CN113072546A - Five-membered heteroaromatic derivative and preparation method and application thereof - Google Patents

Five-membered heteroaromatic derivative and preparation method and application thereof Download PDF

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CN113072546A
CN113072546A CN202011623107.3A CN202011623107A CN113072546A CN 113072546 A CN113072546 A CN 113072546A CN 202011623107 A CN202011623107 A CN 202011623107A CN 113072546 A CN113072546 A CN 113072546A
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alkylene
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deuterium
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潘伟
刘兵
张英俊
何为
李旭珂
王峰
黄九忠
赵斌
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Sunshine Lake Pharma Co Ltd
Guangdong HEC Pharmaceutical
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Abstract

The invention belongs to the technical field of medicines, and particularly relates to five-membered heteroaromatic compounds, and compositions, preparation methods and applications thereof. The compound or the composition can be used as an inhibitor of retinoic acid-related orphan receptor gamma t (ROR gamma t). The invention also relates to methods of preparing such compounds and compositions, and their use in treating or preventing ROR γ t mediated cancer, inflammation or autoimmune disease in a mammal, particularly a human.

Description

Five-membered heteroaromatic derivative and preparation method and application thereof
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 an application thereof, wherein the compound or the composition can be used as an inhibitor of retinoic acid-related orphan receptor gamma t (ROR gamma t) and is used for preventing or treating diseases related to cancer, inflammation or immunity.
Background
Retinoic acid-related nocosomal receptors are a subfamily of transcription factors in the steroid hormone nuclear receptor superfamily. The family of retinoic acid-related orphan nuclear receptors includes ROR α, ROR β, and ROR γ, each encoded by a distinct gene (RORA, RORB, and RORC). Retinoic acid-related orphan nuclear receptors contain four major domains: an N-terminal A/B domain, a DNA binding domain, a hinge domain, and a ligand binding domain.
Retinoic acid-related orphan receptor gamma t (ROR γ t) is one of two isoforms of retinoic acid-related orphan receptor gamma (ROR γ), and may also be referred to as ROR γ 2. It has been shown that ROR γ t is expressed only in lymphoid lineage and embryonic lymphoid tissue inducer cells (Sun et al, Science 288:2369-2372, 2000; Eberl et al, Nat Immunol.5:64-73,2004). ROR gamma T, a characteristic transcription factor of helper T cells (Th17), plays an important role in Th17 cell differentiation, and is a key regulator of Th17 cell differentiation (Ivanov, II, McKenzie BS, Zhou L, Tadokoro CE, Lepelley A, Lafaille JJ, et al. cell 2006; 126(6): 1121-33).
Th17 can secrete interleukin 17 (IL-17) and other proinflammatory cytokines, and has important significance in autoimmune diseases and body defense response. IL-17 is a proinflammatory cytokine for inflammatory progression and various autoimmune diseases, and is closely associated with a variety of autoimmune and inflammatory diseases, such as rheumatoid arthritis, psoriasis, psoriatic arthritis, spondyloarthritis, asthma, inflammatory bowel disease, systemic lupus erythematosus, and multiple sclerosis, among others (Jetten et al, Nucl. Recept. Signal,2009,7: e 003; Manel et al, Nat. Immunol.,2008,9, 641-649). Also in relation to the development of inflammation-associated tumors, Th17 cells are activated during the disease process and are responsible for recruiting other inflammatory cell types, such as neutrophils, to mediate the pathology of the target tissue (Korn et al, annu, rev, immunol, 2009,27: 485-.
The role ROR γ t plays in the pathogenesis of autoimmune diseases or inflammation has been extensively studied and fully elucidated (Jetten et al, adv. Dev. biol., 2006,16: 313-supplement 355; Meier et al Immunity,2007,26: 643-654; Aloisi et al, Nat. Rev. Immunol.,2006,6: 205-supplement 217; Jager et al., J. Immunol.,2009,183: 7169-supplement 7177; Barnes et al, Nat. Rev. Immunol.,2008,8: 183-supplement 192). Therefore, inhibition of ROR γ t will effectively inhibit cell differentiation of Th17, regulate the production and secretion levels of IL-17 and other proinflammatory cytokines, thereby modulating the body's immune system, treating cancer, immune and inflammatory diseases associated with ROR γ t regulation.
Summary of The Invention
The following is a summary of some aspects of the invention only and is not intended to be limiting. These aspects and others are described more fully below. All references in this specification are incorporated herein by reference in their entirety. When the disclosure of the present specification differs from the cited documents, the disclosure of the present specification controls.
The invention provides a compound with retinoic acid-related orphan receptor gamma t (ROR gamma t) inhibitory activity, which is used for preparing a medicament for preventing or treating ROR gamma t-mediated cancer, inflammation or autoimmune diseases, such as cancer, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease, colitis, ulcerative colitis, rheumatoid arthritis, autoimmune eye disease, ankylosing spondylitis, asthma, chronic obstructive pulmonary disease, osteoarthritis, allergic rhinitis, allergic dermatitis, Crohn's disease or Kawasaki disease and the like; the compound can well inhibit ROR gamma t and simultaneously has excellent physicochemical property and biological pharmacological property.
The invention also provides processes for the preparation of these compounds, pharmaceutical compositions containing these compounds and methods of using these compounds or compositions in the treatment of the above-mentioned diseases in mammals, especially humans.
Specifically, the method comprises the following steps:
in one aspect, the invention relates to a compound of formula (I) or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, ester, pharmaceutically acceptable salt of a compound of formula (I) or a prodrug thereof,
Figure BDA0002878710730000021
wherein:
L1is a bond, -O-, -S-, -NH-, -C (═ O) -or- (CR)aRb)n-；
L2Is a word about-S (O)2-NH-、*-NH-S(O)2- (O) -NH-, - (NH-s) (O) -, - (C (═ O) NH-, or ═ NHC (═ O) -;
L3is × -N (R)g)-C(＝O)-、**-C(＝O)-N(Rg)-、**-O-C(＝O)-、**-C(＝O)-O-、**-C(＝O)-、**-S(＝O)2-、**-S(＝O)-、**-S(＝O)2N(Rg) -or-S (═ O) (═ NH) -;
Raand RbEach independently is H, deuterium, F, Cl, Br, I, C1-6Alkyl or C1-6A haloalkyl group;
a is-C0-6alkylene-C6-10Aryl radical, -C0-6Alkylene oxideRadical- (5-10 atom-constituting heteroaryl), -C0-6alkylene-C3-8Cycloalkyl, -C0-6Alkylene- (heterocyclic group consisting of 5 to 10 atoms), -C0-6Alkylene- (7-12 atom spiro carbocyclyl), -C0-6Alkylene- (7-12 atom spiroheterocyclyl) or C1-6An alkyl group; wherein A is substituted by 1, 2, 3, 4, 5 or 6R 1Substitution;
ring B is a heterocyclic group consisting of 5 to 10 atoms; wherein said B ring is optionally substituted with 1, 2, 3, 4, 5 or 6R2Substitution;
the C ring is heteroaryl consisting of 5 atoms; wherein said C ring is optionally substituted with 1, 2 or 3R3Substitution;
d ring is C6-10Aryl, heteroaryl of 5 to 10 atoms, C3-8Cycloalkyl or heterocyclyl consisting of 5 to 10 atoms; wherein said D ring is optionally substituted with 1, 2, 3, 4, 5 or 6R4Substitution;
R1and R2Each independently is deuterium, F, Cl, Br, I, -CN, -NH2、-NO2-OH, -COOH, oxo, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, -C1-6alkylene-O-C1-6Alkyl radical, C3-8Cycloalkyl radical, C6-10Aryl, heterocyclyl of 5 to 10 atoms, heteroaryl of 5 to 10 atoms or-C (═ O) -N (R)dRe) (ii) a Wherein, said C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, -C1-6alkylene-O-C1-6Alkyl radical, C3-8Cycloalkyl radical, C6-10Aryl, heterocyclyl of 5-10 atoms and heteroaryl of 5-10 atoms are independently optionally substituted with 1, 2, 3, 4, 5 or 6RcSubstituted;
each RcIndependently deuterium, F, Cl, Br, I, -OH, -CN, -NH2、C1-6Alkyl radical, C 1-6Alkoxy radical、C1-6Haloalkyl, C1-6Haloalkoxy, C3-8Cycloalkyl, heterocyclic radical consisting of 5-10 atoms, C6-10Aryl or heteroaryl of 5 to 10 atoms;
R3and R4Each independently is deuterium, F, Cl, Br, I, -CN, -NH2、-NO2、-OH、-COOH、C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Haloalkoxy, C1-6Haloalkyl or C1-6An alkoxy group;
R5and R6Each independently of the others being H, deuterium, -OH, -CN, -NH2、-NO2、-COOH、C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Haloalkyl, -C1-6alkylene-O-C1-6Alkyl, -C1-6alkylene-C (═ O) -O-C1-6Alkyl, -C1-6alkylene-C (═ O) -N (R)dRe)、-C1-6alkylene-O-C (═ O) -N (R)dRe)、-C1-6alkylene-N (R)f)-C(＝O)-N(RdRe) or-C1-6alkylene-N (R)dRe) (ii) a Wherein, said C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Haloalkyl, -C1-6alkylene-C (═ O) -O-C1-6Alkyl and-C1-6alkylene-O-C1-6Alkyl is independently optionally substituted by 1, 2 or 3 substituents selected from deuterium, F, Cl, Br, I, -OH, -CN, -COOH, -N (R)dRe)、C1-6Alkyl radical, C1-6Haloalkyl, C1-6Alkoxy or C1-6Substituted with a substituent of haloalkoxy;
or R5、R6Together with the carbon atom to which they are attached form C3-8Cycloalkyl or heterocyclyl consisting of 3 to 8 atoms; wherein, said C3-8Cycloalkyl and heterocyclyl consisting of 3 to 8 atoms are independently optionally substituted by 1, 2, 3 or 4 substituents selected from deuterium, F, Cl, Br, I, -OH, -CN, -COOH, C 1-6Alkyl radical, C1-6Haloalkyl, C1-6Alkoxy or C1-6Substituted by substituents of haloalkoxy；
RdAnd ReEach independently of the others being H, deuterium, -OH, C1-6Alkyl, -C (═ O) H, -C (═ O) -O-C1-6Alkyl, -C (═ O) -C1-6Alkyl, -C1-6alkylene-C (═ O) -O-C1-6Alkyl or-C1-6alkylene-O-C1-6An alkyl group; wherein, said C1-6Alkyl, -C1-6alkylene-C (═ O) -O-C1-6Alkyl and-C1-6alkylene-O-C1-6Alkyl is independently optionally substituted by 1, 2 or 3 substituents selected from deuterium, F, Cl, Br, I, -OH, -CN, -NH2or-COOH;
each RfIndependently of one another H, deuterium, C1-6Alkyl, -C1-6alkylene-O-C1-6Alkyl, -C1-6alkylene-C3-8Cycloalkyl or-C1-6Alkylene- (5-10 atom-constituting heterocyclic group); wherein, said C1-6Alkyl, -C1-6alkylene-O-C1-6Alkyl, -C1-6alkylene-C3-8Cycloalkyl and-C1-6Alkylene- (heterocyclyl consisting of 5 to 10 atoms) is independently optionally substituted by 1, 2 or 3 substituents selected from deuterium, F, Cl, Br, I, -OH, -CN, -NH2or-COOH;
R7is H, deuterium, -COOH, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkylamino radical, C1-6Haloalkyl, C3-8Cycloalkyl radical, C3-8Cycloalkylamino or heterocyclyl consisting of 5 to 10 atoms;
Rgis H, deuterium or C1-6An alkyl group;
m is 0, 1, 2, 3 or 4;
n is 1, 2, 3 or 4.
In some embodiments, RaAnd RbEach independently of the others is H, deuterium, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2, 2-difluoroethyl, 1, 2-difluoroethyl, 2,2, 2-trifluoroethyl, monochloromethyl, dichloromethyl, 2-chloroethyl, 2, 2-dichloroethyl or 1, 2-dichloroethyl.
In some embodiments, A is-C0-4alkylene-C6-10Aryl radical, -C0-4Alkylene- (5-6-atom heteroaryl), -C0-4alkylene-C3-6Cycloalkyl, -C0-4Alkylene- (heterocyclic group consisting of 5 to 7 atoms), -C0-4Alkylene- (7-12 atom spiro carbocyclyl), -C0-4Alkylene- (7-12 atom spiroheterocyclyl) or C1-4An alkyl group; wherein A is substituted by 1,2, 3, 4, 5 or 6R1And (4) substitution.
In some embodiments, a is phenyl, naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolyl, pyrazolyl, imidazolyl, furyl, oxazolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuryl, tetrahydropyranyl, pyrrolidinyl, piperazinyl, pyrazolyl, imidazolyl, furyl, thienyl, pyridyl, pyrimidyl, pyridyl, pyrimidyl,
Figure BDA0002878710730000031
Figure BDA0002878710730000032
methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; wherein A is substituted by 1,2, 3, 4, 5 or 6R 1And (4) substitution.
In some embodiments, ring B is heterocyclyl consisting of 5-7 atoms; wherein said B ring is optionally substituted with 1, 2, 3, 4, 5 or 6R2And (4) substituting.
In some embodiments, ring B is
Figure BDA0002878710730000033
Figure BDA0002878710730000034
Figure BDA0002878710730000035
Wherein said B ring is optionally substituted with 1, 2, 3, 4, 5 or 6R2And (4) substituting.
In some embodiments, the C ring is
Figure BDA0002878710730000041
Figure BDA0002878710730000042
Wherein said C is optionally substituted with 1, 2 or 3R3And (4) substitution.
In some embodiments, the D ring is C6-10Aryl, heteroaryl of 5 to 6 atoms, C3-6Cycloalkyl or heterocyclyl consisting of 5 to 7 atoms; wherein said D ring is optionally substituted with 1, 2, 3, 4, 5 or 6R4And (4) substitution.
In some embodiments, ring D is phenyl, naphthyl, indolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolyl, pyrazolyl, imidazolyl, furyl, oxazolyl, cyclopentyl, cyclohexyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuryl, tetrahydropyranyl, pyrrolidinyl, or piperazinyl; wherein D is optionally substituted with 1, 2, 3, 4, 5 or 6R4And (4) substitution.
In some embodiments, R1And R2Each independently is deuterium, F, Cl, Br, I, -CN, -NH2、-NO2-OH, -COOH, oxo, C1-4Alkyl radical, C 2-4Alkenyl radical, C2-4Alkynyl, C1-4Haloalkyl, C1-4Alkoxy radical, C1-4Haloalkoxy, -C1-4alkylene-O-C1-4Alkyl radical, C3-6Cycloalkyl radical, C6-10Aryl, heterocyclyl of 5 to 7 atoms, heteroaryl of 5 to 6 atoms or-C (═ O) -N (R)dRe) (ii) a Wherein, said C1-4Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C1-4Haloalkyl, C1-4Alkoxy radical, C1-4Haloalkoxy, -C1-4alkylene-O-C1-4Alkyl radical, C3-6Cycloalkyl radical, C6-10Aryl, heterocyclyl of 5-7 atoms and heteroaryl of 5-6 atoms are independently optionally substituted with 1, 2, 3, 4, 5 or 6RcAnd (4) substituting.
In some embodiments, each R iscIndependently deuterium, F, Cl, Br, I, -OH, -CN, -NH2、C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl, C1-4Haloalkoxy, C3-6Cycloalkyl, heterocyclic radical of 5-7 atoms, C6-10Aryl or heteroaryl of 5 to 6 atoms.
In some embodiments, R3And R4Each independently is deuterium, F, Cl, Br, I, -CN, -NH2、-NO2、-OH、-COOH、C1-4Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C1-4Haloalkoxy, C1-4Haloalkyl or C1-4An alkoxy group.
In some embodiments, R5And R6Each independently of the others being H, deuterium, -OH, -CN, -NH2、-NO2、-COOH、C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl, -C1-4alkylene-O-C1-4Alkyl, -C 1-4alkylene-C (═ O) -O-C1-4Alkyl, -C1-4alkylene-C (═ O) -N (R)dRe)、-C1-4alkylene-O-C (═ O) -N (R)dRe)、-C1-4alkylene-N (R)f)-C(＝O)-N(RdRe) or-C1-4alkylene-N (R)dRe) (ii) a Wherein, said C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl, -C1-4alkylene-C (═ O) -O-C1-4Alkyl and-C1-4alkylene-O-C1-4Alkyl is independently optionally substituted with deuterium, F, Cl, Br, I, -OH, -CN, -COOH, -N (R)dRe)、C1-4Alkyl radical, C1-4Haloalkyl, C1-4Alkoxy or C1-4Substituted with a substituent of haloalkoxy;
or R5And R6Together with the carbon atoms to which they are jointly attached form C3-6Cycloalkyl or heterocyclyl consisting of 3 to 6 atoms; wherein, said C3-6Cycloalkyl and heterocyclyl consisting of 3 to 6 atomsOptionally substituted by 1, 2, 3 or 4 substituents selected from deuterium, F, Cl, Br, I, -OH, -CN, -COOH, C1-4Alkyl radical, C1-4Haloalkyl, C1-4Alkoxy or C1-4A haloalkoxy group.
In some embodiments, RdAnd ReEach independently of the others being H, deuterium, -OH, C1-4Alkyl, -C (═ O) H, -C (═ O) -O-C1-4Alkyl, -C (═ O) -C1-4Alkyl, -C1-4alkylene-C (═ O) -O-C1-4Alkyl or-C1-4alkylene-O-C1-4An alkyl group; wherein, said C1-4Alkyl, -C1-4alkylene-C (═ O) -O-C1-4Alkyl and-C1-4alkylene-O-C1-4Alkyl is independently optionally substituted by 1, 2 or 3 substituents selected from deuterium, F, Cl, Br, I, -OH, -CN, -NH 2Or a substituent of-COOH.
In some embodiments, each R isfIndependently of one another H, deuterium, C1-4Alkyl, -C1-4alkylene-O-C1-4Alkyl, -C1-4alkylene-C3-6Cycloalkyl or-C1-4Alkylene- (5-7 atom-constituting heterocyclic group); wherein, said C1-4Alkyl, -C1-4alkylene-O-C1-4Alkyl, -C1-4alkylene-C3-6Cycloalkyl and-C1-4Alkylene- (heterocyclyl consisting of 5 to 7 atoms) is independently optionally substituted by 1, 2 or 3 substituents selected from deuterium, F, Cl, Br, I, -OH, -CN, -NH2Or a substituent of-COOH.
In some embodiments, R7Is H, deuterium, -COOH, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Alkylamino radical, C1-4Haloalkyl, C3-6Cycloalkyl radical, C3-6Cycloalkylamino or heterocyclyl consisting of 5 to 7 atoms;
Rgis H, deuterium or C1-4An alkyl group.
In other embodiments, R1And R2Each independently is deuterium, F, Cl, Br, I, -CN, -NH2、-NO2-OH, -COOH, oxo, methyl, ethyl, n-COOHPropyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, ethenyl, ethynyl, -CH2F、-CH2Cl、-CHF2、-CHCl2、-CF3、-CH2CH2F、-CH2CH2Cl、-CH2CHF2、-CH2CHCl2、-CHFCH2F、-CHClCH2Cl、-CH2CF3、-CH(CF3)2、-CF2CH2CH3、-CH2CH2CH2F、-CH2CH2CHF2、-CH2CH2CF3Methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, -OCH2F、-OCH2Cl、-OCHF2、-OCHCl2、-OCF3、-OCH2CH2F、-OCH2CH2Cl、-OCH2CHF2、-OCH2CHCl2、-OCHFCH2F、-OCHClCH2Cl、-OCH2CF3、-OCH(CF3)2、-OCF2CH2CH3、-OCH2CH2CH2F、-OCH2CH2CHF2、-OCH2CH2CF3、-CH2OCH3、-CH2OCH2CH3、-CH2OCH2CH2CH3、-CH2OCH(CH3)2、-CH2CH2OCH3、-CH2CH2OCH2CH3、-CH2CH2OCH2CH2CH3、-CH2CH2OCH(CH3)2、-CH2CH2CH2OCH3、-CH2CH2CH2OCH2CH3、-CH2CH2CH2OCH2CH2CH3、-CH2CH2CH2OCH(CH3)2Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthaleneA group selected from the group consisting of pyridyl, pyrimidinyl, pyrazolyl, thiazolyl, imidazolyl, oxazolyl, triazolyl, tetrazolyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, pyrrolidinyl and-C (═ O) -N (R) dRe)；
Wherein, the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, vinyl and-CH2F、-CH2Cl、-CHF2、-CHCl2、-CH2CH2F、-CH2CH2Cl、-CH2CHF2、-CH2CHCl2、-CHFCH2F、-CHClCH2Cl、-CH2CF3、-CH(CF3)2、-CF2CH2CH3、-CH2CH2CH2F、-CH2CH2CHF2、-CH2CH2CF3Methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, -OCH2F、-OCH2Cl、-OCHF2、-OCHCl2、-OCH2CH2F、-OCH2CH2Cl、-OCH2CHF2、-OCH2CHCl2、-OCHFCH2F、-OCHClCH2Cl、-OCH2CF3、-OCH(CF3)2、-OCF2CH2CH3、-OCH2CH2CH2F、-OCH2CH2CHF2、-OCH2CH2CF3、-CH2OCH3、-CH2OCH2CH3、-CH2OCH2CH2CH3、-CH2OCH(CH3)2、-CH2CH2OCH3、-CH2CH2OCH2CH3、-CH2CH2OCH2CH2CH3、-CH2CH2OCH(CH3)2、-CH2CH2CH2OCH3、-CH2CH2CH2OCH2CH3、-CH2CH2CH2OCH2CH2CH3、-CH2CH2CH2OCH(CH3)2Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazolyl, thiazolyl, imidazolyl, oxazolyl, triazolyl, tetrazolyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl and pyrrolidinyl being independently optionally substituted by 1, 2, 3, 4, 5 or 6RcAnd (4) substituting.
In other embodiments, each R iscIndependently deuterium, F, Cl, Br, I, -OH, -CN, -NH2Methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, -CH2F、-CHF2、-CF3、-CH2CH2F、-CH2CHF2、-CHFCH2F、-CH2CF3、-CH(CF3)2、-CF2CH2CH3、-CH2CH2CH2F、-CH2CH2CHF2、-CH2CH2CF3Methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, -OCH2F、-OCHF2、-OCF3、-OCH2CH2F、-OCH2CHF2、-OCHFCH2F、-OCH2CF3、-OCH(CF3)2、-OCF2CH2CH3、-OCH2CH2CH2F、-OCH2CH2CHF2、-OCH2CH2CF3Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, pyridyl, pyrimidinyl, pyrazolyl, thiazolyl, imidazolyl, oxazolyl, triazolyl, tetrazolyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl or pyrrolidinyl.
In other embodiments, R3And R4Each independently is deuterium, F, Cl, Br, I, CN, NH2、NO2、OH、COOH, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, ethenyl, ethynyl, -CH2F、-CH2Cl、-CHF2、-CHCl2、-CF3、-CH2CH2F、-CH2CH2Cl、-CH2CHF2、-CH2CHCl2、-CHFCH2F、-CHClCH2Cl、-CH2CF3、-CH(CF3)2、-CF2CH2CH3、-CH2CH2CH2F、-CH2CH2CHF2、-CH2CH2CF3、-OCH2F、-OCH2Cl、-OCHF2、-OCHCl2、-OCF3、-OCH2CH2F、-OCH2CH2Cl、-OCH2CHF2、-OCH2CHCl2、-OCHFCH2F、-OCHClCH2Cl、-OCH2CF3、-OCH(CF3)2、-OCF2CH2CH3、-OCH2CH2CH2F、-OCH2CH2CHF2、-OCH2CH2CF3Methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy or tert-butoxy.
In other embodiments, R5And R6Each independently of the others being H, deuterium, -OH, -CN, -NH2、-NO2-COOH, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, -CH2F、-CH2Cl、-CHF2、-CHCl2、-CF3、-CH2CH2F、-CH2CH2Cl、-CH2CHF2、-CH2CHCl2、-CHFCH2F、-CH2OCH3、-CH2OCH2CH3、-CH2OCH2CH2CH3、-CH2OCH(CH3)2、-CH2CH2OCH3、-CH2CH2OCH2CH3、-CH2CH2OCH2CH2CH3、-CH2CH2OCH(CH3)2、-CH2CH2CH2OCH3、-CH2CH2CH2OCH2CH3、-CH2CH2CH2OCH2CH2CH3、-CH2CH2CH2OCH(CH3)2、-CH2-C(＝O)-OCH3、-CH2-C(＝O)-OCH2CH3、-CH2-C(＝O)-OCH2CH2CH3、-CH2-C(＝O)-OCH(CH3)2、-CH2CH2-C(＝O)-OCH3、-CH2CH2-C(＝O)-OCH2CH3、-CH2CH2-C(＝O)-OCH2CH2CH3、-CH2CH2-C(＝O)-OCH(CH3)2、-CH2CH2CH2-C(＝O)-OCH3、-CH2CH2CH2-C(＝O)-OCH2CH3、-CH2CH2CH2-C(＝O)-OCH2CH2CH3、-CH2CH2CH2-C(＝O)-OCH(CH3)2、-CH2-C(＝O)-N(RdRe)、-CH2CH2-C(＝O)-N(RdRe)、-CH2CH2CH2-C(＝O)-N(RdRe)、-CH2-O-C(＝O)-N(RdRe)、-CH2CH2-O-C(＝O)-N(RdRe)、-CH2CH2CH2-O-C(＝O)-N(RdRe)、-CH2-N(Rf)-C(＝O)-N(RdRe)、-CH2CH2-N(Rf)-C(＝O)-N(RdRe)、-CH2CH2CH2-N(Rf)-C(＝O)-N(RdRe)、-CH2N(RdRe)、-CH2CH2N(RdRe) or-CH2CH2CH2N(RdRe)；
Wherein, the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, -CH2F、-CH2Cl、-CHF2、-CHCl2、-CF3、-CH2CH2F、-CH2CH2Cl、-CH2CHF2、-CH2CHCl2、-CHFCH2F、-CH2-C(＝O)-OCH3、-CH2-C(＝O)-OCH2CH3、-CH2-C(＝O)-OCH2CH2CH3、-CH2-C(＝O)-OCH(CH3)2、-CH2CH2-C(＝O)-OCH3、-CH2CH2-C(＝O)-OCH2CH3、-CH2CH2-C(＝O)-OCH2CH2CH3、-CH2CH2-C(＝O)-OCH(CH3)2、-CH2CH2CH2-C(＝O)-OCH3、-CH2CH2CH2-C(＝O)-OCH2CH3、-CH2CH2CH2-C(＝O)-OCH2CH2CH3、-CH2CH2CH2-C(＝O)-OCH(CH3)2、-CH2OCH3、-CH2OCH2CH3、-CH2OCH2CH2CH3、-CH2OCH(CH3)2、-CH2CH2OCH3、-CH2CH2OCH2CH3、-CH2CH2OCH2CH2CH3、-CH2CH2OCH(CH3)2、-CH2CH2CH2OCH3、-CH2CH2CH2OCH2CH3、-CH2CH2CH2OCH2CH2CH3and-CH2CH2CH2OCH(CH3)2Independently optionally substituted by 1, 2 or 3 substituents selected from deuterium, F, Cl, Br, I, -OH, -CN, -COOH, -N (R)dRe) Methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, trifluoromethyl, -OCH2F、-OCH2Cl、-OCHF2、-OCHCl2、-OCF3、-OCH2CH2F、-OCH2CH2Cl、-OCH2CHF2、-OCH2CHCl2、-OCHFCH2F、-OCHClCH2Cl、-OCH2CF3、-OCH(CF3)2、-OCF2CH2CH3、-OCH2CH2CH2F、-OCH2CH2CHF2or-OCH2CH2CF3Substituted with the substituent(s);
Or R5、R6And together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl or tetrahydropyranyl group; wherein said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, and tetrahydropyranyl are independently optionally substituted with 1, 2, 3, or 4 substituents selected from deuterium, F, Cl, Br, I, -OH, -CN, -COOH, methyl, ethyl, isopropyl, trifluoromethyl, methoxy, or trifluoromethoxy.
In other embodiments, RdAnd ReEach independently is H, deuterium, -OH, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, -C (═ O) H, -C (═ O) -O-CH3、-C(＝O)-O-CH2CH3、-C(＝O)-O-CH2CH2CH3、-C(＝O)-O-CH(CH3)2、-C(＝O)-CH3、-C(＝O)-CH2CH3、-C(＝O)-CH2CH2CH3、-C(＝O)-CH(CH3)2、-CH2OCH3、-CH2OCH2CH3、-CH2OCH2CH2CH3、-CH2OCH(CH3)2、-CH2CH2OCH3、-CH2CH2OCH2CH3、-CH2CH2OCH2CH2CH3、-CH2CH2OCH(CH3)2、-CH2CH2CH2OCH3、-CH2CH2CH2OCH2CH3、-CH2CH2CH2OCH2CH2CH3、-CH2CH2CH2OCH(CH3)2、-CH2-C(＝O)-OCH3、-CH2-C(＝O)-OCH2CH3、-CH2-C(＝O)-OCH2CH2CH3、-CH2-C(＝O)-OCH(CH3)2、-CH2CH2-C(＝O)-OCH3、-CH2CH2-C(＝O)-OCH2CH3、-CH2CH2-C(＝O)-OCH2CH2CH3、-CH2CH2-C(＝O)-OCH(CH3)2、-CH2CH2CH2-C(＝O)-OCH3、-CH2CH2CH2-C(＝O)-OCH2CH3、-CH2CH2CH2-C(＝O)-OCH2CH2CH3or-CH2CH2CH2-C(＝O)-OCH(CH3)2；
Wherein, the methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, -CH2OCH3、-CH2OCH2CH3、-CH2OCH2CH2CH3、-CH2OCH(CH3)2、-CH2CH2OCH3、-CH2CH2OCH2CH3、-CH2CH2OCH2CH2CH3、-CH2CH2OCH(CH3)2、-CH2CH2CH2OCH3、-CH2CH2CH2OCH2CH3、-CH2CH2CH2OCH2CH2CH3、-CH2CH2CH2OCH(CH3)2、-CH2-C(＝O)-OCH3、-CH2-C(＝O)-OCH2CH3、-CH2-C(＝O)-OCH2CH2CH3、-CH2-C(＝O)-OCH(CH3)2、-CH2CH2-C(＝O)-OCH3、-CH2CH2-C(＝O)-OCH2CH3、-CH2CH2-C(＝O)-OCH2CH2CH3、-CH2CH2-C(＝O)-OCH(CH3)2、-CH2CH2CH2-C(＝O)-OCH3、-CH2CH2CH2-C(＝O)-OCH2CH3、-CH2CH2CH2-C(＝O)-OCH2CH2CH3and-CH2CH2CH2-C(＝O)-OCH(CH3)2Independently optionally substituted by 1, 2 or 3 substituents selected from deuterium, F, Cl, Br, I, -OH, -CN, -NH2Or a substituent of-COOH.
In other embodiments, each R isfIndependently H, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, -CH 2OCH3、-CH2OCH2CH3、-CH2OCH2CH2CH3、-CH2OCH(CH3)2、-CH2CH2OCH3、-CH2CH2OCH2CH3、-CH2CH2OCH2CH2CH3、-CH2CH2OCH(CH3)2、-CH2CH2CH2OCH3、-CH2CH2CH2OCH2CH3、-CH2CH2CH2OCH2CH2CH3、-CH2CH2CH2OCH(CH3)2Cyclopropylmethylene, cyclopropylethylene, n-propylidene, cyclobutylmethylene, cyclobutylethylene, n-propylidene, cyclopentylmethylene, cyclopentylethylidene, n-propylidene, cyclohexylmethylene, cyclohexylethylene, n-propylidene, piperazinylmethylene, piperidinylmethylene, morpholinomethylene, thiomorpholinylmethylene, tetrahydropyranylmethylene or pyrrolidinylmethylene; wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, -CH2OCH3、-CH2OCH2CH3、-CH2OCH2CH2CH3、-CH2OCH(CH3)2、-CH2CH2OCH3、-CH2CH2OCH2CH3、-CH2CH2OCH2CH2CH3、-CH2CH2OCH(CH3)2、-CH2CH2CH2OCH3、-CH2CH2CH2OCH2CH3、-CH2CH2CH2OCH2CH2CH3、-CH2CH2CH2OCH(CH3)2Cyclopropylmethylene, cyclopropylethylene, n-propylidene, cyclobutylmethylene, cyclobutylethylene, cyclobutylpropylene, cyclopentylmethylene, cyclopentylethylene, cyclopentylpropylidene, cyclohexylmethylene, cyclohexylethylene, cyclohexyln-propyl, piperazinylmethylene, piperidinylmethylene, morpholinomethylene, thiomorpholinylmethylene, tetrahydropyranylmethylene and pyrrolidinylmethylene are independently optionally substituted by 1, 2 or 3Selected from deuterium, F, Cl, Br, I, -OH, -CN, -NH2Or a substituent of-COOH.
In other embodiments, R 7Is H, deuterium, -COOH, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, methylamino, ethylamino, n-propylamino, isopropylamino, -CH2F、-CH2Cl、-CHF2、-CHCl2、-CF3、-CH2CH2F、-CH2CH2Cl、-CH2CHF2、-CH2CHCl2、-CHFCH2F. Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl or pyrrolidinyl;
Rgis H, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
In another aspect, the present invention relates to a pharmaceutical composition comprising a compound of formula (I) of the present invention, or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, 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 drugs or any combination thereof for preventing or treating inflammatory syndromes, disorders or diseases.
In another aspect, the invention relates to the use of a compound of formula (I) or a pharmaceutical composition thereof in the manufacture of a medicament for the prevention or treatment of cancer, inflammation or autoimmune disease mediated by roryt in a mammal, including a human.
In some embodiments, the present invention relates to the use of a compound of formula (I) or a pharmaceutical composition thereof in the preparation of a medicament for the prevention or treatment of cancer, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease, colitis, ulcerative colitis, rheumatoid arthritis, autoimmune ocular disease, ankylosing spondylitis, asthma, chronic obstructive pulmonary disease, osteoarthritis, allergic rhinitis, allergic dermatitis, crohn's disease, or kawasaki disease.
In another aspect, the invention relates to methods for the preparation, isolation and purification of compounds of formula (I).
Biological test results show that the compound provided by the invention has good inhibitory activity on ROR gamma t and good pharmacokinetic characteristics.
Any embodiment of any aspect of the invention may be combined with other embodiments, as long as they do not contradict. Furthermore, in any embodiment of any aspect of the invention, any feature may be applicable to that feature in other embodiments, so long as they do not contradict.
The foregoing merely summarizes certain aspects of the invention and is not intended to be limiting. These and other aspects will be more fully described below.
Detailed description of the invention
Definitions and general terms
Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated by the accompanying structural and chemical formulas. The invention is intended to cover alternatives, modifications and equivalents, which may be included within the scope of the invention as defined by the appended claims. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the incorporated documents, patents, and similar materials differ or contradict this application (including but not limited to defined terminology, application of terminology, described techniques, and the like), this application controls.
It will be further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference in their entirety.
The following definitions as used herein should be applied unless otherwise indicated. For the purposes of the present invention, the chemical elements are in accordance with the CAS version of the periodic Table of the elements, and the handbook of chemistry and Physics, 75 th edition, 1994. In addition, general principles of Organic Chemistry can be referred to as described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausaltito: 1999, and "March's Advanced Organic Chemistry" by Michael B.Smith and Jerry March, John Wiley & Sons, New York:2007, the entire contents of which are incorporated herein by reference.
The articles "a," "an," and "the" as used herein are intended to include "at least one" or "one or more" unless otherwise indicated or clearly contradicted by context. Thus, as used herein, the articles refer to articles of one or more than one (i.e., at least one) object. For example, "a component" refers to one or more components, i.e., there may be more than one component contemplated for use or use in embodiments of the described embodiments.
The term "subject" as used herein refers to an animal. Typically the animal is a mammal. Subjects, e.g., also primates (e.g., humans, males or females), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In certain embodiments, the subject is a primate. In other embodiments, the subject is a human.
The term "patient" as used herein refers to humans (including adults and children) or other animals. In some embodiments, "patient" refers to a human.
The term "comprising" is open-ended, i.e. includes the elements indicated in the present invention, but does not exclude other elements.
"stereoisomers" refers to compounds having the same chemical structure but differing in the arrangement of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis/trans), atropisomers, and the like.
"chiral" is a molecule having the property of not overlapping its mirror image; and "achiral" refers to a molecule that can overlap with its mirror image.
"enantiomer" refers to two isomers of a compound that are not overlapping but are in mirror image relationship to each other.
"diastereomer" refers to a stereoisomer having two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers may be separated by high resolution analytical procedures such as electrophoresis and chromatography, e.g., HPLC.
The stereochemical definitions and rules used in the present invention generally follow the general definitions of S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E.and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994.
Many organic compounds exist in an optically active form, i.e., they have the ability to rotate the plane of plane polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to denote the absolute configuration of a molecule with respect to one or more of its chiral centers. The prefixes d and l or (+) and (-) are the symbols used to specify the rotation of plane polarized light by the compound, where (-) or l indicates that the compound is left-handed. Compounds prefixed with (+) or d are dextrorotatory. A particular stereoisomer is an enantiomer and a mixture of such isomers is referred to as an enantiomeric mixture. A50: 50 mixture of enantiomers is referred to as a racemic mixture or racemate, which may occur when there is no stereoselectivity or stereospecificity in the chemical reaction or process.
Any asymmetric atom (e.g., carbon, etc.) of a compound disclosed herein can exist in racemic or enantiomerically enriched forms, such as the (R) -, (S) -or (R, S) -configuration. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in the (R) -or (S) -configuration.
Depending on the choice of starting materials and methods, the compounds of the invention may exist as one of the possible isomers or as mixtures thereof, for example as racemates and diastereomeric mixtures (depending on the number of asymmetric carbon atoms). Optically active (R) -or (S) -isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituents may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the substituents of the cycloalkyl group may have cis or trans configuration.
Any resulting mixture of stereoisomers may be separated into pure or substantially pure geometric isomers, enantiomers, diastereomers, depending on differences in the physicochemical properties of the components, for example, by chromatography and/or fractional crystallization.
The racemates of any of the resulting end products or intermediates can be resolved into the optical enantiomers by known methods using methods familiar to those skilled in the art, e.g., by separation of the diastereomeric salts obtained. The racemic product can also be separated by chiral chromatography, e.g., High Performance Liquid Chromatography (HPLC) using a chiral adsorbent. In particular, Enantiomers can be prepared by asymmetric synthesis, for example, see Jacques, et al, Enantiomers, racemes and solutions (Wiley Interscience, New York, 1981); PrinciplesofAsymmetric Synthesis (2) nd Ed.Robert E.Gawley,Jeffrey Aubé,Elsevier,Oxford,UK,2012)；Eliel,E.L.Stereochemistry of Carbon Compounds(McGraw-Hill,NY,1962)；Wilen,S.H.Tables of Resolving Agents and Optical Resolutions p.268(E.L.Eliel,Ed.,Univ.of Notre Dame Press,Notre Dame,IN 1972)；Chiral Separation Techniques:APractical Approach(Subramanian,G.Ed.,Wiley-VCH Verlag GmbH&Co.KGaA,Weinheim,Germany,2007)。
The compounds of the invention may be optionally substituted with one or more substituents, as described herein, in compounds of the general formula above, or as specifically exemplified, sub-classes, and classes of compounds encompassed by the invention.
In general, the term "substituted" means that one or more hydrogen atoms in a given structure are replaced with a particular substituent. Unless otherwise indicated, a substituted group may have one substituent substituted at each substitutable position of the group. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, the substituents may be substituted at each position, identically or differently.
The term "unsubstituted" means that the specified group bears no substituents.
The term "optionally substituted with … …" is used interchangeably with the term "unsubstituted or substituted with … …", i.e., the structure is unsubstituted or substituted with one or more substituents described herein. Substituents described herein include, but are not limited to, deuterium, fluorine, chlorine, bromine, iodine, cyano, hydroxy, amino, nitro, carboxy, aryl, heteroaryl, alkoxy, alkylamino, alkylthio, alkyl, alkenyl, alkynyl, heterocyclyl, cycloalkyl, spiroheterocyclyl, spirocarbocyclyl, oxo, haloalkyl, haloalkoxy, hydroxy-substituted alkyl, hydroxy-substituted alkoxy, amino-substituted alkyl, cyano-substituted alkyl, alkyl-C (═ O) -, alkyl-O-C (═ O) -, alkyl-S (═ O) 2-，NH2-C(＝O)-，NH2-S(＝O)2-, -alkylene-aryl, -alkylene-heteroaryl, -alkylene-heterocyclyl, -alkylene-cycloalkyl, and the like.
In addition, unless otherwise explicitly indicated, the descriptions of the terms "… independently" and "… independently" and "… independently" used in the present invention are interchangeable and should be understood in a broad sense to mean that the specific items expressed between the same symbols do not affect each other in different groups or that the specific items expressed between the same symbols in the same groups do not affect each other.
In the various parts of this specification, substituents of the disclosed compounds are disclosed in terms of group type or range. It is specifically intended that the invention includes each and every independent subcombination of the various members of these groups and ranges. For example, the term "C1-6Alkyl "means in particular independently disclosed methyl, ethyl, C3Alkyl radical, C4Alkyl radical, C5Alkyl and C6An alkyl group.
In each of the parts of the invention, linking substituents are described. Where the structure clearly requires a linking group, the markush variables listed for that group are understood to be linking groups. For example, if the structure requires a linking group and the markush group definition for the variable recites "alkyl" or "aryl," it is understood that the "alkyl" or "aryl" represents an attached alkylene group or arylene group, respectively.
The term "alkyl" or "alkyl group" as used herein, denotes a saturated straight or branched chain monovalent hydrocarbon radical, wherein the alkyl group may be optionally substituted with one or more substituents as described herein. Unless otherwise specified, alkyl groups contain 1-20 carbon atoms. In one embodiment, the alkyl group contains 1 to 12 carbon atoms; in another embodiment, the alkyl group contains 3 to 12 carbon atoms; in another embodiment, the alkyl group contains 1 to 6 carbon atoms; in another embodiment, the alkyl group contains 1 to 4 carbon atoms; in yet another embodiment, the alkyl group contains 1 to 3 carbon atoms.
Examples of alkyl groups include, but are not limited to, methyl (Me, -CH)3) Ethyl group (Et, -CH)2CH3) N-propyl (n-Pr, -CH)2CH2CH3) Isopropyl group (i-Pr, -CH (CH)3)2) N-butyl (n-Bu, -CH)2CH2CH2CH3) Isobutyl (i-Bu, -CH)2CH(CH3)2) Sec-butyl (s-Bu, -CH (CH)3)CH2CH3) Tert-butyl (t-Bu, -C (CH)3)3) N-pentyl (-CH)2CH2CH2CH2CH3) 2-pentyl (-CH (CH)3)CH2CH2CH3) 3-pentyl (-CH (CH)2CH3)2) 2-methyl-2-butyl (-C (CH)3)2CH2CH3) 3-methyl-2-butyl (-CH (CH)3)CH(CH3)2) 3-methyl-1-butyl (-CH)2CH2CH(CH3)2) 2-methyl-1-butyl (-CH)2CH(CH3)CH2CH3) N-hexyl (-CH)2CH2CH2CH2CH2CH3) 2-hexyl (-CH (CH) 3)CH2CH2CH2CH3) 3-hexyl (-CH (CH)2CH3)(CH2CH2CH3) 2-methyl-2-pentyl (-C (CH))3)2CH2CH2CH3) 3-methyl-2-pentyl (-CH (CH)3)CH(CH3)CH2CH3) 4-methyl-2-pentyl (-CH (CH)3)CH2CH(CH3)2) 3-methyl-3-pentyl (-C (CH)3)(CH2CH3)2) 2-methyl-3-pentyl (-CH (CH)2CH3)CH(CH3)2) 2, 3-dimethyl-2-butyl (-C (CH)3)2CH(CH3)2) 3, 3-dimethyl-2-butyl (-CH (CH)3)C(CH3)3) N-heptyl, n-octyl, and the like.
The term "alkylene" refers to a saturated divalent hydrocarbon radical resulting from the removal of two hydrogen atoms from a saturated straight or branched chain hydrocarbon radical. Unless otherwise specified, the alkylene group contains 1 to 12 carbon atoms. In one embodiment, the alkylene groupContaining 1 to 6 carbon atoms; in another embodiment, the alkylene group contains 1 to 4 carbon atoms; in yet another embodiment, the alkylene group contains 1 to 3 carbon atoms; in yet another embodiment, the alkylene group contains 1 to 2 carbon atoms. Examples of this include methylene (-CH)2-, ethylene (-CH)2CH2-, n-propylidene (-CH)2CH2CH2-, isopropylidene (-CH (CH)3)CH2-) and the like.
The term "alkenyl" denotes a straight or branched chain monovalent hydrocarbon radical containing 2 to 12 carbon atoms, wherein at least one carbon-carbon sp is present2A double bond, wherein the alkenyl group may be optionally substituted with one or more substituents described herein, including the positioning of "cis" and "trans", or the positioning of "E" and "Z". In one embodiment, the alkenyl group contains 2 to 8 carbon atoms; in another embodiment, the alkenyl group contains 2 to 6 carbon atoms; in yet another embodiment, the alkenyl group contains 2 to 4 carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl (-CH ═ CH) 2) Allyl (-CH)2CH＝CH2) 1-propenyl (i.e., propenyl, -CH ═ CH-CH)3) And so on.
The term "alkynyl" denotes a straight or branched chain monovalent hydrocarbon radical containing 2 to 12 carbon atoms, wherein there is at least one carbon-carbon sp triple bond, wherein the alkynyl radical may be optionally substituted with one or more substituents as described herein. In one embodiment, alkynyl groups contain 2-8 carbon atoms; in another embodiment, alkynyl groups contain 2-6 carbon atoms; in yet another embodiment, alkynyl groups contain 2-4 carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (-C.ident.CH), propargyl (-CH)2C.ident.CH), 1-propynyl (i.e., propynyl, -C.ident.C-CH)3) And so on.
The term "deuterium" denotes a single deuterium atom. For example, one deuterium atom is substituted for one hydrogen atom in a methyl group to form a mono-deuterated methyl (-CDH)2) Two deuterium atoms replace two hydrogen atoms in a methyl group to form a bis-deuterated methyl (-CD)2H) To do so byAnd three deuterium atoms are substituted for three hydrogen atoms in the methyl group to form tri-deuterated methyl (-CD)3)。
The term "alkoxy" means an alkyl group attached to the rest of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkoxy group contains 1 to 12 carbon atoms. In one embodiment, the alkoxy group contains 1 to 6 carbon atoms; in another embodiment, the alkoxy group contains 1 to 4 carbon atoms; in yet another embodiment, the alkoxy group contains 1 to 3 carbon atoms. The alkoxy group may be optionally substituted with one or more substituents described herein.
Examples of alkoxy groups include, but are not limited to, methoxy (MeO, -OCH)3) Ethoxy (EtO, -OCH)2CH3) 1-propoxy (n-PrO, n-propoxy, -OCH)2CH2CH3) 2-propoxy (i-PrO, i-propoxy, -OCH (CH)3)2) 1-butoxy (n-BuO, n-butoxy, -OCH)2CH2CH2CH3) 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH)2CH(CH3)2) 2-butoxy (s-BuO, s-butoxy, -OCH (CH)3)CH2CH3) 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC (CH)3)3) 1-pentyloxy (n-pentyloxy, -OCH)2CH2CH2CH2CH3) 2-pentyloxy (-OCH (CH)3)CH2CH2CH3) 3-pentyloxy (-OCH (CH))2CH3)2) 2-methyl-2-butoxy (-OC (CH))3)2CH2CH3) 3-methyl-2-butoxy (-OCH (CH)3)CH(CH3)2) 3-methyl-l-butoxy (-OCH)2CH2CH(CH3)2) 2-methyl-l-butoxy (-OCH)2CH(CH3)CH2CH3) And so on.
The term "haloalkyl" or "haloalkoxy" means an alkyl or alkoxy group substituted with one or more halogen atoms, whichWherein the alkyl or alkoxy group has the meaning as described herein, and such examples include, but are not limited to, -CH2F、-CHF2、-CF3、-CH2CH2F、-CH2CHF2、-CHFCH2F、-CH2CF3、-CH(CF3)2、-CF2CH2CH3、-CH2CH2CH2F、-CH2CH2CHF2、-CH2CH2CF3、-OCH2F、-OCHF2、-OCF3、-OCH2CH2F、-OCH2CHF2、-OCHFCH2F、-OCH2CF3、-OCH(CF3)2、-OCF2CH2CH3、-OCH2CH2CH2F、-OCH2CH2CHF2、-OCH2CH2CF3And the like.
The term "alkylamino" denotes the amino group-NH2Substituted with one or two alkyl groups, including "N-alkylamino" and "N, N-dialkylamino"; the alkyl group has the meaning described in the present invention. In some of these examples, the alkylamino group is one or two C 1-6Alkyl groups are attached to the nitrogen atom to form lower alkylamino groups. In other embodiments, the alkylamino group is one or two C1-3To the nitrogen atom to form an alkylamino group. Suitable alkylamino groups can be monoalkylamino or dialkylamino, and such examples include, but are not limited to, N-methylamino, N-ethylamino, N-dimethylamino, N-diethylamino, and the like.
The term "cycloalkyl" denotes a monovalent or polyvalent saturated monocyclic, bicyclic or tricyclic hydrocarbon radical containing from 3 to 12 carbon atoms. In one embodiment, the cycloalkyl group contains 3 to 12 carbon atoms; in yet another embodiment, the cycloalkyl group contains 3 to 8 carbon atoms; in yet another embodiment, the cycloalkyl group contains 3 to 6 carbon atoms. The cycloalkyl groups may be independently unsubstituted or substituted with one or more substituents described herein.
The term "cycloalkylamino" denotes an amino group substituted with one or two cycloalkyl groups, including "N-cycloalkylamino" and "N, N-bicycloalkylamino"; the cycloalkyl radicals have the meanings described in the present invention. Wherein some embodiments are cycloalkylamino is one or two C 3-8Cycloalkyl groups are attached to nitrogen atoms to form cycloalkylamino groups. In other embodiments, the cycloalkylamino group is one or two C3-6Is attached to the nitrogen atom to form a cycloalkylamino group. Suitable cycloalkylamino groups can be monocycloalkylamino or dicycloalkylamino, and examples include, but are not limited to, N-cyclopropylamino, N-cyclobutylamino, N-cyclohexylamino, N-dicyclopropylamino, and the like.
The terms "heterocyclyl" and "heterocycle" are used interchangeably herein and refer to a saturated or partially unsaturated, non-aromatic, monovalent or polyvalent, monocyclic, bicyclic, or tricyclic ring containing from 3 to 12 ring atoms, wherein at least one ring atom is selected from the group consisting of nitrogen, sulfur, and oxygen atoms. Wherein, in some embodiments, heterocyclyl consists of 3-10 ring atoms, wherein said ring atoms contain at least one heteroatom selected from nitrogen, sulfur, and oxygen; in yet other embodiments, heterocyclyl is comprised of 3-8 ring atoms, wherein the ring atoms contain at least one heteroatom selected from nitrogen, sulfur, and oxygen; in yet other embodiments, heterocyclyl is comprised of 3-6 ring atoms, wherein the ring atoms contain at least one heteroatom selected from nitrogen, sulfur, and oxygen; in still other embodiments, heterocyclyl is comprised of 5-10 ring atoms, wherein the ring atoms contain at least one heteroatom selected from nitrogen, sulfur, and oxygen. The heterocyclic group consisting of 5 to 7 atoms in the invention can be a heterocyclic group consisting of 5 atoms, a heterocyclic group consisting of 6 atoms or a heterocyclic group consisting of 7 atoms. Unless otherwise indicated, a heterocyclyl group may be attached to other groups in the molecule through a carbon atom, may be attached to other groups in the molecule through a nitrogen atom, and-CH 2-the group may optionally be replaced by-C (═ O) -. The sulfur atom of the ring may optionally be oxidized to the S-oxide. The nitrogen atom of the ring may optionally be substitutedOxidized to the N-oxygen compound.
Examples of heterocyclyl groups include, but are not limited to: oxirane, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuryl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxolanyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, pyrrolidinyl, pyrazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiopyranyl, 1, 3-dioxolanyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl,
Figure BDA0002878710730000121
morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thiaxanyl, homopiperazinyl, homopiperidinyl, diazepanyl, oxepanyl, thiepanyl, oxazepanyl
Figure BDA0002878710730000122
Radical diaza
Figure BDA0002878710730000123
Radical, sulfur nitrogen hetero
Figure BDA0002878710730000124
Yl, 2-oxa-5-azabicyclo [2.2.1]Hept-5-yl. In heterocyclic radicals of-CH2Examples of-groups substituted by-C (═ O) -include, but are not limited to, 2-oxopyrrolidinyl, oxo-1, 3-thiazolidinyl, 2-piperidinonyl, 3, 5-dioxopiperidinyl and pyrimidinedione. Examples of the sulfur atom in the heterocyclic group being oxidized include, but are not limited to, sulfolane group, 1-dioxothiomorpholinyl group. The heterocyclyl group may be optionally substituted with one or more substituents as described herein.
The term "spirocarbocyclyl" refers to a saturated or partially unsaturated, non-aromatic, monovalent or polyvalent, bicyclic or tricyclic ring containing 5 to 12 ring atoms, wherein the ring shares a carbon atom with the ring. Unless otherwise indicated, the spirocarbocyclyl group may be attached to other groups in the molecule through a carbon atom, and-CH2-the group may optionally be replaced by-C (═ O) -. Carbon of spiroExamples of rings include, but are not limited to:
Figure BDA0002878710730000125
the terms "spiroheterocyclyl" and "spiroheterocycle" are used interchangeably herein and refer to a saturated or partially unsaturated, non-aromatic, monovalent or polyvalent, bicyclic or tricyclic ring containing 5 to 12 ring atoms, wherein at least one ring atom is selected from nitrogen, sulfur and oxygen atoms, and the ring shares a carbon atom with the ring. Wherein, in some embodiments, spiroheterocyclyl consists of 7-12 ring atoms, wherein said ring atoms contain at least one heteroatom. Unless otherwise indicated, spiroheterocyclyl groups may be attached to other groups in the molecule through a carbon atom, or through a nitrogen atom, and-CH2-the group may optionally be replaced by-C (═ O) -. The sulfur atom of the ring may optionally be oxidized to the S-oxide. The nitrogen atom of the ring may optionally be oxidized to an N-oxygen compound. Examples of spiroheterocycles include, but are not limited to:
Figure BDA0002878710730000126
The term "aryl" denotes a monocyclic, bicyclic or tricyclic all carbocyclic ring system containing 6 to 14 ring atoms, or 6 to 12 ring atoms, or 6 to 10 ring atoms, wherein at least one ring is aromatic and has one or more attachment points to the rest of the molecule. The term "aryl" may be used interchangeably with the term "aromatic ring". In some embodiments, aryl is a carbocyclic ring system consisting of 6 to 10 ring atoms and containing at least one aromatic ring therein. Examples of the aryl group may include phenyl, naphthyl and anthracenyl. The aryl group may independently be optionally substituted with one or more substituents described herein.
The term "heteroaryl" denotes a monocyclic, bicyclic or tricyclic ring containing 5 to 12 ring atoms, wherein at least one ring is aromatic and at least one ring contains one or more heteroatoms and has one or more attachment points to the rest of the molecule. The term "heteroaryl" may be used interchangeably with the terms "heteroaromatic ring" or "heteroaromatic compound". Wherein, in some embodiments, heteroaryl is a heteroaryl consisting of 5 to 12 ring atoms containing 1, 2, 3, or 4 heteroatoms independently selected from O, S and N; in other embodiments, heteroaryl is a heteroaryl consisting of 5 to 10 ring atoms containing 1, 2, 3, or 4 heteroatoms independently selected from O, S and N; in still other embodiments, heteroaryl is a heteroaryl consisting of 5 to 6 ring atoms containing 1, 2, 3, or 4 heteroatoms independently selected from O, S and N.
Examples of heteroaryl groups include, but are not limited to, furyl (e.g., 2-furyl, 3-furyl), imidazolyl (e.g., N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), isoxazolyl (e.g., 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), oxadiazolyl (e.g., 1,2, 3-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,2, 4-oxadiazolyl), oxadiazolyl (e.g., 1,2,3, 4-oxadiazolyl), thiazolyl (e.g., 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), isothiazolyl, 2-thiadiazolyl (e.g., 1,3, 4-thiadiazolyl, 1,2, 3-thiadiazolyl, 1,2, 5-thiadiazolyl), thiatriazolyl (e.g., 1,2,3, 4-thiatriazolyl), tetrazolyl (e.g., 2H-1,2,3, 4-tetrazolyl, 1H-1,2,3, 4-tetrazolyl), triazolyl (e.g., 2H-1,2, 3-triazolyl, 1H-1,2, 4-triazolyl, 4H-1,2, 4-triazolyl), thienyl (e.g., 2-thienyl, 3-thienyl), 1H-pyrazolyl (e.g., 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, 1H-pyrazol-5-yl), 1,2, 3-thiadiazolyl, 1,3, 4-thiadiazolyl, 1,2, 5-thiadiazolyl, pyrrolyl (e.g., N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyridazinyl (e.g., 3-pyridazinyl, 4-pyridazinyl), 2-pyrazinyl, triazinyl (e.g., 1,3, 5-triazine), tetrazinyl (e.g., 1,2,4, 5-tetrazine, 1,2,3, 5-tetrazine); the following bicyclic rings are also included, but are in no way limited to these: benzimidazolyl, benzpyrazolyl (e.g. benzimidazolyl, benzopyrazolyl)
Figure BDA0002878710730000131
) Benzofuranyl, benzothienyl, indolyl (e.g., 2-indolyl), purinyl, quinolyl (e.g., 2-quinolyl, 3-quinolyl, 4-quinolyl), isoquinolyl (e.g., 1-isoquinolyl, 3-isoquinolyl, or 4-isoquinolyl), imidazo [1,2-a ] or its salt]Pyridyl, pyrazolo [1,5-a]Pyridyl, pyrazolo [1,5-a]Pyrimidinyl, imidazo [1,2-b ]]Pyridazinyl, [1,2,4 ]]Triazolo [4,3-b]Pyridazinyl, [1,2,4 ]]Triazolo [1,5-a]Pyrimidinyl, [1,2,4 ] or their salts]Triazolo [1,5-a]A pyridyl group,
Figure BDA0002878710730000132
And so on.
The term "carboxy", whether used alone or in combination with other terms, such as "carboxyalkyl", denotes-CO2H or-COOH.
The term "j-k atoms make up" means that the cyclic group consists of j-k ring atoms including carbon atoms and/or heteroatoms such as O, N, S, P; j and k are each independently any non-zero natural number, and k is greater than j; the term "j-k" includes j, k and any natural number therebetween. For example, "5 to 12 atoms make up," "5 to 10 atoms make up," "5 to 6 atoms make up," or "3 to 7 atoms make up" means that the cyclic group consists of 5 to 12 (i.e., 5, 6, 7, 8, 9, 10, 11, or 12), 5 to 10 (i.e., 5, 6, 7, 8, 9, or 10), 5 to 6 (i.e., 5 or 6), or 3 to 7 (i.e., 3, 4, 5, 6, or 7) ring atoms including carbon atoms and/or heteroatoms such as O, N, S, P.
The term "unsaturated" as used herein means that the group contains one or more unsaturations.
The term "heteroatom" refers to O, S, N, P and Si, including N, S and any oxidation state form of P; primary, secondary, tertiary amines and quaternary ammonium salt forms; or a form in which a hydrogen on a nitrogen atom in the heterocycle is substituted, for example, N (like N in 3, 4-dihydro-2H-pyrrolyl), NH (like NH in pyrrolidinyl) or NR (like NR in N-substituted pyrrolidinyl).
The term "halogen" or "halogen atom" means a fluorine atom (F), chlorine atom (Cl), bromine atom (Br) or iodine atom (I).
The term "cyano" or "CN" denotes a cyano structure, which group may be attached to another group.
The term "nitro" or "NO2"denotes a nitro structure, which may be linked to other groups.
As described herein, a ring system formed on a ring wherein a substituent is bonded to the center (as shown in formula b) represents that the substituent may be substituted at any substitutable position on the ring. For example, formula b represents a substituent R' which may be mono-or polysubstituted at any possible substituted position on the ring, including, but not limited to, those shown in formulas b1 through b 9.
Figure BDA0002878710730000141
When a group is attached to the rest of the molecule via two sites, as described herein, the two sites are independently optionally attached to other groups of the molecule, and the groups attached to the two sites may be interchanged, unless otherwise indicated; for example, the piperidine group in formula c may be through E1End and E2The ends being connected to the rest of the molecule, E when the rest of the molecule is unchanged1End and E2The ends may be interchanged.
Figure BDA0002878710730000142
As described herein, a linkage to the ring system (as shown in formula d) means that the linkage can be attached to the rest of the molecule at any point on the ring system that is available for attachment. Formula d represents any possible attachment position on the ring that can be attached to the rest of the molecule, as shown by formulas d 1-d 5.
Figure BDA0002878710730000143
The term "protecting group" or "PG" means that a substituent is initiated with another functional groupWhen reacting, it is usually used to block or protect a particular functionality. For example, "amino protecting group" means a substituent attached to an amino group to block or protect the functionality of the amino group in a compound, and suitable amino protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC ), benzyloxycarbonyl (CBZ ) and 9-fluorenylmethyleneoxycarbonyl (Fmoc). Similarly, "hydroxyl protecting group" refers to the functionality of a substituent of a hydroxyl group to block or protect the hydroxyl group, and suitable protecting groups include acetyl and silyl groups. "carboxy protecting group" refers to the functionality of a substituent of a carboxy group to block or protect the carboxy group, and typical carboxy protecting groups include-CH 2CH2SO2Ph, cyanoethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxymethyl, 2- (p-toluenesulfonyl) ethyl, 2- (p-nitrobenzenesulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitroethyl, and the like. General descriptions of protecting groups can be found in the literature: greene, Protective Groups in Organic Synthesis, John Wiley&Sons,New York,1991；and P.J.Kocienski,Protecting Groups,Thieme,Stuttgart,2005.
The term "prodrug", as used herein, represents a compound that is converted in vivo to a compound of formula (I). Such conversion is effected by hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent structure in the blood or tissue. The prodrug compound of the invention can be ester, and in the prior invention, the ester can be used as the prodrug and comprises phenyl ester and aliphatic (C)1-C24) Esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound of the present invention contains a hydroxy group, i.e., it can be acylated to provide the compound in prodrug form. Other prodrug forms include phosphate esters, such as those obtained by phosphorylation of a hydroxyl group on the parent. For a complete discussion of prodrugs, reference may be made to the following: T.Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems, Vol.14of the A.C.S.symposium Series, Edward B.Roche, ed., Bioreversible Cariers in Drug Design, American Pharmaceutical Association and Pergamon Pres s,1987,J.Rautio et al.,Prodrugs:Design and Clinical Applications,Nature Review Drug Discovery,2008,7,255-270,and S.J.Hecker et al.,Prodrugs of Phosphates and Phosphonates,Journal of Medicinal Chemistry,2008,51,2328-2345。
"metabolite" refers to the product of a particular compound or salt thereof obtained by metabolism in vivo. Metabolites of a compound can be identified by techniques well known in the art, and its activity can be characterized by assay methods as described herein. Such products may be obtained by administering the compound by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, and the like. Accordingly, the present invention includes metabolites of compounds, including metabolites produced by contacting a compound of the present invention with a mammal for a sufficient period of time.
As used herein, "pharmaceutically acceptable salts" refer to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable salts are well known in the art, as are: berge et al, description of the scientific acceptable salts in detail in J. pharmaceutical Sciences,1977,66:1-19. Pharmaceutically acceptable non-toxic acid forming salts include, but are not limited to, inorganic acid salts such as hydrochloride, hydrobromide, phosphate, sulfate, perchlorate, and organic acid salts such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, or obtained by other methods described in the literature above, such as ion exchange. Other pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, cyclopentylpropionates, digluconates, dodecylsulfates, ethanesulfonates, formates, fumarates, glucoheptonates, glycerophosphates, gluconates, hemisulfates, heptanoates, hexanoates, hydroiodides, 2-hydroxy-ethanesulfonates, lactobionates, lactates, laurates, lauryls Sulfates, malates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, palmitates, embonate, pectinates, persulfates, 3-phenylpropionates, picrates, pivalates, propionates, stearates, thiocyanates, p-toluenesulfonates, undecanoates, valerates, and the like. Salts obtained with appropriate bases include alkali metals, alkaline earth metals, ammonium and N+(C1-4Alkyl radical)4A salt. The present invention also contemplates quaternary ammonium salts formed from compounds containing groups of N. Water-soluble or oil-soluble or dispersion products can be obtained by quaternization. Alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and amine cations resistant to formation of counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C1-8Sulfonates and aromatic sulfonates.
"solvate" of the present invention refers to an association of one or more solvent molecules with a compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and aminoethanol. The term "hydrate" refers to an association of solvent molecules that is water.
When the solvent is water, the term "hydrate" may be used. In some embodiments, a molecule of a compound of the present invention may be associated with a molecule of water, such as a monohydrate; in other embodiments, one molecule of the compound of the present invention may be associated with more than one molecule of water, such as a dihydrate, and in still other embodiments, one molecule of the compound of the present invention may be associated with less than one molecule of water, such as a hemihydrate. It should be noted that the hydrates of the present invention retain the biological effectiveness of the compound in its non-hydrated form.
The term "nitroxide" means that when a compound contains several amine functional groups, 1 or more than 1 nitrogen atom can be oxidized to form an N-oxide. Specific examples of N-oxides are N-oxides of tertiary amines or N-oxides of nitrogen-containing heterocyclic nitrogen atoms. The corresponding amines can be treated with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid) to form the N-oxide (see Advanced Organic Chemistry, Wiley Interscience, 4 th edition, Jerry March, pages). In particular, the N-oxide may be prepared by the method of L.W.Deady (Syn.Comm.1977,7,509-514) in which an amine compound is reacted with m-chloroperoxybenzoic acid (MCPBA), for example, in an inert solvent such as 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, known to those skilled in the art (e.g., Remington's Pharmaceutical Sciences,18th Ed. Mack Printing Company,1990, pp. 1289-1329). Except insofar as any conventional carrier is incompatible with the active ingredient, its use in therapeutic or pharmaceutical compositions is contemplated.
The term "treating" any disease or condition, as used herein, means all that can slow, halt, arrest, control or halt the progression of the disease or condition, but does not necessarily mean that all the symptoms of the disease or condition have disappeared, and also includes prophylactic treatment of the symptoms, particularly in patients susceptible to such disease or disorder. In some of these embodiments, refers to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one clinical symptom thereof). In other embodiments, "treating" or "treatment" refers to moderating or improving at least one physical parameter, including physical parameters that may not be perceived by the patient. In other embodiments, "treating" or "treatment" refers to modulating the disease or disorder, either physically (e.g., stabilizing a perceptible symptom) or physiologically (e.g., stabilizing a parameter of the body), or both. In other embodiments, "treating" or "treatment" refers to preventing or delaying the onset, occurrence, or worsening of a disease or disorder.
The term "therapeutically effective amount" or "therapeutically effective dose" as used herein refers to an amount of a compound of the invention that is capable of eliciting a biological or medical response (e.g., reducing or inhibiting enzyme or protein activity, or ameliorating symptoms, alleviating a disorder, slowing or delaying the progression of a disease, or preventing a disease, etc.) in a subject. In one non-limiting embodiment, the term "therapeutically effective amount" refers to an amount that, when administered to a subject, is effective for: (1) at least partially alleviating, inhibiting, preventing and/or ameliorating a disorder or disease (i) mediated by roryt, or (ii) associated with roryt activity, or (iii) characterized by abnormal activity of roryt; or (2) reduces or inhibits the activity of ROR γ t; or (3) reduces or inhibits expression of ROR γ t. In another embodiment, the term "therapeutically effective amount" refers to an amount that, when administered to a cell, or organ, or non-cellular biological substance, or vehicle, at least partially reduces or inhibits ROR γ t activity; or an amount of a compound of the invention effective to at least partially reduce or inhibit ROR γ t expression.
The terms "administration" and "administering" of a compound as used herein shall be understood as providing a compound of the invention or a prodrug of a compound of the invention to a subject in need thereof. It will be appreciated that one skilled in the art can treat a patient currently suffering from such a disorder or prophylactically treat a patient suffering from such a disorder by using an effective amount of a compound of the present invention.
The term "composition" as used herein refers to a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. The meaning of such terms in relation to pharmaceutical compositions includes products comprising the active ingredient(s) and the inert ingredient(s) that make up the carrier, as well as any product which results, directly or indirectly, from mixing, complexation or aggregation of any two or more of the ingredients, or from decomposition of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention include any composition prepared by admixing a compound of the present invention and a pharmaceutically acceptable carrier.
Description of the Compounds of the invention
The invention discloses five-membered heteroaromatic derivatives, pharmaceutically acceptable salts and pharmaceutical preparations thereof, which can be used as ROR gamma t inhibitors and have potential application to treatment of ROR gamma t-mediated cancer, inflammation or autoimmune diseases, such as cancer, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease, colitis, ulcerative colitis, rheumatoid arthritis, autoimmune ophthalmopathy, ankylosing spondylitis, asthma, chronic obstructive pulmonary disease, osteoarthritis, allergic rhinitis, allergic dermatitis, Crohn's disease or Kawasaki disease.
In one aspect, the invention relates to a compound of formula (I) or a stereoisomer, a nitrogen oxide, a solvate, a metabolite, a pharmaceutically acceptable salt of a compound of formula (I) or a prodrug thereof,
Figure BDA0002878710730000161
wherein, A, B, C, D, L1、L2、L3、R5、R6And R7Have the meaning as described in the present invention; and represents L2And L3The direction of connection to ring C and ring D, respectively.
In some embodiments, L is1Is a bond, -O-, -S-, -NH-, -C (═ O) -or- (CR)aRb)n-; wherein R isaAnd RbHave the meaning as described in the present invention.
In some embodiments, S (O)2-NH-、*-NH-S(O)2-, - (O) -NH-, - (NH-s) (O) -, - (C (═ O) NH-, or- (O) -.
In some embodiments, L is3is-N (R)g)-C(＝O)-、**-C(＝O)-N(Rg)-、**-O-C(＝O)-、**-C(＝O)-O-、**-C(＝O)-、**-S(＝O)2-、**-S(＝O)-、**-S(＝O)2N(Rg) -or-S (═ O) (═ NH) -; wherein R isgHave the meaning as described in the present invention.
In some embodiments, RaAnd RbEach independently of the otherGround is H, deuterium, F, Cl, Br, I, C1-6Alkyl or C1-6A haloalkyl group.
In some embodiments, A is-C0-6alkylene-C6-10Aryl radical, -C0-6Alkylene- (5-10 atom-constituting heteroaryl), -C0-6alkylene-C3-8Cycloalkyl, -C0-6Alkylene- (heterocyclic group consisting of 5 to 10 atoms), -C0-6Alkylene- (7-12 atom spiro carbocyclyl), -C0-6Alkylene- (7-12 atom spiroheterocyclyl) or C 1-6An alkyl group; wherein A is substituted by 1, 2, 3, 4, 5 or 6R1Substitution; wherein R is1Have the meaning as described in the present invention.
In some embodiments, ring B is heterocyclyl consisting of 5-10 atoms; wherein said B ring is optionally substituted with 1, 2, 3, 4, 5 or 6R2Substitution; wherein R is2Have the meaning as described in the present invention.
In some embodiments, ring C is a 5 atom heteroaryl; wherein said C ring is optionally substituted with 1, 2 or 3R3Substitution; wherein R is3Have the meaning as described in the present invention.
In some embodiments, the D ring is C6-10Aryl, heteroaryl of 5 to 10 atoms, C3-8Cycloalkyl or heterocyclyl consisting of 5 to 10 atoms; wherein said D ring is optionally substituted with 1, 2, 3, 4, 5 or 6R4Substitution; wherein R is4Have the meaning as described in the present invention.
In some embodiments, R1And R2Each independently is deuterium, F, Cl, Br, I, -CN, -NH2、-NO2-OH, -COOH, oxo, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, -C1-6alkylene-O-C1-6Alkyl radical, C3-8Cycloalkyl radical, C6-10Aryl, heterocyclyl of 5 to 10 atoms, heteroaryl of 5 to 10 atoms or-C (═ O) -N (R) dRe) (ii) a Wherein, said C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, -C1-6alkylene-O-C1-6Alkyl radical, C3-8Cycloalkyl radical, C6-10Aryl, heterocyclyl of 5-10 atoms and heteroaryl of 5-10 atoms are independently optionally substituted with 1, 2, 3, 4, 5 or 6RcSubstituted; wherein R isc、RdAnd ReHave the meaning as described in the present invention.
In some embodiments, each R iscIndependently deuterium, F, Cl, Br, I, -OH, -CN, -NH2、C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Haloalkyl, C1-6Haloalkoxy, C3-8Cycloalkyl, heterocyclic radical consisting of 5-10 atoms, C6-10Aryl or heteroaryl of 5 to 10 atoms.
In some embodiments, R3And R4Each independently is deuterium, F, Cl, Br, I, -CN, -NH2、-NO2、-OH、-COOH、C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Haloalkoxy, C1-6Haloalkyl or C1-6An alkoxy group.
In some embodiments, R5And R6Each independently of the others being H, deuterium, -OH, -CN, -NH2、-NO2、-COOH、C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Haloalkyl, -C1-6alkylene-O-C1-6Alkyl, -C1-6alkylene-C (═ O) -O-C1-6Alkyl, -C1-6alkylene-C (═ O) -N (R)dRe)、-C1-6alkylene-O-C (═ O) -N (R)dRe)、-C1-6alkylene-N (R)f)-C(＝O)-N(RdRe) or-C1-6alkylene-N (R)dRe) (ii) a Wherein, said C1-6Alkyl radical, C 1-6Alkoxy radical, C1-6Haloalkyl, -C1-6alkylene-C (═ O) -O-C1-6Alkyl and-C1-6alkylene-O-C1-6Alkyl is independently optionally substituted by 1, 2 or 3 substituents selected from deuterium, F, Cl, Br, I, -OH, -CN, -COOH, -N (R)dRe)、C1-6Alkyl radical, C1-6Haloalkyl, C1-6Alkoxy or C1-6Substituted with a substituent of haloalkoxy;
or R5、R6Together with the carbon atom to which they are attached form C3-8Cycloalkyl or heterocyclyl consisting of 3 to 8 atoms; wherein, said C3-8Cycloalkyl and heterocyclyl consisting of 3 to 8 atoms are independently optionally substituted by 1, 2, 3 or 4 substituents selected from deuterium, F, Cl, Br, I, -OH, -CN, -COOH, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Alkoxy or C1-6Substituted with a substituent of haloalkoxy;
wherein R isd、ReAnd RfHave the meaning as described in the present invention.
In some embodiments, RdAnd ReEach independently of the others being H, deuterium, -OH, C1-6Alkyl, -C (═ O) H, -C (═ O) -O-C1-6Alkyl, -C (═ O) -C1-6Alkyl, -C1-6alkylene-C (═ O) -O-C1-6Alkyl or-C1-6alkylene-O-C1-6An alkyl group; wherein, said C1-6Alkyl, -C1-6alkylene-C (═ O) -O-C1-6Alkyl and-C1-6alkylene-O-C1-6Alkyl is independently optionally substituted by 1, 2 or 3 substituents selected from deuterium, F, Cl, Br, I, -OH, -CN, -NH2Or a substituent of-COOH.
In some embodiments, each R is fIndependently of one another H, deuterium, C1-6Alkyl, -C1-6alkylene-O-C1-6Alkyl, -C1-6alkylene-C3-8Cycloalkyl or-C1-6Alkylene- (5-10 atom-constituting heterocyclic group); wherein, said C1-6Alkyl, -C1-6alkylene-O-C1-6Alkyl, -C1-6alkylene-C3-8Cycloalkyl and-C1-6Alkylene- (heterocyclyl consisting of 5 to 10 atoms) is independently optionally substituted by 1,2 or 3 substituents selected from deuterium, F, Cl, Br, I, -OH, -CN, -NH2Or a substituent of-COOH.
In some embodiments, R7Is H, deuterium, -COOH, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkylamino radical, C1-6Haloalkyl, C3-8Cycloalkyl radical, C3-8Cycloalkylamino or heterocyclyl consisting of 5 to 10 atoms.
In some embodiments, RgIs H, deuterium or C1-6An alkyl group.
In some embodiments, m is 0, 1,2, 3, or 4.
In some embodiments, n is 1,2, 3, or 4.
In other embodiments, RaAnd RbEach independently of the others is H, deuterium, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2, 2-difluoroethyl, 1, 2-difluoroethyl, 2,2, 2-trifluoroethyl, monochloromethyl, dichloromethyl, 2-chloroethyl, 2, 2-dichloroethyl or 1, 2-dichloroethyl.
In other embodiments, A is-C0-4alkylene-C6-10Aryl radical, -C0-4Alkylene- (5-6-atom heteroaryl), -C0-4alkylene-C3-6Cycloalkyl, -C0-4Alkylene- (heterocyclic group consisting of 5 to 7 atoms), -C0-4Alkylene- (7-12 atom spiro carbocyclyl), -C0-4Alkylene- (7-12 atom spiroheterocyclyl) or C1-4An alkyl group; wherein A is substituted by 1, 2, 3, 4, 5 or 6R1Substitution; wherein R is1Have the meaning as described in the present invention.
In other embodiments, A is phenyl, naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolyl, pyrazolyl, imidazolyl, furyl, oxazolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuryl, tetrahydropyranyl, pyrrolidinyl, piperazinyl, pyrazolyl, imidazolyl, furyl, thienyl, pyridyl, pyrazinyl, piperazinyl, thienyl, and the like,
Figure BDA0002878710730000181
Figure BDA0002878710730000182
Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; wherein A is substituted by 1, 2, 3, 4, 5 or 6R1Substitution; wherein R is1Have the meaning as described in the present invention.
In other embodiments, ring B is heterocyclyl with 5-7 atoms; wherein the B ring is optionally substituted with 1, 2, 3, 4, 5 or 6R 2Substituted; wherein R is2Have the meaning as described in the present invention.
In other embodiments, ring B is
Figure BDA0002878710730000183
Figure BDA0002878710730000184
Figure BDA0002878710730000185
Wherein said B ring is optionally substituted with 1, 2, 3, 4, 5 or 6R2Substituted; wherein R is2Have the meaning as described in the present invention.
In other embodiments, C is
Figure BDA0002878710730000186
Figure BDA0002878710730000187
Wherein said C is optionally substituted with 1, 2 or 3R3Substitution; wherein R is3Have the meaning as described in the present invention.
In other embodiments, the D ring is C6-10Aryl, heteroaryl of 5 to 6 atoms, C3-6Cycloalkyl or heterocyclyl consisting of 5 to 7 atoms; wherein said D ring is optionally substituted with 1, 2, 3, 4, 5 or 6R4Substitution; wherein R is4Have the meaning as described in the present invention.
In yet other embodiments of the present invention, the substrate is,ring D is phenyl, naphthyl, indolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolyl, pyrazolyl, imidazolyl, furanyl, oxazolyl, cyclopentyl, cyclohexyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, or piperazinyl; wherein D is optionally substituted with 1, 2, 3, 4, 5 or 6R4Substitution; wherein R is4Have the meaning as described in the present invention.
In other embodiments, R 1And R2Each independently is deuterium, F, Cl, Br, I, -CN, -NH2、-NO2-OH, -COOH, oxo, C1-4Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C1-4Haloalkyl, C1-4Alkoxy radical, C1-4Haloalkoxy, -C1-4alkylene-O-C1-4Alkyl radical, C3-6Cycloalkyl radical, C6-10Aryl, heterocyclyl of 5 to 7 atoms, heteroaryl of 5 to 6 atoms or-C (═ O) -N (R)dRe) (ii) a Wherein, said C1-4Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C1-4Haloalkyl, C1-4Alkoxy radical, C1-4Haloalkoxy, -C1-4alkylene-O-C1-4Alkyl radical, C3-6Cycloalkyl radical, C6-10Aryl, heterocyclyl of 5-7 atoms and heteroaryl of 5-6 atoms are independently optionally substituted with 1, 2, 3, 4, 5 or 6RcSubstituted; wherein R isc、RdAnd ReHave the meaning as described in the present invention.
In other embodiments, each R iscIndependently deuterium, F, Cl, Br, I, -OH, -CN, -NH2、C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl, C1-4Haloalkoxy, C3-6Cycloalkyl, heterocyclic radical of 5-7 atoms, C6-10Aryl or heteroaryl of 5 to 6 atoms.
In other embodiments, R3And R4Each independently is deuterium, F, Cl, Br, I, -CN, -NH2、-NO2、-OH、-COOH、C1-4Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C1-4Haloalkoxy, C1-4Haloalkyl or C1-4An alkoxy group.
In other embodiments, R5And R6Each independently of the others being H, deuterium, -OH, -CN, -NH2、-NO2、-COOH、C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl, -C1-4alkylene-O-C1-4Alkyl, -C1-4alkylene-C (═ O) -O-C1-4Alkyl, -C1-4alkylene-C (═ O) -N (R)dRe)、-C1-4alkylene-O-C (═ O) -N (R)dRe)、-C1-4alkylene-N (R)f)-C(＝O)-N(RdRe) or-C1-4alkylene-N (R)dRe) (ii) a Wherein, said C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl, -C1-4alkylene-C (═ O) -O-C1-4Alkyl and-C1-4alkylene-O-C1-4Alkyl is independently optionally substituted with deuterium, F, Cl, Br, I, -OH, -CN, -COOH, -N (R)dRe)、C1-4Alkyl radical, C1-4Haloalkyl, C1-4Alkoxy or C1-4Substituted with a substituent of haloalkoxy;
or R5And R6Together with the carbon atoms to which they are jointly attached form C3-6Cycloalkyl or heterocyclyl consisting of 3 to 6 atoms; wherein, said C3-6Cycloalkyl and heterocyclyl consisting of 3 to 6 atoms are independently optionally substituted by 1, 2, 3 or 4 substituents selected from deuterium, F, Cl, Br, I, -OH, -CN, -COOH, C1-4Alkyl radical, C1-4Haloalkyl, C1-4Alkoxy or C1-4Substituted with a substituent of haloalkoxy;
wherein R isd、ReAnd RfHave the meaning as described in the present invention.
In other embodiments, RdAnd ReEach independently of the others being H, deuterium, -OH, C1-4Alkyl, -C (═ O) H, -C (═ O) -O-C 1-4Alkyl, aryl, heteroaryl, and heteroaryl,-C(＝O)-C1-4Alkyl, -C1-4alkylene-C (═ O) -O-C1-4Alkyl or-C1-4alkylene-O-C1-4An alkyl group; wherein, said C1-4Alkyl, -C1-4alkylene-C (═ O) -O-C1-4Alkyl and-C1-4alkylene-O-C1-4Alkyl is independently optionally substituted by 1, 2 or 3 substituents selected from deuterium, F, Cl, Br, I, -OH, -CN, -NH2Or a substituent of-COOH.
In other embodiments, each R isfIndependently of one another H, deuterium, C1-4Alkyl, -C1-4alkylene-O-C1-4Alkyl, -C1-4alkylene-C3-6Cycloalkyl or-C1-4Alkylene- (5-7 atom-constituting heterocyclic group); wherein, said C1-4Alkyl, -C1-4alkylene-O-C1-4Alkyl, -C1-4alkylene-C3-6Cycloalkyl and-C1-4Alkylene- (heterocyclyl consisting of 5 to 7 atoms) is independently optionally substituted by 1, 2 or 3 substituents selected from deuterium, F, Cl, Br, I, -OH, -CN, -NH2Or a substituent of-COOH.
In other embodiments, R7Is H, deuterium, -COOH, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Alkylamino radical, C1-4Haloalkyl, C3-6Cycloalkyl radical, C3-6Cycloalkylamino or heterocyclyl consisting of 5 to 7 atoms.
In other embodiments, RgIs H, deuterium or C1-4An alkyl group.
In still other embodiments, R1And R2Each independently is deuterium, F, Cl, Br, I, -CN, -NH2、-NO2OH, -COOH, oxo, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, vinyl, ethynyl, -CH 2F、-CH2Cl、-CHF2、-CHCl2、-CF3、-CH2CH2F、-CH2CH2Cl、-CH2CHF2、-CH2CHCl2、-CHFCH2F、-CHClCH2Cl、-CH2CF3、-CH(CF3)2、-CF2CH2CH3、-CH2CH2CH2F、-CH2CH2CHF2、-CH2CH2CF3Methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, -OCH2F、-OCH2Cl、-OCHF2、-OCHCl2、-OCF3、-OCH2CH2F、-OCH2CH2Cl、-OCH2CHF2、-OCH2CHCl2、-OCHFCH2F、-OCHClCH2Cl、-OCH2CF3、-OCH(CF3)2、-OCF2CH2CH3、-OCH2CH2CH2F、-OCH2CH2CHF2、-OCH2CH2CF3、-CH2OCH3、-CH2OCH2CH3、-CH2OCH2CH2CH3、-CH2OCH(CH3)2、-CH2CH2OCH3、-CH2CH2OCH2CH3、-CH2CH2OCH2CH2CH3、-CH2CH2OCH(CH3)2、-CH2CH2CH2OCH3、-CH2CH2CH2OCH2CH3、-CH2CH2CH2OCH2CH2CH3、-CH2CH2CH2OCH(CH3)2Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, pyridyl, pyrimidinyl, pyrazolyl, thiazolyl, imidazolyl, oxazolyl, triazolyl, tetrazolyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, pyrrolidinyl, or-C (═ O) -N (R)dRe)；
Wherein, the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, ethyleneradical-CH2F、-CH2Cl、-CHF2、-CHCl2、-CH2CH2F、-CH2CH2Cl、-CH2CHF2、-CH2CHCl2、-CHFCH2F、-CHClCH2Cl、-CH2CF3、-CH(CF3)2、-CF2CH2CH3、-CH2CH2CH2F、-CH2CH2CHF2、-CH2CH2CF3Methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, -OCH2F、-OCH2Cl、-OCHF2、-OCHCl2、-OCH2CH2F、-OCH2CH2Cl、-OCH2CHF2、-OCH2CHCl2、-OCHFCH2F、-OCHClCH2Cl、-OCH2CF3、-OCH(CF3)2、-OCF2CH2CH3、-OCH2CH2CH2F、-OCH2CH2CHF2、-OCH2CH2CF3、-CH2OCH3、-CH2OCH2CH3、-CH2OCH2CH2CH3、-CH2OCH(CH3)2、-CH2CH2OCH3、-CH2CH2OCH2CH3、-CH2CH2OCH2CH2CH3、-CH2CH2OCH(CH3)2、-CH2CH2CH2OCH3、-CH2CH2CH2OCH2CH3、-CH2CH2CH2OCH2CH2CH3、-CH2CH2CH2OCH(CH3)2Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, pyridyl, pyrimidinyl, pyrazolyl, thiazolyl, imidazolyl, oxazolyl, triazolyl, tetrazolyl, piperazinyl, piperidineIndependently, optionally substituted by 1, 2, 3, 4, 5 or 6RcSubstituted;
wherein R isc、RdAnd ReHave the meaning as described in the present invention.
In yet other embodiments, each R iscIndependently deuterium, F, Cl, Br, I, -OH, -CN, -NH2Methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, -CH 2F、-CHF2、-CF3、-CH2CH2F、-CH2CHF2、-CHFCH2F、-CH2CF3、-CH(CF3)2、-CF2CH2CH3、-CH2CH2CH2F、-CH2CH2CHF2、-CH2CH2CF3Methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, -OCH2F、-OCHF2、-OCF3、-OCH2CH2F、-OCH2CHF2、-OCHFCH2F、-OCH2CF3、-OCH(CF3)2、-OCF2CH2CH3、-OCH2CH2CH2F、-OCH2CH2CHF2、-OCH2CH2CF3Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, pyridyl, pyrimidinyl, pyrazolyl, thiazolyl, imidazolyl, oxazolyl, triazolyl, tetrazolyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl or pyrrolidinyl.
In still other embodiments, R3And R4Each independently is deuterium, F, Cl, Br, I, CN, NH2、NO2OH, COOH, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, vinyl, ethynyl, -CH2F、-CH2Cl、-CHF2、-CHCl2、-CF3、-CH2CH2F、-CH2CH2Cl、-CH2CHF2、-CH2CHCl2、-CHFCH2F、-CHClCH2Cl、-CH2CF3、-CH(CF3)2、-CF2CH2CH3、-CH2CH2CH2F、-CH2CH2CHF2、-CH2CH2CF3、-OCH2F、-OCH2Cl、-OCHF2、-OCHCl2、-OCF3、-OCH2CH2F、-OCH2CH2Cl、-OCH2CHF2、-OCH2CHCl2、-OCHFCH2F、-OCHClCH2Cl、-OCH2CF3、-OCH(CF3)2、-OCF2CH2CH3、-OCH2CH2CH2F、-OCH2CH2CHF2、-OCH2CH2CF3Methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy or tert-butoxy.
In still other embodiments, R5And R6Each independently of the others being H, deuterium, -OH, -CN, -NH2、-NO2-COOH, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, -CH2F、-CH2Cl、-CHF2、-CHCl2、-CF3、-CH2CH2F、-CH2CH2Cl、-CH2CHF2、-CH2CHCl2、-CHFCH2F、-CH2OCH3、-CH2OCH2CH3、-CH2OCH2CH2CH3、-CH2OCH(CH3)2、-CH2CH2OCH3、-CH2CH2OCH2CH3、-CH2CH2OCH2CH2CH3、-CH2CH2OCH(CH3)2、-CH2CH2CH2OCH3、-CH2CH2CH2OCH2CH3、-CH2CH2CH2OCH2CH2CH3、-CH2CH2CH2OCH(CH3)2、-CH2-C(＝O)-OCH3、-CH2-C(＝O)-OCH2CH3、-CH2-C(＝O)-OCH2CH2CH3、-CH2-C(＝O)-OCH(CH3)2、-CH2CH2-C(＝O)-OCH3、-CH2CH2-C(＝O)-OCH2CH3、-CH2CH2-C(＝O)-OCH2CH2CH3、-CH2CH2-C(＝O)-OCH(CH3)2、-CH2CH2CH2-C(＝O)-OCH3、-CH2CH2CH2-C(＝O)-OCH2CH3、-CH2CH2CH2-C(＝O)-OCH2CH2CH3、-CH2CH2CH2-C(＝O)-OCH(CH3)2、-CH2-C(＝O)-N(RdRe)、-CH2CH2-C(＝O)-N(RdRe)、-CH2CH2CH2-C(＝O)-N(RdRe)、-CH2-O-C(＝O)-N(RdRe)、-CH2CH2-O-C(＝O)-N(RdRe)、-CH2CH2CH2-O-C(＝O)-N(RdRe)、-CH2-N(Rf)-C(＝O)-N(RdRe)、-CH2CH2-N(Rf)-C(＝O)-N(RdRe)、-CH2CH2CH2-N(Rf)-C(＝O)-N(RdRe)、-CH2N(RdRe)、-CH2CH2N(RdRe) or-CH2CH2CH2N(RdRe)；
WhereinThe methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, -CH 2F、-CH2Cl、-CHF2、-CHCl2、-CF3、-CH2CH2F、-CH2CH2Cl、-CH2CHF2、-CH2CHCl2、-CHFCH2F、-CH2-C(＝O)-OCH3、-CH2-C(＝O)-OCH2CH3、-CH2-C(＝O)-OCH2CH2CH3、-CH2-C(＝O)-OCH(CH3)2、-CH2CH2-C(＝O)-OCH3、-CH2CH2-C(＝O)-OCH2CH3、-CH2CH2-C(＝O)-OCH2CH2CH3、-CH2CH2-C(＝O)-OCH(CH3)2、-CH2CH2CH2-C(＝O)-OCH3、-CH2CH2CH2-C(＝O)-OCH2CH3、-CH2CH2CH2-C(＝O)-OCH2CH2CH3、-CH2CH2CH2-C(＝O)-OCH(CH3)2、-CH2OCH3、-CH2OCH2CH3、-CH2OCH2CH2CH3、-CH2OCH(CH3)2、-CH2CH2OCH3、-CH2CH2OCH2CH3、-CH2CH2OCH2CH2CH3、-CH2CH2OCH(CH3)2、-CH2CH2CH2OCH3、-CH2CH2CH2OCH2CH3、-CH2CH2CH2OCH2CH2CH3and-CH2CH2CH2OCH(CH3)2Independently optionally substituted by 1, 2 or 3 substituents selected from deuterium, F, Cl, Br, I,-OH、-CN、-COOH、-N(RdRe) Methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, trifluoromethyl, -OCH2F、-OCH2Cl、-OCHF2、-OCHCl2、-OCF3、-OCH2CH2F、-OCH2CH2Cl、-OCH2CHF2、-OCH2CHCl2、-OCHFCH2F、-OCHClCH2Cl、-OCH2CF3、-OCH(CF3)2、-OCF2CH2CH3、-OCH2CH2CH2F、-OCH2CH2CHF2or-OCH2CH2CF3Substituted with the substituent(s);
or R5、R6And together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl or tetrahydropyranyl group; wherein said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, and tetrahydropyranyl are independently optionally substituted with 1, 2, 3, or 4 substituents selected from deuterium, F, Cl, Br, I, -OH, -CN, -COOH, methyl, ethyl, isopropyl, trifluoromethyl, methoxy, or trifluoromethoxy;
wherein R isd、ReAnd RfHave the meaning as described in the present invention.
In still other embodiments, RdAnd ReEach independently is H, deuterium, -OH, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, -C (═ O) H, -C (═ O) -O-CH 3、-C(＝O)-O-CH2CH3、-C(＝O)-O-CH2CH2CH3、-C(＝O)-O-CH(CH3)2、-C(＝O)-CH3、-C(＝O)-CH2CH3、-C(＝O)-CH2CH2CH3、-C(＝O)-CH(CH3)2、-CH2OCH3、-CH2OCH2CH3、-CH2OCH2CH2CH3、-CH2OCH(CH3)2、-CH2CH2OCH3、-CH2CH2OCH2CH3、-CH2CH2OCH2CH2CH3、-CH2CH2OCH(CH3)2、-CH2CH2CH2OCH3、-CH2CH2CH2OCH2CH3、-CH2CH2CH2OCH2CH2CH3、-CH2CH2CH2OCH(CH3)2、-CH2-C(＝O)-OCH3、-CH2-C(＝O)-OCH2CH3、-CH2-C(＝O)-OCH2CH2CH3、-CH2-C(＝O)-OCH(CH3)2、-CH2CH2-C(＝O)-OCH3、-CH2CH2-C(＝O)-OCH2CH3、-CH2CH2-C(＝O)-OCH2CH2CH3、-CH2CH2-C(＝O)-OCH(CH3)2、-CH2CH2CH2-C(＝O)-OCH3、-CH2CH2CH2-C(＝O)-OCH2CH3、-CH2CH2CH2-C(＝O)-OCH2CH2CH3or-CH2CH2CH2-C(＝O)-OCH(CH3)2；
Wherein, the methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, -CH2OCH3、-CH2OCH2CH3、-CH2OCH2CH2CH3、-CH2OCH(CH3)2、-CH2CH2OCH3、-CH2CH2OCH2CH3、-CH2CH2OCH2CH2CH3、-CH2CH2OCH(CH3)2、-CH2CH2CH2OCH3、-CH2CH2CH2OCH2CH3、-CH2CH2CH2OCH2CH2CH3、-CH2CH2CH2OCH(CH3)2、-CH2-C(＝O)-OCH3、-CH2-C(＝O)-OCH2CH3、-CH2-C(＝O)-OCH2CH2CH3、-CH2-C(＝O)-OCH(CH3)2、-CH2CH2-C(＝O)-OCH3、-CH2CH2-C(＝O)-OCH2CH3、-CH2CH2-C(＝O)-OCH2CH2CH3、-CH2CH2-C(＝O)-OCH(CH3)2、-CH2CH2CH2-C(＝O)-OCH3、-CH2CH2CH2-C(＝O)-OCH2CH3、-CH2CH2CH2-C(＝O)-OCH2CH2CH3and-CH2CH2CH2-C(＝O)-OCH(CH3)2Independently optionally substituted by 1, 2 or 3 substituents selected from deuterium, F, Cl, Br, I, -OH, -CN, -NH2Or a substituent of-COOH.
In yet other embodiments, each R isfIndependently H, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, -CH2OCH3、-CH2OCH2CH3、-CH2OCH2CH2CH3、-CH2OCH(CH3)2、-CH2CH2OCH3、-CH2CH2OCH2CH3、-CH2CH2OCH2CH2CH3、-CH2CH2OCH(CH3)2、-CH2CH2CH2OCH3、-CH2CH2CH2OCH2CH3、-CH2CH2CH2OCH2CH2CH3、-CH2CH2CH2OCH(CH3)2Cyclopropylmethylene, cyclopropylethylene, n-propylidene, cyclobutylmethylene, cyclobutylethylene, n-propylidene, cyclopentylmethylene, cyclopentylethylidene, n-propylidene, cyclohexylmethylene, cyclohexylethylene, n-propylidene, piperazinylmethylene, piperidinylmethylene, morpholinomethylene, thiomorpholinylmethylene, tetrahydropyranylmethylene or pyrrolidinylmethylene; wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, -CH2OCH3、-CH2OCH2CH3、-CH2OCH2CH2CH3、-CH2OCH(CH3)2、-CH2CH2OCH3、-CH2CH2OCH2CH3、-CH2CH2OCH2CH2CH3、-CH2CH2OCH(CH3)2、-CH2CH2CH2OCH3、-CH2CH2CH2OCH2CH3、-CH2CH2CH2OCH2CH2CH3、-CH2CH2CH2OCH(CH3)2Cyclopropylmethylene, cyclopropylethylene, n-propylidene, cyclobutylmethylene, cyclobutylethylene, cyclobutylpropylene, cyclopentylmethylene, cyclopentylethylene, cyclopentylpropylidene, cyclohexylmethylene, cyclohexylethylene, cyclohexyln-propyl, piperazinylmethylene, piperidinylmethylene, morpholinomethylene, thiomorpholinylmethylene, tetrahydropyranylmethylene and pyrrolidinylmethylene are independently optionally substituted with 1, 2 or 3 substituents selected from deuterium, F, Cl, Br, I, -OH, -CN, -NH 2Or a substituent of-COOH.
In addition toIn some embodiments, R7Is H, deuterium, -COOH, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, methylamino, ethylamino, n-propylamino, isopropylamino, -CH2F、-CH2Cl、-CHF2、-CHCl2、-CF3、-CH2CH2F、-CH2CH2Cl、-CH2CHF2、-CH2CHCl2、-CHFCH2F. Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl or pyrrolidinyl.
In still other embodiments, RgIs H, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
In some embodiments, the present invention relates to compounds, or stereoisomers, nitrogen oxides, solvates, metabolites, pharmaceutically acceptable salts or prodrugs thereof, of one of the following, but in no way limited to these compounds:
Figure BDA0002878710730000221
Figure BDA0002878710730000231
Figure BDA0002878710730000241
Figure BDA0002878710730000251
Figure BDA0002878710730000261
stereoisomers, solvates, metabolites, salts and pharmaceutically acceptable prodrugs of the compounds of formula (I) are included within the scope of the present invention unless otherwise indicated.
In another aspect, the present invention relates to a pharmaceutical composition comprising a compound of formula (I) of the present invention or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, 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 an additional agent or any combination thereof for the prevention or treatment of an inflammatory syndrome, disorder or disease.
In one embodiment, the pharmaceutical composition may be in a liquid, solid, semi-solid, gel or spray dosage form.
In another aspect, the invention relates to the use of a compound of formula (I) or a pharmaceutical composition thereof in the manufacture of a medicament for the prevention or treatment of a disease, disorder or syndrome mediated by roryt in a mammal.
In some embodiments, the present invention relates to the use of a compound of formula (I) or a pharmaceutical composition thereof in the preparation of a medicament for the prevention or treatment of cancer, inflammation or an autoimmune disease.
In some embodiments, the present invention relates to the use of a compound of formula (I) or a pharmaceutical composition thereof in the preparation of a medicament for the prevention or treatment of cancer, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease, colitis, ulcerative colitis, rheumatoid arthritis, autoimmune ocular disease, ankylosing spondylitis, asthma, chronic obstructive pulmonary disease, osteoarthritis, allergic rhinitis, allergic dermatitis, crohn's disease, or kawasaki disease.
In another aspect, the invention relates to a process for the preparation, isolation and purification of a compound of formula (I).
In another aspect, the invention relates to intermediates for the preparation of compounds of formula (I).
The compounds of the present disclosure may contain asymmetric or chiral centers and thus may exist in different stereoisomeric forms. The present invention contemplates that all stereoisomeric forms of the compounds of formula (I), including but not limited to diastereomers, enantiomers, atropisomers and geometric (or conformational) isomers, and mixtures thereof, such as racemic mixtures, are integral to the invention.
In the structures disclosed herein, when the stereochemistry of any particular chiral atom is not specified, then all stereoisomers of that structure are contemplated as within this invention and are included as disclosed compounds in this invention. When stereochemistry is indicated by a solid wedge (solid wedge) or dashed line representing a particular configuration, then the stereoisomers of the structure are so well-defined and defined.
The compounds of formula (I) may exist in different tautomeric forms and all such tautomers are included within the scope of the invention.
The compounds of formula (I) 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 compatible chemically and/or toxicologically with the other ingredients comprising the formulation and/or the mammal being treated therewith. In another embodiment, the salts need not be pharmaceutically acceptable salts and may be intermediates useful in the preparation and/or purification of compounds of formula (I) and/or in the isolation of enantiomers of compounds of formula (I).
Pharmaceutically acceptable acid addition salts may be formed from the disclosed compounds of the invention by the action of an inorganic or organic acid, for example, acetate, aspartate, benzoate, benzenesulfonate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfonate, chloride/hydrochloride, chlorotheyl salt, citrate, edisylate, fumarate, glucoheptonate, gluconate, glucuronate, hippurate, hydroiodide, isethionate, lactate, lactobionate, lauryl sulfate, malate, maleate, malonate, mandelate, methanesulfonate, methylsulfate, naphthoate, naphthalenesulfonate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate/biphosphate/dihydrogen phosphate, phosphate, Polysilonolactates, propionates, stearates, succinates, sulfosalicylates, tartrates, tosylates and trifluoroacetates.
Pharmaceutically acceptable base addition salts may be formed from the disclosed compounds by reaction with an inorganic or organic base.
Inorganic bases from which salts can be derived include, for example, ammonium salts and metals of groups I to XII of the periodic table. In certain embodiments, the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium and magnesium salts.
Organic bases from which salts can be derived include primary, secondary and tertiary amines, and substituted amines include naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like. Some organic amines include, for example, isopropylamine, benzathine (benzathine), choline salts (cholinate), diethanolamine, diethylamine, lysine, meglumine (meglumine), piperazine, and tromethamine.
The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, basic or acidic moiety, by conventional chemical methods. In general, such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of the appropriate base (e.g., Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, etc.), or by reacting the free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are usually carried out in water or an organic solvent or a mixture of both. Generally, where appropriate, it is desirable to use a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile. In, for example, "Remington's Pharmaceutical Sciences", 20 th edition, Mack Publishing Company, Easton, Pa., (1985); and "handbook of pharmaceutically acceptable salts: properties, Selection and application (Handbook of Pharmaceutical Salts: Properties, Selection, and Use) ", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany,2002) may find some additional lists of suitable Salts.
In addition, the compounds disclosed herein, including their salts, may also be obtained in the form of their hydrates or in the form of solvents containing them (e.g., ethanol, DMSO, etc.), for their crystallization. The compounds disclosed herein may form solvates with pharmaceutically acceptable solvents (including water), either inherently or by design; thus, the present invention is intended to include both solvated and unsolvated forms of the disclosed compounds.
Any formulae given herein are also intended to represent the non-isotopically enriched forms as well as the isotopically enriched forms of these compounds. Isotopically enriched compounds have the structure depicted by the formulae given herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as2H、3H、11C、13C、14C、15N、17O、18O、18F、31P、32P、35S、36Cl and125I。
in another aspect, the compounds of the invention include isotopically enriched compounds as defined herein, e.g. wherein a radioisotope, e.g. is present3H、14C and18those compounds of F, or in which a non-radioactive isotope is present, e.g.2H and 13Those of C. The isotopically enriched compounds can be used for metabolic studies (use)14C) Reaction kinetics study (using, for example2H or3H) Detection or imaging techniques such as Positron Emission Tomography (PET) or Single Photon Emission Computed Tomography (SPECT) including drug or substrate tissue distribution determination, or may be used in radiotherapy of a patient.18F-enriched compounds are particularly desirable for PET or SPECT studies. Isotopically enriched compounds of formula (I) can be prepared byThe preparation of the compounds of the invention is described by conventional techniques familiar to those skilled in the art or by the examples and preparation procedures of the invention using suitable isotopically labelled reagents instead of the original used unlabelled reagents.
In addition, heavier isotopes are, in particular, deuterium (i.e.,2substitution of H or D) may provide certain therapeutic advantages resulting from greater metabolic stability. For example, increased in vivo half-life or decreased dosage requirements or improved therapeutic index. It is to be understood that deuterium in the present invention is to be considered as a substituent of the compound of formula (I). The concentration of such heavier isotopes, particularly deuterium, can be defined by isotopic enrichment factors. The term "isotopic enrichment factor" as used herein refers to the ratio between the isotopic and natural abundance of a given isotope. If a substituent of a compound of the invention is designated as deuterium, the compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). Pharmaceutically acceptable solvates of the invention include those in which the crystallization solvent may be isotopically substituted, e.g. D 2O, acetone-d6、DMSO-d6Those solvates of (a).
Pharmaceutical compositions, formulations and administration of the compounds of the invention
The present invention provides a pharmaceutical composition comprising a compound disclosed herein, for example, as set forth in the examples; and a pharmaceutically acceptable excipient, carrier, adjuvant, or combination thereof.
The present invention provides methods of treating, preventing or ameliorating a disease or condition comprising administering a safe and effective amount of a combination comprising a compound of the present disclosure and one or more therapeutically active agents. Wherein the combination comprises one or more additional agents for the prophylaxis or treatment of an inflammatory syndrome, disorder or disease, including but not limited to:
1) a TNF-alpha inhibitor; 2) non-selective COX-1/COX-2 inhibitors; 3) COX-2 inhibitors; 4) other therapeutic agents for the treatment of inflammatory syndromes and autoimmune diseases, including glucocorticoids, methotrexate, leflunomide (leflunomide), sulfasalazine, azathioprine, cyclosporine, tacrolimus (tacrolimus), penicillamine, buclizine, acrilamide, mizoribine, clobenzaprine, ciclesonide, hydroxychloroquine, aurothiomalate, auranofin, cyclophosphamide, BAFF/APRIL inhibitors, CTLA-4-immunoglobulin or the like; 5) a leukotriene biosynthesis inhibitor, a 5-lipoxygenase inhibitor or a 5-lipoxygenase activating protein (FLAP) antagonist; 6) LTD4 receptor antagonists; 7) a PDE4 inhibitor; 8) an anti-histamine HI receptor antagonist; alpha 1 and alpha 2-adrenoceptor agonists; 9) anticholinergic agents; 10) a P-adrenoceptor agonist; 11) an insulin-like growth factor type I analog; 12) kinase inhibitors are selected from Janus kinase inhibitors (JAK1 and/or JAK2 and/or JAK3 and/or TYK2), p38 MAPK and IKK 2; 13) b cell targeting biopharmaceuticals such as rituximab; 14) selective co-stimulatory modulators such as albuterol; 15) an interleukin inhibitor selected from the group consisting of an IL-1 inhibitor such as anakinra, an IL-6 inhibitor such as tollizumab and an IL-12/IL-23 inhibitor such as Ultezumab.
The amount of compound in the pharmaceutical composition disclosed herein is effective to detect inhibition of retinoic acid-related nocosomal receptor gamma t in a biological sample or patient. The dosage of the active ingredient in the composition of the present invention may vary, however, the amount of the active ingredient must be such that a suitable dosage form is obtained. The active ingredient may be administered to patients (animals and humans) in need of such treatment at dosages that provide optimal pharmaceutical efficacy. The selected dosage depends on the desired therapeutic effect, on the route of administration and on the duration of the treatment. The dosage will vary from patient to patient depending on the nature and severity of the disease, the weight of the patient, the particular diet of the patient, the concurrent use of drugs, and other factors that will be recognized by those skilled in the art. In one embodiment, the dosage range is from about 0.5mg to 500mg per patient per day; in another embodiment from about 0.5mg to 200mg per patient per day.
It will also be appreciated that certain compounds of the invention may be present in free form and used in therapy, or if appropriate in the form of a pharmaceutically acceptable derivative thereof. Pharmaceutically acceptable derivatives include pharmaceutically acceptable prodrugs, salts, esters, salts of such esters, or any additional adduct or derivative that upon administration to a patient in need thereof provides, directly or indirectly, a compound of the present invention or a metabolite or residue thereof.
The medicaments or pharmaceutical compositions disclosed herein can be prepared and packaged in bulk form, wherein a safe and effective amount of the compound of formula (I) can be extracted and then administered to a patient in the form of a powder or syrup. Typically, the administration is to the patient at a dosage level of between 0.0001 and 10mg/kg body weight per day to achieve effective inhibition of retinoic acid-related nociceptor γ t. Alternatively, the pharmaceutical compositions disclosed herein can be prepared and packaged in unit dosage forms, wherein each physically discrete unit contains a safe and effective amount of a compound of formula (I). When prepared in unit dosage form, the disclosed pharmaceutical compositions can generally contain an effective amount of a disclosed compound.
When the pharmaceutical composition of the invention contains one or more other active ingredients in addition to the compound of the invention, the compound weight ratio of the compound of the invention to the second active ingredient may vary and depends on the effective dose of each ingredient. Generally, an effective dose of each is used. Thus, for example, when a compound of the invention is mixed with another agent, the weight ratio of the compound of the invention to the other agent typically ranges from about 1000:1 to about 1:1000, e.g., from about 200:1 to about 1: 200. Mixtures of the compounds of the invention with other active ingredients are generally also within the above-mentioned ranges, but in each case an effective dose of each active ingredient should be used.
As used herein, "pharmaceutically acceptable excipient" means a pharmaceutically acceptable material, mixture or vehicle, which is compatible with the dosage form or pharmaceutical composition to be administered. Each excipient, when mixed, must be compatible with the other ingredients of the pharmaceutical composition to avoid interactions that would substantially reduce the efficacy of the disclosed compounds and which would result in a pharmaceutical composition that is not pharmaceutically acceptable when administered to a patient. Furthermore, each excipient must be pharmaceutically acceptable, e.g., of sufficiently high purity.
Suitable pharmaceutically acceptable excipients will vary depending on the particular dosage form selected. In addition, pharmaceutically acceptable excipients may be selected for their specific function in the composition. For example, certain pharmaceutically acceptable excipients may be selected to aid in the production of a uniform dosage form. Certain pharmaceutically acceptable excipients may be selected to aid in the production of stable dosage forms. Certain pharmaceutically acceptable excipients may be selected to facilitate carrying or transporting the disclosed compounds from one organ or portion of the body to another organ or portion of the body when administered to a patient. Certain pharmaceutically acceptable excipients may be selected that enhance patient compliance.
Suitable pharmaceutically acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, taste masking agents, colorants, anti-caking agents, humectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants and buffers. The skilled artisan will recognize that certain pharmaceutically acceptable excipients may provide more than one function, and provide alternative functions, depending on how many such excipients are present in the formulation and which other excipients are present in the formulation.
The skilled person is knowledgeable and skilled in the art to enable them to select suitable amounts of suitable pharmaceutically acceptable excipients for use in the present invention. Furthermore, there is a large amount of resources available to the skilled person, who describes pharmaceutically acceptable excipients and is used to select suitable pharmaceutically acceptable excipients. Examples include Remington's Pharmaceutical Sciences (Mack Publishing Company), The Handbook of Pharmaceutical Additives (Gower Publishing Limited), and The Handbook of Pharmaceutical Excipients (The American Pharmaceutical Association and The Pharmaceutical Press).
Various carriers for formulating pharmaceutically acceptable compositions, and well known techniques for their preparation, are disclosed in Remington, The Science and Practice of Pharmacy,21st edition,2005, ed.D.B.Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds.J.Swarbrick and J.C.Boylan, 1988. Annu 1999, Marcel Dekker, New York, The contents of each of which are incorporated herein by reference. Except insofar as any conventional carrier is incompatible with the disclosed compounds, such as by producing any undesirable biological effect or interacting in a deleterious manner with any other ingredient in a pharmaceutically acceptable composition, its use is contemplated as falling within the scope of the present invention.
The pharmaceutical compositions disclosed herein are prepared using techniques and methods known to those skilled in the art. Some commonly used methods in the art are described in Remington's Pharmaceutical Sciences (Mack Publishing Company).
Thus, in another aspect, the invention relates to a process for preparing a pharmaceutical composition comprising a compound disclosed herein and a pharmaceutically acceptable excipient, carrier, adjuvant or combination thereof, which process comprises admixing the ingredients. Pharmaceutical compositions comprising the disclosed compounds may be prepared by mixing, for example, at ambient temperature and atmospheric pressure.
The compounds disclosed herein are generally formulated in a dosage form suitable for administration to a patient by a desired route. For example, dosage forms include those suitable for the following routes of administration: (1) oral administration, such as tablets, capsules, caplets, pills, troches, powders, syrups, elixirs, suspensions, solutions, emulsions, sachets and cachets; (2) parenteral administration, such as sterile solutions, suspensions, and reconstituted powders; (3) transdermal administration, such as transdermal patches; (4) rectal administration, e.g., suppositories; (5) inhalation, such as aerosols, solutions, and dry powders; and (6) topical administration, such as creams, ointments, lotions, solutions, pastes, sprays, foams and gels.
In one embodiment, the compounds disclosed herein may be formulated in oral dosage forms. In another embodiment, the compounds disclosed herein may be formulated in an inhalation dosage form. In another embodiment, the compounds disclosed herein can be formulated for nasal administration. In yet another embodiment, the compounds disclosed herein can be formulated for transdermal administration. In yet another embodiment, the compounds disclosed herein may be formulated for topical administration.
The pharmaceutical compositions provided by the present invention may be provided as compressed tablets, milled tablets, chewable lozenges, fast-dissolving tablets, double-compressed tablets, or enteric-coated, sugar-coated or film-coated tablets. Enteric coated tablets are compressed tablets coated with a substance that is resistant to the action of gastric acid but dissolves or disintegrates in the intestine, thereby preventing the active ingredient from contacting the acidic environment of the stomach. Enteric coatings include, but are not limited to, fatty acids, fats, phenyl salicylate, waxes, shellac, ammoniated shellac, and cellulose acetate phthalate. Sugar-coated tablets are compressed tablets surrounded by a sugar coating, which can help to mask unpleasant tastes or odors and prevent oxidation of the tablet. Film-coated tablets are compressed tablets covered with a thin layer or film of a water-soluble substance. Film coatings include, but are not limited to, hydroxyethyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Film coatings are endowed with the same general characteristics as sugar coatings. A tabletted tablet is a compressed tablet prepared over more than one compression cycle, including a multi-layer tablet, and a press-coated or dry-coated tablet.
Tablet dosage forms may be prepared from the active ingredient in powder, crystalline or granular form, alone or in combination with one or more carriers or excipients described herein, including binders, disintegrants, controlled release polymers, lubricants, diluents and/or colorants. Flavoring and sweetening agents are particularly useful in forming chewable tablets and lozenges.
The pharmaceutical composition provided by the present invention may be provided in soft or hard capsules, which may be prepared from gelatin, methylcellulose, starch or calcium alginate. The hard gelatin capsules, also known as Dry Fill Capsules (DFC), consist of two segments, one inserted into the other, thus completely encapsulating the active ingredient. Soft Elastic Capsules (SEC) are soft, spherical shells, such as gelatin shells, which are plasticized by the addition of glycerol, sorbitol or similar polyols. The soft gelatin shell may contain a preservative to prevent microbial growth. Suitable preservatives are those as described herein, including methyl and propyl parabens, and sorbic acid. The liquid, semi-solid and solid dosage forms provided by the present invention may be encapsulated in a capsule. Suitable liquid and semi-solid dosage forms include solutions and suspensions in propylene carbonate, vegetable oils or triglycerides. Capsules containing such solutions may be as described in U.S. patent nos.4,328,245; 4,409,239 and 4,410,545. The capsules may also be coated as known to those skilled in the art to improve or maintain dissolution of the active ingredient.
The pharmaceutical compositions provided herein may be provided in liquid and semi-solid dosage forms, including emulsions, solutions, suspensions, elixirs and syrups. Emulsions are two-phase systems in which one liquid is dispersed throughout another in the form of globules, which can be either oil-in-water or water-in-oil. Emulsions may include pharmaceutically acceptable non-aqueous liquids and solvents, emulsifiers and preservatives. Suspensions may include a pharmaceutically acceptable suspending agent and a preservative. The aqueous alcoholic solution may comprise pharmaceutically acceptable acetals, such as di (lower alkyl) acetals of lower alkyl aldehydes, e.g. acetaldehyde diethyl acetal; and water-soluble solvents having one or more hydroxyl groups, such as propylene glycol and ethanol. Elixirs are clear, sweetened, hydroalcoholic solutions. Syrups are concentrated aqueous solutions of sugars, such as sucrose, and may also contain preservatives. For liquid dosage forms, for example, a solution in polyethylene glycol may be diluted with a sufficient amount of a pharmaceutically acceptable liquid carrier, such as water, for precise and convenient administration.
Other useful liquid and semi-solid dosage forms include, but are not limited to, those comprising the active ingredients provided herein and a secondary mono-or poly-alkylene glycol, including: 1, 2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether, where 350, 550, 750 refer to the approximate average molecular weight of the polyethylene glycol. These formulations may further include one or more antioxidants, such as Butylated Hydroxytoluene (BHT), Butylated Hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfite, sodium metabisulfite, thiodipropionic acid and its esters, and dithiocarbamates.
Dosage unit formulations for oral administration may be microencapsulated, where appropriate. They may also be prepared as extended or sustained release compositions, for example by coating or embedding the particulate material in a polymer, wax or the like.
The oral pharmaceutical composition provided by the invention can also be provided in the form of liposome, micelle, microsphere or nano system. Micellar dosage forms can be prepared using the methods described in U.S. Pat. No.6,350,458.
The pharmaceutical compositions provided herein can be provided as non-effervescent or effervescent granules and powders for reconstitution into liquid dosage forms. Pharmaceutically acceptable carriers and excipients used in non-effervescent granules or powders may include diluents, sweeteners and wetting agents. Pharmaceutically acceptable carriers and excipients used in effervescent granules or powders may include organic acids and sources of carbon dioxide.
Coloring and flavoring agents may be used in all of the above dosage forms.
The disclosed compounds may also be conjugated to soluble polymers as targeted drug carriers. Such polymers include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylaspartamidephenol or polyoxyethylene polylysine substituted with palmitoyl residues. In addition, the disclosed compounds may be combined with a class of biodegradable polymers used in achieving controlled release of a drug, such as polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and crosslinked or amphiphilic block copolymers of hydrogels.
The pharmaceutical compositions provided by the present invention may be formulated into immediate or modified release dosage forms, including delayed-, sustained-, pulsed-, controlled-, targeted-, and programmed release forms.
The pharmaceutical compositions provided by the present invention may be co-formulated with other active ingredients that do not impair the intended therapeutic effect, or with substances that supplement the intended effect.
The pharmaceutical compositions provided by the present invention may be administered parenterally by injection, infusion or implantation for local or systemic administration. Parenteral administration as used herein includes intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial and subcutaneous administration.
The pharmaceutical compositions provided herein can be formulated in any dosage form suitable for parenteral administration, including solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems and solid forms suitable for solution or suspension in a liquid prior to injection. Such dosage forms may be prepared according to conventional methods known to those skilled in The art of pharmaceutical Science (see Remington: The Science and Practice of Pharmacy, supra).
Pharmaceutical compositions intended for parenteral administration may include one or more pharmaceutically acceptable carriers and excipients, including, but not limited to, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives to inhibit microbial growth, stabilizers, solubility enhancers, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, cryoprotectants, thickening agents, pH adjusting agents, and inert gases.
Suitable aqueous carriers include, but are not limited to: water, saline, normal saline or Phosphate Buffered Saline (PBS), sodium chloride injection, Ringers injection, isotonic glucose injection, sterile water injection, dextrose and lactated Ringers injection. Non-aqueous vehicles include, but are not limited to, fixed oils of vegetable origin, castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oils, hydrogenated soybean oil, and the medium chain triglycerides of coconut oil, and palm seed oil. Water-miscible vehicles include, but are not limited to, ethanol, 1, 3-butanediol, liquid polyethylene glycols (e.g., polyethylene glycol 300 and polyethylene glycol 400), propylene glycol, glycerol, N-methyl-2-pyrrolidone, N-dimethylacetamide, and dimethylsulfoxide.
Suitable antimicrobial agents or preservatives include, but are not limited to, phenol, cresol, mercurial, benzyl alcohol, chlorobutanol, methyl and propyl parabens, thimerosal, benzalkonium chloride (e.g., benzethonium chloride), methyl and propyl parabens, and sorbic acid. Suitable isotonic agents include, but are not limited to, sodium chloride, glycerol and glucose. Suitable buffers include, but are not limited to, phosphate and citrate. Suitable antioxidants are those as described herein, including bisulfite and sodium metabisulfite. Suitable local anesthetics include, but are not limited to, procaine hydrochloride. Suitable suspending and dispersing agents are those as described herein, including sodium carboxymethylcellulose, hydroxypropylmethylcellulose and polyvinylpyrrolidone. Suitable emulsifiers include those described herein, including polyoxyethylene sorbitan monolaurate. Polyoxyethylene sorbitan monooleate 80 and triethanolamine oleate. Suitable sequestering or chelating agents include, but are not limited to, EDTA. Suitable pH adjusters include, but are not limited to, sodium hydroxide, hydrochloric acid, citric acid, and lactic acid. Suitable complexing agents include, but are not limited to, cyclodextrins, including alpha-cyclodextrin, beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin, sulfobutyl ether-beta-cyclodextrin, and sulfobutyl ether 7-beta-cyclodextrin (f: (f))
Figure BDA0002878710730000321
CyDex,Lenexa,KS)。
The pharmaceutical compositions provided herein may be formulated for single or multiple dose administration. The single dose formulations are packaged in ampoules, vials or syringes. The multi-dose parenteral formulation must contain a bacteriostatic or fungistatic concentration of the antimicrobial agent. All parenteral formulations must be sterile, as is known and practiced in the art.
In one embodiment, the pharmaceutical composition is provided as a ready-to-use sterile solution. In another embodiment, the pharmaceutical compositions are provided as sterile dried soluble products, including lyophilized powders and subcutaneous injection tablets, which are reconstituted with a carrier prior to use. In yet another embodiment, the pharmaceutical composition is formulated as a ready-to-use sterile suspension. In yet another embodiment, the pharmaceutical composition is formulated as a sterile, dry, insoluble product that is reconstituted with a carrier prior to use. In yet another embodiment, the pharmaceutical composition is formulated as a sterile emulsion ready for use.
The pharmaceutical composition may be formulated as a suspension, solid, semi-solid, or thixotropic liquid for depot administration for implantation. In one embodiment, the disclosed pharmaceutical compositions are dispersed in a solid internal matrix surrounded by an outer polymeric membrane that is insoluble in body fluids but allows diffusion therethrough of the active ingredient in the pharmaceutical composition.
Suitable internal matrices include polymethylmethacrylate, polybutylmethacrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene vinyl acetate copolymers, silicone rubber, polydimethylsiloxane, silicone carbonate copolymers, hydrogels of hydrophilic polymers such as esters of acrylic and methacrylic acid, collagen, crosslinked polyvinyl alcohol, and partially hydrolyzed polyvinyl acetate of the class of copolymers.
Suitable outer polymeric films include polyethylene, polypropylene, ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers, ethylene/vinyl acetate copolymers, silicone rubber, polydimethylsiloxane, neoprene, chlorinated polyethylene, polyvinyl chloride, copolymers of chlorinated ethylene and vinyl acetate, vinylidene chloride, ethylene and propylene, ionomers polyethylene terephthalate, butyl rubber chlorohydrin rubber, ethylene/vinyl alcohol copolymers, ethylene/vinyl acetate/vinyl alcohol terpolymers, and ethylene/ethyleneoxyethanol copolymers.
In another aspect, the disclosed pharmaceutical compositions may be formulated in any dosage form suitable for administration to a patient by inhalation, such as a dry powder, aerosol, suspension, or solution composition. In one embodiment, the disclosed pharmaceutical compositions may be formulated in a dosage form suitable for inhalation administration to a patient as a dry powder. In yet another embodiment, the disclosed pharmaceutical compositions may be formulated in a dosage form suitable for inhalation administration to a patient via a nebulizer. Dry powder compositions for delivery to the lung by inhalation typically comprise a finely powdered compound disclosed herein and one or more finely powdered pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients that are particularly suitable for use as dry powders are known to those skilled in the art and include lactose, starch, mannitol, and mono-, di-and polysaccharides. Fine powders may be prepared, for example, by micronization and milling. Generally, the size-reduced (e.g., micronized) compound may pass through a D of about 1 to 10 microns50Values (e.g., measured by laser diffraction).
Aerosols can be formulated by suspending or dissolving the disclosed compounds in a liquefied propellant. Suitable propellants include chlorinated hydrocarbons, hydrocarbons and other liquefied gases. Representative propellants include: trichlorofluoromethane (propellant 11), dichlorofluoromethane (propellant 12), dichlorotetrafluoroethane (propellant 114), tetrafluoroethane (HFA-134a), 1-difluoroethane (HFA-152a), difluoromethane (HFA-32), pentafluoroethane (HFA-12), heptafluoropropane (HFA-227a), perfluoropropane, perfluorobutane, perfluoropentane, butane, isobutane and pentane. Aerosols comprising the compounds disclosed herein are typically administered to a patient via a Metered Dose Inhaler (MDI). Such devices are known to those skilled in the art.
The aerosol may contain additional pharmaceutically acceptable excipients that may be used by MDIs, such as surfactants, lubricants, co-solvents, and other excipients, to improve the physical stability of the formulation, to improve valve characteristics, to improve solubility, or to improve taste.
Pharmaceutical compositions suitable for transdermal administration may be prepared as discrete patches intended to remain in intimate contact with the epidermis of the patient for an extended period of time. For example, the active ingredient may be delivered from a patch agent by iontophoresis, as generally described in Pharmaceutical Research,3(6),318 (1986).
Pharmaceutical compositions suitable for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils. For example, ointments, creams and gels may be formulated with a water or oil base, and suitable thickeners and/or gelling agents and/or solvents. Such bases may include, water, and/or oils such as liquid paraffin and vegetable oils (e.g., peanut oil or castor oil), or solvents such as polyethylene glycol. Thickeners and gelling agents used according to the nature of the base include soft paraffin, aluminium stearate, cetostearyl alcohol, polyethylene glycol, lanolin, beeswax, carbopol and cellulose derivatives, and/or glyceryl monostearate and/or non-ionic emulsifiers.
Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents or thickening agents.
Powders for external use may be formed in the presence of any suitable powder base, for example talc, lactose or starch. Drops may be formulated with an aqueous or non-aqueous base containing one or more dispersing agents, solubilising agents, suspending agents or preservatives.
Topical formulations may be administered by application to the affected area one or more times per day; an occlusive dressing covering the skin is preferably used. Adhesive depot systems allow for continuous or extended administration.
Use of the Compounds and compositions of the invention
The compound or the pharmaceutical composition disclosed by the invention can be used for preparing a medicine for treating, preventing, improving, controlling or relieving cancer, inflammation or autoimmune diseases mediated by ROR gamma t in mammals including human beings, and can also be used for preparing other medicines for inhibiting ROR gamma t.
In particular, the amount of the compound in the composition of the present invention is effective to detectably inhibit ROR γ t, and the compound of the present invention is useful as a medicament for preventing or treating cancer, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease, colitis, ulcerative colitis, rheumatoid arthritis, autoimmune ocular disease, ankylosing spondylitis, asthma, chronic obstructive pulmonary disease, osteoarthritis, allergic rhinitis, allergic dermatitis, crohn's disease, or kawasaki disease in a human.
The compounds or compositions of the present invention may be used, but are in no way limited to, in preventing, treating or alleviating cancer, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease, colitis, ulcerative colitis, rheumatoid arthritis, autoimmune ocular disease, ankylosing spondylitis, asthma, chronic obstructive pulmonary disease, osteoarthritis, allergic rhinitis, allergic dermatitis, crohn's disease or kawasaki disease in a mammal, including a human, by administering to the patient an effective amount of a compound or composition of the present invention.
In addition to being beneficial for human therapy, the compounds and pharmaceutical compositions of the present invention may also find application in veterinary therapy for pets, animals of the introduced species and mammals in farm animals. Examples of other animals include horses, dogs, and cats. Herein, the compound of the present invention includes pharmaceutically acceptable derivatives thereof.
General synthetic procedure
To illustrate the invention, the following examples are set forth. It is to be understood that the invention is not limited to these embodiments, but is provided as a means of practicing the invention.
In general, the compounds of the present invention may be prepared by the methods described herein, wherein the substituents are as defined in formula (I), unless otherwise indicated. The following reaction schemes and examples serve to further illustrate the context of the invention.
Those skilled in the art will recognize that: the chemical reactions described herein may be used to suitably prepare a number of other compounds of the invention, and other methods for preparing the compounds of the invention are considered to be within the scope of the invention. For example, the synthesis of those non-exemplified compounds according to the present invention can be successfully accomplished by those skilled in the art by modification, such as appropriate protection of interfering groups, by the use of other known reagents in addition to those described herein, or by some routine modification of reaction conditions. In addition, the reactions disclosed herein or known reaction conditions are also recognized as being applicable to the preparation of other compounds of the present invention.
The examples described below, unless otherwise indicated, are all temperatures set forth in degrees Celsius. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company and were used without further purification unless otherwise indicated. General reagents were purchased from Shantou Wen Long chemical reagent factory, Guangdong Guanghua chemical reagent factory, Guangzhou chemical reagent factory, Tianjin Haojian Yunyu chemical Co., Ltd, Tianjin Shucheng chemical reagent factory, Wuhan Xin Huayuan scientific and technological development Co., Ltd, Qingdao Tenglong chemical reagent Co., Ltd, and Qingdao Kaolingyi factory.
The anhydrous tetrahydrofuran, dioxane, toluene and ether are obtained through reflux drying of metal sodium. The anhydrous dichloromethane and chloroform are obtained by calcium hydride reflux drying. Ethyl acetate, petroleum ether, N-hexane, N, N-dimethylacetamide and N, N-dimethylformamide were used as they were previously dried over anhydrous sodium sulfate.
The following reactions are generally carried out under positive pressure of nitrogen or argon or by sleeving a dry tube over an anhydrous solvent (unless otherwise indicated), the reaction vial being stoppered with a suitable rubber stopper and the substrate being injected by syringe. The glassware was dried.
The column chromatography is performed using a silica gel column. Silica gel (300 and 400 meshes) was purchased from Qingdao oceanic chemical plants.
NMR spectra were recorded using a Bruker 400MHz or 600MHz NMR spectrometer, CDC13、DMSO-d6、CD3OD or acetone-d6As solvent (in ppm), TMS (0ppm) or chloroform (7.26ppm) was used as a referenceAccording to the standard. When multiple peaks occur, the following abbreviations will be used: s (singleton), d (doublet), t (triplet), m (multiplet), br (broad), dd (doublet of doublets), dt (doublet of triplets). Coupling constants are expressed in hertz (Hz).
The conditions for determining low resolution Mass Spectrometry (MS) data were: agilent 6120 four-stage rod HPLC-MS (column model: Zorbax SB-C18,2.1X30mm,3.5 μm,6min, flow rate 0.6 mL/min. mobile phase: 5% -95% (ACN containing 0.1% formic acid) in (H containing 0.1% formic acid)2O) by electrospray ionization (ESI) at 210nm/254nm, with UV detection.
The purity of the compound was determined by High Performance Liquid Chromatography (HPLC), using Agilent 1260HPLC (column model: Agilent zorbax Eclipse Plus C18) and detected by DAD detector, and finally calculated by area normalization to obtain the purity of the compound.
The following acronyms are used throughout the invention:
AcOH acetic acid; DMF N, N-dimethylformamide
Silver AgOTf triflate; DMAP 4-dimethylaminopyridine;
Boc2di-tert-butyl O-dicarbonate; DIAD diisopropyl azodicarboxylate;
CbzCl benzyl chloroformate; DIPEA N, N-diisopropylethylamine;
DCM dichloromethane; DMSO dimethyl sulfoxide;
DMSO-d6deuterated dimethyl sulfoxide; t-BuOK potassium tert-butoxide;
EtOAc, EA ethyl acetate; TBAF tetrabutylammonium bromide;
EtOH ethanol; TEA triethylamine;
EDCI 1-ethyl- (3-dimethylaminopropyl) carbonyldiimine TMSCF2Br (bromo (difluoro) methyl) trimethylsilane;
a hydrochloride salt; TMSCF3((trifluoromethyl) trimethylsilane;
HATU 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyl Tf2O trifluoromethanesulfonic anhydride;
urea hexafluorophosphate; TLC thin layer chromatography;
HOBt, HOBT 1-hydroxybenzotriazole; THF tetrahydrofuran;
KOAc potassium acetate; TFA trifluoroacetic acid;
MeCN, ACN acetonitrile; g, g;
MeOH with methanol; h hours;
MsCl methanesulfonyl chloride; min;
Pd2(dba)3tris (dibenzylideneacetone) dipalladium; mmol millimole;
PTLC preparative thin layer chromatography; m mol per liter;
PE petroleum ether; DEG C;
Pd/C palladium/carbon; mL, mL;
i-PrOH isopropanol; rpm turns per minute;
ruphos 2-bicyclohexylphosphine-2 ',6' -diisopropyloxybiphenyl; rt retention time;
Sodium STAB triacetoxyborohydride;
typical synthetic procedures for preparing the disclosed compounds of the invention are shown in the following synthetic schemes. In the reaction scheme, A, R unless otherwise stated2、R5、R6And R7Have the meaning as described herein; PG is an amino protecting group; x, Y and Z are halogen atoms; z1Is O, S or NRnWherein R isnIs H or C1-6An alkyl group; z2、Z3、Z4、Z5、Z6、Z7Is N or CH.
Synthesis scheme 1
Figure BDA0002878710730000351
Compound (6a) can be prepared by the following procedure:
the compound (1a) and the compound (1a ') or (1a') generate a compound (2a) through a substitution reaction, the amino protecting group of the compound (2a) is removed to obtain a compound (3a), the compound (3a) and the compound (3a ') generate a compound (4a) through a coupling reaction, the compound (4a) is hydrolyzed under alkaline conditions to obtain a compound (5a), and the compound (5a) and the compound (5a') undergo a condensation reaction to obtain a compound (6 a).
Synthesis scheme 2
Figure BDA0002878710730000361
Compound (6b) can be prepared by the following procedure:
the compound (1b) and the compound (1b ') are subjected to substitution reaction to generate a compound (2b), the amino protecting group of the compound (2b) is removed under an acidic condition to generate a compound (3b), the compound (3b) and the compound (3a ') are subjected to coupling reaction to generate a compound (4b), the compound (4b) is subjected to hydrolysis reaction under an alkaline condition to generate a compound (5b), and the compound (5b) and the compound (5a ') are subjected to condensation reaction to generate a compound (6 b).
Synthesis scheme 3
Figure BDA0002878710730000362
Compound (6c) can be prepared by the following procedure:
the compound (1c) and the compound (1a ') are subjected to coupling reaction to generate a compound (2c), the amino protecting group of the compound (2c) is removed to generate a compound (3c), the compound (3c) and the compound (3a ') are subjected to coupling reaction to generate a compound (4c), the compound (4c) is subjected to hydrolysis reaction under alkaline condition to generate a compound (5c), and the compound (5c) and the compound (5a ') are subjected to condensation reaction to generate a compound (6 c).
The compounds, pharmaceutical compositions and uses thereof provided by the present invention are further illustrated below in connection with the examples.
Synthesis of intermediates
Intermediate 1: (S) -3-amino-3- (4- (ethylsulfonyl) phenyl) propionitrile hydrochloride
Figure BDA0002878710730000371
The method comprises the following steps: synthesis of (3S) -3- (((tert-butoxy) carbonyl) amino) -3- (4- (ethylsulfonyl) phenyl) propanoic acid
LiOH (10g,459.10mmol) in H at room temperature2A solution of O (50mL) was added to a solution of methyl (3S) -3- (((tert-butoxy) carbonyl) amino) -3- (4- (ethylsulfonyl) phenyl) propanoate (18.00g,41.91mmol) in MeOH (50mL) and reacted at room temperature for 16 h. The reaction was concentrated under reduced pressure, the remaining aqueous phase was adjusted to pH 5 by adding concentrated HCl solution (12mol/L), extracted with EtOAc (100 mL. times.2), washed with saturated NaCl solution (80mL), anhydrous Na 2SO4Drying and concentration under reduced pressure gave a white solid (14g, 93%).
MS(ESI,pos.ion)m/z:302.1[M-56+H]+.
Step two: synthesis of tert-butyl (S) - (3-amino-1- (4- (ethylsulfonyl) phenyl) -3-oxopropyl) carbamate
Reacting NH4Cl (6.28g,117.41mmol), HATU (20.00g,52.60mmol), TEA (16.3mL,117.27mmol) were added sequentially to a solution of (3S) -3- (((tert-butoxy) carbonyl) amino) -3- (4- (ethylsulfonyl) phenyl) propanoic acid (14g,39.17mmol) in DCM (160mL) and reacted at room temperature for 16 h. Filtering the reaction solution to obtain a white solid, dissolving the white solid in MeOH, filtering, spin-drying the filtrate to obtain a white solid, washing the filtrate with 0.5mol/L HCl solution (100 mL. times.2), filtering, and adding anhydrous Na to the filtrate2SO4After drying, a large amount of insoluble white solid was precipitated by concentration under reduced pressure and filtered to give a white solid (12.5g, 89%).
MS(ESI,pos.ion)m/z:301.1[M-56+H]+.
Step three: synthesis of tert-butyl (S) - (2-cyano-1- (4- (ethylsulfonyl) phenyl) ethyl) carbamate
TFA (33mL,237.4mmol) was added to a solution of tert-butyl (S) - (3-amino-1- (4- (ethylsulfonyl) phenyl) -3-oxopropyl) carbamate (48g,134.70mmol) and pyridine (40.00mL,497.00mmol) in THF (600mL) at-10 deg.C under nitrogen (ca. 30min), and after 1h was transferred to room temperature for 12 h. Adding saturated NaHCO into the reaction liquid3The reaction was quenched with solution (200mL), concentrated under reduced pressure, and during concentration a white solid product precipitated, filtered and the filter cake washed with water to give a white solid, dissolved in DCM (100mL), washed with saturated NaCl solution (50mL), anhydrous Na 2SO4Drying and concentration under reduced pressure gave a white solid (43.0g, 94%).
MS(ESI,pos.ion)m/z:361.1[M+Na]+.
Step four: synthesis of (S) -3-amino-3- (4- (ethylsulfonyl) phenyl) propionitrile hydrochloride
A solution of HCl in 1, 4-dioxane (100mL,4mol/L) was added dropwise to a solution of tert-butyl (S) - (2-cyano-1- (4- (ethylsulfonyl) phenyl) ethyl) carbamate (45.00g,133.00mmol) in DCM (300mL) at 0 deg.C, after addition was completed, the reaction was allowed to shift to room temperature overnight, and the reaction was filtered to give a white solid (34.2g, 94%).
MS(ESI,pos.ion)m/z:239.1[M+H]+.
1H NMR(400MHz,CD3OD)δ(ppm):8.09(d,J＝8.4Hz,2H),7.87(d,J＝8.3Hz,2H),4.96(t,J＝7.0Hz,1H),3.37(d,J＝6.9Hz,2H),3.29(q,J＝7.4Hz,2H),1.25(t,J＝7.4Hz,3H).
Intermediate 2: 4- (aminomethyl) -N-cyclopropylbenzenesulfonamides
Figure BDA0002878710730000372
After phenylmethylamine (1.00mL,9.16mmol) was dissolved in DCM (2mL), TFA (1mL,10.84mmol) was added dropwise followed by chlorosulfonic acid (10mL,152mmol), and the reaction was stirred at room temperature for 3 h. The stirring was stopped, and the reaction mixture was dropped into ice water (80mL) to quench the reaction. The above mixture was added dropwise to cyclopropylamine (1.7mL,7.29mmol)Saturated NaHCO3To the solution (80mL), the solution was added dropwise over 30min, and the reaction was stirred at room temperature for 8 h. The reaction was extracted with EtOAc (50mL) and the organic phase was extracted with anhydrous Na2SO4Dried, filtered and concentrated under reduced pressure, and the concentrated crude product was isolated by column chromatography on silica gel (eluent: DCM/MeOH (v/v) ═ 10/1) to give a pale yellow solid (708mg, 43%).
MS(ESI,pos.ion)m/z:227.1[M+H]+.
Intermediate 3: (4- (ethylsulfonylimidoyl) phenyl) methylamine
Figure BDA0002878710730000381
The method comprises the following steps: synthesis of 2- (4-bromobenzyl) isoindoline-1, 3-dione
Mixing isoindoline-1, 3-dione (5.20g,35.00mmol), 1-bromo-4- (bromomethyl) benzene (13.00g,52.02mmol), and Cs2CO3(22.00g,67.52mmol) was dissolved in DMF (40mL) and reacted at room temperature for 22 h. Adding H to the reaction solution2O (200mL), DCM (200 mL. times.2) extraction, anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 3/1) to give a white solid (8g, 72.0%).
MS(ESI,pos.ion)m/z:318.1[M+H]+.
Step two: synthesis of 2- (4- (ethylthio) benzyl) isoindoline-1, 3-dione
N2Under protection, 2- (4-bromobenzyl) isoindoline-1, 3-dione (3g,9.49mmol), XantPhos (1.10g,1.90mmol), Pd2(dba)3(890mg,0.97mmol), DIPEA (3.2mL,19.00mmol) was dissolved in 1, 4-dioxane (15mL), ethanethiol (1.1mL,15.00mmol) was added, and the reaction was heated at 110 ℃ for 16 h. The reaction was concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 5/1) to give a yellow solid (1.9g, 66.6%).
MS(ESI,pos.ion)m/z:298.0[M+H]+.
Step three: synthesis of 2- (4- (ethylsulfonimidyl) benzyl) isoindoline-1, 3-dione
Mixing 2- (4- (ethylthio) benzyl) isoindoline-1, 3-dione (1.02g,3.43mmol), PhI (OAc)2(2.76g,8.57mmol), ammonium carbamate (580mg,7.43mmol) in MeOH (15mL) and reacted for 5h at room temperature. Concentrate under reduced pressure to remove MeOH, dilute with DCM (60mL), and saturate NaHCO 3The solution (40 mL. times.2) was washed and the organic phase was Na anhydrous2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 1/1) to give a yellow solid (1.1g, 98.0%).
MS(ESI,pos.ion)m/z:329.0[M+H]+.
Step four: synthesis of (4- (ethylsulfonylimidoyl) phenyl) methylamine
2- (4- (Ethylsulfonimidoyl) benzyl) isoindoline-1, 3-dione (1.15g,3.50mmol) was dissolved in EtOH (15mL) and H2O (6mL), and hydrazine monohydrate (1.2mL) was added to react at 80 ℃ for 18 h. Concentrate under reduced pressure to remove EtOH, dilute with DCM (60mL), wash with KOH solution (2M,40 mL. times.2), and dry Na as the organic phase2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: DCM/MeOH (v/v) ═ 3/1) to give a white solid (600mg, 86.4%).
MS(ESI,pos.ion)m/z:199.1[M+H]+.
Examples
Example 1: 2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) -N- ((R) -1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) thiazole-4-carboxamide
Figure BDA0002878710730000382
The method comprises the following steps: synthesis of 1-tert-butyl 2-methyl (2S,4S) -2- (4- (trifluoromethyl) phenoxy) pyrrolidine-1, 2-dicarboxylate
(2S,4R) -1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1, 2-dicarboxylate (10.00g,40.77mmol), 4- (trifluoromethyl) phenol (6.60g,40.71mmol), PPh 3(11.80g,44.99mmol) was added to THF (120mL), the mixture was removed at 0 deg.C, DIAD (11.0mL,55.87mmol) was added slowly, and after addition, the mixture was stirred at room temperature for 24 h. Pressure reduction of the reaction solutionConcentration, dilution of the residue with methyl tert-butyl ether (80mL), stirring at-20 ℃ to precipitate a large amount of white insoluble solid, filtration, concentration of the filtrate under reduced pressure, and column chromatography (eluent: PE/EtOAc (v/v) ═ 4/1) to give a white solid (13.56g, 85%).
MS(ESI,pos.ion)m/z:412.2[M+Na]+.
Step two: synthesis of tert-butyl (2S,4S) -2- (hydroxymethyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidine-1-carboxylate
1-tert-butyl 2-methyl (2S,4S) -2- (4- (trifluoromethyl) phenoxy) pyrrolidine-1, 2-dicarboxylate (18.00g,46.22mmol) was added to a solution of THF (200mL) and the solution was displaced to 0 deg.C, LiBH was added slowly4(2.00g,91.80mmol), after addition, stirring at room temperature for 14 h. Adding saturated NH into the reaction liquid4The reaction was quenched with Cl (60mL) solution, allowed to settle, the upper organic phase separated, the aqueous phase extracted with EtOAc (30 mL. times.2), the combined organic phases and anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by column chromatography on silica gel (eluent: PE/EtOAc (v/v) ═ 3/1) to give a white solid (14.23g, 85%).
MS(ESI,pos.ion)m/z:306.2[M-56+H]+.
Step three: synthesis of tert-butyl (2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidine-1-carboxylate
H is to be2O(1mL)、KOAc(488mg,4.97mmol)、TMSCF2Br (0.40mL,2.60mmol) was added in succession to a solution of tert-butyl (2S,4S) -2- (hydroxymethyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidine-1-carboxylate (300mg,0.83mmol) in DCM (1mL) and stirred at RT for 24 h. The reaction was diluted with DCM (30mL) and washed with saturated NaCl (15mL) and anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by column chromatography on silica gel (eluent: PE/EtOAc (v/v) ═ 4/1) to give a colorless liquid (280mg, 82%).
MS(ESI,pos.ion)m/z:434.1[M+Na]+.
Step four: synthesis of (2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidine
A solution of HCl in methanol (2mL, 20%) was added to (2S,4S) -2- ((bis)Fluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidine-1-carboxylic acid tert-butyl ester (280mg,0.68mmol) in DCM (6mL) was stirred at room temperature for 24 h. The reaction was concentrated under reduced pressure, the residue was diluted with DCM (30mL) and successively with saturated NaHCO3The solution (15mL) was washed with saturated NaCl solution (15mL) and anhydrous Na2SO4Concentration under reduced pressure after drying gave a brown liquid (211mg, 100%).
MS(ESI,pos.ion)m/z:312.3[M+H]+.
Step five: synthesis of ethyl 2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) thiazole-4-carboxylate
(2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidine (0.50g,2.00mmol), ethyl 2-bromothiazole-4-carboxylate (0.40g,2.00mmol), K 2CO3DMF (5mL) (0.60g,4.00mmol) was added sequentially, and the mixture was heated to 100 ℃ under nitrogen to react for 20 hours. Cooled to room temperature, washed with saturated NaCl, extracted with EtOAc (10 mL. times.2) and anhydrous Na2SO4Dried, concentrated and separated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 5/1) to give a white solid (0.10g, 10%).
MS(ESI,pos.ion)m/z:467[M+H]+.
Step six: synthesis of 2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) thiazole-4-carboxylic acid
LiOH (0.11g,0.80mmol) and ethyl 2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) thiazole-4-carboxylate (0.15g,0.32mmol) were added to MeOH (5mL) and stirred at room temperature for 20 h. Dilute hydrochloric acid was added to adjust the reaction to weak acidity, and EtOAc (10 ml. times.2) was extracted with anhydrous Na2SO4Drying, concentration and separation by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 1/1) gave a white solid (0.12g, 85%).
MS(ESI,pos.ion)m/z:439[M+H]+.
Step seven: 2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) -N- ((R) -1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) thiazole-4-carboxamide
After 2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) thiazole-4-carboxylic acid (52mg,0.12mmol), (R) -2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol (35mg,0.13mmol), HATU (54mg,0.14mmol) was dissolved in DCM (25mL), TEA (0.035mL,0.27mmol) was added, stirring at room temperature, and reaction was carried out for 12 h. Adding saturated NH 4Cl washing, DCM (10 ml. times.2) extraction, anhydrous Na2SO4Dried, concentrated and separated by silica gel column chromatography (eluent: DCM/EtOAc (v/v) ═ 3/1) to give a white solid (0.023g, 30%).
MS(ESI,pos.ion)m/z:650[M+H]+.
1H NMR(400MHz,CDCl3)δ(ppm):8.01(d,J＝7.8Hz,1H),7.91(d,J＝8.2Hz,2H),7.61(t,J＝7.3Hz,4H),7.42(s,1H),6.99(d,J＝8.5Hz,2H),6.27(t,J＝74.1Hz,1H),5.31–5.27(m,1H),5.19(s,1H),4.54(dd,J＝9.9,4.4Hz,1H),4.39(s,1H),4.07–3.89(m,3H),3.80(d,J＝4.6Hz,2H),3.12(q,J＝7.4Hz,2H),2.51(d,J＝11.7Hz,2H),0.86(t,J＝7.4Hz,3H).
Example 2: 5- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) -N- ((R) -1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) thiophene-3-carboxamide
Figure BDA0002878710730000401
The method comprises the following steps: synthesis of methyl 5- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) thiophene-3-carboxylate
Under nitrogen protection, (2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidine (300mg,0.96mmol), Pd2(dba)3(88mg,0.10mmol)、Ruphos(67mg,0.14mmol)、Cs2CO3(320mg,0.98mmol) and methyl 5-bromothiophene-3-carboxylate (225mg,1.15mmol) were sequentially added to 1, 4-dioxane (8mL) and reacted at 100 ℃ for 16 h. The reaction was cooled to room temperature, filtered through celite, concentrated under reduced pressure, and separated by column chromatography (eluent: PE/EtOAc (v/v) ═ 5/1) to give a yellow liquidBody (80mg, 18%). MS (ESI, pos.ion) M/z 452.2[ M + H ]]+.
Step two: synthesis of 5- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) thiophene-3-carboxylic acid
Reacting LiOH.H2O (80mg,3.67mmol) in H2O (2mL) solution was added to a solution of methyl 5- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) thiophene-3-carboxylate (80mg,0.17mmol) in MeOH (2mL) and THF (2mL) and stirred at room temperature for 18 h. The reaction mixture was concentrated under reduced pressure, the remaining solution was adjusted to pH 4 by adding HCl solution (1mol/L), extracted with EtOAc (30mL), washed with saturated NaCl (15mL) solution, and washed with anhydrous Na 2SO4Dried and concentrated under reduced pressure, and the crude product was chromatographed on silica gel (eluent: DCM/EtOAc (v/v) ═ 4/1) to give a brown liquid (30mg, 39%).
MS(ESI,pos.ion)m/z:438.1[M+H]+.
Step three: synthesis of 5- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) -N- ((R) -1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) thiophene-3-carboxamide
HATU (40mg,0.11mmol), (R) -2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol (17mg,0.07mmol), 5- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) thiophene-3-carboxylic acid (30mg,0.07mmol), TEA (14mg,0.14mmol) were added sequentially to DCM (2mL) and stirred at room temperature for 16 h. The reaction was concentrated under reduced pressure, and the residue was diluted with DCM (30mL) and washed successively with HCl solution (15mL,0.5mol/L) and saturated NaCl solution (10mL) over anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by column chromatography on silica gel (eluent: DCM/EtOAc (v/v) ═ 1/2) to give a pale yellow solid (6mg, 13%).
MS(ESI,pos.ion)m/z:652.2[M+H]+.
1H NMR(400MHz,CDCl3)δ(ppm):7.87(d,J＝8.2Hz,2H),7.57(t,J＝7.9Hz,4H),7.08(s,1H),6.96(d,J＝8.5Hz,2H),6.83(d,J＝7.2Hz,1H),6.42–6.02(m,3H),5.25(s,1H),5.12(s,1H),4.20(q,J＝9.6Hz,1H),4.07–4.01(m,1H),3.97(dd,J＝16.4,5.1Hz,3H),3.71(d,J＝10.8Hz,1H),3.60(dd,J＝10.8,4.5Hz,1H),3.09(q,J＝7.4Hz,2H),2.43(s,2H),1.28(t,J＝7.4Hz,3H).
Example 3: n- ((S) -2-cyano-1- (4- (ethylsulfonyl) phenyl) ethyl) -2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) thiazole-4-carboxamide
Figure BDA0002878710730000411
After 2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) thiazole-4-carboxylic acid (27mg,0.062mmol), (S) -3-amino-3- (4- (ethylsulfonyl) phenyl) propionitrile (18mg,0.065mmol), HATU (28mg,0.073mmol) was dissolved in DCM (25mL), TEA (0.035mL,0.27mmol) was added and reacted at room temperature for 12 h. Adding saturated NH 4Washed with Cl solution, extracted with DCM (10 ml. times.2) and dried over Na2SO4Dried, concentrated and separated by silica gel column chromatography (eluent: DCM/EtOAc (v/v) ═ 3/1) to give a white solid (0.012g, 30%).
MS(ESI,pos.ion)m/z:659[M+H]+.
1H NMR(400MHz,CDCl3)δ(ppm):7.98(d,J＝8.3Hz,2H),7.88(d,J＝8.3Hz,1H),7.64(dd,J＝16.5,8.4Hz,4H),7.45(s,1H),6.98(d,J＝8.6Hz,2H),6.26(t,J＝74.1Hz,1H),5.55(dd,J＝13.6,6.1Hz,1H),5.19(s,1H),4.54(dd,J＝10.0,4.4Hz,1H),4.41(s,1H),3.92(t,J＝9.6Hz,2H),3.78(s,2H),3.15(t,J＝7.4Hz,2H),3.11–2.99(m,2H),2.51(q,J＝14.5Hz,2H),1.31(dd,J＝10.2,4.7Hz,3H).
Example 4: 2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) -N- ((1- (methylsulfonyl) piperidin-4-yl) methyl) thiazole-5-carboxamide
Figure BDA0002878710730000412
The method comprises the following steps: synthesis of methyl 2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) thiazole-5-carboxylate
(2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidine (1.12g,3.83mmol), methyl 2-bromothiazole-5-carboxylate (850mg,3.83mmol), K2CO3(800mg,5.74mmol) was added to DMF (8mL) in sequence and reacted at 100 ℃ for 24 h. The reaction was cooled to room temperature, diluted with EtOAc (60mL), and then sequentially with H2O (20 mL. times.2) and saturated NaCl solution (20mL), anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by column chromatography on silica gel (eluent: PE/EtOAc (v/v) ═ 3/1) to give a yellow solid (1.13g, 65%). MS (ESI, pos. ion) M/z 455.1[ M + H ]]+.
Step two: synthesis of 2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) thiazole-5-carboxylic acid
Reacting LiOH & H2O (446mg,10.63mmol) in H2O (3mL) solution was added to a solution of methyl 2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) thiazole-5-carboxylate (1.13g,2.47mmol) in MeOH/THF (3mL/3mL) and reacted at room temperature for 12 h. The reaction mixture was concentrated under reduced pressure, the remaining solution was adjusted to pH 4 by adding HCl solution (1mol/L), extracted with EtOAc (50mL), washed with saturated NaCl (20mL) solution, and washed with anhydrous Na2SO4Drying and concentration under reduced pressure gave a pale yellow solid (1.08g, 100%).
MS(ESI,pos.ion)m/z:439.2[M+H]+.
Step three: synthesis of tert-butyl 4- ((2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) thiazole-5-carboxamido) methyl) piperidine-1-carboxylate
HATU (338mg,0.89mmol), 1- ((tert-butoxy) carbonyl) -4-aminomethylpiperidine (161mg,0.75mmol), 2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) thiazole-5-carboxylic acid (300mg,0.68mmol), TEA (0.2mL,1.40mmol) were added sequentially to DCM (6mL) and stirred at room temperature for 16 h. The reaction solution was concentrated under reduced pressure, and the crude product was isolated by column chromatography on silica gel (eluent: DCM/EtOAc (v/v) ═ 1/1) to give a pale yellow liquid (400mg, 92%).
MS(ESI,pos.ion)m/z:579.1[M-56+H]+.
Step four: synthesis of 2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) -N- ((piperidin-4-yl) methyl) thiazole-5-carboxamide
A solution of HCl in 1, 4-dioxane (1.5mL,4mol/L) was added to a solution of tert-butyl 4- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) thiazole-5-carboxamido) methyl) piperidine-1-carboxylate (400mg,0.63mmol) in DCM (3mL) and stirred at room temperature for 16 h. The reaction was concentrated under reduced pressure, the residue diluted with DCM (50mL) and successively with saturated Na2CO3The solution (20mL) was washed with saturated NaCl solution (20mL) and anhydrous Na2SO4Dried and concentrated under reduced pressure to give a pale yellow liquid (336mg, 100%).
MS(ESI,pos.ion)m/z:535.2[M+H]+.
Step five: synthesis of 2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) -N- ((1- (methylsulfonyl) piperidin-4-yl) methyl) thiazole-5-carboxamide
Under nitrogen, TEA (85mg,0.84mmol), MsCl (50mg,0.44mmol) were added to a solution of 2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) -N- ((piperidin-4-yl) methyl) thiazole-5-carboxamide (150mg,0.28mmol) in DCM (3mL) and stirred at room temperature for 16 h. The reaction was concentrated under reduced pressure and the residue was diluted with DCM (40mL) and successively with HCl solution (15mL,1mol/L), saturated NaHCO3Solution (15mL), saturated NaCl solution (15mL) wash, anhydrous Na 2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by column chromatography on silica gel (eluent: DCM/EtOAc (v/v) ═ 1/1) to give a white solid (80mg, 47%).
MS(ESI,pos.ion)m/z:613.1[M+H]+.
1H NMR(400MHz,CDCl3)δ(ppm):7.61(s,1H),7.58(d,J＝8.6Hz,2H),6.95(d,J＝8.5Hz,2H),6.22(t,J＝74.2Hz,1H),5.92(t,J＝6.0Hz,1H),5.15(s,1H),4.33(d,J＝6.3Hz,2H),4.03(t,J＝10.6Hz,1H),3.86(dd,J＝11.9,4.8Hz,1H),3.83–3.77(m,3H),3.31(t,J＝6.3Hz,2H),2.77(s,3H),2.66(t,J＝11.1Hz,2H),2.54–2.42(m,2H),1.85(d,J＝13.3Hz,2H),1.43–1.31(m,2H).
Example 5: 2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) -N- ((1- (ethylsulfonyl) piperidin-4-yl) methyl) thiazole-5-carboxamide
Figure BDA0002878710730000421
Under nitrogen, TEA (85mg,0.84mmol), ethylsulfonyl chloride (54mg,0.42mmol) were added to a solution of 2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) -N- ((piperidin-4-yl) methyl) thiazole-5-carboxamide (150mg,0.28mmol) in DCM (3mL) and stirred at room temperature for 16 h. The reaction was concentrated under reduced pressure, and the residue was diluted with DCM (40mL) and then with HCl solution (15mL,1mol/L), saturated NaHCO3Solution (15mL), saturated NaCl solution (15mL) wash, anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by column chromatography on silica gel (eluent: DCM/EtOAc (v/v) ═ 1/1) to give a white solid (90mg, 51%).
MS(ESI,pos.ion)m/z:627.1[M+H]+.
1H NMR(400MHz,CDCl3)δ(ppm):7.62(s,1H),7.58(d,J＝8.6Hz,2H),6.95(d,J＝8.6Hz,2H),6.22(t,J＝74.2Hz,1H),6.01(t,J＝6.0Hz,1H),5.15(s,1H),4.33(d,J＝6.2Hz,2H),4.03(t,J＝10.6Hz,1H),3.88–3.76(m,4H),3.30(t,J＝6.2Hz,2H),3.17–3.07(m,1H),2.93(q,J＝7.4Hz,2H),2.77(t,J＝11.5Hz,2H),2.54–2.42(m,2H),1.82(d,J＝11.9Hz,2H),1.42–1.30(m,6H).
Example 6: 2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) -N- ((S) -1- (4- (ethylsulfonyl) phenyl) -3-hydroxypropyl) thiazole-5-carboxamide
Figure BDA0002878710730000431
2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- ( Trifluoromethyl) phenoxy) pyrrolidin-1-yl) thiazole-5-carboxylic acid (232mg,0.53mmol), (S) -3-amino-3- (4- (ethylsulfonyl) phenyl) propan-1-ol (163mg,0.58mmol), HATU (243mg,0.63mmol) dissolved in DCM (25mL), TEA (0.17mL,1.30mmol) added and reacted at room temperature for 10 h. The reaction was quenched with water, extracted with DCM (10 ml. times.2), anhydrous Na2SO4Dried, concentrated and separated by silica gel column chromatography (eluent: DCM/EtOAc (v/v) ═ 3/1) to give a white solid (68mg, 19%). MS (ESI, pos.ion) M/z 664[ M + H [ ]]+.
1H NMR(400MHz,CDCl3)δ(ppm):7.80(d,J＝8.2Hz,3H),7.72(s,1H),7.55(dd,J＝19.6,8.4Hz,4H),6.96(d,J＝8.6Hz,2H),6.22(t,J＝74.3Hz,1H),5.38–5.28(m,1H),5.16(d,J＝2.7Hz,1H),4.32(d,J＝5.9Hz,2H),4.12(q,J＝7.1Hz,1H),4.02(t,J＝10.4Hz,1H),3.84(dd,J＝11.7,4.8Hz,1H),3.79–3.59(m,3H),3.16–3.03(m,2H),2.21–2.09(m,1H),1.94(d,J＝5.8Hz,1H),1.26(dd,J＝10.9,4.1Hz,5H).
Example 7: 2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) -N- (4- (ethylsulfonimidyl) benzyl) thiazole-5-carboxamide
Figure BDA0002878710730000432
After 2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) thiazole-5-carboxylic acid (100mg,0.23mmol), (4- (ethylsulfonimidoyl) phenyl) methylamine (58mg,0.25mmol), and HATU (105mg,0.27mmol) were dissolved in DCM (25mL), TEA (0.17mL,1.30mmol) was added and reacted at room temperature for 10 h. The reaction was quenched with water, extracted with DCM (10 ml. times.2), anhydrous Na2SO4Dried, concentrated and separated by silica gel column chromatography (eluent: DCM/EtOAc (v/v) ═ 3/1) to give a white solid (0.112g, 79%).
MS(ESI,pos.ion)m/z:619[M+H]+.
1H NMR(400MHz,CDCl3)δ(ppm):7.88(d,J＝8.1Hz,2H),7.60(d,J＝8.6Hz,2H),7.48(d,J＝8.1Hz,2H),7.28(s,1H),6.97(d,J＝8.6Hz,2H),6.65(t,J＝5.8Hz,1H),6.24(t,J＝74.2Hz,1H),5.17(s,1H),4.66(d,J＝5.9Hz,2H),4.35(d,J＝6.2Hz,2H),4.05(t,J＝10.5Hz,1H),3.86(d,J＝4.7Hz,1H),3.80(d,J＝11.7Hz,1H),3.25–3.12(m,2H),2.52(s,2H),1.25(t,J＝7.5Hz,3H).
Example 8: n- ((R) -2-cyano-1- (4- (ethylsulfonyl) phenyl) ethyl) -2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) thiazole-5-carboxamide
Figure BDA0002878710730000441
HATU (112mg,0.29mmol), (R) -3-amino-3- (4- (ethylsulfonyl) phenyl) propionitrile hydrochloride (prepared according to the above intermediate synthesis method) (75mg,0.27mmol), 2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) thiazole-5-carboxylic acid (100mg,0.23mmol), TEA (70mg,0.69mmol) were sequentially added to DCM (4mL) and stirred at room temperature for 16 h. The reaction was concentrated under reduced pressure, and the residue was diluted with DCM (40mL) and then with HCl solution (20mL,0.5mol/L), saturated NaHCO3The solution (20mL) was washed with saturated NaCl solution (20mL) and anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by column chromatography on silica gel (eluent: DCM/EtOAc (v/v) ═ 3/1) to give a white solid (100mg, 67%).
MS(ESI,pos.ion)m/z:659.1[M+H]+.
1H NMR(400MHz,CDCl3)δ(ppm):7.86(d,J＝8.3Hz,2H),7.77(s,1H),7.61(d,J＝8.3Hz,2H),7.58(d,J＝8.6Hz,2H),6.95(d,J＝8.6Hz,2H),6.89(d,J＝7.7Hz,1H),6.21(t,J＝74.2Hz,1H),5.52(dd,J＝13.5,6.4Hz,1H),5.15(s,1H),4.37–4.29(m,2H),4.03(dd,J＝14.2,6.7Hz,1H),3.85(dd,J＝11.7,4.8Hz,1H),3.78(d,J＝11.8Hz,1H),3.15–3.02(m,4H),2.80(s,3H),2.53–2.42(m,2H),1.28(t,J＝7.4Hz,3H).
Example 9: n- (4- (N- (cyclopropylamino) sulfonyl) benzyl) -2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) thiazole-5-carboxamide
Figure BDA0002878710730000442
2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) thiazole-5-carboxylic acid (371mg,0.85mmol), 4- (aminomethyl) -N-cyclopropylbenzenesulfonamide (160mg,0.71mmol), HATU (370mg,0.94mmol) and DIPEA (0.15mL,0.85mmol) were dissolved in DCM (25 mL). The reaction solution was stirred at room temperature for 16 h. After the reaction was complete, the reaction was diluted with DCM (20mL) and successively with HCl solution (15mL, 1.0mol/L), saturated NaHCO 3The solution (20mL) and saturated NaCl solution (25mL) were washed and the organic phase was washed with anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by column chromatography on silica gel (eluent: DCM/EtOAc (v/v) ═ 1/1) to give a white solid (123mg, 27%).
MS(ESI,pos.ion)m/z:647.1[M+H]+.
1H NMR(400MHz,CD3OD)δ(ppm):7.84(s,3H),7.62(d,J＝7.5Hz,2H),7.53(d,J＝7.4Hz,2H),7.12(d,J＝7.7Hz,2H),6.39(t,J＝75.0Hz,1H),5.31(s,1H),4.59(s,2H),4.32(s,2H),4.03(s,1H),3.92(d,J＝7.6Hz,1H),3.74(d,J＝11.4Hz,1H),2.54(s,1H),2.44(d,J＝14.2Hz,1H),2.13(s,1H),0.48(s,4H).
Example 10: 2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) -N- ((R) -1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) oxazole-4-carboxamide
Figure BDA0002878710730000443
The method comprises the following steps: synthesis of ((2S,4S) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-2-yl) methanol
Tert-butyl (2S,4S) -2- (hydroxymethyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidine-1-carboxylate (361mg,1.00mmol) was dissolved in DCM (20mL) at room temperature and HCl in methanol (0.5mL,4.0M) was added and the reaction was carried out for 5 h. Adding saturated Na2CO3Adjusting the pH value of the solution to be alkalescent, extracting the solution by DCM (10mL multiplied by 2), combining organic phases and anhydrous Na2SO4Dried, filtered and concentrated to give a colourless liquid (253mg, 97%). MS (ESI, pos.ion) M/z 262[ M + H ]]+.
Step two: synthesis of ethyl 2- ((2S,4S) -2- (hydroxymethyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) oxazole-4-carboxylate
((2S,4S) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-2-yl) methanol (500mg,1.9mmol) and K2CO3(740mg,4.13mmol) was dissolved in ACN (15mL), and ethyl 2-bromooxazole-4-carboxylate (410mg,1.86mmol) was added to the reaction mixture and reacted at room temperature for 13 hours. After completion of the reaction, the reaction mixture was diluted with DCM (20mL) and in turn saturated Na 2CO3The solution (10mL) was washed with saturated NaCl solution (15mL) and anhydrous Na2SO4Dried, filtered and concentrated under reduced pressure, and the crude product was isolated by column chromatography on silica gel (eluent: PE/EtOAc (v/v) ═ 1/1) to give a pale yellow solid (120mg, 16%).
MS(ESI,pos.ion)m/z:401.1[M+H]+.
Step three: synthesis of ethyl 2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) oxazole-4-carboxylate
Ethyl 2- ((2S,4S) -2- (hydroxymethyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) oxazole-4-carboxylate (130mg,0.32mmol) was dissolved with DCM (2mL) and H was added2O (1mL), stirred for 5min and then KOAc (350mg,3.53mmol), and TMSCF were added slowly2Br (0.5mL,3mmol), at room temperature for 12 h. Adding NaHCO into the reaction solution after the reaction is finished3Solution (20mL) and DCM (50mL) was added to dilute the mixture, the aqueous phase was extracted with DCM (20mL), and the combined organic phases were over anhydrous Na2SO4Dried, filtered and concentrated under reduced pressure, and the crude product was isolated by column chromatography on silica gel (eluent: PE/EtOAc (v/v) ═ 10/1) to give a yellow solid (100mg, 68%).
MS(ESI,pos.ion)m/z:451.1[M+H]+.
Step four: synthesis of 2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) oxazole-4-carboxylic acid
2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidine-1- Yl) oxazole-4-carboxylic acid ethyl ester (110mg,0.24mmol) was dissolved in MeOH (5mL), LiOH (90mg,2.10mmol) was added, followed by H2O (1 mL). The reaction was carried out at room temperature for 18 h. After completion of the reaction, HCl solution (15mL,0.1mol/L) was added to the reaction mixture, the mixture was extracted with DCM (20 mL. times.3), the organic phases were combined and washed with saturated NaCl solution (15mL), anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by column chromatography on silica gel (eluent: DCM/MeOH (v/v) ═ 10/1) to give a white solid (100mg, 97%).
MS(ESI,pos.ion)m/z:423.1[M+H]+.
Step five: synthesis of 2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) -N- ((R) -1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) oxazole-4-carboxamide
2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) oxazole-4-carboxylic acid (104mg,0.25mmol), (2R) -2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol (73mg,0.32mmol), HATU (110mg,0.28mmol) and DIPEA (0.15mL,0.85mmol) were dissolved in DCM (15 mL). The reaction was stirred at room temperature for 15 h. After the reaction was complete, the reaction was diluted with DCM (20mL) and successively with HCl solution (15mL, 1.0mol/L), saturated NaHCO3The solution (20mL) and saturated NaCl solution (25mL) were washed and the organic phase was washed with anhydrous Na 2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by column chromatography on silica gel (eluent: DCM/EtOAc (v/v) ═ 1/1) to give a white solid (103mg, 66%).
MS(ESI,pos.ion)m/z:634.1[M+H]+.
1H NMR(400MHz,CD3OD)δ(ppm):7.99–7.84(m,3H),7.76–7.54(m,4H),7.12(d,J＝7.0Hz,2H),6.41(t,J＝75.3Hz,1H),5.23(d,J＝28.1Hz,2H),4.30(d,J＝45.7Hz,2H),4.06(d,J＝23.0Hz,2H),3.95–3.76(m,3H),3.19(q,J＝7.4Hz,2H),2.53(s,1H),2.41(d,J＝13.6Hz,1H),1.21(d,J＝7.4Hz,3H).
Example 11: n- (2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) thiazol-5-yl) -2- (4- (ethylsulfonyl) phenyl) acetamide
Figure BDA0002878710730000461
The method comprises the following steps: synthesis of ((2S,4S) -1- (5-nitrothiazol-2-yl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-2-yl) methanol
((2S,4S) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-2-yl) methanol (500mg,1.9mmol) and K2CO3(940mg,5.25mmol) was dissolved in ACN (15mL), and 2-bromo-5-nitrothiazole (410mg,1.96mmol) was added and reacted at room temperature for 13 h. The reaction was diluted with DCM (50mL) and successively saturated Na2CO3The solution (10mL) was washed with saturated NaCl solution (15mL) and anhydrous Na2SO4Dried, filtered and concentrated under reduced pressure, and the crude product was isolated by column chromatography on silica gel (eluent: PE/EtOAc (v/v) ═ 1/1) to give a pale yellow solid (170mg, 23%).
MS(ESI,pos.ion)m/z:390.1[M+H]+.
Step two: synthesis of 2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) -5-nitrothiazole
((2S,4S) -1- (5-Nitro-thiazol-2-yl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-2-yl) methanol (170mg,0.44mmol) was dissolved with DCM (1mL) and H was added at room temperature 2O (1mL), stirred for 5min and then KOAc (450mg,4.54mmol), and TMSCF were added slowly2Br (0.6mL,4mmol) and then reaction was continued for 10 h. Adding NaHCO into the reaction solution after the reaction is finished3Solution (20mL) and DCM (50mL) was added to dilute the mixture, the aqueous phase was extracted with DCM (20mL), and the combined organic phases were over anhydrous Na2SO4Dried, filtered and concentrated under reduced pressure, and the crude product was isolated by column chromatography on silica gel (eluent: PE/EtOAc (v/v) ═ 10/1) to give a yellow solid (130mg, 68%).
MS(ESI,pos.ion)m/z:440.1[M+H]+.
Step three: synthesis of 2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) -5-aminothiazole
2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) -5-nitrothiazole (50mg,0.12mmol) was dissolved in MeOH (20mL), 10% palladium on charcoal (60mg) was added, and the reaction was reacted at room temperature under a hydrogen atmosphere for 5 h. After completion of the reaction, the reaction mixture was filtered through celite, the filtrate was concentrated under reduced pressure, dried in vacuo, and the crude product was isolated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 2/1) to give a white solid (40mg, 86%).
MS(ESI,pos.ion)m/z:410.1[M+H]+.
Step four: synthesis of N- (2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) thiazol-5-yl) -2- (4- (ethylsulfonyl) phenyl) acetamide
2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) -5-aminothiazole (50mg,0.12mmol), 2- (4- (ethylsulfonyl) phenyl) acetic acid (40mg,0.17mmol), HATU (72mg,0.18mmol) and DIPEA (0.05mL,0.28mmol) were dissolved in DCM (10 mL). The reaction solution was stirred at room temperature for 13 h. After the reaction was complete, the reaction was diluted with DCM (20mL) and successively with HCl solution (15mL, 1.0mol/L), saturated NaHCO3The solution (20mL) and saturated NaCl solution (25mL) were washed and the organic phase was washed with anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was chromatographed on silica gel (eluent: DCM/EtOAc (v/v) ═ 1/1) to give a pale yellow solid (18mg, 24%). MS (ESI, pos.ion) M/z 620.1[ M + H ]]+.
1H NMR(400MHz,CDCl3)δ(ppm):7.90(d,J＝8.2Hz,2H),7.64–7.46(m,4H),6.94(d,J＝6.9Hz,3H),6.19(t,J＝74.6Hz,1H),5.10(s,1H),4.28(d,J＝7.7Hz,2H),3.99(s,1H),3.78(d,J＝15.5Hz,4H),3.12(q,J＝7.4Hz,2H),2.47(d,J＝15.1Hz,2H),1.29(t,J＝7.4Hz,3H).
Example 12: n- ((R) -1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -2- ((2S,4S) -2- ((trifluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) thiazole-5-carboxamide
Figure BDA0002878710730000462
The method comprises the following steps: synthesis of methyl 2- ((2S,4S) -2- (hydroxymethyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) thiazole-5-carboxylate
((2S,4S) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-2-yl) methanol (1.00g,3.83mmol), methyl 2-bromothiazole-5-carboxylate (850mg,3.83mmol), K2CO3(800mg,5.74mmol) was added to DMF (8mL) in sequence and reacted at 90 ℃ for 17 h. The reaction was cooled to room temperature, diluted with EtOAc (60mL), and then sequentially with H 2O (20 mL. times.2) and saturated NaCl solution (20mL), anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by column chromatography on silica gel (eluent: PE/EtOAc (v/v) ═ 2/1) to give a yellow solid (670mg, 44%).
MS(ESI,pos.ion)m/z＝403.1[M+H]+.
Step two: synthesis of methyl 2- ((2S,4S) -2- ((trifluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) thiazole-5-carboxylate
AgOTf (1.25g,4.85mmol), fluorine selective reagent (858mg,2.42mmol), KF (375mg,6.45mmol) and methyl 2- ((2S,4S) -2- (hydroxymethyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) thiazole-5-carboxylate (650mg,1.62mmol) were added sequentially to EtOAc (12mL) under nitrogen, followed by 2-fluoropyridine (0.4mL,4.90mmol) and TMSCCF3(0.7mL,4.90mmol), and reacted at room temperature for 24 h. The reaction mixture was filtered, concentrated under reduced pressure, and the crude product was isolated by column chromatography on silica gel (eluent: PE/EtOAc (v/v) ═ 4/1) to give a white solid (521mg, 69%).
MS(ESI,pos.ion)m/z＝471.1[M+H]+.
Step three: synthesis of 2- ((2S,4S) -2- ((trifluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) thiazole-5-carboxylic acid
Reacting LiOH & H2O (446mg,10.63mmol) in H2O (4mL) solution was added to a solution of methyl 2- ((2S,4S) -2- ((trifluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) thiazole-5-carboxylate (500mg,1.06mmol) in MeOH/THF (3mL/3mL) and reacted at room temperature for 12 h. The reaction mixture was concentrated under reduced pressure, the remaining solution was adjusted to pH 4 by adding HCl solution (1mol/L), extracted with EtOAc (30mL), washed with saturated NaCl (15mL) solution, and washed with anhydrous Na 2SO4Dried and concentrated under reduced pressure to give a pale yellow solid (485mg, 100%).
MS(ESI,pos.ion)m/z＝457.0[M+H]+.
Step four: synthesis of N- ((R) -1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -2- ((2S,4S) -2- ((trifluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) thiazole-5-carboxamide
(R) -2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol (82mg,0.36mmol), HATU (162mg,0.43mmol), 2- ((2S,4S) -2- ((trifluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) thiazole-5-carboxylic acid (150mg,0.33mmol) and TEA (91mg,0.90mmol) were added to DCM (4mL) and reacted at room temperature for 16 h. The reaction was concentrated under reduced pressure and the residue was diluted with DCM (40mL) followed by HCl solution (15mL,1mol/L), saturated NaHCO3The solution (15mL) was washed with saturated NaCl solution (15mL) and anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by column chromatography on silica gel (eluent: DCM/MeOH (v/v) ═ 20/1) to give a white solid (140mg, 64%).
MS(ESI,pos.ion)m/z＝668.1[M+H]+.
1H NMR(400MHz,CDCl3)δ(ppm):7.87–7.80(m,2H),7.58(d,J＝8.6Hz,2H),7.54(d,J＝8.1Hz,2H),6.94(d,J＝8.6Hz,2H),6.93–6.85(m,1H),5.25–5.13(m,2H),4.48–4.37(m,2H),4.14(t,J＝7.9Hz,1H),4.03–3.97(m,1H),3.95–3.90(m,1H),3.82(dd,J＝11.6,4.6Hz,1H),3.74(d,J＝11.5Hz,1H),3.09(q,J＝7.4Hz,2H),2.51(s,2H),1.27(d,J＝7.4Hz,3H).
Example 13: 2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) -N- (3- (4- (ethylsulfonyl) phenyl) oxetan-3-yl) thiazole-5-carboxamide
Figure BDA0002878710730000481
The method comprises the following steps: synthesis of 2-methyl-N- (oxetan-3-alkylidene) propane-2-sulfinamide
Mixing oxetan-3-one (10g,138.8mmol), 2-methylpropaneAlkane-2-sulfinamide (16.82g,138.8mmol) was dissolved in DCM (20mL), tetraisopropyl titanate (40.0g,141mmol) was added thereto, stirred at room temperature for 12h, quenched with water, filtered, extracted with DCM (40 mL. times.2), anhydrous Na2SO4Dried, concentrated and separated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 5/1) to give a pale yellow liquid (5.83g, 24%).
MS(ESI,pos.ion)m/z:176[M+H]+.
Step two: synthesis of N- (3- (4-bromophenyl) oxetan-3-yl) -2-methylpropane-2-sulfinamide
1, 4-dibromobenzene (4.10g,17mmol) was dissolved in THF (10mL), cooled to-78 deg.C, N-BuLi (6.7mL,16mmol,2.4mol/L) was added, after stirring at 78 deg.C for 0.5h, a solution of 2-methyl-N- (oxetan-3-ylidene) propane-2-sulfinamide (2.80g,16mmol) in THF (10mL) was slowly added dropwise, dropwise addition was continued for about half an hour, room temperature was returned, and stirring was continued for 8 h. The reaction was quenched with water, extracted with EtOAc (10 mL. times.2), anhydrous Na2SO4Dried, concentrated and separated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 5/1) to give a yellow liquid (2.10g, 38%). MS (ESI, pos.ion) M/z 332[ M + H ]]+.
Step three: synthesis of N- (3- (4- (ethylsulfonyl) phenyl) oxetan-3-yl) -2-methylpropane-2-sulfinamide
N- (3- (4-bromophenyl) oxetan-3-yl) -2-methylpropane-2-sulfinamide (1.10g,3.30mmol), sodium ethylsulfinate (0.77g,6.60mmol), (2S,4R) -N- (2, 6-dimethylphenyl) -4-hydroxypyrrolidine-2-carboxamide (88mg,0.33mmol), potassium phosphate (0.84g,4.00mmol), and iodoidene (63mg,0.33mmol) were dissolved in DMSO (8mL), purged with nitrogen, heated to 100 ℃ for 24 h. Washing with saturated NaCl solution, EtOAc (10 ml. times.2) extraction, anhydrous Na2SO4Dried, concentrated and separated by silica gel column chromatography (eluent: DCM/EtOAc (v/v) ═ 5/1) to give a colourless liquid (0.56g, 49%).
MS(ESI,pos.ion)m/z:346[M+H]+.
Step four: synthesis of 3- (4- (ethylsulfonyl) phenyl) oxetan-3-amine
Reacting N- (3- (4- (ethylsulfonyl) phenyl) oxetan-3-yl) -2-Methylpropane-2-sulfinamide (250mg,0.72mmol) was dissolved in DCM (5mL), HCl (0.72mL,1.4mmol,2mol/L) was added, and stirred at room temperature for 2 h. Adding saturated Na2CO3The reaction was neutralized with a solution, extracted with DCM (10 ml. times.2) and dried over Na2SO4Dried, concentrated and separated by silica gel column chromatography (eluent: DCM/MeOH (v/v) ═ 20/1) to give a colorless liquid (0.17g, 95%).
MS(ESI,pos.ion)m/z:242[M+H]+.
Step five: synthesis of 2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) -N- (3- (4- (ethylsulfonyl) phenyl) oxetan-3-yl) thiazole-5-carboxamide
After dissolving 2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) thiazole-5-carboxylic acid (160mg,0.37mmol), 3- (4- (ethylsulfonyl) phenyl) oxetan-3-amine (110mg,0.40mmol), HATU (168mg,0.44mmol) in DCM (25mL), TEA (0.17mL,1.30mmol) was added and stirred at room temperature for 20 h. Adding saturated NH4Washed with Cl solution, extracted with DCM (10 ml. times.2) and dried over Na2SO4Dried, concentrated and separated by silica gel column chromatography (eluent: DCM/EtOAc (v/v) ═ 5/1) to give a white solid (0.096g, 40%).
MS(ESI,pos.ion)m/z:662[M+H]+.
1H NMR(400MHz,CD3OD)δ(ppm):7.89(d,J＝8.7Hz,2H),7.81(d,J＝8.3Hz,2H),7.58(dd,J＝17.2,8.4Hz,4H),6.98(d,J＝8.5Hz,2H),6.65(d,J＝8.8Hz,2H),6.23(t,J＝74.5Hz,1H),5.22(d,J＝32.7Hz,2H),4.26–4.10(m,6H),3.90(dd,J＝35.6,7.1Hz,3H),3.78–3.65(m,2H),3.09(q,J＝7.4Hz,2H),2.49(d,J＝14.3Hz,1H),2.39(d,J＝7.6Hz,1H),1.24(t,J＝7.4Hz,3H).
Example 14: 2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- ((2- (trifluoromethyl) pyrimidin-5-yl) oxy) pyrrolidin-1-yl) -N- ((R) -1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) thiazole-5-carboxamide
Figure BDA0002878710730000491
The method comprises the following steps: synthesis of (2S,4R) -1-tert-butyl 2-methyl 4- (((benzyloxy) carbonyl) oxy) pyrrolidine-1, 2-dicarboxylate
CbzCl (18.0mL,126.09mmol) was slowly added dropwise to (2S,4R) -1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1, 2-dicarboxylate (20.00g,81.54mmol) and DMAP (31.46g,244.60mmol) in DCM (200mL) under ice-cooling, and stirred at room temperature for 24 h. The reaction solution is filtered, and the filtrate is saturated NaHCO3The solution (100mL) was washed with saturated NaCl solution (100mL) and anhydrous Na 2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by column chromatography on silica gel (eluent: PE/EtOAc (v/v) ═ 4/1) to give a white solid (30g, 96%).
MS(ESI,pos.ion)m/z:324.2[M-56+H]+.
Step two: synthesis of tert-butyl (2S,4R) -4- (((benzyloxy) carbonyl) oxy) -2- (hydroxymethyl) pyrrolidine-1-carboxylate
(2S,4R) -1-tert-butyl 2-methyl 4- (((benzyloxy) carbonyl) oxy) pyrrolidine-1, 2-dicarboxylate (28.30g,74.59mmol) was added to a solution of THF (80mL) and BH was added at 0 deg.C3The THF solution (370mL,1mol/L) was heated to 45 ℃ for reaction for 11 h. Under vigorous stirring, saturated NH was added to the reaction solution4The reaction was quenched with a solution of Cl (200mL), allowed to settle, the upper organic phase was separated and concentrated under reduced pressure, the aqueous phase was extracted with EtOAc (100 mL. times.2), the organic phases were combined and the concentrated organic phase was dissolved and washed with saturated NaCl solution (100mL), anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by column chromatography on silica gel (eluent: PE/EtOAc (v/v) ═ 3/2) to give a colorless liquid (19.17g, 73%).
MS(ESI,pos.ion)m/z:296.2[M-56+H]+.
Step three: synthesis of tert-butyl (2S,4R) -4- (((benzyloxy) carbonyl) oxy) -2- ((difluoromethoxy) methyl) pyrrolidine-1-carboxylate
H is to be2O(40.0mL)、KOAc(28.00g,285.31mmol)、TMSCF2Br (23.0mL,147.90mmol) was added in succession to a solution of tert-butyl (2S,4R) -4- (((benzyloxy) carbonyl) oxy) -2- (hydroxymethyl) pyrrolidine-1-carboxylate (25.00g,71.15mmol) in DCM (40mL) and stirred at room temperature for 16 h. The reaction was quenched with DCM (100mL) and H2Diluting with O (100mL), extracting, separating, washing organic phase with saturated NaCl solution (50mL), and removing anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by column chromatography on silica gel (eluent: PE/EtOAc (v/v) ═ 4/1) to give a colorless liquid (20g, 70%).
MS(ESI,pos.ion)m/z:346.1[M-56+H]+.
Step four: synthesis of tert-butyl (2S,4R) -2- ((difluoromethoxy) methyl) -4-hydroxypyrrolidine-1-carboxylate
Pd/C (150mg, 10%) was added to (2S,4R) -4- (((benzyloxy) carbonyl) oxy) -2- ((difluoromethoxy) methyl) pyrrolidine-1-carboxylic acid tert-butyl ester (1.50g,3.74mmol) in MeOH (10mL) to displace the hydrogen and react at room temperature for 24 h. The reaction solution was filtered through celite, 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 liquid (959mg, 96%).
MS(ESI,pos.ion)m/z:211.2[M-56+H]+.
Step five: synthesis of tert-butyl (2S,4S) -2- ((difluoromethoxy) methyl) -4- ((2- (trifluoromethyl) pyrimidin-5-yl) oxy) pyrrolidine-1-carboxylate
(2S,4R) -2- ((difluoromethoxy) methyl) -4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (500mg,1.87mmol), 2- (trifluoromethyl) pyrimidin-5-ol (330mg,2.01mmol), PPh3(540mg,2.06mmol) was added to THF (8mL), displaced at 0 deg.C, DIAD (0.50mL,2.54mmol) was added slowly, and after addition, the mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure, the residue was diluted with methyl tert-butyl ether (15mL), stirred at-20 ℃ to precipitate a large amount of white insoluble solid, filtered while cold, the filtrate was concentrated under reduced pressure, and the crude product was chromatographed on silica gel (eluent: PE/EtOAc (v/v) ═ 3/1) to give a pale yellow liquid (650mg, 84%).
MS(ESI,pos.ion)m/z:414.1[M+H]+.
Step six: synthesis of 5- (((3S,5S) -5- ((difluoromethoxy) methyl) pyrrolidin-3-yl) oxy) -2- (trifluoromethyl) pyrimidine
A solution of HCl in 1, 4-dioxane (4mL,4mol/L) was added to (2S,4S) -2- ((difluoromethoxy) methyl) -4- ((2- (trifluoromethyl) pyrimidine-5-yl) oxy) pyrrolidine-1-carboxylic acid tert-butyl ester (600mg,1.45mmol) in DCM (6mL) was stirred at room temperature for 12 h. The reaction was concentrated under reduced pressure, the residue diluted with DCM (40mL) and successively with saturated Na2CO3The solution (15mL) was washed with saturated NaCl solution (15mL) and anhydrous Na2SO4Dried and concentrated under reduced pressure to give a pale yellow solid (454mg, 100%).
MS(ESI,pos.ion)m/z:314.2[M+H]+.
Step seven: synthesis of methyl 2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- ((2- (trifluoromethyl) pyrimidin-5-yl) oxy) pyrrolidin-1-yl) thiazole-5-carboxylate
Mixing 5- (((3S,5S) -5- ((difluoromethoxy) methyl) pyrrolidin-3-yl) oxy) -2- (trifluoromethyl) pyrimidine (250mg,0.80mmol), methyl 2-bromothiazole-5-carboxylate (200mg,0.90mmol), K2CO3(220mg,1.59mmol) was added to DMF (4mL) in sequence and reacted at 90 ℃ for 8 h. The reaction was cooled to room temperature, diluted with EtOAc (40mL) and then successively with H2O (15 mL. times.2) washing, saturated aqueous NaCl solution (15mL), anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by column chromatography on silica gel (eluent: PE/EtOAc (v/v) ═ 3/2) to give a yellow solid (212mg, 58%).
MS(ESI,pos.ion)m/z:455.1[M+H]+.
Step eight: synthesis of 2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- ((2- (trifluoromethyl) pyrimidin-5-yl) oxy) pyrrolidin-1-yl) thiazole-5-carboxylic acid
Reacting LiOH.H2O (200mg,4.77mmol) in H2O (1mL) solution was added to a solution of methyl 2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- ((2- (trifluoromethyl) pyrimidin-5-yl) oxy) pyrrolidin-1-yl) thiazole-5-carboxylate (212mg,0.47mmol) in MeOH (2mL) and THF (2mL) and stirred at room temperature for 24 h. The reaction mixture was concentrated under reduced pressure, the remaining solution was adjusted to pH 4 by adding HCl solution (1mol/L), extracted with EtOAc (30mL), and the organic phase was washed with saturated NaCl solution (10mL) and anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by column chromatography on silica gel (eluent: DCM/MeOH (v/v) ═ 20/1) to give a pale yellow solid (149mg, 72%).
MS(ESI,pos.ion)m/z:440.6[M+H]+.
Step nine: synthesis of 2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- ((2- (trifluoromethyl) pyrimidin-5-yl) oxy) pyrrolidin-1-yl) -N- ((R) -1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) thiazole-5-carboxamide
HATU (157mg,0.41mmol), (R) -2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol (80mg,0.35mmol), 2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- ((2- (trifluoromethyl) pyrimidin-5-yl) oxy) pyrrolidin-1-yl) thiazole-5-carboxylic acid (140mg,0.32mmol), TEA (88mg,0.87mmol) were added in sequence to DCM (4mL) and stirred at room temperature for 16 h. The reaction was concentrated under reduced pressure, the residue was diluted with DCM (40mL) and then with HCl solution (15mL,1mol/L) followed by saturated NaHCO 3The solution (15mL) was washed with saturated NaCl solution (15mL) and anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by column chromatography on silica gel (eluent: DCM/MeOH (v/v) ═ 20/1) to give a white solid (160mg, 77%).
MS(ESI,pos.ion)m/z:652.0[M+H]+.
1H NMR(400MHz,CDCl3)δ(ppm):8.53(s,2H),7.83(d,J＝8.3Hz,2H),7.73(s,1H),7.54(d,J＝8.2Hz,2H),6.99(d,J＝6.9Hz,1H),6.21(t,J＝73.9Hz,1H),5.27(s,1H),5.21(q,J＝6.4Hz,1H),4.40–4.33(m,1H),4.29(dd,J＝9.8,4.6Hz,1H),4.05–3.97(m,2H),3.94(dd,J＝11.8,4.9Hz,2H),3.81(d,J＝12.0Hz,1H),3.09(q,J＝7.4Hz,2H),2.88(s,1H),2.63–2.55(m,1H),2.52(d,J＝14.3Hz,1H),1.27(t,J＝7.4Hz,3H).
Example 15: 2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- ((1-methyl-6-oxo-1, 6-dihydropyridazin-3-yl) oxy) pyrrolidin-1-yl) -N- ((R) -1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) thiazole-5-carboxamide
Figure BDA0002878710730000511
The method comprises the following steps: synthesis of tert-butyl (2S,4S) -2- ((difluoromethoxy) methyl) -4- ((1-methyl-6-oxo-1, 6-dihydropyridazin-3-yl) oxy) pyrrolidine-1-carboxylate
Tert-butyl (2S,4R) -2- ((difluoromethoxy) methyl) -4-hydroxypyrrolidine-1-carboxylate (500mg,1.87mmol), 6-hydroxy-2-methylpyridazin-3 (2H) -one (260mg,2.06mmol), PPh3(540mg,2.06mmol) was added to THF (6mL), displaced at 0 deg.C, DIAD (0.50mL,2.54mmol) was added slowly, and after addition, the mixture was stirred at room temperature for 24 h. The reaction was concentrated under reduced pressure, the residue was diluted with methyl tert-butyl ether (15mL), stirred at-20 ℃ to precipitate a large amount of white insoluble solid, filtered while cold, the filter cake was washed with cold methyl tert-butyl ether, the filtrate was concentrated under reduced pressure, and the crude product was chromatographed on silica gel (eluent: DCM/EtOAc (v/v) ═ 4/1) to give a pale yellow solid (500mg, 71%).
MS(ESI,pos.ion)m/z:376.1[M+H]+.
Step two: synthesis of 6- (((3S,5S) -5- ((difluoromethoxy) methyl) pyrrolidin-3-yl) oxy) -2-methylpyridazin-3 (2H) -one
A solution of HCl in 1, 4-dioxane (3.5mL,4mol/L) was added to a solution of tert-butyl (2S,4S) -2- ((difluoromethoxy) methyl) -4- ((1-methyl-6-oxo-1, 6-dihydropyridazin-3-yl) oxy) pyrrolidine-1-carboxylate (500mg,1.33mmol) in DCM (3mL) and stirred at room temperature for 16 h. The reaction was concentrated under reduced pressure, the residue was diluted with DCM (30mL) and successively with saturated NaHCO3The solution (15mL) was washed with saturated NaCl solution (15mL) and anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by column chromatography on silica gel (eluent: DCM/MeOH (v/v) ═ 10/1) to give a pale yellow liquid (237mg, 65%).
MS(ESI,pos.ion)m/z:276.2[M+H]+.
Step three: synthesis of methyl 2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- ((1-methyl-6-oxo-1, 6-dihydropyridazin-3-yl) oxy) pyrrolidin-1-yl) thiazole-5-carboxylate
6- (((3S,5S) -5- ((difluoromethoxy) methyl) pyrrolidin-3-yl) oxy) -2-methylpyridazin-3 (2H) -one (220mg,0.80mmol), methyl 2-bromothiazole-5-carboxylate (200mg,0.90mmol), K2CO3(165mg,1.19mmol) was added to DMF (4mL) in sequence and reacted at 80 ℃ for 18 h. The reaction was cooled to room temperature, diluted with EtOAc (40mL) and then successively with H 2O (15 mL. times.2) washing, saturated aqueous NaCl solution(15mL) washing with anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was chromatographed on silica gel (eluent: DCM/EtOAc (v/v) ═ 3/1) to give a yellow liquid (210mg, 63%).
MS(ESI,pos.ion)m/z:417.2[M+H]+.
Step four: synthesis of 2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- ((1-methyl-6-oxo-1, 6-dihydropyridazin-3-yl) oxy) pyrrolidin-1-yl) thiazole-5-carboxylic acid
Reacting LiOH.H2O (200mg,4.77mmol) in H2O (1mL) solution was added to a solution of methyl 2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- ((1-methyl-6-oxo-1, 6-dihydropyridazin-3-yl) oxy) pyrrolidin-1-yl) thiazole-5-carboxylate (200mg,0.48mmol) in MeOH (2mL) and THF (2mL) and stirred at room temperature for 12 h. The reaction mixture was concentrated under reduced pressure, the remaining solution was adjusted to pH 4 by adding HCl solution (1mol/L), extracted with EtOAc (30mL), and the organic phase was washed with saturated NaCl solution (15mL) and anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by column chromatography on silica gel (eluent: DCM/MeOH (v/v) ═ 20/1) to give a pale yellow solid (180mg, 93%).
MS(ESI,pos.ion)m/z:403.0[M+H]+.
Step five: synthesis of 2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- ((1-methyl-6-oxo-1, 6-dihydropyridazin-3-yl) oxy) pyrrolidin-1-yl) -N- ((R) -1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) thiazole-5-carboxamide
HATU (122mg,0.32mmol), (R) -2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol (62mg,0.27mmol), 2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- ((1-methyl-6-oxo-1, 6-dihydropyridazin-3-yl) oxy) pyrrolidin-1-yl) thiazole-5-carboxylic acid (100mg,0.25mmol), TEA (50mg,0.49mmol) were added in sequence to DCM (4mL) and stirred at room temperature for 18 h. The reaction was concentrated under reduced pressure, the residue was diluted with DCM (40mL), washed successively with HCl solution (15mL,1mol/L) and saturated NaCl solution (15mL), anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by column chromatography on silica gel (eluent: DCM/MeOH (v/v) ═ 20/1) to give a white solid (80mg, 52%).
MS(ESI,pos.ion)m/z:614.0[M+H]+.
1H NMR(400MHz,CDCl3)δ(ppm):7.85(d,J＝8.3Hz,2H),7.74(s,1H),7.55(d,J＝8.2Hz,2H),6.91(d,J＝10.6Hz,3H),6.24(t,J＝74.2Hz,1H),5.45(d,J＝3.2Hz,1H),5.23(d,J＝6.2Hz,1H),4.35–4.25(m,2H),4.01(dd,J＝10.7,6.6Hz,2H),3.94(dd,J＝11.4,4.9Hz,1H),3.84(dd,J＝12.1,5.1Hz,1H),3.73(d,J＝11.9Hz,1H),3.66(s,3H),3.09(q,J＝7.4Hz,2H),2.48(s,2H),1.27(t,J＝7.4Hz,3H).
Example 16: n- ((R) -1- (4- ((cyclopropylmethyl) sulfonyl) phenyl) -2-hydroxyethyl) -2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) thiazole-5-carboxamide
Figure BDA0002878710730000521
The method comprises the following steps: synthesis of (R) -4- (4- ((cyclopropylmethyl) sulfonyl) phenyl) oxazolidin-2-one
Under nitrogen, sodium cyclopropylmethylsulfinate (760mg,5.35mmol), (4R) -4- (4-iodophenyl) oxazolidin-2-one (700mg,2.42mmol), CuI (90mg,0.45mmol) and (2S,4R) -N- (2, 6-dimethylphenyl) -4-hydroxypyrrolidine-2-carboxamide (11mg,0.05mmol) were dissolved in DMSO (5mL) and K was added 3PO4(650mg,3.54 mmol). The reaction solution was heated to 60 ℃ and reacted for 14 hours. H for reaction solution2O (50mL) and DCM (50mL) were diluted and the organic phase was successively treated with HCl solution (15mL,0.1mol/L), saturated NaHCO3The solution (15mL) and saturated NaCl solution (15mL) were washed and the organic phase was washed with anhydrous Na2SO4Dried, filtered and concentrated under reduced pressure to give a yellow solid (390mg, 57%).
MS(ESI,pos.ion)m/z:282.1[M+H]+.
Step two: synthesis of (R) -2-amino-2- (4- ((cyclopropylmethyl) sulfonyl) phenyl) ethanol
(R) -4- (4- ((cyclopropylmethyl) sulfonyl) phenyl) oxazolidin-2-one (391mg,1.39mmol) was dissolved in MeOH (5mL) and H was added2O (2mL) and KOH (950mg,7.62mmol) was added slowly. The reaction liquid is heated to 80 ℃ and stirredShould be 10 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the crude product was isolated by column chromatography on silica gel (eluent: DCM/MeOH (v/v) ═ 10/1) to give a yellow solid (280mg, 79%). MS (ESI, pos. ion) M/z 256.1[ M + H ]]+.
Step three: synthesis of N- ((R) -1- (4- ((cyclopropylmethyl) sulfonyl) phenyl) -2-hydroxyethyl) -2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) thiazole-5-carboxamide
2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) thiazole-5-carboxylic acid (131mg,0.30mmol), (R) -2-amino-2- (4- ((cyclopropylmethyl) sulfonyl) phenyl) ethanol (70mg,0.27mmol), HATU (130mg,0.33mmol) and DIPEA (0.05mL,0.28mmol) were dissolved in DCM (25 mL). The reaction solution was stirred at room temperature for 16 h. After the reaction was complete, the reaction was diluted with DCM (30mL) and successively with HCl solution (20mL, 1.0mol/L), saturated NaHCO 3The solution (20mL) and saturated NaCl solution (25mL) were washed and the organic phase was washed with anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by column chromatography on silica gel (eluent: DCM/EtOAc (v/v) ═ 1/1) to give a white solid (93mg, 50%).
MS(ESI,pos.ion)m/z:675.2[M+H]+.
1H NMR(400MHz,CDCl3)δ(ppm):7.86(d,J＝7.6Hz,2H),7.76(d,J＝8.5Hz,2H),7.56(dd,J＝16.3,8.0Hz,4H),7.09(d,J＝7.0Hz,1H),6.97(d,J＝8.2Hz,2H),6.64(d,J＝8.3Hz,2H),6.22(t,J＝74.3Hz,1H),5.26(s,1H),5.17(s,1H),4.17(d,J＝8.7Hz,2H),4.07–3.85(m,3H),3.73(dd,J＝17.3,7.1Hz,2H),2.97(d,J＝7.0Hz,2H),2.51(d,J＝14.2Hz,1H),2.39(d,J＝5.6Hz,1H),0.95(s,1H),0.56(d,J＝7.3Hz,2H),0.17(d,J＝3.5Hz,2H).
Example 17: 2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) -N- ((R) -1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) oxazole-5-carboxamide
Figure BDA0002878710730000531
The method comprises the following steps: synthesis of ethyl 2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) oxazole-5-carboxylate
(2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidine (600mg,1.93mmol) and K2CO3(770mg,4.30mmol) was dissolved in ACN (13mL), and ethyl 2-bromooxazole-5-carboxylate (480mg,2.18mmol) was added and reacted at room temperature for 14 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was diluted with DCM (30mL) and, in turn, saturated Na2CO3The solution (30mL) was washed with saturated NaCl solution (35mL) and dried over anhydrous Na2SO4Dried, filtered and concentrated under reduced pressure, and the crude product was isolated by column chromatography on silica gel (eluent: PE/EtOAc (v/v) ═ 1/1) to give a pale yellow solid (550mg, 63%).
MS(ESI,pos.ion)m/z:451.1[M+H]+.
Step two: synthesis of 2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) oxazole-5-carboxylic acid
Ethyl 2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) oxazole-5-carboxylate (550mg,1.2mmol) was dissolved in MeOH (25mL), LiOH (600mg,14.01mmol) was added, followed by H2O (3mL), and reacted at room temperature for 10 h. HCl solution (25mL,0.1mol/L) was added to the reaction, the mixture was extracted with DCM (30 mL. times.3), the organic phases were combined and washed with saturated NaCl solution (25mL), anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by column chromatography on silica gel (eluent: DCM/MeOH (v/v) ═ 10/1) to give a yellow solid (400mg, 78%).
MS(ESI,pos.ion)m/z:423.1[M+H]+.
Step three: synthesis of 2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) -N- ((R) -1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) oxazole-5-carboxamide
(2R) -2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol (240mg,1.05mmol), 2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) oxazole-5-carboxylic acid (420mg,0.99mmol), HATU (50- (trifluoromethyl) phenoxy)0mg,1.28mmol) and DIPEA (0.5mL,2.83mmol) were dissolved in DCM (25mL) and the reaction was stirred at room temperature for 13 h. The reaction was diluted with DCM (50mL) and successively with saturated NaHCO3The solution (30mL) and saturated NaCl solution (35mL) were washed and the organic phase was washed with anhydrous Na 2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by column chromatography on silica gel (eluent: PE/EtOAc (v/v) ═ 1/1) to give a white solid (300mg, 48%).
MS(ESI,pos.ion)m/z:634.1[M+H]+.
1H NMR(400MHz,CD3OD)δ(ppm):7.88(d,J＝8.2Hz,2H),7.64(dd,J＝13.1,8.5Hz,4H),7.56(s,1H),7.11(d,J＝8.6Hz,2H),6.40(t,J＝75.1Hz,1H),5.24(dd,J＝14.0,7.7Hz,2H),4.47–4.36(m,1H),4.24(dd,J＝9.6,4.9Hz,1H),4.11–4.01(m,2H),3.94–3.80(m,3H),3.18(q,J＝7.4Hz,2H),2.54(ddd,J＝13.9,8.4,5.3Hz,1H),2.41(d,J＝14.2Hz,1H),1.20(t,J＝7.4Hz,3H).
Example 18: n- ((S) -2-cyano-1- (4- (ethylsulfonyl) phenyl) ethyl) -2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) oxazole-5-carboxamide
Figure BDA0002878710730000541
(3S) -3-amino-3- (4- (ethylsulfonyl) phenyl) propionitrile (250mg,1.05mmol), 2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) oxazole-5-carboxylic acid (430mg,1.02mmol), HATU (500mg,1.28mmol) and DIPEA (0.5mL,2.83mmol) were dissolved in DCM (25mL) and the reaction solution was stirred warm for 12 h. The reaction was diluted with DCM (50mL) and successively with saturated NaHCO3The solution (30mL) and saturated NaCl solution (35mL) were washed and the organic phase was washed with anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by column chromatography on silica gel (eluent: PE/EtOAc (v/v) ═ 1/1) to give a white solid (390mg, 60%).
MS(ESI,pos.ion)m/z:643.1[M+H]+.
1H NMR(400MHz,CD3OD)δ(ppm):7.92(d,J＝8.1Hz,2H),7.70(d,J＝8.1Hz,2H),7.65–7.51(m,3H),7.11(d,J＝8.4Hz,2H),6.39(t,J＝75.1Hz,1H),5.57(t,J＝7.3Hz,1H),5.26(s,1H),4.42(d,J＝4.1Hz,1H),4.23(dd,J＝9.3,4.7Hz,1H),4.05(dd,J＝11.5,6.0Hz,2H),3.86(d,J＝11.8Hz,1H),3.24–3.11(m,4H),2.60–2.48(m,1H),2.41(d,J＝14.2Hz,1H),1.19(t,J＝7.3Hz,3H).
Example 19: 2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) -N- ((2- (ethylsulfonyl) thiazol-5-yl) methyl) thiazole-5-carboxamide
Figure BDA0002878710730000542
The method comprises the following steps: synthesis of ethyl 2-bromothiazole-5-carboxylate
To a solution of ethyl 2-aminothiazole-5-carboxylate (5.0g,29mmol) in HBr (36mL) at 0 deg.C was added NaNO2(3.0g,43mmol) of H2O (25mL) solution, stirring at 0 ℃ for 1H, adding a solution of CuBr (4.15g,28.9mmol) in HBr (25mL), reacting at 0 ℃ for 4H, stopping the reaction, and adding H2O quench, EtOAc extraction (40 mL. times.3), organic phase combination, saturated NaHCO3Solution (20mL) washed with anhydrous Na2SO4Dried, filtered and concentrated, and the concentrate was isolated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 4/1) to give the product as a colorless oil (5.0g, 73%).
1H NMR(400MHz,CDCl3)δ(ppm):8.14(s,1H),4.37(q,J＝7.1Hz,2H),1.38(t,J＝7.1Hz,3H).
Step two: synthesis of ethyl 2- (ethylsulfonyl) thiazole-5-carboxylate
To a mixture of ethyl 2-bromothiazole-5-carboxylate (2.0g,8.5mmol), sodium ethylsulfinate (1.2g,10mmol), CuI (160mg,0.84mmol), L-proline (200mg,1.74mmol) was added DMSO (13mL), the reaction was stopped after reacting at 110 ℃ for 9 hours under nitrogen protection, and saturated NH was added4Cl dilution (40mL), EtOAc extraction (30 mL. times.3), anhydrous Na2SO4Dried, filtered and concentrated, and the concentrate was isolated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 2/1) to give the product as a yellow oil (1.6g, 76%).
MS(ESI,pos.ion)m/z:250.1[M+H]+.
Step three: synthesis of (2- (ethylsulfonyl) thiazol-5-yl) methanol
To a solution of ethyl 2- (ethylsulfonyl) thiazole-5-carboxylate (800mg,3.21mmol) in THF (12mL) at 0 deg.C was added LiAlH 4(185mg,4.87mmol) and after 5h at RT, the reaction was stopped, quenched by slow addition of EtOH, concentrated by filtration over celite, and the concentrate was chromatographed over a silica gel column (eluent: EtOAc) to give a white solid (430mg, 64.64%).
MS(ESI,pos.ion)m/z:208.1[M+H]+.
Step four: synthesis of (2- (ethylsulfonyl) thiazol-5-yl) methylene methanesulfonate
To a solution of (2- (ethylsulfonyl) thiazol-5-yl) methanol (430mg,2.07mmol) in DCM (12mL,187.2mmol) at 0 deg.C was added TEA (580. mu.L, 4.16mmol), MsCl (200. mu.L, 2.52mmol) in that order, allowed to warm to room temperature for 3h, the reaction was stopped, saturated NH was saturated4Cl solution wash (20mL), anhydrous Na2SO4Dried, filtered and concentrated, and the concentrate was separated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 1/1) to give a colorless oil (520mg, 87.84%).
MS(ESI,pos.ion)m/z:286.1[M+H]+.
Step five: synthesis of 5- (azidomethylene) -2- (ethylsulfonyl) thiazole
To a mixture of (2- (ethylsulfonyl) thiazol-5-yl) methylene methanesulfonate (520mg,1.82mmol) and sodium azide (155mg,2.38mmol) was added DMF (6mL,77.3mmol), and after 1h reaction at room temperature, the reaction was stopped, diluted with DCM (40mL), saturated NH was added4Washed with Cl solution (10mL), saturated NaCl solution (10mL) and concentrated to a pale yellow oil (410mg, 96.87%).
MS(ESI,pos.ion)m/z:233.1[M+H]+.
Step six: synthesis of (2- (ethylsulfonyl) thiazol-5-yl) methylamine hydrochloride
To a mixture of 5- (azidomethylene) -2- (ethylsulfonyl) thiazole (410mg,1.76mmol), 10% Pd/C (40mg,0.37mmol) was added EtOH (8mL), H2Room temperature under atmosphereAfter 2h reaction time, stop the reaction, filter through celite, concentrate, dissolve in DCM (8mL), add slowly HCl/1, 4-dioxane solution (1mL,4M) dropwise, stir for 30min, concentrate, slurry with PE, filter to give an off-white solid (320mg, 4.67%).
MS(ESI,pos.ion)m/z:206.9[M+H]+.
1H NMR(400MHz,DMSO)δ(ppm):8.74(s,3H),8.28(s,1H),4.44(d,J＝4.1Hz,2H),3.58(q,J＝7.3Hz,2H),1.21(t,J＝7.3Hz,3H).
Step seven: synthesis of 2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) -N- ((2- (ethylsulfonyl) thiazol-5-yl) methyl) thiazole-5-carboxamide
To a mixture of 2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) thiazole-5-carboxylic acid (100mg,0.23mmol), (2- (ethylsulfonyl) thiazol-5-yl) methylamine hydrochloride (56mg,0.23mmol), EDCI (89mg,0.46mmol), HOBT (63mg,0.46mmol) was added DCM (6mL) and TEA (100. mu.L, 0.72mmol), reacted at room temperature for 24h, stopped, diluted with DCM (30mL), saturated NH4Cl solution wash (10mL), anhydrous Na2SO4Dried, concentrated and the concentrate was chromatographed on silica gel (eluent: PE/EtOAc (v/v) ═ 2/1) to give a white solid (99mg, 67.76%).
MS(ESI,pos.ion)m/z:627.3[M+H]+.
1H NMR(400MHz,CDCl3)δ(ppm):7.78(d,J＝18.5Hz,2H),7.58(t,J＝8.8Hz,3H),6.96(d,J＝8.5Hz,2H),6.21(t,J＝74.4Hz,1H),5.16(d,J＝2.4Hz,1H),4.74(d,J＝5.8Hz,2H),4.41–4.24(m,2H),4.01(t,J＝10.4Hz,1H),3.83(dd,J＝11.7,4.7Hz,1H),3.74(d,J＝11.7Hz,1H),3.37(q,J＝7.4Hz,2H),2.47(s,2H),1.34(t,J＝7.4Hz,3H).
Example 20: 2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) -N- ((5- (ethylsulfonyl) pyrimidin-2-yl) methyl) thiazole-5-carboxamide
Figure BDA0002878710730000561
The method comprises the following steps: synthesis of 2-cyano-5- (ethylsulfonyl) pyrimidine
To the reaction mixture was added 2-cyano-5-bromopyrimidine (600mg,3.26mmol), K2CO3(1.10g,7.96mmol) was added DMF (6mL), ethanethiol (500. mu.L, 6.94mmol) and reacted at room temperature for 3h, oxone complex salt (2.75g,16.4mmol) was added and stirring was continued at room temperature for 12h, the reaction was stopped, EtOAc (50mL) was added and diluted with saturated NH in sequence4Cl solution (20mL), saturated NaCl solution (15mL), anhydrous Na2SO4Drying, concentrating, adding acetone (20mL) and H2O (5mL), oxone complex salt (2.75g,16.4mmol), stirred at room temperature for 18H, added H2Dilution with O (40mL), EtOAc extraction (30 mL. times.3), combination of organic phases, washing with saturated NaCl solution (20mL), anhydrous Na2SO4Dried, concentrated and the concentrate was chromatographed on silica gel (eluent: PE/EtOAc (v/v) ═ 3/1) to give a white solid (360mg, 55.9%).
MS(ESI,pos.ion)m/z:198.2[M+H]+.
1H NMR(400MHz,CDCl3)δ(ppm):9.31(s,2H),3.29(q,J＝7.4Hz,2H),1.42(t,J＝7.4Hz,3H).
Step two: synthesis of (5- (ethylsulfonyl) pyrimidin-2-yl) methylamine hydrochloride
To a solution of 2-cyano-5- (ethylsulfonyl) pyrimidine (60mg,0.30mmol) in MeOH (6mL) was added Pd/C (30mg,0.03mmol), concentrated HCl (50. mu.L, 0.6mmol), reacted under 18MPa of hydrogen for 12h, the reaction was stopped, filtered through celite, and the filtrate was concentrated to give an off-white solid (59mg, 98%).
MS(ESI,pos.ion)m/z:202.0[M+H]+.
Step three: synthesis of 2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) -N- ((5- (ethylsulfonyl) pyrimidin-2-yl) methyl) thiazole-5-carboxamide
To 2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) thiazole-5-carboxylic acid (23mg,0.05mmol), EDCI (20mg,0.10mmol), HOBT (15mg,0.11mmol), (5- (ethylsulfonyl) pyrimidin-2-yl) methaneAfter DCM (3mL) and TEA (22. mu.L, 0.16mmol) were added to a mixture of amine hydrochloride (11mg,0.05mmol) and reacted at room temperature for 24h, the reaction was stopped and diluted with DCM (50mL) and saturated NH4Cl solution wash (15mL), anhydrous Na2SO4Dried and the concentrate was separated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 2/1) to give a white solid (19mg, 48.24%).
MS(ESI,pos.ion)m/z:621.9[M+H]+.
1H NMR(400MHz,CDCl3)δ(ppm):9.16(s,2H),7.79(s,1H),7.60(d,J＝8.5Hz,2H),7.01(d,J＝4.9Hz,1H),6.98(d,J＝8.5Hz,2H),6.25(t,J＝74.2Hz,1H),5.18(s,1H),4.97(d,J＝5.1Hz,2H),4.40–4.33(m,2H),4.06(dd,J＝13.7,7.4Hz,1H),3.91–3.80(m,2H),3.22(q,J＝7.4Hz,2H),2.58–2.47(m,2H),1.41–1.36(m,3H).
Example 21: n- ((S) -2-cyano-1- (4- (ethylsulfonyl) phenyl) ethyl) -2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- ((4- (trifluoromethyl) cyclohexyl) oxy) pyrrolidin-1-yl) thiazole-5-carboxamide
Figure BDA0002878710730000562
The method comprises the following steps: synthesis of (2S,4S) -1-benzyl 2-methyl 4-hydroxypyrrolidine-1, 2-dicarboxylic acid ester
To a solution of (2S,4S) -1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1, 2-dicarboxylate (6.6g,27mmol) in DCM (25mL,390mmol) was slowly added HCl/1, 4-dioxane (30mL,120mmol) at 0 deg.C, reacted overnight at room temperature, the reaction was stopped, and the solvent was directly concentrated to give a white solid powder. To the above product (4.9g,27mmol), benzyl chloroformate (3.9mL,27mmol) in THF (20mL) and H at 0 deg.C 2TEA (12mL,86.1mmol) was slowly added to the O (20mL) solution, and after 24h at room temperature, the reaction was stopped and saturated NH was added4Cl solution (50mL) diluted, EtOAc extracted (50 mL. times.3), combined organic phases, washed with saturated NaCl solution (20mL), anhydrous Na2SO4Dried, concentrated and the concentrate was chromatographed on silica gel (eluent: PE/EtOAc (v/v) ═ 4/1) to give the product as a colourless oil (5.8g, 77%).
1H NMR(400MHz,CDCl3)δ(ppm):7.49–7.30(m,5H),5.14(dt,J＝22.0,12.4Hz,2H),4.53–4.34(m,2H),3.85–3.58(m,5H),3.32(dd,J＝62.2,9.3Hz,1H),2.35(tdd,J＝14.3,9.8,4.6Hz,1H),2.15(dd,J＝13.9,4.8Hz,1H).
Step two: synthesis of (2S,4S) -1-benzyl 2-methyl 4- ((4- (trifluoromethyl) cyclohexyl) oxy) pyrrolidine-1, 2-dicarboxylate
To a solution of (2S,4S) -1-benzyl 2-methyl 4-hydroxypyrrolidine-1, 2-dicarboxylate (2.40g,8.59mmol), TEA (1.4mL,10mmol) in THF (25mL) at 0 deg.C was added chlorotrimethylsilane (1.2mL,9.2mmol) and reacted at room temperature for 1.5h, after which stirring was stopped, the cake was filtered through celite, the PE washed and concentrated to give the product as a pale yellow oil. To a solution of the above product and 4-trifluoromethylcyclohexanone (1.43g,8.61mmol) in DCM (30mL,468.0mmol) at-60 deg.C was added triethylsilane (1.52mL,9.42mmol) and trimethylsilyl trifluoromethanesulfonate (700. mu.L, 4.168mmol) in that order, the temperature was raised to 0 deg.C, after 12h of reaction, the reaction was stopped, diluted with EtOAc (50mL), saturated NaHCO3Adjusted to neutral, EtOAc extracted (30 mL. times.3), anhydrous Na 2SO4Dried, concentrated and the concentrate was chromatographed on silica gel (eluent: PE/EtOAc (v/v) ═ 8/1) to give a colourless oil (442mg, 12.0%).
MS(ESI,pos.ion)m/z:430.3[M+H]+.
Step three: synthesis of benzyl (2S,4S) -2- (hydroxymethyl) -4- ((4- (trifluoromethyl) cyclohexyl) oxy) pyrrolidine-1-carboxylate
To a solution of (2S,4S) -1-benzyl 2-methyl 4- ((4- (trifluoromethyl) cyclohexyl) oxy) pyrrolidine-1, 2-dicarboxylate (442mg,1.03mmol) in THF (12mL) at 0 deg.C was added LiBH4(30mg,1.38mmol), reaction was stopped after 12h at room temperature, and saturated NH was added4Cl solution quenching (20mL), EtOAc extraction (30 mL. times.3), anhydrous Na2SO4Dried, concentrated and the concentrate was chromatographed on silica gel (eluent: PE/EtOAc (v/v) ═ 2/1) to give a colourless oil (400mg, 96.81%).
MS(ESI,pos.ion)m/z:402.1[M+H]+.
Step four: synthesis of benzyl (2S,4S) -2- ((difluoromethoxy) methyl) -4- ((4- (trifluoromethyl) cyclohexyl) oxy) pyrrolidine-1-carboxylate
To benzyl (2S,4S) -2- (hydroxymethyl) -4- ((4- (trifluoromethyl) cyclohexyl) oxy) pyrrolidine-1-carboxylate (400mg,1.00mmol) in DCM (5mL) and H at 0 deg.C2KOAc (450mg,4.585mmol) and TMSCF were added to the O (6mL) solution2Br (520. mu.L, 3.34mmol), reacted at room temperature for 24h, then stirring was stopped and saturated NH was added4Cl solution quenched (30mL), EtOAc (30 mL. times.3), anhydrous Na 2SO4Dried, concentrated and the concentrate was chromatographed on silica gel (eluent: PE/EtOAc (v/v) ═ 6/1) to give a pale yellow oil (367mg, 81.59%). MS (ESI, pos.ion) M/z 452.1[ M + H ]]+.
Step five: synthesis of (2S,4S) -2- ((difluoromethoxy) methyl) -4- ((4- (trifluoromethyl) cyclohexyl) oxy) pyrrolidine
To a solution of (2S,4S) -2- ((difluoromethoxy) methyl) -4- ((4- (trifluoromethyl) cyclohexyl) oxy) pyrrolidine-1-carboxylic acid benzyl ester (367mg,0.81mmol) in MeOH (10mL) was added Pd/C (56mg, 10%) and reacted at room temperature under a hydrogen atmosphere for 3h, then filtered over celite, washed with DCM, and concentrated directly to give a colorless oil (220mg, 85.28%).
MS(ESI,pos.ion)m/z:318.5[M+H]+.
Step six: synthesis of methyl 2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- ((4- (trifluoromethyl) cyclohexyl) oxy) pyrrolidin-1-yl) thiazole-5-carboxylate
To (2S,4S) -2- ((difluoromethoxy) methyl) -4- ((4- (trifluoromethyl) cyclohexyl) oxy) pyrrolidine (130mg,0.41mmol), methyl 2-bromothiazole-5-carboxylate (137mg,0.62mmol), K2CO3(120mg,0.87mmol) of the mixture was added with ACN (6mL), heated at 60 ℃ for 48h, saturated NH was added4Cl solution (20mL) was quenched, EtOAc extracted (25 mL. times.3), the organic phases combined and washed with saturated NaCl solution (15mL) anhydrous Na 2SO4Dried and the concentrate was separated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 3/1) to give a colourless oil (83mg, 44.19%).
MS(ESI,pos.ion)m/z:459.1[M+H]+.
Step seven: synthesis of 2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- ((4- (trifluoromethyl) cyclohexyl) oxy) pyrrolidin-1-yl) thiazole-5-carboxylic acid
To a solution of methyl 2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- ((4- (trifluoromethyl) cyclohexyl) oxy) pyrrolidin-1-yl) thiazole-5-carboxylate (80mg,0.17mmol) in MeOH (2.5mL) and THF (2.5mL) was added NaOH solution (40mg,1.05mmol), H2O (1mL), heating at 50 ℃ for 12h to stop the reaction, adjusting the pH to 6-7, DCM extracting (25 mL. times.3), anhydrous Na2SO4Dried and concentrated to give a brown solid (79mg, 99%).
MS(ESI,pos.ion)m/z:445.1[M+H]+.
Step eight: synthesis of N- ((S) -2-cyano-1- (4- (ethylsulfonyl) phenyl) ethyl) -2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- ((4- (trifluoromethyl) cyclohexyl) oxy) pyrrolidin-1-yl) thiazole-5-carboxamide
To a mixture of 2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- ((4- (trifluoromethyl) cyclohexyl) oxy) pyrrolidin-1-yl) thiazole-5-carboxylic acid (40mg,0.09mmol), (S) -3-amino-3- (4- (ethylsulfonyl) phenyl) propionitrile hydrochloride (37mg,0.13mmol), EDCI (35mg,0.18mmol), HOBT (25mg,0.18mmol) was added DCM (5mL,78.01mmol), TEA (40. mu.L, 0.29mmol), reacted at room temperature for 24h and then stopped, diluted with DCM (40mL), saturated NH 4Cl solution (10mL) washing, anhydrous Na2SO4Dried and the concentrate was separated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 1/1) to give a white solid (32mg, 51.20%).
MS(ESI,pos.ion)m/z:665.5[M+H]+.
1H NMR(400MHz,CDCl3)δ(ppm):7.83(d,J＝8.1Hz,3H),7.62(d,J＝8.3Hz,2H),7.31–7.26(m,1H),6.25(t,J＝74.6Hz,1H),5.60–5.47(m,1H),4.37(s,1H),4.25(dd,J＝15.9,7.0Hz,2H),4.02(t,J＝8.5Hz,1H),3.60(dd,J＝11.1,4.8Hz,1H),3.50(d,J＝11.0Hz,1H),3.34(ddd,J＝14.3,10.3,4.0Hz,1H),3.11(dt,J＝13.9,7.0Hz,4H),2.34–1.92(m,7H),1.45–1.22(m,7H).
Example 22: 2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- ((4- (trifluoromethyl) cyclohexyl) oxy) pyrrolidin-1-yl) -N- ((R) -1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) thiazole-5-carboxamide
Figure BDA0002878710730000581
To a mixture of 2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- ((4- (trifluoromethyl) cyclohexyl) oxy) pyrrolidin-1-yl) thiazole-5-carboxylic acid (40mg,0.09mmol), (2R) -2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol (37mg,0.16mmol), HOBT (25mg,0.18mmol), EDCI (35mg,0.18mmol) was added DCM (5mL), TEA (40. mu.L, 0.28mmol), reacted at room temperature for 24h, diluted DCM (40mL), saturated NH4Cl solution (20mL) washed with anhydrous Na2SO4Dried and the concentrate was isolated by silica gel column chromatography (eluent: EtOAc) to give a colorless oil (27mg, 41.46%).
MS(ESI,pos.ion)m/z:655.7[M+H]+.
1H NMR(400MHz,CDCl3)δ(ppm):7.83(d,J＝8.3Hz,2H),7.78(s,1H),7.56(d,J＝8.3Hz,2H),7.14(d,J＝7.2Hz,1H),6.26(t,J＝74.6Hz,1H),5.22(dd,J＝11.0,5.3Hz,1H),4.38(s,1H),4.26(dd,J＝15.6,6.7Hz,2H),4.07–3.86(m,3H),3.60(dd,J＝11.1,4.8Hz,1H),3.51(t,J＝10.7Hz,1H),3.35(td,J＝10.4,5.2Hz,1H),3.10(q,J＝7.4Hz,2H),2.33–2.06(m,5H),2.01(d,J＝10.3Hz,3H),1.41–1.24(m,7H).
Example 23: 2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) -N- ((S) -1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) thiazole-5-carboxamide
Figure BDA0002878710730000591
HATU (225mg,0.59mmol), (S) -2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol (140mg,0.61mmol), 2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) thiazole-5-carboxylic acid (200mg,0.46mmol), TEA (140mg,1.38mmol) were added in that order to DCM (4mL) and stirred at room temperature for 16 h. The reaction was concentrated under reduced pressure and the residue was diluted with DCM (40mL) and then with HCl solution (20mL,1mol/L), saturated NaHCO3Solution (20mL), saturated NaCl solution (20mL) wash, anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by column chromatography on silica gel (eluent: DCM/MeOH (v/v) ═ 20/1) to give a white solid (160mg, 54%).
MS(ESI,pos.ion)m/z:650.0[M+H]+.
1H NMR(400MHz,CDCl3)δ(ppm):7.81(d,J＝8.2Hz,2H),7.74(s,1H),7.57(d,J＝8.7Hz,2H),7.53(d,J＝8.2Hz,2H),7.08(d,J＝7.1Hz,1H),6.95(d,J＝8.5Hz,2H),6.21(t,J＝74.2Hz,1H),5.22–5.17(m,1H),5.14(s,1H),4.30(d,J＝6.2Hz,2H),4.03(d,J＝10.5Hz,1H),3.97(dd,J＝11.7,4.2Hz,1H),3.89(dd,J＝11.4,5.4Hz,1H),3.84(dd,J＝11.7,4.8Hz,1H),3.75(d,J＝11.7Hz,1H),3.12–3.05(m,3H),2.47(s,2H),1.25(t,J＝7.4Hz,3H).
Example 24: synthesis of 2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) -N- ((R) -1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -1-methyl-1H-imidazole-5-carboxamide
Figure BDA0002878710730000592
The method comprises the following steps: synthesis of ethyl 2-bromo-1-methyl-1H-imidazole-5-carboxylate
2-bromo-1H-imidazole-5-carboxylic acid ethyl ester (1.97g,8.99mmol), K2CO3(2.49g,18.00mmol) was dissolved in DMF (15mL) and iodomethane (1.70mL,27.00mmol) was added and reacted at room temperature for 20 h. Adding saturated NaHCO into the reaction solution3Solution (100mL), EtOAc (120 mL. times.2) extraction, anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 4/1) to give a colorless oil (577mg, 27.5%).
MS(ESI,pos.ion)m/z:234.9[M+H]+.
Step two: synthesis of ethyl 2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) -1-methyl-1H-imidazole-5-carboxylate
(2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidine (460mg,1.48mmol), ethyl 2-bromo-1-methyl-1H-imidazole-5-carboxylate (372mg,1.60mmol), Pd under nitrogen 2(dba)3(147mg,0.16mmol)，Ruphos(143mg,0.31mmol)，Cs2CO3(1.06g,3.25mmol) was dissolved in toluene (10mL) and the reaction was heated at 110 ℃ for 18 h. Celite was filtered, concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 2/1) to give a yellow oil (310mg, 45.3%).
MS(ESI,pos.ion)m/z:464.0[M+H]+.
Step three: synthesis of 2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) -1-methyl-1H-imidazole-5-carboxylic acid
Ethyl 2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) -1-methyl-1H-imidazole-5-carboxylate (376mg,0.81mmol), LiOH. H2O (371mg,8.84mmol) in THF/MeOH/H2O (2mL/1mL/1mL), and reacted at room temperature for 13 h. Concentrating under reduced pressure, adding 1.0M HCl solution (8mL), adjusting pH to about 4, extracting with EtOAc (30 mL. times.2), and collecting organic layer as anhydrous Na2SO4Dried, concentrated under reduced pressure and the crude product was isolated by column chromatography over silica gel (eluent: DCM/MeOH (v/v) ═ 10/1) to give a brown solid (255mg, 72.2%).
MS(ESI,pos.ion)m/z:436.0[M+H]+.
Step four: synthesis of 2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) -N- ((R) -1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -1-methyl-1H-imidazole-5-carboxamide
2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) -1-methyl-1H-imidazole-5-carboxylic acid (150mg,0.346mmol), (2R) -2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride (118mg,0.44mmol), EDCI (240mg,1.25mmol), HOBT (169mg,1.25mmol) was dissolved in DCM (5mL) and DIPEA (0.45mL,2.70mmol) was added and stirred at room temperature. DCM (50mL), saturated NaHCO was added to the reaction 3(30 mL. times.2) washing with saturated NH4Cl (30mL) washing, anhydrous Na2SO4Drying, concentration under reduced pressure and separation of the crude product by silica gel column chromatography (eluent: DCM/MeOH (v/v) ═ 12/1) gave 160mg of a pale yellow solid which was isolated by preparative separation as a white solid (90mg, 40.4%).
MS(ESI,pos.ion)m/z:647.4[M+H]+.
1H NMR(400MHz,DMSO-d6)δ(ppm):8.43(d,J＝7.2Hz,1H),7.84(d,J＝7.7Hz,2H),7.65(t,J＝7.8Hz,4H),7.57(s,1H),7.17(d,J＝8.0Hz,2H),6.61(t,J＝75.9Hz,1H),5.20(s,1H),5.12–4.99(m,2H),4.34(s,1H),3.89(dd,J＝9.3,4.4Hz,1H),3.80(dd,J＝9.1,6.3Hz,1H),3.67(dd,J＝12.9,7.3Hz,4H),3.57(s,3H),3.30–3.26(m,2H),2.65–2.56(m,1H),1.97(d,J＝13.3Hz,1H),1.10(t,J＝7.0Hz,3H).
Example 25: 2- ((2S,4R) -2- ((difluoromethoxy) methyl) -4- ((4- (trifluoromethyl) piperidin-1-yl) methyl) pyrrolidin-1-yl) -N- ((R) -1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) thiazole-5-carboxamide
Figure BDA0002878710730000601
The method comprises the following steps: synthesis of (2S,4S) -1-tert-butyl 2-methyl 4- (4- (trifluoromethyl) piperidine-1-carbonyl) pyrrolidine-1, 2-dicarboxylate
4- (trifluoromethyl) piperidine (2.00g,13.1mmol), (3S,5S) -1- (tert-butoxycarbonyl) -5- (methoxycarbonyl) pyrrolidine-3-carboxylic acid (4.1g,15mmol), HATU (6.20g,15.8mmol) and DIPEA (2.5mL,14mmol) were dissolved in DCM (30mL) and reacted at room temperature for 18 h. After the reaction was complete, the reaction was diluted with DCM (50mL) and successively with HCl solution (55mL,1.0mol/L), saturated NaHCO3The solution (50mL) and saturated NaCl solution (55mL) were washed, and the organic phase was washed with anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was chromatographed on silica gel (eluent: DCM/EtOAc (v/v) ═ 5/1) to give a colorless liquid (4.60g, 86%).
MS(ESI,pos.ion)m/z:309.2[M-100+H]+.
Step two: synthesis of tert-butyl (2S,4S) -2- (hydroxymethyl) -4- (4- (trifluoromethyl) piperidine-1-carbonyl) pyrrolidine-1-carboxylate
(2S,4S) -1-tert-butyl 2-methyl 4- (4- (trifluoromethyl) piperidine-1-carbonyl) pyrrolidine-1, 2-dicarboxylate (4.60g,11.3mmol) was dissolved in anhydrous THF (30mL) under anhydrous and oxygen-free conditions and LiBH was added portionwise at-10 deg.C4(380mg,17.10mmol) and reacted at room temperature for 10 hours. Adding saturated NH into the reaction solution after the reaction is finished4The reaction was quenched with Cl solution (50mL), the mixture was extracted with EtOAc (20 mL. times.3), the organic phases were combined and washed with saturated NaCl solution (30mL), anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was chromatographed on silica gel (eluent: DCM/EtOAc (v/v) ═ 1/1) to give a colorless liquid (1.05g, 25%).
MS(ESI,pos.ion)m/z:325.2[M-56+H]+.
Step three: synthesis of tert-butyl (2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) piperidine-1-carbonyl) pyrrolidine-1-carboxylate
Tert-butyl (2S,4S) -2- (hydroxymethyl) -4- (4- (trifluoromethyl) piperidine-1-carbonyl) pyrrolidine-1-carboxylate (700mg,1.84mmol) was dissolved with DCM (3mL) and H was added dropwise2O (3mL), stirred for 5min and added KOAc (1.85g,18.7mmol), and TMSCF2Br (1.45mL,9.32mmol), and the reaction mixture was reacted at room temperature for 16 h. After the reaction is finished, NaHCO is slowly added into the reaction liquid3Solution (20mL) and DCM (30mL) was added to dilute the mixture, the aqueous phase was extracted with DCM (20mL), and the combined organic phases were over anhydrous Na 2SO4Dried, filtered and concentrated under reduced pressure, and the crude product was isolated by column chromatography on silica gel (eluent: PE/EtOAc (v/v) ═ 5/1) to give a colorless transparent liquid (400mg, 51%).
MS(ESI,pos.ion)m/z:375.2[M-56+H]+.
Step four: synthesis of tert-butyl (2S,4R) -2- ((difluoromethoxy) methyl) -4- ((4- (trifluoromethyl) piperidin-1-yl) methyl) pyrrolidine-1-carboxylate
(2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) piperidine-1-carbonyl) pyrrolidine-1-carboxylic acid tert-butyl ester (400mg,0.94mmol) was dissolved in THF (40mL) under anhydrous and oxygen-free conditions and BH was added dropwise3Was added to the reaction solution (4.0mL,4.0mmol) and reacted at room temperature for 11 h. The reaction solution is in ice bathSlowly dropwise adding saturated NH under the condition4The reaction was quenched with Cl solution (15mL), the solvent was evaporated under reduced pressure, the residue was extracted with DCM (20mL), and the organic phase was Na2SO4After drying, concentration and separation of the crude product by column chromatography on silica gel (eluent: DCM/EtOAc (v/v) ═ 1/1) gave a colourless liquid (120mg, 31%).
MS(pos.ion)m/z:417.2[M+H]+.
Step five: synthesis of 1- (((3S,5S) -5- ((difluoromethoxy) methyl) pyrrolidin-3-yl) methyl) -4- (trifluoromethyl) piperidine
Tert-butyl (2S,4R) -2- ((difluoromethoxy) methyl) -4- ((4- (trifluoromethyl) piperidin-1-yl) methyl) pyrrolidine-1-carboxylate (90mg,0.22mmol) was dissolved in MeOH (6mL) and HCl in MeOH (8mL, 20%, 32mmol) was slowly added dropwise. The reaction solution was reacted at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure to give a colorless liquid (65mg, 95%).
MS(ESI,pos.ion)m/z:317.2[M+H]+.
Step six: synthesis of methyl 2- ((2S,4R) -2- ((difluoromethoxy) methyl) -4- ((4- (trifluoromethyl) piperidin-1-yl) methyl) pyrrolidin-1-yl) thiazole-5-carboxylate
1- (((3S,5S) -5- ((difluoromethoxy) methyl) pyrrolidin-3-yl) methyl) -4- (trifluoromethyl) piperidine (65mg,0.21mmol) and K2CO3(130mg,0.73mmol) was dissolved in ACN (7mL), methyl 2-bromothiazole-5-carboxylate (62mg,0.28mmol) was added dropwise at room temperature, and the reaction mixture was heated to 75 ℃ for reaction for 17 hours. The reaction was cooled to room temperature and concentrated under reduced pressure, and the residue was diluted with DCM (40mL) and then saturated Na2CO3The solution (30mL) was washed with saturated NaCl solution (35mL) and dried over anhydrous Na2SO4Dried, filtered and concentrated under reduced pressure, and the crude product was isolated by column chromatography on silica gel (eluent: PE/EtOAc (v/v) ═ 3/1) to give a white solid (40mg, 43%).
MS(ESI,pos.ion)m/z:458.1[M+H]+.
Step seven: synthesis of 2- ((2S,4R) -2- ((difluoromethoxy) methyl) -4- ((4- (trifluoromethyl) piperidin-1-yl) methyl) pyrrolidin-1-yl) thiazole-5-carboxylic acid
Mixing 2- ((2S,4R) -2- ((difluoromethoxy) methyl) -4- ((4- (trifluoromethyl) piperazinePyridin-1-yl) methyl) pyrrolidin-1-yl) thiazole-5-carboxylic acid methyl ester (40mg,0.087mmol) was dissolved in MeOH (5mL) and LiOH (40mg,0.92mmol) was added. The reaction was stirred at room temperature for 14 h. After completion of the reaction, HCl solution (5mL,0.1mol/L) was added to the reaction mixture, the mixture was extracted with DCM (20 mL. times.2), the organic phases were combined and washed with saturated NaCl solution (10mL), anhydrous Na 2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by column chromatography on silica gel (eluent: DCM/MeOH (v/v) ═ 10/1) to give a white solid (35mg, 90%).
MS(ESI,pos.ion)m/z:444.1[M+H]+.
Step eight: synthesis of 2- ((2S,4R) -2- ((difluoromethoxy) methyl) -4- ((4- (trifluoromethyl) piperidin-1-yl) methyl) pyrrolidin-1-yl) -N- ((R) -1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) thiazole-5-carboxamide
2- ((2S,4R) -2- ((difluoromethoxy) methyl) -4- ((4- (trifluoromethyl) piperidin-1-yl) methyl) pyrrolidin-1-yl) thiazole-5-carboxylic acid (35mg,0.079mmol), HATU (40mg,0.10mmol) and DIPEA (0.1mL,0.57mmol) were dissolved in DCM (5 mL). The reaction solution was reacted at room temperature for 20 h. The reaction was diluted with DCM (25mL) and successively with saturated NaHCO3The solution (25mL) and saturated NaCl solution (15mL) were washed and the organic phase was washed with anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by column chromatography on silica gel (eluent: DCM/EtOAc (v/v) ═ 1/1) to give a white solid (11mg, 21%).
MS(ESI,pos.ion)m/z:655.2[M+H]+.
1H NMR(400MHz,CDCl3)δ(ppm):7.87(d,J＝8.3Hz,2H),7.72(d,J＝5.1Hz,1H),7.54(dd,J＝19.1,8.3Hz,2H),6.71(d,J＝7.0Hz,1H),6.20(t,J＝74.4Hz,1H),5.28–5.20(m,1H),4.26(s,1H),4.16–4.08(m,1H),4.07–3.98(m,2H),3.92(ddd,J＝25.2,11.3,4.8Hz,1H),3.65–3.57(m,1H),3.18–3.05(m,3H),3.01(d,J＝11.6Hz,1H),2.92(d,J＝11.1Hz,1H),2.83–2.72(m,1H),2.37(d,J＝7.4Hz,2H),2.24–2.14(m,1H),1.90–1.74(m,5H),1.65–1.58(m,4H),1.23(t,J＝7.4Hz,3H).
Example 26: 2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) -N- ((R) -1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) thiazole-5-carboxamide
Figure BDA0002878710730000621
After dissolving 2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) thiazole-5-carboxylic acid (75mg,0.17mmol), (R) -2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol (52mg,0.19mmol), HATU (79mg,0.21mmol) in DCM (25mL), TEA (0.051mL,0.39mmol) was added and the reaction was carried out at room temperature for 12 h. Addition of saturated NH 4The reaction was quenched with Cl, extracted with DCM (10 ml. times.2), and the organic phases combined over anhydrous Na2SO4Dried, filtered, concentrated and separated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 1/1) to give a white solid (58mg, 51%).
MS(ESI,pos.ion)m/z:650[M+H]+.
1H NMR(400MHz,CDCl3)δ(ppm):7.83(d,J＝8.2Hz,2H),7.77(s,1H),7.57(dd,J＝14.9,8.4Hz,4H),7.13(d,J＝7.1Hz,1H),6.97(d,J＝8.6Hz,2H),6.23(t,J＝74.3Hz,1H),5.32(s,1H),5.25–5.14(m,2H),4.32(d,J＝6.4Hz,2H),4.08–3.81(m,4H),3.76(d,J＝11.7Hz,1H),3.10(q,J＝7.4Hz,2H),1.27(t,J＝7.2Hz,3H).
Example 27: n- ((S) -2-cyano-1- (4- (ethylsulfonyl) phenyl) ethyl) -2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) thiazole-5-carboxamide
Figure BDA0002878710730000631
After 2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) thiazole-5-carboxylic acid (75mg,0.17mmol), (S) -3-amino-3- (4- (ethylsulfonyl) phenyl) propionitrile (52mg,0.19mmol), HATU (79mg,0.21mmol) was dissolved in DCM (25mL), TEA (0.051mL,0.39mmol) was added and reacted at room temperature for 12 h. Addition of saturated NH4The reaction was quenched with Cl, extracted with DCM (10 ml. times.2), and the organic phases combined over anhydrous Na2SO4Drying, filtering, concentratingSeparation by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 1/1) gave a white solid (58mg, 51%).
MS(ESI,pos.ion)m/z:659[M+H]+.
1H NMR(400MHz,CDCl3)δ(ppm):7.89(d,J＝8.3Hz,2H),7.79(s,1H),7.62(dd,J＝14.4,8.5Hz,4H),6.97(d,J＝8.5Hz,2H),6.88(d,J＝7.7Hz,1H),6.23(t,J＝74.2Hz,1H),5.55(d,J＝7.0Hz,1H),5.17(s,1H),4.41–4.31(m,2H),4.09–4.00(m,1H),3.88(dd,J＝11.8,4.8Hz,1H),3.79(d,J＝11.7Hz,1H),3.12(dt,J＝10.6,7.0Hz,4H),2.50(d,J＝10.5Hz,2H),1.29(d,J＝8.1Hz,3H).
Example 28: 2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) -N- (4- (ethylsulfonyl) benzyl) thiazole-5-carboxamide
Figure BDA0002878710730000632
After 2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) thiazole-5-carboxylic acid (75mg,0.17mmol), (4- (ethylsulfonyl) phenyl) methylamine (52mg,0.19mmol), and HATU (79mg,0.21mmol) were dissolved in DCM (25mL), TEA (0.051mL,0.39mmol) was added and reacted at room temperature for 12 h. Addition of saturated NH 4The reaction was quenched with Cl solution, extracted with DCM (10 ml. times.2), the organic phases combined, anhydrous Na2SO4Dried, filtered, concentrated and separated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 1/1) to give a white solid (58mg, 51%).
MS(ESI,pos.ion)m/z:620[M+H]+.
1H NMR(400MHz,CDCl3)δ(ppm):7.89(d,J＝8.3Hz,2H),7.79(s,1H),7.62(dd,J＝14.4,8.5Hz,4H),6.97(d,J＝8.5Hz,2H),6.88(d,J＝7.7Hz,1H),6.23(t,J＝74.2Hz,1H),5.55(d,J＝7.0Hz,1H),5.17(s,1H),4.41–4.31(m,2H),4.09(s,2H),3.12(dt,J＝10.6,7.0Hz,4H),2.50(d,J＝10.5Hz,2H),1.29(d,J＝8.1Hz,3H).
Example 29: 2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) -N- ((R) -1- (4- (ethylsulfonyl) phenyl) -2-methoxyethyl) thiazole-5-carboxamide
Figure BDA0002878710730000633
2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenoxy) pyrrolidin-1-yl) -N- ((R) -1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) thiazole-5-carboxamide (82mg,0.126mmol) and NaH (5mg,0.16mmol) were dissolved in DCM (18mL), the reaction was stirred under ice bath conditions and iodomethane (0.1mL,2mmol) was added dropwise, after which the reaction was slowly warmed to room temperature for 6 h. After completion of the reaction, the stirring was stopped, and the reaction mixture was diluted with DCM (30mL) and successively with saturated Na2CO3The solution (35mL) was washed with saturated NaCl solution (25mL) and dried over anhydrous Na2SO4Dried, filtered and concentrated under reduced pressure, and the crude product was isolated by column chromatography on silica gel (eluent: PE/EtOAc (v/v) ═ 1/1) to give a pale yellow solid (32mg, 38%).
MS(ESI,pos.ion)m/z:664.1[M+H]+.
1H NMR(400MHz,CDCl3)δ(ppm):7.84(d,J＝8.3Hz,2H),7.71(s,1H),7.56(t,J＝7.4Hz,4H),6.95(d,J＝8.6Hz,2H),6.73(t,J＝8.5Hz,1H),6.43–6.00(m,1H),5.30(dt,J＝8.3,4.3Hz,1H),5.15(s,1H),4.38–4.27(m,2H),4.03(dd,J＝13.8,7.4Hz,1H),3.85(dd,J＝11.8,4.8Hz,1H),3.81–3.65(m,3H),3.37(s,3H),3.08(q,J＝7.4Hz,2H),2.54–2.42(m,2H),1.27(t,J＝7.4Hz,3H).
Example 30: n- ((S) -2-cyano-1- (4- (ethylsulfonyl) phenyl) ethyl) -2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (((1r,4S) -4-methoxycyclohexyl) amino) pyrrolidin-1-yl) thiazole-5-carboxamide
Figure BDA0002878710730000641
The method comprises the following steps: synthesis of methyl 2- ((2S,4R) -4- (((benzyloxy) carbonyl) oxy) -2- ((difluoromethoxy) methyl) pyrrolidin-1-yl) thiazole-5-carboxylate
Nitrogen gasUnder protection, benzyl ((3R,5S) -5- ((difluoromethoxy) methyl) pyrrolidin-3-yl) carboxylate (202mg,0.67mmol), methyl 2-bromothiazole-5-carboxylate (383mg,1.72mmol), Pd2(dba)3(79mg,0.086mmol)，Ruphos(89mg,0.19mmol)，Cs2CO3(495mg,1.52mmol) was dissolved in toluene (5mL) and the reaction was heated at 110 ℃ for 20 h. Celite was filtered, concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 4/1) to give a yellow oil (260mg, 87.7%).
MS(ESI,pos.ion)m/z:443.6[M+H]+.
Step two: synthesis of methyl 2- ((2S,4R) -2- ((difluoromethoxy) methyl) -4-hydroxypyrrolidin-1-yl) thiazole-5-carboxylate
Methyl 2- ((2S,4R) -4- (((benzyloxy) carbonyl) oxy) -2- ((difluoromethoxy) methyl) pyrrolidin-1-yl) thiazole-5-carboxylate (180mg,0.41mmol), Pd (OH) under a hydrogen atmosphere2the/C (310mg,0.44mmol,20 mass%) was dissolved in THF/MeOH (3mL/3mL) and stirred at room temperature for 4 h. Celite was filtered and concentrated under reduced pressure to give a yellow oil (110mg, 87.7%).
MS(ESI,pos.ion)m/z:309.1[M+H]+.
Step three: synthesis of methyl 2- ((2S,4R) -2- ((difluoromethoxy) methyl) -4- (((trifluoromethyl) sulfonyl) oxy) pyrrolidin-1-yl) thiazole-5-carboxylate
Methyl 2- ((2S,4R) -2- ((difluoromethoxy) methyl) -4-hydroxypyrrolidin-1-yl) thiazole-5-carboxylate (205mg,0.66mmol) was dissolved in DCM (5mL) and DIPEA (0.21mL,1.30mmol) and Tf were added sequentially at-25 deg.C2O (0.16mL,0.95mmol), and stirring was continued at-25 ℃ for 4 h. DCM (30mL) was added to the reaction solution to dilute and saturate NH4Cl (30 mL. times.2) wash, saturated NaHCO3The solution (30mL) was washed, and the organic layer was Na anhydrous2SO4Dried, ice-cooled, and concentrated under reduced pressure to give a yellow oil (270mg, 92.2%).
Step four: synthesis of methyl 2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (((1r,4S) -4-methoxycyclohexyl) amino) pyrrolidin-1-yl) thiazole-5-carboxylate
2- ((2S,4R) -2- ((difluoromethoxy) methyl) -4- (((trifluoromethyl) sulfonyl)) Oxy) pyrrolidin-1-yl) thiazole-5-carboxylic acid methyl ester (270mg,0.61mmol), (1r,4r) -4-methoxycyclohexylamine (173mg,1.34mmol), K2CO3(334mg,2.42mmol) was dissolved in ACN (5mL) and reacted at 80 ℃ for 6 h. Concentrated under reduced pressure, and then saturated NaHCO was added to the residue3Solution (20mL), DCM (30 mL. times.2) extraction, anhydrous Na2SO4Dried, concentrated under reduced pressure and the crude product was isolated by column chromatography over silica gel (eluent: DCM/MeOH (v/v) ═ 10/1) to give a yellow oil (256mg, 99.5%).
MS(ESI,pos.ion)m/z:420.1[M+H]+.
Step five: synthesis of 2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (((1r,4S) -4-methoxycyclohexyl) amino) pyrrolidin-1-yl) thiazole-5-carboxylic acid
Methyl 2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (((1r,4S) -4-methoxycyclohexyl) amino) pyrrolidin-1-yl) thiazole-5-carboxylate (256mg,0.61mmol), LiOH. H2O (274mg,6.53mmol) in THF/MeOH/H2O (2mL/1mL/1mL), and reacted at room temperature for 24 hours. Concentrating under reduced pressure, adding 1.0M HCl solution (10mL), adjusting pH to about 6, extracting with EtOAc (20 mL. times.3), extracting with DCM (20 mL. times.3), and extracting organic layer with anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: DCM/MeOH (v/v) ═ 7/1) to give a white solid (170mg, 68.7%).
MS(ESI,pos.ion)m/z:406.1[M+H]+.
Step six: synthesis of N- ((S) -2-cyano-1- (4- (ethylsulfonyl) phenyl) ethyl) -2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (((1r,4S) -4-methoxycyclohexyl) amino) pyrrolidin-1-yl) thiazole-5-carboxamide
2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (((1r,4S) -4-methoxycyclohexyl) amino) pyrrolidin-1-yl) thiazole-5-carboxylic acid (170mg,0.42mmol), (3S) -3-amino-3- (4- (ethylsulfonyl) phenyl) propionitrile (137mg,0.57mmol), EDCI (268mg,1.40mmol), HOBT (188mg,1.39mmol) was dissolved in DCM (5mL) and DIPEA (0.35mL,2.10mmol) was added and stirred at room temperature for 19 h. DCM (50mL) and saturated NH were added to the reaction solution 4Cl (20 mL. times.2) wash, saturated NaHCO3(20mL) washing withoutWater Na2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: DCM/MeOH (v/v) ═ 10/1) to give 71mg of a yellow solid, and isolated by PTLC to give a yellow solid (31mg, 11.8%).
MS(ESI,pos.ion)m/z:626.2[M+H]+.
1H NMR(400MHz,DMSO-d6)δ(ppm):8.96(d,J＝8.2Hz,1H),7.94(s,1H),7.90(d,J＝8.3Hz,2H),7.70(d,J＝8.3Hz,2H),6.68(t,J＝76Hz,1H),5.44(dd,J＝14.2,8.7Hz,1H),4.28–4.22(m,1H),4.17–4.07(m,2H),3.54(dd,J＝15.2,8.5Hz,3H),3.32–3.27(m,4H),3.21(s,3H),3.14(dd,J＝12.9,7.0Hz,3H),3.07(dd,J＝16.3,8.6Hz,2H),2.42(s,1H),2.33–2.24(m,1H),1.94(dd,J＝34.7,23.8Hz,6H),1.10(t,J＝7.3Hz,3H).
Example 31: n- ((S) -2-cyano-1- (4- (ethylsulfonyl) phenyl) ethyl) -2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (((1r,4S) -4- (trifluoromethyl) cyclohexyl) amino) pyrrolidin-1-yl) thiazole-5-carboxamide
Figure BDA0002878710730000651
The method comprises the following steps: synthesis of methyl 2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (((1r,4S) -4- (trifluoromethyl) cyclohexyl) amino) pyrrolidin-1-yl) thiazole-5-carboxylate
Methyl 2- ((2S,4R) -2- ((difluoromethoxy) methyl) -4- (((trifluoromethyl) sulfonyl) oxy) pyrrolidin-1-yl) thiazole-5-carboxylate (300mg,0.68mmol), (1R,4R) -4- (trifluoromethyl) cyclohexylamine (240mg,1.44mmol), K2CO3(365mg,2.64mmol) was dissolved in ACN (5mL) and reacted at 80 ℃ for 15 h. Concentrated under reduced pressure, and then saturated NaHCO was added to the residue3Solution (20mL), DCM (30 mL. times.2) extraction, anhydrous Na2SO4Dried, concentrated under reduced pressure and the crude product was isolated by column chromatography over silica gel (eluent: DCM/MeOH (v/v) ═ 10/1) to give a yellow oil (202mg, 64.8%).
MS(ESI,pos.ion)m/z:458.1[M+H]+.
Step two: synthesis of 2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (((1r,4S) -4- (trifluoromethyl) cyclohexyl) amino) pyrrolidin-1-yl) thiazole-5-carboxylic acid
Methyl 2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (((1r,4S) -4- (trifluoromethyl) cyclohexyl) amino) pyrrolidin-1-yl) thiazole-5-carboxylate (202mg,0.44mmol), LiOH. H2O (60mg,1.43mmol) in THF/MeOH/H2O (2mL/1mL/0.5mL) was reacted at room temperature for 18 hours. Concentrated under reduced pressure, 3.0M hcl — etoac solution (5mL) was added to the reaction solution, the pH of the system was adjusted to about 6, 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 (163mg, 83.3%).
MS(ESI,pos.ion)m/z:444.0[M+H]+.
Step three: synthesis of N- ((S) -2-cyano-1- (4- (ethylsulfonyl) phenyl) ethyl) -2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (((1r,4S) -4- (trifluoromethyl) cyclohexyl) amino) pyrrolidin-1-yl) thiazole-5-carboxamide
2- ((2S,4S) -2- ((difluoromethoxy) methyl) -4- (((1r,4S) -4- (trifluoromethyl) cyclohexyl) amino) pyrrolidin-1-yl) thiazole-5-carboxylic acid (163mg,0.37mmol), (3S) -3-amino-3- (4- (ethylsulfonyl) phenyl) propionitrile (139mg,0.58mmol), EDCI (234mg,1.22mmol), HOBT (155mg,1.15mmol) was dissolved in DCM (5mL) and DIPEA (0.30mL,2.00mmol) was added and stirred at room temperature for 22 h. DCM (50mL) and saturated NH were added to the reaction solution 4Cl (20 mL. times.2) wash, saturated NaHCO3(20mL) washing with anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: DCM/MeOH (v/v) ═ 10/1) to give 163mg of a yellow solid, and isolated by PTLC to give a pale yellow solid (110mg, 45.1%).
MS(ESI,pos.ion)m/z:664.1[M+H]+.
1H NMR(400MHz,DMSO-d6)δ(ppm):8.96(d,J＝8.1Hz,1H),7.94(s,1H),7.90(d,J＝8.3Hz,2H),7.70(d,J＝8.3Hz,2H),6.68(t,J＝76Hz,1H),5.44(dd,J＝14.3,8.6Hz,1H),4.27–4.22(m,1H),4.14(dd,J＝17.5,7.9Hz,2H),3.56(t,J＝9.3Hz,3H),3.44(s,2H),3.31–3.25(m,3H),3.21–3.05(m,4H),2.33–2.25(m,1H),2.18(d,J＝8.8Hz,1H),1.97(s,3H),1.86(d,J＝12.9Hz,3H),1.10(t,J＝7.3Hz,3H).
Example 32: 2- ((S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) benzyl) piperazin-1-yl) -N- ((R) -1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) thiazole-5-carboxamide
Figure BDA0002878710730000661
The method comprises the following steps: synthesis of (S) -4-benzyl-1-tert-butyl-2- (hydroxymethyl) piperazine-1, 4-dicarboxylate
(S) -4-benzyl-1-tert-butyl-2-methylpiperazine-1, 2, 4-tricarboxylate (5.10g,13.00mmol) was dissolved in THF (15mL) and LiBH was added slowly in portions in an ice bath4(700mg,32.14mmol) and stirred at room temperature for 24 h. Adding saturated NaHCO into the reaction solution3The reaction was quenched with solution (100 mL). Concentrated under reduced pressure to remove THF, extracted with DCM (120 mL. times.2), anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 1/1) to give a colorless oil (4.6g, 97.0%).
MS(ESI,pos.ion)m/z:373.2[M+Na]+.
Step two: synthesis of (S) -4-benzyl-1-tert-butyl-2- ((difluoromethoxy) methyl) piperazine-1, 4-dicarboxylate
(S) -4-benzyl 1-tert-butyl 2- (hydroxymethyl) piperazine-1, 4-dicarboxylate (4.60g,13.00mmol) was dissolved in DCM/H 2O (18mL/18mL) and KOAc (7.70g,78.00mmol) were added and TMSCF was slowly added dropwise in an ice bath2Br (8.20mL,53.00mmol), stir at room temperature for 18 h. Adding saturated NaHCO into the reaction solution3The reaction was quenched with solution (60mL), extracted with DCM (80 mL. times.2), anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 6/1) to give a colorless oil (3.6g, 68.0%). MS (ESI, pos. ion) M/z 423.3[ M + Na ]]+.
Step three: synthesis of tert-butyl (S) -2- ((difluoromethoxy) methyl) piperazine-1-carboxylate
(S) -4-benzyl 1-tert-butyl 2- ((difluoromethoxy) methyl) piperazine-1, 4-dicarboxylate (2.30g,5.70mmol), Pd/C (3.20g,3.00mmol,10 mass%) was dissolved in MeOH/THF (6mL/6mL) under a hydrogen atmosphere and stirred at room temperature for 11 h. Celite was filtered and concentrated under reduced pressure to give a colorless oil (1.3g, 85.0%).
MS(ESI,pos.ion)m/z:267.3[M+H]+.
Step four: synthesis of tert-butyl (S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) benzyl) piperazine-1-carboxylate
Tert-butyl (S) -2- ((difluoromethoxy) methyl) piperazine-1-carboxylate (966mg,3.63mmol), 1- (bromomethyl) -4- (trifluoromethyl) benzene (862mg,3.61mmol), K2CO3(1.10g,8.00mmol) was dissolved in ACN (10mL) and reacted at 90 ℃ for 17 h. Concentrated under reduced pressure, and then saturated NaHCO was added to the residue 3Solution (30mL), DCM (50 mL. times.2) extraction, anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 4/1) to give a yellow oil (1.4g, 91.0%).
MS(ESI,pos.ion)m/z:425.6[M+H]+.
Step five: synthesis of (S) -3- ((difluoromethoxy) methyl) -1- (4- (trifluoromethyl) benzyl) piperazine
Tert-butyl (S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) benzyl) piperazine-1-carboxylate (266mg,0.63mmol) was dissolved in DCM (2mL), and 1, 4-dioxane (3.00mL,12.00mmol,4mol/L) of HCl was added under ice bath and stirred at room temperature for 24 h. Distilling under reduced pressure to remove part of solvent, adding saturated NaHCO3(20mL), adjust the system pH to about 8, extract with DCM (30 mL. times.2), and extract the organic layer with anhydrous Na2SO4Dried and concentrated under reduced pressure to give a yellow oil (200mg, 98.4%).
MS(ESI,pos.ion)m/z:325.2[M+H]+.
Step six: synthesis of methyl (S) -2- (2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) benzyl) piperazin-1-yl) thiazole-5-carboxylate
(S) -3- ((difluoromethoxy) methyl) -1- (4- (trifluoromethyl) benzyl) piperazine (900mg,2.78mmol), methyl 2-bromothiazole-5-carboxylate (1.24g,5.58mmol), Pd under nitrogen blanket2(dba)3(281mg,0.31mmol)，Ruphos(292mg,0.63mmol)，Cs2CO3(1.84g,5.65mmol) was dissolved in toluene (10mL) and the reaction was heated at 110 ℃ for 16 h. Celite was filtered, concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 2/1) to give a yellow solid (1.0g, 77.4%).
MS(ESI,pos.ion)m/z:466.1[M+H]+.
Step seven: synthesis of (S) -2- (2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) benzyl) piperazin-1-yl) thiazole-5-carboxylic acid
Methyl (S) -2- (2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) benzyl) piperazin-1-yl) thiazole-5-carboxylate (1.10g,2.40mmol), LiOH. H2O (1.02g,24.30mmol) in THF/MeOH/H2O (4mL/2mL/2mL), and reacted at room temperature. After concentration under reduced pressure, 1.0M HCl solution (15mL) was added to the reaction mixture to adjust the system pH to about 4, followed by suction filtration under reduced pressure to obtain a yellow solid (1.0g, 87.0%).
MS(ESI,pos.ion)m/z:452.2[M+H]+.
Step eight: synthesis of 2- ((S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) benzyl) piperazin-1-yl) -N- ((R) -1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) thiazole-5-carboxamide
(S) -2- (2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) benzyl) piperazin-1-yl) thiazole-5-carboxylic acid (163mg,0.33mmol), (2R) -2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride (99mg,0.37mmol), EDCI (187mg,0.98mmol), HOBT (156mg,1.15mmol) was dissolved in DCM (5mL) and DIPEA (0.40mL,2.00mmol) was added and stirred at room temperature for 24 h. DCM (20mL), saturated NaHCO was added to the reaction3Washing (10 mL. times.2), washing with saturated NaCl (10mL), anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: DCM/MeOH (v/v) ═ 12/1) to give a pale yellow solid (186mg, 84.0%).
MS(ESI,pos.ion)m/z:663.3[M+H]+.
1H NMR(400MHz,DMSO-d6)δ(ppm):8.62(d,J＝7.8Hz,1H),7.97(s,1H),7.84(d,J＝8.2Hz,2H),7.70(d,J＝8.0Hz,2H),7.62(d,J＝8.2Hz,2H),7.57(d,J＝7.9Hz,2H),6.65(t,J＝75.6Hz,1H),5.07(dd,J＝13.3,7.5Hz,2H),4.32(s,1H),4.19(t,J＝8.6Hz,1H),4.12-4.04(m,1H),3.77-3.65(m,4H),3.56(d,J＝13.9Hz,1H),3.35(s,1H),3.26(q,J＝7.2Hz,2H),2.87(d,J＝11.5Hz,2H),2.26-2.14(m,2H),1.10(t,J＝7.3Hz,3H).
Example 33: 2- ((S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) benzyl) piperazin-1-yl) -N- (4- (ethylsulfonyl) benzyl) thiazole-5-carboxamide
Figure BDA0002878710730000681
(S) -2- (2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) benzyl) piperazin-1-yl) thiazole-5-carboxylic acid (148mg,0.30mmol), (4- (ethylsulfonyl) phenyl) methylamine (81mg,0.41mmol), EDCI (186mg,0.97mmol), HOBT (124mg,0.92mmol) was dissolved in DCM (5mL) and DIPEA (0.42mL,2.50mmol) was added and stirred at room temperature for 14 h. DCM (20mL), saturated NaHCO was added to the reaction3Washing (10 mL. times.2), washing with saturated NaCl (10mL), anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 1/2) to give a pale yellow solid (132mg, 68.8%).
MS(ESI,pos.ion)m/z:633.0[M+H]+.
1H NMR(400MHz,DMSO-d6)δ(ppm):8.91(t,J＝5.7Hz,1H),7.90–7.81(m,3H),7.70(d,J＝7.9Hz,2H),7.56(t,J＝8.1Hz,4H),6.67(t,J＝75.6Hz,1H),4.51(d,J＝5.6Hz,2H),4.32(s,1H),4.20(t,J＝8.6Hz,1H),4.14–4.04(m,1H),3.75(d,J＝12.0Hz,1H),3.63(dd,J＝42.5,13.9Hz,2H),3.39(s,1H),3.26(dd,J＝14.6,7.3Hz,2H),2.88(d,J＝10.4Hz,2H),2.29–2.15(m,2H),1.09(t,J＝7.3Hz,3H).
Example 34: n- ((S) -2-cyano-1- (4- (ethylsulfonyl) phenyl) ethyl) -2- ((S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) benzyl) piperazin-1-yl) thiazole-5-carboxamide
Figure BDA0002878710730000682
(S) -2- (2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) benzyl) piperazin-1-yl) thiazole-5-carboxylic acid (159mg,0.33mmol), (3S) -3-amino-3- (4- (ethylsulfonyl) phenyl) propionitrile hydrochloride (112mg,0.41mmol), EDCI (197mg,1.03mmol), HOBT (146mg,1.08mmol) were dissolved in DCM (5mL) and DIPEA (0.42mL,2.50mmol) was added and stirred at room temperature for 15 h. DCM (20mL), saturated NaHCO was added to the reaction 3Washing (10 mL. times.2), washing with saturated NaCl (10mL), anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 1/2) to give a pale yellow solid (168mg, 76.7%).
MS(ESI,pos.ion)m/z:672.0[M+H]+.
1H NMR(400MHz,DMSO-d6)δ(ppm):8.99(d,J＝8.1Hz,1H),7.96–7.87(m,3H),7.70(d,J＝8.0Hz,4H),7.57(d,J＝7.7Hz,2H),6.67(t,J＝75.5Hz,1H),5.44(dd,J＝14.2,8.1Hz,1H),4.33(s,1H),4.19(t,J＝8.5Hz,1H),4.15–4.07(m,1H),3.77(d,J＝11.5Hz,1H),3.68(d,J＝13.9Hz,1H),3.57(d,J＝13.8Hz,1H),3.40(s,1H),3.32–3.26(m,2H),3.13(td,J＝17.1,9.2Hz,2H),2.88(d,J＝10.6Hz,2H),2.21(dd,J＝23.3,11.4Hz,2H),1.10(t,J＝7.2Hz,3H).
Example 35: (S) -2- (2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) benzyl) piperazin-1-yl) -N- (4- (4- (ethylsulfonyl) phenyl) tetrahydro-2H-pyran-4-yl) thiazole-5-carboxamide
Figure BDA0002878710730000691
The method comprises the following steps: synthesis of 4- (4-bromophenyl) tetrahydro-2H-pyran-4-ol
1, 4-dibromobenzene (4.10g,17.00mmol) was dissolved in THF (10mL), cooled to-78 deg.C, n-BuLi (10mL,16.00mmol,1.6mol/L) was added, after stirring at 78 deg.C for 0.5h, a solution of tetrahydropyran-4-one (1.9g,19.00mmol) in THF (10mL) was slowly added dropwise over about 0.5h, the temperature was returned to room temperature, and stirring was continued for 2 h. Washing with saturated NaCl solution, EtOAc (10 ml. times.2) extraction, anhydrous Na2SO4Dried, concentrated and separated by silica gel column chromatography (eluent:PE/EtOAc (v/v) ═ 5/1) to give a white solid (2.12g, 47%).
MS(ESI,pos.ion)m/z:257[M+H]+.
Step two: synthesis of 4- (4-bromophenyl) tetrahydro-2H-pyran-4-amine
4- (4-bromophenyl) tetrahydro-2H-pyran-4-ol (1.30g,5.10mmol) and sodium azide (0.72g,11.00mmol) were dissolved in DCM (5mL), cooled to-5 deg.C, and a solution of TFA (3.0mL,41.00mmol) in DCM (5mL) was added slowly to return to room temperature and stirring was continued for 12H. Adding saturated NH 4The reaction was quenched with Cl, made weakly alkaline with ammonia, extracted with DCM (10 ml. times.2) and anhydrous Na2SO4Drying, concentrating, adding Et2O (8mL), cooled to 0 ℃ and LiAlH was added4(0.19mg,0.0050mmol), slowly returned to room temperature, stirred for 3h, quenched with aqueous KOH, extracted with EtOAc (10 mL. times.2), anhydrous Na2SO4Dried, concentrated and separated by silica gel column chromatography (eluent: DCM/EtOAc (v/v) ═ 5/1) to give a white solid (1.00g, 77%).
MS(ESI,pos.ion)m/z:256[M+H]+.
Step three: synthesis of (S) -N- (4- (4-bromophenyl) tetrahydro-2H-pyran-4-yl) -2- (2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) benzyl) piperazin-1-yl) thiazole-5-carboxamide
(S) -2- (2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) benzyl) piperazin-1-yl) thiazole-5-carboxylic acid (108mg,0.24mmol), 4- (4-bromophenyl) tetrahydro-2H-pyran-4-amine (70mg,0.24mmol), HATU (110mg,0.29mmol) were dissolved in DCM (25mL), TEA (0.1mL,0.80mmol) was added, stirring was carried out at room temperature for 24H, and saturated NH was added4Cl washing, DCM (10 ml. times.2) extraction, anhydrous Na2SO4Dried, concentrated and separated by silica gel column chromatography (eluent: DCM/EtOAc (v/v) ═ 5/1) to give a white solid (0.12g, 75%).
MS(ESI,pos.ion)m/z:689[M+H]+.
Step four: synthesis of (S) -2- (2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) benzyl) piperazin-1-yl) -N- (4- (4- (ethylsulfonyl) phenyl) tetrahydro-2H-pyran-4-yl) thiazole-5-carboxamide
Will (S)) -N- (4- (4-bromophenyl) tetrahydro-2H-pyran-4-yl) -2- (2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) benzyl) piperazin-1-yl) thiazole-5-carboxamide (200mg,0.29mmol), sodium ethylsulfinate (101mg,0.87mmol), (2S,4R) -N- (2, 6-dimethylphenyl) -4-hydroxypyrrolidine-2-carboxamide (8mg,0.029mmol), K3PO4(73mg,0.34mmol), CuI (6mg,0.029mmol) were dissolved in DMSO (8mL), purged with nitrogen, heated to 100 deg.C, and stirred for 24 h. Washing with saturated NaCl, EtOAc (10 ml. times.2) extraction, anhydrous Na2SO4Dried, concentrated and separated by silica gel column chromatography (eluent: DCM/EtOAc (v/v) ═ 5/1) to give a white solid (0.12g, 59%).
MS(ESI,pos.ion)m/z:703[M+H]+.
1H NMR(400MHz,CDCl3)δ(ppm):7.87(d,J＝8.3Hz,2H),7.70(s,1H),7.67–7.55(m,4H),7.47(d,J＝7.9Hz,2H),6.18(dd,J＝89.1,58.9Hz,2H),4.36(s,1H),4.27(t,J＝8.8Hz,1H),4.11(dd,J＝9.1,6.0Hz,1H),3.94(d,J＝11.0Hz,2H),3.79(t,J＝11.3Hz,3H),3.62(dd,J＝29.9,13.5Hz,2H),3.40(dd,J＝12.4,9.4Hz,1H),3.12(q,J＝7.3Hz,2H),3.00(d,J＝11.8Hz,1H),2.90(d,J＝10.8Hz,1H),2.41(d,J＝13.8Hz,2H),2.37–2.15(m,4H),1.35–1.26(m,3H).
Example 36: 2- ((S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) benzyl) piperazin-1-yl) -N- ((R) -1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) oxazole-5-carboxamide
Figure BDA0002878710730000701
The method comprises the following steps: synthesis of ethyl (S) -2- (2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) benzyl) piperazin-1-yl) oxazole-5-carboxylate
(S) -3- ((difluoromethoxy) methyl) -1- (4- (trifluoromethyl) phenyl) piperazine (690mg,2.13mmol) and K2CO3(770mg,4.29mmol) was dissolved in ACN (13mL), followed by addition of ethyl 2-bromooxazole-5-carboxylate (480mg,2.18mmol) and reaction at room temperature for 16 h. The reaction was concentrated and diluted with DCM (30mL) and in turn with saturated Na 2CO3Solution (30mL) and saturated NaCl solution (35mL), anhydrous Na2SO4Dried, filtered and concentrated under reduced pressure, and the crude product was isolated by column chromatography on silica gel (eluent: PE/EtOAc (v/v) ═ 1/1) to give a colorless liquid (670mg, 68%).
MS(ESI,pos.ion)m/z:464.2[M+H]+.
Step two: synthesis of (S) -2- (2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) benzyl) piperazin-1-yl) oxazole-5-carboxylic acid
Ethyl (S) -2- (2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) benzyl) piperazin-1-yl) oxazole-5-carboxylic acid (670mg,1.45mmol) was dissolved in MeOH (5mL) and LiOH (690mg,16.12mmol) was added on and reacted at room temperature for 13 h. After completion, HCl solution (1.5mL,0.1mol/L) was added to the reaction mixture, the mixture was extracted with DCM (20 mL. times.3), the organic phases were combined and washed with saturated NaCl solution (15mL), anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by column chromatography on silica gel (eluent: DCM/MeOH (v/v) ═ 10/1) to give a white solid (470mg, 75%).
Step three: synthesis of 2- ((S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) benzyl) piperazin-1-yl) -N- ((R) -1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) oxazole-5-carboxamide
(2R) -2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol (50mg,0.22mmol), (S) -2- (2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) benzyl) piperazin-1-yl) oxazole-5-carboxylic acid (80mg,0.18mmol), HATU (100mg,0.26mmol) and DIPEA (0.2mL,1.13mmol) were dissolved in DCM (25mL) and reacted at room temperature for 14 h. After the reaction was complete, the reaction was diluted with DCM (30mL) and successively with saturated NaHCO 3The solution (50mL) and saturated NaCl solution (45mL) were washed and the organic phase was washed with anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by column chromatography on silica gel (eluent: PE/EtOAc (v/v) ═ 1/1) to give a white solid (80mg, 67%).
MS(ESI,pos.ion)m/z:647.2[M+H]+.
1H NMR(400MHz,CDCl3)δ(ppm):7.83(d,J＝8.1Hz,2H),7.60(d,J＝7.9Hz,2H),7.53(d,J＝8.1Hz,2H),7.45(d,J＝7.9Hz,3H),6.86(d,J＝7.3Hz,1H),6.18(t,J＝74.1Hz,1H),5.25–5.16(m,1H),4.40(s,1H),4.19(d,J＝7.2Hz,2H),3.95(td,J＝11.4,6.7Hz,3H),3.60(dd,J＝32.0,13.5Hz,2H),3.37(t,J＝11.1Hz,1H),3.09(q,J＝7.4Hz,2H),2.91(dd,J＝22.6,11.4Hz,2H),2.30(ddd,J＝20.3,11.6,6.0Hz,2H),1.26(t,J＝7.4Hz,3H).
Example 37: n- ((S) -2-cyano-1- (4- (ethylsulfonyl) phenyl) ethyl) -2- ((S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) benzyl) piperazin-1-yl) oxazole-5-carboxamide
Figure BDA0002878710730000711
(3S) -3-amino-3- (4- (ethylsulfonyl) phenyl) propionitrile (50mg,0.21mmol), (S) -2- (2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) benzyl) piperazin-1-yl) oxazole-5-carboxylic acid (80mg,0.18mmol), HATU (90mg,0.23mmol) and DIPEA (0.18mL,1.02mmol) were dissolved in DCM (25mL) and the reaction was stirred at room temperature for 15 h. After the reaction was complete, the reaction was diluted with DCM (50mL) and successively with saturated NaHCO3The solution (30mL) and saturated NaCl solution (35mL) were washed and the organic phase was washed with anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by column chromatography on silica gel (eluent: PE/EtOAc (v/v) ═ 1/1) to give a white solid (80mg, 66%).
MS(ESI,pos.ion)m/z:656.2[M+H]+.
1H NMR(400MHz,CDCl3)δ(ppm):7.91(d,J＝7.8Hz,2H),7.61(s,4H),7.55(s,1H),7.45(d,J＝7.3Hz,2H),6.59(d,J＝7.5Hz,1H),6.16(t,J＝74.1Hz,1H),5.55(d,J＝6.1Hz,1H),4.39(s,1H),4.19(d,J＝5.6Hz,2H),3.99(d,J＝12.3Hz,1H),3.56(dt,J＝33.8,10.0Hz,3H),3.43–3.30(m,1H),3.12(q,J＝7.4Hz,2H),2.90(dd,J＝20.3,11.5Hz,2H),2.80(s,1H),2.31(dd,J＝26.8,11.6Hz,2H),1.27(t,J＝7.4Hz,3H).
Example 38: 2- ((S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) benzyl) piperazin-1-yl) -N- ((R) -1- (4- (ethylsulfonyl) phenyl) -2-methoxyethyl) thiazole-5-carboxamide
Figure BDA0002878710730000712
The method comprises the following steps: synthesis of benzyl (R) - (1- (4- (ethylsulfonyl) phenyl) -2-methoxyethyl) carbamate
Benzyl (R) - (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) carbamate (320mg,0.88mmol), methyl iodide (0.20mL,3.00mmol) were dissolved in DMF (3mL) under nitrogen, t-BuOK (175mg,1.56mmol) was added under ice bath, and the reaction was continued for 10min, then at room temperature for 14 h. Adding saturated NaHCO into the reaction solution3(50mL), DCM (60 mL. times.2) extraction, anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 2/1) to give a colorless oil (200mg, 60.2%). MS (ESI, pos. ion) M/z 378.2[ M + H ]]+.
Step two: synthesis of (R) -1- (4- (ethylsulfonyl) phenyl) -2-methoxyethylamine
Benzyl (R) - (1- (4- (ethylsulfonyl) phenyl) -2-methoxyethyl) carbamate (238mg,0.63mmol), Pd/C (358mg,0.34mmol,10 mass%) was dissolved in THF/MeOH (2mL/2mL) under a hydrogen atmosphere and stirred at room temperature for 22 h. Celite was filtered, concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: DCM/MeOH (v/v) ═ 10/1) to give a yellow oil (63mg, 41.1%).
MS(ESI,pos.ion)m/z:244.2[M+H]+.
Step three: synthesis of 2- ((S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) benzyl) piperazin-1-yl) -N- ((R) -1- (4- (ethylsulfonyl) phenyl) -2-methoxyethyl) thiazole-5-carboxamide
(S) -2- (2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) benzyl) piperazin-1-yl) thiazole-5-carboxylic acid (101mg,0.21mmol), (R) -1- (4- (ethylsulfonyl) phenyl) -2-methoxyethylamine (63mg,0.26mmol), EDCI (135mg,0.70mmol), HOBT (118mg,0.87mmol) were dissolved in DCM (5mL) and DIPEA (0.30mL,2.00mmol) was added and stirred at room temperature for 16 h. DCM (50mL), saturated NaHCO was added to the reaction3Washing (20 mL. times.2), washing with saturated NaCl (20mL), anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (eluent:PE/EtOAc (v/v) ═ 1/2) to give a pale yellow solid (78mg, 55.7%).
MS(ESI,pos.ion)m/z:677.2[M+H]+.
1H NMR(400MHz,DMSO-d6)δ(ppm):8.73(d,J＝8.0Hz,1H),7.97(s,1H),7.86(d,J＝8.3Hz,2H),7.70(d,J＝8.1Hz,2H),7.65(d,J＝8.3Hz,2H),7.57(d,J＝7.9Hz,2H),6.66(t,J＝75.6Hz,1H),5.27(dd,J＝13.6,7.7Hz,1H),4.32(s,1H),4.19(t,J＝8.6Hz,1H),4.08(dd,J＝9.5,6.7Hz,1H),3.78–3.65(m,3H),3.58(dd,J＝14.7,7.6Hz,2H),3.34–3.33(m,1H),3.29(s,3H),3.29–3.24(m,2H),2.87(d,J＝11.3Hz,2H),2.27–2.16(m,2H),1.10(t,J＝7.3Hz,3H).
Example 39: 2- ((S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) benzyl) piperazin-1-yl) -N- ((R) -2-ethoxy-1- (4- (ethylsulfonyl) phenyl) ethyl) thiazole-5-carboxamide
Figure BDA0002878710730000721
The method comprises the following steps: synthesis of benzyl (R) - (2-ethoxy-1- (4- (ethylsulfonyl) phenyl) ethyl) carbamate
Benzyl (R) - (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) carbamate (717mg,1.97mmol), iodoethane (0.63mL,7.90mmol) were dissolved in DMF (3mL) under nitrogen, t-BuOK (243mg,2.17mmol) was added under ice bath, and the reaction was continued for 10min, then at room temperature for 19 h. Adding saturated NaHCO into the reaction solution 3(50mL), DCM (60 mL. times.2) extraction, anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 3/1) to give a colorless oil (330mg, 42.7%). MS (ESI, pos.ion) M/z 392.2[ M + H ]]+.
Step two: synthesis of (R) -2-ethoxy-1- (4- (ethylsulfonyl) phenyl) ethylamine
Benzyl (R) - (2-ethoxy-1- (4- (ethylsulfonyl) phenyl) ethyl) carbamate (330mg,0.84mmol), Pd/C (512mg,0.48mmol,10 mass%) was dissolved in THF/MeOH (5mL/5mL) under a hydrogen atmosphere and stirred at room temperature for 3 h. Celite was filtered and concentrated under reduced pressure to give a yellow oil (136mg, 62.7%).
Step three: synthesis of 2- ((S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) benzyl) piperazin-1-yl) -N- ((R) -2-ethoxy-1- (4- (ethylsulfonyl) phenyl) ethyl) thiazole-5-carboxamide
(S) -2- (2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) benzyl) piperazin-1-yl) thiazole-5-carboxylic acid (90mg,0.18mmol), (R) -2-ethoxy-1- (4- (ethylsulfonyl) phenyl) ethylamine (170mg,0.66mmol), EDCI (132mg,0.69mmol), HOBT (105mg,0.78mmol) were dissolved in DCM (5mL) and DIPEA (0.18mL,1.10mmol) was added and stirred at room temperature for 24 h. DCM (50mL) and saturated NH were added to the reaction solution 4Cl (20 mL. times.2) wash, saturated NaHCO3(20mL) washing with anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 1/2) to give a pale yellow solid (77mg, 60.4%).
MS(ESI,pos.ion)m/z:691.3[M+H]+.
1H NMR(400MHz,DMSO-d6)δ(ppm):8.72(d,J＝8.0Hz,1H),7.97(s,1H),7.86(d,J＝8.3Hz,2H),7.70(d,J＝8.0Hz,2H),7.65(d,J＝8.3Hz,2H),7.57(d,J＝7.9Hz,2H),6.67(t,J＝75.6Hz,1H),5.24(dd,J＝13.6,7.6Hz,1H),4.32(s,1H),4.19(t,J＝8.6Hz,1H),4.14–4.05(m,1H),3.81–3.53(m,6H),3.50(q,J＝6.9Hz,2H),3.27(dd,J＝14.7,7.4Hz,2H),2.88(d,J＝11.0Hz,2H),2.28–2.14(m,2H),1.09(td,J＝7.1,2.6Hz,6H).
Example 40: n- ((R) -2- (difluoromethoxy) -1- (4- (ethylsulfonyl) phenyl) ethyl) -2- ((S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) benzyl) piperazin-1-yl) thiazole-5-carboxamide
Figure BDA0002878710730000731
The method comprises the following steps: synthesis of benzyl (R) - (2- (difluoromethoxy) -1- (4- (ethylsulfonyl) phenyl) ethyl) carbamate
Benzyl (R) - (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) carbamate (815mg,2.24mmol) was dissolved in DCM/H2O (3.5mL/3.5mL), KOAc (1.30g,13.00mmol) was added and TMSCF was slowly added dropwise in an ice bath2Br (1.40mL,9.00mmol), stir at room temperature for 23 h. Adding saturated NaHCO into the reaction solution3The reaction was quenched with solution (50mL), extracted with DCM (60 mL. times.2), anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: DCM/MeOH (v/v) ═ 15/1) to give a colorless oil (286mg, 30.9%).
MS(ESI,neg.ion)m/z:412.1[M-H]-.
Step two: synthesis of (R) -2- (difluoromethoxy) -1- (4- (ethylsulfonyl) phenyl) ethylamine
Benzyl (R) - (2- (difluoromethoxy) -1- (4- (ethylsulfonyl) phenyl) ethyl) carbamate (366mg,0.89mmol), Pd/C (472mg,0.44mmol) was dissolved in THF/MeOH (4mL/4mL) under hydrogen and stirred at room temperature for 3 h. Celite was filtered and concentrated under reduced pressure to give a yellow oil (190mg, 76.8%).
MS(ESI,pos.ion)m/z:280.1[M+H]+.
Step three: synthesis of N- ((R) -2- (difluoromethoxy) -1- (4- (ethylsulfonyl) phenyl) ethyl) -2- ((S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) benzyl) piperazin-1-yl) thiazole-5-carboxamide
(S) -2- (2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) benzyl) piperazin-1-yl) thiazole-5-carboxylic acid (102mg,0.21mmol), (R) -2- (difluoromethoxy) -1- (4- (ethylsulfonyl) phenyl) ethylamine (190mg,0.68mmol), EDCI (120mg,0.63mmol), HOBT (95mg,0.70mmol) were dissolved in DCM (5mL) and DIPEA (0.18mL,1.10mmol) was added and stirred at room temperature for 15 h. DCM (50mL) and saturated NH were added to the reaction solution4Cl (20 mL. times.2) wash, saturated NaHCO3(20mL) washing with anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 1/2) to give a pale yellow solid (81mg, 54.4%).
MS(ESI,pos.ion)m/z:713.0[M+H]+.
1H NMR(400MHz,DMSO-d6)δ(ppm):8.84(d,J＝8.2Hz,1H),7.95(s,1H),7.89(d,J＝8.3Hz,2H),7.70(d,J＝8.3Hz,4H),7.57(d,J＝8.0Hz,2H),6.70(td,J＝75.5,26.5Hz,2H),5.36(dd,J＝14.0,7.5Hz,1H),4.33(s,1H),4.14(tt,J＝16.5,9.7Hz,4H),3.75(d,J＝11.8Hz,1H),3.68(d,J＝14.0Hz,1H),3.57(d,J＝13.9Hz,1H),3.31(s,1H),3.30–3.25(m,2H),2.88(d,J＝11.3Hz,2H),2.27–2.15(m,2H),1.10(t,J＝7.3Hz,3H).
Example 41: 2- (((S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) benzyl) piperazin-1-yl) methyl) -N- ((R) -1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) thiazole-5-carboxamide
Figure BDA0002878710730000732
The method comprises the following steps: synthesis of ethyl (S) -2- ((2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) benzyl) piperazin-1-yl) methyl) thiazole-5-carboxylate
(S) -3- ((difluoromethoxy) methyl) -1- (4- (trifluoromethyl) benzyl) piperazine (151mg,0.47mmol), ethyl 2- (bromomethyl) thiazole-5-carboxylate (187mg,0.75mmol), K 2CO3(155mg,1.12mmol) was dissolved in ACN (5mL) and reacted at 90 ℃ for 5 h. Concentrated under reduced pressure, and then saturated NaHCO was added to the residue3Solution (20mL), DCM (30 mL. times.2) extraction, anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 3/1) to give a yellow oil (192mg, 83.6%).
MS(ESI,pos.ion)m/z:494.2[M+H]+.
Step two: synthesis of (S) -2- ((2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) benzyl) piperazin-1-yl) methyl) thiazole-5-carboxylic acid
Ethyl (S) -2- ((2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) benzyl) piperazin-1-yl) methyl) thiazole-5-carboxylate (192mg,0.39mmol), LiOH. H2O (189mg,4.50mmol) in THF/MeOH/H2O (2mL/1mL/1mL) was reacted at room temperature for 3 hours. To the reaction mixture was added 1.0M HCl solution (10mL), the pH of the system was adjusted to about 5, EtOAc (30 mL. times.2) was used for extraction, and the organic layer was Na anhydrous2SO4Drying, concentrating under reduced pressure, and separating the crude product by silica gel column chromatography (eluent: DCM/MeOH)(v/v) ═ 8/1), giving a yellow solid (174mg, 96.1%).
MS(ESI,pos.ion)m/z:466.1[M+H]+.
Step three: synthesis of 2- (((S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) benzyl) piperazin-1-yl) methyl) -N- ((R) -1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) thiazole-5-carboxamide
(S) -2- ((2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) benzyl) piperazin-1-yl) methyl) thiazole-5-carboxylic acid (174mg,0.37mmol), (2R) -2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride (136mg,0.51mmol), EDCI (229mg,1.19mmol), HOBT (163mg,1.21mmol) were dissolved in DCM (5mL) and DIPEA (0.40mL,2.00mmol) was added and stirred at RT for 20 h. DCM (50mL) and saturated NH were added to the reaction solution4Cl (20 mL. times.2) wash, saturated NaHCO3(20mL) washing with anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: DCM/MeOH (v/v) ═ 10/1) to give a yellow solid (192mg, 75.9%). MS (ESI, pos. ion) M/z 677.2[ M + H ]]+.
1H NMR(400MHz,DMSO-d6)δ(ppm):8.96(d,J＝7.8Hz,1H),8.41(s,1H),7.86(d,J＝8.3Hz,2H),7.67(t,J＝9.2Hz,4H),7.54(d,J＝7.9Hz,2H),6.65(t,J＝76.0Hz,1H),5.16–5.05(m,2H),4.17–3.94(m,4H),3.78–3.66(m,2H),3.57(q,J＝13.9Hz,2H),3.27(q,J＝7.3Hz,2H),2.93(s,1H),2.81(d,J＝5.1Hz,1H),2.55(s,2H),2.41(d,J＝5.6Hz,3H),1.10(t,J＝7.3Hz,3H).
Example 42: 2- ((S) -4- (4- (difluoromethoxy) benzyl) -2- ((difluoromethoxy) methyl) piperazin-1-yl) -N- ((R) -1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) thiazole-5-carboxamide
Figure BDA0002878710730000741
The method comprises the following steps: synthesis of tert-butyl (S) -4- (4- (difluoromethoxy) benzyl) -2- ((difluoromethoxy) methyl) piperazine-1-carboxylate
Tert-butyl (S) -2- ((difluoromethoxy) methyl) piperazine-1-carboxylate (252mg,0.95mmol), 4- (difluoro-methoxy-methyl) piperazineMethoxy) benzaldehyde (0.25mL,1.90mmol) was dissolved in THF/EtOH (3mL/3mL) and AcOH (0.05mL,0.90mmol), STAB (1.0g,4.72mmol) were added and reacted at 60 ℃ for 12 h. Adding saturated NaHCO into the reaction solution 3Solution (50mL), adjusting system pH to about 8, EtOAc (80mL × 2) extraction, organic layer anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 5/1) to give a yellow oil (350mg, 87.6%).
MS(ESI,pos.ion)m/z:423.4[M+H]+.
Step two: synthesis of (S) -1- (4- (difluoromethoxy) benzyl) -3- ((difluoromethoxy) methyl) piperazine
Tert-butyl (S) -4- (4- (difluoromethoxy) benzyl) -2- ((difluoromethoxy) methyl) piperazine-1-carboxylate (350mg,0.83mmol) was dissolved in DCM (2mL), hcl.1, 4-dioxane (2mL,8.00mmol,4mol/L) was added under ice bath, and stirred at room temperature for 2 h. Distilling under reduced pressure to remove part of solvent, adding saturated NaHCO3The solution (30mL) was adjusted to about pH 8, DCM (50 mL. times.2) was extracted, and the organic layer was washed with anhydrous Na2SO4Dried and concentrated under reduced pressure to give a yellow oil (260mg, 97.4%).
Step three: synthesis of methyl (S) -2- (4- (4- (difluoromethoxy) benzyl) -2- ((difluoromethoxy) methyl) piperazin-1-yl) thiazole-5-carboxylate
Under nitrogen protection, (S) -1- (4- (difluoromethoxy) benzyl) -3- ((difluoromethoxy) methyl) piperazine (260mg,0.81mmol), methyl 2-bromothiazole-5-carboxylate (424mg,1.91mmol), Pd2(dba)3(101mg,0.11mmol)，Ruphos(93mg,0.20mmol)，Cs2CO3(595mg,1.83mmol) was dissolved in toluene (5mL) and the reaction was heated at 110 ℃ for 20 h. Celite was filtered, concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 2/1) to give a yellow solid (180mg, 48.2%).
MS(ESI,pos.ion)m/z:464.4[M+H]+.
Step four: synthesis of (S) -2- (4- (4- (difluoromethoxy) benzyl) -2- ((difluoromethoxy) methyl) piperazin-1-yl) thiazole-5-carboxylic acid
Reacting (S) -2- (4- (4- (difluoromethoxy) benzyl) -Methyl 2- ((difluoromethoxy) methyl) piperazin-1-yl) thiazole-5-carboxylate (180mg,0.39mmol), lioh2O (197mg,4.70mmol) in THF/MeOH/H2O (2mL/1mL/1mL), and reacted at room temperature for 12 hours. Concentrated under reduced pressure, 1.0M HCl solution (8mL) was added to the reaction mixture to adjust the pH of the system to about 4, EtOAc (30 mL. times.2) was extracted, and the organic layer was extracted with anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: DCM/MeOH (v/v) ═ 10/1) to give a yellow solid (142mg, 81.4%).
MS(ESI,pos.ion)m/z:450.3[M+H]+.
Step five: synthesis of 2- ((S) -4- (4- (difluoromethoxy) benzyl) -2- ((difluoromethoxy) methyl) piperazin-1-yl) -N- ((R) -1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) thiazole-5-carboxamide
(S) -2- (4- (4- (difluoromethoxy) benzyl) -2- ((difluoromethoxy) methyl) piperazin-1-yl) thiazole-5-carboxylic acid (142mg,0.29mmol), (2R) -2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride (119mg,0.45mmol), EDCI (194mg,1.01mmol), HOBT (124mg,0.92mmol) were dissolved in DCM (5mL) and DIPEA (0.40mL,2.00mmol) was added and stirred at room temperature for 18 h. DCM (30mL), saturated NaHCO was added to the reaction 3Washing (20 mL. times.2), washing with saturated NaCl (10mL), anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: DCM/MeOH (v/v) ═ 12/1) to give a pale yellow solid (181mg, 93.7%).
MS(ESI,pos.ion)m/z:661.0[M+H]+.
1H NMR(400MHz,DMSO-d6)δ(ppm):8.60(d,J＝7.8Hz,1H),7.96(s,1H),7.83(d,J＝8.1Hz,2H),7.61(d,J＝8.1Hz,2H),7.39–7.34(m,2H),7.12(dd,J＝41.2,33.0Hz,3H),6.65(t,J＝75.6Hz,1H),5.05(dd,J＝13.0,7.2Hz,2H),4.31(s,1H),4.16(t,J＝8.6Hz,1H),4.10–4.02(m,1H),3.78–3.64(m,3H),3.50(dd,J＝36.7,13.5Hz,2H),3.32–3.30(m,1H),3.25(dd,J＝14.7,7.3Hz,2H),2.86(t,J＝12.5Hz,2H),2.15(dd,J＝24.6,11.6Hz,2H),1.09(t,J＝7.3Hz,3H).
Example 43: 2- ((S) -4- ((4, 4-difluorocyclohexyl) methyl) -2- ((difluoromethoxy) methyl) piperazin-1-yl) -N- ((R) -1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) thiazole-5-carboxamide
Figure BDA0002878710730000761
The method comprises the following steps: synthesis of tert-butyl (S) -4- ((4, 4-difluorocyclohexyl) methyl) -2- ((difluoromethoxy) methyl) piperazine-1-carboxylate
To a mixture of tert-butyl (S) -2- ((difluoromethoxy) methyl) piperazine-1-carboxylate (50mg,0.93mmol) and 4, 4-difluorocyclohexylformaldehyde (170mg,1.14mmol) was added 1, 2-dichloroethane (5mL), AcOH (280mg,4.6mmol) at room temperature, and after stirring at room temperature for 1h, sodium triacetoxyborohydride (600mg,2.83mmol) was added, the reaction was continued for 12h, stopped, and saturated NaHCO was added3The reaction was quenched with solution (25mL), extracted with DCM (30 mL. times.3), anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 4/1) to give a pale yellow oil (370mg, 99%).
MS(ESI,pos.ion)m/z:399.1[M+H]+.
Step two: synthesis of (S) -1- ((4, 4-difluorocyclohexyl) methyl) -3- ((difluoromethoxy) methyl) piperazine hydrochloride
To a solution of tert-butyl (S) -4- ((4, 4-difluorocyclohexyl) methyl) -2- ((difluoromethoxy) methyl) piperazine-1-carboxylate (390mg,0.98mmol) in DCM (6mL) was added HCl in 1, 4-dioxane (1.0mL,4.0mmol,4M) at room temperature, stirred at room temperature for 12h to stop the reaction and directly concentrated to give a white solid (330mg, 99.5%).
MS(ESI,pos.ion)m/z:299.1[M+H]+.
Step three: synthesis of ethyl (S) -2- (4- ((4, 4-difluorocyclohexyl) methyl) -2- ((difluoromethoxy) methyl) piperazin-1-yl) thiazole-5-carboxylate
To (S) -1- ((4, 4-difluorocyclohexyl) methyl) -3- ((difluoromethoxy) methyl) piperazine hydrochloride (150mg,0.4480mmol), ethyl 2-bromothiazole-5-carboxylate (120mg,0.51mmol), Pd, at room temperature2(dba)3(42mg,0.05mmol), Ruphos (27mg,0.05mmol), t-BuONa (130mg,1.35mmol) in a mixture with toluene(10mL), after heating the reaction at 110 ℃ for 24h, the reaction was stopped, quenched by addition of saturated NaCl solution (40mL), extracted with EtOAc (30 mL. times.3), anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 4/1) to give the product as a brown oil (130mg, 63.98%).
MS(ESI,pos.ion)m/z:454.1[M+H]+.
Step four: synthesis of (S) -2- (4- ((4, 4-difluorocyclohexyl) methyl) -2- ((difluoromethoxy) methyl) piperazin-1-yl) thiazole-5-carboxylic acid
To a solution of (S) -ethyl 2- (4- ((4, 4-difluorocyclohexyl) methyl) -2- ((difluoromethoxy) methyl) piperazin-1-yl) thiazole-5-carboxylate (130mg,0.28mmol) in THF (2mL) and MeOH (2mL) at room temperature was added H2O (1mL) and NaOH solution (46mg,1.15mmol) were reacted at room temperature for 9 hours, then the reaction was stopped, H was added2O dilution (30mL), dilute HCl to pH 6-7, DCM (30 mL. times.3) extraction, anhydrous Na2SO4Dried and concentrated to give the product as a brown oil (112mg, 98.1%).
MS(ESI,pos.ion)m/z:426.1[M+H]+.
Step five: synthesis of 2- ((S) -4- ((4, 4-difluorocyclohexyl) methyl) -2- ((difluoromethoxy) methyl) piperazin-1-yl) -N- ((R) -1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) thiazole-5-carboxamide
To a mixture of (S) -2- (4- ((4, 4-difluorocyclohexyl) methyl) -2- ((difluoromethoxy) methyl) piperazin-1-yl) thiazole-5-carboxylic acid (112mg,0.26mmol), EDCI (103mg,0.53mmol), HOBT (72mg,0.53mmol), (R) -2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol (73mg,0.32mmol) was added DCM (7mL), TEA (150. mu.L, 1.08mmol) at room temperature, reacted at room temperature for 20h, stopped, diluted with DCM (50mL), saturated NH4Cl solution (20mL) washed with anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 2/1) to give a white solid (45mg, 26.84%).
MS(ESI,pos.ion)m/z:637.2[M+H]+.
1H NMR(400MHz,CDCl3)δ(ppm):7.80(d,J＝8.3Hz,2H),7.75(s,1H),7.53(d,J＝8.3Hz,2H),7.27(d,J＝7.7Hz,1H),6.23(t,J＝74.2Hz,1H),5.18(dd,J＝10.9,5.5Hz,1H),4.25(dd,J＝15.9,7.2Hz,2H),3.99(dd,J＝8.4,4.7Hz,1H),3.89(ddd,J＝17.2,11.5,5.0Hz,2H),3.67(d,J＝12.0Hz,2H),3.32(td,J＝12.4,3.3Hz,1H),3.08(q,J＝7.4Hz,2H),3.00(d,J＝11.8Hz,1H),2.84(d,J＝10.7Hz,1H),2.22(d,J＝8.0Hz,6H),2.09(s,2H),1.91–1.53(m,5H),1.27(dd,J＝7.1,4.8Hz,3H).
Example 44: 2- ((S) -2- ((difluoromethoxy) methyl) -4- ((4- (trifluoromethyl) cyclohexyl) methyl) piperazin-1-yl) -N- ((R) -1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) thiazole-5-carboxamide
Figure BDA0002878710730000771
The method comprises the following steps: synthesis of (S) -2- ((difluoromethoxy) methyl) -4- ((4- (trifluoromethyl) cyclohexyl) methyl) piperazine-1-carboxylic acid tert-butyl ester
To a mixture of 4- (trifluoromethyl) cyclohexylformaldehyde (230mg,1.28mmol), (S) -2- ((difluoromethoxy) methyl) piperazine-1-carboxylic acid tert-butyl ester (280mg,1.05mmol) was added 1, 2-dichloroethane (5mL) and AcOH (65mg,1.08mmol) at room temperature, and after stirring for 1h at room temperature, sodium triacetoxyborohydride (670mg,3.1613mmol) was added, the reaction was continued for 12h at room temperature, stopped, and saturated NaHCO was added3The reaction was quenched with solution (25mL), extracted with DCM (30 mL. times.3), anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 4/1) to give the product as a pale yellow oil (420mg, 92.80%).
MS(ESI,pos.ion)m/z:431.4[M+H]+.
Step two: synthesis of (S) -3- ((difluoromethoxy) methyl) -1- ((4- (trifluoromethyl) cyclohexyl) methyl) piperazine hydrochloride
To a solution of (S) -tert-butyl 2- ((difluoromethoxy) methyl) -4- ((4- (trifluoromethyl) cyclohexyl) methyl) piperazine-1-carboxylate (420mg,0.97mmol) in DCM (6mL) was added HCl in 1, 4-dioxane (1.0mL,4.0mmol,4M) at room temperature, and after stirring at room temperature for 12h, the reaction was stopped and directly concentrated to give the product as a white solid (344mg, 99.1%).
MS(ESI,pos.ion)m/z:331.1[M+H]+.
Step three: synthesis of ethyl (S) -2- (2- ((difluoromethoxy) methyl) -4- ((4- (trifluoromethyl) cyclohexyl) methyl) piperazin-1-yl) thiazole-5-carboxylate
To (S) -3- ((difluoromethoxy) methyl) -1- ((4- (trifluoromethyl) cyclohexyl) methyl) piperazine hydrochloride (180mg,0.49mmol), ethyl 2-bromothiazole-5-carboxylate (174mg,0.73mmol), Pd, at room temperature2(dba)3Toluene (10mL) was added to a mixture of (46mg,0.05mmol) and Ruphos (24mg,0.05mmol), t-BuONa (142mg,1.48mmol), the reaction was stopped by heating at 110 ℃ for 24h, and saturated NH was added4Cl solution diluted (40mL), EtOAc (30 mL. times.3) extracted, anhydrous Na2SO4Dried, concentrated under reduced pressure and the crude product was isolated by column chromatography over silica gel (eluent: PE/EtOAc (v/v) ═ 4/1) to give the product as a brown oil (160mg, 67.16%).
MS(ESI,pos.ion)m/z:486.1[M+H]+.
Step four: synthesis of (S) -2- (2- ((difluoromethoxy) methyl) -4- ((4- (trifluoromethyl) cyclohexyl) methyl) piperazin-1-yl) thiazole-5-carboxylic acid
To a solution of ethyl (S) -2- (2- ((difluoromethoxy) methyl) -4- ((4- (trifluoromethyl) cyclohexyl) methyl) piperazin-1-yl) thiazole-5-carboxylate (160mg,0.33mmol) in THF (3mL) and MeOH (3mL) at room temperature were added NaOH solution (53mg,1.32mmol) and H2O (1mL), reacted at room temperature for 16h, and then saturated NH was added4Dilute Cl solution (30mL), adjust pH to 6-7 with dilute HCl, extract with DCM (30mL × 3), anhydrous Na 2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 2/1) to give the product as a brown oil (110mg, 2.96%).
MS(ESI,pos.ion)m/z:458.2[M+H]+.
Step five: synthesis of 2- ((S) -2- ((difluoromethoxy) methyl) -4- ((4- (trifluoromethyl) cyclohexyl) methyl) piperazin-1-yl) -N- ((R) -1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) thiazole-5-carboxamide
To (S) -2- (2- ((difluoromethoxy) methyl) -4- ((4- (trifluoromethyl) cyclohexyl) methyl) piperazine-1 at room temperature-yl) thiazole-5-carboxylic acid (110mg,0.24mmol), (R) -2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol (67mg,0.29mmol), EDCI (117mg,0.60mmol), HOBT (82mg,0.60mmol) to a mixture of DCM (6mL), TEA (170. mu.L, 1.22mmol), reacted at room temperature for 24h, stopped, diluted with DCM (50mL), saturated NH added4Cl solution (20mL) washed with anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 2/1) to give a white solid (46mg, 26.75%).
MS(ESI,pos.ion)m/z:669.2[M+H]+.
1H NMR(400MHz,CDCl3)δ(ppm):7.81(d,J＝8.2Hz,2H),7.76(s,1H),7.54(d,J＝8.2Hz,2H),7.26(d,J＝7.2Hz,1H),6.23(t,J＝74.2Hz,1H),5.19(d,J＝4.9Hz,1H),4.33–4.17(m,2H),4.01(dd,J＝8.2,4.7Hz,1H),3.89(ddd,J＝17.2,11.6,5.0Hz,2H),3.68(d,J＝11.6Hz,1H),3.33(dd,J＝12.2,9.3Hz,1H),3.09(q,J＝7.4Hz,2H),2.99(d,J＝11.7Hz,1H),2.84(d,J＝10.6Hz,1H),2.26–2.13(m,4H),1.97(d,J＝11.6Hz,4H),1.56–1.44(m,1H),1.27(m,6H),0.92(dd,J＝19.7,8.5Hz,2H).
Example 45: n- ((R) -1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -2- ((S) -2- ((trifluoromethoxy) methyl) -4- (4- (trifluoromethyl) benzyl) piperazin-1-yl) thiazole-5-carboxamide
Figure BDA0002878710730000781
The method comprises the following steps: synthesis of (S) -4-benzyl-1-tert-butyl-2- (hydroxymethyl) piperazine-1, 4-dicarboxylate
(S) -4-benzyl-1-tert-butyl-2-methylpiperazine-1, 2, 4-tricarboxylate (5.10g,13.00mmol) was dissolved in THF (15mL) and LiBH was added slowly in portions in an ice bath4(700mg,32.14mmol) and stirred at room temperature for 24 h. Adding saturated NaHCO into the reaction solution3Solution (100mL) and the reaction was quenched. Concentrated under reduced pressure to remove THF, extracted with DCM (120 mL. times.2), anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 1/1) to give a colorless oil (4.6g, 97.0%).
MS(ESI,pos.ion)m/z:373.2[M+Na]+.
Step two: synthesis of (S) -4-benzyl-1-tert-butyl-2- ((trifluoromethoxy) methyl) piperazine-1, 4-dicarboxylic acid
(S) -4-benzyl 1-tert-butyl 2- (hydroxymethyl) piperazine-1, 4-dicarboxylate (930mg,2.65mmol), AgOTf (2.27g,8.83mmol), fluorine-selective agent (1.57g,4.43mmol), KF (726mg,12.50mmol) was dissolved in EtOAc (13mL) under nitrogen, followed by the addition of 2-fluoropyridine (0.70mL,8.00mmol), TMSCF3(1.20mL,8.10mmol), and reacted at room temperature for 24 h. Celite was filtered, concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 3/1) to give a yellow oil (395mg, 35.6%).
Step three: synthesis of tert-butyl (S) -2- ((trifluoromethoxy) methyl) piperazine-1-carboxylate
(S) -4-benzyl-1-tert-butyl-2- ((trifluoromethoxy) methyl) piperazine-1, 4-dicarboxylic acid (395mg,0.94mmol), Pd/C (522mg,0.49mmol, 10% mass) was dissolved in MeOH/THF (3mL/3mL) and the hydrogen was replaced and stirred at room temperature for 5 h. Celite was filtered and concentrated under reduced pressure to give a yellow oil (245mg, 91.3%).
Step four: synthesis of tert-butyl (S) -2- ((trifluoromethoxy) methyl) -4- (4- (trifluoromethyl) benzyl) piperazine-1-carboxylate
Tert-butyl (S) -2- ((trifluoromethoxy) methyl) piperazine-1-carboxylate (245mg,0.86mmol), 4- (trifluoromethyl) benzaldehyde (0.24mL,1.80mmol) were dissolved in EtOH/THF (3mL/3mL) and AcOH (0.05mL,0.90mmol), STAB (1.08g,5.10mmol), reacted at 60 ℃ for 24 h. Adding saturated NaHCO into the reaction solution3The solution (30mL), adjusting the system pH to about 8, EtOAc (50 mL. times.2) extraction, organic phase with anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 5/1) to give a yellow oil (114mg, 29.9%).
MS(ESI,pos.ion)m/z:443.1[M+H]+.
Step five: synthesis of (S) -3- ((trifluoromethoxy) methyl) -1- (4- (trifluoromethyl) benzyl) piperazine
Reacting (S) -2- ((trifluoromethoxy) methyl) Tert-butyl (4- (trifluoromethyl) benzyl) piperazine-1-carboxylate (160mg,0.36mmol) was dissolved in DCM (1mL), and 1, 4-dioxane (2mL,8.00mmol,4mol/L) of HCl was added under ice bath and stirred at rt for 3 h. Distilling under reduced pressure to remove part of solvent, adding saturated NaHCO 3(20mL), adjust the system pH to about 8, extract with DCM (30 mL. times.2), and extract the organic layer with anhydrous Na2SO4Dried and concentrated under reduced pressure to give a yellow oil (120mg, 96.9%).
MS(ESI,pos.ion)m/z:343.12[M+H]+.
Step six: synthesis of methyl (S) -2- (2- ((trifluoromethoxy) methyl) -4- (4- (trifluoromethyl) benzyl) piperazin-1-yl) thiazole-5-carboxylate
(S) -3- ((trifluoromethoxy) methyl) -1- (4- (trifluoromethyl) benzyl) piperazine (150mg,0.44mmol), methyl 2-bromothiazole-5-carboxylate (217mg,0.98mmol), Pd under nitrogen blanket2(dba)3(61mg,0.067mmol)，Ruphos(53mg,0.11mmol)，Cs2CO3(374mg,1.15mmol) was dissolved in toluene (5mL) and the reaction was heated at 110 ℃ for 20 h. Celite was filtered, concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 2/1) to give a yellow oil (32mg, 15.1%).
MS(ESI,pos.ion)m/z:483.9[M+H]+.
Step seven: synthesis of (S) -2- (2- ((trifluoromethoxy) methyl) -4- (4- (trifluoromethyl) benzyl) piperazin-1-yl) thiazole-5-carboxylic acid
Methyl (S) -2- (2- ((trifluoromethoxy) methyl) -4- (4- (trifluoromethyl) benzyl) piperazin-1-yl) thiazole-5-carboxylate (55mg,0.11mmol), LiOH. H2O (60mg,1.43mmol) in THF/MeOH/H2O (1mL/0.5mL/0.5mL) was reacted at room temperature for 16 hours. Concentrating under reduced pressure, adding 1.0M HCl solution (4mL), adjusting pH to about 4, extracting with EtOAc (20 mL. times.2), and extracting the organic phase with anhydrous Na 2SO4Dried, concentrated under reduced pressure and the crude product was isolated by column chromatography over silica gel (eluent: DCM/MeOH (v/v) ═ 10/1) to give a yellow oil (45mg, 84.3%).
MS(ESI,pos.ion)m/z:470.0[M+H]+.
Step eight: synthesis of N- ((R) -1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -2- ((S) -2- ((trifluoromethoxy) methyl) -4- (4- (trifluoromethyl) benzyl) piperazin-1-yl) thiazole-5-carboxamide
(S) -2- (2- ((trifluoromethoxy) methyl) -4- (4- (trifluoromethyl) benzyl) piperazin-1-yl) thiazole-5-carboxylic acid (50mg,0.11mmol), (2R) -2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride (37mg,0.14mmol), EDCI (65mg,0.34mmol), HOBT (53mg,0.39mmol) were dissolved in DCM (3mL) and DIPEA (0.10mL,0.60mmol) was added and stirred at room temperature for 24 h. DCM (30mL), saturated NaHCO was added to the reaction3(20 mL. times.2) washing with saturated NH4Cl (20mL) washing, anhydrous Na2SO4Drying, concentration under reduced pressure and separation of the crude product by silica gel column chromatography (eluent: DCM/MeOH (v/v) ═ 12/1) gave 35mg of a brown solid, preparative isolation afforded a yellow solid (11mg, 15.2%).
MS(ESI,pos.ion)m/z:681.2[M+H]+.
1H NMR(400MHz,DMSO-d6)δ(ppm):8.62(d,J＝7.9Hz,1H),7.97(s,1H),7.83(d,J＝8.1Hz,2H),7.69(d,J＝7.8Hz,2H),7.61(d,J＝8.0Hz,2H),7.56(d,J＝8.0Hz,2H),5.10–5.00(m,2H),4.49–4.38(m,2H),4.27(t,J＝6.0Hz,1H),3.77–3.62(m,4H),3.56(d,J＝13.7Hz,1H),3.28–3.22(m,3H),2.86(d,J＝11.5Hz,2H),2.22(dd,J＝27.1,11.0Hz,2H),1.09(t,J＝7.3Hz,3H).
Example 46 and example 47: 2- ((S) -2- ((difluoromethoxy) methyl) -4- ((R) -1- (4- (trifluoromethyl) phenyl) ethyl) piperazin-1-yl) -N- ((R) -1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) thiazole-5-carboxamide/2- ((S) -2- ((difluoromethoxy) methyl) -4- ((S) -1- (4- (trifluoromethyl) phenyl) ethyl) piperazin-1-yl) -N- ((R) -1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) thiazole-5-carboxamide.
Figure BDA0002878710730000801
The method comprises the following steps: synthesis of 1- (4- (trifluoromethyl) phenyl) ethanol
4- (trifluoromethyl) benzaldehyde (2.40mL,18.00mmol) was dissolved in THF (20mL) and CH was slowly added dropwise at-78 deg.C3MgBr(20mL,20.00mmol,1mol/L) of THF, slowly warmed to room temperature for 5 h. Adding saturated NH to the reaction solution4The reaction was quenched with Cl (100 mL). EtOAc (120 mL. times.2) extraction, anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 4/1) to give a colorless oil (2.67g, 80.0%).
MS(ESI,neg.ion)m/z:189.1[M-H]-.
Step two: synthesis of 1- (1-bromoethyl) -4- (trifluoromethyl) benzene
1- (4- (trifluoromethyl) phenyl) ethanol (1.45g,7.63mmol) was dissolved in DCM (10mL) and PBr was added under ice bath3(0.90mL,10.00mmol) and stirred at room temperature for 2 h. Adding saturated NaHCO into the reaction solution3The reaction was quenched with solution (100mL), extracted with DCM (80 mL. times.2), anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 50/1) to give a yellow oil (1.43g, 74.1%).
MS(ESI,pos.ion)m/z:253.1[M+H]+.
Step three: synthesis of tert-butyl (2S) -2- ((difluoromethoxy) methyl) -4- (1- (4- (trifluoromethyl) phenyl) ethyl) piperazine-1-carboxylate
Tert-butyl (S) -2- ((difluoromethoxy) methyl) piperazine-1-carboxylate (201mg,0.75mmol), 1- (1-bromoethyl) -4- (trifluoromethyl) benzene (208mg,0.82mmol), K 2CO3(222mg,1.61mmol) was dissolved in ACN (8mL) and reacted at 90 ℃ for 11 h. The reaction solution was concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 4/1) to give a yellow oil (280mg, 84.6%).
MS(ESI,pos.ion)m/z:439.1[M+H]+.
Step four: synthesis of (3S) -3- ((difluoromethoxy) methyl) -1- (1- (4- (trifluoromethyl) phenyl) ethyl) piperazine
Tert-butyl (2S) -2- ((difluoromethoxy) methyl) -4- (1- (4- (trifluoromethyl) phenyl) ethyl) piperazine-1-carboxylate (380mg,0.87mmol) was dissolved in DCM (2mL), and 1, 4-dioxane (3mL,12.00mmol,4mol/L) of HCl was added under ice bath and stirred at room temperature for 2 h. Distilling under reduced pressure to remove part of solvent, adding saturated NaHCO3(30mL), adjust the system pH to about 8, extract with DCM (50 mL. times.2), and extract the organic phase with anhydrous Na2SO4Dried and concentrated under reduced pressure to give a yellow oil (287mg, 97.9%).
MS(ESI,pos.ion)m/z:339.6[M+H]+.
Step five: synthesis of methyl 2- ((2S) -2- ((difluoromethoxy) methyl) -4- (1- (4- (trifluoromethyl) phenyl) ethyl) piperazin-1-yl) thiazole-5-carboxylate
(3S) -3- ((difluoromethoxy) methyl) -1- (1- (4- (trifluoromethyl) phenyl) ethyl) piperazine (287mg,0.85mmol), methyl 2-bromothiazole-5-carboxylate (406mg,1.83mmol), Pd under nitrogen blanket2(dba)3(102mg,0.11mmol)，Ruphos(95mg,0.20mmol)，Cs2CO3(575mg,1.76mmol) was dissolved in toluene (8mL) and the reaction was heated at 110 ℃ for 24 h. Celite was filtered, concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 2/1) to give a yellow oil (260mg, 63.9%).
MS(ESI,pos.ion)m/z:480.1[M+H]+.
Step six: synthesis of 2- ((2S) -2- ((difluoromethoxy) methyl) -4- (1- (4- (trifluoromethyl) phenyl) ethyl) piperazin-1-yl) thiazole-5-carboxylic acid
Methyl 2- ((2S) -2- ((difluoromethoxy) methyl) -4- (1- (4- (trifluoromethyl) phenyl) ethyl) piperazin-1-yl) thiazole-5-carboxylate (260mg,0.54mmol), LiOH. H2O (242mg,5.77mmol) in THF/MeOH/H2O (3mL/1.5mL/1.5mL), and reacted at room temperature for 24 h. Concentrating under reduced pressure, adding 1.0M HCl solution (15mL), adjusting pH to about 4, extracting with EtOAc (30 mL. times.2), and extracting the organic phase with anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: DCM/MeOH (v/v) ═ 10/1) to give a yellow solid (250mg, 99.1%).
MS(ESI,pos.ion)m/z:466.1[M+H]+.
Step seven: synthesis of 2- ((2S) -2- ((difluoromethoxy) methyl) -4- (1- (4- (trifluoromethyl) phenyl) ethyl) piperazin-1-yl) -N- ((R) -1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) thiazole-5-carboxamide
2 to (a)(2S) -2- ((difluoromethoxy) methyl) -4- (1- (4- (trifluoromethyl) phenyl) ethyl) piperazin-1-yl) thiazole-5-carboxylic acid (161mg,0.35mmol), (2R) -2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride (137mg,0.52mmol), EDCI (207mg,1.08mmol), HOBT (154mg,1.14mmol) was dissolved in DCM (5mL) and DIPEA (0.45mL,2.70mmol) was added and stirred at room temperature for 19 h. DCM (30mL) and saturated NH were added to the reaction solution 4Cl (20 mL. times.2) wash, saturated NaHCO3(20mL) washing with anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: DCM/MeOH (v/v) ═ 10/1) to give a yellow solid (165mg, 70.5%). MS (ESI, pos. ion) M/z 677.2[ M + H ]]+.
Step eight: chiral resolution of 2- ((S) -2- ((difluoromethoxy) methyl) -4- ((R) -1- (4- (trifluoromethyl) phenyl) ethyl) piperazin-1-yl) -N- ((R) -1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) thiazole-5-carboxamide/2- ((S) -2- ((difluoromethoxy) methyl) -4- ((S) -1- (4- (trifluoromethyl) phenyl) ethyl) piperazin-1-yl) -N- ((R) -1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) thiazole-5-carboxamide.
Chiral resolution was prepared from 2- ((2S) -2- ((difluoromethoxy) methyl) -4- (1- (4- (trifluoromethyl) phenyl) ethyl) piperazin-1-yl) -N- ((R) -1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) thiazole-5-carboxamide (165mg,0.24mmol) (chiral column OA, i-PrOH/ACN ═ 20/1).
Concentrating under reduced pressure to obtain compound A: white solid (55mg, 33.3%) and compound B were: white solid (55mg, 33.3%).
MS(ESI,pos.ion)m/z:677.2[M+H]+.
A compound A:1H NMR(400MHz,DMSO-d6)δ(ppm):8.60(d,J＝7.8Hz,1H),7.96(s,1H),7.84(d,J＝8.1Hz,2H),7.69(d,J＝8.0Hz,2H),7.62(d,J＝8.1Hz,2H),7.56(d,J＝7.9Hz,2H),6.64(t,J＝75.7Hz,1H),5.06(dd,J＝12.6,6.7Hz,2H),4.23(s,1H),4.14(t,J＝8.6Hz,1H),4.04–3.98(m,1H),3.70(dt,J＝10.1,9.6Hz,3H),3.60(dd,J＝13.0,6.4Hz,1H),3.29(d,J＝4.6Hz,1H),3.28–3.23(m,2H),3.07(d,J＝10.2Hz,1H),2.79(d,J＝11.8Hz,1H),2.12(t,J＝10.3Hz,2H),1.32(d,J＝6.5Hz,3H),1.10(t,J＝7.3Hz,3H).
compound B:1H NMR(400MHz,DMSO-d6)δ(ppm):8.60(d,J＝7.8Hz,1H),7.96(s,1H),7.84(d,J＝8.1Hz,2H),7.70(d,J＝8.0Hz,2H),7.60(dd,J＝12.3,8.3Hz,4H),6.68(t,J＝75.6Hz,1H),5.05(dd,J＝13.3,7.9Hz,2H),4.32(s,1H),4.23(t,J＝8.6Hz,1H),4.05(dd,J＝9.2,6.1Hz,1H),3.75–3.60(m,4H),3.26(dd,J＝14.7,7.3Hz,3H),3.08(d,J＝11.4Hz,1H),2.72(d,J＝10.5Hz,1H),2.23(d,J＝8.8Hz,1H),2.10(t,J＝10.3Hz,1H),1.31(d,J＝6.4Hz,3H),1.10(t,J＝7.3Hz,3H).
example 48: 2- ((2S) -2- ((difluoromethoxy) methyl) -4- (2,2, 2-trifluoro-1- (4- (trifluoromethyl) phenyl) ethyl) piperazin-1-yl) -N- ((R) -1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) thiazole-5-carboxamide
Figure BDA0002878710730000821
The method comprises the following steps: synthesis of 2,2, 2-trifluoro-1- (4- (trifluoromethyl) phenyl) ethanol
2,2, 2-trifluoro-1- (4- (trifluoromethyl) phenyl) ethanone (388mg,1.60mmol) was dissolved in MeOH (5mL) and NaBH was added slowly under ice bath4(49mg,1.29mmol), stirred at room temperature for 2 h. Adding saturated NaHCO into the reaction solution3Solution (20mL), quench the reaction. Concentrate under reduced pressure to remove MeOH, extract with DCM (30 mL. times.2), anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 3/1) to give a colorless oil (275mg, 70.3%).
Step two: synthesis of ethyl 2,2, 2-trifluoro-1- (4- (trifluoromethyl) phenyl) trifluoromethanesulfonate
2,2, 2-trifluoro-1- (4- (trifluoromethyl) phenyl) ethanol (918mg,3.76mmol) was dissolved in DCM (10mL) under nitrogen, 2, 6-lutidine (0.90mL,8.00mmol) and Tf were added sequentially at-20 deg.C2O (0.95mL,5.60mmol), then stirred at 10 ℃ for 3 h. Adding saturated NaHCO into the reaction solution3The reaction was quenched with solution (80mL), extracted with DCM (100mL), and the organic phase was washed with HCl solution (50 mL. times.2, 1M) anhydrous Na2SO4Dried and concentrated under reduced pressure to give a yellow oil (1.1g, 78.0%).
Step three: synthesis of tert-butyl (2S) -2- ((difluoromethoxy) methyl) -4- (2,2, 2-trifluoro-1- (4- (trifluoromethyl) phenyl) ethyl) piperazine-1-carboxylate
Tert-butyl (S) -2- ((difluoromethoxy) methyl) piperazine-1-carboxylate (291mg,1.09mmol), ethyl 2,2, 2-trifluoro-1- (4- (trifluoromethyl) phenyl) trifluoromethanesulfonate (1.10g,2.90mmol), K2CO3(344mg,2.49mmol) was dissolved in ACN (5mL) and reacted at 90 ℃ for 16 h. Concentrated under reduced pressure, and then saturated NaHCO was added to the residue3Solution (30mL), DCM (50 mL. times.2) extraction, anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 5/1) to give a yellow oil (450mg, 83.6%). MS (ESI, pos.ion) M/z 493.2[ M + H ]]+.
Step four: synthesis of (3S) -3- ((difluoromethoxy) methyl) -1- (2,2, 2-trifluoro-1- (4- (trifluoromethyl) phenyl) ethyl) piperazine
Tert-butyl (2S) -2- ((difluoromethoxy) methyl) -4- (2,2, 2-trifluoro-1- (4- (trifluoromethyl) phenyl) ethyl) piperazine-1-carboxylate (500mg,1.02mmol) was dissolved in DCM (3mL) and a solution of HCl in 1, 4-dioxane (5mL,20.00mmol,4mol/L) was added under ice-bath and stirred at room temperature for 2 h. Distilling under reduced pressure to remove part of solvent, adding saturated NaHCO3(30mL), adjust the system pH to about 8, extract with DCM (50 mL. times.2), and extract the organic phase with anhydrous Na2SO4Dried and concentrated under reduced pressure to give a yellow oil (390mg, 97.9%).
MS(ESI,pos.ion)m/z:393.0[M+H]+.
Step five: synthesis of methyl 2- ((2S) -2- ((difluoromethoxy) methyl) -4- (2,2, 2-trifluoro-1- (4- (trifluoromethyl) phenyl) ethyl) piperazin-1-yl) thiazole-5-carboxylate
(3S) -3- ((difluoromethoxy) methyl) -1- (2,2, 2-trifluoro-1- (4- (trifluoromethyl) phenyl) ethyl) piperazine (390mg,0.99mmol), methyl 2-bromothiazole-5-carboxylate (456mg,2.05mmol), Pd under nitrogen2(dba)3(97mg,0.11mmol)，Ruphos(99mg,0.21mmol)，Cs2CO3(792mg,2.43mmol), dissolved in toluene (10mL) and heated at 110 ℃ for 22 h. Filtering with diatomite, concentrating under reduced pressure,the crude product was isolated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 4/1) to give a yellow oil (250mg, 47.2%).
MS(ESI,pos.ion)m/z:534.0[M+H]+.
Step six: synthesis of 2- ((2S) -2- ((difluoromethoxy) methyl) -4- (2,2, 2-trifluoro-1- (4- (trifluoromethyl) phenyl) ethyl) piperazin-1-yl) thiazole-5-carboxylic acid
Methyl 2- ((2S) -2- ((difluoromethoxy) methyl) -4- (2,2, 2-trifluoro-1- (4- (trifluoromethyl) phenyl) ethyl) piperazin-1-yl) thiazole-5-carboxylate (250mg,0.47mmol), LiOH. H2O (227mg,5.41mmol) was dissolved in THF/MeOH/H2O (4mL/2mL/2mL) and reacted at room temperature for 16H. Concentrating under reduced pressure, adding 1.0M HCl solution (6mL), adjusting pH to about 5, extracting with EtOAc (30 mL. times.2), and extracting organic phase with anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: DCM/MeOH (v/v) ═ 10/1) to give a yellow solid (85mg, 34.9%).
MS(ESI,pos.ion)m/z:20.2[M+H]+.
Step seven: synthesis of 2- ((2S) -2- ((difluoromethoxy) methyl) -4- (2,2, 2-trifluoro-1- (4- (trifluoromethyl) phenyl) ethyl) piperazin-1-yl) -N- ((R) -1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) thiazole-5-carboxamide
2- ((2S) -2- ((difluoromethoxy) methyl) -4- (2,2, 2-trifluoro-1- (4- (trifluoromethyl) phenyl) ethyl) piperazin-1-yl) thiazole-5-carboxylic acid (85mg,0.16mmol), (2R) -2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride (59mg,0.22mmol), EDCI (127mg,0.66mmol), HOBT (72mg,0.53mmol) was dissolved in DCM (5mL) and DIPEA (0.15mL,0.91mmol) was added and stirred at room temperature for 24 h. DCM (50mL) and saturated NH were added to the reaction solution4Cl (20 mL. times.2) wash, saturated NaHCO3(20mL) washing with anhydrous Na2SO4Drying, concentration under reduced pressure and chromatography on silica gel (eluent: DCM/MeOH (v/v) ═ 10/1) afforded 46mg of a yellow solid, preparative isolation afforded a white solid (29mg, 24.3%).
MS(ESI,pos.ion)m/z:731.1[M+H]+.
1H NMR(400MHz,DMSO-d6)δ(ppm):8.60(d,J＝7.4Hz,1H),7.95(s,1H),7.83(d,J＝8.2Hz,2H),7.76(s,2H),7.64(dd,J＝21.6,7.7Hz,4H),6.62(td,J＝75.6,49.2Hz,1H),5.05(s,2H),4.49(s,1H),4.25(s,1H),4.11–4.02(m,1H),3.67(s,2H),3.59(s,2H),3.26(d,J＝7.2Hz,3H),3.11(d,J＝12.4Hz,2H),2.31–2.20(m,1H),1.99(s,1H),1.10(t,J＝7.2Hz,3H).
Example 49: 2- ((S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenethyl) piperazin-1-yl) -N- ((R) -1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) thiazole-5-carboxamide
Figure BDA0002878710730000831
The method comprises the following steps: synthesis of tert-butyl (S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenethyl) piperazine-1-carboxylate
Tert-butyl (S) -2- ((difluoromethoxy) methyl) piperazine-1-carboxylate (200mg,0.75mmol), 1- (2-bromoethyl) -4- (trifluoromethyl) benzene (0.15mL,0.89mmol), K2CO3(291mg,2.11mmol) was dissolved in ACN (5mL) and reacted at 90 ℃ for 16 h. Concentrated under reduced pressure, and then saturated NaHCO was added to the residue 3Solution (20mL), DCM (30 mL. times.2) extraction, anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 4/1) to give a yellow oil (291mg, 88.4%).
MS(ESI,pos.ion)m/z:439.2[M+H]+.
Step two: synthesis of (S) -3- ((difluoromethoxy) methyl) -1- (4- (trifluoromethyl) phenethyl) piperazine
Tert-butyl (S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenethyl) piperazine-1-carboxylate (291mg,0.66mmol) was dissolved in DCM (3mL), and a solution of HCl in 1, 4-dioxane (3mL,12.00mmol,4mol/L) was added under ice-bath and stirred at room temperature for 4 h. Concentrating under reduced pressure to remove part of the solvent, adding saturated NaHCO3The solution (30mL) was adjusted to about pH 8, DCM (50 mL. times.2) was extracted and the organic phase was treated with anhydrous Na2SO4Dried and concentrated under reduced pressure to give a yellow oil (220mg, 98.0%).
MS(ESI,pos.ion)m/z:339.0[M+H]+.
Step three: synthesis of methyl (S) -2- (2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenethyl) piperazin-1-yl) thiazole-5-carboxylate
(S) -3- ((difluoromethoxy) methyl) -1- (4- (trifluoromethyl) phenethyl) piperazine (220mg,0.65mmol), methyl 2-bromothiazole-5-carboxylate (296mg,1.33mmol), Pd under nitrogen blanket2(dba)3(104mg,0.11mmol)，Ruphos(67mg,0.14mmol)，Cs2CO3(465mg,1.43mmol) was dissolved in toluene (8mL) and the reaction was heated at 110 ℃ for 23 h. Celite was filtered, concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 4/1) to give a yellow oil (129mg, 41.4%).
MS(ESI,pos.ion)m/z:480.0[M+H]+.
Step four: synthesis of (S) -2- (2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenethyl) piperazin-1-yl) thiazole-5-carboxylic acid
Methyl (S) -2- (2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenethyl) piperazin-1-yl) thiazole-5-carboxylate (129mg,0.27mmol), LiOH. H2O (135mg,3.22mmol) in THF/MeOH/H2O (2mL/1mL/1mL), and reacted at room temperature for 24 hours. Concentrating under reduced pressure, adding 1.0M HCl solution (6mL), adjusting pH to about 5, extracting with EtOAc (30 mL. times.2), and extracting organic phase with anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: DCM/MeOH (v/v) ═ 10/1) to give a yellow solid (100mg, 79.9%).
MS(ESI,pos.ion)m/z:466.1[M+H]+.
Step five: synthesis of 2- ((S) -2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenethyl) piperazin-1-yl) -N- ((R) -1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) thiazole-5-carboxamide
(S) -2- (2- ((difluoromethoxy) methyl) -4- (4- (trifluoromethyl) phenethyl) piperazin-1-yl) thiazole-5-carboxylic acid (100mg,0.21mmol), (2R) -2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride (80mg,0.30mmol), EDCI (147mg,0.77mmol), HOBT (88mg,0.65mmol) were dissolved in DCM (5mL)DIPEA (0.20mL,1.00mmol) was added and stirred at room temperature for 15 h. DCM (50mL) and saturated NH were added to the reaction solution 4Cl (20 mL. times.2) wash, saturated NaHCO3(20mL) washing with anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: DCM/MeOH (v/v) ═ 10/1) to give a yellow solid (118mg, 81.2%).
MS(ESI,pos.ion)m/z:677.3[M+H]+.
1H NMR(600MHz,DMSO-d6)δ(ppm):8.61(d,J＝7.7Hz,1H),7.98(s,1H),7.85(d,J＝7.8Hz,2H),7.63(d,J＝7.9Hz,4H),7.48(d,J＝7.8Hz,2H),6.62(t,J＝75.4Hz,1H),5.06(t,J＝5.7Hz,2H),4.31(s,1H),4.04(t,J＝8.6Hz,1H),4.00–3.94(m,1H),3.75–3.65(m,3H),3.27(dd,J＝14.5,7.3Hz,3H),3.03(d,J＝11.7Hz,1H),2.96(d,J＝10.4Hz,1H),2.85(dd,J＝14.6,7.3Hz,2H),2.68–2.62(m,1H),2.60–2.54(m,1H),2.23(d,J＝8.7Hz,1H),2.16(t,J＝10.0Hz,1H),1.10(t,J＝7.2Hz,3H).
Example 50: 2- ((S) -2- ((difluoromethoxy) methyl) -4- (3,3, 3-trifluoropropyl) piperazin-1-yl) -N- ((R) -1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) thiazole-5-carboxamide
Figure BDA0002878710730000841
The method comprises the following steps: synthesis of 3,3, 3-trifluoropropyl trifluoromethanesulfonate
Dissolving 3,3, 3-trifluoropropan-1-ol (812mg,7.12mmol) in DCM (8mL) at-25 deg.C, sequentially adding DIPEA (3.50mL,21.00mmol) and Tf2O (2mL,11.89mmol), and stirring was continued at-25 ℃ for 4 h. Adding saturated NaHCO into the reaction solution3The reaction was quenched with solution (60mL), extracted with DCM (80 mL. times.2), anhydrous Na2SO4Drying and concentration under reduced pressure gave a brown oil (1.2g, 68.0%).
Step two: synthesis of tert-butyl (S) -2- ((difluoromethoxy) methyl) -4- (3,3, 3-trifluoropropyl) piperazine-1-carboxylate
3,3, 3-Trifluoropropyltrifluoromethanesulfonate (300mg,1.22mmol), (S) -2- ((difluoromethoxy) methyl) piperazine-1-carboxylic acid tert-butyl esterButyl ester (161mg,0.60mmol), K2CO3(453mg,3.28mmol) was dissolved in ACN (5mL) and reacted at 90 ℃ for 16 h. Concentrated under reduced pressure, and then saturated NaHCO was added to the residue 3Solution (30mL), DCM (50 mL. times.2) extraction, anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 4/1) to give a yellow oil (200mg, 91.3%).
MS(ESI,pos.ion)m/z:363.2[M+H]+.
Step three: synthesis of (S) -3- ((difluoromethoxy) methyl) -1- (3,3, 3-trifluoropropyl) piperazine
Tert-butyl (S) -2- ((difluoromethoxy) methyl) -4- (3,3, 3-trifluoropropyl) piperazine-1-carboxylate (262mg,0.72mmol) was dissolved in DCM (3mL), and a solution of HCl in 1, 4-dioxane (3mL,12.00mmol,4mol/L) was added under ice-bath and stirred at room temperature for 2 h. Distilling under reduced pressure to remove part of solvent, adding saturated NaHCO3(20mL), adjust the system pH to about 8, extract with DCM (30 mL. times.2), and extract the organic phase with anhydrous Na2SO4Dried and concentrated under reduced pressure to give a yellow oil (180mg, 95.0%).
MS(ESI,pos.ion)m/z:263.2[M+H]+.
Step four: synthesis of methyl (S) -2- (2- ((difluoromethoxy) methyl) -4- (3,3, 3-trifluoropropyl) piperazin-1-yl) thiazole-5-carboxylate
(S) -3- ((difluoromethoxy) methyl) -1- (3,3, 3-trifluoropropyl) piperazine (180mg,0.69mmol), methyl 2-bromothiazole-5-carboxylate (480mg,2.16mmol), Pd under a nitrogen blanket2(dba)3(121mg,0.13mmol)，Ruphos(91mg,0.19mmol)，Cs2CO3(664mg,2.04mmol) was dissolved in toluene (8mL) and the reaction was heated at 110 ℃ for 24 h. Celite was filtered, concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 4/1) to give a yellow oil (125mg, 45.1%).
MS(ESI,pos.ion)m/z:404.0[M+H]+.
Step five: synthesis of (S) -2- (2- ((difluoromethoxy) methyl) -4- (3,3, 3-trifluoropropyl) piperazin-1-yl) thiazole-5-carboxylic acid
Reacting (S) -2- (2- ((difluoromethoxy) methyl) -4-(3,3, 3-trifluoropropyl) piperazin-1-yl) thiazole-5-carboxylic acid methyl ester (160mg,0.40mmol), LiOH. H2O (198mg,4.72mmol) in THF/MeOH/H2O (2mL/1mL/1mL), and reacted at room temperature for 14 h. Concentrating under reduced pressure, adding 1.0M HCl solution (8mL), adjusting pH to about 5, extracting with EtOAc (30 mL. times.2), and extracting organic phase with anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: DCM/MeOH (v/v) ═ 10/1) to give a yellow oil (118mg, 76.4%).
MS(ESI,pos.ion)m/z:390.1[M+H]+.
Step six: synthesis of 2- ((S) -2- ((difluoromethoxy) methyl) -4- (3,3, 3-trifluoropropyl) piperazin-1-yl) -N- ((R) -1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) thiazole-5-carboxamide
(S) -2- (2- ((difluoromethoxy) methyl) -4- (3,3, 3-trifluoropropyl) piperazin-1-yl) thiazole-5-carboxylic acid (118mg,0.30 mmol), (2R) -2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol hydrochloride (102mg,0.38mmol), EDCI (181mg,0.94mmol), HOBT (139mg,1.03mmol) was dissolved in DCM (5mL) and DIPEA (0.20mL,1.00mmol) was added and stirred at room temperature for 24 h. DCM (30mL) and saturated NH were added to the reaction solution 4Cl (20 mL. times.2) wash, saturated NaHCO3(20mL) washing with anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: DCM/MeOH (v/v) ═ 10/1) to give a yellow solid (120mg, 65.9%).
MS(ESI,pos.ion)m/z:601.0[M+H]+.
1H NMR(600MHz,DMSO-d6)δ(ppm):8.61(d,J＝7.9Hz,1H),7.98(s,1H),7.85(d,J＝8.1Hz,2H),7.63(d,J＝8.2Hz,2H),6.68(t,J＝75.4Hz,1H),5.09–5.04(m,2H),4.32(s,1H),4.16–4.10(m,1H),4.07–4.02(m,1H),3.74(d,J＝12.5Hz,1H),3.72–3.65(m,2H),3.27(dd,J＝14.6,7.5Hz,3H),2.98(d,J＝11.8Hz,1H),2.93(d,J＝10.7Hz,1H),2.64–2.57(m,1H),2.54(dd,J＝13.5,7.3Hz,1H),2.46(dd,J＝10.7,7.2Hz,2H),2.22(dd,J＝11.7,3.3Hz,1H),2.18–2.11(m,1H),1.10(t,J＝7.3Hz,3H).
Example 51: n- ((S) -2-cyano-1- (4- (ethylsulfonyl) phenyl) ethyl) -2- ((S) -4- (2- (difluoromethoxy) ethyl) -2- ((difluoromethoxy) methyl) piperazin-1-yl) thiazole-5-carboxamide
Figure BDA0002878710730000861
The method comprises the following steps: synthesis of 1-bromo-2- (difluoromethoxy) ethane
2-Bromoethanol (3g,24.01mmol) was dissolved in DCM/H2O (30mL/30mL), KOAc (14.50g,148.00mmol) was added and (bromo (difluoro) methyl) -trimethylsilane (15mL,96.45mmol) was slowly added dropwise under ice-bath, stirring at room temperature for 18 h. Adding saturated NaHCO into the reaction solution3The reaction was quenched with solution (100mL), extracted with ether (120 mL. times.2), anhydrous Na2SO4Drying, ice-bath and concentration under reduced pressure gave a yellow oil (2g, 47.6%).
Step two: synthesis of tert-butyl (S) -4- (2- (difluoromethoxy) ethyl) -2- ((difluoromethoxy) methyl) piperazine-1-carboxylate
Tert-butyl (S) -2- ((difluoromethoxy) methyl) piperazine-1-carboxylate (360mg,1.35mmol), 1-bromo-2- (difluoromethoxy) ethane (2g,11.43mmol), K2CO3(558mg,4.04mmol) was dissolved in ACN (5mL) and reacted at 90 ℃ for 12 h. Concentrated under reduced pressure, and then saturated NaHCO was added to the residue 3Solution (20mL), DCM (30 mL. times.2) extraction, anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 3/1) to give a yellow oil (106mg, 21.8%).
MS(ESI,pos.ion)m/z:361.3[M+H]+.
Step three: synthesis of (S) -1- (2- (difluoromethoxy) ethyl) -3- ((difluoromethoxy) methyl) piperazine
Tert-butyl (S) -4- (2- (difluoromethoxy) ethyl) -2- ((difluoromethoxy) methyl) piperazine-1-carboxylate (126mg,0.35mmol) was dissolved in DCM (2mL), and a solution of HCl in 1, 4-dioxane (2mL,8.00mmol,4mol/L) was added under ice-bath and stirred at room temperature for 3 h. Distilling under reduced pressure to remove part of solvent, adding saturated NaHCO3(20mL), adjust the system pH to about 8, extract with DCM (30 mL. times.2), and extract the organic layer with anhydrous Na2SO4Dried and concentrated under reduced pressure to give a yellow oil (89mg, 97.8%).
MS(ESI,pos.ion)m/z:261.1[M+H]+.
Step four: synthesis of methyl (S) -2- (4- (2- (difluoromethoxy) ethyl) -2- ((difluoromethoxy) methyl) piperazin-1-yl) thiazole-5-carboxylate
(S) -1- (2- (difluoromethoxy) ethyl) -3- ((difluoromethoxy) methyl) piperazine (89mg,0.34mmol), methyl 2-bromothiazole-5-carboxylate (219mg,0.99mmol), Pd under nitrogen blanket2(dba)3(97mg,0.11mmol)，Ruphos(89mg,0.19mmol)，Cs2CO3(294mg,0.90mmol) was dissolved in toluene (5mL) and the reaction was heated at 110 ℃ for 22 h. Celite was filtered, concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 3/1) to give a yellow oil (106mg, 77.2%).
MS(ESI,pos.ion)m/z:402.0[M+H]+.
Step five: synthesis of (S) -2- (4- (2- (difluoromethoxy) ethyl) -2- ((difluoromethoxy) methyl) piperazin-1-yl) thiazole-5-carboxylic acid
Methyl (S) -2- (4- (2- (difluoromethoxy) ethyl) -2- ((difluoromethoxy) methyl) piperazin-1-yl) thiazole-5-carboxylate (106mg,0.26mmol), LiOH. H2O (149mg,3.55mmol) in THF/MeOH/H2O (2mL/1mL/1mL), and reacted at room temperature for 16 h. Concentrating under reduced pressure, adding 1.0M HCl solution (8mL), adjusting pH to about 5, extracting with EtOAc (20 mL. times.2), and extracting organic phase with anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: DCM/MeOH (v/v) ═ 8/1) to give a yellow solid (51mg, 49.9%).
MS(ESI,pos.ion)m/z:388.1[M+H]+.
Step six: synthesis of N- ((S) -2-cyano-1- (4- (ethylsulfonyl) phenyl) ethyl) -2- ((S) -4- (2- (difluoromethoxy) ethyl) -2- ((difluoromethoxy) methyl) piperazin-1-yl) thiazole-5-carboxamide
(S) -2- (4- (2- (difluoromethoxy) ethyl) -2- ((difluoromethoxy) methyl) piperazin-1-yl) thiazole-5-carboxylic acid (51mg,0.13mmol), (3S) -3-amino-3- (4- (ethylsulfonyl) phenyl)) Propionitrile (49mg,0.21mmol), EDCI (82mg,0.43mmol), HOBT (55mg,0.41mmol) was dissolved in DCM (3mL) and DIPEA (0.11mL,0.67mmol) was added and stirred at RT for 24 h. DCM (50mL) and saturated NH were added to the reaction solution 4Cl (20 mL. times.2) wash, saturated NaHCO3(20mL) washing with anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: DCM/MeOH (v/v) ═ 10/1) to give 45mg yellow. PTLC separation then gave a yellow solid (16mg, 20.0%).
MS(ESI,pos.ion)m/z:608.0[M+H]+.
1H NMR(400MHz,DMSO-d6)δ(ppm):9.03(d,J＝8.0Hz,1H),7.94(s,1H),7.90(d,J＝8.3Hz,2H),7.70(d,J＝8.3Hz,2H),6.67(t,J＝76Hz,1H),6.66(t,J＝76Hz,1H),5.44(dd,J＝14.5,8.5Hz,1H),4.32(s,1H),4.16–4.11(m,1H),4.10–4.04(m,1H),3.93(t,J＝5.5Hz,2H),3.75(d,J＝13.0Hz,1H),3.35(d,J＝6.3Hz,1H),3.29(dd,J＝14.7,7.4Hz,2H),3.19–3.06(m,2H),2.99(d,J＝11.9Hz,1H),2.93(d,J＝11.0Hz,1H),2.67–2.55(m,2H),2.29(dd,J＝11.9,3.5Hz,1H),2.21(dd,J＝11.8,8.3Hz,1H),1.10(t,J＝7.3Hz,3H).
Example 52: n- ((S) -2-cyano-1- (4- (ethylsulfonyl) phenyl) ethyl) -2- ((S) -2- ((difluoromethoxy) methyl) -4- (3- (difluoromethoxy) propyl) piperazin-1-yl) thiazole-5-carboxamide
Figure BDA0002878710730000871
Starting from 2-bromoethanol instead of 3-bromopropan-1-ol (3g,21.58mmol), the title compound was prepared by the method of example 51 step one to step six as a yellow solid (158mg, 41.6%).
MS(ESI,pos.ion)m/z:622.0[M+H]+.
1H NMR(400MHz,DMSO-d6)δ(ppm):8.99(d,J＝8.2Hz,1H),7.96–7.86(m,3H),7.70(d,J＝8.3Hz,2H),6.88–6.43(m,2H),5.44(dd,J＝14.5,8.5Hz,1H),4.32(s,1H),4.15(t,J＝8.7Hz,1H),4.05(dd,J＝9.6,6.9Hz,1H),3.88(t,J＝6.3Hz,2H),3.74(d,J＝12.2Hz,1H),3.29(q,J＝7.4Hz,3H),3.13(qd,J＝16.8,7.6Hz,2H),2.92(dd,J＝27.6,11.3Hz,2H),2.47–2.30(m,2H),2.12(ddd,J＝20.0,11.7,5.9Hz,2H),1.76(dd,J＝13.1,6.5Hz,2H),1.10(t,J＝7.3Hz,3H).
Example 53: n- ((S) -2-cyano-1- (4- (ethylsulfonyl) phenyl) ethyl) -2- ((S) -4- (2- (3- (difluoromethoxy) cyclobutyl) ethyl) -2- ((difluoromethoxy) methyl) piperazin-1-yl) thiazole-5-carboxamide
Figure BDA0002878710730000872
The method comprises the following steps: synthesis of methyl 2- (3- (difluoromethoxy) cyclobutyl) acetate
Methyl 2- (3-Hydroxycyclobutyl) acetate (1.30g,9.00mmol) was dissolved in DCM/H2O (11mL/11mL), KOAc (5.30g,54.00mmol) was added, and (bromo (difluoro) methyl) -trimethylsilane (5.6mL,36.00mmol) was slowly added dropwise under ice-bath, and stirred at room temperature for 20 h. Adding saturated NaHCO into the reaction solution 3The reaction was quenched with solution (80mL), extracted with DCM (100 mL. times.2), anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 5/1) to give a yellow oil (1.5g, 86.0%).
Step two: synthesis of 2- (3- (difluoromethoxy) cyclobutyl) ethanol
Methyl 2- (3- (difluoromethoxy) cyclobutyl) acetate (291mg,1.50mmol) was dissolved in THF (3mL) and LiBH was added slowly under ice-bath4(98mg,4.50mmol) and stirred at room temperature for 18 h. Adding saturated NaHCO into the reaction solution3Solution (20mL), quench the reaction. Concentrated under reduced pressure to remove THF, extracted with DCM (30 mL. times.2), anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 3/1) to give a colorless oil (201mg, 80.7%).
Step three: synthesis of ethyl 2- (3- (difluoromethoxy) cyclobutyl) trifluoromethanesulfonate
2- (3- (difluoromethoxy) cyclobutyl) ethanol (900mg,5.42mmol) was dissolved in DCM (15mL) and DIPEA (2.70mL,16.00mmol) and Tf were added sequentially at-25 deg.C2O(1.80mL,11.00mmol), and stirring was continued at-25 ℃ for 6 h. Adding saturated NaHCO into the reaction solution3The reaction was quenched with solution (100mL), extracted with DCM (80 mL. times.2), anhydrous Na2SO4Drying and concentration under reduced pressure gave a brown oil (1.4g, 87.0%).
Step four: synthesis of tert-butyl (S) -4- (2- (3- (difluoromethoxy) cyclobutyl) ethyl) -2- ((difluoromethoxy) methyl) piperazine-1-carboxylate
Tert-butyl (S) -2- ((difluoromethoxy) methyl) piperazine-1-carboxylate (435mg,1.63mmol), ethyl 2- (3- (difluoromethoxy) cyclobutyl) trifluoromethanesulfonate (1.40g,4.70 mmol), K2CO3(780mg,5.64mmol) was dissolved in ACN (10mL) and reacted at 90 ℃ for 15 h. Concentrated under reduced pressure, and then saturated NaHCO was added to the residue3Solution (30mL), DCM (50 mL. times.2) extraction, anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 3/1) to give a yellow oil (528mg, 78.0%).
MS(ESI,pos.ion)m/z:415.3[M+H]+.
Step five: synthesis of (S) -1- (2- (3- (difluoromethoxy) cyclobutyl) ethyl) -3- ((difluoromethoxy) methyl) piperazine
Tert-butyl (S) -4- (2- (3- (difluoromethoxy) cyclobutyl) ethyl) -2- ((difluoromethoxy) methyl) piperazine-1-carboxylate (648mg,1.56mmol) was dissolved in DCM (3mL), and a solution of HCl in 1, 4-dioxane (5mL,20.00mmol,4mol/L) was added under ice-bath and stirred at room temperature for 4 h. Distilling under reduced pressure to remove part of solvent, adding saturated NaHCO3(30mL), adjusting the pH of the system to about 8, extracting with DCM (30 mL. times.2), and separating the organic layer with anhydrous Na2SO4Dried and concentrated under reduced pressure to give a yellow oil (480mg, 97.7%).
MS(ESI,pos.ion)m/z:315.1[M+H]+.
Step six: synthesis of methyl (S) -2- (4- (2- (3- (difluoromethoxy) cyclobutyl) ethyl) -2- ((difluoromethoxy) methyl) piperazin-1-yl) thiazole-5-carboxylate
Under nitrogen protection, (S) -1- (2- (3- (difluoromethoxy) cyclobutyl) ethyl) -3- ((difluoromethoxy) methyl) piperazine (480mg,1.53mmol), 2-bromothiazole-5-carboxylic acid methyl ester(735mg,3.31mmol)，Pd2(dba)3(175mg,0.19mmol)，Ruphos(178mg,0.38mmol)，Cs2CO3(1.15g,3.53mmol) was dissolved in toluene (10mL) and the reaction was heated at 110 ℃ for 24 h. Celite was filtered, concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 3/1) to give a yellow oil (291mg, 41.8%).
MS(ESI,pos.ion)m/z:456.2[M+H]+.
Step seven: synthesis of (S) -2- (4- (2- (3- (difluoromethoxy) cyclobutyl) ethyl) -2- ((difluoromethoxy) methyl) piperazin-1-yl) thiazole-5-carboxylic acid
Methyl (S) -2- (4- (2- (3- (difluoromethoxy) cyclobutyl) ethyl) -2- ((difluoromethoxy) methyl) piperazin-1-yl) thiazole-5-carboxylate (291mg,0.64mmol), LiOH. H2O (346mg,8.25mmol) in THF/MeOH/H2O (4mL/2mL/2mL) was reacted at room temperature for 17 hours. Concentrating under reduced pressure, adding 1.0M HCl solution (10mL), adjusting pH to about 5, extracting with EtOAc (20 mL. times.2), and extracting organic phase with anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: DCM/MeOH (v/v) ═ 10/1) to give a yellow solid (230mg, 81.6%).
MS(ESI,pos.ion)m/z:442.1[M+H]+.
Step eight: synthesis of N- ((S) -2-cyano-1- (4- (ethylsulfonyl) phenyl) ethyl) -2- ((S) -4- (2- (3- (difluoromethoxy) cyclobutyl) ethyl) -2- ((difluoromethoxy) methyl) piperazin-1-yl) thiazole-5-carboxamide
(S) -2- (4- (2- (3- (difluoromethoxy) cyclobutyl) ethyl) -2- ((difluoromethoxy) methyl) piperazin-1-yl) thiazole-5-carboxylic acid (230mg,0.52mmol), (S) -3-amino-3- (4- (ethylsulfonyl) phenyl) propionitrile (149mg,0.63mmol), EDCI (350mg,1.83mmol), HOBT (255mg,1.89mmol) was dissolved in DCM (5mL) and DIPEA (0.5mL,3mmol) was added and stirred at RT for 16 h. DCM (50mL) and saturated NH were added to the reaction solution4Cl (20 mL. times.2) wash, saturated NaHCO3(20mL) washing with anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: DCM/MeOH (v/v) ═ 10/1) to give a yellow solid (143mg, 41.5%).
MS(ESI,pos.ion)m/z:662.3[M+H]+.
1H NMR(400MHz,DMSO-d6)δ(ppm):8.98(d,J＝7.9Hz,1H),8.03–7.83(m,3H),7.70(d,J＝7.9Hz,2H),6.89–6.37(m,2H),5.44(d,J＝6.1Hz,1H),4.53–4.34(m,1H),4.30(s,1H),4.14(t,J＝8.4Hz,1H),4.09–3.99(m,1H),3.73(d,J＝11.2Hz,1H),3.31–3.24(m,3H),3.19–3.06(m,2H),2.91(dd,J＝23.1,11.0Hz,2H),2.40(s,2H),2.29–2.17(m,2H),2.11(d,J＝9.5Hz,1H),2.02(s,1H),1.84(d,J＝6.7Hz,1H),1.67(d,J＝8.6Hz,2H),1.56(d,J＝5.5Hz,2H),1.10(t,J＝7.1Hz,3H).
Example 54: n- ((S) -2-cyano-1- (4- (ethylsulfonyl) phenyl) ethyl) -2- ((S) -4- (3- (difluoromethoxy) cyclobutyl) -2- ((difluoromethoxy) methyl) piperazin-1-yl) thiazole-5-carboxamide
Figure BDA0002878710730000891
The method comprises the following steps: synthesis of ((3- (difluoromethoxy) cyclobutoxy) methyl) benzene
3-Benzyloxycyclobutanol (2g,11.22mmol) was dissolved in DCM/H2O (13mL/13mL), KOAc (6.80g,69.00mmol) was added and (bromo (difluoro) methyl) -trimethylsilane (7mL,45.01mmol) was slowly added dropwise under ice-bath, stirring at room temperature for 22 h. Adding saturated NaHCO into the reaction solution 3The reaction was quenched with solution (80mL), extracted with DCM (100 mL. times.2), anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 8/1) to give a yellow oil (2.3g, 90.0%).
Step two: synthesis of 3- (difluoromethoxy) cyclobutanol
((3- (difluoromethoxy) cyclobutoxy) methyl) benzene (2.30g,10.00mmol), Pd/C (2.30g,2.20mmol) was dissolved in THF (5mL) under a hydrogen atmosphere and stirred at room temperature for 16 h. Celite was filtered and concentrated under reduced pressure to give a yellow oil (1g, 72.0%).
Step three: synthesis of 3- (difluoromethoxy) cyclobutyl trifluoromethanesulfonate
Reacting 3- (difluoromethoxy)Yl) Cyclobutanol (1g,7.24mmol) was dissolved in DCM (10mL) at-25 deg.C, DIPEA (3.60mL,22.00mmol) and Tf were added sequentially2O (2.50mL,15.00mmol), and stirring was continued at-25 ℃ for 6 h. Adding saturated NaHCO into the reaction solution3The reaction was quenched with solution (20mL), extracted with DCM (30 mL. times.2), anhydrous Na2SO4Drying and concentration under reduced pressure gave a brown oil (1.7g, 87.0%).
Step four: synthesis of tert-butyl (S) -4- (3- (difluoromethoxy) cyclobutyl) -2- ((difluoromethoxy) methyl) piperazine-1-carboxylate
Tert-butyl (S) -2- ((difluoromethoxy) methyl) piperazine-1-carboxylate (421mg,1.58mmol), 3- (difluoromethoxy) cyclobutyl trifluoromethanesulfonate (1.70g,6.30mmol), K 2CO3(875mg,6.33mmol) was dissolved in ACN (10mL) and reacted at 90 ℃ for 20 h. Concentrated under reduced pressure, and then saturated NaHCO was added to the residue3Solution (50mL), DCM (80 mL. times.2) extraction, anhydrous Na2SO4Dried, concentrated under reduced pressure and the crude product was isolated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 3/1) to give a yellow oil (549mg, 89.9%).
MS(ESI,pos.ion)m/z:387.3[M+H]+.
Step five: synthesis of (S) -1- (3- (difluoromethoxy) cyclobutyl) -3- ((difluoromethoxy) methyl) piperazine
Tert-butyl (S) -4- (3- (difluoromethoxy) cyclobutyl) -2- ((difluoromethoxy) methyl) piperazine-1-carboxylate (679mg,1.76mmol) was dissolved in DCM (3mL), and a solution of HCl in 1, 4-dioxane (5mL,20.00mmol,4mol/L) was added under ice-bath and stirred at room temperature for 3 h. Distilling under reduced pressure to remove part of solvent, adding saturated NaHCO3(40mL), adjusting the pH of the system to about 8, extracting with DCM (50 mL. times.2), and separating the organic layer with anhydrous Na2SO4Dried and concentrated under reduced pressure to give a yellow oil (500mg, 99.4%).
MS(ESI,pos.ion)m/z:287.2[M+H]+.
Step six: synthesis of methyl (S) -2- (4- (3- (difluoromethoxy) cyclobutyl) -2- ((difluoromethoxy) methyl) piperazin-1-yl) thiazole-5-carboxylate
Under the protection of nitrogen, (S) -1- (3- (difluoromethoxy) cyclobutyl) -3- ((difluoromethoxy) methyl) Piperazine (500mg,1.75mmol), methyl 2-bromothiazole-5-carboxylate (787mg,3.54mmol), Pd 2(dba)3(180mg,0.20mmol)，Ruphos(208mg,0.45mmol)，Cs2CO3(1.16g,3.56mmol) was dissolved in toluene (10mL) and the reaction was heated at 110 ℃ for 22 h. Celite was filtered, concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 4/1) to give a yellow oil (327mg, 43.8%).
MS(ESI,pos.ion)m/z:428.0[M+H]+.
Step seven: synthesis of (S) -2- (4- (3- (difluoromethoxy) cyclobutyl) -2- ((difluoromethoxy) methyl) piperazin-1-yl) thiazole-5-carboxylic acid
Methyl (S) -2- (4- (3- (difluoromethoxy) cyclobutyl) -2- ((difluoromethoxy) methyl) piperazin-1-yl) thiazole-5-carboxylate (327mg,0.77mmol), LiOH. H2O (410mg,9.77mmol) in THF/MeOH/H2O (4mL/2mL/2mL) at room temperature for 24 h. To the reaction mixture was added 1.0M HCl solution (15mL), the pH of the system was adjusted to about 5, EtOAc (20 mL. times.2) was used for extraction, and the organic layer was Na anhydrous2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by column chromatography over silica gel (eluent: DCM/MeOH (v/v) ═ 10/1) to give a brown solid (244mg, 77.1%).
MS(ESI,pos.ion)m/z:414.2[M+H]+.
Step eight: synthesis of N- ((S) -2-cyano-1- (4- (ethylsulfonyl) phenyl) ethyl) -2- ((S) -4- (3- (difluoromethoxy) cyclobutyl) -2- ((difluoromethoxy) methyl) piperazin-1-yl) thiazole-5-carboxamide
(S) -2- (4- (3- (difluoromethoxy) cyclobutyl) -2- ((difluoromethoxy) methyl) piperazin-1-yl) thiazole-5-carboxylic acid (225mg,0.54mmol), (3S) -3-amino-3- (4- (ethylsulfonyl) phenyl) propionitrile (188mg,0.79mmol), EDCI (344mg,1.79mmol), HOBT (238mg,1.76mmol) were dissolved in DCM (5mL) and DIPEA (0.45mL,2.70mmol) was added and stirred at RT for 14 h. DCM (50mL) and saturated NH were added to the reaction solution 4Cl (20 mL. times.2) wash, saturated NaHCO3(20mL) washing with anhydrous Na2SO4Dried, concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: EtOAc/PE (v/v) ═ 2/1) to give 170mg of a yellow solid, which was separated by PTLC,this gave a pale yellow solid (138mg, 40.0%).
MS(ESI,pos.ion)m/z:634.0[M+H]+.
1H NMR(400MHz,DMSO-d6)δ(ppm):8.99(d,J＝8.2Hz,1H),7.93(s,1H),7.90(d,J＝8.3Hz,2H),7.70(d,J＝8.3Hz,2H),6.67(td,J＝75.7,29.3Hz,2H),5.44(dd,J＝14.5,8.5Hz,1H),4.72–4.59(m,1H),4.34(s,1H),4.21–4.15(m,1H),4.05(dd,J＝9.6,6.9Hz,1H),3.77(d,J＝11.5Hz,1H),3.29(dd,J＝14.8,7.4Hz,3H),3.13(qd,J＝16.8,7.6Hz,2H),2.92(dd,J＝21.1,8.4Hz,3H),2.29(s,1H),2.26–2.08(m,3H),1.99(dd,J＝11.7,3.3Hz,1H),1.90(t,J＝10.0Hz,1H),1.10(t,J＝7.3Hz,3H).
Example 55: n- ((S) -2-cyano-1- (4- (ethylsulfonyl) phenyl) ethyl) -2- ((S) -2- ((difluoromethoxy) methyl) -4- ((1r,3S) -3- (((difluoromethoxy) methyl) cyclobutyl) piperazin-1-yl) thiazole-5-carboxamide
Figure BDA0002878710730000901
The method comprises the following steps: synthesis of tert-butyl ((1s,3s) -3- ((difluoromethoxy) methyl) cyclobutoxy) dimethylsilane
((1s,3s) -3- ((((tert-butyl) dimethyl) silyl) oxy) cyclobutyl) methanol (2.20g,10.00mmol) was dissolved in DCM/H2O (12mL/12mL), KOAc (6.00g,61.14mmol) was added, and (bromo (difluoro) methyl) -trimethylsilane (6.30mL,41.00mmol) was slowly added dropwise under ice-bath, and stirred at room temperature for 22 h. Adding saturated NaHCO into the reaction solution3The reaction was quenched with solution (80mL), extracted with DCM (100 mL. times.2), anhydrous Na2SO4Drying, ice-bath and concentration under reduced pressure gave a yellow oil (2.6g, 96.0%).
Step two: synthesis of (1s,3s) -3- ((difluoromethoxy) methyl) cyclobutanol
Tert-butyl ((1s,3s) -3- ((difluoromethoxy) methyl) cyclobutoxy) dimethylsilane (3.00g,11.26mmol) was dissolved in anhydrous THF (8mL) and TBAF (22mL,22.00mmol,1mol/L) was added and stirred at room temperature for 24 h. The reaction mixture was concentrated under reduced pressure, diluted with DCM (60mL), washed with saturated NaCl solution (40 mL. times.2), and dried Na2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 1/1) to give a yellow oil (1.3g, 76.0%).
Step three: synthesis of ((1s,3s) -3- ((difluoromethoxy) methyl) cyclobutyl) trifluoromethanesulfonate
(1s,3s) -3- ((difluoromethoxy) methyl) cyclobutanol (1.10g,7.20mmol) was dissolved in DCM (15mL) and DIPEA (3.60mL,22.00mmol) and Tf were added sequentially at-25 deg.C2O (2.20mL,13.00mmol), and stirring was continued at-25 ℃ for 1 h. Adding saturated NaHCO into the reaction solution3The reaction was quenched with solution (100mL), extracted with DCM (80 mL. times.2), anhydrous Na2SO4Drying and concentration under reduced pressure gave a brown oil (1.8g, 88.0%).
Step four: synthesis of tert-butyl (S) -2- (((difluoromethoxy) methyl) -4- ((1r,3S) -3- ((difluoromethoxy) methyl) cyclobutyl) piperazine-1-carboxylate
Tert-butyl (S) -2- ((difluoromethoxy) methyl) piperazine-1-carboxylate (431mg,1.62mmol), ((1S,3S) -3- ((difluoromethoxy) methyl) cyclobutyl) trifluoromethanesulfonate (1.80g,6.30mmol), K2CO3(871mg,6.30mmol) was dissolved in ACN (10mL) and reacted at 90 ℃ for 14 h. Celite was filtered, the filtrate was concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 3/1) to give a yellow oil (204mg, 31.5%).
MS(ESI,pos.ion)m/z:401.2[M+H]+.
Step five: synthesis of (S) -3- ((difluoromethoxy) methyl) -1- ((1r,3S) -3- ((difluoromethoxy) methyl) cyclobutyl) piperazine
Tert-butyl (S) -2- ((difluoromethoxy) methyl) -4- ((1r,3S) -3- ((difluoromethoxy) methyl) cyclobutyl) piperazine-1-carboxylate (260mg,0.65mmol) was dissolved in DCM (2mL), and a solution of HCl in 1, 4-dioxane (3mL,12.00mmol,4mol/L) was added under ice-bath and stirred at room temperature for 1 h. Distilling under reduced pressure to remove part of solvent, adding saturated NaHCO3(20mL), adjust the system pH to about 8, extract with DCM (30 mL. times.2), and extract the organic layer with anhydrous Na2SO4Dried and concentrated under reduced pressure to give a yellow oil (190mg, 97.4%).
MS(ESI,pos.ion)m/z:301.2[M+H]+.
Step six: synthesis of methyl 2- ((S) -2- ((difluoromethoxy) methyl) -4- ((1r,3S) -3- ((difluoromethoxy) methyl) cyclobutyl) piperazin-1-yl) thiazole-5-carboxylate
(S) -3- ((difluoromethoxy) methyl) -1- ((1r,3S) -3- ((difluoromethoxy) methyl) cyclobutyl) piperazine (190mg,0.63mmol), methyl 2-bromothiazole-5-carboxylate (358mg,1.61mmol), Pd under nitrogen protection2(dba)3(91mg,0.099mmol)，Ruphos(95mg,0.20mmol)，Cs2CO3(591mg,1.81mmol) in toluene (5mL) and heated at 110 deg.C for 24 h. Celite was filtered, concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 3/1) to give a yellow oil (104mg, 37.2%).
MS(ESI,pos.ion)m/z:442.0[M+H]+.
Step seven: synthesis of 2- ((S) -2- ((difluoromethoxy) methyl) -4- ((1r,3S) -3- ((difluoromethoxy) methyl) cyclobutyl) piperazin-1-yl) thiazole-5-carboxylic acid
Methyl 2- ((S) -2- ((difluoromethoxy) methyl) -4- ((1r,3S) -3- ((difluoromethoxy) methyl) cyclobutyl) piperazin-1-yl) thiazole-5-carboxylate (104mg,0.24mmol), LiOH. H2O (175mg,4.17mmol) in THF/MeOH/H2O (2mL/1mL/1mL), and reacted at room temperature for 24 hours. Concentrating under reduced pressure, adding 1.0M HCl solution (8mL), adjusting pH to about 5, extracting with EtOAc (20 mL. times.2), and collecting organic layer as anhydrous Na2SO4Dried, concentrated under reduced pressure and the crude product was isolated by column chromatography over silica gel (eluent: DCM/MeOH (v/v) ═ 8/1) to give a yellow oil (100mg, 99.3%).
MS(ESI,pos.ion)m/z:428.0[M+H]+.
Step eight: synthesis of N- ((S) -2-cyano-1- (4- (ethylsulfonyl) phenyl) ethyl) -2- ((S) -2- ((difluoromethoxy) methyl) -4- ((1r,3S) -3- (((difluoromethoxy) methyl) cyclobutyl) piperazin-1-yl) thiazole-5-carboxamide
2- ((S) -2- ((difluoromethoxy) methyl) -4- ((1r,3S) -3- ((difluoromethoxy) methyl) cyclobutyl) piperazin-1-yl) thiazole-5-carboxylic acid (100mg,0.23mmol), (3S) -3-amino-3- (4- (ethylsulfonyl) phenyl) propionitrile(83mg,0.35mmol), EDCI (199mg,1.04mmol), HOBT (118mg,0.87mmol) were dissolved in DCM (5mL) and DIPEA (0.19mL,1.10mmol) was added and stirred at RT for 9 h. DCM (50mL) and saturated NH were added to the reaction solution 4Cl (20 mL. times.2) wash, saturated NaHCO3(20mL) washing with anhydrous Na2SO4Drying, concentration under reduced pressure and separation of the crude product by silica gel column chromatography (eluent: DCM/MeOH (v/v) ═ 10/1) gave 102mg of a yellow solid which was isolated by preparative separation as a pale yellow solid (11mg, 7.2%).
MS(ESI,pos.ion)m/z:648.2[M+H]+.
1H NMR(600MHz,DMSO-d6)δ(ppm):9.00(d,J＝8.2Hz,1H),7.93(s,1H),7.90(d,J＝8.4Hz,2H),7.70(d,J＝8.4Hz,2H),6.70(t,J＝75.4Hz,1H),6.67(t,J＝76.3Hz,1H),5.44(td,J＝8.7,6.0Hz,1H),4.32(s,1H),4.19–4.14(m,1H),4.04(dd,J＝9.8,6.8Hz,1H),3.87(d,J＝7.2Hz,2H),3.81–3.71(m,2H),3.29(q,J＝7.4Hz,3H),3.16(dd,J＝16.8,5.7Hz,1H),3.09(dd,J＝16.8,9.4Hz,1H),2.91–2.80(m,3H),2.03–1.96(m,2H),1.95–1.88(m,2H),1.86(dd,J＝9.9,6.2Hz,2H),1.10(t,J＝7.3Hz,3H).
Example 56: n- ((S) -2-cyano-1- (4- (ethylsulfonyl) phenyl) ethyl) -2- ((S) -2- ((difluoromethoxy) methyl) -4- ((6- (difluoromethoxy) spiro [3.3] heptan-2-yl) methyl) piperazin-1-yl) thiazole-5-carboxamide
Figure BDA0002878710730000921
The method comprises the following steps: synthesis of methyl 6- (difluoromethoxy) spiro [3.3] heptane-2-carboxylate
Reacting 6-hydroxy spiro [3.3]]Heptane-2-carboxylic acid methyl ester (1.80g,11.00mmol) dissolved in DCM/H2O (13mL/13mL), KOAc (6.40g,65.00mmol) was added, and (bromo (difluoro) methyl) -trimethylsilane (6.60mL,42.00mmol) was slowly added dropwise under ice-bath, and stirred at room temperature for 18 h. Adding saturated NaHCO into the reaction solution3The reaction was quenched with solution (80mL), extracted with DCM (100 mL. times.2), anhydrous Na2SO4Drying, concentrating under reduced pressure, and separating the crude product by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 8/1) to give yellowOil (2.2g, 94.0%).
Step two: synthesis of (6- (difluoromethoxy) spiro [3.3] hept-2-yl) methanol
Reacting 6- (difluoromethoxy) spiro [3.3]Heptane-2-carboxylic acid methyl ester (2.20g,10.00mmol) was dissolved in THF (10mL) and LiBH was added slowly under ice bath 4(550mg,25.25mmol) was stirred at room temperature for 18 h. Adding saturated NaHCO into the reaction solution3Solution (60mL) and the reaction was quenched. Concentrated under reduced pressure to remove THF, extracted with DCM (80 mL. times.2), anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 3/1) to give a colorless oil (1.6g, 83.0%).
Step three: synthesis of methyl (6- (difluoromethoxy) spiro [3.3] hept-2-yl) trifluoromethanesulfonate
Reacting (6- (difluoromethoxy) spiro [3.3]]Hept-2-yl) methanol (308mg,1.60mmol) was dissolved in DCM (5mL) and DIPEA (0.80mL,5.00mmol) and Tf were added sequentially at-25 deg.C2O (0.6mL,4.00mmol), and stirring was continued at-25 ℃ for 5 h. Adding saturated NaHCO into the reaction solution3The reaction was quenched with solution (20mL), extracted with DCM (30 mL. times.2), anhydrous Na2SO4Dried and concentrated under reduced pressure to give a brown oil (450mg, 86.6%).
Step four: synthesis of tert-butyl (S) -2- ((difluoromethoxy) methyl) -4- ((6- (difluoromethoxy) spiro [3.3] heptan-2-yl) methyl) piperazine-1-carboxylate
(S) -2- ((difluoromethoxy) methyl) piperazine-1-carboxylic acid tert-butyl ester (116mg,0.44mmol), (6- (difluoromethoxy) spiro [ 3.3%]Hept-2-yl) trifluoromethanesulfonic acid methyl ester (450mg,1.39mmol), K2CO3(557mg,4.03mmol) was dissolved in ACN (5mL,100 mass%) and reacted at 90 ℃ for 21 h. Concentrated under reduced pressure, and then saturated NaHCO was added to the residue 3Solution (20mL), DCM (30 mL. times.2) extraction, anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 3/1) to give a yellow oil (150mg, 78.2%). MS (ESI, pos.ion) M/z 441.1[ M + H ]]+.
Step five: synthesis of (S) -3- ((difluoromethoxy) methyl) -1- ((6- (difluoromethoxy) spiro [3.3] hept-2-yl) methyl) piperazine
Mixing (S) -2- ((difluoromethoxy) methyl) -4- ((6- (difluoromethoxy) spiro [ 3.3)]Heptan-2-yl) methyl) piperazine-1-carboxylic acid tert-butyl ester (750mg,1.70mmol) was dissolved in DCM (3mL), and a solution of HCl in 1, 4-dioxane (5mL,20.00mmol,4mol/L) was added under ice-bath and stirred at room temperature for 3 h. Distilling under reduced pressure to remove part of solvent, adding saturated NaHCO3(40mL), adjusting the pH of the system to about 8, extracting with DCM (50 mL. times.2), and separating the organic layer with anhydrous Na2SO4Dried and concentrated under reduced pressure to give a yellow oil (560mg, 96.6%).
Step six: synthesis of methyl (S) -2- (2- ((difluoromethoxy) methyl) -4- ((6- (difluoromethoxy) spiro [3.3] heptan-2-yl) methyl) piperazin-1-yl) thiazole-5-carboxylate
Under the protection of nitrogen, (S) -3- ((difluoromethoxy) methyl) -1- ((6- (difluoromethoxy) spiro [ 3.3)]Hept-2-yl) methyl) piperazine (560mg,1.65mmol), 2-bromothiazole-5-carboxylic acid methyl ester (184mg,0.83mmol), Pd 2(dba)3(192mg,0.21mmol)，Ruphos(191mg,0.41mmol)，Cs2CO3(1.12g,3.44mmol) in toluene (10mL) and heated at 110 ℃ for 24 h. Celite was filtered, concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 4/1) to give a yellow oil (323mg, 40.8%).
MS(ESI,pos.ion)m/z:482.1[M+H]+.
Step seven: synthesis of (S) -2- (2- ((difluoromethoxy) methyl) -4- ((6- (difluoromethoxy) spiro [3.3] heptan-2-yl) methyl) piperazin-1-yl) thiazole-5-carboxylic acid
Mixing (S) -2- (2- ((difluoromethoxy) methyl) -4- ((6- (difluoromethoxy) spiro [ 3.3)]Heptane-2-yl) methyl) piperazin-1-yl) thiazole-5-carboxylic acid methyl ester (323mg,0.67mmol), LiOH H2O (395mg,9.41mmol) was dissolved in THF/MeOH/H2O (4mL/2mL/2mL) at room temperature for 24 h. Concentrating under reduced pressure, adding 1.0M HCl solution (15mL), adjusting pH to about 5, extracting with EtOAc (20 mL. times.2), and collecting organic layer as anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by column chromatography over silica gel (eluent: DCM/MeOH (v/v) ═ 10/1) to give a brown solid (250mg, 79.7%).
MS(ESI,pos.ion)m/z:468.3[M+H]+.
Step eight: synthesis of N- ((S) -2-cyano-1- (4- (ethylsulfonyl) phenyl) ethyl) -2- ((S) -2- ((difluoromethoxy) methyl) -4- ((6- (difluoromethoxy) spiro [3.3] heptan-2-yl) methyl) piperazin-1-yl) thiazole-5-carboxamide
Mixing (S) -2- (2- ((difluoromethoxy) methyl) -4- ((6- (difluoromethoxy) spiro [ 3.3) ]Heptane-2-yl) methyl) piperazin-1-yl) thiazole-5-carboxylic acid (239mg,0.51mmol), (3S) -3-amino-3- (4- (ethylsulfonyl) phenyl) propionitrile (156mg,0.65mmol), EDCI (305mg,1.59mmol), HOBT (223mg,1.65mmol) was dissolved in DCM (5mL) and DIPEA (0.45mL,2.70mmol) was added and stirred at room temperature for 15 h. DCM (50mL) and saturated NH were added to the reaction solution4Cl (20 mL. times.2) wash, saturated NaHCO3(20mL) washing with anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: EtOAc/PE (v/v) ═ 2/1) to give 70mg of a yellow solid, and isolated by PTLC to give a yellow solid (38mg, 10.8%).
MS(ESI,pos.ion)m/z:688.0[M+H]+.
1H NMR(400MHz,DMSO-d6)δ(ppm):8.98(d,J＝8.2Hz,1H),7.92(s,1H),7.90(d,J＝8.3Hz,2H),7.70(d,J＝8.3Hz,2H),6.62(td,J＝75.8,47.8Hz,2H),5.44(dd,J＝14.5,8.5Hz,1H),4.43(dd,J＝14.5,7.2Hz,1H),4.28(s,1H),4.16–4.09(m,1H),4.07–3.99(m,1H),3.71(d,J＝11.6Hz,1H),3.32–3.27(m,3H),3.19–3.07(m,2H),2.84(dd,J＝28.3,11.1Hz,2H),2.47–2.40(m,1H),2.35(dd,J＝11.5,4.7Hz,2H),2.32–2.22(m,2H),2.13(dd,J＝11.4,3.4Hz,2H),2.08–1.96(m,4H),1.71(d,J＝4.3Hz,2H),1.10(t,J＝7.3Hz,3H).
Example 57: 2- ((2S,5R) -2- ((difluoromethoxy) methyl) -5- (4- (trifluoromethyl) phenyl) piperidin-1-yl) -N- ((R) -1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) thiazole-5-carboxamide
Figure BDA0002878710730000941
The method comprises the following steps: synthesis of methyl (2S,5S) -5-hydroxypiperidine-2-carboxylate
(2S,5S) -5-hydroxypiperidine-2-carboxylic acid (20.40g,141mmol) is dissolved in MeOH (200mL) and SOCl is slowly added dropwise in an ice bath2(18mL,248mmol) and stirred at room temperature for 22 h. Concentration under reduced pressure gave a white solid (21g, 94.1%).
MS(ESI,pos.ion)m/z:160.2[M+H]+.
Step two: synthesis of (2S,5S) -1-tert-butyl 2-methyl 5-hydroxypiperidine-1, 2-dicarboxylate
(2S,5S) -5-hydroxypiperidine-2-carboxylic acid methyl ester (21.10g,131.93mmol) is dissolved in THF (240mL) and K is then added 2CO3(46.60g,337mmol) was dissolved in H2O (120mL), slowly dropwise adding Boc when the reaction solution is uniformly mixed in ice bath2O (45mL,200mmol), stirred at room temperature for 24 h. EtOAc (200 mL. times.3) extraction, combined organic phases, anhydrous Na2SO4Dried and concentrated under reduced pressure to give a yellow oil (33g, 96.3%). MS (ESI, pos.ion) M/z 282.3[ M + Na ]]+.
Step three: synthesis of (S) -1-tert-butyl 2-methyl 5-oxopiperidine-1, 2-dicarboxylate
(2S,5S) -1-tert-butyl 2-methyl 5-hydroxypiperidine-1, 2-dicarboxylate (32.01g,123.41mmol) was dissolved in DCM (400mL), and DMP (105.01g,247.60mmol) was added portionwise under ice-bath and stirred at room temperature for 21 h. Filtering with diatomite, adding saturated NaHCO into reaction liquid3The solution (600mL) is adjusted to about pH 8, and DCM (200 mL. times.3) is used for extraction, anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 3/1) to give a yellow oil (30g, 94.2%).
MS(ESI,pos.ion)m/z:280.1[M+Na]+.
Step four: synthesis of (S) -1-tert-butyl 2-methyl 5-bromo-3, 4-dihydropyridine-1, 2(2H) -dicarboxylate
(S) -1-tert-butyl 2-methyl 5-oxopiperidine-1, 2-dicarboxylate (5.10g,20.01mmol), P (OPh)3) (18.08g,58.27mmol) in DCM (50mL) at-20 deg.C TEA (14mL,101.10mmol) was added followed by Br 2(2.8mL,55.03mmol) was diluted with DCM (25mL), added dropwise slowly to the reaction and allowed to warm to room temperature over 40min, followed by stirring for 16 h. Adding into the reaction solutionDCM (80mL), saturated NaHCO3Washing with solution (150 mL. times.2), washing with saturated NaCl (100 mL. times.2), anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 10/1) to give a yellow oil (3.8g, 59.1%).
MS(ESI,pos.ion)m/z:222.0[M+H]+.
Step five: synthesis of (S) -5-bromo-2- (hydroxymethyl) -3, 4-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester
(S) -1-tert-butyl 2-methyl 5-bromo-3, 4-dihydropyridine-1, 2(2H) -dicarboxylate (1.60g,5.00mmol) was dissolved in THF (8mL) and LiBH was added slowly in portions under ice-bath4(342mg,15.70mmol), and reacted at room temperature for 16 h. Adding saturated NaHCO into the reaction solution3Solution (50mL), quench reaction, concentrate under reduced pressure to remove THF, extract with DCM (80 mL. times.2), anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 3/1) to give a colorless oil (450mg, 31.0%).
