Pyrrolo[2,3-D]Pyrimidine Compounds

• US 20110136765A1
• Filed: 10/13/2010
• Published: 06/09/2011
• Est. Priority Date: 10/15/2009
• Status: Active Grant

• Current Assignee: Pfizer Inc.
• Original Assignee: Pfizer Inc.
• Inventors: Wolfson, Sergey Gregory, Acker, Brad A., Xie, Jin, Jacobsen, Eric Jon, Promo, Michele Ann, Hartmann, Susan J., Huang, Horng-Chih
• Granted Patent: US 8,633,206 B2
• Time in Patent Office: Days
• US Class Current: 514/81
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/04 Artificial tears; Irrigation solutions
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/14 : of the thyroid hormones, e.g. T3, T4
• CPC Class Codes: C07D 487/04 : Ortho-condensed systems

Abstract

Described herein are pyrrolo[2,3-d]pyrimidine compounds, their use as Janus Kinase (JAK) inhibitors, pharmaceutical compositions containing these compounds, and methods for their preparation.

Claims

1. A compound of formula I

2. The compound of claim 1, wherein the A ring is selected from the group consisting of optionally substituted piperidinyl, pyrrolidinyl, azetidinyl, and piperazinyl.

3. The compound of claim 2, wherein the A ring is selected from the group consisting of piperidinyl, pyrrolidinyl, azetidinyl, and piperazinyl;

wherein the A ring is optionally substituted with one or more substituents selected from the group consisting of carboxy, cyano, oxo, fluoro, (C₁-C₈)alkyl, phenyl, oxadiazolyl, pyridinyl, pyrimidinyl, tetrazolyl, pyrrolidinyl, —

OP(O)(R¹⁰)_n, —

OR¹¹, —

OC(O)R¹², —

C(O)OR¹², —

C(O)R¹³, —

C(O)NR¹⁴R¹⁵, —

NR¹⁶R¹⁷, —

N(R¹⁸)C(O)R¹⁹, —

N(R¹⁸)S(O)₂R¹⁹, —

SO₂R²⁰, and —

SO₂NR²¹R²²;

wherein the (C₁-C₈)alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, cyano, phenyl, pyridinyl, piperazinyl, pyrazinyl, pyrazolyl, pyridazinyl, isoxazolyl, pyrimidinyl, pyrrolidinyl, —

OR²³, —

OC(O)R²⁴, —

NR²⁵R²⁶, —

C(O)NR²⁷R²⁸, —

SR²⁹, —

SO₂R³⁰, —

SO₂NR³¹R³², and —

N(R³³)C(O)R³⁴;

R¹⁰ is selected from the group consisting of hydroxy and (C₁-C₆)alkoxy;

n is one or two;

R¹¹ is selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, tert-butyl, aminocarbonylmethyl, ethoxyethyl, dimethylaminocarbonylamino, diethylaminocarbonylmethyl, phenyl, and pyrrolidinylcarbonylmethyl;

R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R²¹, R²², R²⁴, R²⁵, R²⁶, R²⁷, R²⁸, R³¹, R³², R³³, and R³⁴ are independently selected from the group consisting of hydrogen, methyl, and ethyl;

R¹⁹ is selected from the group consisting of hydrogen, tert-butoxy, trifluoromethyl, methoxy, and phenylmethoxy;

R²⁰ is selected from the group consisting of hydrogen, methyl, phenyl, benzyl, phenylethyl, and cyclopropylmethyl;

R²³ is selected from the group consisting of hydrogen, methyl, phenyl, pyridinylmethyl, and cyclopropylmethyl;

R²⁹ is selected from the group consisting of hydrogen and pyridinyl; and

R³⁰ is selected from the group consisting of hydrogen, methyl, propyl, and cyclopropylmethyl;

wherein phenyl, wherever it occurs, is optionally substituted with one or more substituents selected from the group consisting of fluoro, cyano, and methoxy;

wherein isoxazolyl, oxadiazolyl, pyridinyl, piperazinyl, and pyridazinyl, wherever they occur in the A ring substituents, the R²³ substituents and the R²⁹ substituents, are optionally and independently substituted with one or more substituents selected from the group consisting of oxo, cyano, methyl, ethyl, methylsulfonylmethyl, and cyclopropylaminocarbonyl.

25. The compound of claim 1, wherein the compound is selected from the group consisting of:

N-(trans-4-{[(3-methoxypiperidin-1-yl)sulfonyl]methyl}cyclohexyl)-N-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine;

1-[({trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}methyl)-sulfonyl]piperidin-3-ol;

(3R)-1-[({trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}-methyl)sulfonyl]piperidin-3-ol;

(3R)-1-[({(1S,3R,4S)-3-methyl-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-cyclohexyl}methyl)sulfonyl]piperidin-3-ol;

trans-(R)-1-((4-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)-methylsulfonyl)piperidin-3-yl pivalate;

(3S)-1-[({trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}-methyl)sulfonyl]-piperidin-3-ol;

Diethyl (3R)-1-[({trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-cyclohexyl}methyl)sulfonyl]piperidin-3-yl phosphate;

N-[trans-4-({[3-(2-methoxyethoxy)piperidin-1-yl]sulfonyl}methyl)cyclohexyl]-N-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine;

N-(trans-4-{[(3-isobutoxypiperidin-1-yl)sulfonyl]methyl}cyclohexyl)-N-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine;

N-(trans-4-{[(3-ethoxypiperidin-1-yl)sulfonyl]methyl}cyclohexyl)-N-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine;

{1-[({trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}methyl)-sulfonyl]piperidin-3-yl}methanol;

N-[trans-4-({[4-(methoxymethyl)piperidin-1-yl]sulfonyl}methyl)cyclohexyl]-N-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine;

(1-((Trans-4-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)-methylsulfonyl)piperidin-4-yl)methanol;

(3S)-1-[({(1S,3R,4S)-3-methyl-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-cyclohexyl}methyl)sulfonyl]piperidin-3-ol;

(3R,4R)-1-[({trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}-methyl)sulfonyl]piperidine-3,4-diol;

1-[({trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}methyl)-sulfonyl]piperidin-4-ol;

(3R,4S)-1-[({trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}-methyl)sulfonyl]piperidine-3,4-diol;

4-(2-methoxyethyl)-1-[({trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-cyclohexyl}methyl)sulfonyl]piperidine-4-carboxamide;

N-(trans-4-{[(4-methoxypiperidin-1-yl)sulfonyl]methyl}cyclohexyl)-N-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine;

(R)-1-(trans-4-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)-methylsulfonyl)-pyrrolidin-3-ol;

{(3r,4r)-4-methyl-1-[({trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-cyclohexyl}methyl)-sulfonyl]pyrrolidin-3-yl}methanol;

{(3R,4R)-4-methyl-1-[({trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-cyclohexyl}methyl)-sulfonyl]pyrrolidin-3-yl}methanol;

3-methyl-1-[({trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}-methyl)sulfonyl]-pyrrolidin-3-ol;

(3R,4S)-1-[({trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}-methyl)sulfonyl]-pyrrolidine-3,4-diol;

N-[trans-4-({[(2R)-2-(methoxymethyl)pyrrolidin-1-yl]sulfonyl}methyl)cyclohexyl]-N-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine;

((3S)-1-((3-methyl-4-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclohexyl)-methylsulfonyl)-pyrrolidin-3-yl)methanol;

(3R,4R)-1-[({trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}-methyl)sulfonyl]-pyrrolidine-3,4-diol;

N-[trans-4-({[(3R)-3-(2-ethoxyethoxy)pyrrolidin-1-yl]sulfonyl}methyl)cyclohexyl]-N-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine;

