CN113072538B - ROR gamma t inhibitor and application thereof in medicines - Google Patents

ROR gamma t inhibitor and application thereof in medicines Download PDF

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CN113072538B
CN113072538B CN202011616145.6A CN202011616145A CN113072538B CN 113072538 B CN113072538 B CN 113072538B CN 202011616145 A CN202011616145 A CN 202011616145A CN 113072538 B CN113072538 B CN 113072538B
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CN113072538A (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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Guangdong HEC Pharmaceutical
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    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

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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 processes for preparing such compounds and pharmaceutical compositions comprising said compounds, and their use in the treatment or prophylaxis of cancer, inflammatory or autoimmune diseases mediated by roryt in mammals, particularly humans.

Description

ROR gamma t inhibitor and application thereof in medicines
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 lone-core receptor gamma t (Retinoid-related orphan receptor gamma t, ROR gamma t) and used for preventing or treating immune related diseases.
Background
Retinoic acid related lone nuclear receptors are subfamilies of transcription factors in the steroid hormone nuclear receptor superfamily. The tretinoin related lone core receptor family includes rorα, rorβ and rorγ, encoded by different genes (RORA, RORB and RORC), respectively. Retinoic acid related lone 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 lone-core receptor γt (Retinoid-related orphan receptor gamma t, rorγt) is one of two isoforms of retinoic acid related lone-core receptor γ (Retinoid-related orphan receptor gamma, rorγ), also known as rorγ2. There were studies showing that roryt 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). RORγt, which is a transcription factor characteristic of helper T cells (Th 17), 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 is capable of secreting interleukin 17 (IL-17) and other pro-inflammatory cytokines, and has important implications in autoimmune diseases and body defense responses. IL-17 is a pro-inflammatory cytokine for the development of inflammation and various autoimmune diseases, and is closely related to various autoimmune diseases and inflammatory diseases, such as rheumatoid arthritis, psoriasis, psoriatic arthritis, spondyloarthritis, asthma, inflammatory bowel disease, systemic lupus erythematosus, multiple sclerosis, and the like (Jetten et al, nucl. Receiver. Signal,2009,7:e003;Manel et al, nat. Immunol.,2008,9,641-649). While also being involved in the development of inflammation-associated tumors, th17 cells are activated during the course of the disease 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, 27:485-517).
The role of rorγt in the pathogenesis of autoimmune diseases or inflammation has been widely studied and fully elucidated (Jetten et al, adv. Dev. Biol,2006,16:313-355;Meier et al.Immunity,2007,26:643-654; aloisi et al, nat. Rev. Immunol.,2006,6:205-217; jager et al, j. Immunol.,2009,183:7169-7177;Barnes et al, nat. Rev. Immunol.,2008, 8:183-192). Thus, inhibition of roryt will effectively inhibit Th17 cell differentiation, regulate IL-17 and other pro-inflammatory cytokine production and secretion levels, and thus regulate the immune system of the body, treating cancer, immune and inflammatory diseases associated with roryt regulation.
Summary of The Invention
The following is merely a general description of some aspects of the invention and is not limited in this regard. 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 is different from that of the cited document, the disclosure of the present specification controls.
The invention provides a compound with retinoic acid related lone nucleus receptor gamma t (Retinoid-related orphan receptor gamma t, ROR gamma t) inhibitory activity, which is used for preparing medicines for preventing or treating cancers, inflammations or autoimmune diseases mediated by ROR gamma t, such as cancers, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease, colitis, ulcerative colitis, rheumatic 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 RORγt and has excellent physicochemical property and pharmacokinetic property.
The invention also provides methods of preparing these compounds and pharmaceutical compositions comprising these compounds and methods of using these compounds or compositions in the treatment of the above-described diseases in mammals, especially humans.
Specifically:
in one aspect, the present invention relates to a compound of formula (I) or a stereoisomer, geometric isomer, tautomer, nitroxide, hydrate, solvate, metabolite, ester, pharmaceutically acceptable salt or prodrug thereof of a compound of formula (I),
wherein:
each Z is 1 、Z 2 、Z 3 And Z 4 Independently CR 1 Or N;
L 1 is a bond, -O-, -S-, -NH-, -C (=O) -or- (CR) a R b ) q -；
L 2 is-C (=O) -NH- (CR) 5 R 6 )-、*-NH-C(＝O)-(CR 5 R 6 )-、*-NH-C(＝O)-、*-S(＝O) 2 -NH-(CR 5 R 6 )-、*-NH-S(＝O) 2 -(CR 5 R 6 )-、*-S(＝O)-NH-(CR 5 R 6 ) -or-NH-S (=o) - (CR 5 R 6 )-；
R a And R is b Each independently is H, deuterium, F, cl, br, I, C 1-4 Alkyl or C 1-4 A haloalkyl group;
ring A is C 6-10 Aryl, heteroaryl consisting of 5-10 atoms, C 3-8 Cycloalkyl or heterocyclyl consisting of 5 to 10 atoms;
ring B is heterocyclic group consisting of 5-10 atoms;
ring D is a heterocyclic group consisting of 4-10 atoms or C 3-8 Cycloalkyl;
each R is 1 Independently H, deuterium, F, cl, br, I, cyano, C 1-4 Alkyl, C 1-4 Alkoxy or C 1-4 A haloalkyl group;
each R is 2 And R is 3 Is independently deuterium, F, cl, br, I, -OH, -CN, -NH 2 、-NO 2 -COOH, oxo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, -C 1-4 alkylene-O-C 1-4 Alkyl, C 3-6 Cycloalkyl, C 6-10 Aryl, heterocyclyl consisting of 5 to 7 atoms, heteroaryl consisting of 5 to 7 atoms or-C (=o) -N (R) d R e ) The method comprises the steps of carrying out a first treatment on the surface of the Wherein the C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, -C 1-4 alkylene-O-C 1-4 Alkyl, C 3-6 Cycloalkyl, C 6-10 Aryl, heteroaryl of 5 to 7 atoms and heterocyclyl of 5 to 7 atoms are independently optionally substituted with 1, 2 or 3R c Substituted;
each R is c Is independently deuterium, F, cl, br, I, -OH, -CN, -NH 2 、C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl or C 1-4 Haloalkoxy groups;
each R is 4 Independently is-S (=o) 2 -C 1-4 Alkyl, -S (=o) 2 -C 1-4 Alkoxy, -S (=o) 2 -C 1-4 Alkylamino, -S (=o) 2 -C 1-4 Haloalkyl, -S (=o) 2 -C 3-6 Cycloalkyl, -S (=o) -C 1-4 Alkyl, -S (=o) 2 H、-COOH、-C(＝O)-N(R g R h )、-N(R g )-C(＝O)-C 1-4 Alkyl, -C (=o) -O-C 1-4 Alkyl, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, carboxyl substituted C 1-4 Alkyl or-C (=o) -C 1-4 A hydroxyalkyl group;
R g and R is h Each independently is H, deuterium or C 1-4 An alkyl group;
R 5 and R is 6 Each independently is H, deuterium, -OH, -CN, -NH 2 、-NO 2 、-COOH、C 1-4 Alkoxy, C 1-4 Halogenated alkyl and hydroxySubstituted C 1-4 Alkyl-and cyano-substituted C 1-4 Alkyl, carboxyl substituted C 1-4 Alkyl, -C 1-4 alkylene-O-C 1-4 Alkyl, -C 1-4 alkylene-C (=O) -O-C 1-4 Alkyl, -C 1-4 alkylene-C (=O) -N (R) d R e )、-C 1-4 alkylene-O-C (=o) -N (R) d R e )、-C 1-4 alkylene-N (R) f )-C(＝O)-N(R d R e ) or-C 1-4 alkylene-N (R) d R e ) The method comprises the steps of carrying out a first treatment on the surface of the Wherein, C is as follows 1-4 Alkoxy, C 1-4 Haloalkyl and-C 1-4 alkylene-O-C 1-4 Alkyl is independently optionally substituted with 1, 2 or 3 groups selected from deuterium, -OH, -COOH, -N (R) d R e ) Or C 1-4 Substituted with alkoxy;
R d and R is e Each independently is H, deuterium, -OH, C 1-4 Alkyl, -C (=o) H, -C (=o) -O-C 1-4 Alkyl, -C (=o) -C 1-4 Alkyl, -C 1-4 alkylene-C (=O) -O-C 1-4 Alkyl or-C 1-4 alkylene-O-C 1-4 An alkyl group; wherein, C is as follows 1-4 Alkyl, -C 1-4 alkylene-C (=O) -O-C 1-4 Alkyl and-C 1-4 alkylene-O-C 1-4 Alkyl is independently optionally substituted with 1, 2 or 3 groups selected from deuterium, F, cl, br, I, -OH, -CN, -NH 2 or-COOH;
each R is f Independently H, deuterium, C 1-4 Alkyl, -C 1-4 alkylene-O-C 1-4 Alkyl or-C 1-4 alkylene-C 3-6 Cycloalkyl; wherein, C is as follows 1-4 Alkyl, -C 1-4 alkylene-O-C 1-4 Alkyl and-C 1-4 alkylene-C 3-6 Cycloalkyl is independently optionally substituted with 1, 2 or 3 groups selected from deuterium, F, cl, br, I, -OH, -CN, -NH 2 Or 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, R a And R is b Each independently is H, deuterium, F, cl, br, I, methyl, ethyl, n-propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2-difluoroethyl, 1, 2-difluoroethyl, 2-trifluoroethyl, monochloromethyl, dichloromethyl, 2-chloroethyl, 2-dichloroethyl or 1, 2-dichloroethyl.
In other embodiments, the a ring is phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolyl, pyrazolyl, imidazolyl, furanyl, oxazolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, or piperazinyl.
In other embodiments, the B ring is
In some embodiments, the D ring is a heterocyclic group consisting of 4 to 7 atoms or C 3-6 Cycloalkyl groups.
In other embodiments, the D ring is piperidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperazinyl, azetidinyl, oxetanyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
In other embodiments, each R 1 Independently 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, -CH 2 F、-CH 2 Cl、-CHF 2 、-CHCl 2 、-CF 3 、-CH 2 CH 2 F、-CH 2 CH 2 Cl、-CH 2 CHF 2 、-CH 2 CHCl 2 、-CHFCH 2 F、-CHClCH 2 Cl、-CH 2 CF 3 、-CH(CF 3 ) 2 、-CF 2 CH 2 CH 3 、-CH 2 CH 2 CH 2 F、-CH 2 CH 2 CHF 2 or-CH 2 CH 2 CF 3 。
In other embodiments, each R 2 And R is 3 Is independently deuterium, F, cl, br, I, -OH, -CN, -NH 2 、-NO 2 -COOH, oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, -CH 2 F、-CHF 2 、-CF 3 、-CH 2 CH 2 F、-CH 2 CHF 2 、-CHFCH 2 F、-CH 2 CF 3 、-CH(CF 3 ) 2 、-CF 2 CH 2 CH 3 、-CH 2 CH 2 CH 2 F、-CH 2 CH 2 CHF 2 、-CH 2 CH 2 CF 3 、-OCH 2 F、-OCHF 2 、-OCF 3 、-OCH 2 CH 2 F、-OCH 2 CHF 2 、-OCHFCH 2 F、-OCH 2 CF 3 、-OCH(CF 3 ) 2 、-OCF 2 CH 2 CH 3 、-OCH 2 CH 2 CH 2 F、-OCH 2 CH 2 CHF 2 、-OCH 2 CH 2 CF 3 、-CH 2 OCH 3 、-CH 2 OCH 2 CH 3 、-CH 2 OCH 2 CH 2 CH 3 、-CH 2 OCH(CH 3 ) 2 、-CH 2 CH 2 OCH 3 、-CH 2 CH 2 OCH 2 CH 3 、-CH 2 CH 2 OCH 2 CH 2 CH 3 、-CH 2 CH 2 OCH(CH 3 ) 2 、-CH 2 CH 2 CH 2 OCH 3 、-CH 2 CH 2 CH 2 OCH 2 CH 3 、-CH 2 CH 2 CH 2 OCH 2 CH 2 CH 3 、-CH 2 CH 2 CH 2 OCH(CH 3 ) 2 Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazolyl, thiazolyl, imidazolyl, oxazolyl, triazolyl, tetrazolyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, pyrrolidinyl or-C (=o) -N (R) d R e ) The method comprises the steps of carrying out a first treatment on the surface of the Wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, -CH 2 F、-CHF 2 、-CH 2 CH 2 F、-CH 2 CHF 2 、-CHFCH 2 F、-CH 2 CF 3 、-CH(CF 3 ) 2 、-CF 2 CH 2 CH 3 、-CH 2 CH 2 CH 2 F、-CH 2 CH 2 CHF 2 、-CH 2 CH 2 CF 3 、-OCH 2 F、-OCHF 2 、-OCH 2 CH 2 F、-OCH 2 CHF 2 、-OCHFCH 2 F、-OCH 2 CF 3 、-OCH(CF 3 ) 2 、-OCF 2 CH 2 CH 3 、-OCH 2 CH 2 CH 2 F、-OCH 2 CH 2 CHF 2 、-OCH 2 CH 2 CF 3 、-CH 2 OCH 3 、-CH 2 OCH 2 CH 3 、-CH 2 OCH 2 CH 2 CH 3 、-CH 2 OCH(CH 3 ) 2 、-CH 2 CH 2 OCH 3 、-CH 2 CH 2 OCH 2 CH 3 、-CH 2 CH 2 OCH 2 CH 2 CH 3 、-CH 2 CH 2 OCH(CH 3 ) 2 、-CH 2 CH 2 CH 2 OCH 3 、-CH 2 CH 2 CH 2 OCH 2 CH 3 、-CH 2 CH 2 CH 2 OCH 2 CH 2 CH 3 、-CH 2 CH 2 CH 2 OCH(CH 3 ) 2 Cyclopropyl groupCyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazolyl, thiazolyl, imidazolyl, oxazolyl, triazolyl, tetrazolyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl and pyrrolidinyl are independently optionally substituted with 1, 2 or 3R c Substituted.
In other embodiments, each R c Is independently deuterium, F, cl, br, I, -OH, -CN, -NH 2 Methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, -CH 2 F、-CHF 2 、-CF 3 、-CH 2 CH 2 F、-CH 2 CHF 2 、-CHFCH 2 F、-CH 2 CF 3 、-CH(CF 3 ) 2 、-CF 2 CH 2 CH 3 、-CH 2 CH 2 CH 2 F、-CH 2 CH 2 CHF 2 、-CH 2 CH 2 CF 3 、-OCH 2 F、-OCHF 2 、-OCF 3 、-OCH 2 CH 2 F、-OCH 2 CHF 2 、-OCHFCH 2 F、-OCH 2 CF 3 、-OCH(CF 3 ) 2 、-OCF 2 CH 2 CH 3 、-OCH 2 CH 2 CH 2 F、-OCH 2 CH 2 CHF 2 or-OCH 2 CH 2 CF 3 。
In other embodiments, each R 4 is-S (=O) 2 -CH 3 、-S(＝O) 2 -CH 2 CH 3 、-S(＝O) 2 -CH 2 CH 2 CH 3 、-S(＝O) 2 -CH(CH 3 )CH 3 、-S(＝O) 2 -OCH 3 、-S(＝O) 2 -OCH 2 CH 3 、-S(＝O) 2 -OCH 2 CH 2 CH 3 、-S(＝O) 2 -OCH(CH 3 )CH 3 、-S(＝O) 2 -NH-CH 3 、-S(＝O) 2 -NH-CH 2 CH 3 、-S(＝O) 2 -NH-CH 2 CH 2 CH 3 、-S(＝O) 2 -NH-CH(CH 3 )CH 3 、-S(＝O) 2 -cyclopropyl, -S (=o) 2 -cyclobutyl, -S (=o) 2 -cyclopentyl, -S (=o) 2 -cyclohexyl, -S (=o) -CH 3 、-S(＝O)-CH 2 CH 3 、-S(＝O)-CH 2 CH 2 CH 3 、-S(＝O)-CH(CH 3 )CH 3 、-S(＝O) 2 H、-COOH、-C(＝O)-N(R g R h )、-N(R g )-C(＝O)-CH 3 、-N(R g )-C(＝O)-CH 2 CH 3 、-N(R g )-C(＝O)-CH 2 CH 2 CH 3 、-N(R g )-C(＝O)-CH(CH 3 )CH 3 、-C(＝O)-O-CH 3 、-C(＝O)-O-CH 2 CH 3 、-C(＝O)-O-CH 2 CH 2 CH 3 、-C(＝O)-O-CH(CH 3 )CH 3 Methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, -CH 2 F、-CHF 2 、-CF 3 、-CH 2 CH 2 F、-CH 2 CHF 2 、-CHFCH 2 F、-CH 2 CF 3 、-CH(CF 3 ) 2 、-CF 2 CH 2 CH 3 、-CH 2 CH 2 CH 2 F、-CH 2 CH 2 CHF 2 、-CH 2 CH 2 CF 3 Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH 2 COOH、-CH 2 CH 2 COOH、-CH 2 CH 2 CH 2 COOH、-C(＝O)-CH 2 OH、-C(＝O)-CH 2 CH 2 OH or-C (=O) -CH 2 CH 2 CH 2 OH。
In other embodiments, R g And R is h Each independently is H, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl or tert-butyl.
