Antagonists of chemokine receptors

Abstract

Compounds are provided that act as potent antagonists of the CCR1 receptor, and have in vivo anti-inflammatory activity. The compounds are generally aryl piperazine derivatives and are useful in pharmaceutical compositions, methods for the treatment of CCR1-mediated diseases, and as controls in assays for the identification of competitive CCR1 antagonists.

What is claimed is: 
     
         1 . A compound having a formula: 
       
         
           
           
               
               
           
         
       
       wherein
 the subscript n is an integer of from 0 to 3; 
 each R 1a  and R 1b  is a member independently selected from the group consisting of H, C 1-8  alkyl, C 1-8  haloalkyl, C 3-6  cycloalkyl, —COR a , —CO 2 R a , —CONR a R b , —NR a R b , —NR a COR b , —OR a , —X 1 COR a , —X 1 CO 2 R a , —X 1 CONR a R b , —X 1 NR a COR b , —X 1 NR a R b , and —X 1 OR a , wherein X 1  is a member selected from the group consisting of C 1-4  alkylene, and each R a  and R b  is independently selected from the group consisting of hydrogen, C 1-8  alkyl, C 1-8  haloalkyl, and C 3-6  cycloalkyl, and optionally two R 1a  groups on adjacent carbon atoms are joined to form a 5-, 6- or 7-membered carbocyclic or heterocyclic ring; 
 each of R 2a  and R 2b  is a member independently selected from the group consisting of H, hydroxyl, C 1-8  alkyl, C 1-8  haloalkyl, C 1-8  alkoxy, C 1-4  alkoxy-C 1-4  alkyl, C 1-8  hydroxyalkyl, C 1-4 alkoxy-C 1-4 alkoxy, C 3-6  cycloalkyl, C 3-6  cycloalkyl-C 1-4  alkyl, 3- to 7-membered heterocycloalkyl, 3- to 7-membered heterocycloalkyl-C 1-4  alkyl, —X 1 CO 2 R a , —X 1 CONR a R b , —X 1 NR a COR b , —X 1 NR a R b , wherein X 1 , R a  and R b  are defined above; 
 Ar 1  is a member selected from the group consisting a six- or ten-membered monocyclic or fused bicyclic aryl ring, and a five- to ten-membered monocyclic or fused bicyclic heteroaryl ring; each of which is substituted with from one to five substituents, R 3 , R 3a , R 3b , R 4  and R 4a  which are independently selected from the group consisting of H, halogen, —OR c , —OC(O)R c , —NR c R d , —SR c , —R e , —CN, —NO 2 , —CO 2 R c , —CONR c R d , —C(O)R c , —OC(O)NR c R d , —NR d C(O)R c , —NR d C(O) 2 R e , —NR c —C(O)NR c R d , —NH—C(NH 2 )═NH, —NR e C(NH 2 )═NH, —NH—C(NH 2 )═NR e , —NH—C(NHR e )═NH, —S(O)R e , —S(O) 2 R e , —NR c S(O) 2 R e , —S(O) 2 NR c R d , —N 3 , —X 2 OR c , —O—X 2 OR c , —X 2 OC(O)R c , —X 2 NR c R d , —O—X 2 NR c R d , —X 2 SR c , —X 2 CN, —X 2 NO 2 , —X 2 CO 2 R c , —O—X 2 CO 2 R c , —X 2 CONR c R d , —O—X 2 CONR c R d , —X 2 C(O)R c , —X 2 OC(O)NR c R d , —X 2 NR d C(O)R c , —X 2 NR d C(O) 2 R e , —X 2 NR c C(O)NR c R d , —X 2 NH—C(NH 2 )═NH, —X 2 NR e C(NH 2 )═NH, —X 2 NH—C(NH 2 )═NR e , —X 2 NH—C(NHR e )═NH, —X 2 S(O)R e , —X 2 S(O) 2 R e , —X 2 NR c S(O) 2 R e , —X 2 S(O) 2 NR c R d , —X 2 N 3 , —NR d —X 2 OR c , —NR d —X 2 NR c R d , —NR d —X 2 CO 2 R c , and —NR d —X 2 CONR c R d , wherein each X 2  is a member independently selected from the group consisting of C 1-4  alkylene, and each R c  and R d  is independently selected from hydrogen, C 1-8  alkyl, C 1-8  hydroxyalkyl, C 1-8  haloalkyl and C 3-6  cycloalkyl, or optionally R c  and R d  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; and each R e  is independently selected from the group consisting of C 1-8  alkyl, C 1-8  hydroxyalkyl, C 1-8  haloalkyl and C 3-6  cycloalkyl; 
