Five-membered heteroaromatic derivatives, their preparation methods and uses

Abstract

The present invention belongs to the field of pharmaceutical technology, and particularly relates to a class of five-membered heteroaromatic compounds and their compositions, preparation methods and uses. The compound or composition can be used as an inhibitor of Retinoid-related orphan receptor gamma t (RORγt). The present invention also relates to methods for preparing such compounds and compositions, and their use in treating or preventing RORγt-mediated cancers, inflammations or autoimmune diseases in mammals, especially humans.

Claims

1. A compound, which is a compound represented by formula (I) or a stereoisomer, geometric isomer, tautomer, or pharmaceutically acceptable salt of the compound represented by formula (I), wherein: L 1 is a key, -O- or -(CR a R b ) n -; L 2 is *-C(=O)NH-; L 3 is a **-S(=O) 2 -; R a and R b each independently is H, deuterium, C 1-6 alkyl or C 1-6 haloalkyl; A is phenyl, pyridyl, cyclopentyl, cyclohexyl, piperidyl, wherein A is substituted by one, two or three Rs 1 substituted; Ring B is wherein Ring B is optionally substituted with 1 or 2 R 2 groups; Ring C is a heteroaryl composed of 5 atoms; Ring D is a phenyl group; R 1 is deuterium, F, Cl, Br, I, -CN, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy or C 1-4 haloalkoxy; R 2 is deuterium, C 1-4 alkyl, or -C 1-4 alkylene - O - C 1-4 alkyl; wherein the C 1-4 alkyl and -C 1-4 alkylene - O - C 1-4 alkyl are each independently optionally substituted by 1, 2 or 3 R c groups; Each R c is independently deuterium, F, Cl, Br, I or C 1-4 haloalkoxy group; R 5 is H or deuterium; R 6 is H, deuterium, C 1-4 alkyl or -C 1-4 alkylene - O - C 1-4 alkyl; wherein the C 1-4 alkyl, C 1-4 haloalkyl and -C 1-4 alkylene - O - C 1-4 alkyl is independently optionally substituted by substituents selected from deuterium, F, Cl, Br, I, -OH, -CN, C 1-4 alkyl, C 1-4 alkoxy or C 1-4 haloalkoxy; or R 5 and R 6 together with the carbon atom to which it is commonly attached form a heterocyclic group composed of 3 to 6 atoms; R 7 is methyl or ethyl; m is 0; n is 1.

2. The compound according to claim 1, wherein, R a and R b each independently is H, deuterium, methyl, ethyl, n-propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 1,2-difluoroethyl, 2,2,2-trifluoroethyl, monochloromethyl, dichloromethyl, 2-chloroethyl, 2,2-dichloroethyl or 1,2-dichloroethyl.

3. The compound according to claim 1, wherein, Ring C is 4. The compound according to claim 1, wherein, R 1 is deuterium, F, Cl, Br, I, -CN, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH 2 F, -CH 2 Cl, -CHF 2 , -CHCl 2 , -CF 3 , -CH 2 CH 2 F, -CH 2 CH 2 Cl, -CH 2 CHF 2 , -CH 2 CHCl 2 , -CHFCH 2 F, -CHClCH 2 Cl, -CH 2 CF 3 , -CH(CF 3 ) 2 , -CF 2 CH 2 CH 3 , -CH 2 CH 2 CH 2 , -CH 2 CH 2 CHF 2 , -CH 2 CH 2 CF 3 , methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, -OCH 2 F, -OCH 2 Cl, -OCHF 2 , -OCHCl 2 , -OCF 3 , -OCH 2 CH 2 F, -OCH 2 CH 2 , -OCH 2 CHF 2 , -OCH 2 CHCl 2 , -OCHFCH 2 F, -OCHClCH 2 , -OCH 2 CF 3 , -OCH(CF 3 ) 2 , -OCF 2 CH 2 CH 3 ,-OCH 2 CH 2 CH 2 F,-OCH 2 CH 2 CHF 2 ,-OCH 2 CH 2 CF 3 ; R 2 is deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH 2 OCH 3 、-CH 2 OCH 2 CH 3 、-CH 2 OCH 2 CH 2 CH 3 、-CH 2 OCH(CH 3 ) 2 、-CH 2 CH 2 OCH 3 、-CH 2 CH 2 OCH 2 CH 3 、-CH 2 CH 2 OCH 2 CH 2 CH 3 、-CH 2 CH 2 OCH(CH 3 ) 2 、-CH 2 CH 2 CH 2 OCH 3 、-CH 2 CH 2 CH 2 OCH 2 CH 3 、-CH 2 CH 2 CH 2 OCH 2 CH 2 CH 3 or -CH 2 CH 2 CH 2 OCH(CH 3 ) 2 ; wherein, the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, -CH 2 OCH 3 、-CH 2 OCH 2 CH 3 、-CH 2 OCH 2 CH 2 CH 3 、-CH 2 OCH(CH 3 ) 2 、-CH 2 CH 2 OCH 3 、-CH 2 CH 2 OCH 2 CH 3 、-CH 2 CH 2 OCH 2 CH 2 CH 3 、-CH 2 CH 2 OCH(CH 3 ) 2 、-CH 2 CH 2 CH 2 OCH 3 、-CH 2 CH 2 CH 2 OCH 2 CH 3 、-CH 2 CH 2 CH 2 OCH 2 CH 2 CH 3 and -CH 2 CH 2 CH 2 OCH(CH 3 ) 2 are each independently optionally substituted with 1, 2 or 3 R c ; Each R c is independently deuterium, F, Cl, Br, I, -OCH 2 F, -OCHF 2 , -OCF 3 , -OCH 2 CH 2 , -OCH 2 CHF 2 , -OCHFCH 2 , -OCH 2 CF 3 , -OCH(CF 3 ) 2 , -OCF 2 CH 2 CH 3 , -OCH 2 CH 2 CH 2 , -OCH 2 CH 2 CHF 2 or -OCH 2 CH 2 CF 3 .

