkyl. A particular example is 3,3,4,4,4-pentafluorobutyl.

[00121] In one embodiment, R 1 is cyano(l-6C)alkyl. A particular example is 2- cyanoethyl. [00122] In one embodiment, R 1 is aminocarbonyl(l-6C)alkyl. A particular example is aminocarbonylmethyl. Another example is methylaminocarbonylmethyl having the formula MeNHC(=0)CH 2 -.

[00123] In one embodiment, R 1 is hydroxy(l-6C)alkyl. Particular examples include 2- hydroxyethyl and 2-hydroxypropyl.

[00124] In one embodiment, R 1 is dihydroxy(2-6C)alkyl. A particular example is the structure:

[00125] In one embodiment, R 1 is (l-6C)alkyl. Examples include methyl, ethyl, and propyl.

[00126] In one embodiment, R 1 is (l-3Calkylamino)(l-3C)alkyl, that is, a (l-3C)alkyl group which is substituted with a (1-3C alkyl)amino group, for example a (l-3Calkyl)NH- group such as methylamino. A particular example is (2-methylamino)ethyl.

[00127] In one embodiment, R 1 is (1-4C alkoxycarbonyl)(l-6C)alkyl. A particular example is methoxycarbonylmethyl, having the structure:

[00128] In one embodiment, R 1 is amino(l-6C)alkyl, such as methylamino(l-6C)alkyl. A particular example is 2-methylaminoethyl.

[00129] In one embodiment, R 1 is hydroxy(l-3C alkoxy)(l-6C)alkyl. Examples include hydroxymethoxy(l-6C)alkyl. Particular examples include the structures:

[00130] In one embodiment, R 1 is di(l-3C alkoxy)(l-6C)alkyl. Examples include dimethoxy(l-6C)alkyl. A particular example includes l,3-dimethoxyprop-2-yl having the structure: [00131] In one embodiment, R 1 is (1-3C alkoxy)trifluoro(l-6C)alkyl. Examples include methoxytrifluoro(l-6C)alkyl. A particular example includes 3,3,3-trifluoro-2-methoxypropyl.

[00132] In one embodiment, R 1 is hydroxytrifluoro(l-6C)alkyl. A particular example includes 3 ,3 ,3-trifluoro-2-hydroxypropyl.

[00133] In one embodiment, R 1 is (1-4C alkoxycarbonyl)(l-3C alkoxy)(l-6C)alkyl. Examples include (methoxycarbonyl)methoxy(l-6C)alkyl. A particular example includes the structure:

[00134] In one embodiment, R 1 is hydroxycarbonyl(l-3C alkoxy)(l-6C)alkyl. Examples include (methoxycarbonyl)hydroxy(l-6C)alkyl. A particular example includes the structure:

[00135] In one embodiment, R 1 is selected from (1-3C alkoxy)(l-6C)alkyl, difluoro(l- 6C)alkyl and trifluoro(l-6C)alkyl.

[00136] In one embodiment, R 2 is H.

[00137] In one embodiment, R 2 is F.

[00138] In one embodiment, R 2 is OH.

[00139] In one embodiment of Formula I, Ring B is Ar 1 , where Ar 1 is phenyl optionally substituted with one or more substituents independently selected from halogen, CF 3 , CF3O-, (l-4C)alkoxy, hydroxy(l-4C)alkyl, (l-6C)alkyl, and CN. In one embodiment, Ar 1 is phenyl optionally substituted with one or more substituents independently selected from halogen, CF 3 , (l-4C)alkoxy and CN. In one embodiment, Ar 1 is phenyl optionally substituted with one or more substituents independently selected from F, CI, CF 3 , MeO and CN.

[00140] In one embodiment of Formula I, Ring B when represented by Ar 1 is phenyl,

2-fluorophenyl, 3 -fluorophenyl, 4-fluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 2,4- difluorophenyl, 2,5-difluorophenyl, 3,4,5-trifluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4- chlorophenyl, 3-trifluoromethylphenyl 3-methoxyphenyl, 3-chloro-4-fluorophenyl, 4-chloro-3- fluorophenyl, 3-chloro-5-fluorophenyl, 3-cyano-5-fluorophenyl, 2-cyanophenyl, 4- cyanophenyl or 3-cyano-4-fluorophenyl. [00141] In one embodiment, Ring B is Ar 1 , wherein Ar 1 is phenyl optionally substituted with one or more halogens. In one embodiment, Ar 1 is phenyl optionally substituted with one or more F or CI. In one embodiment, Ar 1 is phenyl, 3 -fluorophenyl, 4-fluorophenyl, 3,4- difluorophenyl, 3,5-difluorophenyl, 3,4,5-trifluorophenyl, 3-chloro-4-fluorophenyl, 3-chloro-5- fluorophenyl, or 4-chloro-3 -fluorophenyl.

[00142] In one embodiment of Formula I, Ring B is hetAr 1 , where hetAr 1 is a 5-6 membered heteroaryl having 1-3 ring heteroatoms independently selected from N, S and O, and is optionally substituted with one or more groups independently selected from (l-6C)alkyl, halogen, OH, CF 3 , NH 2 and hydroxy(l-2C)alkyl. In one embodiment, Ring B is hetAr 1 , wherein hetAr 1 is a 5-6 membered heteroaryl having 1-2 ring heteroatoms independently selected from N, S and O, and optionally substituted with 1 -2 groups independently selected from (l-6C)alkyl, halogen, OH, CF 3 , NH 2 and hydroxy(l-2C)alkyl. Examples of Ring B include pyridyl, thiophenyl, thiazolyl, oxazolyl, and isoxazolyl rings optionally substituted with 1-2 groups independently selected from (l-6C)alkyl, halogen, OH, CF 3 , N¾ and hydroxy(l-2C)alkyl. In one embodiment, Ring B is a pyridyl, thiophenyl, thiazolyl, oxazolyl, or isoxazolyl ring optionally substituted with 1 -2 groups independently selected from halogen and (l-6C)alkyl.

[00143] Examples of Ring B when represented by hetAr 1 include pyrid-4-yl, pyrid-3-yl, pyrid-2-yl, 5-fluoropyrid-3-yl, thien-2-yl, thiazol-2-yl, 2,4-dimethylthiazol-5-yl, oxazol-5-yl, isoxazol-5-yl, 5-chloropyrid-3-yl, 5-fluoropyrid-2-yl, 3-fluoropyrid-4-yl and 1-methylpyrazol- 4-yl having the structures:

[00144] In one embodiment of Formula I, Ring B is a pyridyl ring optionally substituted with 1-2 groups independently selected from (l-6C)alkyl and halogen.

[00145] In one embodiment of Formula I, Ring C is formula C-l, C-2, C-3, C-4, C-5, C- 6 or C-13, where R 3 , R 3a , R 4 , R 4a , R 5 and R 5a are as defined for Formula I.

[00146] In one embodiment of Formula I, Ring C is formula C-l or C-2

C-1 C-2

[00147] where R 3 and R 5 are as defined for Formula I.

[00148] In one embodiment of formula C- 1 or C-2, R 3 is H.

[00149] In one embodiment of formula C-1 or C-2, R 3 is NH 2 .

[00150] In one embodiment of formula C-1 or C-2, R 3 is CN.

[00151] In one embodiment of formula C-1 or C-2, R is halogen.

[00152] In one embodiment of formula C-1 or C-2, R 3 is (l-3C)alkyl optionally substituted with 1 to 3 fluoros. In one embodiment, R 3 is methyl, ethyl, isopropyl, trifluoromethyl or 2,2,2-trifluoroethyl.

[00153] In one embodiment of formula C-1 or C-2, R 3 is H 2 NC(=0)-, (1- 3Calkyl)NHC(=0)- or di(l-3Calkyl)NHC(=0)-. In one embodiment, R 3 is H 2 NC(=0)-.

[00154] In one embodiment of formula C-1 or C-2, R 3 is hydroxy(l-3C)alkyl. In one embodiment, R 3 is HOCH 2 CH 2 - or HOC(CH 3 ) 2 -.

[00155] In one embodiment of formula C- 1 or C-2, R 3 is CH 3 OCH 2 CH 2 .

[00156] In one embodiment of formula C-1 or C-2, R 3 is (3-4C)cycloalkyl.

[00157] In one embodiment of formula C-1 or C-2, R 3 is (l-3C)alkoxy. In one embodiment, R 3 is methoxy or ethoxy.

[00158] In one embodiment of formula C-1 or C-2, R 3 is (l-3C)alkyl [optionally ssuubbssttiittuutteedd wwiitthh 11 ttoo 3 fluoros] or H 2 NC(=0)-. In one embodiment of Ring C-1 or C-2, R is methyl or H 2 NC(=0)-.

[00159] In one embodiment of formula C-1 or C-2, R 5 is H.

[00160] In one embodiment of formula C-1 or C-2, R 5 is (l-6C)alkyl [optionally substituted with 1-5 fluoros]. In one embodiment, R 5 is methyl, ethyl, isopropyl, trifluoromethyl, or 2,2,2-trifluoroethyl.

[00161] In one embodiment of formula C-1 or C-2, R 5 is halogen. In one embodiment, R 5 is F, CI or Br.

[00162] In one embodiment of formula C- 1 or C-2, R 5 is CN.

[00163] In one embodiment of formula C-1 or C-2, R 5 is (l-4C)alkoxy. In one embodiment, R 5 is methoxy or ethoxy.

[00164] In one embodiment of formula C-1 or C-2, R 5 is hydroxy(l-4C)alkyl. In one embodiment, R 5 is HOCH 2 or HOCH 2 CH 2 . [00165] In one embodiment of formula C-l or C-2, R 5 is (1-3C alkoxy)(l-4C)alkyl. In one embodiment, R 5 is CH 3 OCH 2 CH 2 -.

[00166] In one embodiment of formula C-l or C-2, R 5 is (1-4C alkyl)OC(=0)-. In one embodiment, R 5 is CH 3 OC(=0)-.

[00167] In one embodiment of formula C-l or C-2, R 5 is (l-6C)alkylthio. In one embodiment, R 5 is CH 3 S- or CH 3 CH 2 S-.

[00168] In one embodiment of formula C-l or C-2, R 5 is (3-4C)cycloalkyl.

[00169] In one embodiment of formula C-l or C-2, R 5 is amino. In one embodiment, R 5 is H 2 N-, CH 3 NH-, or (CH 3 ) 2 N-.

[00170] In one embodiment of formula C-l or C-2, R 5 is aminocarbonyl. In one embodiment, R 5 is H 2 NC(=0)-, CH 3 NHC(=0)-, or (CH 3 ) 2 NC(=0)-.

[00171] In one embodiment of formula C-l or C-2, R 5 is trifluoro(l-3C alkyl)amido. In one embodiment, R 5 is CF 3 C(=0)NH-.

[00172] In one embodiment of formula C-l or C-2, R 5 is phenyl optionally substituted with one or more groups independently selected from halogen, (l-6C)alkyl and (l-6C)alkoxy. In one embodiment, R 5 is phenyl optionally substituted with one or more groups independently selected from F, CI, Br, methyl, ethyl, methoxy and ethoxy. In one embodiment, R 5 is phenyl.

[00173] In one embodiment of formula C-l or C-2, R 5 is (l-6C)alkyl [optionally substituted with 1-5 fluoros] or phenyl [optionally substituted with one or more groups independently selected from halogen, (l-6C)alkyl and (l-6C)alkoxy].

[00174] In one embodiment of formula C-l or C-2, R 5 is methyl or phenyl.

[00175] In one embodiment of formula C-l or C-2, R 3 is (l-3C)alkyl [optionally substituted with 1 to 3 fluoros] or H 2 NC(=0)-; and R 5 is (l-6C)alkyl [optionally substituted with 1-5 fluoros] or phenyl [optionally substituted with one or more groups independently selected from halogen, (l-6C)alkyl and (l-6C)alkoxy].

[00176] In one embodiment of formula C-l or C-2, R 3 is (l-3C)alkyl [optionally substituted with 1 to 3 fluoros] or F^NC^O)-; and R 5 is phenyl [optionally substituted with one or more groups independently selected from halogen, (l-6C)alkyl and (l-6C)alkoxy].

[00177] In one embodiment Ring C is formula C-l or C-2 and is selected from the structures:

[00178] In one embodiment of Formula I, Ring C is formula C-3, C-4, C-5, C-6 or C-l 3

C-3 C-4 C-5 C-6 C-13

[00179] where R 3a , R 4 , R 4a , R 5 and R 5a are as defined for Formula I.

[00180] In one embodiment of formula C-5, R 3a is H.

[00181] In one embodiment of formula C-5, R 3a is (l-3C)alkyl.

[00182] In one embodiment of formula C-5, R 3a is CF 3 CH 2 CH 2 , HCF 2 CH 2 CH 2 , H 2 FCCH 2 CH 2 or CF 3 CH 2 .

[00183] In one embodiment of formula C-5, R 3a is HOCH 2 CH 2 .

[00184] In one embodiment of formula C-5, R 3a is MeOCH 2 CH 2 .

[00185] In one embodiment of formula C-5, R 3a is H 2 NC(=0)-, (l-3Calkyl)NHC(=0)-, di(l-3Calkyl)NHC(=0)-. In one embodiment, R 3 is H 2 NC(=0)-.

[00186] In one embodiment of formula C-5, R 3a is (3-4C)cycloalkyl.

[00187] In one embodiment of formula C-3, C-4, C-5, C-6 or C-13, R 5 or R 5a is H.

[00188] In one embodiment of formula C-3, C-4, C-5, or C-13, R 5 is (l-6C)alkyl optionally substituted with 1-5 fluoros. In one embodiment, R 5 is methyl, ethyl or isopropyl.

[00189] In one embodiment of formula C-6, R 5a is (l-6C)alkyl, CF 3 CH 2 CH 2 ,

HCF 2 CH 2 CH 2 , H 2 FCCH 2 CH 2 , or CF 3 CH 2 .

[00190] In one embodiment of formula C-3, C-4, C-5 or C-13, R 5 is halogen.

[00191] In one embodiment of formula C-3, C-4, C-5 or C-13, R 5 is CN.

[00192] In one embodiment of formula C-3, C-4, C-5 or C-13, R 5 is (l-4C)alkoxy. In one embodiment, R 5 is methoxy or ethoxy.

[00193] In one embodiment of formula C-3, C-4, C-5, C-6 or C-13, R 5 or R 5a is hydroxy(l-4C)alkyl. In one embodiment, R 5 or R 5a is HOCH 2 CH 2 -.

[00194] In one embodiment of formula C-3, C-4, C-5, C-6 or C-13, R 5 or R 5a is (1-3C alkoxy)(l-4C)alkyl. In one embodiment, R 5 or R 5a is CH 3 OCH 2 CH 2 -.

[00195] In one embodiment of formula C-3, C-4, C-5 or C-13, R 5 is (1-4C alkyl)OC(=0)-. In one embodiment, R 5 is CH 3 OC(=0)-.

[00196] In one embodiment of formula C-3, C-4, C-5 or C-13, R 5 is (l-6C)alkylthio. In one embodiment, R 5 is CH 3 S-.

[00197] In one embodiment of formula C-3, C-4, C-5, C-6 or C-13, R 5 or R 5a is (3- 4C)cycloalkyl. [00198] In one embodiment of formula C-3, C-4, C-5 or C-13, R 5 is amino. In one embodiment, R 5 is NH 2 .

[00199] In one embodiment of formula C-3, C-4, C-5 or C-13, R 5 is aminocarbonyl or trifluoro(l-3C alkyl)amido.

[00200] In one embodiment of formula C-3, C-4, C-5, C-6 or C-13, R 5 or R 5a is phenyl

[optionally substituted with one or more groups independently selected from halogen, (1-

6C)alkyl and (l-6C)alkoxy]. In one embodiment, R 5 or R 5a is phenyl.

[00201] In one embodiment of formula C-3, C-4, C-5, C-6 or C-l 3, R 4 or R 4a is H.

[00202] In one embodiment of formula C-3, C-4, C-5 or C-6, R 4 is OH.

[00203] In one embodiment of formula C-3, C-4, C-5 or C-6, R 4 is (l-6C)alkyl optionally substituted with 1-5 fluoros. In one embodiment, R 4 is methyl, ethyl, isopropyl, tert-butyl, fluoromethyl, 2-fluoroethyl, difluoromethyl and 2,2-difluoroethyl, trifluoromethyl,

2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 2,2,3,3-tetrafluoropropyl or 2,2,3,3,3- pentafluoropropyl.

[00204] In one embodiment of formula C-13, R 4a is (l-6C)alkyl, CF 3 CH 2 CH 2 , HCF 2 CH 2 CH 2 , H 2 FCCH 2 CH 2 or CF 3 CH 2 ,

[00205] In one embodiment of formula C-3, C-4, C-5, C-6 or C-13, R 4 or R 4a is cyano(l-6C)alkyl. In one embodiment, R 4 or R 4a is cyanomethyl or 2-cyanopropan-2-yl.

[00206] In one embodiment of formula C-3, C-4, C-5, C-6 or C-13, R 4 or R 4a is hydroxy(l-6C)alkyl. In one embodiment, R 4 is hydroxymethyl, 2-hydroxyethyl, 2- hydroxypropyl, 2-hydroxy-2-methylpropyl or l-hydroxy-2-methylpropan-2-yl. In one embodiment, R 4a is 2-hydroxyethyl, 2-hydroxypropyl, 2-hydroxy-2-methylpropyl or 1- hydroxy-2-methylpropan-2-yl.

[00207] In one embodiment of formula C-3, C-4, C-5, C-6 or C-13, R 4 or R 4a is dihydroxy(2-6C)alkyl. In one embodiment, R 4 or R 4a is 2,3-dihydroxypropyl.

[00208] In one embodiment of formula C-3, C-4, C-5, C-6 or C-13, R 4 or R 4a is (1-3C alkoxy)(l-6C)alkyl. In one embodiment, R 4 is methoxymethyl, 2-methoxyethyl or 3- methoxypropyl. In one embodiment, R 4a is 2-methoxyethyl or 3-methoxypropyl.

[00209] In one embodiment of formula C-3, C-4, C-5, C-6 or C-13, R 4 or R 4a is amino(l-6C)alkyl. In one embodiment, R 4 or R 4a is aminomethyl, 2-aminoethyl or 3- aminopropyl.

[00210] In one embodiment of formula C-3, C-4, C-5, C-6 or C-13, R 4 or R 4a is aminocarbonyl(l-6C)alkyl. In one embodiment, R 4 or R 4a is aminocarbonylmethyl or 2- (aminocarbonyl)ethyl. [00211] In one embodiment of formula C-3, C-4, C-5, C-6 or C-13, R 4 or R 4a is (1-

3C)alkylsulfonamido(l-6C)alkyl. In one embodiment, R 4 is CH 3 S0 2 NHCH 2 - or

CH3SO2NHCH2CH2-. In one embodiment, R 4a is CH 3 S0 2 NHCH 2 CH 2 -.

[00212] In one embodiment of formula C-3, C-4, C-5, C-6 or C-13, R 4 or R 4a is hydroxycarbonyl(l-6C)alkyl. In one embodiment, R 4 or R 4a is HOC(=0)CH 2 - or

HOC(=0)CH 2 CH 2 -.

[00213] In one embodiment of formula C-3, C-4, C-5, C-6 or C-13, R 4 or R 4a is hetAr (l-6C)alkyl, where hetAr is a 5-membered heteroaryl ring having 1-3 ring atoms independently selected from N, S and O and optionally substituted with (l-6C)alkyl. In one embodiment, hetAr 3 is a thienyl, furyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl or oxadiazolyl ring optionally substituted with (l-6C)alkyl. In one embodiment, R 4 or R 4a when represented by hetAr 3 (l-6C)alkyl is ( 1 -methyl- 1H- 1,2,4- triazol-3-yl)methyl or (5-methyl-l,3,4-oxadiazol-2-yl)methyl.

[00214] In one embodiment of formula C-3, C-4, C-5, C-6 or C-13, R 4 or R 4a is Ar^l- 6C)alkyl, where phenyl optionally substituted with (l-4C)alkoxy or hydroxy(l-4C)alkyl. In one embodiment, R 4 or R 4a is benzyl.

[00215] In one embodiment of formula C-3, C-4 or C-5 or C-6, R 4 is (l-6C)alkoxy optionally substituted with 1-5 fluoros. In one embodiment, R 4 is methoxy, ethoxy, fluoromethoxy, 2-fluoroethoxy, 2,2-difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy or 2,2-difluoroethoxy. In one embodiment, R 4 is 2-fluoroethoxy.

[00216] In one embodiment of formula C-3, C-4, C-5 or C-6, R 4 is cyano(l-6C)alkoxy. In one embodiment, R 4 is cyanomethoxy or 2-cyanoethoxy.

[00217] In one embodiment of formula C-3, C-4, C-5 or C-6, R 4 is hydroxy(l- 6C)alkoxy. In one embodiment, R 4 is 2-hydroxy-2-methylpropoxy, 2-hydroxyethoxy, 2- hydroxypropoxy, 2-hydroxy-2-methylpropoxy or 2-hydroxybutoxy.

[00218] In one embodiment of formula C-3, C-4, C-5 or C-6, R 4 is dihydroxy(2- 6C)alkoxy. In one embodiment, R 4 is 2,3-dihydroxypropoxy or 3-hydroxy-2- (hydroxymethyl)propoxy.

[00219] In one embodiment of formula C-3, C-4, C-5 or C-6, R 4 is amino(2-6C)alkoxy. In one embodiment, R 4 is H 2 NCH 2 CH 2 0-.

[00220] In one embodiment of formula C-3, C-4, C-5 or C-6, R 4 is hetCyc 2 (l- 6C)alkoxy, where hetCyc is a 4-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O, wherein hetCyc 2 is optionally substituted with 1-2 groups independently selected from (l-6C)alkyl, (1-4C alkoxy)carbonyl, and (l-6C)acyl. In one embodiment, hetCyc 2 is oxetaynyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or and 1,3-dioxolanyl optionally substituted with 1-2 groups independently selected from (l-6C)alkyl, (1-4C alkoxy)carbonyl and (1- 6C)acyl. In one embodiment, R 4 when represented by hetCyc 2 (l-6C)alkoxy is oxetan-2- ylmethoxy, 2-(oxetan-2-yl)propoxy, (2,2-dimethyl-l,3-dioxolan-4-yl)methoxy, (1,3-dioxolan- 4-yl)methoxy, 2-morpholinoethoxy, piperazinylethyoxy or piperidinylethoxy optionally substituted with 1-2 groups independently selected from (l-6C)alkyl, (1-4C alkoxy)carbonyl

[00221] In one embodiment of formula C-3, C-4, C-5 or C-6, R 4 is hetAr 3 (l-6C)alkoxy, where hetAr 3 is a 5-membered heteroaryl ring having 1-3 ring atoms independently selected from N, S and O and optionally substituted with (l-6C)alkyl. In one embodiment, hetAr 3 is a thienyl, furyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl or oxadiazolyl ring optionally substituted with (l-6C)alkyl. In one embodiment, hetAr 3 is triazolyl or oxadiazolyl ring optionally substituted with a (l-6C)alkyl group such as a methyl group. In one embodiment, R 4 when represented by hetAr 3 (l-6C)alkoxy is (1-methyl- lH-l,2,4-triazol-3-yl)methoxy or (5-methyl-l,3,4-oxadiazol-2-yl)methoxy, which can be represented by the structures:

[00222] In one embodiment of formula C-3, C-4, C-5 or C-6, R 4 is Ar 3 (l-6C)alkoxy, where Ar 3 is phenyl optionally substituted with (l-4C)alkoxy. In one embodiment, R 4 is phenylmethoxy or (4-methoxyphenyl)methoxy having the structures: [00223] In one embodiment of formula C-3, C-4, C-5 or C-6, R 4 is (1-4C alkoxy)(l- 6C)alkoxy. In one embodiment, R 4 is (2-methoxy)ethoxy having the structure:

[00224] In one embodiment of formula C-3, C-4, C-5 or C-6, R 4 is (1-

3Calkylsulfonyl)(l-6C)alkoxy. In one embodiment, R 4 is (2-methylsulfonyl)ethoxy having the structure:

[00225] In one embodiment of formula C-3, C-4, C-5, C-6 or C-13, R 4 or R 4a is (3- 6C)cycloalkyl optionally substituted with F, OH, (1-6C alkyl), (l-6C)alkoxy or (1-3C alkoxy)(l-6C)alkyl. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2- hydroxycyclobutyl. In one embodiment, R 4 or R 4a is cyclopropyl or 2-hydroxycyclobutyl. In one embodiment, R 4 is cyclopropyl.

[00226] In one embodiment of formula C-3, C-4, C-5, C-6 or C-13, R 4 or R 4a is hetAr 4 , where hetAr 4 is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, S and O and optionally substituted with one or more substituents independently selected from (l-6C)alkyl, halogen, CN, hydroxy(l-6C)alkyl, trifluoro(l- 6C)alkyl, difluoro(l-6C)alkyl, fluoro(l-6C)alkyl, (3-6C)cycloalkyl, (3-6C cycloalkyl)CH 2 - (3- 6C cycloalkyl)C(O)-, (1-3C alkoxy)(l-6C)alkyl, (l-6C)alkoxy, (l-6C)alkylsulfonyl, NH 2 , (1- 6C alkyl)amino, di(l-6C alkyl)amino, (1-3C trifluoroalkoxy), fluoro(l-6C alkyl)amino, difluoro(l-6C alkyl)amino, trifluoro(l-6C alkyl)amino, and (3-4C cycloalkyl)amino.

[00227] In one embodiment of formula C-3, C-4, C-5, C-6 or C-13, R 4 or R 4a is hetAr 4 where hetAr 4 is pyridyl, pyrimidinyl pyridazinyl, pyrazolyl, imidazolyl, thienyl, 1 ,2,4-triazolyl, 1,2,3-triazolyl, thiazolyl, oxazolyl, 1,3,4-oxadiazolyl, or 1,2,4-oxadiazolyl optionally substituted with one or more substituents independently selected from (l-6C)alkyl, halogen, CN, hydroxy(l-6C)alkyl, trifluoro(l-6C)alkyl, difluoro(l-6C)alkyl, fluoro(l-6C)alkyl, (3- 6C)cycloalkyl, (3-6C cycloalkyl)CH 2 - (3-6C cycloalkyl)C(=0)-, (1-3C alkoxy)(l-6C)alkyl, (1- 6C)alkoxy, (l-6C)alkylsulfonyl, NH 2 , (1-6C alkyl)amino, di(l-6C alkyl)amino, (1-3C trifluoroalkoxy), fluoro(l-6C alkyl)amino, difluoro(l-6C alkyl)amino, trifluoro(l-6C alkyl)amino, and (3-4C cycloalkyl)amino.

[00228] In one embodiment of formula C-3, C-4, C-5, C-6 or C-13, R 4 or R 4a is hetAr 4 where hetAr 4 is pyridyl, pyrimidinyl pyridazinyl, pyrazolyl, imidazolyl, thienyl, 1 ,2,4-triazolyl, 1,2,3-triazolyl, thiazolyl, oxazolyl, 1,3,4-oxadiazolyl, or 1,2,4-oxadiazolyl optionally substituted with one or more substituents independently selected from (l-6C)alkyl, hydroxy(l- 6C)alkyl, trifluoro(l-6C)alkyl, (3-6C)cycloalkyl, (3-6C cycloalkyl)CH 2 - (3-6C cycloalkyl)C(=0)-, (1-3C alkoxy)(l-6C)alkyl, (l-6C)alkoxy, (l-6C)alkylsulfonyl, NH 2 , (1-6C alkyl)amino, di(l-6C alkyl)amino, (1-3C trifluoroalkoxy)(l-3C)trifluoroalkyl and cyclopropylNH-.

[00229] In one embodiment of formula C-3, C-4, C-5, C-6 or C-13, R 4 or R 4a is hetAr 4 , where hetAr 4 is pyridyl, pyrimidinyl pyridazinyl, pyrazolyl, imidazolyl, thionyl, 1,2,4- triazolyl, 1,2,3-triazolyl, thiazolyl, oxazolyl, 1,3,4-oxadiazolyl, or 1 ,2,4-oxadiazolyl optionally substituted with 1-3 substituents independently selected from fluoro, methyl, ethyl, isopropyl, cyclopropylmethyl, cyclopropyl, trifluoromethyl, 2,2,2-trifluoroethyl, methoxy, ethoxy, CN, H 2 N-, (C¾) 2 N-, 2-hydroxyethyl, 2-methoxyethyl, l-(2,2,2-trifiuoroethoxy)-2,2,2- trifluoroethyl, cyclopropylcarbonyl, methylsulfonyl and cyclopropylNH-.

