CN117355508A - Heterocyclic derivative and application thereof in medicine - Google Patents

Heterocyclic derivative and application thereof in medicine Download PDF

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Publication number
CN117355508A
CN117355508A CN202180053180.8A CN202180053180A CN117355508A CN 117355508 A CN117355508 A CN 117355508A CN 202180053180 A CN202180053180 A CN 202180053180A CN 117355508 A CN117355508 A CN 117355508A
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alkyl
amino
substituted
methyl
halogen
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张晨
赵明亮
李路
余彦
叶飞
唐平明
杨定菊
邓华
李瑶
倪佳
严庞科
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Tibet Haisike Pharmaceutical Co ltd
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Tibet Haisike Pharmaceutical 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4192—1,2,3-Triazoles
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4245—Oxadiazoles
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D247/00—Heterocyclic compounds containing rings having two nitrogen atoms as the only ring hetero atoms, according to more than one of groups C07D229/00 - C07D245/00
    • C07D247/02—Heterocyclic compounds containing rings having two nitrogen atoms as the only ring hetero atoms, according to more than one of groups C07D229/00 - C07D245/00 having the nitrogen atoms in positions 1 and 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D261/14—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Abstract

Relates to a compound shown in a general formula (I) or stereoisomers, tautomers, deuterides, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or eutectic crystals thereof, intermediates and preparation methods thereof, and application of the compound or stereoisomers, tautomers, deuterides, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or eutectic crystals in preparation of medicaments for treating diseases related to JAK kinase activity or expression level.

Description

Heterocyclic derivative and application thereof in medicine Technical Field
The invention relates to a compound shown in a general formula (I) or stereoisomers, tautomers, deuterides, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or eutectic crystals thereof, intermediates and preparation methods thereof, and application of the compound or stereoisomers, tautomers, deuterides, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or eutectic crystals thereof in preparation of medicaments for treating diseases related to JAK kinase activity or expression level.
Background
Inflammatory bowel disease, also known as Inflammatory Bowel Disease (IBD), is a idiopathic intestinal inflammatory disease involving the ileum, rectum, and colon. The clinical manifestations of diarrhea and abdominal pain may even be bloody stool. Including Ulcerative Colitis (UC) and Crohn's Disease (CD). Ulcerative colitis is a continuous inflammation of the mucosal and submucosal layers of the colon, with the disease usually involving the rectum and gradually spreading to the whole colon, and crohn's disease may involve the whole digestive tract, a discontinuous full-thickness inflammation, most often in the terminal ileum, colon and perianal regions.
The global incidence of inflammatory bowel disease is high, with the incidence of many countries in north america and europe exceeding 0.3%, rising year by year since 1990 in africa, asia and south america.
Janus kinase/signal transduction and transcription activator (Janus-activated kinase Singal transducers and activators of transcriprion, JAK-STAT) is an intracellular signal transduction pathway closely related to cytokines newly discovered in recent years, and is involved in a plurality of important biological processes such as proliferation, differentiation, apoptosis, immune regulation and the like of cells. Janus kinase is a non-receptor type tyrosine protein kinase. There are 4 family members, JAK1, JAK2, TYK2 and JAK3, respectively. The JAK/STAT signaling pathway is an important intracellular signaling pathway in the growth, activation, differentiation, apoptosis and function of many cells, and many cytokines such as the Interferon (IFN) family, glycoprotein 130 (gp 130) family, gamma-C family and single chain family activate the signaling pathway. The signal transduction chain of the cytokine receptor carries JAK tyrosine protein kinase, when the cytokines are combined with the cell surface specific receptor, JAK molecules on the signal transduction chain are polymerized and phosphorylated mutually to activate, and tyrosine residues (Y) on the intracellular segment of the other receptor chain are phosphorylated to PY by releasing phosphate (P), and the phosphorylated tyrosine sites form a parking site (docking site) with surrounding amino acid sequences, so that transcription factors STAT with SH2 domains are recruited, at the moment, tyrosine in the STAT is also activated by obtaining phosphate from the activated JAK to form homodimers, and after the receptor is separated, nuclear localization signals of the tyrosine molecules are exposed to enter the nucleus to be combined with target genes to regulate the transcription of genes. JAK-STAT intracellular signaling is applicable to interferons, most interleukins, and a variety of cytokines and endocrine factors.
The exact pathogenesis of UC is not known, but the pro-inflammatory cytokines play a critical role in the immune response (s Qiao Bo et al, gastroenterol,2011,140,1756-1767). Many of the most elevated pro-inflammatory cytokines in UC (e.g., IL-4, IL-6, IL-13, IL-15, IL-23, IL-24, ifnγ, and leptin) rely on the JAK family of tyrosine kinases (JAK 1, JAK2, JAK3, and Tyk 2) for signal transduction, and inhibition of the JAK enzyme family can inhibit signaling of a number of key pro-inflammatory cytokines. Thus, inhibition of the JAK enzyme family is expected to have therapeutic benefit for ulcerative colitis and other inflammatory diseases.
Inhibition of the JAK enzyme family inhibits signaling of a variety of key pro-inflammatory cytokines. Therefore, JAK inhibitors are likely to be useful in the treatment of ulcerative colitis and other inflammatory diseases such as Crohn's disease, allergic rhinitis, atopic Dermatitis (AD) and other inflammatory skin disorders. However, due to the modulating effect of the JAK/STAT pathway on the immune system, systemically exposed JAK inhibitors have adverse systemic immunosuppressive effects, and thus, there is a need to provide novel JAK inhibitors that have an effect at the site of action without significant systemic effect. In particular, for the treatment of gastrointestinal inflammatory diseases (e.g., ulcerative colitis, crohn's disease), it is desirable to provide novel JAK inhibitors that can be orally administered and achieve therapeutically relevant exposures in the gastrointestinal tract with minimal systemic exposure. There is also a need to provide novel JAK inhibitors for the treatment of atopic dermatitis with minimal systemic exposure.
Disclosure of Invention
The invention aims to provide a compound capable of inhibiting JAK kinase or stereoisomers, tautomers, deuterides, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or eutectic crystals thereof, intermediates and preparation methods thereof, and application of the compound in preparing medicaments for treating diseases related to JAK activity or expression level.
The compounds of the present invention have good JAK kinase inhibitory activity, anti-inflammatory activity, better safety, intestinal targeting, skin targeting and good skin permeability.
The present invention provides a compound of formula (I) or a stereoisomer, tautomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein
In certain embodiments, L is selected from a bond or NR n2 ；
In certain embodiments, L is selected from NR n2 ；
In certain embodiments, L is selected from a bond;
in certain embodiments, R n1 、R n2 Each independently selected from H, C 1-6 Alkyl or C 3-6 Cycloalkyl, said alkyl or cycloalkyl optionally being further substituted with 0 to 4 groups selected from H, halogen, CF 3 OH, cyano, NH 2 、C 1-6 Alkyl or C 1-6 Substituted with alkoxy;
in certain embodiments, R n2 Selected from H or C 1-6 Alkyl, said alkyl optionally being further substituted with 0 to 4 groups selected from H, halogen, CF 3 OH, cyano, NH 2 、C 1-6 Alkyl or C 1-6 Substituted with alkoxy;
in certain embodiments, R n2 Selected from H or C 1-4 An alkyl group;
in certain embodiments, R n2 Selected from H, methyl or ethyl;
in certain embodiments, R n2 Selected from H or methyl;
in certain embodiments, R n1 、R n2 Selected from H;
in certain embodiments, ring A is selected from 5-8 membered heteroaryl rings, optionally further substituted with 0 to 3R a A substitution, said heteroaryl ring containing 1 to 5 heteroatoms selected from O, S, N;
in certain embodiments, ring a is selected from 5 to 6 membered heteroaryl rings, optionally further substituted with 0, 1 or 2R a Substituted, providedThe heteroaromatic ring contains 1 to 3 heteroatoms selected from O, S, N;
in certain embodiments, ring a is selected from one of the following substituted or unsubstituted: pyrimidinyl, pyrazinyl, pyridazinyl, pyridinyl, triazinyl, pyrazolyl, imidazolyl, pyrrolyl, triazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, thiadiazolyl, optionally further substituted with 0, 1 or 2R a Substituted;
In certain embodiments, ring a is selected from one of the following substituted or unsubstituted: pyrimidinyl, pyrazinyl, triazolyl or oxadiazolyl, optionally further substituted with 0, 1 or 2R a Substituted; in certain embodiments, ring a is selected fromA 1 Selected from O, S, NH, N (CH) 3 ) Or N (CH) 2 CH 3 )，A 2 Selected from CR a Or N;
in certain embodiments, ring a is selected from one of the following substituted or unsubstituted: when substituted, optionally further substituted with 0, 1 or 2R a Substituted, the upper side of which is connected with L;
in certain embodiments, ring a is selected from one of the following substituted or unsubstituted: when substituted, optionally further substituted with 0, 1 or 2R a Substituted, the upper side of which is connected with L;
in certain embodiments, R a Each independently selected from H, halogen, cyano, OH, C 1-6 Alkyl, C 1-6 Alkoxy, - (O-C) 1-6 An alkylene group q -C 1-6 Alkoxy, - (O-C) 1-6 An alkylene group q -OH、-(CH 2 ) q -C(＝O)-NR a1 R a2 、-(CH 2 ) q -NR a1 R a2 、-(CH 2 ) q NR a1 C(＝O)-R a2 、-(CH 2 ) q -C 3-10 Carbocycles, - (CH) 2 ) q -3 to 12 membered heterocycles, (CH) 2 ) q -P(＝O)(C 1-6 Alkyl group 2 OR-OR a3 said-CH 2 -, alkyl, alkoxy, carbocycle or heterocycle optionally further substituted with 0 to 4 groups selected from H, halogen, OH, =o, cyano, NH 2 、C 1-6 Alkyl, halogen substituted C 1-6 Alkyl or C 1-6 Substituted with an alkoxy substituent, said heterocycle containing 1 to 3 heteroatoms selected from O, S, N;
In certain embodiments, R a Each independently selected from H, halogen, cyano, OH, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Carbocycles, 3-to 6-membered heterocycles, - (CH) 2 ) q -C(＝O)-NR a1 R a2 、-(CH 2 ) q NR a1 C(＝O)-R a2 、-(CH 2 ) q -NR a1 R a2 、-(O-C 1-4 An alkylene group q -C 1-4 Alkoxy, CH 2 -3 to 6 memberedHeterocycle, -P (=o) (C 1-4 Alkyl group 2 OR-OR a3 said-CH 2 -, alkyl, alkoxy, carbocycle or heterocycle optionally further substituted with 0 to 4 groups selected from H, halogen, OH, =o, cyano, NH 2 、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl or C 1-4 Substituted with an alkoxy substituent, said heterocycle containing 1 to 3 heteroatoms selected from O, S, N;
in certain embodiments, R a Each independently selected from H, F, cyano, OH, CF 3 、CHF 2 、CH 2 F. Methyl, ethyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, pyrazolyl, triazolyl, thiazolyl, imidazolyl, oxazolyl, thienyl, furyl, pyrrolyl, isoxazolyl, isothiazolyl, pyridyl, pyrimidinyl, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, tetrahydrofuranyl, dihydrofuryl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, -P (=o) (CH 3 ) 2 、-P(＝O)(CH 2 CH 3 ) 2 、-P(＝O)(CH 2 CH 2 CH 3 ) 2 、-OCH 2 CH 2 OCH 3 、-OCH 2 CH 2 OCH 2 CH 2 OCH 3 、-CH 2 NHCH 2 CH 2 CN、-CH 2 NHCH 2 CN、-CH 2 NHCH 2 CH 2 CH 2 CN、-CH 2 C(＝O)NH-Ph-CH 2 OH、-CH 2 C(＝O)NH-Ph-CH 2 CN、-CH 2 C(＝O)NH-Ph-CH 2 F、-CH 2 C(＝O)NH-Ph-CHF 2 、-CH 2 C(＝O)NH-Ph-CF 3 、-CH 2 C(＝O)NHCH 2 -cyclopropyl, -CH 2 C(＝O)NHCH 2 -cyclobutyl, -CH 2 C(＝O)NHCH 2 -cyclopentyl, -CH 2 C(＝O)NHCH 2 -cyclohexyl, -CH 2 C(＝O)NHCH 2 CH 2 NH 2 、-CH 2 C(＝O)NHCH 2 CH 2 NHCH 3 、-CH 2 C(＝O)NHCH 2 CH 2 N(CH 3 ) 2 、-CH 2 C(＝O)NHCH 2 CH 2 N(CH 2 CH 3 ) 2 -NH-pyrazolyl, -NH-thiazolyl, -NH-imidazolyl, -NH-oxazolyl, -NH-thienyl, -NH-furanyl, -NH-pyrrolyl, -NH-isoxazolyl, -NH-isothienyl, -NH-pyridinyl, -NH-pyrimidinyl, -NH-phenyl, -NH-cyclopropyl, -NH-cyclobutyl, -NH-cyclopentyl, -NH-cyclohexyl, -C (=o) NH 2 、-C(＝O)NHCH 3 、-C(＝O)NHCH 2 CH 3 -C (=o) NH-cyclopropyl, -C (=o) NH-cyclobutyl, -C (=o) NH-cyclopentyl, -C (=o) NH-cyclohexyl, -C (=o) NH-phenyl, -NHC (=o) H, -NHC (=o) CH 3 、-NHC(＝O)CH 2 CH 3 、-NHC(＝O)CH 2 CH 2 CH 3 -NHC (=o) -cyclopropyl, -NHC (=o) -cyclobutyl, -NHC (=o) -cyclopentyl, -NHC (=o) -cyclohexyl, -NHC (=o) -phenyl OR-OR a3 The methyl, ethyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrazolyl, triazolyl, thiazolyl, imidazolyl, oxazolyl, thienyl, furyl, pyrrolyl, isoxazolyl, isothiazolyl, pyridyl, pyrimidinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dihydrofuranyl, or phenyl optionally further substituted with 0, 1, 2, 3 or 4 groups selected from H, F, CF 3 OH, =O, cyano, NH 2 A methyl, ethyl, methoxy or ethoxy substituent;
in certain embodiments, R a Each independently selected from H, F, cyano, OH, CF 3 、CHF 2 Methyl, ethyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, pyrazolyl, triazolyl, thiazolyl, imidazolyl, oxazolyl, thienyl, furyl, tetrahydrofuranyl, dihydrofuryl, tetrahydropyranyl, pyrrolyl, isoxazolyl, isothienyl, pyridyl, pyrimidinyl, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, -O-cyclopropyl, -O-cyclopentyl, -O-cyclobutyl, -O-cyclohexyl, -O-azetidinyl, -O-oxetanyl, -O-tetrahydrofuranyl, -O-tetrahydropyranyl, -O-CH 2 -pyrrolidinyl, -OCH 2 N(CH 3 ) 2 、-OCH 2 CH 2 N(CH 3 ) 2 、-OCH(CH 3 )CH 2 N(CH 3 ) 2 、-OCH 2 CH 2 OCH 3 、-OCH 2 CH 2 OCH 2 CH 2 OCH 3 、-P(＝O)(CH 3 ) 2 、-P(＝O)(CH 2 CH 3 ) 2 、-P(＝O)(CH 2 CH 2 CH 3 ) 2 、-C(＝O)NH 2 -C (=o) NH-cyclopropyl, -C (=o) NH-cyclobutyl, -C (=o) NH-cyclopentyl, -C (=o) NH-cyclohexyl, -OCH 2 CH 2 -piperidinyl, -OCH 2 CH 2 -pyrrolidinyl, -OCH 2 CH 2 -azetidinyl, -OCH 2 CH 2 Morpholinyl, -OCH 2 -piperidinyl, -OCH 2 -azetidinyl, -OCH 2 Morpholinyl, -OCH 2 Tetrahydrofuran radical,The methyl, ethyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrazolyl, triazolyl, thiazolyl, imidazolyl, oxazolyl, thienyl, furyl, pyrrolyl, isoxazolyl, isothiazolyl, pyridyl, pyrimidinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, and the like, Or phenyl optionally further substituted with 0, 1, 2, 3 or 4 groups selected from H, F, CF 3 OH, cyano, NH 2 A methyl, ethyl, methoxy, =o, or ethoxy substituent;
in certain embodiments, R a Each independently selected from H, F, CF 3 Methyl, methoxy, ethoxy, isopropoxy, pyrazolyl, imidazolyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, pyridinyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, -O-cyclopentyl, -O-oxetanyl, -O-tetrahydrofuranyl, -O-tetrahydropyranyl, -O-CH 2 -pyrrolidinyl, -OCH 2 CH 2 N(CH 3 ) 2 、-OCH(CH 3 )CH 2 N(CH 3 ) 2 、-OCH 2 CH 2 OCH 3 、-C(＝O)NH 2、 -C (=o) NH-cyclopropyl, -OCH 2 CH 2 -piperidinyl, -OCH 2 CH 2 -pyrrolidinyl, -OCH 2 CH 2 Morpholinyl, -OCH 2 Tetrahydrofuran radical,The methyl, methoxy, ethoxy, cyclopropyl, cyclopentyl, pyrazolyl, imidazolyl, pyridyl, azetidinyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, and the like,Optionally further substituted with 0, 1, 2, 3 or 4 substituents selected from H, F, OH, methyl, methoxy, =o;
in certain embodiments, R a Each independently selected from H, F, -OCH 3 、-OCH(CH 3 ) 2 、-OCH 2 CH 3 、-CF 3 、-CH 2 OH、-CONH 2 -CONH-cyclopropyl, -OCH 2 CH 2 OCH 3 、-OCH 2 CH 2 OH、-OCH 2 CH 2 N(CH 3 ) 2 、-OCH(CH 3 )CH 2 N(CH 3 ) 2 、
In certain embodiments, R a3 Each independently selected from- (CH) 2 ) q -NR a1 R a2 、-(CH 2 ) q NR a1 C(＝O)-R a2 、-(CH 2 ) q -C 3-10 Carbocycle or- (CH) 2 ) q -3 to 12 membered heterocycle, said-CH 2 -, carbocycle, heterocycle is further selected from 0 to 4 groups selected from H, halogen, OH, =o, cyano, NH 2 、C 1-6 Alkyl, halogen substituted C 1-6 Alkyl or C 1-6 Substituted with an alkoxy substituent, said heterocycle containing 1 to 3 heteroatoms selected from O, S, N;
in certain embodiments, R a3 Each independently selected from- (CH) 2 ) q -NR a1 R a2 、-(CH 2 ) q -C 3-10 Carbocycle or- (CH) 2 ) q -3 to 12 membered heterocycle, said-CH 2 -, carbocycle, heterocycle is further selected from 0 to 4 groups selected from H, halogen, OH, =o, cyano, NH 2 、C 1-6 Alkyl, halogen substituted C 1-6 Alkyl or C 1-6 Substituted with an alkoxy substituent, said heterocycle containing 1 to 3 heteroatoms selected from O, S, N;
in certain embodiments, R a3 Each independently selected from- (CH) 2 ) q -NR a1 R a2 、-(CH 2 ) q -C 3-6 Carbocycle or- (CH) 2 ) q -3 to 6 membered heterocycle, said-CH 2 -, carbocycle, heterocycle is further selected from 0 to 4 groups selected from H, halogen, OH, =o, cyano, NH 2 、C 1-6 Alkyl, halogen substituted C 1-6 Alkyl or C 1-6 Substituted with an alkoxy substituent, said heterocycle containing 1 to 3 heteroatoms selected from O, S, N;
in certain embodiments, R a3 Each independently selected from-CH 2 N(CH 3 ) 2 、-CH 2 CH 2 N(CH 3 ) 2 、-CH(CH 3 )CH 2 N(CH 3 ) 2 、-CH 2 CH 2 N(CH 2 CH 3 ) 2 、-CH 2 CH 2 NH 2 、-CH 2 CH 2 NHCH 3 Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, oxetanyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, -CH 2 -cyclopropyl, -CH 2 -cyclobutyl, -CH 2 -cyclopentyl, -CH 2 -cyclohexyl, -CH 2 -azetidinyl, -CH 2 Pyrrolidinyl, -CH 2 -piperidinyl, -CH 2 Morpholinyl, -CH 2 Piperazinyl, -CH 2 -oxetanyl, -CH 2 -tetrahydrofuranyl, -CH 2 Tetrahydropyranyl, -CH 2 CH 2 -piperidinyl, -CH 2 CH 2 Pyrrolidinyl, -CH 2 CH 2 -azetidinyl, -CH 2 CH 2 Morpholinyl group,The cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,Optionally further 0, 1, 2, 3 or 4 are selected from H, F, CF 3 OH, =O, cyano, NH 2 A methyl, ethyl, methoxy or ethoxy substituent;
in certain embodiments, R a3 Each independently selected from-CH 2 CH 2 N(CH 3 ) 2 、-CH(CH 3 )CH 2 N(CH 3 ) 2 Cyclopentyl, oxetanyl, tetrahydrochyseneFuryl, tetrahydropyranyl, -CH 2 Pyrrolidinyl, -CH 2 CH 2 -piperidinyl, -CH 2 CH 2 Morpholinyl group,The cyclopentyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, morpholinyl,Optionally further substituted with 0, 1, 2, 3 or 4 substituents selected from H, F, OH, methyl;
in certain embodiments, R a3 Each independently selected from the following:
in certain embodiments, ring B is selected from non-aromatic C 3-12 Carbocycles, optionally from a single ring, a parallel ring, a bridged ring or a spiro ring, optionally further substituted with 0 to 3R b Substituted by substituents;
in certain embodiments, ring B is selected from C 3-8 Monocycloalkyl, C 4-10 And cycloalkyl, C 5-12 Spirocycloalkyl, C 5-12 Bridged cycloalkyl, said cycloalkyl optionally being further substituted with 0 to 3R b Substituted by substituents;
in certain embodiments, ring B is selected from one of the following substituted or unsubstituted: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl-cyclobutyl, cyclopropyl-cyclopentyl, cyclopropyl-cyclopropylAnd-cyclohexyl, cyclobutyl-cyclobutyl, cyclobutyl-cyclopentyl, cyclobutyl-cyclohexyl, cyclopentyl-cyclopentyl, cyclopentyl-cyclohexyl, cyclohexyl-cyclohexyl, cyclopropyl-spirobutyl, cyclopropyl-spiropentyl, cyclopropyl-spirocyclohexyl, cyclobutyl-spirobutyl, cyclobutyl-spiropentyl, cyclobutylspirocyclohexyl, cyclopentyl-spiropentyl, cyclopentyl-spirocyclohexyl, cyclohexyl-spirocyclohexyl, bicyclo [1.1.1 ] 1 ]Pentanyl and bicyclo [2.1.1]Hexalkyl and bicyclo [2.2.1]Heptyl and bicyclo [3.3.2]Decyl and bicyclo [2.2.2]Octyl and bicyclo [3.2.1]Octyl and bicyclo [3.3.3]Undecyl or adamantyl, when substituted, optionally further substituted with 0 to 3R b Substitution;
in certain embodiments, ring B is selected from a substituted or unsubstituted cyclohexyl or adamantyl, optionally further substituted with 0, 1, or 2R when substituted b Substitution;
in certain embodiments, R b Each independently selected from H, halogen, cyano, OH, C 1-6 Alkyl or C 1-6 Alkoxy, said alkyl or alkoxy optionally being further substituted with 0 to 4 groups selected from H, halogen, OH, cyano, NH 2 、C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 Substituted cycloalkyl;
in certain embodiments, R b Each independently selected from H, halogen, cyano, OH, C 1-6 Alkyl or C 1-6 Alkoxy, said alkyl or alkoxy optionally being further substituted with 0 to 4 groups selected from H, halogen, OH, cyano, NH 2 、C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 Substituted by substituents of cycloalkyl and when B contains 2R b Substituent, any one R b In the case of OH, the other cannot be OH or-CH 2 OH；
In certain embodiments, R b Each independently selected from H, halogen, cyano、OH、C 1-4 Alkyl or C 1-4 Alkoxy, said alkyl or alkoxy optionally being further substituted with 0 to 4 groups selected from H, halogen, OH, cyano, NH 2 、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, C 1-4 Alkoxy or C 3-4 Substituted by substituents of cycloalkyl and when B contains 2R b Substituent, any one R b In the case of OH, the other cannot be OH or-CH 2 OH；
In certain embodiments, R b Each independently selected from H, halogen, cyano, OH, C 1-4 Alkyl or C 1-4 Alkoxy, and when B contains 2R b Substituent, any one R b In the case of OH, the other cannot be OH;
in certain embodiments, R b Each independently selected from H, OH or C 1-4 Alkyl optionally further substituted with cyano and when B contains 2R b Substituent, any one R b In the case of OH, the other cannot be OH;
in certain embodiments, R b Each independently selected from H or F;
in certain embodiments, R b Each independently selected from H;
in certain embodiments, R 1 Selected from 5-to 10-membered heteroaryl or phenyl, said heteroaryl or phenyl optionally being further substituted with 0 to 4R 1a Substitution;
in certain embodiments, R 1 Are each independently selected from m is independently selected from 0, 1 or 2;
In certain embodiments, R 1 Selected from the group consisting ofm is independently selected from 0, 1 or 2;
provided that when R 1 Is thatWhen ring A is not
In certain embodiments, R 1 Selected from the group consisting of
In certain embodiments, R 1 Selected from the group consisting of
In certain embodiments, R 1 Selected from the group consisting of
In certain embodiments, R 1a Each independently selected from H, halogen, OH, cyano, NH 2 、-NH(C 1-6 Alkyl), -N (C) 1-6 Alkyl group 2 、-NH(C 3-6 Cycloalkyl group, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3-to 8-membered heterocyclyl, said alkyl, alkoxy, cycloalkyl or heterocyclyl optionally being further substituted with 0 to 4 groups selected from H, halogen, OH, cyano, NH 2 Halogen-substituted C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 Substituted cycloalkyl;
in certain embodiments, R 1a Each independently selected from H, halogen, OH, cyano, NH 2 、-NH(C 1-4 Alkyl), -N (C) 1-4 Alkyl group 2 、-NH(C 3-4 Cycloalkyl group, C 1-4 Alkyl or C 1-4 Alkoxy, said alkyl or alkoxy optionally being further substituted with 0 to 4 groups selected from H, halogen, OH, cyano, NH 2 Halogen-substituted C 1-4 Alkyl, C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 Substituted cycloalkyl;
in certain embodiments, R 1a Each independently selected from H, F, OH, cyano, methyl, ethyl, isopropyl, propyl, methoxy or ethoxy, said methyl, ethyl, isopropyl, propyl, methoxy or ethoxy optionally being further substituted with 0, 1 or 2 groups selected from H, halogen, OH, cyano, NH 2 Halogen-substituted C 1-4 Alkyl, C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 Substituted cycloalkyl;
in certain embodiments, R 1a Each independently selected from H, methyl, said methyl optionally further substituted with OH;
in certain embodiments, R 1b Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, said alkyl or cycloalkyl optionally being further substituted with 0 to 4 groups selected from H, halogen, OH, cyano, NH 2 、C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 Substituted cycloalkyl;
in certain embodiments, R 1b Selected from C 1-4 Alkyl, C 3-6 Cycloalkyl, said alkyl or cycloalkyl optionally being further substituted with 0 to 4 groups selected from H, halogen, OH, cyano, NH 2 、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 Substituted cycloalkyl;
in certain embodiments, R 1b Selected from methyl, ethyl, isopropyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, said methyl, ethyl, isopropyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl optionally further being 0, 1 or 2 members selected from H, halogen, OH, cyano, NH 2 Halogen-substituted C 1-4 Alkyl, C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 Substituted cycloalkyl;
In certain embodiments, R 2 Selected from halogen, cyano, OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, - (CH) 2 ) q -C(＝O)-R 2a 、-(CH 2 ) q -C(＝O)O-R 2a 、-(CH 2 ) q -S(＝O) 2 -R 2a 、-(CH 2 ) q -NR 2a S(＝O) 2 -R 2b 、-(CH 2 ) q -C(＝O)-NR 2a R 2b 、-(CH 2 ) q -NR 2a R 2b 、-(CH 2 ) q NR 2a C(＝O)-R 2b 、-(CH 2 ) q -C 3-10 Carbocycle or- (CH) 2 ) q -3 to 12 membered heterocycle, said-CH 2 -, alkyl, alkenyl, alkynyl, alkoxy, carbocycle or heterocycle optionally further substituted with 0 to 4 groups selected from H, halogen, OH, cyano, NH 2 、C 1-6 Alkyl, halogen substituted C 1-6 Alkyl-and cyano-substituted C 1-6 Alkyl or C 1-6 Substituted with an alkoxy substituent, said heterocycle containing 1 to 3 heteroatoms selected from O, S, N;
in certain embodiments, R 2 Selected from halogen, cyano, OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, -NH (C) 1-6 Alkyl) - (CH) 2 ) q -C 3-10 Carbocycle or- (CH) 2 ) q -3 to 12 membered heterocycle, said-CH 2 -, alkyl, alkenyl, alkynyl, alkoxy, carbocycle or heterocycle optionally further substituted with 0 to 4 groups selected from H, halogen, OH, cyano, C 1-6 Alkyl, halogen substituted C 1-6 Alkyl-and cyano-substituted C 1-6 Alkyl or C 1-6 Substituted with an alkoxy substituent, said heterocycle containing 1 to 3 heteroatoms selected from O, S, N;
in certain embodiments, R 2 Selected from halogen, cyano, OH, C 1-4 Alkyl, C 1-4 Alkoxy, -NH (C) 1-4 Alkyl) - (CH) 2 ) q -C 3-10 Carbocycle or- (CH) 2 ) q -3 to 10 membered heterocycle, said-CH 2 -, alkyl, alkoxy, carbocycle or heterocycle optionally further substituted with 0 to 4 groups selected from H, halogen, OH, cyano, NH 2 、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl-and cyano-substituted C 1-4 Alkyl or C 1-4 Substituted with an alkoxy substituent, said heterocycle containing 1 to 3 heteroatoms selected from O, S, N;
in certain embodiments, R 2 Selected from halogen, cyano, OH, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Carbocycle, 3-to 6-membered heterocycle, -CH 2 -C 3-6 Carbocycle, -CH 2 -3 to 6 membered heterocycle or-NH (C 1-4 Alkyl), said-CH 2 -, alkyl, alkoxy, carbocycle or heterocycle optionally further substituted with 0 to 4 groups selected from H, halogen, OH, cyano, NH 2 、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl-and cyano-substituted C 1-4 Alkyl or C 1-4 Substituted with an alkoxy substituent, said heterocycle containing 1 to 3 heteroatoms selected from O, S, N;
in certain embodiments, R 2 Selected from F, cyano, OH, -OCH 3 Methyl, ethyl, CF 3 、-CH 2 OH、-CH 2 CH 2 OH、-CH 2 CH 2 CH 2 OH、-CH 2 CN、-CH 2 CH 2 CN、-CH 2 CH 2 CH 2 CN、-CH 2 CH 2 CH 2 CH 2 CN、-NHCH 2 CN、-NHCH 2 CH 2 CN、-NHCH 2 CH 2 CH 2 CN、-NHCH 2 CH 2 CH 2 CH 2 CN、
In certain embodiments, R 2 Selected from OH, -OCH 3 、-CH 2 CN；
In certain embodiments, R 2 Selected from OH, -CH 2 CN；
In certain embodiments, R 2 Selected from OH;
in certain embodiments, R a1 、R a2 、R 2a 、R 2b Each independently selected from H, C 1-6 Alkyl, C 3-12 Carbocyclyl or 3-to 12-membered heterocyclyl, said alkyl, carbocyclyl or heterocyclyl optionally being further substituted with 0 to 4 groups selected from H, halogen, OH, cyano, NH 2 、-NH(C 1-6 Alkyl), -N (C) 1-6 Alkyl group 2 、-NH(C 3-6 Cycloalkyl group, C 1-6 Alkyl, C 3-12 Carbocyclyl, 3-to 12-membered heterocyclyl, hydroxy-substituted C 1-6 Alkyl, halogen substituted C 1-6 Alkyl-and cyano-substituted C 1-6 Alkyl or C 1-6 Substituted with an alkoxy substituent, said heterocyclyl containing 1 to 3 heteroatoms selected from O, S, N;
in certain embodiments, R a1 、R a2 、R 2a 、R 2b Each independently selected from H, C 1-4 Alkyl, C 3-10 Carbocyclyl or 3-to 10-membered heterocyclyl, said alkyl, carbocyclyl or heterocyclyl optionally being further substituted with 0 to 4 groups selected from H, halogen, OH, cyano, NH 2 、-NH(C 1-4 Alkyl), -N (C) 1-4 Alkyl group 2 、-NH(C 3-6 Cycloalkyl group, C 1-4 Alkyl, C 3-8 Carbocyclyl, 3-to 8-membered heterocyclyl, hydroxy-substituted C 1-4 Alkyl, halogen substituted C 1-4 Alkyl-and cyano-substituted C 1-4 Alkyl or C 1-4 Substituted by alkoxy, said heterocyclyl containing 1 to 3 substituents selected from O, S, NA heteroatom;
in certain embodiments, R a1 、R a2 、R 2a 、R 2b Each independently selected from H, C 1-4 Alkyl, C 3-6 Carbocyclyl or 3-to 6-membered heterocyclyl, said alkyl, carbocyclyl or heterocyclyl optionally being further substituted with 0 to 4 groups selected from H, halogen, OH, cyano, NH 2 、-NH(C 1-4 Alkyl), -N (C) 1-4 Alkyl group 2 、-NH(C 3-6 Cycloalkyl group, C 1-4 Alkyl, C 3-6 Carbocyclyl, 3-to 6-membered heterocyclyl, hydroxy-substituted C 1-4 Alkyl, halogen substituted C 1-4 Alkyl-and cyano-substituted C 1-4 Alkyl or C 1-4 Substituted with an alkoxy substituent, said heterocyclyl containing 1 to 3 heteroatoms selected from O, S, N;
in certain embodiments, R a1 、R a2 Each independently selected from H, C 1-4 Alkyl, C 3-6 Carbocyclyl;
in certain embodiments, q is each independently selected from 0, 1, 2, 3, or 4;
in certain embodiments, q is each independently selected from 0, 1, or 2;
in certain embodiments, provided that the compound is not
As a first embodiment of the present invention, a compound represented by the above general formula (I) or a stereoisomer, tautomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein,
l is selected from bond or NR n2 ；
R n1 、R n2 Each independently selected from H, C 1-6 Alkyl or C 3-6 Cycloalkyl, said alkyl or cycloalkyl optionally being further substituted with 0 to 4 groups selected from H, halogen, CF 3 OH, cyano, NH 2 、C 1-6 Alkyl or C 1-6 Substituted with alkoxy;
ring A is selected from 5-8 membered heteroaromatic rings optionally further substituted with 0 to 3R a A substitution, said heteroaryl ring containing 1 to 5 heteroatoms selected from O, S, N;
R a each independently selected from H, halogen, cyano, OH, C 1-6 Alkyl, C 1-6 Alkoxy, - (O-C) 1-6 An alkylene group q -C 1-6 Alkoxy, - (O-C) 1-6 An alkylene group q -OH、-(CH 2 ) q -C(＝O)-NR a1 R a2 、-(CH 2 ) q -NR a1 R a2 、-(CH 2 ) q NR a1 C(＝O)-R a2 、-(CH 2 ) q -C 3-10 Carbocycles, - (CH) 2 ) q -3 to 12 membered heterocycles, (CH) 2 ) q -P(＝O)(C 1-6 Alkyl group 2 OR-OR a3 said-CH 2 -, alkyl, alkoxy, carbocycle or heterocycle optionally further substituted with 0 to 4 groups selected from H, halogen, OH, =o, cyano, NH 2 、C 1-6 Alkyl, halogen substituted C 1-6 Alkyl or C 1-6 Substituted with an alkoxy substituent, said heterocycle containing 1 to 3 heteroatoms selected from O, S, N;
R a3 each independently selected from- (CH) 2 ) q -NR a1 R a2 、-(CH 2 ) q NR a1 C(＝O)-R a2 、-(CH 2 ) q -C 3-10 Carbocycle or- (CH) 2 ) q -3 to 12 membered heterocycle, said-CH 2 -, carbocycle, heterocycle optionally further being 0 to 4 groups selected from H, halogen, OH, =o, cyano, NH 2 、C 1-6 Alkyl, halogen substituted C 1-6 Alkyl or C 1-6 Substituted with an alkoxy substituent, said heterocycle containing 1 to 3 heteroatoms selected from O, S, N;
ring B is selected from non-aromatic C 3-12 Carbocycles, optionally from a single ring, a parallel ring, a bridged ring or a spiro ring, optionally further substituted with 0 to 3R b Substituted by substituents;
R b each independently selected from H, halogen, cyano, OH, C 1-6 Alkyl or C 1-6 Alkoxy, said alkyl or alkoxy optionally being further substituted with 0 to 4 groups selected from H, halogen, OH, cyano, NH 2 、C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 Substituted cycloalkyl;
R 1 selected from 5-to 10-membered heteroaryl or phenyl, said heteroaryl or phenyl optionally being further substituted with 0 to 4R 1a Substitution;
R 1a each independently selected from H, halogen, OH, cyano, NH 2 、-NH(C 1-6 Alkyl), -N (C) 1-6 Alkyl group 2 、-NH(C 3-6 Cycloalkyl group, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3-to 8-membered heterocyclyl, said alkyl, alkoxy, cycloalkyl or heterocyclyl optionally being further substituted with 0 to 4 groups selected from H, halogen, OH, cyano, NH 2 Halogen-substituted C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 Substituted cycloalkyl;
R 2 selected from halogen, cyano, OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, - (CH) 2 ) q -C(＝O)-R 2a 、-(CH 2 ) q -C(＝O)O-R 2a 、-(CH 2 ) q -S(＝O) 2 -R 2a 、-(CH 2 ) q -NR 2a S(＝O) 2 -R 2b 、-(CH 2 ) q -C(＝O)-NR 2a R 2b 、-(CH 2 ) q -NR 2a R 2b 、-(CH 2 ) q NR 2a C(＝O)-R 2b 、-(CH 2 ) q -C 3-10 Carbocycle or- (CH) 2 ) q -3 to 12 membered heterocycle, said-CH 2 -, alkyl, alkenyl, alkynyl, alkoxy, carbocycle or heterocycle optionally further substituted with 0 to 4 groups selected from H, halogen, OH, cyano, NH 2 、C 1-6 Alkyl, halogen substituted C 1-6 Alkyl-and cyano-substituted C 1-6 Alkyl or C 1-6 Substituted with an alkoxy substituent, said heterocycle containing 1 to 3 heteroatoms selected from O, S, N;
R a1 、R a2 、R 2a 、R 2b each independently selected from H, C 1-6 Alkyl, C 3-12 Carbocyclyl or 3-to 12-membered heterocyclyl, said alkyl, carbocyclyl or heterocyclyl optionally being further substituted with 0 to 4 groups selected from H, halogen, OH, cyano, NH 2 、-NH(C 1-6 Alkyl), -N (C) 1-6 Alkyl group 2 、-NH(C 3-6 Cycloalkyl group, C 1-6 Alkyl, C 3-12 Carbocyclyl group3-to 12-membered heterocyclyl, hydroxy-substituted C 1-6 Alkyl, halogen substituted C 1-6 Alkyl-and cyano-substituted C 1-6 Alkyl or C 1-6 Substituted with an alkoxy substituent, said heterocyclyl containing 1 to 3 heteroatoms selected from O, S, N;
q is each independently selected from 0, 1, 2, 3 or 4.
As a second embodiment of the present invention, a compound represented by the following general formula (Ia) or a stereoisomer, tautomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein
R n2 Selected from H, C 1-6 Alkyl or C 3-6 Cycloalkyl, said alkyl or cycloalkyl optionally being further substituted with 0 to 4 groups selected from H, halogen, CF 3 OH, cyano, NH 2 、C 1-6 Alkyl or C 1-6 Substituted with alkoxy;
R a each independently selected from H, halogen, cyano, OH, C 1-6 Alkyl, C 1-6 Alkoxy, - (CH) 2 ) q -C 3-10 Carbocycles, - (CH) 2 ) q -3 to 12 membered heterocycles, - (CH) 2 ) q -C(＝O)-NR a1 R a2 、-(CH 2 ) q NR a1 C(＝O)-R a2 、-(CH 2 ) q -NR a1 R a2 、-(O-C 1-6 An alkylene group q -C 1-6 Alkoxy, - (O-C) 1-6 An alkylene group q -OH、-(CH 2 ) q -P(＝O)(C 1-6 Alkyl group 2 OR-OR a3 said-CH 2 -, alkyl, alkoxy, carbocycle or heterocycle optionally further substituted with 0 to 4 groups selected from H, halogen, OH, =o, cyano, NH 2 、C 1-6 Alkyl, halogen substituted C 1-6 Alkyl or C 1-6 Substituted with an alkoxy substituent, said heterocycle containing 1 to 3 heteroatoms selected from O, S, N;
R a3 Each independently selected from- (CH) 2 ) q -NR a1 R a2 、-(CH 2 ) q -C 3-10 Carbocycle or- (CH) 2 ) q -3 to 12 membered heterocycle, said-CH 2 -, carbocycle, heterocycle optionally further being 0 to 4 groups selected from H, halogen, OH, =o, cyano, NH 2 、C 1-6 Alkyl, halogen substituted C 1-6 Alkyl or C 1-6 Substituted with an alkoxy substituent, said heterocycle containing 1 to 3 heteroatoms selected from O, S, N;
each p is independently selected from 0, 1 or 2;
ring a is selected from 5 to 6 membered heteroaryl rings containing 1 to 3 heteroatoms selected from O, S, N;
ring B is selected from C 3-8 Monocycloalkyl, C 4-10 And cycloalkyl, C 5-12 Spirocycloalkyl, C 5-12 Bridged cycloalkyl, said cycloalkyl optionally being further substituted with 0 to 3R b Substituted by substituents;
R b each independently selected from H, halogen, cyano, OH, C 1-6 Alkyl or C 1-6 Alkoxy, said alkyl or alkoxy optionally being further substituted with 0 to 4 groups selected from H, halogen, OH, cyano, NH 2 、C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 Substituted cycloalkyl;
and when B contains 2R b Substituent, any one R b In the case of OH, the other cannot be OH or-CH 2 OH；
R 1 Selected from the group consisting of
Or R is 1 Selected from the group consisting of
Provided that when R 1 Is thatWhen ring A is not
R 1a Each independently selected from H, halogen, OH, cyano, NH 2 、-NH(C 1-6 Alkyl), -N (C) 1-6 Alkyl group 2 、-NH(C 3-6 Cycloalkyl group, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3-to 8-membered heterocyclyl, said alkyl, alkoxy, cycloalkyl or heterocyclyl optionally being further substituted with 0 to 4 groups selected from H, halogen, OH, cyano, NH 2 Halogen-substituted C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 Substituted cycloalkyl;
m is independently selected from 0, 1 or 2;
R 1b selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, said alkyl or cycloalkyl optionally being further substituted with 0 to 4 substituents selected from H, halogenPlain, OH, cyano, NH 2 、C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 Substituted cycloalkyl;
R 2 selected from halogen, cyano, OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, -NH (C) 1-6 Alkyl) - (CH) 2 ) q -C 3-10 Carbocycle or- (CH) 2 ) q -3 to 12 membered heterocycle, said-CH 2 -, alkyl, alkenyl, alkynyl, alkoxy, carbocycle or heterocycle optionally further substituted with 0 to 4 groups selected from H, halogen, OH, cyano, C 1-6 Alkyl, halogen substituted C 1-6 Alkyl-and cyano-substituted C 1-6 Alkyl or C 1-6 Substituted with an alkoxy substituent, said heterocycle containing 1 to 3 heteroatoms selected from O, S, N;
R a1 、R a2 、R 2a 、R 2b each independently selected from H, C 1-6 Alkyl, C 3-12 Carbocyclyl or 3-to 12-membered heterocyclyl, said alkyl, carbocyclyl or heterocyclyl optionally being further substituted with 0 to 4 groups selected from H, halogen, OH, cyano, NH 2 、-NH(C 1-6 Alkyl), -N (C) 1-6 Alkyl group 2 、-NH(C 3-6 Cycloalkyl group, C 1-6 Alkyl, C 3-12 Carbocyclyl, 3-to 12-membered heterocyclyl, hydroxy-substituted C 1-6 Alkyl, halogen substituted C 1-6 Alkyl-and cyano-substituted C 1-6 Alkyl or C 1-6 Substituted with an alkoxy substituent, said heterocyclyl containing 1 to 3 heteroatoms selected from O, S, N;
q is each independently selected from 0, 1, 2, 3 or 4;
provided that the compound is not
As a third embodiment of the present invention, the compound represented by the aforementioned general formula (Ia) or a stereoisomer, tautomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein,
R n2 selected from H or C 1-4 An alkyl group;
R a each independently selected from H, halogen, cyano, OH, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Carbocycles, 3-to 6-membered heterocycles, - (CH) 2 ) q -C(＝O)-NR a1 R a2 、-(CH 2 ) q NR a1 C(＝O)-R a2 、-(CH 2 ) q -NR a1 R a2 、-(O-C 1-4 An alkylene group q -C 1-4 Alkoxy, CH 2 -3 to 6 membered heterocycle, -P (=o) (C 1-4 Alkyl group 2 OR-OR a3 said-CH 2 -, alkyl, alkoxy, carbocycle or heterocycle optionally further substituted with 0 to 4 groups selected from H, halogen, OH, =o, cyano, NH 2 、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl or C 1-4 Substituted with an alkoxy substituent, said heterocycle containing 1 to 3 heteroatoms selected from O, S, N;
R a3 each independently selected from- (CH) 2 ) q -NR a1 R a2 、-(CH 2 ) q -C 3-6 Carbocycle or- (CH) 2 ) q -3 to 6 membered heterocycle, said-CH 2 -, carbocycle, heterocycle optionally further being 0 to 4 groups selected from H, halogen, OH, =o, cyano, NH 2 、C 1-6 Alkyl, halogen substituted C 1-6 Alkyl or C 1-6 Substituted with an alkoxy substituent, said heterocycle containing 1 to 3 heteroatoms selected from O, S, N;
R b each independently selected from H, halogen, cyano, OH, C 1-4 Alkyl or C 1-4 Alkoxy, said alkyl or alkoxy optionally being further substituted with 0 to 4 groups selected from H, halogen, OH, cyano, NH 2 、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, C 1-4 Alkoxy or C 3-4 Substituted cycloalkyl;
and when B contains 2R b Substituent, any one R b In the case of OH, the other cannot be OH or-CH 2 OH；
R 1a Each independently selected from H, halogen, OH, cyano, NH 2 、-NH(C 1-4 Alkyl), -N (C) 1-4 Alkyl group 2 、-NH(C 3-4 Cycloalkyl group, C 1-4 Alkyl or C 1-4 Alkoxy, said alkyl or alkoxy optionally being further substituted with 0 to 4 groups selected from H, halogen, OH, cyano, NH 2 Halogen-substituted C 1-4 Alkyl, C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 Substituted cycloalkyl;
R 1b selected from C 1-4 Alkyl, C 3-6 Cycloalkyl, said alkyl or cycloalkyl optionally being further substituted with 0 to 4 groups selected from H, halogen, OH, cyano, NH 2 、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 Substituted cycloalkyl;
R 2 selected from halogen, cyano, OH, C 1-4 Alkyl, C 1-4 Alkoxy, -NH (C) 1-4 Alkyl) - (CH) 2 ) q -C 3-10 Carbocycle or- (CH) 2 ) q -3 to 10 membered heterocycle, said-CH 2 -, alkyl, alkoxy, carbocycle or heterocycle optionally further substituted with 0 to 4 groups selected from H, halogen, OH, cyano, NH 2 、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl-and cyano-substituted C 1-4 Alkyl or C 1-4 Substituted with an alkoxy substituent, said heterocycle containing 1 to 3 heteroatoms selected from O, S, N;
R a1 、R a2 、R 2a 、R 2b each independently selected from H, C 1-4 Alkyl, C 3-10 Carbocyclyl or 3-to 10-membered heterocyclyl, said alkyl, carbocyclyl or heterocyclyl optionally being further substituted with 0 to 4 groups selected from H, halogen, OH, cyano, NH 2 、-NH(C 1-4 Alkyl), -N (C) 1-4 Alkyl group 2 、-NH(C 3-6 Cycloalkyl group, C 1-4 Alkyl, C 3-8 Carbocyclyl, 3-to 8-membered heterocyclyl, hydroxy-substituted C 1-4 Alkyl, halogen substituted C 1-4 Alkyl-and cyano-substituted C 1-4 Alkyl or C 1-4 Substituted with an alkoxy substituent, said heterocyclyl containing 1 to 3 heteroatoms selected from O, S, N;
q is each independently selected from 0, 1 or 2,
the remaining definitions are the same as in either the first or the second embodiment.
As a fourth embodiment of the present invention, the compound represented by the aforementioned general formula (Ia) or a stereoisomer, tautomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein,
R n2 Selected from H, methyl or ethyl;
R 1a each independently selected from H, F, OH, cyano, methyl, ethyl, isopropyl, propyl, methoxy or ethoxy, said methyl, ethyl, isopropyl, propyl, methoxy or ethoxy optionally further0, 1 or 2 are selected from H, halogen, OH, cyano, NH 2 Halogen-substituted C 1-4 Alkyl, C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 Substituted cycloalkyl;
R 1b selected from methyl, ethyl, isopropyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, said methyl, ethyl, isopropyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl optionally further being 0, 1, or 2 are selected from H, halogen, OH, cyano, NH 2 Halogen-substituted C 1-4 Alkyl, C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 Substituted cycloalkyl;
ring B is selected from one of the following substituted or unsubstituted: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl-cyclobutyl, cyclopropyl-cyclopentyl, cyclopropyl-cyclohexyl, cyclobutyl-cyclobutyl, cyclobutyl-cyclopentyl, cyclobutyl-cyclohexyl, cyclopentyl-cyclopentyl, cyclopentyl-cyclohexyl cyclohexyl, cyclopropyl spirobutyl, cyclopropyl spiropentyl, cyclopropyl spirohexyl, cyclobutylspirobutyl, cyclobutylspiropentyl, cyclobutylspirohexyl, cyclopentyl spiropentyl, cyclopentyl spirohexyl, cyclohexyl spirohexyl, bicyclo [ 1.1.1.1 ]Pentanyl and bicyclo [2.1.1]Hexalkyl and bicyclo [2.2.1]Heptyl and bicyclo [3.3.2]Decyl and bicyclo [2.2.2]Octyl and bicyclo [3.2.1]Octyl and bicyclo [3.3.3]Undecyl or adamantyl, when substituted, optionally further substituted with 0 to 3R b Substitution;
R b each independently selected from H, halogen, cyano, OH, C 1-4 Alkyl or C 1-4 An alkoxy group;
and when B contains 2R b Substituent, any one R b In the case of OH, the other cannot be OH;
ring a is selected from one of the following groups: pyrimidinyl, pyrazinyl, pyridazinyl, pyridinyl, triazinyl, pyrazolyl, imidazolyl, pyrrolyl, triazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, thiadiazolyl;
R 2 selected from halogen, cyano, OH, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Carbocycle, 3-to 6-membered heterocycle, -CH 2 -C 3-6 Carbocycle, -CH 2 -3 to 6 membered heterocycle or-NH (C 1-4 Alkyl), said-CH 2 -, alkyl, alkoxy, carbocycle or heterocycle optionally further substituted with 0 to 4 groups selected from H, halogen, OH, cyano, NH 2 、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl-and cyano-substituted C 1-4 Alkyl or C 1-4 Substituted with an alkoxy substituent, said heterocycle containing 1 to 3 heteroatoms selected from O, S, N;
the remaining definitions are the same as in any of the first, second or third embodiments of the invention.
As a fifth embodiment of the present invention, the compound represented by the aforementioned general formula (Ia) or a stereoisomer, tautomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein,
ring B is selected from Right side and R 2 Directly connecting;
R 2 selected from F, cyano, OH, -OCH 3 Methyl, ethyl, CF 3 、-CH 2 OH、-CH 2 CH 2 OH、-CH 2 CH 2 CH 2 OH、-CH 2 CN、-CH 2 CH 2 CN、-CH 2 CH 2 CH 2 CN、-CH 2 CH 2 CH 2 CH 2 CN、-NHCH 2 CN、-NHCH 2 CH 2 CN、-NHCH 2 CH 2 CH 2 CN、-NHCH 2 CH 2 CH 2 CH 2 CN、
R 1 Selected from the group consisting of
R a Each independently selected from H, F, cyano, OH, CF 3 、CHF 2 、CH 2 F. Methyl, ethyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, pyrazolyl, triazolyl, thiazolyl, imidazolyl, oxazolyl, thienyl, furyl, pyrrolyl, isoxazolyl, isothiazolyl, pyridyl, pyrimidinyl, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, tetrahydrofuranyl, dihydrofuryl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, -P (=o) (CH 3 ) 2 、-P(＝O)(CH 2 CH 3 ) 2 、-P(＝O)(CH 2 CH 2 CH 3 ) 2 、-OCH 2 CH 2 OCH 3 、-OCH 2 CH 2 OCH 2 CH 2 OCH 3 、-CH 2 NHCH 2 CH 2 CN、-CH 2 NHCH 2 CN、-CH 2 NHCH 2 CH 2 CH 2 CN、-CH 2 C(＝O)NH-Ph-CH 2 OH、-CH 2 C(＝O)NH-Ph-CH 2 CN、-CH 2 C(＝O)NH-Ph-CH 2 F、-CH 2 C(＝O)NH-Ph-CHF 2 、-CH 2 C(＝O)NH-Ph-CF 3 、-CH 2 C(＝O)NHCH 2 -cyclopropyl, -CH 2 C(＝O)NHCH 2 -cyclobutyl, -CH 2 C(＝O)NHCH 2 -cyclopentyl, -CH 2 C(＝O)NHCH 2 -cyclohexyl, -CH 2 C(＝O)NHCH 2 CH 2 NH 2 、-CH 2 C(＝O)NHCH 2 CH 2 NHCH 3 、-CH 2 C(＝O)NHCH 2 CH 2 N(CH 3 ) 2 、-CH 2 C(＝O)NHCH 2 CH 2 N(CH 2 CH 3 ) 2 -NH-pyrazolyl, -NH-thiazolyl, -NH-imidazolyl, -NH-oxazolyl, -NH-thienyl, -NH-furanyl, -NH-pyrrolyl, -NH-isoxazolyl, -NH-isothienyl, -NH-pyridinyl, -NH-pyrimidinyl, -NH-phenyl, -NH-cyclopropyl, -NH-cyclobutyl, -NH-cyclopentyl, -NH-cyclohexyl, -C (=o) NH 2 、-C(＝O)NHCH 3 、-C(＝O)NHCH 2 CH 3 -C (=o) NH-cyclopropyl, -C (=o) NH-cyclobutyl, -C (=o) NH-cyclopentyl, -C (=o) NH-cyclohexyl, -C (=o) NH-phenyl, -NHC (=o) H, -NHC (=o) CH 3 、-NHC(＝O)CH 2 CH 3 、-NHC(＝O)CH 2 CH 2 CH 3 -NHC (=o) -cyclopropyl, -NHC (=o) -cyclobutyl, -NHC (=o) -cyclopentyl, -NHC (=o) -cyclohexyl, -NHC (=o) -phenyl OR-OR a3 The methyl, ethyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrazolyl, triazolyl, thiazolyl, imidazolyl, oxazolyl, thienyl, furyl, pyrrolyl, isoxazolyl, isothiazolyl, pyridyl, pyrimidinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dihydrofuranyl, or phenyl optionally further substituted with 0, 1, 2, 3 or 4 groups selected from H, F, CF 3 OH, =O, cyano, NH 2 A methyl, ethyl, methoxy or ethoxy substituent;
R a3 each independently selected from-CH 2 N(CH 3 ) 2 、-CH 2 CH 2 N(CH 3 ) 2 、-CH(CH 3 )CH 2 N(CH 3 ) 2 、-CH 2 CH 2 N(CH 2 CH 3 ) 2 、-CH 2 CH 2 NH 2 、-CH 2 CH 2 NHCH 3 Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, oxetanyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, -CH 2 -cyclopropyl, -CH 2 -cyclobutyl, -CH 2 -cyclopentyl, -CH 2 -cyclohexyl, -CH 2 -azetidinyl, -CH 2 Pyrrolidinyl, -CH 2 -piperidinyl, -CH 2 Morpholinyl, -CH 2 Piperazinyl, -CH 2 -oxetanyl, -CH 2 -tetrahydrofuranyl, -CH 2 Tetrahydropyranyl, -CH 2 CH 2 -piperidinyl, -CH 2 CH 2 -pyriPyrrolidinyl, -CH 2 CH 2 -azetidinyl, -CH 2 CH 2 Morpholinyl group,The cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,Optionally further 0, 1, 2, 3 or 4 are selected from H, F, CF 3 OH, =O, cyano, NH 2 A methyl, ethyl, methoxy or ethoxy substituent;
the remaining definitions are the same as in any of the first, second, third or fourth embodiments of the present invention.
As a sixth embodiment of the present invention, a compound represented by the following general formula (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg) or a stereoisomer, tautomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein,
ring a is selected from pyrimidinyl, pyrazinyl, triazolyl or oxadiazolyl;
A 1 Selected from O, S, NH, N (CH) 3 ) Or N (CH) 2 CH 3 )；
A 2 Selected from CR a Or N;
R n2 each independently selected from H or methyl;
R 2 selected from OH, -OCH 3 、-CH 2 CN；
R 1 Selected from the group consisting of
R a Each independently selected from H, F, cyano, OH, CF 3 、CHF 2 Methyl, ethyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, pyrazolyl, triazolyl, thiazolyl, imidazolyl, oxazolyl, thienyl, furyl, tetrahydrofuranyl, dihydrofuryl, tetrahydropyranyl, pyrrolyl, isoxazolyl, isothienyl, pyridyl, pyrimidinyl, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, -O-cyclopropyl, -O-cyclopentyl, -O-cyclobutyl, -O-cyclohexyl, -O-azetidinyl, -O-oxetanyl, -O-tetrahydrofuranyl, -O-tetrahydropyranyl, -O-CH 2 -pyrrolidinyl, -OCH 2 N(CH 3 ) 2 、-OCH 2 CH 2 N(CH 3 ) 2 、-OCH(CH 3 )CH 2 N(CH 3 ) 2 、-OCH 2 CH 2 OCH 3 、-OCH 2 CH 2 OCH 2 CH 2 OCH 3 、-P(＝O)(CH 3 ) 2 、-P(＝O)(CH 2 CH 3 ) 2 、-P(＝O)(CH 2 CH 2 CH 3 ) 2 、-C(＝O)NH 2、 -C (=o) NH-cyclopropyl, -C (=o) NH-cyclobutyl, -C (=o) NH-cyclopentyl, -C (=o) NH-cyclohexyl, -OCH 2 CH 2 -piperidinyl, -OCH 2 CH 2 -pyrrolidinyl, -OCH 2 CH 2 -azetidinyl, -OCH 2 CH 2 Morpholinyl, -OCH 2 -piperidinyl, -OCH 2 -azetidinyl, -OCH 2 Morpholinyl, -OCH 2 Tetrahydrofuran radical,The methyl, ethyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrazolyl, triazolyl, thiazolyl, imidazolyl, oxazolyl, thienyl, furyl, pyrrolyl, isoxazolyl, isothiazolyl, pyridyl, pyrimidinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, and the like, Or phenyl optionally further substituted with 0, 1, 2, 3 or 4 groups selected from H, F, CF 3 OH, =O, cyano, NH 2 A methyl, ethyl, methoxy or ethoxy substituent;
each p is independently selected from 0, 1 or 2;
the remaining groups are as defined in any of the first, second, third, fourth or fifth embodiments of the present invention.
The present invention relates to a compound shown below or a stereoisomer, tautomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein the compound is selected from one of the following structures:
in some embodiments of the invention relating to formula (I), L is selected from a bond or NR n2 。
In some embodiments of the invention relating to formula (I), L is selected from NR n2 。
In some embodiments of formula (I), L is selected from a bond.
In some embodiments of the invention, R is a compound of formula (I) n1 Selected from H, C 1-6 Alkyl or C 3-6 Cycloalkyl, said alkyl or cycloalkyl optionally being further substituted with 0 to 4 groups selected from H, halogen, CF 3 OH, cyano, NH 2 、C 1-6 Alkyl or C 1-6 The substituent of the alkoxy group is substituted.
In some embodiments of the invention, R is a compound of formula (I) n1 Selected from H.
The present invention relates to some embodiments of the general formulae (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh) or (IIi), R n2 Each independently selected from H, C 1-6 Alkyl or C 3-6 Cycloalkyl, said alkyl or cycloalkyl optionally being further substituted with 0 to 4 groups selected from H, halogen, CF 3 OH, cyano, NH 2 、C 1-6 Alkyl or C 1-6 The substituent of the alkoxy group is substituted.
The invention relates to the general formula (I), (Ia), (IIa), (IIb), (IIc), (IId),In some embodiments of (IIe), (IIf), (IIg), (IIh) or (IIi), R n2 Selected from H or C 1-6 Alkyl, said alkyl optionally being further substituted with 0 to 4 groups selected from H, halogen, CF 3 OH, cyano, NH 2 、C 1-6 Alkyl or C 1-6 The substituent of the alkoxy group is substituted.
The present invention relates to some embodiments of the general formulae (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh) or (IIi), R n2 Selected from H or C 1-4 An alkyl group.
The present invention relates to some embodiments of the general formulae (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh) or (IIi), R n2 Selected from H, methyl or ethyl.
The present invention relates to some embodiments of the general formulae (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh) or (IIi), R n2 Selected from H or methyl.
The present invention relates to some embodiments of the general formulae (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh) or (IIi), R n1 、R n2 Selected from H.
The present invention relates to some embodiments of the general formula (I), (Ia), (IId) or (IIe) wherein ring A is selected from 5-8 membered heteroaromatic rings optionally further substituted with 0 to 3R a The heteroaryl ring contains 1 to 5 heteroatoms selected from O, S, N.
The present invention relates to some embodiments of the general formula (I), (Ia), (IId) or (IIe) wherein ring A is selected from 5 to 6 membered heteroaromatic rings optionally further substituted with 0, 1 or 2R a The heteroaryl ring contains 1 to 3 heteroatoms selected from O, S, N.
The present invention relates to some embodiments of formula (I), (Ia), (IId) or (IIe) wherein ring A is selected from one of the following substituted or unsubstituted groups: pyrimidinyl, pyrazinyl, pyridazinyl, pyridinyl, triazinyl, pyrazolyl, imidazolyl, pyrrolyl, triazolyl, oxazolylOxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, thiadiazolyl, optionally further substituted with 0, 1 or 2R a Substituted.
The present invention relates to some embodiments of formula (I), (Ia), (IId) or (IIe) wherein ring A is selected from one of the following substituted or unsubstituted groups: pyrimidinyl, pyrazinyl, triazolyl or oxadiazolyl, optionally further substituted with 0, 1 or 2R a Substituted.
The present invention relates to some embodiments of formula (I), (Ia), (IId) or (IIe) wherein ring A is selected from one of the following substituted or unsubstituted groups:when substituted, optionally further substituted with 0, 1 or 2R a Instead, the upper side is connected with L.
The present invention relates to some embodiments of formula (I), (Ia), (IId) or (IIe) wherein ring A is selected from one of the following substituted or unsubstituted groups:when substituted, optionally further substituted with 0, 1 or 2R a Instead, the upper side is connected with L.
The present invention relates to certain embodiments of the general formula (I), (Ia), (IIc) or (IIg) wherein ring A is selected fromA 1 Selected from O, S, NH, N (CH) 3 ) Or N (CH) 2 CH 3 )，A 2 Selected from CR a Or N.
The present invention relates to some embodiments of formula (I), (Ia), (IIc) or (IIg), wherein ring A is selected from one of the following groups: the upper part of the T-shaped groove is connected with L.
The present invention relates to some embodiments of the general formulae (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh) or (IIi), R a Each independently selected from H, halogen, cyano, OH, C 1-6 Alkyl, C 1-6 Alkoxy, - (O-C) 1-6 An alkylene group q -C 1-6 Alkoxy, - (O-C) 1-6 An alkylene group q -OH、-(CH 2 ) q -C(＝O)-NR a1 R a2 、-(CH 2 ) q -NR a1 R a2 、-(CH 2 ) q NR a1 C(＝O)-R a2 、-(CH 2 ) q -C 3-10 Carbocycles, - (CH) 2 ) q -3 to 12 membered heterocycles, (CH) 2 ) q -P(＝O)(C 1-6 Alkyl group 2 OR-OR a3 said-CH 2 -, alkyl, alkoxy, carbocycle or heterocycle optionally further substituted with 0 to 4 groups selected from H, halogen, OH, =o, cyano, NH 2 、C 1-6 Alkyl, halogen substituted C 1-6 Alkyl or C 1-6 The heterocyclic ring contains 1 to 3 hetero atoms selected from O, S, N.
The present invention relates to some embodiments of the general formulae (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh) or (IIi), R a Each independently selected from H, halogen, cyano, OH, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Carbocycles, 3-to 6-membered heterocycles, - (CH) 2 ) q -C(＝O)-NR a1 R a2 、-(CH 2 ) q NR a1 C(＝O)-R a2 、-(CH 2 ) q -NR a1 R a2 、-(O-C 1-4 An alkylene group q -C 1-4 Alkoxy, CH 2 -3 to 6 membered heterocycle, -P (=o) (C 1-4 Alkyl group 2 OR-OR a3 said-CH 2 -, alkyl, alkoxy, carbocycle or heterocycle optionally further substituted with 0 to 4 groups selected from H, halogen, OH, =o, cyano, NH 2 、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl or C 1-4 The heterocyclic ring contains 1 to 3 hetero atoms selected from O, S, N.
The present invention relates to some embodiments of the general formulae (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh) or (IIi), R a Each independently selected from H, F, cyano, OH, CF 3 、CHF 2 、CH 2 F. Methyl, ethyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, pyrazolyl, triazolyl, thiazolyl, imidazolyl, oxazolyl, thienyl, furyl, pyrrolyl, isoxazolyl, isothiazolyl, pyridyl, pyrimidinyl, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, tetrahydrofuranyl, dihydrofuryl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, -P (=o) (CH 3 ) 2 、-P(＝O)(CH 2 CH 3 ) 2 、-P(＝O)(CH 2 CH 2 CH 3 ) 2 、 -OCH 2 CH 2 OCH 3 、-OCH 2 CH 2 OCH 2 CH 2 OCH 3 、-CH 2 NHCH 2 CH 2 CN、-CH 2 NHCH 2 CN、-CH 2 NHCH 2 CH 2 CH 2 CN、-CH 2 C(＝O)NH-Ph-CH 2 OH、-CH 2 C(＝O)NH-Ph-CH 2 CN、-CH 2 C(＝O)NH-Ph-CH 2 F、-CH 2 C(＝O)NH-Ph-CHF 2 、-CH 2 C(＝O)NH-Ph-CF 3 、-CH 2 C(＝O)NHCH 2 -cyclopropyl, -CH 2 C(＝O)NHCH 2 -cyclobutyl, -CH 2 C(＝O)NHCH 2 -cyclopentyl, -CH 2 C(＝O)NHCH 2 -cyclohexyl, -CH 2 C(＝O)NHCH 2 CH 2 NH 2 、-CH 2 C(＝O)NHCH 2 CH 2 NHCH 3 、-CH 2 C(＝O)NHCH 2 CH 2 N(CH 3 ) 2 、-CH 2 C(＝O)NHCH 2 CH 2 N(CH 2 CH 3 ) 2 -NH-pyrazolyl, -NH-thiazolyl, -NH-imidazolyl, -NH-oxazolyl, -NH-thienyl, -NH-furanyl, -NH-pyrrolyl, -NH-isoxazolyl, -NH-isothienyl, -NH-pyridinyl, -NH-pyrimidinyl, -NH-phenyl, -NH-cyclopropyl, -NH-cyclobutyl, -NH-cyclopentyl, -NH-cyclohexyl, -C (=o) NH 2 、-C(＝O)NHCH 3 、-C(＝O)NHCH 2 CH 3 -C (=o) NH-cyclopropyl, -C (=o) NH-cyclobutyl, -C (=o) NH-cyclopentyl, -C (=o) NH-cyclohexyl, -C (=o) NH-phenyl, -NHC (=o) H, -NHC (=o) CH 3 、-NHC(＝O)CH 2 CH 3 、-NHC(＝O)CH 2 CH 2 CH 3 -NHC (=o) -cyclopropyl, -NHC (=o) -cyclobutyl, -NHC (=o) -cyclopentyl, -NHC (=o) -cyclohexyl, -NHC (=o) -phenyl OR-OR a3 The methyl, ethyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrazolyl, triazolyl, thiazolyl, imidazolyl, oxazolyl, thienyl, furyl, pyrrolyl, isoxazolyl, and the like,An isothiocyanato, pyridinyl, pyrimidinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dihydrofuranyl, or phenyl group optionally further substituted with 0, 1, 2, 3, or 4 groups selected from H, F, CF 3 OH, =O, cyano, NH 2 A methyl, ethyl, methoxy or ethoxy substituent.
The present invention relates to some embodiments of the general formulae (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh) or (IIi), R a Each independently selected from H, F, cyano, OH, CF 3 、CHF 2 Methyl, ethyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, pyrazolyl, triazolyl, thiazolyl, imidazolyl, oxazolyl, thienyl, furyl, tetrahydrofuranyl, dihydrofuryl, tetrahydropyranyl, pyrrolyl, isoxazolyl, isothienyl, pyridyl, pyrimidinyl, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, -O-cyclopropyl, -O-cyclopentyl, -O-cyclobutyl, -O-cyclohexyl, -O-azetidinyl, -O-oxetanyl, -O-tetrahydrofuranyl, -O-tetrahydropyranyl, -O-CH 2 -pyrrolidinyl, -OCH 2 N(CH 3 ) 2 、-OCH 2 CH 2 N(CH 3 ) 2 、-OCH(CH 3 )CH 2 N(CH 3 ) 2 、-OCH 2 CH 2 OCH 3 、-OCH 2 CH 2 OCH 2 CH 2 OCH 3 、-P(＝O)(CH 3 ) 2 、-P(＝O)(CH 2 CH 3 ) 2 、-P(＝O)(CH 2 CH 2 CH 3 ) 2 、-C(＝O)NH 2、 -C (=o) NH-cyclopropyl, -C (=o) NH-cyclobutyl, -C (=o) NH-cyclopentyl, -C (=o) NH-cyclohexyl, -OCH 2 CH 2 -piperidinyl, -OCH 2 CH 2 -pyrrolidinyl, -OCH 2 CH 2 -azetidinyl, -OCH 2 CH 2 Morpholinyl, -OCH 2 -piperidinyl, -OCH 2 -azetidinyl, -OCH 2 Morpholinyl, -OCH 2 Tetrahydrofuran radical,The methyl, ethyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrazolyl, triazolyl, thiazolyl, imidazolyl, oxazolyl, thienyl, furyl, pyrrolyl, isoxazolyl, isothiazolyl, pyridyl, pyrimidinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, and the like, Or phenyl optionally further substituted with 0, 1, 2, 3 or 4 groups selected from H, F, CF 3 OH, =O, cyano, NH 2 A methyl, ethyl, methoxy or ethoxy substituent.
The present invention relates to some embodiments of the general formulae (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh) or (IIi), R a Each independently selected from H, F, CF 3 Methyl, methoxy, ethoxy, isopropoxy, pyrazolyl, imidazolyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, pyridinyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, -O-cyclopentyl, -O-oxetanyl, -O-tetrahydrofuranyl, -O-tetrahydropyranyl, -O-CH 2 -pyrrolidinyl, -OCH 2 CH 2 N(CH 3 ) 2 、-OCH(CH 3 )CH 2 N(CH 3 ) 2 、-OCH 2 CH 2 OCH 3 、-C(＝O)NH 2、 -C (=o) NH-cyclopropyl, -OCH 2 CH 2 -piperidinyl, -OCH 2 CH 2 -pyrrolidinyl, -OCH 2 CH 2 Morpholinyl, -OCH 2 Tetrahydrofuran radical,The methyl, methoxy, ethoxy, cyclopropyl, cyclopentyl, pyrazolyl, imidazolyl, pyridyl, azetidinyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, and the like,Optionally further substituted with 0, 1, 2, 3 or 4 substituents selected from H, F, OH, methyl, methoxy, =o.
The present invention relates to some embodiments of the general formulae (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh) or (IIi), R a Each independently selected from H, F, -OCH 3 、-OCH(CH 3 ) 2 、-OCH 2 CH 3 、-CF 3 、-CH 2 OH、-CONH 2 -CONH-cyclopropyl, -OCH 2 CH 2 OCH 3 、-OCH 2 CH 2 OH、-OCH 2 CH 2 N(CH 3 ) 2 、-OCH(CH 3 )CH 2 N(CH 3 ) 2 、
The present invention relates to some embodiments of the general formulae (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh) or (IIi), R a3 Each independently selected from- (CH) 2 ) q -NR a1 R a2 、-(CH 2 ) q NR a1 C(＝O)-R a2 、-(CH 2 ) q -C 3-10 Carbocycle or- (CH) 2 ) q -3 to 12 membered heterocycle, said-CH 2 -, carbocycle, heterocycle optionally further being 0 to 4 groups selected from H, halogen, OH, =o, cyano, NH 2 、C 1-6 Alkyl, halogen substituted C 1-6 Alkyl or C 1-6 The heterocyclic ring contains 1 to 3 hetero atoms selected from O, S, N.
The present invention relates to certain embodiments of the general formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf) or (IIg), R a3 Each independently selected from- (CH) 2 ) q -NR a1 R a2 、-(CH 2 ) q -C 3-10 Carbocycle or- (CH) 2 ) q -3 to 12 membered heterocycle, said-CH 2 -, carbocycle, heterocycle optionally further being 0 to 4 groups selected from H, halogen, OH, =o, cyano, NH 2 、C 1-6 Alkyl, halogen substituted C 1-6 Alkyl or C 1-6 Substituted by alkoxy, said heterocycle containing 1 to 3 hetero atoms selected from O, S, NAn atom.
The present invention relates to some embodiments of the general formulae (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh) or (IIi), R a3 Each independently selected from- (CH) 2 ) q -NR a1 R a2 、-(CH 2 ) q -C 3-6 Carbocycle or- (CH) 2 ) q -3 to 6 membered heterocycle, said-CH 2 -, carbocycle, heterocycle optionally further being 0 to 4 groups selected from H, halogen, OH, =o, cyano, NH 2 、C 1-6 Alkyl, halogen substituted C 1-6 Alkyl or C 1-6 The heterocyclic ring contains 1 to 3 hetero atoms selected from O, S, N.
The present invention relates to some embodiments of the general formulae (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh) or (IIi), R a3 Each independently selected from-CH 2 N(CH 3 ) 2 、-CH 2 CH 2 N(CH 3 ) 2 、-CH(CH 3 )CH 2 N(CH 3 ) 2 、-CH 2 CH 2 N(CH 2 CH 3 ) 2 、-CH 2 CH 2 NH 2 、-CH 2 CH 2 NHCH 3 Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, oxetanyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, -CH 2 -cyclopropyl, -CH 2 -cyclobutyl, -CH 2 -cyclopentyl, -CH 2 -cyclohexyl, -CH 2 -azetidinyl, -CH 2 Pyrrolidinyl, -CH 2 -piperidinyl, -CH 2 Morpholinyl, -CH 2 Piperazinyl, -CH 2 -oxetanyl, -CH 2 -tetrahydrofuranyl, -CH 2 Tetrahydropyranyl, -CH 2 CH 2 -piperidinyl, -CH 2 CH 2 Pyrrolidinyl, -CH 2 CH 2 -azetidinyl, -CH 2 CH 2 Morpholinyl group,The cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,Optionally further 0, 1, 2, 3 or 4 are selected from H, F, CF 3 OH, =O, cyano, NH 2 A methyl, ethyl, methoxy or ethoxy substituent.
The present invention relates to some embodiments of the general formulae (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh) or (IIi), R a3 Each independently selected from-CH 2 CH 2 N(CH 3 ) 2 、-CH(CH 3 )CH 2 N(CH 3 ) 2 Cyclopentyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, -CH 2 Pyrrolidinyl, -CH 2 CH 2 -piperidinyl, -CH 2 CH 2 Morpholinyl group, The cyclopentyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl and piperidinyl groups Morpholinyl group,Optionally further substituted with 0, 1, 2, 3 or 4 substituents selected from H, F, OH, methyl.
The present invention relates to some embodiments of the general formulae (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh) or (IIi), R a3 Each independently selected from the following:
in some embodiments of the invention related to formula (I) or (Ia), ring B is selected from non-aromatic C 3-12 Carbocycles, optionally from a single ring, a parallel ring, a bridged ring or a spiro ring, optionally further substituted with 0 to 3R b Substituted by substituents.
In some embodiments of the invention related to formula (I) or (Ia), ring B is selected from C 3-8 Monocycloalkyl, C 4-10 And cycloalkyl, C 5-12 Spirocycloalkyl, C 5-12 Bridged cycloalkyl, said cycloalkyl optionally being further substituted with 0 to 3R b Substituted by substituents.
In some embodiments of the invention, ring B is selected from one of the following substituted or unsubstituted groups: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl-cyclobutyl, cyclopropyl-cyclopentyl, cyclopropyl-cyclohexyl, cyclobutyl-cyclobutyl, cyclobutyl-cyclopentyl, cyclobutyl-cyclohexyl, cyclopentyl-cyclopentyl, cyclopentyl-cyclohexyl, cyclohexyl-cyclohexyl, cyclopropyl-spirocyclobutyl, cyclopropyl-spirobutyl, cyclopropyl-spiropentyl, cyclopropyl-spirocyclohexyl, cyclobutylspirobutyl, Cyclobutylspiropentyl, cyclobutylspirohexyl, cyclopentylpspiropentyl, cyclopentylpspirohexyl, cyclohexylspirohexyl, bicyclo [1.1.1]Pentanyl and bicyclo [2.1.1]Hexalkyl and bicyclo [2.2.1]Heptyl and bicyclo [3.3.2]Decyl and bicyclo [2.2.2]Octyl and bicyclo [3.2.1]Octyl and bicyclo [3.3.3]Undecyl or adamantyl, when substituted, optionally further substituted with 0 to 3R b And (3) substitution.
In some embodiments of the invention relating to formula (I) or (Ia), ring B is selected from substituted or unsubstituted cyclohexyl or adamantyl, optionally further substituted with 0, 1, or 2R when substituted b And (3) substitution.
The present invention relates to certain embodiments of formula (I) or (Ia), R b Each independently selected from H, halogen, cyano, OH, C 1-6 Alkyl or C 1-6 Alkoxy, said alkyl or alkoxy optionally being further substituted with 0 to 4 groups selected from H, halogen, OH, cyano, NH 2 、C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 The substituents of cycloalkyl groups are substituted.
The present invention relates to certain embodiments of formula (I) or (Ia), R b Each independently selected from H, halogen, cyano, OH, C 1-6 Alkyl or C 1-6 Alkoxy, said alkyl or alkoxy optionally being further substituted with 0 to 4 groups selected from H, halogen, OH, cyano, NH 2 、C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 Substituted by substituents of cycloalkyl and when B contains 2R b Substituent, any one R b In the case of OH, the other cannot be OH or-CH 2 OH。
The present invention relates to certain embodiments of formula (I) or (Ia), R b Each independently selected from H, halogen, cyano, OH, C 1-4 Alkyl or C 1-4 Alkoxy, said alkyl or alkoxy optionally being further substituted with 0 to 4 groups selected from HHalogen, OH, cyano, NH 2 、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, C 1-4 Alkoxy or C 3-4 Substituted by substituents of cycloalkyl and when B contains 2R b Substituent, any one R b In the case of OH, the other cannot be OH or-CH 2 OH。
The present invention relates to certain embodiments of formula (I) or (Ia), R b Each independently selected from H, halogen, cyano, OH, C 1-4 Alkyl or C 1-4 Alkoxy, and when B contains 2R b Substituent, any one R b In the case of OH, the other cannot be OH.
The present invention relates to certain embodiments of formula (I) or (Ia), R b Each independently selected from H, OH or C 1-4 Alkyl optionally further substituted with cyano and when B contains 2R b Substituent, any one R b In the case of OH, the other cannot be OH.
The present invention relates to certain embodiments of formula (I) or (Ia), R b Each independently selected from H or F.
The present invention relates to certain embodiments of formula (I) or (Ia), R b Each independently selected from H.
The present invention relates to some embodiments of the general formulae (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh) or (IIi), R 1 Selected from 5-to 10-membered heteroaryl or phenyl, said heteroaryl or phenyl optionally being further substituted with 0 to 4R 1a And (3) substitution.
The present invention relates to some embodiments of the general formulae (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh) or (IIi), R 1 Are each independently selected from m is each independently selected from 0, 1 or 2, provided that when R 1 Is thatWhen ring A is not
The present invention relates to some embodiments of the general formulae (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh) or (IIi), R 1 Selected from the group consisting ofm is independently selected from 0, 1 or 2.
The present invention relates to some embodiments of the general formulae (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh) or (IIi), R 1 Selected from the group consisting of
The invention relates to the general formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (I)In some embodiments of Ih) or (IIi), R 1 Selected from the group consisting of
The present invention relates to some embodiments of the general formulae (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh) or (IIi), R 1 Selected from the group consisting of
The present invention relates to some embodiments of the general formulae (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh) or (IIi), R 1a Each independently selected from H, halogen, OH, cyano, NH 2 、-NH(C 1-6 Alkyl), -N (C) 1-6 Alkyl group 2 、-NH(C 3-6 Cycloalkyl group, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3-to 8-membered heterocyclyl, said alkyl, alkoxy, cycloalkyl or heterocyclyl optionally being further substituted with 0 to 4 groups selected from H, halogen, OH, cyano, NH 2 Halogen-substituted C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 The substituents of cycloalkyl groups are substituted.
The present invention relates to some embodiments of the general formulae (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh) or (IIi), R 1a Each independently selected from H, halogen, OH, cyano, NH 2 、-NH(C 1-4 Alkyl), -N (C) 1-4 Alkyl group 2 、-NH(C 3-4 Cycloalkyl group, C 1-4 Alkyl or C 1-4 Alkoxy, said alkyl or alkoxy optionally being further substituted with 0 to 4 groups selected from H, halogen, OH, cyano, NH 2 Halogen-substituted C 1-4 Alkyl, C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 The substituents of cycloalkyl groups are substituted.
The present invention relates to some embodiments of the general formulae (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh) or (IIi), R 1a Each independently selected from H, F, OH, cyano, methyl, ethyl, isopropyl, propyl, methoxy or ethoxy, said methyl, ethyl, isopropyl, propyl, methoxy or ethoxy optionally being further substituted with 0, 1 or 2 groups selected from H, halogen, OH, cyano, NH 2 Halogen-substituted C 1-4 Alkyl, C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 The substituents of cycloalkyl groups are substituted.
The present invention relates to some embodiments of the general formulae (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh) or (IIi), R 1a Each independently selected from H, methyl, said methyl optionally further substituted with OH.
The present invention relates to some embodiments of the general formulae (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh) or (IIi), R 1b Selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, said alkyl or cycloalkyl optionally being further substituted with 0 to 4 groups selected from H, halogen, OH, cyano, NH 2 、C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 The substituents of cycloalkyl groups are substituted.
The present invention relates to some embodiments of the general formulae (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh) or (IIi), R 1b Selected from C 1-4 Alkyl, C 3-6 Cycloalkyl, said alkyl or cycloalkyl optionally being further substituted with 0 to 4 groups selected from H, halogen, OH, cyano, NH 2 、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 The substituents of cycloalkyl groups are substituted.
The present invention relates to some embodiments of the general formulae (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh) or (IIi), R 1b Selected from methyl, ethyl, isopropyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, said methyl, ethyl, isopropyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl optionally further being 0, 1 or 2 members selected from H, halogen, OH, cyano, NH 2 Halogen-substituted C 1-4 Alkyl, C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 The substituents of cycloalkyl groups are substituted.
The present invention relates to some embodiments of the general formulae (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh) or (IIi), R 2 Selected from halogen, cyano, OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, - (CH) 2 ) q -C(＝O)-R 2a 、-(CH 2 ) q -C(＝O)O-R 2a 、-(CH 2 ) q -S(＝O) 2 -R 2a 、-(CH 2 ) q -NR 2a S(＝O) 2 -R 2b 、-(CH 2 ) q -C(＝O)-NR 2a R 2b 、-(CH 2 ) q -NR 2a R 2b 、-(CH 2 ) q NR 2a C(＝O)-R 2b 、-(CH 2 ) q -C 3-10 Carbocycle or- (CH) 2 ) q -3 to 12 membered heterocycle, said-CH 2 -, alkyl, alkenyl, alkynyl, alkoxy, carbocycle or heterocycle optionally further substituted with 0 to 4 groups selected from H, halogen, OH, cyano, NH 2 、C 1-6 Alkyl, halogen substituted C 1-6 Alkyl-and cyano-substituted C 1-6 Alkyl or C 1-6 Substituted by substituents of alkoxy groups, saidContaining 1 to 3 heteroatoms selected from O, S, N.
The present invention relates to some embodiments of the general formulae (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh) or (IIi), R 2 Selected from halogen, cyano, OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, -NH (C) 1-6 Alkyl) - (CH) 2 ) q -C 3-10 Carbocycle or- (CH) 2 ) q -3 to 12 membered heterocycle, said-CH 2 -, alkyl, alkenyl, alkynyl, alkoxy, carbocycle or heterocycle optionally further substituted with 0 to 4 groups selected from H, halogen, OH, cyano, C 1-6 Alkyl, halogen substituted C 1-6 Alkyl-and cyano-substituted C 1-6 Alkyl or C 1-6 The heterocyclic ring contains 1 to 3 hetero atoms selected from O, S, N.
The present invention relates to some embodiments of the general formulae (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh) or (IIi), R 2 Selected from halogen, cyano, OH, C 1-4 Alkyl, C 1-4 Alkoxy, -NH (C) 1-4 Alkyl) - (CH) 2 ) q -C 3-10 Carbocycle or- (CH) 2 ) q -3 to 10 membered heterocycle, said-CH 2 -, alkyl, alkoxy, carbocycle or heterocycle optionally further substituted with 0 to 4 groups selected from H, halogen, OH, cyano, NH 2 、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl-and cyano-substituted C 1-4 Alkyl or C 1-4 The heterocyclic ring contains 1 to 3 hetero atoms selected from O, S, N.
The present invention relates to some embodiments of the general formulae (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh) or (IIi), R 2 Selected from halogen, cyano, OH, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Carbocycle, 3-to 6-membered heterocycle, -CH 2 -C 3-6 Carbocycle, -CH 2 -3 to 6 membered heterocycle or-NH (C 1-4 Alkyl), said-CH 2 -, alkyl, alkoxy, carbocycle or heterocycle optionally further substituted with 0 to 4 groups selected from H, halogen, OH, cyano, NH 2 、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl-and cyano-substituted C 1-4 Alkyl or C 1-4 The heterocyclic ring contains 1 to 3 hetero atoms selected from O, S, N.
The present invention relates to some embodiments of the general formulae (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh) or (IIi), R 2 Selected from F, cyano, OH, -OCH 3 Methyl, ethyl, CF 3 、-CH 2 OH、-CH 2 CH 2 OH、-CH 2 CH 2 CH 2 OH、-CH 2 CN、-CH 2 CH 2 CN、-CH 2 CH 2 CH 2 CN、-CH 2 CH 2 CH 2 CH 2 CN、-NHCH 2 CN、-NHCH 2 CH 2 CN、-NHCH 2 CH 2 CH 2 CN、-NHCH 2 CH 2 CH 2 CH 2 CN、
The present invention relates to some embodiments of the general formulae (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh) or (IIi), R 2 Selected from OH, -OCH 3 、-CH 2 CN。
The present invention relates to some embodiments of the general formulae (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh) or (IIi), R 2 Selected from OH, -CH 2 CN。
The present invention relates to some embodiments of the general formulae (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh) or (IIi), R 2 Selected from OH.
The present invention relates to some embodiments of the general formulae (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh) or (IIi), R a1 、R a2 、R 2a 、R 2b Each independently selected from H, C 1-6 Alkyl, C 3-12 Carbocyclyl or 3-to 12-membered heterocyclyl, said alkyl, carbocyclyl or heterocyclyl optionally being further substituted with 0 to 4 groups selected from H, halogen, OH, cyano, NH 2 、-NH(C 1-6 Alkyl), -N (C) 1-6 Alkyl group 2 、-NH(C 3-6 Cycloalkyl group, C 1-6 Alkyl, C 3-12 Carbocyclyl, 3-to 12-membered heterocyclyl, hydroxy-substituted C 1-6 Alkyl, halogen substituted C 1-6 Alkyl-and cyano-substituted C 1-6 Alkyl or C 1-6 The heterocyclic group contains 1 to 3 hetero atoms selected from O, S, N.
The present invention relates to some embodiments of the general formulae (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh) or (IIi), R a1 、R a2 、R 2a 、R 2b Each independently selected from H, C 1-4 Alkyl, C 3-10 Carbocyclyl or 3-to 10-membered heterocyclyl, said alkyl, carbocyclyl or heterocyclyl optionally being further substituted with 0 to 4 groups selected from H, halogen, OH, cyano, NH 2 、-NH(C 1-4 Alkyl), -N (C) 1-4 Alkyl group 2 、-NH(C 3-6 Cycloalkyl group, C 1-4 Alkyl, C 3-8 CarbocyclesA radical, 3-to 8-membered heterocyclyl, hydroxy-substituted C 1-4 Alkyl, halogen substituted C 1-4 Alkyl-and cyano-substituted C 1-4 Alkyl or C 1-4 The heterocyclic group contains 1 to 3 hetero atoms selected from O, S, N.
The present invention relates to some embodiments of the general formulae (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh) or (IIi), R a1 、R a2 、R 2a 、R 2b Each independently selected from H, C 1-4 Alkyl, C 3-6 Carbocyclyl or 3-to 6-membered heterocyclyl, said alkyl, carbocyclyl or heterocyclyl optionally being further substituted with 0 to 4 groups selected from H, halogen, OH, cyano, NH 2 、-NH(C 1-4 Alkyl), -N (C) 1-4 Alkyl group 2 、-NH(C 3-6 Cycloalkyl group, C 1-4 Alkyl, C 3-6 Carbocyclyl, 3-to 6-membered heterocyclyl, hydroxy-substituted C 1-4 Alkyl, halogen substituted C 1-4 Alkyl-and cyano-substituted C 1-4 Alkyl or C 1-4 The heterocyclic group contains 1 to 3 hetero atoms selected from O, S, N.
The present invention relates to some embodiments of the general formulae (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh) or (IIi), R a1 、R a2 Each independently selected from H, C 1-4 Alkyl, C 3-6 Carbocyclyl.
The present invention relates to some embodiments of formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh) or (IIi) wherein each q is independently selected from 0, 1, 2, 3 or 4.
The present invention relates to some embodiments of formula (I), (Ia), (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh) or (IIi) wherein each q is independently selected from 0, 1 or 2.
The present invention relates to some embodiments of formula (Ia), (IIa), (IIb), (IId), (IIe) or (IIf), wherein each p is independently selected from 0, 1 or 2.
In some embodiments of the invention, the compounds of the formula (I), (Ia), (IIa) or (IIb) are not
The present invention relates to a pharmaceutical composition comprising any of the above compounds or stereoisomers, tautomers, deuterides, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals thereof, and a pharmaceutically acceptable carrier.
The present invention relates to the use of any of the above compounds, or stereoisomers, tautomers, deuterides, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or co-crystals thereof, for the manufacture of a medicament for the treatment of a disease associated with JAK kinase activity or expression level, preferably selected from inflammatory diseases.
The art references and monographs describe in detail the synthesis of reactants useful in the preparation of the compounds described herein or articles describing the preparation process are provided for reference. These references and monographs include: "Synthetic Organic Chemistry", john Wiley & Sons, inc., new York; S.R. Sandler et al, "Organic Functional Group Preparations,"2nd Ed., "Academic Press, new York,1983; h.o. house, "Modern Synthetic Reactions",2nd Ed., W.A.Benjamin, inc.Menlo Park, calif 1972; gilchrist, "Heterocyclic Chemistry",2nd Ed., john Wiley & Sons, new York,1992; march, "Advanced Organic Chemistry: reactions, mechanisms and Structure",4th Ed., wiley Interscience, new York,1992; fuhrhop, J.and Penzlin G. "Organic Synthesis: peptides, methods, starting Materials", second, revised and Enlarged Edition (1994) John Wiley & Sons ISBN:3 527-29074-5; hoffman, R.V. "Organic Chemistry, an Intermediate Text" (1996) Oxford University Press, ISBN 0-19-509618-5; larock, R.C. "Comprehensive Organic Transformations: A Guide to Functional Group Preparations"2nd Edition (1999) Wiley-VCH, ISBN:0-471-19031-4; march, J. "Advanced Organic Chemistry: reactions, mechanisms, and Structure"4th Edition (1992) John Wiley & Sons, ISBN:0-471-60180-2; otera, J. (editor) "Modern Carbonyl Chemistry" (2000) Wiley-VCH, ISBN:3-527-29871-1; patai, S. "Patai's 1992 Guide to the Chemistry of Functional Groups" (1992) Interscience ISBN:0-471-93022-9; solomons, T.W.G. "Organic Chemistry"7th Edition (2000) John Wiley & Sons, ISBN:0-471-19095-0; stowell, J.C. "Intermediate Organic Chemistry"2nd Edition (1993) Wiley-Interscience, ISBN:0-471-57456-2; "Industrial Organic Chemicals: starting Materials and Intermediates An Ullmann's Encyclopedia" (1999) John Wiley & Sons, ISBN:3-527-29645-X, in 8 volumes; "Organic Reactions" (1942-2000) John Wiley & Sons, in over 55volumes; and "Chemistry of Functional Groups" John Wiley & Sons, in 73 volumes.
Specific and similar reactants can be selectively identified by indexes of known chemicals prepared by american chemical abstracts, which are available in most public and university libraries and online. Chemicals known but not commercially available in catalogs are optionally prepared by custom chemical synthesis plants, many of which provide custom synthesis services (e.g., those listed above). References to the preparation and selection of pharmaceutically acceptable salts of the compounds described herein are p.h.stahl & c.g.weruth "Handbook of Pharmaceutical Salts", verlag Helvetica Chimica Acta, zurich,2002.
Synthesis method
To accomplish the objects of the present invention, the compounds of the present invention may be prepared by the following schemes:
R 1 、R 2 、R n2 、R a ring A and ring B are as defined for substituents in the compounds of formula (Ia);
x is selected from leaving groups, preferably F, cl, br, I, -OSO 2 -methyl, -OSO 2 -phenyl, said methyl or phenyl optionally being further substituted with 0, 1, 2, 3 or 4 groups selected from F, cl, br, I, C 1-4 Alkyl, C 1-4 Substituted with alkoxy;
the compound of formula (M-1) is converted into a compound of formula (M-2) by conventional nucleophilic substitution reaction; the compound of the general formula (M-2) is subjected to nucleophilic substitution reaction, coupling reaction or hydrogenation reaction to obtain a compound of the general formula (M-3); the compound of the general formula (M-3) is subjected to nucleophilic substitution reaction or coupling reaction to obtain the compound of the general formula (M-4).
Preferably, the compound of formula (M-3) is selected from compounds of formula (M-3 a) or (M-3 b):
R n2 selected from H or methyl; r is R 1 Selected from the group consisting ofX is selected from leaving groups, preferably F, cl, br, I, -OSO 2 -methyl, -OSO 2 -phenyl, said methyl or phenyl optionally being further substituted with 0, 1, 2, 3 or 4 substituents selected from F, cl, br, I, methyl, ethyl, methoxy or ethoxy.
Unless stated to the contrary, the terms used in the specification and claims have the following meanings.
The carbon, hydrogen, carbon monoxide and hydrogen referred to in the radicals and compounds of the invention,Oxygen, sulfur, nitrogen or F, cl, br, I all include their isotopic conditions, and the carbon, hydrogen, oxygen, sulfur or nitrogen involved in the groups and compounds of the present invention are optionally further replaced by one or more of their corresponding isotopes, where the isotopes of carbon include 12 C、 13 C and C 14 Isotopes of C, hydrogen include protium (H), deuterium (D, also known as heavy hydrogen), tritium (T, also known as super heavy hydrogen), isotopes of oxygen include 16 O、 17 O and 18 isotopes of O, sulfur include 32 S、 33 S、 34 S and 36 isotopes of S, nitrogen include 14 N and 15 isotopes of N, fluorine include 17 F and F 19 Isotopes of F, chlorine include 35 Cl and Cl 37 Isotopes of Cl, bromine include 79 Br and 81 Br。
"halogen" means F, cl, br or I.
"alkyl" refers to a straight or branched chain saturated aliphatic hydrocarbon group of 1 to 20 carbon atoms, preferably an alkyl group of 1 to 8 carbon atoms, more preferably an alkyl group of 1 to 6 carbon atoms, and even more preferably an alkyl group of 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl and various branched isomers thereof; the alkyl group may optionally be further substituted with 0 to 6 groups selected from F, cl, br, I, hydroxy, mercapto, nitro, cyano, amino, alkylamino, amido, alkenyl, alkynyl, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, 3 to 8 membered carbocyclyl, 3 to 8 membered heterocyclyl, 3 to 8 membered carbocyclyloxy, 3 to 8 membered heterocyclyloxy, carboxyl or carboxylate groups, where alkyl groups appear are defined in accordance with the present definition.
"halo substituted" means F, cl, br or I substituted, including but not limited to 1 to 10 substituents selected from F, cl, br or I, 1 to 6 substituents selected from F, cl, br or I, and 1 to 4 substituents selected from F, cl, br or I. "halo substituted" is simply referred to as "halo".
"alkoxy" refers to an-O-alkyl group. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclopropoxy and cyclobutoxy. The alkoxy group may be optionally further substituted with 0 to 5 substituents selected from F, cl, br, I, hydroxy, mercapto, nitro, cyano, amino, alkylamino, alkenyl, alkynyl, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, carbocyclyloxy, heterocyclyloxy, carboxy or carboxylate. Alkoxy groups appear herein, the definition of which is consistent with the definition.
"cycloalkyl" refers to a straight or branched chain saturated cyclic aliphatic hydrocarbon group of 3 to 20 carbon atoms, preferably a cycloalkyl group of 3 to 10 carbon atoms. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl. The cycloalkyl group may be optionally further substituted with 0 to 5 substituents selected from F, cl, br, I, hydroxy, mercapto, nitro, cyano, amino, alkylamino, alkenyl, alkynyl, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, carbocyclyloxy, heterocyclyloxy, carboxy or carboxylate. Cycloalkyl groups as herein presented are defined in accordance with the present definition.
"alkenyl" refers to a substituted or unsubstituted straight and branched unsaturated hydrocarbon radical having at least 1, typically 1, 2 or 3 carbon-carbon double bonds, the backbone including but not limited to 2 to 10, 2 to 6 or 2 to 4 carbon atoms, examples of alkenyl include but are not limited to vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 1-octenyl, 3-octenyl, 1-nonenyl, 3-nonenyl, 1-decenyl,4-decenyl, 1, 3-butadiene, 1, 3-pentadiene, 1, 4-hexadiene, and the like; the alkenyl may optionally be further substituted with 0 to 6 groups selected from F, cl, br, I, hydroxy, mercapto, nitro, cyano, amino, alkylamino, amido, alkenyl, alkynyl, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, 3 to 8 membered carbocyclyl, 3 to 8 membered heterocyclyl, 3 to 8 membered carbocyclyloxy, 3 to 8 membered heterocyclyloxy, carboxyl or carboxylate substituents, alkenyl groups appearing herein are defined in accordance with the present definition. Alkenyl groups may be monovalent, divalent, trivalent, or tetravalent.
"alkynyl" refers to substituted or unsubstituted straight and branched monovalent unsaturated hydrocarbon radicals having at least 1, typically 1, 2 or 3 carbon-carbon triple bonds, including but not limited to 2 to 10 carbon atoms, 2 to 6 carbon atoms, 2 to 4 carbon atoms in the backbone, alkynyl embodiments including but not limited to ethynyl, propargyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-1-butynyl, 2-methyl-3-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-1-pentynyl, 2-methyl-1-pentynyl, 1-heptynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 1-octynyl, 3-octynyl, 1-nonynyl, 3-decynyl, 4-decynyl, and the like; the alkynyl may optionally be further substituted with 0 to 6 groups selected from F, cl, br, I, hydroxy, mercapto, nitro, cyano, amino, alkylamino, amido, alkenyl, alkynyl, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, 3 to 8 membered carbocyclyl, 3 to 8 membered heterocyclyl, 3 to 8 membered carbocyclyloxy, 3 to 8 membered heterocyclyloxy, carboxyl or carboxylate substituents, alkynyl groups may be monovalent, divalent, trivalent or tetravalent.
"heterocyclyl" or "heterocycle" refers to a substituted or unsubstituted saturated or unsaturated aromatic or non-aromatic ring which may be a 3 to 8 membered monocyclic, 4 to 12 membered bicyclic or 10 to 15 membered tricyclic ring system and contains 1 to 3 heteroatoms selected from N, O or S, preferably 3 to 8 membered heterocyclyl, wherein N, S which is optionally substituted in the ring of the heterocyclyl may be oxidized to various oxidation states. The heterocyclic group may be attached to a heteroatom or carbon atom, and the heterocyclic group may be attached to a bridged or spiro ring, non-limiting examples include an oxiranyl group, an aziridinyl group, an oxetanyl group, an azetidinyl group, a 1, 3-dioxolanyl group, a 1, 4-dioxolanyl group, a 1, 3-dioxanyl group, an azepanyl group, a pyridyl group, a furyl group, a thienyl group, a pyranyl group, an N-alkylpyrrolyl group, a pyrimidinyl group, a pyrazinyl group, a pyridazinyl group, an imidazolyl group, a piperidyl group, a morpholinyl group, a thiomorpholinyl group, a 1, 3-dithianyl group, a dihydrofuryl group, a dihydropyranyl group, a dithianyl group, a tetrahydrofuranyl group, a tetrahydropyranyl group, a benzimidazolyl group, a benzopyridyl group, a pyrrolopyridinyl group, a benzodihydrofuryl group, an azabicyclo [3.2.1] octyl group, an azabicyclo [5.2.0] nonanyl group, an oxatricyclo [5.3.1.1] dodecyl group, an azaspiro [3.3] adamantyl group. The heterocyclic group may be optionally further substituted with 0 to 5 substituents selected from F, cl, br, I, =o, hydroxy, mercapto, nitro, cyano, amino, alkylamino, amido, alkenyl, alkynyl, alkyl, hydroxyalkyl, alkoxy, carbocyclyl, heterocyclyl, carbocyclyloxy, heterocyclyloxy, carboxy or carboxylate. Heterocyclyl groups as present herein are defined in accordance with the present definition.
"spiro" means a 5 to 20 membered polycyclic group sharing one atom (referred to as spiro atom) between substituted or unsubstituted monocyclic rings, which may contain 0 to 5 double bonds and may contain 0 to 5 groups selected from N, O or S (=o) n Is a heteroatom of (2). Preferably 6 to 14 membered, more preferably 6 to 12 membered, more preferably 6 to 10 membered, non-limiting examples of which include:
. When substituted, the substituents may be 1 to 5 selected from F, cl, br, I, alkyl, cycloalkylGroup, alkoxy, haloalkyl, thiol, hydroxy, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclyl, bridged ring, spirocyclic, and cyclic, hydroxyalkyl, =o, carbonyl, aldehyde, carboxylic acid, formate, - (CH) 2 ) m -C(＝O)-R a 、-O-(CH 2 ) m -C(＝O)-R a 、-(CH 2 ) m -C(＝O)-NR b R c 、-(CH 2 ) m S(＝O) n R a 、-(CH 2 ) m -alkenyl-R a 、OR d Or- (CH) 2 ) m -alkynyl-R a (wherein m, n is 0, 1 or 2), arylthio, thiocarbonyl, silane or-NR b R c Etc., wherein R is b And R is R c Independently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, and optionally R b And R is R c Five-or six-membered cycloalkyl or heterocyclyl groups may be formed. R is R a And R is R d Each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged ring, spirocyclic, or fused ring. Spiro rings appear herein, the definition of which is consistent with the definition.
"parallel ring" means that each ring in the system shares an adjacent pair of atoms of a polycyclic group with the other rings in the system, wherein one or more of the rings may contain 0 or more double bonds and may be substituted or unsubstituted, and each ring in the ring system may contain 0 to 5 atoms selected from N, S (=o) n Or a heteroatom of O. Preferably 5 to 20 membered, more preferably 5 to 14 membered, still more preferably 5 to 12 membered, still more preferably 5 to 10 membered. Non-limiting examples include:
when substituted, the substituents may be 1 to 5 groups selected from F, cl, br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclyl, bridged ring, spirocyclic, and cyclic, hydroxyalkyl, =o, carbonyl, aldehyde, carboxylic acid, formate, - (CH) 2 ) m -C(＝O)-R a 、-O-(CH 2 ) m -C(＝O)-R a 、-(CH 2 ) m -C(＝O)-NR b R c 、-(CH 2 ) m S(＝O) n R a 、-(CH 2 ) m -alkenyl-R a 、OR d Or- (CH) 2 ) m -alkynyl-R a (wherein m, n is 0, 1 or 2), arylthio, thiocarbonyl, silane or-NR b R c Etc., wherein R is b And R is R c Independently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, and optionally R b And R is R c Five-or six-membered cycloalkyl or heterocyclyl groups may be formed. R is R a And R is R d Each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged ring, spirocyclic, or fused ring. The merging rings appearing herein are defined in accordance with the present definition.
"bridged ring" means any two polycyclic groups of atoms not directly attached, which may contain 0 or more double bonds, and which may be substituted or unsubstituted, and any ring in the ring system may contain 0 to 5 atoms selected from N, S (=o) n Or an O heteroatom or group (wherein n is 1, 2). The ring atoms containing 5 to 20 atoms, preferably 5 to 14 atomsAtoms, more preferably 5 to 12, and still more preferably 5 to 10. Non-limiting examples include And adamantane. When substituted, the substituents may be 1 to 5 groups selected from F, cl, br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclyl, bridged ring, spirocyclic, and cyclic, hydroxyalkyl, =o, carbonyl, aldehyde, carboxylic acid, formate, - (CH) 2 ) m -C(＝O)-R a 、-O-(CH 2 ) m -C(＝O)-R a 、-(CH 2 ) m -C(＝O)-NR b R c 、-(CH 2 ) m S(＝O) n R a 、-(CH 2 ) m -alkenyl-R a 、OR d Or- (CH) 2 ) m -alkynyl-R a (wherein m, n is 0, 1 or 2), arylthio, thiocarbonyl, silane or-NR b R c Etc., wherein R is b And R is R c Independently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, and optionally R b And R is R c Five-or six-membered cycloalkyl or heterocyclyl groups may be formed. R is R a And R is R d Each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged ring, spirocyclic, or fused ring. The bridged rings appearing herein are defined in accordance with this definition.
"heteromonocyclic" means "heterocyclyl" or "heterocycle" of a monocyclic ring system, and the heteromonocyclic ring appears herein and is defined in accordance with the present definition.
"heteroacene" refers to a "fused ring" containing heteroatoms. The hybrid rings appearing herein are defined in accordance with this definition.
"heterospiro" refers to a "spiro" containing heteroatoms. The heterospiro ring appearing herein is defined in accordance with this definition.
"heterobridged ring" refers to a "bridged ring" that contains heteroatoms. The heterobridged rings appearing herein are defined in accordance with this definition.
"heteroaryl" or "heteroaryl ring" refers to a substituted or unsubstituted 5 to 14 membered aromatic ring and contains 1 to 5 groups selected from N, O or S (=o) n A heteroatom or group, preferably a 5 to 10 membered heteroaromatic ring, more preferably 5 to 6 membered. Non-limiting examples of heteroaryl groups include, but are not limited to, pyridyl, furyl, thienyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, thiomorpholine, 1, 3-dithiane, benzimidazole, benzopyridine, pyrrolopyridine, and the like. The heteroaryl ring may be 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 includeWhen substituted, the substituents may be 1 to 5 groups selected from F, cl, br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxy, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclyl, bridged ring, spirocyclic, and cyclic, hydroxyalkyl, =o, carbonyl, aldehyde, carboxylic acid, formate, - (CH) 2 ) m -C(＝O)-R a 、-O-(CH 2 ) m -C(＝O)-R a 、-(CH 2 ) m -C(＝O)-NR b R c 、-(CH 2 ) m S(＝O) n R a 、-(CH 2 ) m -alkenyl-R a 、OR d Or- (CH) 2 ) m -alkynyl-R a (wherein m, n is 0, 1 or 2), arylthio, thiocarbonyl, silane or-NR b R c Etc., wherein R is b And R is R c Independently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, and optionally R b And R is R c Five-or six-membered cycloalkyl or heterocyclyl groups may be formed. R is R a And R is R d Each independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged ring, spirocyclic, or fused ring. Heteroaryl or heteroaryl rings as herein defined are consistent with this definition.
"containing 1 to 4 heteroatoms selected from O, S, N" means containing 1, 2, 3 or 4 heteroatoms selected from O, S, N.
"substituted with 0 to X substituents" means substituted with 0, 1, 2, 3 … X substituents, X being selected from any integer between 1 and 10. By "substituted with 0 to 4 substituents" is meant substituted with 0, 1, 2, 3 or 4 substituents. By "substituted with 0 to 5 substituents" is meant substituted with 0, 1, 2, 3, 4 or 5 substituents. By "the hetero-bridge ring is optionally further substituted with 0 to 4 substituents selected from H or F" is meant that the hetero-bridge ring is optionally further substituted with 0, 1, 2, 3 or 4 substituents selected from H or F.
The X-Y membered ring (X is selected from an integer of 3 or less and Y is selected from any integer of 4 to 12) includes X+1, X+2, X+3, X+4 …. The ring includes heterocyclic, carbocyclic, aromatic, aryl, heteroaryl, cycloalkyl, heteromonocyclic, heterobicyclic, heterospiro, or heterobridged rings. For example, "4-7 membered heteromonocyclic ring" means 4-, 5-, 6-or 7-membered heteromonocyclic ring, and "5-10 membered heteromonocyclic ring" means 5-, 6-, 7-, 8-, 9-or 10-membered heteromonocyclic ring.
By "pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" is meant a salt of a compound of the invention that retains the biological effectiveness and properties of the free acid or free base, and the free acid is obtained by reaction with a non-toxic inorganic or organic base.
"pharmaceutical composition" refers to a mixture of one or more compounds of the present invention, pharmaceutically acceptable salts or prodrugs thereof, and other chemical components, wherein "other chemical components" refers to pharmaceutically acceptable carriers, excipients, and/or one or more other therapeutic agents.
By "carrier" is meant a material that does not cause significant irritation to the organism and does not abrogate the biological activity and properties of the administered compound.
"excipient" refers to an inert substance that is added to a pharmaceutical composition to facilitate administration of a compound. Non-limiting examples include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives (including microcrystalline cellulose), gelatin, vegetable oils, polyethylene glycols, diluents, granulating agents, lubricants, binders, and disintegrating agents.
"prodrug" means a compound of the invention which is converted into a biologically active form by in vivo metabolism. Prodrugs of the invention are prepared by modifying amino or carboxyl groups in the compounds of the invention, which modifications may be removed by conventional procedures or in vivo to give the parent compound. When the prodrugs of the invention are administered to a mammalian subject, the prodrugs are cleaved to form the free amino or carboxyl groups.
"co-crystals" refers to crystals of Active Pharmaceutical Ingredient (API) and co-crystal former (CCF) that are bound by hydrogen bonds or other non-covalent bonds, wherein the pure states of the API and CCF are both solid at room temperature and there is a fixed stoichiometric ratio between the components. A co-crystal is a multi-component crystal that includes both binary co-crystals formed between two neutral solids and multi-component co-crystals formed between a neutral solid and a salt or solvate.
