Bycyclic JAK inhibitors and uses thereof
Provided herein are compounds of Formulas (I), (II), (III), and (IV) and subformulas thereof, wherein the variables are defined herein. Also provided herein are pharmaceutical compositions comprising a compound of Formula (I), (II), (III), or (IV) and methods of using the compounds, e.g., in the treatment of immune disorders, inflammatory disorders, and cancer.
1. A compound of formula I, formula II, formula III, or formula IV:
or a pharmaceutically acceptable salt thereof, wherein
For formula I: X is NR 1 , C(R 8 )R 1 , O, S, S(O), or S(O) 2 ;
For formula II: X is N or CR 1 ; and
For formula I, formula II, formula III, and formula (IV):
W is N or CR 5 ;
Y is N or CR 2 ;
Z is N or CR 3 ;
wherein W and Z are not both N;
R 1 is selected from the group consisting of cyano, hydroxyl, NR a R b , C 1-6 alkoxy, and -A-L 1 -R 9 ;
R 2 , R 3 , R 4 , and R 6 are each independently selected from the group consisting of hydrogen, deuterium, halogen, cyano, hydroxyl, —NR a R b , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, and C 1-6 alkoxy;
R 5 is selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, -aryl-C 1-6 alkyl, -heteroaryl-C 1-6 alkyl, -heterocyclyl-C 1-6 alkyl, halogen, cyano, hydroxyl, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, carboxy, aminocarbonyl, —C 1-6 alkyl-aminocarbonylamino, C 1-6 alkylaminocarbonyl, —S(O)—R 8 , —S(O) 2 —R 8 , —NR 8 —S(O) 2 —R 8 , —S(O) 2 —NR a R b , —NR 8 —S(O) 2 —NR a R b , —C 1-6 alkyl-aryl, —C 1-6 alkyl-heteroaryl, —C 1-6 alkyl-heterocycle, and —C 1-6 alkyl-cycloalkyl, wherein said alkyl, aryl, and heteroaryl is optionally substituted with one or substituents independently selected from the group consisting of halo, hydroxyl, methoxy, amino, cyano, alkylamino, dialkylamino, CF 3 , aminocarbonyl, —C 1-6 alkyl-aminocarbonylamino, and C 3-6 cycloalkyl;
R 7 is B-L 2 -R 10 , or R 7 is aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one to four R 17 ;
each R 8 is independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, hydroxy, C 1-6 alkoxy, and —O—C 1-6 haloalkyl;
R 9 is selected from the group consisting of hydrogen, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein any non-hydrogen R 9 is optionally substituted with one to four R 17 ;
R 10 is selected from the group consisting of hydrogen, cyano, hydroxyl, C 1-6 haloalkyl, C 1-6 alkoxy, —O—C 1-6 haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, —C(O)-heterocycloalkyl, and —S(O) 2 -heterocycloalkyl, wherein any R 10 other than hydrogen, cyano, and hydroxyl is optionally substituted with one to four R 17 ;
R 11 , R 12 , R 13 , R 14 , R 15 , and R 16 are each independently selected from the group consisting of hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, aryl, heteroaryl, cycloalkyl, heterocyclyl, -aryl-C 1-6 alkyl, -heteroaryl-C 1-6 alkyl, halogen, cyano, hydroxyl, C 1-6 alkoxy, amino, carboxy, aminocarbonyl, —C 1-6 alkyl-aryl, —C 1-6 alkyl-heteroaryl, —C 1-6 alkyl-heterocycle, and C 1-6 alkyl-cycloalkyl, wherein said alkyl is optionally substituted with one or more substituents independently selected from the group consisting of halo, hydroxyl, methoxy, alkylamino, dialkylamino, CF 3 , and C 3-6 cycloalkyl; or