In other embodiments, R 5 And R is 6 Each independently is H, deuterium, -OH, -CN, -NH 2 、-NO 2 、-COOH、-CH 2 F、-CHF 2 、-CF 3 、-CH 2 CH 2 F、-CH 2 CHF 2 、-CHFCH 2 F、-CH 2 CF 3 、-CH(CF 3 ) 2 、-CF 2 CH 2 CH 3 、-CH 2 CH 2 CH 2 F、-CH 2 CH 2 CHF 2 、-CH 2 CH 2 CF 3 Methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, -CH 2 OH、-CH 2 CH 2 OH、-CH 2 CH 2 CH 2 OH、-CH(CH 3 )CH 2 OH、-CH 2 (CH 2 ) 3 OH、-CH 2 CN、-CH 2 CH 2 CN、-CH 2 CH 2 CH 2 CN、-CH(CH 3 )CH 2 CN、-CH 2 (CH 2 ) 3 CN、-CH 2 COOH、-CH 2 CH 2 COOH、-CH 2 CH 2 CH 2 COOH、-CH(CH 3 )CH 2 COOH、-CH 2 (CH 2 ) 3 COOH、-CH 2 OCH 3 、-CH 2 OCH 2 CH 3 、-CH 2 OCH 2 CH 2 CH 3 、-CH 2 OCH(CH 3 ) 2 、-CH 2 CH 2 OCH 3 、-CH 2 CH 2 OCH 2 CH 3 、-CH 2 CH 2 OCH 2 CH 2 CH 3 、-CH 2 CH 2 OCH(CH 3 ) 2 、-CH 2 CH 2 CH 2 OCH 3 、-CH 2 CH 2 CH 2 OCH 2 CH 3 、-CH 2 CH 2 CH 2 OCH 2 CH 2 CH 3 、-CH 2 CH 2 CH 2 OCH(CH 3 ) 2 、-CH 2 -C(＝O)-OCH 3 、-CH 2 -C(＝O)-OCH 2 CH 3 、-CH 2 -C(＝O)-OCH 2 CH 2 CH 3 、-CH 2 -C(＝O)-OCH(CH 3 ) 2 、-CH 2 CH 2 -C(＝O)-OCH 3 、-CH 2 CH 2 -C(＝O)-OCH 2 CH 3 、-CH 2 CH 2 -C(＝O)-OCH 2 CH 2 CH 3 、-CH 2 CH 2 -C(＝O)-OCH(CH 3 ) 2 、-CH 2 CH 2 CH 2 -C(＝O)-OCH 3 、-CH 2 CH 2 CH 2 -C(＝O)-OCH 2 CH 3 、-CH 2 CH 2 CH 2 -C(＝O)-OCH 2 CH 2 CH 3 、-CH 2 CH 2 CH 2 -C(＝O)-OCH(CH 3 ) 2 、-CH 2 -C(＝O)-N(R d R e )、-CH 2 CH 2 -C(＝O)-N(R d R e )、-CH 2 CH 2 CH 2 -C(＝O)-N(R d R e )、-CH 2 -O-C(＝O)-N(R d R e )、-CH 2 CH 2 -O-C(＝O)-N(R d R e )、-CH 2 CH 2 CH 2 -O-C(＝O)-N(R d R e )、-CH 2 -N(R f )-C(＝O)-N(R d R e )、-CH 2 CH 2 -N(R f )-C(＝O)-N(R d R e )、-CH 2 CH 2 CH 2 -N(R f )-C(＝O)-N(R d R e )、-CH 2 N(R d R e )、-CH 2 CH 2 N(R d R e ) or-CH 2 CH 2 CH 2 N(R d R e )；
Wherein, the-CH 2 F、-CHF 2 、-CH 2 CH 2 F、-CH 2 CHF 2 、-CHFCH 2 F、-CH 2 CF 3 、-CH(CF 3 ) 2 、-CF 2 CH 2 CH 3 、-CH 2 CH 2 CH 2 F、-CH 2 CH 2 CHF 2 、-CH 2 CH 2 CF 3 Methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, -CH 2 OCH 3 、-CH 2 OCH 2 CH 3 、-CH 2 OCH 2 CH 2 CH 3 、-CH 2 OCH(CH 3 ) 2 、-CH 2 CH 2 OCH 3 、-CH 2 CH 2 OCH 2 CH 3 、-CH 2 CH 2 OCH 2 CH 2 CH 3 、-CH 2 CH 2 OCH(CH 3 ) 2 、-CH 2 CH 2 CH 2 OCH 3 、-CH 2 CH 2 CH 2 OCH 2 CH 3 、-CH 2 CH 2 CH 2 OCH 2 CH 2 CH 3 and-CH 2 CH 2 CH 2 OCH(CH 3 ) 2 Independently optionally substituted with 1, 2 or 3 groups selected from deuterium, -OH, -COOH, methoxy, ethoxy, N-propoxy, isopropoxy, N-butoxy, tert-butoxy or-N (R) d R e ) Is substituted by a substituent of (2).
In other embodiments, R d And R is e Each independently is H, deuterium, -OH, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, -C (=O) H, -C (=O) -O-CH 3 、-C(＝O)-O-CH 2 CH 3 、-C(＝O)-O-CH 2 CH 2 CH 3 、-C(＝O)-O-CH(CH 3 ) 2 、-C(＝O)-CH 3 、-C(＝O)-CH 2 CH 3 、-C(＝O)-CH 2 CH 2 CH 3 、-C(＝O)-CH(CH 3 ) 2 、-CH 2 OCH 3 、-CH 2 OCH 2 CH 3 、-CH 2 OCH 2 CH 2 CH 3 、-CH 2 OCH(CH 3 ) 2 、-CH 2 CH 2 OCH 3 、-CH 2 CH 2 OCH 2 CH 3 、-CH 2 CH 2 OCH 2 CH 2 CH 3 、-CH 2 CH 2 OCH(CH 3 ) 2 、-CH 2 CH 2 CH 2 OCH 3 、-CH 2 CH 2 CH 2 OCH 2 CH 3 、-CH 2 CH 2 CH 2 OCH 2 CH 2 CH 3 、-CH 2 CH 2 CH 2 OCH(CH 3 ) 2 、-CH 2 -C(＝O)-OCH 3 、-CH 2 -C(＝O)-OCH 2 CH 3 、-CH 2 -C(＝O)-OCH 2 CH 2 CH 3 、-CH 2 -C(＝O)-OCH(CH 3 ) 2 、-CH 2 CH 2 -C(＝O)-OCH 3 、-CH 2 CH 2 -C(＝O)-OCH 2 CH 3 、-CH 2 CH 2 -C(＝O)-OCH 2 CH 2 CH 3 、-CH 2 CH 2 -C(＝O)-OCH(CH 3 ) 2 、-CH 2 CH 2 CH 2 -C(＝O)-OCH 3 、-CH 2 CH 2 CH 2 -C(＝O)-OCH 2 CH 3 、-CH 2 CH 2 CH 2 -C(＝O)-OCH 2 CH 2 CH 3 or-CH 2 CH 2 CH 2 -C(＝O)-OCH(CH 3 ) 2 The method comprises the steps of carrying out a first treatment on the surface of the Wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl and-CH are as follows 2 OCH 3 、-CH 2 OCH 2 CH 3 、-CH 2 OCH 2 CH 2 CH 3 、-CH 2 OCH(CH 3 ) 2 、-CH 2 CH 2 OCH 3 、-CH 2 CH 2 OCH 2 CH 3 、-CH 2 CH 2 OCH 2 CH 2 CH 3 、-CH 2 CH 2 OCH(CH 3 ) 2 、-CH 2 CH 2 CH 2 OCH 3 、-CH 2 CH 2 CH 2 OCH 2 CH 3 、-CH 2 CH 2 CH 2 OCH 2 CH 2 CH 3 、-CH 2 CH 2 CH 2 OCH(CH 3 ) 2 、-CH 2 -C(＝O)-OCH 3 、-CH 2 -C(＝O)-OCH 2 CH 3 、-CH 2 -C(＝O)-OCH 2 CH 2 CH 3 、-CH 2 -C(＝O)-OCH(CH 3 ) 2 、-CH 2 CH 2 -C(＝O)-OCH 3 、-CH 2 CH 2 -C(＝O)-OCH 2 CH 3 、-CH 2 CH 2 -C(＝O)-OCH 2 CH 2 CH 3 、-CH 2 CH 2 -C(＝O)-OCH(CH 3 ) 2 、-CH 2 CH 2 CH 2 -C(＝O)-OCH 3 、-CH 2 CH 2 CH 2 -C(＝O)-OCH 2 CH 3 、-CH 2 CH 2 CH 2 -C(＝O)-OCH 2 CH 2 CH 3 and-CH 2 CH 2 CH 2 -C(＝O)-OCH(CH 3 ) 2 Is independently optionally substituted with 1, 2 or 3 groups selected from deuterium, F, cl, br, I, -OH, -CN, -NH 2 or-COOH.
In other embodiments, each R f Independently H, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, -CH 2 OCH 3 、-CH 2 OCH 2 CH 3 、-CH 2 OCH 2 CH 2 CH 3 、-CH 2 OCH(CH 3 ) 2 、-CH 2 CH 2 OCH 3 、-CH 2 CH 2 OCH 2 CH 3 、-CH 2 CH 2 OCH 2 CH 2 CH 3 、-CH 2 CH 2 OCH(CH 3 ) 2 、-CH 2 CH 2 CH 2 OCH 3 、-CH 2 CH 2 CH 2 OCH 2 CH 3 、-CH 2 CH 2 CH 2 OCH 2 CH 2 CH 3 、-CH 2 CH 2 CH 2 OCH(CH 3 ) 2 Cyclopropyl methylene, cyclopropyl ethylene, cyclopropyl n-propyl, cyclobutylmethylene, cyclobutylethylene, cyclobutyln-propyl, cyclopentyl methylene, cyclopentyl ethylene, cyclopentyl n-propyl, cyclohexyl methylene or cyclohexyl n-propyl; wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, -CH 2 OCH 3 、-CH 2 OCH 2 CH 3 、-CH 2 OCH 2 CH 2 CH 3 、-CH 2 OCH(CH 3 ) 2 、-CH 2 CH 2 OCH 3 、-CH 2 CH 2 OCH 2 CH 3 、-CH 2 CH 2 OCH 2 CH 2 CH 3 、-CH 2 CH 2 OCH(CH 3 ) 2 、-CH 2 CH 2 CH 2 OCH 3 、-CH 2 CH 2 CH 2 OCH 2 CH 3 、-CH 2 CH 2 CH 2 OCH 2 CH 2 CH 3 、-CH 2 CH 2 CH 2 OCH(CH 3 ) 2 Cyclopropylmethylene, cyclopropylethylene, cyclobutylmethylene, cyclobutylethylene, cyclobutyln-propyl, cyclopentylmethylene, cyclopentylethylene, cyclohexylmethylene, cyclohexylethylene and cyclohexyln-propyl are independently optionally substituted with 1, 2 or 3 groups selected from deuterium, F, cl, br, I, -OH, -CN, -NH 2 or-COOH.
In still other embodiments, the invention relates to a compound of formula (II) or a stereoisomer, geometric isomer, tautomer, nitroxide, hydrate, solvate, metabolite, ester, pharmaceutically acceptable salt or prodrug thereof,
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, geometric isomer, tautomer, nitroxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable excipient, carrier, adjuvant or combination thereof;
the pharmaceutical composition further comprises other agents for preventing or treating inflammatory syndromes, disorders or diseases or any combination thereof.
In another aspect, the invention relates to the use of a compound of formula (I) or formula (II) or a pharmaceutical composition thereof for the manufacture of a medicament for the prevention or treatment of a cancer, inflammation or autoimmune disorder 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 for 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 present 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 better inhibition activity on RORγt and good pharmacokinetic characteristics.
Any of the embodiments of any of the aspects of the invention may be combined with other embodiments, provided that they do not contradict. Furthermore, in any of the embodiments of any of the aspects of the present invention, any technical feature may be applied to the technical feature in other embodiments as long as they do not contradict.
The foregoing merely outlines certain aspects of the invention and is not limited in this regard. These and other aspects are described more fully 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 in the accompanying structural and chemical formulas. The invention is intended to cover all 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 of one or more of the incorporated references, patents and similar materials differing from or contradictory to the present application (including but not limited to defined terms, term application, described techniques, etc.), the present application controls.
It should further be 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 sub-combination.
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, chemical elements are in accordance with CAS version of the periodic Table of the elements, and handbook of chemistry and physics, 75 th edition, 1994. In addition, general principles of organic chemistry may be referenced to the descriptions in "Organic Chemistry", thomas Sorrell, university Science Books, sausalato: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" are intended to include "at least one" or "one or more" unless the context clearly dictates otherwise or otherwise. Thus, as used herein, these articles refer to one or to more than one (i.e., to at least one) object. For example, "a component" refers to one or more components, i.e., more than one component is contemplated as being employed or used in embodiments of the described embodiments.
The term "subject" as used herein refers to an animal. Typically the animal is a mammal. The subject, for example, also refers to a primate (e.g., human, male or female), cow, sheep, goat, horse, dog, cat, rabbit, rat, mouse, fish, bird, and the like. In certain embodiments, the subject is a primate. In other embodiments, the subject is a human.
The term "patient" as used herein refers to a human (including adults and children) or other animals. In some embodiments, "patient" refers to a human.
The term "comprising" is an open-ended expression, i.e., including what is indicated by the invention, but not excluding other aspects.
"stereoisomers" refer to compounds having the same chemical structure but different arrangements of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotamers), geometric isomers (cis/trans), atropisomers, and the like.
"chiral" is a molecule that has properties that do not overlap with its mirror image; and "achiral" refers to a molecule that may overlap with its mirror image.
"enantiomer" refers to two isomers of a compound that do not overlap but are in mirror image relationship to each other.
"diastereoisomers" refers to stereoisomers which have two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting point, boiling point, spectral properties, and reactivity. The diastereomeric mixture 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 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 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 represent the absolute configuration of the molecule with respect to one or more of its chiral centers. The prefixes d and l or (+) and (-) are symbols for specifying the rotation of plane polarized light by a compound, where (-) or l indicates that the compound is left-handed. The compound prefixed with (+) or d is dextrorotatory. One 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 can occur when there is no stereoselectivity or stereospecificity in a chemical reaction or process.
Any asymmetric atom (e.g., carbon, etc.) of the disclosed compounds may exist in racemic or enantiomerically enriched form, such as in 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 be present in the form of one of the possible isomers or mixtures thereof, for example 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 substituent 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.
The resulting mixture of any stereoisomers may be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, e.g., by chromatography and/or fractional crystallization, depending on the differences in the physicochemical properties of the components.
Any of the resulting racemates of the end products or intermediates can be resolved into the optical enantiomers by known methods, e.g., by diastereoisomers thereof obtained, by methods familiar to those skilled in the artThe isomerised salts are separated. The racemic product can also be separated by chiral chromatography, e.g., high Performance Liquid Chromatography (HPLC) using chiral adsorbents. In particular, enantiomers may be prepared by asymmetric synthesis, for example, reference may be made to Jacques, et al, encomers, racemates and Resolutions (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 in the present invention, such as the compounds of the general formula above, or as specific examples within the examples, subclasses, 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 specific substituent. Unless otherwise indicated, a substituted group may have a 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, then the substituents may be the same or different at each position.
The term "unsubstituted" means that the specified group does not carry a substituent.
The term "optionally substituted with … …" may be 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 explicitly indicated otherwise, the descriptions used in this disclosure of the manner in which each … is independently "and" … is independently "and" … is independently "are to be construed broadly as meaning that particular items expressed between the same symbols in different groups do not affect each other, or that particular items expressed between the same symbols in the same groups do not affect each other.
In the various parts of the present specification, substituents of the presently disclosed compounds are disclosed in terms of the type or scope of groups. It is specifically noted that the present invention includes each individual subcombination of the individual members of these group classes and ranges. For example, the term "C 1-6 Alkyl "means in particular methyl, ethyl, C independently disclosed 3 Alkyl, C 4 Alkyl, C 5 Alkyl and C 6 An alkyl group.
In the various parts of the invention, linking substituents are described. When the structure clearly requires a linking group, the markush variables recited for that group are understood to be linking groups. For example, if the structure requires a linking group and the markush group definition for that variable enumerates an "alkyl" or "aryl" group, it will be understood that the "alkyl" or "aryl" represents a linked alkylene group or arylene group, respectively.
The term "alkyl" or "alkyl group" as used herein refers to a saturated, straight or branched chain monovalent hydrocarbon group, wherein the alkyl group may be optionally substituted with one or more substituents as described herein. Unless otherwise specified, alkyl groups contain 1 to 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 (Et, -CH) 2 CH 3 ) N-propyl (n-Pr, -CH) 2 CH 2 CH 3 ) Isopropyl (i-Pr, -CH (CH) 3 ) 2 ) N-butyl (n-Bu, -CH) 2 CH 2 CH 2 CH 3 ) Isobutyl (i-Bu),-CH 2 CH(CH 3 ) 2 ) Sec-butyl (s-Bu, -CH (CH) 3 )CH 2 CH 3 ) Tert-butyl (t-Bu, -C (CH) 3 ) 3 ) N-pentyl (-CH) 2 CH 2 CH 2 CH 2 CH 3 ) 2-pentyl (-CH (CH) 3 )CH 2 CH 2 CH 3 ) 3-pentyl (-CH (CH) 2 CH 3 ) 2 ) 2-methyl-2-butyl (-C (CH) 3 ) 2 CH 2 CH 3 ) 3-methyl-2-butyl (-CH (CH) 3 )CH(CH 3 ) 2 ) 3-methyl-1-butyl (-CH) 2 CH 2 CH(CH 3 ) 2 ) 2-methyl-1-butyl (-CH) 2 CH(CH 3 )CH 2 CH 3 ) N-hexyl (-CH) 2 CH 2 CH 2 CH 2 CH 2 CH 3 ) 2-hexyl (-CH (CH) 3 )CH 2 CH 2 CH 2 CH 3 ) 3-hexyl (-CH (CH) 2 CH 3 )(CH 2 CH 2 CH 3 ) 2-methyl-2-pentyl (-C (CH) 3 ) 2 CH 2 CH 2 CH 3 ) 3-methyl-2-pentyl (-CH (CH) 3 )CH(CH 3 )CH 2 CH 3 ) 4-methyl-2-pentyl (-CH (CH) 3 )CH 2 CH(CH 3 ) 2 ) 3-methyl-3-pentyl (-C (CH) 3 )(CH 2 CH 3 ) 2 ) 2-methyl-3-pentyl (-CH (CH) 2 CH 3 )CH(CH 3 ) 2 ) 2, 3-dimethyl-2-butyl (-C (CH) 3 ) 2 CH(CH 3 ) 2 ) 3, 3-dimethyl-2-butyl (-CH (CH) 3 )C(CH 3 ) 3 ) N-heptyl, n-octyl, and the like.
The term "alkylene" means a saturated divalent hydrocarbon group resulting from the removal of two hydrogen atoms from a saturated straight or branched hydrocarbon group. Unless otherwise specified, alkylene groups contain 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; also in one embodiment Wherein the alkylene group contains 1 to 2 carbon atoms. Examples of this include methylene (-CH) 2 (-), ethylene (-CH) 2 CH 2 (-), n-propylene (-CH) 2 CH 2 CH 2 (-), isopropylidene (-CH (CH) 3 )CH 2 (-), etc.
The term "alkenyl" denotes a straight-chain or branched monovalent hydrocarbon radical containing 2 to 12 carbon atoms, in which there is at least one site of unsaturation, i.e. one carbon-carbon sp 2 A 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 comprises 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) 2 CH＝CH 2 ) 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. one carbon-carbon sp triple bond, wherein the alkynyl group may be optionally substituted with one or more substituents as described herein. In one embodiment, the alkynyl group contains 2 to 8 carbon atoms; in another embodiment, the alkynyl group contains 2 to 6 carbon atoms; in yet another embodiment, the alkynyl group contains 2 to 4 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), propargyl (-CH) 2 C.ident.CH), 1-propynyl (i.e., propynyl, -C.ident.C-CH 3 ) And so on.
The term "deuterium" means a single deuterium atom. For example, one deuterium atom replaces one hydrogen atom in a methyl group, forming a mono-deuterated methyl group (-CDH) 2 ) Two deuterium atoms replace two hydrogen atoms in the methyl group to form a bis-deuterated methyl (-CD) 2 H) And three deuterium atoms replace three hydrogen atoms in the methyl group to form a tri-deuterated methyl (-CD) 3 )。
The term "cyano-substituted alkyl" means that an alkyl group is 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" means that the alkyl group is 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, such as "hydroxy-substituted C 1-4 Alkyl "means an alkyl group having 1 to 4 carbon atoms substituted with one or more hydroxyl groups.
The term "carboxy-substituted alkyl" means that an alkyl group is substituted with one or more carboxy groups, wherein the alkyl group has the meaning as described herein. Examples of such include, but are not limited to, -CH 2 COOH、-CH 2 CH 2 COOH、-CH 2 CH 2 CH 2 COOH、-CH(CH 3 )CH 2 COOH、-CH 2 (CH 2 ) 3 COOH, etc.
The term "alkoxy" means that the alkyl group is attached to the remainder of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkoxy groups contain 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) 2 CH 3 ) 1-propoxy (n-PrO, n-propoxy, -OCH) 2 CH 2 CH 3 ) 2-propoxy (i-PrO, i-propoxy, -OCH (CH) 3 ) 2 ) 1-butoxy (n-BuO, n-butoxy, -OCH) 2 CH 2 CH 2 CH 3 ) 2-methyl-l-propoxy (i-BuO, i-)Butoxy, -OCH 2 CH(CH 3 ) 2 ) 2-butoxy (s-BuO, s-butoxy, -OCH (CH) 3 )CH 2 CH 3 ) 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC (CH) 3 ) 3 ) 1-pentoxy (n-pentoxy, -OCH) 2 CH 2 CH 2 CH 2 CH 3 ) 2-pentoxy (-OCH (CH) 3 )CH 2 CH 2 CH 3 ) 3-pentoxy (-OCH (CH) 2 CH 3 ) 2 ) 2-methyl-2-butoxy (-OC (CH) 3 ) 2 CH 2 CH 3 ) 3-methyl-2-butoxy (-OCH (CH) 3 )CH(CH 3 ) 2 ) 3-methyl-l-butoxy (-OCH) 2 CH 2 CH(CH 3 ) 2 ) 2-methyl-l-butoxy (-OCH) 2 CH(CH 3 )CH 2 CH 3 ) 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, -CH 2 F、-CHF 2 、-CF 3 、-CH 2 CH 2 F、-CH 2 CHF 2 、-CHFCH 2 F、-CH 2 CF 3 、-CH(CF 3 ) 2 、-CF 2 CH 2 CH 3 、-CH 2 CH 2 CH 2 F、-CH 2 CH 2 CHF 2 、-CH 2 CH 2 CF 3 、-OCH 2 F、-OCHF 2 、-OCF 3 、-OCH 2 CH 2 F、-OCH 2 CHF 2 、-OCHFCH 2 F、-OCH 2 CF 3 、-OCH(CF 3 ) 2 、-OCF 2 CH 2 CH 3 、-OCH 2 CH 2 CH 2 F、-OCH 2 CH 2 CHF 2 、-OCH 2 CH 2 CF 3 Etc.
The term "alkylamino" includes "N-alkylamino" and "N, N-dialkylamino" in which the amino groups are each independently substituted with one or two alkyl groupsSubstituted with a group; the alkyl groups have the meaning described in the present invention. Some of these are, for example, alkylamino groups of one or two C 1-6 An alkyl group is attached to a nitrogen atom to form a lower alkylamino group. Other embodiments are where the alkylamino group is one or two C 1-3 Is linked to an alkylamino group formed on the nitrogen atom. Suitable alkylamino groups may be mono-or di-alkylamino, examples of which 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 group containing 3 to 12 carbon atoms. In one embodiment, cycloalkyl groups contain 7 to 12 carbon atoms; in yet another embodiment, cycloalkyl groups contain 3 to 8 carbon atoms; in yet another embodiment, cycloalkyl groups contain 3 to 6 carbon atoms. The cycloalkyl groups may independently be 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" in which the amino groups are each independently substituted with one or two cycloalkyl groups; the cycloalkyl has the meaning described in the present invention. Some of these embodiments are those wherein the cycloalkylamino group is one or two C 3-8 Cycloalkyl groups are attached to nitrogen atoms to form cycloalkylamino groups. Other embodiments are where the cycloalkylamino group is one or two C 3-6 A cycloalkylamino group formed by linking a cycloalkyl group of (a) to a nitrogen atom. Suitable cycloalkylamino groups may be monocycloalkylamino or bicycloalkylamino, such examples include, but are not limited to, N-cyclopropylamino, N-cyclobutylamino, N-cyclohexylamino, N-dicyclohexylamino, and the like.
The terms "heterocyclyl" and "heterocycle" are used interchangeably herein to refer to a saturated or partially unsaturated, non-aromatic, monovalent or polyvalent single, double or triple ring comprising 3 to 12 ring atoms, at least one of which is cyclicAn atom 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 still other embodiments, the heterocyclyl consists of 3 to 8 ring atoms; in still other embodiments, the heterocyclyl consists of 3 to 6 ring atoms; in still other embodiments, the heterocyclyl consists of 5 to 6 ring atoms. Unless otherwise indicated, a heterocyclic 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-CH 2 The group may optionally be replaced by-C (=o) -. The sulfur atom of the ring may optionally be oxidized to an S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxide.
Examples of heterocyclyl groups include, but are not limited to: oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxacyclopentyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, and,Morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thiazalkyl, homopiperazinyl, homopiperidinyl, diazepanyl, oxepinyl, thiepanyl, oxazal->Radical, diaza->Radical, thiazal->Radical, 2-oxa-5-azabicyclo [2.2.1]Hept-5-yl. In heterocyclic groups-CH 2 Examples of substitution of the-group by-C (=o) -include, but are not limited to, 2-oxopyrrolidinyl, oxo-1, 3-thiazolidineA group, a 2-piperidonyl group, a pyridazinonyl group, a 3, 5-dioxopiperidinyl group and a pyrimidinedionyl group. Examples of sulfur atoms in the heterocyclic group that are oxidized include, but are not limited to, sulfolane, 1-dioxothiomorpholino. The heterocyclyl group may be optionally substituted with one or more substituents described herein.
The term "aryl" means a monocyclic, bicyclic or tricyclic, fully 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 attached to the remainder of the molecule. The term "aryl" may be used interchangeably with the term "aromatic ring". In one embodiment, aryl groups are carbocyclic ring systems consisting of 6 to 10 ring atoms and containing at least one aromatic ring therein. Examples of aryl groups may include phenyl, naphthyl and anthracenyl. The aryl groups may independently be optionally substituted with one or more substituents described herein.
The term "heteroaryl" means a monocyclic, bicyclic or tricyclic ring containing 5-12 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 remainder of the molecule. The term "heteroaryl" may be used interchangeably with the term "heteroaromatic ring" or "heteroaromatic compound". Wherein in some embodiments, from 1 to 9 carbon atoms are contained in 5 to 12 ring atoms of the heteroaryl group; in still other embodiments, from 1 to 7 carbon atoms in 5 to 12 ring atoms of the heteroaryl group; in still other embodiments, from 1 to 5 carbon atoms are contained in 5 to 12 ring atoms of the heteroaryl group; the heteroaryl group is optionally substituted with one or more substituents described herein. In one embodiment, heteroaryl is a heteroaryl group consisting of 5-12 ring atoms comprising 1, 2, 3, or 4 heteroatoms independently selected from O, S and N; in another embodiment, heteroaryl is a heteroaryl group consisting of 5 to 10 ring atoms comprising 1, 2, 3, or 4 heteroatoms independently selected from O, S and N; in yet another embodiment, heteroaryl is a heteroaryl group consisting of 5-7 ring atoms comprising 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), oxazolyl (e.g., 1,2,3, 4-oxazolyl), 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-thiodiazolyl, 1,3, 4-thiodiazolyl, 1,2, 5-thiodiazolyl, pyrrolyl (e.g., N-pyrrolyl), 2-pyrrolyl, 3-pyrrolyl), pyridinyl (e.g., 2-pyridinyl, 3-pyridinyl, 4-pyridinyl), 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: benzimidazolyl and benzopyrazolyl (e.g ) Benzofuranyl, benzothienyl, benzodioxazolyl, indolyl (e.g., 2-indolyl), purinyl, quinolinyl (e.g., 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), isoquinolinyl (e.g., 1-isoquinolinyl, 3-isoquinolinyl, or 4-isoquinolinyl), imidazo [1,2-a ]]Pyridinyl, pyrazolo [1,5-a ]]Pyridinyl, 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 ]]Triazolo [1,5-a ]]Pyridyl,/->Etc.
The term "j-k atoms" means that the cyclic group consists of j-k ring atoms including carbon atoms and/or O, N, S, P and like heteroatoms; each of j and k is independently any non-zero natural number, and k > j; the term "j-k" includes j, k and any natural number therebetween. For example, "5-12 atom composition", "5-10 atom composition" or "3-7 atom composition" means that the cyclic group is composed of 5-12 (i.e., 5, 6, 7, 8, 9, 10, 11 or 12), 5-10 (i.e., 5, 6, 7, 8, 9 or 10), 5-6 (i.e., 5 or 6), or 3-7 (i.e., 3, 4, 5, 6 or 7) ring atoms, including heteroatoms such as carbon atoms and/or O, N, S, P. The term "unsaturated" as used in the present invention means that the group contains one or more unsaturations.
The term "carboxy", whether used alone or in combination with other terms, such as "carboxyalkyl", means-CO 2 H or-COOH.
The term "heteroatom" refers to O, S, N, P and Si, including N, S and any oxidation state forms of P; primary, secondary, tertiary and quaternary ammonium salt forms; or a form in which the hydrogen on the 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" refers to a fluorine atom (F), a chlorine atom (Cl), a bromine atom (Br) or an iodine atom (I).
The term "cyano" or "CN" means a cyano structure, which group may be attached to other groups.
The term "nitro" or "NO 2 "means a nitro structure, which may be attached to other groups.
As described herein, a ring system (represented by formula b) in which substituents are depicted as a ring attached to the central ring represents that any substitutable position on the ring may be substituted. For example, formula C represents that substituent R may be mono-or polysubstituted at any position on the C-ring that may be substituted, as shown in formulas C1-C19.
As described herein, the attachment of a linkage to a ring system (as shown in formula d) represents that the linkage may be attached to the remainder of the molecule at any available position on the ring system. The formula d represents any possible attachment position on the ring to the remainder of the molecule, as shown in formulas d 1-d 5.
When a group is attached to the remainder of the molecule through two sites, as described herein, the two sites are independently optionally attached to the remainder of the molecule, and the groups to which the two sites are attached may be interchanged, unless otherwise indicated; for example, the piperidine group in formula E may be represented by E 1 End and E 2 The ends being connected to other parts of the molecule, E when the other parts of the molecule are unchanged 1 End and E 2 The ends may be interchanged.
The term "protecting group" or "PG" refers to a substituent that is commonly used to block or protect a particular functionality when reacted with other functional groups. For example, by "protecting group for an amino group" is meant a substituent attached to the amino group to block or protect the functionality of the amino group in the compound, suitable amino protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC ), benzyloxycarbonyl (CBZ ) and 9-fluorenylmethoxycarbonyl (Fmoc). Similarly, "hydroxy protecting group" refers to the functionality that a substituent of a hydroxy group serves to block or protect the hydroxy group, and suitable protecting groups include acetyl and silyl. "carboxyl protecting group" refers to the functionality of a substituent of a carboxyl group to block or protect the carboxyl group, and typically the carboxyl protecting group includes-CH 2 CH 2 SO 2 Ph, cyanoethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxymethyl, 2- (p-toluenesulfonyl) ethyl, 2- (p-nitrobenzenesulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitroethyl, and the like. General description of protecting groups can be found in the literature: t W.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 means 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 enzymatic conversion to the parent structure in the blood or tissue. The prodrug of the invention can be ester, and in the prior invention, the ester can be phenyl ester, aliphatic (C 1 -C 24 ) Esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, one compound of the invention may contain a hydroxyl group, i.e., it may be acylated to provide the compound in a prodrug form. Other prodrug forms include phosphates, 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 documents: higuchi and V.stilla, pro-drugs as Novel Delivery Systems, vol.14of the A.C.S. symposium Series, edward B.Roche, ed., bioreversible Carriers in Drug Design, american Pharmaceutical Association and Pergamon Press,1987,J.Rautio et al, prodrug: 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 a product obtained by metabolizing a specific compound or salt thereof in vivo. The metabolites of a compound may be identified by techniques well known in the art and their activity may be characterized by employing the assay methods as described herein. Such products may be obtained by oxidation, reduction, hydrolysis, amidization, deamination, esterification, degreasing, enzymatic cleavage, etc. of the administered compound. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a period of time sufficient.
As used herein, "pharmaceutically acceptable salts" refers to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as in the literature: S.M. Berge et al describe pharmaceutically 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 by other methods described in the book literature such as ion exchange. Other pharmaceutically acceptable salts include adipic acid salts, alginates, ascorbates, aspartic acid salts, benzenesulfonates, benzoic acid salts, bisulfate salts, borates, butyric acid salts, camphoric acid salts, cyclopentylpropionates, digluconate, dodecylsulfate, ethanesulfonate, formate, fumaric acid salts, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, caproate, hydroiodic acid salts, 2-hydroxy-ethanesulfonate, lactobionic acid salts, lactate, laurate, lauryl sulfate, malate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts obtained by suitable bases include alkali metals, alkaline earth metals, ammonium and N + (C 1-4 Alkyl group 4 Is a salt of (a). The present invention also contemplates quaternary ammonium salts formed from any compound containing a group of N. The water-soluble or oil-soluble or dispersible product may be obtained by quaternization. Alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesiumAnd so on. The pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and counter-ion forming amine cations, such as halides, hydroxides, carboxylates, sulphates, phosphates, nitrates, C 1-8 Sulfonate and aromatic sulfonate.
"solvate" according to the present invention refers to an association of one or more solvent molecules with a compound according to the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethylsulfoxide, ethyl acetate, acetic acid, and aminoethanol. The term "hydrate" refers to an association of solvent molecules that are water.
When the solvent is water, the term "hydrate" may be used. In some embodiments, a molecule of a compound of the invention may be associated with a water molecule, such as a monohydrate; in other embodiments, one of the present compound molecules may be associated with more than one water molecule, such as a dihydrate, and in still other embodiments, one of the present compound molecules may be associated with less than one water molecule, such as a hemihydrate. It should be noted that the hydrates described in the present invention retain the biological effectiveness of the compounds in a non-hydrated form.
The term "nitroxide" refers to the oxidation of 1 or more than 1 nitrogen atom to form an N-oxide when the compound contains several amine functions. Specific examples of N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen atoms of nitrogen-containing heterocycles. The corresponding amine may be treated with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid) to form an N-oxide (see Advanced Organic Chemistry, wiley Interscience, 4 th edition, jerry March, pages). In particular, the N-oxides can be prepared by the method 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, for example methylene chloride.
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, all of which are known to those of skill in the art (as described in 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 disorder as used herein refers to all slowing, interrupting, arresting, controlling or stopping the progression of the disease or disorder, but does not necessarily mean that the symptoms of all diseases or disorders are all absent, and includes prophylactic treatment of such symptoms, particularly in patients susceptible to such diseases or disorders. In some embodiments, ameliorating a disease or disorder (i.e., slowing or preventing or alleviating the progression of the disease or at least one clinical symptom thereof). In other embodiments, "treating" 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" refers to modulating a disease or disorder physically (e.g., stabilizing a perceived symptom) or physiologically (e.g., stabilizing a parameter of the body) or both. In other embodiments, "treating" refers to preventing or delaying the onset, or exacerbation 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 in an individual (e.g., reducing or inhibiting enzyme or protein activity, or ameliorating symptoms, alleviating a condition, slowing or delaying the progression of a disease, or preventing a disease, etc.). In one non-limiting embodiment, the term "therapeutically effective amount" refers to an amount that, when administered to an individual, is effective for: (1) At least partially alleviating, inhibiting, preventing and/or ameliorating a disorder or disease that is (i) mediated by roryt, or (ii) associated with roryt activity, or (iii) characterized by aberrant activity of roryt; or (2) reduce or inhibit roryt activity; or (3) reduce or inhibit expression of roryt. In another embodiment, the term "therapeutically effective amount" means an amount that, when administered to a cell, or organ, or non-cellular biological substance, or medium, at least partially reduces or inhibits roryt activity; or an amount of a compound of the invention that is effective to at least partially reduce or inhibit roryt expression.
The terms "administration" and "administering" of a compound as used herein should be understood to mean providing a compound of the invention or a prodrug of a compound of the invention to an individual in need thereof. It will be appreciated that one skilled in the art treats a patient presently suffering from such a disorder or prophylactically treats a patient suffering from such a disorder by administering 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 that 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 products that result directly or indirectly from mixing, compounding or aggregation of any two or more ingredients, or from decomposition of one or more ingredients, or from other types of reactions or interactions of one or more 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 a (hetero) aryl derivative, pharmaceutically acceptable salts, pharmaceutical preparations and compositions thereof, which can be used as ROR gamma t inhibitors and have potential application in the treatment of 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, rheumatic arthritis, autoimmune eye disease, ankylosing spondylitis, asthma, chronic obstructive pulmonary disease, osteoarthritis, allergic rhinitis, allergic dermatitis, crohn's disease or Kawasaki disease.
In one aspect, the present invention relates to a compound of formula (I) or a stereoisomer, nitroxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof of a compound of formula (I),
therein, A, B, D, L 1 、L 2 、R 2 、R 3 、R 4 、Z 1 、Z 2 、Z 3 、Z 4 N, m and p have the meaning described in the present invention, and represents L 2 Is used for the connection direction of the connecting rod.
In some embodiments, each Z 1 、Z 2 、Z 3 And Z 4 Independently CR 1 Or N; wherein R is 1 Having the meaning described in the present invention.
In some embodiments, L 1 Is a bond, -O-, -S-, -NH-, -C (=O) -or- (CR) a R b ) q -; wherein R is a 、R b And q has the meaning described in the present invention.
In some embodiments, L 2 is-C (=O) -NH- (CR) 5 R 6 )-、*-NH-C(＝O)-(CR 5 R 6 )-、*-NH-C(＝O)-、*-S(＝O) 2 -NH-(CR 5 R 6 )-、*-NH-S(＝O) 2 -(CR 5 R 6 )-、*-S(＝O)-NH-(CR 5 R 6 ) -or-NH-S (=o) - (CR 5 R 6 ) -; wherein R is 5 And R is 6 Having the meaning described in the present invention.
In some embodiments, R a And R is b Each independently is H, deuterium, F, cl, br, I, C 1-4 Alkyl or C 1-4 A haloalkyl group.
In some embodiments, ring a is C 6-10 Aryl, heteroaryl consisting of 5-10 atoms, C 3-8 Cycloalkyl or heterocyclyl consisting of 5 to 10 atoms.
In some embodiments, the B ring is a heterocyclic group consisting of 5 to 10 atoms.
In some embodiments, the D ring is 4-10 primordiaHeterocyclic groups or C of sub-compositions 3-8 Cycloalkyl groups.
In some embodiments, each R 1 Independently H, deuterium, F, cl, br, I, cyano, C 1-6 Alkyl, C 1-6 Alkoxy or C 1-6 A haloalkyl group.
In some embodiments, each R 2 And R is 3 Is independently deuterium, F, cl, br, I, -OH, -CN, -NH 2 、-NO 2 -COOH, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -C 1-6 alkylene-O-C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-10 Aryl, heterocyclyl consisting of 5 to 10 atoms, heteroaryl consisting of 5 to 10 atoms or-C (=o) -N (R) d R e ) The method comprises the steps of carrying out a first treatment on the surface of the Wherein the C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -C 1-6 alkylene-O-C 1-6 Alkyl, C 3-8 Cycloalkyl, C 6-10 Aryl, heteroaryl of 5 to 10 atoms and heterocyclyl of 5 to 10 atoms are independently optionally substituted with 1, 2 or 3R c Substituted;
wherein R is c 、R d And R is e Having the meaning described in the present invention.
In some embodiments, each R 4 Independently is-S (=o) 2 -C 1-6 Alkyl, -S (=o) 2 -C 1-6 Alkoxy, -S (=o) 2 -C 1-6 Alkylamino, -S (=o) 2 -C 1-6 Haloalkyl, -S (=o) 2 -C 3-8 Cycloalkyl, -S (=o) -C 1-6 Alkyl, -S (=o) 2 H、-COOH、-C(＝O)-N(R g R h )、-N(R g )-C(＝O)-C 1-6 Alkyl, -C (=o) -O-C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 3-8 Cycloalkyl, carboxyl substituted C 1-6 Alkyl or-C (=o) -C 1-6 A hydroxyalkyl group; wherein R is g And R is h Having the meaning described in the present invention.
In some embodiments, R g And R is h Each independently is H, deuterium or C 1-6 An alkyl group.
In some embodiments, R 5 And R is 6 Each independently is H, deuterium, -OH, -CN, -NH 2 、-NO 2 、-COOH、C 1-6 Alkoxy, C 1-6 Haloalkyl, hydroxy-substituted C 1-6 Alkyl-and cyano-substituted C 1-6 Alkyl, carboxyl substituted C 1-6 Alkyl, -C 1-6 alkylene-O-C 1-6 Alkyl, -C 1-6 alkylene-C (=O) -O-C 1-6 Alkyl, -C 1-6 alkylene-C (=O) -N (R) d R e )、-C 1-6 alkylene-O-C (=o) -N (R) d R e )、-C 1-6 alkylene-N (R) f )-C(＝O)-N(R d R e ) or-C 1-6 alkylene-N (R) d R e ) The method comprises the steps of carrying out a first treatment on the surface of the Wherein, C is as follows 1-6 Alkoxy, C 1-6 Haloalkyl and-C 1-6 alkylene-O-C 1-6 Alkyl is independently optionally substituted with 1, 2 or 3 groups selected from deuterium, -OH, -COOH, -N (R) d R e ) Or C 1-6 Substituted with alkoxy;
wherein R is d 、R e And R is f Having the meaning described in the present invention.
In some embodiments, each R c Is independently deuterium, F, cl, br, I, -OH, -CN, -NH 2 、C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl or C 1-6 Haloalkoxy groups.
In some embodiments, R d And R is e Each independently is H, deuterium, -OH, C 1-6 Alkyl, -C (=o) H, -C (=o) -O-C 1-6 Alkyl, -C (=o) -C 1-6 Alkyl, -C 1-6 alkylene-C (=O) -O-C 1-6 Alkyl or-C 1-6 alkylene-O-C 1-6 An alkyl group; wherein, C is as follows 1-6 Alkyl, -C 1-6 alkylene-C (=O) -O-C 1-6 Alkyl and-C 1-6 alkylene-O-C 1-6 Alkyl is independently optionally substituted with 1, 2 or 3 groups selected from deuterium,F、Cl、Br、I、-OH、-CN、-NH 2 or-COOH.
In some embodiments, each R f Independently H, deuterium, C 1-6 Alkyl, -C 1-6 alkylene-O-C 1-6 Alkyl or-C 1-6 alkylene-C 3-8 Cycloalkyl; wherein, C is as follows 1-6 Alkyl, -C 1-6 alkylene-O-C 1-6 Alkyl and-C 1-6 alkylene-C 3-8 Cycloalkyl is independently optionally substituted with 1, 2 or 3 groups selected from deuterium, F, cl, br, I, -OH, -CN, -NH 2 Or 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, R a And R is b Each independently is H, deuterium, F, cl, br, I, methyl, ethyl, n-propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2-difluoroethyl, 1, 2-difluoroethyl, 2-trifluoroethyl, monochloromethyl, dichloromethyl, 2-chloroethyl, 2-dichloroethyl or 1, 2-dichloroethyl.
In other embodiments, the A ring is C 6-10 Aryl, heteroaryl consisting of 5-7 atoms, C 3-6 Cycloalkyl or heterocyclyl consisting of 5 to 7 atoms.
In still other embodiments, the a ring is phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolyl, pyrazolyl, imidazolyl, furanyl, oxazolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, or piperazinyl.
In other embodiments, the B ring is a heterocyclic group consisting of 5 to 7 atoms.
In still other embodiments, the B ring is
In other embodiments, the D ring is a heterocyclic group consisting of 4 to 7 atoms or C 3-6 Cycloalkyl groups.
In still other embodiments, the D ring is piperidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperazinyl, azetidinyl, oxetanyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
In other embodiments, each R 1 Independently H, deuterium, F, cl, br, I, cyano, C 1-4 Alkyl, C 1-4 Alkoxy or C 1-4 A haloalkyl group.
In other embodiments, each R 2 And R is 3 Is independently deuterium, F, cl, br, I, -OH, -CN, -NH 2 、-NO 2 -COOH, oxo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, -C 1-4 alkylene-O-C 1-4 Alkyl, C 3-6 Cycloalkyl, C 6-10 Aryl, heterocyclyl consisting of 5 to 7 atoms, heteroaryl consisting of 5 to 7 atoms or-C (=o) -N (R) d R e ) The method comprises the steps of carrying out a first treatment on the surface of the Wherein the C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, -C 1-4 alkylene-O-C 1-4 Alkyl, C 3-6 Cycloalkyl, C 6-10 Aryl, heteroaryl of 5 to 7 atoms and heterocyclyl of 5 to 7 atoms are independently optionally substituted with 1, 2 or 3R c Substituted;
wherein R is c 、R d And R is e Having the meaning described in the present invention.
In other embodiments, each R c Is independently deuterium, F, cl, br, I, -OH, -CN, -NH 2 、C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Halogenated compoundsAlkyl or C 1-4 Haloalkoxy groups.
In other embodiments, each R 4 Independently is-S (=o) 2 -C 1-4 Alkyl, -S (=o) 2 -C 1-4 Alkoxy, -S (=o) 2 -C 1-4 Alkylamino, -S (=o) 2 -C 1-4 Haloalkyl, -S (=o) 2 -C 3-6 Cycloalkyl, -S (=o) -C 1-4 Alkyl, -S (=o) 2 H、-COOH、-C(＝O)-N(R g R h )、-N(R g )-C(＝O)-C 1-4 Alkyl, -C (=o) -O-C 1-4 Alkyl, C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 3-6 Cycloalkyl, carboxyl substituted C 1-4 Alkyl or-C (=o) -C 1-4 A hydroxyalkyl group;
wherein R is g And R is h Having the meaning described in the present invention.
In other embodiments, R g And R is h Each independently is H, deuterium or C 1-4 An alkyl group.
In other embodiments, R 5 And R is 6 Each independently is H, deuterium, -OH, -CN, -NH 2 、-NO 2 、-COOH、C 1-4 Alkoxy, C 1-4 Haloalkyl, hydroxy-substituted C 1-4 Alkyl-and cyano-substituted C 1-4 Alkyl, carboxyl substituted C 1-4 Alkyl, -C 1-4 alkylene-O-C 1-4 Alkyl, -C 1-4 alkylene-C (=O) -O-C 1-4 Alkyl, -C 1-4 alkylene-C (=O) -N (R) d R e )、-C 1-4 alkylene-O-C (=o) -N (R) d R e )、-C 1-4 alkylene-N (R) f )-C(＝O)-N(R d R e ) or-C 1-4 alkylene-N (R) d R e ) The method comprises the steps of carrying out a first treatment on the surface of the Wherein, C is as follows 1-4 Alkoxy, C 1-4 Haloalkyl and-C 1-4 alkylene-O-C 1-4 Alkyl is independently optionally substituted with 1, 2 or 3 groups selected from deuterium, -OH, -COOH, -N (R) d R e ) Or C 1-4 Substituted with alkoxy;
wherein the method comprises the steps of ，R d 、R e And R is f Having the meaning described in the present invention.
In other embodiments, R d And R is e Each independently is H, deuterium, -OH, C 1-4 Alkyl, -C (=o) H, -C (=o) -O-C 1-4 Alkyl, -C (=o) -C 1-4 Alkyl, -C 1-4 alkylene-C (=O) -O-C 1-4 Alkyl or-C 1-4 alkylene-O-C 1-4 An alkyl group; wherein, C is as follows 1-4 Alkyl, -C 1-4 alkylene-C (=O) -O-C 1-4 Alkyl and-C 1-4 alkylene-O-C 1-4 Alkyl is independently optionally substituted with 1, 2 or 3 groups selected from deuterium, F, cl, br, I, -OH, -CN, -NH 2 or-COOH.
In other embodiments, each R f Independently H, deuterium, C 1-4 Alkyl, -C 1-4 alkylene-O-C 1-4 Alkyl or-C 1-4 alkylene-C 3-6 Cycloalkyl; wherein, C is as follows 1-4 Alkyl, -C 1-4 alkylene-O-C 1-4 Alkyl and-C 1-4 alkylene-C 3-6 Cycloalkyl is independently optionally substituted with 1, 2 or 3 groups selected from deuterium, F, cl, br, I, -OH, -CN, -NH 2 Or COOH.
In still other embodiments, each R 1 Independently 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, -CH 2 F、-CH 2 Cl、-CHF 2 、-CHCl 2 、-CF 3 、-CH 2 CH 2 F、-CH 2 CH 2 Cl、-CH 2 CHF 2 、-CH 2 CHCl 2 、-CHFCH 2 F、-CHClCH 2 Cl、-CH 2 CF 3 、-CH(CF 3 ) 2 、-CF 2 CH 2 CH 3 、-CH 2 CH 2 CH 2 F、-CH 2 CH 2 CHF 2 or-CH 2 CH 2 CF 3 。
In still other embodiments, each R 2 And R is 3 Is independently deuterium, F, cl, br, I, -OH, -CN, -NH 2 、-NO 2 -COOH, oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, -CH 2 F、-CHF 2 、-CF 3 、-CH 2 CH 2 F、-CH 2 CHF 2 、-CHFCH 2 F、-CH 2 CF 3 、-CH(CF 3 ) 2 、-CF 2 CH 2 CH 3 、-CH 2 CH 2 CH 2 F、-CH 2 CH 2 CHF 2 、-CH 2 CH 2 CF 3 、-OCH 2 F、-OCHF 2 、-OCF 3 、-OCH 2 CH 2 F、-OCH 2 CHF 2 、-OCHFCH 2 F、-OCH 2 CF 3 、-OCH(CF 3 ) 2 、-OCF 2 CH 2 CH 3 、-OCH 2 CH 2 CH 2 F、-OCH 2 CH 2 CHF 2 、-OCH 2 CH 2 CF 3 、-CH 2 OCH 3 、-CH 2 OCH 2 CH 3 、-CH 2 OCH 2 CH 2 CH 3 、-CH 2 OCH(CH 3 ) 2 、-CH 2 CH 2 OCH 3 、-CH 2 CH 2 OCH 2 CH 3 、-CH 2 CH 2 OCH 2 CH 2 CH 3 、-CH 2 CH 2 OCH(CH 3 ) 2 、-CH 2 CH 2 CH 2 OCH 3 、-CH 2 CH 2 CH 2 OCH 2 CH 3 、-CH 2 CH 2 CH 2 OCH 2 CH 2 CH 3 、-CH 2 CH 2 CH 2 OCH(CH 3 ) 2 Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazolyl, thiazolyl, imidazolyl, oxazolyl, triazolyl, tetrazolyl, piperazinyl, piperonylPyridyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, pyrrolidinyl or-C (=o) -N (R) d R e ) The method comprises the steps of carrying out a first treatment on the surface of the Wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, -CH 2 F、-CHF 2 、-CH 2 CH 2 F、-CH 2 CHF 2 、-CHFCH 2 F、-CH 2 CF 3 、-CH(CF 3 ) 2 、-CF 2 CH 2 CH 3 、-CH 2 CH 2 CH 2 F、-CH 2 CH 2 CHF 2 、-CH 2 CH 2 CF 3 、-OCH 2 F、-OCHF 2 、-OCH 2 CH 2 F、-OCH 2 CHF 2 、-OCHFCH 2 F、-OCH 2 CF 3 、-OCH(CF 3 ) 2 、-OCF 2 CH 2 CH 3 、-OCH 2 CH 2 CH 2 F、-OCH 2 CH 2 CHF 2 、-OCH 2 CH 2 CF 3 、-CH 2 OCH 3 、-CH 2 OCH 2 CH 3 、-CH 2 OCH 2 CH 2 CH 3 、-CH 2 OCH(CH 3 ) 2 、-CH 2 CH 2 OCH 3 、-CH 2 CH 2 OCH 2 CH 3 、-CH 2 CH 2 OCH 2 CH 2 CH 3 、-CH 2 CH 2 OCH(CH 3 ) 2 、-CH 2 CH 2 CH 2 OCH 3 、-CH 2 CH 2 CH 2 OCH 2 CH 3 、-CH 2 CH 2 CH 2 OCH 2 CH 2 CH 3 、-CH 2 CH 2 CH 2 OCH(CH 3 ) 2 Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazolyl, thiazolyl, imidazolyl, oxazolyl, triazolyl, tetrazolyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl and pyrrolidinyl independently optionallyIs covered by 1, 2 or 3R c Substituted;
wherein R is c Having the meaning described in the present invention.
