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EP-4477271-B1 - N-(PHENYL)-5-(HETEROARYL)-1H-PYRAZOL-3-AMINE DERIVATIVES AS TNIK INHIBITORS FOR USE IN THE TREATMENT OF CANCER

EP4477271B1EP 4477271 B1EP4477271 B1EP 4477271B1EP-4477271-B1

Inventors

  • CHANG, SUNG YOUN
  • PARK, SANG YOUN
  • LEE, HYUK
  • KIM, KI YOUNG
  • KIM, BUM TAE
  • KIM, SUNG SOO
  • KIM, SEONG HWAN
  • LIM, Hwan Jung
  • HEO, JUNG NYOUNG
  • SHIN, SANG JOON

Dates

Publication Date
20260513
Application Date
20190131

Claims (13)

  1. A compound of Chemical Formula 1: or a pharmaceutically acceptable salt thereof, in the Chemical Formula 1 W is a substituted or unsubstituted heteroaryl or fused heteroaryl, A is H, halogen, -OH, -CO 2 -C 1-6 alkyl, -CO 2 H, -CN, -C 1-6 alkyl, -C 1-6 haloalkyl,-OR 1 , -NH 2 , -NHR 2 , -substituted or unsubstituted piperazine, -NHSO 2 R 3 , -NHCO 2 -C 1-6 alkyl,-NHCON-C 1-6 alkyl, or -NHCOR 4 , B is -C 1-6 haloalkyl, C 1-6 alkyl, halogen, or C 1-6 alkoxy, V is H, -CH 2 OH, halogen, -CO 2 H, -CO 2 -C 1-6 alkyl, -OH, -NH 2 , phenoxy, or-NHCO-C 1-6 alkyl, X is H or F, wherein, R 1 is C 1-6 alkyl, benzyl, C 1-6 haloalkyl, or phenyl, R 2 is C 1-6 alkyl, C 1-6 haloalkyl, -CH 2 CH 2 -morpholin, or phenyl, R 3 is C 1-6 alkyl, C 1-6 haloalkyl, or substituted or unsubstituted phenyl, R 4 is C 1-6 alkyl, C 1-6 haloalkyl, -CH 2 CH 2 Cl, -CH 2 CH 2 NMe 2 , -CH 2 NMe 2 , or -CH 2 CH 2 - morpholin.
  2. The compound of Claim 1, in the Chemical Formula 1, W is substituted or unsubstituted pyridyl, thiophene, thiazole, pyrrole, benzothiophene, indole, oxazole, pyrazole, imidazole, pyrimidine, benzopyrazole, benzothiazole, benzoxazole, benzoimidazole, or benzothiophene, A is H, halogen, -OH, -CO 2 -C 1-3 alkyl, -CO 2 H, -CN, -C 1-3 alkyl, , -OR 1 , -NH 2 ,-NHR 2 , -NHSO 2 R 3 , -NHCO 2 -C 1-6 alkyl, -NHCON-C 1-6 alkyl, or -NHCOR 4 , B is -C 1-3 haloalkyl, C 1-3 alkyl, halogen, or C 1-3 alkoxy, V is H, -CH 2 OH, halogen, -CO 2 H, -CO 2 -C 1-3 alkyl, -OH, -NH 2 , phenoxy, or-NHCO-C 1-3 alkyl, X is H or F, wherein, R 1 is benzyl, C 1-3 haloalkyl, or phenyl, R 2 is CF 3 , C 1-3 alkyl, -CH 2 CH 2 -morpholin, or phenyl, R 3 is C 1-3 alkyl, or substituted or unsubstituted phenyl, R 4 is C 1-3 alkyl, CF 3 , -CH 2 CH 2 Cl, -CH 2 CH 2 NMe 2 , -CH 2 NMe 2 , or -CH 2 CH 2 -morpholin.