5. The compound according to claim 1, wherein, R 5 is H or deuterium; R 6 is H, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH 2 OCH 3 、-CH 2 OCH 2 CH 3 、-CH 2 OCH 2 CH 2 CH 3 、-CH 2 OCH(CH 3 ) 2 、-CH 2 CH 2 OCH 3 、-CH 2 CH 2 OCH 2 CH 3 、-CH 2 CH 2 OCH 2 CH 2 CH 3 、-CH 2 CH 2 OCH(CH 3 ) 2 、-CH 2 CH 2 CH 2 OCH 3 、-CH 2 CH 2 CH 2 OCH 2 CH 3 、-CH 2 CH 2 CH 2 OCH 2 CH 2 CH 3 or -CH 2 CH 2 CH 2 OCH(CH 3 ) 2 ; wherein, the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -CH 2 OCH 3 、-CH 2 OCH 2 CH 3 、-CH 2 OCH 2 CH 2 CH 3 、-CH 2 OCH(CH 3 ) 2 、-CH 2 CH 2 OCH 3 、-CH 2 CH 2 OCH 2 CH 3 、-CH 2 CH 2 OCH 2 CH 2 CH 3 、-CH 2 CH 2 OCH(CH 3 ) 2 、-CH 2 CH 2 CH 2 OCH 3 、-CH 2 CH 2 CH 2 OCH 2 CH 3 、-CH 2 CH 2 CH 2 OCH 2 CH 2 CH 3 and -CH 2 CH 2 CH 2 OCH(CH 3 ) 2 1, 2 or 3 radicals selected from deuterium, F, Cl, Br, I, -OH, -CN, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, -OCH 2 F, -OCH 2 Cl, -OCHF 2 ,-OCHCl 2 、-OCF 3 、-OCH 2 CH 2 F, -OCH 2 CH 2 Cl, -OCH 2 CHF 2 、-OCH 2 CHCl 2 、-OCHFCH 2 F, -OCHClCH 2 Cl, -OCH 2 CF 3 、 -OCH(CF 3 ) 2 、 -OCF 2 CH 2 CH 3 、 -OCH 2 CH 2 CH 2 F, -OCH 2 CH 2 CHF 2 or -OCH 2 CH 2 CF 3 substituted by substituents of; or R 5 , R 6 together with the carbon atoms to which they are attached form an oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuryl, piperidinyl or tetrahydropyranyl group.

6. A compound, which has one of the following structures or its stereoisomer, geometric isomer, tautomer, or pharmaceutically acceptable salt:

7. A pharmaceutical composition, which comprises the compound according to any one of claims 1 - 6, and a pharmaceutically acceptable excipient, carrier, adjuvant, or a combination thereof.

8. The pharmaceutical composition according to claim 7, wherein, the pharmaceutical composition comprises other drugs for preventing or treating inflammatory syndromes, disorders or diseases, or any combination thereof.

9. Use of the compound according to any one of claims 1 - 6 or the pharmaceutical composition according to any one of claims 7 - 8 in the manufacture of a drug for preventing or treating a RORγt-mediated disease, disorder or syndrome in a mammal.

10. The use according to claim 9, wherein, the RORγt-mediated disease, disorder or syndrome is cancer, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease, rheumatic arthritis, autoimmune eye disease, ankylosing spondylitis, asthma, chronic obstructive pulmonary disease, osteoarthritis, allergic rhinitis, atopic dermatitis, or Kawasaki disease.

11. The use according to claim 10, wherein, the inflammatory bowel disease is colitis.

12. The use according to claim 11, wherein, the colitis is ulcerative colitis or Crohn's disease.

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