RAF Inhibitors and Uses Thereof

Abstract

The present invention provides imidazooxazole and imidazothiazole compounds and their synthesis. The compounds of the present invention are capable of inhibiting the activity of RAF kinase, such as B-RAF V600E . The compounds are useful for the treatment of cell proliferative disorders such as cancer.

1 - 33 . (canceled) 
   
   
       34 . A compound of Formula II, or pharmaceutically acceptable salts thereof: 
     
       
         
         
             
             
         
       
       wherein 
       X is O, S(O) p ; 
       m is an integer from 1 to 3; 
       n is an integer from 1 to 3; 
       p is an integer from 0 to 2; 
       Z is hydrogen, a bond, —C(O)—, —C(O)NR 11 —, —S(O) 2 —, —C(O)NH—S(O) 2 —, or CH(OH)—CH 2 —Y—, wherein Y is CH 2 , O, S, NH, or a bond; 
       R 1  is halogen, —CN, —NO 2 , —OH, —NR 6 R 7 , NR 8 —C(O)R 9 , —(CH 2 ) 0-3 —C(O)NR 6 R 7 , —NR 8 SO 2 R 9 , —NR 8 C(O)NR 6 R 7 , —NR 8 C(S)NR 6 R 7 , —OSO 2 NR 5 R 7 , —C(N—OH)NH 2 , —C(N—OH)R 8 , —CH 2 OR 8 , —OC(O)NR 6 R 7 , —SR 9 , or —C(O)NR 8 SO 2 R 9 ; 
       R 2  is hydrogen, halogen, —CN, —NO 2 , —OH, —NR 6 R 7 , NR 8 —C(O)R 9 , —(CH 2 ) 0-3 —C(O)NR 6 R 7 , —NR 8 SO 2 R 9 , —NR 8 C(O)NR 6 R 7 , —NR 8 C(S)NR 6 R 7 , —OSO 2 NR 5 R 7 , —C(N—OH)NH 2 , —C(N—OH)R 8 , —CH 2 OR 8 , —OC(O)NR 6 R 7 , —SR 9 , or —C(O)NR 8 SO 2 R 9 , and R 1  and R 2 , taken together, may form a ring; 
       R 3  and R 4  are independently hydrogen, substituted or unsubstituted, branched or unbranched (C 1 -C 6 )alkyl, —COOH, —COOR 8 , or —C(O)NR 10 R 11 ; 
       each R 6  and each R 7  are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heterocyclyl, and R 6  and R 7 , taken together, may form a ring; each R 8  is independently hydrogen, or substituted or unsubstituted, branched or unbranched (C 1 -C 6 )alkyl; each R 9  is independently substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl; 
       R 10  is substituted or unsubstituted, branched or unbranched (C 1 -C 6 )alkyl, or substituted or unsubstituted aryl; 
       R 11  is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl, and R 11 , taken together with R 10 , may form a ring; 
       R 12  is substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclyl, or substituted or unsubstituted heteroaryl; and 
       R 13  is independently selected from the group consisting of hydrogen, C 1 -C 9  alkyl, C 1 -C 9  fluoro-substituted alkyl, C 3 -C 8  cycloalkyl, C 3 -C 8  fluoro-substituted cycloalkyl, aryl, halogen-substituted aryl, heteroaryl, and halogen-substituted heteroaryl. 
     
   
   
       35 . The compound of  claim 34  wherein R 3  and R 4  are hydrogen. 
   
   
       36 . The compound of  claim 34  wherein R 13  is hydrogen. 
   
   
       37 . The compound of  claim 34  wherein m+n=4, if m is not equal to n, then the preferred configuration is R. 
   
   
       38 . The compound of  claim 34  wherein Z is —S(O) 2 —. 
   
   
       39 . The compound of  claim 34  wherein m is an integer from 1 to 2; n is an integer from 1 to 2; Z is —C(O)—, —C(O)NR 11 —, —S(O) 2 —; and R 3 , R 4  and R 13  are hydrogen. 
   
   
       40 . The compound of  claim 34  or  38  wherein, R 12  is a heteroaromatic group having one, two or three aromatic rings containing from 1 to 4 heteroatoms in the aromatic ring or a non-aromatic 3 to 7 membered monocyclic heterocyclic ring structure or 8 to 11 membered bicyclic heterocyclic ring structure. 
   
   
       41 . A pharmaceutical composition comprising a compound as defined in  claim 34  or a pharmaceutically acceptable salt thereof together with one or more pharmaceutically acceptable carriers or excipients. 
   
   
       42 . The pharmaceutical composition of  claim 41  further comprising a second chemotherapeutic agent. 
   