  3. The compound of Claim 2, in the Chemical Formula 1, W is substituted or unsubstituted pyridyl, thiophene, thiazole, pyrrole, benzothiophene, or indole, A is -OH, -CO 2 -C 1-2 alkyl, -methyl, -OR 1 , -NH 2 , -NHR 2 , -NHSO 2 R 3 , -NHCO 2 -C 1-6 alkyl, -NHCON-C 1-6 alkyl, or -NHCOR 4 , B is -C 1-3 haloalkyl, C 1-3 alkyl, halogen, or C 1-3 alkoxy, V is H, -CH 2 OH, F, -CO 2 H, -CO 2 -C 1-2 alkyl, -OH, -NH 2 , phenoxy, or -NHCOCH 3 , X is H or F, wherein, R 1 is benzyl, CF 3 , or phenyl, R 2 is CF 3 , C 1-3 alkyl, -CH 2 CH 2 -morpholin, or phenyl, R 3 is C 1-3 alkyl, or substituted or unsubstituted phenyl, R 4 is C 1-3 alkyl, CF 3 , -CH 2 CH 2 Cl, -CH 2 CH 2 NMe 2 , -CH 2 NMe 2 , or -CH 2 CH 2 -morpholin.
  4. The compound of Claim 3, in the Chemical Formula 1, W is A is -OH, -NHR 2 , -NHSO 2 R 3 , -NHCO 2 -C 1-6 alkyl, -NHCON-C 1-6 alkyl, or - NHCOR 4 , B is -C 1-3 haloalkyl, C 1-3 alkyl, halogen, or C 1-3 alkoxy, V is H, -CH 2 OH, F, -OH, or -NHCOCH 3 , X is H or F, wherein, R 2 is CF 3 , C 1-3 alkyl, -CH 2 CH 2 -morpholin, or phenyl, R 3 is C 1-3 alkyl, or substituted or unsubstituted phenyl, R 4 is C 1-3 alkyl, CF 3 , -CH 2 CH 2 Cl, -CH 2 CH 2 NMe 2 , -CH 2 NMe 2 , or -CH 2 CH 2 -morpholin.
  5. The compound of Claim 4, in the Chemical Formula 1, W is A is -OH, -NHR 2 , -NHSO 2 R 3 , -NHCO 2 -C 1-6 alkyl, -NHCON-C 1-6 alkyl, or-NHCOR 4 , B is -C 1-3 haloalkyl, C 1-3 alkyl, halogen, or C 1-3 alkoxy, V is H, F, -OH, or -NHCOCH 3 , X is H or F, wherein, R 2 is CF 3 , or C 1-3 alkyl, R 3 is C 1-3 alkyl, R 4 is C 1-3 alkyl, CF 3 , -CH 2 CH 2 Cl, -CH 2 CH 2 NMe 2 , -CH 2 NMe 2 , or -CH 2 CH 2 -morpholin.
  6. The compound of Claim 5, in the Chemical Formula 1, W is A is -OH, -NHCF 3 , -NHSO 2 R 3 , -NHCO 2 -C 1-6 alkyl, -NHCON-C 1-3 alkyl, or-NHCOR 4 , B is C 1-3 alkyl or halogen, V is H or F, X is H or F, wherein, R 3 is C 1-3 alkyl, R 4 is C 1-3 alkyl, CF 3 , -CH 2 CH 2 Cl, -CH 2 CH 2 NMe 2 , -CH 2 NMe 2 , or -CH 2 CH 2 -morpholin.
  7. The compound of Claim 1, wherein the compound is 3-methyl-4-((5-(pyridin-3-yl)-1H-pyrazol-3-yl)amino)phenol, 4-((5-(6-chloropyridin-3-yl)-1H-pyrazol-3-yl)amino)-3-methylphenol, 4-((5-(6-(benzyloxy)pyridin-3-yl)-1H-pyrazol-3-yl)amino)-3-methylphenol, 3-methyl-4-((5-(5-methylthiophen-2-yl)-1H-pyrazol-3-yl)amino)phenol, 3-methyl-4-((5-(thiophen-2-yl)-1H-pyrazol-3-yl)amino)phenol, N-(3-methyl-4-((5-(5-methylthiophen-2-yl)-1H-pyrazol-3-yl)amino)phenyl)acetamide, 4-((5-(5-chlorothiophen-2-yl)-1H-pyrazol-3-yl)amino)-3-methylphenol, 3-methyl-4-((5-(thiazol-2-yl)-1H-pyrazol-3-yl)amino)phenol, N-(4-((5-(5-chlorothiophen-2-yl)-1H-pyrazol-3-yl)amino)-3-methylphenyl)acetamide, 