WO2019213470A1 - Benzimidazole derivatives as modulators of retinoid-related orphan receptor gamma (rorϒ) and pharmaceutical uses thereof - Google Patents

Benzimidazole derivatives as modulators of retinoid-related orphan receptor gamma (rorϒ) and pharmaceutical uses thereof Download PDF

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WO2019213470A1
WO2019213470A1 PCT/US2019/030526 US2019030526W WO2019213470A1 WO 2019213470 A1 WO2019213470 A1 WO 2019213470A1 US 2019030526 W US2019030526 W US 2019030526W WO 2019213470 A1 WO2019213470 A1 WO 2019213470A1
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Prior art keywords
alkyl
group
heterocyclyl
cycloalkyl
heteroaryl
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PCT/US2019/030526
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English (en)
French (fr)
Inventor
Yinfa Yan
Minsheng Zhang
Dong Liu
Fengqi Zhang
Suxing Liu
Rumin Zhang
Feng He
Weikang Tao
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Eternity Bioscience Inc
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Eternity Bioscience Inc
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Priority to CN202310017171.4A priority Critical patent/CN116514722A/zh
Priority to US17/052,451 priority patent/US11512055B2/en
Priority to HRP20230643TT priority patent/HRP20230643T1/hr
Priority to EP19796430.7A priority patent/EP3781161B1/en
Priority to UAA202007544A priority patent/UA128161C2/uk
Priority to AU2019262169A priority patent/AU2019262169B2/en
Priority to CA3097519A priority patent/CA3097519A1/en
Priority to JP2020560186A priority patent/JP7351851B2/ja
Priority to BR112020021967-3A priority patent/BR112020021967A2/pt
Priority to ES19796430T priority patent/ES2949366T3/es
Priority to CN201980027956.1A priority patent/CN112135611B/zh
Application filed by Eternity Bioscience Inc filed Critical Eternity Bioscience Inc
Priority to PL19796430.7T priority patent/PL3781161T3/pl
Priority to RS20230505A priority patent/RS64348B1/sr
Priority to SM20230212T priority patent/SMT202300212T1/it
Priority to KR1020207032236A priority patent/KR102709804B1/ko
Priority to MX2020011405A priority patent/MX2020011405A/es
Priority to MYPI2020005364A priority patent/MY208400A/en
Publication of WO2019213470A1 publication Critical patent/WO2019213470A1/en
Anticipated expiration legal-status Critical
Priority to US18/057,537 priority patent/US12187684B2/en
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Definitions

  • the present invention relates to modulators of retinoid-related orphan receptor gamma (RORg) and their uses as therapeutic agents for treatment of RORg-mediated diseases or conditions, including various inflammation and autoimmune diseases and cancers.
  • RORg retinoid-related orphan receptor gamma
  • Nuclear receptors are ligand-regulated transcription factors that regulate development, immunity, and cellular metabolism, one of the major classes of drug targets for human diseases.
  • the retinoid-related orphan receptor gamma (RORg) protein is a member of the NR1 subfamily of nuclear receptors and exhibits a typical nuclear receptor domain structure, consisting of the DNA binding domain; ligand binding domain; a hinge domain and activation function 2 domain (Benoit G, et al, Pharmacological Reviews, 58 (4):798–836, 2006; Zhang, Y., et al., Acta Pharmacogica Sinica, 36:71-87, 2015).
  • RORg recognizes and binds as monomers, as opposed to most other nuclear receptors, which bind as dimers. It binds to specific DNA sequences, typically consisting of TAAA/ TNTAGGTCA, termed ROR response elements (ROREs).
  • RORg1 and RORg2 are produced from the same RORC gene, probably by selection of alternative promoters (Villey I, et al, Eur. J. Immunol., 29(12):4072-80, 1999).
  • RORg2 also known as RORgt
  • RORg1 produced from an mRNA identical to that of RORg1 except for a replacement of an alternative exon with two 5’-most exons, leading to a truncated form of RORg1.
  • the two isoforms exhibit distinct patterns of tissue-specific expression.
  • RORgt is preferentially expressed in the thymus and several distinct cell types of the immune system, whereas RORg1 is expressed in many tissues, thymus, lung, kidney, muscle, and liver.
  • RORgt is a master regulator of the development of T helper 17 cells (Th17 cells) (Ruan, Q., et al., J. Exp. Med., 208(11):2321-2333, 2011; Ivanov, I. I. et al., Cell, 126:1121- 1133, 2006).
  • Th17 cells produce numerous cytokines, including interleukin-17 (IL-17), that are known to enhance inflammatory processes.
  • IL-17 interleukin-17
  • IL-17 interleukin-17
  • a critical role of RORgt was shown in non-Th17 lymphoid cells expressing Thy1, SCA-1 and IL-23R proteins (Buonocore, S., et al., Nature, 464:1371-1375, 2010).
  • RORgt plays an important role in the development of secondary lymphoid tissues, thymopoiesis, lymphocyte development ((Jetten, A. M., Nucl. Recep. Signal, 7:e300, DOI:10.1621/nrs.07003, 2009).
  • RORg1 appears to be involved in the regulation of circadian rhythms (Guillaumond, F. et al, J. Biol. Rhythms, 20 (5):391–403, 2005; Akashi M and Takumi T., Nat. Struct. Mol. Biol., 12 (5):441–448, 2005).
  • RORg has been identified as a key mediator in the pathogenesis of several diseases such as rheumatoid arthritis, psoriasis, multiple sclerosis, inflammatory bowel disease, Crohn's disease, Sjögren’s syndrome and asthma, etc.
  • diseases such as rheumatoid arthritis, psoriasis, multiple sclerosis, inflammatory bowel disease, Crohn's disease, Sjögren’s syndrome and asthma, etc.
  • Some other diseases such as chronic dry eye disease, Kawasaki Disease, mucosal leishmaniasis, and Hashimoto's thyroiditis, are characterized by increased Thl7 proportions and/or elevated levels of Thl7 hallmark cytokines such as IL-17, IL-22 and IL-23 (Chen, Y., et al., Mucosal. Immunol., 7(1):38-45, 2014; Jia, S., et al., Clin. Exp. Immunol., 162:131-137, 2010; Boaventura, V. S., et al, Eur. J. Immunol., 40: 2830-2836, 2010; Figueroa-Vega, N., et al, J.
  • RORgt inhibitors are currently under development for the treatment of autoimmune diseases such as psoriasis and rheumatoid arthritis. See Jun R. Huh and Dan R. Littman, Eur. J. Immunol., 42(9): 2232–2237 (2012), WO 2012/027965, WO 2013/029338, and US 2015/291607.
  • the present invention describes a series of new compounds that display potent inhibition against RORg, therefore, can provide a potential therapeutic approach to RORg- mediated diseases or conditions.
  • the present invention is directed to a compound of formula ( I ):
  • ring A is selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R1, R2 and R3 are identical or different and each is independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, cyano, amino, hydroxy, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • each R 4 is identical or different and each is independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, cyano, amino, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR8, - C(O)OR 8 , -COR 9 , -NR 10 COR 9 , -S(O) 2 R 9 , -NR 10 S(O) 2 R 9 , -CONR 11 R 12 , -NR 11 R 12 and - S(O)2NR11R12, wherein said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted by one or more groups selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alk
  • R5a and R5b are identical or different and each is independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, cyano, amino, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 8 , -NR 10 COR 9 , - NR10COCH2OR8, -(CH2)xC(O)OR8, -(CH2)xCONR11R12 and -(CH2)xNR11R12, wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted by one or more groups selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, cyano, amino, nitro, hydroxy, -CONR 11 R 12 , -NR 10 COR 9 , cycloalkyl, heterocyclyl, aryl
  • R6 is selected from the group consisting of alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and NR 11 R 12 , wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted by one or more groups selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, cyano, amino, nitro, hydroxy, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • each R7 is identical or different and each is independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, cyano, amino, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR8, -C(O)OR8, -COR9, - NR 10 COR 9 , -S(O) 2 R 9 , -NR 10 S(O) 2 R 9 , -CONR 11 R 12 , -NR 11 R 12 and -S(O) 2 NR 11 R 12 , wherein said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted by one or more group(s) selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, cyan
  • R8 is selected from the group consisting of hydrogen, alkyl, haloalkyl, cycloalkyl and heterocyclyl, wherein said alkyl, aryl and heteroaryl are each optionally substituted by one or more groups selected from the group consisting of halogen and alkoxy;
  • R9 is is selected from the group consisting of hydrogen, alkyl, hydroxyl, alkoxy, cycloalkyl, aryl and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted by one or more groups selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, cyano, amino, nitro, hydroxy, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R10 is selected from the group consisting of hydrogen, alkyl, haloalkyl, cycloalkyl and heterocyclyl;
  • R11 and R12 are identical or different and each is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, - COR13, aryl and heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted by one or more groups selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, cyano, amino, nitro, hydroxy, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • heterocyclyl has one or more heteroatoms selected from the group consisting of O, N and S, and is optionally substituted by one or more groups selected from the group consisting of alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R13 is selected from the group consisting of hydrogen, alkyl, hydroxyl, alkoxy, cycloalkyl, aryl and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted by one or more groups selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, cyano, amino, nitro, hydroxy, cycloalkyl
  • n 0, 1, 2, 3, or 4;
  • s 0, 1, 2, 3 or 4;
  • x 0, 1, 2, 3 or 4.
  • the present invention is directed to a compound of formula ( IA ),
  • the present invention is directed to a compound of formula ( IC ) or formula ( ID ) as an intermediate for the synthesis of compounds of formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a
  • R a and R b is hydrogen
  • ring A, R1 ⁇ R4, R5a, R5b, R6, R7, n and s are as defined in formula ( I ).
  • the present invention is directed to various processes for preparing the compound of formula ( I ).
  • the present invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula ( I ), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.
  • the present invention is directed to a method for inhibiting a retinoid-related orphan receptor gamma (RORg) or treating a retinoid-related orphan receptor gamma (RORg) protein mediated disease or disorder in a subject using a therapeutically effective amount of the compound of formula (I), or the tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof.
  • RORg retinoid-related orphan receptor gamma
  • RORg retinoid-related orphan receptor gamma
  • the present invention is directed to a compound of formula ( I ):
  • ring A is selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R1, R2 and R3 are identical or different and each is independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, cyano, amino, hydroxy, cycloalkyl, heterocyclyl, aryl and heteroaryl; each R4 is identical or different and each is independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, haloalkoxy, cyano, amino, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR8, - C(O)OR 8 , -COR 9 , -NR 10 COR 9 , -S(O) 2 R 9 , -NR 10 S(O) 2 R 9 , -CONR 11 R 12 , -NR 11 R 12 and - S(O)2NR11
  • R 5a and R 5b are identical or different and each is independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, hydroxy, hydroxyalkyl, alkoxy, cyano, amino, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR8, -NR10COR9, - NR10COCH2OR8, -(CH2)xC(O)OR8, -(CH2)xCONR11R12 and -(CH2)xNR11R12, wherein said alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted by one or more groups selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, cyano, amino, nitro, hydroxy, -CONR 11 R 12 , -NR 10 COR 9 , cycloalkyl, heterocyclyl, aryl and heteroary
  • R 6 is selected from the group consisting of alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and NR11R12, wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted by one or more groups selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, cyano, amino, nitro, hydroxy, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • each R7 is identical or different and each is independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkenyl, alkynyl, alkoxy, cyano, amino, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR 8 , -C(O)OR 8 , -COR 9 , - NR10COR9, -S(O)2R9, -NR10S(O)2R9, -CONR11R12, -NR11R12 and -S(O)2NR11R12, wherein said alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted by one or more group(s) selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, cyano
  • R 8 is selected from the group consisting of hydrogen, alkyl, haloalkyl, cycloalkyl and heterocyclyl, wherein said alkyl, aryl and heteroaryl are each optionally substituted by one or more groups selected from the group consisting of halogen and alkoxy;
  • R9 is is selected from the group consisting of hydrogen, alkyl, hydroxyl, alkoxy, cycloalkyl, aryl and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted by one or more groups selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, cyano, amino, nitro, hydroxy, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R 10 is selected from the group consisting of hydrogen, alkyl, haloalkyl, cycloalkyl and heterocyclyl;
  • R11 and R12 are identical or different and each is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, - COR13, aryl and heteroaryl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted by one or more groups selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, cyano, amino, nitro, hydroxy, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • heterocyclyl has one or more heteroatoms selected from the group consisting of O, N and S, and is optionally substituted by one or more groups selected from the group consisting of alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • R13 is selected from the group consisting of hydrogen, alkyl, hydroxyl, alkoxy, cycloalkyl, aryl and heteroaryl, wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted by one or more groups selected from the group consisting of halogen, alkyl, alkenyl, alkynyl, alkoxy, cyano, amino, nitro, hydroxy, cycloalkyl, heterocyclyl, aryl and heteroaryl;
  • n 0, 1, 2, 3, or 4;
  • s 0, 1, 2, 3 or 4;
  • x 0, 1, 2, 3 or 4.
  • the compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof is a compound of formula ( Ia ) or formula (Ib):
  • R1 ⁇ R4, R5a, R5b, R6, R7, n and s are as defined in formula (I).
  • ring A is selected from the group consisting of phenyl, C3-6 cycloalkyl and 5 or 6 member heteroaryl, preferably piperidinyl, phenyl, thienyl, furyl and pyridinyl.
  • the compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof is a compound of formula ( II ):
  • Ra, Rb, R1 ⁇ R4, R5a, R5b, R6, R7, n and s are as defined in formula ( I ) .
  • the compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof is a compound of formula ( IIa ):
  • the compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof is a compound of formula ( III ):
  • R a , R b , R 1 ⁇ R 4 , R 5a , R 5b , R 6 , R 7 , n and s are as defined in formula ( I ) .
  • the compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof is a compound of formula ( IIIa ):
  • R 4a and R 4b are identical or different and each is independently selected from the group consisting of halogen, hydrogen, alkyl and haloalkyl; Ra, Rb, R1 ⁇ R3, R5a, R5b, R6, R7 and n are as defined in formula ( I ).
  • each R4 is identical or different and each is independently selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, cyano, amino, -OR8 and -NR11R12;
  • R 8 , R 11 and R 12 are as defined in formula ( I ).
  • R1, R2, and R3 are identical or different and each is independently selected from the group consisting of hydrogen, halogen and alkyl.
  • R 5a and R 5b are identical or different and each is independently selected from the group consisting of hydrogen, hydroxy, hydroxyalkyl, -OR8, -NR10COR9, -NR10COCH2OR8, -(CH2)xC(O)OR8, -(CH2)xCONR11R12 and -(CH 2 ) x NR 11 R 12 ; or R 5a and R 5b are together form R 8 to R 12 and x are as defined in formula
  • R6 is selected from the group consisting of alkyl, haloalkyl, cycloalkyl, heterocyclyl and -NR 11 R 12 , wherein said alkyl is optionally substituted by one or more groups selected from the group consisting of alkoxy and cycloalkyl.
  • R 7 is selected from the group consisting of hydrogen, halogen and alkyl.
  • Typical compounds of the present invention include, but are not limited to,
  • the present invention is directed to a compound of formula ( IA ),
  • Ra, Rb, R1 ⁇ R3, R5a, R5b, R6, R7 and n are as defined in formula ( I ) .
  • the present invention is directed to a compound of formula ( IC ) or formula ( ID ), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof,
  • Ra and Rb is hydrogen
  • R 1 ⁇ R 4 , R 5a , R 5b , R 6 , R 7 , n and s are as defined in formula ( I ).
  • ring A is selected from the group consisting of phenyl, C3-6 cycloalkyl and 5 or 6 member heteroaryl, preferably piperidinyl, phenyl, thienyl, furyl and pyridinyl.
  • Typical intermediate compounds of the present invention include, but are not limited to, the compounds listed in the following table.
  • the present invention is directed to a process for preparing the compound of formula ( I ), comprising a step of coupling a compound of formula ( IA ) with a compound of formula ( IB ) under an alkaline condition in the presence of a catalyst to give the compound of formula ( I ):
  • G is leaving group, preferably boronic acid or borate, and more preferably or
  • ring A, , , R a , R b , R 1 ⁇ R 4 , R 5a , R 5b , R 6 , R 7 , n and s are as defined in formula ( I ) .
  • the present invention is directed to a process for preparing the compound of formula ( I ), comprising a step of cyclization of a compound of formula (IC) or (ID) to give the compound of formula (I):
  • ring A, , , Ra, Rb, R1 ⁇ R4, R5a, R5b, R6, R7, n and s are as defined in formula ( I ) .
  • the present invention is directed to a process for preparing the compound of formula ( II ), comprising a step of cyclization of a compound of formula ( IIC ) or formula (IID) to give the compound of formula ( II ):
  • the present invention is directed to a process for preparing the compound of formula ( III ), comprising a step of cyclization of a compound of formula ( IIIC ) or formula (IIID) is subject to intramolecular reaction to give a formula ( III ):
  • the present invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of the compound of formula ( I ), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.
  • the present invention is directed to a method for inhibiting a retinoid-related orphan receptor gamma (RORg) in a subject, comprising administering to the subject a therapeutically effective amount of the compound of formula (I), or the tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or the pharmaceutically acceptable salt, solvate or prodrug thereof.
  • RORg retinoid-related orphan receptor gamma
  • the present invention is directed to a method for treating a retinoid- related orphan receptor gamma (RORg) protein mediated disease or disorder in a subject, comprising administering to the subject a therapeutically effective amount of the compound of formula (I), or the tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof.
  • RORg retinoid- related orphan receptor gamma
  • the present invention is directed to use of the compound of formula ( I ), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, in the preparation of a medicament for inhibiting RORg.
  • the present invention is directed to use of the compound of formula ( I ), or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt, solvate or prodrug thereof, in the preparation of a medicament for treating a RORg protein mediated disease or disorder.
  • the present invention further relates to a compound of the formula (I), or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof for use as a medicament.
  • the present invention further relates to a compound of the formula (I), or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof for use as a RORg inhibitor.
  • the present invention further relates to a compound of the formula (I), or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof for use as a medicament for treating a RORg protein mediated disease or disorder.
  • RORg protein mediated diseases or disorders include, but are not limited to, inflammation and autoimmune diseases and cancers, wherein inflammation and autoimmune diseases include, but are not limited to, arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, psoriasis, psoriatic arthritis, osteoarthritis, regional entrritis, ulcerative colitis, ankylosing spondylitis, autoimmune diabetes, type I diabetes, autoimmune ocular disease, autoimmune thyroid disease, autoimmune polyedocrine syndrome type I, autoimmune polyendocrine syndrome type II, multiple sclerosis, inflammatory bowel disease, inflammatory bowel syndrome, juvenile idiopathic arthritis, Sjögren’s syndrome, Crohn's disease, asthma, Kawasaki Disease, Hashimoto's thyroiditis, infectious diseases, ankylosing spondylitis, chronic obstructive pulmonary disease (COPD), pulmonary disease, glomerulonephritis, myocarditis, thyroiditis, dry eye, U
  • Alkyl refers to a linear or branched saturated aliphatic hydrocarbon group having 1 to 20 carbon atoms, preferably C 1 -C 12 alkyl, more preferably C 1 -C 6 alkyl, sometimes more preferably C1-C4 alkyl.
  • Nonlimiting examples include methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2- dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2- dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4- methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5- methylhexyl,
  • an alkyl group is a lower alkyl having 1 to 6 carbon atoms
  • the nonlimiting examples include methyl, ethyl, n- propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2- dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1- ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2- dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4- methylpentyl, 2,3-dimethylbutyl, and the like.
  • the alkyl group can be substituted or unsubstituted. When substituted, the substituent group(s) can be substituted at any available connection point.
  • the substituent group(s) is preferably one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocylic alkoxy, cycloalkylthio, heterocyclylthio, oxo, carboxyl, and carboxylic ester.
  • Alkylene refers to a hydrogen atom of an alkyl which is further substituted. For example, methylene(-CH 2 -), 1,2-ethylene(-CH 2 CH 2 -), 1,3-propylene(-CH 2 CH 2 CH 2 -), 1,4- butylene(-CH2CH2CH2CH2-), and the like.
  • Alkenyl refers to an alkyl defined as above that has at least two carbon atoms, preferably 2-10 carbons, more preferably 2-6 carbons, sometimes more preferably 2-4 carbons, and at least one carbon-carbon double bond, for example, ethenyl, 1-propenyl, 2- propenyl, 1-, 2- or 3-butenyl and the like.
