TYPE II RAF KINASE INHIBITORS
The present invention relates to novel compounds which are able to modulate b-raf kinases, and the use of such compounds in the treatment of various diseases, disorders or conditions.
1 . A compound of formula I:
or a pharmaceutically acceptable salt, ester or prodrug thereof,
wherein,
ring D is aryl or heteroaryl;
R is H, halo, or -A-B;
A is NR A C(O), O, S(O) m , C(O), C(O)O, C(O)NR A , NR A C(O)NR A , or absent;
B is H, alkyl, alkoxy, cycloalkyl, or aryl, each of which is optionally substituted;
R 1 is hydroxyl, alkyl, alkoxy, C(O)OR A , C(O)NR A R B , or NR A R B , each of which may be optionally substituted; or H or halo;
R′ is absent, or R and R′ together with the atoms to which each is attached, form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring, each of which is optionally substituted;
Z is NR A , O, NR A C(O), C(O)NR A , CR 3 R 4 or S(O) m ;
R 3 is H or alkyl;
R 4 is H, alkyl, or absent;
or R 3 and R 4 together with the carbon to which each is attached form C(O);
ring E is monocyclic or bicyclic heteroaryl;
R z is NR A R 2 ;
R 2 is H, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, C(O)R A , C(O)OR A , C(O)NR A R B , C(NR B )R A , or C(NR B )OR A ;
R 5 is H, halo, alkyl, alkoxy, or thioalkoxy;
R 6 is H, NR A R B , or OR A ;
each R A is independently H, alkyl, alkenyl, cycloalkyl, heterocyclic, aryl or heteroaryl, each of which may be optionally substituted;
each R B is independently H, alkyl, alkenyl, cycloalkyl, heterocyclic, aryl or heteroaryl, each of which may be optionally substituted;
or, for each occurrence of NR A R B , R A and R B are taken together with the nitrogen atom to which they are attached to form a 3-7 membered heterocycloalkyl ring;
each m is independently 0, 1, or 2; and
each n is independently 0 or 1.
2 . The compound of claim 1 , wherein ring D is selected from phenyl, naphthyl, tetrahydronaphthyl, indanyl, idenyl, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, pyrrolo pyridinyl, thiazolo pyridinyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, indazolyl, indolonyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzooxazolyl, and quinoxalinyl.
3 . The compound of claim 2 , wherein ring D is selected from phenyl, naphthyl, pyrazinyl, pyrimidinyl, pyrrolo pyridinyl, thiazolo pyridinyl, indazolyl, indolonyl, and quinolinyl.
4 . The compound of claim 1 , wherein ring E is selected from phenyl, naphthyl, tetrahydronaphthyl, indanyl, idenyl, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiophenyl, furanyl, indazolyl, indolonyl, quinolinyl, isoquinolinyl, quinazolinyl, 1H-pyrrolo[2,3-b]pyridine, 9H-purine, 7H-pyrrolo[2,3-d]pyrimidine, 1H-pyrazolo[3,4-d]pyrimidine, and quinoxalinyl.
5 . The compound of claim 4 , wherein ring E is selected from phenyl, naphthyl, pyridinyl, pyrazinyl, and pyrimidinyl.
6 . The compound of claim 1 , of formula II:
or a pharmaceutically acceptable salt, ester or prodrug thereof,
wherein,
Z is NH or O;
R is H or -A-B;
A is NR A C(O), O, S(O) m , C(O), C(O)O, C(O)NR A , or absent;
B is alkyl, alkoxy, or aryl, each of which is optionally substituted;
R 1 is H, alkyl, alkoxy, or halo; each of which may be optionally substituted;
R 2 is H, C(O)R A , C(O)OR A , C(O)NR A R B , C(NR B )R A , or C(NR B )OR A ;
each R A is independently H, alkyl, alkenyl, cycloalkyl, heterocyclic, aryl or heteroaryl, each of which may be optionally substituted;
each R B is independently H, alkyl, alkenyl, cycloalkyl, heterocyclic, aryl or heteroaryl, each of which may be optionally substituted; and
m is 0, 1, or 2.
7 . The compound of claim 6 , wherein R 2 is H, C(O)R A , C(O)OR A , or C(O)NR A R B .
8 . The compound of claim 7 , wherein each R A is independently H, alkyl, or cycloalkyl, each of which may be optionally substituted; and R B is H.
9 . The compound of claim 6 , wherein R 2 is H,
10 . The compound of claim 6 , wherein R 1 is H, alkyl, alkoxy, or halo.
11 . The compound of claim 10 , wherein R 1 is H, methyl, methoxy, or chloro.
12 . The compound of claim 6 , wherein R is H or -A-B; A is NR A C(O), C(O), C(O)O, C(O)NR A , or absent; and B is alkyl, alkoxy, or aryl, each of which is optionally substituted.
13 . The compound of claim 12 , wherein A is NHC(O), C(O)O, C(O)NH, or absent.
14 . The compound of claim 12 , wherein B is phenyl, methyl, or methoxy; each of which is optionally substituted.
15 . The compound of claim 14 , wherein B is optionally substituted with alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or hydroxyl, each of which is optionally substituted.
16 . The compound of claim 12 , wherein R is selected from H, methyl, methoxy,
17 . The compound of claim 1 , of formula III:
or a pharmaceutically acceptable salt, ester or prodrug thereof,
wherein,
ring D is aryl or heteroaryl;
R is H, halo, or -A-B;
A is NR A C(O), O, S(O) m , C(O), C(O)O, C(O)NR A , or absent;
B is H, alkyl, cycloalkyl, or aryl, each of which is optionally substituted;
R 1 is H, hydroxyl, alkyl, alkoxy, C(O)OR A , C(O)NR A R B , NR A R B , or halo; each of which may be optionally substituted;
or R and R′ together with the atoms to which each is attached, form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl ring, each of which is optionally substituted;
R 2 is H, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, C(O)R A , C(O)OR A , C(O)NR A R B , C(NR B )R A , or C(NR B )OR A ;
each R A is independently H, alkyl, alkenyl, cycloalkyl, heterocyclic, aryl or heteroaryl, each of which may be optionally substituted;
each R B is independently H, alkyl, alkenyl, cycloalkyl, heterocyclic, aryl or heteroaryl, each of which may be optionally substituted; and
m is 0, 1, or 2.
18 . The compound of claim 17 , wherein R 2 is H, optionally substituted aryl, or optionally substituted heteroaryl.
19 . The compound of claim 18 , wherein R 2 is H, phenyl, pyridyl, pyrimidinyl, each of which is optionally substituted.
20 . The compound of claim 19 , wherein R 2 is H,
21 . The compound of claim 17 , wherein ring D is phenyl, pyrrolo pyridine, benzothiazole, indazole, pyrazine, or indolinone.
22 . The compound of claim 17 , wherein R 1 is H, hydroxyl, alkyl, NR A R B , or halo; each of which may be optionally substituted.
23 . The compound of claim 17 , wherein R is H, halo, or -A-B; A is NR A C(O), O, S(O) m , C(O), C(O)O, C(O)NR A , or absent; and B is alkyl, cycloalkyl, or aryl, each of which is optionally substituted.
24 . The compound of claim 23 , wherein A is NHC(O), C(O)O, C(O)NH, or absent.
25 . The compound of claim 23 , wherein B is H, alkyl, cycloalkyl, or aryl, each of which is optionally substituted.
26 . The compound of claim 25 , wherein B is optionally substituted with alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, halo, or hydroxyl, each of which is optionally substituted.
27 . The compound of claim 23 , wherein R is H, methyl, Cl, F, COOH, C(O)NHCH 3 ,
28 . The compound of claim 1 , of formula IV:
or a pharmaceutically acceptable salt, ester or prodrug thereof,
wherein,
R is H or -A-B;
A is NR A C(O), O, S(O) m , C(O), C(O)O, C(O)NR A , or absent;
B is alkyl or aryl, each of which is optionally substituted;
R 1 is H, alkyl, alkoxy, or halo; each of which may be optionally substituted;
Z is NR A , O, or S(O) m ;
R 3 is H or alkyl;
R 4 is H or alkyl;
or R 3 and R 4 together with the carbon to which each is attached form C(O);
R 5 is H, halo, alkoxy, or thioalkoxy,
each R A is independently H, alkyl, alkenyl, cycloalkyl, heterocyclic, aryl or heteroaryl, each of which may be optionally substituted; and
each m is independently 0, 1, or 2.
29 . The compound of claim 28 , wherein Z is NR A or O; R 3 is H; R 4 is H; or R 3 and R 4 together with the carbon to which each is attached form C(O).
30 . The compound of claim 29 , wherein Z is NH or O.
31 . The compound of claim 28 , wherein R 5 is H, halo, alkoxy, or thioalkoxy.
32 . The compound of claim 31 , wherein R 5 is H, Cl, methoxy, or S(i-Pr).
33 . The compound of claim 28 , wherein R 1 is H, alkyl, or alkoxy; each of which may be optionally substituted.
34 . The compound of claim 28 , wherein R is -A-B; A is NR A C(O) or C(O)NR A ; and B is alkyl or aryl, each of which is optionally substituted.
35 . The compound of claim 28 , wherein A is NHC(O) or C(O)NH.
36 . The compound of claim 28 , wherein B is alkyl or aryl, each of which is optionally substituted.
37 . The compound of claim 36 , wherein B is optionally substituted with alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, halo, or hydroxyl, each of which is optionally substituted.
