CN113072538A - ROR gamma t inhibitor and application thereof in medicine - Google Patents

ROR gamma t inhibitor and application thereof in medicine Download PDF

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CN113072538A
CN113072538A CN202011616145.6A CN202011616145A CN113072538A CN 113072538 A CN113072538 A CN 113072538A CN 202011616145 A CN202011616145 A CN 202011616145A CN 113072538 A CN113072538 A CN 113072538A
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CN113072538B (en
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刘兵
潘伟
张英俊
王峰
李旭珂
何为
许娟
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Sunshine Lake Pharma Co Ltd
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Abstract

The invention belongs to the technical field of medicines, and particularly relates to a ROR gamma t inhibitor and application thereof in medicines. The invention also relates to methods for preparing such compounds and pharmaceutical compositions comprising said compounds, and their use in the treatment or prevention of cancer, inflammation or autoimmune disease mediated by roryt in mammals, particularly humans.

Description

ROR gamma t inhibitor and application thereof in medicine
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a small molecular compound, a composition, a preparation method and application thereof, wherein the compound or the composition can be used as an inhibitor of retinoic acid-related orphan receptor gamma t (ROR gamma t) and is used for preventing or treating diseases related to immunity.
Background
Retinoic acid-related nocosomal receptors are a subfamily of transcription factors in the steroid hormone nuclear receptor superfamily. The family of retinoic acid-related orphan nuclear receptors includes ROR α, ROR β, and ROR γ, each encoded by a distinct gene (RORA, RORB, and RORC). Retinoic acid-related orphan nuclear receptors contain four major domains: an N-terminal A/B domain, a DNA binding domain, a hinge domain, and a ligand binding domain.
Retinoic acid-related orphan receptor gamma t (ROR γ t) is one of two isoforms of retinoic acid-related orphan receptor gamma (ROR γ), and may also be referred to as ROR γ 2. It has been shown that ROR γ t is expressed only in lymphoid lineage and embryonic lymphoid tissue inducer cells (Sun et al, Science 288:2369-2372, 2000; Eberl et al, Nat Immunol.5:64-73,2004). ROR gamma T, a characteristic transcription factor of helper T cells (Th17), plays an important role in Th17 cell differentiation, and is a key regulator of Th17 cell differentiation (Ivanov, II, McKenzie BS, Zhou L, Tadokoro CE, Lepelley A, Lafaille JJ, et al. cell 2006; 126(6): 1121-33).
Th17 can secrete interleukin 17 (IL-17) and other proinflammatory cytokines, and has important significance in autoimmune diseases and body defense response. IL-17 is a proinflammatory cytokine for inflammatory progression and various autoimmune diseases, and is closely associated with a variety of autoimmune and inflammatory diseases, such as rheumatoid arthritis, psoriasis, psoriatic arthritis, spondyloarthritis, asthma, inflammatory bowel disease, systemic lupus erythematosus, and multiple sclerosis, among others (Jetten et al, Nucl. Recept. Signal,2009,7: e 003; Manel et al, Nat. Immunol.,2008,9, 641-649). Also in relation to the development of inflammation-associated tumors, Th17 cells are activated during the disease process and are responsible for recruiting other inflammatory cell types, such as neutrophils, to mediate the pathology of the target tissue (Korn et al, annu, rev, immunol, 2009,27: 485-.
The role ROR γ t plays in the pathogenesis of autoimmune diseases or inflammation has been extensively studied and fully elucidated (Jetten et al, adv. Dev. biol., 2006,16: 313-supplement 355; Meier et al Immunity,2007,26: 643-654; Aloisi et al, Nat. Rev. Immunol.,2006,6: 205-supplement 217; Jager et al., J. Immunol.,2009,183: 7169-supplement 7177; Barnes et al, Nat. Rev. Immunol.,2008,8: 183-supplement 192). Therefore, inhibition of ROR γ t will effectively inhibit cell differentiation of Th17, regulate the production and secretion levels of IL-17 and other proinflammatory cytokines, thereby modulating the body's immune system, treating cancer, immune and inflammatory diseases associated with ROR γ t regulation.
Summary of The Invention
The following is a summary of some aspects of the invention only and is not intended to be limiting. These aspects and others are described more fully below. All references in this specification are incorporated herein by reference in their entirety. When the disclosure of the present specification differs from the cited documents, the disclosure of the present specification controls.
The invention provides a compound with retinoic acid-related orphan receptor gamma t (ROR gamma t) inhibitory activity, which is used for preparing a medicament for preventing or treating ROR gamma t-mediated cancer, inflammation or autoimmune diseases, such as cancer, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease, colitis, ulcerative colitis, rheumatoid arthritis, autoimmune eye disease, ankylosing spondylitis, asthma, chronic obstructive pulmonary disease, osteoarthritis, allergic rhinitis, allergic dermatitis, Crohn's disease or Kawasaki disease and the like; the compound can well inhibit ROR gamma t, and has excellent physicochemical property and pharmacokinetic property.
The invention also provides processes for the preparation of these compounds, pharmaceutical compositions containing these compounds and methods of using these compounds or compositions in the treatment of the above-mentioned diseases in mammals, especially humans.
Specifically, the method comprises the following steps:
in one aspect, the invention relates to a compound of formula (I) or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, ester, pharmaceutically acceptable salt of a compound of formula (I) or a prodrug thereof,
Figure BDA0002874960740000021
wherein:
each Z1、Z2、Z3And Z4Independently is CR1Or N;
L1is a bond, -O-, -S-, -NH-, -C (═ O) -or- (CR)aRb)q-；
L2is-C (═ O) -NH- (CR)5R6)-、*-NH-C(＝O)-(CR5R6)-、*-NH-C(＝O)-、*-S(＝O)2-NH-(CR5R6)-、*-NH-S(＝O)2-(CR5R6)-、*-S(＝O)-NH-(CR5R6) -or-NH-S (═ O) - (CR)5R6)-；
RaAnd RbEach independently is H, deuterium, F, Cl, Br, I, C1-4Alkyl or C1-4A haloalkyl group;
ring A is C6-10Aryl, heteroaryl of 5 to 10 atoms, C3-8Cycloalkyl or heterocyclyl consisting of 5 to 10 atoms;
ring B is a heterocyclic group consisting of 5 to 10 atoms;
the D ring is heterocyclic group consisting of 4-10 atoms or C3-8A cycloalkyl group;
each R1Independently H, deuterium, F, Cl, Br, I, cyano, C1-4Alkyl radical, C1-4Alkoxy or C1-4A haloalkyl group;
each R2And R3Independently deuterium, F, Cl, Br, I, -OH, -CN, -NH2、-NO2-COOH, oxo, C1-4Alkyl radical, C1-4Haloalkyl, C1-4Alkoxy radical, C1-4Haloalkoxy, -C1-4alkylene-O-C1-4Alkyl radical, C3-6Cycloalkyl radical, C6-10Aryl, heterocyclyl of 5 to 7 atoms, heteroaryl of 5 to 7 atoms or-C (═ O) -N (R)dRe) (ii) a Wherein, the C1-4Alkyl radical, C1-4Haloalkyl, C1-4Alkoxy radical, C1-4Haloalkoxy, -C1-4alkylene-O-C1-4Alkyl radical, C3-6Cycloalkyl radical, C6-10Aryl, heteroaryl of 5-7 atoms and heterocyclyl of 5-7 atoms are independently optionally substituted with 1,2 or 3RcSubstituted;
each RcIndependently deuterium, F, Cl, Br, I, -OH, -CN, -NH2、C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl or C1-4A haloalkoxy group;
each R4Independently is-S (═ O)2-C1-4Alkyl, -S (═ O)2-C1-4Alkoxy, -S (═ O)2-C1-4Alkylamino, -S (═ O)2-C1-4Haloalkyl, -S (═ O)2-C3-6Cycloalkyl, -S (═ O) -C1-4Alkyl, -S (═ O)2H、-COOH、-C(＝O)-N(RgRh)、-N(Rg)-C(＝O)-C1-4Alkyl, -C (═ O) -O-C1-4Alkyl radical, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl, C3-6Cycloalkyl, carboxy substituted C1-4Alkyl or-C (═ O) -C1-4A hydroxyalkyl group;
Rgand RhEach independently is H, deuterium or C1-4An alkyl group;
R5and R6Each independently of the others being H, deuterium, -OH, -CN, -NH2、-NO2、-COOH、C1-4Alkoxy radical, C1-4Haloalkyl, hydroxy-substituted C1-4Alkyl, cyano-substituted C1-4Alkyl, carboxy substituted C1-4Alkyl, -C1-4alkylene-O-C1-4Alkyl, -C1-4alkylene-C (═ O) -O-C1-4Alkyl, -C1-4alkylene-C (═ O) -N (R)dRe)、-C1-4alkylene-O-C (═ O) -N (R)dRe)、-C1-4alkylene-N (R)f)-C(＝O)-N(RdRe) or-C1-4alkylene-N (R)dRe) (ii) a Wherein, said C1-4Alkoxy radical, C1-4Haloalkyl and-C1-4alkylene-O-C1-4Alkyl is independently optionally substituted by 1,2 or 3 substituents selected from deuterium, -OH, -COOH, -N (R)dRe) Or C1-4Substituted by a substituent of alkoxy;
Rdand ReEach independently of the others being H, deuterium, -OH, C1-4Alkyl, -C (═ O) H, -C (═ O) -O-C1-4Alkyl, -C (═ O) -C1-4Alkyl, -C1-4alkylene-C (═ O) -O-C1-4Alkyl or-C1-4alkylene-O-C1-4An alkyl group; wherein, said C1-4Alkyl, -C1-4alkylene-C (═ O) -O-C1-4Alkyl and-C1-4alkylene-O-C1-4Alkyl is independently optionally substituted by 1,2 or 3 substituents selected from deuterium, F, Cl, Br, I, -OH, -CN, -NH2Or of-COOHSubstituted by a substituent;
each RfIndependently of one another H, deuterium, C1-4Alkyl, -C1-4alkylene-O-C1-4Alkyl or-C1-4alkylene-C3-6A cycloalkyl group; wherein, said C1-4Alkyl, -C1-4alkylene-O-C1-4Alkyl and-C1-4alkylene-C3-6Cycloalkyl is independently optionally substituted with 1,2 or 3 substituents selected from deuterium, F, Cl, Br, I, -OH, -CN, -NH2Or COOH;
n is 0, 1,2 or 3;
m is 0, 1,2 or 3;
p is 0, 1,2 or 3;
q is 0, 1,2 or 3.
In some embodiments, RaAnd RbEach independently of the others is H, deuterium, F, Cl, Br, I, 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.
In other embodiments, ring a is phenyl, naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolyl, pyrazolyl, imidazolyl, furyl, oxazolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, or piperazinyl.
In other embodiments, ring B is
Figure BDA0002874960740000031
Figure BDA0002874960740000032
In some embodiments, ring D is heterocyclyl consisting of 4-7 atoms or C3-6A cycloalkyl group.
In other embodiments, ring D is piperidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperazinyl, azetidinyl, oxetanyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
In other embodiments, each R is1Independently H, deuterium, F, Cl, Br, I, cyano, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, -CH2F、-CH2Cl、-CHF2、-CHCl2、-CF3、-CH2CH2F、-CH2CH2Cl、-CH2CHF2、-CH2CHCl2、-CHFCH2F、-CHClCH2Cl、-CH2CF3、-CH(CF3)2、-CF2CH2CH3、-CH2CH2CH2F、-CH2CH2CHF2or-CH2CH2CF3。
In other embodiments, each R is2And R3Independently deuterium, F, Cl, Br, I, -OH, -CN, -NH2、-NO2-COOH, oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, -CH2F、-CHF2、-CF3、-CH2CH2F、-CH2CHF2、-CHFCH2F、-CH2CF3、-CH(CF3)2、-CF2CH2CH3、-CH2CH2CH2F、-CH2CH2CHF2、-CH2CH2CF3、-OCH2F、-OCHF2、-OCF3、-OCH2CH2F、-OCH2CHF2、-OCHFCH2F、-OCH2CF3、-OCH(CF3)2、-OCF2CH2CH3、-OCH2CH2CH2F、-OCH2CH2CHF2、-OCH2CH2CF3、-CH2OCH3、-CH2OCH2CH3、-CH2OCH2CH2CH3、-CH2OCH(CH3)2、-CH2CH2OCH3、-CH2CH2OCH2CH3、-CH2CH2OCH2CH2CH3、-CH2CH2OCH(CH3)2、-CH2CH2CH2OCH3、-CH2CH2CH2OCH2CH3、-CH2CH2CH2OCH2CH2CH3、-CH2CH2CH2OCH(CH3)2Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, pyridyl, pyrimidinyl, pyrazolyl, thiazolyl, imidazolyl, oxazolyl, triazolyl, tetrazolyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, pyrrolidinyl, or-C (═ O) -N (R)dRe) (ii) a Wherein the methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, tert-butyl group, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, tert-butoxy group, -CH2F、-CHF2、-CH2CH2F、-CH2CHF2、-CHFCH2F、-CH2CF3、-CH(CF3)2、-CF2CH2CH3、-CH2CH2CH2F、-CH2CH2CHF2、-CH2CH2CF3、-OCH2F、-OCHF2、-OCH2CH2F、-OCH2CHF2、-OCHFCH2F、-OCH2CF3、-OCH(CF3)2、-OCF2CH2CH3、-OCH2CH2CH2F、-OCH2CH2CHF2、-OCH2CH2CF3、-CH2OCH3、-CH2OCH2CH3、-CH2OCH2CH2CH3、-CH2OCH(CH3)2、-CH2CH2OCH3、-CH2CH2OCH2CH3、-CH2CH2OCH2CH2CH3、-CH2CH2OCH(CH3)2、-CH2CH2CH2OCH3、-CH2CH2CH2OCH2CH3、-CH2CH2CH2OCH2CH2CH3、-CH2CH2CH2OCH(CH3)2Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazolyl, thiazolyl, imidazolyl, oxazolyl, triazolyl, tetrazolyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl and pyrrolidinyl independently optionally substituted with 1,2 or 3RcAnd (4) substituting.
In other embodiments, each R iscIndependently deuterium, F, Cl, Br, I, -OH, -CN, -NH2Methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, -CH2F、-CHF2、-CF3、-CH2CH2F、-CH2CHF2、-CHFCH2F、-CH2CF3、-CH(CF3)2、-CF2CH2CH3、-CH2CH2CH2F、-CH2CH2CHF2、-CH2CH2CF3、-OCH2F、-OCHF2、-OCF3、-OCH2CH2F、-OCH2CHF2、-OCHFCH2F、-OCH2CF3、-OCH(CF3)2、-OCF2CH2CH3、-OCH2CH2CH2F、-OCH2CH2CHF2or-OCH2CH2CF3。
In other embodiments, each R is4is-S (═ O)2-CH3、-S(＝O)2-CH2CH3、-S(＝O)2-CH2CH2CH3、-S(＝O)2-CH(CH3)CH3、-S(＝O)2-OCH3、-S(＝O)2-OCH2CH3、-S(＝O)2-OCH2CH2CH3、-S(＝O)2-OCH(CH3)CH3、-S(＝O)2-NH-CH3、-S(＝O)2-NH-CH2CH3、-S(＝O)2-NH-CH2CH2CH3、-S(＝O)2-NH-CH(CH3)CH3、-S(＝O)2-cyclopropyl, -S (═ O)2-cyclobutyl, -S (═ O)2-cyclopentyl, -S (═ O)2-cyclohexyl, -S (═ O) -CH3、-S(＝O)-CH2CH3、-S(＝O)-CH2CH2CH3、-S(＝O)-CH(CH3)CH3、-S(＝O)2H、-COOH、-C(＝O)-N(RgRh)、-N(Rg)-C(＝O)-CH3、-N(Rg)-C(＝O)-CH2CH3、-N(Rg)-C(＝O)-CH2CH2CH3、-N(Rg)-C(＝O)-CH(CH3)CH3、-C(＝O)-O-CH3、-C(＝O)-O-CH2CH3、-C(＝O)-O-CH2CH2CH3、-C(＝O)-O-CH(CH3)CH3Methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, -CH2F、-CHF2、-CF3、-CH2CH2F、-CH2CHF2、-CHFCH2F、-CH2CF3、-CH(CF3)2、-CF2CH2CH3、-CH2CH2CH2F、-CH2CH2CHF2、-CH2CH2CF3Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2COOH、-CH2CH2COOH、-CH2CH2CH2COOH、-C(＝O)-CH2OH、-C(＝O)-CH2CH2OH or-C (═ O) -CH2CH2CH2OH。
In other embodiments, RgAnd RhEach independently is H, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, or tert-butyl.
In other embodiments, R5And R6Each independently of the others being H, deuterium, -OH, -CN, -NH2、-NO2、-COOH、-CH2F、-CHF2、-CF3、-CH2CH2F、-CH2CHF2、-CHFCH2F、-CH2CF3、-CH(CF3)2、-CF2CH2CH3、-CH2CH2CH2F、-CH2CH2CHF2、-CH2CH2CF3Methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, -CH2OH、-CH2CH2OH、-CH2CH2CH2OH、-CH(CH3)CH2OH、-CH2(CH2)3OH、-CH2CN、-CH2CH2CN、-CH2CH2CH2CN、-CH(CH3)CH2CN、-CH2(CH2)3CN、-CH2COOH、-CH2CH2COOH、-CH2CH2CH2COOH、-CH(CH3)CH2COOH、-CH2(CH2)3COOH、-CH2OCH3、-CH2OCH2CH3、-CH2OCH2CH2CH3、-CH2OCH(CH3)2、-CH2CH2OCH3、-CH2CH2OCH2CH3、-CH2CH2OCH2CH2CH3、-CH2CH2OCH(CH3)2、-CH2CH2CH2OCH3、-CH2CH2CH2OCH2CH3、-CH2CH2CH2OCH2CH2CH3、-CH2CH2CH2OCH(CH3)2、-CH2-C(＝O)-OCH3、-CH2-C(＝O)-OCH2CH3、-CH2-C(＝O)-OCH2CH2CH3、-CH2-C(＝O)-OCH(CH3)2、-CH2CH2-C(＝O)-OCH3、-CH2CH2-C(＝O)-OCH2CH3、-CH2CH2-C(＝O)-OCH2CH2CH3、-CH2CH2-C(＝O)-OCH(CH3)2、-CH2CH2CH2-C(＝O)-OCH3、-CH2CH2CH2-C(＝O)-OCH2CH3、-CH2CH2CH2-C(＝O)-OCH2CH2CH3、-CH2CH2CH2-C(＝O)-OCH(CH3)2、-CH2-C(＝O)-N(RdRe)、-CH2CH2-C(＝O)-N(RdRe)、-CH2CH2CH2-C(＝O)-N(RdRe)、-CH2-O-C(＝O)-N(RdRe)、-CH2CH2-O-C(＝O)-N(RdRe)、-CH2CH2CH2-O-C(＝O)-N(RdRe)、-CH2-N(Rf)-C(＝O)-N(RdRe)、-CH2CH2-N(Rf)-C(＝O)-N(RdRe)、-CH2CH2CH2-N(Rf)-C(＝O)-N(RdRe)、-CH2N(RdRe)、-CH2CH2N(RdRe) or-CH2CH2CH2N(RdRe)；
Wherein, said-CH2F、-CHF2、-CH2CH2F、-CH2CHF2、-CHFCH2F、-CH2CF3、-CH(CF3)2、-CF2CH2CH3、-CH2CH2CH2F、-CH2CH2CHF2、-CH2CH2CF3Methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, -CH2OCH3、-CH2OCH2CH3、-CH2OCH2CH2CH3、-CH2OCH(CH3)2、-CH2CH2OCH3、-CH2CH2OCH2CH3、-CH2CH2OCH2CH2CH3、-CH2CH2OCH(CH3)2、-CH2CH2CH2OCH3、-CH2CH2CH2OCH2CH3、-CH2CH2CH2OCH2CH2CH3and-CH2CH2CH2OCH(CH3)2Independently optionally substituted with 1,2 or 3 substituents selected from deuterium, -OH, -COOH, methoxy, ethoxy, N-propoxy, isopropoxy, N-butoxy, tert-butoxy or-N (R)dRe) Substituted with the substituent(s).
In other embodiments, RdAnd ReEach independently is H, deuterium, -OH, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, -C (═ O) H, -C (═ O) -O-CH3、-C(＝O)-O-CH2CH3、-C(＝O)-O-CH2CH2CH3、-C(＝O)-O-CH(CH3)2、-C(＝O)-CH3、-C(＝O)-CH2CH3、-C(＝O)-CH2CH2CH3、-C(＝O)-CH(CH3)2、-CH2OCH3、-CH2OCH2CH3、-CH2OCH2CH2CH3、-CH2OCH(CH3)2、-CH2CH2OCH3、-CH2CH2OCH2CH3、-CH2CH2OCH2CH2CH3、-CH2CH2OCH(CH3)2、-CH2CH2CH2OCH3、-CH2CH2CH2OCH2CH3、-CH2CH2CH2OCH2CH2CH3、-CH2CH2CH2OCH(CH3)2、-CH2-C(＝O)-OCH3、-CH2-C(＝O)-OCH2CH3、-CH2-C(＝O)-OCH2CH2CH3、-CH2-C(＝O)-OCH(CH3)2、-CH2CH2-C(＝O)-OCH3、-CH2CH2-C(＝O)-OCH2CH3、-CH2CH2-C(＝O)-OCH2CH2CH3、-CH2CH2-C(＝O)-OCH(CH3)2、-CH2CH2CH2-C(＝O)-OCH3、-CH2CH2CH2-C(＝O)-OCH2CH3、-CH2CH2CH2-C(＝O)-OCH2CH2CH3or-CH2CH2CH2-C(＝O)-OCH(CH3)2(ii) a Wherein, the methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, -CH2OCH3、-CH2OCH2CH3、-CH2OCH2CH2CH3、-CH2OCH(CH3)2、-CH2CH2OCH3、-CH2CH2OCH2CH3、-CH2CH2OCH2CH2CH3、-CH2CH2OCH(CH3)2、-CH2CH2CH2OCH3、-CH2CH2CH2OCH2CH3、-CH2CH2CH2OCH2CH2CH3、-CH2CH2CH2OCH(CH3)2、-CH2-C(＝O)-OCH3、-CH2-C(＝O)-OCH2CH3、-CH2-C(＝O)-OCH2CH2CH3、-CH2-C(＝O)-OCH(CH3)2、-CH2CH2-C(＝O)-OCH3、-CH2CH2-C(＝O)-OCH2CH3、-CH2CH2-C(＝O)-OCH2CH2CH3、-CH2CH2-C(＝O)-OCH(CH3)2、-CH2CH2CH2-C(＝O)-OCH3、-CH2CH2CH2-C(＝O)-OCH2CH3、-CH2CH2CH2-C(＝O)-OCH2CH2CH3and-CH2CH2CH2-C(＝O)-OCH(CH3)2Independently optionally substituted by 1,2 or 3 substituents selected from deuterium, F, Cl, Br, I, -OH, -CN, -NH2Or a substituent of-COOH.