"animal" is meant to include mammals, such as humans, companion animals, zoo animals and livestock, preferably humans, horses or dogs.
"stereoisomers" refers to isomers arising from the spatial arrangement of atoms in a molecule, and include cis-trans isomers, enantiomers and conformational isomers.
"optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "a heterocyclic group optionally substituted with an alkyl group" means that the alkyl group may be, but is not necessarily, present, and the description includes cases where the heterocyclic group is substituted with an alkyl group, and cases where the heterocyclic group is not substituted with an alkyl group.
“IC 50 "is the concentration of drug or inhibitor required to inhibit half of a given biological process (or a component of the process such as an enzyme, receptor, cell, etc.).
Detailed Description
For the purpose of the present invention, starting from commercially available chemicals and/or compounds described in the chemical literature, the compounds "commercially available chemicals" used in the reactions described herein are prepared from standard commercial sources, including Shanghai Allatin Biotechnology Co., ltd, shanghai Michelin Biochemical Co., sigma-Aldrich, alfa Elisa (China) chemical Co., ltd, boschiza (Shanghai) chemical industry development Co., an Naiji chemical, shanghai Tetan technology Co., kelong chemical, bailingwei Co., etc., according to organic synthesis techniques known to those skilled in the art.
The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or (sum) Mass Spectrometry (MS). NMR shift (. Delta.) is given in units of 10-6 (ppm). NMR was performed using a (Bruker Avance III and Bruker Avance 300) magnetonuclear instrument with deuterated dimethyl sulfoxide (DMSO-d 6), deuterated chloroform (CDCl 3), deuterated methanol (CD 3 OD) and an internal standard of Tetramethylsilane (TMS);
MS measurement (Agilent 6120B (ESI) and Agilent 6120B (APCI));
HPLC was performed using an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18X14.6mm, 3.5. Mu.M);
the thin layer chromatography silica gel plate uses a smoke table yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification of the silica gel plate used by the Thin Layer Chromatography (TLC) is 0.15mm-0.20mm, and the specification of the thin layer chromatography separation and purification product is 0.4mm-0.5mm;
column chromatography generally uses tobacco stage yellow sea silica gel 200-300 mesh silica gel as carrier.
Example 1: trans-4- [ (4-methoxy-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (compound 1 g)
Trans-4-[(4-methoxy-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)amino]adamantan-1-ol
Cis-4- [ (4-methoxy-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (compound 1H)
Cis-4-[(4-methoxy-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)amino]adamantan-1-ol
The first step: 2, 6-dichloro-N- (3-methyl-1H-pyrazol-5-yl) pyrimidin-4-amine (1 c)
2，6-dichloro-N-(3-methyl-1H-pyrazol-5-yl)pyrimidin-4-amine
N, N-diisopropylethylamine (2.00 g,15.26 mmol) was added to a solution of 2,4, 6-trichloropyrimidine (1 b) (1.40 g,7.63 mmol), 3-methyl-1H-pyrazol-5-amine (1 a) (1.11 g,11.45 mmol) in ethanol (15 ml) at room temperature. After reacting at room temperature for 4 hours, 20mL of water was added to the reaction mixture, and the reaction was continued with stirring for 1 hour. Filtration gave 2, 6-dichloro-N- (3-methyl-1H-pyrazol-5-yl) pyrimidin-4-amine (1 c) (1.00 g, 54%) as a white solid.
LCMS m/z＝244.0，246.1[M+1] +
And a second step of: 4- [ (4-chloro-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (1 f)
4-[(4-chloro-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)amino]adamantan-1-ol
N, N-diisopropylethylamine (317 mg,2.45 mmol) was added to a solution of 4-aminoadamantane-1-ol hydrochloride (1 d) (100 mg,0.49 mmol), 2, 6-dichloro-N- (3-methyl-1H-pyrazol-5-yl) pyrimidin-4-amine (1 c) (251 mg,1.03 mmol) in DMSO (2 ml) at room temperature. The temperature was raised to 100℃and the reaction was carried out for 14 hours. After cooling to room temperature, the reaction was quenched with water (10 mL), extracted with ethyl acetate (10 mL. Times.2), the organic phases were combined, backwashed with saturated brine (10 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and the mother liquor concentrated to give crude product. The crude product was isolated and purified by column chromatography (dichloromethane: methanol (v/v) =10:1) to give 4- [ (4-chloro-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (1 f) (100 mg, 54%).
LCMS m/z＝375.2[M+1] +
And a third step of: trans-4- [ (4-methoxy-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (compound 1 g)
Trans-4-[(4-methoxy-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)amino]adamantan-1-ol
Cis-4- [ (4-methoxy-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (compound 1H)
Cis-4-[(4-methoxy-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)amino]adamantan-1-ol
Sodium methoxide (146 mg,2.70 mmol) was added to 4- [ (4-chloro-6- [ (5-methyl-1H-pyrazol-3-yl) amino) at room temperature ]Pyrimidine2-yl) amino group]Adamantan-1-ol (1 f) (100 mg,0.27 mmol) in methanol (2 ml). In the tube sealing, the temperature is raised to 100 ℃ for reaction for 14 hours. After cooling to room temperature, the reaction mixture was poured into water (10 mL) to quench the reaction, ethyl acetate (10 ml×2) was extracted, the organic phases were combined, washed with saturated brine (10 ml×2), dried over anhydrous sodium sulfate, filtered, and the mother liquor was concentrated to give a crude product. Purifying the crude product by Pre-HPLC (instrument and preparation column: preparation of liquid phase by Waters 2767, preparation column model XBIdge@Prep C 18 Inner diameter x length = 19mm x 250 mm). The preparation method comprises the following steps: the crude product was dissolved in DMF (N, N-dimethylformamide) and filtered through a 0.45 μm filter to prepare a sample solution. Mobile phase system: acetonitrile/water (0.05% ammonia). The gradient elution method comprises the following steps: acetonitrile was eluted 55% by a 10% gradient (flow rate: 12mL/min; elution time 17 min), and lyophilized to give:
trans-4- [ (4-methoxy-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (compound 1 g) (30 mg, 30%)
LCMS m/z＝371.3[M+1] +
Cis-4- [ (4-methoxy-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (compound 1H) (12 mg, 12%)
LCMS m/z＝371.3[M+1] +
1 H NMR(400MHz,DMSO-d 6 +D 2 O)δ6.12(s,1H),5.66(s,1H),3.79-3.76(m,1H),3.72(s,3H),2.24-2.07(d,5H),2.05-2.00(m,1H),1.88-1.78(m,2H),1.67-1.57(m,6H),1.46-1.38(d,2H).
Example 2: trifluoroacetate salt of trans-2- [4- [ (4-methoxy-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] cyclohexyl ] acetonitrile (compound 2)
trans-2-[4-[(4-methoxy-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)amino]cyclohexyl]acetonitrile trifluoroacetate
The first step: trans-2- [4- [ (4-chloro-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] cyclohexyl ] acetonitrile (2 b)
trans-2-[4-[(4-chloro-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)amino]cyclohexyl]acetonitrile
N, N-diisopropylethylamine (265 mg,2.05 mmol) was added to a solution of 2, 6-dichloro-N- (3-methyl-1H-pyrazol-5-yl) pyrimidin-4-amine (1 c) (100 mg,0.41 mmol), 2- [ (1 s,4 s) -4-aminocyclohexyl ] acetonitrile (2 a) (57 mg,0.41 mmol) in DMSO (2 ml) at room temperature, and the temperature was raised to 100℃for 14 hours. After cooling to room temperature, the reaction solution was poured into 10mL of water, extracted with ethyl acetate (10 ml×2), the organic phases were combined, backwashed with saturated brine (10 ml×2), dried over anhydrous sodium sulfate, filtered, and the mother liquor was concentrated to obtain a crude product. The crude product was isolated and purified by column chromatography (dichloromethane: methanol (v/v) =10:1) to give trans-2- [4- [ (4-chloro-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] cyclohexyl ] acetonitrile (2 b) (120 mg, 85%).
LCMS m/z＝346.2[M+1] +
And a second step of: trifluoroacetate salt of trans-2- [4- [ (4-methoxy-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] cyclohexyl ] acetonitrile (compound 2)
trans-2-[4-[(4-methoxy-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)amino]cyclohexyl]acetonitrile trifluoroacetate
Sodium methoxide (157 mg,2.90 mmol) was added to trans-2- [4- [ (4-chloro-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] at room temperature]Pyrimidin-2-yl) amino groups]Cyclohexyl group]Acetonitrile (2 b) (100 mg,0.29 mmol) in methanol (2 ml). In a sealed tube, heating to 100 ℃ for reaction 14 hours. Then cooled to room temperature, the reaction solution was poured into 10mL of water, extracted with ethyl acetate (10 mL x 2), the organic phases were combined, backwashed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and the mother liquor was concentrated to obtain a crude product. Purifying the crude product by Pre-HPLC (instrument and preparation column: preparation of liquid phase by Waters 2767, preparation column model is Sunfire@Prep C 18 5 μm, inner diameter = length = 19mm x 250 mm). The preparation method comprises the following steps: the crude product was dissolved in DMF and filtered through a 0.45 μm filter to prepare a sample solution. Mobile phase system: acetonitrile/water (containing 1% trifluoroacetic acid). The gradient elution method comprises the following steps: acetonitrile was eluted with a gradient of 50% (flow rate: 15mL/min; elution time: 15 min) from 5%, and lyophilized to give trans-2- [4- [ (4-methoxy-6- [ (5-methyl-1H-pyrazol-3-yl) amino]Pyrimidin-2-yl) amino groups]Cyclohexyl group]Acetonitrile (compound 2) trifluoroacetate salt (25 mg, 25%).
LCMS m/z＝342.2[M+1] +
Example 3: cis-4- [ (4-methoxy-6- [ (1-methyl-1H-imidazol-4-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (compound 3)
Cis-4-[(4-methoxy-6-[(1-methyl-1H-imidazol-4-yl)amino]pyrimidin-2-yl)amino]adamantan-1-ol
The first step: 2, 6-dichloro-N- (1-methyl-1H-imidazol-4-yl) pyrimidin-4-amine (3 c)
2,6-dichloro-N-(1-methyl-1H-imidazol-4-yl)pyrimidin-4-amine
N, N-diisopropylethylamine (704 mg,5.45 mmol) was added to a solution of 2,4, 6-trichloropyrimidine (1 b) (200 mg,1.09 mmol) and 1-methyl-1H-imidazol-4-amine (159 mg,1.64 mmol) in ethanol (5 ml) at room temperature. After reacting at room temperature for 4 hours, 20mL of water was added to the reaction mixture, and the reaction was continued with stirring for 1 hour. Filtration gave 2, 6-dichloro-N- (1-methyl-1H-imidazol-4-yl) pyrimidin-4-amine (3 c) as the target product (200 mg, 75%).
LCMS m/z＝244.0，246.1[M+1] +
And a second step of: cis-4- [ (4-chloro-6- [ (1-methyl-1H-imidazol-4-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (3 f)
Cis-4-[(4-chloro-6-[(1-methyl-1H-imidazol-4-yl)amino]pyrimidin-2-yl)amino]adamantan-1-ol
N, N-diisopropylethylamine (424 mg,3.28 mmol) was added to a solution of 2, 6-dichloro-N- (1-methyl-1H-imidazol-4-yl) pyrimidin-4-amine (3 c) (200 mg,0.82 mmol), cis-4-aminoadamantan-1-ol hydrochloride (3 d) (184 mg,0.90 mmol) in DMSO (4 ml) at room temperature. The temperature was raised to 100℃and the reaction was carried out for 14 hours. After cooling to room temperature, the reaction was quenched with water (10 mL), extracted with ethyl acetate (10 mL. Times.2), the organic phases were combined, backwashed with saturated brine (10 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and the mother liquor concentrated to give crude product. The crude product was purified by column chromatography (dichloromethane: methanol (v/v) =10:1) to give Cis-4- [ (4-chloro-6- [ (1-methyl-1H-imidazol-4-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (3 f) (200 mg, 65%).
LCMS m/z＝375.2[M+1] +
And a third step of: cis-4- [ (4-methoxy-6- [ (1-methyl-1H-imidazol-4-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (compound 3)
Cis-4-[(4-methoxy-6-[(1-methyl-1H-imidazol-4-yl)amino]pyrimidin-2-yl)amino]adamantan-1-ol
Sodium methoxide (284 mg,5.30 mmol) was added to Cis-4- [ (4-chloro-6- [ (1-methyl-1H) at room temperature-imidazol-4-yl) amino group]Pyrimidin-2-yl) amino groups]Adamantan-1-ol (3 f) (200 mg,0.53 mmol) in methanol (5 ml). In the tube sealing, the temperature is raised to 100 ℃ for reaction for 14 hours. After cooling to room temperature, the reaction mixture was poured into water (10 mL), quenched, extracted with ethyl acetate (10 ml×2), the organic phases were combined, backwashed with saturated brine (10 ml×2), dried over anhydrous sodium sulfate, and filtered. Concentrating the mother solution to obtain crude product, purifying the crude product by Pre-HPLC (instrument and preparation column: preparation of liquid phase by Waters 2767, preparation column model is XBIdge@PrepC) 18 Inner diameter x length = 19mm x 250 mm). The preparation method comprises the following steps: the crude product was dissolved in DMF and filtered through a 0.45 μm filter to prepare a sample solution. Mobile phase system: acetonitrile/water (0.05% ammonia). The gradient elution method comprises the following steps: acetonitrile was eluted with a gradient of 55% (flow rate: 12mL/min; elution time: 17 min) from 10%, and lyophilized to give Cis-4- [ (4-methoxy-6- [ (1-methyl-1H-imidazol-4-yl) amino group]Pyrimidin-2-yl) amino groups]Adamantan-1-ol (compound 3) (30 mg, 15%).
LCMS m/z＝371.2[M+1] +
1 H NMR(400MHz,DMSO-d 6 )δ9.04(s,1H),7.45-7.05(m,2H),6.21(s,1H),5.42(s,1H),4.35(s,1H),3.80-3.75(d,1H),3.72(s,3H),3.60(s,3H),2.35-2.20(m,2H),2.08-2.03(m,1H),1.97-1.85(m,2H),1.75-1.53(m,6H),1.43-1.34(m,2H).
Example 4: cis-4- [ (4- [ (5-methyl-1H-pyrazol-3-yl) amino ] -6- (propan-2-yloxy) pyrimidin-2-yl) amino ] adamantan-1-ol (compound 4)
Cis-4-[(4-[(5-methyl-1H-pyrazol-3-yl)amino]-6-(propan-2-yloxy)pyrimidin-2-yl)amino]adamantan-1-ol
The first step: cis-4- [ (4-chloro-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (4 b)
Cis-4-[(4-chloro-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)amino]adamantan-1-ol
N, N-diisopropylethylamine (6.35 g,49.10 mmol) was added to a solution of Cis-4-aminoadamantan-1-ol hydrochloride (3 d) (2.00 g,9.82 mmol), 2, 6-dichloro-N- (5-methyl-1H-pyrazol-3-yl) pyrimidin-4-amine (1 c) (2.64 g,10.80 mmol) in DMSO (20 ml) at room temperature. The temperature was raised to 100℃and the reaction was carried out for 14 hours. Then, the reaction mixture was cooled to room temperature, poured into water (50 mL), and stirred for half an hour. Then filtering, washing the filter cake with ethanol, and obtaining the target product Cis-4- [ (4-chloro-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (4 b) (1.30 g, 35%).
LCMS m/z＝375.2[M+1] +
1 H NMR(400MHz,DMSO)δ11.76(s,1H),9.33(s,1H),6.90-5.90(d,3H),4.02(s,1H),3.81-3.74(m,1H),2.27-2.15(d,5H),2.08-2.00(m,1H),1.96-1.87(d,2H),1.72–1.56(m,6H),1.46-1.34(d,2H).
And a second step of: cis-4- [ (4- [ (5-methyl-1H-pyrazol-3-yl) amino ] -6- (propan-2-yloxy) pyrimidin-2-yl) amino ] adamantan-1-ol (compound 4)
Cis-4-[(4-[(5-methyl-1H-pyrazol-3-yl)amino]-6-(propan-2-yloxy)pyrimidin-2-yl)amino]adamantan-1-ol
Sodium isopropoxide (90 mg,1.10 mmol) was added to a solution of Cis-4- [ (4-chloro-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (4 b) (40 mg,0.11 mmol) in isopropanol (5 ml) at room temperature. The temperature is raised to 100 ℃ and the reaction is carried out for 36 hours. After the reaction is completed, the reaction solution is concentrated to dryness to obtain a crude product. The crude product was purified by Pre-HPLC (apparatus and preparation column: preparation of liquid phase using Waters 2767, preparation column model xbridge@prepc18, inner diameter x length=19 mm x 250 mm). The preparation method comprises the following steps: the crude product was dissolved in DMF and filtered through a 0.45 μm filter to prepare a sample solution. Mobile phase system: acetonitrile/water (0.05% ammonia). The gradient elution method comprises the following steps: acetonitrile was eluted 55% gradient (flow rate: 12mL/min; elution time: 17 min) and lyophilized to give Cis-4- [ (4- [ (5-methyl-1H-pyrazol-3-yl) amino ] -6- (propan-2-yloxy) pyrimidin-2-yl) amino ] adamantan-1-ol (compound 4) (4 mg, 9%).
LCMS m/z＝399.3[M+1] +
Example 5: cis-4- [ (4- [ (5-methyl-1H-pyrazol-3-yl) amino ] -6- (trifluoromethyl) pyrimidin-2-yl) amino ] adamantan-1-ol (compound 5)
Cis-4-[(4-[(5-methyl-1H-pyrazol-3-yl)amino]-6-(trifluoromethyl)pyrimidin-2-yl)amino]adaman tan-1-ol
The first step: 2-chloro-N- (3-methyl-1H-pyrazol-5-yl) -6- (trifluoromethyl) pyrimidin-4-amine (5 b)
2-chloro-N-(3-methyl-1H-pyrazol-5-yl)-6-(trifluoromethyl)pyrimidin-4-amine
N, N-diisopropylethylamine (2.38 g,18.44 mmol) was added to a solution of 2, 4-dichloro-6- (trifluoromethyl) pyrimidine (5 a) (1.00 g,4.61 mmol), 3-methyl-1H-pyrazol-5-amine (490 mg,5.07 mmol) in DMF (10 ml) at room temperature. After 16H at room temperature, the reaction was quenched with water (10 mL), extracted with ethyl acetate (30 mL. Times.2), the combined organic phases were backwashed with saturated brine (10 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and the mother liquor concentrated to give crude product, which was slurried with ethyl acetate to give 2-chloro-N- (3-methyl-1H-pyrazol-5-yl) -6- (trifluoromethyl) pyrimidin-4-amine (5 b) (1.00 g, 78%).
LCMS m/z＝278.0[M+1] + 。
And a second step of: cis-4- [ (4- [ (5-methyl-1H-pyrazol-3-yl) amino ] -6- (trifluoromethyl) pyrimidin-2-yl) amino ] adamantan-1-ol (compound 5)
Cis-4-[(4-[(5-methyl-1H-pyrazol-3-yl)amino]-6-(trifluoromethyl)pyrimidin-2-yl)amino]adamantan-1-ol
N, N-diisopropylethylamine (317 mg,2.45 mmol) was added to a solution of Cis-4-aminoadamantane-1-ol hydrochloride (3 d) (100 mg,0.49 mmol), 2-chloro-N- (3-methyl-1H-pyrazol-5-yl) -6- (trifluoromethyl) pyrimidin-4-amine (5 b) (136 mg,0.49 mmol) in DMSO (2 ml) at room temperature. The temperature was raised to 100℃and the reaction was carried out for 14 hours. After the reaction was completed, the reaction mixture was poured into water (10 mL), quenched, extracted with ethyl acetate (10 ml×2), the organic phases were combined, backwashed with saturated brine (10 ml×2), dried over anhydrous sodium sulfate, filtered, and the mother liquor was concentrated to obtain a crude product. The crude product was purified by Pre-HPLC (apparatus and preparation column: preparation of liquid phase using Waters2767, preparation column model xbridge@prepc18, inner diameter x length=19 mm x 250 mm). The preparation method comprises the following steps: the crude product was dissolved in DMF and filtered through a 0.45 μm filter to prepare a sample solution. Mobile phase system: acetonitrile/water (0.05% ammonia). The gradient elution method comprises the following steps: acetonitrile was eluted 55% by 10% gradient (flow rate: 12mL/min; elution time: 17 min) and lyophilized to give Cis-4- [ (4- [ (5-methyl-1H-pyrazol-3-yl) amino ] -6- (trifluoromethyl) pyrimidin-2-yl) amino ] adamantan-1-ol (compound 5) (150 mg, 75%).
LCMS m/z＝409.3[M+1] + 。
1 H NMR(400MHz,DMSO-d 6 )δ11.80(s,1H),9.60(s,1H),6.80-6.20(m,3H),4.01(s,1H),3.85-3.78(m,1H),2.28-2.18(m,5H),2.08-2.03(m,1H),1.98-1.91(m,2H),1.70-1.59(m,6H),1.45-1.35(m,2H).
Example 6: cis-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] -2- [ (5-hydroxyadamantan-2-yl) amino ] pyrimidine-4-carboxamide (Compound 6)
Cis-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-[(5-hydroxyadamantan-2-yl)amino]pyrimidine-4-carboxamide
The first step: 2-chloro-6- [ (3-methyl-1H-pyrazol-5-yl) amino ] pyrimidine-4-carboxylic acid methyl ester (6 b)
methyl 2-chloro-6-[(3-methyl-1H-pyrazol-5-yl)amino]pyrimidine-4-carboxylate
N, N-diisopropylethylamine (2.00 g,15.26 mmol) was added to a solution of methyl 2, 6-dichloropyrimidine-4-carboxylate (6 a) (1.60 g,7.63 mmol), 3-methyl-1H-pyrazol-5-amine (680 mg,9.16 mmol) in DMSO (15 ml) at room temperature. The reaction was kept at room temperature for 12 hours. Then, 30mL of water was added to the reaction mixture, and the reaction was continued with stirring for 1 hour, and filtered to give a yellow solid, namely, the target product methyl 2-chloro-6- [ (3-methyl-1H-pyrazol-5-yl) amino ] pyrimidine-4-carboxylate (6 b) (2.00 g, 98%).
LCMS m/z＝268.1[M+1] + 。
And a second step of: cis-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] methyl-2- [ (5-hydroxyadamantan-2-yl (amino ] pyrimidine-4-carboxylic acid methyl ester (6 c)
Cis-Methyl-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-[(5-hydroxyadamantan-2-yl)amino]pyrimidine-4-carboxylate
N, N-diisopropylethylamine (4.83 g,37.35 mmol) was added to a solution of methyl 2-chloro-6- [ (3-methyl-1H-pyrazol-5-yl) amino ] pyrimidine-4-carboxylate (6 b) (2.00 g,7.47 mmol), cis-4-aminoadamantan-1-ol hydrochloride (3 d) (1.52 g,7.47 mmol) in DMSO (15 ml) at room temperature. The reaction was maintained at 100℃for 12 hours. After the completion of the reaction, 50mL of water was added to the reaction mixture, and the reaction was continued with stirring for 1 hour, followed by filtration to give Cis-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] methyl-2- [ 5-hydroxyadamantan-2-yl (amino ] pyrimidine-4-carboxylic acid methyl ester (6 c) (1.30 g, 44%).
LCMS m/z＝399.2[M+1] + 。
And a third step of: cis-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] -2- [ (5-hydroxyadamantan-2-yl) amino ] pyrimidine-4-carboxamide (Compound 6)
Cis-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-[(5-hydroxyadamantan-2-yl)amino]pyrimidine-4-carboxamide
Cis-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] methyl-2- [ (5-hydroxyadamantan-2-yl) amino ] pyrimidine-4-carboxylic acid methyl ester (6 c) (30 mg,0.08 mmol) was added to a lock tube containing a 4M methanolic ammonia solution (5 ml) at room temperature, and then the temperature was raised to 100℃for reaction for 12 hours. After cooling to room temperature, the solution was concentrated to give a crude product, which was purified by prep-HPLC (apparatus and column preparation: using Waters 2767 for the preparation of the liquid phase, column model xbridge@prepc18, inner diameter =19mm ×250mm). The preparation method comprises the following steps: the crude product was dissolved in DMF and filtered through a 0.45 μm filter to prepare a sample solution. Mobile phase system: acetonitrile/water (0.05% ammonia). The gradient elution method comprises the following steps: acetonitrile was eluted with a 10% gradient of 55% (flow rate: 12mL/min; elution time: 17 min) and lyophilized to give Cis-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] -2- [ (5-hydroxyadamantan-2-yl) amino ] pyrimidine-4-carboxamide (compound 6) (16 mg, 55%).
LCMS m/z＝384.2[M+1] +
1 H NMR(400MHz,DMSO-d 6 )δ11.89(s,1H),9.74(s,1H),7.75-7.45(m,2H),6.85-6.20(m,3H),4.33(s,1H),3.95-3.75(m,1H),2.27-2.13(m,5H),2.08-2.02(m,1H),1.97-1.85(m,2H),1.80-1.55(m,6H),1.45-1.36(m,2H).
Example 7: cis-N-cyclopropyl-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] -2- [ (5-hydroxyadamantan-2-yl) amino ] pyrimidine-4-carboxamide (Compound 7)
Cis-N-cyclopropyl-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-[(5-hydroxyadamantan-2-yl)amino]pyrimidine-4-carboxamide
Cyclopropylamine (43 mg,0.75 mmol) was added to a solution of Cis-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] methyl-2- [ (5-hydroxyadamantan-2-yl (amino) pyrimidine-4-carboxylate (6C) (30 mg,0.08 mmol) in methanol (5 mL) (tube-sealing) at room temperature, then warmed to 100 ℃ for 12 hours, after the reaction was completed, the reaction solution was concentrated to dryness to give a crude product, which was purified by Pre-HPLC (instrument and preparative column: preparation of liquid phase using Waters 2767; preparative column model xbridge@prep C18, inner diameter =19mm @). Preparation method: crude product was dissolved in DMF and filtered with 0.45 μm filter membrane to prepare a sample solution, mobile phase system: acetonitrile/water (aqueous 0.05% ammonia). Gradient elution method: 55% (flow rate: 12mL/min; elution time 17 min), after which Cis-6-N-cyclopropyl-5- [ (5-methyl-3-amino ] pyrimidine-2-carboxylate (16 mg) was lyophilized).
LCMS m/z＝424.2[M+1] +
1 H NMR(400MHz,DMSO-d 6 )δ11.90(s,1H),9.76(s,1H),8.22(s,1H),6.85-6.15(m,3H),4.33(s,1H),3.89-3.75(m,1H),2.86-2.76(m,1H),2.26-2.15(m,5H),2.09-2.03(m,1H),1.94-1.82(m,2H),1.74-1.58(m,6H),1.44-1.37(m,2H),0.76-0.68(m,2H),0.61–0.52(m,2H).
Example 8: cis-4- [ (4-ethoxy-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (compound 8)
Cis-4-[(4-ethoxy-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)amino]adamantan-1-ol
Compound 8 was synthesized from Cis-4- [ (4-chloro-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (4 b) and sodium ethoxide as starting materials, according to the method of reference example 3, to give Cis-4- [ (4-ethoxy-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (Compound 8)
LCMS m/z＝385.2[M+1]+
1 H NMR(400MHz,DMSO-d 6 )δ11.57(s,1H),8.63(s,1H),6.17(s,1H),5.84-5.63(m,2H), 4.21(q,2H),4.03(s,1H),3.83-3.75(m,1H),2.25-1.80(m,8H),1.70-1.55(m,6H),1.46-1.36(m,2H),1.25(t,3H).
Example 9: cis-4- [ (4- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (compound 9)
Cis-4-[(4-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)amino]adamantan-1-ol
Cis-4- [ (4-chloro-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (4 b) (50 mg,0.13 mmol) was dissolved in a mixed solution of methanol (10 mL) and tetrahydrofuran (10 mL), and after three times of hydrogen substitution, the mixture was vigorously stirred under a hydrogen atmosphere for 48 hours. The residue was purified by Pre-HPLC (apparatus and preparative column: prepare liquid phase using water 2767, model X select C18,5 μm, inner diameter length=19 mm X150 mm). The preparation method comprises the following steps: the crude product was dissolved in dimethyl sulfoxide and filtered through a 0.45 μm filter to prepare a sample solution. Mobile phase system: acetonitrile/water. The gradient elution method comprises the following steps: acetonitrile was eluted by a 5% gradient 50% (elution time 15 min). Freeze-drying afforded Cis-4- [ (4- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (compound 9) as a white solid (25 mg, 56%).
LCMS m/z＝341.3[M+1] +
1 H NMR(400MHz,CD 3 OD)δ7.79(d,1H),6.37-5.96(m,2H),3.94-3.86(m,1H),2.33-2.22(m,5H),2.16-2.10(m,1H),2.01-1.92(m,2H),1.85-1.71(m,6H),1.63-1.54(m,2H).
Example 10: trifluoroacetate salt of Cis-4- [ (4- [ (5-methyl-1H-pyrazol-3-yl) amino ] -6- { [ (2S) -1-methylpyrrolidin-2-yl ] methoxy } pyrimidin-2-yl) amino ] adamantan-1-ol (compound 10)
Cis-4-[(4-[(5-methyl-1H-pyrazol-3-yl)amino]-6-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}pyrimidin-2-yl)amino]adamantan-1-ol trifluoroacetate
To a reaction flask containing N-methyl-L-prolinol (2 mL) was added sodium metal (74 mg,3.20 mmol), and after heating to 60℃for 5H, cis-4- [ (4-chloro-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (4 b) (60 mg,0.16 mmol) was added thereto. After heating to 100deg.C for 16h, the reaction was quenched by the addition of water (1 mL). The crude product was purified by Pre-HPLC (instrument and column: liquid phase prepared using Gilson Gx-281, column model number Sunfire,5 μm, inner diameter =30 mm ×150 mm). The preparation method comprises the following steps: the crude product was dissolved in methanol and filtered through a 0.45 μm filter to prepare a sample solution. Mobile phase system: acetonitrile/water (containing 0.5% trifluoroacetic acid). The gradient elution method comprises the following steps: acetonitrile was eluted 60% by a 10% gradient (elution time 16 min) and lyophilized to give the trifluoroacetate salt of Cis-4- [ (4- [ (5-methyl-1H-pyrazol-3-yl) amino ] -6- { [ (2S) -1-methylpyrrolidin-2-yl ] methoxy } pyrimidin-2-yl) amino ] adamantan-1-ol (compound 10) (30 mg, 33%) as a white solid.
LCMS m/z＝454.2[M+1] +
1 H NMR(400MHz,CD 3 OD)δ5.86(s,1H),5.70(s,1H),4.80-4.74(m,1H),4.64-4.54(m,1H),4.10-3.95(m,1H),3.91-3.80(m,1H),3.80-3.70(m,1H),3.28-3.19(m,1H),3.04(s,3H),2.40-2.31(m,5H),2.24-1.91(m,7H),1.88-1.72(m,6H),1.69-1.60(m,2H).
Example 11: trifluoroacetate salt of Cis-4- [ (4- [ (5-methyl-1H-pyrazol-3-yl) amino ] -6- { [ (2R) -1-methylpyrrolidin-2-yl ] methoxy } pyrimidin-2-yl) amino ] adamantan-1-ol (compound 11)
Cis-4-[(4-[(5-methyl-1H-pyrazol-3-yl)amino]-6-{[(2R)-1-methylpyrrolidin-2-yl]methoxy}pyrimidin-2-yl)amino]adamantan-1-ol trifluoroacetate
Compound 11 the procedure of example 10 was followed starting from Cis-4- [ (4-chloro-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (4 b) and N-methyl-D-prolinol to give the trifluoroacetate salt of Cis-4- [ (4- [ (5-methyl-1H-pyrazol-3-yl) amino ] -6- { [ (2R) -1-methylpyrrolidin-2-yl ] methoxy } pyrimidin-2-yl) amino ] adamantan-1-ol (Compound 11).
LCMS m/z＝454.2[M+1] +
1 H NMR(400MHz,CD 3 OD)δ5.87(s,1H),5.69(s,1H),4.79-4.75(m,1H),4.61-4.54(m,1H),4.11-3.95(m,1H),3.91-3.81(m,1H),3.78-3.68(m,1H),3.29-3.19(m,1H),3.04(s,3H),2.41-2.31(m,5H),2.26-1.90(m,7H),1.89-1.70(m,6H),1.69-1.59(m,2H).
Example 12: trifluoroacetate salt of Cis-4- [ (4- (2- (dimethylamino) ethoxy) -6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (compound 12)
Cis-4-[(4-(2-(dimethylamino)ethoxy)-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)amino]adamantan-1-ol trifluoroacetate
Compound 12 the procedure of example 10 was followed using Cis-4- [ (4-chloro-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (4 b) and N, N-dimethylethanolamine as starting materials to give the trifluoroacetate salt of Cis-4- [ (4- (2- (dimethylamino) ethoxy) -6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (compound 12).
LCMS m/z＝428.3[M+1] +
1 H NMR(400MHz,CD 3 OD)δ5.86(s,1H),5.69(s,1H),4.74-4.69(m,2H),4.10-3.98(m,1H),3.63-3.57(m,2H),2.98(s,6H),2.39-2.30(m,5H),2.20-2.12(m,1H),2.02-1.93(m,2H),1.87-1.72(m,6H),1.67-1.59(m,2H).
EXAMPLE 13 trifluoroacetate salt of cis-4- [ (4- [ (5-methyl-1H-pyrazol-3-yl) amino ] -6- (2- (piperidin-1-yl) ethoxy) pyrimidin-2-yl) amino ] adamantan-1-ol (compound 13)
Cis-4-[(4-[(5-methyl-1H-pyrazol-3-yl)amino]-6-(2-(piperidin-1-yl)ethoxy)pyrimidin-2-yl)amino]adamantan-1-ol trifluoroacetate
Compound 13 was synthesized from Cis-4- [ (4-chloro-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (4 b) and 1-piperidineethanol as starting materials according to the method of reference example 10 to give the trifluoroacetate salt of Cis-4- [ (4- [ (5-methyl-1H-pyrazol-3-yl) amino ] -6- (2- (piperidin-1-yl) ethoxy) pyrimidin-2-yl) amino ] adamantan-1-ol (Compound 13).
LCMS m/z＝468.4[M+1] +
1 H NMR(400MHz,CD 3 OD)δ5.86(s,1H),5.68(s,1H),4.76-4.67(m,2H),4.10-3.90(m,1H),3.67-3.52(m,4H),3.04(t,2H),2.40-2.27(m,5H),2.20-2.12(m,1H),2.02-1.90(m,4H),1.90-1.72(m,9H),1.67-1.59(m,2H),1.59-1.48(m,1H).
Example 14: trifluoroacetate salt of Cis-4- [ (4- [ (5-methyl-1H-pyrazol-3-yl) amino ] -6- (2- (morpholin-4-yl) ethoxy) pyrimidin-2-yl) amino ] adamantan-1-ol (compound 14)
Cis-4-[(4-[(5-methyl-1H-pyrazol-3-yl)amino]-6-(2-(morpholin-4-yl)ethoxy)pyrimidin-2-yl)amino]adamantan-1-ol trifluoroacetate
Compound 14 the synthesis of reference example 10 starting from Cis-4- [ (4-chloro-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (4 b) and 2-morpholinoethanol gave the trifluoroacetate salt of Cis-4- [ (4- [ (5-methyl-1H-pyrazol-3-yl) amino ] -6- (2- (morpholin-4-yl) ethoxy) pyrimidin-2-yl) amino ] adamantan-1-ol (compound 14).
LCMS m/z＝470.3[M+1] +
1 H NMR(400MHz,CD 3 OD)δ5.86(s,1H),5.68(s,1H),4.78-4.73(m,2H),4.12-3.85(m,5H),3.67-3.60(m,2H),3.53-3.32(m,4H),2.40-2.30(m,5H),2.20-2.12(m,1H),2.02-1.93(m,2H),1.87-1.72(m,6H),1.67-1.59(m,2H).
Example 15: trifluoroacetate salt of Cis-4- [ (4- { [ (2S) -4, 4-difluoro-1-methylpyrrolidin-2-yl ] methoxy } -6- [ (1-methyl-1H-imidazol-4-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (compound 15)
Cis-4-[(4-{[(2S)-4,4-difluoro-1-methylpyrrolidin-2-yl]methoxy}-6-[(1-methyl-1H-imidazol-4-yl)amino]pyrimidin-2-yl)amino]adamantan-1-ol trifluoroacetate
Compound 15 was synthesized from Cis-4- [ (4-chloro-6- [ (1-methyl-1H-imidazol-4-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (3 f) and [ (2S) -4, 4-difluoro-1-methylpyrrolidin-2-yl ] methanol (prepared according to the method of synthesis of patent US 2016/168890) starting from N-BOC-4, 4-difluoro-L-proline methyl ester as starting material by the method of reference example 10 to give the trifluoroacetate salt of Cis-4- [ (4- { [ (2S) -4, 4-difluoro-1-methylpyrrolidin-2-yl ] methoxy } -6- [ (1-methyl-1H-imidazol-4-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (Compound 15).
LCMS m/z＝490.3[M+1] +
1 H NMR(400MHz,CD 3 OD)δ8.34(s,1H),7.14(s,1H),5.54(s,1H),4.70(dd,1H),4.57(dd, 1H),4.01-3.91(m,3H),3.87(s,3H),3.64-3.50(m,1H),2.94(s,3H),2.88-2.74(m,1H),2.62-2.48(m,1H),2.37-2.26(m,2H),2.19-2.11(m,1H),2.01-1.93(m,2H),1.83-1.71(m,6H),1.66-1.54(m,2H).
Example 16: trifluoroacetate salt of Cis-4- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) -6- ((tetrahydrofuran-3-yloxy) pyrimidin-2-yl) amino) adamantan-1-ol (compound 16)
Cis-4-((4-((5-methyl-1H-pyrazol-3-yl)amino)-6-((tetrahydrofuran-3-yl)oxy)pyrimidin-2-yl)amino)adamantan-1-ol trifluoroacetate
Compound 16 was synthesized from Cis-4- [ (4-chloro-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (4 b) and 3-hydroxytetrahydrofuran (CAS: 453-20-3) as starting materials according to the method of reference example 10 to give the trifluoroacetate salt of Cis-4- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) -6- ((tetrahydrofuran-3-yloxy) pyrimidin-2-yl) amino) adamantan-1-ol (Compound 16).
LCMS m/z＝427.1[M+1] + 。
1 H NMR(400MHz,DMSO-d6)δ11.64(s,1H),8.90(s,1H),6.20-5.80(m,2H),5.57(s,1H),5.39-5.35(m,1H),4.14-3.95(m,1H),3.91-3.86(m,1H),3.83-3.78(m,2H),3.75-3.67(m,2H),2.25-2.12(m,6H),2.06-2.02(m,1H),1.98-1.87(m,3H),1.71-1.63(m,4H),1.63-1.55(m,2H),1.44-1.38(m,2H).
Example 17: cis-4- ((4- ((1- (dimethylamino) propan-2-yl) oxy) -6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) amantadine-1-ol (compound 17)
Cis-4-((4-((1-(dimethylamino)propan-2-yl)oxy)-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-2-yl)amino)adamantan-1-ol；
Compound 17 the procedure of reference example 10 was followed using Cis-4- [ (4-chloro-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (4 b) and 1- (dimethylamino) propan-2-ol as starting materials to give Cis-4- ((4- ((1- (dimethylamino) propan-2-yl) oxy) -6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-2-yl) aminoadamantan-1-ol (Compound 17).
LCMS m/z＝442.2[M+1] + 。
1 H NMR(400MHz,DMSO-d6)δ11.72(s,1H),8.83(s,1H),6.47-5.73(m,2H),5.52(s,1H),5.29-5.17(m,1H),4.05(s,1H),3.84-3.75(m,1H),2.47-2.40(m,1H),2.34-2.27(m,1H),2.23-2.13(m,10H),2.06-2.01(m,1H),1.96-1.86(m,2H),1.75-1.55(m,6H),1.47-1.37(m,2H),1.28-1.24(m,1H)，1.21(d,3H).
EXAMPLE 18 trifluoroacetate salt of cis-4- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) -6- (oxetan-3-yloxy) pyrimidin-2-yl) amino) adamantan-1-ol (compound 18)
Cis-4-((4-((5-methyl-1H-pyrazol-3-yl)amino)-6-(oxyradicalbut-3-ylhydroxy)pyridin-2-yl)amino)adamantane-1-ol trifluoroacetate
The first step: 2, 4-dichloro-6- (oxetan-3-yloxy) pyrimidine (18 b)
2,4-dichloro-6-(oxetan-3-yloxy)pyrimidine
2,4, 6-trichloropyrimidine (1 a) (1.40 g,7.65 mmol), oxetan-3-ol (849 mg,11.47 mmol), potassium carbonate (3.17 g,22.95 mmol) were added to dimethyl sulfoxide (15 mL) and reacted at room temperature for 16h at room temperature. The reaction solution was poured into water (40 mL), extracted with ethyl acetate (30 mL x 2), the organic phases were combined, backwashed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered off with suction, and the filtrate concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel (ethyl acetate: petroleum ether (v/v) =0:1-1:0) to give 2, 4-dichloro-6- (oxetan-3-yloxy) pyrimidine (18 b) (1.0 g, 56%) as a white solid.
LCMS m/z＝221.0[M+1] + 。
And a second step of: cis-4- [ (4-chloro-6- (oxetan-3-oxy) pyrimidin-2-yl) amino ] adamantan-1-ol (18 c)
Cis-4-[(4-chloro-6-(oxetan-3-yloxy)pyrimidin-2-yl)amino]adamantan-1-ol
2, 4-dichloro-6- (oxetan-3-yloxy) pyrimidine (18 b) (300 mg,1.36 mmol), cis-4-aminoadamantan-1-ol hydrochloride (3 d) (330 mg,1.63 mmol), potassium carbonate (563 mg,4.08 mmol) were added to dimethyl sulfoxide (15 mL) and reacted at room temperature for 16h at room temperature. The reaction solution was poured into water (40 mL), extracted with ethyl acetate (30 mL x 2), the organic phases were combined, backwashed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, suction filtered, and the filtrate concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel (ethyl acetate: petroleum ether (v/v) =0:1-1:0) to give Cis-4- [ (4-chloro-6- (oxetan-3-oxy) pyrimidin-2-yl) amino ] adamantan-1-ol (18 c) (200 mg, 42%)
LCMS m/z＝352.3[M+1] +
And a third step of: cis-tert-butyl 3- ((2- ((5-hydroxyadamantan-2-yl) amino) -6- (oxetan-3-yloxy) pyrimidin-4-yl) amino) -5-methyl-1H-pyrazole-1-carboxylic acid ester (18 d)
Cis-tert-butyl-3-((2-((5-hydroxyadamantan-2-yl)amino)-6-(oxetan-3-yloxy)pyrimidin-4-yl)amino)-5-methyl-1H-pyrazole-1-carboxylate
Cis-4- [ (4-chloro-6- (oxetan-3-yloxy) pyrimidin-2-yl) amino ] adamantan-1-ol (18 c) (120 mg,0.34 mmol), 3-amino-5-methyl-pyrazole-1-carboxylic acid tert-butyl ester (80 mg,0.41 mmol), tris (dibenzylideneacetone) dipalladium (20 mg,0.03 mmol), 2- (dicyclohexylphosphine) -3, 6-dimethoxy-2 ',4',6 '-triisopropyl-1, 1' -biphenyl (10 mg,0.03 mmol), cesium carbonate (220 mg,0.68 mmol) were added to 1, 4-dioxane (3 mL), purged with nitrogen, and the mixture was heated to 100 ℃ to react for 24h. Cooled to room temperature, filtered over celite, rinsed with ethyl acetate (2 ml x 2), and the filtrate concentrated under reduced pressure to give crude Cis-tert-butyl 3- ((2- ((5-hydroxyadamantan-2-yl) amino) -6- (oxetan-3-yloxy) pyrimidin-4-yl) amino) -5-methyl-1H-pyrazole-1-carboxylate (18 d) (150 mg, 86%) which was used directly in the next step.
LCMS m/z＝513.2[M+1] + 。
Fourth step: trifluoroacetate salt of Cis-4- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) -6- (oxetan-3-yloxy) pyrimidin-2-yl) amino) adamantan-1-ol (compound 18)
Cis-4-((4-((5-methyl-1H-pyrazol-3-yl)amino)-6-(oxyradicalbut-3-ylhydroxy)pyridin-2-yl)amino)adamantane-1-ol trifluoroacetate
Cis-tert-butyl 3- ((2- ((5-hydroxyadamantan-2-yl) amino) -6- (oxetan-3-yloxy) pyrimidin-4-yl) amino) -5-methyl-1H-pyrazole-1-carboxylate (18 d) (150 mg,0.29 mmol) was dissolved in dichloromethane (6 mL), trifluoroacetic acid (3 mL) was then added and reacted for 1H at 20 ℃, followed by spin-drying under reduced pressure to give a residue which was purified by Pre-HPLC (instrument and preparative column: preparation of liquid phase using Gilson Gx-281, preparative column model Sunfire,5 μm, inner diameter =30mm x 150 mm). The preparation method comprises the following steps: the crude product was dissolved in methanol and filtered through a 0.45 μm filter to prepare a sample solution. Mobile phase system: acetonitrile/water (containing 0.5% trifluoroacetic acid). The gradient elution method comprises the following steps: acetonitrile was eluted with a 10% gradient 60% (elution time 16 min), and lyophilized to give the trifluoroacetate salt of Cis-4- ((4- ((5-methyl-1H-pyrazol-3-yl) amino) -6- (oxetan-3-yloxy) pyrimidin-2-yl) amino) adamantan-1-ol (compound 18) (10 mg, 9%),
LCMS m/z＝413.2[M+1] + 。
1 H NMR(400MHz,CD 3 OD)δ6.58-6.38(m,1H),5.93-5.71(m,1H),5.37-5.23(m,1H),4.44(t,1H),4.36-4.30(m,1H),4.10-4.04(m,1H),4.01-3.94(m,1H),3.82-3.72(m,1H),2.54-2.41(m,2H),2.30(s,3H),2.21-2.14(m,1H),2.05-1.94(m,2H),1.87-1.71(m,6H),1.65-1.57(m,2H).
EXAMPLE 19 cis-4- ((2-methoxy-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-4-yl) amino) adamantan-1-ol (compound 19)
Cis-4-((2-methoxy-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)amino)adamantan-1-ol
Compound 19 the procedure of reference example 18 was followed using 2,4, 6-trichloropyrimidine (1 a) and Cis-4-aminoadamantan-1-ol hydrochloride (3 d) as starting materials to give Cis-4- ((2-methoxy-6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-4-yl) amino) adamantan-1-ol (Compound 19).
LCMS m/z＝371.1[M+1] + 。
1 H NMR(400MHz,DMSO-d6)δ11.72(s,1H),8.77(s,1H),6.73(s,1H),6.07(s,1H),5.94(s,1H),4.28(s,1H),3.85-3.64(m,4H),2.18(s,3H),2.14-2.07(m,2H),2.04-1.97(m,1H),1.95-1.87(m,2H),1.70-1.50(m,6H),1.39-1.29(m,2H).
Example 20: cis-4- [ (4- [ (1-methyl-1H-imidazol-4-yl) amino ] -6- (2- (morpholin-4-yl) ethoxy) pyrimidin-2-yl) amino ] adamantan-1-ol (compound 20)
Cis-4-[(4-[(1-methyl-1H-imidazol-4-yl)amino]-6-(2-(morpholin-4-yl)ethoxy)pyrimidin-2-yl)amino]adamantan-1-ol
Compound 20 was synthesized from Cis-4- [ (4-chloro-6- [ (1-methyl-1H-imidazol-4-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (3 f) and 2-morpholinoethanol according to the procedure of example 10 to give Cis-4- [ (4- [ (1-methyl-1H-imidazol-4-yl) amino ] -6- (2- (morpholin-4-yl) ethoxy) pyrimidin-2-yl) amino ] adamantan-1-ol (Compound 20).
LCMS m/z＝470.4[M+1] +
1 H NMR(400MHz,CD 3 OD)δ7.36(s,1H),7.19(s,1H),5.41(s,1H),4.35(t,2H),3.97-3.90(m,1H),3.73-3.68(m,7H),2.76(t,2H),2.62-2.53(m,4H),2.36-2.28(m,2H),2.17-2.10(m,1H),2.00-1.91(m,2H),1.82-1.71(m,6H),1.63-1.53(m,2H)
Example 21: cis-4- [ (4- (azetidin-1-yl) -6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (compound 21)
Cis-4-[(4-(azetidin-1-yl)-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)amino]adamantan-1-ol
Cis-4- [ (4-chloro-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (4 b) (50 mg,0.13 mmol) and azetidine (21 b) (22 mg,0.39 mmol) were dissolved in dimethyl sulfoxide (5 mL) at room temperature, then N, N-diisopropylethylamine (84 mg,0.65 mmol) was added thereto, and the mixture was heated to 100℃and stirred overnight. The reaction solution was purified by Pre-HPLC (apparatus and preparation column: prepare liquid phase using water 2767, preparation column model X select C18,5 μm, inner diameter =19mm × 150 mm). The preparation method comprises the following steps: the crude product was dissolved in dimethyl sulfoxide and filtered through a 0.45 μm filter to prepare a sample solution. Mobile phase system: acetonitrile/water. The gradient elution method comprises the following steps: acetonitrile was eluted by a 5% gradient 50% (elution time 15 min). Freeze-drying yields Cis-4- [ (4- (azetidin-1-yl) -6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (compound 21) (15 mg, 29%).
LCMS m/z＝396.3[M+1] +
1 H NMR(400MHz,CD 3 OD)δ6.05(s,1H),5.19(s,1H),3.97(t,4H),3.93-3.86(m,1H), 2.42-2.32(m,2H),2.31-2.17(m,5H),2.16-2.10(m,1H),1.97-1.88(m,2H),1.81-1.68(m,6H),1.61-1.53(m,2H)
Example 22: acetate of Cis-4- [ (4- [ (5-methyl-1H-pyrazol-3-yl) amino ] -6- (morpholin-4-yl) pyrimidin-2-yl) amino ] adamantan-1-ol (compound 22)
Cis-4-[(4-[(5-methyl-1H-pyrazol-3-yl)amino]-6-(morpholin-4-yl)pyrimidin-2-yl)amino]adamantan-1-ol acetate
Compound 22Cis-4- [ (4-chloro-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (4 b) and morpholine were used as starting materials, and acetate of Cis-4- [ (4- [ (5-methyl-1H-pyrazol-3-yl) amino ] -6- (morpholin-4-yl) pyrimidin-2-yl) amino ] adamantan-1-ol (compound 22) was obtained by the synthesis method of example 21.
LCMS m/z＝426.2[M+1] +
1 H NMR(400MHz,DMSO-d 6 )δ11.94(s,1H),8.99(s,1H),6.89-5.13(m,3H),4.31(s,1H),3.78-3.72(m,1H),3.67-3.59(m,4H),3.39-3.33(m,4H),2.22-2.16(m,2H),2.14(s,3H),2.07-1.99(m,1H),1.94-1.86(m,3.5H),1.68-1.60(m,4H),1.59-1.53(m,2H),1.43-1.31(m,2H).
Example 23: trifluoroacetate salt of Cis-4- [ (4- (1H-imidazol-1-yl) -6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (compound 23)
Cis-4-[(4-(1H-imidazol-1-yl)-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)amino]adamantan-1-ol trifluoroacetate
Cis-4- [ (4-chloro-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (4 b) (50 mg,0.13 mmol), 1H-imidazole (156 mg,2.3 mmol), N-diisopropylethylamine (310 mg,2.41 mmol) and N-methylpyrrolidone (2 mL) were added to a microwave tube at room temperature, and the reaction was carried out for 2 hours under microwave conditions at 175 ℃. The reaction solution was purified by Pre-HPLC (apparatus and preparation column: prepare liquid phase using water 2767, preparation column model X select C18,5 μm, inner diameter =19mm × 150 mm). The preparation method comprises the following steps: the crude product was dissolved in dimethyl sulfoxide and filtered through a 0.45 μm filter to prepare a sample solution. Mobile phase system: acetonitrile/water (containing 0.1% trifluoroacetic acid). The gradient elution method comprises the following steps: acetonitrile was eluted by a 5% gradient 50% (elution time 15 min). Lyophilization afforded Cis-4- [ (4- (1H-imidazol-1-yl) -6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (compound 23) as a white solid as trifluoroacetate (2 mg, 3%).
LCMS m/z＝407.2[M+1] +
1 H NMR(400MHz,CD 3 OD)δ9.70-9.22(m,1H),8.15(s,1H),7.63(s,1H),6.48(s,1H),4.12–3.96(m,1H),2.42-2.26(m,5H),2.18-2.12(m,1H),2.05-1.95(m,2H),1.90-1.73(m,6H),1.66-1.56(m,2H)
Example 24: trifluoroacetate salt of Cis-4- (2- ((5-hydroxyadamantan-2-yl) amino) -6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-4-yl) thiomorpholine-1, 1-dioxide (compound 24)
Cis-4-(2-((5-hydroxyadamantan-2-yl)amino)-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)thiomorpholine-1,1-dioxide trifluoroacetate
Compound 24 was synthesized from Cis-4- [ (4-chloro-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (4 b) and thiomorpholine-1, 1-dioxide as starting materials by the method of reference example 23 to give the trifluoroacetate salt of Cis-4- (2- ((5-hydroxyadamantan-2-yl) amino) -6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-4-yl) thiomorpholine-1, 1-dioxide (compound 24).
LCMS m/z＝474.1[M+1] +
1 H NMR(400MHz,CD 3 OD)δ5.79(s,1H),5.65-5.60(m,1H),4.27-4.10(m,4H),4.05-3.87(m,1H),3.24-3.17(m,4H),2.36-2.28(m,5H),2.20-2.11(m,1H),2.00-1.91(m,2H),1.85-1.74(m,6H),1.66-1.58(m,2H).
EXAMPLE 25 trifluoroacetate salt of cis-4- [ (5-fluoro-4-methoxy-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (Compound 25)
Cis-4-[(5-fluoro-4-methoxy-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)amino]adamantan-1-ol trifluoroacetate
The first step: 2, 6-dichloro-5-fluoro-N- (5-methyl-1H-pyrazol-3-yl) pyrimidin-4-amino (25 b)
2,6-dichloro-5-fluoro-N-(5-methyl-1H-pyrazol-3-yl)pyrimidin-4-amine
5-methyl-1H-pyrazol-3-amino (960 mg,9.93 mmol), N, N-diisopropylethylamine (2.57 g,19.86 mmol) was dissolved in tetrahydrofuran (20 mL), a solution of 2,4, 6-trichloro-5-fluoropyrimidine (25 a) (2.00 g,9.93 mmol) in tetrahydrofuran (2 mL) was added dropwise at 0℃and reacted at 25℃for 16 hours, then water (20 mL) was added to the reaction mixture, and filtration was carried out to obtain 2, 6-dichloro-5-fluoro-N- (5-methyl-1H-pyrazol-3-yl) pyrimidin-4-amino (25 b) (2.00 g, 77%) as a white solid.
LCMS m/z＝262.1[M+1] + 。
And a second step of: cis-4- [ (4-chloro-5-fluoro-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (25 c)
Cis-4-[(4-chloro-5-fluoro-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)amino]adamantan-1-ol
2, 6-dichloro-5-fluoro-N- (5-methyl-1H-pyrazol-3-yl) pyrimidin-4-amino (25 b) (500 mg,1.91 mmol), cis-4-aminoadamantane-1-ol hydrochloride (390 mg,1.91 mmol), N, N-diisopropylethylamine (740 mg,5.73 mmol) were added sequentially to dimethyl sulfoxide (6 mL), reacted at 80℃for 16H, cooled to room temperature, the reaction mixture was poured into water (60 mL), ethyl acetate (30 mL. Times.3) was extracted, the organic phases were combined, saturated brine (20 mL) was backwashed, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a residue which was purified by column chromatography on silica gel (ethyl acetate: petroleum ether (v/v) =0:1-1:0) to give Cis-4- [ (4-chloro-5-fluoro-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] butan-1-ol as a yellow solid (25 mg, 40%).
LCMS m/z＝393.2[M+1] + 。
And a third step of: trifluoroacetate salt of Cis-4- [ (5-fluoro-4-methoxy-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (compound 25)
Cis-4-[(5-fluoro-4-methoxy-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)amino]adamantan-1-ol trifluoroacetate
Cis-4- [ (4-chloro-5-fluoro-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (25 c) (51 mg,0.13 mmol) was dissolved in methanol (2 mL), a 20% sodium methoxide methanol solution (63 mg,0.39 mmol) was added, and after reaction at 80℃for 48 hours, the reaction was stopped. The reaction was neutralized with 1N HCl and purified by Pre-HPLC (instrument and column preparation: liquid phase prepared using Gilson Gx-281, column preparation model is Sunfire,5 μm, inner diameter =30 mm ×150 mm). The preparation method comprises the following steps: the reaction solution was filtered through a 0.45 μm filter membrane to prepare a sample solution. Mobile phase system: acetonitrile/water (containing 0.5% trifluoroacetic acid). The gradient elution method comprises the following steps: acetonitrile was eluted 60% by 10% gradient (elution time 16 min), and lyophilized to give the trifluoroacetate salt of Cis-4- [ (5-fluoro-4-methoxy-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (compound 25) (10 mg, 15%)
LCMS m/z＝389.3[M+1] + 。
1 H NMR(400MHz,CD 3 OD)δ6.03(s,1H),4.00(s,3H),3.95-3.85(m,1H),2.42-2.26(m,5H),2.18-2.10(m,1H),2.00-1.90(m,2H),1.85-1.70(m,6H),1.66-1.54(m,2H).
EXAMPLE 26 trifluoroacetate salt of cis-4- [ (6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrazin-2-yl) amino ] adamantan-1-ol (Compound 26)
Cis-4-[(6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrazin-2-yl)amino]adamantan-1-oltrifluoroacetate
Compound 26 was prepared from 2, 6-dichloropyrazine, 3-methyl-1H-pyrazol-5-amine, and the hydrochloride salt of Cis-4-aminoadamantan-1-ol by the method of reference example 5, to give the trifluoroacetate salt of Cis-4- [ (6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrazin-2-yl) amino ] adamantan-1-ol (Compound 26).
LCMS m/z＝341.2[M+1] + 。
1 H NMR(400MHz,CD 3 OD)δ7.50(s,1H),7.38(s,1H),6.17(s,1H),3.94-3.88(m,1H),2.38-2.26(m,5H),2.21-2.10(m,1H),2.04-1.93(m,2H),1.89-1.71(m,6H),1.66-1.55(m,2H).
EXAMPLE 27 cis-3- [ (4- [ (5-methyl-1H-pyrazol-3-yl) amino ] -6- (1-methyl-1H-pyrazol-4-yl) pyrimidin-2-yl) amino ] adamantan-1-ol (compound 27)
Cis-3-[(4-[(5-methyl-1H-pyrazol-3-yl)amino]-6-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)amino]adamantan-1-ol
Cis-4- [ (4-chloro-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (4 b) (20 mg,0.053 mmol) was dissolved in 1, 4-dioxane (2 mL) at room temperature. (1-methyl-1H-pyrazol-4-yl) boronic acid (13.41 mg,0.11 mmol), [1,1' -bis (diphenylphosphino) ferrocene ] dichloropalladium (II) (7.76 mg,0.01 mmol), cesium carbonate (51.81 mg,0.16 mmol) and water (0.2 ml) were added. The mixture was reacted at 100℃for 2 hours under nitrogen atmosphere, and the reaction was completed by LCMS. Then cooled to room temperature, the reaction solution was poured into water (10 mL), extracted with ethyl acetate (10 ml×2), the organic phases were combined, backwashed with saturated brine (10 ml×2), dried over anhydrous sodium sulfate, filtered, and the mother liquor was concentrated to give crude product. The crude product was purified by Pre-HPLC (apparatus and preparation column: preparation of liquid phase using Waters 2767, preparation column model xbridge@prepc18, inner diameter x length=19 mm x 250 mm). The preparation method comprises the following steps: the crude product was dissolved in DMF and filtered through a 0.45 μm filter to prepare a sample solution. Mobile phase system: acetonitrile/water (0.05% ammonia). The gradient elution method comprises the following steps: acetonitrile was eluted 55% by 10% gradient (flow rate: 12mL/min; elution time: 17 min) and lyophilized to give Cis-3- [ (4- [ (5-methyl-1H-pyrazol-3-yl) amino ] -6- (1-methyl-1H-pyrazol-4-yl) pyrimidin-2-yl) amino ] adamantan-1-ol (compound 27) (10 mg, 45%).
LCMS m/z＝421.1[M+1] + 。
1 H NMR(400MHz,DMSO-d 6 )δ9.40(s,1H),8.07(s,1H),7.78(s,1H),6.69-5.70(m,3H),4.32(s,1H),3.90-3.82(m,4H),2.27-2.23(m,2H),2.17(s,3H),2.08-2.03(m,1H),1.96-1.89(m,2H),1.75-1.63(m,4H),1.62-1.58(m,2H),1.43-1.37(m,2H)。
EXAMPLE 28 cis-3- [ (4- (5-methoxypyridin-3-yl) -6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (compound 28)
Cis-3-[(4-(5-methoxypyridin-3-yl)-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)amino]adamantan-1-ol
Compound 28 was synthesized from Cis-4- [ (4-chloro-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (4 b) and 5-methoxypyridine-3-boronic acid using the procedure of example 27 as starting materials to give Cis-3- [ (4- (5-methoxypyridine-3-yl) -6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (Compound 28).
LCMS m/z＝448.2[M+1] +
1 H NMR(400MHz,DMSO-d 6 )δ11.85(s,1H),9.53(s,1H),8.66(s,1H),8.36(d,1H),7.87-7.80(m,1H),6.83-6.28(m,2H),4.33(s,1H),4.06-3.74(m,4H),2.38-2.25(m,2H),2.19(s,3H),2.10-2.05(m,1H),2.01-1.94(m,2H),1.80-1.65(m 4H),1.62-1.57(m 2H),1.48-1.34(m 2H).
EXAMPLE 29 cis-4- [ (4- (2-methoxyethoxy) -6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (compound 29)
Cis-4-[(4-(2-methoxyethoxy)-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)amino]adamantan-1-ol
Compound 29 was synthesized from Cis-4- [ (4-chloro-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (4 b) and ethylene glycol monomethyl ether using the method of reference example 10 to give Cis-4- [ (4- (2-methoxyethoxy) -6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (Compound 29)
LCMS m/z＝415.1[M+1] +
1 H NMR(400MHz,DMSO-d 6 )δ11.62(s,1H),8.77(s,1H),6.47-5.36(m,3H),4.29(t,2H),4.04(s,1H),3.82-3.76(m,1H),3.59(t,2H),3.29(s,3H),2.25-2.14(m,5H),2.09-1.96(m,1H),1.94-1.86(m,2H),1.69-1.64(m,4H),1.62-1.58(m 2H),1.44-1.39(m 2H).
Example 30: trifluoroacetate salt of Cis-4- [ (4- (2-hydroxyethoxy) -6- [ (1-methyl-1H-imidazol-4-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (compound 30)
Cis-4-[(4-(2-hydroxyethoxy)-6-[(1-methyl-1H-imidazol-4-yl)amino]pyrimidin-2-yl)amino]adamantan-1-ol trifluoroacetate
Compound 30 the synthesis of reference example 10 using Cis-4- [ (4-chloro-6- [ (1-methyl-1H-imidazol-4-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (3 f) and ethylene glycol as starting materials gave the trifluoroacetate salt of Cis-4- [ (4- (2-hydroxyethoxy) -6- [ (1-methyl-1H-imidazol-4-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (Compound 30).
LCMS m/z＝401.2[M+1] +
1 H NMR(400MHz,CD 3 OD)δ8.10(s,1H),7.05(s,1H),5.51(s,1H),4.37(t,2H),4.00-3.90(m,1H),3.87-3.80(m,5H),2.39-2.28(m,2H),2.20-2.11(m,1H),2.01-1.90(m,2H),1.86-1.72(m,6H),1.66-1.56(m,2H).
Example 31: trifluoroacetate salt of Cis-4- [ (5-fluoro-4- (2-hydroxyethoxy) -6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (compound 31)
Cis-4-[(5-fluoro-4-(2-hydroxyethoxy)-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)amino]adamantan-1-ol trifluoroacetate
Compound 31 the procedure of reference example 10 was followed using Cis-4- [ (4-chloro-5-fluoro-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (25 c) and ethylene glycol as starting materials to give the trifluoroacetate salt of Cis-4- [ (5-fluoro-4- (2-hydroxyethoxy) -6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (compound 31).
LCMS m/z＝419.2[M+1] +
1 H NMR(400MHz,CD 3 OD)δ6.03(s,1H),4.48(t,2H),3.91-3.87(m,3H),2.35(s,3H),2.33-2.30(m,2H),2.17-2.12(m,1H),1.99-1.92(m,2H),1.82-1.74(m,6H),1.65-1.57(m,2H).
Example 32: trifluoroacetate salt of Cis-4- [ (4- (2-hydroxyethoxy) -6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (compound 32)
Cis-4-[(4-(2-hydroxyethoxy)-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)amino]adamantan-1-ol trifluoroacetate
Compound 32 preparation of the trifluoroacetate salt of Cis-4- [ (4- (2-hydroxyethoxy) -6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (Compound 32) using Cis-4- [ (4-chloro-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (Compound 32) and ethylene glycol as starting materials according to the method of reference example 10.
LCMS m/z＝401.1[M+1] +
1 H NMR(400MHz,CD 3 OD)δ5.82(s,1H),5.62(s,1H),4.43(t,2H),4.09-3.98(m,1H),3.85(t,2H),2.39-2.34(m,2H),2.32(s,3H),2.20-2.12(m,1H),2.01-1.93(m,2H),1.85-1.74(m,6H),1.67-1.60(m,2H).
Example 33: trifluoroacetate salt of Cis-4- [ (4- [ (5-methyl-1H-pyrazol-3-yl) amino ] -6- (2- (pyrrolidin-1-yl) ethoxy) pyrimidin-2-yl) amino ] adamantan-1-ol (compound 33)
Cis-4-[(4-[(5-methyl-1H-pyrazol-3-yl)amino]-6-(2-(pyrrolidin-1-yl)ethoxy)pyrimidin-2-yl)amino]adamantan-1-ol trifluoroacetate
Compound 33 the procedure of reference example 10 was followed using Cis-4- [ (4-chloro-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (4 b) and N- (2-hydroxyethyl) -pyrrolidine as starting materials to give the trifluoroacetate salt of Cis-4- [ (4- [ (5-methyl-1H-pyrazol-3-yl) amino ] -6- (2- (pyrrolidin-1-yl) ethoxy) pyrimidin-2-yl) amino ] adamantan-1-ol (compound 33).
LCMS m/z＝454.3[M+1] +
1 H NMR(400MHz,CD 3 OD)δ5.86(s,1H),5.69(s,1H),4.72-4.68(m,2H),4.09-3.95(m,1H),3.81-3.60(m,4H),3.25-3.11(m,2H),2.40-2.29(m,5H),2.23-2.03(m,5H),2.01-1.93(m,2H),1.87-1.71(m,6H),1.68-1.59(m,2H).
Example 34: trifluoroacetate salt of Cis-4- [ (4- [ (5-methyl-1H-pyrazol-3-yl) amino ] -6- { [ (2R) -oxapent-2-yl ] methoxy } pyrimidin-2-yl) amino ] adamantan-1-ol (compound 34)
Cis-4-[(4-[(5-methyl-1H-pyrazol-3-yl)amino]-6-{[(2R)-oxolan-2-yl]methoxy}pyrimidin-2-yl)amino]adamantan-1-ol trifluoroacetate
Compound 34 the procedure of example 10 was followed using Cis-4- [ (4-chloro-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (4 b) and [ (2R) -oxapent-2-yl ] methanol as starting materials to give the trifluoroacetate salt of Cis-4- [ (4- [ (5-methyl-1H-pyrazol-3-yl) amino ] -6- { [ (2R) -oxapent-2-yl ] methoxy } pyrimidin-2-yl) amino ] adamantan-1-ol (compound 34).
LCMS m/z＝441.2[M+1] +
1 H NMR(400MHz,CD 3 OD)δ5.84(s,1H),5.60(s,1H),4.44-4.37(m,1H),4.35-4.28(m,1H),4.27-4.20(m,1H),4.08-3.93(m,1H),3.92-3.85(m,1H),3.84-3.77(m,1H),2.42-2.24(m,5H),2.20-2.13(m,1H),2.12-2.02(m,1H),2.02-1.90(m,4H),1.89-1.67(m,7H),1.66-1.60(m,2H).
Example 35: trifluoroacetate salt of Cis-4- [ (4- [ (5-methyl-1H-pyrazol-3-yl) amino ] -6- { [ (2S) -oxapent-2-yl ] methoxy } pyrimidin-2-yl) amino ] adamantan-1-ol (compound 35)
Cis-4-[(4-[(5-methyl-1H-pyrazol-3-yl)amino]-6-{[(2S)-oxolan-2-yl]methoxy}pyrimidin-2-yl)amino]adamantan-1-ol trifluoroacetate
Compound 35 the procedure of example 10 was followed using Cis-4- [ (4-chloro-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (4 b) and [ (2S) -oxapent-2-yl ] methanol as starting materials to give the trifluoroacetate salt of Cis-4- [ (4- [ (5-methyl-1H-pyrazol-3-yl) amino ] -6- { [ (2S) -oxapent-2-yl ] methoxy } pyrimidin-2-yl) amino ] adamantan-1-ol (Compound 35).
LCMS m/z＝441.3[M+1] +
1 H NMR(400MHz,CD 3 OD)δ5.82(s,1H),5.59(s,1H),4.44-4.38(m,1H),4.35-4.28(m,1H),4.27-4.20(m,1H),4.07-3.96(m,1H),3.92-3.85(m,1H),3.84-3.76(m,1H),2.39-2.27(m,5H),2.19-2.13(m,1H),2.12-2.03(m,1H),2.01-1.90(m,4H),1.86-1.67(m,7H),1.67-1.59(m,2H).
Example 36: trifluoroacetate salt of (3R) -1- (5-fluoro-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] -2- [ (Cis-5-hydroxyadamantan-2-yl) amino ] pyrimidin-4-yl) pyrrolidin-3-ol (compound 36)
(3R)-1-(5-fluoro-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-[(Cis-5-hydroxyadamantan-2-yl)amino]pyrimidin-4-yl)pyrrolidin-3-ol trifluoroacetate
Cis-4- [ (4-chloro-5-fluoro-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (25 c) (30 mg,0.076 mml) and (R) -3-pyrrolidinol (13 mg,0.15 mmol) were dissolved in DMSO (2 mL), and N, N-diisopropylethylamine (40 mg,0.31 mmol) was added. The temperature is raised to 100 ℃ to react for 5 hours. The reaction solution was purified by Pre-HPLC (instrument and preparation column: preparation of liquid phase using Gilson Gx-281, preparation column model is Sunfire,5 μm, inner diameter =30 mm ×150 mm). The preparation method comprises the following steps: the crude product was dissolved in DMSO and filtered through a 0.45 μm filter to prepare a sample solution. Mobile phase system: acetonitrile/water (containing 0.5% trifluoroacetic acid). The gradient elution method comprises the following steps: acetonitrile was eluted 60% by a 10% gradient (elution time 16 min) and lyophilized to give the trifluoroacetate salt of (3R) -1- (5-fluoro-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] -2- [ (Cis-5-hydroxyadamantan-2-yl) amino ] pyrimidin-4-yl) pyrrolidin-3-ol (compound 36) (8 mg, 19%).
LCMS m/z＝444.2[M+1] +
1 H NMR(400MHz,CD 3 OD)δ5.87(s,1H),4.50(s,1H),3.99-3.67(m,5H),2.37-2.28(m,5H),2.17-2.12(m,1H),2.11-1.98(m,2H),1.97-1.89(m,2H),1.82-1.72(m,6H),1.64-1.56(m,2H).
Example 37: trifluoroacetate salt of (3S) -1- (5-fluoro-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] -2- [ (Cis-5-hydroxyadamantan-2-yl) amino ] pyrimidin-4-yl) pyrrolidin-3-ol (compound 37)
(3S)-1-(5-fluoro-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-[(Cis-5-hydroxyadamantan-2-yl)amino]pyrimidin-4-yl)pyrrolidin-3-ol trifluoroacetate
Compound 37 was synthesized from Cis-4- [ (4-chloro-5-fluoro-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (25 c) and (S) -3-pyrrolidinol as starting materials according to the procedure of reference example 36 to give the trifluoroacetate salt of (3S) -1- (5-fluoro-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] -2- [ (Cis-5-hydroxyadamantan-2-yl) amino ] pyrimidin-4-yl) pyrrolidin-3-ol (Compound 37).
LCMS m/z＝444.3[M+1] +
1H NMR(400MHz,CD3OD)δ5.87(s,1H),4.50(s,1H),3.95-3.71(m,5H),2.37-2.28(m,5H),2.17-2.12(m,1H),2.11-1.98(m,2H),1.97-1.89(m,2H),1.82-1.72(m,6H),1.64-1.55(m,2H).
Example 38: trans-4- [ (4- (2-hydroxyethoxy) -6- [ (1-methyl-1H-imidazol-4-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (compound 38)
Trans-4-[(4-(2-hydroxyethoxy)-6-[(1-methyl-1H-imidazol-4-yl)amino]pyrimidin-2-yl)amino]adamantan-1-ol
The first step: trans-4- [ (4-chloro-6- [ (1-methyl-1H-imidazol-4-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (38 b)
Trans-4-[(4-chloro-6-[(1-methyl-1H-imidazol-4-yl)amino]pyrimidin-2-yl)amino]adamantan-1-ol
2, 6-dichloro-N- (1-methyl-1H-imidazol-4-yl) pyrimidin-4-amine (3 c) (0.50 g,2.05 mmol) and DMSO (10 mL) were added to a lock tube, N-diisopropylethylamine (1.05 g,8.21 mmol) and Trans-4-amino-1-hydroxyadamantane hydrochloride (0.62 g,3.07 mml) were added in this order, and the temperature was raised to 100℃for 16H. After cooling to room temperature, water (50 mL) was added to the reaction solution, extraction was performed with ethyl acetate (15 ml×3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane: methanol=95:5 to 90:10) to give Trans-4- [ (4-chloro-6- [ (1-methyl-1H-imidazol-4-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (38 b) (0.2 g, 26%) as a pale yellow solid.
LCMS m/z＝375.2[M+1] +
And a second step of: trans-4- [ (4- (2-hydroxyethoxy) -6- [ (1-methyl-1H-imidazol-4-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (compound 38)
Trans-4-[(4-(2-hydroxyethoxy)-6-[(1-methyl-1H-imidazol-4-yl)amino]pyrimidin-2-yl)amino]adamantan-1-ol
To a reaction flask containing ethylene glycol (2 mL) was added sodium metal (60 mg,2.60 mmol), and after reacting at 60℃for 5 hours, trans-4- [ (4-chloro-6- [ (1-methyl-1H-imidazol-4-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (38 b) (50 mg,0.13 mmol) was added thereto. After heating to 100deg.C for 16h, the reaction was quenched by the addition of water (1 mL). The crude product was purified by Pre-HPLC (instrument and column: liquid phase prepared using Gilson Gx-281, column model number Sunfire,5 μm, inner diameter =30 mm ×150 mm). The preparation method comprises the following steps: the crude product was dissolved in methanol and filtered through a 0.45 μm filter to prepare a sample solution. Mobile phase system: acetonitrile/water (0.5% ammonia). The gradient elution method comprises the following steps: acetonitrile was eluted 60% gradient (elution time 16 min), and lyophilized to give Trans-4- [ (4- (2-hydroxyethoxy) -6- [ (1-methyl-1H-imidazol-4-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (compound 38) as a white solid.
LCMS m/z＝401.2[M+1] +
1 H NMR(400MHz,CD 3 OD)δ7.36(s,1H),7.19(s,1H),5.44(s,1H),4.23(t,2H),4.04-4.00(m,1H),3.81(t,2H),3.71(s,3H),2.28-2.21(m,2H),2.13-2.08(m,1H),1.98-1.88(m,4H),1.84-1.76(m,4H),1.54-1.46(m,2H).
Example 39: trans-4- [ (5-fluoro-4- (hydroxymethyl) -6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) (methyl) amino ] adamantan-1-ol (compound 39)
Trans-4-[(5-fluoro-4-(hydroxymethyl)-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)(methyl)amino]adamantan-1-ol
The first step: 6- { [ (tert-Butoxycarbonyl ] ethyl ] (1- [ (tert-Butoxycarbonyl) carbonyl ] -5-methyl-1H-pyrazol-3-yl) amino } -2-chloro-5-fluoropyrimidine-4-carboxylic acid ethyl ester (39 b)
Ethyl 6-{[(tert-butoxy)carbonyl](1-[(tert-butoxy)carbonyl]-5-methyl-1H-pyrazol-3-yl)amino}-2-chloro-5-fluoropyrimidine-4-carboxylate
Di-tert-butyl dicarbonate (1.82 g,8.35 mmol) was added to a solution of ethyl 2-chloro-5-fluoro-6- [ ((5-methyl-1H-pyrazol-3-yl) amino ] pyrimidine-4-carboxylate (39 a) (prepared by the synthesis method of reference CN111247142A starting from 5-fluoroorotic acid) (1.00 g,3.34 mmol), 4-dimethylaminopyridine (1.02 g,8.35 mmol) in dichloromethane (10 mL), followed by a reaction at room temperature for 5 hours.
1 H NMR(400MHz,CD 3 OD)δ6.46(s,1H),4.48(q,2H),2.55(s,3H),1.60(s,9H),1.49(s,9H),1.42(t,3H).
And a second step of: trans-6- { [ (tert-Butoxycarbonyl ] (1- [ (tert-Butoxycarbonyl) carbonyl ] -5-methyl-1H-pyrazol-3-yl) amino } -5-fluoro-2- (methyl [ 5-hydroxyadamantan-2-yl ] amino) pyrimidine-4-carboxylic acid ethyl ester (39 d)
Trans-ethyl-6-{[(tert-butoxy)carbonyl](1-[(tert-butoxy)carbonyl]-5-methyl-1H-pyrazol-3-yl)amino}-5-fluoro-2-(methyl[5-hydroxyadamantan-2-yl]amino)pyrimidine-4-carboxylate
N, N-diisopropylethylamine (558.32 mg,4.32 mmol) was added to a solution of 6- { [ (tert-butoxy) carbonyl ] ethyl ] (1- [ (tert-butoxy) carbonyl ] -5-methyl-1H-pyrazol-3-yl) amino } -2-chloro-5-fluoropyrimidine-4-carboxylic acid ethyl ester (39 b) (500 mg,1.08 mmol), trans-4- (methylamino) adamantan-1-ol trifluoroacetate (39 c) (350.82 mg,1.19 mmol) in dimethyl sulfoxide (3 ml) at room temperature. The temperature was raised to 100℃and the reaction was carried out for 14 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, poured into water (10 mL), quenched, extracted with ethyl acetate (10 mL. Times.2), combined with the organic phases, backwashed with saturated brine (10 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude compound Trans-6- { [ (tert-butoxy) carbonyl ] (1- [ (tert-butoxy) carbonyl ] -5-methyl-1H-pyrazol-3-yl) amino } -5-fluoro-2- (methyl [ 5-hydroxyadamantan-2-yl ] amino) pyrimidine-4-carboxylic acid ethyl ester (39 d) (250 mg, yield: 34.41%) without purification, and taken directly to the next step.
LCMS m/z＝545.3[M-99] +
And a third step of: trans-5-fluoro-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] -2- (methyl [ -5-hydroxyadamantan-2-yl ] amino) pyrimidine-4-carboxylic acid ethyl ester (39 f)
Trans-ethyl-5-fluoro-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-(methyl[5-hydroxyadamantan-2-yl]amino)pyrimidine-4-carboxylate
Trifluoroacetic acid (4 ml) was added to a solution of Trans-6- { [ (tert-butoxy) carbonyl ] (1- [ (tert-butoxy) carbonyl ] -5-methyl-1H-pyrazol-3-yl) amino } -5-fluoro-2- (methyl [ 5-hydroxyadamantan-2-yl ] amino) pyrimidine-4-carboxylic acid ethyl ester (39 d) (250 mg,0.39 mmol) in dichloromethane (4 ml) at room temperature. The reaction was carried out at room temperature for 4 hours. After the reaction, the reaction solution was concentrated under reduced pressure to obtain a crude product. Separating and purifying the crude product by a C18 reverse preparation column (the purification method is that the crude product is dissolved by DMF and filtered to prepare a sample liquid, the mobile phase system is acetonitrile/water (containing 0.5 percent of ammonia water), the gradient elution method is that acetonitrile is eluted by 10 percent gradient by 80 percent (the flow rate is 60mL/min; the elution time is 20 min)), and the Trans-5-fluoro-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] -2- (methyl [ 5-hydroxyadamantan-2-yl ] amino) pyrimidine-4-carboxylic acid ethyl ester (39 f) (120 mg, YIeld:69.22 percent) is obtained after freeze drying.
LCMS m/z＝445.3[M+1] +
Fourth step: trans-4- [ (5-fluoro-4- (hydroxymethyl) -6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) (methyl) amino ] adamantan-1-ol (compound 39)
Trans-4-[(5-fluoro-4-(hydroxymethyl)-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)(methyl)amino]adamantan-1-ol
Anhydrous calcium chloride (137.62 mg,1.24 mmol), sodium borohydride (93.82 mg,2.48 mmol) were added sequentially to a mixture of Trans-5-fluoro-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] -2- (methyl [ 5-hydroxyadamantan-2-yl ] amino) pyrimidine-4-carboxylic acid ethyl ester (39 f) (140 mg,0.31 mmol) in THF (2 ml) ethanol (2 ml) under an ice-water bath. The reaction was carried out at room temperature for 4 hours. After the completion of the reaction, the reaction was quenched by addition of saturated sodium carbonate solution (5 mL). Insoluble materials were removed by filtration. Concentrating the mother liquor under reduced pressure to obtain a crude product. The crude product was purified by Pre-HPLC (apparatus and preparation column: preparation of liquid phase using Waters2767, preparation column model xbridge@prepc18, inner diameter x length=19 mm x 250 mm). The preparation method comprises the following steps: the crude product was dissolved in DMF and filtered through a 0.45 μm filter to prepare a sample solution. Mobile phase system: acetonitrile/water (0.05% ammonia). The gradient elution method comprises the following steps: acetonitrile was eluted 55% by 10% gradient (flow rate: 12mL/min; elution time: 17 min) and lyophilized to give Trans-4- [ (5-fluoro-4- (hydroxymethyl) -6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) (methyl) amino ] adamantan-1-ol (compound 39) (82 mg, yield: 65.72%)
LCMS m/z＝403.3[M+1] +
1 H NMR(400MHz,CD 3 OD)δ6.46(s,1H),4.54(d,2H),4.26-4.21(m,1H),3.35(s,3H),2.47-2.42(m,2H),2.30(s,3H),2.19-2.15(m,1H),2.05-1.99(m,2H),1.97-1.90(m,2H),1.80-1.72(m,4H),1.58-1.50(m,2H).
EXAMPLE 40 cis-4- [ (4- (hydroxymethyl) -6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) (methyl) amino ] adamantan-1-ol (compound 40)
Cis-4-[(4-(hydroxymethyl)-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)(methyl)amino]adamantan-1-ol
The first step: formate salt of Cis-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] -2- (methyl [ 5-hydroxyadamantan-2-yl ] amino) pyrimidine-4-carboxylic acid n-butyl ester (40 b)
Cis-butyl-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-(methyl[5-hydroxyadamantan-2-yl]amino)pyrimidine-4-carboxylate formate
2-chloro-6- [ ((5-methyl-1H-pyrazol-3-yl) amino ] pyrimidine-4-carboxylic acid methyl ester (6 b) (100 mg,0.37 mmol), cis-4- (methylamino) adamantan-1-ol trifluoroacetate (110 mg,0.37 mmol), N, N-diisopropylethylamine (240 mg,1.85 mmol) were added to N-butanol (4 mL), heated to 160 ℃, microwaved for 38H, and then reduced to room temperature, reduced pressure concentration to give a residue, which was purified by Pre-HPLC (instrument and preparative column: prepared as liquid phase using Gilson Gx-281, preparative column model: sunfire,5 μm, inner diameter=30 mm. 150 mm.) the preparation method: crude product was dissolved with methanol and filtered with a 0.45 μm filter membrane, and prepared into a sample solution, mobile phase system: acetonitrile/water (formic acid containing 0.5% gradient elution method: acetonitrile was eluted 60% gradient (elution time 16 min), and then 5- [ (5% methyl-6-amino ] methyl-6-1-hydroxy ] pyrimidine-4-carboxylic acid (70 mg) was obtained by freeze-drying the N-butyl ester).
LCMS m/z＝455.3[M+1] + 。
And a second step of: cis-4- [ (4- (hydroxymethyl) -6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) (methyl) amino ] adamantan-1-ol (compound 40)
Cis-4-[(4-(hydroxymethyl)-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)(methyl)amino]adamantan-1-ol
The formate salt (45 mg,0.09 mmol) of Cis-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] -2- (methyl [ 5-hydroxyadamantan-2-yl ] amino) pyrimidine-4-carboxylic acid n-butyl ester (40 b) was dissolved in MeOH (10 mL), and solid sodium borohydride (17 mg,0.45 mmol) and calcium chloride (50 mg,0.45 mmol) were added under ice-water bath, and heated to react until the starting material disappeared. Water (10 mL), ethyl acetate (10 mL x 2) were added, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a residue, which was purified by Pre-HPLC (apparatus and preparative column: gilson Gx-281 for preparing a liquid phase, type of preparative column is Sunfire,5 μm, inner diameter =30mm ×150mm). The preparation method comprises the following steps: the crude product was dissolved in methanol and filtered through a 0.45 μm filter to prepare a sample solution. Mobile phase system: acetonitrile/water (containing 0.5% ammonium acetate). The gradient elution method comprises the following steps: acetonitrile was eluted 60% by a 10% gradient (elution time 16 min), and after lyophilization Cis-4- [ (4- (hydroxymethyl) -6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) (methyl) amino ] adamantan-1-ol (compound 40) (1.09 mg, 3.1%).
LCMS m/z＝385.2[M+1] +
1 H NMR(400MHz,CD 3 OD)δ6.42-6.17(m,2H),4.39(s,2H),4.29-4.20(m,1H),3.34(s,3H),2.59-2.47(m,2H),2.33-2.12(m,4H),2.08-1.99(m,2H),1.96-1.82(m,2H),1.81-1.68(m,4H),1.66-1.56(m,2H).
EXAMPLE 41 Trans-4- [ (4- (hydroxymethyl) -6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) (methyl) amino ] adamantan-1-ol (compound 41)
Trans-4-[(4-(hydroxymethyl)-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)(methyl)amino]adamantan-1-ol
The first step: formate salt of Trans-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] -2- (methyl [ 5-hydroxyadamantan-2-yl ] amino) pyrimidine-4-carboxylic acid butyl ester (41 b)
Trans-butyl-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-(methyl[5-hydroxyadamantan-2-yl]amino)pyrimidine-4-carboxylate formate
Methyl 2-chloro-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidine-4-carboxylate (6 b) (100 mg,0.37 mmol), trans-4- (methylamino) adamantan-1-ol trifluoroacetate (110 mg,0.37 mmol), N, N-diisopropylethylamine (240 mg,1.85 mmol) were added to N-butanol (4 mL), and the mixture was heated to 160℃for microwave reaction for 38 hours, followed by cooling to room temperature. After spin-drying under reduced pressure, the residue was purified by Pre-HPLC (apparatus and preparation column: liquid phase prepared using Gilson Gx-281, preparation column model is Sunfire,5 μm, inner diameter =30 mm ×150 mm). The preparation method comprises the following steps: the crude product was dissolved in methanol and filtered through a 0.45 μm filter to prepare a sample solution. Mobile phase system: acetonitrile/water (0.5% formic acid). The gradient elution method comprises the following steps: acetonitrile was eluted 60% by 10% gradient (elution time 16 min), and lyophilized to give formate salt (65 mg, 35%) of Trans-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] -2- (methyl [ 5-hydroxyadamantan-2-yl ] amino) pyrimidine-4-carboxylic acid butyl ester (41 b).
LCMS m/z＝455.2[M+1] + 。
And a second step of: trans-4- [ (4- (hydroxymethyl) -6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) (methyl) amino ] adamantan-1-ol (compound 41)
Trans-4-[(4-(hydroxymethyl)-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)(methyl)amino]adamantan-1-ol
Formate salt (50 mg,0.1 mmol) of Trans-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] -2- (methyl [ 5-hydroxyadamantan-2-yl ] amino) pyrimidine-4-carboxylic acid butyl ester (41 b) was dissolved in MeOH (10 mL), and solid sodium borohydride (19 mg,0.5 mmol) and calcium chloride (55 mg,0.5 mmol) were added under ice-water bath, and the reaction was heated under reflux until the starting material disappeared. Water (10 mL), ethyl acetate (10 mL x 2) were added to extract, the organic phases were combined, dried over anhydrous sodium sulfate, and spin-dried under reduced pressure to give a residue, which was purified by Pre-HPLC (apparatus and preparative column: gilson Gx-281 was used to prepare a liquid phase, preparative column model number was Sunfire,5 μm, inner diameter =30 mm x 150 mm). The preparation method comprises the following steps: the crude product was dissolved in methanol and filtered through a 0.45 μm filter to prepare a sample solution. Mobile phase system: acetonitrile/water (containing 0.5% ammonium acetate). The gradient elution method comprises the following steps: acetonitrile was eluted 60% by a 10% gradient (elution time 16 min), and after lyophilization Trans-4- [ (4- (hydroxymethyl) -6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) (methyl) amino ] adamantan-1-ol (compound 41) (1.09 mg, 2.8%).
LCMS m/z＝385.3[M+1] +
1 H NMR(400MHz,CD 3 OD)δ6.41-6.15(m,2H),4.39(s,2H),4.35-4.29(m,1H),3.34(s,3H),2.51-2.41(m,2H),2.28(s,3H),2.21-2.14(m,1H),2.08-1.92(m,4H),1.83-1.72(m,4H),1.59-1.50(m,2H).
EXAMPLE 42 cis-4- [ (5-fluoro-4- (hydroxymethyl) -6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (compound 42)
Cis-4-[(5-fluoro-4-(hydroxymethyl)-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)amino]adamantan-1-ol
The first step: cis-6- { [ (tert-butoxy) carbonyl ] (1- [ (tert-butoxy) carbonyl ] -5-methyl-1H-pyrazol-3-yl) amino } -5-fluoro-2- [ (5-hydroxyadamantan-2-yl) amino ] pyrimidine-4-carboxylic acid ethyl ester (42 a)
Cis-ethyl-6-{[(tert-butoxy)carbonyl](1-[(tert-butoxy)carbonyl]-5-methyl-1H-pyrazol-3-yl)amino}-5-fluoro-2-[(5-hydroxyadamantan-2-yl)amino]pyrimidine-4-carboxylate
6- { [ (tert-Butoxycarbonyl ] ethyl ] (1- [ (tert-Butoxycarbonyl) carbonyl ] -5-methyl-1H-pyrazol-3-yl) amino } -2-chloro-5-fluoro-pyrimidine-4-carboxylic acid ethyl ester (39 b) (280 mg,0.57 mmol), cis-4-aminoadamantane-1-ol hydrochloride (120 mg,0.57 mmol), N, N-diisopropylethylamine (370 mg,2.85 mmol) were added to DMSO (5 mL), allowed to react at 100℃for 16H, and then cooled to room temperature. The reaction solution was poured into water (10 mL), extracted with ethyl acetate (20 mL x 2), the organic phases were combined, backwashed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, suction filtered, and the filtrate concentrated under reduced pressure to give Cis-6- { [ (tert-butoxy) carbonyl ] (1- [ (tert-butoxy) carbonyl ] -5-methyl-1H-pyrazol-3-yl) amino } -5-fluoro-2- [ (5-hydroxyadamantan-2-yl) amino ] pyrimidine-4-carboxylic acid ethyl ester (42 a) (210 mg, 58%) crude product which was used directly in one step without further purification.
LCMS m/z＝531.1[M-99] + 。
And a second step of: trifluoroacetate salt of Cis-5-fluoro-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] -2- [ (5-hydroxyadamantan-2-yl) amino ] pyrimidine-4-carboxylic acid ethyl ester (42 b)
Cis-ethyl-5-fluoro-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-[(5-hydroxyadamantan-2-yl)amino]pyrimidine-4-carboxylate trifluoroacetate
Cis-6- { [ (tert-butoxy) carbonyl ] (1- [ (tert-butoxy) carbonyl ] -5-methyl-1H-pyrazol-3-yl) amino } -5-fluoro-2- [ (5-hydroxyadamantan-2-yl) amino ] pyrimidine-4-carboxylic acid ethyl ester (42 a) (200 mg,0.32 mmol) was dissolved in dichloromethane (6 mL), trifluoroacetic acid (3 mL) was then added thereto, after reacting at 20 ℃ for 1H, the reaction mixture was concentrated under reduced pressure to give a residue, and the residue was purified by Pre-HPLC (instrument and preparative column: preparation of liquid phase using Gilson Gx-281, preparative column model is Sunfire,5 μm, inner diameter =30mm x 150 mm). The preparation method comprises the following steps: the crude product was dissolved in methanol and filtered through a 0.45 μm filter to prepare a sample solution. Mobile phase system: acetonitrile/water (containing 0.5% trifluoroacetic acid). The gradient elution method comprises the following steps: acetonitrile was eluted 60% by a 10% gradient (elution time 16 min) and lyophilized to give the trifluoroacetate salt of Cis-5-fluoro-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] -2- [ (5-hydroxyadamantan-2-yl) amino ] pyrimidine-4-carboxylic acid ethyl ester (42 b) (160 mg, 75%).
LCMS m/z＝431.3[M+1] + 。
And a third step of: cis-4- [ (5-fluoro-4- (hydroxymethyl) -6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (compound 42)
Cis-4-[(5-fluoro-4-(hydroxymethyl)-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)amino]adamantan-1-ol
The trifluoroacetate salt (50 mg,0.09 mmol) of Cis-5-fluoro-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] -2- [ (5-hydroxyadamantan-2-yl) amino ] pyrimidine-4-carboxylic acid ethyl ester (42 b) was dissolved in MeOH (5 mL), and solid sodium borohydride (14 mg,0.37 mmol) and calcium chloride (20 mg,0.18 mmol) were added under ice-water bath, and reacted at room temperature until the original disappearance. Water (10 mL), ethyl acetate (10 mL x 2) were added, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a residue, which was purified by Pre-HPLC (apparatus and preparative column: gilson Gx-281 for preparing a liquid phase, type of preparative column is Sunfire,5 μm, inner diameter =30mm ×150mm). The preparation method comprises the following steps: the crude product was dissolved in methanol and filtered through a 0.45 μm filter to prepare a sample solution. Mobile phase system: acetonitrile/water (containing 0.5% ammonium acetate). The gradient elution method comprises the following steps: acetonitrile was eluted 60% by 10% gradient (elution time 16 min) and lyophilized to give Cis-4- [ (5-fluoro-4- (hydroxymethyl) -6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (compound 42) (6.8 mg, 19%).
LCMS m/z＝389.3[M+1] +
1 H NMR(400MHz,CD 3 OD)δ6.38(s,1H),4.51(d,2H),3.91-3.85(m,1H),2.36-2.22(m,5H),2.16-2.09(m,1H),2.01-1.91(m,2H),1.84-1.68(m,6H),1.61-1.52(m,2H).
EXAMPLE 43 Trans-4- [ (5-fluoro-4- (hydroxymethyl) -6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (compound 43)
Trans-4-[(5-fluoro-4-(hydroxymethyl)-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)amino]adamantan-1-ol
The first step: trans-6- { [ (tert-Butoxycarbonyl ] (1- [ (tert-Butoxycarbonyl) carbonyl ] -5-methyl-1H-pyrazol-3-yl) amino } -5-fluoro-2- [ (5-hydroxyadamantan-2-yl) amino ] pyrimidine-4-carboxylic acid ethyl ester (43 b)
Trans-ethyl 6-{[(tert-butoxy)carbonyl](1-[(tert-butoxy)carbonyl]-5-methyl-1H-pyrazol-3-yl)amino}-5-fluoro-2-[(5-hydroxyadamantan-2-yl)amino]pyrimidine-4-carboxylate
6- { [ (tert-Butoxycarbonyl ] ethyl ] (1- [ (tert-Butoxycarbonyl) carbonyl ] -5-methyl-1H-pyrazol-3-yl) amino } -2-chloro-5-fluoro-pyrimidine-4-carboxylic acid ethyl ester (39 b) (280 mg,0.57 mmol), trans-4-aminoadamantane-1-ol hydrochloride (120 mg,0.57 mmol), N, N-diisopropylethylamine (370 mg,2.85 mmol) was added to DMSO (5 mL), allowed to react at 100℃for 16H, and then cooled to room temperature. The reaction solution was poured into water (10 mL), extracted with ethyl acetate (20 mL x 2), the organic phases combined, backwashed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, suction filtered, and the filtrate concentrated under reduced pressure to give crude Trans-6- { [ (tert-butoxy) carbonyl ] (1- [ (tert-butoxy) carbonyl ] -5-methyl-1H-pyrazol-3-yl) amino } -5-fluoro-2- [ (5-hydroxyadamantan-2-yl) amino ] pyrimidine-4-carboxylic acid ethyl ester (43 b) (200 mg, 55%) which was used directly in one step without further purification.
LCMS m/z＝531.1[M-99] + 。
And a second step of: trifluoroacetate salt of Trans-5-fluoro-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] -2- [ (5-hydroxyadamantan-2-yl) amino ] pyrimidine-4-carboxylic acid ethyl ester (43 c)
Trans-ethyl 5-fluoro-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-[(5-hydroxyadamantan-2-yl)amino]pyrimidine-4-carboxylate trifluoroacetate
Trans-6- { [ (tert-butoxy) carbonyl ] (1- [ (tert-butoxy) carbonyl ] -5-methyl-1H-pyrazol-3-yl) amino } -5-fluoro-2- [ (5-hydroxyadamantan-2-yl) amino ] pyrimidine-4-carboxylic acid ethyl ester (43 b) (200 mg,0.32 mmol) was dissolved in dichloromethane (6 mL), trifluoroacetic acid (3 mL) was then added thereto, and after reaction at 20℃for 1H, the residue was concentrated under reduced pressure and purified by Pre-HPLC (instrument and preparative column: preparation of liquid phase using Gilson Gx-281, preparative column model was Sunfire,5 μm, inner diameter =30mm. Times.150mm). The preparation method comprises the following steps: the crude product was dissolved in methanol and filtered through a 0.45 μm filter to prepare a sample solution. Mobile phase system: acetonitrile/water (containing 0.5% trifluoroacetic acid). The gradient elution method comprises the following steps: acetonitrile was eluted 60% by a 10% gradient (elution time 16 min), and lyophilized to give the trifluoroacetate salt of ethyl Trans-5-fluoro-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] -2- [ (5-hydroxyadamantan-2-yl) amino ] pyrimidine-4-carboxylate (43 c) (150 mg, 71%),
LCMS m/z＝431.3[M+1] + 。
and a third step of: trans-4- [ (5-fluoro-4- (hydroxymethyl) -6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (compound 43)
Trans-4-[(5-fluoro-4-(hydroxymethyl)-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)amino]adamantan-1-ol
Trifluoro acetate (63 mg,0.12 mmol) of Trans-5-fluoro-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] -2- [ (5-hydroxyadamantan-2-yl) amino ] pyrimidine-4-carboxylic acid ethyl ester (43 c) was dissolved in MeOH (5 mL), and solid sodium borohydride (18 mg,0.48 mmol) and calcium chloride (27 mg,0.24 mmol) were added under ice water bath, and reacted at room temperature until the starting material disappeared. Water (10 mL) was added, the extracts were performed with ethyl acetate (10 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to give a residue, which was purified by Pre-HPLC (instrument and preparative column: gilson Gx-281 was used to prepare a liquid phase, the type of preparative column was Sunfire,5 μm, internal diameter =30mm. Times.150mm). The preparation method comprises the following steps: the crude product was dissolved in methanol and filtered through a 0.45 μm filter to prepare a sample solution. Mobile phase system: acetonitrile/water (containing 0.5% ammonium acetate). The gradient elution method comprises the following steps: acetonitrile was eluted 60% by 10% gradient (elution time 16 min), and after lyophilization Trans-4- [ (5-fluoro-4- (hydroxymethyl) -6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (compound 43) (6.7 mg, 14%).
LCMS m/z＝389.3[M+1] +
1 H NMR(400MHz,CD 3 OD)δ6.46(s,1H),4.51(d,2H),4.01-3.96(m,1H),2.35-2.20(m,5H),2.14-2.07(m,1H),2.00-1.87(m,4H),1.84-1.75(m,4H),1.55-1.43(m,2H).
EXAMPLE 44 trifluoroacetate salt of Trans-4- [ (4- (hydroxymethyl) -6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (Compound 44)
Trans-4-[(4-(hydroxymethyl)-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)amino]adamantan-1-ol trifluoroacetate
The first step: trans-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] -2- [ (5-hydroxyadamantan-2-yl) amino ] pyrimidine-4-carboxylic acid methyl ester (44 b)
Trans-methyl-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-[(5-hydroxyadamantan-2-yl)amino]pyrimidine-4-carboxylate
Methyl 2-chloro-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidine-4-carboxylate (6 b) (200 mg,0.75 mmol), trans-4-aminoadamantane-1-ol hydrochloride (150 mg,0.75 mmol), N, N-diisopropylethylamine (480 mg,3.75 mmol) were added to DMSO (10 mL), heated to 100℃for reaction 46H, and then cooled to room temperature. Concentrating under reduced pressure to obtain a residue, purifying the residue by Pre-HPLC (instrument and preparation column: prepared liquid phase by Gilson Gx-281, preparation column model is Sunfire,5 μm, inner diameter=30mm×150mm). The preparation method comprises the following steps: the crude product was dissolved in methanol and filtered through a 0.45 μm filter to prepare a sample solution. Mobile phase system: acetonitrile/water (0.5% formic acid). The gradient elution method comprises the following steps: acetonitrile was eluted 60% by a 10% gradient (elution time 16 min), and after lyophilization Trans-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] -2- [ (5-hydroxyadamantan-2-yl) amino ] pyrimidine-4-carboxylic acid methyl ester (44 b) (40 mg, 13%).
LCMS m/z＝399.3[M+1] + 。
And a second step of: trifluoroacetic acid of Trans-4- [ (4- (hydroxymethyl) -6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (compound 44)
Trans-4-[(4-(hydroxymethyl)-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)amino]adamantan-1-ol trifluoroacetate
Trans-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] -2- [ (5-hydroxyadamantan-2-yl) amino ] pyrimidine-4-carboxylic acid methyl ester (44 b) (40 mg,0.1 mmol) was dissolved in MeOH (10 mL), and solid sodium borohydride (19 mg,0.5 mmol) and calcium chloride (110 mg,1 mmol) were added under ice-water bath and reacted at room temperature until the starting material disappeared. Water (10 mL), ethyl acetate (10 mL x 2) were added, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a residue, which was purified by Pre-HPLC (apparatus and preparative column: gilson Gx-281 for preparing a liquid phase, type of preparative column is Sunfire,5 μm, inner diameter =30mm ×150mm). The preparation method comprises the following steps: the crude product was dissolved in methanol and filtered through a 0.45 μm filter to prepare a sample solution. Mobile phase system: acetonitrile/water (containing 0.5% trifluoroacetic acid). The gradient elution method comprises the following steps: acetonitrile was eluted 60% by 10% gradient (elution time 16 min), and after lyophilization, the trifluoroacetate salt of Trans-4- [ (4- (hydroxymethyl) -6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (compound 44) (10 mg, 20.6%) was obtained.
LCMS m/z＝371.2[M+1] +
1 H NMR(400MHz,CD 3 OD)δ6.50(s,1H),6.20(s,1H),4.57(s,2H),4.25-4.10(m,1H),2.38-2.20(m,5H),2.19-2.13(m,1H),1.95-1.76(m,8H),1.64-1.54(m,2H).
Example 45: trifluoroacetate salt of Cis-4- [ (4- [ (5-methyl-1H-pyrazol-3-yl) amino ] -6- (propan-2-yloxy) pyrimidin-2-yl) amino ] adamantan-1-ol (compound 45)
Cis-4-[(4-[(5-methyl-1H-pyrazol-3-yl)amino]-6-(propan-2-yloxy)pyrimidin-2-yl)amino]adamantan-1-ol trifluoroacetate
Compound 45 was synthesized from Cis-4- [ (4-chloro-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (4 b) and cyclopentanol as starting materials according to the method of reference example 10 to give the trifluoroacetate salt of Cis-4- [ (4- [ (5-methyl-1H-pyrazol-3-yl) amino ] -6- (propan-2-yloxy) pyrimidin-2-yl) amino ] adamantan-1-ol (Compound 45)
LCMS m/z＝425.3[M+1] +
Example 46: trifluoroacetate salt of Cis-4- [ (4- { [ (3 s,3ar,6 as) -3a,6 a-dihydro-hexahydrofuro [2,3-b ] furan-3-yl ] oxy } -6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (compound 46)
Cis-4-[(4-{[(3S,3aR,6aS)-3a,6a-dihydrogenio-hexahydrofuro[2,3-b]furan-3-yl]oxy}-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)amino]adamantan-1-ol trifluoroacetate
Compound 46 was synthesized from Cis-4- [ (4-chloro-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (4 b) and (3S, 3aR,6 aS) -hexahydrofuro [2,3-b ] furan-3-ol (CAS: 156928-10-8) by the method of reference example 10 to give the trifluoroacetate salt of Cis-4- [ (4- { [ (3S, 3aR,6 aS) -3a,6 a-dihydro-hexahydrofuro [2,3-b ] furan-3-yl ] oxy } -6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (Compound 46)
LCMS m/z＝469.3[M+1] +
1 HNMR(400MHz,DMSO-d 6 +D 2 O)δ5.86(s,1H),5.66-5.61(m,1H),5.35-5.25(m,1H),4.09-4.02(m,1H),3.90-3.80(m,2H),3.75-3.68(m,3H),3.17-3.05(m,1H),2.30-2.10(m,5H),2.07-2.00(m,1H),1.95-1.75(m,4H),1.70-1.55(m,6H),1.54-1.42(m,2H).
Example 47: trifluoroacetate salt of Cis-4- [ (4- (hydroxymethyl) -6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (compound 47)
Cis-4-[(4-(hydroxymethyl)-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)amino]adamantan-1-ol trifluoroacetate
At room temperature, 6- [ (5-methyl-1H-pyrazol-3-yl) amino group was cleaved]Methyl-2- [ (Cis-5-hydroxyadamantan-2-yl) (amino)]A solution of pyrimidine-4-carboxylic acid methyl ester (6 c) (29.88 mg,0.08 mmol) in THF (2 ml) was added to a solution of sodium borohydride (28.37 mg,0.75 mmol) in MeOH (2 ml), and the temperature was raised to 70℃for 24 hours. After cooling to room temperature, the reaction solution was poured into 10mL of water, extracted with ethyl acetate (10 ml×2), the organic phases were combined, backwashed with saturated brine (10 ml×2), dried over anhydrous sodium sulfate, filtered, and the mother liquor was concentrated under reduced pressure to give a crude product. Purifying the crude product by Pre-HPLC (instrument and preparation column: preparation of liquid phase by Waters2767, preparation column model is Sunfire@PrepC 18 5 μm, inner diameter = length = 19mm x 250 mm). The preparation method comprises the following steps: the crude product was dissolved in DMF and filtered through a 0.45 μm filter to prepare a sample solution. Mobile phase system: acetonitrile/water (containing 1% trifluoroacetic acid). The gradient elution method comprises the following steps: acetonitrile was eluted with a gradient of 50% (flow rate: 15mL/min; elution time: 15 min) from 5%, and lyophilized to give Cis-4- [ (4- (hydroxymethyl) -6- [ (5-methyl-1H-pyrazol-3-yl) amino) ]Pyrimidin-2-yl) amino groups]Trifluoroacetate salt of adamantan-1-ol (Compound 47) (6 mg, YIeld: 16%)
LCMS m/z＝371.3[M+1] +
1H NMR(400MHz,DMSO-d 6 )δ12.33(s,1H),12.05-11.40(m，1H)11.15(s,1H),8.07(d,1H),6.65(s,1H),6.48(s,1H),4.50(s,1H),3.99-3.85(m,1H),3.53-3.15(m,3H),2.29-2.16(m,5H),2.11-2.05(m,1H),1.90-1.77(m,2H),1.74-1.57(m,6H),1.53-1.45(m,2H).
Example 48: cis- (3R, 4S) -4- [ (6- [ (5-methyl-1H-pyrazol-3-yl) amino ] -2- { [ 5-hydroxyadamantan-2-yl ] amino } pyrimidin-4-yl) oxy ] oxa-3-ol (compound 48)
Cis-(3R,4S)-4-[(6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-{[5-hydroxyadamantan-2-yl]amino}pyrimidin-4-yl)oxy]oxolan-3-ol
Compound 48 Synthesis of reference example 10 from Cis-4- [ (4-chloro-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (4 b) and Cis-tetrahydrofuran-3, 4-diol gave Cis- (3R, 4S) -4- [ (6- [ (5-methyl-1H-pyrazol-3-yl) amino ] -2- { [ 5-hydroxyadamantan-2-yl ] amino } pyrimidin-4-yl) oxy ] oxa-3-ol (Compound 48)
LCMS m/z＝443.3[M+1] +
1 H NMR(400MHz,CD 3 OD)δ6.15(s,1H),5.67(s,1H),5.30-5.20(m,1H),4.50-4.40(m,H),4.18-4.10(m,1H),4.00-3.90(m,1H),3.92-3.86(m,1H),3.85-3.80(m,1H),3.76-3.70(m,1H),2.35-2.20(m,5H),2.16-2.09(m,1H),2.04-1.93(m,2H),1.84-1.67(m,6H),1.60-1.52(m,2H).
Example 49: trans (3R, 4S) -4- [ (6- [ (5-methyl-1H-pyrazol-3-yl) amino ] -2- { [ -5-hydroxyadamantan-2-yl ] amino } pyrimidin-4-yl) oxy ] oxa-3-ol (compound 49)
Trans-(3R,4S)-4-[(6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-{[-5-hydroxyadamantan-2-yl]amino}pyrimidin-4-yl)oxy]oxolan-3-ol
Compound 49 Trans- ((3R, 4S) -4- [ (6- [ (5-methyl-1H-pyrazol-3-yl) amino ] -2- { [ 5-hydroxyadamantan-2-yl ] amino } pyrimidin-4-yl) oxy ] oxa-3-ol (Compound 49) was obtained by the method of synthesis of reference example 38 starting from 2, 6-dichloro-N- (3-methyl-1H-pyrazol-5-yl) pyrimidin-4-amine (1 c), trans-4-aminoadamantan-1-ol hydrochloride and cis-tetrahydrofuran-3, 4-diol
LCMS m/z＝443.3[M+1] +
1 H NMR(400MHz,CD 3 OD)δ6.27-5.77(m,1H),5.62(s,1H),5.30-5.19(m,1H),4.50-4.42(m,1H),4.17-4.10(m,1H),4.04-3.94(m,2H),3.86-3.80(m,1H),3.77-3.70(m,1H),2.30-2.15(m, 5H),2.14-2.07(m,1H),2.03-1.94(m,2H),1.92-1.84(m,2H),1.82-1.75(m,4H),1.55-1.45(m,2H).
Example 50: cis- (3R, 6R) -6- [ (6- [ (5-methyl-1H-pyrazol-3-yl) amino ] -2- { [ 5-hydroxyadamantan-2-yl ] amino } pyrimidin-4-yl) oxy ] -hexahydrofuro [3,2-b ] furan-3-ol (compound 50)
Cis-(3R,6R)-6-[(6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-{[5-hydroxyadamantan-2-yl]amino}pyrimidin-4-yl)oxy]-hexahydrofuro[3,2-b]furan-3-ol
Compound 50 was synthesized from Cis-4- [ (4-chloro-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (4 b) and 1,4:3, 6-dianhydro-mannitol (CAS: 641-74-7) as starting materials according to the method of reference example 10 to give Cis- (3R, 6R) -6- [ (6- [ (5-methyl-1H-pyrazol-3-yl) amino ] -2- { [ 5-hydroxyadamantan-2-yl ] amino } pyrimidin-4-yl) oxy ] -hexahydrofuran [3,2-b ] furan-3-ol (Compound 50)
LCMS m/z＝485.3[M+1] +
1H NMR(400MHz,CD 3 OD)δ6.12(s,1H),5.66(s,1H),5.35-5.25(m,1H),4.80-4.76(m,1H),4.45(t,1H),4.30-4.24(m,1H),4.21-4.41(m,1H),3.94-3.87(m,2H),3.85-3.80(m,1H),3.54(t,1H),2.35-2.17(m,5H),2.16-2.09(m,1H),2.05-1.92(m,2H),1.84-1.70(m,6H),1.61-1.52(m,2H).
Example 51: cis- (3R, 4S) -4- [ (5-fluoro-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] -2- { [ 5-hydroxyadamantan-2-yl ] amino } pyrimidin-4-yl) oxy ] oxa-3-ol (compound 51)
Cis-(3R,4S)-4-[(5-fluoro-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-{[5-hydroxyadamantan-2-yl]amino}pyrimidin-4-yl)oxy]oxolan-3-ol
Compound 51 Cis- (3R, 4S) -4- [ (5-fluoro-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] -2- { [ 5-hydroxyadamantan-2-yl ] amino } pyrimidin-4-yl) oxy ] oxa-3-ol (Compound 51) was obtained by the method of reference example 10 starting from Cis-4- [ (4-chloro-5-fluoro-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (25 c) and Cis-tetrahydrofuran-3, 4-diol
LCMS m/z＝461.3[M+1] +
1H NMR(400MHz,CD 3 OD)δ6.06(s,1H),5.38-5.29(m,1H),4.53-4.47(m,1H),4.18-4.10(m,1H),4.02-3.96(m,1H),3.92-3.86(m,1H),3.82-3.72(m,2H),2.35-2.20(m,5H),2.15-2.09(m,1H),2.02-1.94(m,2H),1.82-1.70(m,6H),1.60-1.52(m,2H).
Example 52: trans- (3R, 4S) -4- [ (5-fluoro-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] -2- { [ 5-hydroxyadamantan-2-yl ] amino } pyrimidin-4-yl) oxy ] oxa-3-ol (compound 52)
Trans-(3R,4S)-4-[(5-fluoro-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-{[5-hydroxyadamantan-2-yl]amino}pyrimidin-4-yl)oxy]oxolan-3-ol
Compound 52 Synthesis of reference example 38 from 2, 6-dichloro-5-fluoro-N- (5-methyl-1H-pyrazol-3-yl) pyrimidin-4-amino (25 b), trans-4-aminoadamantane-1-ol hydrochloride and cis-tetrahydrofuran-3, 4-diol gave Trans- (3R, 4S) -4- [ (5-fluoro-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] -2- { [ 5-hydroxyadamantan-2-yl ] amino } pyrimidin-4-yl) oxy ] oxa-3-ol (Compound 52)
LCMS m/z＝461.3[M+1] +
1 H NMR(400MHz,CD 3 OD)δ6.06(s,1H),5.38-5.28(m,1H),4.55-4.47(m,1H),4.18-4.11(m,1H),4.02-3.96(m,1H),3.92-3.86(m,2H),3.79-3.73(m,1H),2.28-2.16(m,5H),2.13-2.07(m,1H),2.01-1.94(m,2H),1.91-1.83(m,2H),1.82-1.75(m,4H),1.52-1.45(m,2H).
Example 53: trifluoroacetate salt of Cis-4- [ (4- (4, 5-dihydrofuran-2-yl) -6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (compound 53)
Cis-4-[(4-(4,5-dihydrofuran-2-yl)-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)amino]adamantan-1-ol trifluoroacetate
The first step: 2- (4, 5-Dihydrofuran-2-yl) -4, 5-tetramethyl-1, 3, 2-dioxaborolan (53 a)
2-(4,5-dihydrofuran-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
2, 3-Dihydrofuran (53 a) (1.4 g,19.97 mmol), pinacol biborate (2.54 g,9.98 mmol), 4 '-di-tert-butyl-2, 2' -bipyridine (110 mg,0.4 mmol) and n-hexane (20 mL) were added to a glass vial at room temperature, and after nitrogen substitution, methoxy (cyclooctadiene) iridium dimer (130 mg,0.2 mmol) was added, followed by heating to 80℃and reacting for 16 hours. After the reaction is finished, cooling to room temperature, and spin-drying the reaction liquid to obtain a crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate (v/v) =93:7) to give 2- (4, 5-dihydrofuran-2-yl) -4, 5-tetramethyl-1, 3, 2-dioxaborolan (53 b) (700 mg, 18%).
LCMS m/z＝197.2[M+1] +
And a second step of: trifluoroacetate salt of Cis-4- [ (4- (4, 5-dihydrofuran-2-yl) -6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (compound 53)
Cis-4-[(4-(4,5-dihydrofuran-2-yl)-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)amino]adamantan-1-ol trifluoroacetate
Cis-4- [ (4-chloro-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (4 b) (100 mg,3.6 mmol), 2- (4, 5-dihydrofuran-2-yl) -4, 5-tetramethyl-1, 3, 2-dioxaborolan (53 b) (71 mg,3.6 mmol) and potassium phosphate (918 mg,4.33 mmol) were dissolved in a mixed solvent of 1, 4-dioxane (16 mL) and water (4 mL) in a microwave tube. After adding [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (52.7 mg,0.072 mmol), nitrogen was bubbled for 3 minutes, then the temperature was raised to 110℃and the reaction was carried out for 45 minutes by microwave. After the reaction was completed, the reaction mixture was cooled to room temperature, filtered, the solvent was removed from the filtrate under reduced pressure, and the residue was purified by Pre-HPLC, and the crude product was purified by Pre-HPLC (apparatus and preparative column: prepare liquid phase using water 2767, preparative column model X select C18,5 μm, inner diameter length=19mm×150mm). The preparation method comprises the following steps: the crude product was dissolved in dimethyl sulfoxide and filtered through a 0.45 μm filter to prepare a sample solution. Mobile phase system: acetonitrile/water (containing 0.5% trifluoroacetic acid). The gradient elution method comprises the following steps: acetonitrile was eluted by a 5% gradient 50% (elution time 15 min). Freeze-drying yields the trifluoroacetate salt (50 mg, 27%) of Cis-4- [ (4- (4, 5-dihydrofuran-2-yl) -6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (compound 53).
LCMS m/z＝409.2[M+1] +
1 H NMR(400MHz,CD 3 OD)δ7.44(s,1H),6.50(s,1H),5.97(s,1H),4.67(t,2H),4.14-4.02(m,1H),2.97(t,2H),2.46-2.33(m,2H),2.30(s,3H),2.23-2.09(m,1H),1.92-1.73(m,8H),1.71-1.60(m,2H).
Example 54: trifluoroacetate salt of Cis-4- [ (4- [ (5-methyl-1H-pyrazol-3-yl) amino ] -6- (oxazolidin-2-yl) pyrimidin-2-yl) amino ] adamantan-1-ol (compound 54)
Cis-4-[(4-[(5-methyl-1H-pyrazol-3-yl)amino]-6-(oxolan-2-yl)pyrimidin-2-yl)amino]adamantan-1-ol trifluoroacetate
Cis-4- [ (4- (4, 5-dihydrofuran-2-yl) -6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (compound 53) (30 mg,0.073 mmol) was dissolved in 15mL of methanol at room temperature, and 10% palladium on carbon was further added thereto, and the mixture was stirred at room temperature for 16 hours under hydrogen. Filtering, removing solvent from the filtrate under reduced pressure to obtain crude product, purifying the crude product by Pre-HPLC (instrument and preparation column: prepare liquid phase by WATERS 2767, preparation column model is X select C18,5 μm, inner diameter =19mm ×150mm). The preparation method comprises the following steps: the crude product was dissolved in dimethyl sulfoxide and filtered through a 0.45 μm filter to prepare a sample solution. Mobile phase system: acetonitrile/water (containing 0.1% trifluoroacetic acid). The gradient elution method comprises the following steps: acetonitrile was eluted by a 5% gradient 50% (elution time 15 min). Lyophilization gives the trifluoroacetate salt of Cis-4- [ (4- [ (5-methyl-1H-pyrazol-3-yl) amino ] -6- (oxazolidin-2-yl) pyrimidin-2-yl) amino ] adamantan-1-ol (compound 54) (20 mg, 67%).
LCMS m/z＝411.2[M+1] +
1 H NMR(400MHz,CD 3 OD)δ6.50(s,1H),6.18(s,1H),4.13-4.02(m,2H),4.00-3.89(m,2H),3.87-3.76(m,1H),3.45-3.35(m,1H),2.54-2.41(m,1H),2.40-2.27(m,5H),2.23-2.11(m,1H),2.10-1.98(m,1H),1.92-1.73(m,8H),1.71-1.62(m,2H)
Example 55: trifluoroacetate salt of Cis-4- [ (4- (2, 5-dihydrofuran-3-yl) -6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (compound 55)
Cis-4-[(4-(2,5-dihydrofuran-3-yl)-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)amino]adamantan-1-ol trifluoroacetate
Compound 55 is obtained from the preparation of the trifluoroacetate salt of Cis-4- [ (4- (2, 5-dihydrofuran-3-yl) -6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (4 b) and 2- (2, 5-dihydrofuran-3-yl) -4, 5-tetramethyl-1, 3, 2-dioxaborolan by the method of reference example 53 starting from Cis-4- [ (4- (2, 5-dihydrofuran-3-yl) -6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (Compound 55)
LCMS m/z＝409.2[M+1] +
1 H NMR(400MHz,CD 3 OD)δ6.87(s,1H),6.54(s,1H),6.05(s,1H),4.97-4.86(m,4H),4.14-4.05(m,1H),2.46-2.33(m,2H),2.31(s,3H),2.23-2.12(m,1H),1.94-1.75(m,8H),1.73-1.62(m,2H).
Example 56: trifluoroacetate salt of Cis-4- [ (4- [ (5-methyl-1H-pyrazol-3-yl) amino ] -6- (oxazol-3-yl) pyrimidin-2-yl) amino ] adamantan-1-ol (compound 56)
Cis-4-[(4-[(5-methyl-1H-pyrazol-3-yl)amino]-6-(oxolan-3-yl)pyrimidin-2-yl)amino]adamantan-1-ol trifluoroacetate
Compound 56 preparation of the trifluoroacetate salt of Cis-4- [ (4- [ (5-methyl-1H-pyrazol-3-yl) amino ] -6- (oxazol-3-yl) pyrimidin-2-yl) amino ] adamantan-1-ol (Compound 56) Using the procedure of reference example 54 as starting material
LCMS m/z＝411.3[M+1] +
1 H NMR(400MHz,CD 3 OD)δ6.51(s,1H),6.18(s,1H),4.16-4.02(m,2H),4.00-3.88(m,2H),3.87-3.76(m,1H),3.46-3.36(m,1H),2.52-2.41(m,1H),2.40-2.25(m,5H),2.23-2.13(m,1H),2.10-1.97(m,1H),1.92-1.73(m,8H),1.71-1.61(m,2H).
Example 57: trifluoroacetate salt of Trans-1- (6- [ (5-methyl-1H-pyrazol-3-yl) amino ] -2- [ (5-hydroxyadamantan-2-yl) amino ] pyrimidin-4-yl) azetidin-3-ol (compound 57)
Trans-1-(6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-[(5-hydroxyadamantan-2-yl)amino]pyrimidin-4-yl)azetidin-3-ol trifluoroacetate
Compound 57 was obtained by the method of reference example 21 starting with 2, 6-dichloro-N- (3-methyl-1H-pyrazol-5-yl) pyrimidin-4-amine (1 c), trans-4-aminoadamantan-1-ol hydrochloride and azetidin-3-ol, by the method of reference example 21, as the trifluoroacetate salt of Trans-1- (6- [ (5-methyl-1H-pyrazol-3-yl) amino ] -2- [ (5-hydroxyadamantan-2-yl) amino ] pyrimidin-4-yl) azetidin-3-ol (Compound 57)
LCMS m/z＝412.2[M+1] +
1 H NMR(400MHz,CD 3 OD)δ5.81(s,1H),5.12(s,1H),4.74-4.66(m,1H),4.43-4.26(m,2H),4.10-3.98(m,1H),3.95-3.84(m,2H),2.30(s,3H),2.27-2.21(m,2H),2.17-2.09(m,1H),1.97-1.75(m,8H),1.59-1.48(m,2H).
Example 58: acetate of Cis-1- (6- [ (5-methyl-1H-pyrazol-3-yl) amino ] -2- [ (5-hydroxyadamantan-2-yl) amino ] pyrimidin-4-yl) azetidin-3-ol (compound 58)
Cis-1-(6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-[(5-hydroxyadamantan-2-yl)amino]pyrimidin-4-yl)azetidin-3-ol acetate
Compound 58 acetate salt of Cis-1- (6- [ (5-methyl-1H-pyrazol-3-yl) amino ] -2- [ (5-hydroxyadamantan-2-yl) amino ] pyrimidin-4-yl) azetidin-3-ol (Compound 58) obtained by the synthesis method of reference example 21 starting from Cis-4- [ (4-chloro-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (4 b) and azetidin-3-ol
LCMS m/z＝412.3[M+1] +
1 H NMR(400MHz,DMSO-d 6 )δ12.58-11.39(m,2H),8.93(s,1H),6.42–5.45(m,3H),5.16(s,1H)，4.56-4.45(m，1H)，4.29(s,1H),4.04(t,2H),3.79–3.71(m,1H),3.62-3.53(m,2H),2.23-2.16(m,2H),2.13(s,3H),2.06–1.99(m,1H),1.94-1.83(m,4H),1.68–1.54(m,6H),1.42-1.31 (m,2H)
Example 59: trans-4- [ (4- (1H-imidazol-1-yl) -6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (compound 59)
Trans-4-[(4-(1H-imidazol-1-yl)-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)amino]adamantan-1-ol
Compound 59 Trans-4- [ (4- (1H-imidazol-1-yl) -6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (Compound 59) was obtained by the synthesis method of reference example 23 starting from 2, 6-dichloro-N- (3-methyl-1H-pyrazol-5-yl) pyrimidin-4-amine (1 c), trans-4-aminoadamantan-1-ol and imidazole
LCMS m/z＝407.2[M+1] +
1 H NMR(400MHz,CD 3 OD)δ8.42(s,1H),7.73(t,1H),7.10(t,1H),6.49-6.06(m,2H),4.11-4.07(m,1H),2.35-2.20(m,5H),2.17-2.09(m,1H),2.05-1.97(m,2H),1.96-1.89(m,2H),1.86-1.76(m,4H),1.56-1.47(m,2H)
Example 60: trifluoroacetate salt of Trans-4- (2- ((5-hydroxy adamantan-2-yl) amino) -6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-4-yl) thiomorpholin-1, 1-dioxide (compound 60)
Trans-4-(2-((5-hydroxyadamantan-2-yl)amino)-6-((5-methyl-1H-pyrazol-3-yl)amino)pyrimidin-4-yl)thiomorpholine-1,1-dioxide trifluoroacetate
Compound 60 was synthesized using the procedure of reference example 23 starting from 2, 6-dichloro-N- (3-methyl-1H-pyrazol-5-yl) pyrimidin-4-amine (1 c), trans-4-aminoadamantane-1-ol hydrochloride, and thiomorpholine-1, 1-dioxide to give the trifluoroacetate salt of Trans-4- (2- ((5-hydroxyadamantane-2-yl) amino) -6- ((5-methyl-1H-pyrazol-3-yl) amino) pyrimidin-4-yl) thiomorpholine-1, 1-dioxide (compound 60).
LCMS m/z＝474.2[M+1] +
1 H NMR(400MHz,CD 3 OD)δ5.79(s,1H),5.63(s,1H),4.25-4.13(m,4H),4.12-3.97(m,1H),3.24-3.17(m,4H),2.31(s,3H),2.28-2.23(m,2H),2.19-2.11(m,1H),2.00-1.75(m,8H),1.60-1.52(m,2H).
Example 61: trifluoroacetate salt of Trans-4- [ (4- (2-hydroxyethoxy) -6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) (methyl) amino ] adamantan-1-ol (Compound 61)
Trans-4-[(4-(2-hydroxyethoxy)-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)(methyl)amino]adamantan-1-ol trifluoroacetate
The first step: trans-4- [ (4-chloro-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) (methyl) amino ] adamantan-1-ol (61 a)
Trans-4-[(4-chloro-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)(methyl)amino]adamantan-1-ol
2, 6-dichloro-N- (3-methyl-1H-pyrazol-5-yl) pyrimidin-4-amine (1 c) (1.2 g,4.92 mmol), trans-4- (methylamino) adamantan-1-ol was reacted at room temperatureTrifluoroacetate (39 c) (1.55 g,5.26 mmol) was dissolved in dimethyl sulfoxide (15 ml), followed by the addition of potassium phosphate (3.13 g,14.76 mmol). The temperature was raised to 100℃and the reaction was carried out for 14 hours. After cooling to room temperature, the reaction was quenched with water (10 mL), extracted with ethyl acetate (10 mL. Times.2), the organic phases were combined, backwashed with saturated brine (10 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and the mother liquor concentrated to give crude product. Purifying the crude product by Pre-HPLC (instrument and preparation column: preparation of liquid phase by Waters 2767, preparation column model XBIdge@Prep C 18 Inner diameter x length = 19mm x 250 mm). The preparation method comprises the following steps: the crude product was dissolved in DMF and filtered through a 0.45 μm filter to prepare a sample solution. Mobile phase system: acetonitrile/water. The gradient elution method comprises the following steps: acetonitrile was eluted 55% by 10% gradient (flow rate: 12mL/min; elution time: 17 min), lyophilized to obtain Trans-4- [ (4-chloro-6- [ (5-methyl-1H-pyrazol-3-yl) amino]Pyrimidin-2-yl) (methyl) amino]Adamantan-1-ol (61 a) (300 mg, 16%).
LCMS m/z＝389.1[M+1] +
And a second step of: trifluoroacetate salt of Trans-4- [ (4- (2-hydroxyethoxy) -6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) (methyl) amino ] adamantan-1-ol (Compound 61)
Trans-4-[(4-(2-hydroxyethoxy)-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)(methyl)amino]adamantan-1-ol trifluoroacetate
To a reaction flask containing ethylene glycol (2 mL) was added sodium metal (97 mg,4.20 mmol) at room temperature, and after complete disappearance of the sodium metal, trans-4- [ (4-chloro-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) (methyl) amino ] adamantan-1-ol (61 a) (80 mg,0.21 mmol) was added thereto. After heating to 100deg.C for 16h, the reaction was quenched by the addition of water (1 mL). The crude product was purified by Pre-HPLC (instrument and column: liquid phase prepared using Gilson Gx-281, column model number Sunfire,5 μm, inner diameter =30 mm ×150 mm). The preparation method comprises the following steps: the crude product was dissolved in methanol and filtered through a 0.45 μm filter to prepare a sample solution. Mobile phase system: acetonitrile/water (containing 0.5% trifluoroacetic acid). The gradient elution method comprises the following steps: acetonitrile was eluted 60% by 10% gradient (elution time 16 min), and lyophilized to give the trifluoroacetate salt of Trans-4- [ (4- (2-hydroxyethoxy) -6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) (methyl) amino ] adamantan-1-ol (compound 61) (20 mg, 23%).
LCMS m/z＝415.3[M+1] +
1 H NMR(400MHz,CD 3 OD)δ5.83(s,1H),5.65(s,1H),4.49-4.44(m,2H),4.31-4.27(m,1H),3.89-3.83(m,2H),3.46(s,3H),2.55-2.46(m,2H),2.32(s,3H),2.28-2.22(m,1H),2.10-1.97(m,4H),1.91-1.80(m,4H),1.72-1.61(m,2H).
Example 62: trifluoroacetate salt of Trans-4- [ (6- [ (5-methyl-1H-pyrazol-3-yl) amino ] -2- (methyl (-5-hydroxyadamantan-2-yl) amino) pyrimidin-4-yl) oxy ] oxazol-3-ol (compound 62)
Trans-4-[(6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-(methyl(-5-hydroxyadamantan-2-yl)amino)p yrimidin-4-yl)oxy]oxolan-3-ol trifluoroacetate
Compound 62 was synthesized from Trans-4- [ (4-chloro-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) (methyl) amino ] adamantan-1-ol (61 a) and cis-tetrahydrofuran-3, 4-diol as starting materials according to the method of reference example 10 to give the trifluoroacetate salt of Trans-4- [ (6- [ (5-methyl-1H-pyrazol-3-yl) amino ] -2- (methyl (-5-hydroxyadamantan-2-yl) amino) pyrimidin-4-yl) oxy ] oxazol-3-ol (compound 62).
LCMS m/z＝457.3[M+1] +
1 H NMR(400MHz,CD 3 OD)δ5.85(s,1H),5.71(s,1H),5.50-5.44(m,1H),4.54-4.48(m,1H),4.31-4.25(m,1H),4.18-4.11(m,1H),4.04-3.97(m,1H),3.94-3.87(m,1H),3.77-3.69(m,1H),3.46(s,3H),2.54-2.46(m,2H),2.32(s,3H),2.29-2.21(m,1H),2.08-1.98(m,4H),1.91-1.80(m,4H),1.71-1.63(m,2H).
EXAMPLE 63 cis-4- [ (4- [ (5-methyl-1H-pyrazol-3-yl) amino ] -6- [ (3R) -oxopent-3-yloxy ] pyrimidin-2-yl) amino ] adamantan-1-ol (compound 63)
Cis-4-[(4-[(5-methyl-1H-pyrazol-3-yl)amino]-6-[(3R)-oxolan-3-yloxy]pyrimidin-2-yl)amino]adamantan-1-ol
Compound 63 was synthesized from Cis-4- [ (4-chloro-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (4 b) and (R) - (-) -3-hydroxytetrahydrofuran as starting materials, according to the procedure of example 3, to give Cis-4- [ (4- [ (5-methyl-1H-pyrazol-3-yl) amino ] -6- [ (3R) -oxopent-3-yloxy ] pyrimidin-2-yl) amino ] adamantan-1-ol (Compound 63)
LCMS m/z＝427.2[M+1] +
1 H NMR(400MHz,DMSO-d 6 )δ11.73(s,1H),9.14(s,1H),6.15(s,1H),5.50(s,1H),5.36(s, 1H),4.35(s,1H),3.92-3.59(m,5H),2.27-2.09(m,6H),2.07-2.00(m,1H),1.99-1.85(m,3H),1.72-1.54(m,7H),1.46-1.32(m 2H).
EXAMPLE 64 trifluoroacetate salt of cis-4- [ ((4- [ (5-methyl-1H-pyrazol-3-yl) amino ] -6- (epoxyhexane-3-yloxy) pyrimidin-2-yl) amino ] adamantan-1-ol (compound 64)
Cis-4-[(4-[(5-methyl-1H-pyrazol-3-yl)amino]-6-(oxepan-3-yloxy)pyrimidin-2-yl)amino]adamantan-1-ol trifluoroacetate
Compound 64 was synthesized from Cis-4- [ (4-chloro-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (4 b) and 3-hydroxytetrahydropyran using the method of synthesis example 3, to give the trifluoroacetate salt of Cis-4- [ ((4- [ (5-methyl-1H-pyrazol-3-yl) amino ] -6- (epoxyhexane-3-yloxy) pyrimidin-2-yl) amino ] adamantan-1-ol (Compound 64)
LCMS m/z＝441.2[M+1] +
1 H NMR(400MHz,CD3OD)δ5.81(s,1H),5.05(s,1H),4.79-4.70(m,1H),4.09-3.81(m,2H),3.76-3.59(m,3H),2.44-2.24(m,5H),2.20-2.04(m,2H),2.02-1.71(m,10H),1.66-1.52(m 3H).
EXAMPLE 65 trifluoroacetate salt of cis-4- [ (4- [ (5-methyl-1H-pyrazol-3-yl) amino ] -6- [ (tetrahydrofuran-3-yl) methoxy ] pyrimidin-2-yl) amino ] adamantan-1-ol (compound 65)
Cis-4-[(4-[(5-methyl-1H-pyrazol-3-yl)amino]-6-[(oxolan-3-yl)methoxy]pyrimidin-2-yl)amino]adamantan-1-ol trifluoroacetate
Compound 65 was synthesized from Cis-4- [ (4-chloro-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (4 b) and tetrahydrofuran-3-methanol, according to the procedure of example 3, to give the trifluoroacetate salt of Cis-4- [ (4- [ (5-methyl-1H-pyrazol-3-yl) amino ] -6- [ (tetrahydrofuran-3-yl) methoxy ] pyrimidin-2-yl) amino ] adamantan-1-ol (Compound 65)
LCMS m/z＝441.2[M+1] +
1 H NMR(400MHz,CD3OD)δ5.82(s,1H),5.58(s,1H),4.47-4.23(m,2H),4.11-3.94(m,1H),3.93-3.82(m,2H),3.79-3.71(m,1H),3.68-3.60(m,1H),2.80-2.67(m,1H),2.44-2.25(m5H),2.21-2.05(m,2H),2.02-1.91(m,2H),1.90-1.56(m,9H).
EXAMPLE 66 Trans-4- [ (4- [ (5-methyl-1H-pyrazol-3-yl) amino ] -6- [ (3R) -oxopent-3-yloxy ] pyrimidin-2-yl) amino ] adamantan-1-ol (compound 66)
Trans-4-[(4-[(5-methyl-1H-pyrazol-3-yl)amino]-6-[(3R)-oxolan-3-yloxy]pyrimidin-2-yl)amino]adamantan-1-ol
Compound 66 Trans-4- [ (4-methyl-1H-pyrazol-3-yl) amino ] -6- [ (3R) -oxopent-3-yloxy ] pyrimidin-2-yl) amino ] adamantan-1-ol and (R) - (-) -3-hydroxytetrahydrofuran were obtained by the synthesis method of example 3 starting from Trans-3- [ (4-chloro-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] -6- [ (3R) -oxopent-3-yloxy ] pyrimidin-2-yl) amino ] adamantan-1-ol (Compound 66)
LCMS m/z＝427.3[M+1] +
1 H NMR(400MHz,CD 3 OD)δ5.79-5.16(m,2H),4.05-3.79(m,5H),3.30-3.25(m,1H),2.34-2.18(m,6H),2.15-2.06(m,2H),2.03-1.93(m,2H),1.92-1.84(m,2H),1.83-1.74(m,4H),1.56-1.43(m,2H).
Example 67: trifluoroacetate salt of Trans-4- [ (4- [ (5-methyl-1H-pyrazol-3-yl) amino ] -6- (trifluoromethyl) pyrimidin-2-yl) amino ] adamantan-1-ol (compound 67)
Trans-4-[(4-[(5-methyl-1H-pyrazol-3-yl)amino]-6-(trifluoromethyl)pyrimidin-2-yl)amino]adamantan-1-ol trifluoroacetate
Compound 67 was synthesized by the method of reference example 5 starting from 2, 4-dichloro-6- (trifluoromethyl) pyrimidine and Trans-4-aminoadamantane-1-ol hydrochloride to give the trifluoroacetate salt of Trans-4- [ (4- [ (5-methyl-1H-pyrazol-3-yl) amino ] -6- (trifluoromethyl) pyrimidin-2-yl) amino ] adamantan-1-ol (Compound 67)
LCMS m/z＝409.2[M+1] +
1 H NMR(400MHz,CD 3 OD)δ6.44(s,1H),6.07(s,1H),4.13-4.05(m,1H),2.52-2.20(m,5H),2.18-2.09(m,1H),2.05-1.74(m,8H),1.62-1.43(m,2H).
Example 68: trifluoroacetate salt of Cis-4- [ (4- (3, 6-dihydro-2H-pyran-4-yl) -6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (compound 68)
Cis-4-[(4-(3,6-dihydro-2H-pyran-4-yl)-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)amino]adamantan-1-ol trifluoroacetate
Compound 68 preparation of the trifluoroacetate salt of Cis-4- [ (4- (3, 6-dihydro-2H-pyran-4-yl) -6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (4 b) and 3, 6-dihydro-2H-pyran-4-boronic acid pinacol ester (CAS: 287944-16-5) starting from the procedure of example 27 gave the trifluoroacetate salt of Cis-4- [ (4- (3, 6-dihydro-2H-pyran-4-yl) -6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (Compound 68)
LCMS m/z＝425.3[M+1] +
1 H NMR(400MHz,CD 3 OD)δ6.51(s,1H),6.15(s,1H),4.13-4.00(m,3H),3.61-3.47(m,2H),2.91-2.78(m,1H),2.44-2.26(m,5H),2.22-2.11(m,1H),1.91-1.63(m,14H).
Example 69: cis-4- [ (4- [ (5-methyl-1H-pyrazol-3-yl) amino ] -6- [ (3S) -oxazolidin-3-yloxy ] pyrimidin-2-yl) amino ] adamantan-1-ol (compound 69)
Cis-4-[(4-[(5-methyl-1H-pyrazol-3-yl)amino]-6-[(3S)-oxolan-3-yloxy]pyrimidin-2-yl)amino]adamantan-1-ol
Compound 69 the procedure of reference example 10 was followed using Cis-4- [ (4-chloro-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (4 b) and (S) - (+) -3-hydroxytetrahydrofuran as starting materials to give Cis-4- [ (4- [ (5-methyl-1H-pyrazol-3-yl) amino ] -6- [ (3S) -oxazolidin-3-yloxy ] pyrimidin-2-yl) amino ] adamantan-1-ol (Compound 69).
LCMS m/z＝427.2[M+1] +
Example 70: trifluoroacetate salt of Cis-1- (5-fluoro-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] -2- { [ 5-hydroxyadamantan-2-yl ] amino } pyrimidin-4-yl) piperidin-4-ol (compound 70)
Cis-1-(5-fluoro-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-{[5-hydroxyadamantan-2-yl]amino}pyrimidin-4-yl)piperidin-4-ol trifluoroacetate
Compound 70 the procedure of example 36 was followed using Cis-4- [ (4-chloro-5-fluoro-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (25 c) and 4-hydroxypiperidine as starting materials to give the trifluoroacetate salt of Cis-1- (5-fluoro-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] -2- { [ 5-hydroxyadamantan-2-yl ] amino } pyrimidin-4-yl) piperidin-4-ol (compound 70).
LCMS m/z＝458.2[M+1] +
1 H NMR(400MHz,CD 3 OD)δ5.89(s,1H),4.30-4.18(m,2H),3.99-3.81(m,2H),3.57-3.46(m,2H),2.35-2.28(m,5H),2.19-2.11(m,1H),2.00-1.91(m,4H),1.82-1.73(m,6H), 1.64-1.51(m,4H).
Example 71: trifluoroacetate salt of Trans-1- (5-fluoro-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] -2- { [ cis-5-hydroxyadamantan-2-yl ] amino } pyrimidin-4-yl) azetidin-3-ol (compound 71)
Trans-1-(5-fluoro-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-{[cis-5-hydroxyadamantan-2-yl]amino}pyrimidin-4-yl)azetidin-3-ol trifluoroacetate
Compound 71 from 2, 6-dichloro-5-fluoro-N- (5-methyl-1H-pyrazol-3-yl) pyrimidin-4-amino (25 b), trans-4-aminoadamantan-1-ol hydrochloride and azetidin-3-ol as starting materials reference example 38, the trifluoroacetate salt of Trans-1- (5-fluoro-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] -2- { [ cis-5-hydroxyadamantan-2-yl ] amino } pyrimidin-4-yl) azetidin-3-ol (compound 71) was obtained.
LCMS m/z＝430.2[M+1] +
1 H NMR(400MHz,CD 3 OD)δ5.88(s,1H),4.76-4.68(m,1H),4.60-4.48(m，2H),4.15-4.04(m,2H),4.01-3.93(m,1H)，2.31(s,3H)2.26-2.21(m,2H),2.16-2.10(m,1H),1.96-1.76(m,8H),1.57-1.49(m,2H).
Example 72: trifluoroacetate salt of Trans-4- [ (5-fluoro-4-methoxy-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (compound 72)
Trans-4-[(5-fluoro-4-methoxy-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)amino]adamantan-1-ol trifluoroacetate
Compound 72 was synthesized from 2, 6-dichloro-5-fluoro-N- (5-methyl-1H-pyrazol-3-yl) pyrimidin-4-yl (25 b), trans-4-aminoadamantane-1-yl hydrochloride and sodium methoxide as starting materials according to the method of reference example 25 to give the trifluoroacetate salt of Trans-4- [ (5-fluoro-4-methoxy-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (Compound 72).
LCMS m/z＝389.2[M+1] +
1 H NMR(400MHz,CD 3 OD)δ6.03(s,1H),4.06-3.96(m,4H),2.34(s,3H)2.29-2.22(m,2H),2.17-2.11(m,1H),2.02-1.93(m,2H),1.93-1.76(m,6H),1.60-1.47(m,2H).
Example 73: trifluoroacetate salt of Trans-4- [ (5-fluoro-4- (2-hydroxyethoxy) -6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (compound 73)
Trans-4-[(5-fluoro-4-(2-hydroxyethoxy)-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)amino]adamantan-1-ol trifluoroacetate
Compound 73 the trifluoroacetate salt of Trans-4- [ (5-fluoro-4- (2-hydroxyethoxy) -6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (compound 73) was obtained by the method of the synthesis of reference example 38 starting from 2, 6-dichloro-5-fluoro-N- (5-methyl-1H-pyrazol-3-yl) pyrimidin-4-amino (25 b), trans-4-aminoadamantane-1-ol hydrochloride and ethylene glycol.
LCMS m/z＝419.2[M+1] +
1 H NMR(400MHz,CD 3 OD)δ6.03(s,1H),4.51-4.45(m,2H),4.01-3.95(m,1H),3.91-3.86(m,2H),2.35(s,3H),2.28-2.22(m,2H),2.18-2.10(m,1H),2.02-1.92(m,2H),1.92-1.75(m,6H),1.59-1.50(m,2H).
EXAMPLE 74 trifluoroacetate salt of cis-4- [ (4- [ (5- (hydroxymethyl) -1H-pyrazol-3-yl) amino ] -6-methoxypyrimidin-2-yl) amino ] adamantan-1-ol (Compound 74)
Cis-4-[(4-[(5-(hydroxymethyl)-1H-pyrazol-3-yl)amino]-6-methoxypyrimidin-2-yl)amino]adamantan-1-ol trifluoroacetate
The first step: n- (5- [ (benzyloxy) methyl ] -1H-pyrazol-3-yl) -2, 6-dichloropyrimidine-4-amino (74 b)
N-(5-[(benzyloxy)methyl]-1H-pyrazol-3-yl)-2,6-dichloropyrimidin-4-amine
N, N-diisopropylethylamine (1.70 g,13.15 mmol) was added to a solution of 2,4, 6-trichloropyrimidine (1 b) (0.6 g,3.27 mmol), 5- [ (benzyloxy) methyl ] -1H-pyrazol-3-amino hydrochloride (74 a) (1.17 g,4.91 mmol) in ethanol (30 ml) at room temperature. After reacting at room temperature for 4 hours, 20mL of water was added to the reaction mixture, and the reaction was continued with stirring for 1 hour. Filtration gave N- (5- [ (benzyloxy) methyl ] -1H-pyrazol-3-yl) -2, 6-dichloropyrimidine-4-amino (74 b) (0.7 g, 61%) as a white solid.
LCMS m/z＝350.1[M+1] +
And a second step of: cis-4- [ (4- [ (5- [ (benzyloxy) methyl ] -1H-pyrazol-3-yl) amino ] -6-chloropyrimidin-2-yl) amino ] adamantan-1-ol (74 c)
Cis-4-[(4-[(5-[(benzyloxy)methyl]-1H-pyrazol-3-yl)amino]-6-chloropyrimidin-2-yl)amino]adamantan-1-ol
N, N-diisopropylethylamine (775 mg,6.00 mmol) was added to a solution of 4-aminoadamantane-1-ol hydrochloride (1 d) (4476 mg,2.20 mmol), N- (5- [ (benzyloxy) methyl ] -1H-pyrazol-3-yl) -2, 6-dichloropyrimidine-4-amino (74 b) (700 mg,2.00 mmol) in DMSO (7 ml) at room temperature. The temperature was raised to 100℃and the reaction was carried out for 14 hours. After cooling to room temperature, the reaction was quenched with water (70 mL), extracted with ethyl acetate (100 mL. Times.2), the organic phases were combined, backwashed with saturated brine (100 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and the mother liquor concentrated to give crude product. The crude product was isolated and purified by column chromatography (dichloromethane: methanol (v/v) =10:1) to give Cis-4- [ (4- [ (5- [ (benzyloxy) methyl ] -1H-pyrazol-3-yl) amino ] -6-chloropyrimidin-2-yl) amino ] adamantan-1-ol (74 c) (375 mg, 39%).