38 . The compound of claim 28 , wherein R is
39 . The compound of claim 1 , of formula V:
or a pharmaceutically acceptable salt, ester or prodrug thereof,
wherein,
R is H or -A-B;
A is NR A C(O), O, S(O) m , C(O), C(O)O, C(O)NR A , or absent;
B is alkyl or aryl, each of which is optionally substituted;
R 1 is H, alkyl, alkoxy, or halo; each of which may be optionally substituted;
R 5 is H, halo, alkoxy, or thioalkoxy,
each R A is independently H, alkyl, alkenyl, cycloalkyl, heterocyclic, aryl or heteroaryl, each of which may be optionally substituted; and
m is 0, 1, or 2.
40 . The compound of claim 39 , wherein R 5 is halo or alkoxy.
41 . The compound of claim 40 , wherein R 5 is Cl or methoxy.
42 . The compound of claim 39 , wherein R 1 is alkyl, which may be optionally substituted.
43 . The compound of claim 39 , wherein R is -A-B; A is NR A C(O) or C(O)NR A ; and B is alkyl or aryl, each of which is optionally substituted.
44 . The compound of claim 43 , wherein A is NHC(O) or C(O)NH.
45 . The compound of claim 43 , wherein B is alkyl or aryl, each of which is optionally substituted.
46 . The compound of claim 45 , wherein B is optionally substituted with alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, halo, or hydroxyl, each of which is optionally substituted.
47 . The compound of claim 39 , wherein R is
48 . The compound of claim 1 , of formula VI:
or a pharmaceutically acceptable salt, ester or prodrug thereof,
wherein,
ring D is aryl or heteroaryl;
R is H, halo, or -A-B;
A is NR A C(O), O, S(O) m , C(O), C(O)O, C(O)NR A , or absent;
B is alkyl, cycloalkyl, or aryl, each of which is optionally substituted;
R 1 is H, hydroxyl, alkyl, alkoxy, C(O)OR A , C(O)NR A R B , NR A R B , or halo; each of which may be optionally substituted;
R 6 is H, NR A R B , or OR A ;
R 5 is H, halo, alkoxy, or thioalkoxy,
each R A is independently H, alkyl, alkenyl, cycloalkyl, heterocyclic, aryl or heteroaryl, each of which may be optionally substituted;
each R B is independently H, alkyl, alkenyl, cycloalkyl, heterocyclic, aryl or heteroaryl, each of which may be optionally substituted; and
m is 0, 1, or 2.
49 . The compound of claim 48 , wherein R 6 is H or NR A R B .
50 . The compound of claim 49 , wherein R A is an optionally substituted aryl and R B is H.
51 . The compound of claim 48 , wherein R 5 is H or Cl.
52 . The compound of claim 48 , wherein ring D is phenyl, naphthyl, indolonyl, or quinolinyl.
53 . The compound of claim 52 , wherein R 1 is H.
54 . The compound of claim 53 , wherein R is -A-B; A is NR A C(O) or C(O)NR A ; and B is alkyl or aryl, each of which is optionally substituted.
55 . The compound of claim 54 , wherein A is NHC(O) or C(O)NH.
56 . The compound of claim 54 , wherein B is alkyl or phenyl, each of which is optionally substituted.
57 . The compound of claim 56 , wherein B is optionally substituted with alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, halo, or hydroxyl, each of which is optionally substituted.
58 . The compound of claim 54 , wherein R is
59 . The compound of claim 1 , selected from a compound in any one of Tables 1-13.
60 . A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable ester, salt, or prodrug thereof, together with a pharmaceutically acceptable carrier.
61 . A method of inhibiting a b-raf kinase in a subject, comprising administering administering to the subject a compound of formula I.
62 . The method of claim 61 , wherein the b-raf kinase is a mutant b-raf kinase.
63 . The method of claim 62 , wherein the mutation of the mutant b-raf kinase is V600E, T529I, or V600E/T529I.
64 . A method of treating a disease related to kinase modulation in a subject comprising administering to the subject a compound or pharmaceutically acceptable salt of formula I; wherein the kinase is selected from b-raf, Abl, Csf1R, EGFR, EphA8, FGFR1,2,3,4, FLT3, KIT, Lok, MAP4K1, MUSK, p38alpha, beta, PDGFRalpha, beta, Ret, Taok3, TNNI3K, Fes, Lyn SRPK1, STK36, TIE2, DDR1, EPHA2, ROIK1, RIOK3, NKF1LK, Src, Tak1, BLK, EphA4, EphB2, Fgr, FLT4, MAP4K2, ANKK1, Frk, Lck, Map4K5, Erbb4, Map4k4, MKNK2, Tec, Flt1, Hck, Tnk2, Txk, BTK, SLK, RiPK1, RIPK2, BIKE, CIT, CDKL2, DRAK, EphB1, JNK2, MLK1, MYLK2, TrkA,B,C, VEGFR2, IKKalpha, PTK2B, MAP4K3, Tie2, Fyn, Zak, DDR2, AurC, Lyn, Hpk1, and Gck.