  • the alkenyl group may be substituted or unsubstituted.
  • the substituent group(s) is preferably one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxyl, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxyl, heterocylic alkoxyl, cycloalkylthio and heterocyclylthio.
  • Cycloalkyl refers to a saturated and/or partially unsaturated monocyclic or polycyclic hydrocarbon group having 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 8 carbon atoms, and most preferably 3 to 6 carbon atoms.
  • Nonlimiting examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like.
  • Polycyclic cycloalkyl includes a cycloalkyl having a spiro ring, fused ring or bridged ring.
  • “Spiro cycloalkyl” refers to a 5 to 20 membered polycyclic group with rings connected through one common carbon atom (called a spiro atom), wherein one or more rings may contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system, preferably 6 to 14 membered spiro cycloalkyl, and more preferably 7 to 10 membered spiro cycloalkyl.
  • spiro cycloalkyl may be divided into mono-spiro cycloalkyl, di-spiro cycloalkyl, or poly-spiro cycloalkyl, and preferably a mono-spiro cycloalkyl or di-spiro cycloalkyl, more preferably 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, or 5-membered/6-membered mono-spiro cycloalkyl.
  • spiro cycloalkyls include, but are not limited to:
  • “Fused cycloalkyl” refers to a 5 to 20 membered full-carbon polycyclic group, wherein each ring in the system shares an adjacent pair of carbon atoms with another ring, wherein one or more rings may contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system, preferably 6 to 14 membered fused cycloalkyl, more preferably 7 to 10 membered fused cycloalkyl.
  • fused cycloalkyl may be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, preferably bicyclic, tricyclic or tetracyclic fused cycloalkyl, and more preferably bicyclic or tricyclic.
  • fused cycloalkyl include, but are not limited to: .
  • “Bridged cycloalkyl” refers to a 5 to 20 membered full-carbon polycyclic group, wherein every two rings in the system share two disconnected atoms, wherein the rings may have one or more double bonds, but none of the rings has a completely conjugated pi-electron system, preferably 6 to 14 membered bridged cycloalkyl, and more preferably 7 to 10 membered bridged cycloalkyl.
  • bridged cycloalkyl may be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, and preferably bicyclic, tricyclic or tetracyclic bridged cycloalkyl, and more preferably bicyclic or tricyclic bridged cycloalkyl.
  • bridged cycloalkyls include , but are not limited to:
  • Said cycloalkyl include above cycloalkyl fused to aryl, heteroaryl or heterocyclyl, wherein the ring bound to the parent structure is cycloalkyl.
  • Nonlimiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl and the like.
  • the cycloalkyl may be optionally substituted or unsubstituted.
  • the substituent group(s) is preferably one or more group(s) independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocylic alkoxy, cycloalkylthio, heterocyclylthio, oxo, carboxyl, carboxylic ester.
  • Heterocyclyl refers to a 3 to 20 membered saturated and/or partially unsaturated monocyclic or polycyclic hydrocarbon group having one or more heteroatoms selected from the group consisting of N, O, and S(O)m (wherein m is an integer selected from 0 to 2) as ring atoms, but excluding -O-O-, -O-S- or -S-S- in the ring, and the remaining ring atoms being carbon atoms.
  • heterocyclyl has 3 to 12 atoms with 1 to 4 heteroatoms, more preferably 3 to 6 atoms.
  • Nonlimiting examples of monocyclic heterocyclyl include, but are not limited to, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl and the like.
  • Polycyclic heterocyclyl includes a heterocyclyl having a spiro ring, fused ring or bridged ring.
  • “Spiro heterocyclyl” refers to a 5 to 20 membered polycyclic heterocyclyl with rings connected through one common atom (called a spiro atom), wherein said rings have one or more heteroatoms selected from the group consisting of N, O, and S(O)m (wherein m is an integer selected from 0 to 2) as ring atoms and the remaining ring atoms being carbon atoms, wherein one or more rings may contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system; preferably 6 to 14 membered spiro heterocyclyl, and more preferably 7 to 10 membered spiro heterocyclyl.
  • spiro heterocyclyl may be divided into mono-spiro heterocyclyl, di- spiro heterocyclyl, or poly-spiro heterocyclyl, preferably mono-spiro heterocyclyl or di-spiro heterocyclyl, and more preferably 4-membered/4-membered, 4-membered/5-membered, 4- membered/6-membered, 5-membered/5-membered, or 5-membered/6-membered mono-spiro heterocyclyl.
  • spiro heterocyclyls include, but are not limited to:
  • “Fused heterocyclyl” refers to a 5 to 20 membered polycyclic heterocyclyl group, wherein each ring in the system shares an adjacent pair of atoms with another ring, wherein one or more rings may contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system, and wherein said rings have one or more heteroatoms selected from the group consisting of N, O, and S(O)m (wherein m is an integer selected from 0 to 2) as ring atoms, and the remaining ring atoms being carbon atoms; preferably 6 to 14 membered fused heterocyclyl, and more preferably 7 to 10 membered fused heterocyclyl.
  • fused heterocyclyl may be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclyl, preferably bicyclic or tricyclic fused heterocyclyl, and more preferably 5-membered/5-membered, or 5- membered/6-membered bicyclic fused heterocyclyl.
  • fused heterocyclyl include, but are not limited to:
  • “Bridged heterocyclyl” refers to a 5 to 14 membered polycyclic heterocyclyl group, wherein every two rings in the system share two disconnected atoms, wherein the rings may have one or more double bonds, but none of the rings has a completely conjugated pi-electron system, and the rings have one or more heteroatoms selected from the group consisting of N, O, and S(O)m (wherein m is an integer selected from 0 to 2) as ring atoms, and the remaining ring atoms being carbon atoms; preferably 6 to 14 membered bridged heterocyclyl, and more preferably 7 to 10 membered bridged heterocyclyl.
  • bridged heterocyclyl may be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclyl, and preferably bicyclic, tricyclic or tetracyclic bridged heterocyclyl, and more preferably bicyclic or tricyclic bridged heterocyclyl.
  • bridged heterocyclyls include, but are not limited to: .
  • Said heterocyclyl includes above heterocyclyl fused to aryl, heteroaryl or cycloalkyl, wherein the ring bound to the parent structure is heterocyclyl.
  • Nonlimiting examples include, but are not limited to:
  • the heterocyclyl may be optionally substituted or unsubstituted.
  • the substituent group(s) is preferably one or more group(s) independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocylic alkoxy, cycloalkylthio, heterocylylthio, oxo, carboxyl, carboxylic ester.
  • Aryl refers to a 6 to 14 membered full-carbon monocyclic ring or polycyclic fused ring (i.e. each ring in the system shares an adjacent pair of carbon atoms with another ring in the system) group having a completely conjugated pi-electron system; preferably 6 to 10 membered aryl, more preferably phenyl and naphthyl, and most preferably phenyl.
