Substituted tetrahydropyrans as ccr2 modulators

Abstract

and are useful in pharmaceutical compositions, methods for the treatment of diseases and disorders involving the pathologic activation of CCR2 receptors.

1 .- 55 . (canceled) 
     
     
         56 . A method of treating cancer in a mammal in need thereof, comprising administering to the mammal an effective amount of a compound selected from the group consisting of 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         57 . The method of  claim 56 , wherein said cancer is selected from the group consisting of Melanoma, Small Cell Lung Carcinoma, Non Small Cell Lung Carcinoma, Pancreatic Cancer, Breast Cancer, Bladder Cancer, Renal Cell Carcinoma, Colorectal Cancer, Hepatocellular Carcinoma, Head and Neck Squamous Cell Carcinoma, Esophageal Cancer, Ovarian Cancer, Prostate Cancer, Gastric Cancer, Acute myelogenous leukemia, leukemia. 
     
     
         58 . The method of  claim 56 , wherein said cancer is selected from the group consisting of Small Cell Lung Carcinoma, Non Small Cell Lung Carcinoma, Pancreatic Cancer, Breast Cancer, Bladder Cancer, Renal Cell Carcinoma, Colorectal Cancer, Esophageal Cancer, Ovarian Cancer, Prostate Cancer, Gastric Cancer. 
     
     
         59 . The method of  claim 56 , wherein said cancer is Colorectal Cancer. 
     
     
         60 . A pharmaceutical composition comprising a compound having the formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, hydrate, stereoisomer or rotamer thereof; wherein 
         the subscripts m and n are each independently 0, 1, or 2, wherein the sum of m and n is less than or equal to 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: 
         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 —CONR 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 f , —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 1 , —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 —R j , —X 1 —NR g R h , —X 1 —CONR g R h , —X 1 —NR h C(O)R g , —NHR j , —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; 
         and the subscript q is 1, 2, 3, 4, or 5, and wherein said compound is substantially free of other stereoisomers. 
       
     
     
         61 . The pharmaceutical composition of  claim 60 , wherein R 3  is a member selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, cyclopropyl, cyclopropylmethyl, cyclobutyl and cyclobutylmethyl. 
     
     
         62 . The pharmaceutical composition of  claim 60 , wherein m and n are both 0. 
     
     
         63 . The pharmaceutical composition of  claim 60 , wherein m and n are both 1. 
     
     
         64 . The pharmaceutical composition of  claim 60 , wherein m is 1 and n is 0. 
     
     
         65 . The pharmaceutical composition of  claim 60 , wherein m is 1 and n is 2. 
     
     
         66 . The pharmaceutical composition of  claim 60 , wherein —N(R 1 )(R 2 ) is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         67 . The pharmaceutical composition of  claim 60 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         68 . The pharmaceutical composition of  claim 60 , wherein the compound is selected from the group consisting of 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof.