Jak inhibitors

Abstract

Described herein are Janus kinase (JAK) inhibitors and methods of utilizing JAK inhibitors in the treatment of diseases, disorders or conditions. Also described herein are pharmaceutical compositions containing such compounds.

What is claimed is: 
     
         1 . A compound of Formula (I′):
                     
 wherein: 
                     
 is phenyl or a C 2 -C 9 heteroaryl ring; 
                     
 is a C 2 -C 9 heterocycloalkyl ring; 
 X is C(R 11 ) or N; 
 L 1  is C 1 -C 6 alkyl or C 1 -C 6 heteroalkyl; 
 L 2  is a bond or C 1 -C 6 alkyl; 
 R 1  is C 3 -C 9 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, or C 2 -C 9 heteroaryl, wherein C 3 -C 9 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, or C 2 -C 9 heteroaryl are optionally substituted with 1, 2, or 3 R 5 ; 
 each R 3  is independently selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, —OR 7 , —N(R 7 ) 2 , —CN, —C(═O)R 8 , —C(═O)OR 7 , —C(═O)N(R 7 ) 2 , —NR 7 C(═O)R 8 , —NR 7 S(═O) 2 R 8 , —S(═O) 2 R 8 , and —S(═O) 2 N(R 7 ) 2 ; 
 R 4  is hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 heteroalkyl; 
 each R 5  is independently selected from halogen, oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, —OR 7 , —N(R 7 ) 2 , —CN, —C(═O)R 8 , —C(═O)OR 7 , —C(═O)N(R 7 ) 2 , —NR 7 C(═O)R 8 , —NR 7 S(═O) 2 R 8 , —S(═O) 2 R 8 , and —S(═O) 2 N(R 7 ) 2 ; 
 each R 7  is independently selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 haloalkyl, and C 1 -C 6 heteroalkyl; 
 each R 8  is independently selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl, and C 2 -C 9 heterocycloalkyl; 
 R 11  is hydrogen or C 1 -C 6 alkyl optionally substituted with 1, 2, or 3 R 5 ; 
 R 12  is hydrogen, halogen, or C 1 -C 6 alkyl; 
 R 13  is selected from hydrogen and C 1 -C 6 alkyl; 
 each R 14  is independently selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, —OR 7 , —N(R 7 ) 2 , and oxo; 
 n is 0, 1, 2, or 3; and 
 p is 0, 1, 2, or 3; 
 or a pharmaceutically acceptable salt or solvate thereof. 
 
     
     
         2 . The compound of  claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein
                       is a C   2 -C 9 heteroaryl ring. 
     
     
         3 . The compound of  claim 1  or  claim 2 , or a pharmaceutically acceptable salt or solvate thereof, wherein
                     
 is selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl. 
 
     
     
         4 . The compound of any one of  claims 1-3 , or a pharmaceutically acceptable salt or solvate thereof, wherein
                       is selected from pyrazolyl, pyrrolyl, and imidazolyl.   
     
     
         5 . The compound of any one of  claims 1-4 , or a pharmaceutically acceptable salt or solvate thereof, having the structure of Formula (Ia′):
                     
 
     
     
         6 . The compound of any one of  claims 1-5 , or a pharmaceutically acceptable salt or solvate thereof, wherein
                       is a pyrrolidine ring.   
     
     
         7 . The compound of any one of  claims 1-6 , or a pharmaceutically acceptable salt or solvate thereof, wherein each R 14  is independently selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and oxo. 
     
     
         8 . The compound of any one of  claims 1-7 , or a pharmaceutically acceptable salt or solvate thereof, wherein each R 14  is independently selected from C 1 -C 6 alkyl. 
     
     
         9 . The compound of any one of  claims 1-8 , or a pharmaceutically acceptable salt or solvate thereof, wherein p is 1. 
     
     
         10 . The compound of any one of  claims 1-6 , or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0. 
     
     
         11 . A compound of Formula (I):
                       wherein:                         is phenyl or a C 2 -C 9 heteroaryl ring;   X is C(R 11 ) or N;   L 1  is C 1 -C 6 alkyl or C 1 -C 6 heteroalkyl;   L 2  is a bond or C 1 -C 6 alkyl;   R 1  is C 3 -C 9 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, or C 2 -C 9 heteroaryl, wherein C 3 -C 9 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, or C 2 -C 9 heteroaryl are optionally substituted with 1, 2, or 3 R 5 ;   R 2  is —C(═O)OR 6 ;   each R 3  is independently selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, —OR 7 , —N(R 7 ) 2 , —CN, —C(═O)R 8 , —C(═O)OR 7 , —C(═O)N(R 7 ) 2 , —NR 7 C(═O)R 8 , —NR 7 S(═O) 2 R 8 , —S(═O) 2 R 8 , and —S(═O) 2 N(R 7 ) 2 ;   R 4  is hydrogen, C 1 -C 6 alkyl, or C 1 -C 6 heteroalkyl;   each R 5  is independently selected from halogen, oxo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, —OR 7 , —N(R 7 ) 2 , —CN, —C(═O)R 8 , —C(═O)OR 7 , —C(═O)N(R 7 ) 2 , —NR 7 C(═O)R 8 , —NR 7 S(═O) 2 R 8 , —S(═O) 2 R 8 , and —S(═O) 2 N(R 7 ) 2 ;   R 6  is C 2 -C 9 heterocycloalkyl substituted with 2 groups selected from C 1 -C 6 alkyl and —C(═O)OR 13 ;   each R 7  is independently selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 haloalkyl, and C 1 -C 6 heteroalkyl;   each R 8  is independently selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl, and C 2 -C 9 heterocycloalkyl;   R 11  is hydrogen or C 1 -C 6 alkyl optionally substituted with 1, 2, or 3 R 5 ;   R 12  is hydrogen, halogen, or C 1 -C 6 alkyl;   each R 13  is independently selected from hydrogen and C 1 -C 6 alkyl; and   n is 0, 1, 2, or 3;   or a pharmaceutically acceptable salt or solvate thereof.   
     
     
         12 . The compound of  claim 11 , or a pharmaceutically acceptable salt or solvate thereof, wherein
                       is phenyl.   
     
     
         13 . The compound of  claim 11 , or a pharmaceutically acceptable salt or solvate thereof, wherein
                       is a C   2 -C 9 heteroaryl ring. 
     
     
         14 . The compound of  claim 13 , or a pharmaceutically acceptable salt or solvate thereof, wherein
                       is selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl.   
     
     
         15 . The compound of  claim 14 , or a pharmaceutically acceptable salt or solvate thereof, wherein
                       is selected from pyrazolyl, pyrrolyl, and imidazolyl.   
     
     
         16 . The compound of  claim 15 , or a pharmaceutically acceptable salt or solvate thereof, wherein
                       is selected from                                                                     .   
     
     
         17 . The compound of  claim 16 , or a pharmaceutically acceptable salt or solvate thereof, wherein
                       is                         .   
     
     
         18 . The compound of any one of  claims 1-17 , or a pharmaceutically acceptable salt or solvate thereof, wherein L 2  is C 1 -C 6 alkyl. 
     
     
         19 . The compound of any one of  claims 1-17 , or a pharmaceutically acceptable salt or solvate thereof, wherein L 2  is a bond. 
     
     
         20 . The compound of any one of  claims 1-19 , or a pharmaceutically acceptable salt or solvate thereof, wherein L 1  is C 1 -C 6 alkyl. 
     
     
         21 . The compound of any one of  claims 1-20 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 1  is C 3 -C 9 alkyl, C 3 -C 6 cycloalkyl, or C 2 -C 9 heteroaryl, wherein C 3 -C 9 alkyl, C 3 -C 6 cycloalkyl, or C 2 -C 9 heteroaryl are optionally substituted with 1, 2, or 3 R 5  and the C 2 -C 9 heteroaryl is selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, and thiadiazolyl. 
     
     
         22 . The compound of any one of  claims 1-21 , or a pharmaceutically acceptable salt or solvate thereof, wherein each R 5  is independently selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —OR 7 , and —N(R 7 ) 2 . 
     
     
         23 . The compound of any one of  claims 1-21 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 1  is unsubstituted C 3 -C 9 alkyl. 
     
     
         24 . The compound of any one of  claims 1-21 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 1  is unsubstituted C 3 -C 6 cycloalkyl. 
     
     
         25 . The compound of any one of  claims 1-21 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 1  is unsubstituted C 2 -C 9 heteroaryl selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, and thiadiazolyl. 
     
     
         26 . The compound of any one of  claims 1-25 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 4  is hydrogen. 
     
     
         27 . The compound of any one of  claims 1-25 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 4  is C 1 -C 6 alkyl. 
     
     
         28 . The compound of any one of  claims 1-27 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 12  is hydrogen. 
     
     
         29 . The compound of any one of  claims 1-27 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 12  is halogen. 
     
     
         30 . The compound of any one of  claims 1-27 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 12  is C 1 -C 6 alkyl. 
     
     
         31 . The compound of any one of  claims 1-30 , or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0. 
     
     
         32 . The compound of any one of  claims 1-30 , or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1. 
     
     
         33 . The compound of  claim 32 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 3  is selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —OR 7 , and —N(R 7 ) 2 . 
     
     
         34 . The compound of any one of  claims 1-33 , or a pharmaceutically acceptable salt or solvate thereof, wherein each R 7  is independently selected from hydrogen and C 1 -C 6 alkyl. 
     
     
         35 . The compound of  claim 34 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 3  is C 1 -C 6 alkyl. 
     