  • the aryl includes above aryl fused to heteroaryl, heterocyclyl or cycloalkyl, wherein the ring bound to parent structure is aryl. Nonlimiting examples include, but are not limited to:
  • the aryl may be optionally substituted or unsubstituted.
  • the substituent group(s) is preferably one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocylic alkoxy, cycloalkylthio, heterocyclylthio, amino, haloalkyl, hydroxyalkyl, carboxyl, and carboxylic ester.
  • Heteroaryl refers to 5 to 14 membered aryl having 1 to 4 heteroatoms selected from the group consisting of O, S and N as ring atoms and remaining ring atoms being carbon atoms; preferably 5 to 10 membered heteroaryl, more preferably 5- or 6- membered heteroaryl such as imidazolyl, furyl, thienyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, and the like, preferably imidazolyl, pyrazolyl, pyimidinyl or thiadiazole; more preferably pyrazolyl.
  • the heteroaryl includes above heteroaryl fused to aryl, heterocyclyl or cycloalkyl, wherein the ring bound to parent structure is heteroaryl. Nonlimiting examples include, but are not limited to:
  • the heteroaryl may be optionally substituted or unsubstituted.
  • the substituent group(s) is preferably one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocylic alkoxy, cycloalkylthio, heterocyclylthio, carboxyl, and carboxylic ester.
  • Alkoxy refers to an -O-(alkyl) or an -O-(unsubstituted cycloalkyl) group, wherein the alkyl is as defined above. Nonlimiting examples include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like. The alkoxy may be optionally substituted or unsubstituted.
  • the substituent is preferably one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocylic alkoxy, cycloalkylthio, heterocyclylthio, amino, haloalkyl, hydroxyalkyl, carboxyl, and carboxylic ester.
  • Haloalkyl refers to an alkyl substituted with one or more halogen, wherein alkyl is as defined above.
  • Haloalkoxy refers to an alkoxy substituted with one or more halogen, wherein alkoxy is as defined above.
  • Hydroalkyl refers to an alkyl substituted with hydroxy, wherein alkyl is as defined above.
  • Haldroxy refers to an -OH group.
  • Halogen refers to fluorine, chlorine, bromine or iodine.
  • Amino refers to an–NH2 group.
  • Cyano refers to a -CN group.
  • Niro refers to an–NO 2 group.
  • Carboxyl refers to a -C(O)OH group.
  • Carboxylic ester refers to a -C(O)O(alkyl) or -C(O)O(cycloalkyl) group, wherein the alkyl and cycloalkyl are as defined above.
  • “Optional” or “optionally” means that the event or circumstance described subsequently can be, but need not be, and such descriptions include the situation in which the event or circumstance may or may not occur.
  • “the heterocyclic group optionally substituted with an alkyl” means that an alkyl group can be, but need not be, present, and such description includes the situation of the heterocyclic group being substituted with an alkyl and the heterocyclic group being not substituted with an alkyl.
  • “Substituted” refers to one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, independently substituted with a corresponding number of substituents. It goes without saying that the substituents only exist in their possible chemical position. The person skilled in the art is able to determine whether the substitution is possible or impossible by experiments or theory without paying excessive efforts. For example, when amino or hydroxy with free hydrogen is bound to a carbon atoms having unsaturated bonds (such as olefinic) may be unstable.
  • any alkyl is preferably C 1 -C 6 alkyl, sometimes more preferably C 1 -C 4 alkyl;
  • any alkenyl is preferably C 2 - C6 alkenyl, sometimes more preferably C1-C4 alkenyl;
  • any alkynyl is preferably C2-C6 alkynyl, sometimes more preferably C 1 -C 4 alkynyl;
  • any cycloalkyl is preferably C 3 -C 6 cycloalkyl;
  • any heterocyclyl is preferably 5- to 10-membered, sometimes more preferably 5- or 6-membered heterocyclyl;
  • any aryl is
  • A“pharmaceutical composition” refers to a mixture of one or more of the compounds according to the present invention or physiologically/pharmaceutically acceptable salts or prodrugs thereof and other chemical components such as physiologically/pharmaceutically acceptable carriers and excipients.
  • the purpose of a pharmaceutical composition is to facilitate administration of a compound to an organism and the absorption of the active ingredient and thus displaying biological activity.
  • compositions of the present disclosure can exist as pharmaceutically acceptable salts or solvates.
  • Pharmaceutically acceptable salts may be any acid addition salt formed by a compound of formula I and a pharmaceutically acceptable acid such as phosphoric, sulfuric, hydrochloric, hydrobromic, citric, maleic, malonic, mandelic, succinic, fumaric, acetic, lactic, nitric, sulfonic, p-toluene sulfonic, methane sulfonic acid, or the like.
  • Solidvate refers to a physical association of a compound of this invention with one or more, preferably one to three, solvent molecules, whether organic or inorganic. This physical association includes hydrogen bonding. In certain instances the solvate will be capable of isolation, for example, when one or more, preferably one to three, solvent molecules are incorporated in the crystal lattice of the crystalline solid. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Methods of solvation are generally known in the art.
  • “Therapeutically effective amount” refers to the total amount of each active component that is sufficient to show a meaningful patient benefit, e.g., a sustained reduction in viral load.
  • a meaningful patient benefit e.g., a sustained reduction in viral load.
  • the term refers to that ingredient alone.
  • the term refers to combined amounts of the active ingredients that result in the therapeutic effect, whether administered in combination, serially, or simultaneously.
  • “Pharmaceutically acceptable” refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio, and are effective for their intended use.
  • Patient or“subject” includes both human and other mammalian animals, including but not limited to cats, dogs, cows, horses, or the like.
  • Treating refers to: (i) inhibiting the disease, disorder, or condition, i.e., arresting its development; and (ii) relieving the disease, disorder, or condition, i.e., causing regression of the disease, disorder, and/or condition.
  • the present invention also includes use of a compound according to any embodiment disclosed for preventing a disease, disorder or condition from occurring in a patient that may be predisposed to the disease, disorder, and/or condition but has not yet been diagnosed as having it;
  • Step 1 the compound of the formula ( I-1 ) is subjected to a condensation reaction with formula ( I-2 ) under alkaline conditions to obtain a compound of the formula ( I-3 ) or formula ( I-3’) ;
  • Step 2 the formula ( I-3 ) or formula ( I-3’) is subjected to an intramolecular reaction in the presence of an acid to give a compound of the formula ( IA );
  • Step 3 the compound of formula ( IA ) is subject to coupling reaction with formula ( IB ) under an alkaline condition in the presence of catalyst to give a formula ( I );
  • X is halogen, preferably bromine; G is leaving group, preferably boronic acid or borate; more preferably or
  • Alkaline reagents include organic base and inorganic base, wherein said organic base includes, but is not limited to, triethylamine, N,N-disopropylethylamine, n-butyllithium, lithium diisopropylamide, potassium acetate, sodium tert-butoxide or potassium tert- butoxide, wherein said inorganic base includes, but is not limited to, sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate or cesium carbonate.
  • Phosphine palladium-based catalysts include, but are not limited to, 2- (dicyclohexylphosphino)-2,4,6-triisopropylbiphenyl, ( ⁇ )-2,2'-bis(diphenylphosphino) -1,1'-binaphthyl, tris(dibenzylideneacetone)dipalladium(0), palladium diacetate, [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium, triphenylphosphine and tetrakis(triphenylphosphine)palladium.
  • the above reactions are preferably carried out in a solvent.
  • the solvent used includes, but is not limited to, acetic acid, methanol, ethanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-dioxane, water, N,N-dimethylformamide, and mixtures thereof.
  • the formula ( IC ) or formula ( ID) is subjected to an intramolecular reaction in the presence of an acid to give a compound of the formula ( I );
  • ring A, , , Ra , Rb, R1 ⁇ R4, R5a, R5b, R6, R7, n and s are as defined formula ( I ).
  • the reagents that provide an acidic condition include, but are not limited to, acetic acid, pyridine hydrobromide, trifluoroacetic acid, formic acid, hydrochloric acid, sulfuric acid and methanesulfonic acid, preferably pyridine hydrobromide or hydrochloric acid.
  • the above reactions are preferably carried out in a solvent.
  • the solvent used includes, but not limited to, acetic acid, methanol, ethanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-dioxane, water, N,N- dimethylformamide, and mixtures thereof.
  • the reagents that provide an acidic condition include, but are not limited to, acetic acid, pyridine hydrobromide, trifluoroacetic acid, formic acid, hydrochloric acid, sulfuric acid and methanesulfonic acid, preferably pyridine hydrobromide or hydrochloric acid.
  • the above reactions are preferably carried out in a solvent.
  • the solvent used includes, but not limited to, acetic acid, methanol, ethanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-dioxane, water, N,N- dimethylformamide, and mixtures thereof.
  • the formula ( IIIC ) or formula ( IIID) is subjected to an intramolecular reaction in the presence of an acid to give a compound of the formula ( III );
  • the reagents that provide an acidic condition include, but are not limited to, acetic acid, pyridine hydrobromide, trifluoroacetic acid, formic acid, hydrochloric acid, sulfuric acid and methanesulfonic acid, preferably pyridine hydrobromide or hydrochloric acid.
  • the above reactions are preferably carried out in a solvent.
  • the solvent used includes, but not limited to, acetic acid, methanol, ethanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, dimethyl sulfoxide, 1,4-dioxane, water, N,N- dimethylformamide, and mixtures thereof.
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • HPLC High performance liquid chromatography
  • MS was determined by a SHIMADZU (ESI) liquid chromatography-mass spectrometer (manufacturer: Shimadzu, type: LC-20AD, LCMS-2020).
  • the known raw materials of the present invention were prepared by the conventional synthesis methods in the art, or purchased from Aldrich Chemical Company, Fisher Scientific or Combi-Blocks, etc.
  • nitrogen atmosphere or“argon atmosphere” means that a reaction flask was equipped with a 1 L nitrogen or argon balloon.
  • reaction temperature in the reactions refers to room temperature, and the range of the temperature was 20°C to 30°C.
  • the reaction process was monitored by thin layer chromatography (TLC), and the developing solvent system includes: A: dichloromethane and methanol, B: hexane and ethyl acetate. The ratio of the volume of the solvent was adjusted according to the polarity of the compounds.
  • the elution system for purification of the compounds by column chromatography, thin layer chromatography and CombiFlash flash rapid preparation instrument includes: A: dichloromethane and methanol, B: hexane and ethyl acetate. The ratio of the volume of the solvent was adjusted according to the polarity of the compounds, and sometimes a small amount of basic reagent such as ammonia or acidic reagent such as acetic acid was added.
  • TEA is triethylamine
  • DIPEA is N,N-diisopropylethylamine
  • EDCI is N-(3-Dimethylaminopropyl)-N ⁇ -ethylcarbodiimide hydrochloride
  • HOBt is 1-Hydroxybenzotriazole hydrate
  • DCM is dichloromathene
  • HBTU O-(Benzotriazol-1-yl)-N,N,N ⁇ ,N ⁇ -tetramethyluronium hexafluorophosphate
  • DMF is N,N-dimethylformamide
  • NMR is proton nuclear magnetic resonance
  • N-(6-amino-3-bromo-2,4-dichlorophenyl)-2-(4-(ethylsulfonyl)phenyl)acetamide(step 6) (3.5 g, 0.0075 mol) was mixed with acetic acid (25 ml) and the mixture was heated to 100 o C for 4 hours, cooled. The solvent was evaporated under reduce pressure and the residue was dissolved in dichloromethane and washed with saturated sodium bicarbonate, dried over MgSO4. This product was purified by flash chromatography with hexane/ethyl acetate to afford the product as a white solid (2.7 g, 80%), MS (+) ES: 448 (M+H) + .
  • Step 8 Preparation of 5-bromo-4,6-dichloro-2-(4-(ethylsulfonyl)-2-fluorobenzyl)-1H- benzo[d]imidazole N-(6-amino-3-bromo-2,4-dichlorophenyl)-2-(4-(ethylsulfonyl)-2- fluorophenyl)acetamide (step 7) (1.7 g, 3.5 mmol) was mixed with acetic acid (10 ml) and the mixture was heated to 100 o C for 4 hours, cooled. The solvent was evaporated under reduce pressure and the residue was dissolved in dichloromethane and washed with saturated sodium bicarbonate, dried over MgSO4. This product was purified by flash chromatography with hexane/ethyl acetate to afford the product as a white solid (1.2 g, 73%), MS (+) ES: 466 (M+H) + .
  • step 8 A mixture of 5-bromo-4,6-dichloro-2-(4-(ethylsulfonyl)-2-fluorobenzyl)-1H- benzo[d]imidazole (step 8) (47 mg, 0.1 mmol), 2-trifluoromethoxyphenylboronic acid (62 mg, 0.3 mmol), tris-(dibenzylideneacetone)dipalladium(0) (6 mg), tri(tert-butyl)phosphonium tetrafluoroboronate (6 mg) and sodium carbonate (2M solution) in 1,4-dioxane (0.6 ml) was degassed and heated to 100 °C under Microwave irradiation for 1h.
  • step 4 N-(6-amino-3-bromo-2,4-difluorophenyl)-2-(4-(ethylsulfonyl)phenyl)acetamide (step 4) (3.5 g, 0.0075 mol) was mixed with acetic acid (25 ml) and the mixture was heated to 100 o C for 4 hours, cooled. The solvent was evaporated under reduce pressure and the residue was dissolved in dichloromethane and washed with saturated sodium bicarbonate, dried over MgSO 4 . This product was purified by flash chromatography with hexane/ethyl acetate to afford the product as a white solid (2.8 g, 85%), MS (+) ES: 415 (M+H) + .
