CN117043162A - TYK2 selective inhibitors and uses thereof - Google Patents

TYK2 selective inhibitors and uses thereof Download PDF

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CN117043162A
CN117043162A CN202280021571.6A CN202280021571A CN117043162A CN 117043162 A CN117043162 A CN 117043162A CN 202280021571 A CN202280021571 A CN 202280021571A CN 117043162 A CN117043162 A CN 117043162A
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alkyl
formula
disease
halo
compound
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王利莎
陈弘道
王琳
王婕
李进
赵树海
杨民民
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Maba Pharmaceutical Nanjing Co ltd
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Maba Pharmaceutical Nanjing Co ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Abstract

The present application provides a compound of formula (I), or a tautomer, mesomer, racemate, enantiomer, diastereomer or a pharmaceutically acceptable salt thereof, and the use thereof for the manufacture of a medicament for the treatment of TYK2 mediated diseases.

Description

TYK2 selective inhibitors and uses thereof Technical Field
The application belongs to the field of chemical medicines, and particularly relates to a TYK2 selective inhibitor and application thereof.
Background
Autoimmune diseases are a family of at least 80 diseases, such as rheumatoid arthritis, systemic lupus erythematosus, inflammatory enteritis, etc., and are a group of diseases that falsely attack self-organs, tissues, and cells by immune cell activation and excessive production of autoantibodies. Autoimmune diseases affect 5% -10% of the worldwide population (Shoenfeld Y, tincani A, gershwin ME (2012) Sex gene and autoimmunity. J autoimmunity 38:J 71-J73). Autoimmune diseases are chronic and debilitating diseases, and have high medical costs and reduced quality of life for patients, which have become a great burden for patients, their families and society. Although the pathogenesis of these diseases is not completely understood, studies have shown that many factors, such as genetics, environment and immune response, play an important role in the development and progression of the disease.
Kinases play a very important role in regulating immune cell function (Deng, benllanti, zheng. Essential Kinases and Transcriptional Regulators and Their Roles in Autoimmunity [ J ]. Biomacules, 2019,9 (4)). Members of the Janus kinase (JAK) family include JAK1, JAK2, JAK3, and TYK2, non-receptor tyrosine kinases of the JAK family play an important role in mediating a variety of cytokines leading to inflammation (O "shear J J, schwartz D M, villarino A V, et al, the JAK-STAT Pathway: impact on Human Disease and Therapeutic Intervention [ J ]. Annual Review ofMedicine,2015, 66 (1): 311-328). Other variants of tyrosine kinase 2 (TYK 2) have been shown to be associated with autoimmune diseases such as Crohn' S disease, psoriasis, systemic lupus erythematosus and rheumatoid arthritis, further demonstrating the importance of TYK2 in autoimmunity (Ellinghaus D, ellinghaus E, nair RP, stuart PE, esko T, metspiu A, et al, combinated analysis of genome-wide association studies for Crohn disease and psoriasis identifies seven shared susceptibility loci.am J Hum Genet. (2012) 90:636-47.10.1016/j.ajhg.2012.02.020; graham D S C, akil M, asse T J.Association of polymorphisms across the tyrosine kinase gene, TYK2 in UKSLE families [ J ]. Rheumatology,2007 (6): 927-930;Eyre S,et al.High-density genetic mapping identifies new susceptibility loci for rheumatoid arthris. Nat Genet.2012; 44:1336-40). TYK2 is critical in the regulatory signaling cascade downstream of IL-12, IL-23 and type I interferon receptors (Karaghiosoff M, steinborn R, kovarik P, et al Central role for type I interferons and Tyk2 in lipopolysaccharide-induced endotoxin shock [ J ]. Nature Immunology,2003,4 (5): 471.). IL-12 and IL-23 activate antigen presenting cells and are capable of promoting differentiation and proliferation of Th1 and Th 17. Human genomics studies have found that IL-12R and IL-23B (encoding the p40 subunit) polymorphisms have a strong correlation with inflammatory enteritis (Stahl EA, raychaudhuri S, remmers EF, xie G, eyr S, thomson BP, et al Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci Nat genet.2010;42 (6): 508-514.R.H.Duerr, K.D.Taylor, S.R.Brant, et al. A Genome-Wide Association Study Identifies IL. R as an Inflammatory Bowel Disease Gene [ J ]. Science, 2006.). Type I interferons have a variety of effects on the innate and adaptive immune systems, including activating cellular and humoral immunity and enhancing expression and release of autoantigens (Hall J C, rosen A.type I interons: crucial participants in disease amplification in autoimmunity [ J ]. Nature Reviews Rheumatology,2010,6 (1): 40.). Elevated serum IFN levels were observed in patients with Systemic Lupus Erythematosus (SLE) and correlated with disease activity and severity (Bengtsson A, sturfelt G, truedsson L, et al Activate of type I interferon system in systemic Lupus erythematosus correlates with disease activity but not with antiretroviral antibodies [ J ]. Lupus,2000,9 (9): 664.). In summary, drugs that inhibit the effects of IL-12, IL-23 and type I interferons have therapeutic benefit in human autoimmune disease species.
Studies have shown that selective inhibition of TYK2 activity can be used as a novel approach to the treatment of various autoimmune diseases that balances the relationship between therapy and safety (Leitner, nicole, R, et al. Tyrosine kinase 2-Surveillant of tumours and bona fide oncogene [ J ]. Cytoine, 2017.). TYK2 and other members of the JAK family are characterized by dual kinase domains, tyrosine kinase domain (JH 1) and pseudokinase domain (JH 2), respectively. In the JAK family, the JH1 region has very high sequence homology, which presents challenges for the design of TYK2 selective inhibitors. JH2 plays an important role in the regulation of JAKs function (Lead Optimization of a-Aminopyridine Benzamide Scaffold To Identify Potent, selective, and Orally Bioavailable TYK2 Inhibitors [ J ]. Journal of Medicinal Chemistry,2013, 56 (11): 4521.), and mutations in JH2 portions of JAKs have been shown to be associated with hematological and immunological diseases. Thus, TYK2 JH2 selective inhibitors may inhibit TYK2 activity more specifically.
In conclusion, the synthesis of novel TYK2 JH2 selective inhibitors can benefit patients with autoimmune diseases by modulating IL-12, IL-23, type I interferon, etc. in vivo.
Disclosure of Invention
The application discloses a compound which can be used as a TYK2 selective inhibitor and application thereof in preparing medicines for preventing or treating TYK 2-mediated related diseases.
In one aspect, the application discloses a compound of formula (I):
or a tautomer, meso, racemate, enantiomer, diastereomer or a pharmaceutically acceptable salt thereof,
wherein ring a is selected from aryl, heteroaryl or partially unsaturated heterocyclyl;
x, Y is selected from C or N;
R 1 selected from hydrogen, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, halo C 1 -C 6 Alkyl, deuterated C 1 -C 6 Alkyl, halogenated C 2 -C 6 Alkenyl, halo C 2 -C 6 Alkynyl, halogen, cyano, nitro, -C (O) NR a R b 、-C(O)R a 、-C(O)OR a 、-OR a 、-R a OR b 、-OC(O)R a 、-OC(O)OR a 、-OC(O)NR a R b 、-NR a R b 、-SR a 、-S(O)R a 、-S(O) 2 R a Or a 3-10 membered saturated or unsaturated ring containing 0-3 heteroatoms, said 3-10 membered saturated or unsaturated ring containing 0-3 heteroatoms optionally substituted with 1-3R a Substitution;
R 2 selected from hydrogen, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, halo C 1 -C 6 Alkyl, deuterated C 1 -C 6 Alkyl, halogenated C 2 -C 6 Alkenyl, halo C 2 -C 6 Alkynyl, halogen and cyanoNitro, -C (O) NR a R b 、-C(O)R a 、-C(O)OR a 、-OR a 、-R a OR b 、-OC(O)R a 、-OC(O)OR a 、-OC(O)NR a R b 、-NR a R b 、-SR a 、-S(O)R a 、-S(O) 2 R a Or a 3-10 membered saturated or unsaturated ring containing 0-3 heteroatoms, said 3-10 membered saturated or unsaturated ring containing 0-3 heteroatoms optionally substituted with 1-3R a Substitution;
R 3 selected from hydrogen, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, halo C 1 -C 6 Alkyl, deuterated C 1 -C 6 Alkyl, halogenated C 2 -C 6 Alkenyl, halo C 2 -C 6 Alkynyl, halogen, cyano, nitro, carbonyl, -C (O) NR a R b 、-C(O)R a 、-C(O)OR a 、-OR a 、-R a OR b 、-OR a OR b 、-OC(O)R a 、-OR a C(O)R b 、-OC(O)OR a 、-OC(O)NR a R b 、-NR a R b 、-NC(O)R a 、-RcNR a R b 、-SR a 、-S(O)R a 、-S(O) 2 R a 、-R a CN or a 3-10 membered saturated or unsaturated ring containing 0-3 hetero atoms, said 3-10 membered saturated or unsaturated ring containing 0-3 hetero atoms being optionally substituted with 1-3R a Substitution;
R 4 selected from hydrogen,Or alternatively by 1-3R a Substituted 3-10 membered saturated or unsaturated ring containing 0-3 hetero atoms, Z being-NH-, -N (CH) 2 ) -or a direct bond;
R 5 selected from hydrogen, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, halo C 1 -C 6 Alkyl, deuterated C 1 -C 6 Alkyl, halogenated C 2 -C 6 Alkenyl, halo C 2 -C 6 Alkynyl, halogen, cyano, nitro, -C (O) NR a R b 、-C(O)R a 、-C(O)OR a 、-OR a 、-R a OR b 、-OC(O)R a 、-OC(O)OR a 、-OC(O)NR a R b 、-NR a R b 、-SR a 、-S(O)R a 、-S(O) 2 R a Or a 3-10 membered saturated or unsaturated ring containing 0-3 heteroatoms, said 3-10 membered saturated or unsaturated ring containing 0-3 heteroatoms optionally substituted with 1-3R a Substitution;
R 6 selected from hydrogen, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, halo C 1 -C 6 Alkyl, deuterated C 1 -C 6 Alkyl, halogenated C 2 -C 6 Alkenyl, halo C 2 -C 6 Alkynyl, halogen, cyano, nitro, -C (O) NR a R b 、-C(O)R a 、-C(O)OR a 、-OR a 、-R a OR b 、-OC(O)R a 、-OC(O)OR a 、-OC(O)NR a R b 、-NR a R b 、-SR a 、-S(O)R a 、-S(O) 2 R a Or a 3-10 membered saturated or unsaturated ring containing 0-3 heteroatoms, said 3-10 membered saturated or unsaturated ring containing 0-3 heteroatoms optionally substituted with 1-3R a Substitution;
each R a 、R b 、R c Each independently selected from hydrogen, deuterium, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, halo C 1 -C 6 Alkyl, deuterated C 1 -C 6 Alkyl, halogenated C 2 -C 6 Alkenyl, halo C 2 -C 6 Alkynyl, halogen, cyano, nitro, amino, carboxyl, carbonyl, hydroxyl, hydroxyalkyl, alkoxy, haloalkoxy, deuteroalkoxy, C 3 -C 6 Cycloalkyl, halo C 3 -C 6 Cycloalkyl, alkoxy substituted C 3 -C 6 Cycloalkyl, C 3 -C 6 Heterocyclyl, halo C 3 -C 6 Heterocyclyl, alkyl substituted C 3 -C 6 Heteroaryl, -S (O) 2 R d 、-OR d OR e 、-R d OR e 、-C(O)R d or-OC (O) R d Each R is d 、R e Each independently selected from C 1 -C 6 An alkyl group; and
n=0, 1, 2 or 3.
In other embodiments, wherein ring a is selected from phenyl, pyridyl, pyrazinyl, tetrahydropyridinyl, pyrazolyl, benzothiazolyl, or imidazo [1,5-a ] pyridyl.
In other embodiments, R 4 Selected from the group consisting of Z is-NH-, -N (CH) 2 ) -or a direct bond.
In other embodiments, R 4 Selected from the group consisting of
In other embodiments, formula (I) is formula (Ia):
R 2 ' selected from hydrogen, C 1 -C 6 Alkyl, halogenated C 1 -C 6 Alkyl, deuterated C 1 -C 6 Alkyl, C3-C6 cycloalkyl, halogen, -NH 2 or-NHCH 3 ；
n、X、Y、Z、R 1 、R 3 、R 5 、R 6 As defined above.
In other embodiments, formula (I) is formula (Ib):
R 1 、R 2 ’、R 3 、R 5 、R 6 as defined above.
In other embodiments, formula (I) is formula (Ic):
R 2 ' selected from hydrogen, C 1 -C 6 Alkyl, halogenated C 1 -C 6 Alkyl, deuterated C 1 -C 6 Alkyl, C3-C6 cycloalkyl, halogen, -NH 2 or-NHCH 3 ；
n、X、Y、Z、R 1 、R 3 、R 5 、R 6 As defined above.
In other embodiments, formula (I) is formula (Id):
R 1 、R 3 、R 5 、R 6 r is as defined in claim 1 2 ' as defined above.
In other embodiments, R 1 Selected from hydrogen, methyl, -CD 3 Ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl,
In other embodiments, R 3 Selected from hydrogen, methyl, ethyl, fluoro, chloro, cyano, methoxy, ethoxy, hydroxymethyl, carbonyl, carboxyl, -CHF 2 、-OCHF 2 、-CF 3 、-OCF 3 、-OCD 3 、
In other embodiments, the compound of formula (I) is selected from:
in another aspect, the application also provides the use of the aforementioned compounds, isomers thereof or pharmaceutically acceptable salts thereof for the preparation of a medicament for treating a disease mediated by TYK 2.
In some embodiments, the TYK 2-mediated disease is an autoimmune disease, an inflammatory disease, a proliferative disease, an endocrine disease, a neurological disease, or a disease associated with transplantation.
In other embodiments, the disease is an autoimmune disease.
In other embodiments, the autoimmune disease is selected from type 1 diabetes, ankylosing spondylitis, systemic lupus erythematosus, multiple sclerosis, systemic sclerosis, psoriasis, crohn's disease, ulcerative colitis, or inflammatory bowel disease.
In other embodiments, the disease is an inflammatory disease.
In other embodiments, the inflammatory disease is selected from the group consisting of rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, psoriasis, crohn's disease, ulcerative colitis, and inflammatory bowel disease.
In another aspect, the application also provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of the foregoing, an isomer thereof, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier or excipient.
Terminology:
unless stated to the contrary, the terms used in the specification and claims have the following meanings.
The term "isomer" includes enantiomeric, diastereomeric, and geometric (or conformational) isomeric forms of a given structure. For example, the application includes R and S configuration, Z and E double bond isomers, Z and E conformational isomers, single stereochemical isomers and mixtures of enantiomers, diastereomers and geometric (or conformational) isomers of each asymmetric center.
The term "pharmaceutically acceptable salt" refers to, for example, an acid addition salt and/or a base salt thereof. Suitable acid addition salts are formed from acids which form non-toxic salts, such as hydrochloride/chloride salts. Suitable base salts are formed from bases which form non-toxic salts such as calcium and sodium salts. Semi-salts of acids and bases, such as hemisulfate and hemicalcium salts, may also be formed.
The term "therapeutically effective amount" refers to that amount of a compound of the application that (i) treats a particular disease, condition, or disorder; (ii) Alleviating, or eliminating one or more symptoms of a particular disease, condition, or disorder; or (iii) preventing or delaying the onset of one or more symptoms of a particular disease, condition, or disorder described herein.
The term "pharmaceutically acceptable carrier or excipient" refers to a non-toxic carrier, adjuvant or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated.
The term "alkyl" refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing from 1 to 20 carbon atoms, preferably an alkyl group containing from 1 to 12 carbon atoms, more preferably an alkyl group containing from 1 to 6 carbon atoms. Non-limiting examples of lower alkyl groups containing 1 to 6 carbon atoms include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl and the like.
The term "alkenyl" refers to aliphatic hydrocarbons having at least one carbon-carbon double bond, including straight and branched chains having at least one carbon-carbon double bond. In some embodiments, the alkenyl group has 2 to 20 carbon atoms, 2 to 10 carbon atoms, 2 to 6 carbon atoms, 3 to 6 carbon atoms, or 2 to 4 carbon atoms. For example, the term "C 2-6 Alkenyl "includes straight or branched chain unsaturated groups of 2 to 6 carbon atoms (having at least one carbon-carbon double bond) including, but not limited to, vinyl, 1-propenyl, 2-propenyl (allyl), isopropenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, and the like.
The term "alkynyl" refers to aliphatic hydrocarbons having at least one carbon-carbon triple bond, including straight and branched chains having at least one carbon-carbon triple bond. In some embodiments, alkynyl groups have 2 to 20 carbon atoms, 2 to 10 carbon atoms, 2 to 6 carbon atoms, or 3 to 6 carbon atoms. For example, "C 2-6 Alkynyl "includes straight or branched chain unsaturated groups of 2 to 6 carbon atoms (having at least one carbon-carbon triple bond).
The term "alkoxy" refers to-O- (alkyl) and-O- (unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexyloxy.
The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably from 3 to 6 carbon atoms (e.g., 3, 4, 5, or 6 carbon atoms), and most preferably from 5 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups.
The term "spirocycloalkyl" refers to a polycyclic group sharing one carbon atom (referred to as a spiro atom) between 5-to 20-membered monocyclic rings, which may contain one or more double bonds, but each ring does not have a fully conjugated pi-electron system. Preferably 6 to 14 membered, more preferably 7 to 10 membered (e.g. 7, 8, 9 or 10 membered). The spirocycloalkyl group is classified into a single spirocycloalkyl group, a double spirocycloalkyl group or a multiple spirocycloalkyl group according to the number of common spiro atoms between rings, preferably a single spirocycloalkyl group and a double spirocycloalkyl group, more preferably a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered single spirocycloalkyl group.
The term "fused ring alkyl" refers to a 5 to 20 membered, all carbon polycyclic group wherein each ring in the system shares an adjacent pair of carbon atoms with the other rings in the system, wherein one or more of the rings may contain one or more double bonds, but each ring does not have a fully conjugated pi electron system. Preferably 6 to 14 membered, more preferably 7 to 10 membered. The number of constituent rings may be classified as a bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyl group, preferably a bicyclic or tricyclic, more preferably a 5-membered/5-membered or 5-membered/6-membered bicycloalkyl group.
The term "bridged cycloalkyl" refers to an all-carbon polycyclic group of 5 to 20 members, any two rings sharing two carbon atoms not directly attached, which may contain one or more double bonds, but each ring does not have a fully conjugated pi-electron system. Preferably 6 to 14 membered, more preferably 7 to 10 membered. Cycloalkyl groups which may be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged according to the number of constituent rings are preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic.
The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising 3 to 20 ring atoms, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S (O) m (where m is an integer from 0 to 2), but excluding the ring portion of-O-, -O-S-or-S-, the remaining ring atoms being carbon. Preferably containing 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably 3 to 8 ring atoms, of which 1 to 3 are heteroatoms; most preferably from 5 to 6 ring atoms, of which 1 to 2 or 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like, with tetrahydropyranyl, piperidinyl, pyrrolidinyl being preferred. Polycyclic heterocyclic groups include spiro heterocyclic groups, fused heterocyclic groups, and bridged heterocyclic groups.
The term "spiroheterocyclyl" refers to a polycyclic heterocyclic group having one atom (referred to as a spiro atom) shared between 5-to 20-membered monocyclic rings, wherein one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen or S (O) m (where m is an integer from 0 to 2) and the remaining ring atoms are carbon. Which may contain one or more double bonds, but each ring does not have a fully conjugated pi-electron system. Preferably 6 to 14 membered, more preferably 7 to 10 membered. The spiroheterocyclyl group is classified into a single spiroheterocyclyl group, a double spiroheterocyclyl group or a multiple spiroheterocyclyl group according to the number of common spiro atoms between rings, preferably a single spiroheterocyclyl group and a double spiroheterocyclyl group, more preferably a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered single spiroheterocyclyl group.
The term "fused heterocyclyl" refers to a 5 to 20 membered, polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with the other rings in the system, one or more of which may contain one or more double bonds, but each ring does not have a fully conjugated pi electron system, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S (O) m (where m is an integer from 0 to 2) and the remaining ring atoms are carbon. Preferably 6 to 14 membered, more preferably 7 to 10 membered. The number of constituent rings may be classified as a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably a bicyclic or tricyclic, more preferably a 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic group.
The term "bridged heterocyclyl" refers to a 5 to 14 membered, polycyclic heterocyclic group in which any two rings share two atoms which are not directly attached, which may contain one or more double bonds, but each ring does not have a fully conjugated pi electron system, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S (O) m (where m is an integer from 0 to 2), and the remaining ring atoms are carbon. Preferably 6 to 14 membered, more preferably 7 to 10 membered. Heterocyclic groups which may be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged according to the number of constituent rings are preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic.
Such heterocyclyl groups include those described above (including monocyclic, spiro, fused and bridged) fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is a heterocyclyl group, non-limiting examples of which include:
the term "aryl" refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 10 membered, such as phenyl and naphthyl.
The term "heteroaryl" refers to a heteroaromatic system containing from 1 to 4 heteroatoms, from 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl groups are preferably 5 to 10 membered, containing 1 to 3 heteroatoms; more preferably 5 or 6 membered, containing 1 to 2 heteroatoms; preferred are, for example, imidazolyl, furanyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, pyridazinyl and the like.
The heteroaryl groups include those wherein the heteroaryl groups as described above are fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl ring, non-limiting examples of which include:
the term "saturated or unsaturated ring" includes the aforementioned aryl, heteroaryl, cycloalkyl or heterocycloalkyl groups.
The term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.
The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.
The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group is as defined above.
The term "deuterated alkyl" refers to an alkyl group substituted with one or more deuterium atoms, wherein alkyl is as defined above.
The term "deuteroalkoxy" refers to an alkoxy group substituted with one or more deuterium atoms, wherein alkoxy is as defined above.
The term "cycloalkylalkyl" refers to an alkyl group substituted with one or more cycloalkyl groups, wherein cycloalkyl and alkyl are as defined above.
The term "cycloalkyloxy" refers to an-O-cycloalkyl group, wherein cycloalkyl is as defined above.
The term "heterocyclylalkyl" refers to an alkyl group substituted with one or more heterocyclyl groups, where heterocyclyl and alkyl are as defined above.
The term "arylalkyl" refers to an alkyl group substituted with one or more aryl groups, wherein aryl and alkyl are as defined above.
The term "hydroxy" refers to an-OH group.
The term "halogen" refers to fluorine, chlorine, bromine or iodine.
The term "amino" refers to-NH 2 。
The term "cyano" refers to-CN.
The term "nitro" refers to-NO 2 。
The term "carboxy" refers to-C (O) OH.
Detailed Description
Intermediate 1: preparation of 3- (4-bromo-2-methylphenyl) -1-methyl-1H-1, 2, 4-triazole (IM-1)
Step one: preparation of 3- (4-bromo-2-methylphenyl) -1H-1,2, 4-triazole. 4-bromo-2-methylbenzamide (1.900 g,8.876mmol,1 eq.) was dissolved in DMF-DMA (1.279 g,10.651mmol,1.2 eq.) and heated to 90℃for 20 minutes, the system was concentrated to dryness, acetic acid (30 mL), acetonitrile (30 mL), hydrazine hydrate (568.867 mg, 17.552 mmol,2 eq.) were added and reacted for 2 hours at room temperature, the system was dried by spin-drying, 50mL of water was added, the solid was precipitated, filtered, and the filter cake was dried to give the title compound (1.140 g,4.788 mmol).
Step two: preparation of 3- (4-bromo-2-methylphenyl) -1-methyl-1H-1, 2, 4-triazole (IM-1).
The method comprises the following steps: 3- (4-bromo-2-methylphenyl) -1H-1,2, 4-triazole (1.140 g,4.788mmol,1 eq.) was dissolved in DMF (20 mL), cesium carbonate (4.680 g,14.365mmol,3 eq.) was added, methyl iodide (1.399 g,9.576mmol,2 eq.) was reacted at room temperature for 20 hours, the system was dried by spin-drying, 50mL of water was added, solids were precipitated, filtered, and the filter cake was dried to give the title compound (0.800 g,3.173 mmol).
The second method is as follows: in a 500mL single-necked flask, 3- (4-bromo-2-methylphenyl) -1H-1,2, 4-triazole (5.69 g, 22.390 mmol,1 eq.) and DMF-DMA (13.343g, 111.971mmol,5 eq.) were added sequentially, DMF (60 mL) was heated to 90℃and reacted for 5 hours. Concentrated to dryness, 150mL ice water was added, extracted with dimethyltetrahydrofuran (50 mL x 2) and the organic phase was chromatographed (PE: ea=1 to 5:1) to give the title compound.
The intermediates of examples 11, 24, 25, 26, 28, 29, 46, 53, 168, 171 were prepared as described above.
Intermediate 2: preparation of N- (3-bromo-5- (trifluoromethyl) phenyl) methanesulfonamide (IM-2)
Step one: preparation of N- (3-bromo-5- (trifluoromethyl) phenyl) -N- (methylsulfonyl) methanesulfonamide. In a 250mL single vial was added 3-bromo-5- (trifluoromethyl) aniline (10.00 g,41.663mmol,1 eq.) in DCM (100 mL), TEA (21.08 g,208.32mmol,5.0 eq.) in ice-bath chilled water and methanesulfonic anhydride (21.77 g,125.0mmol,3.0 eq.) in DCM phase water washed (200 mL. Times.2), dried over anhydrous magnesium sulfate, filtered, concentrated, and column chromatographed (PE: EA=3:1) to give the title compound (6.80 g,17.163 mmol).
Step two: preparation of N- (3-bromo-5- (trifluoromethyl) phenyl) methanesulfonamide (IM-2). In a 250mL single vial was added N- (3-bromo-5- (trifluoromethyl) phenyl) -N- (methylsulfonyl) methanesulfonamide (6.80 g,17.163mmol,1 eq.) H 2 O (20 mL), THF (50 mL), naOH (1.373 g,34.326mmol,2 eq.) was slowly added, reacted for 10 hours at room temperature, saturated sodium chloride (150 mL), EA (100 mL), separated, the organic phase washed with saturated sodium chloride (150 mL. Times.1), concentrated, column chromatographed (PE: EA=1-3:1) to give the title compound (3.50 g,11.002mmol, yield 64.106%).
The intermediates of examples 6, 23, 31, 33, 49, 52, 58, 60, 62, 228, 229 were prepared according to the above procedure.
Intermediate 3: preparation of N- (3-bromo-5- (methylsulfonyl) phenyl) acetamide (IM-3)
3-bromo-5- (methylsulfonyl) aniline (2.00 g,7.996mmol,1 eq.) was dissolved in DCM (20 mL), TEA (2.427 g,23.989mmol,3 eq.) was added, acetyl chloride (19.991 mmol,2.5 eq.) was added, and reacted at 20℃for 1 hour, 50mL of water was added to the system, after stirring thoroughly, the solid was separated out, filtered off with suction, and dried to give the title compound (2.00 g,6.846mmol, yield 85.611%).
The intermediate of example 34 was prepared as described above.
Intermediate 4: preparation of 1-bromo-3-methoxy-5- (methylsulfonyl) benzene (IM-4)
Step one: preparation of (3-bromo-5-methoxyphenyl) (methyl) sulfide. 3-bromo-5-methoxyaniline (2.60 g,12.868mmol,1 eq.) was dissolved in acetonitrile (30 mL), isoamyl nitrite (3.015 g,25.736mmol,2 eq.) was added, dimethyl disulfide (2.424 g,25.736mmol,2 eq.) was replaced 3 times with nitrogen, the temperature was controlled at 70 ℃, reacted for 1 hour, concentrated, and column chromatographed (PE: ea=10:1) to give the title compound (600 mg, 2.514 mmol, yield 20.001%).
Step two: preparation of 1-bromo-3-methoxy-5- (methylsulfonyl) benzene (IM-4). (3-bromo-5-methoxyphenyl) (methyl) sulfide (600 mg, 2.514 mmol,1 eq.) was dissolved in DCM (10 mL), m-chloroperoxybenzoic acid (1.322 g, 7.015 mmol,3 eq.) was added, nitrogen was displaced 3 times, the temperature was controlled at 20℃and reacted for 15 hours, aqueous ice was added to the system, the organic phase was washed with saturated sodium carbonate, dried, and column chromatography (PE: EA=5:1 to 1:1) gave the title compound (900 mg, 3.015 mmol, yield 131.896%).
The intermediates of examples 35, 36, 38, 39, 41, 48, 50, 67, 71, 73, 104 were prepared by reference to the procedure for the intermediates of the compounds described above.
Intermediate 5: preparation of N- (3-bromo-5- (difluoromethyl) phenyl) methanesulfonamide (IM-5)
Step one: preparation of 1-bromo-3- (difluoromethyl) -5-nitrobenzene. 3-bromo-5-nitrobenzaldehyde (5.00 g,21.73mmol,1.0 eq.) was dissolved in DCM (250 mL), DAST (7.00 g,43.47mmol,2.0 eq.) was added under ice-bath, reacted at room temperature for 12 hours, after the reaction was completed, ice-water was added, stirring was sufficient, the liquid was separated, the organic phase was dried, and column chromatography (PE: EA-5:1) was performed to give the title compound. MS (m/z) =253.06[M+H] + 。
Step two: preparation of 3-bromo-5- (difluoromethyl) aniline. 1-bromo-3- (difluoromethyl) -5-nitrobenzene (5.00 g,21.73mmol,1.0 eq.) was dissolved in acetic acid (50 mL), iron powder (12.20 g,217.3mmol,10.0 eq.) was added at room temperature, reacted for 15 hours at room temperature, after the reaction was completed ice water, EA were added, stirring was sufficient, the separated organic phase was dried, and dried by spin-drying, column chromatography (PE: ea=3:1) to give the title compound (2.90 g, yield 60%). MS (m/z) =223.06 [ m+h ] ] + 。
Step three, referring to the preparation method of the step one of the intermediate 2.
And step four, referring to the preparation method of the step two of the intermediate 2.
The intermediates of examples 3, 37, 40, 42, 54, 55, 57 were prepared by reference to the preparation methods described above.
Intermediate 6: preparation of 1-bromo-3- (difluoromethoxy) -5- (methylsulfonyl) benzene (IM-6)
Step one: preparation of 3-bromo-5- (methylsulfonyl) phenol. 3-bromo-5- (methylsulfonyl) aniline (3.00 g,11.995mmol,1 eq.) was suspended in 10% H 2 SO 4 (100 mL) under ice bath, naNO was added 2 (910.258 mg,13.194mmol,1.1 eq.) in water (5 mL), stirring for 30 min at constant temperature, heating to 100deg.C for 12 h, cooling to room temperature, extracting with EA (100 mL), washing the organic phase with saturated sodium chloride (100 mL. Times.2), drying over anhydrous magnesium sulfate, filtering, concentrating, and column chromatography (PE: EA=1:1) to give the title compound (1.4 g,5.57mmol, yield 46.48%).
Step two: preparation of 1-bromo-3- (difluoromethoxy) -5- (methylsulfonyl) benzene (IM-6). 3-bromo-5- (methylsulfonyl) phenol (1.01 g,4.022mmol,1 eq.) was dissolved in DMF (10 mL) and Cs was added 2 CO 3 (2.521 g,8.045mmol,2 eq.) sodium difluorochloroacetate (1.53 g,10.056mmol,2.5 eq.) was reacted for 2 hours at 90℃with heating,the reaction solution was poured into 50mL of ice water, EA extracted (30 ml×2), EA phase washed with water (50 ml×3), saturated sodium chloride washed (50 ml×2), dried over anhydrous magnesium sulfate, filtered, concentrated, and column chromatographed (PE: ea=10 to 20:1) to give the title compound (1.080 g,3.587mmol, yield 89.172%).
The intermediate of example 66 was prepared as described above.
Intermediate 7: preparation of 1-bromo-3- (2, 2-difluoroethoxy) -5- (methylsulfonyl) benzene (IM-7)
3-bromo-5- (methylsulfonyl) phenol (1.00 g,3.983mmol,1 eq.) was dissolved in DMF (20 mL) and K was added 2 CO 3 (1.651 g,11.948mmol,3 eq.) 1, 1-difluoro-2-iodoethane (764.428 mg,3.983mmol,1 eq.) was heated to 60 ℃ for 12 hours, ice water (100 mL) was added, EA (50 mL. Times.2) was extracted, the organic phase was washed with saturated sodium chloride (100 mL. Times.2), dried over anhydrous magnesium sulfate, filtered and concentrated, and column chromatographed (PE: ea=1-10:1) to give the title compound (1.10 g,3.49mmol, yield 87.65%).
The intermediates of examples 43, 45, 56, 65, 68, 75, 77, 83, 84, 85, 86, 87, 90, 97, 100, 102 were prepared as described above.
Intermediate 8: preparation of 1-bromo-3- (methoxymethyl) -5- (methylsulfonyl) benzene (IM-8)
Step one: preparation of (3-bromo-5- (methylsulfonyl) phenyl) methanol. 3-bromo-5- (methylsulfonyl) benzoic acid methyl ester (3.00 g,10.234mmol,1 eq.) in THF (200 mL) at 0deg.C was added lithium aluminum hydride (388.389 mg,10.234mmol,1 eq.) and reacted for 4 hours at 15deg.C, after completion of the reaction, cooled to 0deg.C, added water (0.4 mL), 15% sodium hydroxide (0.4 mL), water (1.2 mL), stirred for 30min, filtered with celite, the filtrate was spin-dried to give sand, and column chromatography (EA: PE=1:1) gave the title compound (2.50 g,10.23mmol, yield 100%).
Step two: preparation of 1-bromo-3- (methoxymethyl) -5- (methylsulfonyl) benzene (IM-8). (3-bromo-5- (methylsulfonyl) phenyl) methanol (2.50 g,10.23mmol,1.0 eq.) was dissolved in THF (50 mL), cooled to 0 ℃ under nitrogen, naH (304.134 mg,12.673mmol,1.2 eq.) was added in portions, stirred for 30 min, meI (2.249 g,15.842mmol,1.5 eq.) was added, warmed to room temperature and stirred for 12 h, quenched with saturated ammonium chloride (100 mL), extracted with EA (50 mL x 2), washed with saturated sodium chloride in organic phase (100 mL x 2), dried over anhydrous magnesium sulfate, filtered, concentrated, column chromatographed (PE: ea=3:1) to give the title compound (2.50 g,8.95mmol, yield 84.8%).
The intermediates of examples 44, 51, 103 were prepared as described above.
Intermediate 9: preparation of (3-bromophenyl) dimethylphosphine oxide (IM-9)
1, 3-dibromobenzene (1.511 g,6.406mmol,1 eq.) methyl phosphonomethane (0.500 g,6.406mmol,1 eq.) Pd (dppf) Cl 2 (468.741mg, 640.616 μmol,0.1 eq.), triethylamine (1.945 g,19.218mmol,3 eq.) in acetonitrile (30 mL), nitrogen substitution 3 times, reaction at 80 ℃ for 12 hours, concentration, DCM (50 mL) dissolution, water washing (100 mL x 2), saturated sodium chloride washing (100 mL x 2), dried over anhydrous magnesium sulfate, filtration concentration, column chromatography (DCM: meoh=20:1) to give the title compound (0.900 g,3.862mmol, yield 60.285%).
The intermediate of example 61 was prepared as described above.
Intermediate 10: preparation of 4- (3-bromo-5- (methylsulfonyl) phenyl) -1, 5-dimethyl-1H-pyrazole (IM-10)
Step one: preparation of 1, 3-dibromo-5- (methylsulfonyl) benzene. Sequentially adding NaHCO into a single-mouth bottle 3 (5.024g，59.806mmol，2.0eq.)，Na 2 SO 3 (5.653g，44.855mmol，1.5eq.)，H 2 O (75 mL), heating to 95deg.C, dissolving completely, cooling to 45deg.C, adding 3, 5-dibromobenzenesulfonyl chloride (10.00 g, 29.803 mmol,1 eq.) under stirring for 0.5 hr, heating to 90deg.C overnight (15 hr), cooling to 40deg.C, adding THF (10 mL), meI (4.24 g,29.9mmol,1.0 eq.) under reaction for 20 hr at 40deg.C, detecting completion of reaction by TLC, adding EA (50 mL. Times.2) for extraction, combining organic phases, drying over anhydrous magnesium sulfate, filtering, concentrating, and column chromatography (PE: EA=3:1) to give the title compound (5.02 g,15.99mmol, yield 53.46%).
Step two: preparation of 4- (3-bromo-5- (methylsulfonyl) phenyl) -1, 5-dimethyl-1H-pyrazole (IM-10). 1, 3-dibromo-5- (methylsulfonyl) benzene (1.00 g,3.185mmol,1 eq.) in a single-necked flask was added sequentially to 1, 4-dioxane (15 mL), 1, 5-dimethyl-4- (4, 5-tetramethyl- [1,3, 2)]Dioxaborane-2-yl) -1H-pyrazole (707.3 mg,3.185mmol,1.0 eq) Pd (dppf) Cl 2 (116.516mg，159.239μmol，0.05eq.)，K 2 CO 3 (1.320g，9.554mmol，3eq.)，H 2 O (5 mL), nitrogen was replaced three times, heated to 100deg.C, reacted for 15 hours, concentrated, and column chromatographed (PE: EA=1:1) to give the title compound (368.4 mg,1.12mmol, 35.14%).
The intermediates of examples 74, 79, 91, 94, 95, 96, 106, 107, 109, 110, 111, 112, 114, 117, 118, 128, 133, 134, 136, 142 were prepared by reference to the methods of the intermediates described above.
Intermediate 11: preparation of 3-bromo-5-chloro-1-cyclopropyl-1H-pyrrolo [2,3-c ] pyridine (IM-11)
3-bromo-5-chloro-1H-pyrrolo [2,3-c]Pyridine (1 g,4.32mmol,1.0 eq.) was dissolved in DMF, 2' -bipyridine (674.19 mg,4.32mmol,1.0 eq.) sodium carbonate (915.7 mg,8.64mmol,2.0 eq.), copper acetate (776.25 mg,3.88mmol,0.9 eq.) cyclopropylboronic acid (743.48 mg,8.64mmol,2.0 eq.) was added at room temperature, the reaction was allowed to proceed to 70℃for 14 h under air balloon protection, after the reaction was completed, the system was poured into ice water (30 mL), EA was extracted, the organic phase was dried by spin, and column chromatography 272 (EA: PE=1:10) gave the title compound (0.56 g, yield: 47.74%) MS (m/z) =M+H)] + 。
The intermediate of example 78 was prepared by reference to the procedure for the intermediate described above.