R 11 and R 12 , R 13 and R 14 , or R 15 and R 16 can be taken together including the atom to which they are attached to form a 3-6-membered spiro-fused ring optionally substituted by 1-3 substituents independently selected from the group consisting of halogen, C 1-6 alkyl, and C 1-6 haloalkyl;
R 17 is, independently for each occurrence, selected from the group consisting of halogen, cyano, hydroxyl, —NR a R b , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, CF 3 , —SH, —S—C 1-6 alkyl, —COOH, —CO 2 —C 1-6 alkyl, —C 1-6 alkyl-CN, —C(O) NR a R b , —C(O)—C 1-6 alkyl-NR a R b , —C(O)—NR a —S(O) 2 —C 1-6 alkyl, —S(O) 2 —C 1-6 alkyl, —S(O) 2 —NR a R b , —S(O) 2 —C 1-6 alkyl-NR a R b ;
A is selected from the group consisting of —C(O)—, —S(O)—, and —S(O) 2 —, or A is absent;
B is selected from the group consisting of —C(O)—, —S(O) 2 —NR 8 —, —CH 2 —NR 8 —, and —C(O)NR 8 —;
L 1 is selected from the group consisting of a bond, C 1-6 alkylene, C 1-6 heteroalkylene, C 2-6 alkenylene, and C 2-6 alkynylene, wherein L 1 is optionally substituted with one to four R 17 groups;
L 2 is selected from the group consisting of a bond, C 1-6 alkylene, C 2-6 alkenylene, and C 2-6 alkynylene, wherein any CH 2 group of C 1-6 alkylene can be replaced with a moeity selected from the group consisting of —O—, —NR a —, and —S(O) 2 —, and one CH 2 group of C 1-6 alkylene can be replaced with a moiety selected from the group consisting of cycloalkylene, heterocycloalkylene, arylene, and heteroarylene, and wherein L 2 is optionally substituted with one to four R 17 groups; or
when B is —S(O) 2 —NR 8 —, —CH 2 —NR 8 —, or —C(O)NR 8 —, R 8 and L 2 can be taken together including the nitrogen atom to which they are attached to form a 3-7-membered heterocycloalkyl optionally substituted with one to four R 17 groups; and
each of R a and R b are, independently for each occurrence, selected from the group consisting of hydrogen, C 1-6 alkyl, and C 1-6 haloalkyl, or R a and R b are taken together, including the nitrogen to which they are attached, to form a heterocycloalkyl ring.
2. The compound of claim 1 , wherein the compound is of formula I or formula II.
3. The compound of claim 1 , wherein W is CR 5 .
4. The compound of claim 1 , wherein X is NR 1 or O.
5. The compound of claim 1 , wherein Y is N.
6. The compound of claim 1 , wherein Z is CR 3 .
7. The compound of claim 1 , wherein R 11 , R 12 , R 13 , R 14 , R 15 , and R 16 are each hydrogen.
8. The compound of claim 1 , wherein R 3 , R 4 , R 5 , and R 6 are each hydrogen.
9. The compound of claim 1 , wherein R 1 is -L 1 -R 9 .
10. The compound of claim 9 , wherein R 9 is aryl or heteroaryl.
11. The compound of claim 1 , wherein L 1 is C 1-6 alkylene optionally substituted with one to four substituents.
12. The compound of claim 1 , wherein R 1 is C 1-6 alkyl or hydrogen.
13. The compound of claim 1 , wherein R 7 is B-L 2 -R 10 .
14. The compound of claim 1 , wherein B is —C(O)NH—.
15. The compound of claim 1 , wherein L 2 is C 1-6 alkylene substituted with one R 17 at a terminal carbon position.
16. The compound of claim 1 , wherein R 7 is —C(O)NR 8 —C 3-7 cycloalkyl-R 17 .
17. The compound of claim 1 , wherein R 17 is selected from the group consisting of C 1-6 haloalkyl, —CO 2 —C 1-6 alkyl, —C 1-6 alkyl-CN, —C(O)NR a R b , and —C(O)—NR a —S(O) 2 —C 1-6 alkyl.
18. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
19. A method of treating a disease which can be treated with a JAK3 inhibitor, the method comprising administering a pharmaceutically effective amount of a compound or composition of claim 1 to a patient in need thereof.
20. A method of treating a disease, the method comprising administering a pharmaceutically effective amount of a compound of claim 1 to a patient in need thereof, wherein the disease is selected from the group consisting of rheumatoid arthritis, myositis, vasculitis, pemphigus, bullous pemphigoid, inflammatory bowel disease including Crohn's disease and ulcerative colitis, celiac diseases, proctitis, eosinophilic gastroenteritis, or mastocytosis, Alzheimer's disease, lupus, nephritis, systemic lupus erythematosus, psoriasis, eczema dermatitis, pruritus or other pruritic conditions, vitiligo, alopecia, autoimmune thyroid disorders, multiple sclerosis, major depression disorder, allergy, asthma, Sjogren's disease, Reiter's syndrome, polymyositis-dermatomyositis, systemic sclerosis, polyarteritis nodosa, dry eye syndrome, Hashimoto's thyroiditis, autoimmune hemolytic anemia, autoimmune atrophic gastritis of pernicious anemia, autoimmune encephalomyelitis, autoimmune orchitis, Goodpasture's disease, autoimmune thrombocytopenia, sympathetic ophthalmia, myasthenia gravis, Graves' disease, primary biliary cirrhosis, chronic aggressive hepatitis, membranous glomerulopathy, organ transplant rejection, graft-versus-host disease, organ and cell transplant rejection such as bone marrow, cartilage, cornea, heart, intervertebral disc, islet, kidney, limb, liver, lung, muscle, myoblast, nerve, pancreas, skin, small intestine, or trachea, or xeno transplantation, including Cogan's syndrome, ankylosing spondylitis, Wegener's granulomatosis, autoimmune alopecia, Type I or juvenile onset diabetes, and complications from diabetes, or thyroiditis, chronic pulmonary obstructive disorder, acute respiratory disease, cachexia, cancer, including alimentary/gastrointestinal tract cancer, colon cancer, liver cancer, skin cancer including mast cell tumor and squamous cell carcinoma, breast and mammary cancer, ovarian cancer, prostate cancer, leukemia, adult T cell leukemia activated B-cell like, diffuse large B cell lymphoma, kidney cancer, lung cancer, muscle cancer, bone cancer, bladder cancer, brain cancer, melanoma including oral and metastatic melanoma, Kaposi's sarcoma septic shock, cardiopulmonary dysfunction, acute myeloid leukemia, T cell acute lymphoblastic leukemia, multiple myeloma, myeloproliferative disorders, proliferative diabetic retinopathy, or angiogenic-associated disorders including solid tumors, pancreatic cancer, brain tumors, gliomas including astrocytoma, oligodendroglioma, and glioblastoma, acute CNS trauma including traumatic brain injury, encephalitis, stroke, and spinal cord injury, epilepsy, seizures, chronic neuroinflammation associated with neurodegeneration including Alzheimer's disease, Parkinson's disease, Amyotropic Lateral Sclerosis, Huntington's disease, cerebral ischemia, fronto-temporal lobe dementia, and with neuropsychiatric disorders including schizophrenia, bipolar disorder, treatment resistant depression, Post Traumatic Stress Disorder, anxiety, and auto-antibodies mediated encephalopathies, Eye diseases, disorders or conditions including autoimmune diseases of the eye, keratoconjunctivitis, vernal conjunctivitis, uveitis including uveitis associated with Behcet's disease and lens-induced uveitis, keratitis, herpetic keratitis, conical keratitis, corneal epithelial dystrophy, keratoleukoma, ocular premphigus, Mooren's ulcer, scleritis, Grave's ophthalmopathy, Vogt-Koyanagi-Harada syndrome, keratoconjunctivitis sicca (dry eye), phlyctenule, iridocyclitis, sarcoidosis, endocrine ophthalmopathy, sympathetic ophthalmitis, allergic conjunctivitis, and ocular neovascularization.