In other embodiments, each R isfIndependently H, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, -CH2OCH3、-CH2OCH2CH3、-CH2OCH2CH2CH3、-CH2OCH(CH3)2、-CH2CH2OCH3、-CH2CH2OCH2CH3、-CH2CH2OCH2CH2CH3、-CH2CH2OCH(CH3)2、-CH2CH2CH2OCH3、-CH2CH2CH2OCH2CH3、-CH2CH2CH2OCH2CH2CH3、-CH2CH2CH2OCH(CH3)2Cyclopropylmethylene, cyclopropylethylene, n-propylidene, cyclobutylmethylene, cyclobutylethylene, n-propylidene, cyclopentylmethylene, cyclopentylethylidene, n-propylidene, cyclohexylmethylene, cyclohexylethylene or cyclohexyln-propylidene; wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, -CH2OCH3、-CH2OCH2CH3、-CH2OCH2CH2CH3、-CH2OCH(CH3)2、-CH2CH2OCH3、-CH2CH2OCH2CH3、-CH2CH2OCH2CH2CH3、-CH2CH2OCH(CH3)2、-CH2CH2CH2OCH3、-CH2CH2CH2OCH2CH3、-CH2CH2CH2OCH2CH2CH3、-CH2CH2CH2OCH(CH3)2Cyclopropylmethylene, cyclopropylethylene, n-propylidene, cyclobutylmethylene, cyclobutylethylene, n-propylidene, cyclopentylmethylene, cyclopentylethylidene, n-propylidene, cyclohexylmethylene, cyclohexylethylene and n-propylidene are independently optionally substituted with 1,2 or 3 substituents selected from deuterium, F, Cl, Br, I, -OH, -CN, -NH2Or a substituent of-COOH.
In still other embodiments, the invention relates to a compound of formula (II) or a stereoisomer, a geometric isomer, a tautomer, a nitrogen oxide, a hydrate, a solvate, a metabolite, an ester, a pharmaceutically acceptable salt of a compound of formula (II), or a prodrug thereof,
Figure BDA0002874960740000061
in another aspect, the present invention relates to a pharmaceutical composition comprising a compound of formula (I) or formula (II) of the present invention, or a stereoisomer, a geometric isomer, a tautomer, a nitrogen oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt, or a prodrug thereof, and a pharmaceutically acceptable excipient, carrier, adjuvant, or a combination thereof;
the pharmaceutical composition further comprises other drugs or any combination thereof for preventing or treating inflammatory syndromes, disorders or diseases.
In another aspect, the present invention relates to the use of a compound of formula (I) or formula (II) or a pharmaceutical composition thereof in the preparation of a medicament for preventing or treating a cancer, inflammation or autoimmune disease mediated by roryt in a mammal.
In some embodiments, the present invention relates to the use of a compound of formula (I) or formula (II) or a pharmaceutical composition thereof in the preparation of a medicament for the prevention or treatment of cancer, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease, colitis, ulcerative colitis, rheumatoid arthritis, autoimmune ocular disease, ankylosing spondylitis, asthma, chronic obstructive pulmonary disease, osteoarthritis, allergic rhinitis, allergic dermatitis, crohn's disease, or kawasaki disease.
In another aspect, the invention relates to methods for the preparation, isolation and purification of compounds of formula (I) or formula (II).
Biological test results show that the compound provided by the invention has good inhibitory activity on ROR gamma t and good pharmacokinetic characteristics.
Any embodiment of any aspect of the invention may be combined with other embodiments, as long as they do not contradict. Furthermore, in any embodiment of any aspect of the invention, any feature may be applicable to that feature in other embodiments, so long as they do not contradict.
The foregoing merely summarizes certain aspects of the invention and is not intended to be limiting. These and other aspects will be more fully described below.
Detailed description of the invention
Definitions and general terms
Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated by the accompanying structural and chemical formulas. The invention is intended to cover alternatives, modifications and equivalents, which may be included within the scope of the invention as defined by the appended claims. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the incorporated documents, patents, and similar materials differ or contradict this application (including but not limited to defined terminology, application of terminology, described techniques, and the like), this application controls.
It will be further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference in their entirety.
The following definitions as used herein should be applied unless otherwise indicated. For the purposes of the present invention, the chemical elements are in accordance with the CAS version of the periodic Table of the elements, and the handbook of chemistry and Physics, 75 th edition, 1994. In addition, general principles of Organic Chemistry can be referred to as described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausaltito: 1999, and "March's Advanced Organic Chemistry" by Michael B.Smith and Jerry March, John Wiley & Sons, New York:2007, the entire contents of which are incorporated herein by reference.
The articles "a," "an," and "the" as used herein are intended to include "at least one" or "one or more" unless otherwise indicated or clearly contradicted by context. Thus, as used herein, the articles refer to articles of one or more than one (i.e., at least one) object. For example, "a component" refers to one or more components, i.e., there may be more than one component contemplated for use or use in embodiments of the described embodiments.
The term "subject" as used herein refers to an animal. Typically the animal is a mammal. Subjects, e.g., also primates (e.g., humans, males or females), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In certain embodiments, the subject is a primate. In other embodiments, the subject is a human.
The term "patient" as used herein refers to humans (including adults and children) or other animals. In some embodiments, "patient" refers to a human.
The term "comprising" is open-ended, i.e. includes the elements indicated in the present invention, but does not exclude other elements.
"stereoisomers" refers to compounds having the same chemical structure but differing in the arrangement of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis/trans), atropisomers, and the like.
"chiral" is a molecule having the property of not overlapping its mirror image; and "achiral" refers to a molecule that can overlap with its mirror image.
"enantiomer" refers to two isomers of a compound that are not overlapping but are in mirror image relationship to each other.
"diastereomer" refers to a stereoisomer having two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers may be separated by high resolution analytical procedures such as electrophoresis and chromatography, e.g., HPLC.
The stereochemical definitions and rules used in the present invention generally follow the general definitions of S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E.and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994.
Many organic compounds exist in an optically active form, i.e., they have the ability to rotate the plane of plane polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to denote the absolute configuration of a molecule with respect to one or more of its chiral centers. The prefixes d and l or (+) and (-) are the symbols used to specify the rotation of plane polarized light by the compound, where (-) or l indicates that the compound is left-handed. Compounds prefixed with (+) or d are dextrorotatory. A particular stereoisomer is an enantiomer and a mixture of such isomers is referred to as an enantiomeric mixture. A50: 50 mixture of enantiomers is referred to as a racemic mixture or racemate, which may occur when there is no stereoselectivity or stereospecificity in the chemical reaction or process.
Any asymmetric atom (e.g., carbon, etc.) of a compound disclosed herein can exist in racemic or enantiomerically enriched forms, such as the (R) -, (S) -or (R, S) -configuration. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in the (R) -or (S) -configuration.
Depending on the choice of starting materials and methods, the compounds of the invention may exist as one of the possible isomers or as mixtures thereof, for example as racemates and diastereomeric mixtures (depending on the number of asymmetric carbon atoms). Optically active (R) -or (S) -isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituents may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the substituents of the cycloalkyl group may have cis or trans configuration.
Any resulting mixture of stereoisomers may be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, depending on differences in the physicochemical properties of the components, for example, by chromatography and/or fractional crystallization.
The racemates of any of the resulting end products or intermediates can be resolved into the optical enantiomers by known methods using methods familiar to those skilled in the art, e.g., by separation of the diastereomeric salts obtained. The racemic product can also be separated by chiral chromatography, e.g., High Performance Liquid Chromatography (HPLC) using a chiral adsorbent. In particular, Enantiomers can be prepared by asymmetric synthesis, for example, see Jacques, et al, Enantiomers, racemes and solutions (Wiley Interscience, New York, 1981); PrinciplesofAsymmetric Synthesis (2)nd Ed.Robert E.Gawley,Jeffrey Aubé,Elsevier,Oxford,UK,2012)；Eliel,E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；Wilen,S.H.Tables of Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of Notre Dame Press,Notre Dame,IN 1972)；Chiral Separation Techniques:A Practical Approach(Subramanian,G.Ed.,Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim,Germany,2007)。
The compounds of the invention may be optionally substituted with one or more substituents, as described herein, in compounds of the general formula above, or as specifically exemplified, sub-classes, and classes of compounds encompassed by the invention.
In general, the term "substituted" means that one or more hydrogen atoms in a given structure are replaced with a particular substituent. Unless otherwise indicated, a substituted group may have one substituent substituted at each substitutable position of the group. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, the substituents may be substituted at each position, identically or differently.
The term "unsubstituted" means that the specified group bears no substituents.
The term "optionally substituted with … …" is used interchangeably with the term "unsubstituted or substituted with … …", i.e., the structure is unsubstituted or substituted with one or more substituents described herein.
In addition, unless otherwise explicitly indicated, the descriptions of the terms "… independently" and "… independently" and "… independently" used in the present invention are interchangeable and should be understood in a broad sense to mean that the specific items expressed between the same symbols do not affect each other in different groups or that the specific items expressed between the same symbols in the same groups do not affect each other.
In the various parts of this specification, substituents of the disclosed compounds are disclosed in terms of group type or range. It is specifically intended that the invention includes each and every independent subcombination of the various members of these groups and ranges. For example, the term "C1-6Alkyl "means in particular independently disclosed methyl, ethyl, C3Alkyl radical, C4Alkyl radical, C5Alkyl and C6An alkyl group.
In each of the parts of the invention, linking substituents are described. Where the structure clearly requires a linking group, the markush variables listed for that group are understood to be linking groups. For example, if the structure requires a linking group and the markush group definition for the variable recites "alkyl" or "aryl," it is understood that the "alkyl" or "aryl" represents an attached alkylene group or arylene group, respectively.
The term "alkyl" or "alkyl group" as used herein, denotes a saturated straight or branched chain monovalent hydrocarbon radical, wherein the alkyl group may be optionally substituted with one or more substituents as described herein. Unless otherwise specified, alkyl groups contain 1-20 carbon atoms. In one embodiment, the alkyl group contains 1 to 12 carbon atoms; in another embodiment, the alkyl group contains 3 to 12 carbon atoms; in another embodiment, the alkyl group contains 1 to 6 carbon atoms; in another embodiment, the alkyl group contains 1 to 4 carbon atoms; in yet another embodiment, the alkyl group contains 1 to 3 carbon atoms.
Examples of alkyl groups include, but are not limited to, methyl (Me, -CH)3) Ethyl group (Et, -CH)2CH3) N-propyl (n-Pr, -CH)2CH2CH3) Isopropyl group (i-Pr, -CH (CH)3)2) N-butyl (n-Bu, -CH)2CH2CH2CH3) Isobutyl (i-Bu, -CH)2CH(CH3)2) Sec-butyl (s-Bu, -CH (CH)3)CH2CH3) Tert-butyl (t-Bu, -C (CH)3)3) N-pentyl (-CH)2CH2CH2CH2CH3) 2-pentyl (-CH (CH)3)CH2CH2CH3) 3-pentyl (-CH (CH)2CH3)2) 2-methyl-2-butyl (-C (CH)3)2CH2CH3) 3-methyl-2-butyl (-CH (CH)3)CH(CH3)2) 3-methyl-1-butyl (-CH)2CH2CH(CH3)2) 2-methyl-1-butyl (-CH)2CH(CH3)CH2CH3) N-hexyl (-CH)2CH2CH2CH2CH2CH3) 2-hexyl (-CH (CH)3)CH2CH2CH2CH3) 3-hexyl (-CH (CH)2CH3)(CH2CH2CH3) 2-methyl-2-pentyl (-C (CH))3)2CH2CH2CH3) 3-methyl-2-pentyl (-CH (CH)3)CH(CH3)CH2CH3) 4-methyl-2-pentyl (-CH (CH)3)CH2CH(CH3)2) 3-methyl-3-pentyl (-C (CH)3)(CH2CH3)2) 2-methyl-3-pentyl (-CH (CH)2CH3)CH(CH3)2) 2, 3-dimethyl-2-butyl (-C (CH)3)2CH(CH3)2) 3, 3-dimethyl-2-butyl (-CH (CH)3)C(CH3)3) N-heptyl, n-octyl, and the like.
The term "alkylene" refers to a saturated divalent hydrocarbon radical resulting from the removal of two hydrogen atoms from a saturated straight or branched chain hydrocarbon radical. Unless otherwise specified, the alkylene group contains 1 to 12 carbon atoms. In one embodiment, the alkylene group contains 1 to 6 carbon atoms; in another embodiment, the alkylene group contains 1 to 4 carbon atoms; in yet another embodiment, the alkylene group contains 1 to 3 carbon atoms; in yet another embodiment, the alkylene group contains 1 to 2 carbon atoms. Examples of this include methylene (-CH)2-, ethylene (-CH)2CH2-, n-propylidene (-CH)2CH2CH2-, isopropylidene (-CH (CH)3)CH2-) and the like.
The term "alkenyl" denotes a straight or branched chain monovalent hydrocarbon radical containing 2 to 12 carbon atoms, wherein there is at least one site of unsaturation, i.e. one carbon-carbon sp2A double bond, wherein the alkenyl group may be optionally substituted with one or more substituents described herein, including the positioning of "cis" and "trans", or the positioning of "E" and "Z". In one embodiment, the alkenyl group contains 2 to 8 carbon atoms; in another embodiment, the alkenyl group contains 2 to 6 carbon atoms; in yet another embodiment, the alkenyl group contains 2 to 4 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl (-CH ═ CH)2) Allyl (-CH)2CH＝CH2) 1-propenyl (i.e., propenyl, -CH ═ CH-CH)3) And so on.
The term "alkynyl" denotes a straight or branched chain monovalent hydrocarbon radical containing 2 to 12 carbon atoms, wherein there is at least one site of unsaturation, i.e. a carbon-carbon sp triple bond, wherein said alkynyl radical may optionally be substituted with one or more substituents as described herein. In an implementation methodIn one embodiment, the alkynyl group contains 2 to 8 carbon atoms; in another embodiment, alkynyl groups contain 2-6 carbon atoms; in yet another embodiment, alkynyl groups contain 2-4 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (-C.ident.CH), propargyl (-CH)2C.ident.CH), 1-propynyl (i.e., propynyl, -C.ident.C-CH)3) And so on.
The term "deuterium" denotes a single deuterium atom. For example, one deuterium atom is substituted for one hydrogen atom in a methyl group to form a mono-deuterated methyl (-CDH)2) Two deuterium atoms replace two hydrogen atoms in a methyl group to form a bis-deuterated methyl (-CD)2H) And three deuterium atoms are substituted for three hydrogen atoms in the methyl group to form a tri-deuterated methyl (-CD)3)。
The term "cyano-substituted alkyl" denotes an alkyl group substituted with one or more cyano groups, wherein the alkyl group has the meaning as described herein. Examples include, but are not limited to, cyanomethyl, cyanoethyl, and the like.
The term "hydroxy-substituted alkyl" denotes an alkyl group substituted with one or more hydroxy groups, wherein alkyl and haloalkyl groups have the meaning as described herein, examples of which include, but are not limited to, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, and the like, e.g., "hydroxy-substituted C1-4Alkyl "means an alkyl group having 1 to 4 carbon atoms substituted with one or more hydroxyl groups.
The term "carboxy-substituted alkyl" denotes an alkyl group substituted with one or more carboxy groups, wherein the alkyl group has the meaning as described herein. Examples include, but are not limited to, -CH2COOH、-CH2CH2COOH、-CH2CH2CH2COOH、-CH(CH3)CH2COOH、-CH2(CH2)3COOH, etc.
The term "alkoxy" means an alkyl group attached to the rest of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkoxy group contains 1 to 12 carbon atoms. In one embodiment, the alkoxy group contains 1 to 6 carbon atoms; in another embodiment, the alkoxy group contains 1 to 4 carbon atoms; in yet another embodiment, the alkoxy group contains 1 to 3 carbon atoms. The alkoxy group may be optionally substituted with one or more substituents described herein.
Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH)3) Ethoxy (EtO, -OCH)2CH3) 1-propoxy (n-PrO, n-propoxy, -OCH)2CH2CH3) 2-propoxy (i-PrO, i-propoxy, -OCH (CH)3)2) 1-butoxy (n-BuO, n-butoxy, -OCH)2CH2CH2CH3) 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH)2CH(CH3)2) 2-butoxy (s-BuO, s-butoxy, -OCH (CH)3)CH2CH3) 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC (CH)3)3) 1-pentyloxy (n-pentyloxy, -OCH)2CH2CH2CH2CH3) 2-pentyloxy (-OCH (CH)3)CH2CH2CH3) 3-pentyloxy (-OCH (CH))2CH3)2) 2-methyl-2-butoxy (-OC (CH))3)2CH2CH3) 3-methyl-2-butoxy (-OCH (CH)3)CH(CH3)2) 3-methyl-l-butoxy (-OCH)2CH2CH(CH3)2) 2-methyl-l-butoxy (-OCH)2CH(CH3)CH2CH3) And so on.
The term "haloalkyl" or "haloalkoxy" means an alkyl or alkoxy group substituted with one or more halogen atoms, wherein the alkyl or alkoxy group has the meaning as described herein, examples of which include, but are not limited to, -CH2F、-CHF2、-CF3、-CH2CH2F、-CH2CHF2、-CHFCH2F、-CH2CF3、-CH(CF3)2、-CF2CH2CH3、-CH2CH2CH2F、-CH2CH2CHF2、-CH2CH2CF3、-OCH2F、-OCHF2、-OCF3、-OCH2CH2F、-OCH2CHF2、-OCHFCH2F、-OCH2CF3、-OCH(CF3)2、-OCF2CH2CH3、-OCH2CH2CH2F、-OCH2CH2CHF2、-OCH2CH2CF3And the like.
The term "alkylamino" includes "N-alkylamino" and "N, N-dialkylamino" in which the amino groups are each independently substituted with one or two alkyl groups; the alkyl group has the meaning described in the present invention. In some of these examples, the alkylamino group is one or two C1-6Alkyl groups are attached to the nitrogen atom to form lower alkylamino groups. In other embodiments, the alkylamino group is one or two C1-3To the nitrogen atom to form an alkylamino group. Suitable alkylamino groups can be monoalkylamino or dialkylamino, and such examples include, but are not limited to, N-methylamino, N-ethylamino, N-dimethylamino, N-diethylamino, and the like.
The term "cycloalkyl" denotes a monovalent or polyvalent saturated monocyclic, bicyclic or tricyclic hydrocarbon radical containing from 3 to 12 carbon atoms. In one embodiment, cycloalkyl groups contain 7 to 12 carbon atoms; in yet another embodiment, the cycloalkyl group contains 3 to 8 carbon atoms; in yet another embodiment, the cycloalkyl group contains 3 to 6 carbon atoms. The cycloalkyl groups may be independently unsubstituted or substituted with one or more substituents described herein. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
The term "cycloalkylamino" includes "N-cycloalkylamino" and "N, N-bicycloalkylamino", wherein the amino groups are each independently substituted with one or two cycloalkyl groups; the cycloalkyl radicals have the meanings described in the present invention.Wherein some embodiments are cycloalkylamino is one or two C3-8Cycloalkyl groups are attached to nitrogen atoms to form cycloalkylamino groups. In other embodiments, the cycloalkylamino group is one or two C3-6Is attached to the nitrogen atom to form a cycloalkylamino group. Suitable cycloalkylamino groups can be monocycloalkylamino or dicycloalkylamino, and examples include, but are not limited to, N-cyclopropylamino, N-cyclobutylamino, N-cyclohexylamino, N-dicyclopropylamino, and the like.
The terms "heterocyclyl" and "heterocycle" are used interchangeably herein and both refer to a saturated or partially unsaturated, non-aromatic, monovalent or polyvalent, monocyclic, bicyclic, or tricyclic ring containing from 3 to 12 ring atoms, wherein at least one ring atom is selected from the group consisting of nitrogen, sulfur, and oxygen atoms; polycyclic heterocyclic groups include spiro heterocyclic groups and fused heterocyclic groups. Heterocyclyl consists of 3 to 10 ring atoms; in yet other embodiments, heterocyclyl consists of 3-8 ring atoms; in yet other embodiments, heterocyclyl consists of 3-6 ring atoms; in still other embodiments, heterocyclyl consists of 5-6 ring atoms. Unless otherwise indicated, a heterocyclyl group may be attached to other groups in the molecule through a carbon atom, may be attached to other groups in the molecule through a nitrogen atom, and-CH2-the group may optionally be replaced by-C (═ O) -. The sulfur atom of the ring may optionally be oxidized to the S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxygen compound.
Examples of heterocyclyl groups include, but are not limited to: oxirane, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuryl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxolanyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, pyrrolidinyl, pyrazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiopyranyl, 1, 3-dioxolanyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl,
Figure BDA0002874960740000101
morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thiaOxaalkyl, homopiperazinyl, homopiperidinyl, diazepanyl, oxepanyl, thiacycloheptyl, oxazepinyl
Figure BDA0002874960740000104
Radical diaza
Figure BDA0002874960740000102
Radical, sulfur nitrogen hetero
Figure BDA0002874960740000103
Yl, 2-oxa-5-azabicyclo [2.2.1]Hept-5-yl. In heterocyclic radicals of-CH2Examples of-groups substituted by-C (═ O) -include, but are not limited to, 2-oxopyrrolidinyl, oxo-1, 3-thiazolidinyl, 2-piperidinonyl, pyridazinonyl, 3, 5-dioxopiperidinyl and pyrimidinedione. Examples of the sulfur atom in the heterocyclic group being oxidized include, but are not limited to, sulfolane group, 1-dioxothiomorpholinyl group. The heterocyclyl group may be optionally substituted with one or more substituents as described herein.
The term "aryl" denotes a monocyclic, bicyclic or tricyclic all carbocyclic ring system containing 6 to 14 ring atoms, or 6 to 12 ring atoms, or 6 to 10 ring atoms, wherein at least one ring is aromatic and has one or more attachment points to the rest of the molecule. The term "aryl" may be used interchangeably with the term "aromatic ring". In one embodiment, aryl is a carbocyclic ring system consisting of 6 to 10 ring atoms and containing at least one aromatic ring therein. Examples of the aryl group may include phenyl, naphthyl and anthracenyl. The aryl group may independently be optionally substituted with one or more substituents described herein.
The term "heteroaryl" denotes a monocyclic, bicyclic or tricyclic ring containing 5 to 12 ring atoms, wherein at least one ring is aromatic and at least one ring contains one or more heteroatoms; the heteroaryl group has one or more attachment points to the rest of the molecule. The term "heteroaryl" may be used interchangeably with the terms "heteroaromatic ring" or "heteroaromatic compound". Wherein, in some embodiments, the 5-12 ring atoms of the heteroaryl group contain 1-9 carbon atoms; in still other embodiments, the heteroaryl group contains 1 to 7 carbon atoms in 5 to 12 ring atoms; in still other embodiments, the heteroaryl group contains 1 to 5 carbon atoms in 5 to 12 ring atoms; the heteroaryl group is optionally substituted with one or more substituents described herein. In one embodiment, heteroaryl is a heteroaryl consisting of 5 to 12 ring atoms containing 1,2,3, or 4 heteroatoms independently selected from O, S and N; in another embodiment, heteroaryl is a heteroaryl consisting of 5 to 10 ring atoms containing 1,2,3, or 4 heteroatoms independently selected from O, S and N; in yet another embodiment, heteroaryl is a heteroaryl consisting of 5 to 7 ring atoms containing 1,2,3, or 4 heteroatoms independently selected from O, S and N.
Examples of heteroaryl groups include, but are not limited to, furyl (e.g., 2-furyl, 3-furyl), imidazolyl (e.g., N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), isoxazolyl (e.g., 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), oxadiazolyl (e.g., 1,2, 3-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,2, 4-oxadiazolyl), oxadiazolyl (e.g., 1,2,3, 4-oxadiazolyl), thiazolyl (e.g., 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), isothiazolyl, 2-thiadiazolyl (e.g., 1,3, 4-thiadiazolyl, 1,2, 3-thiadiazolyl, 1,2, 5-thiadiazolyl), thiatriazolyl (e.g., 1,2,3, 4-thiatriazolyl), tetrazolyl (e.g., 2H-1,2,3, 4-tetrazolyl, 1H-1,2,3, 4-tetrazolyl), triazolyl (e.g., 2H-1,2, 3-triazolyl, 1H-1,2, 4-triazolyl, 4H-1,2, 4-triazolyl), thienyl (e.g., 2-thienyl, 3-thienyl), 1H-pyrazolyl (e.g., 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, 1H-pyrazol-5-yl), 1,2, 3-thiadiazolyl, 1,3, 4-thiadiazolyl, 1,2, 5-thiadiazolyl, pyrrolyl (e.g., N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyridazinyl (e.g., 3-pyridazinyl, 4-pyridazinyl), 2-pyrazinyl, triazinyl (e.g., 1,3, 5-triazine), tetrazinyl (e.g., 1,2,4, 5-tetrazine, 1,2,3, 5-tetrazine); the following bicyclic rings are also included, but are in no way limited to these: benzimidazolyl, benzpyrazolyl (e.g. benzimidazolyl, benzopyrazolyl)
Figure BDA0002874960740000111
) Benzofuranyl, benzothienyl, benzodioxazolyl, indolyl (e.g., 2-indolyl), purinyl, quinolyl (e.g., 2-quinolyl, 3-quinolyl, 4-quinolyl), isoquinolyl (e.g., 1-isoquinolyl, 3-isoquinolyl, or 4-isoquinolyl), imidazo [1,2-a ] group]Pyridyl, pyrazolo [1,5-a]Pyridyl, pyrazolo [1,5-a]Pyrimidinyl, imidazo [1,2-b ]]Pyridazinyl, [1,2,4 ]]Triazolo [4,3-b]Pyridazinyl, [1,2,4 ]]Triazolo [1,5-a]Pyrimidinyl, [1,2,4 ] or their salts]Triazolo [1,5-a]A pyridyl group,
Figure BDA0002874960740000112
And so on.
The term "j-k atoms make up" means that the cyclic group consists of j-k ring atoms including carbon atoms and/or heteroatoms such as O, N, S, P; j and k are each independently any non-zero natural number, and k is greater than j; the term "j-k" includes j, k and any natural number therebetween. For example, "5 to 12 atoms make up," "5 to 10 atoms make up," or "3 to 7 atoms make up" means that the cyclic group is made up of 5 to 12 (i.e., 5, 6, 7, 8,9, 10, 11, or 12), 5 to 10 (i.e., 5, 6, 7, 8,9, or 10), 5 to 6 (i.e., 5 or 6), or 3 to 7 (i.e., 3,4, 5, 6, or 7) ring atoms including carbon atoms and/or heteroatoms such as O, N, S, P. The term "unsaturated" as used herein means that the group contains one or more unsaturations.
The term "carboxy", whether used alone or in combination with other terms, such as "carboxyalkyl", denotes-CO2H or-COOH.
The term "heteroatom" refers to O, S, N, P and Si, including N, S and any oxidation state form of P; primary, secondary, tertiary amines and quaternary ammonium salt forms; or a form in which a hydrogen on a nitrogen atom in the heterocycle is substituted, for example, N (like N in 3, 4-dihydro-2H-pyrrolyl), NH (like NH in pyrrolidinyl) or NR (like NR in N-substituted pyrrolidinyl).
The term "halogen" or "halogen atom" means a fluorine atom (F), chlorine atom (Cl), bromine atom (Br) or iodine atom (I).
The term "cyano" or "CN" denotes a cyano structure, which group may be attached to another group.
The term "nitro" or "NO2"denotes a nitro structure, which may be linked to other groups.
As described herein, a ring system formed on a ring wherein a substituent is bonded to the center (as shown in formula b) represents that the substituent may be substituted at any substitutable position on the ring. For example, the substituent R represented by the formula C may be mono-or polysubstituted at any possible substituted position on the C ring, as shown in the formulae C1 to C19.
Figure BDA0002874960740000121
As described herein, a linkage to the ring system (as shown in formula d) means that the linkage can be attached to the rest of the molecule at any point on the ring system that is available for attachment. Formula d represents any possible attachment position on the ring that can be attached to the rest of the molecule, as shown by formulas d 1-d 5.
Figure BDA0002874960740000122
When a group is attached to the rest of the molecule via two sites, as described herein, the two sites are independently optionally attached to other groups of the molecule, and the groups attached to the two sites may be interchanged, unless otherwise indicated; for example, the piperidine group in formula E may be through E1End and E2The ends being connected to the rest of the molecule, E when the rest of the molecule is unchanged1End and E2The ends may be interchanged.
Figure BDA0002874960740000123
The term "protectProtecting group "or" PG "means that a substituent is usually used to block or protect a particular functionality when reacted with other functional groups. For example, "amino protecting group" means a substituent attached to an amino group to block or protect the functionality of the amino group in a compound, and suitable amino protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC ), benzyloxycarbonyl (CBZ ) and 9-fluorenylmethyleneoxycarbonyl (Fmoc). Similarly, "hydroxyl protecting group" refers to the functionality of a substituent of a hydroxyl group to block or protect the hydroxyl group, and suitable protecting groups include acetyl and silyl groups. "carboxy protecting group" refers to the functionality of a substituent of a carboxy group to block or protect the carboxy group, and typical carboxy protecting groups include-CH2CH2SO2Ph, cyanoethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxymethyl, 2- (p-toluenesulfonyl) ethyl, 2- (p-nitrobenzenesulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitroethyl, and the like. General descriptions of protecting groups can be found in the literature: greene, Protective Groups in Organic Synthesis, John Wiley&Sons,New York,1991；and P.J.Kocienski,Protecting Groups,Thieme,Stuttgart,2005.
The term "prodrug", as used herein, represents a compound that is converted in vivo to a compound of formula (I). Such conversion is effected by hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent structure in the blood or tissue. The prodrug compound of the invention can be ester, and in the prior invention, the ester can be used as the prodrug and comprises phenyl ester and aliphatic (C)1-C24) Esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound of the present invention contains a hydroxy group, i.e., it can be acylated to provide the compound in prodrug form. Other prodrug forms include phosphate esters, such as those obtained by phosphorylation of a hydroxyl group on the parent. For a complete discussion of prodrugs, reference may be made to the following: T.Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems, Vol.14of the A.C.S.symposium Series, Edward B.Roche, ed., Bioreversible Cariers inDrug Design,American Pharmaceutical Association and Pergamon Press,1987,J.Rautio et al.,Prodrugs:Design and Clinical Applications,Nature Review Drug Discovery,2008,7,255-270,and S.J.Hecker et al.,Prodrugs of Phosphates and Phosphonates,Journal of Medicinal Chemistry,2008,51,2328-2345。
"metabolite" refers to the product of a particular compound or salt thereof obtained by metabolism in vivo. Metabolites of a compound can be identified by techniques well known in the art, and its activity can be characterized by assay methods as described herein. Such products may be obtained by administering the compound by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, and the like. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a sufficient period of time.
As used herein, "pharmaceutically acceptable salts" refer to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as are: berge et al, description of the scientific acceptable salts in detail in J. pharmaceutical Sciences,1977,66:1-19. Pharmaceutically acceptable non-toxic acid forming salts include, but are not limited to, inorganic acid salts such as hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, and organic acid salts such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, or obtained by other methods described in the literature above, such as ion exchange. Other pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, cyclopentylpropionates, digluconates, dodecylsulfates, ethanesulfonates, formates, fumarates, glucoheptonates, glycerophosphates, gluconates, hemisulfates, heptanoates, hexanoates, hydroiodides, 2-hydroxy-ethanesulfonatesSulfonates, lactobionates, lactates, laurates, malates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, palmitates, pamoates, pectinates, persulfates, 3-phenylpropionates, picrates, pivalates, propionates, stearates, thiocyanates, p-toluenesulfonates, undecanoates, valerates, and the like. Salts obtained with appropriate bases include alkali metals, alkaline earth metals, ammonium and N+(C1-4Alkyl radical)4A salt. The present invention also contemplates quaternary ammonium salts formed from compounds containing groups of N. Water-soluble or oil-soluble or dispersion products can be obtained by quaternization. Alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and amine cations resistant to formation of counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C1-8Sulfonates and aromatic sulfonates.
"solvate" of the present invention refers to an association of one or more solvent molecules with a compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol. The term "hydrate" refers to an association of solvent molecules that is water.
When the solvent is water, the term "hydrate" may be used. In some embodiments, a molecule of a compound of the present invention may be associated with a molecule of water, such as a monohydrate; in other embodiments, one molecule of the compound of the present invention may be associated with more than one molecule of water, such as a dihydrate, and in still other embodiments, one molecule of the compound of the present invention may be associated with less than one molecule of water, such as a hemihydrate. It should be noted that the hydrates of the present invention retain the biological effectiveness of the compound in its non-hydrated form.
The term "nitroxide" means that when a compound contains several amine functional groups, 1 or more than 1 nitrogen atom can be oxidized to form an N-oxide. Specific examples of N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen-containing heterocyclic nitrogen atoms. The corresponding amines can be treated with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid) to form the N-oxide (see Advanced Organic Chemistry, Wiley Interscience, 4 th edition, Jerry March, pages). In particular, the N-oxide may be prepared by the method of L.W.Deady (Syn.Comm.1977,7,509-514) in which an amine compound is reacted with m-chloroperbenzoic acid (MCPBA), for example, in an inert solvent such as dichloromethane.
The term "carrier" includes any solvent, dispersion medium, coating, surfactant, antioxidant, preservative (e.g., antibacterial, antifungal), isotonic agent, salt, Pharmaceutical stabilizer, binder, excipient, dispersant, lubricant, sweetener, flavoring agent, coloring agent, or combination thereof, known to those skilled in the art (e.g., Remington's Pharmaceutical Sciences,18th Ed. Mack Printing Company,1990, pp. 1289-1329). Except insofar as any conventional carrier is incompatible with the active ingredient, its use in therapeutic or pharmaceutical compositions is contemplated.
The term "treating" any disease or condition, as used herein, means all that can slow, halt, arrest, control or halt the progression of the disease or condition, but does not necessarily mean that all the symptoms of the disease or condition have disappeared, and also includes prophylactic treatment of the symptoms, particularly in patients susceptible to such disease or disorder. In some of these embodiments, refers to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one clinical symptom thereof). In other embodiments, "treating" or "treatment" refers to moderating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, "treating" or "treatment" refers to modulating the disease or disorder, either physically (e.g., stabilizing a perceptible symptom) or physiologically (e.g., stabilizing a parameter of the body), or both. In other embodiments, "treating" or "treatment" refers to preventing or delaying the onset, occurrence, or worsening of a disease or disorder.
The term "therapeutically effective amount" or "therapeutically effective dose" as used herein refers to an amount of a compound of the invention that is capable of eliciting a biological or medical response (e.g., reducing or inhibiting enzyme or protein activity, or ameliorating symptoms, alleviating a disorder, slowing or delaying the progression of a disease, or preventing a disease, etc.) in a subject. In one non-limiting embodiment, the term "therapeutically effective amount" refers to an amount that, when administered to a subject, is effective for: (1) at least partially alleviating, inhibiting, preventing and/or ameliorating a disorder or disease (i) mediated by roryt, or (ii) associated with roryt activity, or (iii) characterized by abnormal activity of roryt; or (2) reduces or inhibits the activity of ROR γ t; or (3) reduces or inhibits expression of ROR γ t. In another embodiment, the term "therapeutically effective amount" refers to an amount that, when administered to a cell, or organ, or non-cellular biological substance, or vehicle, at least partially reduces or inhibits ROR γ t activity; or an amount of a compound of the invention effective to at least partially reduce or inhibit ROR γ t expression.
The terms "administration" and "administering" of a compound as used herein shall be understood as providing a compound of the invention or a prodrug of a compound of the invention to a subject in need thereof. It will be appreciated that one skilled in the art can treat a patient currently suffering from such a disorder or prophylactically treat a patient suffering from such a disorder by using an effective amount of a compound of the present invention.
The term "composition" as used herein refers to a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. The meaning of such terms in relation to pharmaceutical compositions includes products comprising the active ingredient(s) and the inert ingredient(s) that make up the carrier, as well as any product which results, directly or indirectly, from mixing, complexation or aggregation of any two or more of the ingredients, or from decomposition of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention include any composition prepared by admixing a compound of the present invention and a pharmaceutically acceptable carrier.
Description of the Compounds of the invention
The invention discloses (hetero) aryl derivatives, pharmaceutically acceptable salts thereof, pharmaceutical preparations and compositions thereof, which can be used as ROR gamma t inhibitors and have potential application in treating inflammatory or autoimmune diseases mediated by ROR gamma t, such as psoriasis, rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease, colitis, ulcerative colitis, rheumatoid arthritis, autoimmune ocular disease, ankylosing spondylitis, asthma, chronic obstructive pulmonary disease, osteoarthritis, allergic rhinitis, allergic dermatitis, Crohn's disease or Kawasaki disease.
In one aspect, the invention relates to a compound of formula (I) or a stereoisomer, a nitrogen oxide, a solvate, a metabolite, a pharmaceutically acceptable salt of a compound of formula (I) or a prodrug thereof,
Figure BDA0002874960740000141
wherein, A, B, D, L1、L2、R2、R3、R4、Z1、Z2、Z3、Z4N, m and p have the meanings given in the description of the invention, and represent L2The direction of connection of (a).
In some embodiments, each Z is1、Z2、Z3And Z4Independently is CR1Or N; wherein R is1Have the meaning as described in the present invention.
In some embodiments, L is1Is a bond, -O-, -S-, -NH-, -C (═ O) -or- (CR)aRb)q-; wherein R isa、RbAnd q has the meaning described in the present invention.
In some embodiments, L is2is-C (═ O) -NH- (CR)5R6)-、*-NH-C(＝O)-(CR5R6)-、*-NH-C(＝O)-、*-S(＝O)2-NH-(CR5R6)-、*-NH-S(＝O)2-(CR5R6)-、*-S(＝O)-NH-(CR5R6) -or-NH-S (═ O) - (CR)5R6) -; wherein R is5And R6Have the meaning as described in the present invention.
In some embodiments, RaAnd RbEach independently is H, deuterium, F, Cl, Br, I, C1-4Alkyl or C1-4A haloalkyl group.
In some embodiments, ring a is C6-10Aryl, heteroaryl of 5 to 10 atoms, C3-8Cycloalkyl or heterocyclyl consisting of 5 to 10 atoms.
In some embodiments, ring B is a heterocyclyl consisting of 5-10 atoms.
In some embodiments, ring D is heterocyclyl consisting of 4-10 atoms or C3-8A cycloalkyl group.
In some embodiments, each R is1Independently H, deuterium, F, Cl, Br, I, cyano, C1-6Alkyl radical, C1-6Alkoxy or C1-6A haloalkyl group.
In some embodiments, each R is2And R3Independently deuterium, F, Cl, Br, I, -OH, -CN, -NH2、-NO2-COOH, oxo, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, -C1-6alkylene-O-C1-6Alkyl radical, C3-8Cycloalkyl radical, C6-10Aryl, heterocyclyl of 5 to 10 atoms, heteroaryl of 5 to 10 atoms or-C (═ O) -N (R)dRe) (ii) a Wherein, the C1-6Alkyl radical, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, -C1-6alkylene-O-C1-6Alkyl radical, C3-8Cycloalkyl radical, C6-10Aryl, heteroaryl of 5-10 atoms and heterocyclyl of 5-10 atoms are independently optionally substituted with 1,2 or 3RcSubstituted;
wherein R isc、RdAnd ReHave the meaning as described in the present invention.
In some embodiments, each R is4Independently is-S (═ O)2-C1-6Alkyl, -S (═ O)2-C1-6Alkoxy, -S (═ O)2-C1-6Alkylamino, -S (═ O)2-C1-6Haloalkyl, -S (═ O)2-C3-8Cycloalkyl, -S (═ O) -C1-6Alkyl, -S (═ O)2H、-COOH、-C(＝O)-N(RgRh)、-N(Rg)-C(＝O)-C1-6Alkyl, -C (═ O) -O-C1-6Alkyl radical, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Haloalkyl, C3-8Cycloalkyl, carboxy substituted C1-6Alkyl or-C (═ O) -C1-6A hydroxyalkyl group; wherein R isgAnd RhHave the meaning as described in the present invention.
In some embodiments, RgAnd RhEach independently is H, deuterium or C1-6An alkyl group.
In some embodiments, R5And R6Each independently of the others being H, deuterium, -OH, -CN, -NH2、-NO2、-COOH、C1-6Alkoxy radical, C1-6Haloalkyl, hydroxy-substituted C1-6Alkyl, cyano-substituted C1-6Alkyl, carboxy substituted C1-6Alkyl, -C1-6alkylene-O-C1-6Alkyl, -C1-6alkylene-C (═ O) -O-C1-6Alkyl, -C1-6alkylene-C (═ O) -N (R)dRe)、-C1-6alkylene-O-C (═ O) -N (R)dRe)、-C1-6alkylene-N (R)f)-C(＝O)-N(RdRe) or-C1-6alkylene-N (R)dRe) (ii) a Wherein, said C1-6Alkoxy radical, C1-6Haloalkyl and-C1-6alkylene-O-C1-6Alkyl is independently optionally substituted by 1,2 or 3 substituents selected from deuterium, -OH, -COOH, -N (R)dRe) Or C1-6Substituted by a substituent of alkoxy;
wherein R isd、ReAnd RfHave the meaning as described in the present invention.
In some embodiments, each R iscIndependently deuterium, F, Cl, Br, I, -OH, -CN, -NH2、C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Haloalkyl or C1-6A haloalkoxy group.
In some embodiments, RdAnd ReEach independently of the others being H, deuterium, -OH, C1-6Alkyl, -C (═ O) H, -C (═ O) -O-C1-6Alkyl, -C (═ O) -C1-6Alkyl, -C1-6alkylene-C (═ O) -O-C1-6Alkyl or-C1-6alkylene-O-C1-6An alkyl group; wherein, said C1-6Alkyl, -C1-6alkylene-C (═ O) -O-C1-6Alkyl and-C1-6alkylene-O-C1-6Alkyl is independently optionally substituted by 1,2 or 3 substituents selected from deuterium, F, Cl, Br, I, -OH, -CN, -NH2Or a substituent of-COOH.
In some embodiments, each R isfIndependently of one another H, deuterium, C1-6Alkyl, -C1-6alkylene-O-C1-6Alkyl or-C1-6alkylene-C3-8A cycloalkyl group; wherein, said C1-6Alkyl, -C1-6alkylene-O-C1-6Alkyl and-C1-6alkylene-C3-8Cycloalkyl is independently optionally substituted with 1,2 or 3 substituents selected from deuterium, F, Cl, Br, I, -OH, -CN, -NH2Or a substituent of COOH.
In some embodiments, n is 0, 1,2, or 3.
In some embodiments, m is 0, 1,2, or 3.
In some embodiments, p is 0, 1,2, or 3.
In some embodiments, q is 0, 1,2, or 3.
In other embodiments, RaAnd RbEach independently of the others is H, deuterium, F, Cl, Br, I, 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.
In other embodimentsIn embodiments, ring A is C6-10Aryl, heteroaryl of 5 to 7 atoms, C3-6Cycloalkyl or heterocyclyl consisting of 5 to 7 atoms.
In still other embodiments, ring a is phenyl, naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolyl, pyrazolyl, imidazolyl, furyl, oxazolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, or piperazinyl.
In other embodiments, ring B is a heterocyclyl consisting of 5-7 atoms.
In still other embodiments, ring B is
Figure BDA0002874960740000161
Figure BDA0002874960740000162
In other embodiments, ring D is heterocyclyl consisting of 4-7 atoms or C3-6A cycloalkyl group.
In still other embodiments, ring D is piperidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperazinyl, azetidinyl, oxetanyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
In other embodiments, each R is1Independently H, deuterium, F, Cl, Br, I, cyano, C1-4Alkyl radical, C1-4Alkoxy or C1-4A haloalkyl group.
In other embodiments, each R is2And R3Independently deuterium, F, Cl, Br, I, -OH, -CN, -NH2、-NO2-COOH, oxo, C1-4Alkyl radical, C1-4Haloalkyl, C1-4Alkoxy radical, C1-4Haloalkoxy, -C1-4alkylene-O-C1-4Alkyl radical, C3-6Cycloalkyl radical, C6-10Aryl, heterocyclyl of 5 to 7 atoms, heteroaryl of 5 to 7 atoms or-C (═ O) -N (R)dRe) (ii) a Wherein, the C1-4Alkyl radical, C1-4Haloalkyl, C1-4Alkoxy radical, C1-4Haloalkoxy, -C1-4alkylene-O-C1-4Alkyl radical, C3-6Cycloalkyl radical, C6-10Aryl, heteroaryl of 5-7 atoms and heterocyclyl of 5-7 atoms are independently optionally substituted with 1,2 or 3RcSubstituted;
wherein R isc、RdAnd ReHave the meaning as described in the present invention.
In other embodiments, each R iscIndependently deuterium, F, Cl, Br, I, -OH, -CN, -NH2、C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl or C1-4A haloalkoxy group.
In other embodiments, each R is4Independently is-S (═ O)2-C1-4Alkyl, -S (═ O)2-C1-4Alkoxy, -S (═ O)2-C1-4Alkylamino, -S (═ O)2-C1-4Haloalkyl, -S (═ O)2-C3-6Cycloalkyl, -S (═ O) -C1-4Alkyl, -S (═ O)2H、-COOH、-C(＝O)-N(RgRh)、-N(Rg)-C(＝O)-C1-4Alkyl, -C (═ O) -O-C1-4Alkyl radical, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl, C3-6Cycloalkyl, carboxy substituted C1-4Alkyl or-C (═ O) -C1-4A hydroxyalkyl group;
wherein R isgAnd RhHave the meaning as described in the present invention.
In other embodiments, RgAnd RhEach independently is H, deuterium or C1-4An alkyl group.
In other embodiments, R5And R6Each independently of the others being H, deuterium, -OH, -CN, -NH2、-NO2、-COOH、C1-4Alkoxy radical, C1-4Haloalkyl, hydroxy-substituted C1-4Alkyl, cyano-substituted C1-4Alkyl, carboxyl substitutedC of (A)1-4Alkyl, -C1-4alkylene-O-C1-4Alkyl, -C1-4alkylene-C (═ O) -O-C1-4Alkyl, -C1-4alkylene-C (═ O) -N (R)dRe)、-C1-4alkylene-O-C (═ O) -N (R)dRe)、-C1-4alkylene-N (R)f)-C(＝O)-N(RdRe) or-C1-4alkylene-N (R)dRe) (ii) a Wherein, said C1-4Alkoxy radical, C1-4Haloalkyl and-C1-4alkylene-O-C1-4Alkyl is independently optionally substituted by 1,2 or 3 substituents selected from deuterium, -OH, -COOH, -N (R)dRe) Or C1-4Substituted by a substituent of alkoxy;
wherein R isd、ReAnd RfHave the meaning as described in the present invention.
In other embodiments, RdAnd ReEach independently of the others being H, deuterium, -OH, C1-4Alkyl, -C (═ O) H, -C (═ O) -O-C1-4Alkyl, -C (═ O) -C1-4Alkyl, -C1-4alkylene-C (═ O) -O-C1-4Alkyl or-C1-4alkylene-O-C1-4An alkyl group; wherein, said C1-4Alkyl, -C1-4alkylene-C (═ O) -O-C1-4Alkyl and-C1-4alkylene-O-C1-4Alkyl is independently optionally substituted by 1,2 or 3 substituents selected from deuterium, F, Cl, Br, I, -OH, -CN, -NH2Or a substituent of-COOH.
In other embodiments, each R isfIndependently of one another H, deuterium, C1-4Alkyl, -C1-4alkylene-O-C1-4Alkyl or-C1-4alkylene-C3-6A cycloalkyl group; wherein, said C1-4Alkyl, -C1-4alkylene-O-C1-4Alkyl and-C1-4alkylene-C3-6Cycloalkyl is independently optionally substituted with 1,2 or 3 substituents selected from deuterium, F, Cl, Br, I, -OH, -CN, -NH2Or a substituent of COOH.
In yet other embodiments, each R is1Independently is H, deuterium, F, Cl, Br, I, cyano, methyl,Ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, -CH2F、-CH2Cl、-CHF2、-CHCl2、-CF3、-CH2CH2F、-CH2CH2Cl、-CH2CHF2、-CH2CHCl2、-CHFCH2F、-CHClCH2Cl、-CH2CF3、-CH(CF3)2、-CF2CH2CH3、-CH2CH2CH2F、-CH2CH2CHF2or-CH2CH2CF3。
In yet other embodiments, each R is2And R3Independently deuterium, F, Cl, Br, I, -OH, -CN, -NH2、-NO2-COOH, oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, -CH2F、-CHF2、-CF3、-CH2CH2F、-CH2CHF2、-CHFCH2F、-CH2CF3、-CH(CF3)2、-CF2CH2CH3、-CH2CH2CH2F、-CH2CH2CHF2、-CH2CH2CF3、-OCH2F、-OCHF2、-OCF3、-OCH2CH2F、-OCH2CHF2、-OCHFCH2F、-OCH2CF3、-OCH(CF3)2、-OCF2CH2CH3、-OCH2CH2CH2F、-OCH2CH2CHF2、-OCH2CH2CF3、-CH2OCH3、-CH2OCH2CH3、-CH2OCH2CH2CH3、-CH2OCH(CH3)2、-CH2CH2OCH3、-CH2CH2OCH2CH3、-CH2CH2OCH2CH2CH3、-CH2CH2OCH(CH3)2、-CH2CH2CH2OCH3、-CH2CH2CH2OCH2CH3、-CH2CH2CH2OCH2CH2CH3、-CH2CH2CH2OCH(CH3)2Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, pyridyl, pyrimidinyl, pyrazolyl, thiazolyl, imidazolyl, oxazolyl, triazolyl, tetrazolyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, pyrrolidinyl, or-C (═ O) -N (R)dRe) (ii) a Wherein the methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, tert-butyl group, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, tert-butoxy group, -CH2F、-CHF2、-CH2CH2F、-CH2CHF2、-CHFCH2F、-CH2CF3、-CH(CF3)2、-CF2CH2CH3、-CH2CH2CH2F、-CH2CH2CHF2、-CH2CH2CF3、-OCH2F、-OCHF2、-OCH2CH2F、-OCH2CHF2、-OCHFCH2F、-OCH2CF3、-OCH(CF3)2、-OCF2CH2CH3、-OCH2CH2CH2F、-OCH2CH2CHF2、-OCH2CH2CF3、-CH2OCH3、-CH2OCH2CH3、-CH2OCH2CH2CH3、-CH2OCH(CH3)2、-CH2CH2OCH3、-CH2CH2OCH2CH3、-CH2CH2OCH2CH2CH3、-CH2CH2OCH(CH3)2、-CH2CH2CH2OCH3、-CH2CH2CH2OCH2CH3、-CH2CH2CH2OCH2CH2CH3、-CH2CH2CH2OCH(CH3)2Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazolyl, thiazolyl, imidazolyl, oxazolyl, triazolyl, tetrazolyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl and pyrrolidinyl independently optionally substituted with 1,2 or 3RcSubstituted;
wherein R iscHave the meaning as described in the present invention.
In yet other embodiments, each R iscIndependently deuterium, F, Cl, Br, I, -OH, -CN, -NH2Methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, -CH2F、-CHF2、-CF3、-CH2CH2F、-CH2CHF2、-CHFCH2F、-CH2CF3、-CH(CF3)2、-CF2CH2CH3、-CH2CH2CH2F、-CH2CH2CHF2、-CH2CH2CF3、-OCH2F、-OCHF2、-OCF3、-OCH2CH2F、-OCH2CHF2、-OCHFCH2F、-OCH2CF3、-OCH(CF3)2、-OCF2CH2CH3、-OCH2CH2CH2F、-OCH2CH2CHF2or-OCH2CH2CF3。
In yet other embodiments, each R is4is-S (═ O)2-CH3、-S(＝O)2-CH2CH3、-S(＝O)2-CH2CH2CH3、-S(＝O)2-CH(CH3)CH3、-S(＝O)2-OCH3、-S(＝O)2-OCH2CH3、-S(＝O)2-OCH2CH2CH3、-S(＝O)2-OCH(CH3)CH3、-S(＝O)2-NH-CH3、-S(＝O)2-NH-CH2CH3、-S(＝O)2-NH-CH2CH2CH3、-S(＝O)2-NH-CH(CH3)CH3、-S(＝O)2-cyclopropyl, -S (═ O)2-cyclobutyl, -S (═ O)2-cyclopentyl, -S (═ O)2-cyclohexyl, -S (═ O) -CH3、-S(＝O)-CH2CH3、-S(＝O)-CH2CH2CH3、-S(＝O)-CH(CH3)CH3、-S(＝O)2H、-COOH、-C(＝O)-N(RgRh)、-N(Rg)-C(＝O)-CH3、-N(Rg)-C(＝O)-CH2CH3、-N(Rg)-C(＝O)-CH2CH2CH3、-N(Rg)-C(＝O)-CH(CH3)CH3、-C(＝O)-O-CH3、-C(＝O)-O-CH2CH3、-C(＝O)-O-CH2CH2CH3、-C(＝O)-O-CH(CH3)CH3Methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, -CH2F、-CHF2、-CF3、-CH2CH2F、-CH2CHF2、-CHFCH2F、-CH2CF3、-CH(CF3)2、-CF2CH2CH3、-CH2CH2CH2F、-CH2CH2CHF2、-CH2CH2CF3Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2COOH、-CH2CH2COOH、-CH2CH2CH2COOH、-C(＝O)-CH2OH、-C(＝O)-CH2CH2OH or-C (═ O) -CH2CH2CH2OH；
Wherein R isgAnd RhHave the meaning as described in the present invention.
In still other embodiments, RgAnd RhEach independently is H, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, or tert-butyl.
In still other embodiments, R5And R6Each independently of the others being H, deuterium, -OH, -CN, -NH2、-NO2、-COOH、-CH2F、-CHF2、-CF3、-CH2CH2F、-CH2CHF2、-CHFCH2F、-CH2CF3、-CH(CF3)2、-CF2CH2CH3、-CH2CH2CH2F、-CH2CH2CHF2、-CH2CH2CF3Methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, -CH2OH、-CH2CH2OH、-CH2CH2CH2OH、-CH(CH3)CH2OH、-CH2(CH2)3OH、-CH2CN、-CH2CH2CN、-CH2CH2CH2CN、-CH(CH3)CH2CN、-CH2(CH2)3CN、-CH2COOH、-CH2CH2COOH、-CH2CH2CH2COOH、-CH(CH3)CH2COOH、-CH2(CH2)3COOH、-CH2OCH3、-CH2OCH2CH3、-CH2OCH2CH2CH3、-CH2OCH(CH3)2、-CH2CH2OCH3、-CH2CH2OCH2CH3、-CH2CH2OCH2CH2CH3、-CH2CH2OCH(CH3)2、-CH2CH2CH2OCH3、-CH2CH2CH2OCH2CH3、-CH2CH2CH2OCH2CH2CH3、-CH2CH2CH2OCH(CH3)2、-CH2-C(＝O)-OCH3、-CH2-C(＝O)-OCH2CH3、-CH2-C(＝O)-OCH2CH2CH3、-CH2-C(＝O)-OCH(CH3)2、-CH2CH2-C(＝O)-OCH3、-CH2CH2-C(＝O)-OCH2CH3、-CH2CH2-C(＝O)-OCH2CH2CH3、-CH2CH2-C(＝O)-OCH(CH3)2、-CH2CH2CH2-C(＝O)-OCH3、-CH2CH2CH2-C(＝O)-OCH2CH3、-CH2CH2CH2-C(＝O)-OCH2CH2CH3、-CH2CH2CH2-C(＝O)-OCH(CH3)2、-CH2-C(＝O)-N(RdRe)、-CH2CH2-C(＝O)-N(RdRe)、-CH2CH2CH2-C(＝O)-N(RdRe)、-CH2-O-C(＝O)-N(RdRe)、-CH2CH2-O-C(＝O)-N(RdRe)、-CH2CH2CH2-O-C(＝O)-N(RdRe)、-CH2-N(Rf)-C(＝O)-N(RdRe)、-CH2CH2-N(Rf)-C(＝O)-N(RdRe)、-CH2CH2CH2-N(Rf)-C(＝O)-N(RdRe)、-CH2N(RdRe)、-CH2CH2N(RdRe) or-CH2CH2CH2N(RdRe)；
Wherein, said-CH2F、-CHF2、-CH2CH2F、-CH2CHF2、-CHFCH2F、-CH2CF3、-CH(CF3)2、-CF2CH2CH3、-CH2CH2CH2F、-CH2CH2CHF2、-CH2CH2CF3Methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, -CH2OCH3、-CH2OCH2CH3、-CH2OCH2CH2CH3、-CH2OCH(CH3)2、-CH2CH2OCH3、-CH2CH2OCH2CH3、-CH2CH2OCH2CH2CH3、-CH2CH2OCH(CH3)2、-CH2CH2CH2OCH3、-CH2CH2CH2OCH2CH3、-CH2CH2CH2OCH2CH2CH3and-CH2CH2CH2OCH(CH3)2Independently optionally substituted with 1,2 or 3 substituents selected from deuterium, -OH, -COOH, methoxy, ethoxy, N-propoxy, isopropoxy, N-butoxy, tert-butoxy or-N (R)dRe) Substituted with the substituent(s);
wherein R isd、ReAnd RfHave the meaning as described in the present invention.
In still other embodiments, RdAnd ReEach independently is H, deuterium, -OH, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, -C (═ O) H, -C (═ O) -O-CH3、-C(＝O)-O-CH2CH3、-C(＝O)-O-CH2CH2CH3、-C(＝O)-O-CH(CH3)2、-C(＝O)-CH3、-C(＝O)-CH2CH3、-C(＝O)-CH2CH2CH3、-C(＝O)-CH(CH3)2、-CH2OCH3、-CH2OCH2CH3、-CH2OCH2CH2CH3、-CH2OCH(CH3)2、-CH2CH2OCH3、-CH2CH2OCH2CH3、-CH2CH2OCH2CH2CH3、-CH2CH2OCH(CH3)2、-CH2CH2CH2OCH3、-CH2CH2CH2OCH2CH3、-CH2CH2CH2OCH2CH2CH3、-CH2CH2CH2OCH(CH3)2、-CH2-C(＝O)-OCH3、-CH2-C(＝O)-OCH2CH3、-CH2-C(＝O)-OCH2CH2CH3、-CH2-C(＝O)-OCH(CH3)2、-CH2CH2-C(＝O)-OCH3、-CH2CH2-C(＝O)-OCH2CH3、-CH2CH2-C(＝O)-OCH2CH2CH3、-CH2CH2-C(＝O)-OCH(CH3)2、-CH2CH2CH2-C(＝O)-OCH3、-CH2CH2CH2-C(＝O)-OCH2CH3、-CH2CH2CH2-C(＝O)-OCH2CH2CH3or-CH2CH2CH2-C(＝O)-OCH(CH3)2；
Wherein, the methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, -CH2OCH3、-CH2OCH2CH3、-CH2OCH2CH2CH3、-CH2OCH(CH3)2、-CH2CH2OCH3、-CH2CH2OCH2CH3、-CH2CH2OCH2CH2CH3、-CH2CH2OCH(CH3)2、-CH2CH2CH2OCH3、-CH2CH2CH2OCH2CH3、-CH2CH2CH2OCH2CH2CH3、-CH2CH2CH2OCH(CH3)2、-CH2-C(＝O)-OCH3、-CH2-C(＝O)-OCH2CH3、-CH2-C(＝O)-OCH2CH2CH3、-CH2-C(＝O)-OCH(CH3)2、-CH2CH2-C(＝O)-OCH3、-CH2CH2-C(＝O)-OCH2CH3、-CH2CH2-C(＝O)-OCH2CH2CH3、-CH2CH2-C(＝O)-OCH(CH3)2、-CH2CH2CH2-C(＝O)-OCH3、-CH2CH2CH2-C(＝O)-OCH2CH3、-CH2CH2CH2-C(＝O)-OCH2CH2CH3and-CH2CH2CH2-C(＝O)-OCH(CH3)2Independently optionally substituted by 1,2 or 3 substituents selected from deuterium, F, Cl, Br, I, -OH, -CN, -NH2Or a substituent of-COOH.
In yet other embodiments, each R isfIndependently H, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, -CH2OCH3、-CH2OCH2CH3、-CH2OCH2CH2CH3、-CH2OCH2(CH3)2、-CH2CH2OCH3、-CH2CH2OCH2CH3、-CH2CH2OCH2CH2CH3、-CH2CH2OCH(CH3)2、-CH2CH2CH2OCH3、-CH2CH2CH2OCH2CH3、-CH2CH2CH2OCH2CH2CH3、-CH2CH2CH2OCH(CH3)2Cyclopropylmethylene, cyclopropylethylene, n-propylidene, cyclobutylmethylene, cyclobutylethylene, n-propylidene, cyclopentylmethylene, cyclopentylethylidene, n-propylidene, cyclohexylmethylene, cyclohexylethylene or cyclohexyln-propylidene;
wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, -CH2OCH3、-CH2OCH2CH3、-CH2OCH2CH2CH3、-CH2OCH(CH3)2、-CH2CH2OCH3、-CH2CH2OCH2CH3、-CH2CH2OCH2CH2CH3、-CH2CH2OCH(CH3)2、-CH2CH2CH2OCH3、-CH2CH2CH2OCH2CH3、-CH2CH2CH2OCH2CH2CH3、-CH2CH2CH2OCH(CH3)2Cyclopropylmethylene, cyclopropylethylene, n-propylidene, cyclobutylmethylene, cyclobutylethylene, n-propylidene, cyclopentylmethylene, cyclopentylethylidene, n-propylidene, cyclohexylmethylene, cyclohexylethylene and n-propylidene are independently optionally substituted with 1,2 or 3 substituents selected from deuterium, F, Cl, Br, I, -OH, -CN, -NH2Or a substituent of-COOH.
In still other embodiments, the invention relates to a compound of formula (II) or a stereoisomer, a geometric isomer, a tautomer, a nitrogen oxide, a hydrate, a solvate, a metabolite, an ester, a pharmaceutically acceptable salt of a compound of formula (II), or a prodrug of a compound of formula (II),
Figure BDA0002874960740000191
in some embodiments, the present invention relates to compounds, or stereoisomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof, of one of the following, but in no way limited to these compounds:
Figure BDA0002874960740000201
stereoisomers, solvates, metabolites, salts and pharmaceutically acceptable prodrugs of the compounds of formula (I) or formula (II) are included within the scope of the present invention unless otherwise specified.
In another aspect, the present invention relates to a pharmaceutical composition comprising a compound of formula (I) or formula (II) of the present invention, or a stereoisomer, a geometric isomer, a tautomer, a nitrogen oxide, a hydrate, a solvate, a metabolite, a pharmaceutically acceptable salt, or a prodrug thereof, and a pharmaceutically acceptable excipient, carrier, adjuvant, or a combination thereof.
In some embodiments, the pharmaceutical composition comprises an additional agent or any combination thereof for the prevention or treatment of an inflammatory syndrome, disorder or disease.
In one embodiment, the pharmaceutical composition may be in a liquid, solid, semi-solid, gel or spray dosage form.
In another aspect, the present invention relates to the use of a compound of formula (I) or formula (II) or a pharmaceutical composition thereof in the preparation of a medicament for preventing or treating a cancer, inflammation or autoimmune disease mediated by roryt in a mammal.
In some embodiments, the present invention relates to the use of a compound of formula (I) or formula (II) or a pharmaceutical composition thereof in the preparation of a medicament for the prevention or treatment of cancer, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease, colitis, ulcerative colitis, rheumatoid arthritis, autoimmune ocular disease, ankylosing spondylitis, asthma, chronic obstructive pulmonary disease, osteoarthritis, allergic rhinitis, allergic dermatitis, crohn's disease, or kawasaki disease.
In another aspect, the invention relates to a process for the preparation, isolation and purification of a compound of formula (I) or formula (II).
In another aspect, the invention relates to intermediates for the preparation of compounds of formula (I) or formula (II).
The compounds of the present disclosure may contain asymmetric or chiral centers and thus may exist in different stereoisomeric forms. The present invention contemplates that all stereoisomeric forms of the compounds of formula (I) or formula (II), including but not limited to diastereomers, enantiomers, atropisomers and geometric (or conformational) isomers, and mixtures thereof, such as racemic mixtures, are integral to the invention.
In the structures disclosed herein, when the stereochemistry of any particular chiral atom is not specified, then all stereoisomers of that structure are contemplated as within this invention and are included as disclosed compounds in this invention. When stereochemistry is indicated by a solid wedge (solid wedge) or dashed line representing a particular configuration, then the stereoisomers of the structure are so well-defined and defined.
The compounds of formula (I) or formula (II) may exist in different tautomeric forms and all such tautomers are included within the scope of the invention.
The compounds of formula (I) or formula (II) may be present in the form of a salt. In one embodiment, the salt refers to a pharmaceutically acceptable salt. The term "pharmaceutically acceptable" means that the substance or composition must be compatible chemically and/or toxicologically with the other ingredients comprising the formulation and/or the mammal being treated therewith. In another embodiment, the salt need not be a pharmaceutically acceptable salt, and may be an intermediate useful in the preparation and/or purification of a compound of formula (I) or formula (II) and/or in the isolation of an enantiomer of a compound of formula (I) or formula (II).
Pharmaceutically acceptable acid addition salts may be formed from the disclosed compounds of the invention by the action of an inorganic or organic acid, for example, acetate, aspartate, benzoate, benzenesulfonate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfonate, chloride/hydrochloride, chlorotheyl salt, citrate, edisylate, fumarate, glucoheptonate, gluconate, glucuronate, hippurate, hydroiodide, isethionate, lactate, lactobionate, lauryl sulfate, malate, maleate, malonate, mandelate, methanesulfonate, methylsulfate, naphthoate, naphthalenesulfonate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate/biphosphate/dihydrogen phosphate, phosphate, Polysilonolactates, propionates, stearates, succinates, sulfosalicylates, tartrates, tosylates and trifluoroacetates.
Pharmaceutically acceptable base addition salts may be formed from the disclosed compounds by reaction with an inorganic or organic base.
Inorganic bases from which salts can be derived include, for example, ammonium salts and metals of groups I to XII of the periodic table. In certain embodiments, the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium and magnesium salts.
Organic bases from which salts can be derived include primary, secondary and tertiary amines, and substituted amines include naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like. Some organic amines include, for example, isopropylamine, benzathine (benzathine), choline salts (cholinate), diethanolamine, diethylamine, lysine, meglumine (meglumine), piperazine, and tromethamine.
The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, basic or acidic moiety, by conventional chemical methods. In general, such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of the appropriate base (e.g., Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, etc.), or by reacting the free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are usually carried out in water or an organic solvent or a mixture of both. Generally, where appropriate, it is desirable to use a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile. In, for example, "Remington's Pharmaceutical Sciences", 20 th edition, Mack Publishing Company, Easton, Pa., (1985); and "handbook of pharmaceutically acceptable salts: properties, Selection and application (Handbook of Pharmaceutical Salts: Properties, Selection, and Use) ", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002) may find some additional lists of suitable Salts.
In addition, the compounds disclosed herein, including their salts, may also be obtained in the form of their hydrates or in the form of solvents containing them (e.g., ethanol, DMSO, etc.), for their crystallization. The compounds disclosed herein may form solvates with pharmaceutically acceptable solvents (including water), either inherently or by design; thus, the present invention is intended to include both solvated and unsolvated forms of the disclosed compounds.
Any formulae given herein are also intended to represent the non-isotopically enriched forms as well as the isotopically enriched forms of these compounds. Isotopically enriched compounds have the structure depicted by the formulae given herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as2H、3H、11C、13C、14C、15N、17O、18O、18F、31P、32P、35S、36Cl and125I。
in another aspect, the compounds of the invention include isotopically enriched compounds as defined herein, e.g. wherein a radioisotope, e.g. is present3H、14C and18of FThose compounds, or in which non-radioactive isotopes are present, e.g.2H and13those of C. The isotopically enriched compounds can be used for metabolic studies (use)14C) Reaction kinetics study (using, for example2H or3H) Detection or imaging techniques such as Positron Emission Tomography (PET) or Single Photon Emission Computed Tomography (SPECT) including drug or substrate tissue distribution determination, or may be used in radiotherapy of a patient.18F-enriched compounds are particularly desirable for PET or SPECT studies. Isotopically enriched compounds of formula (I) or formula (II) can be prepared by conventional techniques known to those skilled in the art or by employing suitable isotopically labelled reagents in place of the original used unlabelled reagents as described in the examples and preparations of this invention.
In addition, heavier isotopes are, in particular, deuterium (i.e.,2substitution of H or D) may provide certain therapeutic advantages resulting from greater metabolic stability. For example, increased in vivo half-life or decreased dosage requirements or improved therapeutic index. It is to be understood that deuterium in the present invention is to be considered as a substituent of the compound of formula (I) or formula (II). The concentration of such heavier isotopes, particularly deuterium, can be defined by isotopic enrichment factors. The term "isotopic enrichment factor" as used herein refers to the ratio between the isotopic and natural abundance of a given isotope. If a substituent of a compound of the invention is designated as deuterium, the compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). Pharmaceutically acceptable solvates of the invention include those in which the crystallization solvent may be isotopically substituted, e.g. D2O, acetone-d6、DMSO-d6Those solvates of (a).
Pharmaceutical compositions, formulations and administration of the compounds of the invention
The present invention provides a pharmaceutical composition comprising a compound disclosed herein, for example, as set forth in the examples; and a pharmaceutically acceptable excipient, carrier, adjuvant, or combination thereof.
The present invention provides methods of treating, preventing or ameliorating a disease or condition comprising administering a safe and effective amount of a combination comprising a compound of the present disclosure and one or more therapeutically active agents. Wherein the combination comprises one or more additional agents for the prophylaxis or treatment of an inflammatory syndrome, disorder or disease, including but not limited to:
1) a TNF-alpha inhibitor; 2) non-selective COX-1/COX-2 inhibitors; 3) COX-2 inhibitors; 4) other therapeutic agents for the treatment of inflammatory syndromes and autoimmune diseases, including glucocorticoids, methotrexate, leflunomide (leflunomide), sulfasalazine, azathioprine, cyclosporine, tacrolimus (tacrolimus), penicillamine, buclizine, acrilamide, mizoribine, clobenzaprine, ciclesonide, hydroxychloroquine, aurothiomalate, auranofin, cyclophosphamide, BAFF/APRIL inhibitors, CTLA-4-immunoglobulin or the like; 5) a leukotriene biosynthesis inhibitor, a 5-lipoxygenase inhibitor or a 5-lipoxygenase activating protein (FLAP) antagonist; 6) LTD4 receptor antagonists; 7) a PDE4 inhibitor; 8) an anti-histamine HI receptor antagonist; alpha 1 and alpha 2-adrenoceptor agonists;
9) anticholinergic agents; 10) a P-adrenoceptor agonist; 11) an insulin-like growth factor type I analog; 12) kinase inhibitors are selected from Janus kinase inhibitors (JAK1 and/or JAK2 and/or JAK3 and/or TYK2), p38 MAPK and IKK 2; 13) b cell targeting biopharmaceuticals such as rituximab; 14) selective co-stimulatory modulators such as albuterol; 15) an interleukin inhibitor selected from the group consisting of an IL-1 inhibitor such as anakinra, an IL-6 inhibitor such as tollizumab and an IL-12/IL-23 inhibitor such as Ultezumab.
The amount of compound in the pharmaceutical composition disclosed herein is effective to detect inhibition of retinoic acid-related nocosomal receptor gamma t in a biological sample or patient. The dosage of the active ingredient in the composition of the present invention may vary, however, the amount of the active ingredient must be such that a suitable dosage form is obtained. The active ingredient may be administered to patients (animals and humans) in need of such treatment at dosages that provide optimal pharmaceutical efficacy. The selected dosage depends on the desired therapeutic effect, on the route of administration and on the duration of the treatment. The dosage will vary from patient to patient depending on the nature and severity of the disease, the weight of the patient, the particular diet of the patient, the concurrent use of drugs, and other factors that will be recognized by those skilled in the art. In one embodiment, the dosage range is from about 0.5mg to 500mg per patient per day; in another embodiment from about 0.5mg to 200mg per patient per day.
It will also be appreciated that certain compounds of the invention may be present in free form and used in therapy, or if appropriate in the form of a pharmaceutically acceptable derivative thereof. Pharmaceutically acceptable derivatives include pharmaceutically acceptable prodrugs, salts, esters, salts of such esters, or any additional adduct or derivative that upon administration to a patient in need thereof provides, directly or indirectly, a compound of the present invention or a metabolite or residue thereof.
The medicaments or pharmaceutical compositions disclosed herein can be prepared and packaged in bulk form, wherein a safe and effective amount of a compound of formula (I) or formula (II) can be extracted and then administered to a patient in the form of a powder or syrup. Typically, the administration is to the patient at a dosage level of between 0.0001 and 10mg/kg body weight per day to achieve effective inhibition of retinoic acid-related nociceptor γ t. Alternatively, the pharmaceutical compositions disclosed herein can be prepared and packaged in unit dosage forms, wherein each physically discrete unit contains a safe and effective amount of a compound of formula (I) or formula (II). When prepared in unit dosage form, the disclosed pharmaceutical compositions can generally contain an effective amount of a disclosed compound.
When the pharmaceutical composition of the invention contains one or more other active ingredients in addition to the compound of the invention, the compound weight ratio of the compound of the invention to the second active ingredient may vary and depends on the effective dose of each ingredient. Generally, an effective dose of each is used. Thus, for example, when a compound of the invention is mixed with another agent, the weight ratio of the compound of the invention to the other agent typically ranges from about 1000:1 to about 1: 1000. Mixtures of the compounds of the invention with other active ingredients are generally also within the above-mentioned ranges, but in each case an effective dose of each active ingredient should be used.
As used herein, "pharmaceutically acceptable excipient" means a pharmaceutically acceptable material, mixture or vehicle, which is compatible with the dosage form or pharmaceutical composition to be administered. Each excipient, when mixed, must be compatible with the other ingredients of the pharmaceutical composition to avoid interactions that would substantially reduce the efficacy of the disclosed compounds and which would result in a pharmaceutical composition that is not pharmaceutically acceptable when administered to a patient. Furthermore, each excipient must be pharmaceutically acceptable, e.g., of sufficiently high purity.
Suitable pharmaceutically acceptable excipients will vary depending on the particular dosage form selected. In addition, pharmaceutically acceptable excipients may be selected for their specific function in the composition. For example, certain pharmaceutically acceptable excipients may be selected to aid in the production of a uniform dosage form. Certain pharmaceutically acceptable excipients may be selected to aid in the production of stable dosage forms. Certain pharmaceutically acceptable excipients may be selected to facilitate carrying or transporting the disclosed compounds from one organ or portion of the body to another organ or portion of the body when administered to a patient. Certain pharmaceutically acceptable excipients may be selected that enhance patient compliance.
Suitable pharmaceutically acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, taste masking agents, colorants, anti-caking agents, humectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants and buffers. The skilled artisan will recognize that certain pharmaceutically acceptable excipients may provide more than one function, and provide alternative functions, depending on how many such excipients are present in the formulation and which other excipients are present in the formulation.
The skilled person is knowledgeable and skilled in the art to enable them to select suitable amounts of suitable pharmaceutically acceptable excipients for use in the present invention. Furthermore, there is a large amount of resources available to the skilled person, who describes pharmaceutically acceptable excipients and is used to select suitable pharmaceutically acceptable excipients. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (The American Pharmaceutical Association and The Pharmaceutical Press).
Various carriers for formulating pharmaceutically acceptable compositions, and well known techniques for their preparation, are disclosed in Remington, The Science and Practice of Pharmacy,21st edition,2005, ed.D.B.Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds.J.Swarbrick and J.C.Boylan, 1988. Annu 1999, Marcel Dekker, New York, The contents of each of which are incorporated herein by reference. Except insofar as any conventional carrier is incompatible with the disclosed compounds, such as by producing any undesirable biological effect or interacting in a deleterious manner with any other ingredient in a pharmaceutically acceptable composition, its use is contemplated as falling within the scope of the present invention.
The pharmaceutical compositions disclosed herein are prepared using techniques and methods known to those skilled in the art. Some commonly used methods in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing Company).
Thus, in another aspect, the invention relates to a process for preparing a pharmaceutical composition comprising a compound disclosed herein and a pharmaceutically acceptable excipient, carrier, adjuvant or combination thereof, which process comprises admixing the ingredients. Pharmaceutical compositions comprising the disclosed compounds may be prepared by mixing, for example, at ambient temperature and atmospheric pressure.
The compounds disclosed herein are generally formulated in a dosage form suitable for administration to a patient by a desired route. For example, dosage forms include those suitable for the following routes of administration: (1) oral administration, such as tablets, capsules, caplets, pills, troches, powders, syrups, elixirs, suspensions, solutions, emulsions, sachets and cachets; (2) parenteral administration, such as sterile solutions, suspensions, and reconstituted powders; (3) transdermal administration, such as transdermal patches; (4) rectal administration, e.g., suppositories; (5) inhalation, such as aerosols, solutions, and dry powders; and (6) topical administration, such as creams, ointments, lotions, solutions, pastes, sprays, foams and gels.
In one embodiment, the compounds disclosed herein may be formulated in oral dosage forms. In another embodiment, the compounds disclosed herein may be formulated in an inhalation dosage form. In another embodiment, the compounds disclosed herein can be formulated for nasal administration. In yet another embodiment, the compounds disclosed herein can be formulated for transdermal administration. In yet another embodiment, the compounds disclosed herein may be formulated for topical administration.
The pharmaceutical compositions provided by the present invention may be provided as compressed tablets, milled tablets, chewable lozenges, fast-dissolving tablets, double-compressed tablets, or enteric-coated, sugar-coated or film-coated tablets. Enteric coated tablets are compressed tablets coated with a substance that is resistant to the action of gastric acid but dissolves or disintegrates in the intestine, thereby preventing the active ingredient from contacting the acidic environment of the stomach. Enteric coatings include, but are not limited to, fatty acids, fats, phenyl salicylate, waxes, shellac, ammoniated shellac, and cellulose acetate phthalate. Sugar-coated tablets are compressed tablets surrounded by a sugar coating, which can help to mask unpleasant tastes or odors and prevent oxidation of the tablet. Film-coated tablets are compressed tablets covered with a thin layer or film of a water-soluble substance. Film coatings include, but are not limited to, hydroxyethyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Film coatings are endowed with the same general characteristics as sugar coatings. A tabletted tablet is a compressed tablet prepared over more than one compression cycle, including a multi-layer tablet, and a press-coated or dry-coated tablet.
Tablet dosage forms may be prepared from the active ingredient in powder, crystalline or granular form, alone or in combination with one or more carriers or excipients described herein, including binders, disintegrants, controlled release polymers, lubricants, diluents and/or colorants. Flavoring and sweetening agents are particularly useful in forming chewable tablets and lozenges.
The pharmaceutical composition provided by the present invention may be provided in soft or hard capsules, which may be prepared from gelatin, methylcellulose, starch or calcium alginate. The hard gelatin capsules, also known as Dry Fill Capsules (DFC), consist of two segments, one inserted into the other, thus completely encapsulating the active ingredient. Soft Elastic Capsules (SEC) are soft, spherical shells, such as gelatin shells, which are plasticized by the addition of glycerol, sorbitol or similar polyols. The soft gelatin shell may contain a preservative to prevent microbial growth. Suitable preservatives are those as described herein, including methyl and propyl parabens, and sorbic acid. The liquid, semi-solid and solid dosage forms provided by the present invention may be encapsulated in a capsule. Suitable liquid and semi-solid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils or triglycerides. Capsules containing such solutions may be as described in U.S. patent nos.4,328,245; 4,409,239 and 4,410,545. The capsules may also be coated as known to those skilled in the art to improve or maintain dissolution of the active ingredient.
The pharmaceutical compositions provided herein may be provided in liquid and semi-solid dosage forms, including emulsions, solutions, suspensions, elixirs and syrups. Emulsions are two-phase systems in which one liquid is dispersed throughout another in the form of globules, which can be either oil-in-water or water-in-oil. Emulsions may include pharmaceutically acceptable non-aqueous liquids and solvents, emulsifiers and preservatives. Suspensions may include a pharmaceutically acceptable suspending agent and a preservative. The aqueous alcoholic solution may comprise pharmaceutically acceptable acetals, such as di (lower alkyl) acetals of lower alkyl aldehydes, e.g. acetaldehyde diethyl acetal; and water-soluble solvents having one or more hydroxyl groups, such as propylene glycol and ethanol. Elixirs are clear, sweetened, hydroalcoholic solutions. Syrups are concentrated aqueous solutions of sugars, such as sucrose, and may also contain preservatives. For liquid dosage forms, for example, a solution in polyethylene glycol may be diluted with a sufficient amount of a pharmaceutically acceptable liquid carrier, such as water, for precise and convenient administration.
Other useful liquid and semi-solid dosage forms include, but are not limited to, those comprising the active ingredients provided herein and a secondary mono-or poly-alkylene glycol, including: 1, 2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether, where 350, 550, 750 refer to the approximate average molecular weight of the polyethylene glycol. These formulations may further include one or more antioxidants, such as Butylated Hydroxytoluene (BHT), Butylated Hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfite, sodium metabisulfite, thiodipropionic acid and its esters, and dithiocarbamates.
Dosage unit formulations for oral administration may be microencapsulated, where appropriate. They may also be prepared as extended or sustained release compositions, for example by coating or embedding the particulate material in a polymer, wax or the like.
The oral pharmaceutical composition provided by the invention can also be provided in the form of liposome, micelle, microsphere or nano system. Micellar dosage forms can be prepared using the methods described in U.S. Pat. No.6,350,458.
The pharmaceutical compositions provided herein can be provided as non-effervescent or effervescent granules and powders for reconstitution into liquid dosage forms. Pharmaceutically acceptable carriers and excipients used in non-effervescent granules or powders may include diluents, sweeteners and wetting agents. Pharmaceutically acceptable carriers and excipients used in effervescent granules or powders may include organic acids and sources of carbon dioxide.
Coloring and flavoring agents may be used in all of the above dosage forms.
The disclosed compounds may also be conjugated to soluble polymers as targeted drug carriers. Such polymers include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol or polyoxyethylene polylysine substituted with palmitoyl residues. In addition, the disclosed compounds may be combined with a class of biodegradable polymers used in achieving controlled release of a drug, such as polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and crosslinked or amphiphilic block copolymers of hydrogels.
The pharmaceutical compositions provided by the present invention may be formulated into immediate or modified release dosage forms, including delayed-, sustained-, pulsed-, controlled-, targeted-, and programmed release forms.
The pharmaceutical compositions provided by the present invention may be co-formulated with other active ingredients that do not impair the intended therapeutic effect, or with substances that supplement the intended effect.
The pharmaceutical compositions provided by the present invention may be administered parenterally by injection, infusion or implantation for local or systemic administration. Parenteral administration as used herein includes intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial and subcutaneous administration.
The pharmaceutical compositions provided herein can be formulated in any dosage form suitable for parenteral administration, including solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems and solid forms suitable for solution or suspension in a liquid prior to injection. Such dosage forms may be prepared according to conventional methods known to those skilled in The art of pharmaceutical Science (see Remington: The Science and Practice of Pharmacy, supra).
Pharmaceutical compositions intended for parenteral administration may include one or more pharmaceutically acceptable carriers and excipients, including, but not limited to, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives to inhibit microbial growth, stabilizers, solubility enhancers, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, cryoprotectants, thickening agents, pH adjusting agents, and inert gases.
Suitable aqueous carriers include, but are not limited to: water, saline, normal saline or Phosphate Buffered Saline (PBS), sodium chloride injection, Ringers injection, isotonic glucose injection, sterile water injection, dextrose and lactated Ringers injection. Non-aqueous vehicles include, but are not limited to, fixed oils of vegetable origin, castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oils, hydrogenated soybean oil, and the medium chain triglycerides of coconut oil, and palm seed oil. Water-miscible vehicles include, but are not limited to, ethanol, 1, 3-butanediol, liquid polyethylene glycols (e.g., polyethylene glycol 300 and polyethylene glycol 400), propylene glycol, glycerol, N-methyl-2-pyrrolidone, N-dimethylacetamide, and dimethylsulfoxide.
Suitable antimicrobial agents or preservatives include, but are not limited to, phenol, cresol, mercurial, benzyl alcohol, chlorobutanol, methyl and propyl parabens, thimerosal, benzalkonium chloride (e.g., benzethonium chloride), methyl and propyl parabens, and sorbic acid. Suitable isotonic agents include, but are not limited to, sodium chloride, glycerol and glucose. Suitable buffers include, but are not limited to, phosphate and citrate. Suitable antioxidants are those as described herein, including bisulfite and sodium metabisulfite. Suitable local anesthetics include, but are not limited to, procaine hydrochloride. Suitable suspending and dispersing agents are those as described herein, including sodium carboxymethylcellulose, hydroxypropylmethylcellulose and polyvinylpyrrolidone. Suitable emulsifiers include those described herein, including polyoxyethylene sorbitan monolaurate. Polyoxyethylene sorbitan monooleate 80 and triethanolamine oleate. Suitable sequestering or chelating agents include,but are not limited to EDTA. Suitable pH adjusters include, but are not limited to, sodium hydroxide, hydrochloric acid, citric acid, and lactic acid. Suitable complexing agents include, but are not limited to, cyclodextrins, including alpha-cyclodextrin, beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin, sulfobutyl ether-beta-cyclodextrin, and sulfobutyl ether 7-beta-cyclodextrin (f: (f))
Figure BDA0002874960740000261
CyDex,Lenexa,KS)。
The pharmaceutical compositions provided herein may be formulated for single or multiple dose administration. The single dose formulations are packaged in ampoules, vials or syringes. The multi-dose parenteral formulation must contain a bacteriostatic or fungistatic concentration of the antimicrobial agent. All parenteral formulations must be sterile, as is known and practiced in the art.
In one embodiment, the pharmaceutical composition is provided as a ready-to-use sterile solution. In another embodiment, the pharmaceutical compositions are provided as sterile dried soluble products, including lyophilized powders and subcutaneous injection tablets, which are reconstituted with a carrier prior to use. In yet another embodiment, the pharmaceutical composition is formulated as a ready-to-use sterile suspension. In yet another embodiment, the pharmaceutical composition is formulated as a sterile, dry, insoluble product that is reconstituted with a carrier prior to use. In yet another embodiment, the pharmaceutical composition is formulated as a sterile emulsion ready for use.
The pharmaceutical composition may be formulated as a suspension, solid, semi-solid, or thixotropic liquid for depot administration for implantation. In one embodiment, the disclosed pharmaceutical compositions are dispersed in a solid internal matrix surrounded by an outer polymeric membrane that is insoluble in body fluids but allows diffusion therethrough of the active ingredient in the pharmaceutical composition.
Suitable internal matrices include polymethylmethacrylate, polybutylmethacrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene vinyl acetate copolymers, silicone rubber, polydimethylsiloxane, silicone carbonate copolymers, hydrogels of hydrophilic polymers such as esters of acrylic and methacrylic acid, collagen, crosslinked polyvinyl alcohol, and partially hydrolyzed polyvinyl acetate of the class of copolymers.
Suitable outer polymeric films include polyethylene, polypropylene, ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers, ethylene/vinyl acetate copolymers, silicone rubber, polydimethylsiloxane, neoprene, chlorinated polyethylene, polyvinyl chloride, copolymers of chlorinated ethylene and vinyl acetate, vinylidene chloride, ethylene and propylene, ionomers polyethylene terephthalate, butyl rubber chlorohydrin rubber, ethylene/vinyl alcohol copolymers, ethylene/vinyl acetate/vinyl alcohol terpolymers, and ethylene/ethyleneoxyethanol copolymers.
In another aspect, the disclosed pharmaceutical compositions may be formulated in any dosage form suitable for administration to a patient by inhalation, such as a dry powder, aerosol, suspension, or solution composition. In one embodiment, the disclosed pharmaceutical compositions may be formulated in a dosage form suitable for inhalation administration to a patient as a dry powder. In yet another embodiment, the disclosed pharmaceutical compositions may be formulated in a dosage form suitable for inhalation administration to a patient via a nebulizer. Dry powder compositions for delivery to the lung by inhalation typically comprise a finely powdered compound disclosed herein and one or more finely powdered pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients that are particularly suitable for use as dry powders are known to those skilled in the art and include lactose, starch, mannitol, and mono-, di-and polysaccharides. Fine powders may be prepared, for example, by micronization and milling. Generally, the size-reduced (e.g., micronized) compound may pass through a D of about 1 to 10 microns50Values (e.g., measured by laser diffraction).
Aerosols can be formulated by suspending or dissolving the disclosed compounds in a liquefied propellant. Suitable propellants include chlorinated hydrocarbons, hydrocarbons and other liquefied gases. Representative propellants include: trichlorofluoromethane (propellant 11), dichlorofluoromethane (propellant 12), dichlorotetrafluoroethane (propellant 114), tetrafluoroethane (HFA-134a), 1-difluoroethane (HFA-152a), difluoromethane (HFA-32), pentafluoroethane (HFA-12), heptafluoropropane (HFA-227a), perfluoropropane, perfluorobutane, perfluoropentane, butane, isobutane and pentane. Aerosols comprising the compounds disclosed herein are typically administered to a patient via a Metered Dose Inhaler (MDI). Such devices are known to those skilled in the art.
The aerosol may contain additional pharmaceutically acceptable excipients that may be used by MDIs, such as surfactants, lubricants, co-solvents, and other excipients, to improve the physical stability of the formulation, to improve valve characteristics, to improve solubility, or to improve taste.
Pharmaceutical compositions suitable for transdermal administration may be prepared as discrete patches intended to remain in intimate contact with the epidermis of the patient for an extended period of time. For example, the active ingredient may be delivered from a patch agent by iontophoresis, as generally described in Pharmaceutical Research,3(6),318 (1986).
Pharmaceutical compositions suitable for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils. For example, ointments, creams and gels may be formulated with a water or oil base, and suitable thickeners and/or gelling agents and/or solvents. Such bases may include, water, and/or oils such as liquid paraffin and vegetable oils (e.g., peanut oil or castor oil), or solvents such as polyethylene glycol. Thickeners and gelling agents used according to the nature of the base include soft paraffin, aluminium stearate, cetostearyl alcohol, polyethylene glycol, lanolin, beeswax, carbopol and cellulose derivatives, and/or glyceryl monostearate and/or non-ionic emulsifiers.
Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents or thickening agents.
Powders for external use may be formed in the presence of any suitable powder base, for example talc, lactose or starch. Drops may be formulated with an aqueous or non-aqueous base containing one or more dispersing agents, solubilising agents, suspending agents or preservatives.
Topical formulations may be administered by application to the affected area one or more times per day; an occlusive dressing covering the skin is preferably used. Adhesive depot systems allow for continuous or extended administration.
Use of the Compounds and compositions of the invention
The compound or the pharmaceutical composition disclosed by the invention can be used for preparing a medicine for treating, preventing, improving, controlling or relieving cancer, inflammation or autoimmune diseases mediated by ROR gamma t in mammals including human beings, and can also be used for preparing other medicines for inhibiting ROR gamma t.
In particular, the amount of the compound in the composition of the present invention is effective to detectably inhibit ROR γ t, and the compound of the present invention is useful as a medicament for preventing or treating cancer, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease, colitis, ulcerative colitis, rheumatoid arthritis, autoimmune ocular disease, ankylosing spondylitis, asthma, chronic obstructive pulmonary disease, osteoarthritis, allergic rhinitis, allergic dermatitis, crohn's disease, or kawasaki disease in a human.
The compounds or compositions of the present invention may be used, but are in no way limited to, in preventing, treating or alleviating cancer, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease, colitis, ulcerative colitis, rheumatoid arthritis, autoimmune ocular disease, ankylosing spondylitis, asthma, chronic obstructive pulmonary disease, osteoarthritis, allergic rhinitis, allergic dermatitis, crohn's disease or kawasaki disease in a mammal, including a human, by administering to the patient an effective amount of a compound or composition of the present invention.
In addition to being beneficial for human therapy, the compounds and pharmaceutical compositions of the present invention may also find application in veterinary therapy for pets, animals of the introduced species and mammals in farm animals. Examples of other animals include horses, dogs, and cats. Herein, the compound of the present invention includes pharmaceutically acceptable derivatives thereof.
General synthetic procedure
To illustrate the invention, the following examples are set forth. It is to be understood that the invention is not limited to these embodiments, but is provided as a means of practicing the invention.
In general, the compounds of the invention may be prepared by the methods described herein, wherein the substituents are as defined in formula (I) or formula (II), unless otherwise indicated. The following reaction schemes and examples serve to further illustrate the context of the invention.
Those skilled in the art will recognize that: the chemical reactions described herein may be used to suitably prepare a number of other compounds of the invention, and other methods for preparing the compounds of the invention are considered to be within the scope of the invention. For example, the synthesis of those non-exemplified compounds according to the present invention can be successfully accomplished by those skilled in the art by modification, such as appropriate protection of interfering groups, by the use of other known reagents in addition to those described herein, or by some routine modification of reaction conditions. In addition, the reactions disclosed herein or known reaction conditions are also recognized as being applicable to the preparation of other compounds of the present invention.
The examples described below, unless otherwise indicated, are all temperatures set forth in degrees Celsius. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company and were used without further purification unless otherwise indicated. General reagents were purchased from Shantou Wen Long chemical reagent factory, Guangdong Guanghua chemical reagent factory, Guangzhou chemical reagent factory, Tianjin Haojian Yunyu chemical Co., Ltd, Tianjin Shucheng chemical reagent factory, Wuhan Xin Huayuan scientific and technological development Co., Ltd, Qingdao Tenglong chemical reagent Co., Ltd, and Qingdao Kaolingyi factory.
The anhydrous tetrahydrofuran, dioxane, toluene and ether are obtained through reflux drying of metal sodium. The anhydrous dichloromethane and chloroform are obtained by calcium hydride reflux drying. Ethyl acetate, petroleum ether, N-hexane, N, N-dimethylacetamide and N, N-dimethylformamide were used as they were previously dried over anhydrous sodium sulfate.
The following reactions are generally carried out under positive pressure of nitrogen or argon or by sleeving a dry tube over an anhydrous solvent (unless otherwise indicated), the reaction vial being stoppered with a suitable rubber stopper and the substrate being injected by syringe. The glassware was dried.
The column chromatography is performed using a silica gel column. Silica gel (300 and 400 meshes) was purchased from Qingdao oceanic chemical plants.
NMR spectra were recorded using a Bruker 400MHz or 600MHz NMR spectrometer, CDC13、DMSO-d6、CD3OD or acetone-d6TMS (0ppm) or chloroform (7.26ppm) was used as a reference standard for the solvent (in ppm). When multiple peaks occur, the following abbreviations will be used: s (singleton), d (doublet), t (triplet), m (multiplet), br (broad), dd (doublet of doublets), dt (doublet of triplets). Coupling constants are expressed in hertz (Hz).
The conditions for determining low resolution Mass Spectrometry (MS) data were: agilent 6120 four-stage rod HPLC-MS (column model: Zorbax SB-C18,2.1X30mm,3.5 μm,6min, flow rate 0.6 mL/min. mobile phase 5% -95% (CH with 0.1% formic acid)3CN) in (H containing 0.1% formic acid)2O) by electrospray ionization (ESI) at 210nm/254nm, with UV detection.
The purity of the compound was determined by High Performance Liquid Chromatography (HPLC), using Agilent 1260HPLC (column model: Agilent zorbax Eclipse Plus C18) and detected by DAD detector, and finally calculated by area normalization to obtain the purity of the compound.
The following acronyms are used throughout the invention:
Figure BDA0002874960740000281
Figure BDA0002874960740000291
typical synthetic procedures for preparing the disclosed compounds of the invention are shown in the following synthetic schemes. In the reaction scheme, m, A, R are3、R4、R5、R6、Z1、Z2、Z3And Z4Have the meaning as described herein; PG is an amino protecting group; x1And X2Each independently is a halogen atom; each Z5And Z6Independently CH or N.
Synthetic schemes
Figure BDA0002874960740000292
Compound (6a) can be prepared by the following procedure:
the compound (1a) and the compound (1a ') or (1a') generate a compound (2a) through a substitution reaction, the amino protecting group of the compound (2a) is removed to obtain a compound (3a), the compound (3a) and the compound (3a ') generate a compound (4a) through a coupling reaction, the compound (4a) is hydrolyzed under alkaline conditions to obtain a compound (5a), and the compound (5a) and the compound (5a') undergo a condensation reaction to obtain a compound (6 a).
The compounds, pharmaceutical compositions and uses thereof provided by the present invention are further illustrated below in connection with the examples.
Examples
Example 1: 4- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) -N- ((1- (methylsulfonyl) piperidin-4-yl) methyl) benzamide
Figure BDA0002874960740000293
The method comprises the following steps: synthesis of (2S,4S) -1-tert-butyl 2-methyl 2- (4- (trifluoromethyl) phenoxy) pyrrolidine-1, 2-dicarboxylate
(2S,4R) -1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1, 2-dicarboxylate (10.00g,40.77mmol), 4- (trifluoromethyl) phenol (6.60g,40.71mmol), PPh3(11.80g,44.99mmol) was addedTHF (120mL) was displaced at 0 deg.C, DIAD (11.0mL,55.87mmol) was added slowly, and after addition, the mixture was stirred at room temperature for 24 h. The reaction was concentrated under reduced pressure, the residue was diluted with methyl tert-butyl ether (80mL), stirred at-20 ℃ to precipitate a large amount of white insoluble solid, filtered while cold, the filter cake was washed with cold methyl tert-butyl ether, the filtrate was concentrated under reduced pressure, and the crude product was isolated by column chromatography on silica gel (eluent: PE/EtOAc (v/v) ═ 4/1) to give the product as a white solid (13.56g, 85%).
MS(ESI,pos.ion)m/z:412.2[M+Na]+.
Step two: synthesis of tert-butyl (2S,4S) -2- (hydroxymethyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidine-1-carboxylate
(2S,4S) -1-tert-butyl 2-methyl 2- (4- (trifluoromethyl) phenoxy) pyrrolidine-1, 2-dicarboxylate (18.00g,46.22mmol) was added to a solution of THF (200mL), and the solution was displaced to 0 deg.C, LiBH was slowly added4(2.00g,91.80mmol), after addition, stirring at room temperature for 14 h. Adding saturated NH into the reaction liquid4The reaction was quenched with Cl (60mL) solution, allowed to settle, the upper organic phase separated, the aqueous phase extracted with EtOAc (30 mL. times.2), the combined organic phases and anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by column chromatography on silica gel (eluent: PE/EtOAc (v/v) ═ 3/1) to give a white solid (14.23g, 85%).
MS(ESI,pos.ion)m/z:306.2[M-56+H]+.
Step three: synthesis of tert-butyl (2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidine-1-carboxylate
H is to be2O(1mL)、KOAc(488mg,4.97mmol)、TMSCF2Br (0.40mL,2.60mmol) was added in succession to a solution of tert-butyl (2S,4S) -2- (hydroxymethyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidine-1-carboxylate (300mg,0.83mmol) in DCM (1mL) and stirred at RT for 24 h. The reaction was diluted with DCM (30mL) and washed with saturated NaCl (15mL) and anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by column chromatography on silica gel (eluent: PE/EtOAc (v/v) ═ 4/1) to give a colorless liquid (280mg, 82%).
MS(ESI,pos.ion)m/z:434.1[M+Na]+.
Step four: synthesis of (2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidine
A solution of HCl in methanol (2mL, 20%) was added to a solution of tert-butyl (2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidine-1-carboxylate (280mg,0.68mmol) in DCM (6mL) and stirred at room temperature for 24 h. The reaction was concentrated under reduced pressure, the residue was diluted with DCM (30mL) and successively with saturated NaHCO3The solution (15mL) was washed with saturated NaCl solution (15mL) and anhydrous Na2SO4Concentration under reduced pressure after drying gave a brown liquid (211mg, 100%).
MS(ESI,pos.ion)m/z:312.3[M+H]+.
Step five: synthesis of methyl 4- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) benzoate
Under nitrogen protection, (2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidine (200mg,0.64mmol), Pd2(dba)3(58mg,0.06mmol)、XantPhos(55mg,0.10mmol)、Cs2CO3(418mg,1.28mmol) and methyl 4-iodobenzoate (252mg,0.96mmol) were added in this order to 1, 4-dioxane (6mL) and reacted at 100 ℃ for 24 hours. The reaction was cooled to room temperature, concentrated under reduced pressure, and the residue was diluted with DCM (50mL) and sequentially with saturated NaHCO3The solution (15mL) was washed with saturated NaCl solution (15mL) and anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by column chromatography on silica gel (eluent: PE/EtOAc (v/v) ═ 5/1) to give a yellow liquid (220mg, 77%).
MS(ESI,pos.ion)m/z:446.2[M+H]+.
Step six: synthesis of 4- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) benzoic acid
Reacting LiOH & H2O (414mg,9.87mmol) in H2O (2mL) solution was added to a solution of methyl 4- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) benzoate (220mg,0.49mmol) in MeOH (3mL) and THF (3mL) and stirred at room temperature for 16 h. Concentrating the reaction solution under reduced pressure, adding HCl solution (1mol/L) into the residual solution to adjust the solutionpH to about 4, extraction with EtOAc (20 mL. times.2), combination of the organic phases, washing with saturated NaCl (15mL) solution, anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by column chromatography on silica gel (eluent: DCM/MeOH (v/v) ═ 20/1) to give a white solid (170mg, 80%).
MS(ESI,pos.ion)m/z:432.2[M+H]+.
Step seven: synthesis of tert-butyl 4- ((4- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) benzamido) methyl) piperidine-1-carboxylate
HATU (1.06g,2.79mmol), 1- (tert-butoxycarbonyl) -4- (aminomethyl) piperidine (546mg,2.55mmol), 4- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) benzoic acid (1.00g,2.32mmol), TEA (0.65mL,4.70mmol) were added sequentially to DCM (12mL) and stirred at room temperature for 16 h. The reaction was concentrated under reduced pressure, and the crude product was isolated by column chromatography on silica gel (eluent: DCM/EtOAc (v/v) ═ 4/1) to give a light yellow liquid (1.22g, 83%).
MS(ESI,pos.ion)m/z:572.2[M-56+H]+.
Step eight: synthesis of 4- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) -N- ((piperidin-4-yl) methyl) benzamide
A solution of HCl in 1, 4-dioxane (3.0mL,4mol/L) was added to a solution of tert-butyl 4- ((4- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) benzoylamino) methyl) piperidine-1-carboxylate (1.20g,1.91mmol) in DCM (8mL) and stirred at room temperature for 17 h. The reaction was concentrated under reduced pressure, the residue diluted with DCM (50mL) and successively with saturated Na2CO3The solution (20mL) was washed with saturated NaCl solution (20mL) and anhydrous Na2SO4Dried and concentrated under reduced pressure to give a pale yellow liquid (850mg, 84%).
MS(ESI,pos.ion)m/z:528.1[M+H]+.
Step nine: synthesis of 4- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) -N- ((1- (methylsulfonyl) piperidin-4-yl) methyl) benzamide
Under nitrogen, TEA (172mg,1.71mmol), MsCl (97mg,0.85mmol) were added to a solution of 4- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) -N- ((piperidin-4-yl) methyl) benzamide (300mg,0.57mmol) in DCM (6mL) and stirred at room temperature for 22 h. The reaction was concentrated under reduced pressure and the residue was diluted with DCM (40mL) and successively with HCl solution (15mL,1mol/L), saturated NaHCO3Solution (15mL), saturated NaCl solution (15mL) wash, anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by column chromatography on silica gel (eluent: DCM/EtOAc (v/v) ═ 1/1) to give a white solid (200mg, 58%).
MS(ESI,pos.ion)m/z:606.2[M+H]+.
1H NMR(400MHz,CDCl3)δ(ppm):7.70(d,J＝8.8Hz,2H),7.58(d,J＝8.6Hz,2H),6.97(d,J＝8.6Hz,2H),6.64(d,J＝8.8Hz,2H),6.40–6.02(m,2H),5.17(t,J＝4.6Hz,1H),4.23–4.14(m,2H),3.95(t,J＝9.3Hz,1H),3.78(dd,J＝16.9,12.1Hz,3H),3.69(dd,J＝11.4,4.7Hz,1H),3.40–3.30(m,2H),2.76(s,3H),2.69–2.62(m,2H),2.51(d,J＝14.4Hz,1H),2.42–2.35(m,1H),1.89–1.75(m,3H),1.43–1.33(m,2H).
Example 2: 4- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) -N- ((1- (ethylsulfonyl) piperidin-4-yl) methyl) benzamide
Figure BDA0002874960740000311
Under nitrogen, TEA (172mg,1.71mmol), ethylsulfonyl chloride (109mg,0.85mmol) were added to a solution of 4- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) -N- ((piperidin-4-yl) methyl) benzamide (300mg,0.57mmol) in DCM (6mL) and stirred at room temperature for 22 h. The reaction was concentrated under reduced pressure, and the residue was diluted with DCM (40mL) and then with HCl solution (15mL,1mol/L), saturated NaHCO3Solution (15mL), saturated NaCl solution (15mL) wash, anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by column chromatography on silica gel (eluent: DCM/EtOAc (v/v) ═ 1/1)Obtained as a white solid (200mg, 57%).
MS(ESI,pos.ion)m/z:620.1[M+H]+.
1H NMR(400MHz,CDCl3)δ(ppm):7.70(d,J＝8.8Hz,2H),7.58(d,J＝8.6Hz,2H),6.97(d,J＝8.6Hz,2H),6.64(d,J＝8.8Hz,2H),6.18(t,J＝74.3Hz,1H),6.17(t,J＝6.0Hz,1H),5.17(t,J＝4.6Hz,1H),4.23–4.13(m,2H),3.95(t,J＝9.3Hz,1H),3.82(d,J＝12.1Hz,2H),3.76(d,J＝11.4Hz,1H),3.69(dd,J＝11.3,4.6Hz,1H),3.39–3.29(m,2H),2.93(q,J＝7.4Hz,2H),2.77(t,J＝11.4Hz,2H),2.51(d,J＝14.3Hz,1H),2.42–2.35(m,1H),1.84(d,J＝12.2Hz,3H),1.35(t,J＝7.4Hz,5H).
Example 3: n- ((1- (cyclopropylsulfonyl) piperidin-4-yl) methyl) -4- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) benzamide
Figure BDA0002874960740000321
Under nitrogen, TEA (140mg,1.38mmol), cyclopropylsulfonyl chloride (71mg,0.51mmol) were added to a solution of 4- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) -N- ((piperidin-4-yl) methyl) benzamide (180mg,0.34mmol) in DCM (4mL) and stirred at room temperature for 18 h. The reaction was concentrated under reduced pressure, and the residue was diluted with DCM (40mL) and then with HCl solution (15mL,1mol/L), saturated NaHCO3Solution (15mL), saturated NaCl solution (15mL) wash, anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by column chromatography on silica gel (eluent: DCM/EtOAc (v/v) ═ 3/1) to give a pale yellow solid (130mg, 60%).
MS(ESI,pos.ion)m/z:632.1[M+H]+.