[00230] In one embodiment of formula C-3, C-4, C-5, C-6 or C-13, R 4 or R 4a is hetAr 4 , where hetAr 4 is pyridyl, pyrimidinyl or pyridazinyl optionally substituted with 1-3 substituents independently selected from fluoro, methyl, ethyl, isopropyl, cyclopropylmethyl, cyclopropyl, trifluoromethyl, 2,2,2-trifluoroethyl, methoxy, ethoxy, CN, H 2 N-, CH 3 NH-, (CH 3 ) 2 N-, and cyclopropylNH-. In one embodiment of formula C-3, C-4, C-5, C-6 or C-13, R 4 or R 4a is selected from the structures:

[00231] In one embodiment of formula C-3, C-4, C-5 or C-6, R 4 is hetAr 4 -0-. In one embodiment, R 4 is the structure:

[00232] In one embodiment of formula C-3, C-4, C-5, C-6 or C-13, R 4 or R 4a is Ar 4 , where Ar 4 is phenyl optionally substituted with one or more groups independently selected from (l-6C)alkyl, halogen, CN, CF 3 , CF 3 0-, (l-6C)alkoxy, (l-6Calkyl)OC(=0)-, aminocarbonyl, (l-6C)alkylthio, hydroxy(l-6C)alkyl, (1-6C alkyl)S0 2 -, HOC(=0)- and (1-3C alkoxy)(l-3C alkyl)OC(=0)-. In one embodiment, Ar 4 is phenyl optionally substituted with one or more groups independently selected from methyl, F, CI, CN, methoxy, CH 3 OC(=0)-, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, methylthio, CH 3 S0 2 -, HOC(=0)- and CH 3 OCH 2 CH 2 OC(=0)-. In one embodiment, Ar 4 is phenyl optionally substituted with one or two of said substituents. In one embodiment, Ar 4 is selected from the

[00233] In one embodiment of formula C-3, C-4, C-5 or C-6, R 4 is hetCyc 2 (0)CH 2 , where hetCyc 2 is a 4-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O, wherein hetCyc is optionally substituted with 1-2 groups independently selected from (l-6C)alkyl, (1-4C alkoxy)carbonyl, and (l-6C)acyl. Examples of hetCyc include oxetaynyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, and 1,3-dioxolanyl rings optionally substituted with 1-2 groups independently selected from (l-6C)alkyl, (1-4C alkoxy)carbonyl and (l-6C)acyl. In one embodime 4 when represented by hetCyc 2 (0)CH 2 is selected from the structures:

[00234] In one embodiment of formula C-3, C-4, C-5 or C-6, R 4 is (1-4C alkoxycarbonyl)(l-6C)alkoxy. In one embodiment, R 4 is methoxycarbonyl(l-6C)alkoxy or ethyoxycarbonyl(l-6C)alkoxy. A particular example is ethoxycarbonylmethoxy.

[00235] In one embodiment of formula C-3, C-4, C-5 or C-6, R 4 is hydroxycarbonyl(l- 6C)alkoxy. In one embodiment, R 4 is hydroxycarbonylmethoxy.

[00236] In one embodiment of formula C-3, C-4, C-5 or C-6, R 4 is aminocarbonyl(l- 6C)alkoxy. In one embodiment, R 4 is H 2 NC(=0)(l-6C)alkoxy, (1-6C alkyl)NHC(=0)(l- 6C)alkoxy, or di(l-6Calkyl)NC(=0)(l-6C)alkoxy. In one embodiment, R 4 is CH 3 CH 2 NC(=0)CH 2 0-, H 2 NC(=0)CH 2 0- or H 2 NC(=0)CH 2 CH 2 0-.

[00237] In one embodiment of formula C-3, C-4, C-5 or C-6, R 4 is hetCyc 2 C(=0)(l- 6C)alkoxy, where hetCyc 2 is a 4-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O and optionally substituted with 1-2 groups independently selected from (l-6C)alkyl, (1-4C alkoxy)carbonyl, and (l-6C)acyl. In one embodiment, hetCyc 2 is oxetaynyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, pipendinyl, piperazinyl, morpholinyl, or 1,3-dioxolanyl optionally substituted with 1-2 groups independently selected from (l-6C)alkyl, (1-4C alkoxy)carbonyl and (l-6C)acyl. In one embodiment, hetCyc 2 is morpholinyl. In one embodiment, R 4 when represented by hetCyc 2 C(=0)(l-6C)alkoxy has the

[00238] In one embodiment of formula C-3, C-4, C-5 or C-6, R 4 is hydroxy(l-3C alkoxy)(l-6C)alkoxy. In one embodiment, R 4 is 2-hydroxy-3-methoxypropoxy having the structure:

[00239] In one embodiment of formula C-3, C-4, C-5 or C-6, R 4 is hydroxytrifluoro(l- 6C)alkoxy. In one embodiment, R 4 is 3,3,3-difluoro-2-hydroxypropoxy having the structure:

A

OH

[00240] In one embodiment of formula C-3, C-4, C-5 or C-6, R 4 is (1- 3C)alkylsulfonamido(l-6C)alkoxy. In one embodiment, R 4 is methanesulfonamido(l- 6C)alkoxy. In one embodiment, R 4 is 2-methanesulfonamidoethoxy having the structure:

Me0 2 S ^ O

[00241] In one embodiment of formula C-3, C-4, C-5 or C-6, R 4 is (l-3C)alkylamido(l- 6C)alkoxy. In one embodiment, R 4 is -(methylamido)ethoxy having the structure:

[00242] In one embodiment of formula C-3, C-4, C-5 or C-6, R 4 is di(l-3C alkyl)aminocarboxy. In one embodiment, R 4 is dimethylaminocarboxy having the structure:

[00243] In one embodiment of formula C-3, C-4, C-5 or C-6, R 4 is hetCyc 2 C(=0)0-, where hetCyc 2 is a 4-6 membered heterocyclic ring having 1-2 ring heteroatoms independently selected from N and O and optionally substituted with 1-2 groups independently selected from (l-6C)alkyl, (1-4C alkoxy)carbonyl and (l-6C)acyl. In one embodiment, hetCyc is oxetaynyl, tetrahydrofuranyl, tetrahydropyranyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or 1,3-dioxolanyl optionally substituted with 1-2 groups independently selected from (l-6C)alkyl, (1-4C alkoxy)carbonyl and (l-6C)acyl. In one embodiment, hetCyc 2 is morpholinyl. In one embodiment, R 4 when represented by hetCyc 2 C(=0)0- is the structure:

[00244] In one embodiment of formula C-3, C-4, C-5, C-6 or C-13, R 4 or R 4a is hydroxydifluoro(l-6C)alkyl. In one embodiment, R 4 or R 4a is 2,2-difluro-2-hydroxyethyl.

[00245] In one embodiment of formula C-3, C-4, C-5, C-6 or C-13, R 4 or R 4a is (1-4C alkylcarboxy)(l-6C)alkyl. In one embodiment, R 4 or R 4a is methylcarboxy(l-6C)alkyl. In one embodiment, R 4 or R 4a is 2-(methylcarboxy)ethyl.

[00246] In one embodiment of formula C-3, C-4, C-5 or C-6, R 4 is (1- 6C)alkoxycarbonyl. In one embodiment, R 4 is methoxycarbonyl or ethoxycarbonyl.

[00247] In one embodiment of formula C-3, C-4, C-5 or C-6, R 4 is hydroxy carbonyl.

[00248] In one embodiment of formula C-3, C-4, C-5 or C-6, R 4 is aminocarbonyl, that is, a RR'NCO- radical where R and R' are independently hydrogen or (l-6C)alkyl as defined herein. In one embodiment, R 4 is aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, ethylcarbonyl or isopropylaminocarbonyl.

[00249] In one embodiment of formula C-3, C-4, C-5 or C-6, R 4 is (1-3C alkoxy)aminocarbonyl. In one embodiment, R 4 is methoxyaminocarbonyl.

[00250] In one embodiment of formula C-3, C-4, C-5, C-6 or C-13, R 4 or R 4a is hetCyc 3 , where is a 4-7 membered heterocycle having 1 -2 ring heteroatoms independently selected from N and O and optionally substituted with one or more substituents independently selected from F, CN, CF 3 , (l-6C)alkyl, hydroxy(l-6C)alkyl, (1-3C alkoxy)(l-6C)alkyl, (l-6C)acyl-, (1- 6C)alkylsulfonyl, trifluoromethylsulfonyl and (1-4C alkoxy)carbonyl. In one embodiment, hetCyc 3 is tetrahydropyranyl, piperidinyl, pyrrolidinyl or azetidinyl optionally substituted with one or more substituents independently selected from F, CN, (l-6C)alkyl, trifluoro(l-6C)alkyl, hydroxy(l-6C)alkyl, (1-3C alkoxy)(l-6C)alkyl, (l-6C)acyl-, (l-6C)alkylsulfonyl, trifluoromethylsulfonyl and (1-4C alkoxy)carbonyl. In one embodiment, hetCyc 3 is optionally substituted with one or two of said substituents. In one embodiment, hetCyc 3 is tetrahydropyranyl, piperidinyl, pyrrolidinyl or azetidinyl optionally substituted with CN, Me, CH 3 C(=0)-, MeS0 2 -, or CF 3 S0 2 -. In one embodiment of formula C-3, C-4, C-5, C-6 or C-13, R 4 or R 4a when re resented by hetCyc 3 is selected from the structures:

[00251] In one embodiment of formula C-3, C-4, C-5 or C-6, R 4 is halogen. In one embodiment, R 4 is Br.

[00252] In one embodiment of formula C-3, C-4, C-5 or C-6, R 4 is CN.

[00253] In one embodiment of formula C-3, C-4, C-5 or C-6, R 4 is trifluoromethylsulfonyl.

[00254] In one embodiment of formula C-3, C-4, C-5, C-6 or C-13, R 4 or R 4a is hetAr 5 ,

[00255] where R z is (3-4C)cycloalkyl or (l-3C)alkyl (optionally substituted with 1-3 fluoros), wherein each of said hetAr 5 groups is optionally further substituted with one or more groups independently selected from F and (l-3C)alkyl optionally substituted with 1-3 fluoros. [00256] In one embodiment of formula C-3, C-4, C-5, C-6 or C-13, R 4 or R 4a when represented by hetAr 5 is selected from the structures:

[00257] In one embodiment of formula C-3, C-4, C-5, C-6 or C-13, R 4 or R 4a is N-(1-3C alkyl)oxadiazolonyl. In one embodiment, R 4 is represented by the structures:

[00258] In one embodiment of formula C-3, C-4, C-5 or C-13, R 4 is selected from H, (l-6C)alkyl, (l-6C)alkyl [optionally substituted with 1-5 fluoros], hydroxy(l-6C)alkyl, (1-3C alkoxy)(l-6C)alkyl, (3-6C)cycloalkyl, di(l-3C alkyl)amino-carboxy, hetAr 4 , hetAr 4 -0-, Ar 4 , and hetAr 5 .

[00259] In one embodiment of formula C-6, R 4a is selected from H, (l-6C)alkyl, CF 3 CH 2 CH 2 , HCF 2 CH 2 CH 2 , H 2 FCCH 2 CH 2 , CF 3 CH 2 , (l-6C)alkyl, hydroxy(l-6C)alkyl, cyano(l-6C)alkyl, (1-3C alkoxy)(l-6C)alkyl, (3-6C)cycloalkyl, hetAr 4 , Ar 4 , and hetAr 5 .

[00260] In one embodiment of formula C-3, C-4, C-5, C-6 or C-13, R 4 or R 4a is selected from (l-6C)alkyl, hydroxy(l-6C)alkyl, hetAr 4 , Ar 4 , and hetAr 5 .

[00261] In one embodiment of formula C-3, C-4, C-5, C-6 or C-13, R 4 or R 4a is hetAr 4 , Ar 4 , or hetAr 5 .

[00262] In one embodiment of formulaC-3, C-4, C-5, C-6 or C-13, R 4 or R 4a is hetAr 4 or hetAr 5 .

[00263] In one embodiment of formula C-3, C-4, C-5, C-6 or C-13, R 4 or R 4a is hetAr 5 .

[00264] In one embodiment of formula C-3, C-4, C-5, C-6 or C-13, R 4 or R 4a is pyrazolyl optionally substituted with one or more groups independently selected from (1- 6C)alkyl, or a hetAr 5 group having the structure:

[00265] where R 2 is (3-4C)cycloalkyl or (l-3C)alkyl (optionally substituted with 1-3 fluoros), wherein said hetAr 5 group is optionally further substituted with one or more groups independently selected from F and (l-3C)alkyl optionally substituted with 1-3 fluoros.

[00266] In one embodiment of Formula I, Ring C is formula C-3, C-4, C-5, C-6 or C-13, where R 3a is (l-3C)alkyl; R 4 is selected from (l-6C)alkyl, hydroxy(l-6C)alkyl, (1- 6C)alkoxycarbonyl, aminocarbonyl, hetAr 4 , Ar 4 , and hetAr 5 ; R 4a is selected from (1- 6C)alkyl, hydroxy(l-6C)alkyl, (l-6C)alkoxycarbonyl, aminocarbonyl, hetAr 4 , Ar 4 , and hetAr 5 ; R 5 is halogen or (l-6C)alkyl [optionally substituted with 1-5 fluoros] or phenyl [optionally substituted with one or more groups independently selected from halogen, (1- 6C)alkyl and (l-6C)alkoxy], and R 5a is (l-6C)alkyl, CF 3 CH 2 CH 2 , HCF 2 CH 2 CH 2 , H 2 FCCH 2 CH 2 , CF 3 CH 2 , or phenyl [optionally substituted with one or more groups independently selected from halogen, (l-6C)alkyl and (l-6C)alkoxy].

[00267] In one embodiment of Formula I, formulas C-3, C-4, C-5, C-6 and C-13 are selected from the structures:

[00268] In one embodiment of Formula I, Ring C is formula C-7

[00269] where R 3a , R 4a and R 5 are as defined for Formula I.

[00270] In one embodiment of formula C-7, R 3a is (l-3C)alkyl, CF 3 CH 2 CH 2 , HCF 2 CH 2 CH 2 , H 2 FCCH 2 CH 2 , or CF 3 CH 2 .

[00271] In one embodiment of formula C-7, R 3a is (1 -3C)alkyl.

[00272] In one embodiment of formula C-7, R 3a is CF 3 CH 2 CH 2 , HCF 2 CH 2 CH 2 , H 2 FCCH 2 CH 2 , or CF 3 CH 2 .

[00273] In one embodiment of formula C-7, R 3a is HOCH 2 CH 2 or MeOCH 2 CH 2 .

[00274] In one embodiment of formula C-7, R 3a is (3-4C)cycloalkyl.

[00275] In one embodiment of formula C-7, R 5 is any of the above described substituents as defined for formulas C-1 and C-2. In one embodiment of formula C-7, R 5 is phenyl optionally substituted with one or more groups independently selected from halogen, (l-6C)alkyl and (l-6C)alkoxy. In one embodiment of formula C-7, R 5 is phenyl optionally substituted with one or more groups independently selected from F, CI, Br, methyl, ethyl, methoxy or ethoxy. In one embodiment, R 5 is phenyl.

]00276] In one embodiment of formula C-7, R 4a is any of the above described substituents as defined for formula C-13. In one embodiment of formula C-7, R 4a is (1- 6C)alkyl, hetAr 4 , hetAr 5 or Ar 4 . In one embodiment of formula C-7, R 4a is (l-6C)alkyl.

[00277] In one embodiment, Ring C is formula C-7, wherein R 3a is (l-3C)alkyl; R 4a is (l-6C)alkyl; and R 5 is phenyl optionally substituted with one or more groups independently selected from halogen, (l-6C)alkyl and (l-6C)alkoxy.

[00278] In one embodiment formula C-7 is selected fr m he structures:

[00279] In one embodiment of Formula I Ring C is formula C-8 or C-9

C-8 C-9

[00280] where R 7 , R 8a and R 8b are as defined for Formula I. [00281] In one embodiment of formula C-8 or C-9, R 7 is (l-6C)alkyl. In one embodiment, R 7 is methyl.

[00282] In one embodiment of formula C-8 or C-9, R 7 is (3-6C)cycloalkyl. In one embodiment, R 7 is cyclopropyl.

[00283] In one embodiment of formula C-8 or C-9, R 7 is phenyl optionally substituted with one or more groups independently selected from halogen, (l-6C)alkyl, (l-6C)alkoxy, (3- 4C)cycloalkyl, amino, aminocarbonyl, and trifluoro(l-3C)alkylamido. In one embodiment of formula C-8 or C-9, R 7 is phenyl optionally substituted with one or two groups independently selected from halogen, (l-6C)alkyl, (l-6C)alkoxy, (3-4C)cycloalkyl, amino, aminocarbonyl, and trifluoro(l-3C)alkylamido. In one embodiment, R 7 is phenyl optionally substituted with one or more groups independently selected from F, CI, methoxy, ethoxy, cyclopropyl, NH 2 , NH 2 C(=0)- and CF 3 C(=0)NH-. In one embodiment, R 7 is phenyl.

[00284] In one embodiment of formula C-8 or C-9, R 7 is ( 1 -6C)alkyl or phenyl.

[00285] In one embodiment of formula C-8, R 8a and R 8b are independently H, halogen, CN, NH 2 , (l-6C)alkyl [optionally substituted with 1-5 fluoros], (l-6C)alkoxy, (1-3C alkoxy)(l-6C)alkyl, (1-3C alkoxy)(l-6C)alkoxy, (1-6C alkyl)sulfonyl, (3-6C cycloalkyl)sulfonyl, (3-4C)cycloalkyl, amino, (l-6Calkyl)NH-, phenyl [optionally substituted with (1-6C alkyl)S0 2 -] or hetAr 4 , wherein only one of R 8a and R 8b can be phenyl [optionally substituted with (1-6C alkyl)S0 2 -] or hetAr 4 ; and R 7 is as defined for Formula I. In one embodiment, R 7 is (l-6C)a!kyl or phenyl [optionally substituted with one or more groups independently selected from F, CI, methoxy, ethoxy, cyclopropyl, NH 2 , NH 2 C(=0)- and CF 3 C(=0)NH-].

[00286] In one embodiment of formula C-8, R 8a is H, halogen, CN, NH 2 , (l-6C)alkyl [optionally substituted with 1-5 fluoros], (l-6C)alkoxy, (1-3C alkoxy)(l-6C)alkyl, (1-3C alkoxy)(l-6C)alkoxy, (1-6C alkyl)sulfonyl, (3-6C cycloalkyl)sulfonyl, (3-4C)cycloalkyl, amino, (l-6Calkyl)NH-, phenyl [optionally substituted with (1-6C alkyl)S0 2 -] or hetAr 4 ; and R 8b is H, halogen, (l-6C)alkyl, trifluoro(l-6C)alkyl or (l-6C)alkoxy; and R 7 is as defined for Formula I. In one embodiment, R is (l-6C)alkyl or phenyl [optionally substituted with one or more groups independently selected from F, CI, methoxy, ethoxy, cyclopropyl, NH 2 , NH 2 C(=0)- and CF 3 C(=0)NH-].

[00287] In one embodiment of formula C-8, R 8a is H, halogen, CN, NH 2 , (l-6C)alkyl [optionally substituted with 1-5 fluoros], (l-6C)alkoxy, (1-3C alkoxy)(l-6C)alkyl, (1-3C alkoxy)(l-6C)alkoxy, (1-6C alkyl)sulfonyl, (3-6C cycloalkyl)sulfonyl, (3-4C)cycloalkyl, amino, (l-6Calkyl)NH-, phenyl [optionally substituted with (1-6C alkyl)S0 2 -] or hetAr 4 ; and R 8b is H.

[00288] In one embodiment of formula C-8, R 8a is H, halogen, (l-6C)alkyl [optionally substituted with 1-5 fluoros], (l-6C)alkoxy, (1-3C alkoxy)(l-6C)alkoxy, (1-6C alkyl)sulfonyl, (3-6C cycloalkyl)sulfonyl, phenyl or hetAr 4 ; and R 8b is H; and R 7 is as defined for Formula I. In one embodiment, R 7 is (l-6C)alkyl or phenyl [optionally substituted with one or more groups independently selected from F, CI, methoxy, ethoxy, cyclopropyl, NH 2 , NH 2 C(=0)- and CF 3 C(=0)NH-].

[00289] In one embodiment of formula C-8, R 8a is H, halogen, (l-6C)alkyl [optionally substituted with 1-5 fluoros], (l-6C)alkoxy, (1-3C alkoxy)(l-6C)alkoxy, (1-6C alkyl)sulfonyl, (3-6C cycloalkyI)sulfonyl, phenyl or hetAr 4 ; and R 8b is H, where hetAr 4 is a 6-membered heteroaryl having 1 -2 ring nitrogen atoms and optionally substituted with one or more groups independently selected from (l-6C)alkyl [optionally substituted with 1-3 fluoros], halogen, (1- 6C alkyl)amino, fluoro(l-6C alkyl)amino, difluoro(l-6C alkyl)amino, trifluoro(l-6C alkyl)amino, and (3-4C cycloalkyl)amino; and R 7 is as defined for Formula I. In one embodiment, R 7 is (l-6C)alkyl or phenyl [optionally substituted with one or more groups independently selected from F, CI, methoxy, ethoxy, cyclopropyl, NH 2 , NH 2 C(=0)- and CF 3 C(=0)NH-].

[00290] In one embodiment of formula C-8, R 8a is H, CI, Br, methyl, ethyl, isopropyl, methoxy, ethoxy, CH 3 OCH 2 CH 2 0-, cyclopropylsulfonyl, MeS0 2 , phenyl or pyridyl; and R 8b is H; and R 7 is as defined for Formula I. In one embodiment, R 7 is (l-6C)alkyl or phenyl [optionally substituted with one or more groups independently selected from F, CI, methoxy, ethoxy, cyclopropyl, NH 2 , NH 2 C(=0)- and CF 3 C(=0)NH-].

[00291] In one embodiment of formula C-8, R 8b is H, halogen, CN, NH 2 , (l-6C)alkyl, trifluoro(l-6C)alkyl, (l-6C)alkoxy, (1-3C alkoxy)(l-6C)alkyl, (1-3C alkoxy)(l-6C)alkoxy, (1- 6C alkyl)sulfonyl, (3-6C cycloalkyl)sulfonyl, (3-4C)cycloalkyl, amino, (l-6Calkyl)NH-, phenyl [optionally substituted with (1-6C alkyl)S0 2 -] or hetAr 4 ; and R 8a is H, halogen, (1- 6C)alkyl [optionally substituted with 1-5 fluoros], or (l-6C)alkoxy; and R 7 is as defined for Formula I. In one embodiment, R 7 is (l-6C)alkyl or phenyl [optionally substituted with one or more groups independently selected from F, CI, methoxy, ethoxy, cyclopropyl, NH 2 , NH 2 C(=0)- and CF 3 C(=0)NH-].

[00292] In one embodiment of formula C-8, R 8b is H, halogen, CN, NH 2 , (l-6C)alkyl [optionally substituted with 1-5 fluoros], (l-6C)alkoxy, (1-3C alkoxy)(l-6C)alkyl, (1-3C alkoxy)(l-6C)alkoxy, (1-6C alkyl)sulfonyl, (3-6C cycloalkyl)sulfonyl, (3-4C)cycloalkyl, amino, (l-6Calkyl)NH-, phenyl [optionally substituted with (1-6C alkyl)S0 2 -] or hetAr 4 ; and R 8a is H.

[00293] In one embodiment of formula C-8, R 8b is H, halogen, (l-6C)alkyl [optionally substituted with 1-5 fluoros], (l-6C)alkoxy, (1-3C alkoxy)(l-6C)alkoxy, (1-6C alkyl)sulfonyl, (3-6C cycloalkyl)sulfonyl, phenyl or hetAr 4 ; and R 8a is H; and R 7 is as defined for Formula I. In one embodiment, R 7 is (l-6C)alkyl or phenyl [optionally substituted with one or more groups independently selected from F, CI, methoxy, ethoxy, cyclopropyl, NH 2 , NH 2 C(=0)- and CF 3 C(=0)NH-].

[00294] In one embodiment of formula C-8, R 8b is H, halogen, (l-6C)alkyl [optionally substituted with 1-5 fluoros], (l-6C)alkoxy, (1-3C alkoxy)(l-6C)alkoxy, (1-6C alkyl)sulfonyl, (3-6C cycloalkyl)sulfonyl, phenyl or hetAr 4 ; and R 8a is H, where hetAr 4 is a 6-membered heteroaryl having 1-2 ring nitrogen atoms and optionally substituted with one or more groups independently selected from (l-6C)alkyl [optionally substituted with 1-3 fluoros], halogen, (1- 6C alkyl)amino, fluoro(l-6C alkyl)amino, difluoro(l-6C alkyl)amino, trifluoro(l-6C alkyl)amino, and (3-4C cycloalkyl)amino; and R 7 is as defined for Formula I. In one embodiment, R 7 is (l-6C)alkyl or phenyl [optionally substituted with one or more groups independently selected from F, CI, methoxy, ethoxy, cyclopropyl, NH 2 , NH 2 C(=0)- and CF 3 C(=0)NH-].

[00295] In one embodiment of formula C-8, R 8b is H, CI, Br, methyl, ethyl, isopropyl, methoxy, ethoxy, CH 3 0CH 2 CH 2 0-, cyclopropylsulfonyl, MeS0 2 , phenyl or pyridyl; and R 8a is H; and R 7 is as defined for Formula I. In one embodiment, R 7 is (l-6C)alkyl or phenyl [optionally substituted with one or more groups independently selected from F, CI, methoxy, ethoxy, cyclopropyl, NH 2 , NH 2 C(=0)- and CF 3 C(=0)NH-].

[00296] In one embodiment, formula -8 has the structure:

[00297] In one embodiment, formulas C-8 and C-9 are selected from the structures:

[00299] where R 9 and R 10 are as defined for Formula I.

[00300] In one embodiment of formula C- 10, C- 11 or C- 12, R 9 is H.

[00301] In one embodiment of formula C-10, C-11 or C-12, R 9 is (l-6C)alkyl. In embodiment, R 9 is methyl or ethyl.

[00302] In one embodiment of formula C-10, C-11 or C-12, R 9 is CF 3 CH 2 - CF 3 CH 2 CH 2 -. [00303] In one embodiment of formula C-10, C-l l or C-12, R 9 is (l-3Calkoxy)(l- 6C)alkyl. In one embodiment, R 9 is CH 3 OCH 2 -.

[00304] In one embodiment of formula C-10, C-l 1 or C-12, R 9 is (3-4C)cycloalkyl.

[00305] In one embodiment of formula C-10, C-l 1 or C-12, R 10 is (3-6C)cycloalkyl.

[00306] In one embodiment of formula C-10, C-l l or C-12, R 10 is phenyl optionally substituted with one or more substituents independently selected from halogen, (l-6C)alkyl, (l-6C)alkoxy, (3-4C)cycloalkyl, amino, aminocarbonyl and trifluoro(l-3C alkyl)amido. In one embodiment of formula C-10, C-l l or C-12, R 10 is phenyl optionally substituted with one or more substituents independently selected from halogen, (l-6C)alkyl, (l-6C)alkoxy, and amino. In one embodiment, R 10 is phenyl.

[00307] In one embodiment, formulas C-10, C-l l or C-12 are selected from the

[00308] In one embodiment, Formula I comprises compounds of Formula I-a, wherein:

[00309] Ring B and the NH-C(=X)-NH moiety are in the trans configuration;

[00310] R a , R b , R c and R d are H;

[00311] X is O;

[00312] R 1 is (1-3C alkoxy)(l-6C)alkyl;

[00313] R 2 is H;

[00314] Ring B is Ar 1 ;

[00315] Ar 1 is phenyl optionally substituted with one or more substituents independently selected from halogen, CF 3 , CF 3 0-, (l-4C)alkoxy, hydroxy(l-4C)alkyl, (l-6C)alkyl and CN;

[00316] Ring C is selected from formulas C-l through C-l 3; and R 3 , R 3a , R 4 , R 4a , R 5 ,

R 5a , R 7 , R 8a , R 8b , R 9 and R 10 are as defined for Formula I.

[00317] In one embodiment of Formula I-a,

[00318] R 3 is (l-3C)alkyl [optionally substituted with 1 to 3 fluoros] or H 2 NC(=0)-;

[00319] R 3a is H, (l-6C)alkyl, CF 3 CH 2 CH 2 , HCF 2 CH 2 CH 2 , H 2 FCCH 2 CH 2 , or CF 3 CH 2 ;

[00320] R 4 is selected from (l-6C)alkyl, hydroxy(l-6C)alkyl, (l-6C)alkoxycarbonyl, aminocarbonyl, hetAr 4 , Ar 4 , and hetAr 5 ;

[00321] R 4a is selected from ( 1 -6C)alkyl, hydroxy( 1 -6C)alkyl, hetAr 4 , Ar 4 , and hetAr 5 ; [00322] R 5 is halogen (l-6C)alkyl [optionally substituted with 1-5 fluoros] or phenyl [optionally substituted with one or more groups independently selected from halogen, (1- 6C)alkyl and (l-6C)alkoxy];

[00323] R 5a is (l-6C)alkyl, CF 3 CH 2 CH 2 , HCF 2 CH 2 CH 2 , H 2 FCCH 2 CH 2 , CF 3 CH 2 , or phenyl [optionally substituted with one or more groups independently selected from halogen, (l-6C)alkyl and (l-6C)alkoxy];

[00324] R is (l-6C)alkyl or phenyl [optionally substituted with one or more groups independently selected from F, CI, methoxy, ethoxy, cyclopropyl, NH 2 , NH 2 C(=0)- and CF 3 C(=0)NH-]; and

[00325] R 8a is H, halogen, CN, NH 2 , (l-6C)alkyl [optionally substituted with 1-5 fluoros], (l-6C)alkoxy, (1-3C alkoxy)(l-6C)alkyl, (1-3C alkoxy)(l-6C)alkoxy, (1-6C alkyl)sulfonyl, (3-6C cycloalkyl)sulfonyl, (3-4C)cycloalkyl, amino, (l-6Calkyl)NH-, phenyl [optionally substituted with (1-6C alkyl)S0 2 -] or hetAr 4 ; and R 8b is H, or

[00326] R 8b is H, halogen, CN, NH 2 , (l-6C)alkyl [optionally substituted with 1-5 fluoros], (l-6C)alkoxy, (1-3C alkoxy)(l-6C)alkyl, (1-3C alkoxy)(l-6C)alkoxy, (1-6C alkyl)sulfonyl, (3-6C cycloalkyl)sulfonyl, (3-4C)cycloalkyl, amino, (l-6Calkyl)NH-, phenyl [optionally substituted with (1-6C alkyl)S0 2 -] or hetAr 4 ; and R 8a is H;

[00327] R 9 is H, (l-6C)alkyl, CF 3 CH 2 -, CF 3 CH 2 CH 2 -, (l-3Calkoxy)(l-6C)alkyl or (3- 4C)cycloalkyl; and

[00328] R 10 is phenyl optionally substituted with one or more substituents independently selected from halogen, (l-6C)alkyl, (l-6C)alkoxy, and amino.