  • Step 4 Preparation of4-((5-bromo-4,6-dichloro-1H-benzo[d]imidazol-2-yl)methyl)-N- ethylbenzenesulfinamide N-(2-amino-4-bromo-3,5-dichlorophenyl)-2-(4-(N- cyclopropylsulfamoyl)phenyl)acetamide (490 mg, 1 mmol) in acetic acid (5 ml) was heated to 80 o C for 3 h. After cooling, the solvent was evaporated to dryness and dissolved in ethyl acetate 910 ml), washed with saturated sodium bicarbonate solution and brine, dried over MgSO4.
  • step 4 A mixture of 4-((5-bromo-4,6-dichloro-1H-benzo[d]imidazol-2-yl)methyl)-N- cyclopropylbenzenesulfinamide (step 4) (238 mg, 0.5 mmol), 2- trifluoromethoxyphenylboronic acid (308 mg, 1.5 mmol), tris- (dibenzylideneacetone)dipalladium(0) (24 mg), tri(tert-butyl)phosphonium tetrafluoroboronate (24 mg) and sodium carbonate (1 ml, 2M solution) in 1,4-dioxane (2.5 ml) was degassed, sealed and heated to 100 °C under Microwave irradiation for 1h.
  • step 4 N-(2-amino-5-bromo-4-chlorophenyl)-2-(4-((cyclopropylmethyl)sulfonyl)phenyl)acetamide (step 4) (3.42 g, 7.5 mmol) was mixed with acetic acid (25 ml) and the mixture was heated to 80 o C for 4 hours, cooled. The solvent was evaporated under reduce pressure and the residue was dissolved in EtOAc and washed with saturated sodium bicarbonate, dried over MgSO4. This product was purified by flash chromatography with hexane/ethyl acetate to afford the product as a white solid 2.6 g (80%), MS (+) ES: 439 (M+H) + .
  • step 5 A mixture of 5-bromo-6-chloro-2-(4-((cyclopropylmethyl)sulfonyl)benzyl)-1H- benzo[d]imidazole (step 5) (439 mg, 1 mmol), (2-isopropoxyphenyl)boronic acid (495 mg, 3 mmol), tris-(dibenzylideneacetone)dipalladium(0) (60 mg), tri(tert-butyl)phosphonium tetrafluoroboronate (60 mg) and sodium carbonate (2 ml ml, 2M solution) in 1,4-dioxane (8 ml) was degassed, sealed and heated to 100 °C under Microwave irradiation for 60 min.
  • 6-chloro-2-(4-((cyclopropylmethyl)sulfonyl)benzyl)-5-(2-isopropoxyphenyl)-1H- benzo[d]imidazole (49.5 mg, 0.1 mmol) was dissolved in 1 ml anhydrous DMSO, paraformylaldehyde (6 mg, 0.2 mmol) wan added with stirring, followed by the addition of powder sodium ethoxide (12 mg, 0.2 mmol). The mixture was stirred at room temp for 60 min. (Check LCMS for completion). The mixture then was treated with EtOAc (10 ml) and washed with sat. NH4Cl solution, followed by water. The organic phase was dried with MgSO4.
  • reaction solution was absorbed onto 20 g of silica gel, loaded to a silica gel column, and eluted with 30% ethyl acetate in hexanes, to get the 2,4-dichloro-3-(4,4-difluoropiperidin-1-yl)-6-nitrobenzenamine (4.72 g, 70.0 % yield) as a brightly yellow solid MS (+) ES: :326(M+H) + .
  • Step 4 Preparation of N-(6-amino-2,4-dichloro-3-(4,4-difluoropiperidin-1-yl)phenyl)-2-(4- (ethylsulfonyl)phenyl)acetamide and N-(2-amino-3,5-dichloro-4-(4,4-difluoropiperidin-1- yl)phenyl)-2-(4-(ethylsulfonyl)phenyl)acetamide
  • Step4 Preparation of N-(6-amino-2,4-dichloro-3-(4,4-difluoropiperidin-1-yl)phenyl)-2-(4- (cyclopropylmethylsulfonyl)phenyl)acetamide and N-(2-amino-3,5-dichloro-4-(4,4- difluoropiperidin-1-yl)phenyl)-2-(4-(cyclopropylmethylsulfonyl)phenyl)acetamide
  • Step 1 Preparation of 4-ethoxy-2-(4-(ethylsulfonyl)phenyl)-4-oxobutanoic acid
  • Step 2 Preparation of ethyl 4-((2-amino-3,5-dichloro-4-(4,4-difluoropiperidin-1- yl)phenyl)amino)-3-(4-(ethylsulfonyl)phenyl)-4-oxobutanoate
  • Step 3 Preparation of ethyl 3-(4,6-dichloro-5-(4,4-difluoropiperidin-1-yl)-1H- benzo[d]imidazol-2-yl)-3-(4-(ethylsulfonyl)phenyl)propanoate
  • Step 4 Preparation of 3-(4,6-dichloro-5-(4,4-difluoropiperidin-1-yl)-1H-benzo[d]imidazol-2- yl)-3-(4-(ethylsulfonyl)phenyl)propanoic acid
  • Step 1 Preparation of ethyl 2-(4-(ethylthio)phenyl)acetate
  • a solution of (4-mercaptophenyl) acetic acid (5.0 g, 29.7 mmol) in N,N- dimethylformamide (DMF) (100 ml) was added K 2 CO 3 (16.4 g, 118.8 mmol) and Iodoethane (9.7 g, 62.2 mmol).
  • the reaction mixture was stirred at RT. After 12 hours, the starting material was totally consumed.
  • the reaction mixture was partitioned between ethyl acetate (100 ml) and water (50 ml).
  • Step 8 Preparation of ethyl 4-((2-amino-3,5-dichloro-4-(4,4-difluoropiperidin-1- yl)phenyl)amino)-3-(4-(ethylsulfonyl)phenyl)-4-oxobutanoate and ethyl 4-((6-amino-2,4- dichloro-3-(4,4-difluoropiperidin-1-yl)phenyl)amino)-3-(4-(ethylsulfonyl)phenyl)-4- oxobutanoate
  • the column was eluted with 45 % of ethyl acetate in hexanes to get a mixture of ethyl 4-((2-amino-3,5-dichloro-4-(4,4-difluoropiperidin-1-yl)phenyl)amino)-3-(4- (ethylsulfonyl)phenyl)-4-oxobutanoate and ethyl 4-((6-amino-2,4-dichloro-3-(4,4- difluoropiperidin-1-yl)phenyl)amino)-3-(4-(ethylsulfonyl)phenyl)-4-oxobutanoate (385 mg, 45.4 % yield) as a white solid.