   
       43 . The pharmaceutical composition of  claim 42 , wherein said second chemotherapeutic agent is selected from the group consisting of tamoxifen, raloxifene, anastrozole, exemestane, letrozole, cisplatin, carboplatin, paclitaxel, cyclophosphamide, lovastatin, minosine, gemcitabine, araC, 5-fluorouracil, methotrexate, docetaxel, goserelin, vincristin, vinblastin, nocodazole, teniposide, etoposide, epothilone, navelbine, camptothecin, daunonibicin, dactinomycin, mitoxantrone, amsacrine, doxorubicin, epirubicin, idarubicin imatanib, gefitinib, erlotinib, sorafenib, sunitinib malate, trastuzumab, rituximab, cetuximab, and bevacizumab. 
   
   
       44 . A method of treating a cell proliferative disorder, said method comprising administering to a subject having cells with said cell proliferative disorder a therapeutically effective amount of a compound of formula II as claimed in claim  1 , or a pharmaceutically acceptable salt thereof, or a prodrug or metabolite thereof, in combination with a pharmaceutically acceptable carrier, wherein said cells with said cell proliferative disorder contain DNA encoding a RAF, and wherein said cell proliferative disorder is treated. 
   
   
       45 . The method of  claim 44  wherein R 3  and R 4  are hydrogen. 
   
   
       46 . The method of  claim 44  wherein R 13  is hydrogen. 
   
   
       47 . The method of  claim 45  wherein m+n=4, if m is not equal to n, then the configuration is R. 
   
   
       48 . The method of  claim 45  wherein Z is —S(O) 2 — and R -12  is 4-chlorophenyl, 4-fluorophenyl, 4-cyanophenyl, methyl, or cyclopropyl. 
   
   
       49 . The method of  claim 44  wherein the compound is selected from the group consisting of 3-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}phenyl carbamate, 3-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}phenyl sulfamate, 3-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4-yl]imidazo[2,1-b][1,3]oxazol-6-yl}phenyl sulfamate, 3-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino) pyrimidin-4-yl]imidazo[2,1-b][1,3]oxazol-6-yl}phenyl carbamate, (1E)-1-(3-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}phenyl)ethanone oxime, 2-chloro-5-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}phenol, 3-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4-yl]imidazo[2,1-b][1,3]oxazol-6-yl}phenol, 4-{[(3R)-3-({4-[6-(3-hydroxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2-yl}amino)piperidin-1-yl]sulfonyl}benzonitrile, 4-{[(3R)-3-({4-[6-(3-hydroxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2-yl}amino)piperidin-1-yl]sulfonyl}benzoic acid, 3-{[(3R)-3-({4-[6-(3-hydroxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2-yl}amino)piperidin-1-yl]sulfonyl}phenol, 2-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}benzene-1,4-diol, 3-[5-(2-{[(3R)-1-(methylsulfonyl)piperidin-3-yl]amino}pyrimidin-4-yl) imidazo[2,1-b][1,3]thiazol-6-yl]phenol, 3-{5-[2-({1-[(4-fluorophenyl)sulfonyl]piperidin-4-yl}amino)pyrimidin-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}phenol, 3-{5-[2-({1-[(4-chlorophenyl)sulfonyl]piperidin-4-yl}amino)pyrimidin-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}phenol, N-ethyl-4-({4-[6-(3-hydroxyphenyl)imidazo[2,1-b][1,3]thiazol-5-yl]pyrimidin-2-yl}amino)piperidine-1-carboxamide, 3-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}phenol, 4-{[4-({4-[6-(3-hydroxyphenyl) imidazo[2,1-b][1,3]oxazol-5-yl]pyrimidin-2-yl}amino)piperidin-1-yl]sulfonyl}benzonitrile, 4-{[4-({4-[6-(3-hydroxyphenyl)imidazo[2,1-b][1,3]oxazol-5-yl]pyrimidin-2-yl}amino)piperidin-1-yl]sulfonyl}benzamide, 4-{[(3R)-3-({4-[6-(3-hydroxyphenyl)imidazo[2,1-b][1,3]oxazol-5-yl]pyrimidin-2-yl}amino)piperidin-1-yl]sulfonyl}benzonitrile, 3-{5-[2-({1-[(4-chlorophenyl)sulfonyl]piperidin-4-yl}amino)pyrimidin-4-yl]imidazo[2,1-b][1,3]oxazol-6-yl}-phenol, 3-{5-[2-({1-[(4-fluorophenyl)sulfonyl]piperidin-4-yl}amino)pyrimidin-4-yl]imidazo[2,1-b][1,3]oxazol-6-yl}phenol, 5-{5-[2-({(3R)-1-[(4-chlorophenyl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}-2-fluorophenol, 3-{5-[2-({(3R)-1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}phenol, 3-[5-(2-{[(3R)-1-(3-thienylsulfonyl)piperidin-3-yl]amino}pyrimidin-4-yl)imidazo[2,1-b][1,3]thiazol-6-yl]phenol, 3-[5-(2-{[(3R)-1-(2-thienylsulfonyl)piperidin-3-yl]amino}pyrimidin-4-yl)imidazo[2,1-b][1,3]thiazol-6-yl]phenol, 3-[5-(2-{[(3R)-1-(phenylsulfonyl)piperidin-3-yl]amino}pyrimidin-4-yl)imidazo[2,1-b][1,3]thiazol-6-yl]phenol, 3-{5-[2-{(3R)-1-[(1-methyl-1H-pyrazol-3-yl)sulfonyl]piperidin-3-yl}amino)pyrimidin-4-yl]imidazo[2,1-b][1,3]thiazol-6-yl}phenol, 3-[5-(2-{[(3R)-1-(4H-1,2,4-triazol-3-ylsulfonyl)piperidin-3-yl]amino}pyrimidin-4-yl)imidazo[2,1-b][1,3]thiazol-6-yl]phenol, 3-[5-(2-{[(3R)-1-(2-thienylsulfonyl)piperidin-3-yl]amino}pyrimidin-4-yl)imidazo[2,1-b][1,3]oxazol-6-yl]phenol, 3-[5-(2-{[(3R)-1-(phenylsulfonyl)piperidin-3-yl]amino}pyrimidin-4-yl)imidazo[2,1-b][1,3]oxazol-6-yl]phenol, 3-[5-(2-{[1-(cyclopropylsulfonyl)piperidin-4-yl]amino}pyrimidin-4-yl) imidazo[2,1-b][1,3]thiazol-6-yl]phenol, 3-[5-(2-{[1-(methylsulfonyl)piperidin-4-yl]amino}pyrimidin-4-yl)imidazo[2,1-b][1,3]thiazol-6-yl]phenol, 3-[5-(2-{[1-(cyclopropylsulfonyl)piperidin-4-yl]amino}pyrimidin-4-yl)imidazo[2,1-b][1,3]oxazol-6-yl]phenol, 3-[5-(2-{[1-(methylsulfonyl)piperidin-4-yl]amino}pyrimidin-4-yl)imidazo[2,1-b][1,3]oxazol-6-yl]phenol, 5-[5-(2-{[1-(cyclopropylsulfonyl)piperidin-4-yl]amino}pyrimidin-4-yl)imidazo[2,1-b][1,3]thiazol-6-yl]-2-fluorophenol, and 3-[5-(2-{[(3R)-1-(cyclopropylsulfonyl)piperidin-3-yl]amino}pyrimidin-4-yl)imidazo[2,1-b][1,3]oxazol-6-yl]phenol. 
   
   
       50 . The method of  claim 44  wherein said cells with said cell proliferative disorder contain DNA encoding a RAF, and wherein the RAF is A-RAF, B-RAF, or C-RAF. 
   
   
       51 . The method of  claim 50  wherein the RAF is B-RAF. 
   
   
       52 . The method of  claim 51  wherein the B-RAF is selected from the group consisting of wild-type B-RAF, a B-RAF mutant and B-RAF V600E . 
   
   
       53 . The method of  claim 44  wherein the cells have a constitutively enhanced RAF activity. 
   
   
       54 . The method of  claim 44 , wherein said compound or a pharmaceutically acceptable salt thereof, or a prodrug or metabolite thereof, is administered in combination with a second chemotherapeutic agent. 
   
   
       55 . The method of  claim 54 , wherein said second chemotherapeutic agent is selected from the group consisting of tamoxifen, raloxifene, anastrozole, exemestane, letrozole, cisplatin, carboplatin, paclitaxel, cyclophosphamide, lovastatin, minosine, gemcitabine, araC, 5-fluorouracil, methotrexate, docetaxel, goserelin, vincristin, vinblastin, nocodazole, teniposide, etoposide, epothilone, navelbine, camptothecin, daunonibicin, dactinomycin, mitoxantrone, amsacrine, doxorubicin, epirubicin, idarubicin imatanib, gefitinib, erlotinib, sorafenib, sunitinib malate, trastuzumab, rituximab, cetuximab, and bevacizumab. 
   
   
       56 . The use of  claim 44  wherein said cell proliferative disorder is melanoma, a papillary thyroid cancer or Congenital Nevi.