 Ar 2  is a member selected from the group consisting of a six- or ten-membered monocyclic or fused bicyclic aryl ring, and a five- to ten-membered monocyclic or fused bicyclic heteroaryl ring; each of which is substituted with from one to five substituents, R 5 , R 6 , R 7 , R 8  and R 9 , independently selected from the group consisting of H, halogen, —OR f , —OC(O)R f , —NR f R g , —SR f , —R h , —CN, —NO 2 , —CO 2 R f , —CONR f R g , —C(O)R f , —OC(O)NR f R g , —NR g C(O)R f , —NR g C(O) 2 R h , —NR f —C(O)NR f R g , —NH—C(NH 2 )═NH, —NR h C(NH 2 )═NH, —NH—C(NH 2 )═NR h , —NH—C(NHR h )═NH, —S(O)R h , —S(O) 2 R h , —NR f S(O) 2 R h , —S(O) 2 NR f R g , —NR f S(O) 2 NR f R g , —N 3 , —X 3 OR f , —X 3 OC(O)R f , —X 3 NR f R g , —X 3 SR f , —X 3 CN, —X 3 NO 2 , —X 3 CO 2 R f , —X 3 CONR f R g , —X 3 C(O)R f , —X 3 OC(O)NR f R g , —X 3 NR g C(O)R f , —X 3 NR g C(O) 2 R h , —X 3 NR f —C(O)NR f R g , —X 3 NH—C(NH 2 )═NH, —X 3 NR h C(NH 2 )═NH, —X 3 NH—C(NH 2 )═NR h , —X 3 NH—C(NHR h )═NH, —X 3 S(O)R h , —X 3 S(O) 2 R h , —X 3 NR f S(O) 2 R h , —X 3 S(O) 2 NR f R g , —Y, —X 3 Y, —S(O) 2 Y, —C(O)Y, —X 3 N 3 , —O—X 3 OR f , —O—X 3 NR f R g , —O—X 3 CO 2 R f , —O—X 3 CONR f R g , —NR g —X 3 OR f , —NR g —X 3 NR f R g , —NR g —X 3 CO 2 R f , and —NR g —X 3 CONR f R g , wherein Y is a five or six-membered aryl, heteroaryl or heterocyclic ring, optionally substituted with from one to three substitutents selected from the group consisting of halogen, —OR f , —OC(O)R f , —NR f R g , —R h , —SR f , —CN, —NO 2 , —CO 2 R f , —CONR f R g , —C(O)R f , —NR g C(O)R f , —NR g C(O) 2 R h , —S(O)R h , —S(O) R h , —NR f S(O) 2 R h , —S(O) 2 NR f R g , —X 3 OR f , X 3 SR f , —X 3 CN, —X 3 NO 2 , —X 3 CO 2 R f , —X 3 CONR f R g , —X 3 C(O)R f , —X 3 OC(O)NR f R g , —X 3 NR g C(O)R f , —X 3 NR g C(O) 2 R h , —X 3 NR f —C(O)NR f R g , —X 3 OC(O)R f , —X 3 S(O)R h , —X 3 S(O) 2 R h , —X 3 NR f R g , —X 3 NR f S(O) 2 R h , —X 3 S(O) 2 NR f R g , —O—X 3 OR f , —O—X 3 NR f R g , —O—X 3 CO 2 R f , —O—X 3 CONR f R g , —NR g —X 3 OR f , —NR g —X 3 NR f R g , —NR g —X 3 CO 2 R f , and —NR g —X 3 CONR f R g  and wherein each X 3  is independently selected from the group consisting of C 1-4  alkylene, and each R f  and R g  is independently selected from hydrogen, C 1-8  alkyl, C 1-8  hydroxyalkyl, C 1-8  haloalkyl and C 3-6  cycloalkyl, 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, and each R h  is independently selected from the group consisting of C 1-8  alkyl, C 2-8  alkenyl, C 2-8  alkynyl, C 1-8  hydroxyalkyl, C 1-8  haloalkyl and C 3-6  cycloalkyl; or when two of R 5 , R 6 , R 7 , R 8  and R 9 , are attached to adjacent ring vertices of Ar 2 , are optionally combined to form a five or six membered ring having zero, one or two heteroatoms selected from O and N as ring members; 
 or a salt, rotamer or optical isomers thereof. 
 