3-methyl-1-[({trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclohexyl}-methyl)sulfonyl]-pyrrolidin-3-ol;

tert-butyl{(3S)-1-[({trans-4-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-cyclohexyl}methyl)-sulfonyl]pyrrolidin-3-yl}carbamate;

N-[trans-4-({[(3R,4R)-3,4-difluoropyrrolidin-1-yl]sulfonyl}methyl)cyclohexyl]-N-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine;

N-[trans-4-({[3-(methoxymethyl)pyrrolidin-1-yl]sulfonyl}methyl)cyclohexyl]-N-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine; and

N-[trans-4-({[(3R)-3-methoxypyrrolidin-1-yl]sulfonyl}methyl)cyclohexyl]-N-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine;

or

a pharmaceutically acceptable salt thereof.

4. A compound of formula Ia

5. The compound of claim 4,

wherein the A ring is optionally substituted with one or more substituents selected from the group consisting of carboxy, cyano, oxo, fluoro, (C₁-C₈)alkyl, phenyl, oxadiazolyl, pyridinyl, pyrimidinyl, tetrazolyl, pyrrolidinyl, —

OP(O)(R¹⁰)_n, —

OR¹¹, —

OC(O)R¹², —

C(O)OR¹², —

C(O)R¹³, —

C(O)NR¹⁴R¹⁵, —

NR¹⁶R¹⁷, —

N(R¹⁸)C(O)R¹⁹, —

N(R¹⁸)S(O)₂R¹⁹, —

SO₂R²⁰, and —

SO₂NR²¹R²²;

wherein the (C₁-C₈)alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, cyano, phenyl, pyridinyl, piperazinyl, pyrazinyl, pyrazolyl, pyridazinyl, isoxazolyl, pyrimidinyl, pyrrolidinyl, —

OR²³, —

OC(O)R²⁴, —

NR²⁵R²⁶, —

C(O)NR²⁷R²⁸, —

SR²⁹, —

SO₂R³⁰, —

SO₂NR³¹R³², and —

N(R³³)C(O)R³⁴;

R¹⁰ is selected from the group consisting of hydroxy and (C₁-C₆)alkoxy;

n is one or two;

R¹¹ is selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, tert-butyl, aminocarbonylmethyl, ethoxyethyl, dimethylaminocarbonylamino, diethylaminocarbonylmethyl, phenyl, and pyrrolidinylcarbonylmethyl;

R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸, R²¹, R²², R²⁴, R²⁵, R²⁶, R²⁷, R²⁸, R³¹, R³², R³³, and R³⁴ are independently selected from the group consisting of hydrogen, methyl, and ethyl;

R¹⁹ is selected from the group consisting of hydrogen, tert-butoxy, trifluoromethyl, methoxy, and phenylmethoxy;

R²⁰ is selected from the group consisting of hydrogen, methyl, phenyl, benzyl, phenylethyl, and cyclopropylmethyl;

R²³ is selected from the group consisting of hydrogen, methyl, phenyl, pyridinylmethyl, and cyclopropylmethyl;

R²⁹ is selected from the group consisting of hydrogen and pyridinyl; and

R³⁰ is selected from the group consisting of hydrogen, methyl, propyl, and cyclopropylmethyl;

wherein phenyl, wherever it occurs, is optionally substituted with one or more substituents selected from the group consisting of fluoro, cyano, and methoxy;

wherein isoxazolyl, oxadiazolyl, pyridinyl, piperazinyl, and pyridazinyl, wherever they occur in the A ring substituents, the R²³ substituents and the R²⁹ substituents, are optionally and independently substituted with one or more substituents selected from the group consisting of oxo, cyano, methyl, ethyl, methylsulfonylmethyl, and cyclopropylaminocarbonyl.