3-methyl-4-((5-(1-methyl-1H-pyrrol-3-yl)-1H-pyrazol-3-yl)amino)phenol, 4-((5-(benzo[b]thiophen-2-yl)-1H-pyrazol-3-yl)amino)-3-methylphenol, 4-((5-(benzo[b]thiophen-2-yl)-1H-pyrazol-3-yl)amino)-3-ethylphenol, 4-((5-(benzo[b]thiophen-3-yl)-1H-pyrazol-3-yl)amino)-3-methylphenol, 4-((5-(benzo[b]thiophen-3-yl)-1H-pyrazol-3-yl)amino)-3-ethylphenol, 4-((5-(5-chlorothiophen-2-yl)-1H-pyrazol-3-yl)amino)-3-methylphenol, 4-((5-(5-chlorothiophen-2-yl)-1H-pyrazol-3-yl)amino)-3-ethylphenol, 3-methyl-4-((5-(thiazol-2-yl)-1H-pyrazol-3-yl)amino)phenol, 3-ethyl-4-((5-(thiazol-2-yl)-1H-pyrazol-3-yl)amino)phenol, tert-butyl 3-(3-((4-hydroxy-2-methylphenyl)amino)-1H-pyrazol-5-yl)-1H-indole-1-carboxylate, tert-butyl 3-(3-((2-ethyl-4-hydroxyphenyl)amino)-1H-pyrazol-5-yl)-1H-indole-1-carboxylate, N-(4-((5-(benzo[b]thiophen-2-yl)-1H-pyrazol-3-yl)amino)-3-methylphenyl)acetamide, N-(4-((5-(benzo[b]thiophen-3-yl)-1H-pyrazol-3-yl)amino)-3-methylphenyl)acetamide, 4-((5-(6-bromopyridin-2-yl)-1H-pyrazol-3-yl)amino)-3-methylphenol, 4-((5-(6-bromopyridin-2-yl)-1H-pyrazol-3-yl)amino)-3-ethylphenol, 3-methyl-4-((5-(pyridin-2-yl)-1H-pyrazol-3-yl)amino)phenol, 3-ethyl-4-((5-(pyridin-2-yl)-1H-pyrazol-3-yl)amino)phenol, 4-((5-(5-bromopyridin-3-yl)-1H-pyrazol-3-yl)amino)-3-methylphenol, 4-((5-(4-bromopyridin-2-yl)-1H-pyrazol-3-yl)amino)-3-ethylphenol, N-(3-methyl-4-((5-(thiazol-2-yl)-1H-pyrazol-3-yl)amino)phenyl)methanesulfonamide, N-(4-((5-(6-bromopyridin-2-yl)-1H-pyrazol-3-yl)amino)-3-methylphenyl)methanesulfonamide, 4-((5-(1H-indol-3-yl)-1H-pyrazol-3-yl)amino)-3-methylphenol, 4-((5-(1H-indol-3-yl)-1H-pyrazol-3-yl)amino)-3-ethylphenol, 4-((5-(6-chloropyridin-3-yl)-1H-pyrazol-3-yl)amino)-3-methylphenol, N-(4-((5-(1H-indol-3-yl)-1H-pyrazol-3-yl)amino)-3-methylphenyl)methanesulfonamide, 4-((5-(6-methoxypyridin-3-yl)-1H-pyrazol-3-yl)amino)-3-methylphenol, N-(4-((5-(6-methoxypyridin-3-yl)-1H-pyrazol-3-yl)amino)-3-methylphenyl)methanesulfonamide, N-(4-((5-(6-methoxypyridin-3-yl)-1H-pyrazol-3-yl)amino)-3-methylphenyl)acetamide, 4-((5-(6-(1H-pyrazol-1-yl)pyridin-3-yl)-1H-pyrazol-3-yl)amino)-3-methylphenol, N-(4-((5-(6-(1H-pyrazol-1-yl)pyridin-3-yl)-1H-pyrazol-3-yl)amino)-3-methylphenyl)acetamide, N-(4-((5-(6-(1H-pyrazol-1-yl)pyridin-3-yl)-1H-pyrazol-3-yl)amino)-3-methylphenyl)methanesulfonamide, N-(4-((5-(benzo[b]thiophen-2-yl)-1H-pyrazol-3-yl)amino)-3-methylphenyl)methanesulfonamide, 1-(4-((5-(benzo[b]thiophen-2-yl)-1H-pyrazol-3-yl)amino)-3-methylphenyl)-3-methylurea, ethyl (4-((5-(benzo[b]thiophen-2-yl)-1H-pyrazol-3-yl)amino)-3-methylphenyl)carbamate, methyl (4-((5-(benzo[b]thiophen-2-yl)-1H-pyrazol-3-yl)amino)-3-methylphenyl)carbamate, or 4-((4-fluoro-5-(1H-indol-3-yl)-1H-pyrazol-3-yl)amino)-3-methylphenol.
  8. The compound of claim 1, wherein the compound is: 4-((5-(benzo[b]thiophen-2-yl)-1H-pyrazol-3-yl)amino)-3-methylphenol, 4-((5-(benzo[b]thiophen-2-yl)-1H-pyrazol-3-yl)amino)-3-ethylphenol, 4-((5-(benzo[b]thiophen-3-yl)-1H-pyrazol-3-yl)amino)-3-ethylphenol, 4-((5-(5-chlorothiophen-2-yl)-1H-pyrazol-3-yl)amino)-3-ethylphenol, 4-((5-(5-bromopyridin-3-yl)-1H-pyrazol-3-yl)amino)-3-methylphenol, 4-((5-(1H-indol-3-yl)-1H-pyrazol-3-yl)amino)-3-methylphenol, 4-((5-(1H-indol-3-yl)-1H-pyrazol-3-yl)amino)-3-ethylphenol, 4-((5-(6-chloropyridin-3-yl)-1H-pyrazol-3-yl)amino)-3-methylphenol, N-(4-((5-(1H-indol-3-yl)-1H-pyrazol-3-yl)amino)-3-methylphenyl)methanesulfonamide, 4-((5-(6-methoxypyridin-3-yl)-1H-pyrazol-3-yl)amino)-3-methylphenol, N-(4-((5-(6-methoxypyridin-3-yl)-1H-pyrazol-3-yl)amino)-3-methylphenyl)methanesulfonamide, N-(4-((5-(6-methoxypyridin-3-yl)-1H-pyrazol-3-yl)amino)-3-methylphenyl)acetamide, 4-((5-(6-(1H-pyrazol-1-yl)pyridin-3-yl)-1H-pyrazol-3-yl)amino)-3-methylphenol, N-(4-((5-(6-(1H-pyrazol-1-yl)pyridin-3-yl)-1H-pyrazol-3-yl)amino)-3-methylphenyl)acetamide, N-(4-((5-(6-(1H-pyrazol-1-yl)pyridin-3-yl)-1H-pyrazol-3-yl)amino)-3-methylphenyl)methanesulfonamide, N-(4-((5-(benzo[b]thiophen-2-yl)-1H-pyrazol-3-yl)amino)-3-methylphenyl)methanesulfonamide, 1-(4-((5-(benzo[b]thiophen-2-yl)-1H-pyrazol-3-yl)amino)-3-methylphenyl)-3-methylurea, ethyl (4-((5-(benzo[b]thiophen-2-yl)-1H-pyrazol-3-yl)amino)-3-methylphenyl)carbamate, methyl (4-((5-(benzo[b]thiophen-2-yl)-1H-pyrazol-3-yl)amino)-3-methylphenyl)carbamate, or 4-((4-fluoro-5-(1H-indol-3-yl)-1H-pyrazol-3-yl)amino)-3-methylphenol.
  9. A composition comprising a compound of any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  10. A compound of any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof for use in treatment or prevention of cancer.
  11. The compound for use according to claim 10, wherein the compound is administered with irinotecan or pharmaceutically acceptable salt thereof.
  12. The compound for use according to claim 10 or 11, wherein the cancer is colorectal cancer, breast cancer, brain tumor, gastric cancer, liver cancer, ovarian cancer, lung cancer, gastrointestinal cancer, leukemia, or melanoma.
  13. The compound for use according to claim 12, wherein the cancer is colorectal cancer.

Description

Technical Field This application claims priority to Patent Application No. 10-2018-0015170 in the Republic of Korea on February 7, 2018. The present disclosure relates to a group of compounds having an activity inhibiting Traf2and Nck-interacting kinase (TNIK). The present disclosure also relates to pharmaceutical compositions comprising the compound. The present disclosure relates to compounds for use in methods useful for treating specific diseases, including cancer or tumor. Background Art It is well known that inhibitors of Traf2- and Nck-interacting kinase (TNIK) are useful for treating cancer (e.g., U.S. Patent Application Publication no. 2010/0216795). More concretely, it is well known that inhibitors of Traf2- and Nck-interacting kinase (TNIK) are useful for treating cancer (e.g., U.S. Patent Application Publication no. 2010/0216795). More concretely, it is known that TNIK is hyperactive in colorectal cancer, breast cancer, brain tumor, gastric cancer, liver cancer, ovarian cancer and so on (J.S. Boehm et al., Cell 129, 1065-1079, 2007). Specifically, TNIK plays an important role in the growth of colorectal cancer, and TNIK was reported to be a target that is able to control aberrant Wnt signaling in colorectal cancer (Cancer Res 2010;70:5024-5033). TNIK gene was over-expressed in 7% of gastric cancer patients' tissue samples, and TNIK was reported to be a new target for treating gastric cancer (Oncogenesis 2014, 3, e89). In addition, TNIK was reported to be associated with proliferation and differentiation of leukemia stem cells in chronic myelogenous leukemia (The journal of clinical investigation 2012 122 624). In addition to these cancers or tumors, hepatocellular carcinoma, desmoid tumor, medulloblastoma (pediatric brain tumor), Wilms tumor (pediatric kidney cancer), thyroid tumor and so no is related to aberrant Wnt signaling, and thus medicine for these diseases can be developed based on TNIK inhibition. proliferation and differentiation of leukemia stem cells in chronic myelogenous leukemia (The journal of clinical investigation 2012 122 624). In addition to these cancers or tumors, hepatocellular carcinoma, desmoid tumor, medulloblastoma (pediatric brain tumor), Wilms tumor (pediatric kidney cancer), thyroid tumor and so no is related to aberrant Wnt signaling, and thus medicine for these diseases can be developed based on TNIK inhibition. Therefore, drugs inhibiting TNIK block the pathway of TNIK signaling, thereby inhibiting proliferation, survival, and angiogenesis of cancers. Drugs inhibiting TNIK thus are expected to be useful as medicine for treating cancer (See WO2010-100431 and WO2009-030890). Meanwhile, TNIK inhibition was reported to be useful in treating chronic obstructive pulmonary disease (COPD), lupus nephritis, diabetic nephropathy, focal segmental glomerulosclerosis, renal fibrosis, Pulmonary fibrosis, scleroderma and so on. Thus, TNIK inhibitors are expected to be useful in treating or preventing various diseases including inflammatory diseases as well as cancers. Disclosure of Invention Technical Problem Thus one object of the present disclosure is to provide a compound having activity inhibiting TNIK (Traf2- and Nck-interacting kinase), pharmaceutical compositions comprising the compound as an effective agent, and compounds and pharmaceutical compositions for medical-uses for treating or preventing cancers. Another object of the present disclosure is to provide compounds for use in a method for treating or ameliorating cancer comprising administering to a subject in need of treatment, amelioration or prevention of cancer a compound inhibiting TNIK activity according to the present disclosure. Yet another object of the present disclosure is to provide a compound exhibiting synergic effect with other anticancer drugs by co-administration, pharmaceutical compositions comprising the compound as an effective agent, and the compound for medical uses for treating or preventing cancer. Yet another object of the present disclosure is to provide a compound for use in a method for treating or ameliorating cancer comprising administering to a subject in need of treatment, amelioration or prevention of cancer a compound inhibiting TNIK activity and anti-cancer drug having other mechanism simultaneously or sequentially. Solution to Problem Summary To achieve the object, in one embodiment, there is provided a compound of Chemical Formula 1: or a pharmaceutically acceptable salt thereof,in the Chemical Formula 1A is H, halogen, -OH, -CO2-C1-6 alkyl, -CO2H, -CN, -C1-6 alkyl, -C1-6 haloalkyl, -OR1, - NH2, -NHR2, -substituted or unsubstituted piperazine, -NHSO2R3, -NHCO2-C1-6 alkyl, -NHCON-C1-6 alkyl, or -NHCOR4,B is -C1-6 haloalkyl, C1-6 alkyl, halogen, or C1-6 alkoxy,V is H, -CH2OH, halogen, -CO2H, -CO2-C1-6 alkyl, -OH, -NH2, phenoxy, or -NHCO-C1-6 alkyl,X is H or F,W is a substituted or unsubstituted heteroaryl or fused heteroaryl,wherein,R1 is C1-6 alkyl, benzyl, C1-6 haloalkyl, or ph