1H NMR(400MHz,CDCl3)δ(ppm):7.72(d,J＝8.7Hz,2H),7.61(d,J＝8.6Hz,2H),6.99(d,J＝8.6Hz,2H),6.67(d,J＝8.8Hz,2H),6.24(t,J＝74.3Hz,1H),6.19(t,J＝6.0Hz,1H),5.19(t,J＝4.6Hz,1H),4.26–4.16(m,2H),3.98(t,J＝9.4Hz,1H),3.84(d,J＝11.9Hz,2H),3.78(d,J＝11.4Hz,1H),3.72(dd,J＝11.4,4.7Hz,1H),3.40–3.35(m,2H),2.83(t,J＝11.3Hz,2H),2.54(d,J＝14.3Hz,1H),2.45–2.36(m,1H),2.27(ddd,J＝12.7,8.0,4.8Hz,1H),1.87(d,J＝11.8Hz,2H),1.46–1.35(m,2H),1.20–1.14(m,2H),1.01–0.95(m,2H).
Example 4: 2- (4- ((4- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) benzoylamino) methyl) piperidin-1-yl) acetic acid
Figure BDA0002874960740000322
The method comprises the following steps: synthesis of methyl 2- (4- ((4- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) benzamido) methyl) piperidin-1-yl) acetate
Under the protection of nitrogen, adding K2CO3(46mg,0.33mmol), methyl 2-chloroacetate (13mg,0.12mmol) was added to a solution of 4- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) -N- ((piperidin-4-yl) methyl) benzamide (60mg,0.11mmol) in DMF (2mL) and stirred at room temperature for 4 h. The reaction was diluted with EtOAc (40mL) and successively with H2O solution (15 mL. times.2), saturated NaCl solution (15mL), anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by column chromatography on silica gel (eluent: DCM/MeOH (v/v) ═ 10/1) to give a white solid (40mg, 59%).
MS(ESI,pos.ion)m/z:599.8[M+H]+.
Step two: synthesis of 2- (4- ((4- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) benzamido) methyl) piperidin-1-yl) acetic acid
Reacting LiOH & H2O (30mg,0.72mmol) in H2A solution of O (0.5mL) was added to a solution of methyl 2- (4- ((4- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) benzoylamino) methyl) piperidin-1-yl) acetate (40mg,0.07mmol) in MeOH (2mL) and reacted at room temperature for 16 h. Adding HCl solution (1mol/L) to the reaction solution to adjust the pH of the solution to about 4, concentrating under reduced pressure, and separating the crude product by silica gel column chromatography (eluent: DCM/MeOH (silica gel column))v/v) ═ 4/1), giving a pale yellow solid (25mg, 64%).
MS(ESI,pos.ion)m/z:586.4[M+H]+.
1H NMR(400MHz,CD3OD)δ(ppm):7.75(d,J＝8.7Hz,2H),7.62(d,J＝8.5Hz,2H),7.12(d,J＝8.5Hz,2H),6.73(d,J＝8.8Hz,2H),6.38(t,J＝75.1Hz,1H),5.30(s,1H),4.25–4.19(m,1H),4.12(dd,J＝9.8,4.4Hz,1H),3.94(t,J＝9.4Hz,1H),3.73(s,2H),3.64(s,3H),3.34(s,1H),2.99(s,1H),2.44(s,1H),1.99(d,J＝14.3Hz,2H),1.62(q,J＝11.7Hz,2H),1.34–1.25(m,5H).
Example 5: 4- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) -N- ((1- (2-hydroxyacetyl) piperidin-4-yl) methyl) benzamide
Figure BDA0002874960740000331
HATU (216mg,0.57mmol), glycolic acid (32mg,0.42mmol), 4- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) -N- ((piperidin-4-yl) methyl) benzamide (200mg,0.38mmol), TEA (115mg,1.14mmol) were added sequentially to DCM (4mL) and stirred at room temperature for 16 h. The reaction was concentrated under reduced pressure, the residue was diluted with DCM (30mL) and then successively with HCl solution (15mL,1mol/L) and saturated NaHCO3Washed with saturated NaCl solution (15mL) and anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by column chromatography on silica gel (eluent: DCM/MeOH (v/v) ═ 10/1) to give a white solid (140mg, 63%). MS (ESI, pos. ion) M/z 586.2[ M + H ]]+.
1H NMR(400MHz,CDCl3)δ(ppm):7.69(d,J＝8.6Hz,2H),7.59(d,J＝8.6Hz,2H),6.97(d,J＝8.5Hz,2H),6.65(d,J＝8.7Hz,2H),6.22(t,J＝74.3Hz,1H),6.14(t,J＝5.6Hz,1H),5.17(t,J＝4.5Hz,1H),4.59(d,J＝13.1Hz,1H),4.24–4.10(m,4H),3.95(t,J＝9.3Hz,1H),3.76(d,J＝11.4Hz,1H),3.72–3.63(m,2H),3.50(d,J＝13.0Hz,1H),3.45–3.36(m,1H),3.34–3.24(m,1H),2.96(t,J＝11.8Hz,1H),2.71(t,J＝12.0Hz,1H),2.52(d,J＝14.3Hz,1H),2.42–2.36(m,1H),1.97–1.89(m,1H),1.84(d,J＝12.7Hz,2H),1.24–1.16(m,2H).
Example 6: (1S,4R) -4- ((4- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) benzamido) methyl) cyclohexanecarboxylic acid
Figure BDA0002874960740000341
HATU (343mg,0.90mmol), tranexamic acid (109mg,0.69mmol), 4- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) benzoic acid (300mg,0.70mmol), TEA (140mg,1.38mmol) were added successively to DCM (8mL) and stirred at room temperature for 18 h. The reaction was concentrated under reduced pressure, and the residue was diluted with DCM (40mL), washed successively with HCl solution (20mL,1mol/L) and saturated NaCl solution (20mL), anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was chromatographed on silica gel (eluent: DCM/EtOAc (v/v) ═ 1/1) to give a pale yellow solid (60mg, 15%).
MS(ESI,pos.ion)m/z:571.3[M+H]+.
1H NMR(400MHz,DMSO-d6)δ(ppm):8.14(t,J＝4.4Hz,1H),7.72(d,J＝8.7Hz,2H),7.67(d,J＝8.6Hz,2H),7.17(d,J＝8.3Hz,2H),6.67(d,J＝8.3Hz,2H),6.56(t,J＝75.8Hz,1H),5.31(s,1H),4.21–4.14(m,1H),4.06–4.01(m,1H),3.88–3.82(m,2H),3.06(s,2H),2.23(d,J＝14.0Hz,1H),2.11(t,J＝11.8Hz,1H),1.87(d,J＝12.6Hz,2H),1.74(d,J＝13.2Hz,2H),1.46(s,1H),1.28–1.18(m,4H),0.98–0.86(m,2H).
Example 7: 4- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) -N- ((1- (methylsulfonyl) pyrrolidin-3-yl) methyl) benzamide
Figure BDA0002874960740000342
The method comprises the following steps: synthesis of tert-butyl 3- ((4- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) benzamido) methyl) pyrrolidine-1-carboxylate
HATU (530mg,1.39mmol), tert-butyl 3- (aminomethyl) pyrrolidine-1-carboxylate (255mg,1.27mmol), 4- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) benzoic acid (500g,1.16mmol), TEA (234mg,2.32mmol) were added sequentially to DCM (8mL) and stirred at room temperature for 16 h. The reaction was concentrated under reduced pressure, and the residue was diluted with DCM (40mL) and then with HCl solution (20mL,1mol/L), saturated NaHCO3Solution (20mL), saturated NaCl solution (20mL) wash, anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was chromatographed on silica gel (eluent: DCM/EtOAc (v/v) ═ 3/1) to give a light yellow liquid (600g, 84%). MS (ESI, pos.ion) M/z 557.9[ M-56+ H]+.
Step two: synthesis of 4- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) -N- ((pyrrolidin-3-yl) methyl) benzamide
A solution of HCl in 1, 4-dioxane (3.0mL,4mol/L) was added to a solution of tert-butyl 3- ((4- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) benzoylamino) methyl) pyrrolidine-1-carboxylate (600mg,0.98mmol) in DCM (8mL) and stirred at room temperature for 16 h. The reaction was concentrated under reduced pressure, and the residue was diluted with EtOAc (40mL) and successively with saturated Na2CO3The solution (20mL) was washed with saturated NaCl solution (20mL) and anhydrous Na2SO4Dried and concentrated under reduced pressure to give a pale yellow liquid (450mg, 90%).
MS(ESI,pos.ion)m/z:514.2[M+H]+.
Step three: synthesis of 4- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) -N- ((1- (methylsulfonyl) pyrrolidin-3-yl) methyl) benzamide
Under nitrogen, TEA (236mg,2.34mmol), MsCl (116mg,1.01mmol) were added to a solution of 4- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) -N- ((pyrrolidin-3-yl) methyl) benzamide (400mg,0.78mmol) in DCM (6mL) and stirred at room temperature for 24 h. The reaction was concentrated under reduced pressure and the residue was diluted with DCM (40mL) and successively with saturated NaHCO3Solution (15mL), saturated NaCl solution (15mL) wash, anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by column chromatography on silica gel (eluent: DCM/MeOH (v/v) ═ 10/1) to give a white solid (300mg, 65%).
MS(ESI,pos.ion)m/z:592.4[M+H]+.
1H NMR(400MHz,CDCl3)δ(ppm):7.69(d,J＝8.7Hz,2H),7.59(d,J＝8.6Hz,2H),6.97(d,J＝8.6Hz,2H),6.65(d,J＝8.8Hz,2H),6.24(s,1H),6.22(t,J＝74.3Hz,1H),5.17(t,J＝4.7Hz,1H),4.24–4.14(m,2H),3.96(t,J＝9.2Hz,1H),3.76(d,J＝11.2Hz,1H),3.70(dd,J＝11.3,4.7Hz,1H),3.54–3.41(m,4H),3.37–3.30(m,1H),3.18(dd,J＝9.9,6.2Hz,1H),2.86(s,3H),2.68–2.61(m,1H),2.52(d,J＝14.2Hz,1H),2.43–2.34(m,1H),2.16–2.08(m,1H),1.82–1.74(m,1H).
Example 8: 4- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) -N- ((1- (methylsulfonyl) azetidin-3-yl) methyl) benzamide
Figure BDA0002874960740000351
The method comprises the following steps: synthesis of benzyl 3- ((4- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) benzamido) methyl) azetidine-1-carboxylate
HATU (1.06g,2.79mmol), benzyl 3- (aminomethyl) azetidine-1-carboxylate (562mg,2.55mmol), 4- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) benzoic acid (1.00g,2.32mmol), TEA (0.50mL,3.60mmol) were added sequentially to DCM (12mL) and stirred at room temperature for 16 h. The reaction was concentrated under reduced pressure, and the residue was diluted with DCM (40mL) and then with HCl solution (20mL,1mol/L), saturated NaHCO3Solution (20mL), saturated NaCl solution (20mL) wash, anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was chromatographed on silica gel (eluent: DCM/EtOAc (v/v) ═ 4/1) to give a pale yellow liquid (900mg, 61%).
MS(ESI,pos.ion)m/z:634.2[M+H]+.
Step two: synthesis of N- ((azetidin-3-yl) methyl) -4- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) benzamide
Pd/C (100mg, 10%) was added to a solution of benzyl 3- ((4- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) benzoylamino) methyl) azetidine-1-carboxylate (900mg,1.42mmol) in MeOH (10mL) to displace the hydrogen and stir at room temperature for 12 h. The reaction solution was filtered through celite, concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: DCM/MeOH (v/v) ═ 1/1) to give a pale yellow liquid (400mg, 56%).
MS(ESI,pos.ion)m/z:500.2[M+H]+.
Step three: synthesis of 4- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) -N- ((1- (methylsulfonyl) azetidin-3-yl) methyl) benzamide
TEA (0.35mL,2.50mmol), MsCl (119mg,1.04mmol) were added to a solution of N- ((azetidin-3-yl) methyl) -4- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) benzamide (400mg,0.80mmol) in DCM (8mL) under nitrogen and stirred at room temperature for 16 h. The reaction was concentrated under reduced pressure and the residue was diluted with DCM (40mL) and successively with saturated NaHCO3Solution (20mL), saturated NaCl solution (20mL) wash, anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by column chromatography on silica gel (eluent: DCM/EtOAc (v/v) ═ 1/1) to give a white solid (300mg, 65%).
MS(ESI,pos.ion)m/z:578.1[M+H]+.
1H NMR(400MHz,CDCl3)δ(ppm):7.71(d,J＝8.8Hz,2H),7.58(d,J＝8.6Hz,2H),6.97(d,J＝8.6Hz,2H),6.64(d,J＝8.8Hz,2H),6.38(t,J＝5.8Hz,1H),6.22(t,J＝74.3Hz,1H),5.17(t,J＝4.6Hz,1H),4.24–4.13(m,2H),4.03–3.93(m,3H),3.81–3.72(m,3H),3.72–3.63(m,3H),2.97–2.89(m,1H),2.85(s,3H),2.51(d,J＝14.3Hz,1H),2.43–2.33(m,1H).
Example 9: 4- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) -N- ((1- (ethylsulfonyl) azetidin-3-yl) methyl) benzamide
Figure BDA0002874960740000361
Under nitrogen, TEA (182mg,1.80mmol), ethylsulfonyl chloride (115mg,0.89mmol) were added to a solution of N- ((azetidin-3-yl) methyl) -4- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) benzamide (300mg,0.60mmol) in DCM (6mL) and stirred at room temperature for 16 h. The reaction was concentrated under reduced pressure and the residue was diluted with DCM (40mL) and successively with saturated NaHCO3Solution (20mL), saturated NaCl solution (20mL) wash, anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by column chromatography on silica gel (eluent: DCM/MeOH (v/v) ═ 20/1) to give a pale yellow solid (30mg, 8%).
MS(ESI,pos.ion)m/z:592.2[M+H]+.
1H NMR(400MHz,CDCl3)δ(ppm):7.55(d,J＝7.4Hz,4H),6.94(d,J＝8.5Hz,2H),6.69(d,J＝8.9Hz,2H),6.19(t,J＝74.3Hz,1H),5.15(s,1H),4.24(d,J＝6.3Hz,2H),4.21–4.15(m,1H),4.10(dd,J＝10.0,4.5Hz,1H),3.93(t,J＝9.5Hz,1H),3.71(s,2H),3.66(dd,J＝13.6,4.4Hz,2H),3.41(dd,J＝13.6,7.4Hz,2H),3.17(q,J＝7.4Hz,2H),1.37(t,J＝7.4Hz,3H),1.31(dd,J＝14.1,6.8Hz,1H),1.22(s,2H).
Example 10: n- (4- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) phenyl) -4- (ethylsulfonyl) piperazine-1-carboxamide
Figure BDA0002874960740000362
The method comprises the following steps: synthesis of phenyl (4-bromophenyl) carbamate
Phenyl chloroformate (1.60mL,1.50mmol) was slowly added dropwise to a solution of 4-bromoaniline (2.00g,11.63mmol) in EtOAc (25mL) at 0 ℃ and room temperatureThe reaction is carried out for 2 h. The reaction was diluted with EtOAc (50mL) and H2O (20 mL. times.3) and saturated NaCl solution (20mL), anhydrous Na2SO4Drying and concentration under reduced pressure gave a pink solid (3.33g, 97%).
MS(ESI,pos.ion)m/z:294.1[M+H]+.
Step two: synthesis of tert-butyl 4- ((4-bromophenyl) carbamoyl) piperazine-1-carboxylate
TEA (2.0mL,14.39mmol), phenyl (4-bromophenyl) carbamate (3.00g,10.27mmol), and tert-butyl piperazine-1-carboxylate (2.10g,11.28mmol) were added to ACN (30mL) and stirred at 85 ℃ for 6 h. The reaction solution was concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 3/2) to give a pale yellow solid (3.85g, 91%).
MS(ESI,pos.ion)m/z:330.0[M-56+H]+.
Step three: synthesis of tert-butyl 4- ((4- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) phenyl) carbamoyl) piperazine-1-carboxylate
Under nitrogen protection, (2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidine (500mg,1.61mmol), Pd2(dba)3(147mg,0.16mmol)、Ruphos(112mg,0.24mmol)、Cs2CO3(523mg,1.61mmol) and tert-butyl 4- ((4-bromophenyl) carbamoyl) piperazine-1-carboxylate (740mg,1.93mmol) were successively added to 1, 4-dioxane (10mL) and reacted at 100 ℃ for 16 hours. The reaction was cooled to room temperature, filtered through celite, the filtrate was concentrated under reduced pressure, and the crude product was chromatographed on silica gel (eluent: DCM/EtOAc (v/v) ═ 4/1) to give a yellow solid (810mg, 82%).
MS(ESI,pos.ion)m/z:615.3[M+H]+.
Step four: synthesis of N- (4- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) phenyl) piperazine-1-carboxamide
A solution of HCl in 1, 4-dioxane (3mL,4mol/L) was added to a solution of tert-butyl 4- ((4- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) phenyl) carbamoyl) piperazine-1-carboxylate (800mg,1.30mmol) in DCM (5mL) and stirred at rt for 16 h. The reaction was concentrated under reduced pressure, the residue was dissolved in DCM (30mL) and a little TEA, concentrated under reduced pressure, and the crude product was isolated by column chromatography on silica gel (eluent: DCM/MeOH (v/v) ═ 4/1) to give a pale yellow solid (340mg, 51%).
MS(ESI,pos.ion)m/z:515.3[M+H]+.
Step five: synthesis of N- (4- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) phenyl) -4- (ethylsulfonyl) piperazine-1-carboxamide
Under nitrogen, TEA (0.30mL,2.16mmol), ethylsulfonyl chloride (0.25mL,2.64mmol) were added to a solution of N- (4- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) phenyl) piperazine-1-carboxamide (340mg,0.66mmol) in DCM (6mL) and stirred at room temperature for 16 h. The reaction was concentrated under reduced pressure, the residue was dissolved in DCM (40mL) and successively saturated NaHCO3The solution (15mL) was washed with saturated NaCl solution (15mL) and anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by column chromatography on silica gel (eluent: DCM/EtOAc (v/v) ═ 4/1) to give a pale green solid (300mg, 75%).
MS(ESI,pos.ion)m/z:607.3[M+H]+.
1H NMR(400MHz,CDCl3)δ(ppm):7.57(d,J＝8.7Hz,2H),7.18(d,J＝8.8Hz,2H),6.97(d,J＝8.6Hz,2H),6.60(d,J＝8.8Hz,2H),6.21(dd,J＝77.4,71.9Hz,2H),5.13(t,J＝4.5Hz,1H),4.17–4.05(m,2H),3.91(t,J＝9.4Hz,1H),3.71(d,J＝10.8Hz,1H),3.63–3.52(m,5H),3.36–3.29(m,4H),2.97(q,J＝7.4Hz,2H),2.46(d,J＝14.4Hz,1H),2.40–2.31(m,1H),1.38(t,J＝7.4Hz,3H).
Biological activity assay
Biological example 1 Fluorescence Resonance Energy Transfer (FRET) assay
1) Test method
(1) ROR gamma t experiment buffer and 10mM DTT are prepared
100mL of 1 Xbasic assay buffer HEPES (pH 7.4), 100mM NaCl, 0.01% BSA) was prepared and 154.25mg DTT was added and mixed well.
(2) Formulation of gradient concentrations of Compounds
a. Standard compounds were prepared, diluted to 2.5mM with 100% DMSO, then 3-fold diluted, 11-step dilutions to a final concentration of 42.34 nM;
b. experimental compounds were prepared with reference to standard compounds.
(3) Preparation of 1x protein solution mixture
a. The required amount of 2x B-ROR γ t LBD/SA-APC protein mixture was formulated. The concentration of B-ROR γ LBD was 40nM and the concentration of SA-APC was 20nM, mixed by gentle inversion and incubated for 15 min at room temperature. Then adding 400nM biotin, mixing by gentle inversion, and incubating for 10 min at room temperature;
b. the required amount of 2X Biotin-SRC1/SA-eu protein mixture was formulated. Bioin-SRC1 was 40nM and SA-eu was 20nM, mixed by gentle inversion and incubated for 15 min at room temperature. Then adding 200nM biotin, mixing by gentle inversion, and incubating for 10 min at room temperature;
c.1:1, mixing the protein mixture prepared in the step a and the step b uniformly, and incubating for 5 minutes at room temperature;
d. adding 25 μ L of the mixture of step c to a 384 well plate containing the test compound;
e.1000rpm for one minute;
f. incubate at room temperature for 1 hour.
(4) Data collection and computation
After 1 hour of incubation at room temperature, the fluorescence values at 665nm and 615nm were measured with an EnVision plate reader, respectively, and the inhibition was calculated to obtain the IC50The values are shown in Table 1;
the inhibition ratio (%) [ (X-Min)/(Max-Min) ]. times.100%
X is the ratio of the fluorescence values of "665 nm/615 nm" of the test compounds; min is the average value of the ratio of the fluorescence values of "665 nm/615 nm" of the DMSO blank; max is the mean value of the ratio of fluorescence values of "665 nm/615 nm" for 10. mu.M SRC.
2) Test results
Table 1 evaluation of inhibitory Activity of the Compounds of the present invention on ROR γ t
Example numbering IC50(nM)
Example 1 29
Example 3 82
And (4) conclusion: experimental results show that the compound has good inhibitory activity on ROR gamma t.
Biological example 2 pharmacokinetic evaluation
ICR mice are fasted overnight for 15h and then weighed, and randomly grouped according to body weight, and the tested compound is prepared into a solvent of 5% DMSO + 5% Solutol + 90% Saline. For the test group administered intravenously, the test animals were given a dose of 1 mg/kg; for the orally administered test group, the test animals were given a dose of 5 mg/kg. Venous blood (approximately 0.2mL) was then taken at time points 0, 0.083 (intravenous only group), 0.25, 0.5, 1.0, 2.0, 5.0, 7.0 and 24h and placed in the EDTAK2In an anticoagulation tube, centrifuge at 11000rpm for 2min, collect plasma, and store at-20 ℃ or-70 ℃ until LC/MS/MS analysis. The drug concentration in plasma was measured at each time point and pharmacokinetic parameters were calculated from the drug concentration-time curve.
The pharmacokinetic properties of the compounds of the invention were tested by the above assay. The experimental result shows that the compound has good pharmacokinetic characteristics in an ICR mouse.
Finally, it should be noted that there are other ways of implementing the invention. Accordingly, the embodiments of the present invention will be described by way of illustration, but not limitation to the description of the present invention, and modifications made within the scope of the present invention or equivalents added to the claims are possible. All publications or patents cited herein are incorporated by reference.

Claims (15)

1. A compound which is a compound represented by formula (I) or a stereoisomer, a geometric isomer, a tautomer, a nitrogen oxide, a hydrate, a solvate, a metabolite, an ester, a pharmaceutically acceptable salt of a compound represented by formula (I), or a prodrug thereof,
Figure FDA0002874960730000011
wherein:
each Z1、Z2、Z3And Z4Independently is CR1Or N;
L1is a bond, -O-, -S-, -NH-, -C (═ O) -or- (CR)aRb)q-；
L2is-C (═ O) -NH- (CR)5R6)-、*-NH-C(＝O)-(CR5R6)-、*-NH-C(＝O)-、*-S(＝O)2-NH-(CR5R6)-、*-NH-S(＝O)2-(CR5R6)-、*-S(＝O)-NH-(CR5R6) -or-NH-S (═ O) - (CR)5R6)-；
RaAnd RbEach independently is H, deuterium, F, Cl, Br, I, C1-4Alkyl or C1-4A haloalkyl group;
ring A is C6-10Aryl, heteroaryl of 5 to 10 atoms, C3-8Cycloalkyl or heterocyclyl consisting of 5 to 10 atoms;
ring B is a heterocyclic group consisting of 5 to 10 atoms;
the D ring is heterocyclic group consisting of 4-10 atoms or C3-8A cycloalkyl group;
each R1Independently H, deuterium, F, Cl, Br, I, cyano, C1-4Alkyl radical, C1-4Alkoxy or C1-4A haloalkyl group;
each R2And R3Independently deuterium, F, Cl, Br, I, -OH, -CN, -NH2、-NO2-COOH, oxo, C1-4Alkyl radical, C1-4Haloalkyl, C1-4Alkoxy radical, C1-4Haloalkoxy, -C1-4alkylene-O-C1-4Alkyl radical, C3-6Cycloalkyl radical, C6-10Aryl, heterocyclyl of 5 to 7 atoms, heteroaryl of 5 to 7 atoms or-C (═ O) -N (R)dRe) (ii) a Wherein, the C1-4Alkyl radical, C1-4Haloalkyl, C1-4Alkoxy radical, C1-4Haloalkoxy, -C1-4alkylene-O-C1-4Alkyl radical, C3-6Cycloalkyl radical, C6-10Aryl, heteroaryl of 5-7 atoms and heterocyclyl of 5-7 atoms are independently optionally substituted with 1,2 or 3RcSubstituted;
each RcIndependently deuterium, F, Cl, Br, I, -OH, -CN, -NH2、C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl or C1-4A haloalkoxy group;
each R4Independently is-S (═ O)2-C1-4Alkyl, -S (═ O)2-C1-4Alkoxy, -S (═ O)2-C1-4Alkylamino, -S (═ O)2-C1-4Haloalkyl, -S (═ O)2-C3-6Cycloalkyl, -S (═ O) -C1-4Alkyl, -S (═ O)2H、-COOH、-C(＝O)-N(RgRh)、-N(Rg)-C(＝O)-C1-4Alkyl, -C (═ O) -O-C1-4Alkyl radical, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl, C3-6Cycloalkyl, carboxy substituted C1-4Alkyl or-C (═ O) -C1-4A hydroxyalkyl group;
Rgand RhEach independently is H, deuterium or C1-4An alkyl group;
R5and R6Each independently of the others being H, deuterium, -OH, -CN, -NH2、-NO2、-COOH、C1-4Alkoxy radical, C1-4A halogenated alkyl group,Hydroxy-substituted C1-4Alkyl, cyano-substituted C1-4Alkyl, carboxy substituted C1-4Alkyl, -C1-4alkylene-O-C1-4Alkyl, -C1-4alkylene-C (═ O) -O-C1-4Alkyl, -C1-4alkylene-C (═ O) -N (R)dRe)、-C1-4alkylene-O-C (═ O) -N (R)dRe)、-C1-4alkylene-N (R)f)-C(＝O)-N(RdRe) or-C1-4alkylene-N (R)dRe) (ii) a Wherein, said C1-4Alkoxy radical, C1-4Haloalkyl and-C1-4alkylene-O-C1-4Alkyl is independently optionally substituted by 1,2 or 3 substituents selected from deuterium, -OH, -COOH, -N (R)dRe) Or C1-4Substituted by a substituent of alkoxy;
Rdand ReEach independently of the others being H, deuterium, -OH, C1-4Alkyl, -C (═ O) H, -C (═ O) -O-C1-4Alkyl, -C (═ O) -C1-4Alkyl, -C1-4alkylene-C (═ O) -O-C1-4Alkyl or-C1-4alkylene-O-C1-4An alkyl group; wherein, said C1-4Alkyl, -C1-4alkylene-C (═ O) -O-C1-4Alkyl and-C1-4alkylene-O-C1-4Alkyl is independently optionally substituted by 1,2 or 3 substituents selected from deuterium, F, Cl, Br, I, -OH, -CN, -NH2or-COOH;
each RfIndependently of one another H, deuterium, C1-4Alkyl, -C1-4alkylene-O-C1-4Alkyl or-C1-4alkylene-C3-6A cycloalkyl group; wherein, said C1-4Alkyl, -C1-4alkylene-O-C1-4Alkyl and-C1-4alkylene-C3-6Cycloalkyl is independently optionally substituted with 1,2 or 3 substituents selected from deuterium, F, Cl, Br, I, -OH, -CN, -NH2Or COOH;
n is 0, 1,2 or 3;
m is 0, 1,2 or 3;
p is 0, 1,2 or 3;
q is 0, 1,2 or 3.
2. The compound of claim 1, wherein RaAnd RbEach independently of the others is H, deuterium, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2, 2-difluoroethyl, 1, 2-difluoroethyl, 2,2, 2-trifluoroethyl, monochloromethyl, dichloromethyl, 1-chloroethyl, 2, 2-dichloroethyl or 1, 2-dichloroethyl.
3. The compound of claim 1, wherein ring a is phenyl, naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolyl, pyrazolyl, imidazolyl, furyl, oxazolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, or piperazinyl;
ring B is
Figure FDA0002874960730000021
Figure FDA0002874960730000022
4. The compound of claim 1, wherein ring D is heterocyclyl consisting of 4-7 atoms or C3-6A cycloalkyl group.
5. The compound of claim 1, wherein ring D is piperidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuryl, tetrahydropyranyl, pyrrolidinyl, piperazinyl, azetidinyl, oxetanyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
6. The compound of claim 1, wherein each R1Independently H, deuterium, F, Cl, Br, I, cyano, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, n-propylOxy, isopropoxy, n-butoxy, tert-butoxy, -CH2F、-CH2Cl、-CHF2、-CHCl2、-CF3、-CH2CH2F、-CH2CH2Cl、-CH2CHF2、-CH2CHCl2、-CHFCH2F、-CHClCH2Cl、-CH2CF3、-CH(CF3)2、-CF2CH2CH3、-CH2CH2CH2F、-CH2CH2CHF2or-CH2CH2CF3；
Each R2And R3Independently deuterium, F, Cl, Br, I, -OH, -CN, -NH2、-NO2-COOH, oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, -CH2F、-CHF2、-CF3、-CH2CH2F、-CH2CHF2、-CHFCH2F、-CH2CF3、-CH(CF3)2、-CF2CH2CH3、-CH2CH2CH2F、-CH2CH2CHF2、-CH2CH2CF3、-OCH2F、-OCHF2、-OCF3、-OCH2CH2F、-OCH2CHF2、-OCHFCH2F、-OCH2CF3、-OCH(CF3)2、-OCF2CH2CH3、-OCH2CH2CH2F、-OCH2CH2CHF2、-OCH2CH2CF3、-CH2OCH3、-CH2OCH2CH3、-CH2OCH2CH2CH3、-CH2OCH(CH3)2、-CH2CH2OCH3、-CH2CH2OCH2CH3、-CH2CH2OCH2CH2CH3、-CH2CH2OCH(CH3)2、-CH2CH2CH2OCH3、-CH2CH2CH2OCH2CH3、-CH2CH2CH2OCH2CH2CH3、-CH2CH2CH2OCH(CH3)2Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, pyridyl, pyrimidinyl, pyrazolyl, thiazolyl, imidazolyl, oxazolyl, triazolyl, tetrazolyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, pyrrolidinyl, or-C (═ O) -N (R)dRe) (ii) a Wherein the methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, tert-butyl group, methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, tert-butoxy group, -CH2F、-CHF2、-CH2CH2F、-CH2CHF2、-CHFCH2F、-CH2CF3、-CH(CF3)2、-CF2CH2CH3、-CH2CH2CH2F、-CH2CH2CHF2、-CH2CH2CF3、-OCH2F、-OCHF2、-OCH2CH2F、-OCH2CHF2、-OCHFCH2F、-OCH2CF3、-OCH(CF3)2、-OCF2CH2CH3、-OCH2CH2CH2F、-OCH2CH2CHF2、-OCH2CH2CF3、-CH2OCH3、-CH2OCH2CH3、-CH2OCH2CH2CH3、-CH2OCH(CH3)2、-CH2CH2OCH3、-CH2CH2OCH2CH3、-CH2CH2OCH2CH2CH3、-CH2CH2OCH(CH3)2、-CH2CH2CH2OCH3、-CH2CH2CH2OCH2CH3、-CH2CH2CH2OCH2CH2CH3、-CH2CH2CH2OCH(CH3)2Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazolyl, thiazolyl, imidazolyl, oxazolyl, triazolyl, tetrazolyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl and pyrrolidinyl independently optionally substituted with 1,2 or 3RcSubstituted;
each RcIndependently deuterium, F, Cl, Br, I, -OH, -CN, -NH2Methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, -CH2F、-CHF2、-CF3、-CH2CH2F、-CH2CHF2、-CHFCH2F、-CH2CF3、-CH(CF3)2、-CF2CH2CH3、-CH2CH2CH2F、-CH2CH2CHF2、-CH2CH2CF3、-OCH2F、-OCHF2、-OCF3、-OCH2CH2F、-OCH2CHF2、-OCHFCH2F、-OCH2CF3、-OCH(CF3)2、-OCF2CH2CH3、-OCH2CH2CH2F、-OCH2CH2CHF2or-OCH2CH2CF3。
7. The compound of claim 1, wherein each R4is-S (═ O)2-CH3、-S(＝O)2-CH2CH3、-S(＝O)2-CH2CH2CH3、-S(＝O)2-CH(CH3)CH3、-S(＝O)2-OCH3、-S(＝O)2-OCH2CH3、-S(＝O)2-OCH2CH2CH3、-S(＝O)2-OCH(CH3)CH3、-S(＝O)2-NH-CH3、-S(＝O)2-NH-CH2CH3、-S(＝O)2-NH-CH2CH2CH3、-S(＝O)2-NH-CH(CH3)CH3、-S(＝O)2-cyclopropyl, -S (═ O)2-cyclobutyl, -S (═ O)2-cyclopentyl, -S (═ O)2-cyclohexyl, -S (═ O) -CH3、-S(＝O)-CH2CH3、-S(＝O)-CH2CH2CH3、-S(＝O)-CH(CH3)CH3、-S(＝O)2H、-COOH、-C(＝O)-N(RgRh)、-N(Rg)-C(＝O)-CH3、-N(Rg)-C(＝O)-CH2CH3、-N(Rg)-C(＝O)-CH2CH2CH3、-N(Rg)-C(＝O)-CH(CH3)CH3、-C(＝O)-O-CH3、-C(＝O)-O-CH2CH3、-C(＝O)-O-CH2CH2CH3、-C(＝O)-O-CH(CH3)CH3Methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, -CH2F、-CHF2、-CF3、-CH2CH2F、-CH2CHF2、-CHFCH2F、-CH2CF3、-CH(CF3)2、-CF2CH2CH3、-CH2CH2CH2F、-CH2CH2CHF2、-CH2CH2CF3Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH2COOH、-CH2CH2COOH、-CH2CH2CH2COOH、-C(＝O)-CH2OH、-C(＝O)-CH2CH2OH or-C (═ O) -CH2CH2CH2OH；
RgAnd RhEach independently is H, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, or tert-butyl.
8. The compound of claim 1, wherein R5And R6Each independently of the others being H, deuterium, -OH, -CN, -NH2、-NO2、-COOH、-CH2F、-CHF2、-CF3、-CH2CH2F、-CH2CHF2、-CHFCH2F、-CH2CF3、-CH(CF3)2、-CF2CH2CH3、-CH2CH2CH2F、-CH2CH2CHF2、-CH2CH2CF3Methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, -CH2OH、-CH2CH2OH、-CH2CH2CH2OH、-CH(CH3)CH2OH、-CH2(CH2)3OH、-CH2CN、-CH2CH2CN、-CH2CH2CH2CN、-CH(CH3)CH2CN、-CH2(CH2)3CN、-CH2COOH、-CH2CH2COOH、-CH2CH2CH2COOH、-CH(CH3)CH2COOH、-CH2(CH2)3COOH、-CH2OCH3、-CH2OCH2CH3、-CH2OCH2CH2CH3、-CH2OCH(CH3)2、-CH2CH2OCH3、-CH2CH2OCH2CH3、-CH2CH2OCH2CH2CH3、-CH2CH2OCH(CH3)2、-CH2CH2CH2OCH3、-CH2CH2CH2OCH2CH3、-CH2CH2CH2OCH2CH2CH3、-CH2CH2CH2OCH(CH3)2、-CH2-C(＝O)-OCH3、-CH2-C(＝O)-OCH2CH3、-CH2-C(＝O)-OCH2CH2CH3、-CH2-C(＝O)-OCH(CH3)2、-CH2CH2-C(＝O)-OCH3、-CH2CH2-C(＝O)-OCH2CH3、-CH2CH2-C(＝O)-OCH2CH2CH3、-CH2CH2-C(＝O)-OCH(CH3)2、-CH2CH2CH2-C(＝O)-OCH3、-CH2CH2CH2-C(＝O)-OCH2CH3、-CH2CH2CH2-C(＝O)-OCH2CH2CH3、-CH2CH2CH2-C(＝O)-OCH(CH3)2、-CH2-C(＝O)-N(RdRe)、-CH2CH2-C(＝O)-N(RdRe)、-CH2CH2CH2-C(＝O)-N(RdRe)、-CH2-O-C(＝O)-N(RdRe)、-CH2CH2-O-C(＝O)-N(RdRe)、-CH2CH2CH2-O-C(＝O)-N(RdRe)、-CH2-N(Rf)-C(＝O)-N(RdRe)、-CH2CH2-N(Rf)-C(＝O)-N(RdRe)、-CH2CH2CH2-N(Rf)-C(＝O)-N(RdRe)、-CH2N(RdRe)、-CH2CH2N(RdRe) or-CH2CH2CH2N(RdRe)；
Wherein, said-CH2F、-CHF2、-CH2CH2F、-CH2CHF2、-CHFCH2F、-CH2CF3、-CH(CF3)2、-CF2CH2CH3、-CH2CH2CH2F、-CH2CH2CHF2、-CH2CH2CF3Methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, -CH2OCH3、-CH2OCH2CH3、-CH2OCH2CH2CH3、-CH2OCH(CH3)2、-CH2CH2OCH3、-CH2CH2OCH2CH3、-CH2CH2OCH2CH2CH3、-CH2CH2OCH(CH3)2、-CH2CH2CH2OCH3、-CH2CH2CH2OCH2CH3、-CH2CH2CH2OCH2CH2CH3and-CH2CH2CH2OCH(CH3)2Independently optionally substituted with 1,2 or 3 substituents selected from deuterium, -OH, -COOH, methoxy, ethoxy, N-propoxy, isopropoxy, N-butoxy, tert-butoxy or-N (R)dRe) Substituted with the substituent(s).
9. The compound of claim 1, wherein RdAnd ReEach independently is H, deuterium, -OH, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, -C (═ O) H, -C (═ O) -O-CH3、-C(＝O)-O-CH2CH3、-C(＝O)-O-CH2CH2CH3、-C(＝O)-O-CH(CH3)2、-C(＝O)-CH3、-C(＝O)-CH2CH3、-C(＝O)-CH2CH2CH3、-C(＝O)-CH(CH3)2、-CH2OCH3、-CH2OCH2CH3、-CH2OCH2CH2CH3、-CH2OCH(CH3)2、-CH2CH2OCH3、-CH2CH2OCH2CH3、-CH2CH2OCH2CH2CH3、-CH2CH2OCH(CH3)2、-CH2CH2CH2OCH3、-CH2CH2CH2OCH2CH3、-CH2CH2CH2OCH2CH2CH3、-CH2CH2CH2OCH(CH3)2、-CH2-C(＝O)-OCH3、-CH2-C(＝O)-OCH2CH3、-CH2-C(＝O)-OCH2CH2CH3、-CH2-C(＝O)-OCH(CH3)2、-CH2CH2-C(＝O)-OCH3、-CH2CH2-C(＝O)-OCH2CH3、-CH2CH2-C(＝O)-OCH2CH2CH3、-CH2CH2-C(＝O)-OCH(CH3)2、-CH2CH2CH2-C(＝O)-OCH3、-CH2CH2CH2-C(＝O)-OCH2CH3、-CH2CH2CH2-C(＝O)-OCH2CH2CH3or-CH2CH2CH2-C(＝O)-OCH(CH3)2(ii) a Wherein, the methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, -CH2OCH3、-CH2OCH2CH3、-CH2OCH2CH2CH3、-CH2OCH(CH3)2、-CH2CH2OCH3、-CH2CH2OCH2CH3、-CH2CH2OCH2CH2CH3、-CH2CH2OCH(CH3)2、-CH2CH2CH2OCH3、-CH2CH2CH2OCH2CH3、-CH2CH2CH2OCH2CH2CH3、-CH2CH2CH2OCH(CH3)2、-CH2-C(＝O)-OCH3、-CH2-C(＝O)-OCH2CH3、-CH2-C(＝O)-OCH2CH2CH3、-CH2-C(＝O)-OCH(CH3)2、-CH2CH2-C(＝O)-OCH3、-CH2CH2-C(＝O)-OCH2CH3、-CH2CH2-C(＝O)-OCH2CH2CH3、-CH2CH2-C(＝O)-OCH(CH3)2、-CH2CH2CH2-C(＝O)-OCH3、-CH2CH2CH2-C(＝O)-OCH2CH3、-CH2CH2CH2-C(＝O)-OCH2CH2CH3and-CH2CH2CH2-C(＝O)-OCH(CH3)2Independently optionally substituted by 1,2 or 3 substituents selected from deuterium, F, Cl, Br, I, -OH, -CN, -NH2or-COOH;
each RfIndependently H, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, -CH2OCH3、-CH2OCH2CH3、-CH2OCH2CH2CH3、-CH2OCH(CH3)2、-CH2CH2OCH3、-CH2CH2OCH2CH3、-CH2CH2OCH2CH2CH3、-CH2CH2OCH(CH3)2、-CH2CH2CH2OCH3、-CH2CH2CH2OCH2CH3、-CH2CH2CH2OCH2CH2CH3、-CH2CH2CH2OCH(CH3)2Cyclopropylmethylene, cyclopropylethylene, n-propylpropyleneCyclobutyl methylene, cyclobutyl ethylene, cyclobutyl n-propylene, cyclopentyl methylene, cyclopentyl ethylene, cyclopentyl n-propylene, cyclohexyl methylene, cyclohexyl ethylene or cyclohexyl n-propylene; wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, -CH2OCH3、-CH2OCH2CH3、-CH2OCH2CH2CH3、-CH2OCH(CH3)2、-CH2CH2OCH3、-CH2CH2OCH2CH3、-CH2CH2OCH2CH2CH3、-CH2CH2OCH(CH3)2、-CH2CH2CH2OCH3、-CH2CH2CH2OCH2CH3、-CH2CH2CH2OCH2CH2CH3、-CH2CH2CH2OCH(CH3)2Cyclopropylmethylene, cyclopropylethylene, n-propylidene, cyclobutylmethylene, cyclobutylethylene, n-propylidene, cyclopentylmethylene, cyclopentylethylidene, n-propylidene, cyclohexylmethylene, cyclohexylethylene and n-propylidene are independently optionally substituted with 1,2 or 3 substituents selected from deuterium, F, Cl, Br, I, -OH, -CN, -NH2Or a substituent of-COOH.
10. The compound of claim 1, which is a compound of formula (II) or a stereoisomer, a geometric isomer, a tautomer, a nitrogen oxide, a hydrate, a solvate, a metabolite, an ester, a pharmaceutically acceptable salt of a compound of formula (II) or a prodrug thereof,
Figure FDA0002874960730000041
11. the compound of claim 1, having a structure of one of the following or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, ester, pharmaceutically acceptable salt, or prodrug thereof:
Figure FDA0002874960730000051
12. a pharmaceutical composition comprising a compound of any one of claims 1-11, and a pharmaceutically acceptable excipient, carrier, adjuvant, or combination thereof.
13. The pharmaceutical composition of claim 12, wherein the pharmaceutical composition comprises an additional agent or any combination thereof for the prevention or treatment of an inflammatory syndrome, disorder or disease.
14. Use of a compound of any one of claims 1-11 or a pharmaceutical composition of any one of claims 12-13 in the manufacture of a medicament for preventing or treating a disease, disorder or syndrome mediated by roryt in a mammal.
15. The use of claim 14, wherein the roryt mediated disease, disorder or syndrome is cancer, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease, colitis, ulcerative colitis, rheumatoid arthritis, autoimmune ocular disease, ankylosing spondylitis, asthma, chronic obstructive pulmonary disease, osteoarthritis, allergic rhinitis, allergic dermatitis, crohn's disease or kawasaki disease.
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