6. A compound of Formula II

7. The compound of claim 6, wherein

R^1a, R^1b, R^2a, R^2b, R^3a, R^3b, R^4a, R^4b, R^5a, and R^5b are independently selected from the group consisting of hydrogen, fluoro, carboxy, cyano, (C₁-C₈)alkyl, phenyl, oxadiazolyl, —

OP(O)(R¹⁰)_n, —

OR¹¹, —

OC(O)R¹², —

C(O)R¹³, —

C(O)NR¹⁴R¹⁵, —

NR¹⁶R¹⁷, and —

N(R¹⁸)C(O)R¹⁹;

wherein the (C₁-C₈)alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolidinyl, —

OR²³, —

C(O)NR²⁷R²⁸, —

SO₂R³⁰, —

SO₂NR³¹R³², and —

N(R³³)C(O)R³⁴;

R¹⁰ is selected from the group consisting of hydroxy and ethoxy;

n is one or two;

R¹¹ is selected from the group consisting of hydrogen, methyl, ethyl, tert-butyl, isopropyl, and aminocarbonylmethyl;

R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷ R¹⁸, R²⁷, R²⁸, R³¹, R³², R³³, and R³⁴ are independently selected from the group consisting of hydrogen, methyl, and ethyl;

R¹⁹ is selected from the group consisting of hydrogen and phenylmethoxy;

R²³ is selected from the group consisting of hydrogen, methyl, cyclopropylmethyl, and phenyl; and

R³⁰ is selected from the group consisting of hydrogen, methyl, propyl, and cyclopropylmethyl;

wherein phenyl, wherever it occurs, is optionally substituted with one or more fluoro;

wherein oxadiazolyl or pyridazinyl, wherever they occur, are optionally and independently substituted with one or more substituents selected from the group consisting of methyl and methylsulfonylmethyl.

8. The compound of claim 7, wherein

R^1a, R^1b, R^5a, and R^5b are hydrogen;

R^2a and R^2b are independently selected from the group consisting of hydrogen, ethyl, methoxy, and benzyloxycarbonylamino;

R^3a and R^3b are independently selected from the group consisting of hydrogen, cyano, hydroxy, hydroxymethyl, hydroxypropyl, methyl, ethyl, methoxy, methoxymethyl, methoxyethyl, methylaminocarbonyl, diethylaminocarbonyl, amino, aminocarbonyl, aminocarbonylmethyl, phenyl, methylsulfonylmethyloxadiazolyl, pyrimidinylmethyl, methylpyridazinyl, cyclopropylmethoxymethyl, and cyclopropylmethylsulfonylmethyl; and

R^4a and R^4b are independently selected from the group consisting of hydrogen, hydroxy, carboxy, fluoro, trifluoromethyl, cyano, methyl, ethoxy, methylcarbonyl, methylcarbonylamino, methylcarbonylaminomethyl, methylsulfonylmethyl, dimethylaminosulfonylmethyl, propylsulfonylmethyl, hydroxymethyl, aminocarbonyl, aminocarbonylmethoxy, aminosulfonylmethyl, methyloxadiazolyl, pyridinylmethyl, pyrrolidinylmethyl, and fluorophenoxymethyl.

9. The compound of claim 8, wherein

R^1a, R^1b, R^5a, and R^5b are hydrogen;

R^2a and R^2b are selected from the group consisting of hydrogen, ethyl, methoxy, and benzyloxycarbonylamino;

R^3a and R^3b are selected from the group consisting of hydrogen, cyano, hydroxy, hydroxymethyl, hydroxypropyl, methyl, ethyl, methoxy, methoxymethyl, methoxyethyl, methylaminocarbonyl, diethylaminocarbonyl, amino, aminocarbonyl, aminocarbonylmethyl, phenyl,

10. The compound of claim 6, wherein

R^1a, R^1b, R^2a, R^2b, R^3a, R^3b, R^4a, R^4b, R^5a, and R^5b are independently selected from the group consisting of (C₁-C₈)alkyl, —

