Pyrazolopyridinone derivatives as lpa receptor antagonists

A method for modulating an LPA receptor wherein said LPA receptor is selected from LPA receptor 1, LPA receptor 2, LPA receptor 3, LPA receptor 4, LPA receptor 5 and LPA receptor 6 said method comprising modulating said receptor with a compound according to formula (I):

• wherein:
• R1 denotes aryl, heteroaryl, cycloalkyl, heterocyclyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocyclylalkyl, which in each case is unsubstituted or substituted with one or more substituents selected from alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halogen, —F, —Cl, —Br, —I, —CN, —CF3, —N3, —NH2, —NHZ1, —NZ2Z3, —NO2, —OH, —OCF3, —SH, —O—SO3H, —OP(O)(OH)2, —CHO, —COOH, —C(O)NH2, —SO3H, —P(O)(OH)2, —C(O)—Z4, —C(O)O—Z5, —C(O)NH—Z6, —C(O)NZ7Z8, —O—Z9, —O(—Z10-O)a—H, —O(—Z11-O)b—Z12, —OC(O)—Z13, —OC(O)—O—Z14, —OC(O)—NHZ15, —O—C(O)—NZ16Z17, —OP(O)(OZ18)(OZ19), —OSi(Z20)(Z21)(Z22), —OS(O2)—Z23, —NHC(O)—NH2, —NHC(O)—Z24, —NZ25C(O)—Z26, —NH—C(O)—O—Z27, —NH—C(O)—NH—Z28, —NH—C(O)—NZ29Z30, —NZ31-C(O)—O—Z32, —NZ33-C(O)—NH—Z34, —NZ35-C(O)—NZ36Z37, —NHS(O2)—Z38, —NZ39S(O2)—Z40, —S—Z41, —S(O)—Z42, —S(O2)—Z43, —S(O2)NH—Z44, —S(O2)NZ45Z46, —S(O2)O—Z47, —P(O)(OZ48)(OZ49), —Si(Z50)(Z51)(Z52), —C(NH)—NH2, —C(NZ53)-NH2, —C(NH)—NHZ54, —C(NH)—NZ55Z56, —C(NZ57)-NHZ58, —C(NZ59)-NZ60Z61, —NH—C(O)—NH—O—Z62, —NH—C(O)—NZ63-O—Z64, —NZ65-C(O)—NZ66-O—Z67, —N(—C(O)—NH—O—Z68)2, —N(—C(O)—NZ69-O—Z70)2, —N(—C(O)—NH—O—Z71)(-C(O)—NZ72-O—Z73), —C(S)—Z74, —C(S)—O—Z75, —C(S)—NH—Z76, —C(S)—NZ77Z78, —C(O)—NH—O—Z79, —C(O)—NZ80-O—Z81, —C(S)—NH—O—Z82, —C(S)—NZ83-O—Z84, —C(O)—NH—NH—Z85, —C(O)—NH—NZ86Z87, —C(O)—NZ88-NZ89Z90, —C(S)—NH—NH—Z91, —C(S)—NH—NZ92Z93, —C(S)—NZ94-NZ95Z96, —C(O)—C(O)—O—Z97, —C(O)—C(O)—NH2, —C(O)—C(O)—NHZ98, —C(O)—C(O)—NZ99Z100, —C(S)—C(O)—O—Z101, —C(O)—C(S)—O—Z102, —C(S)—C(S)—O—Z103, —C(S)—C(O)—NH2, —C(S)—C(O)—NHZ104, —C(S)—C(O)—NZ105Z106, —C(S)—C(S)—NH2, —C(S)—C(S)—NHZ107, —C(S)—C(S)—NZ108Z109, —C(O)—C(S)—NH2, —C(O)—C(S)—NHZ110, —C(O)—C(S)—NZ111Z112;
• Z1, Z2, Z3, Z4, Z5, Z6, Z7, Z8, Z9, Z10, Z11, Z12, Z13, Z14, Z15, Z16, Z17, Z18, Z19, Z20, Z21, Z22, Z23, Z24, Z25, Z26, Z27, Z28, Z29, Z30, Z31, Z32, Z33, Z34, Z35, Z36, Z37, Z38, Z39, Z40, Z41, Z42, Z43, Z44, Z45, Z46, Z47, Z48, Z49, Z50, Z51, Z52, Z53, Z54, Z55, Z56, Z57, Z58, Z59, Z60, Z61, Z62, Z63, Z64, Z65, Z66, Z67, Z68, Z69, Z70, Z71, Z72, Z73, Z74, Z75, Z76, Z77, Z78, Z79, Z80, Z81, Z82, Z83, Z84, Z85, Z86, Z87, Z88, Z89, Z90, Z91, Z92, Z93, Z94, Z95, Z96, Z97, Z98, Z99, Z100, Z101, Z102, Z103, Z104, Z105, Z106, Z107, Z108, Z109, Z110, Z111, Z112 are each, independently from each other, selected from alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, and wherein alternatively Z7, Z8 and/or Z16, Z17 and/or Z29, Z30 and/or Z36, Z37 and/or Z45, Z46 and/or Z55, Z56 and/or Z60, Z61 and/or Z77, Z78 and/or Z86, Z87 and/or Z89, Z90 and/or Z92, Z93 and/or Z95, Z96 and/or Z99, Z100 and/or Z105, Z106 and/or Z108, Z109 and/or Z111, Z112 can each, respectively, together form a heterocyclyl;
• a is 1, 2, 3, 4, or 5;
• b is 1, 2, 3, 4, or 5;
• R2 denotes H or alkyl;
• R3 denotes H or alkyl;
• R4, R5 independently from each other denote H, alkyl, OH-alkyl, alkoxy, halogen, F, Cl, Br, I, CN, NHR, NH2 NR2, S-alkyl or NH-alkyl-OH;
• R independently from each other denotes alkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl;
• R4 and R5 together can also form cycloalkyl or heterocyclyl;
• R6 denotes H;
• X denotes O;
• and the physiologically acceptable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios,
• with the proviso that the following compound is excluded from formula (I):

A method comprising at least one compound according for the treatment of a physiological and/or pathophysiological condition selected from the group consisting of:

• cancer, tumor, malignant tumors, benign tumors, solid tumors, sarcomas, carcinomas, hyperproliferative disorders, carcinoids, Ewing sarcomas, Kaposi sarcomas, brain tumors, tumors originating from the brain and/or the nervous system and/or the meninges, gliomas, glioblastomas, neuroblastomas, stomach cancer, kidney cancer, kidney cell carcinomas, prostate cancer, prostate carcinomas, connective tissue tumors, soft tissue sarcomas, pancreas tumors, liver tumors, head tumors, neck tumors, laryngeal cancer, esophageal cancer, thyroid cancer, osteosarcomas, retinoblastomas, thymoma, testicular cancer, lung cancer, lung adenocarcinoma, small cell lung carcinoma, bronchial carcinomas, breast cancer, mamma carcinomas, intestinal cancer, colorectal tumors, colon carcinomas, rectum carcinomas, gynecological tumors, ovary tumors/ovarian tumors, uterine cancer, cervical cancer, cervix carcinomas, cancer of body of uterus, corpus carcinomas, endometrial carcinomas, urinary bladder cancer, urogenital tract cancer, bladder cancer, skin cancer, epithelial tumors, squamous epithelial carcinoma, basaliomas, spinaliomas, melanomas, intraocular melanomas, leukemias, monocyte leukemia, chronic leukemia, chronic myelotic leukemia, chronic lymphatic leukemia, acute leukemia, acute myelotic leukemia, acute lymphatic leukemia, lymphomas, opthalmic diseases, choroidal neovascularization, diabetic retinopathy, inflammatory diseases, arthritis, neurodegeneration, transplant rejection, metastatic growth, fibrosis, restenosis, HIV infection, atherosclerosis, inflammation, heart failure, cardiomyopathy, myocardial infarction, myocardial remodeling, vascular remodeling, hypertension, peripheral arterial occlusive disease, restenosis, thrombosis, vascular permeability disorders, inflammatory diseases, rheumatoid arthritis, osteoarthritis, renal diseases, renal papillary necrosis, renal failure, pulmonary diseases, chronic obstructive pulmonary disease, asthma, acute respiratory distress syndrome, immunological diseases, allergic diseases, tumor growth, metastasis, metabolic diseases, fibrotic diseases, pulmonary fibrosis, cardiac fibrosis, vascular fibrosis, perivascular fibrosis, renal fibrosis, liver fibrosis, fibrosing skin conditions, psoriasis, pain, pruritus, retinal ischemia/reperfusion damage, macular degeneration, psychiatric disorders, neurodegenerative diseases, cerebral nerve disorders, peripheral nerve disorders, endocrinic disorders, hyperthyroidism, scarring disorders or for cardioprotection or renoprotection and disorders of wound healing, angiogenesis, cardiovascular system, bone, CNS and/or PNS, said method comprising administering to a patient in need thereof a compound according to formula (I):
• wherein:
• R1 denotes aryl, heteroaryl, cycloalkyl, heterocyclyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl or heterocyclylalkyl, which in each case is unsubstituted or substituted with one or more substituents selected from alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halogen, —F, —Cl, —Br, —I, —CN, —CF3, —N3, —NH2, —NHZ1, —NZ2Z3, —NO2, —OH, —OCF3, —SH, —O—SO3H, —OP(O)(OH)2, —CHO, —COOH, —C(O)NH2, —SO3H, —P(O)(OH)2, —C(O)—Z4, —C(O)O—Z5, —C(O)NH—Z6, —C(O)NZ7Z8, —O—Z9, —O(—Z10-O)a—H, —O(—Z11-O)b—Z12, —OC(O)—Z13, —OC(O)—O—Z14, —OC(O)—NHZ15, —O—C(O)—NZ16Z17, —OP(O)(OZ18)(OZ19), —OSi(Z20)(Z21)(Z22), —OS(O2)—Z23, —NHC(O)—NH2, —NHC(O)—Z24, —NZ25C(O)—Z26, —NH—C(O)—O—Z27, —NH—C(O)—NH—Z28, —NH—C(O)—NZ29Z30, —NZ31-C(O)—O—Z32, —NZ33-C(O)—NH—Z34, —NZ35-C(O)—NZ36Z37, —NHS(O2)—Z38, —NZ39S(O2)—Z40, —S—Z41, —S(O)—Z42, —S(O2)—Z43, —S(O2)NH—Z44, —S(O2)NZ45Z46, —S(O2)O—Z47, —P(O)(OZ48)(OZ49), —Si(Z50)(Z51)(Z52), —C(NH)—NH2, —C(NZ53)-NH2, —C(NH)—NHZ54, —C(NH)—NZ55Z56, —C(NZ57)-NHZ58, —C(NZ59)-NZ60Z61, —NH—C(O)—NH—O—Z62, —NH—C(O)—NZ63-O—Z64, —NZ65-C(O)—NZ66-O—Z67, —N(—C(O)—NH—O—Z68)2, —N(—C(O)—NZ69-O—Z70)2, —N(—C(O)—NH—O—Z71)(-C(O)—NZ72-O—Z73), —C(S)—Z74, —C(S)—O—Z75, —C(S)—NH—Z76, —C(S)—NZ77Z78, —C(O)—NH—O—Z79, —C(O)—NZ80-O—Z81, —C(S)—NH—O—Z82, —C(S)—NZ83-O—Z84, —C(O)—NH—NH—Z85, —C(O)—NH—NZ86Z87, —C(O)—NZ88-NZ89Z90, —C(S)—NH—NH—Z91, —C(S)—NH—NZ92Z93, —C(S)—NZ94-NZ95Z96, —C(O)—C(O)—O—Z97, —C(O)—C(O)—NH2, —C(O)—C(O)—NHZ98, —C(O)—C(O)—NZ99Z100, —C(S)—C(O)—O—Z101, —C(O)—C(S)—O—Z102, —C(S)—C(S)—O—Z103, —C(S)—C(O)—NH2, —C(S)—C(O)—NHZ104, —C(S)—C(O)—NZ105Z106, —C(S)—C(S)—NH2, —C(S)—C(S)—NHZ107, —C(S)—C(S)—NZ108Z109, —C(O)—C(S)—NH2, —C(O)—C(S)—NHZ110, —C(O)—C(S)—NZ111Z112;
• Z1, Z2, Z3, Z4, Z5, Z6, Z7, Z8, Z9, Z10, Z11, Z12, Z13, Z14, Z15, Z16, Z17, Z18, Z19, Z20, Z21, Z22, Z23, Z24, Z25, Z26, Z27, Z28, Z29, Z30, Z31, Z32, Z33, Z34, Z35, Z36, Z37, Z38, Z39, Z40, Z41, Z42, Z43, Z44, Z45, Z46, Z47, Z48, Z49, Z50, Z51, Z52, Z53, Z54, Z55, Z56, Z57, Z58, Z59, Z60, Z61, Z62, Z63, Z64, Z65, Z66, Z67, Z68, Z69, Z70, Z71, Z72, Z73, Z74, Z75, Z76, Z77, Z78, Z79, Z80, Z81, Z82, Z83, Z84, Z85, Z86, Z87, Z88, Z89, Z90, Z91, Z92, Z93, Z94, Z95, Z96, Z97, Z98, Z99, Z100, Z101, Z102, Z103, Z104, Z105, Z106, Z107, Z108, Z109, Z110, Z111, Z112 are each, independently from each other, selected from alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, and heteroarylalkyl, and wherein alternatively Z7, Z8 and/or Z16, Z17 and/or Z29, Z30 and/or Z36, Z37 and/or Z45, Z46 and/or Z55, Z56 and/or Z60, Z61 and/or Z77, Z78 and/or Z86, Z87 and/or Z89, Z90 and/or Z92, Z93 and/or Z95, Z96 and/or Z99, Z100 and/or Z105, Z106 and/or Z108, Z109 and/or Z111, Z112 can each, respectively, together form a heterocyclyl;
• a is 1, 2, 3, 4, or 5;
• b is 1, 2, 3, 4, or 5;
• R2 denotes H or alkyl;
• R3 denotes H or alkyl;
• R4, R5 independently from each other denote H, alkyl, OH-alkyl, alkoxy, halogen, F, Cl, Br, I, CN, NHR, NH2 NR2, S-alkyl or NH-alkyl-OH;
• R independently from each other denotes alkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl;
• R4 and R5 together can also form cycloalkyl or heterocyclyl;
• R6 denotes H;
• X denotes O;
• and the physiologically acceptable salts, tautomers and stereoisomers thereof, including mixtures thereof in all ratios,
• with the proviso that the following compound is excluded from formula (I):