     
     
         2 . A compound of  claim 1 , wherein Ar 1  is selected from the group consisting of phenyl, naphthyl, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl, quinolinyl, quinoxalinyl and purinyl, each of which is optionally substituted with R 3 , R 3a , R 3b , R 4  and R 4a . 
     
     
         3 . A compound of  claim 1 , wherein Ar 2  is selected from the group consisting of phenyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, oxathiadiazolyl, pyrrolyl, thiazolyl, isothiazolyl, benzimidazolyl, benzoxazolyl, benzopyrazolyl, benzotriazolyl, pyrazolo[3,4-b]pyridine, pyrazolo[3,4-c]pyrimidine, imidazo[4,5-b]pyridine, imidazo[1,5-a]pyridine, and pyrrolo[2,3-b]pyridine, each of which is optionally substituted with R 5 , R 6  and R 7 . 
     
     
         4 . A compound of  claim 1 , wherein Ar 1  is selected from the group consisting of phenyl, naphthyl and pyridyl, each of which is substituted with from one to five substituents, R 3 , R 3a , R 3b , R 4  and R 4a . 
     
     
         5 . A compound of  claim 1 , wherein Ar 2  is selected from the group consisting of pyrazolyl, imidazolyl and triazolyl, each of which is substituted with R 5 , R 6  and R 7 . 
     
     
         6 . A compound of  claim 1 , wherein Ar 1  is selected from the group consisting of phenyl, naphthyl and pyridyl, each of which is substituted with from one to five substituents, R 3 , R 3a , R 3b , R 4  and R 4a ; and Ar 2  is selected from the group consisting of pyrazolyl, imidazolyl and triazolyl, each of which is substituted with R 5 , R 6  and R 7 . 
     
     
         7 . A compound of  claim 1 , wherein Ar 1  is phenyl, which is substituted with from one to five substituents, R 3 , R 3a , R 3b , R 4  and R 4a , and Ar 2  is selected from the group consisting of pyrazolyl, imidazolyl, benzimidazolyl, benzopyrazolyl, pyrazolo[3,4-b]pyridine, pyrazolo[3,4-d]pyrimidine, imidazo[4,5-b]pyridine, imidazo[1,5-c]pyridine, and pyrrolo[2,3-b]pyridine, each of which is optionally substituted with R 5 , R 6  and R 7 . 
     
     
         8 . A compound of  claim 1 , wherein said compound has the formula: 
       
         
           
           
               
               
           
         
       
       wherein R 3  and R 4  are independently selected from the group consisting of H, halogen, —R e , —CN, and —SO 2 R e . 
     
     
         9 . A compound of  claim 8 , wherein Ar 2  is a heteroaryl group. 
     
     
         10 . A compound of  claim 8 , wherein Ar 2  is a heteroaryl group, optionally substituted and attached to the remainder of the molecule through a nitrogen atom ring vertex. 
     
     
         11 . A compound of  claim 10 , wherein said Ar 2  has the formula: 
       
         
           
           
               
               
           
         
       
       wherein R 5 , R 6 , and R 7  are independently selected from the group consisting of H, halogen, —R h , —CN, —SO 2 R h , —CO 2 R f , —CONR f R g , and Y. 
     
     
         12 . A compound of  claim 11 , having the formula: 
       
         
           
           
               
               
           
         
       
       wherein R 4  is selected from the group consisting of F and Cl. 
     
