US 8,912,204 B2 · Compounds and methods for kinase modulation, and indications therefor

Abstract

Compounds of 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 arthritis, 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.

A compound having the chemical structure of Formula I,

or a salt, a tautomer or a stereoisomer thereof,
wherein:
L1 is selected from the group consisting of —C(R7R8)—, —C(O)—, —C(S)—, —N(R9)—, —O—, —S—, —S(O)—, and —S(O)2—;
Ar is selected from the group consisting of:
wherein
indicates the point of attachment of Ar to L1 of Formula I;
R2 is selected from the group consisting of —[C(R10R11)]r—R19, —[C(R10R11)]p—N(R18)—[C(R10R11)]q—R19, —[C(R10R11)]p—O—[C(R10R11)]q—R19, —[O—[C(R10R11)]2]a—R21, —[C(R10R11)]p—S—[C(R10R11)]q—R19, —[C(R10R11)]p—C(O)—[C(R10R11)]q—R19, —[C(R10R11)]p—C(S)—[C(R10R11)]q—R19, —[C(R10R11)]p—S(O)—[C(R10R11)]q—R19, —[C(R10R11)]p—S(O)2—[C(R10R11)]q—R19, —[C(R10R11)]p—C(O)—N(R18)—[C(R10R11)]q—R19, —[C(R10R11)]p—C(S)—N(R18)—[C(R10R11)]q—R19, —[C(R10R11)]p—S(O)—N(R18)—[C(R10R11)]q—R19, —[C(R10R11)]p—S(O)2—N(R18)—[C(R10R11)]qR19, and —N(R18)—R20;
a is 1 or 2;
p, q and r are independently 0, 1, 2, or 3;
s is 1, 2, or 3;
R4 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, —NO2, —O—R22, —S—R24, —N(R22)—R23, —C(O)—R24, —C(S)—R24, —C(O)—N(R22)—R23, —C(S)—N(R22)—R23, —C(O)—N(R25)—OR22, —C(S)—N(R25)—OR22, —C(O)—N(R25)—S(O)2—R24, —C(S)—N(R25)—S(O)2—R24, —C(O)—O—R22, —S(O)—R24, —S(O)2—R24, —S(O)—N(R22)—R23, —S(O)2—N(R22)—R23, —S(O)2—N(R25)—C(O)R24, —S(O)2—N(R25)—C(S)R24, —N(R25)—C(O)—R24, —N(R25)—C(S)—R24, —N(R25)—S(O)—R24, —N(R25)—S(O)2—R24, —N(R25)—C(O)—N(R22)—R23, —N(R25)—C(S)—N(R22)—R23, and —N(R25)—S(O)2—N(R22)—R23;
R5 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, —NO2, —O—R28, —S—R28, —C(O)—R28, —C(S)—R28, —C(O)—N(R26)—R27, —C(S)—N(R26)—R27, —C(O)—N(R29)—OR26, —C(S)—N(R29)—OR26, —C(O)—N(R29)—S(O)2—R28, —C(S)—N(R29)—S(O)2—R28, —C(O)—O—R26, —S(O)—R28, —S(O)2—R28, —S(O)—N(R26)—R27, —S(O)2—N(R26)—R27, —S(O)2—N(R29)—C(O)R28, —S(O)2—N(R29)—C(S)R28, —N(R29)—C(O)—R28, —N(R29)—C(S)—R28, —N(R29)—S(O)—R28, —N(R29)—S(O)2—R28, —N(R29)—C(O)—N(R26)—R27, —N(R29)—C(S)—N(R26)—R27, and —N(R29)—S(O)2—N(R26)—R27;
R6 is selected from the group consisting of hydrogen, halogen, 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, —NO2, —O—R30, —S—R32, —N(R30)—R31, —C(O)—R32, —C(S)—R32, —C(O)—N(R30)—R31, —C(S)—N(R30)—R31, —C(O)—N(R33)—OR30, —C(S)—N(R33)—OR30, —C(O)—N(R33)—S(O)2—R32, —C(S)—N(R33)—S(O)2—R32, —C(O)—O—R30, —S(O)—R32, —S(O)2—R32, —S(O)—N(R30)—R31, —S(O)2—N(R30)—R31, —S(O)2—N(R33)—C(O)R32, —S(O)2—N(R33)—C(S)R32, —N(R33)—C(O)—R32, —N(R33)—C(S)—R32, —N(R33)—S(O)—R32, —N(R33)—S(O)2—R32, —N(R33)—C(O)—N(R30)—R31, —N(R33)—C(S)—N(R30)—R31, and —N(R33)—S(O)2—N(R30)—R31;
R7, R8, R10, and R11, at each occurrence, are independently selected from the group consisting of hydrogen, fluoro, —OH, —NH2, lower alkyl, lower alkoxy, lower alklylthio, mono-alkylamino, di-alkylamino, and —N(R34)—R35, wherein the alkyl chain(s) of lower alkyl, lower alkoxy, lower alkylthio, mono-alkylamino, or di-alkylamino are optionally substituted with one or more substituents selected from the group consisting of fluoro, —OH, —NH2, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino;
or
R7 and R8, or any two of R10 and R11 on the same or different carbons, combine to form a 3-7 membered monocyclic cycloalkyl or 5-7 membered monocyclic heterocycloalkyl and any others of R10 and R11 are independently selected from the group consisting of hydrogen, fluoro, —OH, —NH2, lower alkyl, lower alkoxy, lower alklylthio, mono-alkylamino, di-alkylamino, and —N(R34)—R35, wherein the alkyl chain(s) of lower alkyl, lower alkoxy, lower alkylthio, mono-alkylamino, or di-alkylamino are optionally substituted with one or more substituents selected from the group consisting of fluoro, —OH, —NH2, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino, and wherein the 3-7 membered monocyclic cycloalkyl or 5-7 membered monocyclic heterocycloalkyl are optionally substituted with one or more substituents selected from the group consisting of halogen, —OH, —NH2, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino;
R9, R25, R29, and R33 are 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)—R36, —C(S)—R36, —S(O)—R36, —S(O)2—R36, —C(O)—N(H)—R36, —C(S)—N(H)—R36, and —S(O)2—N(H)—R36;
R15 and R16 are independently selected from the group consisting of hydrogen, halogen, optionally substituted lower alkyl, —N(R37)—R38, —O—R37, and —S—R39;
R18 at each occurrence is independently hydrogen, lower alkyl, or lower alkyl substituted with one or more substituents selected from the group consisting of fluoro, —OH, —NH25 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 —N(R34)—R35;
R19 is selected from the group consisting of optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
R20 is selected from the group consisting of optionally substituted lower alkyl, optionally substituted lower alkenyl, and optionally substituted lower alkynyl;
R21 is selected from the group consisting of hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and —O—R40;
R24, R28 and R32 are independently selected from the group consisting of 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;
R22, R23, R26, R27, R30 and R31 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;
R34 and R35 at each occurrence combine with the nitrogen to which they are attached to form a 5-7 membered heterocycloalkyl optionally substituted with one or more substituents selected from the group consisting of fluoro, —OH, —NH2, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, and fluoro substituted lower alkylthio;
R36 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;
R37 and R38 at each occurrence are independently hydrogen or optionally substituted lower alkyl;
and
R39 and R40 at each occurrence are independently optionally substituted lower alkyl.

26 more elements

Compounds and methods for kinase modulation, and indications therefor

Life of this patent

Compounds and methods for kinase modulation, and indications therefor

Life of this patent

Abstract

Claims15