Quinazoline derivatives as medicaments

Abstract

The invention is directed to methods to inhibit TGF-βand/or p38-α kinase using compounds of the formula or the pharmaceutically acceptable salts thereof wherein R 3 is a noninterfering substituent; each Z is CR 2 or N, wherein no more than two Z positions in ring A are N, and wherein two adjacent Z positions in ring A cannot be N; each R 2 is independently a noninterfering substituent; L is a linker; n is 0 or 1;and Ar′ is the residue of a cyclic aliphatic, cyclic heteroaliphatic, aromatic or heteroaromatic moiety optionally substituted with 1-3 noninterfering substituents.

1 . A method to treat conditions characterized by enhanced p38-α activity and/or enhanced TGF-β activity, which method comprises administering to a subject in need of such treatment a compound of the formula:  
       
         
           
           
               
               
           
         
       
       or the pharmaceutically acceptable salts thereof 
 wherein R 3  is a noninterfering substituent;  
 each Z is CR 2  or N, wherein no more than two Z positions in ring A are N, and wherein two adjacent Z positions in ring A cannot be N;  
 each R 2  is independently a noninterfering substituent;  
 L is a linker;  
 n is 0 or 1; and  
 Ar′ is the residue of a cyclic aliphatic, cyclic heteroaliphatic, aromatic or heteroaromatic moiety optionally substituted with 1-3 noninterfering substituents:  
 
     
     
         2 . The method of  claim 1  wherein said condition is a proinflammation response or a fibroproliferative response or both.  
     
     
         3 . The method of  claim 2  wherein said proinflammation response is multiple sclerosis, IBD, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis, other arthritic conditions, sepsis, septic shock, endotoxic shock, Gram-negative sepsis, toxic shock syndrome, asthma, adult respiratory distress syndrome, stroke, reperfusion injury, CNS injury, psoriasis, restenosis, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcosis, a bone resorption disease, graft-versus-host reaction, Crohn's Disease, ulcerative colitis, or pyresis.  
     
     
         4 . The method of  claim 2  wherein said fibroproliferative response is associated with a renal disorder, a vascular disorder, a fibrosis, an autoimmune disorder, an eye disease, excessive scarring, a neurological condition, myelofibrosis, tissue thickening, nasal polyposis, a polyp, liver cirrhosis, or osteoporosis.  
     
     
         5 . The method of  claim 4  wherein said renal disorder, is glomerulonephritis, diabetic nephropathy, renal interstitial fibrosis, renal fibrosis in transplant patients receiving cyclosporin, and HIV-associated nephropathy; and 
 wherein said vascular disorder is progressive systemic sclerosis, polymyositis, scleroderma, dermatomyositis, eosinophilic fascitis, morphea, or Raynaud's syndrome; and  
 wherein said fibrosis is associated with adult respiratory distress syndrome, idiopathic pulmonary fibrosis, interstitial pulmonary fibrosis, cardiac fibrosis, keloid formation, or hypertrophic scarring; and  
 wherein said autoimmune disorder is systemic lupus erythematosus, scleroderma, or rheumatoid arthritis; and  
 wherein said eye disease is retinal detachment, cataracts, or glaucoma; and  
 wherein said neurological condition is CNS injury, Alzheimer's disease, or Parkinson's disease.  
 
     
     
         6 . The method of  claim 1  wherein R 3  is a hydrocarbyl residue (1-20C) containing 0-5 heteroatoms selected from O, S and N.  
     
     
         7 . The method of  claim 6  wherein R 3  is alkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, or heteroarylalkyl, each unsubstituted or substituted with 1-3 substituents.  
     
     
         8 . The method of  claim 7  wherein said substituents are independently selected from the group consisting of halo, OR, NR 2 , SR, —SOR, —SO 2 R, —OCOR, —NRCOR, —NRCONR 2 , —NRCOOR, —NRSOR, —NRSO 2 R, —OCONR 2 , RCO, —COOR, —SO 3 R, —CONR 2 , SO 2 NR 2 , CN, CF 3 , and NO 2 , wherein each R is independently H or alkyl (1-4C) and with respect to any aryl or heteroaryl moiety, said group further including alkyl (1-6C).  
     
     
         9 . The method of  claim 1  wherein said substituents on substituted Ar are independently selected from the group consisting of optionally substituted alkyl, alkenyl, alkynyl, aryl, alkylaryl, aroyl, N-aryl, NH-alkylaryl, NH-aroyl, halo, OR, NR 2 , SR, —SOR, —SO 2 R, —OCOR, —NRCOR, —NRCONR 2 , —NRCOOR, —NRSOR, —NRSO 2 R, —OCONR 2 , RCO, —COOR, —SO 3 R, —CONR 2 , SO 2 NR 2 , CN, CF 3 , and NO 2 , wherein each R is independently H or alkyl (1-4C), 
 and wherein any aryl or aroyl groups on said substituents may be further. substituted by alkyl, alkenyl, alkynyl, halo, OR, NR 2 , SR, —SOR, —SO 2 R, —OCOR, —NRCOR, —NRCONR 2 , —NRCOOR, —NRSOR, —NRSO 2 R, —OCONR 2 , RCO, —COOR, —SO 3 R, —CONR 2 , SO 2 NR 2 , CN, CF 3 , and NO 2 , wherein each R is independently H or alkyl (1-4C).  
 
     
     
         10 . The method of  claim 9  wherein Ar is phenyl, 2-, 3-, or 4-pyridyl, 2- or 4-pyrimidyl, indolyl, isoquinolyl, quinolyl, benzimidazolyl, benzotriazolyl, benzothiazolyl, benzofuranyl, pyridyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, or morpholinyl, all of which may optionally be substituted.  
     
     
         11 . The method of  claim 1  wherein each R 2  is independently a hydrocarbyl residue (1-20C) containing 0-5 heteroatoms selected from O, S and N.  
     
     
         12 . The method of  claim 11  wherein each R 2  is independently H, alkyl, alkenyl, alkynyl, acyl or hetero-forms thereof or is aryl, arylalkyl, heteroalkyl, heteroaryl, or heteroarylalkyl, each unsubstituted or substituted with 1-3 substituents selected independently from the group consisting of alkyl, alkenyl, alkynyl, aryl, alkylaryl, aroyl, N-aryl, NH-alkylaryl, NH-aroyl, halo, OR, NR 2 , SR, —SOR, —SO 2 R, —OCOR, —NRCOR, —NRCONR 2 , —NRCOOR, —NRSOR, —NRSO 2 R, —OCONR 2 , RCO, —COOR, —SO 3 R, —CONR 2 , SO 2 NR 2 , CN, CF 3 , and NO 2 , wherein each R is independently H or alkyl (1-4C), 
 and wherein any aryl or aroyl groups on said substituents may be further substituted by alkyl, alkenyl, alkynyl, halo, OR, NR 2 , SR, —SOR, —SO 2 R, —OCOR, —NRCOR, —NRCONR 2 , —NRCOOR, —NRSOR, —NRSO 2 R, —OCONR 2 , RCO, —COOR, —SO 3 R, —CONR 2 , SO 2 NR 2 , CN, CF 3 , and NO 2 , wherein each R is independently H or alkyl (1-4C), or  
 R 2  is selected from the group consisting of halo, OR, NR 2 , SR, —SOR, —SO 2 R, —OCOR, —NRCOR, —NRCONR 2 , —NRCOOR, NRSOR, NRSO 2 R, —OCONR 2 , RCO, —COOR, —SO 3 R, NRSOR, NRSO 2 R, —CONR 2 , SO 2 NR 2 , CN, CF 3 , and NO 2 , wherein each R is independently H or alkyl (1 -4C).  
 
     
     
         13 . The method of  claim 11  wherein said substituents on R 2  are independently selected from the group consisting of R 4 , halo, OR 4 , NR 2 , SR 4 , —OOCR 4 , —NROCR 4 , —COOR 4 , R 4 CO, —CONR 4   2 , —SO 2 NR 2 , CN, CF 3 , and NO 2 , wherein each R 4  is independently H, or optionally substituted alkyl (1-6C), or optionally substituted arylalkyl (7-12C) and wherein two R 4  or two substituents on said alkyl or arylalkyl taken together may form a fused aliphatic ring of 5-7 members.  
     
     
         14 . The method of  claim 1  wherein n is 0 or n is 1 and L is a bivalent residue that provides a distance of 2-8 Å between ring B and Ar′.  
     
     
         15 . The method of  claim 14  wherein L is S(CR 2   2 ) m , —NR 1 SO 2 (CR 2   2 ) l , SO 2 (CR 2   2 ) m , SO 2 NR 1 (CR 2   2 ) l , NR 3 (CR 2   2 ) m , NR 1 CO(CR 2   2 ) l , O(CR 2   2 ) m , or OCO(CR 2   2 ) l ,  
       
         
           
           
               
               
           
         
       
       wherein Z is N or CH and wherein m is 0-4 and l is 0-3; 
 R 1  is H, alkyl or arylalkyl where the aryl moiety may be substituted by 1-3 substituents selected independently from the group consisting of alkyl, alkenyl, alkynyl, aryl, alkylaryl, aroyl, N-aryl, NH-alkylaryl, NH-aroyl, halo, OR, NR 2 , SR, —SOR, —SO 2 R, —OCOR, —NRCOR, —NRCONR 2 , —NRCOOR, —NRSOR, —NRSO 2 R, —OCONR 2 , RCO, —COOR, —SO 3 R, —CONR 2 , SO 2 NR 2 , CN, CF 3 , and NO 2 , wherein each R is independently H or alkyl (1-4 C);  
 and wherein any aryl or aroyl groups on said substituents may be further substituted by alkyl, alkenyl, alkynyl, halo, OR, NR 2 , SR, —SOR, —SO 2 R, —OCOR, —NRCOR, —NRCONR 2 , —NRCOOR, —NRSOR, —NRSO 2 R, —OCONR 2 , RCO, —COOR, —SO 3 R, —CONR 2 , SO 2 NR 2 , CN, CF 3 , and NR 2 , wherein each R is independently H or alkyl (1-4C); and  
 R 2  is as defined in  claim 12 .  
 
     
     
         16 . The method of  claim 1  wherein the compound of formula (1) is selected from the group consisting of compounds 1-87 herein.  
     
     
         17 . The method of  claim 1  wherein the compound of formula (1) is selected from the group consisting of compounds shown in FIGS.  1 A- 1 C herein.  
     
     
         18 . A pharmaceutical composition for treating conditions characterized by enhanced p38-α activity and/or enhanced TGF-β activity which composition comprises 
 a therapeutically effective amount of a compound of the formula  
                     
 or the pharmaceutically acceptable salts thereof  
 wherein R 3  is a noninterfering substituent;  
 each Z is CR 2  or N, wherein no more than two Z positions in ring A are N, and wherein two adjacent Z positions in ring A cannot be N;  
 each R 2  is independently a noninterfering substituent;  
 L is a linker;  
 n is 0 or 1; and  
 Ar′ is the residue of a cyclic aliphatic, cyclic heteroaliphatic, aromatic or heteroaromatic moiety optionally substituted with 1-3 noninterfering substituents in admixture with at least one pharmaceutically acceptable excipient.  
 
     
     
         19 . The composition of  claim 18  which further contains an additional therapeutic agent.  
     
     
         20 . The composition of  claim 19  wherein said additional therapeutic agent is a corticosteroid, a monoclonal antibody, or an inhibitor of cell division.  
     
     
         21 . A compound of the formula:  
       
         
           
           
               
               
           
         
       
       and the pharmaceutically acceptable salts thereof 
 wherein each R 2  is independently a noninterfering substituent;  
 m is an integer of 0-4;  
 Z is CH;  
 R 1  is alkyl (1-6C) or arylalkyl optionally substituted on the aryl group with 1-3 substituents independently selected from alkyl (1-6C), halo, OR, NR 2 , SR, —OOCR, —NROCR, RCO, —COOR, —CONR 2 , —SO 2 NR 2 , CN, CF 3 , and NO 2 , wherein each R is independently H or lower alkyl (1-4C);  
 n is 0, 1 or 2; and  
 (a) Ar is phenyl, substituted with at least one group selected from the group consisting of optionally substituted alkyl (1-6C), halo, OR, NR 2 , SR, —OOCR, —NROCR, RCO, —COOR, —CONR 2 , SO 2 NR 2 , CN, CF 3 , and NO 2 , wherein each R is independently H or lower alkyl (1-4C), or pyridyl, indolyl, or pyrimidyl, each optionally substituted with at least one group selected from the group consisting of optionally substituted alkyl (1-6C), halo, OR, NR 2 , SR, —OOCR, —NROCR, RCO, —COOR, —CONR 2 , SO 2 NR 2 , CN, CF 3 , and NO 2 , wherein each R is independently H or lower alkyl (1-4C); and 
 R 3  is a branched or cyclic alkyl group (5-7C) or is phenyl optionally substituted with 1-2 substituents which substituents are selected from the group consisting of alkyl (1-6C), halo, OR, NR 2 , SR, —OOCR, —NROCR, RCO, —COOR, —CONR 2 , —SO 2 NR 2 , CN, CF 3 , and NO 2 , wherein each R is independently H or lower alkyl (1-4C); or  
 
 (b) Ar is phenyl, pyridyl, indolyl, or pyrimidyl, each optionally substituted with a group selected from the group consisting of optionally substituted alkyl (1-6C), halo, OR, NR 2 , SR, —OOCR, —NROCR, RCO, —COOR, —CONR 2 , SO 2 NR 2 , CN, CF 3 , and NO 2 , wherein each R is independently H or lower alkyl (1 -4C); and 
 R 3  is a branched or cyclic alkyl group (5-7C) or is phenyl substituted with 1-2 substituents which substituents are selected from the group consisting of alkyl (1-6C), halo, SR, —OOCR, —NROCR, RCO, —COOR, —CONR 2 , —SO 2 NR 2 , CN, and CF 3 , wherein each R is independently H or lower alkyl (1-4C); or  
 
 (c) Ar is phenyl substituted with a group selected from the group consisting of optionally substituted NR 2 , SR, —NROCR, RCO, —CONR 2 , SO 2 NR 2 , CN, and CF 3 , wherein each R is independently H or lower alkyl (1-4C); or pyridyl substituted with a group selected from the group consisting of optionally substituted alkyl (1-6C), halo, OR, NR 2 , SR, —OOCR, —NROCR, RCO, —COOR, —CONR 2 , SO 2 NR 2 , CN, CF 3 , and NO 2 , wherein each R is independently H or lower alkyl (1-4C); or indolyl or pyrimidyl, each optionally substituted with a group selected from the group consisting of optionally substituted alkyl (1-6C), halo, OR, NR 2 , SR, —OOCR, —NROCR, RCO, —COOR, —CONR 2 , SO 2 NR 2 , CN, CF 3 , and NO 2 , wherein each R is independently H or lower alkyl (1-4 C); and 
 R 3  is a branched or cyclic alkyl group (5-7C) or is phenyl optionally substituted with 1-2 substituents which substituents are selected from the group consisting of allyl (1-6C), halo, OR, NR 2 , SR, —OOCR, —NROCR, RCO, —COOR, —CONR 2 , —SO 2 NR 2 , CN, CF 3 , and NO 2 , wherein each R is independently H or lower alkyl (1-4C); or  
 
 (d) Ar is phenyl, pyridyl, indolyl, or pyrimidyl, each optionally substituted with a group selected from the group consisting of optionally substituted alkyl (1-6C), halo, OR, NR 2 , SR, —OOCR, —NROCR, RCO, —COOR, —CONR 2 , SO 2 NR 2 , CN, CF 3 , and NO 2 , wherein each R is independently H or lower alkyl (1-4C); and 
 R 3  is a branched or cyclic alkyl group (5-7C) or is phenyl substituted with 1-2 substituents which substituents are selected from the group consisting of alkyl (1-6C), halo, OR, SR, —OOCR, —NROCR, RCO, —COOR, —CONR 2 , —SO 2 NR 2 , CN, CF 3 , and NO 2 , wherein each R is independently H or lower alkyl (1-4C).  
 
 
     
     
         22 . The compound of  claim 1  which is selected from the group consisting of 
 2-phenyl-4-(4-pyridylamino)-quinazoline;  
 2-(2-bromophenyl)-4-(4-pyridylamino)-quinazoline;  
 2-(2-chlorophenyl)-4-(4-pyridylamino)-quinazoline;  
 2-(2-fluorophenyl)-4-(4-pyridylamino)-quinazoline;  
 2-(2-methylphenyl)-4-(4-pyridylamino)-quinazoline;  
 2-(4-fluorophenyl)-4-(4-pyridylamino)-quinazoline;  
 2-(3 -methoxyanilyl)-4-(4-pyridylamino)-quinazoline;  
 2-(2,6-dichlorophenyl)-4-(4-pyridylarnino)-quinazoline;  
 2-(2,6-dibromophenyl)-4-(4-pyridylamino)-quinazoline;  
 2-(2,6-difluorophenyl)-4-(4-pyridylamino)-quinazoline;  
 2-(2-fluorophenyl)-4-(4-pyridylamino)-6,7-dimethoxyquinazoline;  
 2-(4-fluorophenyl)-4-(4-pyridylamino)-6,7-dimethoxyquinazoline;  
 2-(2-fluorophenyl)-4-(4-pyridylamino)-6-nitroquinazoline;  
 2-(2-fluorophenyl)-4-(4-pyridylamino -6-aminoquinazoline;  
 2-(2-fluorophenyl)-4-(4-pyridylamino)-7-aminoquinazoline;  
 2-(2-fluorophenyl)-4-(4-pyridylamino)-6-(3-methoxybenzylamino)-quinazoline;  
 2-(2-fluorophenyl)-4-(4-pyridylamino)-6-(4-methoxybenzylamino)-quinazoline;  
 2-(2-fluorophenyl)-4-(4-pyridylamino)-6-(2-isobutylamino)-quinazoline; and  
 2-(2-fluorophenyl)-4-(4-pyridylamino)-6-(4-methylmercaptobenzylamino)-quinazoline.