     
         36 . The compound of any one of  claims 1-35 , or a pharmaceutically acceptable salt or solvate thereof, wherein X is C(R 11 ). 
     
     
         37 . The compound of any one of  claims 1-36 , or a pharmaceutically acceptable salt or solvate thereof, wherein X is C(H). 
     
     
         38 . The compound of any one of  claims 1-35 , or a pharmaceutically acceptable salt or solvate thereof, wherein X is N. 
     
     
         39 . A compound of Formula (Ia):
                       wherein:   L 1  is a bond or C 1 -C 6 alkyl;   L 2  is C 1 -C 6 alkyl;   R 1  is C 1 -C 9 alkyl, C 3 -C 6 cycloalkyl, or C 2 -C 9 heteroaryl, wherein C 1 -C 9 alkyl, C 3 -C 6 cycloalkyl, or C 2 -C 9 heteroaryl are optionally substituted with 1, 2, or 3 R 5 ;   R 2  is —C(═O)OR 6 ;   each R 5  is independently selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, —OR 7 , —N(R 7 ) 2 , —CN, —C(═O)R 8 , —C(═O)OR 7 , —C(═O)N(R 7 ) 2 , —NR 7 C(═O)R 8 , —NR 7 S(═O) 2 R 8 , —S(═O) 2 R 8 , and —S(═O) 2 N(R 7 ) 2 ;   R 6  is C 2 -C 9 heterocycloalkyl substituted with 2 groups selected from C 1 -C 6 alkyl and —C(═O)OR 13 ;   each R 7  is independently selected from hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 haloalkyl, and C 1 -C 6 heteroalkyl;   each R 8  is independently selected from C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 heteroalkyl, C 3 -C 6 cycloalkyl, and C 2 -C 9 heterocycloalkyl; and   each R 13  is independently selected from hydrogen and C 1 -C 6 alkyl;   or a pharmaceutically acceptable salt or solvate thereof.   
     
     
         40 . The compound of  claim 39 , or a pharmaceutically acceptable salt or solvate thereof, wherein L 1  is C 1 -C 6 alkyl. 
     
     
         41 . The compound of  claim 39  or  claim 40 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 1  is C 3 -C 9 alkyl, C 3 -C 6 cycloalkyl, or C 2 -C 9 heteroaryl, wherein C 3 -C 9 alkyl, C 3 -C 6 cycloalkyl, or C 2 -C 9 heteroaryl are optionally substituted with 1, 2, or 3 R 5  and the C 2 -C 9 heteroaryl is selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, and thiadiazolyl. 
     
     
         42 . The compound of any one of  claims 39-41 , or a pharmaceutically acceptable salt or solvate thereof, wherein each R 5  is independently selected from halogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, —OR 7 , and —N(R 7 ) 2 . 
     
     
         43 . The compound of any one of  claims 39-42 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 1  is unsubstituted C 3 -C 9 alkyl. 
     
     
         44 . The compound of any one of  claims 39-42 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 1  is unsubstituted C 3 -C 6 cycloalkyl. 
     
     
         45 . The compound of any one of  claims 39-42 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 1  is unsubstituted C 2 -C 9 heteroaryl selected from oxazolyl, thiazolyl, pyrazolyl, furanyl, thienyl, pyrrolyl, imidazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, and thiadiazolyl. 
     
     
         46 . The compound of any one of  claims 11-45 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 6  is C 2 -C 9 heterocycloalkyl substituted with 2 groups selected from C 1 -C 6 alkyl and —C(═O)OR 13 , wherein one group is C 1 -C 6 alkyl and one group is —C(═O)OR 13 . 
     
     
         47 . The compound of any one of  claims 11-46 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 6  is pyrrolidinyl substituted with 2 groups selected from C 1 -C 6 alkyl and —C(═O)OR 13 , wherein one group is C 1 -C 6 alkyl and one group is —C(═O)OR 13 . 
     
     
         48 . The compound of any one of  claims 1-47 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 13  is C 1 -C 6 alkyl. 
     
     
         49 . The compound of any one of  claims 1-47 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 13  is hydrogen. 
     
     
         50 . A compound selected from:
                                                                                                               or a pharmaceutically acceptable salt or solvate thereof.   
     
     
         51 . A compound selected from:
                                             or a pharmaceutically acceptable salt or solvate thereof.   
     
     
         52 . A pharmaceutical composition comprising a compound of any one of  claims 1-51 , or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient. 
     
     
         53 . A method of treating an inflammatory or autoimmune disease in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of any one of  claims 1-51 , or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         54 . The method of  claim 53 , wherein the disease is selected from rheumatoid arthritis, multiple sclerosis, psoriasis, lupus, intestinal bowel disease, Crohn’s disease, ulcerative colitis, ankylosing spondylitis, vitiligo, and atopic dermatitis.