OP(O)(R¹³)_n, —

OR¹¹, —

OC(O)R¹², and —

C(O)NR¹⁴R¹⁵;

wherein the (C₁-C₈)alkyl is optionally substituted with —

OR²³;

R¹⁰ is selected from the group consisting of hydroxy and (C₁-C₆)alkoxy;

n is one or two;

R¹¹ is selected from the group consisting of hydrogen (C₁-C₆)alkyl, and (C₁-C₆)alkoxy(C₁-C₆)alkyl;

R¹², R¹⁴, and R¹⁵ are independently selected from the group consisting of hydrogen and (C₁-C₆)alkyl;

R²³ is selected from the group consisting of hydrogen and (C₁-C₆)alkyl.

11. A compound of Formula III

12. The compound of claim 11, wherein

R^6a, R^6b, R^7a, R^7b, R^8a, R^8b, R^9a, and R^9b are independently selected from the group consisting of hydrogen, cyano, fluoro, (C₁-C₈)alkyl, phenyl, pyridinyl, pyrimidinyl, —

OR¹¹, —

OC(O)R¹², —

C(O)NR¹⁴R¹⁵, —

NR¹⁶R¹⁷, —

N(R¹⁸)C(O)R¹⁹, —

SO₂R²⁰, and —

SO₂NR²¹R²²;

wherein the (C₁-C₈)alkyl is optionally substituted with one or more substituents selected from the group consisting of cyano, phenyl, isoxazolyl, piperazinyl, pyrazinyl, pyrazolyl, pyridinyl, pyrrolidinyl, —

OR²³, —

NR²⁵R²⁶, and —

SR²⁹;

R¹¹ is selected from the group consisting of hydrogen, methyl, tert-butyl, isopropyl, ethoxyethyl, dimethylaminocarbonylmethyl, diethylaminocarbonylmethyl, phenyl, and pyrrolidinylcarbonylmethyl;

R¹², R¹⁶, R¹⁷, R¹⁸, R²¹, R²², R²⁵, and R²⁶ are independently selected from the group consisting of hydrogen, methyl, and ethyl;

R¹⁹ is selected from the group consisting of hydrogen, tert-butoxy, and trifluoromethyl;

R²⁰ selected from the group consisting of hydrogen, methyl, benzyl, and phenylethyl;

R²³ is selected from the group consisting of hydrogen, methyl, phenyl, and pyridinylmethyl; and

R²⁹ is selected from the group consisting of hydrogen and pyridinyl;

wherein phenyl, wherever it occurs, is optionally substituted with one or more substituents independently selected from the group consisting of fluoro and methoxy;

wherein isoxazolyl, pyridinyl, or piperazinyl, wherever they occur, are optionally and independently substituted with one or more substituents selected from the group consisting of oxo, methyl, and ethyl.

13. The compound of claim 12, wherein

R^6a, R^6b, and R^9b are hydrogen;

R^7a and R^7b are independently selected from the group consisting of hydrogen, fluoro, hydroxy, cyano, methyl, methoxy, methoxymethyl, hydroxymethyl, phenyl, pyridinyl, and

14. The compound of claim 13, wherein

R^6a, R^6b, and R^9b are hydrogen;

R^7a and R^7b are independently selected from the group consisting of hydrogen, fluoro, hydroxy, cyano, methyl, methoxy, methoxymethyl, hydroxymethyl, phenyl,

15. The compound of claim 11, wherein

R^6a, R^6b, R^7a, R^7b, R^8a, R^8b, R^9a, and R^9b are independently selected from the group consisting of halo, (C₁-C₈)alkyl, —

OR¹¹, and —

N(R¹⁸)C(O)R¹⁹;

wherein the (C₁-C₈)alkyl is optionally substituted with —

OR²³;

R¹¹ is selected from the group consisting of hydrogen and (C₁-C₆)alkoxy(C₁-C₆)alkyl;

R¹⁸ is selected from the group consisting of hydrogen and (C₁-C₆)alkyl;

R¹⁹ is selected from the group consisting of hydrogen and (C₁-C₆)alkoxy;

R²³ is selected from the group consisting of hydrogen and (C₁-C₆)alkyl.