MS(ESI,pos.ion)m/z:302.1[M+H-56]+.
Step six: synthesis of (S) -2- (hydroxymethyl) -5- (4- (trifluoromethyl) phenyl) -3, 4-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester
Under the protection of nitrogen, (2S) -5-bromo-2- (hydroxymethyl) -3, 4-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (376mg,1.27mmol), [4- (trifluoromethyl) phenyl ]Boric acid (395mg,2.08mmol), Pd (dppf) Cl2(128mg,0.17mmol)，Cs2CO3(468mg,1.44mmol) was dissolved in 1, 4-dioxane (8mL) and the reaction was heated at 90 ℃ for 17 h. Celite was filtered, the mother liquor was concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 3/1) to give a yellow oil (224mg, 49.3%).
MS(ESI,pos.ion)m/z:380.1[M+Na]+.
Step seven: synthesis of tert-butyl (2S) -2- (hydroxymethyl) -5- (4- (trifluoromethyl) phenyl) piperidine-1-carboxylate
(S) -2- (hydroxymethyl) -5- (4- (trifluoromethyl) phenyl) -3, 4-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (2.60g,7.30mmol), Pd/C (3.70g,35.00mmol) was dissolved in MeOH/THF (10mL/10mL) under a hydrogen atmosphere and stirred at room temperature for 24H. Celite was filtered and concentrated under reduced pressure to give a colorless oil (2.6g, 99.0%).
MS(ESI,pos.ion)m/z:382.2[M+Na]+.
Step eight: synthesis of tert-butyl (2S,5R) -2- (hydroxymethyl) -5- (4- (trifluoromethyl) phenyl) piperidine-1-carboxylate
(2S) -2- (hydroxymethyl) -5- (4- (trifluoromethyl) phenyl) piperidine-1-carboxylic acid tert-butyl ester (4g,11.13mmol), LiOH. H2O (4.60g,110.00mmol) was dissolved in MeOH/THF/H2O (6mL/12mL/6mL) was reacted at room temperature for 21 hours. Adding H to the reaction solution2O (10mL), EtOAc (30 mL. times.2) extraction, organic layer anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 2/1) to give a colorless oil (1.0g, 25.1%).
MS(ESI,pos.ion)m/z:304.1[M+H-56]+.
Step nine: synthesis of tert-butyl (2S,5R) -2- ((difluoromethoxy) methyl) -5- (4- (trifluoromethyl) phenyl) piperidine-1-carboxylate
Tert-butyl (2S,5R) -2- (hydroxymethyl) -5- (4- (trifluoromethyl) phenyl) piperidine-1-carboxylate (1.01g,2.81mmol) was dissolved in DCM/H2O (2.2mL/2.2mL) and KOAc (1.65g,16.80mmol) was added and then (bromo (difluoro) methyl) -trimethylsilane (1.4mL,9.0mmol) was slowly added dropwise and stirred at room temperature for 18H. Adding saturated NaHCO into the reaction solution3The reaction was quenched with solution (20mL), extracted with DCM (30 mL. times.2), anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 6/1) to give a colorless oil (904mg, 79.2%).
MS(ESI,pos.ion)m/z:432.1[M+Na]+.
Step ten: synthesis of (2S,5R) -2- ((difluoromethoxy) methyl) -5- (4- (trifluoromethyl) phenyl) piperidine
Tert-butyl (2S,5R) -2- ((difluoromethoxy) methyl) -5- (4- (trifluoromethyl) phenyl) piperidine-1-carboxylate (904mg,2.21mmol) was dissolved in DCM (2mL), and a solution of HCl in 1, 4-dioxane (8mL,32.00mmol,4mol/L) was added under ice-bath and stirred at room temperature for 5 h. Distilling off under reduced pressurePartially dissolving, adding saturated NaHCO3(20mL), adjust the system pH to about 8, extract with DCM (40 mL. times.2), and extract the organic layer with anhydrous Na2SO4Dried and concentrated under reduced pressure to give a yellow oil (662mg, 97.0%).
MS(ESI,pos.ion)m/z:310.1[M+H]+.
Step eleven: synthesis of methyl 2- ((2S,5R) -2- ((difluoromethoxy) methyl) -5- (4- (trifluoromethyl) phenyl) piperidin-1-yl) thiazole-5-carboxylate
Under nitrogen protection, (2S,5R) -2- ((difluoromethoxy) methyl) -5- (4- (trifluoromethyl) phenyl) piperidine (91mg,0.30mmol), methyl 2-bromothiazole-5-carboxylate (148mg,0.67mmol), Pd2(dba)3(34mg,0.037mmol)，Ruphos(46mg,0.098mmol)，Cs2CO3(188mg,0.58mmol) was dissolved in toluene (5mL) and the reaction was heated at 110 ℃ for 20 h. Celite was filtered, concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 2/1) to give a yellow solid (54mg, 41.6%).
MS(ESI,pos.ion)m/z:451.1[M+H]+.
Step twelve: synthesis of 2- ((2S,5R) -2- ((difluoromethoxy) methyl) -5- (4- (trifluoromethyl) phenyl) piperidin-1-yl) thiazole-5-carboxylic acid
Methyl 2- ((2S,5R) -2- ((difluoromethoxy) methyl) -5- (4- (trifluoromethyl) phenyl) piperidin-1-yl) thiazole-5-carboxylate (245mg,0.54mmol), LiOH. H2O (308mg,7.34mmol) was dissolved in THF/MeOH/H2O (2mL/1mL/1mL) and reacted at room temperature for 20H. Concentrating under reduced pressure, adding 1.0M HCl solution (8mL), adjusting pH to about 4, extracting with EtOAc (30 mL. times.2), and collecting organic layer as anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: DCM/MeOH (v/v) ═ 10/1) to give a yellow solid (216mg, 91.5%).
MS(ESI,pos.ion)m/z:437.3[M+H]+.
Step thirteen: synthesis of 2- ((2S,5R) -2- ((difluoromethoxy) methyl) -5- (4- (trifluoromethyl) phenyl) piperidin-1-yl) -N- ((R) -1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) thiazole-5-carboxamide
2- ((2S,5R) -2- ((difluoromethane)Oxy) methyl) -5- (4- (trifluoromethyl) phenyl) piperidin-1-yl) thiazole-5-carboxylic acid (140mg,0.32mmol), (2R) -2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol (89mg,0.39mmol), EDCI (127mg,0.66mmol), HOBT (91mg,0.67mmol) was dissolved in DCM (5mL) and DIPEA (0.28mL, 1.70 mmol) was added and stirred at room temperature for 18 h. DCM (50mL) and saturated NH were added to the reaction solution4Cl (20 mL. times.2) wash, saturated NaCl (20mL) wash, anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: DCM/MeOH (v/v) ═ 12/1) to give a yellow solid (168mg, 80.8%).
MS(ESI,pos.ion)m/z:648.3[M+H]+.
1H NMR(400MHz,DMSO-d6)δ(ppm):8.60(d,J＝7.7Hz,1H),7.97(s,1H),7.84(d,J＝7.9Hz,2H),7.71(d,J＝7.8Hz,2H),7.62(d,J＝7.8Hz,4H),6.72(t,J＝75.7Hz,1H),5.06(d,J＝5.2Hz,2H),4.44(s,1H),4.33–4.23(m,1H),4.22–4.13(m,1H),3.93(d,J＝9.4Hz,1H),3.69(d,J＝4.4Hz,2H),3.34(s,1H),3.26(dd,J＝14.3,7.0Hz,2H),2.93(s,1H),1.89(dd,J＝43.8,13.2Hz,4H),1.10(t,J＝7.2Hz,3H).
Example 58: n- ((S) -2-cyano-1- (4- (ethylsulfonyl) phenyl) ethyl) -2- ((2S,5R) -2- ((difluoromethoxy) methyl) -5- (4- (trifluoromethyl) phenyl) piperidin-1-yl) thiazole-5-carboxamide
Figure BDA0002878710730000961
2- ((2S,5R) -2- ((difluoromethoxy) methyl) -5- (4- (trifluoromethyl) phenyl) piperidin-1-yl) thiazole-5-carboxylic acid (123mg,0.28mmol), (3S) -3-amino-3- (4- (ethylsulfonyl) phenyl) propionitrile (100mg,0.36mmol), EDCI (112mg,0.58mmol), HOBT (87mg,0.64mmol) was dissolved in DCM (5mL) and DIPEA (0.25mL,1.50mmol) was added and stirred at room temperature. DCM (50mL) and saturated NH were added to the reaction solution 4Cl (20 mL. times.2) wash, saturated NaCl (20mL) wash, anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 1/3) to give a white solid (120mg, 65%).
MS(ESI,pos.ion)m/z:657.3[M+H]+.
1H NMR(400MHz,DMSO-d6)δ(ppm):8.98(d,J＝8.1Hz,1H),7.95–7.88(m,3H),7.71(d,J＝6.2Hz,4H),7.63(d,J＝8.0Hz,2H),6.73(t,J＝75.6Hz,1H),5.45(dd,J＝14.3,7.9Hz,1H),4.46(s,1H),4.29(t,J＝9.0Hz,1H),4.18(dd,J＝10.2,6.9Hz,1H),3.95(d,J＝10.1Hz,1H),3.40(d,J＝12.4Hz,1H),3.29(dd,J＝14.7,7.3Hz,2H),3.13(qd,J＝16.8,7.6Hz,2H),2.94(t,J＝11.0Hz,1H),2.01–1.92(m,2H),1.90–1.76(m,2H),1.10(t,J＝7.3Hz,3H).
Example 59: 2- ((2S,5R) -2- ((difluoromethoxy) methyl) -5- (4- (trifluoromethyl) phenyl) piperidin-1-yl) -N- (4- (ethylsulfonyl) benzyl) thiazole-5-carboxamide
Figure BDA0002878710730000971
2- ((2S,5R) -2- ((difluoromethoxy) methyl) -5- (4- (trifluoromethyl) phenyl) piperidin-1-yl) thiazole-5-carboxylic acid (93mg,0.21mmol), (4- (ethylsulfonyl) phenyl) methylamine (82mg,0.41mmol), EDCI (91mg,0.47mmol), HOBT (68mg,0.50mmol) was dissolved in DCM (5mL,100 mass%) and DIPEA (0.18mL,1.10mmol) was added and stirred at room temperature for 17 h. DCM (50mL) and saturated NH were added to the reaction solution4Cl (20 mL. times.2) wash, saturated NaCl (20mL) wash, anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 1/3) to give a pale yellow solid (95mg, 71.8%).
MS(ESI,pos.ion)m/z:618.3[M+H]+.
1H NMR(400MHz,DMSO-d6)δ(ppm):8.90(t,J＝5.8Hz,1H),7.88–7.84(m,3H),7.72(d,J＝8.2Hz,2H),7.63(d,J＝8.1Hz,2H),7.55(d,J＝8.2Hz,2H),6.73(t,J＝75.7Hz,1H),4.51(d,J＝5.7Hz,2H),4.44(s,1H),4.28(t,J＝9.0Hz,1H),4.19(dd,J＝10.4,6.9Hz,1H),3.95(d,J＝10.6Hz,1H),3.39(d,J＝12.6Hz,1H),3.26(q,J＝7.3Hz,2H),2.94(t,J＝11.3Hz,1H),1.97–1.89(m,2H),1.87–1.74(m,2H),1.09(t,J＝7.3Hz,3H).
Example 60: n- (2- ((2S,5R) -2- ((difluoromethoxy) methyl) -5- (4- (trifluoromethyl) phenyl) piperidin-1-yl) thiazol-5-yl) -2- (4- (ethylsulfonyl) phenyl) acetamide
Figure BDA0002878710730000972
The method comprises the following steps: synthesis of 2- ((2S,5R) -2- ((difluoromethoxy) methyl) -5- (4- (trifluoromethyl) phenyl) piperidin-1-yl) -5-nitrothiazole
Under nitrogen protection, (2S,5R) -2- ((difluoromethoxy) methyl) -5- (4- (trifluoromethyl) phenyl) piperidine (197mg,0.64mmol), 2-bromo-5-nitrothiazole (425mg,2.03mmol), Pd2(dba)3(66mg,0.072mmol)，Ruphos(63mg,0.14mmol)，Cs2CO3(462mg,1.42mmol) was dissolved in toluene (5mL) and the reaction was heated at 110 ℃ for 16 h. Celite was filtered, concentrated under reduced pressure, and the crude product was isolated by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 2/1) to give a yellow oil (200mg, 71.8%).
MS(ESI,pos.ion)m/z:438.1[M+H]+.
Step two: synthesis of 2- ((2S,5R) -2- ((difluoromethoxy) methyl) -5- (4- (trifluoromethyl) phenyl) piperidin-1-yl) thiazol-5-amine
2- ((2S,5R) -2- ((difluoromethoxy) methyl) -5- (4- (trifluoromethyl) phenyl) piperidin-1-yl) -5-nitrothiazole (141mg,0.32mmol), Na2S2O4(390mg,2.02mmol) was dissolved in EtOH/H2O (6mL/3mL) and reacted at 60 ℃ for 0.5H. Adding saturated NaHCO into the reaction solution3(15mL), EtOAc (30 mL. times.2) extraction, organic layer anhydrous Na2SO4Dried and concentrated under reduced pressure to give a yellow oil (100mg, 76.1%).
MS(ESI,pos.ion)m/z:408.3[M+H]+.
Step three: synthesis of N- (2- ((2S,5R) -2- ((difluoromethoxy) methyl) -5- (4- (trifluoromethyl) phenyl) piperidin-1-yl) thiazol-5-yl) -2- (4- (ethylsulfonyl) phenyl) acetamide
2- ((2S,5R) -2- ((difluoromethoxy) methyl) -5- (4- (trifluoromethyl) phenyl) piperidin-1-yl) thiazol-5-amine (100mg,0.25mmol), 2- (4- (ethylsulfonyl) was added ) Phenyl) acetic acid (136mg,0.59mmol), EDCI (109mg,0.57mmol), HOBT (68mg,0.50mmol) was dissolved in DCM (5mL) and DIPEA (0.20mL,1.00mmol) was added and stirred at room temperature for 15 h. DCM (50mL) and saturated NH were added to the reaction solution4Cl (20 mL. times.2) wash, saturated NaCl (20mL) wash, anhydrous Na2SO4Drying, concentration under reduced pressure and separation of the crude product by silica gel column chromatography (eluent: PE/EtOAc (v/v) ═ 1/2) gave 40mg of a brown solid and preparative separation gave a yellow solid (11mg, 7.2%). MS (ESI, pos. ion) M/z 618.0[ M + H ]]+.
1H NMR(400MHz,DMSO-d6)δ(ppm):11.10(s,1H),7.84(d,J＝8.2Hz,2H),7.70(d,J＝8.2Hz,2H),7.58(dd,J＝13.5,8.2Hz,4H),6.89(s,1H),6.61(d,J＝75.8Hz,1H),4.31–4.26(m,1H),4.21–4.14(m,2H),3.79(d,J＝3.7Hz,1H),3.76(s,2H),3.30(d,J＝5.9Hz,1H),3.25(dd,J＝18.8,11.1Hz,3H),2.90(t,J＝11.5Hz,1H),1.98–1.89(m,2H),1.81(t,J＝15.0Hz,2H),1.10(t,J＝7.3Hz,3H).
Example 61: (R) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -2- (4- (4- (trifluoromethyl) benzyl) -1, 4-diazepan-1-yl) thiazole-5-carboxamide
Figure BDA0002878710730000981
The method comprises the following steps: synthesis of 1- (4- (trifluoromethyl) benzyl) -1, 4-diazepane
1, 4-diazepane (1.01g,10.1mmol) and K2CO3(900mg,5.03mmol) was dissolved in ACN (15mL,287mmol) and 1- (bromomethyl) -4- (trifluoromethyl) benzene (1.00g,4.18mmol) was added and the reaction stirred at room temperature for 16 h. After completion of the reaction, the reaction mixture was diluted with DCM (30mL) and successively saturated Na2CO3The solution (20mL) was washed with saturated NaCl solution (25mL) and dried over anhydrous Na2SO4Dried, filtered and concentrated under reduced pressure, and the crude product was isolated by column chromatography on silica gel (eluent: PE/EtOAc (v/v) ═ 1/1) to give a colorless liquid (600mg, 56%). MS (ESI, pos. ion) M/z 259.1[ M + H ] ]+.
Step two: synthesis of methyl 2- (4- (4- (trifluoromethyl) benzyl) -1, 4-diazepan-1-yl) thiazole-5-carboxylate
1- (4- (trifluoromethyl) benzyl) -1, 4-diazepane (600mg,2.32mmol) and K2CO3(1.30g,7.30mmol) was dissolved in ACN (10mL), the reaction mixture was stirred at room temperature and methyl 2-bromothiazole-5-carboxylate (620mg,2.79mmol) was added dropwise, and the reaction mixture was heated to 75 ℃ for reaction for 10 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was diluted with DCM (40mL) and saturated Na2CO3The solution (30mL) was washed with saturated NaCl solution (35mL) and dried over anhydrous Na2SO4Dried, filtered and concentrated under reduced pressure, and the crude product was isolated by column chromatography on silica gel (eluent: PE/EtOAc (v/v) ═ 3/1) to give a white solid (900mg, 97%).
MS(ESI,pos.ion)m/z:400.1[M+H]+.
Step three: synthesis of 2- (4- (4- (trifluoromethyl) benzyl) -1, 4-diazepan-1-yl) thiazole-5-carboxylic acid
Methyl 2- (4- (4- (trifluoromethyl) benzyl) -1, 4-diazepan-1-yl) thiazole-5-carboxylate (900mg,2.25mmol) was dissolved in MeOH (5mL), LiOH (910mg,21.25mmol) was added and the reaction stirred at room temperature for 13 h. After completion of the reaction, HCl solution (5.5mL,0.1mol/L) was added to the reaction mixture, the mixture was extracted with DCM (20 mL. times.3), the organic phases were combined and washed with saturated NaCl solution (15mL), anhydrous Na 2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by column chromatography on silica gel (eluent: DCM/EtOAc (v/v) ═ 1/1) to give a white solid (770mg, 89%).
MS(ESI,pos.ion)m/z:386.1[M+H]+.
Step four: synthesis of (R) -N- (1- (4- (ethylsulfonyl) phenyl) -2-hydroxyethyl) -2- (4- (4- (trifluoromethyl) benzyl) -1, 4-diazepan-1-yl) thiazole-5-carboxamide
(2R) -2-amino-2- (4- (ethylsulfonyl) phenyl) ethanol (79mg,0.34mmol), 2- (4- (4- (trifluoromethyl) benzyl) -1, 4-diazepan-1-yl) thiazole-5-carboxylic acid (150mg,0.39mmol), HATU (180mg,0.46mmol) and DIPEA (0.3mL,1.70mmol) were dissolved in DCM (10mL) and the reaction solution was allowed to react warm for 15 h. After the reaction was complete, the reaction was diluted with DCM (40mL) and concentratedRepeatedly using saturated NaHCO3The solution (33mL) and saturated NaCl solution (45mL) were washed and the organic phase was washed with anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was chromatographed on silica gel (eluent: DCM/EtOAc (v/v) ═ 1/1) to give a white solid (110mg, 47%).
MS(ESI,pos.ion)m/z:597.2[M+H]+.
1H NMR(400MHz,CDCl3)δ(ppm):8.01(s,1H),7.81(d,J＝8.2Hz,2H),7.74(d,J＝8.1Hz,2H),7.51(d,J＝8.2Hz,2H),7.37(dd,J＝8.6,2.0Hz,1H),7.24(d,J＝4.0Hz,1H),7.20(d,J＝8.0Hz,3H),7.13(td,J＝8.9,2.2Hz,1H),5.61(s,2H),5.21(d,J＝6.4Hz,1H),3.94(ddd,J＝15.9,11.2,4.1Hz,2H),3.07(q,J＝7.4Hz,2H),1.25(t,J＝7.4Hz,3H).
Example 62: (S) -N- (2-cyano-1- (4- (ethylsulfonyl) phenyl) ethyl) -2- (4- (4- (trifluoromethyl) benzyl) -1, 4-diazepan-1-yl) thiazole-5-carboxamide
Figure BDA0002878710730000991
(3S) -3-amino-3- (4- (ethylsulfonyl) phenyl) propionitrile (102mg,0.43mmol), 2- (4- (4- (trifluoromethyl) benzyl) -1, 4-diazepan-1-yl) thiazole-5-carboxylic acid (147mg,0.38mmol), HATU (190mg,0.49mmol) and DIPEA (0.3mL,1.70mmol) were dissolved in DCM (10mL) and reacted at room temperature for 16 h. The reaction was diluted with DCM (40mL) and successively with saturated NaHCO 3The solution (30mL) and saturated NaCl solution (40mL) were washed and the organic phase was washed with anhydrous Na2SO4Dried and concentrated under reduced pressure, and the crude product was isolated by column chromatography on silica gel (eluent: DCM/EtOAc (v/v) ═ 1/1) to give a white solid (90mg, 39%).
MS(ESI,pos.ion)m/z:606.2[M+H]+.
1H NMR(400MHz,CDCl3)δ(ppm):7.84(d,J＝8.3Hz,2H),7.77(s,1H),7.60(d,J＝8.3Hz,2H),7.56(d,J＝8.1Hz,2H),7.43(d,J＝8.0Hz,2H),6.95(d,J＝7.8Hz,1H),5.53(dd,J＝13.7,6.4Hz,1H),3.67(t,J＝16.5Hz,6H),3.15–3.03(m,4H),2.80–2.72(m,2H),2.70–2.60(m,2H),2.03–1.93(m,2H),1.26(t,J＝7.3Hz,3H).
Biological activity assay
Biological example 1 Fluorescence Resonance Energy Transfer (FRET) assay
1) Test method
(1) ROR gamma t experiment buffer and 10mM DTT are prepared
100mL of 1 Xbasic assay buffer HEPES (pH 7.4), (100mM NaCl, 0.01% BSA) was prepared, and 154.25mg of DTT was added and mixed well.
(2) Formulation of gradient concentrations of Compounds
a. Standard compounds were prepared, diluted to 2.5mM with 100% DMSO, then 3-fold diluted, 11-step dilutions to a final concentration of 42.34 nM;
b. experimental compounds were prepared with reference to standard compounds.
(3) Preparation of 1x protein solution mixture
a. The required amount of 2x B-ROR γ t LBD/SA-APC protein mixture was formulated. The concentration of B-ROR γ LBD was 40nM and the concentration of SA-APC was 20nM, mixed by gentle inversion and incubated for 15 min at room temperature. Then adding 400nM biotin, mixing by gentle inversion, and incubating for 10 min at room temperature;
b. the required amount of 2X Biotin-SRC1/SA-eu protein mixture was formulated. Bioin-SRC1 was 40nM and SA-eu was 20nM, mixed by gentle inversion and incubated for 15 min at room temperature. Then adding 200nM biotin, mixing by gentle inversion, and incubating for 10 min at room temperature;
c.1:1, mixing the protein mixture prepared in the step a and the step b uniformly, and incubating for 5 minutes at room temperature;
d. adding 25 μ L of the mixture of step c to a 384 well plate containing the test compound;
e.1000rpm for one minute;
f. incubate at room temperature for 1 hour.
(4) Data collection and computation
After 1 hour of incubation at room temperature, the fluorescence values at 665nm and 615nm were measured with an EnVision plate reader, respectively, and the inhibition was calculated to obtain the IC50The values are shown in Table 1;
the inhibition ratio (%) [ (X-Min)/(Max-Min) ]. times.100%
X is the ratio of the fluorescence values of "665 nm/615 nm" of the test compounds; min is the average value of the ratio of the fluorescence values of "665 nm/615 nm" of the DMSO blank; max is the mean value of the ratio of fluorescence values of "665 nm/615 nm" for 10. mu.M SRC.
2) Test results
Table 1 evaluation of inhibitory Activity of the Compounds of the present invention on ROR γ t
Example numbering IC50(nM) Example numbering IC50(nM)
Example 2 114 Example 6 62
Example 13 104 Example 16 32.4
Example 21 10.8 Example 22 87
Example 26 4.8 Practice ofExample 27 63
Example 29 15 Example 32 61
Example 34 87 Example 38 32
Example 42 58 Example 43 87
Example 44 41 Example 45 83
Example 47 22 Example 56 82
Example 57 55 Example 58 25
Example 59 30 / /
And (4) conclusion: experimental results show that the compound has good inhibitory activity on ROR gamma t.
Biological example 2 pharmacokinetic evaluation
ICR mice are fasted overnight for 15h and then weighed, and randomly grouped according to body weight, and the tested compound is prepared into a solvent of 5% DMSO + 5% Solutol + 90% Saline. For the test group administered intravenously, the test animals were given a dose of 1 mg/kg; for the orally administered test group, the test animals were given a dose of 5 mg/kg. Venous blood (approximately 0.2mL) was then taken at time points 0, 0.083 (intravenous only group), 0.25, 0.5, 1.0, 2.0, 5.0, 7.0 and 24h and placed in the EDTAK2In an anticoagulation tube, centrifuge at 11000rpm for 2min, collect plasma, and store at-20 ℃ or-70 ℃ until LC/MS/MS analysis. The drug concentration in plasma was measured at each time point and pharmacokinetic parameters were calculated from the drug concentration-time curve.
The pharmacokinetic properties of the compounds of the invention were tested by the above assay. The experimental result shows that the compound has good pharmacokinetic characteristics in an ICR mouse.
Finally, it should be noted that there are other ways of implementing the invention. Accordingly, the embodiments of the present invention will be described by way of illustration, but not limitation to the description of the present invention, and modifications made within the scope of the present invention or equivalents added to the claims are possible. All publications or patents cited herein are incorporated by reference.

Claims (24)

1. A compound which is a compound represented by formula (I) or a stereoisomer, a geometric isomer, a tautomer, a nitrogen oxide, a hydrate, a solvate, a metabolite, an ester, a pharmaceutically acceptable salt of a compound represented by formula (I), or a prodrug thereof,
Figure FDA0002878710720000011
wherein:
L1is a bond, -O-, -S-, -NH-, -C (═ O) -or- (CR)aRb)n-；
L2Is a word about-S (O)2-NH-、*-NH-S(O)2- (O) -NH-, - (NH-s) (O) -, - (C (═ O) NH-, or ═ NHC (═ O) -;
L3is one x-N (R)g)-C(＝O)-、**-C(＝O)-N(Rg)-、**-O-C(＝O)-、**-C(＝O)-O-、**-C(＝O)-、**-S(＝O)2-、**-S(＝O)-、**-S(＝O)2N(Rg) -or-S (═ O) (═ NH);
Raand RbEach independently is H, deuterium, F, Cl, Br, I, C1-6Alkyl or C1-6A haloalkyl group;
a is-C0-6alkylene-C6-10Aryl radical, -C0-6Alkylene- (5-10 atom-constituting heteroaryl), -C0-6alkylene-C3-8Cycloalkyl, -C0-6Alkylene- (heterocyclic group consisting of 5 to 10 atoms), -C0-6Alkylene- (7-12 atom spiro carbocyclyl), -C0-6Alkylene- (7-12 atom spiroheterocyclyl) or C1-6An alkyl group; wherein A is substituted by 1, 2, 3, 4, 5 or 6R1Substitution;
ring B is a heterocyclic group consisting of 5 to 10 atoms; wherein said B ring is optionally substituted with 1, 2, 3, 4, 5 or 6R2Substitution;
the C ring is heteroaryl consisting of 5 atoms; wherein said C ring is optionally substituted with 1, 2 or 3R3Substitution;
D ring is C6-10Aryl, heteroaryl of 5 to 10 atoms, C3-8Cycloalkyl or heterocyclyl consisting of 5 to 10 atoms; wherein said D ring is optionally substituted with 1, 2, 3, 4, 5 or 6R4Substitution;
R1and R2Each independently is deuterium, F, Cl, Br, I, -CN, -NH2、-NO2-OH, -COOH, oxo, C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, -C1-6alkylene-O-C1-6Alkyl radical, C3-8Cycloalkyl radical, C6-10Aryl, heterocyclyl of 5 to 10 atoms, heteroaryl of 5 to 10 atoms or-C (═ O) -N (R)dRe) (ii) a Wherein, said C1-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Haloalkoxy, -C1-6alkylene-O-C1-6Alkyl radical, C3-8Cycloalkyl radical, C6-10Aryl, heterocyclyl of 5-10 atoms and heteroaryl of 5-10 atoms are independently optionally substituted with 1, 2, 3, 4, 5 or 6RcSubstituted;
each RcIndependently deuterium, F, Cl, Br, I, -OH, -CN, -NH2、C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Haloalkyl, C1-6Haloalkoxy, C3-8Cycloalkyl, heterocyclic radical consisting of 5-10 atoms, C6-10Aryl or heteroaryl of 5 to 10 atoms;
R3and R4Each independently is deuterium, F, Cl, Br, I, -CN, -NH2、-NO2、-OH、-COOH、C1-6Alkyl radical, C 2-6Alkenyl radical, C2-6Alkynyl, C1-6Haloalkoxy, C1-6Haloalkyl or C1-6An alkoxy group;
R5and R6Each independently of the others being H, deuterium, -OH, -CN, -NH2、-NO2、-COOH、C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Haloalkyl, -C1-6alkylene-O-C1-6Alkyl, -C1-6alkylene-C (═ O) -O-C1-6Alkyl, -C1-6alkylene-C (═ O) -N (R)dRe)、-C1-6alkylene-O-C (═ O) -N (R)dRe)、-C1-6alkylene-N (R)f)-C(＝O)-N(RdRe) or-C1-6alkylene-N (R)dRe) (ii) a It is composed ofIn (b), the C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Haloalkyl, -C1-6alkylene-C (═ O) -O-C1-6Alkyl and-C1-6alkylene-O-C1-6Alkyl is independently optionally substituted by 1, 2 or 3 substituents selected from deuterium, F, Cl, Br, I, -OH, -CN, -COOH, -N (R)dRe)、C1-6Alkyl radical, C1-6Haloalkyl, C1-6Alkoxy or C1-6Substituted with a substituent of haloalkoxy;
or R5、R6Together with the carbon atom to which they are attached form C3-8Cycloalkyl or heterocyclyl consisting of 3 to 8 atoms; wherein, said C3-8Cycloalkyl and heterocyclyl consisting of 3 to 8 atoms are independently optionally substituted by 1, 2, 3 or 4 substituents selected from deuterium, F, Cl, Br, I, -OH, -CN, -COOH, C1-6Alkyl radical, C1-6Haloalkyl, C1-6Alkoxy or C1-6Substituted with a substituent of haloalkoxy;
Rdand ReEach independently of the others being H, deuterium, -OH, C1-6Alkyl, -C (═ O) H, -C (═ O) -O-C1-6Alkyl, -C (═ O) -C1-6Alkyl, -C 1-6alkylene-C (═ O) -O-C1-6Alkyl or-C1-6alkylene-O-C1-6An alkyl group; wherein, said C1-6Alkyl, -C1-6alkylene-C (═ O) -O-C1-6Alkyl and-C1-6alkylene-O-C1-6Alkyl is independently optionally substituted by 1,2 or 3 substituents selected from deuterium, F, Cl, Br, I, -OH, -CN, -NH2or-COOH;
each RfIndependently of one another H, deuterium, C1-6Alkyl, -C1-6alkylene-O-C1-6Alkyl, -C1-6alkylene-C3-8Cycloalkyl or-C1-6Alkylene- (5-10 atom-constituting heterocyclic group); wherein, said C1-6Alkyl, -C1-6alkylene-O-C1-6Alkyl, -C1-6alkylene-C3-8Cycloalkyl and-C1-6Alkylene- (heterocyclyl consisting of 5 to 10 atoms) is independently optionally substituted by 1,2 or 3 substituents selected from deuterium, F, Cl, Br, I, -OH, -CN, -NH2or-COOH;
R7is H, deuterium, -COOH, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkylamino radical, C1-6Haloalkyl, C3-8Cycloalkyl radical, C3-8Cycloalkylamino or heterocyclyl consisting of 5 to 10 atoms;
Rgis H, deuterium or C1-6An alkyl group;
m is 0, 1,2, 3 or 4;
n is 1,2, 3 or 4.
2. The compound of claim 1, wherein RaAnd RbEach independently of the others is H, deuterium, F, Cl, Br, I, methyl, ethyl, n-propyl, isopropyl, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2, 2-difluoroethyl, 1, 2-difluoroethyl, 2,2, 2-trifluoroethyl, monochloromethyl, dichloromethyl, 2-chloroethyl, 2, 2-dichloroethyl or 1, 2-dichloroethyl.
3. The compound of claim 1, wherein a is-C0-4alkylene-C6-10Aryl radical, -C0-4Alkylene- (5-6-atom heteroaryl), -C0-4alkylene-C3-6Cycloalkyl, -C0-4Alkylene- (heterocyclic group consisting of 5 to 7 atoms), -C0-4Alkylene- (7-12 atom spiro carbocyclyl), -C0-4Alkylene- (7-12 atom spiroheterocyclyl) or C1-4An alkyl group; wherein A is substituted by 1, 2, 3, 4, 5 or 6R1And (4) substitution.
4. The compound of claim 1, wherein A is phenyl, naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolyl, pyrazolyl, imidazolyl, furyl, oxazolyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperazinyl, pyridazinyl, pyrazolyl, imidazolyl, furyl, oxazolyl, thienyl, and the like,
Figure FDA0002878710720000021
Figure FDA0002878710720000022
Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; wherein A is substituted by 1, 2, 3, 4, 5 or 6R1And (4) substitution.
5. The compound of claim 1, wherein ring B is heterocyclyl consisting of 5-7 atoms; wherein said B ring is optionally substituted with 1, 2, 3, 4, 5 or 6R2And (4) substituting.
6. The compound of claim 1, wherein ring B is
Figure FDA0002878710720000023
Figure FDA0002878710720000024
Figure FDA0002878710720000025
Wherein said B ring is optionally substituted with 1, 2, 3, 4, 5 or 6R2And (4) substituting.
7. The compound of claim 1, wherein ring C is
Figure FDA0002878710720000031
Figure FDA0002878710720000032
Wherein said C is optionally substituted with 1, 2 or 3R3And (4) substitution.
8. The compound of claim 1, wherein the D ring is C6-10Aryl, heteroaryl of 5 to 6 atoms, C3-6Cycloalkyl or heterocyclyl consisting of 5 to 7 atoms; wherein said D ring is optionally substituted with 1, 2, 3, 4, 5 or 6R4And (4) substitution.
9. The compound of claim 1, wherein ring D is phenyl, naphthyl, indolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazolyl, pyrazolyl, imidazolyl, furanyl, oxazolyl, cyclopentyl, cyclohexyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, or piperazinyl; wherein D is optionally substituted with 1, 2, 3, 4, 5 or 6R4And (4) substitution.
10. The compound of claim 1, wherein R1And R2Each independently is deuterium, F, Cl, Br, I, -CN, -NH2、-NO2-OH, -COOH, oxo, C1-4Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C1-4Haloalkyl, C1-4Alkoxy radical, C1-4Haloalkoxy, -C1-4alkylene-O-C 1-4Alkyl radical, C3-6Cycloalkyl radical, C6-10Aryl, heterocyclyl of 5 to 7 atoms, heteroaryl of 5 to 6 atoms or-C (═ O) -N (R)dRe) (ii) a Wherein, said C1-4Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C1-4Haloalkyl, C1-4Alkoxy radical, C1-4Haloalkoxy, -C1-4alkylene-O-C1-4Alkyl radical, C3-6Cycloalkyl radical, C6-10Aryl, heterocyclyl of 5-7 atoms and heteroaryl of 5-6 atoms are independently optionally substituted with 1, 2, 3, 4, 5 or 6RcSubstituted;
each RcIndependently deuterium, F, Cl, Br, I, -OH, -CN, -NH2、C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl, C1-4Haloalkoxy, C3-6Cycloalkyl, heterocyclic radical of 5-7 atoms, C6-10Aryl or heteroaryl of 5 to 6 atoms.
11. The compound of claim 1, wherein R3And R4Each independently is deuterium, F, Cl, Br, I, -CN, -NH2、-NO2、-OH、-COOH、C1-4Alkyl radical, C2-4Alkenyl radical, C2-4Alkynyl, C1-4Haloalkoxy, C1-4Haloalkyl or C1-4An alkoxy group.
12. The compound of claim 1, wherein R5And R6Each independently of the others being H, deuterium, -OH, -CN, -NH2、-NO2、-COOH、C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl, -C1-4alkylene-O-C1-4Alkyl, -C1-4alkylene-C (═ O) -O-C1-4Alkyl, -C1-4alkylene-C (═ O) -N (R)dRe)、-C1-4alkylene-O-C (═ O) -N (R) dRe)、-C1-4alkylene-N (R)f)-C(＝O)-N(RdRe) or-C1-4alkylene-N (R)dRe) (ii) a Wherein, said C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Haloalkyl, -C1-4alkylene-C (═ O) -O-C1-4Alkyl and-C1-4alkylene-O-C1-4Alkyl is independently optionally substituted with deuterium, F, Cl, Br, I, -OH, -CN, -COOH, -N (R)dRe)、C1-4Alkyl radical, C1-4Haloalkyl, C1-4Alkoxy or C1-4Substituted with a substituent of haloalkoxy;
or R5And R6Together with the carbon atoms to which they are jointly attached form C3-6Cycloalkyl or heterocyclyl consisting of 3 to 6 atoms; wherein, said C3-6Cycloalkyl and heterocyclyl consisting of 3 to 6 atoms are independently optionally substituted by 1, 2, 3 or 4 substituents selected from deuterium, F, Cl, Br, I, -OH, -CN, -COOH, C1-4Alkyl radical, C1-4Haloalkyl, C1-4Alkoxy or C1-4A haloalkoxy group.
13. The compound of claim 1, wherein RdAnd ReEach independently of the others being H, deuterium, -OH, C1-4Alkyl, -C (═ O) H, -C (═ O) -O-C1-4Alkyl, -C (═ O) -C1-4Alkyl, -C1-4alkylene-C (═ O) -O-C1-4Alkyl or-C1-4alkylene-O-C1-4An alkyl group; wherein, said C1-4Alkyl, -C1-4alkylene-C (═ O) -O-C1-4Alkyl and-C1-4alkylene-O-C1-4Alkyl is independently optionally substituted by 1, 2 or 3 substituents selected from deuterium, F, Cl, Br, I, -OH, -CN, -NH2or-COOH;
Each RfIndependently of one another H, deuterium, C1-4Alkyl, -C1-4alkylene-O-C1-4Alkyl, -C1-4alkylene-C3-6Cycloalkyl or-C1-4Alkylene- (5-7 atom-constituting heterocyclic group); wherein, said C1-4Alkyl, -C1-4alkylene-O-C1-4Alkyl, -C1-4alkylene-C3-6Cycloalkyl and-C1-4Alkylene- (heterocyclyl consisting of 5 to 7 atoms) is independently optionally substituted by 1, 2 or 3 substituents selected from deuterium, F, Cl, Br, I, -OH, -CN, -NH2Or a substituent of-COOH.
14. The compound of claim 1, wherein R7Is H, deuterium, -COOH, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Alkylamino radical, C1-4Haloalkyl, C3-6Cycloalkyl radical, C3-6Cycloalkylamino or heterocyclyl consisting of 5 to 7 atoms;
Rgis H, deuterium or C1-4An alkyl group.
15. The compound of claim 1, wherein R1And R2Each independently is deuterium, F, Cl, Br, I, -CN, -NH2、-NO2OH, -COOH, oxo, methyl, ethyl, n-propyl, isopropyl and n-butylAlkyl, isobutyl, sec-butyl, tert-butyl, ethenyl, ethynyl, -CH2F、-CH2Cl、-CHF2、-CHCl2、-CF3、-CH2CH2F、-CH2CH2Cl、-CH2CHF2、-CH2CHCl2、-CHFCH2F、-CHClCH2Cl、-CH2CF3、-CH(CF3)2、-CF2CH2CH3、-CH2CH2CH2F、-CH2CH2CHF2、-CH2CH2CF3Methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, -OCH2F、-OCH2Cl、-OCHF2、-OCHCl2、-OCF3、-OCH2CH2F、-OCH2CH2Cl、-OCH2CHF2、-OCH2CHCl2、-OCHFCH2F、-OCHClCH2Cl、-OCH2CF3、-OCH(CF3)2、-OCF2CH2CH3、-OCH2CH2CH2F、-OCH2CH2CHF2、-OCH2CH2CF3、-CH2OCH3、-CH2OCH2CH3、-CH2OCH2CH2CH3、-CH2OCH(CH3)2、-CH2CH2OCH3、-CH2CH2OCH2CH3、-CH2CH2OCH2CH2CH3、-CH2CH2OCH(CH3)2、-CH2CH2CH2OCH3、-CH2CH2CH2OCH2CH3、-CH2CH2CH2OCH2CH2CH3、-CH2CH2CH2OCH(CH3)2Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, pyridyl, pyrimidyl Pyrazolyl, thiazolyl, imidazolyl, oxazolyl, triazolyl, tetrazolyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, pyrrolidinyl or-C (═ O) -N (R)dRe)；
Wherein, the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, vinyl and-CH2F、-CH2Cl、-CHF2、-CHCl2、-CH2CH2F、-CH2CH2Cl、-CH2CHF2、-CH2CHCl2、-CHFCH2F、-CHClCH2Cl、-CH2CF3、-CH(CF3)2、-CF2CH2CH3、-CH2CH2CH2F、-CH2CH2CHF2、-CH2CH2CF3Methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, -OCH2F、-OCH2Cl、-OCHF2、-OCHCl2、-OCH2CH2F、-OCH2CH2Cl、-OCH2CHF2、-OCH2CHCl2、-OCHFCH2F、-OCHClCH2Cl、-OCH2CF3、-OCH(CF3)2、-OCF2CH2CH3、-OCH2CH2CH2F、-OCH2CH2CHF2、-OCH2CH2CF3、-CH2OCH3、-CH2OCH2CH3、-CH2OCH2CH2CH3、-CH2OCH(CH3)2、-CH2CH2OCH3、-CH2CH2OCH2CH3、-CH2CH2OCH2CH2CH3、-CH2CH2OCH(CH3)2、-CH2CH2CH2OCH3、-CH2CH2CH2OCH2CH3、-CH2CH2CH2OCH2CH2CH3、-CH2CH2CH2OCH(CH3)2Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazolyl, thiazolyl, imidazolyl, oxazolyl, triazolyl, tetrazolyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl and pyrrolidinyl being independently optionally substituted by 1, 2, 3, 4, 5 or 6RcSubstituted;
each RcIndependently deuterium, F, Cl, Br, I, -OH, -CN, -NH2Methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, -CH2F、-CHF2、-CF3、-CH2CH2F、-CH2CHF2、-CHFCH2F、-CH2CF3、-CH(CF3)2、-CF2CH2CH3、-CH2CH2CH2F、-CH2CH2CHF2、-CH2CH2CF3Methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, -OCH2F、-OCHF2、-OCF3、-OCH2CH2F、-OCH2CHF2、-OCHFCH2F、-OCH2CF3、-OCH(CF3)2、-OCF2CH2CH3、-OCH2CH2CH2F、-OCH2CH2CHF2、-OCH2CH2CF3Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, pyridyl, pyrimidinyl, pyrazolyl, thiazolyl, imidazolyl, oxazolyl, triazolyl, tetrazolyl, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl or pyrrolidinyl.
16. The compound of claim 1, wherein R3And R4Each independently is deuterium, F, Cl, Br, I, CN, NH2、NO2OH, COOH, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, vinyl, ethynyl, -CH2F、-CH2Cl、-CHF2、-CHCl2、-CF3、-CH2CH2F、-CH2CH2Cl、-CH2CHF2、-CH2CHCl2、-CHFCH2F、-CHClCH2Cl、-CH2CF3、-CH(CF3)2、-CF2CH2CH3、-CH2CH2CH2F、-CH2CH2CHF2、-CH2CH2CF3、-OCH2F、-OCH2Cl、-OCHF2、-OCHCl2、-OCF3、-OCH2CH2F、-OCH2CH2Cl、-OCH2CHF2、-OCH2CHCl2、-OCHFCH2F、-OCHClCH2Cl、-OCH2CF3、-OCH(CF3)2、-OCF2CH2CH3、-OCH2CH2CH2F、-OCH2CH2CHF2、-OCH2CH2CF3Methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy or tert-butoxy.
17. The compound of claim 1, wherein R5And R6Each independently of the others being H, deuterium, -OH, -CN, -NH2、-NO2-COOH, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, -CH2F、-CH2Cl、-CHF2、-CHCl2、-CF3、-CH2CH2F、-CH2CH2Cl、-CH2CHF2、-CH2CHCl2、-CHFCH2F、-CH2OCH3、-CH2OCH2CH3、-CH2OCH2CH2CH3、-CH2OCH(CH3)2、-CH2CH2OCH3、-CH2CH2OCH2CH3、-CH2CH2OCH2CH2CH3、-CH2CH2OCH(CH3)2、-CH2CH2CH2OCH3、-CH2CH2CH2OCH2CH3、-CH2CH2CH2OCH2CH2CH3、-CH2CH2CH2OCH(CH3)2、-CH2-C(＝O)-OCH3、-CH2-C(＝O)-OCH2CH3、-CH2-C(＝O)-OCH2CH2CH3、-CH2-C(＝O)-OCH(CH3)2、-CH2CH2-C(＝O)-OCH3、-CH2CH2-C(＝O)-OCH2CH3、-CH2CH2-C(＝O)-OCH2CH2CH3、-CH2CH2-C(＝O)-OCH(CH3)2、-CH2CH2CH2-C(＝O)-OCH3、-CH2CH2CH2-C(＝O)-OCH2CH3、-CH2CH2CH2-C(＝O)-OCH2CH2CH3、-CH2CH2CH2-C(＝O)-OCH(CH3)2、-CH2-C(＝O)-N(RdRe)、-CH2CH2-C(＝O)-N(RdRe)、-CH2CH2CH2-C(＝O)-N(RdRe)、-CH2-O-C(＝O)-N(RdRe)、-CH2CH2-O-C(＝O)-N(RdRe)、-CH2CH2CH2-O-C(＝O)-N(RdRe)、-CH2-N(Rf)-C(＝O)-N(RdRe)、-CH2CH2-N(Rf)-C(＝O)-N(RdRe)、-CH2CH2CH2-N(Rf)-C(＝O)-N(RdRe)、-CH2N(RdRe)、-CH2CH2N(RdRe) or-CH2CH2CH2N(RdRe)；
Wherein, the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, -CH2F、-CH2Cl、-CHF2、-CHCl2、-CF3、-CH2CH2F、-CH2CH2Cl、-CH2CHF2、-CH2CHCl2、-CHFCH2F、-CH2-C(＝O)-OCH3、-CH2-C(＝O)-OCH2CH3、-CH2-C(＝O)-OCH2CH2CH3、-CH2-C(＝O)-OCH(CH3)2、-CH2CH2-C(＝O)-OCH3、-CH2CH2-C(＝O)-OCH2CH3、-CH2CH2-C(＝O)-OCH2CH2CH3、-CH2CH2-C(＝O)-OCH(CH3)2、-CH2CH2CH2-C(＝O)-OCH3、-CH2CH2CH2-C(＝O)-OCH2CH3、-CH2CH2CH2-C(＝O)-OCH2CH2CH3、-CH2CH2CH2-C(＝O)-OCH(CH3)2、-CH2OCH3、-CH2OCH2CH3、-CH2OCH2CH2CH3、-CH2OCH(CH3)2、-CH2CH2OCH3、-CH2CH2OCH2CH3、-CH2CH2OCH2CH2CH3、-CH2CH2OCH(CH3)2、-CH2CH2CH2OCH3、-CH2CH2CH2OCH2CH3、-CH2CH2CH2OCH2CH2CH3and-CH2CH2CH2OCH(CH3)2Independently optionally substituted by 1, 2 or 3 substituents selected from deuterium, F, Cl, Br, I, -OH, -CN, -COOH, -N (R)dRe) Methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, trifluoromethyl, -OCH 2F、-OCH2Cl、-OCHF2、-OCHCl2、-OCF3、-OCH2CH2F、-OCH2CH2Cl、-OCH2CHF2、-OCH2CHCl2、-OCHFCH2F、-OCHClCH2Cl、-OCH2CF3、-OCH(CF3)2、-OCF2CH2CH3、-OCH2CH2CH2F、-OCH2CH2CHF2or-OCH2CH2CF3Substituted with the substituent(s);
or R5、R6And together with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl or tetrahydropyranyl group; wherein said cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, and tetrahydropyranyl are independently optionally substituted with 1, 2, 3, or 4 substituents selected from deuterium, F, Cl, Br, I, -OH, -CN, -COOH, methyl, ethyl, isopropyl, trifluoromethyl, methoxy, or trifluoromethoxy.
18. The compound of claim 1, wherein RdAnd ReEach independently is H, deuterium, -OH, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, -C (═ O) H, -C (═ O) -O-CH3、-C(＝O)-O-CH2CH3、-C(＝O)-O-CH2CH2CH3、-C(＝O)-O-CH(CH3)2、-C(＝O)-CH3、-C(＝O)-CH2CH3、-C(＝O)-CH2CH2CH3、-C(＝O)-CH(CH3)2、-CH2OCH3、-CH2OCH2CH3、-CH2OCH2CH2CH3、-CH2OCH(CH3)2、-CH2CH2OCH3、-CH2CH2OCH2CH3、-CH2CH2OCH2CH2CH3、-CH2CH2OCH(CH3)2、-CH2CH2CH2OCH3、-CH2CH2CH2OCH2CH3、-CH2CH2CH2OCH2CH2CH3、-CH2CH2CH2OCH(CH3)2、-CH2-C(＝O)-OCH3、-CH2-C(＝O)-OCH2CH3、-CH2-C(＝O)-OCH2CH2CH3、-CH2-C(＝O)-OCH(CH3)2、-CH2CH2-C(＝O)-OCH3、-CH2CH2-C(＝O)-OCH2CH3、-CH2CH2-C(＝O)-OCH2CH2CH3、-CH2CH2-C(＝O)-OCH(CH3)2、-CH2CH2CH2-C(＝O)-OCH3、-CH2CH2CH2-C(＝O)-OCH2CH3、-CH2CH2CH2-C(＝O)-OCH2CH2CH3or-CH2CH2CH2-C(＝O)-OCH(CH3)2；
Wherein, the methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, -CH2OCH3、-CH2OCH2CH3、-CH2OCH2CH2CH3、-CH2OCH(CH3)2、-CH2CH2OCH3、-CH2CH2OCH2CH3、-CH2CH2OCH2CH2CH3、-CH2CH2OCH(CH3)2、-CH2CH2CH2OCH3、-CH2CH2CH2OCH2CH3、-CH2CH2CH2OCH2CH2CH3、-CH2CH2CH2OCH(CH3)2、-CH2-C(＝O)-OCH3、-CH2-C(＝O)-OCH2CH3、-CH2-C(＝O)-OCH2CH2CH3、-CH2-C(＝O)-OCH(CH3)2、-CH2CH2-C(＝O)-OCH3、-CH2CH2-C(＝O)-OCH2CH3、-CH2CH2-C(＝O)-OCH2CH2CH3、-CH2CH2-C(＝O)-OCH(CH3)2、-CH2CH2CH2-C(＝O)-OCH3、-CH2CH2CH2-C(＝O)-OCH2CH3、-CH2CH2CH2-C(＝O)-OCH2CH2CH3and-CH2CH2CH2-C(＝O)-OCH(CH3)2Independently optionally substituted by 1, 2 or 3 substituents selected from deuterium, F, Cl, Br, I, -OH, -CN, -NH2or-COOH;
each RfIndependently H, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, -CH 2OCH3、-CH2OCH2CH3、-CH2OCH2CH2CH3、-CH2OCH(CH3)2、-CH2CH2OCH3、-CH2CH2OCH2CH3、-CH2CH2OCH2CH2CH3、-CH2CH2OCH(CH3)2、-CH2CH2CH2OCH3、-CH2CH2CH2OCH2CH3、-CH2CH2CH2OCH2CH2CH3、-CH2CH2CH2OCH(CH3)2Cyclopropylmethylene, cyclopropylethylene, n-propylidene, cyclobutylmethylene, cyclobutylethylene, n-propylidene, cyclopentylmethylene, cyclopentylethylidene, n-propylidene, cyclohexylmethylene, cyclohexylethylene, n-propylidene, piperazinylmethylene, piperidinylmethylene, morpholinomethylene, thiomorpholinylmethylene, tetrahydropyranylmethylene or pyrrolidinylmethylene; wherein the methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, -CH2OCH3、-CH2OCH2CH3、-CH2OCH2CH2CH3、-CH2OCH(CH3)2、-CH2CH2OCH3、-CH2CH2OCH2CH3、-CH2CH2OCH2CH2CH3、-CH2CH2OCH(CH3)2、-CH2CH2CH2OCH3、-CH2CH2CH2OCH2CH3、-CH2CH2CH2OCH2CH2CH3、-CH2CH2CH2OCH(CH3)2Cyclopropylmethylene, cyclopropylethylene, n-propylidene, cyclobutylmethylene, cyclobutylethylene, n-propylidene, cyclopentylmethylene, cyclopentylethylidene, n-propylidene, cyclohexylmethylene, cyclohexylethylene, n-propylidene, piperazinylmethylene, piperidinylmethylene, morpholoneThe linylmethylene, thiomorpholinylmethylene, tetrahydropyranylmethylene and pyrrolidinylmethylene are independently optionally substituted with 1, 2 or 3 substituents selected from deuterium, F, Cl, Br, I, -OH, -CN, -NH2Or a substituent of-COOH.
19. The compound of claim 1, wherein R 7Is H, deuterium, -COOH, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, n-propoxy, isopropoxy, methylamino, ethylamino, n-propylamino, isopropylamino, -CH2F、-CH2Cl、-CHF2、-CHCl2、-CF3、-CH2CH2F、-CH2CH2Cl、-CH2CHF2、-CH2CHCl2、-CHFCH2F. Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino, piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl or pyrrolidinyl;
Rgis H, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl.
20. The compound of claim 1, having a structure of one of the following or a stereoisomer, geometric isomer, tautomer, nitrogen oxide, hydrate, solvate, metabolite, ester, pharmaceutically acceptable salt, or prodrug thereof:
Figure FDA0002878710720000061
Figure FDA0002878710720000071
Figure FDA0002878710720000081
Figure FDA0002878710720000091
Figure FDA0002878710720000101
21. a pharmaceutical composition comprising a compound of any one of claims 1-20, and a pharmaceutically acceptable excipient, carrier, adjuvant, or combination thereof.
22. The pharmaceutical composition of claim 21, wherein the pharmaceutical composition comprises an additional agent or any combination thereof for the prevention or treatment of an inflammatory syndrome, disorder or disease.
23. Use of a compound of any one of claims 1-20 or a pharmaceutical composition of any one of claims 21-22 in the manufacture of a medicament for preventing or treating a disease, disorder or syndrome mediated by roryt in a mammal.
24. The use of claim 23, wherein the roryt mediated disease, disorder or syndrome is cancer, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease, colitis, ulcerative colitis, rheumatoid arthritis, autoimmune ocular disease, ankylosing spondylitis, asthma, chronic obstructive pulmonary disease, osteoarthritis, allergic rhinitis, allergic dermatitis, crohn's disease or kawasaki disease.
CN202011623107.3A 2020-01-06 2020-12-31 Five-membered heteroaromatic derivative and preparation method and application thereof Pending CN113072546A (en)

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