  • Step 8 Preparation of ethyl 3-(6-chloro-5-(2-isopropoxyphenyl)-1H-benzo[d] imidazol-2-yl)- 3-(4-((cyclopropylmethyl)sulfonyl)phenyl)propanoate
  • Step 2 Preparation of ethyl 4-((4-amino-6-chloro-2'-(difluoromethoxy)-[1,1'-biphenyl]-3- yl)amino)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)-4-oxobutanoate and ethyl 4-((5-amino- 2-chloro-2'-(difluoromethoxy)-[1,1'-biphenyl]-4-yl)amino)-3-(4- ((cyclopropylmethyl)sulfonyl)phenyl)-4-oxobutanoate
  • Step 4 Preparation of ethyl (S)-3-(6-chloro-5-(2-(difluoromethoxy)phenyl)-1H- benzo[d]imidazol-2-yl)-3-(4-((cyclopropylmethyl)sulfonyl)phenyl)propanamide and (R)-3- (6-chloro-5-(2-(difluoromethoxy)phenyl)-1H-benzo[d]imidazol-2-yl)-3-(4- ((cyclopropylmethyl)sulfonyl)phenyl)propanamide

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CN201980027956.1A CN112135611B (zh) 2018-05-03 2019-05-03 作为维甲酸相关孤儿受体γ（RORγ）的调节剂的苯并咪唑衍生物及其药物用途
HRP20230643TT HRP20230643T1 (hr) 2018-05-03 2019-05-03 Derivati benzimidazola kao modulatori receptora siroče gama (rory) povezanih s retinoidima i njihova farmaceutska upotreba
EP19796430.7A EP3781161B1 (en) 2018-05-03 2019-05-03 Benzimidazole derivatives as modulators of retinoid-related orphan receptor gamma (rory) and pharmaceutical uses thereof
UAA202007544A UA128161C2 (uk) 2018-05-03 2019-05-03 ПОХІДНІ БЕНЗІМІДАЗОЛУ ЯК МОДУЛЯТОРИ РЕТИНОЇД-СПОРІДНЕНОГО ОРФАННОГО РЕЦЕПТОРА ГАММА (ROR<font face="Symbol">g</font>) ТА ЇХ ФАРМАЦЕВТИЧНЕ ЗАСТОСУВАННЯ
AU2019262169A AU2019262169B2 (en) 2018-05-03 2019-05-03 Benzimidazole derivatives as modulators of retinoid-related orphan receptor gamma (RORy) and pharmaceutical uses thereof
CA3097519A CA3097519A1 (en) 2018-05-03 2019-05-03 Benzimidazole derivatives as modulators of retinoid-related orphan receptor gamma (ror.gamma.) and pharmaceutical uses thereof
JP2020560186A JP7351851B2 (ja) 2018-05-03 2019-05-03 レチノイド関連オルファン受容体ガンマ（ＲＯＲγ）のモジュレーターとしてのベンジイミダゾール誘導体およびそれらの医薬品用途
BR112020021967-3A BR112020021967A2 (pt) 2018-05-03 2019-05-03 derivados de benzimidazol como moduladores de receptor gama órfão relacionado a retinoides (ror¿) e usos farmacêuticos dos mesmos
PL19796430.7T PL3781161T3 (pl) 2018-05-03 2019-05-03 Pochodne benzimidazolu jako modulatory receptora sierocego gamma związanego z retinoidami (rory) oraz ich zastosowania farmaceutyczne
CN202310017171.4A CN116514722A (zh) 2018-05-03 2019-05-03 作为维甲酸相关孤儿受体γ（RORγ）的调节剂的苯并咪唑衍生物及其药物用途
US17/052,451 US11512055B2 (en) 2018-05-03 2019-05-03 Benzimidazole derivatives as modulators of retinoid-related orphan receptor gamma (RORγ) and pharmaceutical uses thereof
ES19796430T ES2949366T3 (es) 2018-05-03 2019-05-03 Derivados de bencimidazol como moduladores del receptor huérfano gamma relacionado con retinoides (rory) y usos farmacéuticos de los mismos
RS20230505A RS64348B1 (sr) 2018-05-03 2019-05-03 Derivati benzimidazola kao modulatori orfan gama receptora (rorγ) srodnih retinoida i njihova farmaceutska upotreba
SM20230212T SMT202300212T1 (it) 2018-05-03 2019-05-03 Derivati di benzimidazolo come modulatori del recettore gamma orfano correlato al retinoide (rory) e usi farmaceutici di essi
KR1020207032236A KR102709804B1 (ko) 2018-05-03 2019-05-03 레티노이드-관련 희귀 수용체 감마(ＲＯＲγ)의 조절제로서 벤즈이미다졸 유도체 및 이의 약학적 용도
MX2020011405A MX2020011405A (es) 2018-05-03 2019-05-03 Derivados de bencimidazol como moduladores del receptor gamma huerfano (rory) relacionado con retinoide y usos farmaceuticos de los mismos.
MYPI2020005364A MY208400A (en) 2018-05-03 2019-05-03 Benzimidazole derivatives as modulators of retinoid-related orphan receptor gamma (ror) and pharmaceutical uses thereof
US18/057,537 US12187684B2 (en) 2018-05-03 2022-11-21 Benzimidazole derivatives as modulators of retinoid-related orphan receptor gamma (RORγ) and pharmaceutical use thereof

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JP2023521107A (ja) * 2020-04-07 2023-05-23 ユーシービー バイオファルマ エスアールエル Ｉｌ－１７モジュレータとしてのジフルオロシクロヘキシル誘導体

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WO2022245067A1 (ko) * 2021-05-17 2022-11-24 서울대학교 산학협력단 RORα의 활성자 JC1-40을 포함하는 근감소증 예방, 개선, 또는 치료를 위한 약학적 조성물
CN121045325A (zh) * 2024-05-31 2025-12-02 中国科学院广州生物医药与健康研究院 磺酰胺基乙酰胺类化合物及其制备方法和应用

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CN112745268B (zh) * 2019-10-31 2022-09-16 江苏恒瑞医药股份有限公司 苯并咪唑衍生物的晶型及制备方法
CN112745268A (zh) * 2019-10-31 2021-05-04 江苏恒瑞医药股份有限公司 苯并咪唑衍生物的晶型及制备方法
WO2021083311A1 (zh) * 2019-10-31 2021-05-06 江苏恒瑞医药股份有限公司 一种RORγ调节剂的酸加成盐
JP2023500291A (ja) * 2019-10-31 2023-01-05 江▲蘇▼恒瑞医▲薬▼股▲フン▼有限公司 ＲＯＲγモジュレーターの酸付加塩
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WO2021139599A1 (zh) * 2020-01-06 2021-07-15 东莞市东阳光新药研发有限公司 RORγt抑制剂及其制备方法和用途
WO2021139595A1 (zh) * 2020-01-06 2021-07-15 东莞市东阳光新药研发有限公司 RORγt抑制剂及其制备方法和用途
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CN111269126B (zh) * 2020-03-12 2023-04-07 北京理工大学重庆创新中心 一种熔铸载体1,2-二氟-4,5-二硝基苯的制备方法
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WO2021228215A1 (zh) * 2020-05-15 2021-11-18 上海辉启生物医药科技有限公司 可用作RORγ调节剂的联芳基类化合物

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