16. A compound of Formula IV

17. The compound of claim 16, wherein

R^37a, R^37b, R^38a, R^38b, R^39a and R^39b are independently selected from the group consisting of hydrogen, hydroxy, fluoro, pyrimidinyl, pyridinyl, tetrazolyl, cyclopropylmethylsulfonyl, phenylsulfonyl, and methoxycarbonylamino.

18. The compound of claim 17, wherein

R^37a, R^37b, R^38b, R^39a, and R^39b are hydrogen;

and

R^38a is selected from the group consisting of hydrogen, fluoro, hydroxy, methoxycarbonylamino, cyclopropylmethylsulfonyl, phenylsulfonyl, pyrimidinyl, pyridinyl, and tetrazolyl.

19. The compound of claim 18, wherein

R^37a, R^37b, R^38b, R^39a, and R^39b are hydrogen;

and

R^38a is selected from the group consisting of hydrogen, fluoro, hydroxy, methoxycarbonylamino,

20. A compound of Formula V

21. The compound of claim 20,

wherein R⁴⁰, R⁴¹, R⁴², R⁴³, and R⁴⁴ are independently selected from the group consisting of hydrogen, methyl, pyridinyl, and pyridinylmethyl;

and

wherein pyridinyl, wherever it occurs, is optionally substituted with one or more substituents selected from the group consisting of cyano, methyl, and cyclopropylaminocarbonyl.

22. The compound of claim 21, wherein

R⁴⁰, R⁴¹, and R⁴³ are hydrogen;

R⁴² is selected from the group consisting of methyl, pyridinyl, pyridinylmethyl, methylpyridinyl, cyanopyridinyl, and cyclopropylaminocarbonylpyridinyl; and

R⁴⁴ is selected from the group consisting of hydrogen and methyl.

23. The compound of claim 22, wherein

R⁴⁰, R⁴¹, and R⁴³ are hydrogen;

R⁴² is selected from the group consisting of methyl,

24. A compound or pharmaceutically acceptable salt thereof, having the structure:

26. A pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

27. A pharmaceutical composition comprising a compound of Formula Ia or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

28. A pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof, having the structure:

29. A method for the treatment of a Janus Kinase mediated condition in a subject in need of such treatment, wherein the method comprises administering to the subject an amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein the amount of the compound is effective for the treatment of the Janus Kinase mediated condition.

32. The method of claim 29, wherein the Janus Kinase mediated condition is Alzheimer'"'"'s disease, arthritis, autoimmune thyroid disorders, cancer, diabetes, leukemia, T-cell prolymphocytic leukemia, lymphoma, myeloproliferation disorders, lupus, multiple myeloma, multiple sclerosis, osteoarthritis, sepsis, psoriatic arthritis, prostate cancer, T-cell autoimmune disease, inflammatory diseases, chronic and acute allograft transplant rejection, bone marrow transplant, stroke, asthma, chronic obstructive pulmonary disease, allergy, bronchitis, viral diseases, or Type I diabetes and complications from diabetes.

33. The method of claim 29, wherein the Janus Kinase mediated condition is selected from the group consisting of asthma, Crohn'"'"'s disease, dry eye, uveitis, inflammatory bowel disease, organ transplant rejection, psoriasis, rheumatoid arthritis and ulcerative colitis.

30. A method for the treatment of a Janus Kinase mediated condition in a subject in need of such treatment, wherein the method comprises administering to the subject an amount of a compound of Formula Ia or a pharmaceutically acceptable salt thereof, wherein the amount of the compound is effective for the treatment of the Janus Kinase mediated condition.

31. A method for the treatment of a Janus Kinase mediated condition in a subject in need of such treatment, wherein the method comprises administering to the subject an amount of the compound or pharmaceutically acceptable salt thereof, having the structure: