Compounds and methods for kinase modulation, and indications therefor
Compounds Formula I: and salts thereof, formulations thereof, conjugates thereof, derivatives thereof, forms thereof and uses thereof are described. In certain aspects and embodiments, the described compounds or salts thereof, formulations thereof, conjugates thereof, derivatives thereof, forms thereof are active on at least one of Fms protein kinase or Kit protein kinase. Also described are methods of use thereof to treat diseases and conditions, including diseases and conditions associated with activity of Fms protein kinases and/or Kit protein kinases, including rheumatoid arthiritis, osteoarthritis, osteoporosis, peri-prosthetic osteolysis, systemic sclerosis, demyelinating disorders, multiple sclerosis, Charcot Marie Tooth syndrome, amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, ulcerative colitis, Crohn's disease, immune thrombocytopenic purpura, myelopreparation for autologous transplantation, transplant rejection, nephritis, nephropathy, type I diabetes, acute pain, inflammatory pain, neuropathic pain, breast cancer, prostate cancer, pancreatic cancer, lung cancer, ovarian cancer, gliomas, glioblastomas, neurofibromatosis, osteolytic bone metastases, and giant cell tumors.
1. A compound having the chemical structure of Formula I,
or a salt, a tautomer or a stereoisomer thereof,
wherein:
L 1 is —CH 2 — or —C(O)—;
Ar is
wherein
indicates the point of attachment of Ar to L 1 of Formula I;
R 1 is —N(H)—[C(H 2 )] q —R 19 ;
q is 1, 2, or 3;
R 4 is hydrogen;
R 5 is selected from the group consisting of hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, —CN, —NO 2 , —O—R 28 , —S—R 28 , —C(O)—R 28 , —C(S)—R 28 , —C(O)—N(R 26 )—R 27 , —C(S)—N(R 26 )—R 27 , —C(O)—N(R 29 )—OR 26 , —C(S)—N(R 29 )—OR 26 , —C(O)—N(R 29 )—S(O) 2 —R 28 , —C(S)—N(R 29 )—S(O) 2 —R 28 , —C(O)—O—R 26 , —S(O)—R 28 , —S(O) 2 —R 28 , —S(O)—N(R 26 )—R 27 , —S(O) 2 —N(R 26 )—R 27 , —S(O) 2 —N(R 29 )—C(O)R 28 , —S(O) 2 —N(R 29 )—C(S)R 28 , —N(R 29 )—C(O)—R 28 , —N(R 29 )—C(S)—R 28 , —N(R 29 )—S(O)—R 28 , —N(R 29 )—S(O) 2 —R 28 , —N(R 29 )—C(O)—N(R 26 )—R 27 , —N(R 29 )—C(S)—N(R 26 )—R 27 , and —N(R 29 )—S(O) 2 —N(R 26 )—R 27 ;
R 6 is hydrogen;
R 29 is independently selected from the group consisting of hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, —C(O)—R 36 , —C(S)—R 36 , —S(O)—R 36 , —S(O) 2 —R 36 , —C(O)—N(H)—R 36 , —C(S)—N(H)—R 36 , and —S(O) 2 —N(H)—R 36 ;
R 12 and R 16 are independently selected from the group consisting of hydrogen, halogen, optionally substituted lower alkyl, —N(R 37 )—R 38 , —O—R 37 , and —S—R 39 ;
R 19 is selected from the group consisting of optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
R 28 is optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
R 26 and R 27 are independently selected from the group consisting of hydrogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
R 36 at each occurrence is independently selected from the group consisting of optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
R 37 and R 38 at each occurrence are independently hydrogen or optionally substituted lower alkyl; and
R 39 is optionally substituted lower alkyl.
2. The compound of claim 1 , wherein:
R 19 is selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents R 75 ;
R 75 at each occurrence is independently selected from the group consisting of —OH, —NH 2 , —NO 2 , —CN, —C(O)—OH, —S(O)—NH 2 , —S(O) 2 —NH 2 , —C(O)—NH 2 , —O—R 76 , —S—R 76 , —N(R 77 )—R 76 , —N(R 77 )—C(O)—R 76 , —N(R 77 )—S(O)—R 76 , —N(R 77 )—S(O) 2 —R 76 , —S(O)—R 76 , —S(O) 2 —R 76 , —C(O)—R 76 , —C(O)—O—R 76 , —C(O)—N(R 77 )—R 76 , —S(O)—N(R 77 )—R 76 , —S(O) 2 —N(R 77 )—R 76 , halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R 75 , or as substituents of lower alkyl, are optionally substituted with one or more substituents selected from the group consisting of —OH, —NH 2 , —NO 2 , —CN, —C(O)—OH, —S(O) 2 —NH 2 , —C(O)—NH 2 , —O—R 78 , —S—R 78 , —N(R 77 )—R 78 , —N(R 77 )—C(O)—R 78 , —N(R 77 )—S(O) 2 —R 78 , —S(O)—R 78 , —S(O) 2 —R 78 , —C(O)—R 78 , —C(O)—O—R 78 , —C(O)—N(R 77 )—R 78 , —S(O) 2 —N(R 77 )—R 78 , halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino;
R 76 at each occurrence is independently selected from the group consisting of lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R 76 or as substituents of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of —OH, —NH 2 , —CN, —NO 2 , —C(O)—OH, —S(O) 2 —NH 2 , —C(O)—NH 2 , —O—R 80 , —S—R 80 , —N(R 79 )—R 80 , —N(R 79 )—C(O)—R 80 , —N(R 79 )—S(O) 2 —R 80 , —C(O)—R 80 , —S(O)—R 80 , —S(O) 2 —R 80 , —C(O)—O—R 80 , —C(O)—N(R 79 )—R 80 , —S(O) 2 —N(R 79 )—R 80 , halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino;
R 77 and R 79 at each occurrence are independently hydrogen, lower alkyl, or lower alkyl substituted with one or more substituents selected from the group consisting of fluoro, —OH, —NH 2 , lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, fluoro substituted mono-alkylamino, di-alkylamino, fluoro substituted di-alkylamino, and cycloalkylamino; and
R 78 and R 80 at each occurrence are independently selected from the group consisting of lower alkyl, heterocycloalkyl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino, and wherein heterocycloalkyl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, —CN, lower alkyl, fluoro substituted lower alkyl, lower alkoxy and fluoro substituted lower alkoxy.
3. The compound of claim 1 , wherein:
R 5 is selected from the group consisting of hydrogen, —CN, —O—R 100 , —S—R 100 , and lower alkyl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino; and
R 100 is lower alkyl optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino.
4. A composition comprising a pharmaceutically acceptable carrier; and a compound according to claim 1 .