In still other embodiments, each R c Is independently deuterium, F, cl, br, I, -OH, -CN, -NH 2 Methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, -CH 2 F、-CHF 2 、-CF 3 、-CH 2 CH 2 F、-CH 2 CHF 2 、-CHFCH 2 F、-CH 2 CF 3 、-CH(CF 3 ) 2 、-CF 2 CH 2 CH 3 、-CH 2 CH 2 CH 2 F、-CH 2 CH 2 CHF 2 、-CH 2 CH 2 CF 3 、-OCH 2 F、-OCHF 2 、-OCF 3 、-OCH 2 CH 2 F、-OCH 2 CHF 2 、-OCHFCH 2 F、-OCH 2 CF 3 、-OCH(CF 3 ) 2 、-OCF 2 CH 2 CH 3 、-OCH 2 CH 2 CH 2 F、-OCH 2 CH 2 CHF 2 or-OCH 2 CH 2 CF 3 。
In still other embodiments, each R 4 is-S (=O) 2 -CH 3 、-S(＝O) 2 -CH 2 CH 3 、-S(＝O) 2 -CH 2 CH 2 CH 3 、-S(＝O) 2 -CH(CH 3 )CH 3 、-S(＝O) 2 -OCH 3 、-S(＝O) 2 -OCH 2 CH 3 、-S(＝O) 2 -OCH 2 CH 2 CH 3 、-S(＝O) 2 -OCH(CH 3 )CH 3 、-S(＝O) 2 -NH-CH 3 、-S(＝O) 2 -NH-CH 2 CH 3 、-S(＝O) 2 -NH-CH 2 CH 2 CH 3 、-S(＝O) 2 -NH-CH(CH 3 )CH 3 、-S(＝O) 2 -cyclopropyl, -S (=o) 2 -cyclobutyl, -S (=o) 2 -cyclopentyl, -S (=o) 2 -cyclohexyl, -S (=o) -CH 3 、-S(＝O)-CH 2 CH 3 、-S(＝O)-CH 2 CH 2 CH 3 、-S(＝O)-CH(CH 3 )CH 3 、-S(＝O) 2 H、-COOH、-C(＝O)-N(R g R h )、-N(R g )-C(＝O)-CH 3 、-N(R g )-C(＝O)-CH 2 CH 3 、-N(R g )-C(＝O)-CH 2 CH 2 CH 3 、-N(R g )-C(＝O)-CH(CH 3 )CH 3 、-C(＝O)-O-CH 3 、-C(＝O)-O-CH 2 CH 3 、-C(＝O)-O-CH 2 CH 2 CH 3 、-C(＝O)-O-CH(CH 3 )CH 3 Methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, -CH 2 F、-CHF 2 、-CF 3 、-CH 2 CH 2 F、-CH 2 CHF 2 、-CHFCH 2 F、-CH 2 CF 3 、-CH(CF 3 ) 2 、-CF 2 CH 2 CH 3 、-CH 2 CH 2 CH 2 F、-CH 2 CH 2 CHF 2 、-CH 2 CH 2 CF 3 Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CH 2 COOH、-CH 2 CH 2 COOH、-CH 2 CH 2 CH 2 COOH、-C(＝O)-CH 2 OH、-C(＝O)-CH 2 CH 2 OH or-C (=O) -CH 2 CH 2 CH 2 OH；
Wherein R is g And R is h Having the meaning described in the present invention.
In still other embodiments, R g And R is h Each independently is H, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl or tert-butyl.
In still other embodiments, R 5 And R is 6 Each independently is H, deuterium, -OH, -CN, -NH 2 、-NO 2 、-COOH、-CH 2 F、-CHF 2 、-CF 3 、-CH 2 CH 2 F、-CH 2 CHF 2 、-CHFCH 2 F、-CH 2 CF 3 、-CH(CF 3 ) 2 、-CF 2 CH 2 CH 3 、-CH 2 CH 2 CH 2 F、-CH 2 CH 2 CHF 2 、-CH 2 CH 2 CF 3 Methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, -CH 2 OH、-CH 2 CH 2 OH、-CH 2 CH 2 CH 2 OH、-CH(CH 3 )CH 2 OH、-CH 2 (CH 2 ) 3 OH、-CH 2 CN、-CH 2 CH 2 CN、-CH 2 CH 2 CH 2 CN、-CH(CH 3 )CH 2 CN、-CH 2 (CH 2 ) 3 CN、-CH 2 COOH、-CH 2 CH 2 COOH、-CH 2 CH 2 CH 2 COOH、-CH(CH 3 )CH 2 COOH、-CH 2 (CH 2 ) 3 COOH、-CH 2 OCH 3 、-CH 2 OCH 2 CH 3 、-CH 2 OCH 2 CH 2 CH 3 、-CH 2 OCH(CH 3 ) 2 、-CH 2 CH 2 OCH 3 、-CH 2 CH 2 OCH 2 CH 3 、-CH 2 CH 2 OCH 2 CH 2 CH 3 、-CH 2 CH 2 OCH(CH 3 ) 2 、-CH 2 CH 2 CH 2 OCH 3 、-CH 2 CH 2 CH 2 OCH 2 CH 3 、-CH 2 CH 2 CH 2 OCH 2 CH 2 CH 3 、-CH 2 CH 2 CH 2 OCH(CH 3 ) 2 、-CH 2 -C(＝O)-OCH 3 、-CH 2 -C(＝O)-OCH 2 CH 3 、-CH 2 -C(＝O)-OCH 2 CH 2 CH 3 、-CH 2 -C(＝O)-OCH(CH 3 ) 2 、-CH 2 CH 2 -C(＝O)-OCH 3 、-CH 2 CH 2 -C(＝O)-OCH 2 CH 3 、-CH 2 CH 2 -C(＝O)-OCH 2 CH 2 CH 3 、-CH 2 CH 2 -C(＝O)-OCH(CH 3 ) 2 、-CH 2 CH 2 CH 2 -C(＝O)-OCH 3 、-CH 2 CH 2 CH 2 -C(＝O)-OCH 2 CH 3 、-CH 2 CH 2 CH 2 -C(＝O)-OCH 2 CH 2 CH 3 、-CH 2 CH 2 CH 2 -C(＝O)-OCH(CH 3 ) 2 、-CH 2 -C(＝O)-N(R d R e )、-CH 2 CH 2 -C(＝O)-N(R d R e )、-CH 2 CH 2 CH 2 -C(＝O)-N(R d R e )、-CH 2 -O-C(＝O)-N(R d R e )、-CH 2 CH 2 -O-C(＝O)-N(R d R e )、-CH 2 CH 2 CH 2 -O-C(＝O)-N(R d R e )、-CH 2 -N(R f )-C(＝O)-N(R d R e )、-CH 2 CH 2 -N(R f )-C(＝O)-N(R d R e )、-CH 2 CH 2 CH 2 -N(R f )-C(＝O)-N(R d R e )、-CH 2 N(R d R e )、-CH 2 CH 2 N(R d R e ) or-CH 2 CH 2 CH 2 N(R d R e )；
Wherein, the-CH 2 F、-CHF 2 、-CH 2 CH 2 F、-CH 2 CHF 2 、-CHFCH 2 F、-CH 2 CF 3 、-CH(CF 3 ) 2 、-CF 2 CH 2 CH 3 、-CH 2 CH 2 CH 2 F、-CH 2 CH 2 CHF 2 、-CH 2 CH 2 CF 3 Methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, -CH 2 OCH 3 、-CH 2 OCH 2 CH 3 、-CH 2 OCH 2 CH 2 CH 3 、-CH 2 OCH(CH 3 ) 2 、-CH 2 CH 2 OCH 3 、-CH 2 CH 2 OCH 2 CH 3 、-CH 2 CH 2 OCH 2 CH 2 CH 3 、-CH 2 CH 2 OCH(CH 3 ) 2 、-CH 2 CH 2 CH 2 OCH 3 、-CH 2 CH 2 CH 2 OCH 2 CH 3 、-CH 2 CH 2 CH 2 OCH 2 CH 2 CH 3 and-CH 2 CH 2 CH 2 OCH(CH 3 ) 2 Independently optionally substituted with 1, 2 or 3 groups selected from deuterium, -OH, -COOH, methoxy, ethoxy, N-propoxy, isopropoxy, N-butoxy, tert-butoxy or-N (R) d R e ) Is substituted by a substituent of (2);
wherein R is d 、R e And R is f Having the meaning described in the present invention.
In still other embodiments, R d And R is e Each independently is H, deuterium, -OH, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, -C (=O) H, -C (=O) -O-CH 3 、-C(＝O)-O-CH 2 CH 3 、-C(＝O)-O-CH 2 CH 2 CH 3 、-C(＝O)-O-CH(CH 3 ) 2 、-C(＝O)-CH 3 、-C(＝O)-CH 2 CH 3 、-C(＝O)-CH 2 CH 2 CH 3 、-C(＝O)-CH(CH 3 ) 2 、-CH 2 OCH 3 、-CH 2 OCH 2 CH 3 、-CH 2 OCH 2 CH 2 CH 3 、-CH 2 OCH(CH 3 ) 2 、-CH 2 CH 2 OCH 3 、-CH 2 CH 2 OCH 2 CH 3 、-CH 2 CH 2 OCH 2 CH 2 CH 3 、-CH 2 CH 2 OCH(CH 3 ) 2 、-CH 2 CH 2 CH 2 OCH 3 、-CH 2 CH 2 CH 2 OCH 2 CH 3 、-CH 2 CH 2 CH 2 OCH 2 CH 2 CH 3 、-CH 2 CH 2 CH 2 OCH(CH 3 ) 2 、-CH 2 -C(＝O)-OCH 3 、-CH 2 -C(＝O)-OCH 2 CH 3 、-CH 2 -C(＝O)-OCH 2 CH 2 CH 3 、-CH 2 -C(＝O)-OCH(CH 3 ) 2 、-CH 2 CH 2 -C(＝O)-OCH 3 、-CH 2 CH 2 -C(＝O)-OCH 2 CH 3 、-CH 2 CH 2 -C(＝O)-OCH 2 CH 2 CH 3 、-CH 2 CH 2 -C(＝O)-OCH(CH 3 ) 2 、-CH 2 CH 2 CH 2 -C(＝O)-OCH 3 、-CH 2 CH 2 CH 2 -C(＝O)-OCH 2 CH 3 、-CH 2 CH 2 CH 2 -C(＝O)-OCH 2 CH 2 CH 3 or-CH 2 CH 2 CH 2 -C(＝O)-OCH(CH 3 ) 2 ；
Wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl and-CH are as follows 2 OCH 3 、-CH 2 OCH 2 CH 3 、-CH 2 OCH 2 CH 2 CH 3 、-CH 2 OCH(CH 3 ) 2 、-CH 2 CH 2 OCH 3 、-CH 2 CH 2 OCH 2 CH 3 、-CH 2 CH 2 OCH 2 CH 2 CH 3 、-CH 2 CH 2 OCH(CH 3 ) 2 、-CH 2 CH 2 CH 2 OCH 3 、-CH 2 CH 2 CH 2 OCH 2 CH 3 、-CH 2 CH 2 CH 2 OCH 2 CH 2 CH 3 、-CH 2 CH 2 CH 2 OCH(CH 3 ) 2 、-CH 2 -C(＝O)-OCH 3 、-CH 2 -C(＝O)-OCH 2 CH 3 、-CH 2 -C(＝O)-OCH 2 CH 2 CH 3 、-CH 2 -C(＝O)-OCH(CH 3 ) 2 、-CH 2 CH 2 -C(＝O)-OCH 3 、-CH 2 CH 2 -C(＝O)-OCH 2 CH 3 、-CH 2 CH 2 -C(＝O)-OCH 2 CH 2 CH 3 、-CH 2 CH 2 -C(＝O)-OCH(CH 3 ) 2 、-CH 2 CH 2 CH 2 -C(＝O)-OCH 3 、-CH 2 CH 2 CH 2 -C(＝O)-OCH 2 CH 3 、-CH 2 CH 2 CH 2 -C(＝O)-OCH 2 CH 2 CH 3 and-CH 2 CH 2 CH 2 -C(＝O)-OCH(CH 3 ) 2 Is independently optionally substituted with 1, 2 or 3 groups selected from deuterium, F, cl, br, I, -OH, -CN, -NH 2 or-COOH.
In still other embodiments, each R f Independently H, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, -CH 2 OCH 3 、-CH 2 OCH 2 CH 3 、-CH 2 OCH 2 CH 2 CH 3 、-CH 2 OCH 2 (CH 3 ) 2 、-CH 2 CH 2 OCH 3 、-CH 2 CH 2 OCH 2 CH 3 、-CH 2 CH 2 OCH 2 CH 2 CH 3 、-CH 2 CH 2 OCH(CH 3 ) 2 、-CH 2 CH 2 CH 2 OCH 3 、-CH 2 CH 2 CH 2 OCH 2 CH 3 、-CH 2 CH 2 CH 2 OCH 2 CH 2 CH 3 、-CH 2 CH 2 CH 2 OCH(CH 3 ) 2 Cyclopropyl methylene, cyclopropyl ethylene, cyclopropyl n-propyl, cyclobutylmethylene, cyclobutylethylene, cyclobutyln-propyl, cyclopentyl methylene, cyclopentyl ethylene, cyclopentyl n-propyl, cyclohexyl methylene or cyclohexyl n-propyl;
wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl,-CH 2 OCH 3 、-CH 2 OCH 2 CH 3 、-CH 2 OCH 2 CH 2 CH 3 、-CH 2 OCH(CH 3 ) 2 、-CH 2 CH 2 OCH 3 、-CH 2 CH 2 OCH 2 CH 3 、-CH 2 CH 2 OCH 2 CH 2 CH 3 、-CH 2 CH 2 OCH(CH 3 ) 2 、-CH 2 CH 2 CH 2 OCH 3 、-CH 2 CH 2 CH 2 OCH 2 CH 3 、-CH 2 CH 2 CH 2 OCH 2 CH 2 CH 3 、-CH 2 CH 2 CH 2 OCH(CH 3 ) 2 Cyclopropylmethylene, cyclopropylethylene, cyclobutylmethylene, cyclobutylethylene, cyclobutyln-propyl, cyclopentylmethylene, cyclopentylethylene, cyclohexylmethylene, cyclohexylethylene and cyclohexyln-propyl are independently optionally substituted with 1, 2 or 3 groups selected from deuterium, F, cl, br, I, -OH, -CN, -NH 2 or-COOH.
In still other embodiments, the invention relates to a compound of formula (II) or a stereoisomer, a geometric isomer, a tautomer, a nitroxide, a hydrate, a solvate, a metabolite, an ester, a pharmaceutically acceptable salt or a prodrug thereof of a compound of formula (II),
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in some embodiments, the present invention relates to compounds of one of the following, or stereoisomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof, but in no way limited to these compounds:
stereoisomers, solvates, metabolites, salts and pharmaceutically acceptable prodrugs of the compounds of formula (I) or formula (II) are included within the scope of the 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, geometric isomer, tautomer, nitroxide, hydrate, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable excipient, carrier, adjuvant or combination thereof.
In some embodiments, the pharmaceutical composition comprises other agents that prevent or treat an inflammatory syndrome, disorder, or disease, or any combination thereof.
In one embodiment, the pharmaceutical composition may be in the form of a liquid, solid, semi-solid, gel or spray.
In another aspect, the invention relates to the use of a compound of formula (I) or formula (II) or a pharmaceutical composition thereof for the manufacture of a medicament for the prevention or treatment of a cancer, inflammation or autoimmune disorder 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 for 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 present invention relates to methods for the preparation, isolation and purification of compounds of formula (I) or formula (II).
In another aspect, the present invention relates to intermediates for preparing compounds of formula (I) or formula (II).
The disclosed compounds may contain asymmetric or chiral centers and thus may exist in different stereoisomeric forms. The present invention is intended to encompass all stereoisomeric forms of the compounds of formula (I) or (II), including but not limited to diastereomers, enantiomers, atropisomers and geometric (or conformational) isomers, as well as mixtures thereof, such as racemic mixtures, as part of the present invention.
In the structures disclosed herein, when the stereochemistry of any particular chiral atom is not indicated, then all stereoisomers of that structure are contemplated as being within the present invention and are included as presently disclosed compounds. When stereochemistry is indicated by the solid wedge (solid wedge) or dashed line representing a particular configuration, then the stereoisomers of that structure are so defined and defined.
The compounds of formula (I) or (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 (II) may be present in the form of salts. In one embodiment, the salt refers to a pharmaceutically acceptable salt. The term "pharmaceutically acceptable" means that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients comprising the formulation and/or the mammal being treated therewith. In another embodiment, the salt is not necessarily a pharmaceutically acceptable salt, and may be an intermediate for preparing and/or purifying a compound of formula (I) or formula (II) and/or for isolating an enantiomer of a compound of formula (I) or formula (II).
Pharmaceutically acceptable acid addition salts may be formed from the reaction of a compound of the present disclosure with an inorganic or organic acid, such as acetate, aspartate, benzoate, benzenesulfonate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfonate, chloride/hydrochloride, chlorotheophylline salt, citrate, ethanedisulfonate, fumarate, glucoheptonate, gluconate, glucuronate, hippurate, hydroiodite/iodide, isethionate, lactate, lactobionic aldehyde, lauryl sulfate, malate, maleate, malonate, mandelate, methanesulfonate, methylsulfate, naphthoate, naphthalenesulfonate, nicotinate, nitrate, stearate, oleate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, polygalactoate, propionate, stearate, succinate, sulfosalicylate, tartrate, tosylate and trifluoroacetate.
Pharmaceutically acceptable base addition salts may be formed from the compounds of the present disclosure by reaction with inorganic or organic bases.
Inorganic bases from which salts may be derived include, for example, ammonium salts and metals of groups I to XII of the periodic Table. In certain embodiments, the salt is 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 may be derived include primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like. Some organic amines include, for example, isopropylamine, benzathine (benzathine), choline salts (choline), diethanolamine, diethylamine, lysine, meglumine (meglumine), piperazine and tromethamine.
Pharmaceutically acceptable salts of the invention can be synthesized from the parent compound, basic or acidic moiety using conventional chemical methods. In general, such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of a suitable 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 a suitable acid. Such reactions are generally carried out in water or an organic solvent or a mixture of both. Generally, it is desirable to use a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile where appropriate. In, for example, "Remington's Pharmaceutical Sciences", 20 th edition, mack Publishing Company, easton, pa., (1985); and "manual of pharmaceutically acceptable salts: a list of further suitable salts can be found in Properties, selection and application (Handbook of Pharmaceutical Salts: properties, selection, and Use) ", stahl and Wermuth (Wiley-VCH, weinheim, germany, 2002).
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 (e.g., ethanol, DMSO, etc.) containing them, for their crystallization. The disclosed compounds may form solvates inherently or by design with pharmaceutically acceptable solvents (including water); accordingly, the present invention is intended to include both solvated and unsolvated forms of the presently disclosed compounds.
Any formulae given herein are also intended to represent non-isotopically enriched forms as well as isotopically enriched forms of such compounds. Isotopically enriched compounds have structures depicted by the formulae given herein except that one or more atoms are replaced by an atom having a selected atomic 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 as 2 H、 3 H、 11 C、 13 C、 14 C、 15 N、 17 O、 18 O、 18 F、 31 P、 32 P、 35 S、 36 Cl and Cl 125 I。
In another aspect, the compounds of the invention include isotopically enriched compounds defined in the invention, e.g., wherein a radioisotope, such as 3 H、 14 C and C 18 F, or in which non-radioactive isotopes are present, e.g 2 H and 13 Those of C. Such isotopically enriched compounds are useful in metabolic studies (using 14 C) Reaction kinetics studies (using, for example 2 H or 3 H) Detection or imaging techniques, such as Positron Emission Tomography (PET) or Single Photon Emission Computed Tomography (SPECT) including drug or substrate tissue distribution assays, or may be used in radiation therapy of a patient. 18 F-enriched compounds are particularly desirable for PET or SPECT studies. Isotopically enriched compounds of formula (I) or (II) can be described by conventional techniques familiar to those skilled in the art or by the examples and procedures of the invention using suitable isotopically labeling reagentsPrepared in place of the originally used unlabeled reagent.
In addition, heavier isotopes are in particular deuterium (i.e., 2 substitution of H or D) may provide certain therapeutic advantages, which are brought about by a higher metabolic stability. For example, increased in vivo half-life or reduced dosage requirements or improved therapeutic index. It is to be understood that deuterium in the present invention is 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 an isotopic enrichment factor. The term "isotopically enriched factor" as used herein refers to the ratio between the isotopic abundance and the natural abundance of a specified 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 wherein the crystallization solvent may be isotopically substituted, e.g. D 2 O, acetone-d 6 、DMSO-d 6 Those solvates of (a).
Pharmaceutical compositions, formulations and administration of the compounds of the invention
The present invention provides a pharmaceutical composition comprising a compound of the present disclosure, such as the compounds listed 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 disorder 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 other agents for preventing or treating inflammatory syndromes, disorders or diseases, including but not limited to:
1) TNF-alpha inhibitors; 2) A non-selective COX-1/COX-2 inhibitor; 3) COX-2 inhibitors; 4) Other therapeutic agents useful in the treatment of inflammatory syndromes and autoimmune diseases, including glucocorticoids, methotrexate, leflunomide (leflunomide), sulfasalazine, azathioprine, cyclosporine, tacrolimus (tacrolimus), penicillamine, buspiramine, aclitalopril, mizoribine, clozapride, ciclesonide, hydroxychloroquine, gold thiomalate (aurothiomalate), auranofin, cyclophosphamide, BAFF/APRIL inhibitors, CTLA-4-immunoglobulins, or the like; 5) Leukotriene biosynthesis inhibitors, 5-lipoxygenase inhibitors or 5-lipoxygenase activating protein (FLAP) antagonists; 6) LTD4 receptor antagonists; 7) PDE4 inhibitors; 8) Antihistaminic HI receptor antagonists; α1 and α2-adrenoreceptor agonists;
9) Anticholinergic agents; 10 P-adrenergic receptor agonists; 11 Insulin-like growth factor type I analogues; 12 Kinase inhibitors selected from the group consisting of Janus kinase inhibitors (JAK 1 and/or JAK2 and/or JAK3 and/or TYK 2), p38 MAPK and IKK2;13 B cell targeted biologic agents such as rituximab; 14 Selective co-stimulatory modulators such as abafpu; 15 Interleukin inhibitor selected from the group consisting of IL-1 inhibitors such as anakinra, IL-6 inhibitors such as tolizumab and IL-12/IL-23 inhibitors such as Utilizumab.
The amount of the compound in the pharmaceutical composition disclosed by the invention means that the inhibition of retinoic acid related lone-core receptor gamma t in a biological sample or a patient can be effectively detected. The dosage of the active ingredient in the compositions of the present invention may vary, however, the amount of active ingredient must be such that an appropriate dosage form is obtained. The active ingredient may be administered to patients (animals and humans) in need of such treatment in a dosage that provides optimal pharmaceutical efficacy. The selected dosage depends on the desired therapeutic effect, on the route of administration and 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 medication, and other factors that will be recognized by those skilled in the art. In one embodiment, the dosage ranges from about 0.5mg to 500mg per patient per day; in another embodiment about 0.5mg to 200mg per patient per day.
It will also be appreciated that certain compounds of the invention may exist in free form and for use in therapy, or if appropriate in the form of pharmaceutically acceptable derivatives thereof. Pharmaceutically acceptable derivatives include pharmaceutically acceptable prodrugs, salts, esters, salts of such esters, or any additional adducts or derivatives that provide, directly or indirectly, the compounds of the invention or metabolites or residues thereof when administered to a patient in need thereof.
The disclosed pharmaceutical or pharmaceutical compositions may be prepared and packaged in bulk form, wherein a safe and effective amount of a compound of formula (I) or formula (II) may be extracted and then administered to a patient in the form of a powder or syrup. Typically, the patient is administered at a dosage level of between 0.0001 and 10mg/kg body weight per day to obtain an effective inhibition of retinoic acid related lone core receptor γt. Alternatively, the pharmaceutical compositions disclosed herein may be prepared and packaged in unit dosage form, 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 presently disclosed pharmaceutical compositions may generally contain an effective amount of a presently disclosed compound.
When the pharmaceutical compositions of the present invention contain one or more other active ingredients in addition to the compound of the present invention, the compound weight ratio of the compound of the present invention to the second active ingredient may vary and will depend on the effective dose of each ingredient. Typically, an effective dose of each is used. Thus, for example, when a compound of the present invention is mixed with another agent, the weight ratio of the compound of the present invention to the other agent typically ranges from about 1000:1 to about 1:1000. Mixtures of the compounds according to the invention with other active ingredients are generally also within the abovementioned 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 associated with consistency of administration dosage form or pharmaceutical composition. Each excipient must be compatible with the other ingredients of the pharmaceutical composition when mixed to avoid interactions that would greatly reduce the efficacy of the disclosed compounds and interactions that 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 upon the particular dosage form selected. Furthermore, pharmaceutically acceptable excipients may be selected according to their particular function in the composition. For example, certain pharmaceutically acceptable excipients may be selected that can aid in the production of a uniform dosage form. Certain pharmaceutically acceptable excipients that can aid in the production of stable dosage forms can be selected. Certain pharmaceutically acceptable excipients that 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 may be selected. Certain pharmaceutically acceptable excipients that enhance patient compliance may be selected.
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, tackifiers, antioxidants, preservatives, stabilizers, surfactants, and buffers. The skilled artisan will recognize that certain pharmaceutically acceptable excipients may provide more than one function, and alternative functions, depending on how much of the excipient is present in the formulation and which other excipients are present in the formulation.
The skilled artisan will know and be familiar with the art to which they will be able to select the appropriate amount of suitable pharmaceutically acceptable excipients for use in the present invention. Furthermore, there are a number of resources available to the skilled person, who describe pharmaceutically acceptable excipients and are used to select the appropriate pharmaceutically acceptable excipient. 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,1988-1999,Marcel Dekker,New York, the contents of each of which are incorporated herein by reference. It is within the scope of the present invention to contemplate its use in addition to any common carrier that is incompatible with the disclosed compounds of the present invention, such as by producing any undesirable biological effect, or by interacting in a deleterious manner with any other component of the pharmaceutically acceptable composition.
The pharmaceutical compositions disclosed herein are prepared using techniques and methods known to those skilled in the art. Some methods commonly used in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing Company).
Thus, in another aspect, the present invention relates to a process for preparing a pharmaceutical composition comprising a compound of the present disclosure and a pharmaceutically acceptable excipient, carrier, adjuvant or combination thereof, which process comprises mixing the various ingredients. Pharmaceutical compositions comprising the compounds of the present disclosure 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 the 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 patch tablets; (4) rectal administration, such as suppositories; (5) inhalations, 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 presently disclosed compounds may be formulated into oral dosage forms. In another embodiment, the presently disclosed compounds may be formulated into an inhalation dosage form. In another embodiment, the presently disclosed compounds may be formulated for nasal administration. In yet another embodiment, the presently disclosed compounds may be formulated into transdermal dosage forms. In yet another embodiment, the presently disclosed compounds may be formulated into topical dosage forms.
The pharmaceutical compositions provided herein may be provided in compressed tablets, developed tablets, chewable lozenges, instant tablets, reconstituted tablets, or enteric tablets, sugar-coated or film-coated tablets. Enteric-coated tablets are compressed tablets coated with a substance that resists 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, aminated shellac, and cellulose acetate phthalate. Dragees are dragee-enclosed compressed tablets that can facilitate masking of unpleasant tastes or odors and prevent oxidation of the tablet. The film coated tablet is a compressed tablet 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. The film coating imparts the same general characteristics as the sugar coating. The composite tablet is a compressed tablet prepared through more than one compression cycle, and comprises a multi-layer tablet and a compression coated or dry coated tablet.
Tablet dosage forms may be prepared from the active ingredient in powder, crystalline or particulate 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 invention can be provided in a soft capsule or a hard capsule, and can be prepared from gelatin, methylcellulose, starch or calcium alginate. The hard gelatin capsule, also known as a Dry Filled Capsule (DFC), consists of two segments, one segment being filled 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 described herein, including methyl and propyl parabens, and sorbic acid. Liquid, semi-solid and solid dosage forms provided herein may be encapsulated in capsules. Suitable liquid and semi-solid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils or triglycerides. Capsules containing such solutions can be prepared 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 completely dispersed in the form of pellets in another liquid, which may be oil-in-water or water-in-oil. The emulsion may include pharmaceutically acceptable non-aqueous liquids and solvents, emulsifiers, and preservatives. Suspensions may include pharmaceutically acceptable suspending agents and preservatives. The aqueous alcohol solution may include a pharmaceutically acceptable acetal, such as a di (lower alkyl) acetal of a lower alkyl aldehyde, for example, acetaldehyde diethyl acetal; and water-soluble solvents having one or more hydroxyl groups, such as propylene glycol and ethanol. Elixirs are clear, sweet aqueous alcoholic solutions. Syrups are concentrated aqueous solutions of a sugar, for example sucrose, and may also contain a preservative. 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 accurate and convenient administration.
Other useful liquid and semi-solid dosage forms include, but are not limited to, those comprising the active ingredient 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, wherein 350, 550, 750 refer to the approximate average molecular weight of 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, bisulphite, sodium metabisulfite, thiodipropionic acid and esters thereof, and dithiocarbamates.
Dosage unit formulations for oral administration may be microencapsulated, as appropriate. It may also be formulated in an extended-release or sustained-release composition, for example, by coating or embedding the particulate material in a polymer, wax or the like.
The oral pharmaceutical compositions provided by the present invention may also be provided in the form of liposomes, micelles, microspheres or nanosystems. Micelle dosage forms may be prepared using the methods described in U.S. Pat. No.6,350,458.
The pharmaceutical compositions provided herein may be provided in 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 carbon dioxide sources.
Coloring and flavoring agents may be used in all of the above dosage forms.
The disclosed compounds may also be combined with soluble polymers as targeted drug carriers. Such polymers include polyvinylpyrrolidone, pyran copolymers, polyhydroxypropyl methacrylamide-phenol, polyhydroxyethyl asparaginol or palmitoyl residue substituted polyoxyethylene polylysine. In addition, the disclosed compounds may be combined with a class of biodegradable polymers used in achieving controlled release of drugs, such as polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and cross-linked or amphiphilic block copolymers of hydrogels.
The pharmaceutical compositions provided herein may be formulated in immediate or modified release dosage forms, including delayed-, sustained-, pulsed-, controlled-, targeted-, and programmed release forms.
The pharmaceutical compositions provided herein 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 herein may be administered parenterally, by injection, infusion or implantation, for topical or systemic administration. Parenteral administration as used in the present invention includes intravenous, intra-arterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial and subcutaneous administration.
The pharmaceutical compositions provided herein may be formulated in any dosage form suitable for parenteral administration, including solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems, and solid forms suitable for making solutions or suspensions in liquids prior to injection. Such dosage forms may be prepared according to conventional methods known to those skilled in The art of pharmaceutical sciences (see Remington: the Science and Practice of Pharmacy, supra).
Pharmaceutical compositions contemplated 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 or antimicrobial growth preservatives, stabilizers, dissolution enhancers, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, freezing point depressants, cryoprotectants, thickening agents, pH adjusting agents, and inert gases.
Suitable aqueous vehicles include, but are not limited to: water, saline, normal saline or Phosphate Buffered Saline (PBS), sodium chloride injection, ringers injection, isotonic dextrose 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, medium chain triglycerides of hydrogenated soybean oil and 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, mercuric agents, benzyl alcohol, chlorobutanol, methyl and propyl p-hydroxybenzoates, 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, phosphates and citrates. Suitable antioxidants are those as described herein, including bisulfites and sodium metabisulfites. Suitable local anesthetics include, but are not limited to procaine hydrochloride. Suitable suspending and dispersing agents are those as described herein, including sodium carboxymethyl cellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone. Suitable emulsifiers include those described herein, including polyoxyethylene sorbitan monolaurate. Polyoxyethylene tax refund sorbitol monooleate 80 and triethanolamine oleate. Suitable sequestering or chelating agents include, but are not limited to, EDTA. Suitable pH adjusting agents 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 CyDex,Lenexa,KS)。
The pharmaceutical compositions provided by the invention can be formulated for single or multiple dose administration. The single dose formulation is packaged in ampules, vials or syringes. The multi-dose parenteral formulation must contain antimicrobial agents at bacteriostatic or fungistatic concentrations. 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 composition is provided as a sterile dry soluble product, including lyophilized powder 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 reconstituted with a carrier prior to use. In yet another embodiment, the pharmaceutical composition is formulated as a sterile ready-to-use emulsion.
The pharmaceutical compositions may be formulated as suspensions, solids, semi-solids, or thixotropic liquids for administration as an implanted depot. In one embodiment, the disclosed pharmaceutical compositions are dispersed in a solid inner matrix surrounded by an outer polymeric membrane that is insoluble in body fluids but allows the active ingredient in the pharmaceutical composition to diffuse through.
Suitable internal matrices include polymethyl methacrylate, polymethyl butyl acrylate, 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 for coaches.
Suitable external 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, ionomer polyethylene terephthalate, butyl rubber chlorohydrin rubber, ethylene/vinyl alcohol copolymers, ethylene/vinyl acetate/vinyl alcohol terpolymers, and ethylene/ethyleneoxy ethanol copolymers.
In another aspect, the disclosed pharmaceutical compositions may be formulated in any dosage form suitable for inhaled administration to a patient, such as dry powder, aerosol, suspension or solution compositions. In one embodiment, the disclosed pharmaceutical compositions can be formulated into dosage forms suitable for administration by inhalation to a patient using dry powders. In yet another embodiment, the disclosed pharmaceutical compositions may be formulated in a dosage form suitable for administration by inhalation to a patient via a nebulizer. Dry powder compositions for delivery to the lungs by inhalation typically comprise a finely powdered compound as disclosed herein and one or more finely powdered pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients 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. The fine powder can be prepared by, for example, micronization and grinding. In general, the size-reduced (e.g., micronized) compound may be produced by a D of about 1 to 10 microns 50 Values (e.g., measured using laser diffraction methods) are defined.
Aerosols may be formulated by suspending or dissolving the presently 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-134 a), 1-difluoroethane (HFA-152 a), difluoromethane (HFA-32), pentafluoroethane (HFA-12), heptafluoropropane (HFA-227 a), perfluoropropane, perfluorobutane, perfluoropentane, butane, isobutane and pentane. Aerosols comprising the disclosed compounds are typically administered to patients by means of Metered Dose Inhalers (MDI). Such devices are known to those skilled in the art.
The aerosols 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, improve valve characteristics, improve solubility, or improve taste.
Pharmaceutical compositions suitable for transdermal administration may be formulated 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 by ion permeation, 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 water or oil bases, with appropriate thickening and/or gelling agents and/or solvents. Such a base 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. Thickening and gelling agents used according to the nature of the matrix include soft paraffin, aluminum stearate, cetostearyl alcohol, polyethylene glycol, lanolin, beeswax, carbopol and cellulose derivatives, and/or glyceryl monostearate and/or nonionic emulsifiers.
Lotions may be formulated with water or oil and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents or thickening agents.
The topical powders may be formed in the presence of any suitable powder base such as talc, lactose or starch. Drops may be formulated with an aqueous or nonaqueous 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; a occlusive dressing covering the skin is preferably used. The adhesive reservoir system may allow for continuous or prolonged administration.
Use of the compounds and compositions of the invention
The compounds or pharmaceutical compositions disclosed herein may be used in the preparation of a medicament for the treatment, prevention, amelioration, control or alleviation of roryt-mediated cancer, inflammation or autoimmune diseases in a mammal, including a human, and may also be used in the preparation of other medicaments for inhibiting roryt.
Specifically, the amount of the compound in the composition of the present invention can effectively and detectably inhibit rorγt, and the compound of the present invention can be used as a medicament for preventing or treating human cancers, 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.
The compounds or compositions of the invention may be applied to, but are in no way limited to, the use of an effective amount of a compound or composition of the invention to prevent, treat or ameliorate 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, to a patient.
The compounds and pharmaceutical compositions of the present invention are useful for veterinary treatment of mammals, in addition to human therapy, in pets, in animals of introduced species and in farm animals. Examples of other animals include horses, dogs, and cats. Herein, the compounds of the present invention include pharmaceutically acceptable derivatives thereof.
General synthetic procedure
For the purpose of illustrating the invention, examples are set forth below. It is to be understood that the invention is not limited to these examples but provides a method 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 for formula (I) or formula (II), unless otherwise indicated. The following reaction schemes and examples are provided to further illustrate the present invention.
Those skilled in the art will recognize that: the chemical reactions described herein may be used to suitably prepare many other compounds of the present invention, and other methods for preparing the compounds of the present invention are considered to be within the scope of the present invention. For example, the synthesis of those non-exemplified compounds according to the invention can be successfully accomplished by modification methods, such as appropriate protection of interfering groups, by use of other known reagents in addition to those described herein, or by some conventional modification of the reaction conditions, by those skilled in the art. In addition, the reactions disclosed herein or known reaction conditions are also well-known to be applicable to the preparation of other compounds of the present invention.
The examples described below are given unless otherwise indicated that all temperatures are given 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 Shandong Chemicals, guangdong Chemicals, guangzhou Chemicals, tianjin good Chemies, tianjin Fuchen Chemies, wuhan Xinhua Yuan technology development Co., ltd., qingdao Teng Chemies Co., and Qingdao sea chemical Co.
Anhydrous tetrahydrofuran, dioxane, toluene and diethyl ether are obtained by reflux drying of metallic sodium. The anhydrous methylene chloride and chloroform are obtained by reflux drying of calcium hydride. Ethyl acetate, petroleum ether, N-hexane, N-dimethylacetamide and N, N-dimethylformamide were dried over anhydrous sodium sulfate in advance for use.
The following reaction is typically carried out under nitrogen or argon pressure or with a dry tube (unless otherwise indicated) over anhydrous solvent, the reaction flask is capped with a suitable rubber stopper and the substrate is injected through a syringe. The glassware was all dried.
The chromatographic column is a silica gel column. Silica gel (300-400 mesh) was purchased from Qingdao ocean chemical plant.
Nuclear magnetic resonance spectra were recorded using Bruker 400MHz or 600MHz nuclear magnetic resonance spectrometer with CDC1 3 、DMSO-d 6 、CD 3 OD or acetone-d 6 TMS (0 ppm) or chloroform (7.26 ppm) was used as a reference standard for the solvent (in ppm). When multiple peaks occur, the following abbreviations will be used: s (the number of the single-ended,singlet), d (doublet ), t (triplet), m (multiplet), br (broad), dd (doublet of doublets, doublet), dt (doublet of triplets, doublet). Coupling constants are expressed in hertz (Hz).
The measurement conditions for low resolution Mass Spectrometry (MS) data are: agilent 6120 four-stage HPLC-MS (column type: zorbax SB-C18,2.1X30mm,3.5 μm,6min, flow rate 0.6mL/min. Mobile phase: 5% -95% (CH containing 0.1% formic acid) 3 CN) in (H containing 0.1% formic acid) 2 O), using electrospray ionization (ESI), at 210nm/254nm, using UV detection.
The purity of the compound was determined by High Performance Liquid Chromatography (HPLC), using Agilent 1260HPLC (column model: agilent zorbax Eclipse Plus C), and detected by a DAD detector, and finally calculated by area normalization.
The following abbreviations are used throughout the present invention:
typical synthetic procedures for preparing the disclosed compounds are shown in the synthetic schemes below. In the formulae, m, A, R, unless otherwise specified 3 、R 4 、R 5 、R 6 、Z 1 、Z 2 、Z 3 And Z 4 Having the meaning as described in the present invention; PG is an amino protecting group; x is X 1 And X 2 Each independently is a halogen atom; each Z is 5 And Z 6 And is independently CH or N.
Synthetic scheme
Compound (6 a) can be prepared by the following procedure:
the compound (1 a) and the compound (1 a ') or (1 a') are subjected to substitution reaction to generate a compound (2 a), the amino protecting group of the compound (2 a) is removed to obtain a compound (3 a), the compound (3 a) and the compound (3 a ') are subjected to coupling reaction to generate a compound (4 a), the compound (4 a) is subjected to hydrolysis reaction under alkaline conditions to obtain a compound (5 a), and the compound (5 a) and the compound (5 a') are subjected to condensation reaction to obtain a compound (6 a).
The compounds, pharmaceutical compositions and uses thereof provided by the present invention are further described below in conjunction 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
Step one: synthesis of (2S, 4S) -1-tert-butyl 2-methyl 2- (4- (trifluoromethyl) phenoxy) pyrrolidine-1, 2-dicarboxylic acid ester
(2S, 4R) -1-tert-butyl 2-methyl-4-hydroxypyrrolidine-1, 2-dicarboxylic acid ester (10.00 g,40.77 mmol), 4- (trifluoromethyl) phenol (6.60 g,40.71 mmol), PPh 3 (11.80 g,44.99 mmol) was added to THF (120 mL) and DIAD (11.0 mL,55.87 mmol) was slowly added at 0deg.C, and stirred at room temperature for 24h after addition. The reaction solution was concentrated under reduced pressure, the remaining solution was diluted with methyl tert-butyl ether (80 mL), and stirred at-20 ℃ to precipitate a large amount of white insoluble solid, which was 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 separated by silica gel column chromatography (eluent: PE/EtOAc (v/v) =4/1) to give the product as a white solid (13.56 g, 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) methyl)Radical) phenoxy) pyrrolidine-1, 2-dicarboxylic acid ester (18.00 g,46.22 mmol) was added to a solution of THF (200 mL) at 0℃displacement, liBH was slowly added 4 (2.00 g,91.80 mmol) and stirred at room temperature for 14h. Saturated NH is added into the reaction solution 4 The reaction was quenched with Cl (60 mL), allowed to stand and separate the upper organic phase, the aqueous phase extracted with EtOAc (30 mL. Times.2), the organic phases combined, anhydrous Na 2 SO 4 Dried, concentrated under reduced pressure, and the crude product was separated by column chromatography on silica gel (eluent: PE/EtOAc (v/v) =3/1) to give a white solid (14.23 g, 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
Will H 2 O(1mL)、KOAc(488mg,4.97mmol)、TMSCF 2 Br (0.40 mL,2.60 mmol) was added sequentially to a solution of tert-butyl (2S, 4S) -2- (hydroxymethyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidine-1-carboxylate (300 mg,0.83 mmol) in DCM (1 mL) and stirred at room temperature for 24h. The reaction mixture was diluted with DCM (30 mL), washed with saturated NaCl (15 mL) solution, and dried Na 2 SO 4 Dried, concentrated under reduced pressure, and the crude product was separated by column chromatography on silica gel (eluent: PE/EtOAc (v/v) =4/1) to give a colorless liquid (280 mg, 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 (2 mL, 20%) was added to a solution of (2S, 4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidine-1-carboxylic acid tert-butyl ester (280 mg,0.68 mmol) in DCM (6 mL) and stirred at room temperature for 24h. The reaction was concentrated under reduced pressure, the residue was diluted with DCM (30 mL) and taken up in sequence with saturated NaHCO 3 Solution (15 mL) and saturated NaCl solution (15 mL), anhydrous Na 2 SO 4 Concentrated under reduced pressure to give a brown liquid (211 mg, 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
(2S, 4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidine (200 mg,0.64 mmol), pd under the protection of nitrogen 2 (dba) 3 (58mg,0.06mmol)、XantPhos(55mg,0.10mmol)、Cs 2 CO 3 (418 mg,1.28 mmol) and methyl 4-iodobenzoate (252 mg,0.96 mmol) were added sequentially to 1, 4-dioxane (6 mL) and reacted at 100℃for 24h. The reaction was cooled to room temperature, concentrated under reduced pressure, and the residue was diluted with DCM (50 mL) and taken up in sequence with saturated NaHCO 3 Solution (15 mL) and saturated NaCl solution (15 mL), anhydrous Na 2 SO 4 Dried, concentrated under reduced pressure, and the crude product was separated by column chromatography on silica gel (eluent: PE/EtOAc (v/v) =5/1) to give a yellow liquid (220 mg, 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
LiOH.H 2 O (414 mg,9.87 mmol) H 2 A solution of O (2 mL) was added to a solution of methyl 4- ((2S, 4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) benzoate (220 mg,0.49 mmol) in MeOH (3 mL) and THF (3 mL) and stirred at room temperature for 16h. The reaction mixture was concentrated under reduced pressure, the pH of the residue was adjusted to about 4 by adding HCl (1 mol/L), extracted with EtOAc (20 mL. Times.2), the organic phases were combined, washed with saturated NaCl (15 mL) solution, and dried over Na 2 SO 4 Dried, concentrated under reduced pressure, and the crude product was separated by column chromatography on silica gel (eluent: DCM/MeOH (v/v) =20/1) to give a white solid (170 mg, 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) benzoylamino) methyl) piperidine-1-carboxylate
HATU (1.06 g,2.79 mmol), 1- (tert-butoxycarbonyl) -4- (aminomethyl) piperidine (540 mg,2.55 mmol), 4- ((2S, 4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) benzoic acid (1.00 g,2.32 mmol), TEA (0.65 mL,4.70 mmol) were added sequentially to DCM (12 mL) and stirred at room temperature for 16h. The reaction was concentrated under reduced pressure, and the crude product was separated by column chromatography on silica gel (eluent: DCM/EtOAc (v/v) =4/1) to give a pale yellow liquid (1.22 g, 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 (3.0 mL,4 mol/L) was added to a solution of 4- ((4- ((2S, 4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) benzoylamino) methyl) piperidine-1-carboxylic acid tert-butyl ester (1.20 g,1.91 mmol) in DCM (8 mL) and stirred at room temperature for 17h. The reaction solution was concentrated under reduced pressure, and the residue was diluted with DCM (50 mL) and successively taken up in saturated Na 2 CO 3 Solution (20 mL) and saturated NaCl solution (20 mL), anhydrous Na 2 SO 4 Dried, concentrated under reduced pressure to give a pale yellow liquid (850 mg, 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
TEA (172 mg,1.71 mmol), msCl (97 mg,0.85 mmol) 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 (300 mg,0.57 mmol) in DCM (6 mL) under nitrogen and stirred at room temperature for 22h. The reaction was concentrated under reduced pressure, the residue was diluted with DCM (40 mL) and successively diluted with HCl solution (15 mL,1 mol/L) and saturated NaHCO 3 Solution (15 mL), saturated NaCl solution (15 mL), anhydrous Na 2 SO 4 Dried, concentrated under reduced pressure, and the crude product was separated by column chromatography on silica gel (eluent: DCM/EtOAc (v/v) =1/1) to give a white solid (200 mg, 58%).
MS(ESI,pos.ion)m/z:606.2[M+H] + .
1 H NMR(400MHz,CDCl 3 )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
TEA (172 mg,1.71 mmol) and ethylsulfonyl chloride (109 mg,0.85 mmol) 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 (300 mg,0.57 mmol) in DCM (6 mL) under nitrogen and stirred at room temperature for 22h. The reaction was concentrated under reduced pressure, the residue was diluted with DCM (40 mL) and successively diluted with HCl solution (15 mL,1 mol/L) and saturated NaHCO 3 Solution (15 mL), saturated NaCl solution (15 mL), anhydrous Na 2 SO 4 Dried, concentrated under reduced pressure, and the crude product was separated by column chromatography on silica gel (eluent: DCM/EtOAc (v/v) =1/1) to give a white solid (200 mg, 57%).
MS(ESI,pos.ion)m/z:620.1[M+H] + .
1 H NMR(400MHz,CDCl 3 )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
TEA (140 mg,1.38 mmol) and cyclopropylsulfonyl chloride (71 mg,0.51 mmol) are added to a solution of 4- ((2S, 4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) -N- ((piperidin-4-yl) methyl) benzamide (180 mg,0.34 mmol) in DCM (4 mL) under nitrogen and stirred at room temperature for 18h. The reaction was concentrated under reduced pressure, the residue was diluted with DCM (40 mL) and successively diluted with HCl solution (15 mL,1 mol/L) and saturated NaHCO 3 Solution (15 mL), saturated NaCl solution (15 mL), anhydrous Na 2 SO 4 Dried, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (eluent: DCM/EtOAc (v/v) =3/1) to give a pale yellow solid (130 mg, 60%).
MS(ESI,pos.ion)m/z:632.1[M+H] + .
1 H NMR(400MHz,CDCl 3 )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
Step one: synthesis of methyl 2- (4- ((4- ((2S, 4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) benzoylamino) methyl) piperidin-1-yl) acetate
Under the protection of nitrogen, K is added 2 CO 3 (46 mg,0.33 mmol), methyl 2-chloroacetate (13 mg,0.12 mmol) 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 (60 mg,0.11 mmol) in DMF (2 mL) and stirred at room temperature for 4h. The reaction was diluted with EtOAc (40 mL) and washed successively with H 2 O solution (15 mL. Times.2), saturated NaCl solution (15 mL), anhydrous Na 2 SO 4 Dried, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (eluent: DCM/MeOH (v/v) =10/1) to give a white solid (40 mg, 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) benzoylamino) methyl) piperidin-1-yl) acetic acid
LiOH.H 2 O (30 mg,0.72 mmol) H 2 A solution of O (0.5 mL) 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 (40 mg,0.07 mmol) in MeOH (2 mL) and reacted at room temperature for 16h. The reaction mixture was added with HCl (1 mol/L) to adjust the pH of the solution to about 4, and concentrated under reduced pressure, and the crude product was separated by column chromatography on silica gel (eluent: DCM/MeOH (v/v) =4/1) to give a pale yellow solid (25 mg, 64%).
MS(ESI,pos.ion)m/z:586.4[M+H] + .
1 H NMR(400MHz,CD 3 OD)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
HATU (216 mg,0.57 mmol), glycolic acid (32 mg,0.42 mmol), 4- ((2 s,4 s) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) -N- ((piperidin-4-yl) methyl) benzamide (200 mg,0.38 mmol), TEA (115 mg,1.14 mmol) were added sequentially to DCM (4 mL) and stirred at room temperature for 16h. The reaction was concentrated under reduced pressure, the remainder was diluted with DCM (30 mL) and successively diluted with HCl solution (15 mL,1 mol/L), saturated NaHCO 3 Liquid (15 mL) saturated NaCl solution (15 mL) washing, anhydrous Na 2 SO 4 Dried, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (eluent: DCM/MeOH (v/v) =10/1) to give a white solid (140 mg, 63%). MS (ESI, pos.ion) m/z 586.2[ M+H ]] + .
1 H NMR(400MHz,CDCl 3 )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) benzoylamino) methyl) cyclohexyl carboxylic acid
HATU (343 mg,0.90 mmol), tranexamic acid (109 mg,0.69 mmol), 4- ((2S, 4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) benzoic acid (300 mg,0.70 mmol), TEA (140 mg,1.38 mmol) were added sequentially to DCM (8 mL) and stirred at room temperature for 18h. Concentrating the reaction solution under reduced pressure to obtain residueThe resultant was diluted with DCM (40 mL), washed successively with HCl solution (20 mL,1 mol/L), saturated NaCl solution (20 mL), and anhydrous Na 2 SO 4 Dried, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (eluent: DCM/EtOAc (v/v) =1/1) to give a pale yellow solid (60 mg, 15%).
MS(ESI,pos.ion)m/z:571.3[M+H] + .
1 H NMR(400MHz,DMSO-d 6 )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
Step one: synthesis of tert-butyl 3- ((4- ((2S, 4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) benzoylamino) methyl) pyrrolidine-1-carboxylate
HATU (530 mg,1.39 mmol), tert-butyl 3- (aminomethyl) pyrrolidine-1-carboxylate (255 mg,1.27 mmol), 4- ((2S, 4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) benzoic acid (500 g,1.16 mmol), TEA (234 mg,2.32 mmol) were added sequentially to DCM (8 mL) and stirred at room temperature for 16h. The reaction was concentrated under reduced pressure, the residue was diluted with DCM (40 mL) and successively diluted with HCl solution (20 mL,1 mol/L) and saturated NaHCO 3 Solution (20 mL), saturated NaCl solution (20 mL), anhydrous Na 2 SO 4 Dried, concentrated under reduced pressure, and the crude product was separated by column chromatography on silica gel (eluent: DCM/EtOAc (v/v) =3/1) to give a pale yellow liquid (600 g, 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 (3.0 mL,4 mol/L) was added to a solution of 3- ((4- ((2S, 4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) benzoylamino) methyl) pyrrolidine-1-carboxylic acid tert-butyl ester (600 mg,0.98 mmol) in DCM (8 mL) and stirred at room temperature for 16h. The reaction was concentrated under reduced pressure, the residue was diluted with EtOAc (40 mL) and taken up in sequence with saturated Na 2 CO 3 Solution (20 mL) and saturated NaCl solution (20 mL), anhydrous Na 2 SO 4 Dried, concentrated under reduced pressure to give a pale yellow liquid (450 mg, 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
TEA (236 mg,2.34 mmol), msCl (116 mg,1.01 mmol) 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 (400 mg,0.78 mmol) in DCM (6 mL) under nitrogen and stirred at room temperature for 24h. The reaction was concentrated under reduced pressure, and the residue was diluted with DCM (40 mL) and successively saturated with NaHCO 3 Solution (15 mL), saturated NaCl solution (15 mL), anhydrous Na 2 SO 4 Dried, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (eluent: DCM/MeOH (v/v) =10/1) to give a white solid (300 mg, 65%).
MS(ESI,pos.ion)m/z:592.4[M+H] + .