[00329] In one embodiment, Formula I comprises compounds of Formula I-b, wherein:

[00330] Ring B and the NH-C(=X)-NH moiety are in the trans configuration;

[00331] R a , R b , R c and R d are H;

[00332] X is O;

[00333] R 1 is (1-3C alkoxy)(l-6C)alkyl;

[00334] R 2 is H;

[00335] Ring B is Ar 1 ;

[00336] Ar 1 is phenyl optionally substituted with one or more substituents independently selected from halogen, CF 3 , CF 3 0-, (l-4C)alkoxy, hydroxy(l-4C)alkyl, (l-6C)alkyl and CN;

[00337] Ring C is formula C-l or C-2; and

[00338] R 3 and R 5 are as defined for Formula I. [00339] In one embodiment of Formula I-b, R 3 is (l-3C)alkyl [optionally substituted with 1 to 3 fluoros] or H 2 NC(=0)-; and R 5 is phenyl [optionally substituted with one or more groups independently selected from halogen, (l-6C)alkyl and (l-6C)alkoxy].

[00340] In one embodiment, Formula I comprises compounds of Formula I-c, wherein:

[00341] Ring B and the NH-C(=X)-NH moiety are in the trans configuration;

[00342] R a , R b , R c and R d are H;

[00343] X is O;

[00344] R 1 is (1-3C alkoxy)(l-6C)alkyl;

[00345] R 2 is H;

[00346] Ring B is Ar 1 ;

[00347] Ar 1 is phenyl optionally substituted with one or more substituents independently selected from halogen, CF 3 , CF 3 0-, (l-4C)alkoxy, hydroxy(l-4C)alkyl, (l-6C)alkyl and CN;

[00348] Ring C is formula C-3, C-4, C-5, C-6 or C-13; and

[00349] R 3a , R 4 , R 4a , R 5 , and R 5a are as defined for Formula I.

[00350] In one embodiment of Formula I-c, R 3a is (l-3C)alkyl; R 4 is selected from (1-

6C)alkyl, hydroxy(l-6C)alkyl, (l-6C)alkoxycarbonyl, aminocarbonyl, hetAr 4 , Ar 4 , and hetAr 5 ; R 4a is selected from (l-6C)alkyl, hydroxy(l-6C)alkyl, (l-6C)alkoxycarbonyl, aminocarbonyl, hetAr 4 , Ar 4 , and hetAr 5 ; R 5 is halogen, (l-6C)alkyl [optionally substituted with 1-5 fluoros] or phenyl [optionally substituted with one or more groups independently selected from halogen, (l-6C)alkyl and (l-6C)alkoxy]; and R 5a is (l-6C)alkyl, CF 3 CH 2 CH 2 , HCF 2 CH 2 CH 2 , H 2 FCCH 2 CH 2 , CF 3 CH 2 , or phenyl [optionally substituted with one or more groups independently selected from halogen, (l-6C)alkyl and (l-6C)alkoxy].

[00351] In one embodiment, Formula I comprises compounds of Formula I-d, wherein:

[00352] Ring B and the NH-C(=X)-NH moiety are in the trans configuration;

[00353] R a , R b , R c and R d are H;

[00354] X is O;

[00355] R 1 is (1-3C alkoxy)(l-6C)alkyl;

[00356] R 2 is H;

[00357] Ring B is Ar 1 ;

[00358] Ar 1 is phenyl optionally substituted with one or more substituents independently selected from halogen, CF 3 , CF 3 0-, (l-4C)alkoxy, hydroxy(l-4C)alkyl, (l-6C)alkyl and CN;

[00359] Ring C is formula C-7; and

[00360] R 3a , R 4a and R 5 are as defined for Formula I. [00361] In one embodiment of Formula I-d, R 3a is (l-3C)alkyl, CF 3 CH 2 CH 2 , HCF 2 CH 2 CH 2 , H 2 FCCH 2 CH 2 , or CF 3 CH 2 ; R 4a is (l-6C)alkyl; and R 5 is phenyl optionally substituted with one or more groups independently selected from halogen, (l-6C)alkyl and (1-

6C)alkoxy.

[00362] In one embodiment, Formula I comprises compounds of Formula I-e, wherein:

[00363] Ring B and the NH-C(=X)-NH moiety are in the trans configuration;

[00364] R a , R b , R c and R d are H;

[00365] X is O;

[00366] R 1 is (1-3C alkoxy)(l-6C)alkyl;

[00367] R 2 is H;

[00368] Ring B is Ar 1 ;

[00369] Ar L is phenyl optionally substituted with one or more substituents independently selected from halogen, CF 3 , CF 3 0-, (l-4C)alkoxy, hydroxy(l-4C)alkyl, (l-6C)alkyl and CN;

[00370] Ring C is formula C-8 or C-9; and

[00371] R 7 , R 8a and R 9 are as defined for Formula I.

[00372] In one embodiment of Formula I-e, R 7 is (l-6C)alkyl or phenyl [optionally substituted with one or more groups independently selected from F, CI, methoxy, ethoxy, cyclopropyl, NH 2 , NH 2 C(=0)- and CF 3 C(=0)NH-].

[00373] In one embodiment of Formula I-e, R 7 is (l-6C)alkyl or phenyl [optionally substituted with one or more groups independently selected from F, CI, methoxy, ethoxy, cyclopropyl, NH 2 , NH 2 C(=0)- and CF 3 C(=0)NH-]; R 8a is H, halogen, CN, NH 2 , (l-6C)alkyl [optionally substituted with 1-5 fluoros], (l-6C)alkoxy, (1-3C alkoxy)(l-6C)alkyl, (1-3C alkoxy)(l-6C)alkoxy, (1-6C alkyl)sulfonyl, (3-6C cycloalkyl)sulfonyl, (3-4C)cycloalkyl, amino, (l-6Calkyl)NH-, phenyl [optionally substituted with (1-6C alkyl)S0 2 -] or hetAr 4 ; and R 8b is H.

[00374] In one embodiment of Formula I-e, R 7 is (l-6C)alkyl or phenyl [optionally substituted with one or more groups independently selected from F, CI, methoxy, ethoxy, cyclopropyl, NH 2 , NH 2 C(=0)- and CF 3 C(=0)NH-]; R 8a is H, halogen, (l-6C)alkyl [optionally substituted with 1-5 fluoros], (l-6C)alkoxy, (1-3C alkoxy)(l-6C)alkoxy, (1-6C alkyl)sulfonyl, (3-6C cycloalkyl)sulfonyl, phenyl or hetAr 4 ; and hetAr 4 is a 6-membered heteroaryl having 1-2 ring nitrogen atoms and optionally substituted with one or more groups independently selected from (l-6C)alkyl [optionally substituted with 1-3 fluoros], halogen, (1-6C alkyl)amino, fluoro(l-6C alkyl)amino, difluoro(l-6C alkyl)amino, trifluoro(l-6C alkyl)amino, and (3-4C cycloalkyl)amino; and R is H. [00375] In one embodiment of Formula I-e, R 7 is (l-6C)alkyl or phenyl [optionally substituted with one or more groups independently selected from F, CI, methoxy, ethoxy, cyclopropyl, NH 2 , NH 2 C(=0)- and CF 3 C(=0)NH-]; R 8a is H, CI, Br, methyl, ethyl, isopropyl, methoxy, ethoxy, CH 3 OCH 2 CH 2 0-, cyclopropylsulfonyl, MeS0 2 , phenyl or pyridyl; and R 8b is H.

[00376] In one embodiment of Formula I-e, R 7 is (l-6C)alkyl or phenyl [optionally substituted with one or more groups independently selected from F, CI, methoxy, ethoxy, cyclopropyl, NH 2 , NH 2 C(-0)- and CF 3 C(=0)NH-]; R 8b is H, halogen, CN, NH 2 , (l-6C)alkyl [optionally substituted with 1-5 fluoros], (l-6C)alkoxy, (1-3C alkoxy)(l-6C)alkyl, (1-3C alkoxy)(l-6C)alkoxy, (1-6C alkyl)sulfonyl, (3-6C cycloalkyl)sulfonyl, (3-4C)cycloalkyl, amino, (l-6Calkyl)NH-, phenyl [optionally substituted with (1-6C alkyl)S0 2 -] or hetAr 4 ; and R 8a is H.

[00377] In one embodiment of Formula I-e, R 7 is (l-6C)alkyl or phenyl [optionally substituted with one or more groups independently selected from F, CI, methoxy, ethoxy, cyclopropyl, NH 2 , NH 2 C(=0)- and CF 3 C(=0)NH-]; R 8b is H, halogen, (l-6C)alkyl [optionally substituted with 1-5 fluoros], (l-6C)alkoxy, (1-3C alkoxy)(l-6C)alkoxy, (1-6C alkyl)sulfonyl, (3-6C cycloalkyl)sulfonyl, phenyl or hetAr 4 ; and hetAr 4 is a 6-membered heteroaryl having 1-2 ring nitrogen atoms and optionally substituted with one or more groups independently selected from (l-6C)alkyl [optionally substituted with 1-3 fluoros], halogen, (1- 6C alkyl)amino, fluoro(l-6C alkyl)amino, difluoro(l-6C alkyl)amino, trifluoro(l-6C alkyl)amino, and (3-4C cycloalkyl)amino; and R 8a is H.

[00378] In one embodiment of Formula I-e, R 7 is (l-6C)alkyl or phenyl [optionally substituted with one or more groups independently selected from F, CI, methoxy, ethoxy, cyclopropyl, NH 2 , NH 2 C(=0)- and CF 3 C(=0)NH-]; R 8b is H, CI, Br, methyl, ethyl, isopropyl, methoxy, ethoxy, CH 3 OCH 2 CH 2 0-, cyclopropylsulfonyl, MeS0 2 , phenyl or pyridyl; and R 8a is H.

[00379] In one embodiment, Formula I comprises compounds of Formula I-f, wherein:

[00380] Ring B and the NH-C(=X)-NH moiety are in the trans configuration;

[00381] R a , R b , R c and R d are H;

[00382] X is O;

[00383] R 1 is (1 -3C alkoxy)(l -6C)alkyl;

[00384] R 2 is H;

[00385] Ring B is Ar 1 ; [00386] AT 1 is phenyl optionally substituted with one or more substituents independently selected from halogen, CF 3 , CF 3 0-, (l-4C)alkoxy, hydroxy(l-4C)alkyl, (l-6C)alkyl and CN;

[00387] Ring C is formula C- 10, C- 1 1 or C- 12; and

[00388] R 9 and R 10 are as defined for Formula I.

[00389] As noted, Ring B and the -NH-C(=X)-NH- moiety of Formulas I, IA and IB are in the trans configuration on the pyrrolidine ring, which relative stereochemistry can be illustrated by either generic structure A or B:

[00390] in which the straight thick bars (— ) and straight dashed bars ( ) indicate relative stereochemistry.

[00391] In one embodiment of Formulas I, IA and IB, Ring B and the -NH-C(=X)-NH- moiety trans in the absolute configuration which can be illustrated by generic structure C and D:

[00392] in which the solid wedges ( ) and dashed wedges ( ) indicate absolute stereochemistry.

[00393] It will be appreciated that certain compounds according to the invention may contain one or more centers of asymmetry and may therefore be prepared and isolated in a mixture of isomers such as a racemic mixture, or in an enantiomerically pure form.

[00394] It will further be appreciated that the compounds of Formula I or their salts may be isolated in the form of solvates, and accordingly that any such solvate is included within the scope of the present invention. For example, compounds of Formula I can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like.

[00395] The compounds of Formula I include pharmaceutically acceptable salts thereof.

In addition, the compounds of Formula I also include other salts of such compounds which are not necessarily pharmaceutically acceptable salts, and which are useful as intermediates for preparing and/or purifying compounds of Formula I and/or for separating enantiomers of compounds of Formula I. Particular examples of salts include hydrochloride salts, trifluoroacetate salts, and di-(trifluoroacetate) salts.

[00396] In one embodiment, the compounds of Formula I include the free base form of compounds of Examples 1-5, or pharmaceutically acceptable salts thereof.

[00397] In one embodiment, the compounds of Formula I include the hydrochloride salts of compounds of Examples 1-56.

[00398] In one embodiment, the compounds of Formula I include the trifluoroacetate salts of compounds of Examples 1-56.

[00399] In one embodiment, the compounds of Formula I include the di(trifluoroacetate) salts of compounds of Examples 1-56.

[00400] The term "pharmaceutically acceptable" indicates that the substance or composition is compatible chemically and/or toxicologically, with the other ingredients comprising a formulation, and/or the mammal being treated therewith.

[00401] The present invention also provides a process for the preparation of a compound of Formula I or a salt thereof as defined herein, which comprises:

[00402] (a) for a compound of Formula I where X is O, coupling a corresponding compound having the formula II

II

[00403] with a corresponding compound having the formula III

III

[00404] in the presence carbonyldiimidazole or triphosgene and a base; or [00405] (b) for a compound of Formula I where X is S, coupling a corresponding compound having the formula II

[00406] with a corresponding com ound having the formula III

III

[00407] in the presence di(lH-imidazol-2-yl)methanethione and a base; or

[00408] (c) for a compound of Formula I where X is O, coupling a corresponding compound having the formula II

[00409] with a corresponding c g the formula IV

IV

[00410] where L is a leaving group, in the presence of a base; or

[00411] (d) for a compound of Formula I where X is O, coupling a corresponding compound having the formula V

[00412] where L is a leaving group, with a corresponding compound having the formula III

ΠΙ

[00413] in the presence of a base; or

[00414] (e) for a compound of Formula I where X is O, activating a corresponding compound having the formula VI

VI

[00415] with diphenylphosphoryl azide followed by coupling the activated intermediate with a corresponding compound having the formula III

III

[00416] in the presence a base; or

[00417] (f) for a compound of Formula I where X is O, coupling a corresponding compound having the formula II

II

[00418] with a corresponding compound having the formula VII

vn

[00419] in the presence of a base; or [00420] (g) for a compound of Formula I where X is O, coupling a corresponding compound having the formula VIII

VIII

[00421] a corresponding compound having the formula III

III

[00422] in the presence of a base; and

[00423] optionally removing protecting groups and optionally preparing a pharmaceutically acceptable salt thereof.

[00424] In the above methods, the term "corresponding" means that the definitions for the "corresponding compound" are as defined for Formula I unless stated otherwise.

[00425] Referring to method (a), the base may be an amine base, such as triethylamine or diisopropylethylamine. Suitable solvents include dichloromethane, dichloroethane, THF,

DMA and DMF. The reaction is conveniently performed at ambient temperature.

[00426] Referring to method (b), the base may be an amine base, such as triethylamine or diisopropylethylamine. Suitable solvents include dichloromethane, dichloroethane, THF,

DMA and DMF. The reaction is conveniently performed at ambient temperature.

[00427] Referring to method (c), the leaving group may be, for example, phenoxy or 4- nitrophenoxy. The base may be an amine base, such as triethylamine or diisopropylethylamine. Suitable solvents include DMA, DMF and DCE. The reaction is conveniently performed at ambient temperature.

[00428] Referring to method (d), the leaving group may be, for example, phenoxy or 4- nitrophenoxy. The base may be an amine base, such as triethylamine or diisopropylethylamine. Suitable solvents include DCE, DMA and DMF. The reaction is conveniently performed at ambient temperature.

[00429] Referring to method (e), the base may be an amine base, such as triethylamine or diisopropylethylamine. Suitable solvents include toluene and DMF. The reaction is conveniently performed at elevated temperatures, for example the reflux temperature of the solvent.

[00430] Referring to methods (f) and (g), the base may be an amine base, such as triethylamine or diisopropylethylamine. Suitable solvents include DCM, DCE, DMF and THF. The reaction is conveniently performed at temperatures between about 0 °C and ambient temperature.

[00431] Amine groups in compounds described in any of the above methods may be protected with any convenient amine protecting group, for example as described in Greene & Wuts, eds., "Protecting Groups in Organic Synthesis", 2 nd ed. New York; John Wiley & Sons, Inc., 1991. Examples of amine protecting groups include acyl and alkoxycarbonyl groups, such as t-butoxycarbonyl (BOC), phenoxycarbonyl, and [2-(trimethylsilyl)ethoxy]methyl (SEM). Likewise, carboxyl groups may be protected with any convenient carboxyl protecting group, for example as described in Greene & Wuts, eds., "Protecting Groups in Organic Synthesis", 2 nd ed. New York; John Wiley & Sons, Inc., 1991. Examples of carboxyl protecting groups include (l-6C)alkyl groups, such as methyl, ethyl and t-butyl. Alcohol groups may be protected with any convenient alcohol protecting group, for example as described in Greene & Wuts, eds., "Protecting Groups in Organic Synthesis", 2 nd ed. New York; John Wiley & Sons, Inc., 1991. Examples of alcohol protecting groups include benzyl, trityl, silyl ethers, and the like.

[00432] Amine groups in compounds described in any of the above methods may be protected with any convenient amine protecting group, for example as described in Greene & Wuts, eds., "Protecting Groups in Organic Synthesis", 2 nd ed. New York; John Wiley & Sons, Inc., 1991. Examples of amine protecting groups include acyl and alkoxycarbonyl groups, such as t-butoxycarbonyl (BOC) [2-(Mmethylsilyl)ethoxy] methyl (SEM). Likewise, carboxyl groups may be protected with any convenient carboxyl protecting group, for example as described in Greene & Wuts, eds., "Protecting Groups in Organic Synthesis", 2 nd ed. New York; John Wiley & Sons, Inc., 1991. Examples of carboxyl protecting groups include (1- 6C)alkyl groups, such as methyl, ethyl and t-butyl. Alcohol groups may be protected with any convenient alcohol protecting group, for example as described in Greene & Wuts, eds., "Protecting Groups in Organic Synthesis", 2 nd ed. New York; John Wiley & Sons, Inc., 1991. Examples of alcohol protecting groups include benzyl, trityl, silyl ethers, and the like.

[00433] The compounds of the formulas II, III, IV, V, VI and VII are also provided as further aspects of the invention. In one embodiment, the compounds of the formulas II, III, IV, V, VI and VII are useful as intermediates for the preparation of compounds of Formula I. [00434] In one embodiment of the above-described processes (a), (b), (c), and (f), where ring B is Ar 1 and R a , R b , R c , R d and R 2 are hydrogen, a single enantiomer of intermediate II, namely enantiomer 1 of II-A is prepared by chiral crystallization prior to use. Accordingly, in one embodiment, a process for preparing enantiomer 1 of II-A comprises:

[00435] preparing racemic trans -A

II-A

[00436] where Ring B and the NH 2 group are in the trans configuration; Ring B is Ar 1 or hetAr 1 ; Ar 1 is phenyl optionally substituted with one or more substituents independently selected from halogen, CF 3 , CF 3 0-, (l-4C)alkoxy, hydroxy(l-4C)alkyl, (l-6C)alkyl and CN; and hetAr 1 is a 5-6 membered heteroaryl having 1-3 ring heteroatoms independently selected from N, S and O, and optionally substituted with 1-2 groups independently selected from (1- 6C)alkyl, halogen, OH, CF 3 , NH 2 and hydroxy(l-2C)alkyl; said method comprising:

[00437] treating racemic trans II-A with di-p-toluoyl-D-tartaric acid to provide the di-p- toluoyl-D-tartaric acid salt of racemic trans II-A;

[00438] recrystallizing the di-p-toluoyl-D-tartaric acid salt of trans II-A to provide the di-p-toluoyl-D-tartaric acid salt of enantiomer 1 of trans II-A; and

[00439] treating the di-p-toluoyl-D-tartaric acid salt of enantiomer 1 of trans II-A with an inorganic base to provide free base of enantiomer 1 of trans II-A having the absolute configuration as illustrated:

enantiomer 1 of II-A

[00440] In one embodiment of enantiomer 1 of trans II-A, R 1 is 2-methoxyethoxy and Ring B is 4-fluorophenyl, and racemic trans II-A is prepared by the process comprising:

[00441] reacting 4-fluorobenzaldehyde with nitromethane in the presence of acetic acid and ammonium acetate to provide (E)-l-fluoro-4-(2-nitrovinyl)benzene [00442] reacting (E)-l-fluoro-4-(2-nitrovinyl)benzene with 2-methoxy-N-

(methoxymethyl)-N-((trimethylsilyl)methyl)ethanamine in the presence of a catalytic amount of an acid (such as TFA) to provide trans-3-(4-fluorophenyl)-l-(2-methoxyethyl)-4- nitropyrrolidine

[00443] treating trans-3-(4-fluorophenyl)-l-(2-methoxyethyl)-4-nitropyrrolidi ne with platinum (IV) oxide or Raney Nickel in a hydrogen atmosphere to provide trans-4-(4- fluorophenyl)- 1 -(2-methoxyethyl)pyrrolidin-3 -amine

[00444] wherein the 4-fluorophenyl and amino group are in the trans configuration.

[00445] In one embodiment of enantiomer 1 of trans II-A, R 1 is 2-methoxyethoxy and Ring B is 3,4-difluorophenyl.

[00446] In one embodiment of the method for preparing racemic trans II-A, the inorganic base is an alkali metal hydroxide such as sodium hydroxide.

[00447] A similar process as above may be used utilizing di-p-toluoyl-L-tartaric acid to provide enantiomer 2 of II-A:

enantiomer 2 of II-A

[00448] where R 1 and Ring B are as defined for Formula I. In one embodiment of enantiomer 2 of trans II-A, R 1 is 2-methoxyethoxy and Ring B is 4-fluorophenyl. In one embodiment of enantiomer 2 of trans II-A, R 1 is 2-methoxyethoxy and Ring B is 3,4- difluorophenyl.

[00449] The ability of compounds of the invention to act as TrkA inhibitors may be demonstrated by the assay described in Example A.

[00450] Compounds of Formula I are useful in the treatment of pain, cancer, inflammation/inflammatory diseases, neurodegenerative diseases, certain infectious diseases, Sjogren's syndrome, endometriosis, diabetic peripheral neuropathy, prostatitis or pelvic pain syndrome.

[00451] In one embodiment, compounds of Formula I are useful for treating pain, including chronic and acute pain. For example, compounds of Formula I are useful in the treatment of multiple types of pain including inflammatory pain, neuropathic pain, and pain associated with cancer, surgery or bone fracture.

[00452] In one embodiment, compounds of Formula I are useful for treating acute pain. Acute pain, as defined by the International Association for the Study of Pain, results from disease, inflammation, or injury to tissues. This type of pain generally comes on suddenly, for example, after trauma or surgery, and may be accompanied by anxiety or stress, and is confined to a given period of time and severity. In some instances, it can become chronic.

[00453] In one embodiment, compounds of Formula I are useful for treating chronic pain. Chronic pain, as defined by the International Association for the Study of Pain, is widely believed to represent a disease in itself. It can be made much worse by environmental and psychological factors. Chronic pain persists over a longer period than acute pain and is resistant to most medical treatments, generally over 3 months or more. It can and often does cause severe problems for patients.

[00454] Compounds of Formula I are also useful for treating cancer. Particular examples include neuroblastoma, ovarian, pancreatic, colorectal and prostate cancer.

[00455] Compounds of Formula I are also useful for treating inflammation and certain infectious diseases. For example, compounds of Formula I may be used to treat interstitial cystitis (IC), painful bladder syndrome (PBS), urinary incontinence, asthma, atopic dermatitis, and psoriasis.

[00456] Compounds of Formula I are also useful for treating a neurodegenerative disease in a mammal, comprising administering to said mammal one or more compounds of Formula I or a pharmaceutically acceptable salt thereof in an amount effective to treat said neurodegenerative disease. In one embodiment, compounds of Formula I may also be used to treat demyelination and dysmyelination by promoting myelination, neuronal survival, and oligodendrocyte differentiation via blocking Sp35-TrkA interaction. In one embodiment, the neurodegenerative disease is multiple sclerosis. In one embodiment, the neurodegenerative disease is Parkinson's disease. In one embodiment, the neurodegenerative disease is Alzheimer's disease.

[00457] Compounds of Formula I are also useful for treating certain infectious diseases such as Trypanosoma cruzi infection in a mammal. [00458] Compounds of Formula I are also useful for treating Sjogren's syndrome in a mammal.

[00459] Compounds of Formula I are also useful for treating endometriosis in a mammal.

[00460] Compounds of Formula I are also useful for treating diabetic peripheral neuropathy in a mammal.

[00461] Compounds of Formula I are also useful for treating prostatitis in a mammal.

[00462] Compounds of Formula I are also useful for treating pelvic pain syndrome in a mammal.

[00463] Compounds of Formula I are also useful in treating diseases related to an imbalance of the regulation of bone remodeling, such as osteoporosis, rheumatoid arthritis, and bone metastases.

[00464] As used herein, terms "treat" or "treatment" refer to therapeutic or palliative measures. Beneficial or desired clinical results include, but are not limited to, alleviation, in whole or in part, of symptoms associated with a disorder or condition, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. "Treatment" can also mean prolonging survival as compared to expected survival if not receiving treatment.

[00465] In certain embodiments, compounds of Formula I are useful for preventing diseases and disorders as defined herein. The term "preventing" as used herein means the prevention of the onset, recurrence or spread, in whole or in part, of the disease or condition as described herein, or a symptom thereof, and includes to the administration of a compound of Formula I prior to the onset of symptoms.

[00466] Accordingly, one embodiment of this invention provides a method of treating pain in a mammal, comprising administering to said mammal in need thereof one or more compounds of Formula I or a pharmaceutically acceptable salt thereof in an amount effective to treat said pain. In one embodiment, the pain is chronic pain. In one embodiment, the pain is acute pain. In one embodiment, the pain is inflammatory pain, neuropathic pain, or pain associated with cancer, surgery, or bone fracture.

[00467] Another embodiment of this invention provides a method of preventing pain in a mammal, comprising administering to said mammal in need thereof one or more compounds of Formula I or a pharmaceutically acceptable salt thereof in an amount effective to prevent said pain. In one embodiment, the pain is chronic pain. In one embodiment, the pain is acute pain. In one embodiment, the pain is inflammatory pain, neuropathic pain, or pain associated with cancer, surgery, or bone fracture.

[00468] Another embodiment of this invention provides a method of treating cancer in a mammal, comprising administering to said mammal in need thereof one or more compounds of Formula I or a pharmaceutically acceptable salt thereof in an amount effective to treat said cancer.

[00469] In one embodiment, provided herein is a method for treating a patient diagnosed with a cancer having a dysregulation of TrkA, comprising administering to the patient a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof.

[00470] In one embodiment, the dysregulation of TrkA comprises overexpression of wild-type TrkA (autocrine activation).

[00471] In one embodiment, the dysregulation of TrkA comprises one or more chromosome translocations or inversions resulting in TrkA gene fusions. In one embodiment, the dysregulation is a result of genetic translocations in which the expressed protein is a fusion protein containing residues from non-TrkA and TrkA proteins, and at a minimum the TrkA kinase domain. In one embodiment, the TrkA fusion protein is LMNA-TrkA, TFG-TrkA, TPM3-TrkA, CD74-TrkA, NFASC-TrkA, MPRIP-TrkA, BCAN-TrkA, or TPR-TrkA, where:

LMNA = Prelamin-A/C;

TFG TRK-fused gene protein;

TPM3 Tropomysin alpha-3;

CD74 HLA class II histocompatibility antigen gamma chain;

NFASC = Neurofascin;

MPRIP = MPRIP protein;

BCAN Brevican core protein; and

TPR Nucleoprotein TPR

[00472] In one embodiment, the dysregulation of TrkA comprises one or more deletions, insertions or mutations in the TrkA protein. In one embodiment, the dysregulation comprises a deletion of one or more residues from the TrkA protein, resulting in constitutive activity of TrkA kinase. In one embodiment the deletion includes deletion of residues 303-377 in TrkA Isoform 2.

[00473] In one embodiment, the dysregulation of TrkA comprises a splice variation in which the expressed protein is an alternatively spliced variant of TrkA having one or more residues deleted resulting in constitutive activity of TrkA kinase. In one embodiment, an alternatively spliced form of TrkA with constitutive activity has deletions of exons 8, 9, and 11 resulting in an expressed protein missing residues 192-284 and 393-398 relative to TrkA Isoform 2.

[00474] Cancers identified as having dysregulation of TrkA (see literature references below; also see www.cancer.gov and www.nccn.org) include:

[00475] (A) Cancers wherein the dysregulation of TrkA comprises one or more chromosome translocations or inversions resulting in TrkA gene fusions, including:

[00476] (B) Cancers wherein the dysregulation of TrkA comprises one or more deletions, insertions or mutations in the TrkA protein, including:

Cancer Literature reference(s) Standard of care

(C) Cancers driven by overexpression of wild-type TrkA (autocrine activation),

Cancer Literature Reference(s) Standard of care

Prostate Carcinoma Walch et al: Clinical & Radiotherapy (e.g. radium 223

Experimental Metastasis 17: 307- therapy) or chemotherapeutics 314 (e.g. abiraterone, cabazitaxel,

Papatsoris et al 2007: Expert degarelix, denosumab, docetaxel, Opinion on Investigational Drugs enzalutamide, leuprolide, 16(3): 303-309 prednisone, sipuleucel-T)

Neuroblastoma Van Noesel et al 2004: Gene 325: Chemotherapeutics (e.g.

1-15 cyclophosphamide, doxorubicin, vincristine)

Pancreatic Zhang et al 2005: Oncology Chemotherapeutics as single Carcinoma Reports 14: 161-171 agents (e.g. erlotinib,

fluorouracil, gemcitabine, mitomycin C) or combinations (e.g. gemcitabine-oxaliplatin)

Melanoma Truzzi et al 2008: Journal of Chemotherapeutics (e.g.

Investigative Dermatology 128(8): aldesleukin, dabrafenib,

2031 dacarbazine, interferon alfa-2b, ipilimumab, peginterferon alfa- 2b, trametinib, vemurafenib)

Head and Neck Kolokythas et al 2010: Journal of Radiotherapy and/or

Squamous Cell Oral and Maxillofacial Surgery chemotherapeutics (e.g.

Carcinoma 68(6):1290-1295 bleomycin, cetuximab, cisplatin, docetaxel, fluorouracil, methotrexate)

Gastric Carcinoma Ni et al 2012: Asian Pacific Chemotherapeutics (e.g.

Journal of Cancer Prevention 13: docetaxel, doxorubucin,

1511 fluorouracil, mitomycin C,

[00478] In one embodiment, provided herein is a method for treating a patient diagnosed with a cancer having a dysregulation of TrkA, comprising administering to the patient a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, wherein the cancer is selected from non-small cell lung cancer, papillary thyroid carcinoma, glioblastoma multiforme, acute myeloid leukemia, colorectal carcinoma, large cell neuroendocrine carcinoma, prostate cancer, neuroblastoma, pancreatic carcinoma, melanoma, head and neck squamous cell carcinoma and gastric carcinoma.

[00479] In one embodiment, the compounds of the present invention are useful for treating cancer in combination with one or more additional therapeutic agents or therapies that work by the same or a different mechanism of action.

[00480] In one embodiment, the additional therapeutic agent(s) is selected from receptor tyrosine kinase-targeted therapeutic agents, including cabozantinib, crizotinib, erlotinib, gefitinib, imatinib, lapatinib, nilotinib, pazopanib, pertuzumab, regorafenib, sunitinib, and trastuzumab.

[00481] In one embodiment, the additional therapeutic agent(s) is selected from signal transduction pathway inhibitors, including Ras-Raf-MEK-ERK pathway inhibitors (e.g. sorafenib, trametinib, vemurafenib), PI3K-Akt-mTOR-S6K pathway inhibitors (e.g. everolimus, rapamycin, perifosine, temsirolimus) and modulators of the apoptosis pathway (e.g. obataclax).

[00482] In one embodiment, the additional therapeutic agent(s) is selected from cytotoxic chemotherapeutics, including arsenic trioxide, bleomycin, cabazitaxel, capecitabine, carboplatin, cisplatin, cyclophosphamide, cytarabine, dacarbazine, daunorubicin, docetaxel, doxorubicin, etoposide, fluorouracil, gemcitabine, irinotecan, lomustine, methotrexate, mitomycin C, oxaliplatin, paclitaxel, pemetrexed, temozolomide, and vincristine.

[00483] In one embodiment, the additional therapeutic agent(s) is selected from angiogenesis-targeted therapies, including aflibercept and bevacizumab.

[00484] In one embodiment, the additional therapeutic agent(s) is selected from immune-targeted agents, including aldesleukin, ipilimumab, lambrolizumab, nivolumab, sipuleucel-T. [00485] In one embodiment, the additional therapeutic agent(s) is selected from agents active against the TrkA pathway, including NGF-targeted biopharmaceuticals such as NGF antibodies, and panTrk inhibitors.

[00486] In one embodiment, the additional therapeutic agent or therapy is radiotherapy, including radioiodide therapy, external-beam radiation and radium 223 therapy.

[00487] In one embodiment, the additional therapeutic agent(s) includes any one of the above listed therapies or therapeutic agents which are standards of care in cancers wherein the cancer has a dysregulation of TrkA.

[00488] In one embodiment, provided herein is a method of treating cancer in a patient, comprising administering to said patient a compound of the invention or a pharmaceutically acceptable salt thereof, in combination with at least one additional therapy or therapeutic agent selected from radiotherapy (e.g. radioiodide therapy, external-beam radiation, radium 223 therapy), cytotoxic chemotherapeutics (e.g. arsenic trioxide, bleomycin, cabazitaxel, capecitabine, carboplatin, cisplatin, cyclophosphamide, cytarabine, dacarbazine, daunorubicin, docetaxel, doxorubicin, etoposide, fluorouracil, gemcitabine, irinotecan, lomustine, methotrexate, mitomycin C, oxaliplatin, paclitaxel, pemetrexed, temozolomide, vincristine), tyrosine kinase targeted-therapeutics (e.g. afatinib, cabozantinib, cetuximab, crizotinib, dabrafenib, erlotinib, gefitinib, imatinib, lapatinib, nilotinib, pazopanib, panitumumab, pertuzumab, regorafenib, sunitinib, trastuzumab), apoptosis modulators and signal transduction inhibitors (e.g. everolimus, perifosine, rapamycin, sorafenib, temsirolimus, trametinib, vemurafenib), immune-targeted therapies (e.g. aldesleukin, interferon alfa-2b, ipilimumab, lambrolizumab, nivolumab, prednisone, sipuleucel-T) and angiogenesis-targeted therapies (e.g. aflibercept, bevacizumab), wherein the amount of the compound of the invention or a pharmaceutically acceptable salt thereof is, in combination with the additional therapy or therapeutic agent, is effective in treating said cancer. These additional therapeutic agents may be administered with one or more compounds of the invention as part of the same or separate dosage forms, via the same or different routes of administration, and on the same or different administration schedules according to standard pharmaceutical practice known to one skilled in the art.

[00489] Also provided herein is (i) a pharmaceutical combination for treating cancer in a patient in need thereof, which comprises (a) a compound of the invention or a pharmaceutically acceptable salt thereof, (b) an additional therapeutic agent and (c) optionally at least one pharmaceutically acceptable carrier for simultaneous, separate or sequential use for the treatment of a tumor disease, wherein the amounts of the compound or salt thereof and of the additional therapeutic agent are together effective in treating said cancer; (ii) a pharmaceutical composition comprising such a combination; (iii) the use of such a combination for the preparation of a medicament for the treatment of cancer; and (iv) a commercial package or product comprising such a combination as a combined preparation for simultaneous, separate or sequential use; and to a method of treatment of cancer a patient in need thereof.

[00490] In one embodiment, the combination therapy is for treating a cancer is selected from non-small cell lung cancer, papillary thyroid carcinoma, glioblastoma multiforme, acute myeloid leukemia, colorectal carcinoma, large cell neuroendocrine carcinoma, prostate cancer, neuroblastoma, pancreatic carcinoma, melanoma, head and neck squamous cell carcinoma and gastric carcinoma.

[00491] Another embodiment of this invention provides a method of treating inflammation or an inflammatory disease or disorder in a mammal, comprising administering to said mammal in need thereof one or more compounds of Formula I or a pharmaceutically acceptable salt thereof in an amount effective to treat said inflammation. In one embodiment, the inflammatory disease is inflammatory lung diseases (such as asthma), interstitial cystitis, bladder pain syndrome, inflammatory bowel diseases (including ulcerative colitis and Crohn's disease), and inflammatory skin diseases such as atopic dermatitis.

[00492] In one embodiment, the method of treating inflammation or an inflammatory disease or disorder comprises administering a compound of the invention in combination with one or more additional agents. Examples of additional agents include anti-TNF treatments (for example monoclonal antibody such as infliximab (Remicade), adalimumab (Humira), certolizumab pegol (Cimzia), and golimumab (Simponi), or a circulating receptor fusion protein such as etanercept (Enbrel)), antimetabolite and antifolate drug (for example Methotrexate), or targeted kinase inhibitors (for example JAK family inhibitors Ruxolitinib, Tofacitinib, CYT387, Lestaurtinib, Pacritinib and TG101348).

[00493] Another embodiment of this invention provides a method of treating Trypanosoma cruzi infection in a mammal, comprising administering to said mammal in need thereof one or more compounds of Formula I or a pharmaceutically acceptable salt thereof in an amount effective to treat said Trypanosoma cruzi infection.

[00494] Another embodiment of this invention provides a method of treating Sjogren's syndrome in a mammal, comprising administering to said mammal in need thereof one or more compounds of Formula I or a pharmaceutically acceptable salt thereof in an amount effective to treat said syndrome. [00495] Another embodiment of this invention provides a method of treating endometriosis in a mammal, comprising administering to said mammal in need thereof one or more compounds of Formula I or a pharmaceutically acceptable salt thereof in an amount effective to treat said endometriosis.

[00496] Another embodiment of this invention provides a method of treating diabetic peripheral neuropathy in a mammal, comprising administering to said mammal in need thereof one or more compounds of Formula I or a pharmaceutically acceptable salt thereof in an amount effective to treat said diabetic peripheral neuropathy.

[00497] Another embodiment of this invention provides a method of treating prostatitis in a mammal, comprising administering to said mammal in need thereof one or more compounds of Formula I or a pharmaceutically acceptable salt thereof in an amount effective to treat said prostatitis.

[00498] Another embodiment of this invention provides a method of treating pelvic pain syndrome in a mammal, comprising administering to said mammal in need thereof one or more compounds of Formula I or a pharmaceutically acceptable salt thereof in an amount effective to treat said pelvic pain syndrome.

[00499] Another embodiment of this invention provides a method of treating a neurodegenerative disease in a mammal, comprising administering to said mammal in need thereof one or more compounds of Formula I or a pharmaceutically acceptable salt thereof in an amount effective to treat said neurodegenerative disease.

[00500] Another embodiment of this invention provides a method of treating diseases related to an imbalance of the regulation of bone remodeling in a mammal, comprising administering to said mammal in need thereof one or more compounds of Formula I or a pharmaceutically acceptable salt thereof in an amount effective to treat said disease. In one embodiment, the disease is osteoporosis, rheumatoid arthritis, and bone metastases.

[00501] In one embodiment, the method for treating diseases related to an imbalance of the regulation of bone remodeling in a mammal comprises administering a TrkA inhibitor of the invention in combination with one or more additional therapeutic agents or therapies. Examples of additional therapeutic agents or therapies include anti-TNF treatments (for example monoclonal antibody such as infliximab (Remicade), adalimumab (Humira), certolizumab pegol (Cimzia), and golimumab (Simponi), or with a circulating receptor fusion protein such as etanercept (Enbrel)), antimetabolite and antifolate drug (for example Methotrexate), or targeted kinase inhibitors (for example JAK family inhibitors Ruxolitinib, Tofacitinib, CYT387, Lestaurtinib, Pacritinib and TG101348). [00502] As used herein, an "effective amount" means an amount of compound that, when administered to a mammal in need of such treatment, is sufficient to (i) treat a particular disease, condition, or disorder which can be treated with a compound of Formula I, or (ii) attenuate, ameliorate, or eliminate one or more symptoms of the particular disease, condition, or disorder described herein.

[00503] The amount of a compound of Formula I that will correspond to such an amount will vary depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight) of the mammal in need of treatment, but can nevertheless be routinely determined by one skilled in the art.

[00504] As used herein, the term "mammal" refers to a warm-blooded animal that has or is at risk of developing a disease described herein and includes, but is not limited to, guinea pigs, dogs, cats, rats, mice, hamsters, and primates, including humans.

[00505] The compounds of the present invention can be used in combination with one or more additional therapeutic agents that work by the same or a different mechanism of action. Examples of additional therapeutic agents include anti-inflammatory compounds, steroids (e.g., dexamethasone, cortisone and fluticasone), analgesics such as NSAIDs (e.g., aspirin, ibuprofen, ' indomethacin, and ketoprofen), and opioids (such as morphine), and chemotherapeutic agents.

[00506] Also provided herein is a pharmaceutical combination comprising an effective amount of: (a) at least one compound of Formula I; and (b) at least one additional therapeutic agent selected from anti-inflammatory compounds, steroids (e.g., dexamethasone, cortisone and fluticasone), analgesics such as NSAIDs (e.g., aspirin, ibuprofen, indomethacin, and ketoprofen), and opioids (such as morphine), for use in the treatment of pain in a mammal, wherein (a) and (b) can be in separate dosage forms or in the same dosage form.

[00507] The term "pharmaceutical combination" as used herein refers to a pharmaceutical therapy resulting from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients. The term "fixed combination" means that at least one of the compounds of Formula I, and at least one additional therapeutic agent are both administered to a patient simultaneously in the form of a single entity or dosage. The term "non-fixed combination" means that at least one of the compounds of Formula I, and at least one additional therapeutic agent, are administered to a patient as separate entities either simultaneously or sequentially with variable intervening time limits, wherein such administration provides effective levels of the two or more compounds in the body of the patient. These also apply to cocktail therapies, e.g. the administration of three or more active ingredients.

[00508] Also provided herein is a method of treating pain in a mammal, comprising coadministering to a mammal in need thereof an effective amount of: (a) at least one compound of Formula I; and (b) at least one additional therapeutic agent selected from anti-inflammatory compounds, steroids (e.g., dexamethasone, cortisone and fluticasone), analgesics such as NSAIDs (e.g., aspirin, ibuprofen, indomethacin, and ketoprofen), opioids (such as morphine), calcitonin gene-related peptide receptor antagonists, subtype-selective ion channel modulators, anticonvulsants (for example Pregabalin and gabapentin), dual serotonin-norepinephrin reuptake inhibitors (for example duloxetine, venlafaxine and milnacipran), and tricyclic antidepressants (such as amitriptyline, nortriptyline and desipramine).

[00509] The term "co-administering" is meant to encompass administration of the selected therapeutic agents to a single patient, and is intended to include treatment regimens in which the agents are administered by the same or different route of administration or at the same or different times. This term encompasses administration of two or more agents to a mammal so that both agents and/or their metabolites are present in the mammal at the same time. It includes simultaneous administration in separate compositions, administration at different times in separate compositions, and/or administration in a composition in which both agents are present. In some embodiments, the compound(s) of the invention and the other therapeutic agent(s) are administered in a single composition. In some embodiments, compound(s) of the invention and the other agent(s) are admixed in the composition.

[00510] Also provided herein is a medicament containing a compound of Formula I for treatment of pain in a mammal in combination with an additional therapeutic agent selected from anti-inflammatory compounds, steroids (e.g., dexamethasone, cortisone and fluticasone), analgesics such as NSAIDs (e.g., aspirin, ibuprofen, indomethacin, and ketoprofen), and opioids (such as morphine).

[00511] Also provided herein is a medicament containing a therapeutic agent selected from anti-inflammatory compounds, steroids (e.g., dexamethasone, cortisone and fluticasone), analgesics such as NSAIDs (e.g., aspirin, ibuprofen, indomethacin, and ketoprofen), and opioids (such as morphine) for treatment of pain in a mammal in combination with a compound of Formula I.

[00512] Compounds of the invention may be administered by any convenient route, e.g. into the gastrointestinal tract (e.g. rectally or orally), the nose, lungs, musculature or vasculature, or transdermally or dermally. Compounds may be administered in any convenient administrative form, e.g. tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches etc. Such compositions may contain components conventional in pharmaceutical preparations, e.g. diluents, carriers, pH modifiers, sweeteners, bulking agents, and further active agents. If parenteral administration is desired, the compositions will be sterile and in a solution or suspension form suitable for injection or infusion. Such compositions form a further aspect of the invention.

[00513] Another formulation may be prepared by mixing a compound described herein and a carrier or excipient. Suitable carriers and excipients are well known to those skilled in the art and are described in detail in, e.g., Ansel, Howard C, et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R., et al. Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. The formulations may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents, diluents and other known additives to provide an elegant presentation of the drug (i.e., a compound described herein or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament).

[00514] Accordingly, another aspect of the present invention provides a pharmaceutical composition, which comprises a compound of Formula I or a pharmaceutically acceptable salt thereof, as defined hereinabove, together with a pharmaceutically acceptable diluent or carrier.

[00515] According to another embodiment, the present invention provides a compound of Formula I or a pharmaceutically acceptable salt thereof, for use in the treatment of pain in a mammal. In one embodiment, the pain is chronic pain. In one embodiment the pain is acute pain. In one embodiment, the pain is inflammatory pain, neuropathic pain, or pain associated with cancer, surgery, or bone fracture.

[00516] According to another embodiment, the present invention provides a compound of Formula I or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer in a mammal.

[00517] In another embodiment, the present invention provides a compound of Formula I or a pharmaceutically acceptable salt thereof, for use in the treatment of inflammation or an inflammatory disease or disorder in a mammal. In one embodiment, the inflammatory disease is inflammatory lung diseases (such as asthma), interstitial cystitis, bladder pain syndrome, inflammatory bowel diseases (including ulcerative colitis and Crohn's disease), and inflammatory skin diseases such as atopic dermatitis.

[00518] In another embodiment, the present invention provides a compound of Formula I or a pharmaceutically acceptable salt thereof, for use in the treatment of infectious diseases, for example Trypanosoma cruzi infection, in a mammal.

[00519] In another embodiment, the present invention provides a compound of Formula I or a pharmaceutically acceptable salt thereof, for use in the treatment of Sjogren's syndrome in a mammal.

[00520] In another embodiment, the present invention provides a compound of Formula I or a pharmaceutically acceptable salt thereof, for use in the treatment of endometriosis in a mammal.

[00521] In another embodiment, the present invention provides a compound of Formula I or a pharmaceutically acceptable salt thereof, for use in the treatment of diabetic peripheral neuropathy in a mammal,

[00522] In another embodiment, the present invention provides a compound of Formula I or a pharmaceutically acceptable salt thereof, for use in the treatment of prostatitis in a mammal,

[00523] In another embodiment, the present invention provides a compound of Formula I or a pharmaceutically acceptable salt thereof, for use in the treatment of pelvic pain syndrome in a mammal,

[00524] In another embodiment, the present invention provides a compound of Formula I or a pharmaceutically acceptable salt thereof, for use in the treatment of a neurodegenerative disease in a mammal.

[00525] According to a further aspect, the present invention provides the use of a compound of Formula I or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a condition selected from pain, cancer, inflammation, neurodegenerative disease or Trypanosoma cruzi infection. In one embodiment, the condition is chronic pain. In one embodiment, the condition is acute pain. In one embodiment, the pain is inflammatory pain, neuropathic pain, or pain associated with cancer, surgery, or bone fracture. In one embodiment, the condition is cancer. In one embodiment, the condition is inflammation. In one embodiment, the condition is a neurodegenerative disease. In one embodiment, the condition is Trypanosoma cruzi infection. In one embodiment, the condition is Sjogren's syndrome. In one embodiment, the condition is endometriosis. In one embodiment, the condition is diabetic peripheral neuropathy. In one embodiment, the condition is prostatitis. In one embodiment, the condition is pelvic pain syndrome.

Examples

[00526] The following examples illustrate the invention. In the examples described below, unless otherwise indicated all temperatures are set forth in degrees Celsius. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Lancaster, TCI or Maybridge, and were used without further purification unless otherwise indicated.

[00527] The reactions set forth below were done generally under a positive pressure of nitrogen or argon or with a drying tube (unless otherwise stated) in anhydrous solvents, and the reaction flasks were typically fitted with rubber septa for the introduction of substrates and reagents via syringe. Glassware was oven dried and/or heat dried.

[00528] Column chromatography was done on a Biotage system (Manufacturer: Dyax Corporation) having a silica gel or C-18 reverse phase column, or on a silica SepPak cartridge (Waters).

Biological assays

Example A-l

TrkA Kinase Binding Assay

[00529] TrkA binding activity was determined in a TrkA LanthaScreen™ Eu Kinase Binding Assay. 5 nM His-tagged recombinant human TrkA (6HIS tagged cytoplasmic domain from Invitrogen,Cat. No. PV3144) was incubated with 4 nM Alexa-Fluor® Tracer 236 (Invitrogen Cat. No.PV5592), 2 nM biotinylated anti-His (Invitrogen Cat. No. PV6090), and 2 nM europium-labeled Streptavidin (Invitrogen Cat. No. PV5899), in buffer (25 mM MOPS, pH 7.5, 5 mM MgCl 2 , 0.005% Triton X-100). Three fold serial dilutions of compounds of the invention in DMSO were added to a final percentage of 2% DMSO. After 60-minute incubation at 22 °C, the reaction was measured using the EnVision mutlimode plate reader (PerkinElmer) via TR-FRET dual wavelength detection at 615 nM and 665 nM. The percent of control was calculated using a ratiometric emission factor. The IC 50 values were determined by fitting a four parameter model to the percent of control data.

[00530] Table A provides averaged IC 50 values for compounds of the invention when tested in the assay of Example A, where A represents an averaged IC 50 value <100 nM; and B represents an averaged IC 50 value from 100 to 1,000 nM. Table A

Example A-2

p38 Kinase Binding Assay

[00531] p38a binding activity was determined in a p38a LanthaScreen Eu Kinase Binding Assay. 5 nM of inactive, GST-tagged recombinant human p38a (GST-tagged cytoplasmic domain from Invitrogen, Catalog No. PV3305) was incubated with 5 nM Alexa- Fluor® Tracer 199 (Invitrogen Cat. No. PV5830), and 2 nM europium labeled anti-GST antibody (Invitrogen Cat. No. PV5594), in buffer (25 niM [Na + ] HEPES pH 7.3, 10 mM MgCl 2 , 100 μΜ NaV0 4 ). Three fold serial dilutions of compounds of the invention in DMSO were added to a final percentage of 2% DMSO. After 60-minute incubation at 22 °C, the reaction was measured using the En Vision multimode plate reader (PerkinElmer) via TR- FRET dual wavelength detection at 615 nM and 665 nM. The percent of control was calculated using a ratiometric emission factor. The IC 50 values were determined by fitting a four parameter model to the percent of control data. The compounds of Examples 1-56 were tested in this assay, and all compounds were found to be 1000 fold more potent against TrkA than p38a.

Example B

Off-Target Kinase Profiling

[00532] A representative compound of the invention (Example 48) was tested for off- target kinase activity at a concentration of 10 μΜ by Millipore, Inc. in their KinaseProfiler™ service against all the kinases available in their full kinase panel. The compound was run in duplicate at a concentration of ATP near the Km for each individual kinase according to Millipore's specifications. The results are shown in Table B. Data are reported as percent of control (POC) and are the average of the two replicates.

[00533] In the KinaseProfiler™ the representative compound showed remarkable and unexpected selectivity for inhibiting TrkA and TrkB versus other kinases in the panel. In fact, the compound was largely inactive against off-target kinases at a concentration of 10 μΜ, and thus would not be expected to inhibit off-target kinases at therapeutic doses in mammals. The ability of compounds of the invention to selectively inhibit the Trk pathway without inhibiting other off-target kinases could translate into drug profiles that are essentially free of side-effects related to inhibition of off-target kinases. Such a drug profile would represent a safer approach to treating pain, inflammation, cancer and certain skin diseases than has been previously reported.

Table B

Preparation of Synthetic Intermediates

Preparation A

fert-butyl tnms-4-phenylpyrrolidin-3 - ylcarbamate

[00534] Step A: Preparation of tra» , -l-benzyl-3-nitro-4-phenylpyrrolidine: To a DCM (2 L) solution of (E)-(2-nitrovinyl)benzene (149 g, 1.00 mol) was added TFA (19.5 mL, 0.250 mol), followed by cooling to -15 °C and then slow addition of a DCM (500 mL) solution of N- methoxymethyl-N-(trimethylsilylmethyl)benzylamine (274 g, 1.00 mol) over 3 hours, maintaining the reaction temperature between -15 and -10 °C. The reaction was warmed up to ambient temperature and stirred for 18 hours, then washed with 2 N NaOH (500 mL) and treated with 2 N HC1 (1 L). The resulting white suspension

[00535] was stirred for 1 hour before being filtered and washed with DCM. DCM (1 L) and 2 N NaOH (750 mL) were then added to the collected white solid and stirred until all the solids dissolved. After phase-separation, the aqueous layer was extracted with DCM (2 χ 1 L). The combined organic layers were dried with MgS0 4 , filtered and concentrated to afford the title product as an off-white solid (205 g, 73% yield). MS (apci) m/z = 283.1 (M+H).

[00536] Step B: Preparation of traw5 , -l-benzyl-4-phenylpyrrolidin-3-amine: To a suspension of trans- l-benzyl-3-nitro-4-phenyl-pyrrolidine (93.9 g, 333 mmol) in EtOH (1.20 L) was added concentrated HC1 (450 mL), followed by addition of zinc dust (173 g, 2.66 mol) in small portions over 1.5 hours while maintaining the temperature between 55-60 °C. The reaction mixture was stirred at ambient temperature for 18 hours, then cooled in an ice/water bath followed by addition of concentrated NH 4 OH (900 mL). The mixture (pH = 10-11) was filtered and the collected zinc was washed with CHC1 3 . The filtrate was then phase-separated, and the aqueous layer was extracted with CHC1 3 (2 χ 400 mL). The combined organics was washed with ¾0, brine, dried with MgS0 4 , filtered and concentrated to afford the title compound as an amber oil (85.0 g, 100% yield). MS (apci) m/z = 253.2 (M+H).

[00537] Step C: Preparation of tr ¾ -(l-benzyl-4-phenyl-pyrrolidin-3-yl -carbamic acid tert-butyl ester: To a mixture of trans- l-benzyl-4-phenylpyrrolidin-3 -amine (85.0 g, 333 mmol), THF (750 mL) and triethylamine (69.6 mL, 500 mmol), was slowly added (Boc) 2 0 (72.7 g, 333 mmol) in portions over 30 minutes. The reaction mixture was stirred at ambient temperature for 16 hours and was concentrated under vacuum. The residue was dissolved in CHCI3 and was washed with aqueous Na 2 C0 3 and brine. The organic layer was dried with MgS0 4 , filtered and concentrated to afford the title compound as a pale-yellow solid (116 g, 99% yield). MS (apci) m/z = 353.0 (M+H).

[00538] Step D: Preparation of tert-butyl trflns-4-phenylpyrrolidin-3-yl carbamate: A 2 gallon Parr reactor was charged with tra«5-(l-benzyl-4-phenyl-pyrrolidin-3-yl)-carbamic acid tert-butyl ester (114 g, 323 mmol), EtOH (2 L) and 10% Pd/C (50% wet, 11.0 g). The reactor was purged with N 2 several times, filled with H 2 to 56-57 psi and agitated at 80 °C. When the reaction was complete according to HPLC analysis, the reaction mixture was filtered and the filtrate concentrated to provide the crude product as a yellow solid. The crude material was triturated from toluene to afford the title product as a white solid (68.4 g, 78% yield). MS (apci) m/z = 262.9 (M+H).

Preparation B trans- 1 -(2-methoxyethyl -4-phenylpyrrolidin-3-amine dihydrochloride

[00539] Step A: Preparation of tert-butyl tra»5 , -l-(2-methoxyethyl)-4-phenylpyrrolidin- 3-ylcarbamate. To a solution of fert-butyl traHs-4-phenylpyrrolidin-3-ylcarbamate (Preparation A, 4.82 g, 17.5 mmol) in dry DMF (50 mL) was added sequentially DIE A (9.12 mL, 52.4 mmol) and l-bromo-2-methoxyethane (1.97 mL, 20.9 mmol). The mixture was stirred at ambient temperature for 46 hours and then poured into H 2 0 (300 mL). The mixture was extracted with EtOAc (3 x 150 mL) and the combined extracts were washed with brine, dried over MgS0 4 /activated carbon, filtered through a Si0 2 plug capped with packed MgS0 4 , and eluted with EtOAc. The solution was concentrated and dried under vacuum yielding the product as a white solid (5.15 g, 92% yield). MS (apci) m/z = 321.1 (M+H).

[00540] Step B: Preparation of trans-l -(2-methoxyethyl)-4-phenylpyrrolidin-3 -amine dihydrochloride: To a solution of ter/-butyl trara-l-(2-methoxyethyl)-4-phenylpyrrolidin-3- ylcarbamate (5.10 g, 15.9 mmol) in 2:1 EtOAc-MeOH (150 mL) was added 4 N HC1 in dioxane (59.7 mL, 239 mmol). The mixture was stirred at ambient temperature for 90 minutes and then concentrated under vacuum. The resulting foam was treated with EtOAc (200 mL), sonicated for 5 minutes and stirred vigorously until a fine white suspension formed. The suspension was filtered, washed with EtOAc and dried under vacuum to afford the title compound as a white powder (5.10 g, 100% yield). MS (apci) m/z = 221.1 (M+H).

Preparation CI

(3S, 4RY 1 -(2-methoxyethyl)-4-phenylpyrrolidin-3-amine dihydrochloride

[00541] Step A: Preparation of (j?)-3-cinnamoyl-4-phenyloxazolidin-2-one: A THF (50 mL) solution of (i?)-4-phenyloxazolidin-2-one (5.90 g, 36.2 mmol) was cooled to -78 °C and treated with lithium bis(trimethylsilyl)amide (36.9 mL, 36.9 mmol, 1.0 M in THF) dropwise over 15 minutes. After stirring for 15 minutes at -78 °C, a THF (10 mL) solution of cinnamoyl chloride (6.33 g, 38.0 mmol) was then introduced. The mixture was stirred for 1 hour at -78 °C and 2 hours at ambient temperature before it was quenched with saturated NaHC0 3 (50 mL) and stirred for 1 hour. The mixture was diluted with EtOAc (200 mL), washed with water and brine, dried over MgS0 4 , filtered and concentrated to give the product as a pale yellow solid (10.6 g, 99.9% yield). MS (apci) m/z = 293.9 (M+H).

[00542] Step B: Preparation of (i?V3-((3S.4i?)-l-(2-methoxyethyl)-4-phenylpyrrolidine- 3-carbonyl)-4-phenyloxazolidin-2-one: A toluene (500 mL) solution of (R)-3-cinnamoyl-4- phenyloxazolidin-2-one (8.00 g, 27.3 mmol) and TFA (0.210 mL, 2.73 mmol) was first cooled to 5-10 °C, followed by dropwise addition of a toluene (30 mL) solution of 2-methoxy-N- (methoxymethyl)-N-((trimethylsilyl)methyl)ethanamine (Preparation C, 8.40 g, 40.9 mmol). The resulting mixture was warmed up to ambient temperature and stirred for 3 hours, then washed with saturated NaHC0 3 and water, dried with MgS0 4 , filtered and concentrated under vacuum. The crude material was purified by silica column chromatography, eluting with 16- 20% EtOAc/hexanes, to afford the product (6.5 g, 60% yield). MS (apci) m/z = 395.2 (M+H).

[00543] Step C: Preparation of (3 .4i?)-l-(2-methoxyethvn-4-phenylpyrrolidine-3- carboxylic acid: To a 1M aqueous solution of LiOH (41.2 mL, 41.2 mmol) at 0 °C was added H 2 0 2 (3.37 mL, 33.0 mmol, 30 wt%). The mixture was then added to solution of (R)-3- ((35,47?)- 1 -(2-methoxyethyl)-4-phenylpyrrolidine-3-carbonyl)-4-phenylox azolidin-2-one (6.50 g, 16.5 mmol) in THF (100 mL) over 10 minutes at 0 °C. After 1 hour stirring, 2.0 M aqueous Na 2 S0 3 (33.0 mL, 65.9 mmol) was introduced at 0 °C and the reaction mixture was warmed to ambient temperature. After stirring for 10 minutes, the mixture was washed with EtOAc (50 mL). The aqueous layer was acidified with 1 N HC1 until pH 3-5, then treated with NaCl (10 g), then extracted with 10% iPrOH/DCM. The organic layer was dried with MgS0 4 , filtered and concentrated to give the product (4.11 g, 100% yield). MS (apci) m/z = 250.1 (M+H).

[00544] Step D: Preparation of benzyl (3^4i?)-l-(2-methoxyethyl)-4-phenylpyrrolidin- 3-ylcarbamate: To a solution of (3S,4i?)-l-(2-methoxyethyl)-4-phenylpyrrolidine-3-carboxylic acid (4.11 g, 16.5 mmol) in toluene (70 mL) was added TEA (5.74 mL, 41.2 mmol) followed by diphenyl phosphoryl azide (4.99 mL, 23.1 mmol). The mixture was stirred at ambient temperature for 1 hour and then heated to reflux for 1 hour. Benzyl alcohol (3.42 mL, 33.0 mmol) was then added and the reaction mixture was refluxed for 15 hours. The reaction mixture was treated with EtOAc, washed with water, dried over MgS0 4 , filtered and concentrated under vacuum. The crude material was purified by silica column chromatography, eluting with 1% MeOH/DCM to afford the product (2.5 g, 43% yield). MS (apci) m/z = 355.2 (M+H). [00545] Step E: Preparation of (3SAR)- 1 -(2-methoxyethyl V4-phenylpyrrolidin-3 -amine dihydrochloride: Benzyl (3S,4i?)-l-(2-methoxyethyl)-4-phenylpyrrolidin-3-ylcarbamate (0.257 g, 0.725 mmol) and TFA (3.91 mL, 50.8 mmol) were heated at 60 °C for 17 hours. The reaction mixture was concentrated under vacuum, using toluene to azeotrope, then treated with 2 N HCl in Et 2 0 and concentrated again to give the title compound (0.21 g, 100% yield) as an off-white solid. MS (apci) m/z = 221.2 (M+H).

[00546] The following pyrrolidine intermediates were made according to the method of Preparation CI, using the appropriately substituted cinnamoyl chloride in Step A. The corresponding trifluoroacetate salts could be prepared by substituting HCl with TFA in an appropriate solvent such as DCM or CHC1 3 in Step E.

Pre aration D

2-methoxy-N-(methoxymethyl ' )-N-((trimethylsilyl)methyl)ethanamine

[00547] Step A: Preparation of 2-methoxy-N-((trimethylsilyl)methvnethanamine: To a DMSO solution (15 mL) of 2-methoxyethanamine (14.2 mL, 163 mmol) at 90 °C was added a DMSO (10 mL) solution of (chloromethyl)trimethylsilane (11.4 mL, 81.5 mmol) by addition funnel over 40 minutes. The mixture was heated at 90 °C for 3.5 hours, then cooled to ambient temperature, diluted with H 2 0 (150 mL) and extracted with EtOAc (2 χ 150 mL). The combined organic extracts were washed with brine (150 mL), dried with MgS0 4 , filtered and concentrated to yield the product as a yellow oil (8.14 g, 62% yield). MS (apci) m/z = 162.0 (M+H). [00548] Step B: Preparation of 2-methoxy-N-(methoxymethyl -N-

((trimethylsilyl)methyl)ethanamine: A MeOH (2.45 mL) solution of formaldehyde (37% aqueous, 4.91 g, 60.6 mmol) was cooled to 0 °C, and treated with a dropwise addition of 2- methoxy-N-((trimethylsilyl)methyl)ethanamine (8.14 g, 50.5 mmol). The biphasic mixture was stirred at 0 °C for 3 hours, then K2CO3 (6.97 g, 50.5 mmol) was added and the mixture was stirred at 0 °C for 1 hour. The yellow oil was decanted onto K 2 C0 3 (2.00 g, 14.4 mmol), and the mixture was stirred at ambient temperature for 2 hours. After the yellow oil was decanted, the solid K 2 C0 3 was washed with Et 2 0 (2 x 10 mL), and the Et 2 0 washings were combined with the decanted yellow oil and concentrated on a rotary evaporator to yield the title compound as a yellow oil (9.92 g, 96% yield). 1H NMR (CDC1 3 ) δ 4.00 (s, 2H), 3.37-3.43 (m, 2H), 3.29 (s, 3H), 3.19 (s, 3H), 2.77-2.82 (m, 2H), 2.18 (s, 2H), 0.00 (s, 9H).

Preparation El

(3 1 S l ,4i?)-4-(4-fluorophenyl)- 1 -(2-methoxyethyl)pyrrolidin-3-amine

[00549] Step A: Preparation of (E)-l-fluoro-4-(2-nitrovinyl benzene: Acetic acid (2.0 L, 35.5 mol) and ammonium acetate (310.5 g, 4.03 mol) were stirred at ambient temperature for 1 hour, then nitromethane (611 mL, 11.3 mol) and 4-fluorobenzaldehyde (200 g, 1.61 mol) were added and the reaction mixture was heated to 90 °C for 3 hours. The reaction was allowed to cool to ambient temperature, then H 2 0 (4 L) was added over 2 hours with mechanical stirring. The suspension was stirred 1 hour, then filtered and washed with 2:1 water/acetic acid (500 mL). The solids were dried in a vacuum oven (50 °C) to afford the title product as a pale yellow solid (238 g, 1.42 mol, 88% yield). 1H NMR (CDC1 3 ) δ 7.98 (1H), 7.55 (3H), 7.16 (2H).

[00550] Step B: Preparation of trans-3 -(4-fluorophenyl)- 1 -(2-methoxyeth yl)-4-nitro- pyrrolidine: To a suspension of (E)-l-fluoro-4-(2-nitrovinyl)benzene (201 g, 1.20 mol) in DCM (1.09 L) and TFA (9.3 mL, 120 mmol) was added dropwise over 30 minutes 2-methoxy- N-(methoxymethyl)-N-((trimethylsilyl)methyl)ethanamine (Preparation A; 383 g, 1.86 mol) and the internal reaction temperature was maintained between 23-36 °C by cooling in an ice bath. The reaction mixture was poured into aqueous phosphate buffer solution (pH 7, 500 mL) and diluted with DCM (300 mL). The phases were separated and the aqueous phase was extracted with DCM (400 mL). The organic phases were combined, washed with brine (300 mL), dried (MgS0 4 ), filtered and concentrated under reduced pressure. The crude oil was purified by silica column chromatography eluting with 40% EtO Ac/heptane to afford the title compound as a yellow oil (245 g, 76% yield). MS (apci) m/z = 269.1 (M+H).

[00551] Step C: Preparation of tram-4-(4-fluorophenylV 1 -(2-methoxyethyl)pyrrolidin- 3 -amine: To a solution of tra«5-3-(4-fluorophenyl)-l-(2-methoxyethyl)-4-nitropyrrolid ine (289 g, 1.08 mol) in EtOH (1 L) was added platinum(IV) oxide (24.5 g, 108 mmol) in a Pan- vessel and installed into a Parr shaker. The vessel was evacuated and backfilled with nitrogen (3x), then evacuated and backfilled with hydrogen (60 psi). The vessel was recharged with hydrogen as needed until the reaction was complete. The reaction mixture was filtered through Celite® and rinsed with MeOH (50 mL), then concentrated under reduced pressure to afford the title compound as a yellow oil (243 g, 95% yield). MS (apci) m/z = 239.1 (M+H).

[00552] Step D: Preparation of f3S,4R)-4-(4-fluorophenylVl-(2- methoxyethyl)pyreolidin-3 -amine (2S,3S)-2,3-bis(4-methylbenzoyloxy)succinate: To a solution of (3S,4R)-4-(4-fluorophenyl)-l-(2-methoxyethyl)pynolidin-3-ami ne (120 g, 504 mmol) in THF (3.0 L) and H 2 0 (333 mL) was added di-p-toluoyl-D-tartaric acid (195 g, 504 mmol). The mixture was stirred at ambient temperature for 1 hour, then placed in a freezer (- 11 °C) for 18 hours. The mixture was stirred to give a slurry, filtered, and rinsed with Et 2 0 (4 x 100 mL). The solid was dried in vacuum oven (40 °C) for 4 hours, then recrystallized twice by the following procedure: the solid was dissolved in THF (1.06 mL) and H 2 0 (118 mL) with heating to 45 °C, then allowing to cool to ambient temperature over 2 hours, then placed in a freezer (-11 °C) for 18 hours; the mixture was stined to give a slurry, filtered, and rinsed with Et 2 0 (4 x 100 mL). After two recrystallizations, the solid was dried in vacuum oven (40 °C) for 18 hours to afford the title compound as a white crystalline solid (96 g, 31% yield). MS (apci) m/z = 239.2 (M+H).

[00553] Step E: Preparation of (3S.4i?V4-(4-fluorophenyl)-l-(2- methoxyethyl)pynolidin-3 -amine : (3S,4R)-4-(4-fluorophenyl)-l -(2-methoxyethyl)pynolidin- 3-amine (2S,3S)-2,3-bis(4-methylbenzoyloxy)succinate (20 g, 32.0 mmol) was dissolved in DCM (300 mL) and washed with 1M NaOH (2 x 200 mL). The combined aqueous phases were extracted with DCM (200 mL). The combined organic extracts were washed with brine (200 mL), dried (MgS0 4 ), filtered and concentrated, then dried under vacuum to afford the title compound as a yellow oil (6.17 g, 81%, >99% ee). MS (apci) m/z = 239.1 (M+H).

[00554] The following pyrcolidine intermediates were made according to the method of Preparation El, using the appropriate benzaldehyde in Step A and replacing EtOH and platinum(IV) oxide with MeOH and Raney nickel respectively in Step C. For preparation E3, the 90% THF/H 2 0 in Step D was replaced with 85% MeOH/H 2 0.

Preparation D-100

(3S, 4R)- 1 -(2-methoxyethyl)-4-phenylpyrrolidin-3 -amine dihydrochloride

[00555] Step A: Preparation of (J?)-3-cinnamoyl-4-phenyloxazolidin-2-one: A THF (50 mL) solution of (i?)-4-phenyloxazolidin-2 -one (5.90 g, 36.2 mmol) was cooled to -78 °C and treated with lithium bis(trimethylsilyl)amide (36.9 mL, 36.9 mmol, 1.0 M in THF) dropwise over 15 minutes. After 15-minute stirring at -78 °C, a THF (10 mL) solution of cinnamoyl chloride (6.33 g, 38.0 mmol) was then introduced. The mixture was stirred for 1 hour at -78 °C and 2 hours at ambient temperature before it was quenched with saturated NaHC0 3 (50 mL) and stirred for 1 hour. The mixture was diluted with EtOAc (200 mL), washed with water and brine, dried over MgS0 4 , filtered and concentrated to give the product as a pale yellow solid (10.6 g, 99.9% yield). MS (apci) m/z = 293.9 (M+H).

[00556] Step B: Preparation of (^)-3-((3S.4i?Vl-(2-methoxyethyl)-4-phenylpyrrolidine- 3 -carbonv0-4-phenyloxazolidin-2-one : A toluene (500 mL) solution of (R)-3-cinnamoyl-4- phenyloxazolidin-2-one (8.00 g, 27.3 mmol) and TFA (0.210 mL, 2.73 mmol) was first cooled to 5-10 °C, followed by dropwise addition of a toluene (30 mL) solution of 2-methoxy-N- (methoxymethyl)-N-((trimethylsilyl)methyl)ethanamine (Preparation C, 8.40 g, 40.9 mmol). The resulting mixture was warmed up to ambient temperature and stirred for 3 hours, then washed with saturated NaHC0 3 and water, dried with MgS0 4 , filtered and concentrated in vacuo. The crude material was purified by silica column chromatography, eluting with 16-20% EtOAc/hexanes, to afford the product (6.5 g, 60% yield). MS (apci) m/z = 395.2 (M+H).

[00557] Step C: Preparation of (3S.4i?)-l-(2-methoxyethyl)-4-phenylpyrrolidine-3- carboxylic acid: To a 1M aqueous solution of LiOH (41.2 mL, 41.2 mmol) at 0 °C was added H 2 0 2 (3.37 mL, 33.0 mmol, 30 wt%). The mixture was then added to solution of (i?)-3- ((3S,4i?)-l-(2-methoxyethyl)-4-phenylpyrrolidine-3-carbonyl) -4-phenyloxazolidin-2-one (6.50 g, 16.5 mmol) in THF (100 mL) over 10 minutes at 0 °C. After 1 hour stirring, 2.0 M aqueous Na 2 S0 3 (33.0 mL, 65.9 mmol) was introduced at 0 °C and the reaction mixture was warmed to ambient temperature. After stirring for 10 minutes, the mixture was washed with EtOAc (50 mL). The aqueous layer was acidified with 1 N HC1 until pH 3-5, then treated with NaCl (10 g), then extracted with 10% iPrOH/DCM. The organic layer was dried with MgS0 4 , filtered and concentrated to give the product (4.11 g, 100% yield). MS (apci) m/z = 250.1 (M+H).

[00558] Step D: Preparation of benzyl (35 , ,4i?)-l-(2-methoxyethyl)-4-phenylpyrrolidin- 3-ylcarbamate: To a solution of (3S,4i?)-l-(2-methoxyethyl)-4-phenylpyrrolidine-3-carboxylic acid (4.11 g, 16.5 mmol) in toluene (70 mL) was added TEA (5.74 mL, 41.2 mmol) followed by diphenyl phosphoryl azide (4.99 mL, 23.1 mmol). The mixture was stirred at ambient temperature for 1 hour and then heated to reflux for 1 hour. Benzyl alcohol (3.42 mL, 33.0 mmol) was then added and the reaction mixture was refluxed for 15 hours. The reaction mixture was treated with EtOAc, washed with water, dried over MgS0 4 , filtered and concentrated in vacuo. The crude material was purified by silica column chromatography, eluting with 1% MeOH/DCM to afford the product (2.5 g, 43% yield). MS (apci) m/z = 355.2 (M+H).

[00559] Step E: Preparation of (3SAR)- 1 -(2-methoxyethyl)-4-phenylpyrrolidin-3-amine dihydrochloride: Benzyl (3S,4i?)-l-(2-methoxyethyl)-4-phenylpyrrolidin-3-ylcarbamate (0.257 g, 0.725 mmol) and TFA (3.91 mL, 50.8 mmol) were heated at 60 °C for 17 hours. The reaction mixture was concentrated in vacuo, using toluene to azeotrope, then treated with 2 N HC1 in Et 2 0 and concentrated again to give the title compound (0.21 g, 100% yield) as an off- white solid. MS (apci) m/z = 221.2 (M+H). Preparation G-100

(iS,4i?)-l-(2-methoxyethyl)-4-0-(trifluoromethyl)phenyl)pyiT olidin-3-amine dihydrochloride

[00560] Step A: Preparation of tert-butyl (3S.4i? -l-(2-methoxyethvn-4-(3- (trifluoromethyl Vphenyl)pyrrolidin-3 -ylcarbamate : A solution of tert-butyl (3S,4i?)-4-(3- (trifluoromethyl)phenyl)-pyrrolidin-3-ylcarbamate (100 mg, 0.303 mmol, commercially available), N,N-diethylpropan-2-amine (0.145 mL, 0.908 mmol) and l-bromo-2- methoxyethane (0.0361 mL, 0.363 mmol) in DMF (1 mL) was stirred at ambient temperature for 2 hours, then heated to 60 °C for 4 hours, then cooled to ambient temperature overnight. After partitioning between EtOAc and saturated NaHC0 3 (10 mL each), the organic layer was washed with water and brine (2 x 10 mL each), dried over Na 2 S0 4 , filtered and concentrated to yield the crude product as white solid (80 mg, 68% yield). LCMS (apci) m/z = 389.1 (M+H).

[00561] Step B: Preparation of (3SAR)- 1 -(2-methoxyethvn-4-(3- (trifluoromethyl)phenylV pyrrolidin-3 -amine dihydrochloride : A solution of tert-butyl (3S,4R)- l-(2-methoxyethyl)-4-(3-(trifluoromethyl)phenyl)pyrrolidin-3 -ylcarbamate (80.0 mg, 0.206 mmol) in 5-6 N HC1 in IPA (4.12 mL, 20.6 mmol) was stirred at ambient temperature for 1 hour, followed by concentrating in vacuo and triturating with Et 2 0 to afford the product as beige solid (74 mg, 99.5% yield). LCMS (apci) m/z = 289.1 (M+H).

Preparation H-100

(3.S',4i?)-4-(3-fluorophenvn-l-(2-methoxyethyl)pyrrolidin-3- amine dihydrochloride

[00562] Prepared according to the method of Preparation G-100, replacing tert-butyl (35',4^)-4-(3-(trifluoromethyl)phenyl)-pyrrolidin-3-ylcarbam ate with tert-butyl (3S,4R)-4-(3- fluorophenyl)pyrrolidin-3-ylcarbamate to afford the title compound. LCMS (apci) m/z = 239.1 (M+H).

Preparation 1-100

(3S,4i?)-4-(2,4-difluorophenyl)- 1 -(2-methoxyethyl)pyrrolidin-3-amine dihydrochloride

[00563] Prepared according to the method of Preparation G-100, replacing tert-butyl (3S,4i?)-4-(3-(trifluoromethyl)phenyl)-pyrrolidin-3-ylcarbam ate with tert-butyl (35,4i?)-4-(2,4 di-fluoro-phenyl)pyrrolidin-3-ylcarbamate to afford the title compound. LCMS (apci) m/z = 257.1 (M+H).

Preparation J-100

(3£4i?)-4-(2,5-difluorophenyl)- 1 -(2-methoxyethyl)pyrrolidin-3 -amine dihydrochloride

[00564] Prepared according to the method of Preparation G-100, replacing tert-butyl (3S,4i?)-4-(3-(trifluoromethyl)phenyl)-pyrrolidin-3-ylcarbam ate with tert-butyl (3S,4J?)-4-(2,5 di-fluoro-phenyl)pyrrolidin-3-ylcarbamate to afford the title compound. LCMS (apci) m/z = 257.1 (M+H).

Preparation K-100

(3S,4i?)-4-(4-fluorophenyl)- 1 -(2-methoxyethyl)pyrrolidin-3 -amine dihydrochloride

[00565] Prepared according to the method described in Preparation D-100, replacing cinnamoyl chloride with (E)-3-(4-fluorophenyl)acryloyl chloride. MS (apci) m/z = 239.1 (M+H). [00566] The following pyrrolidine intermediates were made according to the method of Preparation El, using the appropriate benzaldehyde in Step A and replacing EtOH and platinum(IV) oxide with MeOH and Raney nickel respectively in Step C.

Preparation Structure Name Data

#

L-100 trans-4-(3 -chloro-4-fluoro- MS (apci) m/z phenyl)- 1 -(2-methoxyethyl) 273.1 (M+H) pyrrolidin-3 -amine

L-101 trans-4-(4-c \oTO-3 -fluoroMS (apci) m/z phenyl)- 1 -(2-methoxyethyl) = 273.1 (M+H)

NH 2 F pyrrolidin-3 -amine

' L-102 F trans-4-(3-chloro-5-fluoro- MS (apci) m/z = phenyl)- 1 -(2-methoxyethyl) 273.1 (M+H) pyrrolidin-3 -amine

NH 2 CI

L-103 trans-4-(3-chlorophenyl)- 1 - MS (apci) m/z =

(2-methoxyethyl)pyrrolidin- 255.1 (M+H) 3 -amine

L-104 trans-4-(2,4- MS (apci) m/z difluorophenyl)- 1 -(2- = 256.1 (M+H) methoxyethyl)pyrrolidin-3 -

NH 2 amine

L-105 trara-4-(5-fluoropyridin-3- MS (apci) m/z = yl)-l-(2- 240.1 (M+H) methoxyethyl)pyrrolidin-3 - amine

L-106 /raws-4-(5-fluoropyridin-2- 'H NMR

yl)-l-(2- consistent with methoxyethyl)pyrrolidin-3 - expected

NH 2 amine product

L-107 trans-4-{2> -fluoropyridin-4- Not available yl)-l-(2- methoxyethyl)pyrrolidin-3 -

NH 2 amine

L-108 /mM5-4-(5-chloropyridin-3- MS (apci) m/z = yl)-l-(2- 256.1 (M+H) methoxyethyl)pyrrolidin-3-

NH 2 CI amine

L-109 trans- 1 -(2-methoxyethyl)-4- 'H NMR

( 1 -methyl- 1 H-pyrazol-4-yl) consistent with pyrrolidin-3 -amine expected

H 2 product Preparation Structure Name Data

#

L-110 trans- 1 -(2-methoxyethyl)-4- Not available

(l,2,3-thiadiazol-4- yl)pyrrolidin-3 -amine

H 2

Preparation L-l 11

4-(trans-4-amino- 1 -(2-methoxyethyl)pyrrolidin-3 -yPbenzonitrile

[00567] Prepared according to the method described in Preparation El, Steps A to C, replacing 4-fluorobenzaldehyde with 4-formylbenzonitrile in Step A and replacing EtOH and platinum(IV) oxide with MeOH, Zn (dust) and saturated N¾C1, respectively in Step C. MS (apci) m/z = 246.1 (M+H).

Preparation L-l 12

3 -(tra;»-4-amino- 1 -(2-methoxyethyl)pyrrolidin-3 -yPbenzonitrile

[00568] Prepared according to the method described in Preparation El, Steps A to C, replacing 4-fluorobenzaldehyde with 3-formylbenzonitrile in Step A, and replacing EtOH and platinum(IV) oxide with MeOH, Zn (dust) and saturated NH 4 CI, respectively, in Step C. MS (apci) m/z = 246.2 (M+H).

Preparation M-100

(3S,4R)-l-(2-methoxyethyl)-4-(3,4,5-trifluorophenyl)pyrrolid in-3-amine dihydrochloride

[00569] Prepared according to the method described in Preparation D-100, replacing cinnamoyl chloride with (E)-3-(3,4,5-trifluorophenyl)acryloyl chloride. 1H NMR (D 2 0) δ 7.06-7.10 (m, 2H), 4.13-4.20 (m, 1H), 3.92-3.99 (m, 2H), 3.71-3.74 (m, 1H), 3.57-3.63 (m, 3H), 3.41-3.49 (m, 3H), 3.25 (s, 3H). Preparation N-100

rran -5-(4-amino-l-(2-methoxyethyl)pyrrolidin-3-yl)-2-fluorobenzo nitrile

[00570] Step A: (E)-2-fluoro-5-(2-nitrovinyl)benzonitrile. To a solution of 2-fluoro-5- formylbenzonitrile (3.84 g, 25.0 mmol) in 3:1 CH 3 N0 2 /CH 3 CN (25 mL) was added DMAP (0.305 g, 2.50 mmol) and the mixture stirred at ambient temperature for 23 hours. The mixture was cooled on an ice bath and Ac 2 0 (3.54 mL, 37.5 mmol) was added. The mixture was stirred for 5 minutes, allowed to reach ambient temperature and stirred for 1 hour. The mixture was concentrated to a yellow solid. The solid was suspended in iPrOH (70 mL) and stirred for 10 minutes. The suspension was collected via vacuum filtration, the cake washed with iPrOH and dried in vacuum to afford the title compound as a light tan powder (3.36 g, 70%). 1H NMR (CDC1 3 ) δ 7.96 (d, 1H), 7.79-7.88 (m, 2H), 7.57 (d, 1H), 7.36 (t, 1H).

[00571] Step B: 7rarcs-2-fluoro-5-( 1 -(2-methoxyethylV4-nitropyrrolidin-3- vDbenzonitrile: Using (E)-2-fluoro-5-(2-nitrovinyl)benzonitrile in Step B of the procedure describe in Preparation El, the title compound was prepared as light gold syrup (1.56 g, 53%). MS (apci) m/z - 294.1 (M+H).

[00572] Step C: 7ra?7.y-5-(4-amino- 1 -(2-methoxyethvnpyrrolidin-3-vn-2- fluorobenzonitrile: A solution of irara-2-fluoro-5-(l-(2-methoxyethyl)-4-nitropyrrolidin-3- yl)benzonitrile (450 mg, 1.53 mmol) in MeOH (6.0 mL) was cooled to 0 °. Zn dust (1.00 mg, 15.3 mmol) and saturated aqueous NHjCl (1.0 mL) were added sequentially and the mixture was stirred for 5 minutes. The mixture was allowed to reach ambient temperature and stirred until complete by LCMS analysis. The mixture was filtered through packed Celite® using MeOH for rinsing and elution and the filtrate was concentrated to a colorless syrup. The syrup was treated with 1M 2 C0 3 (15 mL), mixed and extracted with CH 2 C1 2 (3X). The combined CH2CI2 extracts were dried over Na 2 S0 4 , filtered and concentrated to provide the title compound as a colorless syrup (412 mg, 100%). MS (apci) m/z = 264.1 (M+H).

rra^-3-(4-amino-l-(2-methoxyethyl)pyrrolidin-3-ylV5-fluorobe nzonitrile

[00573] Step A: 3 -fluoro-5 -formylbenzonitrile : A solution of 3-bromo-5- fluorobenzonitrile (5.00 g, 25.0 mmol) in dry THF (25 mL) was cooled to 0 °C and 2M iPrMgCl (15.0 mL, 30.0 mmol) in THF was added dropwise over 5 minutes. The mixture was stirred at 0 °C for 15 minutes then at ambient temperature for 1 hour. The mixture was cooled to 0 °C and dry DMF (5.81 mL, 75.0 mmol) was added. The mixture was stirred for 17 hours during which time the temperature reached ambient temperature after 2 hours. The mixture was added to ice water (150 mL) and Et 2 0 (100 mL). The biphasic mixture was stirred and treated with 6M HCl to aqueous pH=3. The organic layer was removed and the aqueous layer extracted with Et 2 0 (2X). The combined Et 2 0 fractions were washed with saturated NaCl and dried over MgSCVactivated carbon. The dried solution was filtered through a Si0 2 plug eluting with Et 2 0. The filtrate was concentrated to give the title compound as a yellow solid that was dried in vacuum (3.68 g, 99%). 1H NMR (CDC1 3 ) δ 10.0 (s, 1H), 8.00 (s, 1H), 7.81- 7.86 (m, 1H), 7.62-7.67 (m, 1H).

[00574] Step B: 7> » -3-(4-amino-l-(2-methoxyethyl)pyrrolidin-3-yl)-5- fluorobenzonitrile : The tile compound was prepared using 3-fluoro-5-formylbenzonitrile in the procedure described for the preparation of tra«5 , -5-(4-amino-l-(2-methoxyethyl)pyrrolidin-3- yl)-2-fluorobenzonitrile (Preparation N-100). The compound was isolated as a colorless syrup (542 mg, 93%). MS (apci) m/z = 264.1 (M+H).

Preparation P-100

7V « -l-(2-methoxyethyl)-4-(4-chlorophenyl)pyrrolidin-3-amine

[00575] Step A: 7 « -3-(4-chlorophenyl)-l-(2-methoxyethyl)-4-nitropyrrolidine: Using (E)-l-chloro-4-(2-nitrovinyl)benzene in Step B of the procedure describe in Preparation El, the title compound was prepared as viscous colorless oil (5.10 g, 64%). MS (apci) m/z = 285.0 (M+H). [00576] Step B: Trans- 1 -(2-methoxyethyl)-4-(4-chlorophenyl)pyrrolidin-3 -amine : To a suspension of 2800 Raney Nickel (50 wt% in H 2 0, 0.873 g, 5.10 mmol) in MeOH (25 mL) was added trara-3-(4-chlorophenyl)-l-(2-methoxyethyl)-4-nitropyrrolidi ne (2.90 g, 10.2 mmol) in MeOH (25 mL). The mixture was flushed with H 2 gas and stirred under a balloon atmosphere of H 2 for 16 hours. The mixture was purged with N 2 gas and filtered through packed Celite® using MeOH for rinsing and elution. The filtrate was concentrated to a cloudy oil. The oil was dissolved in CH 2 C1 2 and dried over Na 2 S0 4 /activated carbon. The solution was filtered and concentrated to provide the title compound as a light gold oil that was dried in vacuum (2.46 g, 95%). MS (apci) m/z = 255.1 (M+H).

Preparation of Synthetic Examples

Example 1

1 -(trans- 1 -(2-methoxyethyl)-4-phenylpyrrolidin-3 -yl)-3 -(2-phenylpyridin-3 -vDurea

[00577] Step A: Preparation of 2-phenylpyridin-3 -amine: Phenyl boronic acid (92 mg, 0.75 mmol), K 2 C0 3 (320 mg, 2.31 mmol) and Pd(PPh 3 ) 4 (67 mg, 0.06 mmol) were combined in toluene (3 mL), water (1.5 mL) and EtOH (0.75 mL) then treated with 2-bromopyridin-3- amine (100 mg, 0.58 mmol). The mixture was warmed to 95 °C in a sealed tube for 16 hours then cooled and partitioned between EtOAc (20 mL) and water (20 mL). The aqueous layer was extracted with EtOAc (2 x 10 mL) and the combined organic phases were washed with brine (10 mL), dried over Na 2 S0 4 , filtered and concentrated under vacuum. The residue was purified by silica column chromatography eluting with 9:1 to 4:1 hexanes/EtOAc, to afford 2- phenylpyridin-3 -amine (83 mg, 84% yield) as a pale yellow gum. MS (apci) m/z = 171.2 (M+H).

[00578] Step B: Preparation of phenyl (2-phenylpyridin-3-yl)carbamate: To a solution of 2-phenylpyridin-3-amine (83 mg, 0.49 mmol) in EtOAc (2 mL) was added 2 M NaOH (488 μί, 0.97 mmol) followed by phenyl chloroformate (86 μΕ, 0.68 mmol). The mixture was stirred vigorously for 16 hours then partitioned between EtOAc (10 mL) and water (10 mL). The aqueous layer was extracted with EtOAc (2 x 10 mL) and the combined organic phases were washed with saturated NaHC0 3 (10 mL) and brine (10 mL) then dried over Na 2 S0 4 , filtered and concentrated under vacuum to afford phenyl (2-phenylpyridin-3-yl)carbamate (121 mg, 85% yield) as a white foam. MS (apci) m/z = 291.1 (M+H).

[00579] Step C: Preparation of 1 -(trans- 1 -(2-methoxyethyl)-4-phenylpyrrolidin-3 -yl)-3 - (2-phenylpyridin-3-yl)urea: To a solution of tra«5-l-(2-methoxyethyl)-4-phenylpyrrolidin-3- amine dihydrochloride [Preparation B] (50 mg, 0.17 mmol) and phenyl (2-phenylpyridin-3- yl)carbamate (54.5 mg, 0.19 mmol) in DMA (2 mL) was added DIEA (104 μί, 0.60 mmol). The mixture was stirred at ambient temperature for 16 hours then partitioned between saturated NH4CI (20 mL) and EtOAc (10 mL). The aqueous layer was extracted with EtOAc (2 x 10 mL) and the combined organic phases were washed with water (5 x 10 mL) and brine (10 mL) then dried over Na 2 S0 4 , filtered and concentrated under vacuum. The residue was purified by silica column chromatography eluting with 2-4% MeOH/DCM to afford the title product (47 mg, 66% yield) as a white foam. MS (apci) m/z = 417.2 (M+H).

Example 2

l-(5-chloro-2-phenylpyridin-3-yl)-3-(tra?7 -l-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl)urea

[00580] Prepared according to the procedure of Example 1, replacing 2-bromopyridin-3- amine with 2-bromo-5-chloropyridin-3 -amine in Step A. Material was purified by silica column chromatography eluting with 2% MeOH/DCM to afford the title compound (75 mg, 61% yield) as a colorless glass. MS (apci) m/z = 451.3 (M+H).

Example 3

l-(5-bromo-2-phenylpyridin-3-vn-3-(trans)-l-(2-methoxyethyl) -4-phenylpyrrolidin-3-yl)urea

[00581] Prepared according to the procedure of Example 1, replacing 2-bromopyridin-3- amine with 2,5-dibromopyridin-3-amine in Step A. Material was purified by silica column chromatography eluting with 2% MeOH/DCM to afford the title compound (57 mg, 75% yield) as a white foam. MS (apci) m/z = 495.1 (M+).

Example 4

l-(tran -l-(2-methoxyethvn-4-phenylpwolidin-3-yl)-3-(5-(methylsulfon yl)-2-phenylpyridin-

3-yl)urea

[00582] 1 -(5-Bromo-2-phenylpyridin-3-yl)-3-(trans)- 1 -(2-methoxyethyl)-4- phenylpyrrolidin-3-yl)urea [Example 3] (50 mg, 0.1 mmol), methane sulfinic acid, sodium salt (41.2 mg, 0.4 mmol) and copper iodide (21.1 mg, 0.11 mmol) were combined in DMSO (1 mL) and purged with argon for 5 minutes. The mixture was stirred at 100 °C in a sealed tube for 16 hours then treated with copper iodide (40 mg) and stirred at 100 °C for 6 hours. The cooled mixture was partitioned between water (10 mL) and EtOAc (10 mL) and a few drops of NH OH were added. The aqueous layer was extracted with EtOAc (2 x 10 mL) and the combined organic phases were washed with water (5 x 10 mL) and brine (10 mL) then dried over Na 2 S04, filtered and concentrated under vacuum. The residue was purified by silica column chromatography eluting with 2-5% MeOH/DCM to afford the title compound (6 mg, 12% yield) as a pale yellow gum. MS (apci) m/z = 495.3 (M+H).

Example 5

l-(5-bromo-2-phenylpyridin-3-yl)-3-((3S,4R)-l-(2-methoxyethy l)-4-phenylpyrrolidin-3- yPurea

[00583] Prepared according to the procedure of Example 1, replacing trans-\-(2- methoxyethyl)-4-phenylpyrrolidin-3 -amine dihydrochloride [Preparation B] with (35,47?)- 1 -(2- methoxyethyl)-4-phenylpyrrolidin-3-amine dihydrochloride [Preparation CI] in Step C. The crude material was purified by silica column chromatography eluting with 2% MeOH/DCM to afford the title compound (46 mg, 60% yield) as a white foam. MS (apci) m/z = 497.2 (M+H).

Example 6

l-(5-bromo-2-phenylpyridin-3-vn-3-((3S,4R)-4-(3,4-difluoroph envn-l-(2- methoxyethvDpyrrolidin-3-yl)urea

[00584] Prepared according to the procedure of Example 1 , replacing trans- 1 -(2- methoxyethyl)-4-phenylpyrrolidin-3-amine dihydrochloride [Preparation B] with (3S,4 ?)-4- (3,4-difluorophenyl)-l-(2-methoxyethyl)pyrrolidin-3-amine dihydrochloride [Preparation C3] in Step C. The crude material was purified by silica column chromatography eluting with 2% MeOH/DCM to afford the title compound (49 mg, 56% yield) as a colorless glass. MS (apci) m/z = 533.2 (M+H).

Example 7

1 -(2,5 -diphenylp yridin-3 -yl)-3 -((3 S ,4PQ- 1 -(2-methoxyethyl)-4-phenylpyrrolidin-3 -yl)urea

[00585] Prepared according to the procedure of Example 1, replacing 2-bromopyridin-3- amine with 2,5-dibromopyridin-3-amine in Step A (isolating 2,5-diphenylpyridin-3-amine) and traii5-l-(2-methoxyethyl)-4-phenylpyrrolidin-3-amine dihydrochloride [Preparation B] with (35,4i?)-l-(2-methoxyethyl)-4-phenylpyrrolidin-3-amine dihydrochloride [Preparation CI] in Step C. The crude material was purified by silica column chromatography eluting with 2% MeOH/DCM to afford the title compound (20 mg, 61% yield) as a colorless glass. MS (apci) m/z = 493.2 (M+).

1 -((3 S ,4R)- 1 -(2-methoxyethyl)-4-phenylp yrrolidin-3 - yl)-3 -(2-methyl-6-phenylpyridin-3 - vDurea

[00586] Prepared according to the procedure of Example 1, replacing 2-bromopyridin-3- amine with 6-bromo-2-methylpyridin-3-amine in Step A and trara-l -(2-methoxyethyl)-4- phenylpyrrolidin-3 -amine dihydrochloride [Preparation B] with (3S,4i?)-l-(2-methoxyethyl)-4- phenylpyrrolidin-3 -amine dihydrochloride [Preparation CI] in Step C. The crude material was purified by silica column chromatography eluting with 2% MeOH/DCM to afford the title compound (18 mg, 63% yield) as a colorless glass. MS (apci) m/z = 431.0 (M+H).

Example 9

l-((3S.4R)-4-(3.4-difluorophenyl -l-(2-methoxyethvnpyrrolidin-3-ylV3-(2-methyl-6- phenylpyridin-3 -vPurea

[00587] Prepared according to the procedure of Example 8, replacing (35,4 ?)- 1 -(2- methoxyethyl)-4-phenylpyrrolidin-3-amine dihydrochloride [Preparation CI] with (3S,4./?)-4- (3,4-difluorophenyl)-l -(2-methoxyethyl)pyrrolidin-3-amine dihydrochloride [Preparation C3] in Step C. Material was purified by silica column chromatography eluting with 2% MeOH/DCM to afford the title compound (19 mg, 66% yield) as a white solid. MS (apci) m/z = 467.2 (M+H). Example 10

1 -( ( 3 S,4RV4-(3.4-difluorophenylV 1 -(2-n ethoxyethyl pyrrolidin-3-yl)-3-(2-methyl-5- phenylpyridin-3 - vPurea

[00588] Prepared according to the procedure of Example 1 , replacing 2-bromopyridin-3- amine with 5-bromo-2-methylpyridin-3-amine in Step A and tra«s-l-(2-methoxyethyl)-4- phenylpyrrolidin-3 -amine dihydrochloride [Preparation B] with (3S,4R)-4-(3,4- difluorophenyl)-l-(2-methoxyethyl)pyrrolidin-3 -amine dihydrochloride [Preparation C3] in Step C. Material was purified by silica column chromatography eluting with 2-5% MeOH/DCM to afford the title compound (16 mg, 55% yield) as a colorless glass. MS (apci) m/z = 467.2 (M+H).

Example 11

1 -( 6-bromo-2-phenv yridin-3 -yl)-3 -((3 S,4RV4-( 3.4-difluorophenylV 1 -(2- methoxyethyl)pyrrolidin-3-yl)urea

[00589] Prepared according to the procedure of Example 1, replacing 2-bromopyridin-3- amine with 2,6-dibromopyridin-3-amine in Step A and trans- l-(2-methoxyethyl)-4- phenylpyrrolidin-3 -amine dihydrochloride [Preparation B] with (3S,4i?)-4-(3,4- difluorophenyl)-l-(2-methoxyethyl)pyrrolidin-3-amine dihydrochloride [Preparation C3] in Step C. Material was purified by silica column chromatography eluting with 2% MeOH/DCM to afford the title compound (58 mg, 62%» yield) as a white solid. MS (apci) m/z = 533.0 (M+H). Example 12

1 -(( 3 S,4R)-4-(3,4-difluorophenylV 1 -(2-methoxyethyl)pyrrolidin-3-yl)-3-(6-(methylsulfonyl)-

2-phenylpyridin-3 - vDurea

[00590] Step A: Preparation of 6-bromo-2-phenylpyridin-3-amine: Prepared according to the procedure of Example 1, Step A, replacing 2-bromopyridin-3-amine with 2,6- dibromopyridin-3 -amine. MS (apci) m/z = 249.1 (M+).

[00591] Step B: Preparation of 6-(methylsulfonyl)-2-phenylpyridin-3-amine: 6-Bromo-

2- phenylpyridin-3 -amine (50 mg, 0.20 mmol), methane sulfinic acid, sodium salt (82 mg, 0.80 mmol) and copper iodide (42 mg, 0.22 mmol) were combined in DMSO (1 mL) and purged with argon for 5 minutes. The mixture was stirred at 100 °C in a sealed tube for 3.5 hours then cooled and partitioned between water (10 mL) and EtOAc (10 mL) and a few drops of NH 4 OH. The aqueous layer was extracted with EtOAc (2 x 10 mL) and the combined organic phases were washed with water (5 x 10 mL) and brine (10 mL) then dried over Na 2 S0 4 , filtered and concentrated under vacuum. The residue was purified by silica column chromatography eluting with 1% MeOH/DCM to afford 6-(methylsulfonyl)-2-phenylpyridin-

3- amine (39 mg, 78% yield) as a colorless glass. MS (apci) m/z = 249.1 (M+).

[00592] Step C: Preparation of l-((3S.4RV4-(3.4-difluorophenvn-l-(2- methoxyethyl)pyrrolidin-3-yl)-3-(6-(methylsulfonyl)-2-phenyl pyridin-3-yl)urea: Prepared according to the procedure of Example 1, replacing 2-phenylpyridin-3 -amine with 6- (methylsulfonyl)-2-phenylpyridin-3-amine in Step B and tra«5 , -l-(2-methoxyethyl)-4- phenylpyrrolidin-3-amine dihydrochloride [Preparation B] with (3S,4i?)-4-(3,4- difluorophenyl)-l-(2-methoxyethyl)pyrrolidin-3-amine dihydrochloride [Preparation C3] in Step C. The crude material was purified by silica column chromatography eluting with 2% MeOH/DCM to afford the title compound (34 mg, 52% yield) as a white foam. MS (apci) m/z = 531.0 (M+H). Example 13

l-((3S,4R)-4-(3^-difluorophenyl>l-(2-m^

2-phenylpyridin-3 -vPurea

[00593] l-(5-Bromo-2-phenylpyridin-3-yl)-3-((3S,4R)-4-(3,4-difluorop henyl)-l-(2- methoxyethyl)pyrrolidin-3-yl)urea [Example 6] (30 mg, 0.06 mmol), methane sulfinic acid, sodium salt (23 mg, 0.23 mmol) and copper iodide (12 mg, 0.06 mmol) were combined in DMSO (1 mL) and purged with argon for 5 minutes. The mixture was stirred at 100 °C in a sealed tube for 16 hours then cooled and partitioned between water (10 mL) and EtOAc (10 mL) and a few drops of N¾OH. The aqueous layer was extracted with EtOAc (2 x 10 mL) and the combined organic phases were washed with water (5 x 10 mL) and brine (10 mL) then dried over Na 2 S0 4 , filtered and concentrated under vacuum. The residue was purified by silica column chromatography eluting with 2% MeOH/DCM to afford the title compound (6 mg, 20% yield) as a white solid. MS (apci) m/z = 531.0 (M+H).

Example 14

l- (( 3S,4R -4- ( 3.4-difluorophenvn-l-(2-methoxyethyl)pyrrolidin-3-vn-3 -(6-methyl-r2.3'- bipyridin ~ |-5-yl)urea

[00594] Prepared according to the procedure of Example 9, replacing phenyl boronic acid with pyridin-3-ylboronic acid in Step A. Material was purified by silica column chromatography eluting with 2-10% MeOH/DCM to afford the title compound (38 mg, 61%) as a white solid. MS (apci) m/z = 468.1 (M+H). Example 15

1 -((3 S .4RV4-(3.4-difluorophenyl)- 1 -(2-methoxyethyl)pyrrolidin-3 - yl)-3 -( 6-methyl- Γ3.3 '- bipyridin] -5 - vPurea

[00595] Prepared according to the procedure of Example 10, replacing phenyl boronic acid with pyridin-3-ylboronic acid in Step A. The crude material was purified by silica column chromatography eluting with 5-10% MeOH/DCM to afford the title compound (14 mg, 24%) as a white solid. MS (apci) m/z = 468.1 (M+H).

Example 16

1 -( ( 3 S.4RV4-( 3.4-difluorophenylV 1 -(2-methoxyethvnpyrrolidin-3-yl)-3 -( 6-methoxy-2- phenylpyridin-3 - vPurea

[00596] Prepared according to the procedure of Example 1, replacing 2-bromopyridin-3- amine with 2-bromo-6-methoxypyridin-3 -amine in Step A and tm«5 , -l-(2-methoxyethyl)-4- phenylpyrrolidin-3 -amine dihydrochloride [Preparation B] with (3S,4i?)-4-(3,4- difluorophenyl)-l-(2-methoxyethyl)pyrrolidin-3-amine dihydrochloride [Preparation C3] in Step C. The crude material was purified by silica column chromatography eluting with 2% MeOH/DCM to afford the title compound (109 mg, 63% yield) as a white solid. MS (apci) m/z = 483.0 (M+H). Example 17

l-((3S^RV4-(3.4-difluorophenvin-g-m^^

(methylsulfonyl)phenyl)pyridin-3-yl)urea

[00597] Prepared according to the procedure of Example 9, replacing phenyl boronic acid with 4-(methylsulfonyl)phenylboronic acid in Step A. Material was purified by silica column chromatography eluting with 2-6% MeOH/DCM to afford the title compound (34 mg, 50%) as a colorless glass. MS (apci) m/z = 545.0 (M+H).

Example 18

1 -((3 S,4R)-4-( 3 ,4-difluorophenyl)- 1 -(2-methoxyethvnpyrrolidin-3-yl)-3 -(2-methyl-6-(3-

(methylsulfonyl)phenyl)pyridin-3-yl)urea

[00598] Prepared according to the procedure of Example 9, replacing phenyl boronic acid with 3-(methylsulfonyl)phenylboronic acid in Step A. Material was purified by silica column chromatography eluting with 2-6% MeOH/DCM to afford the title compound (31 mg, 46%) as a white foam. MS (apci) m/z = 545.0 (M+H). Example 19

l-((3S,4R)-4-0,4-difluorophenyl)-l-(2-methoxyethv pyrrolidin-3-vn-3-(2-phenylpyridin-3- yPurea

[00599] Prepared according to the procedure of Example 1, replacing trans-\-(2- methoxyethyl)-4-phenylpyrrolidin-3-amine dihydrochloride [Preparation B] with (3S,4i?)-l-(2- methoxyethyl)-4-phenylpyrrolidin-3-amine dihydrochloride [Preparation CI] in Step C. Material was purified by silica column chromatography eluting with 2.5% MeOH/DCM to afford the title compound (19 mg, 25% yield) as a colorless gum. MS (apci) m/z = 453.0 (M+H).

Example 20

l-((3S,4R)-4-(3,4-difluorophenyl)-l-(2-methoxyethyl pyrrolidin-3-yl)-3-(6-oxo-2-phenyl-L6- dihydropyridin-3 - vDurea

[00600] A suspension of l-((3S,4R)-4-(3,4-difluorophenyl)-l-(2- methoxyethyl)pyrrolidin-3-yl)-3-(6-methoxy-2-phenylpyridin-3 -yl)urea [Example 16] (20 mg, 0.04 mmol) in 4N HC1 / dioxanes (1 mL) was heated to 100 °C in a sealed tube for 1.5 hours. The cooled mixture was concentrated and the residue partitioned between IN NaOH (15 mL) and DCM (15 mL). The aqueous layer was extracted with DCM (2 x 10 mL) and the combined organic phases were washed with brine (10 mL), dried over Na 2 S0 4 , filtered and concentrated under vacuum. The residue was purified by silica column chromatography eluting with 5-10% MeOH/DCM to afford the title compound (4 mg, 21% yield) as a white solid. MS (apci) m/z = 469.1 (M+H).

l-(6-cliloro-2-phenv yridin-3-vn-3-((3S.4RV4-(3,4-difluorophenvn-l -(2- methoxyethyl)pyrrolidin-3-yl)urea

[00601] Prepared according to the procedure of Example 1 , replacing 2-bromopyridin-3- amine with 2-bromo-6-chloropyridin-3 -amine in Step A and /ra«s-l-(2-methoxyethyl)-4- phenylpyrrolidin-3-amine dihydrochloride [Preparation B] with (3S,4/?)-4-(3,4- difluorophenyl)-l -(2-methoxyethyl)pyrrolidin-3-amine dihydrochloride [Preparation C3] in Step C. The crude material was purified by silica column chromatography eluting with 2% MeOH/DCM to afford the title compound (95 mg, 63% yield) as a cream foam. MS (apci) m/z = 487.0 (M+H).

Example 22

1 -(6-( cvclopropylsulfonyl)-2-phenylpyridin-3-vn-3-r(3S.4RV4-(3.4-d ifluorophenvn- 1 -(2- methoxyethyl)pyrrolidin-3-yl)urea

[00602] Prepared according to the procedure of Example 12, replacing methane sulfinic acid, sodium salt with sodium cyclopropanesulfinate in Step B. Material was purified by silica column chromatography eluting with 2% MeOH/DCM to afford the title compound (14 mg, 35% yield) as a white foam. MS (apci) m/z = 557.0 (M+H). Example 23

1 -((3 S,4R)-4-(3 ,4-difluorophenyl - 1 -(2-methoxyethyl)pyrrolidin-3 - yl)-3 -(4-phenylpyrimidin-

5-v urea

[00603] Step A: Preparation of 4-phenylpyrimidin-5-amine: Prepared according to the procedure of Example 1, Step A, replacing 2-bromopyridin-3 -amine with 4-bromopyrimidin-5- amine. Material was purified by silica column chromatography eluting with 2% MeOH/DCM to afford 4-phenylpyrimidin-5 -amine (60 mg, 61% yield) as a yellow solid. MS (apci) m/z = 172.0 (M+H).

[00604] Step B: Preparation of l-((3S.4R)-4-(3.4-difluorophenylVl-(2- methoxyethyl)pyrrolidin-3 - yl)-3 -(4-phenylpyrimidin-5 -vDurea: To a solution of 4- phenylpyrimidin-5-amine (37 mg, 0.22 mmol) and CDI (74 mg, 0.45 mmol) in DMF (1 mL) was added DIEA (151 μί, 0.86 mmol) and the solution stirred at ambient temperature for 16 hours. To this mixture was added a solution of (3S,4i?)-4-(3 ,4-difluorophenyl)- 1 -(2- methoxyethyl)pyrrolidin-3 -amine dihydrochloride [Preparation C3] (149 mg, 0.45 mmol) and DIEA (151 μί, 0.86 mmol) in DMF (1 mL) and stirring was continued for 16 hours. The mixture was partitioned between saturated NH4CI (20 mL) and EtOAc (20 mL) and the aqueous layer extracted with EtOAc (2 x 10 mL). The combined organic phases were washed with water (5 x 10 mL) and brine (10 mL) then dried over Na 2 S0 4 , filtered and concentrated under vacuum. The residue was purified by silica column chromatography eluting with 2% MeOH/DCM to afford the title compound (26 mg, 27% yield) as a pale yellow foam. MS (apci) m/z = 454.0 (M+H).

1 -(6-cvano-2-phenylpyridin-3 -yl>3 -( ( 3 S.4RV4-( 3.4-difluorophenylV 1 -( 2- methoxyethyl)pyrrolidin-3-yl)urea

[00605] Prepared according to the procedure of Example 1, replacing 2-bromopyridin-3- amine with 5-amino-6-bromopicolinonitrile in Step A and /rara-l-(2-methoxyethyl)-4- phenylpyrrolidin-3 -amine dihydrochloride [Preparation B] with (3S,4i?)-4-(3,4- difluorophenyl)-l -(2-methoxyethyl)pyrrolidin-3-amine dihydrochloride [Preparation C3] in Step C. The crude material was purified by silica column chromatography eluting with 2% MeOH/DCM to afford the title compound (82 mg, 57% yield) as a white foam. MS (apci) m/z = 478.0 (M+H).

Example 25

1 -( ( 3 S.4P -4-( 3.4-difluorophenvD- 1 -(2-methoxyethyl rrolidin-3-ylV 3 - ( 6-ethoxy-2- phenylpyridin-3 -yl " )urea

[00606] Step A: Preparation of 2-bromo-6-ethoxypyridin-3 -amine: To a solution of 6- ethoxypyridin-3 -amine (100 mg, 0.72 mmol) in acetonitrile (2 mL) was added N- bromosuccinimide (129 mg, 0.72 mmol). The mixture was stirred at ambient temperature for 3 hours then concentrated under vacuum. The residue was purified by silica column chromatography eluting with 4: 1 hexanes / EtOAc to afford 2-bromo-6-ethoxypyridin-3 -amine (68 mg, 43% yield) as a dark orange/brown oil. MS (apci) m/z = 216.9 (M+).

[00607] Step B: Preparation of l-((3S.4R)-4-(3.4-difluorophenyr)-l-(2- methoxyethyl)pyrrolidin-3 -yl)-3 -(6-ethoxy-2-phenylpyridin-3 - vDurea: Prepared according to the procedure of Example 1 , replacing 2-bromopyridin-3 -amine with 2-bromo-6- ethoxypyridin-3 -amine in Step A and tm«5 , -l-(2-methoxyethyl)-4-phenylpyrrolidin-3 -amine dihydrochloride [Preparation B] with (3S,4J?)-4-(3,4-difluorophenyl)-l-(2- methoxyethyl)pyrrolidin-3 -amine dihydrochloride [Preparation C3] in Step C. The crude material was purified by silica column chromatography eluting with 2% MeOH/DCM to afford the title compound (66 mg, 76% yield) as a white solid. MS (apci) m/z = 497.1 (M+H).

Example 26

l-((3S,4R)-4-(3,4-difluorophenyl)-l-(2-methoxyethyl)pyrrolid in-3-ylV3-(5-methoxy-2- phenylpyridin-3 -vDurea

[00608] Prepared according to the procedure of Example 1, replacing 2-bromopyridin-3- amine with 2-bromo-5-methoxypyridin-3 -amine in Step A and trans-l-(2-methoxyethyl)-4- phenylpyrrolidin-3 -amine dihydrochloride [Preparation B] with (3iS,4i?)-4-(3,4- difluorophenyl)-l-(2-methoxyethyl)pyrrolidin-3 -amine dihydrochloride [Preparation C3] in Step C. Material was purified by silica column chromatography eluting with 2% MeOH/DCM to afford the title compound (46 mg, 59% yield) as a white solid. MS (apci) m z 483.1 (M+H).

Example 27

1 -((3 S,4Pv)-4-(3 ,4-difluorophenviy 1 -( 2-methoxyethyl)pyrrolidin-3 - yl)-3 -(6-(2- methoxyethoxy)-2-phenylpyridin-3-yl)urea

[00609] Prepared according to the procedure of Example 25, replacing 6-ethoxypyridin- 3 -amine with 6-(2-methoxyethoxy)pyridin-3 -amine in Step A. The crude material was purified by silica column chromatography eluting with 2% MeOH/DCM to afford the title compound (50 mg, 63% yield) as a colorless glass. MS (apci) m/z 527.1 (M+H).

Example 28

1 -(T3 S .4RV4-(3.4-difluorophenvD- 1 -( 2-methoxyethyl)pyrrolidin-3 - yl)-3 -(6-ethyl-2- phenylpyridin-3 - vDurea

[00610] Step A: Preparation of 6-ethyl-2-phenylpyridin-3-amine: 6-Bromo-2- phenylpyridin-3 -amine [Example 11 , Step A] (85 mg, 0.34 mmol), Pd(PPh 3 ) 4 (39 mg, 0.034 mmol) and ethyl boronic acid (252 mg, 3.41 mmol) were combined in dioxane (3 mL) in a sealed vessel then treated with K 2 C0 3 (0.68 mL, 2M, 1.36 mmol). The mixture was stirred at 110 °C for 16 hours then cooled and partitioned between water (20 mL) and EtOAc (20 mL). The aqueous layer was extracted with EtOAc (2 x 10 mL) and the combined organic phases were washed with brine (10 mL), dried over Na 2 S0 4 , filtered and concentrated under vacuum. The residue was purified by silica column chromatography eluting with 4:1 hexanes / EtOAc to afford 6-ethyl-2-phenylpyridin-3 -amine (18 mg, 27% yield) as a colorless gum. MS (apci) m/z 199.1 (M+H).

[00611] Step B: Preparation of l-((3S,4RV4-(3.4-difluorophenyl)-l-(2- methoxyethyl)pyrrolidin-3-yl)-3-(6-ethyl-2-phenylpyridin-3-y l urea: Prepared according to the procedure of Example 1, replacing 2-bromopyridin-3 -amine with 6-ethyl-2-phenylpyridin- 3 -amine in Step A and tr n5-l-(2-methoxyethyl)-4-phenylpyrrolidin-3 -amine dihydrochloride [Preparation B] with (3S,4i?)-4-(3,4-difluorophenyl)-l-(2-methoxyethyl)pyrrolidin -3-amine dihydrochloride [Preparation C3] in Step C. The crude material was purified by silica column chromatography eluting with 2% MeOH/DCM to afford the title compound (21 mg, 53% yield) as a white solid. MS (apci) m/z = 481.1 (M+H). Example 29

1 -((3 S.4R)-4-( 3.4-difluorophenyl)- 1 -(2-methoxyethyl pyrrolidin-3-yl)-3 -( 6-methyl-2- phenylpyridin-3-yl)urea

[00612] Prepared according to the procedure of Example 28, replacing ethyl boronic acid with methyl boronic acid in Step A. The crude material was purified by silica column chromatography eluting with 2% MeOH/DCM to afford the title compound (21 mg, 76% yield) as a white solid. MS (apci) m/z = 467.1 (M+H).

Example 30

1 -( ( 3 S.4R)-4-( 3.4-difluorophenyl)- 1 -(2-methoxyethyl)pyrrolidin-3- yl)-3 -(5-methyl-2- phenylpyridin-3 - vDurea

[00613] Step A: Preparation of 2-bromo-5-methylpyridin-3-amine: Acetic acid (5 mL) was added dropwise to iron powder (1.11 g, 19.8 mmol) and the mixture was warmed to 80 °C. A solution of 2-bromo-5-methyl-3-nitropyridine (1.0 g, 4.61 mmol) in AcOH (5 mL) was then added dropwise over 20 minutes and the mixture stirred for a further 30 minutes. The mixture was stirred at ambient temperature for 16 hours then diluted with EtOAc (20 mL) and filtered through Celite®. The Celite® pad was washed well with EtOAc and the filtrate concentrated under vacuum. The residue was slowly treated with saturated NaHC0 3 solution (50 mL) followed by portions of solid NaHC0 3 until all the AcOH was neutralized. The mixture was then extracted with EtOAc (3 x 30 mL) and the combined organic phases were washed with brine (20 mL), dried over Na 2 S0 4 , filtered and concentrated to afford 2-bromo-5- methylpyridin-3 -amine (799 mg, 93% yield) as a bright yellow crystalline solid which darkened to a green color after drying under vacuum. MS (apci) m/z = 188.9 (M+H).

