Ep4 inhibitors and use thereof

Abstract

The present invention provides use of an agent that inhibits EP4 activity and an immuno-oncology agent, or a composition thereof, for treatment of a cancer.

1 . A method for treating a cancer in a patient comprising administering to the patient an agent that inhibits prostaglandin EP4 receptor (EP4) activity in combination an immuno-oncology agent, wherein the cancer is small cell lung cancer, non-small cell lung cancer, colorectal cancer, breast cancer, gastric cancer, multiple myeloma, acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), pancreatic cancer, liver cancer, hepatocellular cancer, neuroblastoma, other solid tumors or other hematological cancers. 
     
     
         2 . (canceled) 
     
     
         3 . The method of  claim 1 , wherein the agent that inhibits EP4 activity is a compound of formula I: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein
 Y 1 , Y 2 , Y 3  and Y 4  are independently selected from N, CH or C(L); 
 R 1  is H, C 1-8  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, C 3-7  cycloalkyl, C 1-8  alkoxy, halo-substituted C 1-8  alkoxy, C 1-8  alkyl-S(O)m-, Q 1 -, pyrrolidinyl, piperidyl, oxopyrrolidinyl, oxopiperidyl, amino, mono- or di-(C 1-8  alkyl)amino, C 1-4 alkyl-C(═O)—N(R 3 )— or C 1-4 alkyl-S(O)m-N(R 3 )—, wherein said C 1-8  alkyl, C 2-8  alkenyl and C 2-8  alkynyl are optionally substituted with halo, C 1-3  alkyl, hydroxy, oxo, C 1-4  alkoxy-, C 1-4  alkyl-S(O)m-, C 3-7  cycloalkyl-, cyano, indanyl, 1,2,3,4-tetrahydronaphtyl, 1,2-dihydronaphtyl, pyrrolidinyl, piperidyl, oxopyrrolidinyl, oxopiperidyl, Q 1 -, Q 1 -C(═O)—, Q 1 -O—, Q 1 -S(O)m-, Q 1 -C 1-4 alkyl-O—, Q 1 -C 1-4  alkyl-S(O)m-, Q 1 -C 1-4 alkyl-C(O)—N(R 3 )—, Q 1 -C 1-4 alkyl-N(R 3 )— or C 1-4 alkyl-C(O)—N(R 3 )—; 
 Q 1  is a 5-12 membered monocyclic or bicyclic aromatic ring optionally containing up to 4 heteroatoms selected from O, N and S, and is optionally substituted with halo, C 1-4  alkyl, halo-substituted C 1-4  alkyl, hydroxy, C 1-4  alkoxy, halo-substituted C 1-4  alkoxy, C 1-4  alkylthio, nitro, amino, mono- or di-(C 1-4  alkyl)amino, cyano, HO—C 1-4  alkyl, C 1-4  alkoxy-C 1-4 alkyl, C 1-4  alkylsulfonyl, aminosulfonyl, C 1-4  alkylC(═O)—, HO(O═)C—, C 1-4 alkyl-O(O═)C—, R 3 N(R 4 )C(═O)—, C 1-4  alkylsulfonylamino, C 3-7  cycloalkyl, R 3 C(═O)N(R 4 )— or NH 2 (HN═)C—; 
 A is a 5-6 membered monocyclic aromatic ring optionally containing up to 3 heteroatoms selected from O, N and S, wherein said 5-6 membered monocyclic aromatic ring is optionally substituted with up to 3 substituents selected from halo, C 1-4  alkyl, halo-substituted C 1-4  alkyl, hydroxy, C 1-4  alkoxy, halo-substituted C 1-4  alkoxy, C 1-4 alkylthio, nitro, amino, mono- or di-(C 1-4  alkyl)amino, cyano, HO—C 1-4  alkyl, C 1-4  alkoxy-C 1-4 alkyl, C 1-4  alkylsulfonyl, aminosulfonyl, acetyl, R 3 N(R 4 )C(═O)—, HO(O═)C—, C 1-4 alkyl-O(O═)C—, C 1-4  alkylsulfonylamino, C 3-7  cycloalkyl, R 3 C(═O)N(R 4 )— and NH 2 (HN═)C—; 
 B is halo-substituted C 1-6  alkylene, C 3-7  cycloalkylene, C 2-6  alkenylene, C 2-6  alkynylene, —O—C 1-5  alkylene, C 1-2  alkylene-O—C 1-2  alkylene or C 1-6  alkylene optionally substituted with an oxo group or C 1-3  alkyl; 
 W is NH, N—C 1-4  alkyl, O, S, N—OR 5  or a covalent bond; 
 R 2  is H, C 1-4  alkyl, OH or C 1-4  alkoxy; 
 Z is a 5-12 membered monocyclic or bicyclic aromatic ring optionally containing up to 3 heteroatoms selected from O, N and S, wherein said 5-12 membered monocyclic or bicyclic aromatic ring is optionally substituted with halo, C 1-4  alkyl, halo-substituted C 1-4  alkyl, C 1-4  alkenyl, C 1-4  alkynyl, hydroxy, C 1-4  alkoxy, halo-substituted C 1-4  alkoxy, C 1-4  alkylthio, nitro, amino, mono- or di-(C 1-4  alkyl)amino, cyano, HO—C 1-4  alkyl, C 1-4  alkoxy-C 1-4 alkyl, C 1-4  alkylsulfonyl, aminosulfonyl, C 1-4 alkylC(═O)—, R 3 C(═O)N(R 4 )—, HO(O═)C, C 1-4 alkyl-O(O═)C—, C 1-4  alkylsulfonylamino, C 3-7  cycloalkyl, NH 2 (HN═)C—, Q 2 -S(O)m-, Q 2 -O—, Q 2 -N(R 3 )— or Q 2 -; 
 L is halo, C 1-4  alkyl, halo-substituted C 1-4  alkyl, hydroxy, C 1-4  alkoxy, halo-substituted C 1-4  alkoxy, C 1-4  alkylthio, nitro, amino, mono- or di-(C 1-4  alkyl)amino, cyano, HO—C 1-4  alkyl, C 1-4  alkoxy-C 1-4 alkyl, C 1-4  alkylsulfonyl, aminosulfonyl, C 1-4 alkylC(═O)—, HO(O═)C—, C 1-4 alkyl-O(O═)C—, C 1-4  alkylsulfonylamino, C 3-7  cycloalkyl, R 3 C(═O)N(R 4 )—, NH 2 (HN═)C—, R 3 N(R 4 )C(═O)—, R 3 N(R 4 )S(O)m-, Q 2 -, Q 2 -C(═O)—, Q 2 -O—, Q 2 -C 1-4 alkyl-O—, or two adjacent L groups are optionally joined together to form an alkylene chain having 3 or 4 members in which one or two (non-adjacent) carbon atoms are optionally replaced by oxygen atoms; 
 m is 0, 1 or 2; 
 R 3  and R 4  are independently selected from H and C 1-4  alkyl; 
 R 5  is H, C 1-4  alkyl, C 1-4  alkyl-(O═)C— or C 1-4  alkyl-O—(O═)C—; and 
 Q 2  is a 5-12 membered monocyclic or bicyclic aromatic ring, or a 5-12 membered tricyclic ring optionally containing up to 3 heteroatoms selected from O, N and S, wherein said 5-12 membered monocyclic or bicyclic aromatic ring is optionally substituted with halo, C 1-4  alkyl, halo-substituted C 1-4  alkyl, C 1-4  alkenyl, C 1-4  alkynyl, hydroxy, C 1-4  alkoxy, halo-substituted C 1-4  alkoxy, C 1-4  alkylthio, nitro, amino, mono- or di-(C 1-8  alkyl)amino, cyano, HO—C 1-4  alkyl, C 1-4  alkoxy-C 1-4 alkyl, C 1-4  alkylsulfonyl, aminosulfonyl, C 1-4 alkyl-(O═)C, R 3 (R 4 )C(═O)N—, HO(O═)C—, C 1-4  alkyl-O(O═)C—, C 1-4  alkylsulfonylamino, C 3-7  cycloalkyl, C 1-4  alkyl-C(═O)NH— or NH 2 (HN═)C—. 
 
     
     
         4 - 9 . (canceled) 
     
     
         10 . The method ofclaim  3 , wherein
 Y 1 , Y 2 , Y 3  and Y 4  are selected from the group consisting of
 a) Y 1  and Y 3  are C(L), Y 2  is CH and Y 4  is N; 
 b) Y 1  is CH, Y 2  and Y 3  are C(L) and Y 4  is N; 
 c) Y 1 , Y 2  and Y 3  are C(L) and Y 4  is N; 
 d) Y 1  and Y 3  are C(L), Y 2  is N and Y 4  is CH; 
 e) Y 1  is C(L) and Y 2 , Y 3  and Y 4  are CH; 
 f) Y 1 , Y 3  and Y 4  are CH, and Y 2  is C(L); 
 g) Y 1 , Y 2  and Y 3  are CH, and Y 4  is C(L); 
 h) Y 1  and Y 2  are C(L), and Y 3  and Y 4  are CH; 
 i) Y 1  and Y 3  are C(L), and Y 2  and Y 4  are CH; 
 j) Y 1  and Y 4  are CH, and Y 2  and Y 3  are C(L); 
 k) Y 1  and Y 2  are CH, Y 3  is C(L) and Y 4  is N; 
 l) Y 1  and Y 3  are CH, Y 2  is C(L) and Y 4  is N; 
 m) Y 1 , Y 2 , Y 3  and Y 4  are CH; 
 n) Y 1  and Y 2  are C(L), Y 3  is CH and Y 4  is N; 
 o) Y 1 , Y 2  and Y 4  are CH, and Y 3  is C(L); 
 p) Y 1  and Y 2  are C(L), Y 3  is N and Y 4  is CH; 
 q) Y 1  and Y 3  are C(L), and Y 2  and Y 4  are N; 
 r) Y 1  is C(L), Y 2  and Y 3  are CH, and Y 4  is N; and 
 s) Y 2  is C(L), Y 1  and Y 3  are CH, and Y 4  is N; 
   R 1  is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, neopentyl, thiazolylethyl methylamino, dimethylamino, pyrrolidinyl, pyridyl, or 1-acetylamino-1-methylethyl;   A is phenyl;   B is ethylene or propylene;   W is NH, N—CH 3  or O;   R 2  is H;   Z is phenyl, pyrazolyl, thiazolyl, thiadiazolyl, thienyl, naphthyl or benzothienyl, said phenyl, pyrazolyl, thiazolyl, thiadiazolyl and thienyl being optionally substituted with one to three substituents independently selected from chloro, bromo, methyl, acetylamino, pivaloylamino, nitro and phenyl; and   L is chloro, methyl, trifuluoromethyl, hydroxy, methoxy, cyano, acetyl, —C(═O)NH 2 , trifuluoromethyloxy, methanesulfonyl, or 1-hydroxy-1-methyl-ethyl, or two adjacent L groups are joined together to form a methylenedioxy group.   
     
     
         11 - 15 . (canceled) 
     
     
         16 . The method of  claim 1 , wherein the agent that inhibits EP4 activity is a compound of the formula (I′): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 A′ represents a phenyl group or a pyridyl group; 
 B′ represents an aryl group or a heteroaryl group; 
 E′ represents a 1,4-phenylene group; 
 R 1′  and R 2′  independently represent a hydrogen atom, a halogen atom, an alkyl group having from 1 to 4 carbon atoms, an alkoxy group having from 1 to 4 carbon atoms, a haloalkyl group having from 1 to 4 carbon atoms, a haloalkoxy group having from 1 to 4 carbon atoms, a cyano group or an aminocarbonyl group; 
 R 3′  and R 4′  independently represent a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms; or R 3′  and R 4′  groups may be joined together to form an alkylene chain having 2 to 6 carbon atoms; 
 R 5′  represents 
 
       —CO 2 H, —CO 2 W′, 
       
         
           
           
               
               
           
         
         R 6′  represents an alkyl group having from 1 to 6 carbon atoms, a cycloalkyl group having from 3 to 7 ring atoms, an aryl group or a heteroaryl group; 
         X′ represents a methylene group, an oxygen atom or a sulfur atom; 
         said aryl groups have from 6 to 10 carbon atoms; 
         said heteroaryl groups are 5- to 10-membered aromatic heterocyclic groups containing from 1 to 3 heteroatoms selected from the group consisting of sulfur atoms, oxygen atoms and nitrogen atoms; 
         said aryl groups and said heteroaryl groups referred to in the definitions of B′ are unsubstituted or are substituted by at least one substituent selected from the group consisting of substituents α; 
         said 1,4-phenylene group referred to in the definition of E′ is unsubstituted or is substituted by at least one substituent selected from the group consisting of substituents (3; 
         said aryl groups and said heteroaryl groups referred to in the definitions of R 6′  and a are unsubstituted or are substituted by at least one substituent selected from the group consisting of substituents β; 
         said substituents α are selected from the group consisting of halogen atoms, alkyl groups having from 1 to 4 carbon atoms, alkoxy groups having from 1 to 4 carbon atoms, haloalkyl groups having from 1 to 4 carbon atoms, haloalkoxy groups having from 1 to 4 carbon atoms, cyano groups, alkynyl groups having from 2 to 6 carbon atoms, alkanoyl groups having from 1 to 5 carbon atoms, cycloalkyl groups having from 3 to 7 ring atoms, heteroaryl groups, aryl groups, aralkoxy groups having from 7 to 10 carbon atoms, arylcarbonyl groups, two adjacent a groups are optionally joined together to form an alkylene or an alkenylene chain having 3 or 4 carbon atoms, aminocarbonyl groups, alkenyl groups having from 2 to 5 carbon atoms, alkylthio groups having from 1 to 4 carbon atoms, aminosulfinyl groups, aminosulfonyl groups, hydroxy groups, hydroxyalkyl groups having from 1 to 4 carbon atoms, nitro groups, amino groups, carboxy groups, alkoxycarbonyl groups having from 2 to 5 carbon atoms, alkoxyalkyl groups having from 1 to 4 carbon atoms, alkylsulfonyl groups having from 1 to 4 carbon atoms, alkanoylamino groups having from 1 to 4 carbon atoms, alkanoyl(alkyl)amino groups having from 1 to 6 carbon atoms, alkanoylaminoalkyl groups having from 1 to 6 carbon atoms in both the alkanoyl and alkyl part, alkanoyl(alkyl)aminoalkyl groups having from 1 to 6 carbon atoms in both the alkanoyl and each alkyl part, alkylsulfonylamino groups having from 1 to 4 carbon atoms, mono- or di-alkylaminocarbonyl groups having from 1 to 6 carbon atoms, mono- or di-alkylaminosulfinyl groups having from 1 to 6 carbon atoms, mono- or di-alkylaminosulfonyl groups having from 1 to 6 carbon atoms, aminoalkyl groups having from 1 to 4 carbon atoms, mono- or di-alkylamino groups having from 1 to 6 carbon atoms, mono- or di-alkylaminoalkyl groups having from 1 to 6 carbon atoms in each alkyl part, aralkyl groups having from 7 to 10 carbon atoms, heteroarylalkyl groups having from 1 to 4 carbon atoms in the alkyl part, heteroarylalkoxy groups having from 1 to 4 carbon atoms in the alkoxy part and alkylsulfonylamino groups having from 1 to 4 carbon atoms; 
         said substituents β are selected from the group consisting of halogen atoms, alkyl groups having from 1 to 4 carbon atoms, alkoxy groups having from 1 to 4 carbon atoms, haloalkyl groups having from 1 to 4 carbon atoms, haloalkoxy groups having from 1 to 4 carbon atoms and cyano groups; 
         W′ is a pharmaceutically acceptable ester pro-drug group; 
       
       with the proviso R 1′  and R 2′  do not represent a hydrogen atom simultaneously. 
     
     
         17 - 26 . (canceled) 
     
     
         27 . The method of  claim 16 , wherein:
 E′ represents an unsubstituted 1,4-phenylene group;   B′ represents a phenyl or pyridyl group; wherein:
 said group is unsubstituted or is substituted by at least one substituent selected from the group consisting of substituents; 
 said substituents α are selected from the group consisting halogen atoms, alkyl groups having from 1 to 4 carbon atoms, alkoxy groups having from 1 to 4 carbon atoms, haloalkoxy groups having from 1 to 4 carbon atoms, cyano groups, alkynyl groups having from 2 to 6 carbon atoms, alkanoyl groups having from 1 to 5 carbon atoms, cycloalkyl groups having from 3 to 7 ring atoms, heteroaryl groups, aryl groups, aralkoxy groups having from 7 to 10 carbon atoms, arylcarbonyl groups, two adjacent a groups are optionally joined together to form an alkylene chain having 3 carbon atoms, alkylthio groups having from 1 to 4 carbon atoms, and di-alkylaminoalkyl groups having from 1 to 6 carbon atoms in the alkyl part; and 
 said heteroaryl groups referred to in the definitions of a are unsubstituted or are substituted by alkyl groups having from 1 to 4 carbon atoms; 
   X′ represents a methylene group or an oxygen atom;   R 1′  represents a halogen atom and R 2′  represents a hydrogen atom;   R 3′  and R 4′  independently represent a hydrogen atom or an alkyl group having from 1 to 4 carbon atoms;   R 5′  represents   
       —CO 2 H, 
       
         
           
           
               
               
           
         
       
       and
 R 6′  represents an aryl group optionally substituted by halogen atoms or an heteroaryl group. 
 
     
     
         28 - 37 . (canceled) 
     
     
         38 . The method of a  claim 1 , wherein the agent that inhibits EP4 activity is the compound: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         39 . The method of  claim 1 , wherein the agent that inhibits EP4 activity is the compound: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         40 . The method of  claim 1 , wherein the immuno-oncology agent is (i) an antagonist of a protein that inhibits T cell activation which is selected from CTLA-4, PD-1, PD-L1, PD-L2, LAG-3, TIM-3, Galectin 9, CEACAM-1, BTLA, CD69, Galectin-1, TIGIT, CD113, GPR56, VISTA, 2B4, CD48, GARP, PD1H, LAIR1, TIM-1, and TIM-4; or (ii) an agonist of a protein that stimulates T cell activation which is selected from B7-1, B7-2, CD28, 4-1BB (CD137), 4-1BBL, ICOS, ICOS-L, OX40, OX40L, GITR, GITRL, CD70, CD27, CD40, DR3 and CD28H. 
     
     
         41 . The method of  claim 40 , wherein the immuno-oncology agent is an immune checkpoint inhibitor. 
     
     
         42 . The method of  claim 41 , wherein the immune checkpoint inhibitor is selected from a PD-1 antagonist, a PD-L1 antagonist, and a CTLA-4 antagonist. 
     
     
         43 . The method of  claim 1 , wherein the immuno-oncology agent is an antagonist of inhibitory receptors on NK cells or an agonists of activating receptors on NK cells. 
     
     
         44 . The method of  claim 1 , wherein the immuno-oncology agent is an agent that inhibits or depletes macrophages or monocytes. 
     
     
         45 . The method of  claim 1 , wherein the immuno-oncology agent is a cancer vaccine. 
     
     
         46 . The method of  claim 45 , wherein the cancer vaccine is an oncolytic viral therapy. 
     
     
         47 . The method of  claim 1 , wherein the immuno-oncology agent is a T-cell engineered to express a chimeric antigen receptor. 
     
     
         48 . The method of  claim 1 , wherein the immuno-oncology agent is an activator of retinoic acid receptor-related orphan receptor γ(RORγt). 
     
     
         49 . The method of  claim 1 , wherein the immuno-oncology agent is an agonist or activator of atoll-like receptor (TLR). 
     
     
         50 . The method of  claim 1 , wherein the immuno-oncology agent is recombinant human interleukin 15 or recombinant human interleukin 12. 
     
     
         51 - 54 . (canceled)