1 H NMR(400MHz,CDCl 3 )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
Step one: synthesis of benzyl 3- ((4- ((2S, 4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) benzoylamino) methyl) azetidine-1-carboxylate
HATU (1.06 g,2.79 mmol), benzyl 3- (aminomethyl) azetidine-1-carboxylate (562 mg,2.55 mmol), 4- ((2S, 4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) benzoic acid (1.00 g,2.32 mmol), TEA (0.50 mL,3.60 mmol) were added sequentially to DCM (12 mL) and stirred at room temperature for 16h. The reaction was concentrated under reduced pressure, the residue was diluted with DCM (40 mL) and successively diluted with HCl solution (20 mL,1 mol/L) and saturated NaHCO 3 Solution (20 mL), saturated NaCl solution (20 mL), anhydrous Na 2 SO 4 Dried, concentrated under reduced pressure, and the crude product was separated by column chromatography on silica gel (eluent: DCM/EtOAc (v/v) =4/1) to give a pale yellow liquid (900 mg, 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 (100 mg, 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 (900 mg,1.42 mmol) in MeOH (10 mL) in place of hydrogen and stirred at room temperature for 12h. The reaction was filtered through celite, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (eluent: DCM/MeOH (v/v) =1/1) to give pale yellow liquid (400 mg, 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 (0.35 mL,2.50 mmol), msCl (119 mg,1.04 mmol) was added to a solution of N- ((azetidin-3-yl) methyl) -4- ((2S, 4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) benzamide (400 mg,0.80 mmol) in DCM (8 mL) under nitrogen and stirred at room temperature for 16h. The reaction was concentrated under reduced pressure, and the residue was diluted with DCM (40 mL) and successively saturated with NaHCO 3 Solution (20 mL), saturated NaCl solution (20 mL), anhydrous Na 2 SO 4 Dried, concentrated under reduced pressure, and the crude product was separated by column chromatography on silica gel (eluent: DCM/EtOAc (v/v) =1/1) to give a white solid (300 mg, 65%).
MS(ESI,pos.ion)m/z:578.1[M+H] + .
1 H NMR(400MHz,CDCl 3 )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
TEA (182 mg,1.80 mmol) and ethylsulfonyl chloride (115 mg,0.89 mmol) are added to a solution of N- ((azetidin-3-yl) methyl) -4- ((2S, 4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) benzamide (300 mg,0.60 mmol) in DCM (6 mL) under nitrogen and stirred at room temperature for 16h. The reaction was concentrated under reduced pressure, and the residue was diluted with DCM (40 mL) and successively saturated with NaHCO 3 Solution(20 mL), saturated NaCl solution (20 mL), anhydrous Na 2 SO 4 Dried, concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (eluent: DCM/MeOH (v/v) =20/1) to give a pale yellow solid (30 mg, 8%).
MS(ESI,pos.ion)m/z:592.2[M+H] + .
1 H NMR(400MHz,CDCl 3 )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
Step one: synthesis of phenyl (4-bromophenyl) carbamate
Phenyl chloroformate (1.60 mL,1.50 mmol) was slowly added dropwise to a solution of 4-bromoaniline (2.00 g,11.63 mmol) in EtOAc (25 mL) at 0deg.C and reacted at room temperature for 2h. The reaction was diluted with EtOAc (50 mL) and concentrated with H 2 O (20 mL. Times.3) and saturated NaCl solution (20 mL), anhydrous Na 2 SO 4 Drying and concentration under reduced pressure gave a pink solid (3.33 g, 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 (2.0 mL,14.39 mmol), phenyl (4-bromophenyl) carbamate (3.00 g,10.27 mmol), tert-butyl piperazine-1-carboxylate (2.10 g,11.28 mmol) was added to ACN (30 mL) and stirred at 85℃for 6h. The reaction was concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (eluent: PE/EtOAc (v/v) =3/2) to give a pale yellow solid (3.85 g, 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
(2S, 4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidine (500 mg,1.61 mmol), pd under the protection of nitrogen 2 (dba) 3 (147mg,0.16mmol)、Ruphos(112mg,0.24mmol)、Cs 2 CO 3 (803 mg,1.61 mmol) and tert-butyl 4- ((4-bromophenyl) carbamoyl) piperazine-1-carboxylate (740 mg,1.93 mmol) were added sequentially to 1, 4-dioxane (10 mL) and reacted at 100℃for 16h. The reaction was cooled to room temperature, filtered through celite, and the filtrate was concentrated under reduced pressure, and the crude product was separated by column chromatography on silica gel (eluent: DCM/EtOAc (v/v) =4/1) to give a yellow solid (720 mg, 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 (3 mL,4 mol/L) was added to a solution of 4- ((4- ((2S, 4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) phenyl) carbamoyl) piperazine-1-carboxylic acid tert-butyl ester (800 mg,1.30 mmol) in DCM (5 mL) and stirred at room temperature for 16h. The reaction was concentrated under reduced pressure, the remainder was dissolved in DCM (30 mL) and a little TEA, and the crude product was isolated by column chromatography over silica gel (eluent: DCM/MeOH (v/v) =4/1) to give a pale yellow solid (340 mg, 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
TEA (0.30 mL,2.16 mmol), ethylsulfonyl chloride (0.25 mL,2.64 mmol) was added to N- (4- ((2S, 4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) phenyl) piperazine-1-carboxamide under nitrogen(340 mg,0.66 mmol) in DCM (6 mL) and stirred at room temperature for 16h. The reaction was concentrated under reduced pressure, the residue was dissolved in DCM (40 mL) and taken up in sequence with saturated NaHCO 3 Solution (15 mL) and saturated NaCl solution (15 mL), anhydrous Na 2 SO 4 Dried, concentrated under reduced pressure, and the crude product was separated by column chromatography on silica gel (eluent: DCM/EtOAc (v/v) =4/1) to give a pale green solid (300 mg, 75%).
MS(ESI,pos.ion)m/z:607.3[M+H] + .
1 H NMR(400MHz,CDCl 3 )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 test
Biological example 1 Fluorescence Resonance Energy Transfer (FRET) assay
1) Test method
(1) Preparation of RORγt assay buffer and 10mM DTT
100mL of 1 Xbasic assay buffer HEPES (pH 7.4), 100mM NaCl,0.01%BSA) was prepared, and 154.25mg of DTT was added and thoroughly mixed.
(2) Preparing gradient concentration of compound
a. Standard compounds were formulated and diluted to 2.5mM with 100% dmso, then 3-fold dilution, 11 gradients to a final concentration of 42.34nM;
b. Experimental compounds were formulated and reference standard compounds were used.
(3) Preparation of 1x protein solution mixture
a. The required amount of 2x B-RORγt LBD/SA-APC protein mixture is prepared. The concentration of B-RORgamma LBD was 40nM and the concentration of SA-APC was 20nM, and the mixture was gently mixed upside down and incubated at room temperature for 15 minutes. Then 400nM biotin was added and mixed gently upside down and incubated for 10 minutes at room temperature;
b. the desired amount of 2x Biotin-SRC1/SA-eu protein mixture was formulated. The concentration of Bioin-SRC1 was 40nM and the concentration of SA-eu was 20nM, mixed gently upside down and incubated for 15 min at room temperature. Then 200nM biotin was added and mixed gently upside down and incubated for 10 minutes at room temperature;
c.1, 1 uniformly mixing the protein mixture prepared in the step a and the step b, and incubating for 5 minutes at room temperature;
d. adding 25 μl of the mixture in step c to a 384 well plate containing the test compound;
e.1000rpm for one minute;
f. incubate for 1 hour at room temperature.
(4) Data acquisition and calculation
After incubation at room temperature for 1 hour, fluorescence values at 665nm and 615nm were measured with EnVision plate reader, respectively, and inhibition ratios were calculated, and the IC finally obtained 50 The values are shown in Table 1;
inhibition ratio (%) = [ (X-Min)/(Max-Min) ]. Times.100%
X is the fluorescence value ratio of "665nm/615nm" of the test compound; min is the average value of the ratio of fluorescence values of 665nm/615nm of DMSO blank; max is the average value of the ratio of fluorescence values of "665nm/615nm" of 10. Mu.M SRC.
2) Test results
TABLE 1 evaluation of the inhibition Activity of the Compounds of the invention on ROR gamma t
Examples numbering IC 50 (nM)
Example 1 29
Example 3 82
Conclusion: experimental results show that the compound has better inhibition activity on RORγt.
Biological example 2 pharmacokinetic evaluation
ICR mice were weighed after 15h overnight fast and randomized according to body weight, and test compound formulation vehicle was 5% dmso+5% solutol+90% saline. For the intravenous administration test group, a dose of 1mg/kg was administered to the test animals; for the test group for oral administration, a dose of 5mg/kg was administered to the test animals. Venous blood (about 0.2 mL) was then taken at time points 0, 0.083 (intravenous only), 0.25, 0.5, 1.0, 2.0, 5.0, 7.0 and 24h and placed in EDTAK 2 In an anticoagulation tube, plasma was collected by centrifugation at 11000rpm for 2min and stored at-20℃or-70℃until LC/MS/MS analysis was performed. The drug concentration in the plasma at each time point was determined 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 assays. Experimental results show that the compound has good pharmacokinetic characteristics in ICR mice.
Finally, it should be noted that there are other ways to implement the invention. Accordingly, the embodiments of the present invention are to be construed as illustrative, not restrictive of the invention, but may be modified and equivalents added to the scope of the invention as defined by the appended claims. All publications or patents cited herein are incorporated by reference.

Claims (9)

1. A compound which is a compound represented by the formula (I) or a stereoisomer, a geometric isomer, a tautomer or a pharmaceutically acceptable salt of the compound represented by the formula (I),
wherein:
each Z is 1 、Z 2 、Z 3 And Z 4 Independent and independentGround is CR 1 Or N;
L 1 is-O-;
L 2 is-C (=O) -NH- (CR) 5 R 6 ) -or-NH-C (=o) -;
ring A is phenyl, pyridyl, pyrimidinyl, pyrazinyl or pyridazinyl;
ring B isRing D is a heterocyclic group consisting of 4-7 atoms or C 3-6 Cycloalkyl;
each R is 1 Independently H, deuterium or C 1-4 An alkyl group;
each R is 2 And R is 3 Is independently deuterium, F, cl, br, I, -OH, -CN, -NH 2 、-NO 2 -COOH, oxo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, -C 1-4 alkylene-O-C 1-4 Alkyl or C 3-6 Cycloalkyl; wherein the C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, -C 1-4 alkylene-O-C 1-4 Alkyl and C 3-6 Cycloalkyl is independently optionally substituted with 1, 2 or 3R c Substituted;
each R is c Independently deuterium, F, cl, br or I;
each R is 4 Independently is-S (=o) 2 -C 1-4 Alkyl, -S (=o) 2 -C 1-4 Haloalkyl, -S (=o) 2 -C 3-6 Cycloalkyl, -COOH, -C (=o) -O-C 1-4 Alkyl, carboxyl substituted C 1-4 Alkyl or-C (=o) -C 1-4 A hydroxyalkyl group;
R 5 and R is 6 Each independently is H;
n is 0, 1, 2 or 3;
m is 0, 1, 2 or 3;
p is 1, 2 or 3.
2. The compound of claim 1, wherein the D ring is piperidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperazinyl, azetidinyl, oxetanyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
3. The compound of claim 1, wherein each R 1 Independently H, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl;
each R is 2 And R is 3 Is independently deuterium, F, cl, br, I, -OH, -CN, -NH 2 、-NO 2 -COOH, oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, -CH 2 F、-CHF 2 、-CF 3 、-CH 2 CH 2 F、-CH 2 CHF 2 、-CHFCH 2 F、-CH 2 CF 3 、-CH(CF 3 ) 2 、-CF 2 CH 2 CH 3 、-CH 2 CH 2 CH 2 F、-CH 2 CH 2 CHF 2 、-CH 2 CH 2 CF 3 、-OCH 2 F、-OCHF 2 、-OCF 3 、-OCH 2 CH 2 F、-OCH 2 CHF 2 、-OCHFCH 2 F、-OCH 2 CF 3 、-OCH(CF 3 ) 2 、-OCF 2 CH 2 CH 3 、-OCH 2 CH 2 CH 2 F、-OCH 2 CH 2 CHF 2 、-OCH 2 CH 2 CF 3 、-CH 2 OCH 3 、-CH 2 OCH 2 CH 3 、-CH 2 OCH 2 CH 2 CH 3 、-CH 2 OCH(CH 3 ) 2 、-CH 2 CH 2 OCH 3 、-CH 2 CH 2 OCH 2 CH 3 、-CH 2 CH 2 OCH 2 CH 2 CH 3 、-CH 2 CH 2 OCH(CH 3 ) 2 、-CH 2 CH 2 CH 2 OCH 3 、-CH 2 CH 2 CH 2 OCH 2 CH 3 、-CH 2 CH 2 CH 2 OCH 2 CH 2 CH 3 、-CH 2 CH 2 CH 2 OCH(CH 3 ) 2 Cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, -CH 2 F、-CHF 2 、-CH 2 CH 2 F、-CH 2 CHF 2 、-CHFCH 2 F、-CH 2 CF 3 、-CH(CF 3 ) 2 、-CF 2 CH 2 CH 3 、-CH 2 CH 2 CH 2 F、-CH 2 CH 2 CHF 2 、-CH 2 CH 2 CF 3 、-OCH 2 F、-OCHF 2 、-OCH 2 CH 2 F、-OCH 2 CHF 2 、-OCHFCH 2 F、-OCH 2 CF 3 、-OCH(CF 3 ) 2 、-OCF 2 CH 2 CH 3 、-OCH 2 CH 2 CH 2 F、-OCH 2 CH 2 CHF 2 、-OCH 2 CH 2 CF 3 、-CH 2 OCH 3 、-CH 2 OCH 2 CH 3 、-CH 2 OCH 2 CH 2 CH 3 、-CH 2 OCH(CH 3 ) 2 、-CH 2 CH 2 OCH 3 、-CH 2 CH 2 OCH 2 CH 3 、-CH 2 CH 2 OCH 2 CH 2 CH 3 、-CH 2 CH 2 OCH(CH 3 ) 2 、-CH 2 CH 2 CH 2 OCH 3 、-CH 2 CH 2 CH 2 OCH 2 CH 3 、-CH 2 CH 2 CH 2 OCH 2 CH 2 CH 3 、-CH 2 CH 2 CH 2 OCH(CH 3 ) 2 Cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl independentlyOptionally substituted with 1, 2 or 3R c Substituted;
each R is c Independently deuterium, F, cl, br or I.
4. The compound of claim 1, wherein each R 4 Independently is-S (=o) 2 -CH 3 、-S(＝O) 2 -CH 2 CH 3 、-S(＝O) 2 -CH 2 CH 2 CH 3 、-S(＝O) 2 -CH(CH 3 )CH 3 、-S(＝O) 2 -cyclopropyl, -S (=o) 2 -cyclobutyl, -S (=o) 2 -cyclopentyl, -S (=o) 2 -cyclohexyl, -COOH, -C (=o) -O-CH 3 、-C(＝O)-O-CH 2 CH 3 、-C(＝O)-O-CH 2 CH 2 CH 3 、-C(＝O)-O-CH(CH 3 )CH 3 、-CH 2 COOH、-CH 2 CH 2 COOH、-CH 2 CH 2 CH 2 COOH、-C(＝O)-CH 2 OH、-C(＝O)-CH 2 CH 2 OH or-C (=O) -CH 2 CH 2 CH 2 OH。
5. The compound according to claim 1, which is a compound represented by the formula (II) or a stereoisomer, a geometric isomer, a tautomer or a pharmaceutically acceptable salt of the compound represented by the formula (II),
6. the compound of claim 1, having a structure of one of the following or a stereoisomer, geometric isomer, tautomer, or pharmaceutically acceptable salt thereof:
7. a pharmaceutical composition comprising a compound of any one of claims 1-6, and a pharmaceutically acceptable excipient, carrier, adjuvant, or combination thereof.
8. The pharmaceutical composition of claim 7, wherein the pharmaceutical composition comprises other agents that prevent or treat inflammatory syndromes, disorders or diseases or any combination thereof.
9. Use of a compound according to any one of claims 1-6 or a pharmaceutical composition according to any one of claims 7-8 for the manufacture of a medicament for the prevention or treatment of a roryt mediated disease, disorder or syndrome in a mammal.
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013029338A1 (en) * 2011-09-01 2013-03-07 Glaxo Group Limited Novel compounds
CN103153949A (en) * 2010-10-05 2013-06-12 先正达参股股份有限公司 Insecticidal pyrrolidin-yl-aryl-carboxamides
WO2018116285A1 (en) * 2016-12-23 2018-06-28 Glenmark Pharmaceuticals S.A. Substituted morpholine derivatives as ror gamma modulators
CN110506037A (en) * 2017-03-31 2019-11-26 爱瑞制药公司 Aryl cyclopropyl-amino-isoquinolin amide compound

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3581561A4 (en) * 2017-02-09 2020-12-09 Fudan University Biaryl compound, preparation method and use therefor

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103153949A (en) * 2010-10-05 2013-06-12 先正达参股股份有限公司 Insecticidal pyrrolidin-yl-aryl-carboxamides
WO2013029338A1 (en) * 2011-09-01 2013-03-07 Glaxo Group Limited Novel compounds
WO2018116285A1 (en) * 2016-12-23 2018-06-28 Glenmark Pharmaceuticals S.A. Substituted morpholine derivatives as ror gamma modulators
CN110506037A (en) * 2017-03-31 2019-11-26 爱瑞制药公司 Aryl cyclopropyl-amino-isoquinolin amide compound

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CAS rn 1809064-46-7 et al.;STN on the web;STN International;3-18 *
Yonghui Wang,et al..From RORγt Agonist to Two Types of RORγt Inverse Agonists.ACS Med. Chem.Lett..2018,120-124. *

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