65 . The method of claim 64 , wherein the kinase is selected from b-raf b-raf, Abl, Csf1R, EGFR, EphA8, FGFR1,2,3,4, FLT3, KIT, Lok, MAP4K1, MUSK, p38alpha, beta, PDGFRalpha, beta, Ret, Taok3, TNNI3K, Fes, Lyn SRPK1, STK36, TIE2, DDR1, EPHA2, ROIK1, RIOK3, NKF1LK, Src, Tak1, BLK, EphA4, EphB2, Fgr, FLT4, MAP4K2, ANKK1, Frk, Lck, Map4K5, Erbb4, Map4k4, MKNK2, Tec, Flt1, Hck, Tnk2, Txk, BTK, SLK, RiPK1, RIPK2, BIKE, CIT, CDKL2, DRAK, EphB1, JNK2, MLK1, MYLK2, TrkA,B,C, VEGFR2, IKKalpha, PTK2B, MAP4K3, Tie2, Fyn, Zak, DDR2, AurC, Lyn, Hpk1, and Gck.
66 . A method of treating a disease related to b-raf or b-raf mutation modulation in a subject comprising administering to the subject a compound or pharmaceutically acceptable salt of formula I.
67 . A method of treating a disease related to b-raf or b-raf mutation modulation in a subject comprising: administering to the subject identified as in need thereof a compound or pharmaceutically acceptable salt of formula I.
68 . The method of claim 66 or 67 , wherein the modulation is inhibition.
69 . The method of claim 66 or 67 , wherein the b-raf mutation is V600E, T529I, or V600E/T529I.
70 . The method of claim 66 or 67 wherein the disease is cancer or a proliferation disease.
71 . The method of claim 70 , wherein the disease is melanoma, lung cancer, colon cancer, breast cancer, prostate cancer, liver cancer, pancreas cancer, brain cancer, kidney cancer, ovarian cancer, stomach cancer, skin cancer, bone cancer, gastric cancer, breast cancer, pancreatic cancer, glioma, gliobastoma, hepatocellular carcinoma, papillary renal carcinoma, head and neck squamous cell carcinoma, leukemias, lymphomas, myelomas, and solid tumors.
72 . The method of claim 66 or 67 , wherein the subject is administered an additional therapeutic agent.
73 . The method of claim 72 , wherein the compound and the additional therapeutic agent are administered simultaneously or sequentially.
74 . The method of claim 72 , wherein the additional therapeutic is a b-raf inhibitor.
75 . The method of claim 72 , wherein the additional therapeutic is a clinical b-raf inhibitor that directly targets the b-raf ATP site.
76 . The method of claim 75 , wherein the additional therapeutic is sorafenib, Raf265, AZ628, PLX-4032, PLX-4720, gefitinib, erlotinib, lapatinib, XL-647, HKI-272, BIBW2992, AV-412, CI-1033, PF00299804, BMS 690514, cetuximab, panitumumab, or matuzumab.
77 . A method of treating a disease related to b-raf or b-raf mutation modulation in a subject, wherein the disease is resistant to drug resistant mutations in b-raf, comprising administering to the subject a compound or pharmaceutically acceptable salt of formula I.
78 . The method of claim 76 , wherein the b-raf mutation is V600E, T529I, or V600E/T529I.
79 . A method of treating cancer in a subject, wherein the cancer comprises b-raf activated tumors, comprising administering to the subject a compound or pharmaceutically acceptable salt of formula I.
80 . A method of treating cancer in a subject, cancer comprises b-raf activated tumors, wherein the subject is identified as being in need of b-raf inhibition for the treatment of cancer, comprising administering to the subject a compound or pharmaceutically acceptable salt of formula I.
81 . The method of claim 79 or 80 , wherein the disease is melanoma, lung cancer, colon cancer, breast cancer, prostate cancer, liver cancer, pancreas cancer, brain cancer, kidney cancer, ovarian cancer, stomach cancer, skin cancer, bone cancer, gastric cancer, breast cancer, pancreatic cancer, glioma, gliobastoma, hepatocellular carcinoma, papillary renal carcinoma, head and neck squamous cell carcinoma, leukemias, lymphomas, myelomas, and solid tumors.
82 . The method of any one of claims 61 - 81 , wherein the subject is a human.
83 . A kit comprising a compound or pharmaceutically acceptable salt of formula I capable of inhibiting b-raf or b-raf mutation activity; and instructions for use in treating cancer.