Intermediate 12: preparation of 1-bromo-3, 5-bis (methylsulfonyl) benzene (IM-12):
1, 3-dibromo-5- (methylsulfonyl) benzene (1.00 g,3.185mmol,1 eq.) was added sequentially to a single-port flask, DMSO (10 mL), sodium methane sulfinate (357.647 mg,3.503mmol,1.1 eq.), cuI (60.254 mg, 318.477. Mu. Mol,0.1 eq.), L-proline (73.333 mg, 636.955. Mu. Mol,0.2 eq.), naOH (25.476 mg, 636.955. Mu. Mol,0.2 eq.) was replaced with nitrogen three times, heated to 80℃and reacted for 48 hours, cooled to room temperature, filtered with ice water (50 mL), dried filter cake, dissolved in THF, and purified by column chromatography (PE: EA=1 to 2:1) to give the title compound (210 mg, 670.523. Mu. Mol, yield 21.054%).
The intermediates of examples 81, 113 were prepared by reference to the preparation methods described above.
Intermediate 13: preparation of 1-bromo-3- ((difluoromethoxy) methyl) -5- (methylsulfonyl) benzene (IM-13)
(3-bromo-5- (methylsulfonyl) phenyl) methanol (1.00 g,3.772mmol,1 eq.) was dissolved in acetonitrile (12 mL), heated to 50deg.C, a solution of 2-fluorosulfonyldifluoroacetic acid (1.008 g, 5.618 mmol,1.5 eq.) in acetonitrile (1 mL) was added dropwise at this temperature, after which the reaction was continued for 0.5 h at this temperature, the system was dried, EA (20 mL) was added, filtered and column chromatographed (PE: EA=5:1) to give the title compound (0.40 g,1.269mmol, yield 33.652%).
The intermediate of example 82 was prepared by reference to the procedure for the intermediate described above.
Intermediate 14: preparation of 2- (3-bromo-5- (methylsulfonyl) phenyl) propanol (IM-14)
Methyl 3-bromo-5- (methylsulfonyl) benzoate (1.00 g,3.411mmol,1 eq.) was dissolved in THF (10 mL), cooled to-78 ℃, 2-methyltetrahydrofuran solution of methylmagnesium bromide (3 m,3.5 mL) was added dropwise, and after addition, naturally warmed to room temperature and reacted for 15 hours, saturated ammonium chloride was added to the system to quench, the organic phase was separated, dried, spun-dried, sand-made, column chromatography (PE: ea=3:1) to give the title compound (0.90 g,3.070mmol, yield 89.987%).
The intermediate of example 88 was prepared by reference to the procedure for the intermediate described above.
Intermediate 15: preparation of 4- (3-bromo-5- (methylsulfonyl) phenyl) morpholine (IM-15)
Step one: preparation of 1-bromo-3-fluoro-5- (methylsulfonyl) benzene. The preparation method of the step one refers to the intermediate 10 by taking 3-bromo-5-fluorobenzenesulfonyl chloride as a raw material.
Step two: preparation of 4- (3-bromo-5- (methylsulfonyl) phenyl) morpholine (IM-15). 1-bromo-3-fluoro-5- (methylsulfonyl) benzene (1.00 g,3.951mmol,1 eq.), DMAc (10.000 mL), morphine (1.033 g,11.854mmol,3 eq.) were added to a 100mL single port flask, heated to 100deg.C for 20 hours, cooled to room temperature, ice water (50 mL) was added, filtered, and dried to give the title compound (1.10 g,3.435mmol, yield 86.944%).
Examples 92, 93, 99, 116, 119, 120, 124, 125, 126, 129, 135, 137, 138, 139, 140, 141, 143, 144, 145, 146, 148, 149, 151, 152, 153, 154, 155, 156, 157, 158, 169, 172, 181, 182, 183, 185, 193, 196, 197, 198, 199, 200, 203, 204, 205, 206, 208, 209, 210, 211, 213, 214, 215, 216, 217, 218, 219 were prepared by the process of the intermediates described above.
Intermediate 16: preparation of 1- ((3-bromophenyl) sulfonyl) propan-2-ol (IM-16)
Step one: preparation of 1- ((3-bromophenyl) sulfonyl) propan-2-one. 1, 3-dibromo-5- (methylsulfonyl) benzene (2.00 g,6.370mmol,1 eq.) was dissolved in THF (20 mL), cooled to-78 ℃, N-butyllithium (2.5M, 6.370mmol,1 eq.) was added dropwise, the reaction was kept warm for 0.5 hours after the addition, N-methoxy-N-methylacetamide (656.284 mg,6.370mmol,1 eq.) was added, the reaction was carried out for 0.5 hours after the addition, saturated ammonium chloride was added to quench the system, the EA split solution was added, the organic phase was dried, spun dry, sand was made, and column chromatography (PE: EA=5:1) was carried out to give the title compound (0.500 g,1.804mmol, yield 22.660%), MS (m/z) =278.13 [ M+H ]] + 。
Step two: preparation of 1- ((3-bromophenyl) sulfonyl) propan-2-ol (IM-16). 1- ((3-bromophenyl) sulfonyl) propan-2-one (0.500 g, 1.514 mmol,1 eq.) in methanol (10 mL) was added NaBH4 (68.256 mg, 1.514 mmol,1 eq.) under ice-bath and the addition was completed and allowed to react naturally to room temperature for 0.5 h, the system was dried, sand-made and column chromatographed (PE: EA=3:1) to give the title compound (0.400 g,1.433mmol, yield 79.422%).
The intermediate of example 105 was prepared by reference to the procedure for the intermediate described above.
Intermediate 17: preparation of 1- (3-bromo-5- (methylsulfonyl) phenyl) -4-fluoro-1H-pyrazole (IM-17)
1-bromo-3-fluoro-5- (methylsulfonyl) benzene (1.00 g,3.951mmol,1 eq.) was dissolved in DMAC (20 mL), cesium carbonate (1.545 g,4.741mmol,1.2 eq.) and 4-fluoropyrazole (1.020g, 11.254 mmol,3 eq.) were added, the mixture was heated to 90℃and reacted for 54 hours, the system was poured into ice water, stirred thoroughly and filtered with suction, and the filter cake was washed with water and dried to give the title compound (1.20 g,3.760mmol, yield 95.161%).
The intermediate of example 115 was prepared by reference to the procedure for the intermediate described above.
Intermediate 18: preparation of 3-bromo-N, N-dimethyl-5- (1- (oxetan-3-yl) -1H-pyrazol-4-yl) benzenesulfonamide (IM-18)
Step one: preparation of 3, 5-dibromobenzenesulfonyl chloride. 3, 5-dibromoaniline (5.00 g,19.927mmol,1 eq.) and AcOH (57 mL), concentrated hydrochloric acid (31 mL) were added into a four-necked flask, the temperature was reduced to about 0deg.C in an ice bath, and NaNO was added dropwise 2 (1.512 g,21.919mmol,1.1 eq.) +4.5mL of water, stirred for 10 minutes and reacted for 0.5 hours. Adding NaHSO into another single-mouth bottle 3 (5.806 g,55.795mmol,2.8 eq.) +8.7mL of water, concentrated hydrochloric acid (31 mL), acOH (57 mL), cuCl (0.5 g,5.051mmol, 0.255 eq.) the diazonium salt solution prepared above was slowly poured into the system, stirred at room temperature for 0.5 hours, ice water (400 mL) was added, EA extracted (100 mL x 1), the organic phase washed (300 mL x 1), saturated sodium chloride washed (300 mL x 1), anhydrous magnesium sulfate dried, filtered, concentrated to dryness, and the title compound (4.65 g, 13.015 mmol, 69.780%) was directly put into the next step.
Step two: preparation of 3, 5-dibromo-N, N-dimethylbenzenesulfonamide. 3, 5-dibromobenzenesulfonyl chloride (4.65 g, 13.015 mmol,1 eq.) was dissolved in THF (10 mL), dimethylamine methanol solution (30 mL) was added under ice-bath, stirred for 1 hour, concentrated to dryness, ice water (150 mL) was added, filtered, the filter cake was washed with a small amount of ice water, dried, and column chromatographed (PE: ea=3-10:1) to give the title compound (2.65 g, 7.015 mmol, yield 55.557%).
Step three: 3-bromo-N, N-dimethyl-5- (1- (oxetan-3-yl) -1H-pyrazol-4-yl) benzenesulfonamide (IM-18) was prepared by the method of step two with reference to intermediate 10.
The intermediates of examples 130, 131 were prepared by reference to the methods for the intermediates described above.
Intermediate 19: preparation of 3-bromo-5- (3-methoxyazetidin-1-yl) -N, N-dimethylbenzenesulfonamide (IM-19)
Step one: preparation of 3-bromo-5-fluorobenzenesulfonyl chloride. Prepared by the preparation method of the step one with reference to the intermediate 18.
Step two: preparation of 3-bromo-5-fluoro-N, N-dimethylbenzenesulfonamide. Reference is made to the intermediate 18, step two.
Step three: preparation of 3-bromo-5- (3-methoxyazetidin-1-yl) -N, N-dimethylbenzenesulfonamide (IM-19). Reference is made to the preparation method of the intermediate 15 step two.
The intermediates of examples 132, 159, 160, 161, 162, 163, 165, 166, 167, 174, 175, 176, 177, 178, 184, 186, 187, 188, 189, 190, 191, 192, 232 were prepared by reference to the methods of the intermediates described above.
Intermediate 20: preparation of 3-bromo-5- (2, 2-difluoroethoxy) -N, N-dimethylbenzenesulfonamide (IM-20)
2, 2-difluoroethanol (872.463 mg,10.633mmol,3 eq.) was dissolved in DMAc (15 mL), naH (425.301 mg,10.633mmol,60% purity,3 eq.) was added portionwise under nitrogen protection, stirred for 0.5 h at room temperature, 3-bromo-5-fluoro-N, N-dimethylbenzenesulfonamide (1.00 g,3.544mmol,1 eq.) was added, the reaction was carried out for 2 h at 50 ℃ and cooled to room temperature, ice water 80mL was added, EA extraction (30 mL x 2), EA phase water washing (100 mL x 2), saturated sodium chloride washing (100 mL x 2), anhydrous sodium sulfate drying, filtration, concentration, column chromatography (PE: ea=3 to 5:1) gave the title compound (1.00 g,2.906mmol, yield 81.973%).
The intermediate of example 150 was prepared by reference to the procedure for the intermediate described above.
Intermediate 21: preparation of (3-bromo-5- (methylsulfonyl) phenyl) (3-methoxyazetidin-1-yl) methanone (IM-21)
3-bromo-5-methanesulfonyl-benzoic acid (1 g,3.583mmol,1 eq.) was dissolved in DMAc (20 mL), HATU (1.235 g,4.299mmol,1.2 eq.) was added, DIPEA (1.389 g,10.749mmol,3 eq.) was added followed by 3-methoxyazetidine hydrochloride (374.560 mg,4.299mmol,1.2 eq.) and the reaction was carried out at this temperature for 5 hours, the system was poured into ice water, the EA was added, the organic phase was dried, spun dry, sand-making, column chromatography (PE: EA=1:1) to give the title compound (0.800 g,2.297mmol, yield 64.124%).
The intermediate of example 164 was prepared by reference to the procedure for the intermediates described above.
Intermediate 22: preparation of 2-chloro-4-methoxy-6- (methylsulfonyl) pyridine (IM-22)
2, 6-dichloro-4-methoxypyridine (3.75 g,21.06mmol,1 eq.) was dissolved in DMSO (30 mL) and 40% aqueous sodium methyl mercaptide (7.60 g,21.06mmol,1 eq.) was added and the resulting mixture was heated to 40℃and reacted for 1 hour. The reaction solution was diluted with water and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous magnesium sulfate and spin-dried under reduced pressure to give 2-chloro-4-methoxy-6-methylthiopyridine (3.80 g,20.03mmol, yield 95%).
2-chloro-4-methoxy-6-methylthiopyridine (3.80 g,20.03mmol,1 eq.) was dissolved in a mixed solvent of tetrahydrofuran (40 mL) and water (40 mL), ruthenium trichloride (418 mg,2.00mmol,0.1 eq.) and sodium periodate (8.57 g,40.06mmol,2 eq.) were added in this order, and the resulting mixture was heated to 50℃for reaction for 2 hours. The reaction solution was extracted with ethyl acetate. The organic phases were combined, dried over anhydrous magnesium sulfate and spun dry under reduced pressure. Purification of the crude product by column chromatography (PE/ea=2/1) gave the title compound (IM-22) (2.30 g,10.37mmol, yield 51.7%).
The intermediates of examples 220, 221, 222, 223, 224, 225, 230, 231, 233, 234, 235, 236 were synthesized by reference to the methods described above.
Intermediate 23: preparation of 2-chloro-4- (3-methoxyazetidin-1-yl) -6- (methylsulfonyl) pyridine (IM-23)
2, 6-dichloro-4-iodopyridine (3.00 g,10.95mmol,1 eq.) was dissolved in 1, 4-dioxane (10 mL), and 3-methoxyazetidine hydrochloride (1.61 g,13.08mmol,1.2 eq.), cesium carbonate (10.70 g,32.84mmol,3 eq.), pd were added separately 2 (dba) 3 (501 mg,0.54mmol,0.05 eq.) and XantPhos (633 mg,1.09mmol,0.1 eq.) the resulting mixture was reacted with nitrogen and heated to 100℃for 14 hours. The reaction solution was cooled, filtered, and the filter cake was washed with ethyl acetate. The organic phases were combined and dried under reduced pressure, and the resulting crude product was purified by column chromatography (PE/ea=5/1) to give the first step reaction product (1.30 g,5.57mmol, yield 50.9%).
The first step reaction product, referred to the synthesis of intermediate 22 (IM-22), gives intermediate 23 (IM-23).
Intermediate 24: preparation of 2- (3-bromo-5- (methylsulfonyl) phenyl) -4, 4-dimethyl-4, 5-dihydro-oxazole (IM-24)
3-bromo-5-methylsulfonylbenzoic acid (1.00 g,3.58mmol,1 eq.) was dissolved in dichloromethane (15 mL), one drop of DMF was added, cooled in an ice bath, oxalyl chloride (682 mg,5.37mmol,1.5 eq.) was added dropwise, and the resulting mixture was stirred at room temperature for 3 hours. The solvent was dried under reduced pressure, redissolved in dichloromethane (30 mL), triethylamine (1.08 g,10.74mmol,3 eq.) was added, 1-dimethyl-2-hydroxyethylamine (319 mg,3.58mmol,1 eq.) was added and the resulting mixture was stirred at room temperature for 15 hours. The solvent was dried under reduced pressure, the crude product was diluted with water and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous magnesium sulfate and spun dry under reduced pressure. Purification of the crude product by column chromatography (PE/ea=1/1) afforded the amide intermediate (1.20 g,3.42mmol, 95.6% yield).
The above amide intermediate (1.20 g,3.42mmol,1 eq.) was dissolved in a mixed solvent of toluene (10 mL) and methylene chloride (5 mL), and thionyl chloride (1.63 g,13.70mmol,4 eq.) was added thereto, and the resultant mixture was stirred at room temperature for 15 hours. The solvent was dried under reduced pressure, the crude product was diluted with ice water, neutralized with saturated sodium bicarbonate and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous magnesium sulfate and spun dry under reduced pressure. Purification of the crude product by column chromatography (PE/ea=1/1) afforded intermediate IM-24 (0.74 g,2.22mmol, 65.0% yield).
Intermediate 25: preparation of tert-butyl ((3-bromophenyl) (methyl) (oxy) -l 6-sulfonylimide) carbamate (IM-25)
3-methylthiobromobenzene (5.00 g,24.61mmol,1 eq.) was dissolved in methanol (50 mL), and iodobenzene diacetic acid (19.82 g,61.54mmol,2.5 eq.) and ammonium carbamate (3.84 g,49.23mmol,2 eq.) were added separately and the resulting mixture was stirred at room temperature for 5 hours. The solvent was dried under reduced pressure, and the obtained crude product was purified by column chromatography (PE/ea=1/1) to give a sulfoximine intermediate (4.38 g,18.70mmol, yield 75.9%).
The above sulfoximine intermediate (4.38 g,18.70mmol,1 eq.) was dissolved in tetrahydrofuran (50 mL), cooled in an ice bath, 60% sodium hydrogen (1.27 g,31.80mmol,1.7 eq.) was added and stirred at room temperature for 1 hour. Boc anhydride (6.94 g,31.80mmol,1.7 eq.) was added and stirred at room temperature for 15 hours. The reaction mixture was quenched with ice water and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous magnesium sulfate and spun dry under reduced pressure. Purification of the crude product by column chromatography (PE/ea=1/1) afforded intermediate IM-25 (3.53 g,10.56mmol, yield 56.4%).
The intermediate of example 180 was synthesized with reference to the procedure described above.
Intermediate 26: preparation of N- (3-bromo-1-cyclopropyl-1H-pyrrolo [2,3-c ] pyridin-5-yl) acetamide (IM-26)
N- (3-bromo-1H-pyrrolo [2,3-c ] pyridin-5-yl) acetamide (3.00 g,11.80mmol,1 eq.) was dissolved in DMF (20 mL) and cyclopropylboronic acid (2.00 g,23.28mmol,2 eq.), sodium carbonate (2.50 g,23.58mmol,2 eq.), 2-bipyridine (1.84 g,11.78mmol,1 eq.) and copper acetate (2.35 g,11.77mmol,1 eq.) were added separately and the resulting mixture was heated to 70℃for 16 hours under an air atmosphere. The reaction solution was diluted with water and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crude product was obtained by beating with a small amount of ethyl acetate to give the title compound (IM-26) (1.50 g, yield 43.1%).
The intermediates of examples 237, 238, 239, 240, 264, 265, 266, 267, 268, 271 were synthesized as described above.
Intermediate 27: preparation of 2-chloro-4- (methoxy-d 3) -6- (methylsulfonyl) pyridine (IM-27)
2, 6-dichloro-4-hydroxypyridine (6.00 g,36.58mmol,1 eq.) was dissolved in DMF (30 mL), cesium carbonate (17.94 g,55.06mmol,1.5 eq.) and deuterated methyl iodide (5.87 g,40.49mmol,1.1 eq.) were added sequentially, and the resulting mixture was stirred at room temperature for 1 hour. The reaction solution was diluted with water and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous magnesium sulfate, and the solvent was dried under reduced pressure. The crude product was obtained directly used in the next step (7.72 g).
Intermediate 27 (IM-27) was obtained as described above with reference to the synthesis of intermediate 22 (IM-22).
Intermediates of examples 222, 256, 267 were synthesized as described above.
Intermediate 28: preparation of 2-chloro-4- (2, 2-difluoroethoxy) -6- (methylsulfonyl) pyridine (IM-28)
Intermediate IM-22 (9.00 g,47.34mmol,1.0 eq.) was added to NMP (100 mL), lithium chloride (8.60 g,202.8mmol,5.0 eq.) and p-toluene sulfonic acid (38.62 g,203.0mmol,5.0 eq.) were added and the resulting mixture was heated to 170 ℃ under nitrogen for 3 hours. Pouring the reaction solution into water, and extracting with ethyl acetate; the organic phases were combined, dried and spun dry under reduced pressure. Purification of the crude product by column chromatography (PE/ea=1/1) afforded intermediate (9.83 g,47.34mmol, 100% yield).
The intermediate (1.00 g,4.81mmol,1.0 eq.) obtained above was dissolved in DMF (10 mL), cesium carbonate (2.36 g,7.24mmol,1.5 eq.) and difluoroiodoethane (1.14 g,5.32mmol,1.1 eq.) were added and the resulting mixture was reacted for 2 hours at room temperature. Pouring the reaction solution into water, and extracting with ethyl acetate; the organic phases were combined, dried and spun dry under reduced pressure. Intermediate IM-28 (1.15 g,4.23mmol, yield 87.8%) was obtained.
The intermediates of examples 241, 243, 244, 249, 250, 253, 262, 263, 265, 266, 268, 269, 270 were synthesized by reference to the methods described above.
Example 1:4- (5-acetamido-1-methyl-1H-pyrrolo [2,3-c ] pyridin-3-yl) -N,2, 6-trimethylbenzamide
Step one: preparation of 4-bromo-N, 2, 6-trimethylbenzamide. 4-bromo-2, 6-dimethylbenzoic acid (3.000 g,13.096mmol,1 eq.) was dissolved in SOCl 2 (3.895 g,32.741mmol,2.5 eq.) in DMF (9.573 mg, 130.964. Mu. Mol,0.01 eq.) is heated to 50deg.C for 1 hour, the system is cooled, dried by rotation, dissolved in DCM, added dropwise to a solution of methylamine alcohol (733.496 mg,26.196mmol,2 eq.) in DCM (80 mL) at-25deg.C, warmed to room temperature, poured into water, separated, and the organic phase is saturated with NaHCO 3 The aqueous solution was washed once, the organic phase was washed once with saturated aqueous NaCl solution, the solution was separated, and the organic phase was dried over anhydrous magnesium sulfate, filtered, and concentrated. The title compound (3.05 g,12.60mmol, yield 96.178%) was obtained.
Step two: preparation of N,2, 6-trimethyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzamide. 4-bromo-N, 2, 6-trimethylbenzamide (0.500 g,2.065mmol,1 eq.) was dissolved in 1, 4-dioxane (10.0 mL) and coupled pinacol borate (576.865 mg,2.272mmol,1.1 eq.) Pd (dppf) Cl was added 2 (150.963 mg, 206.516. Mu. Mol,0.1 eq.) potassium acetate (608.037 mg,6.195mmol,3 eq.) nitrogen was replaced three times, nitrogen blanket, heated to 100℃and reacted for 2 hours, directly fed to the next step.
Step three: 4- (5-chloro-1-methyl-1H-pyrrolo [2, 3-c)]Preparation of pyridin-3-yl) -N,2, 6-trimethylbenzamide. Adding 3-bromo-5-chloro-1-methyl-1H-pyrrolo [2,3-c ] to the solution obtained in step two]Pyridine (507.003mg, 2.065mmol,1 eq.), potassium carbonate (856.803 mg,6.195mmol,3 eq.), pd (dppf) Cl 2 (150.963 mg, 206.516. Mu. Mol,0.1 eq.) water (10.000 mL), nitrogen gas was replaced three times, nitrogen gasProtection, heating to 100deg.C, reacting for 2 hours, cooling the system, pouring into water (100 mL), extracting with EtOAC (200 mL), separating the organic phase, washing once with saturated aqueous NaCl, separating the organic phase, drying the organic phase over anhydrous magnesium sulfate, filtering, concentrating, column chromatography (n-heptane: etOAC=2:1) to give the title compound (0.270 g, 823.655. Mu. Mol, yield 39.883%). MS (m/z) =328.8 [ m+h ]] + 。
Step four: 4- (5-acetamido-1-methyl-1H-pyrrolo [2, 3-c)]Preparation of pyridin-3-yl) -N,2, 6-trimethylbenzamide. 4- (5-chloro-1-methyl-1H-pyrrolo [2, 3-c) ]Pyridin-3-yl) -N,2, 6-trimethylbenzamide (0.270 g, 823.65. Mu. Mol,1 eq.) was dissolved in 1, 4-dioxane (20 mL), acetamide (145.950 mg,2.471mmol,3 eq.) was added, cesium carbonate (805.087 mg,2.471mmol,3 eq.) and Pd 2 (dba) 3 (75.264 mg, 82.365. Mu. Mol,0.1 eq.), X-Phos (39.206 mg, 82.365. Mu. Mol,0.1 eq.) with nitrogen substitution three times, nitrogen protection, heating to 120℃for 2 hours, cooling the system, pouring into water (100 mL), extracting with EtOAC (200 mL), separating the liquid, washing the organic phase once with saturated aqueous NaCl solution, separating the liquid, drying the organic phase over anhydrous magnesium sulfate, filtering, concentrating, column chromatography (n-heptane: etOAC=2:1) to give the title compound (0.002 g, 5.708. Mu. Mol, yield 0.693%). MS (M/z) [ M+H ]] + ＝351.1。
Examples 8,9, 10, 11, 12, 14, 15, 19, 20, 21, 22, 23, 24, 26, 27, 28, 31, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 56, 59, 61, 97, 101, 102, 165, 166, 167, 168, 169, 171, 172, 174, 175, 176, 177, 178, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 227 were prepared as described above.
Example 2:1- (6- (5-acetamido-1-methyl-1H-pyrrolo [2,3-c ] pyridin-3-yl) pyridin-2-yl) cyclopropane-1-carboxylic acid
Step one: preparation of 5-chloro-1-methyl-1H-pyrrolo [2,3-c ] pyridine. A250 mL single-necked flask was charged with 5-chloro-1H-pyrrolo [2,3-c ] pyridine (5.00 g,32.770mmol,1 eq.), DMF (50 mL), cesium carbonate (12.812 g,39.323mmol,1.2 eq.) and methyl iodide (5.581 g,39.323mmol,1.2 eq.) and the mixture was heated to 100℃for 3 hours. The reaction solution was poured into ice water, extracted with ethyl acetate, and the organic phases were combined, dried over anhydrous magnesium sulfate, and dried by filtration to give the title compound (5.05 g,30.311mmol, yield 92.497%).
Step two: n- (1-methyl-1H-pyrrolo [2, 3-c)]Pyridin-5-yl) acetamides. Taking 250mL single-mouth bottle, adding 5-chloro-1-methyl-1H-pyrrolo [2,3-c]Pyridine (5.00 g,30.01 mmol,1 eq.), acetamide (5.318 g,90.032mmol,3 eq.), X-PHOS (2.861 g,6.002mmol,0.2 eq.), pd 2 (DBA) 3 (2.748g，3.001mmol，0.1eq.)，Cs 2 CO 3 (29.334 g,90.032mmol,3 eq.) 1, 4-dioxane (100 mL), nitrogen displacement 3 times, temperature control at 120℃for 3 hours, cooling to room temperature, addition of saturated sodium chloride (100 mL), EA (50 mL), liquid separation, concentration of the organic phase, column chromatography (DCM: meOH=10-20:1) afforded the title compound (4.00 g,21.140mmol, yield 70.442%).
Step three: preparation of N- (3-bromo-1-methyl-1H-pyrrolo [2,3-c ] pyridin-5-yl) acetamide. A100 mL single port flask was used to add N- (1-methyl-1H-pyrrolo [2,3-c ] pyridin-5-yl) acetamide (4.00 g,21.140mmol,1 eq.) DMF (20 mL), NBS (4.515 g, 25.365 mmol,1.2 eq.) and reacted at room temperature for 2 hours, ice water (100 mL), EA extract (50 mL. Times.2), EA phase water wash (100 mL. Times.2), saturated sodium chloride wash (100 mL. Times.2), anhydrous magnesium sulfate dry, concentrate, column chromatography (EA: meOH=20:1) to give the title compound (1.20 g,4.476mmol, yield 21.172%).
Step four: 1- (6- (5-acetamido-1-methyl-1H-pyrrolo [2, 3-c)]Pyridin-3-yl) pyridin-2-yl) cyclopropane-1-carboxylic acid methyl ester. A100 mL single-necked flask was charged with methyl 1- (6-bromopyridin-2-yl) -cyclopropanecarboxylate (200 mg, 745.964. Mu. Mol,1 eq.) and pinacol borate (378.8)57mg,1.492mmol,2 eq.), potassium acetate (219.292 mg,2.238mmol,3 eq.) and Pd (dppf) Cl 2 (54.478 mg, 74.596. Mu. Mol,0.1 eq.) nitrogen was replaced 3 times, the temperature was lowered to 100℃and reacted for 2 hours, cooled to room temperature, and N- (3-bromo-1-methyl-1H-pyrrolo [2, 3-c) was added thereto]Pyridin-5-yl) acetamide (382.077 mg,1.492mmol,2 eq.) Pd (dppf) Cl 2 (54.478 mg, 74.596. Mu. Mol,0.1 eq.), potassium carbonate (309.289 mg,2.238mmol,3 eq.) water (5 mL), nitrogen substitution 3 times, heating to 100℃and reacting for 3 hours, concentrating, column chromatography (DCM: meOH=20:1) to give the title compound (150 mg, 411.639. Mu. Mol, yield 55.182%).
Step five: 1- (6- (5-acetamido-1-methyl-1H-pyrrolo [2, 3-c)]Pyridin-3-yl) pyridin-2-yl) cyclopropane-1-carboxylic acid. A100 mL single-necked flask was taken and charged with 1- (6- (5-acetamido-1-methyl-1H-pyrrolo [2, 3-c)]Pyridin-3-yl) pyridin-2-yl) cyclopropane-1-carboxylic acid methyl ester (120 mg, 329.311. Mu. Mol,1 eq.) LiOH.H 2 O (39.433 mg,1.647mmol,5 eq.), methanol (5 mL) and water (5 mL), nitrogen were replaced 3 times, the temperature was controlled at 50℃and the reaction was carried out for 3 hours, ice water (50 mL) was added, the pH was adjusted to around 5-6, EA was extracted (30 mL. Times.2), the organic phase was dried over anhydrous magnesium sulfate, concentrated, and column chromatographed (DCM: meOH=10-20:1) to give the title compound (80 mg, 228.330. Mu. Mol, yield 69.336%). MS (M/z) [ M+H ]] + ＝351.4。 1 HNMR(400MHz，DMSO-d6)δ(ppm)：10.28(s，1H)，8.97(s，1H)，8.62(s，1H)，8.26(s，1H)，7.72-7.76(m，1H)，7.56-7.58(d，1H)，7.36-7.38(d，1H)，3.92(s，3H)，2.09(s，3H)，1.65(m，2H)，1.53-1.54(m，2H)。
Example 29 was prepared as described above.
Example 3: n- (3- (3- (2-methoxyethoxy) -5- (methylsulfonylamino) phenyl) -1-methyl-1H-pyrrolo [2,3-c ] pyridin-5-yl) acetamide
Step one: preparation of N- (4-methyl-5-nitropyridin-2-yl) acetamide. In a 3000mL single vial was added 4-methyl-5-nitropyridin-2-amine (226.50 g,1.479mol,1 eq.) acetic anhydride (2260 mL), heated to 95℃for 15 hours, concentrated to dryness, toluene distilled as a water-carrying agent (500 mL. Times.2), MTBE slurried, filtered, a small amount of MTBE washed the filter cake, and dried to give the title compound (276.50 g,1.417mol, yield 95.783%).
Step two: preparation of N- (4- (2- (dimethylamino) vinyl) -5-nitropyridin-2-yl) acetamide. N- (4-methyl-5-nitropyridin-2-yl) acetamide (276.50 g,1.417mol,1 eq.) was dissolved in DMF (2760 mL), N-dimethylformamide dimethyl acetal (371.399 g,3.117mol,2.2 eq.) was added and heated to 80℃for reaction for 5 hours, concentrated to dryness, toluene was distilled as a water-carrying agent (500 mL. Times.1), MTBE was slurried (1500 mL), filtered, dried to give the title compound (306.50 g,1.23mol, yield 86.5%).
Step three: preparation of N- (1H-pyrrolo [2,3-c ] pyridin-5-yl) acetamide. N- (4- (2- (dimethylamino) vinyl) -5-nitropyridin-2-yl) acetamide (303.50 g,1.213mol,1 eq.) was dissolved in THF (700.000 mL), 5% palladium on carbon (11.50 g,1.213mol,1 eq.) was added, reacted under hydrogen atmosphere for 3 days, nitrogen was replaced three times, meOH (1L) was added, filtered, the filter cake was washed with a small amount of MeOH, and the filtrate was concentrated to dryness to give the title compound (210.46 g,1.201mol, yield 99.058%).
Step four: preparation of N- (3-bromo-1H-pyrrolo [2,3-c ] pyridin-5-yl) acetamide. N- (1H-pyrrolo [2,3-c ] pyridin-5-yl) acetamide (210.46 g,1.201mol,1 eq.) was dissolved in DMF (1200 mL), NBS (213.75 g,1.201mol,1 eq.) was added under ice bath, stirred for 1 hour, the reaction was poured into ice water (5.0L), N-heptane: MTBE=1:1 (400 mL) was added, stirred overnight, filtered, the filter cake was washed with ice water (1L), filtered again, and dried to give the title compound (240.01 g,944.613mmol, yield 78.630%).
Step five: n- (3-bromo-1-methyl-1H-pyrrolo [2, 3-c)]Pyridin-5-yl) acetamides. N- (3-bromo-1H-pyrrolo [2, 3-c)]Pyridin-5-yl) acetamide (223.00 g,877.666mmol,1 eq.) was dissolved in MeCN (6600 mL), cs 2 CO 3 (571.920 g,1.75 mol,2.0 eq.) sulfuric acid was added dropwiseDimethyl ester (116.235 g,921.549mmol,1.05 eq.) was stirred for 1 hour, THF (4L) was added, the filtrates were combined, concentrated to dryness, washed with ice water, and dried to give the title compound (235.06 g,876.731mmol, yield 99.894%).
Step six: n- (3- (3- (2-methoxyethoxy) -5- (methylsulfonylamino) phenyl) -1-methyl-1H-pyrrole [2,3-c ]]Pyridin-5-yl) acetamides. N- (3-bromo-5- (2-methoxyethoxy) phenyl) methanesulfonamide (0.300 g, 925.380. Mu. Mol,1 eq.) was dissolved in 1, 4-dioxane (10 mL), and coupled pinacol borate (258.258 mg,1.018mmol,1.1 eq.) was added, potassium acetate (272.458 mg,2.776mmol,3 eq.) and Pd (dppf) Cl 2 (33.855 mg, 46.269. Mu. Mol,0.05 eq.) after nitrogen substitution, the reaction was heated to 100℃for 2 hours, cooled and N- (3-bromo-1-methyl-1H-pyrrolo [2, 3-c) was added]Pyridin-5-yl) acetamide (173.672 mg, 647.766. Mu. Mol,0.7 eq.), potassium carbonate (383.679 mg,2.776mmol,3 eq.), pd (dppf) Cl 2 (13.552 mg, 18.508. Mu. Mol,0.02 eq.) in water (1 mL), nitrogen displacement followed by heating to 75℃for 0.5 h, cooling to room temperature, collecting the supernatant, and column chromatography (DCM: meOH=20:1) to give the title compound (0.055 g, 126.580. Mu. Mol, yield 13.68%). MS (M/z) [ M+H ]] + 433.1。 1 H NMR(400MHz，DMSO)δ10.34(s，1H)，9.85(s，1H)，8.65(s，1H)，8.53(s，1H)，7.92(s，1H)，7.08(s，1H)，6.91(s，1H)，6.68(s，1H)，4.13(t，2H)，3.93(s，3H)，3.70(t，2H)，3.35(s，3H)，3.07(s，3H)，2.09(s，3H)。
Examples 53, 54, 57, 58, 62, 63, 64, 68, 69, 70, 71, 72, 74, 79, 81, 82, 88, 89, 91, 92, 93, 94, 95, 96, 99, 100, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 170, 173, 180, 193, 196, 197, 198, 199, 200, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 225, and 225.
Example 4:1- (1-methyl-3- (3- (methylsulfonyl) phenyl) -1H-pyrrolo [2,3-c ] pyridin-5-yl) urea
Step one: preparation of 3-bromo-1-methyl-1H-pyrrolo [2,3-c ] pyridin-5-amine. N- (3-bromo-1-methyl-1H-pyrrolo [2,3-c ] pyridin-5-yl) acetamide (2.5 g,9.32mmol,1.0 eq.) was dissolved in 1, 4-dioxane (31 mL), 5N hydrochloric acid solution (9.32 mL) was added at room temperature, reacted at 85℃for 2 hours, after the reaction was completed, the system was dried, and the mixed solvent of DCM: meOH=10:1 was added for dissolution, and the organic phase was dried and dried to give the title compound (1.20 g, yield 54%).
Step two: preparation of 1- (3-bromo-1-methyl-1H-pyrrolo [2,3-c ] pyridin-5-yl) urea. 3-bromo-1-methyl-1H-pyrrolo [2,3-c ] pyridin-5-amine (1.20 g,5.31mmol,1.0 eq.) was dissolved in THF (45.5 mL), DIPEA (2.06 g,15.92mmol,3.0 eq.) was added, 15% triphosgene toluene solution (1.254 g,5.57mmol,1.1 eq.) (11.5 mL) was added at-78℃and reacted at 78℃for 20 minutes, then 7N ammonia methanol solution (7 mL) was added dropwise at this temperature, and after completion of the reaction, saturated brine (50 mL) was added to the system, suction filtration was performed, and the filter cake was rinsed with EA: meOH=10:1 mixed solvent and dried to give the title compound (0.85 g, yield 59.8%);
Step three: 1- (1-methyl-3- (3- (methylsulfonyl) phenyl) -1H-pyrrolo [2, 3-c)]Pyridin-5-yl) urea. In a single vial was added 3-methylsulfonylphenyl boronic acid (163.525 mg, 817.547. Mu. Mol,1.1 eq.) and 1- (3-bromo-1-methyl-1H-pyrrolo [2, 3-c)]Pyridin-5-yl) urea (0.2 g, 743.225. Mu. Mol,1 eq.) Pd (dppf) Cl 2 (54.382mg，74.322μmol，0.1eq.)，K 2 CO 3 (308.154 mg,2.230mmol,3.0 eq.) 1, 4-dioxane (30 mL), water (2 mL), and nitrogen were warmed to 9The reaction was carried out at 0℃for 14 hours, dried by spin, and then sanded, and column chromatographed (EA: MEOH=20:1) to give the title compound (107.1 mg,0.31mmol, yield 41.84%). MS (M/z) [ M+H ]] + ＝345.5。 1 HNMR(400MHz，DMSO-d6)δ(ppm)8.88(s，1H)，8.58(s，1H)，7.67-8.10(m，6H)，6.57(br，2H)，3.91(s，3H)，3.29(s，3H)。
Examples 51, 52, 55, 60, 65, 66, 67, 73 were prepared as described above.
Example 5: n- (1- ((1 s,3 s) -3-cyanochlorobutyl) -3- (6- (1-cyanochloropropyl) pyridin-2-yl) -1H-pyrrolo [2,3-c ] pyridin-5-yl) acetamide
Step one: preparation of (1 r,3 r) -3-cyanocyclobutylmesylate. (1 r,3 r) -3-hydroxycyclobutane-1-carbonitrile (1.00 g, 10.294 mmol,1 eq.) and diisopropylethylamine (1.597 g,12.356mmol,1.2 eq.) were added at room temperature, methanesulfonic anhydride (2.152 g,12.356mmol,1.2 eq.) was added dropwise, the reaction was reacted for 2 hours, the reaction was added to water, extracted with DCM, the organic phases separated, combined, dried over anhydrous magnesium sulfate, filtered and dried by spin-drying to give the crude title compound (1.90 g,10.844mmol, yield 105.316%) which was directly taken to the next step.
Step two: preparation of (1 s,3 s) -3- (3-bromo-5-chloro-1H-pyrrolo [2,3-c ] pyridin-1-yl) cyclobutane-1-carbonitrile. A single-port flask was taken, 3-bromo-5-chloro-1H-pyrrolo [2,3-c ] pyridine (1.986 g,13.013mmol,1.2 eq.), (1 r,3 r) -3-cyanocyclobutyl methane sulfonate (1.90 g,10.844mmol,1 eq.), cesium carbonate (5.300 g,16.267mmol,1.5 eq.), DMF (20 mL) was added, the reaction was warmed to 100℃for 2 hours, the reaction solution was poured into ice water, filtered, and the cake was dried to give the title compound (2.60 g,11.222mmol, yield 103.485%).
Step three: preparation of (1 s,3 s) -3- (5-chloro-3- (6- (1-cyanochloropropyl) pyridin-2-yl) -1H-pyrrolo [2,3-c ] pyridin-1-yl) cyclobutane-1-carbonitrile. Reference is made to example 1, steps two and three.
Step four: n- (1- ((1 s,3 s) -3-cyanochlorobutyl) -3- (6- (1-cyanochloropropyl) pyridin-2-yl) -1H-pyrrolo [2, 3-c)]Pyridin-5-yl) acetamides. Reference is made to example 1, procedure four. MS (M/z) [ M+H ]] + ＝398.0。 1 H NMR(400MHz，DMSO)δ10.28(s，1H)，8.97(s，1H)，8.78(s，1H)，8.63(s，1H)，7.85(d，2H)，7.45-7.47(m，1H)，5.13-5.19(m，1H)，3.23-3.28(m，1H)，2.90-2.98(m，4H)，1.99-2.10(m，5H)，1.83-1.84(d，2H)。
Examples 13, 16, 17, 18, 25, 30, 32, 75, 77, 78, 83, 84, 85, 86, 87, 90, 98, 194, 195 were prepared as described above.
Example 6: n- (3- (1-methyl-5- (3-methylureido) -1H-pyrrolo [2,3-c ] pyridin-3-yl) -5-morpholinophenyl) methylsulfonamide
Step one: preparation of 1- (3-bromo-1-methyl-1H-pyrrolo [2,3-c ] pyridin-5-yl) -3-methylurea. 3-bromo-1-methyl-1H-pyrrolo [2,3-c ] pyridin-5-amine (1.00 g,4.423mmol,1 eq.) was dissolved in THF (38 mL), DIPEA (1.715 g,13.270mmol,3 eq.) was added, cooled to-78deg.C under nitrogen protection, a solution of triphosgene (1.378 g, 4.640 mmol,1.05 eq.) in toluene (12 mL) was added dropwise, followed by incubation for 15 minutes, 33% aqueous methanol (4 mL) was added, incubated for 15 minutes, followed by reaction at room temperature for 1 minute, saturated brine (20 mL) was added, EA (10 mL) was added, the organic phase was dried, spun dry, and sand was prepared, followed by column chromatography (EA: meOH=30:1) to give the title compound (0.170 g, 600.443. Mu. Mol), yield 13.574%).
Step two: n- (3- (1-methyl-5- (3-methylureido) -1H-pyrrolo [2, 3-c)]Preparation of pyridin-3-yl) -5-morpholinophenyl-methylsulfonamide. N- (3-bromo-5-morpholinophenyl) methanesulfonamide (0.250 g, 745.786. Mu. Mol,1 eq.) was dissolved in 1, 4-dioxane (10 mL) and coupled pinacol borate (208.322 mg, 820.365. Mu. Mol) was added1.1 eq.), potassium acetate (219.579 mg,2.237mmol,3 eq.) Pd (dppf) Cl 2 (27.284 mg, 37.289. Mu. Mol,0.05 eq.) after nitrogen substitution, the reaction was heated to 100deg.C and allowed to react for 2 hours, cooled, and 1- (3-bromo-1-methyl-1H-pyrrolo [2, 3-c) was added ]Pyridin-5-yl) -3-methylurea (168.920 mg, 596.629. Mu. Mol,0.8 eq.) potassium carbonate (309.216 mg,2.237mmol,3 eq.) Pd (dppf) Cl 2 (10.910 mg, 14.916. Mu. Mol,0.02 eq.) in water (1 mL), nitrogen displacement after 0.5 hour, the supernatant was collected, and sand was prepared, followed by column chromatography (EA: meOH=20:1) to give the title compound (32.100 mg, 69.699. Mu. Mol, yield 9.346%). MS (M/z) [ M+H ]] + ＝459.0。 1 H NMR(400MHz，DMSO)δ9.65(s，1H)，8.99(s，1H)，8.54(s，1H)，7.87(m，2H)，7.78(s，1H)，6.93(s，1H)，6.90(s，1H)，6.67(s，1H)，3.88(s，3H)，3.78(m，4H)，3.16(m，4H)，3.04(s，3H)，2.73-2.74(d，3H)。
Example 80 was prepared as described above.
Example 7: n- (1-methyl-3- (3- (methylsulfonyl) phenyl) -1H-pyrrolo [2,3-c ] pyridin-5-yl) acetamide-2, 2-d3
Step one: preparation of 1-methyl-3- (3- (methylsulfonyl) phenyl) -1H-pyrrolo [2,3-c ] pyridin-5-amine. N- (1-methyl-3- (3- (methylsulfonyl) phenyl) -1H-pyrrolo [2,3-c ] pyridin-5-yl) acetamide (0.500 g, 1.458 mmol,1 eq.) was dissolved in 5N hydrochloric acid (1.48 mL) and dioxane (6.2 mL), heated to 85℃for 2 hours, the system was dried, mixed solvent (30 mL) of DCM: meOH=10:1 was added for dissolution, drying, filtration, and drying to give the title compound (0.438 g, 1.457 mmol, yield 99.819%) which was directly fed to the next step.
Step two: n- (1-methyl-3- (3- (methylsulfonyl) phenyl) -1H-pyrrolo [2, 3-c) ]Pyridin-5-yl) acetamide-2, 2-d 3. 1-methyl-3- (3- (methylsulfonyl) phenyl) -1H-pyrrolo [2,3-c]Pyridin-5-amine (0.500 g,1.659mmol,1 eq.) in DMF (10 mL), HATU (757.019 mg,1.991mmol,1.2 eq.) tetradeuterated acetic acid (116.803 mg, 1.8235 mmol,1.1 eq.), DIPEA (643.284 mg,4.977mmol,3 eq.) were added and reacted at 20℃for 1 hour, the system was poured into ice water (30 mL), EA was added to extract (50 mL), the organic phase was dried, concentrated, DCM: meOH=10:1 mixed solvent (10 mL) was slurried, filtered off with suction, the filter cake was washed with water, and dried to give the title compound (0.300 g, 866.006. Mu. Mol, yield 52.196%). MS (M/z) [ M+H ]] + ＝347.4。 1 H NMR(400MHz，DMSO)δ10.38(s，1H)，8.69(s，1H)，8.61(s，1H)，8.12-8.14(m，2H)，7.95-7.97(d，1H)，7.73-7.81(m，2H)，3.96(s，3H)，3.29(s，3H)。
Example 179 was synthesized as described above.
Example 202: n- (3- (4-methoxy-6- (methylsulfonyl) pyridin-2-yl) -1-methyl-1H-pyrrolo [2,3-c ] pyridin-5-yl) acetamide
Step one: intermediate 2-4 (500 mg,1.86mmol,1 eq.) was dissolved in DMF (10 mL) and coupled pinacol borate (704 mg,2.79mmol,1.5 eq.), potassium acetate (549 mg,5.59mmol,3 eq.), X-Phos (88 mg,0.18mmol,0.1 eq.) and Pd were added separately 2 (dba) 3 (170 mg,0.18mmol,0.1 eq.) the resulting mixture was reacted for 4 hours under nitrogen with heating to 90 ℃. The reaction solution was cooled to room temperature, and intermediate 22 (IM-22) (413 mg,1.86mmol,1 eq.), potassium carbonate (773 mg,5.59mmol,3 eq.), water (2 mL), X-Phos (88 mg,0.18mmol,0.1 eq.) and Pd were added 2 (dba) 3 (170 mg,0.18mmol,0.1 eq.) the resulting mixture was blanketed with nitrogen and heated to 90℃for a further 2 hours. The reaction solution was diluted with water and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous magnesium sulfate and spun dry under reduced pressure. The crude product obtained was chromatographed (EA/meoh=5/1) to give the title product (27 mg, yield 3.8%).
Examples 201, 220, 221, 222, 223, 224, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271 were synthesized with reference to the above method.
Experimental example 1 TYK2 JH2 kinase Activity inhibition assay
TYK2 JH2 kinase Activity inhibition assay
TYK2 JH2 (N-His-Tev, 575-869) was expressed in Sf9, a protein from this laboratory, a fluorescein-labeled probe was synthesized by this company, and Anti-6XHis-terbium labled antibody was purchased from Cisbio. High purity 4-hydroxyethyl piperazine ethane sulfonic acid (Hepes), naCl, mgCl 2 Dithiothreitol (DTT), bovine Serum Albumin (BSA), polysorbate-20 (Tween-20) and dimethyl sulfoxide (DMSO) were purchased from Sigma.
The assay buffer used in the experiment is composed of 20mM Hepes pH 7.5, 150mM NaCl and 10mM MgCl 2 2mM DTT, 50. Mu.g/mL BSA and 0.015% Tween-20. Test compound DMSO storage stock solutions were prepared and three-fold concentration gradient dilutions were made with DMSO as required for the experiment at 12 points. The compound of 4% DMSO, TYK2 JH2 enzyme, fluorescein-labeled probe, anti-6XHis-terbium labled antibody were formulated using an assay buffer, after completion of the formulation, 5. Mu.L of 4% DMSO compound, 5. Mu.L of TYK2 JH2 enzyme, 5. Mu.L of fluorescein-labeled probe, and 5. Mu.L of Anti-6XHis-terbium labled antibody were added to the OptiPlate-384 White Opaque plate, covered with a membrane, and incubated at room temperature for 1.5 hours, respectively. The final concentrations of the compound in 4% DMSO, TYK2 JH2 enzyme, fluorescein labeled probe and Anti-6XHis-terbium labled antibody were 1%, 2.5nM, 50nM, 1x, respectively. After 1.5h, the plates were read on a SPARK multi-template reader of TECAN (Switzerland) with excitation wavelengths of 340nm and emission wavelengths of 520nm and 485nm, respectively. IC of inhibitor 50 Values were obtained by using Prism 8 (La Jolla, calif.).
TYK2 JH2 kinase Activity inhibition assay IC of representative Compounds of the application 50 The values are shown in Table 1.
TABLE 1
Examples numbering TYK2 JH2(nM) Examples numbering TYK2 JH2(nM)
1 110 137 2.7
2 62 138 4
3 1.3 139 4.5
4 1.8 140 3.9
5 3.1 141 3.1
6 2.1 142 3.1
7 2 143 0.5
8 2 144 3.5
9 8.8 145 3.1
10 2 146 2.9
11 10.4 147 1.9
12 6.8 148 4.2
13 1.9 149 4.5
14 5.3 150 3.5
15 1.8 151 1.6
16 43 152 4.3
17 15 153 3.6
18 1.9 154 4.6
19 54 155 7.1
20 2.7 156 2.2
21 3.3 157 3.1
22 3.7 158 4
23 1.9 159 2.9
24 6.6 160 4.1
25 4.9 161 2.6
26 9.8 162 3.3
27 4.8 163 2.1
28 5.9 164 5.8
29 7.2 165 N/A
30 4.9 166 N/A
31 2.8 167 N/A
32 9.5 168 N/A
33 2.5 169 2.5
34 3.8 170 2.2
35 2 171 3.5
36 1.8 172 N/A
37 1.6 173 12
38 6 174 5.1
39 1.5 175 4.8
40 1.4 176 4.2
41 1.7 177 12
42 1.9 178 5.8
43 1.7 179 13
44 1.3 180 7.8
45 2.5 181 3.4
46 9.8 182 4.1
47 1.3 183 5.1
48 1.7 184 2.7
49 1.7 185 3.5
50 1.9 186 4.5
51 4 187 3.7
52 1.6 188 4
53 1.7 189 5.3
54 1.6 190 5.7
55 1.7 191 5.5
56 2.9 192 2.5
57 2.9 193 1.7
58 1.5 194 2.1
59 88 195 2.4
60 1.5 196 6.4
61 4.5 197 3.1
62 1.6 198 1.7
63 21 199 2.7
64 37 200 3.9
65 3.5 201 2.8
66 1.8 202 0.7
67 3.8 203 0.7
68 3 204 0.5
69 5.3 205 0.6
70 7.4 206 0.7
71 2.5 207 0.5
72 2.5 208 0.8
73 1.9 209 0.5
74 2.1 210 0.6
75 2.9 211 0.6
76 11 212 3.1
77 3.9 213 2.8
78 2 214 3.6
79 5.1 215 2.6
80 2.9 216 1.4
81 11 217 1.7
82 3.4 218 1.6
83 8.3 219 3.8
84 3.3 220 1.5
85 4.2 221 1.2
86 1.9 222 2.1
87 2.3 223 1.4
88 3.3 224 1.9
89 2.1 225 2.4
90 2 226 2
91 2.5 227 2.5
92 2.3 228 2.5
93 2.6 229 6.1
94 1.9 230 1.8
95 2.1 231 24
96 2 232 2.9
97 425 233 2
98 5.4 234 1.6
99 1.8 235 2
100 4.8 236 0.5
101 5 237 1.2
102 8.1 238 1.1
103 4.7 239 1
104 12 240 2.1
105 8.4 241 0.6
106 2.5 242 1.7
107 3 243 1.2
108 5.6 244 2
109 3.9 245 0.7
110 5.5 246 2.4
111 3.9 247 1.7
112 4.4 248 1.9
113 11 249 0.3
114 3.1 250 0.7
115 3.7 251 0.8
116 3.2 252 0.9
117 5.5 253 1.3
118 3.6 254 0.2
119 2.5 255 1
120 3.7 256 0.8
121 3.9 257 1
122 3.6 258 1.2
123 3.3 259 0.9
124 2 260 0.5
125 3.7 261 0.6
126 3.8 262 0.4
127 2 263 1.1
128 3.2 264 0.7
129 3.2 265 0.7
130 2.3 266 1.1
131 1.7 267 1.2
132 1.8 268 0.7
133 1.7 269 0.4
134 1.9 270 0.3
135 3.9 271 1.3
136 6.2
Experimental example 2 pharmacokinetic testing
1. Summary
The purpose of this test was to investigate the pharmacokinetic profile of the test compound in CD1 mice by single intravenous and intragastric administration.
2. Test protocol
2.1 test drug
Control compound 1, example 10 compound, example 40 compound, example 43 compound, example 99 compound, example 132 compound, example 202 compound, example 220 compound, example 222 compound, example 241 compound.
Reference compound 1 was prepared by the method described in International patent publication WO2019178079A 1.
2.2 test animals
Each test drug was purchased from Shanghai Ji Hui laboratory animal feeding Co., ltd in 18 CD1 mice, male, 6-8 week old, male, 22-28 g.
2.3 pharmaceutical formulation
Intravenous (IV) and intragastric (PO) formulations were formulated with 80% peg400+20% water. The concentrations of the groups IV and PO were 0.2mg/mL, except that the concentration of the group IV was 0.4mg/mL in example 99.
2.4 dosing regimen
The animals of group IV of examples 99, 202, 220, 222 and 241 were given 2mg/kg of the test drug via the tail vein, the other animals of group IV were given 1mg/kg of the test drug via the tail vein, and the animals of group PO were given 10mg/kg of the test drug via the gavage.
Plasma was collected 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 8 hours, 24 hours after dosing of both group IV and PO.
3. Pharmacokinetic analysis
The test adopts LC-MS/MS to measure the content of the test drug in the plasma of the CD1 mouse, adopts WinNonlin 6.4 software (U.S.) to calculate the pharmacokinetic parameters of the plasma according to a non-atrioventricular model according to the drug concentration-time data, and comprises the clearance rate CL and the apparent distribution volume V ss Area under drug-time curve AUC, mean residence time MRT, elimination half-life T 1/2 Peak concentration C max Peak time of sum T max Etc. The calculation formula of oral bioavailability is F (%) = (Dose) IV *AUC- PO )/(Dose PO *AUC- IV ) *100. The test results are shown in Table 2.
TABLE 2
The results show that representative compounds of the present application have significant pharmacokinetic advantages over control compound 1.

Claims (18)

  1. A compound of formula (I):
    or a tautomer, meso, racemate, enantiomer, diastereomer or a pharmaceutically acceptable salt thereof,
    wherein ring a is selected from aryl, heteroaryl or partially unsaturated heterocyclyl;
    x, Y is selected from C or N;
    R 1 selected from hydrogen, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, halo C 1 -C 6 Alkyl, deuterated C 1 -C 6 Alkyl, halogenated C 2 -C 6 Alkenyl, halo C 2 -C 6 Alkynyl, halogen, cyano, nitro, -C (O) NR a R b 、-C(O)R a 、-C(O)OR a 、-OR a 、-R a OR b 、-OC(O)R a 、-OC(O)OR a 、-OC(O)NR a R b 、-NR a R b 、-SR a 、-S(O)R a 、-S(O) 2 R a Or a 3-10 membered saturated or unsaturated ring containing 0-3 heteroatoms, said 3-10 membered saturated or unsaturated ring containing 0-3 heteroatoms optionally substituted with 1-3R a Substitution;
    R 2 selected from hydrogen, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, halo C 1 -C 6 Alkyl, deuterated C 1 -C 6 Alkyl, halogenated C 2 -C 6 Alkenyl, halo C 2 -C 6 Alkynyl, halogen, cyano, nitro, -C (O) NR a R b 、-C(O)R a 、-C(O)OR a 、-OR a 、-R a OR b 、-OC(O)R a 、-OC(O)OR a 、-OC(O)NR a R b 、-NR a R b 、-SR a 、-S(O)R a 、-S(O) 2 R a Or a 3-10 membered saturated or unsaturated ring containing 0-3 heteroatoms, said 3-10 membered saturated or unsaturated ring containing 0-3 heteroatoms optionally substituted with 1-3R a Substitution;
    R 3 selected from hydrogen, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, halo C 1 -C 6 Alkyl, deuterated C 1 -C 6 Alkyl, halogenated C 2 -C 6 Alkenyl, halo C 2 -C 6 Alkynyl, halogen, cyano, nitro, carbonyl, -C (O) NR a R b 、-C(O)R a 、-C(O)OR a 、-OR a 、-R a OR b 、-OR a OR b 、-OC(O)R a 、-OR a C(O)R b 、-OC(O)OR a 、-OC(O)NR a R b 、-NR a R b 、-NC(O)R a 、-RcNR a R b 、-SR a 、-S(O)R a 、-S(O) 2 R a 、-R a CN or a 3-10 membered saturated or unsaturated ring containing 0-3 hetero atoms, said 3-10 membered saturated or unsaturated ring containing 0-3 hetero atoms being optionally substituted with 1-3R a Substitution;
    R 4 selected from hydrogen,Or alternatively by 1-3R a Substituted 3-10 membered saturated or unsaturated ring containing 0-3 hetero atoms, Z being-NH-, -N (CH) 2 ) -or a direct bond;
    R 5 selected from hydrogen, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, halo C 1 -C 6 Alkyl, deuterated C 1 -C 6 Alkyl, halogenated C 2 -C 6 Alkenyl, halo C 2 -C 6 Alkynyl, halogen, cyano, nitro, -C (O) NR a R b 、-C(O)R a 、-C(O)OR a 、-OR a 、-R a OR b 、-OC(O)R a 、-OC(O)OR a 、-OC(O)NR a R b 、-NR a R b 、-SR a 、-S(O)R a 、-S(O) 2 R a Or a 3-10 membered saturated or unsaturated ring containing 0-3 heteroatoms, said 3-10 membered saturated or unsaturated ring containing 0-3 heteroatoms optionally substituted with 1-3R a Substitution;
    R 6 selected from hydrogen, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, halo C 1 -C 6 Alkyl, deuterated C 1 -C 6 Alkyl, halogenated C 2 -C 6 Alkenyl, halo C 2 -C 6 Alkynyl, halogen, cyano, nitro, -C (O) NR a R b 、-C(O)R a 、-C(O)OR a 、-OR a 、-R a OR b 、-OC(O)R a 、-OC(O)OR a 、-OC(O)NR a R b 、-NR a R b 、-SR a 、-S(O)R a 、-S(O) 2 R a Or a 3-10 membered saturated or unsaturated ring containing 0-3 heteroatoms, said 3-10 membered saturated or unsaturated ring containing 0-3 heteroatoms optionally substituted with 1-3R a Substitution;
    each R a 、R b 、R c Each independently selected from hydrogen, deuterium, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl, C 2 -C 6 Alkynyl, halo C 1 -C 6 Alkyl, deuterated C 1 -C 6 Alkyl, halogenated C 2 -C 6 Alkenyl, halo C 2 -C 6 Alkynyl, halogen, cyano, nitro, amino, carboxyl, carbonyl, hydroxyl, hydroxyalkyl, alkoxy, haloalkoxy, deuteroalkoxy, C 3 -C 6 Cycloalkyl, halo C 3 -C 6 Cycloalkyl, alkoxy substituted C 3 -C 6 Cycloalkyl, C 3 -C 6 Heterocyclyl, halo C 3 -C 6 Heterocyclyl, alkyl substituted C 3 -C 6 Heteroaryl, -S (O) 2 R d 、-OR d OR e 、-R d OR e 、-C(O)R d or-OC (O) R d Each R is d 、R e Each independently selected from C 1 -C 6 An alkyl group; and
    n=0, 1, 2 or 3.
  2. A compound of formula (I) according to claim 1, wherein ring a is selected from phenyl, pyridinyl, pyrazinyl, tetrahydropyridinyl, pyrazolyl, benzothiazolyl or imidazo [1,5-a ] pyridinyl.
  3. The compound of formula (I) according to claim 1, wherein R 4 Selected from the group consisting of Z is-NH-, -N (CH) 2 ) -or a direct bond.
  4. A compound of formula (I) according to claim 3, wherein R 4 Selected from the group consisting of
  5. The compound of formula (I) according to claim 1, wherein formula (I) is formula (Ia):
    R 2 ' selected from hydrogen, C 1 -C 6 Alkyl, halogenated C 1 -C 6 Alkyl, deuterated C 1 -C 6 Alkyl, C3-C6 cycloalkyl, halogen, -NH 2 or-NHCH 3 ；
    n、X、Y、Z、R 1 、R 3 、R 5 、R 6 As defined in claim 1.
  6. The compound of formula (I) according to claim 1, wherein formula (I) is formula (Ib):
    R 1 、R 3 、R 5 、R 6 r is as defined in claim 1 2 ' as defined in claim 5.
  7. The compound represented by formula (I) according to claim 1, wherein formula (I) is formula (Ic):
    R 2 ' selected from hydrogen, C 1 -C 6 Alkyl, halogenated C 1 -C 6 Alkyl, deuterated C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, halogen, -NH 2 or-NHCH 3 ；
    n、X、Y、Z、R 1 、R 3 、R 5 、R 6 As defined in claim 1.
  8. The compound represented by formula (I) according to claim 1, wherein formula (I) is formula (Id):
    R 1 、R 3 、R 5 、R 6 r is as defined in claim 1 2 ' as defined in claim 5.
  9. The compound of formula (I) according to claim 1, wherein R 1 Selected from hydrogen, methyl, -CD 3 Ethyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl,
  10. The compound of formula (I) according to claim 1, wherein R 3 Selected from hydrogen, methyl, ethyl, fluoro, chloro, cyano, methoxy, ethoxy, hydroxymethyl, carbonyl, carboxyl, -CHF 2 、-OCHF 2 、-CF 3 、-OCF 3 、-OCD 3 、
  11. A compound of formula (I) according to claim 1, selected from:
  12. use of a compound according to any one of claims 1-11, an isomer thereof or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for diseases mediated by TYK 2.
  13. The use of claim 12, wherein the TYK 2-mediated disease is an autoimmune disease, an inflammatory disease, a proliferative disease, an endocrine disease, a neurological disease, or a disease associated with transplantation.
  14. The use according to claim 13, wherein the disease is an autoimmune disease.
  15. The use of claim 14, wherein the autoimmune disease is selected from type 1 diabetes, ankylosing spondylitis, systemic lupus erythematosus, multiple sclerosis, systemic sclerosis, psoriasis, crohn's disease, ulcerative colitis, or inflammatory bowel disease.
  16. The use according to claim 13, wherein the disease is an inflammatory disease.
  17. The use according to claim 16, wherein the inflammatory disease is selected from the group consisting of rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, psoriasis, crohn's disease, ulcerative colitis, and inflammatory bowel disease.
  18. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of claims 1-9, an isomer thereof, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier or excipient.
CN202280021571.6A 2021-05-19 2022-05-19 TYK2 selective inhibitors and uses thereof Pending CN117043162A (en)

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