[00614] Step B: Preparation of l-((3S.4RV4-i3.4-difluorophenvn-l-i2- methoxyethyl)pyrrolidin-3-yl)-3-(5-methyl-2-phenylpyridin-3- yl)urea: Prepared according to the procedure of Example 1, replacing 2-bromopyridin-3-amine with 2-bromo-5- methylpyridin-3 -amine in Step A and tra«s-l-(2-methoxyethyl)-4-phenylpyrrolidin-3 -amine dihydrochloride [Preparation B] with (3S,4i?)-4-(3,4-difluorophenyl)-l-(2- methoxyethyl)pyrrolidin-3 -amine dihydrochloride [Preparation C3] in Step C. The crude material was purified by silica column chromatography eluting with 2% MeOH/DCM to afford the title compound (51 mg, 72% yield) as a white foam. MS (apci) m/z = 467.1 (M+H).

Example 31

1 -( ( 3 S.4RV4-( 3.5-difluorophenvn- 1 -(2-methoxyethyl)pyrrolidin-3 -yl - 3-( 6-methyl-2- phenylpyridin-3 -vPurea

[00615] Prepared according to the procedure of Example 29, replacing (35',47?)-4-(3,4- difluorophenyl)-l-(2-methoxyethyl)pyrrolidin-3-amine dihydrochloride [Preparation C3] with (3S,4i?)-4-(3,5-difluorophenyl)-l-(2-methoxyethyl)pyrrolidin -3-amine dihydrochloride [Preparation C2] in Step C. The crude material was purified by silica column chromatography eluting with 2% MeOH/DCM to afford the title compound (37 mg, 52% yield) as a white foam. MS (apci) m z = 467.2 (M+H).

Example 32

l-r(3S.4RV4-(4-fluorophenylVl-(2-methoxyethvnpyiTolidin-3-yl V3-(6-methyl-2- phenylpyridin-3 - vDurea

[00616] Prepared according to the procedure of Example 29, replacing (3S,4i?)-4-(3,4- difluorophenyl)-l-(2-methoxyethyl)pyrrolidin-3-amine dihydrochloride [Preparation C3] with (35,4i?)-4-(4-fluorophenyl)- 1 -(2-methoxyethyl)pyrrolidin-3-amine dihydrochloride [Preparation C4] in Step C. The crude material was purified by silica column chromatography eluting with 2% MeOH/DCM to afford the title compound (40 mg, 55% yield) as a cream solid. MS (apci) m/z = 449.2 (M+H).

Example 33

l-((3S,4R)-4-(3.4-difluorophenyl)-l-(2-methoxyethvnpyrrolidi n-3-yl)-3-(l-methyl-2-oxo-3- phenyl- 1 ,2-dihvdropyridin-4-yl)urea

[00617] Step A: Preparation of 4-amino-l -methylpyridin-2(lH)-one: 4-Amino-l- methylpyridin-2(lH)-one hydrochloride (500 mg, 3.11 mmol) was suspended in DCM (30 mL) and methanol (1 mL) added. The resulting solution was treated with MP-carbonate (3.23 g, 2.89 mmol/g, 9.34 mmol) and gently stirred for 4 hours. The mixture was filtered, resin washed well with DCM and the filtrate carefully concentrated (no heat) to afford 4-amino-l - methylpyridin-2(lH)-one (317 mg, 82% yield) as a fluffy white solid. 1H NMR (CDC1 3 ) δ 7.07 (d, J = 7.3 Hz, 1H), 5.74 (dd, J = 7.3, 2.5 Hz, 1H), 5.64 (d, J = 2.5 Hz, 1H), 3.43 (s, 3H), 2.82 (s, 2H) ppm.

[00618] Step B: Preparation of 4-amino-3-bromo-l-methylpyridin-2(lH)-one: To a solution of 4-amino-l -methylpyridin-2(lH)-one (50 mg, 0.40 mmol) in ACN (2 mL) was added N-bromosuccinimide (72 mg, 0.40 mmol). The mixture was stirred at ambient temperature for 3 hours then concentrated under vacuum. The residue was purified by silica column chromatography eluting with 2% MeOH/DCM to afford 4-amino-3-bromo-l- methylpyridin-2(lH)-one (56 mg, 68% yield) as a white solid. MS (apci) m/z = 202.9 (M+).

[00619] Step C: Preparation of 4-amino-l-methyl-3-phenylpyridin-2(lH)-one: 4- amino-3-bromo-l-methylpyridin-2(lH)-one (56 mg, 0.28 mmol), phenyl boronic acid (44 mg, 0.36 mmol), K 2 C0 3 (152 mg, 1.1 mmol) and Pd(PPh 3 ) 4 (32 mg, 0.03 mmol) were combined in toluene (1 mL), water (0.5 mL) and EtOH (0.25 mL). The mixture was warmed to 95 °C in a sealed tube for 16 hours then cooled and partitioned between EtOAc (10 mL) and saturated NH4CI (10 mL). The aqueous layer was extracted with EtOAc (2 x 10 mL) and the combined organic phases were washed with brine (10 mL), dried over Na 2 S0 4 , filtered and concentrated under vacuum. The residue was purified by silica column chromatography eluting with 2% MeOH/DCM to afford 4-amino-l-methyl-3-phenylpyridin-2(lH)-one (24 mg, 43% yield) as a white solid. MS (apci) m/z = 201.1 (M+H).

[00620] Step D: Preparation of l-((3S.4R)-4-(3,4-difluorophenyl)-l-(2- methoxyethyl)pyrrolidin-3-yl)-3-(l-methyl-2-oxo-3-phenyl-L2- dihvdropyridin-4-yl)urea: To a solution of 4-amino-l-methyl-3-phenylpyridin-2(lH)-one (24 mg, 0.12 mmol) in DCM (1 mL) was added triphosgene (18 mg, 0.06 mmol) followed by DIEA (62 μί, 0.36 mmol). The mixture was stirred at ambient temperature for 30 minutes then treated with (3S,4/?)-4-(3,4- difluorophenyl)-l-(2-methoxyethyl)pyrrolidin-3-amine dihydrochloride [Preparation C3] (39 mg, 0.12 mmol) and DIEA (62 μί, 0.36 mmol). After stirring for a further 16 hours the mixture was partitioned between saturated NtLCl (10 mL) and DCM (10 mL) and the aqueous layer extracted with DCM (2 x 10 mL). The combined organic phases were washed with brine (10 mL), dried over Na 2 S0 4 and concentrated under vacuum. The residue was purified by silica column chromatography eluting with 2.5-5% MeOH/DCM to 5% to afford the title compound (22 mg, 38% yield) as a white solid. MS (apci) m/z = 483.2 (M+H).

Example 34

1 -( ( 3S.4R)-4-( 3.4-difluorophenvD- 1 -(2-methoxyethyl)pyrrolidin-3- yl)-3 -( 1 -methyl-6-oxo-3- phenyl- 1 ,6-dihvdropyridazin-4-yl)urea

[00621] Step A: Preparation of 3,4-dichloro-5-phenylfuran-2(5H)-one: To a suspension of AICI3 (10.0 g, 75.0 mmol) in dry benzene (50 mL) was added 3,4-dichloro-5-hydroxyfuran- 2(5H)-one (8.45 g, 50.0 mmol) in portions over 5 minutes (immediate deep orange color). The mixture was stirred at ambient temperature for 2.5 hours and was poured into an ice- water slurry (300 mL). The mixture was stirred until ambient temperature was reached and extracted with Et 2 0 (3X). The combined extracts were washed with H 2 0 and saturated NaHC0 3 (3X). The Et 2 0 solution was dried over MgS0 4 and filtered through a Si0 2 plug eluting with Et 2 0. The filtrate was concentrated to provide the title compound a colorless syrup that solidified upon drying to a white solid (8.72 g, 76% yield). 1H NMR (CDC1 3 ) δ 7.47-7.42 (m, 3H), 7.31- 7.28 (m, 2H), 5.85 (s, 1H) ppm.

[00622] Step B: Preparation of 5-chloro-2-methyl-6-phenylpyridazin-3(2H)-one: A solution of 3,4-dichloro-5-phenylfuran-2(5H)-one (1.00 g, 4.37 mmol) in absolute EtOH (15 mL) was cooled to 0 °C and methylhydrazine (0.511 mL, 9.60 mmol) was added. The mixture was stirred for 3 hours during which time the temperature gradually became ambient. The mixture was heated at reflux for 16 hours, cooled to ambient temperature and diluted with ice- water (50 mL). The resulting suspension was stirred for 30 minutes and the suspension collected by vacuum filtration. The solid was washed with H 2 0 then Et 2 0 and dried in vacuum to afford the title compound a light tan powder (378 mg, 39%). 1H NMR (DMSOd 6 ) δ 7.57-7.54 (m, 2H), 7.51-7.48 (m, 3H), 7.40 (s, 1H), 3.70 (s, 3H) ppm.

[00623] Step C: Preparation of 5-azido-2-methyl-6-phenylpyridazin-3(2H)-one: To a solution of 5-chloro-2-methyl-6-phenylpyridazin-3(2H)-one (360 mg, 1.63 mmol) in dry DMF (2 mL) was added NaN 3 (318 mg, 4.89 mmol) in one portion. The mixture was heated at 60 °C for 1.5 hours then at 80 °C for 1 hour. The mixture was cooled to ambient temperature and treated with ice- water (15 mL). The resulting suspension was stirred for 5 minutes, the solid collected by vacuum filtration, washed with H 2 0 and dried in vacuum to provide the title compound as a tan powder (262 mg, 71%). 1H NMR (DMSOd 6 ) δ 7.62-7.58 (m, 2H), 7.48- 7.44 (m, 3H), 6.91 (s, 1H), 3.69 (s, 3H) ppm.

[00624] Step D: Preparation of 5-amino-2-methyl-6-phenylpyridazin-3(2H)-one: To a solution of 5-azido-2-methyl-6-phenylpyridazin-3(2H)-one (250 mg, 1.10 mmol) in dry MeOH (5 mL) was added 10 wt. % Pd on carbon (234 mg, 0.110 mmol, 50 wt. % H 2 0). The reaction flask was purged with ¾ gas for 2 minutes and the mixture was stirred under a balloon of H 2 at ambient temperature for 4 hours. The mixture was purged with N 2 gas, diluted with Et 2 0 (5 mL) and filtered through packed Celite® layer eluting and rinsing with EtOAc. The filtrate was concentrated to a white foam that was washed with dry Et 2 0. The resulting granular white solid was dried in vacuum to furnish the title compound (188 mg, 85% yield). 1H NMR (DMSOd 6 ) δ 7.48 (br s, 5H), 5.94 (br s, 2H), 5.80 (s, 1H), 3.54 (s, 3H) ppm.

[00625] Step E: Preparation of phenyl l-methyl-6-oxo-3-phenyl-l,6-dihvdropyridazin-4- ylcarbamate: A fine suspension of 5-amino-2-methyl-6-phenylpyridazin-3(2H)-one (175 mg, 0.870 mmol) in EtOAc (3 mL) was cooled to 0 °C and 2M NaOH (1.30 mL, 2.61 mmol) was added. The mixture was stirred for 5 minutes (solid dissolved) and phenylchloroformate (163 ih, 1.30 mmol) was added. The mixture was allowed to reach ambient temperature and was stirred for 16 hours. The mixture was diluted with EtOAc (2 mL), washed with H 2 0 (2X) and saturated NaCl and dried over MgSCVactivated charcoal. The dried solution was filtered through packed Celite® (EtOAc elution), concentrated and the residue purified by silica column chromatography (50% EtOAc-hexanes) to provide the title compound as a white solid (26 mg, 9.3%). 1H NMR (CDC1 3 ) δ 7.72 (s, 1H), 7.64-7.48 (m, 5H), 7.38 (t, J= 7.7 Hz, 2H), 7.30-7.22 (m, 2H), 7.12 (d, J= 7.8 Hz, 2H), 6.93 (s, 1H), 3.81 (s, 3H) ppm.

[00626] Step F: 1 -((3SAR)-4-(3 ,4-difluorophenvn-l -(2-methoxyethvnpyrrolidm-3-vn- 3-( 1 -methyl-6-oxo-3 -phenyl- 1 ,6-dihvdropyridazin-4-yl)urea: A mixture of phenyl l-methyl-6- oxo-3-phenyl-l,6-dihydropyridazin-4-ylcarbamate (25.0 mg, 0.078 mmol) and (3S,4i?)-4-(3,4- difluorophenyl)-l-(2-methoxyethyl)pyrrolidin-3-amine dihydrochloride (Preparation C3, 38.4 mg, 0.117 mmol) in dry DCM (1.0 mL) was treated with DIEA (54.4 0.31 1 mmol) and the resulting homogeneous solution was stirred at ambient temperature for 17 hours. The mixture was diluted with DCM (3 mL) and was washed with H 2 0 (2X), 1M NaOH (3X) and H 2 0. The DCM solution was dried over Na 2 S0 4 and was eluted through a short Si0 2 column eluting with 50% EtOAc-hexanes, EtOAc then 10% MeOH-EtOAc. The 10% MeOH-EtOAc product pool was concentrated to a cloudy film. The film was treated with 1 : 1 Et 2 0-DCM and concentrated. The residual solid was dried in vacuum to provide the title compound (29 mg, 77% yield) as a white solid. MS (apci) m/z = 484.2 (M+H).

Example 35

l-((35,4j?)-4-(3,4-difluorophenvn-l-(2-methoxyethyl)pyrrolid in-3-yl)-3-(6-oxo-3-phenyl-l- (2,2,2-trifluoroethyl)- 1 ,6-dihydropyridazin-4-yl)urea

[00627] Step A: Preparation of 5-chloro-6-phenylpyridazin-3(2H)-one: To a solution of 3,4-dichloro-5-phenylfuran-2(5H)-one (Example 34 Step A, 4.00 g, 17.5 mmol) in absolute EtOH (35 mL) was added hydrazine (1.65 mL, 52.4 mmol) by syringe over 1-2 minutes. The mixture was stirred at ambient temperature for 15 minutes then heated at reflux for 3 hours. The mixture was cooled to ambient temperature, treated with ice- water (50 mL) and mixed for 5 minutes. The resulting suspension was collected by vacuum filtration, the solid washed with H 2 0 and Et 2 0 and dried in vacuum to afford the title compound (2.22 g, 61% yield) as a light peach colored powder. 1H NMR (DMSOd 6 ) δ 13.4 (br s, 1H), 7.56-7.54 (m, 2H), 7.50-7.47 (m, 3H), 7.33 (s, lH) ppm.

[00628] Step B: Preparation of 5-azido-6-phenylpyridazin-3(2H)-one: To a solution of 5-chloro-6-phenylpyridazin-3(2H)-one (2.10 g, 10.2 mmol) in dry DMF (9 mL) was added NaN 3 (1.98 g, 30.5 mmol) and the mixture was heated at 60 °C for 3 hours. The mixture was cooled to ambient temperature and treated with ice-water (50 mL). The resulting suspension was stirred for 10 minutes, the solid collected, washed with H 2 0 and dried in vacuum to afford the title compound as light peach colored powder (2.10 g, 97%). 1H NMR (DMSOd 6 ) δ 13.2 (br s, 1H), 7.61-7.55 (m, 2H), 7.48-7.43 (m, 3H), 6.82 (s, 1H) ppm.

[00629] Step C: Preparation of 5-azido-6-phenyl-2-(2,2,2-trifluoroethyl)pyridazin- 3(2H)-one: A suspension of 5-azido-6-phenylpyridazin-3(2H)-one (300 mg, 1.41 mmol) in dry DMF (4mL) was cooled to 0 °C and NaH (53.3 mg, 2.11 mmol) was added in one portion. The ice bath was removed and the mixture was stirred at ambient temperature for 15 minutes. The resulting thick, pink slurry was treated with 2,2,2-trifluoroethyl trifluoromethanesulfonate (505 mg, 2.11 mmol) and the mixture was stirred for 3 hours. The deep orange reaction mixture was diluted with ice-water (25 mL) and the resulting orange suspension was stirred for 10 minutes at ambient temperature. The solid was collected by filtration, the cake washed with H 2 0 and 1 :1 Et 2 0-hexanes. The solid was recrystallized from MTBE to give the title compound as a light peach-colored solid (125 mg, 30%). 1H NMR (DMSOd 6 ) δ 7.65-7.58 (m, 2H), 7.53-7.44 (m, 3H), 7.03 (s, 1H); 5.00 (q, J= 9.1 Hz, 2H) ppm.

[00630] Step D: Preparation of 5-amino-6-phenyl-2-(2,2,2-trifluoroethyDpyridazin- 3(2HVone: To a fine suspension of 5-azido-6-phenyl-2-(2,2,2-trifluoroethyl)pyridazin-3(2H)- one (110 mg, 0.373 mmol) in dry MeOH (3 mL) was added 10 wt. % Pd on carbon (79.3 mg, 0.0373 mmol, 50 wt. % H 2 0). The reaction flask was purged with H 2 gas for 2 minutes and the mixture was stirred under a balloon of H 2 at ambient temperature for 20 hours. The reaction mixture was purged with N 2 gas, diluted with Et 2 0 (3 mL) and filtered through packed Celite® eluting and rinsing with EtOAc. The filtrate was concentrated and the residual solid was dried in vacuum to provide the title compound (89 mg, 89%) as white solid. 1H NMR (DMSOd 6 ) δ 7.51 (br s, 5H), 6.29 (br s, 2H), 5.82 (s, 1H), 4.82 (q, J= 9.0 Hz, 2H) ppm.

[00631] Step E: Preparation of l-(r3 l S.4i?)-4-( , 3.4-difluorophenyl)-l-(2- methoxyethyl)pyrrolidin-3-yl)-3-(6-oxo-3-phenyl-l-(2,2,2-tri fluoroethyl -l,6- dihydropyridazin-4-yl)urea: To solution of triphosgene (35.4 mg, 0.117 mmol) in dry DCM (1.0 mL) was added a solution of 5-amino-6-phenyl-2-(2,2,2-trifluoroethyl)pyridazin-3(2H)- one (85 mg, 0.316 mmol) and DIEA (165 iL, 0.947 mmol) in dry DCM (2.0 mL) dropwise over 30 minutes. The mixture was stirred for 30 minutes and (3S,4i?)-4-(3,4-difluorophenyl)- l-(2-methoxyethyl)pyrrolidin-3 -amine dihydrochloride (Preparation C3, 156 mg, 0.474 mmol) and DIEA (1 10 0.631 mmol) were sequentially added. The reaction mixture was stirred at ambient temperature for 18 hours. Additional (3S,4i?)-4-(3,4-difluorophenyl)-l-(2- methoxyethyl)pyrrolidin-3 -amine dihydrochloride (Preparation C3, 60 mg) and DIEA (100 μί) were added and the mixture heated at reflux for 4 hours. The mixture was cooled to ambient temperature, washed with H 2 0 (3X) and dried over Na 2 S0 4 . The dried solution was filtered through packed Celite®, concentrated and the crude residue was purified by silica column chromatography (50% EtOAc-hexanes, EtOAc, 5% MeOH-EtOAc step gradient elution) to provide the title compound as a white solid (18 mg, 10% yield). MS (apci) m/z = 552.2 (M+H).

Example 36

4-(3 -((3S.4i?>4-(3.4-difluorophenyl - 1 -( 2-methoxyethyl)pyrrolidin-3 - vDureido V3 - phenylisothiazole-5-carboxamide

[00632] Step A: Preparation of (Z)-N-(tosyloxy)benzimidoyl cyanide: A solution of (Z)- N-hydroxybenzimidoyl cyanide (3.01 g, 20.0 mmol) and triethylamine (5.58 mL, 40.0 mmol) in dry DCM (40 mL) was cooled to 0 °C and tosyl chloride (4.19 g, 22.0 mmol) was added in one portion. The mixture was stirred for 16 hours during which time the temperature increased to ambient after 2 hours. The mixture was diluted with chilled 1M HC1 (80 mL) and stirred for 15 minutes. The organic layer was separated and was washed with H 2 0 and saturated NaHC0 3 . The solution was dried over Na 2 S0 4 and eluted through a thin Si0 2 plug capped with a layer of MgS0 4 using DCM for elution. The eluate was concentrated and the residual solid dried in vacuum to furnish the title compound as a white crystalline solid (6.10 g, 102% yield). MS (apci) m/z = 299.1 (M-H).

[00633] Step B: Preparation of methyl 4-amino-3-phenylisothiazole-5-carboxylate: To a suspension of (Z)-N-(tosyloxy)benzimidoyl cyanide (3.16 g, 10.0 mmol) in dry MeOH (30 mL) was added methyl 2-mercaptoacetate (1.05 mL, 1 1.0 mmol) followed by triethylamine (3.07 mL, 22.0 mmol). The mixture was stirred at ambient temperature for 3 hours and was added to chilled H 2 0 (150 mL) with stirring. The resulting suspension was stirred for 15 minutes, the solid collected by vacuum filtration and the cake washed with H 2 0 and hexanes. The solid was dissolved in DCM and dried over Na 2 S0 4 /activated charcoal. The dried solution was eluted through a thin Si0 2 plug capped with a layer of MgS0 4 (DCM elution) and concentrated. The residual white solid was dried in vacuum to give the title compound (1.43 g, 61% yield). 1H NMR (CDC1 3 ) δ 7.73-7.70 (m, 2H), 7.53-7.44 (m, 3H), 5.40 (br s, 2H), 3.91 (s, 3H) ppm.

[00634] Step C: Preparation of 4-amino-3-phenylisothiazole-5-carboxamide: In a glass pressure vessel, methyl 4-amino-3-phenylisothiazole-5-carboxylate (300 mg, 1.28 mmol) was dissolved in 7M NH 3 (11 mL, 76.8 mmol) in MeOH and the solution was purged with NH 3 gas for 5 minutes. The reaction vessel was sealed and the mixture heated at 100 °C for 24 hours. The mixture was cooled to ambient temperature, concentrated and the residual solid was washed thoroughly with Et 2 0. The solid was dried in vacuum to give the title compound as a white solid (98 mg, 35% yield). 1H NMR (DMSOd 6 ) δ 7.75 (d, J = 8.0 Hz, 2H), 7.58 (br s, 2H), 7.57-7.46 (m, 3H), 6.19 (s, 2H) ppm.

[00635] Step D: Preparation of 4-(3-((3S.4j?V4-(3,4-difluorophenyl)-l-(2- methoxyethyl)pyrrolidin-3-yl ureido)-3-phenylisothiazole-5-carboxamide: A solution of triphosgene (44.3 mg, 0.142 mmol) in dry DCM (1 mL) was cooled to 0 °C and a solution of (3S",4i?)-4-(3 ,4-difluorophenyl)- 1 -(2-methoxyethyl)pyrrolidin-3 -amine dihydrochloride (Preparation C3, 139 mg, 0.421 mmol) and DIEA (220 μί, 1.26 mmol) in dry DCM (0.5 mL) was added dropwise over 40 minutes. The mixture was stirred for 1 hour during which time temperature increased to ambient. 4-amino-3-phenylisothiazole-5-carboxamide (84.0 mg, 0.383 mmol) was added in one portion and the mixture stirred at ambient temperature for 10 minutes. The DCM was evaporated under a stream of N 2 gas and the residue treated with dry CH 3 CN (2 mL). The mixture was heated at 40 °C for 6 hours, cooled to ambient temperature and diluted with chilled H 2 0 (4 mL). The cold mixture (pH=3) was treated with 2M NaOH to pH=10. The mixture was extracted with EtOAc (3X) and the combined extracts were washed with H 2 0 and saturated NaCl. The EtOAc solution was dried over MgS0 4 and eluted through a short Si0 2 column eluting with EtOAc then 10% MeOH/EtOAc. The product pool was concentrated to a colorless glass. The glass was treated with Et 2 0 and agitated until a granular suspension formed. The solvent was decanted and the residual solid was washed with Et 2 0 (2X) and dried in vacuum to afford the title compound as a white solid (120 mg, 63% yield). MS (apci) m/z = 502.1 (M+H). Example 37

l-((tram)-l-(2-methoxyethyl)-4-phenylpyrrol

yPurea

[00636] To a DCM (512 μΐ,) solution of 5-methyl-3-phenylisoxazol-4-amine (18 mg, 0.10 mmol) [purchased from Maybridge TL01028DA, CAS 21 169-65-3] was added CDI (17 mg, 0.10 mmol), followed by DIEA (71 μί, 0.41 mmol). After stirring at ambient temperature for 3 days, (tra«5')-l-(2-methoxyethyl)-4-phenylpyrrolidin-3-amine dihydrochloride [Preparation B] (30 mg, 0.10 mmol) was added to the reaction mixture in one portion and stirred for 16 hours. The reaction mixture was directly purified by reverse-phase chromatography (CI 8, eluent acetonitrile/water 5 to 54%) to yield the product as white solid (25 mg, 58% yield). MS (apci) m/z = 421.0 (M+H).

Example 38

1 -( ( 3S.4i?)-4-( 3.4-difluorophenvD- 1 -(2-methoxyethyl)pyrrolidin-3-yl)-3 - ( 1.2-dimethyl-4- phenyl- 1 H-imidazol-5-yl)urea

[00637] To a mixture of l,2-dimethyl-4-phenyl-lH-imidazol-5-amine (25 mg, 0.13 mmol) [purchased from Nanjing Chemlin 1040040-76-3, CAS 1040040-76-3] in DCM (1 mL) at 0 °C was added DIEA (0.047 ml, 0.27 mmol) followed by triphosgene (16 mg, 0.053 mmol) in one portion. The reaction was allowed to warm up to ambient temperature and stirred for 2 hours. It was then added to a mixture of (35',4i?)-4-(3,4-difluorophenyl)-l-(2- methoxyethyl)pyrrolidin-3 -amine dihydrochloride (Preparation C3, 30 mg, 0.0911 mmol) and N-ethyl-N-isopropylpropan-2-amine (79.4 μΐ,). After stirring at room temperature for 1 hour, the reaction mixture was directly purified by reverse-phase chromatography (CI 8, eluent 5 to 52% acetonitrile/water) to yield the product as white solid (15 mg, 32% yield). MS (apci) m/z = 470.0 (M+H).

Example 39

1 -((3S.4 j ?V4-(3,4-difluorophenylH -(2-methoxyethyl)pyrrolidin-3-yl)-3-( 1 ,2-dimethyl-5-oxo-

4-phenyl-2,5-dihvdro-lH-pyrazol-3-yl)urea

[00638] Step A: Preparation of 5-amino-l-methyl-4-phenyl-lH-pyrazol-3(2H)-one: To a suspension of ethyl 2-cyano-2-phenylacetate (2.56 g, 13.3 mmol) in EtOH (10 mL) was added dropwise methylhydrazine (1.09 mL, 19.9 mmol). The reaction was heated at 85 °C for 16 hours. The reaction mixture was cooled to 0 °C and filtered. The solid was washed with cold EtOH (20 mL) and Et 2 0 (20 mL) to give final product (2.1 g, 84%). 1H NMR (d 6 - DMSO) δ 9.46 (br s,l H),7.48-7.52 (m, 2 H), 7.24-7.30 (m, 2 H), 7.01-7.06 (m, 1 H), 5.72 (br s, 2 H), 3.23 (s, 3 H).

[00639] Step B: Preparation of 5-amino-L2-dimethyl-4-phenyl-lH-pyrazol-3(2H)-one: To a suspension of 5-amino-l-methyl-4-phenyl-lH-pyrazol-3(2H)-one (208 mg, 1.10 mmol) and K 2 C0 3 (456 mg, 3.30 mmol) in DMF (5 mL) was added dropwise iodomethane (172 mg, 1.21 mmol). The reaction was stirred at ambient temperature for 16 hours. The solvent was removed under reduced pressure and the residue was purified by silica column chromatography eluting with 1 :2 EtOAc / hexanes to yield the desired product (lower Rf, 136 mg, 61%) and a side-product 3-methoxy-l-methyl-4-phenyl-lH-pyrazol-5-amine (higher Rf, 68 mg, 30%). MS (apci) m/z = 204.1 (M+H).

[00640] Step C: Preparation of l-((3S.4i?V4-(3.4-difluorophenyl)-l-(2- methoxyethyl)pyrrolidin-3-yl)-3-(l,2-dimethyl-5-oxo-4-phenyl -2,5-dihvdro-lH-pyrazol-3- vDurea: To a suspension of 5-amino-l,2-dimethyl-4-phenyl-lH-pyrazol-3(2H)-one (85 mg, 0.418 mmol) in dichloroethane (5 mL) at 0 °C was added portionwise bis(trichloromethyl) carbonate (62.1 mg, 0.209 mmol), followed by dropwise addition of triethylamine (87.4 μί, 0.627 mmol). Cold bath was then removed and the reaction was stirred at ambient temperature for two hours. The solvent was then removed under reduced pressure, and to the residue was added DMF (5 mL), triethylamine (87.4 μί, 0.627 mmol) and (3S,4i?)-4-(3,4-difluorophenyl)- l-(2-methoxyethyl)pyrrolidin-3-amine dihydrochloride (Preparation C3, 138 mg, 0.418 mmol). The reaction mixture was stirred at ambient temperature for two hours then concentrated under vacuum. The residue was purified by silica column chromatography eluting with 10% MeOH/DCM to yield the title product. MS (apci) m/z = 486.0 (M+H).

Example 40

1 -( ( 3SAR)-4-( 3.4-difluorophenyl )- 1 -(2-methoxyethvnpyrrolidin-3-yl )-3 -( 1 -ethyl-2-methyl-5- oxo-4-phenyl-2,5-dihvdro-lH-pyrazol-3-yl)urea

[00641] Step A: Preparation of 5 -amino-2-ethyl- 1 -methyl-4-phenyl- 1 H-pyrazol-3 ( 2H)- one: To a suspension of 5-amino-l-methyl-4-phenyl-lH-pyrazol-3(2H)-one (465 mg, 2.46 mmol) and K 2 C0 3 (1.02 g, 7.37 mmol) in DMF (10 mL) was added dropwise iodoethane (218 μί, 2.70 mmol). The reaction was stirred for 16 hours then concentrated under vacuum. The residue was purified by silica column chromatography eluting with 1 :2 EtOAc / hexanes to yield the desired product (lower Rf, 220 mg, 41%) and a side-product 3-ethoxy-l-methyl-4- phenyl-lH-pyrazol-5-amine (higher Rf, 230 mg, 43%). MS (apci) m/z = 218.1 (Μ+Η).

[00642] Step B: Preparation of l-((3S.4i?)-4-(3.4-difluorophenyl)-l-( ' 2- methoxyethyl)pyrrolidin-3-yl)-3-(l-ethyl-2-methyl-5-oxo-4-ph enyl-2,5-dihydro-lH-pyrazol-3- yDurea: To a suspension of 5-amino-2-ethyl-l-methyl-4-phenyl-lH-pyrazol-3(2H)-one (75 mg, 0.345 mmol) in dichloroethane (5 mL) at 0 °C was added portionwise bis(trichloromethyl) carbonate (51.2 mg, 0.173 mmol), followed by dropwise addition of triethylamine (72.2 μί, 0.518 mmol). Cold bath was then removed and the reaction was stirred at ambient temperature for two hours. The solvent was then removed under reduced pressure, and to the residue was added DMF (5 mL), triethylamine (72.2 μί, 0.518 mmol) and (3S,4 )-4-(3,4-difIuorophenyl)- l-(2-methoxyethyl)pyrrolidin-3 -amine dihydrochloride (Preparation C3, 114 mg, 0.345 mmol). The reaction mixture was stirred at ambient temperature for two hours then concentrated under vacuum. The residue was purified by silica column chromatography eluting with 10% MeOH/DCM to yield the title product. MS (apci) m/z = 500.0 (M+H). Example 41

1 -((3 S.4RV4-C 3.4-difluorophenylV 1 -(2-methoxyethyl pyrrolidin-3-yl)-3 -(2-methyl-4- phenyloxazol-5-yl)urea

[00643] Preparation of 2-aminopropanenitrile: Acetaldehyde (15.9 mL, 316 mmol) was added slowly to a slurry of N¾C1 (16.9 g, 316 mmol) and KCN (19.5 g, 300 mmol) in 150 mL of concentrated ammonium hydroxide. The reaction was stirred for 30 minutes and transferred to a liquid-liquid extraction apparatus containing DCM (1 L). TsOH (54.3 g, 316 mmol) was added to the collection flask and liquid-liquid extraction was performed for 34 hours. The collected suspension was extracted with IN NaOH (500 mL) and brine, dried over MgS0 4 , filtered and concentrated to provide the title compound (15.9 g, 71.9 % yield) as yellowish oil. 1H NMR (D4-MeOH) 3.80-3.86 (m, 1H), 1.43 (d, J = 7.1 Hz,

3H).

[00644] Preparation of N-(l-cyanoethyl)benzamide: 2-Aminopropanenitrile

(1.65 g, 23.5 mmol), 4-methylbenzenesulfonic acid (3.68 g, 21.3 mmol) and benzoyl chloride (3.00 g, 21.3 mmol) were combined in NMP (20 mL) and stirred at ambient temperature for 4 days. The reaction was poured into a mixture of IN NaOH (50 mL) and ice (50 g), extracted with EtOAc (2 x 100 mL), dried over MgS0 4 , filtered and concentrated to afford the title compound (3.33 g, 89.6 % yield) as a brownish oil. MS (apci) m/z = 175.1 (M+H).

[00645] Step C: Preparation of 4-methyl-2-phenyloxazol-5-amine: N-(l - cyanoethyl)benzamide (1.8 g, 10.3 mmol) was dissolved in 20 mL of dioxane and hydrogen chloride (20.7 mL, 82.7 mmol) in dioxane added. The reaction was stirred at ambient temperature overnight, concentrated, taken up in DCM (20 mL) and sonicated. The obtained brown solid was collected and partitioned between EtOAc (50 mL) and IN NaOH (30 mL). The EtOAc layer was washed with brine, dried over MgS0 4 , filtered and concentrated to provide a mixture of the title compound with 4-methyl-2-phenyloxazol-5(4H)-imine (1.20 g, 66.7 % yield) as a brown solid. MS (apci) m/z = 349.0 (dimer+H). [00646] Step D: Preparation of phenyl 4-methyl-2-phenyloxazol-5-ylcarbamate: To a suspension of 4-methyl-2-phenyloxazol-5 -amine hydrochloride (300 mg, 1.42 mmol) in EtOAc (5 mL) was added NaOH (2848 μί, 2.85 mmol) followed by phenyl carbonochloridate (177 iL, 1.42 mmol). The reaction was stirred for 5 hours, adding additional phenyl carbonochloridate (177 μί, 1.42 mmol) after 2 hours. The reaction was treated with EtOAc (50 mL), washed with water (10 mL) and brine (10 mL), dried over MgS0 4 , filtered and concentrated under vacuum. The residue was purified by silica column chromatography eluting with 25% EtOAc-hexanes to provide the title compound (255 mg, 60.8 % yield) as a white solid. MS (apci) m/z = 295.0 (M+H).

[00647] Step E: Preparation of l-((3S,4R)-4-(3,4-difluorophenyl)-l-(2- methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-2-phenyloxazol-5-y l)urea: Phenyl 4-methyl-2- phenyloxazol-5-ylcarbamate (6.1 mg, 0.021 mmol), (3S,4R)-4-(3,4-difluorophenyl)-l -(2- methoxyethyl)pyrrolidin-3-amine bis(2,2,2-trifluoroacetate) (10 mg, 0.021 mmol) and DIEA (18 μί, 0.10 mmol) were combined in 0.2 mL of DMF and stirred at ambient temperature for lhour. The mixture was loaded onto a samplet and purified by reverse-phase column chromatography, eluting with 0-55% acetonitrile/water, to afford the title compound (5.9 mg, 62 % yield). MS (apci) m/z = 457.0 (M+H).

Example 42

l-((3S,4R)-l -(2-methoxyethyl)-4-phenylpyrrolidin-3-yl)-3-(4-methyl-2-phe nyloxazol-5- yPurea

[00648] Prepared according to the procedure of Example 41, Step E using (3S,4R)-l -(2- methoxyethyl)-4-phenylpyrrolidin-3-amine bis(2,2,2-trifluoroacetate) instead of (3S,4R)-4- (3,4-difluorophenyl)-l-(2-methoxyethyl)pyrrolidin-3-amine bis(2,2,2-trifluoroacetate). The material was purified by reverse-phase column chromatography using 0-60% acetonitrile/H 2 0 as the eluent to provide the title compound (4.1 mg, 47 % yield). MS (apci) m/z = 421.1 (M+H).

1 -((3 S.4R -4-( 3 ^-difluorophenylV 1 -(2-methoxyethvDpyrrolidin-3-yl>3 -(2-isopropyl-

4-phenyloxazol-5-yl urea

[00649] Step A: Preparation of N- cyano phenvOmethvDisobutyramide: 2-amino-2- phenylacetonitrile hydrochloride (2.00 g, 11.9 mmol), DIEA (5.16 mL, 29.7 mmol) and isobutyryl chloride (1.20 g, 11.3 mmol) were combined in DCM (40 mL) and stirred at ambient temperature for 16 hours. Brine (25 mL) was added and the reaction was extracted with DCM (2 x 50 mL). The combined organic extracts were dried over MgS0 4 , filtered and concentrated to afford the title compound (2.1 g, 96.3 % yield). MS (apci) m/z = 405.1 (dimer+H).

[00650] Step B: Preparation of l-f(3S,4R)-4-(3.4-difluorophenvn-l-(2- methoxyethyl)pyrrolidin-3-vn-3-(2-isopropyl-4-phenyloxazol-5 -yl)urea: Prepared from N- (cyano(phenyl)methyl)isobutyramide using the procedures described in Example 41, Steps C- E. The final product was purified by reverse-phase column chromatography, eluting with 0- 60% acetonitrile/water, to afford the title compound (5.2 mg, 25 % yield for 3 steps). MS (apci) m/z = 485.1 (M+H).

Example 44

11 -(2-isopropyl-4-phenyloxazol-5-yl)-3-((3 S,4RV 1 -(2-methoxyethyl)-4- phenylpyrrolidin-3 - vDurea

[00651] Prepared according to the procedure of Example 43, using (3S,4R)-l-(2- methoxyethyl)-4-phenylpyrrolidin-3 -amine bis(2,2,2-trifluoroacetate) instead of (3S,4R)-4- (3,4-difluorophenyl)-l-(2-methoxyethyl)pynOlidin-3-amine bis(2,2,2-trifluoroacetate). The material was purified by reverse-phase column chromatography using 0-60% acetonitrile/H 2 0 as the eluent to provide the title compound (4.7 mg, 55 % yield). MS (apci) m/z = 449.1 (M+H).

Example 45

11 -((3 S.4R -4-( 3 ,4-difluorophenylV 1 -(2-methoxyethyl)pyrrolidin-3 -yf)-3 -( 4-methyl-2- phenylthiazol-5-yl)urea

[00652] Step A: Preparation of 4-methyl-2-phenylthiazol-5-amine: N-(l- cyanoethyl)benzamide (500 mg, 2.87 mmol, prepared as described in Example 41 , Step B) and Lawesson's Reagent (1277 mg, 3.16 mmol) were combined in 2 mL of toluene in a sealed vessel and heated at 100 °C for 2 days. The reaction was cooled, concentrated and purified by silica column chromatography eluting with 10-25% EtOAc-hexanes to provide the title compound (148 mg, 27.1 % yield). MS (apci) m/z = 191.0 (M+H).

[00653] Step B: Preparation of l l-((3S,4R)-4-(3,4-difluorophenyl)-l-(2- methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-2-phenylthiazol-5- yl)urea: Prepared from 4- methyl-2-phenylthiazol-5 -amine using the procedures described in Example 41 , Steps D-E. The final product was purified by reverse-phase column chromatography, eluting with 0-60% acetonitrile/water, to afford the title compound (6.2 mg, 52 % yield for 2 steps). MS (apci) m/z = 473.0 (M+H).

l-((3S,4R)-l-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl)-3-(4- methyl-2-phenylthiazol-5- yPurea

[00654] Prepared according to the procedure of Example 45, step B using (3S,4R)-l-(2- methoxyethyl)-4-phenylpyrrolidin-3-amine bis(2,2,2-trifluoroacetate) instead of (3S,4R)-4- (3,4-difluorophenyl)-l-(2-methoxyethyl)pyrrolidin-3-amine bis(2,2,2-trifluoroacetate). The final product was purified by reverse-phase column chromatography using 0-60% acetonitrile/H 2 0 as the eluent to provide the title compound (6.3 mg, 73 % yield). MS (apci) m/z = 437.0 (M+H).

Example 47

1 -((3 S,4R)-4-( 3.4-difluorophenvD- 1 -(2-methoxyethyl)pyrrolidin-3-yl)-3-(2-isopropyl-

4-phenylthiazol-5-yl)urea

[00655] Prepared from N-(cyano(phenyl)methyl)isobutyramide (prepared as described in Example 43, Step A) using the procedures described in Example 45, Steps A-B. The final product was purified by reverse-phase column chromatography, eluting with 0-70% acetonitrile/water, to afford the title compound (4.5 mg, 19 % yield for 3 steps). MS (apci) m/z = 501.0 (M+H).

l-(2-isopropyl-4-phenylthiazol-5-ylV3-((3S,4RVl-(2-methoxyet hylV4- phenylpyrrolidin-3 - vDurea

[00656] Prepared according to the procedure of Example 47, using (3S,4R)-l-(2- methoxyethyl)-4-phenylpyrrolidin-3-amine bis(2,2,2-trifluoroacetate) instead of (3S,4R)-4- (3 ,4-difluorophenyl)- 1 -(2-methoxyethyl)pyrrolidin-3-amine bis(2,2,2-trifluoroacetate). The final product was purified by reverse-phase column chromatography using 0-60% acetonitrile/H 2 0 as the eluent to provide the title compound (3.7 mg, 44 % yield). MS (apci) m/z = 465.1 (M+H).

Example 49

methyl 5-(3-(Y3 S.4R)-4-(3.4-difluorophenyl)- 1 -(2-methoxyethyl)pyrrolidin-3- vDureidoy4-phenylthiazole-2-carboxylate

[00657] Prepared according to the procedure of Example 47, using methyl 2-chloro-2- oxoacetate instead of isobutyryl chloride. The final compound was purified by reverse-phase column chromatography using 5-80% acetonitrile/H 2 0 as the eluent to provide the title compound (53 mg, 2 % yield for 4 steps). MS (apci) m/z = 517.2 (M+H). Example 50

l-((3S^R)-4-(3.4-difluorophenyl)-l-(2-methoxyethvnpyrrolidin -3-vn-3-(2-(2- hydroxypropan-2-yl)-4-phenylthiazol-5-yl)urea

[00658] Methyl 5-(3-((3S,4R)-4-(3,4-difluorophenyl)-l-(2-methoxyethyl)pyrro lidin-3- yl)ureido)-4-phenylthiazole-2-carboxylate (40 mg, 0.0774 mmol, prepared as described in Example 49) was dissolved in 3 mL of THF and cooled to 0 °C. LiAlH 4 (1M in THF, 96.8 μί, 0.194 mmol) was added dropwise and the reaction was allowed to warm to ambient temperature. Additional THF (5 mL) was added followed by Na 2 SO 4 xl0H 2 O (249 mg, 0.774 mmol). The reaction was stirred at ambient temperature for 16 hours, filtered, concentrated and purified by reverse-phase column chromatography using 5-70% acetonitrile/H 2 0 as the eluent to provide the title compound (8.96 mg, 23.6 % yield). MS (apci) m/z = 489.2 (M+H)

Example 51

l-((3S.4R)-4-(3,4-difluorophenyl)-l-(2-methoxyethyl)pyrrolid in-3-vn-3-(2-(2- hvdroxypropan-2-yl)-4-phenylthiazol-5-yl)urea

[00659] Methyl 5-(3-((3S,4R)-4-(3,4-difluorophenyl)-l-(2-methoxyethyl)pyrro lidin-3- yl)ureido)-4-phenylthiazole-2-carboxylate (20 mg, 0.039 mmol) was dissolved in 1 mL of THF and cooled to 0 °C. MeMgBr (1M in THF, 116 μί, 0.12 mmol) was added and the reaction was allowed to warm to ambient temperature, quenched with brine (1 mL), extracted with several portions of DCM in a PS frit and concentrated. The crude product was purified by reverse-phase column chromatography using 10-80% acetonitrile/H 2 0 as the eluent to provide the title compound (2.8 mg, 14 % yield). MS (apci) m/z = 517.2 (M+H).

Example 52

5-(3 -((3 S.4R)-4-( 3 ,4-difluorophenyl)- 1 -(2-methoxyethyl)pyrrolidin-3 -yl)ureido)-N.N- dimethyl-4-phenylthiazole-2-carboxamide

[00660] Step A: 5 -(3 -((3 S .4R)-4-(3.4-difluorophenylV 1 -(2-methoxyethvnpyrrolidin-3 - yDureidoV4-phenylthiazole-2-carboxylic acid: Methyl 5-(3-((3S,4R)-4-(3,4-difluorophenyl)-l- (2-methoxyethyl)pyrrolidin-3-yl)ureido)-4-phenylthiazole-2-c arboxylate (200 mg, 0.387 mmol) was dissolved in 2 mL of MeOH and NaOH (103 mg, 0.774 mmol) was added. The reaction was stirred at ambient temperature for 16 hours and HCl (5N in IPA, 310 μί, 1.55 mmol) added. The reaction was concentrated, taken up in acetone (5 mL) and filtered through Celite®. The Celite® was washed with several portions of acetone and the combined acetone solutions were concentrated to afford the title compound containing about 50%/weight of NaCl (359 mg, 92.3 % yield). MS (apci) m/z = 503.1 (M+H).

[00661] Step B: Preparation of 5-(3-((3S,4R)-4-(3,4-difluorophenvn-l-(2- methoxyethyl)pyrrolidin-3-yl)ureido)-N,N-dimethyl-4-phenylth iazole-2-carboxamide: 5-(3- ((3 S,4R)-4-(3 ,4-difluorophenyl)- 1 -(2-methoxyethyl)pyrrolidin-3 -yl)ureido)-4-phenylthiazole- 2-carboxylic acid (50% pure, 25 mg, 0.025 mmol), HBTU (23 mg, 0.060 mmol), dimethylamine hydrochloride (12 mg, 0.15 mmol) and DIEA (52 μί, 0.30 mmol) were combined in 0.5 mL of DMF and stirred at ambient temperature for 2 days. The reaction was loaded onto a samplet and purified by reverse-phase column chromatography, eluting with 0- 80% acetonitrile/water, to afford the title compound (5.4 mg, 40 % yield). MS (apci) m/z = 530.2 (M+H). Example 53

1 -(( 3 S,4R)-4-( 3 ,4-d ifluorophenyl )- 1 -( 2-methoxyethyl)pyrrolidin-3 -yl)-3 -(3 -methyl- 1 -phenyl-

1 H- 1 ,2,4-triazol-5-yl)urea

[00662] Step A: Preparation of 3-methyl-l-phenyl-lH-l,2,4-triazol-5-amine: To a solution of methyl N-cyanoacetimidate (100 mg, 1.019 mmol) in MeOH (4 mL) was added phenylhydrazine (0.121 mL, 1.223 mmol). The reaction mixture was refluxed for 4 hours, then cooled to ambient temperature. The reaction mixture was purified by silica column chromatography eluting with 0-80% acetone/hexane, to afford the title compound as a white solid (147 mg, 83% yield). MS (apci) m/z = 175.1 (M+H).

[00663] Step B: Preparation of l-((3S,4R -4-(3,4-difluorophenyl)-l-(2- methoxyethyl)pyrrolidin-3-yl)-3 -(3 -methyl- 1 -phenyl- 1 H- 1 ,2,4-triazol-5-yl)urea: To a solution of 3-methyl-l -phenyl- lH-l,2,4-triazol-5-amine (15 mg, 0.086 mmol) in DCM (1 mL) was added CDI (14 mg, 0.086 mmol), followed by addition of DIEA (0.030 mL, 0.172 mmol). The reaction mixture was stirred at ambient temperature for 5 hours, and a solution of (3S,4R)-4- (3,4-difluorophenyl)-l-(2-methoxyethyl)pyrrolidin-3-amine (2S,3S)-2,3-bis((4- methylbenzoyl)oxy)succinate [Preparation E3] (58 mg, 0.090 mmol) and DIEA (0.030 mL, 0.172 mmol) in DCM (1 mL) was added. The reaction mixture was stirred at ambient temperature for 16 hour, then was diluted with H 2 0 (20 mL) and extracted with DCM (3 x 20 mL). The combined organic phases were dried (MgS0 4 ), filtered and concentrated. The crude product was purified by reverse-phase column chromatography, eluting with 5-70% acetonitrile/water, to afford the title compound as a colorless glass (20.6 mg, 52% yield). MS (apci) m/z = 457.2 (M+H). Example 54

1 -((3 S.4RV4-( 3 ,4-difluorophenylV 1 -( 2-methoxyethyl)pyrrolidin-3 -yl -3-( 1 -methyl-3 -phenyl-

1 H- 1 ,2,4-triazol-5-yl)urea

[00664] Prepared according to the procedure for Example 54, Step B, replacing 3- methyl- 1 -phenyl- 1 H- 1 ,2,4-triazol-5-amine with 1 -methyl-3 -phenyl- 1 H- 1 ,2,4-triazol-5-amine hydrochloride hydrate (ChemBridge, 25 mg, 0.109 mmol), to afford the title compound as a white solid (27.3 mg, 55% yield). MS (apci) m/z = 457.2 (M+H).

Example 55

1 -( (3 S,4R)-4-( 3 ,4-difluorophenylV 1 -(2-methoxyethvnpyrrolidin-3-vn-3 -(2-( 1 -methyl- 1 H- pyrazol-4-yl)-4-phenylthiazol-5-yl)urea

[00665] Step A: Preparation of ethyl 2-amino-4-phenylthiazole-5-carboxylate: A suspension of ethyl 2-bromo-3-oxo-3-phenylpropanoate (4.9 g, 18.1 mmol) and thiourea (1.38 g, 18.1 mmol) in ethanol (50 mL) was warmed to reflux and stirred for 4 hours. After standing at ambient temperature for 16 hours the mixture was concentrated under reduced pressure. The residue was partitioned between DCM (100 mL) and saturated NaHC0 3 (100 mL) and the aqueous layer was extracted with DCM (2 x 50 mL). The combined organic phases were washed with brine (50 mL), dried over Na 2 S0 4 , filtered and concentrated. The resulting solid was triturated with DCM, filtered and dried under vacuum to afford ethyl 2-amino-4- phenylthiazole-5-carboxylate (3.09 g, 69% yield) as a solid. MS (apci) m/z = 249.1 (M+H).

[00666] Step B: Preparation of ethyl 2-bromo-4-phenylthiazole-5-carboxylate: A suspension of copper bromide (3.34 g, 14.9 mmol) in anhydrous acetonitrile (50 mL) was degassed with N 2 for 10 minutes and cooled to 0 °C, then treated with t-butyl nitrite (2.2 mL, 18.7 mmol). This mixture was treated with a suspension of ethyl 2-amino-4-phenylthiazole-5- carboxylate (3.09 g, 12.4 mmol) in acetonitrile (50 mL) and the dark mixture was allowed to warm slowly to ambient temperature over 16 hours. The mixture was concentrated and the residue was dissolved in EtOAc (100 mL) and washed with NaHC0 3 (100 mL). The aqueous layer was extracted with EtOAc (2 x 50 mL), and the combined organic phases were washed with water and brine, dried over Na 2 S0 4 , filtered and concentrated to afford ethyl 2-bromo-4- phenylthiazole-5-carboxylate (3.8 g, 98% yield) as a brown, crystalline solid. MS (apci) m/z = 312.0 (M+).

[00667] Step C: Preparation of 2-bromo-4-phenylthiazole-5-carboxylic acid: To a solution of ethyl 2-bromo-4-phenylthiazole-5-carboxylate (3.80 g, 12.17 mmol) in THF (100 mL) was added water (30 mL) followed by potassium hydroxide (908 mg, 16.2 mmol). The mixture was stirred at ambient temperature for 16 hours then acidified with IN HCl and extracted with EtOAc. The combined organic phases were washed with brine, dried over Na 2 S0 4 , filtered and concentrated to afford 2-bromo-4-phenylthiazole-5-carboxylic acid (3.4 g, 98% yield) as a yellow solid. MS (apci) m/z = 285.9 (M+H).

[00668] Step D: Preparation of 2-(2-methylpyrimidin-5-yl)-4-phenylthiazole-5- carboxylic acid: 2-Bromo-4-phenylthiazole-5-carboxylic acid (300 mg, 1.06 mmol), 2-methyl- 5-(4,4,5,5,-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidine (465 mg, 2.11 mmol), K 2 C0 3 (584 mg, 4.22 mmol) and Pd(PPh 3 ) 4 (122 mg, 0.11 mmol) were combined in toluene (2 mL), water (1 mL) and EtOH (0.5 mL) and warmed to 95 °C in a sealed vessel for 16 hours. The cooled mixture was filtered through GF paper and the filtrate partitioned between water (10 mL) and EtOAc (10 mL). The aqueous layer was extracted with EtOAc and then adjusted to pH 5 with IN HCl. The resulting solids were filtered, washed with water and Et 2 0 and then dried under vacuum to afford 2-(2-methylpyrimidin-5-yl)-4-phenylthiazole-5-carboxylic acid (195 mg, 62% yield) as a cream solid. MS (apci) m/z = 298.1 (M+H).

[00669] Step E: Preparation of te -butyl (2-(2-methylpyrimidin-5-yl)-4-phenylthiazol- 5-ylcarbamate: 2-(2-Methylpyrimidin-5-yl)-4-phenylthiazole-5-carboxylic acid (195 mg, 0.66 mmol) was suspended in /-BuOH (5 mL) and treated with DPPA (142 \\L, 0.66 mmol) followed by Et 3 N (91 μί, 0.66 mmol). The mixture was warmed to reflux and stirred for 16 hours. The cooled mixture was concentrated and then partitioned between EtOAc (10 mL) and water (10 mL), followed by addition of IN NaOH and a small amount of MeOH. The aqueous layer was extracted with EtOAc (2 x 10 mL) and the combined organic phases were washed with brine, dried over Na 2 S0 4 , filtered and concentrated. The residue was purified by silica column chromatography eluting with hexanes:EtOAc, 4:1, to afford tert-butyl (2-(2- methylpyrimidin-5-yl)-4-phenylthiazol-5-ylcarbamate (80 mg, 33% yield) as a pale pink solid. MS (apci) m/z = 369.1 (M+H).

[00670] Step F: Preparation of 2-(2-methylpyrimidin-5-yl)-4-phenylthiazol-5-amine: To a solution of tert-butyl (2-(2-methylpyrimidin-5-yl)-4-phenylthiazol-5-ylcarbamate (80 mg, 0.22 mmol) in anhydrous DCM (5 mL) was added TFA (2 mL). The solution was stirred at ambient temperature for 3.5 hours, then concentrated and partitioned between 2N NaOH (10 mL) and DCM (10 mL). The aqueous layer was extracted with DCM and the combined organic phases were washed with brine (10 mL), dried over Na 2 S0 4 , filtered and concentrated to afford 2-(2-methylpyrimidin-5-yl)-4-phenylthiazol-5-amine (42 mg, 72% yield) as a yellow solid. MS (apci) m/z = 269.1 (M+H).

[00671] Step G: Preparation of l-((3S.4R)-4-(3.4-difluorophenyl)-l-(2- methoxyethyl)pyrrolidin-3-yl)-3-(2-(l-methyl-lH-pyrazol-4-vn -4-phenylthiazol-5-yl)urea: To a solution of 2-(2-methylpyrimidin-5-yl)-4-phenylthiazol-5-amine (42 mg, 0.16 mmol) in DCM (2 mL) was added triphosgene (23 mg, 0.08 mmol) followed by DIEA (82 μΐ, 0.47 mmol). The mixture was stirred for 30 minutes at ambient temperature. The mixture was then treated with (3S,4R)-4-(3,4-difluorophenyl)-l-(2-methoxyethyl)pyrrolidin- 3-amine [Preparation CI] (50 mg, 0.19 mmol) and DIEA (82 μί, 0.47 mmol) and stirred for 16 hours. The mixture was partitioned between water (10 mL) and DCM (10 mL) and the aqueous layer was extracted with DCM. The combined organic phases were washed with brine (10 mL), dried over Na 2 S0 4 , filtered and concentrated. The residue was purified by silica column chromatography eluting with 2.5% MeOH/DCM. The fractions containing the desired product were then purified by reverse phase HPLC (5-95% ACN/H 2 O/0.1% TFA over 20 minutes). Clean fractions containing the desired product were combined and concentrated, and the residue was worked up with 2N NaOH / DCM to afford the title compound (8 mg, 9% yield) as a white solid. MS (apci) m/z = 551.2 (M+H).

Example 56

1 -((3 S,4Fv>4-( 3.4-difluorophenylV 1 -(2-methoxyethvnpyrrolidin-3-yiy3 -(2-( 1 -methyl- 1 H- pyrazol-4-yl)-4-phenylthiazol-5-yl)urea di(trifluoroacetate)

[00672] Step A: Preparation of 2-(l-methyl-lH-pyrazol-4-yl)-4-phenylthiazole-5- carboxylic acid: Prepared according to the procedure for Example 55, substituting 2-methyl-5- (4,4,5,5,-tetramethyl-l ,3,2-dioxaborolan-2-yl)pyrimidine for 1 -methyl-4-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)-lH-pyrazole in Step D, to provide the title compound (500 mg, 99% yield) as a cream solid. MS (apci) m/z = 286.0 (M+H).

[00673] Step B: Preparation of l-((3S,4R)-4-(3,4-difluorophenvn-l-(2- methoxyethyl pyrrolidin-3-yl)-3-(2-(l-methyl-lH-pyrazol-4-yl)-4-phenylthi azol-5-yl urea di(trifluoroacetate) : 2-(l -Methyl- lH-pyrazol-4-yl)-4-phenylthiazole-5-carboxylic acid (50 mg, 0.18 mmol) and (3S,4R)-4-(3,4-difluorophenyl)-l-(2-methoxyethyl)pyrrolidin- 3-amine [Preparation CI] (135 mg, 0.53 mmol) were combined in toluene (3 mL) and treated with DPPA (53 μί, 0.25 mmol) followed by Et 3 N (98 μί, 0.70 mmol). The mixture was warmed to reflux, stirred for 16 h then cooled and partitioned between water (10 mL) and EtOAc (10 mL). The aqueous layer was extracted with EtOAc (2 x 10 mL) and the combined organic phases were washed with brine (10 mL), dried over Na 2 S0 4 , filtered and concentrated. The residue was purified by silica column chromatography eluting with 2% MeOH/DCM, then by reverse phase HPLC (5-95% ACN/water/0/1% TFA over 20 min) to afford the title compound as the di-trifiuoroacetate salt (17 mg, 13% yield) as a colorless glass. MS (apci) m/z = 539.2 (M+H).