     
         13 . A compound of  claim 12 , wherein Y is selected from the group consisting of pyridyl, pyrimidinyl, imidazolyl, oxazolyl, oxadiazolyl, triazolyl, thiazolyl, imidazolinyl and pyrazolyl. 
     
     
         14 . A compound of  claim 12 , having the formula: 
       
         
           
           
               
               
           
         
       
       wherein R 3  is selected from the group consisting of H, halogen, C 1-8  alkyl, C 1-8  haloalkyl and C 1-8  alkoxy; R 1a  and R 2a  are independently selected from the group consisting of H, C 1-8  alkyl, C 1-8  haloalkyl, C 1-8  alkoxy and C 1-8  hydroxyalkyl. 
     
     
         15 . A compound of  claim 1 , having the formula: 
       
         
           
           
               
               
           
         
       
       wherein R 1a  and R 2a  are independently selected from the group consisting of H, C 1-8  alkyl, C 1-8  haloalkyl, C 1-8  alkoxy and C 1-8  hydroxyalkyl; and R 5 , R 6 , and R 7  are independently selected from the group consisting of H, halogen, —R h , —CN, —SO 2 R h , —CO 2 R f , —CONR f R g , and Y. 
     
     
         16 . A compound of  claim 1 , having the formula: 
       
         
           
           
               
               
           
         
       
       Where R 1a  and R 2a  are independently selected from the group consisting of H, C 1-8  alkyl, C 1-8  haloalkyl, C 1-8  alkoxy and C 1-8  hydroxyalkyl; and R 5 , R 6 , and R 7  are independently selected from the group consisting of H, halogen, —R h , —CN, —SO 2 R h , —CO 2 R f , —CONR f R g , and Y. 
     
     
         17 . A compound of  claim 1 , having the formula: 
       
         
           
           
               
               
           
         
       
       wherein R 1a  and R 2a  are each independently selected from the group consisting of H, C 1-8  alkyl, C 1-8  haloalkyl, C 1-8  alkoxy, and C 1-8  hydroxyalkyl; and R 5  and R 7  are each independently selected from the group consisting of H, halogen, —R h , —CN, —SO 2 R h , —CO 2 R f , —CONR f R g , and Y. 
     
     
         18 . A compound of  claim 1 , selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         19 . A compound of  claim 1 , wherein said compound is selected from those set forth in Table 1, or a pharmaceutically acceptable salt or N-oxide thereof. 
     
     
         20 . A pharmaceutical composition comprising a pharmaceutically acceptable excipient or carrier and a compound of  claim 1 . 
     
     
         21 . A pharmaceutical composition of  claim 20 , wherein said composition is formed as a stent or stent-graft device. 
     
     
         22 . A method of treating CCR1-mediated diseases or conditions comprising administering to a subject in need thereof a therapeutically effective amount of a compound or a composition of  claim 1 . 
     
     
         23 . A method in accordance with  claim 22 , wherein said CCR1-mediated disease or condition is an inflammatory condition. 
     
     
         24 . A method in accordance with  claim 22 , wherein said CCR1-mediated disease or condition is an immunoregulatory disorder. 
     
     
         25 . A method in accordance with  claim 22 , wherein said CCR1-mediated disease or condition is selected from the group consisting of rheumatoid arthritis, multiple sclerosis, transplant rejection, dermatitis, eczema, urticaria, vasculitis, inflammatory bowel disease, food allergy, asthma, Alzheimer's disease, Parkinson's disease, psoriasis, lupus erythematosus, osteoarthritis, stroke, restenosis, radiation-induced pulmonary disease and encephalomyelitis. 
     
     
         26 . A method in accordance with  claim 22 , wherein said administering is oral, parenteral, rectal, transdermal, sublingual, nasal or topical. 
     
     
         27 . A method in accordance with  claim 22 , wherein said compound is administered in combination with an anti-inflammatory agent, analgesic agent, an anti-proliferative agent, a metabolic inhibitor, a leukocyte migration inhibitor or an immuno-modulator.