Methods of treating solid tumors with ccr2 antagonists

Abstract

The present disclosure provides, inter alia, methods of treating a solid-tumor by administering an effective amount of a Chemokine Receptor 2 (CCR2) antagonist. Also provided herein are methods of reducing the number of macrophages in a solid tumor microenvironment, said method comprising administering effective amount of a Chemokine Receptor 2 (CCR2) antagonist. In an additional aspect, the current disclosure further provides methods of increasing the number CD8+ T cells in a solid tumor microenvironment, said method comprising administering effective amount of a Chemokine Receptor 2 (CCR2) antagonist. In some embodiments, the CCR2 antagonist has the formula I or Formula III:

1 . A method of treating a solid tumor, said method comprising administering an effective amount of a Chemokine Receptor 2 (CCR2) antagonist. 
     
     
         2 . The method of  claim 1 , wherein said CCR2 antagonist has the formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, hydrate, stereoisomer or rotamer thereof; wherein A is C(R 5 )(R 6 ) or N(R 5 ) 
         the subscripts m and n are each independently integers of from 0 to 2, and m+n is ≤3; 
         R 1  is selected from the group consisting of aryl, aryl-C 1-4  alkyl, heteroaryl and heteroaryl-C 1-4  alkyl, wherein the heteroaryl portion has from 1-3 heteroatoms as ring members selected from N, O and S; and wherein said aryl and heteroaryl groups or portions are optionally substituted with from 1 to 5 R x  substituents; 
         R 2  is selected from the group consisting of H, C 1-8  alkyl, C 3-8  cycloalkyl, C 3-8  cycloalkyl-C 1-4  alkyl, aryl, aryl-C 1-4  alkyl, heteroaryl and heteroaryl-C 1-4  alkyl, wherein the heteroaryl portion has from 1-3 heteroatoms as ring members selected from N, O and S; and wherein said aryl and heteroaryl groups or portions are optionally substituted with from 1 to 4 R x  substituents; 
         or optionally, R 1  and R 2  are combined with the nitrogen atom to which each is attached to form a 6- to 11-membered monocyclic or fused bicyclic-heterocyclic or heteroaryl ring, wherein the —NR 1 R 2  is optionally further substituted with from 1 to 4 R x  substituents; 
         R 3  is selected from the group consisting of H, C 1-8  alkyl, C 3-8  cycloalkyl and C 3-8  cycloalkyl-C 1-4  alkyl, each of which is optionally substituted with from 1-3 R y  substituents; 
         R 4  is selected from the group consisting of H, C 1-8  alkyl optionally substituted with 1 to 2 R y , and CO 2 H: 
         R 5  is selected from the group consisting of C 1-8  alkyl, C 1-8  alkoxy, C 3-8  cycloalkyl, C 3-8  cycloalkyloxy, C 3-8  cycloalkyl-C 1-4  alkyl, C 1-8  alkylamino, di-C 1-8  alkylamino, aryl, aryloxy, arylamino, aryl-C 1-4  alkyl, heteroaryl, heteroaryloxy, heteroarylamino and heteroaryl-C 1-4  alkyl, each of which is optionally substituted with from 1 to 5 R z  substituents; 
         R 6  is selected from the group consisting of H, F, OH, C 1-8  alkyl and C 1-8  alkoxy, wherein the C 1-8  alkyl and C 1-8  alkoxy groups are optionally substituted with from 1 to 3 R z  substituents; 
         or optionally, R 5  and R 6  are joined to form a spirocyclic 5- or 6-membered cycloalkyl ring which is optionally unsaturated, and has a fused aryl group which is optionally substituted with from 1 to 4 R z  substituents; 
         each R x  is independently selected from the group consisting of halogen, —CN, —R c , —CO 2 R a , —CONR a R b , —C(O)R a , —OC(O)NR a R b , —NR b C(O)R a , —NR b C(O) 2 R c , —NR a —C(O)NR a R b , —NR a C(O)NR a R b , —NR a R b , —OR a , —O—X 1 —OR a , —O—X 1 —NR a R b , —O—X 1 —CO 2 R a , —O—X 1 —CNR a R b , —X 1 —OR a , —X 1 —NR a R b , —X 1 —CO 2 R a , —X 1 —CONR a R b , —SF 5 , —S(O) 2 NR a R b , and 5- or 6-membered aryl or heteroaryl, wherein each X 1  is a C 1-4  alkylene; each R a  and R b  is independently selected from hydrogen, C 1-8  alkyl, and C 1-8  haloalkyl, or when attached to the same nitrogen atom can be combined with the nitrogen atom to form a five or six-membered ring having from 0 to 2 additional heteroatoms as ring members selected from N, O or S, and optionally substituted with oxo; each R c  is independently selected from the group consisting of C 1-8  alkyl, C 1-8 haloalkyl and C 3-6  cycloalkyl; and optionally when two R x  substituents are on adjacent atoms, are combined to form a fused five or six-membered carbocyclic ring, and wherein the aryl or heteroaryl groups are optionally substituted with 1-3 members selected from halogen, hydroxyl, C 1-4  alkyl, C 1-4  alkoxy, C 1-4 haloalkyl, and C 1-4 haloalkoxy; 
         each R y  is independently selected from the group consisting of halogen, —CN, —R e , —CO 2 R d , —CONR d R e , —C(O)R d , —OC(O)NR d R e , —NR e C(O)R d , —NR e C(O) 2 R f , —NR d C(O)NR d R e , —NR d C(O)NR d R e , —NR d R e , —OR d , and —S(O) 2 NR d R e ; wherein each R d  and R e  is independently selected from hydrogen, C 1-8  alkyl, and C 1-8  haloalkyl, or when attached to the same nitrogen atom can be combined with the nitrogen atom to form a five or six-membered ring having from 0 to 2 additional heteroatoms as ring members selected from N, O or S; each R f  is independently selected from the group consisting of C 1-8  alkyl, C 1-8  haloalkyl and C 3-6  cycloalkyl;
 each R z  is independently selected from the group consisting of halogen, —CN, —R i , —CO 2 R g , —CONR g R h , —C(O)R g , —OC(O)NR g R h , —NR h C(O)R g , —NR h C(O) 2 R i , —NR g C(O)NR g R h , —NR g R h , —OR g , —S(O) 2 NR g R h , —X 1 —NR g R h , —X 1 —CONR g R h , —X 1 —NR h C(O)R g , —NHCH 2 R j , and tetrazole; wherein each R g  and R h  is independently selected from hydrogen, C 1-8  alkyl, C 3-6  cycloalkyl and C 1-8  haloalkyl, or when attached to the same nitrogen atom can be combined with the nitrogen atom to form a five or six-membered ring having from 0 to 2 additional heteroatoms as ring members selected from N, O or S and is optionally substituted with one or two oxo; each R i  is independently selected from the group consisting of C 1-8  alkyl, C 1-8  haloalkyl and C 3-6  cycloalkyl; and each R j  is selected from the group consisting of C 3-6  cycloalkyl, pyrrolinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, and tetrahydropyranyl. 
 
       
     
     
         3 . The method of  claim 1 , wherein said CCR2 antagonist is selected from the group consisting of 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         4 . The method of  claim 1 , wherein said CCR2 antagonist has the formula of Compound 1 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         5 . The method of  claim 1 , wherein said CCR2 antagonist has the formula of Compound 2 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         6 . The method of  claim 1 , wherein said CCR2 antagonist has the formula of Compound 3 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         7 . The method of  claim 1 , wherein said CCR2 antagonist has the formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, hydrate, stereoisomer or rotamer thereof; wherein 
         Ar is selected from the group consisting of substituted or unsubstituted C 6-10  aryl and substituted or unsubstituted 5- to 10-membered heteroaryl; 
         R 1  is selected from the group consisting of hydrogen, substituted or unsubstituted C 1-8  alkyl, substituted or unsubstituted C 2-6  alkenyl, substituted or unsubstituted C 2-6  alkynyl, and substituted or unsubstituted 3- to 10-membered heterocyclyl; 
         Y 1  is selected from the group consisting of —CR 2a —, —N—, and —N + (O) − —; 
         Y 2  is selected from the group consisting of —CR 2b —, —N—, and —N + (O) − —; 
         Y 3  is selected from the group consisting of —CR 2c —, —N—, and —N + (O) − —; 
         R 2a , R 2b , and R 2c  are each independently selected from the group consisting of hydrogen, halogen, —CN, —C(O)R 3 , —CO 2 R 3 , —C(O)NR 3 R 4 , —OR 3 , —OC(O)R 3 , —OC(O)NR 3 R 4 , —SR 3 , —S(O)R 3 , —S(O) 2 R 3 , —S(O) 2 NR 3 R 4 , —NO 2 , —NR 3 NR 3 R 4 , —NR 3 C(O)R 4 , —NR 3 C(O)OR 4 , —NR 3 S(O) 2 R 4 , —NR 3 C(O)NR 4 R 5 , substituted or unsubstituted C 1-8  alkyl, substituted or unsubstituted C 2-8  alkenyl, substituted or unsubstituted C 2-8  alkynyl, substituted or unsubstituted 3- to 10-membered heterocyclyl, substituted or unsubstituted C 6-10  aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl; 
         R 3 , R 4 , and R 5  are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1-8  alkyl, substituted or unsubstituted C 2-8  alkenyl, substituted or unsubstituted C 2-8  alkynyl, substituted or unsubstituted C 6-10  aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, and substituted or unsubstituted 3- to 10-membered heterocyclyl; 
         R 3  and R 4 , R 4  and R 5  or R 3  and R 5  may, together with the atoms to which they are attached, form a substituted or unsubstituted 5-, 6-, or 7-membered ring; 
         Y 4  is selected from the group consisting of —N— and —N + (O) − —; 
         L is selected from the group consisting of a bond, —O—, —S—, —S(O)—, —S(O) 2 —, —CR 6 R 7 —, —NR 8 —, —C(O)—, —C(O)NR 8 —, and —NR 8 C(O)—; 
         R 6  and R 7  are each independently selected from the group consisting of hydrogen, halogen, substituted or unsubstituted C 1-8  alkyl, substituted or unsubstituted 3- to 10-membered heterocyclyl, substituted or unsubstituted C 2-6  alkenyl, substituted or unsubstituted C 2-6  alkynyl, —CN, —OR 9 , —NR 10 R 11 , —S(O)R 9 , and —S(O) 2 R 9 ; 
         R 6  and R 7  may, together with the carbon atom to which they are attached, form substituted or unsubstituted C 3-8  cycloalkyl or substituted or unsubstituted 3- to 10-membered heterocyclic ring; 
         R 9  is selected from the group consisting of hydrogen, substituted or unsubstituted C 1-8  alkyl, substituted or unsubstituted C 2-8  alkenyl, substituted or unsubstituted C 2-8  alkynyl, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, and substituted or unsubstituted 3- to 10-membered heterocyclyl; 
         R 10  and R 11  are each independently selected from the group consisting of substituted or unsubstituted C 1-8  alkyl, substituted or unsubstituted 3- to 10-membered heterocyclyl, substituted or unsubstituted C 6-10  aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, substituted or unsubstituted C 2-8  alkenyl, and substituted or unsubstituted C 2-8  alkynyl; 
         R 10  and R 11  of —NR 10 R 11  may, together with the nitrogen, form substituted or unsubstituted 3- to 10-membered heterocyclyl; 
         R 8  is selected from the group consisting of hydrogen, C(O)R 12 , S(O) 2 R 12 , CO 2 R 12 , substituted or unsubstituted C 1-8  alkyl, substituted or unsubstituted 3- to 10-membered heterocyclyl, substituted or unsubstituted C 2-6  alkenyl, and substituted or unsubstituted C 2-6  alkynyl; 
         R 12  is selected from the group consisting of substituted or unsubstituted C 1-8  alkyl, substituted or unsubstituted C 2-6  alkenyl, substituted or unsubstituted C 2-6  alkynyl, substituted or unsubstituted 3- to 10-membered heterocyclyl, substituted or unsubstituted C 6-10  aryl, and substituted or unsubstituted 5- to 10-membered heteroaryl; 
         Z 1  is selected from the group consisting of substituted or unsubstituted C 6-10  aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, substituted or unsubstituted 3- to 10-membered heterocyclyl, and —NR 13 R 14 ; 
         R 13  and R 14  are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C 1-8  alkyl, substituted or unsubstituted C 2-8  alkenyl, substituted or unsubstituted C 2-8  alkynyl, substituted or unsubstituted 3- to 10-membered heterocyclyl, substituted or unsubstituted C 6-10  aryl, substituted or unsubstituted 5- to 10-membered heteroaryl, substituted or unsubstituted (C 1-4  alkyl)-(C 6-10  aryl), and substituted or unsubstituted (C 1-4  alkyl)-(5- to 10-membered heteroaryl); 
         R 13  and R 14  may, together with the nitrogen, form a substituted or unsubstituted 4-, 5-, 6-, or 7-membered heterocyclyl. 
       
     
     
         8 . The method of  claim 7 , wherein said CCR2 antagonist has the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, hydrate, stereoisomer or rotamer thereof; wherein Y 11  is —CH—, —N—, and —N + (O) − —. 
     
     
         9 . The method of  claim 1 , wherein said CCR2 antagonist is selected from the group consisting of 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         10 . The method of  claim 1 , wherein said CCR2 inhibitor has the formula of Compound 4 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         11 . The method of  claim 1 , wherein said CCR2 inhibitor has the formula of Compound 5 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         12 . The method of  claim 1 , wherein said CCR2 inhibitor has the formula of Compound 6 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         13 . The method of  claim 1 , wherein said solid tumor is selected from the group consisting of skin cancer, brain cancer, breast cancer, triple negative breast cancer, bladder cancer, bone cancer, colorectal cancer, lung cancer, kidney cancer, liver cancer, stomach cancer, prostate cancer, sarcoma, melanoma, carcinoma, and a lymphoma. 
     
     
         14 . The method of  claim 1 , wherein said solid tumor is selected from the group consisting of skin cancer, prostate cancer, breast cancer, colorectal cancer, pancreatic cancer, and a lymphoma. 
     
     
         15 . The method of  claim 1 , wherein said solid tumor is a lymphoma. 
     
     
         16 . The method of  claim 15 , wherein said lymphoma is cutaneous T cell lymphoma (CTCL). 
     
     
         17 . The method of  claim 1 , wherein said treatment provides tumor size reduction as compared to an individual who was not administered said CCR2 antagonist. 
     
     
         18 . The method of  claim 1 , wherein said treatment blocks tumor growth. 
     
     
         19 - 27 . (canceled) 
     
     
         28 . A method of increasing the number CD8+ T cells in a solid tumor microenvironment, said method comprising administering an effective amount of a Chemokine Receptor 2 (CCR2) antagonist. 
     
     
         29 - 33 . (canceled) 
     
     
         34 . A method of reducing the number of macrophages in a solid tumor microenvironment, said method comprising administering an effective amount of a Chemokine Receptor 2 (CCR2) antagonist. 
     
     
         35 - 45 . (canceled) 
     
     
         46 . A method of treating cutaneous T cell lymphoma (CTCL), said method comprising administering to a subject in need thereof an effective amount of a Chemokine Receptor 2 (CCR2) antagonist. 
     
     
         47 . The method of  claim 46 , wherein the subject in need thereof has Stage IA CTCL. 
     
     
         48 . The method of  claim 46 , wherein the subject in need thereof has Stage IB CTCL. 
     
     
         49 . The method of  claim 46 , wherein the subject in need thereof has Stage IIA CTCL. 
     
     
         50 . The method of  claim 46 , wherein the subject in need thereof has Stage IIB CTCL. 
     
     
         51 . The method of  claim 46 , wherein the subject in need thereof has Stage III CTCL. 
     
     
         52 . The method of  claim 46 , wherein the subject in need thereof has Stage IV CTCL. 
     
     
         53 . (canceled) 
     
     
         54 . The method of  claim 46 , wherein said CCR2 antagonist is selected from the group consisting of 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         55 - 59 . (canceled) 
     
     
         60 . The method of  claim 46 , wherein said CCR2 antagonist is selected from the group consisting of 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         61 - 70 . (canceled)