LCMS m/z＝481.2[M+1] +
And a third step of: cis-4- [ (4-chloro-6- [ (5- (hydroxymethyl) -1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (74 d)
Cis-4-[(4-chloro-6-[(5-(hydroxymethyl)-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)amino]adamantan-1-ol
A solution of boron tribromide in methylene chloride (1M, 3 mL) was slowly added dropwise to Cis-4- [ (4- [ (5- [ (benzyloxy) methyl ] in ice bath]-1H-pyrazol-3-yl) amino]-6-chloropyrimidin-2-yl) amino]Adamantan-1-ol (74 c) (370 mg,0.77 mmol) in dichloromethane (10 mL) was added after completion of the dropwise addition. After the reaction is finished, slowly dropwise adding methanol to quench the reaction, adding a small amount of saturated sodium bicarbonate solution to adjust the pH value to 7-8, concentrating the reaction solution under reduced pressure to obtain a residue, and separating and purifying the residue by column chromatography (dichloromethane: methanol (v/v) =10:1) to obtain Cis-4- [ (4-chloro-6- [ (5- (hydroxymethyl) -1H-pyrazol-3-yl) amino]Pyrimidin-2-yl) amino groups]Adamantan-1-ol (74 d) (222 mg, 74%).
LCMS m/z＝391.1[M+1] +
Fourth step: trifluoroacetate salt of Cis-4- [ (4- [ (5- (hydroxymethyl) -1H-pyrazol-3-yl) amino ] -6-methoxypyrimidin-2-yl) amino ] adamantan-1-ol (compound 74)
Cis-4-[(4-[(5-(hydroxymethyl)-1H-pyrazol-3-yl)amino]-6-methoxypyrimidin-2-yl)amino]adamantan-1-ol trifluoroacetate
Sodium methoxide in methanol (30%, 70mg,0.39 mmol) was added to Cis-4- [ (4-chloro-6- [ (5- (hydroxymethyl) -1H-pyrazol-3-yl) amino) at room temperature]Pyrimidin-2-yl) amino groups]Adamantan-1-ol (74 e) (50 mg,0.13 mmol) in methanol (2 ml). In the tube sealing, the temperature is raised to 100 ℃ for reaction for 14 hours. After cooling to room temperature, the reaction mixture was poured into water (10 mL) to quench the reaction, ethyl acetate (10 ml×2) was extracted, the organic phases were combined, washed with saturated brine (10 ml×2), dried over anhydrous sodium sulfate, filtered, and the mother liquor was concentrated to give a crude product. Purifying the crude product by Pre-HPLC (instrument and preparation column: collecting) Preparation of liquid phase with Waters 2767, column model XBIdge@Prep C 18 Inner diameter x length = 19mm x 250 mm). The preparation method comprises the following steps: the crude product was dissolved in DMF and filtered through a 0.45 μm filter to prepare a sample solution. Mobile phase system: acetonitrile/water (containing 0.05% trifluoroacetic acid). The gradient elution method comprises the following steps: acetonitrile was eluted 55% by a 10% gradient (flow rate: 12mL/min; elution time 17 min), and lyophilized to give: cis-4- [ (5- (hydroxymethyl) -1H-pyrazol-3-yl) amino]-6-methoxypyrimidin-2-yl) amino group]Trifluoroacetic acid salt of adamantan-1-ol (compound 74) (20 mg, 31%).
LCMS m/z＝387.2[M+1] +
1 H NMR(400MHz,CD 3 OD)δ5.99(s,1H),5.61(s,1H),4.64(s,2H),4.12-3.89(m,4H),2.44-2.33(m,2H),2.20-2.10(m,1H),2.01-1.92(m,2H),1.90-1.70(m,6H),1.70-1.60(m,2H).
Example 75: cis-4- [ (5-fluoro-4- (hydroxymethyl) -6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) (methyl) amino ] adamantan-1-ol (compound 75)
Cis-4-[(5-fluoro-4-(hydroxymethyl)-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)(methyl)amino]adamantan-1-ol
The first step: cis-6- { [ (tert-butoxy) carbonyl ] (1- [ (tert-butoxy) carbonyl ] -5-methyl-1H-pyrazol-3-yl) amino } -5-fluoro-2- (methyl [ 5-hydroxyadamantan-2-yl ] amino) pyrimidine-4-carboxylic acid ethyl ester (75 d)
Cis-ethyl 6-{[(tert-butoxy)carbonyl](1-[(tert-butoxy)carbonyl]-5-methyl-1H-pyrazol-3-yl)amino}-5-fluoro-2-(methyl[5-hydroxyadamantan-2-yl]amino)pyrimidine-4-carboxylate
N, N-diisopropylethylamine (516.96 mg,4.00 mmol) was added to a solution of 6- { [ (tert-butoxy) carbonyl ] ethyl ] (1- [ (tert-butoxy) carbonyl ] -5-methyl-1H-pyrazol-3-yl) amino } -2-chloro-5-fluoropyrimidine-4-carboxylic acid ethyl ester (39 b) (500.00 mg,1.00 mmol), cis-4- (methylamino) adamantan-1-ol trifluoroacetate (75 c) (324.83 mg,1.10 mmol) in dimethyl sulfoxide (10 ml) at room temperature. The temperature was raised to 100℃and the reaction was carried out for 14 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, poured into water (10 mL) to quench the reaction, ethyl acetate (10 mL. Times.2) was extracted, the organic phases were combined, washed with saturated brine (10 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and the mother liquor was concentrated under reduced pressure to give the crude compound Cis-6- { [ (tert-butoxy) carbonyl ] (1- [ (tert-butoxy) carbonyl ] -5-methyl-1H-pyrazol-3-yl) amino } -5-fluoro-2- (methyl [ 5-hydroxyadamantan-2-yl ] amino) pyrimidine-4-carboxylic acid ethyl ester (75 d) (500.00 mg, YIeld: 77.55%) without purification, which was directly taken as the next step.
LCMS m/z＝545.3[M-99] +
And a second step of: cis-5-fluoro-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] -2- (methyl [ -5-hydroxyadamantan-2-yl ] amino) pyrimidine-4-carboxylic acid ethyl ester (75 f)
Cis-ethyl 5-fluoro-6-[(5-methyl-1H-pyrazol-3-yl)amino]-2-(methyl[5-hydroxyadamantan-2-yl]amino)pyrimidine-4-carboxylate
Trifluoroacetic acid (2 ml) was added to Cis-6- { [ (tert-butoxy) carbonyl at room temperature](1- [ (tert-butoxy) carbonyl)]-5-methyl-1H-pyrazol-3-yl) amino } -5-fluoro-2- (methyl [ 5-hydroxyadamantan-2-yl)]Amino) pyrimidine-4-carboxylic acid ethyl ester (75 d) (502.89 mg,0.78 mmol) in dichloromethane (4 ml). The reaction was carried out at room temperature for 4 hours. After the reaction, the reaction solution was concentrated under reduced pressure to obtain a crude product. Crude product is passed through C 18 Reverse column separation and purification (purification method: dissolving crude product in DMF, filtering to obtain sample solution, mobile phase system: acetonitrile/water (containing 0.5% ammonia water)), gradient elution method: acetonitrile gradient eluting 80% from 10% (flow rate: 60mL/min; elution time)20 min)), and freeze-drying to obtain Cis-5-fluoro-6- [ (5-methyl-1H-pyrazol-3-yl) amino]-2- (methyl [ 5-hydroxyadamantan-2-yl)]Amino) pyrimidine-4-carboxylic acid ethyl ester (75 f) (300.00 mg, yield: 86.53%).
LCMS m/z＝445.3[M+1] +
1 H NMR(400MHz,DMSO-d 6 )δ12.07(s,1H),9.65(s,1H),6.37(s,1H),4.40(s,1H),4.32(q,2H),4.07-3.99(m,1H),3.26(s,3H),2.43-2.35(m,2H),2.22(s,3H),2.10-2.03(m,1H),1.93-1.83(m,2H),1.77-1.68(m,2H),1.66-1.56(m,4H),1.53-1.43(m,2H),1.30(t,3H).
And a third step of: cis-4- [ (5-fluoro-4- (hydroxymethyl) -6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) (methyl) amino ] adamantan-1-ol (compound 75)
Cis-4-[(5-fluoro-4-(hydroxymethyl)-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)(methyl)amino]adamantan-1-ol
Anhydrous calcium chloride (297.43 mg,2.68 mmol), sodium borohydride (202.77 mg,5.36 mmol) were added sequentially to a mixture of Cis-5-fluoro-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] -2- (methyl [ 5-hydroxyadamantan-2-yl ] amino) pyrimidine-4-carboxylic acid ethyl ester (75 f) (300.00 mg,0.67 mmol) in THF (2 ml) ethanol (2 ml) under an ice-water bath. The reaction was carried out at room temperature for 4 hours. After the completion of the reaction, the reaction was quenched by addition of saturated sodium carbonate solution (5 mL). Insoluble materials were removed by filtration. Concentrating the mother liquor under reduced pressure to obtain a crude product. The crude product was purified by Pre-HPLC (apparatus and preparation column: preparation of liquid phase using Waters2767, preparation column model xbridge@prepc18, inner diameter x length=19 mm x 250 mm). The preparation method comprises the following steps: the crude product was dissolved in DMF and filtered through a 0.45 μm filter to prepare a sample solution. Mobile phase system: acetonitrile/water (0.05% ammonia). The gradient elution method comprises the following steps: acetonitrile was eluted 55% by 10% gradient (flow rate: 12mL/min; elution time: 17 min) and lyophilized to give Cis-4- [ (5-fluoro-4- (hydroxymethyl) -6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) (methyl) amino ] adamantan-1-ol (compound 75) (70.00 mg, yield: 24.56%)
LCMS m/z＝403.3[M+1] +
1 H NMR(400MHz,CD 3 OD)δ6.35(s,1H),4.54(d,2H),4.17-4.13(m,1H),3.35(s,3H),2.55-2.48(m,2H),2.27(s,3H),2.18-2.10(m,1H),2.06-1.98(m,2H),1.90-1.80(m,2H),1.76-1.70(m,4H),1.65-1.57(m,2H).
Example 76: cis-4- [ (5-fluoro-4- [ (5-methyl-1H-pyrazol-3-yl) amino ] -6- (oxazolidin-2-yl) pyrimidin-2-yl) amino ] adamantan-1-ol (compound 76)
Cis-4-[(5-fluoro-4-[(5-methyl-1H-pyrazol-3-yl)amino]-6-(oxolan-2-yl)pyrimidin-2-yl)amino]adamantan-1-ol
The first step: cis-4- [ (4- (4, 5-dihydrofuran-2-yl) -5-fluoro-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (76 a)
Cis-4-[(4-(4,5-dihydrofuran-2-yl)-5-fluoro-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl)amino]adamantan-1-ol
Cis-4- [ (4-chloro-5-fluoro-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (25 c) (50 mg,0.13 mmol), 2- (4, 5-dihydrofuran-2-yl) -4, 5-trimethyl-1, 3, 2-dioxaborolan (53 b) (33 mg,0.17 mmol) and potassium phosphate (59 mg,0.28 mmol) were dissolved in a mixed solvent of 1, 4-dioxan (8 mL) and water (2 mL) in a microwave tube. After adding [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (19 mg,0.026 mmol), nitrogen was bubbled for 3 minutes, then the temperature was raised to 110℃and the reaction was carried out for 45 minutes by microwave. After the reaction was completed, the mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to remove the solvent, and the residue was purified by column chromatography (dichloromethane: methanol (v/v) =10:1) to give Cis-4- [ (4- (4, 5-dihydrofuran-2-yl) -5-fluoro-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (76 a) (20 mg, 36%).
LCMS m/z＝427.2[M+1] +
And a second step of: cis-4- [ (5-fluoro-4- [ (5-methyl-1H-pyrazol-3-yl) amino ] -6- (oxazolidin-2-yl) pyrimidin-2-yl) amino ] adamantan-1-ol (compound 76)
Cis-4-[(5-fluoro-4-[(5-methyl-1H-pyrazol-3-yl)amino]-6-(oxolan-2-yl)pyrimidin-2-yl)amino]adamantan-1-ol
Cis-4- [ (4- (4, 5-dihydrofuran-2-yl) -5-fluoro-6- [ (5-methyl-1H-pyrazol-3-yl) amino ] pyrimidin-2-yl) amino ] adamantan-1-ol (76 a) (20 mg,0.047 mmol) was dissolved in 15mL of methanol at room temperature, 10% palladium on carbon was further added, and the mixture was stirred at room temperature for 16 hours under a hydrogen atmosphere. After filtration, concentration of the filtrate under reduced pressure to remove the solvent, the residue was purified by Pre-HPLC and the crude product was purified by Pre-HPLC (apparatus and column preparation: preparation of liquid phase using water 2767, column preparation model X select C18,5 μm, inner diameter =19mm ×150mm). The preparation method comprises the following steps: the crude product was dissolved in dimethyl sulfoxide and filtered through a 0.45 μm filter to prepare a sample solution. Mobile phase system: acetonitrile/water (containing 0.1% ammonium bicarbonate). The gradient elution method comprises the following steps: acetonitrile was eluted by a 5% gradient 50% (elution time 15 min). Lyophilization afforded Cis-4- [ (5-fluoro-4- [ (5-methyl-1H-pyrazol-3-yl) amino ] -6- (oxazolidin-2-yl) pyrimidin-2-yl) amino ] adamantan-1-ol (compound 76) (8 mg, 40%).
LCMS m/z＝429.3[M+1] +
1 H NMR(400MHz,CD 3 OD)δ6.45(s,1H),4.21-4.07(m,1H),4.04-3.89(m,3H),3.88-3.75(m,2H),2.57-2.41(m,1H),2.39-2.23(m,5H),2.20-2.03(m,2H),1.94-1.72(m,8H),1.69-1.59(m,2H).
Biological test case
Test example 1: inhibitory Activity against JAK1, JAK2, JAK3 and Tyk2 kinases
Detection was performed using the HTRF KinEASE-TK kit (cat# 62TK0 PEC) from Cisbio, as follows:
diluting the compound with 1x kinase buffer to a final concentration of 2.5 times; enzymes JAK1, JAK2, JAK3 and Tyk2 (Carna; 08-144, 08-045, 08-046 and 08-147) were diluted to 15. Mu.g/mL, 0.185. Mu.g/mL, 1.665. Mu.g/mL and 5. Mu.g/mL, respectively; ATP was diluted to 19.6. Mu.M (JAK 1), 19.8. Mu.M (JAK 2), 7.15. Mu.M (JAK 3) and 25.3. Mu.M (Tyk 2), respectively; TK Substrate-biotin stock was diluted to 10. Mu.M.
10. Mu.L kinase reaction was performed with 1 Xkinase buffer: after the example compounds or 1x kinase buffer 4. Mu.L+TK Substrate-biotin 2. Mu.L+enzyme 2. Mu.L+ATP 2. Mu.L, were mixed and incubated at room temperature for 2 hours (JAK 1), 30 minutes (JAK 2 and JAK 3) or 50 minutes (Tyk 2), 5. Mu.L of strepitavidin-XL 665 (500 nM) and 5. Mu.L of TK anti-cryptate (1X) were added and the incubation at room temperature was continued for 1 hour. The fluorescence values at 665nm and 620nm were measured by a microplate reader (PHERAstar FSX). The signal Ratio was calculated according to equation (1) and IC50 was calculated and analyzed using Origin 9.2.
Ratio＝[Signal 665]/[Signal 620]*10 4 (1)
The inhibitory activity of the compounds JAK1, JAK2, JAK3 and Tyk2 kinase of the present invention was measured by the above experiments.
TABLE 1 inhibitory Activity of Compounds against JAK1, JAK2, JAK3 and Tyk2 kinases
Conclusion: the compound has inhibiting effect on JAK1, JAK2, JAK3 and Tyk2 kinase and inhibiting activity IC on JAK1 kinase 50 Inhibitory Activity against JAK2 kinase IC of =0.1-10 nM 50 Inhibitory Activity against JAK3 kinase IC=0.1-20 nM 50 Inhibitory Activity against Tyk2 kinase IC=0.1-30 nM 50 ＝0.1～20nM。
Test example 2: IL-2 and anti-CD3 stimulation of hBMC secretion IFNgamma experiment
Peripheral blood of healthy volunteers was taken into an anticoagulant tube (heparin sodium), and an equal volume of sterile PBS was added and thoroughly mixed to reduce blood viscosity and reduce erythrocyte aggregation. Ficoll (GE Healthcare; 17-1440-02) with a density of 1.077 was added to a 50mL centrifuge tube, and the diluted blood was then aspirated with a pipette and slowly added to the stratified liquid surface along the tube wall 1 cm above the stratified liquid surface (final volume ratio of peripheral blood, PBS to Ficoll 1:1). 400g, and centrifuging for 30min at room temperature, wherein the lifting rate is adjusted to be 1 during centrifugation. The mononuclear cells are inserted into a mononuclear cell layer along the periphery of the tube wall by a liquid-transferring gun, the mononuclear cells are sucked into another centrifuge tube, PBS with more than 5 times of volume is added, the mixture is centrifuged for 10min at 300g and room temperature (the lifting speed is adjusted to be 9), and the cells are washed twice. The supernatant was discarded, 1mL of complete medium (RPMI 1640+10% foetal calf serum+1 x penicillin-streptomycin solution) was added to resuspend the cells and counted, and the cell density was adjusted to 4X 10 6 /mL。
At 2X 10 per well 5 Individual cells (50. Mu.L) were plated in 96-well plates at 37℃with 5% CO 2 Incubation for 1h at 37℃and 5% CO was continued by adding 100. Mu.L/well of compound 2 Incubate for 1h under conditions. 50. Mu.L of IL-2 (R) was added to each well at a final concentration of 100ng/mL&D Systems; 202-IL-050) with anti-CD3 (BD Pharmingen;555329 At 37℃with 5% CO 2 Incubate under conditions for 24h. Centrifuge at 500g for 5min at 4℃and take 150. Mu.L of supernatant. Human ifnγ Quantikine ELISA kit (R&D Systems; SIF 50C) detects ifnγ concentration in supernatant and fits and calculates IC of compound using Origin 2019b 50 Values.
TABLE 2 inhibitory Activity of Compounds against IL-2 and anti-CD3 induced secretion of IFNγ by human PBMC IC 50 Value of
Sequence number Compounds of formula (I) IC 50 (nM)
1 Compound 5 A
2 Trifluoroacetate salt of Compound 31 A
3 Compound 42 A
4 Compound 75 A
Note that: a is less than or equal to 50nM.
Conclusion the inventive example compounds have inhibitory activity against IL-2 and anti-CD 3-induced secretion of IFNγ by human PBMC, e.g. Compound 5, the trifluoroacetate salt of Compound 31, compound 42, IC of Compound 75 against IL-2 and anti-CD 3-induced secretion of IFNγ by human PBMC 50 The values were all less than 50nM.
Test example 3: IL-13-induced BEAS-2B cell STAT6 phosphorylation assay
BEAS-2B cells (ATCC) were cultured in DMEM medium (AT) containing 10% fetal bovine serum (Hyclone, cat#SH 30406.05) and 1X penicillin-streptomycin solution (Gibco, cat# 15140122) CC, cat # 30-2002). 7500 cells (20. Mu.L) per well were inoculated into 384 well plates (Perkin Elmer, catalog # 6007680) and incubated overnight at 37℃under 5% CO 2. Test compounds were dissolved in DMSO and diluted in gradient to 3000 times final concentration and then 1000 times further diluted in culture medium. After pipetting 10. Mu.L of the medium, 5. Mu.L of the test compound was added and incubated at 37℃for 1 hour under 5% CO 2. mu.L of IL-13 (final concentration 40 ng/mL) was added to each well and incubated at 37℃for 30 minutes under 5% CO 2. p-STAT6 levels were detected using the AlphaLISA kit (Perkin Elmer, catalog#ALSU-PST 6-A500). The specific operation is as follows: after removing the culture medium (containing the test compound and IL-13), 10. Mu.L of 1 XLysis Buffer was added to each well, and the plates were closed and shaken for 10 minutes. 2.5. Mu.L of acceptors Mix was added to each well, the plates were closed and incubated at room temperature for 2 hours after shaking for 2 minutes in the absence of light. Thereafter, 2.5. Mu.L of Donor Mix was added to each well, the plates were closed, shaken for 2 minutes in the absence of light and incubated at room temperature for 2 hours. The alpha Screen method (Ex 680/Em 570) using an Envision microplate reader. The resulting data were fitted to the IC of the test compound using Origin 9.2 software (DoseResp function) 50 Values.
TABLE 3 inhibitory Activity of Compounds against IL-13-induced BEAS-2B cell STAT6 phosphorylation IC 50 Value of
Sequence number Compounds of formula (I) IC 50 (nM)
1 Compound 1h A
2 Compound 5 A
3 Compound 40 A
4 Compound 42 A
5 Compound 75 A
Note that: a is less than or equal to 40nM.
Conclusion: the inventive example compounds have inhibitory activity against IL-13-induced BEAS-2B cell STAT6 phosphorylation, e.g. Compounds 1h, 5, 40, 42, 75 IC for IL-13-induced BEAS-2B cell STAT6 phosphorylation 50 The values were all less than 40nM.
Test example 4: IL-2/anti-CD3 induces STAT5 phosphorylation experiments in human PBMC cells
Peripheral blood of healthy volunteers was taken into an anticoagulant tube, which was thoroughly mixed with PBS and diluted 1:1. A proper amount of Ficoll is added to the bottom of a 10mL centrifuge tube (Greiner bio, cat # 163290), diluted blood is slowly added along the tube wall, centrifuged at 400 Xg for 30 minutes at room temperature, and after centrifugation, the mononuclear cells are aspirated and placed into another centrifuge tube, and 5 volumes of PBS are added. After centrifugation at 300 Xg for 10 minutes at room temperature, washingCells were washed twice. After the last centrifugation, the supernatant was discarded, and 1mL HBSS was added to resuspend the cells and counted. Dissolving the compound with DMSO to prepare a 10mM mother solution, and diluting with HBSS to 3 times of final concentration for standby; 4. Mu.L of cell fluid and 2. Mu.L of compound were added to each well of 384 well plates at 37℃with 5% CO 2 Incubation was carried out for 1 hour (blank wells and negative control wells plus 2. Mu.L of HBSS with 3% DMSO). mu.L of IL-2 (R) containing 400ng/mL was added &D, cat#202-IL-050) and 4. Mu.g/mL anti-CD3 (BD, cat# 555329) at 37℃with 5% CO 2 Incubate for 0.5 hours under conditions. The subsequent use of the p-STAT5AlphaLisa kit (PE, cat#ALSU-PST5-B500) was tested as follows: adding 2 mu L of 5X lysate into each hole, sealing the plates, and vibrating at a low speed for 10 minutes; preparing a receptor mixed solution (comprising a reaction buffer solution 1, a reaction buffer solution 2, an activation buffer solution and receptor microbeads), adding 2.5 mu L of the receptor mixed solution into each hole, sealing a plate, vibrating for 2 minutes at a low speed in a dark place, and incubating for 1.5 hours at room temperature; donor cocktail (comprising dilution buffer and recipient microbeads) was prepared and 2.5 μl of donor cocktail was added to each well, and the plates were closed and incubated at room temperature for 1.5 hours after shaking at low speed for 2 minutes in the absence of light. After detection with a BMG microplate reader (PHERAstar FSX), IC was obtained using a DoseResp function fit in Origin 9.2 software 50 Values.
TABLE 4 inhibitory Activity of Compounds IC for IL-2/anti-CD3 induction of STAT5 phosphorylation in human PBMC cells 50 Value of
Sequence number Compounds of formula (I) IC 50 (nM)
1 Compound 5 B
2 Trifluoroacetate salt of Compound 31 B
3 Compound 42 A
4 Compound 48 A
5 Compound 75 A
Note that: a is less than or equal to 100nM,100nM is less than or equal to 200nM.
Conclusion: the compounds of the examples of the invention have inhibitory activity against IL-2/anti-CD3 inducing STAT5 phosphorylation in human PBMC cells, e.g. Compounds 42, 48, 75 have inhibitory activity IC against IL-2/anti-CD3 inducing STAT5 phosphorylation in human PBMC cells 50 Inhibitory Activity of Compound 5, compound 31, trifluoroacetate salt on IL-2/anti-CD3 to induce STAT5 phosphorylation in human PBMC cells IC with a value less than 100nM 50 The value is 100 nM-200 nM.
Test example 5: rat skin application experiment 1
5.1. Test animals: SD rats, 200-250g, male, 6-8 weeks old, 18 purchased from Hunan Srilickida laboratory animals Co., ltd., production license number: SCXK (Hunan) 2016-0002.
5.2. Experiment design:
5.3 formulation recipe
Component Chinese names Component English name Content of
Compounds of formula (I) Compound 0.5％*
Ethylhexyl hydroxystearate Ethylhexyl Hydroxystearate 5％
Medium chain triglycerides Medium chain triglyceride 5％
Vaseline Vaseline 79.5％
N-methylpyrrolidone N-Methylpyrrolidone 10％
* Calculated as mass percent of free base.
Isoflurane anesthetized before and after administration and blood is collected from the orbit in 0.1mL and placed in EDTAK 2 CentrifugingIn the tube, the plasma was collected by centrifugation at 5000rpm at 4℃for 10 min. Blood collection time point: 3,7,24,48,72 and 96h; all plasma samples were stored at-80 ℃ prior to analytical testing.
Time point of epidermis, dermis tissue sample collection: 3,7,24,48,72 and 96h. Animals at each time point were euthanized after blood collection, skin at the area of application was taken, epidermis dermis was separated after cleaning, and after accurate weighing, 50% acetonitrile was used according to 1: homogenizing at 10 proportion to obtain homogenate, and storing at-80deg.C in refrigerator for analysis.
Conclusion: the example compounds of the present invention have good skin targeting, show good exposure in the dermis, and have a high dermis/plasma drug exposure ratio, for example, the dermis/plasma exposure ratio of example compound 75 exceeds 8000 times.
Test example 6: intestinal blood ratio experiment in mice
6.1. Test animals: BALB/c mice, 25g, male, 6-8 weeks old, 120 purchased from Chengdu laboratory animal Co., ltd., production license number: SCXK 2020-030.
6.2. Experiment design:
intravenous administration vehicle: 5% DMA+5% Solutol+90% Saline; gastric lavage dosing vehicle: 0.5% MC
Isoflurane was anesthetized before and after dosing to obtain 0.06mL of blood through the orbit, placed in an EDTAK2 centrifuge tube, centrifuged at 5000rpm at 4 ℃ for 10min, and plasma was collected. Blood collection time point: 0min,5min,0.25h,0.5h,1h,2h,3h,4h,6h,8h and 24h. All plasma samples were stored at-80 ℃ prior to analytical testing.
Time point of colon tissue sample collection in dosing group: 0.5h,2h,6h,8h and 24h. The colon tissue is taken after the animal is bled and euthanized, and the colon tissue is preserved by a refrigerator of-80 degrees after being homogenized by 50 percent methanol according to the ratio of m/v=1:9 after being cleaned by normal saline.
Conclusion: the compounds of the examples of the present invention showed good exposure in the colon and the colon/plasma drug exposure ratio was high, e.g. compound 5, compound 63 colon to plasma ratio was more than 100 times, compound 48 colon to plasma ratio was more than 500 times, compound 31 colon to plasma ratio was more than 1000 times.
Test example 7: small-sized cataplasm Ma Zhupi skin application experiment
7.1. Test animals: miniature Bama pigs, 8-10kg, male, 3 from Chengdu laboratory animal Co., ltd., production license number: SCXK 2020-030.
7.2. Experiment design:
7.3 formulation recipe
Component Chinese names Component English name Content of
Compounds of formula (I) Compound 1.5％*
Medium chain triglycerides Medium chain triglyceride 10％
Vaseline Vaseline 78.5％
N-methylpyrrolidone N-Methylpyrrolidone 10％
* Calculated as mass percent of free base.
Blood is taken from the four limbs vein to 0.5mL before and after administration, and placed in EDTAK 2 The tube was centrifuged at 5000rpm at 4℃for 10min and the plasma was collected. Blood collection time point: 2,8,24,48,72,96,120,144 and 168h; all plasma samples were stored at-80 ℃ prior to analytical testing.
Time point of epidermis, dermis tissue sample collection: 2,8,24,48,72,96,120,144 and 168h. Sampling at the skin administration position at each time point, cleaning skin with soapy water, cleaning clean water, sucking water, separating epidermis and dermis, accurately weighing, and using 50% acetonitrile according to the following formula 1: homogenizing at 10 proportion to obtain homogenate, and storing at-80deg.C in refrigerator for analysis.
TABLE 5 pharmacokinetic parameters of test compounds in Bama pig plasma and skin tissue
Conclusion: the example compound of the present invention has good skin targeting, shows good exposure in dermis, and has a high ratio of dermis to plasma drug exposure, for example, the ratio of dermis to plasma exposure of example compound 75 exceeds 3000 times, which is at least 2 times or more that of compound (I) (CAS: 2311888-19-2) in WO2019084383 A1.
Test example 8: rat skin application experiment 2
8.1. Test animals: SD rats, 200-250g, male, 6-8 weeks old, 18 purchased from Hunan Srilickida laboratory animals Co., ltd., production license number: SCXK (Hunan) 2019-0004.
8.2. Experiment design:
isoflurane anesthetized before and after administration and blood is collected from the orbit in 0.1mL and placed in EDTAK 2 The tube was centrifuged at 5000rpm at 4℃for 10min and the plasma was collected. Blood collection time point: 3,7,24,48,72 and 96h; all plasma samples were stored at-80 ℃ prior to analytical testing.
Time point of epidermis, dermis tissue sample collection: 3,7,24,48,72 and 96h. Animals at each time point were euthanized after blood collection, skin at the area of application was taken, epidermis dermis was separated after cleaning, and after accurate weighing, 50% acetonitrile was used according to 1: homogenizing at 10 proportion to obtain homogenate, and storing at-80deg.C in refrigerator for analysis.
TABLE 6 pharmacokinetic parameters of test compounds in rat plasma and skin tissues
Remarks: "NA" means that the effective concentration in plasma is too small to calculate the pharmacokinetic parameters.
Conclusion: the compounds of the examples of the present invention have good skin targeting and show good exposure in the dermis.

Claims (10)

  1. A compound or a stereoisomer, tautomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, the compound being selected from compounds of formula (I), wherein,
    L is selected from bond or NR n2 ；
    R n1 、R n2 Each independently selected from H, C 1-6 Alkyl or C 3-6 Cycloalkyl, said alkyl or cycloalkyl optionally being further substituted with 0 to 4 groups selected from H, halogen, CF 3 OH, cyano, NH 2 、C 1-6 Alkyl or C 1-6 Substituted with alkoxy;
    ring A is selected from 5-8 membered heteroaromatic rings optionally further substituted with 0 to 3R a A substitution, said heteroaryl ring containing 1 to 5 heteroatoms selected from O, S, N;
    R a each independently selected from H, halogen, cyano, OH, C 1-6 Alkyl, C 1-6 Alkoxy, - (O-C) 1-6 An alkylene group q -C 1-6 Alkoxy, - (O-C) 1-6 An alkylene group q -OH、-(CH 2 ) q -C(＝O)-NR a1 R a2 、-(CH 2 ) q -NR a1 R a2 、-(CH 2 ) q NR a1 C(＝O)-R a2 、-(CH 2 ) q -C 3-10 Carbocycles, - (CH) 2 ) q -3 to 12 membered heterocycles, (CH) 2 ) q -P(＝O)(C 1-6 Alkyl group 2 OR-OR a3 said-CH 2 -, alkyl, alkoxy, carbocycle or heterocycle optionally further being 0 to 4 groups selected from H, halogen, OH, =o, cyano,NH 2 、C 1-6 Alkyl, halogen substituted C 1-6 Alkyl or C 1-6 Substituted with an alkoxy substituent, said heterocycle containing 1 to 3 heteroatoms selected from O, S, N;
    R a3 each independently selected from- (CH) 2 ) q -NR a1 R a2 、-(CH 2 ) q NR a1 C(＝O)-R a2 、-(CH 2 ) q -C 3-10 Carbocycle or- (CH) 2 ) q -3 to 12 membered heterocycle, said-CH 2 -, carbocycle, heterocycle optionally further being 0 to 4 groups selected from H, halogen, = O, OH, cyano, NH 2 、C 1-6 Alkyl, halogen substituted C 1-6 Alkyl or C 1-6 Substituted with an alkoxy substituent, said heterocycle containing 1 to 3 heteroatoms selected from O, S, N;
    Ring B is selected from non-aromatic C 3-12 Carbocycles, optionally from a single ring, a parallel ring, a bridged ring or a spiro ring, optionally further substituted with 0 to 3R b Substituted by substituents;
    R b each independently selected from H, halogen, cyano, OH, C 1-6 Alkyl or C 1-6 Alkoxy, said alkyl or alkoxy optionally being further substituted with 0 to 4 groups selected from H, halogen, OH, cyano, NH 2 、C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 Substituted cycloalkyl;
    R 1 selected from 5-to 10-membered heteroaryl or phenyl, said heteroaryl or phenyl optionally being further substituted with 0 to 4R 1a Substitution;
    R 1a each independently selected from H, halogen, OH, cyano, NH 2 、-NH(C 1-6 Alkyl), -N (C) 1-6 Alkyl group 2 、-NH(C 3-6 Cycloalkyl group, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3-to 8-membered heterocyclyl, said alkyl, alkoxy, cycloalkyl or heterocyclyl optionally being further substituted with 0 to 4 groups selected from H, halogen, OH, cyano, NH 2 Halogen-substituted C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 Substituted cycloalkyl;
    R 2 selected from halogen, cyano, OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, - (CH) 2 ) q -C(＝O)-R 2a 、-(CH 2 ) q -C(＝O)O-R 2a 、-(CH 2 ) q -S(＝O) 2 -R 2a 、-(CH 2 ) q -NR 2a S(＝O) 2 -R 2b 、-(CH 2 ) q -C(＝O)-NR 2a R 2b 、-(CH 2 ) q -NR 2a R 2b 、-(CH 2 ) q NR 2a C(＝O)-R 2b 、-(CH 2 ) q -C 3-10 Carbocycle or- (CH) 2 ) q -3 to 12 membered heterocycle, said-CH 2 -, alkyl, alkenyl, alkynyl, alkoxy, carbocycle or heterocycle optionally further substituted with 0 to 4 groups selected from H, halogen, OH, cyano, NH 2 、C 1-6 Alkyl, halogen substituted C 1-6 Alkyl-and cyano-substituted C 1-6 Alkyl or C 1-6 Substituted with an alkoxy substituent, said heterocycle containing 1 to 3 heteroatoms selected from O, S, N;
    R a1 、R a2 、R 2a 、R 2b each independently selected from H, C 1-6 Alkyl, C 3-12 Carbocyclyl or 3-to 12-membered heterocyclyl, said alkyl, carbocyclyl or heterocyclyl optionally being further substituted with 0 to 4 groups selected from H, halogen, OH, cyano, NH 2 、-NH(C 1-6 Alkyl), -N (C) 1-6 Alkyl group 2 、-NH(C 3-6 Cycloalkyl group, C 1-6 Alkyl, C 3-12 Carbocyclyl, 3-to 12-membered heterocyclyl, hydroxy-substituted C 1-6 Alkyl, halogen substituted C 1-6 Alkyl-and cyano-substituted C 1-6 Alkyl or C 1-6 Substituted with an alkoxy substituent, said heterocyclyl containing 1 to 3 heteroatoms selected from O, S, N;
    q is each independently selected from 0, 1, 2, 3 or 4.
  2. The compound according to claim 1, or a stereoisomer, tautomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein the compound is selected from the group consisting of formula (Ia),
    R n2 selected from H, C 1-6 Alkyl or C 3-6 Cycloalkyl, said alkyl or cycloalkyl optionally being further substituted with 0 to 4 groups selected from H, halogen, CF 3 OH, cyano, NH 2 、C 1-6 Alkyl or C 1-6 Substituted with alkoxy;
    R a each independently selected from H, halogen, cyano, OH, C 1-6 Alkyl, C 1-6 Alkoxy, - (CH) 2 ) q -C 3-10 Carbocycles, - (CH) 2 ) q -3 to 12 membered heterocycles, - (CH) 2 ) q -C(＝O)-NR a1 R a2 、-(CH 2 ) q NR a1 C(＝O)-R a2 、-(CH 2 ) q -NR a1 R a2 、-(O-C 1-6 An alkylene group q -C 1-6 Alkoxy, - (O-C) 1-6 An alkylene group q -OH、-(CH 2 ) q -P(＝O)(C 1-6 Alkyl group 2 OR-OR a3 said-CH 2 -, alkyl, alkoxy, carbocycle or heterocycle optionally further substituted with 0 to 4 groups selected from H, halogen, OH, =o, cyano, NH 2 、C 1-6 Alkyl, halogen substituted C 1-6 Alkyl or C 1-6 Substituted with an alkoxy substituent, said heterocycle containing 1 to 3 heteroatoms selected from O, S, N;
    R a3 each independently selected from- (CH) 2 ) q -NR a1 R a2 、-(CH 2 ) q -C 3-10 Carbocycle or- (CH) 2 ) q -3 to 12 membered heterocycle, said-CH 2 -, carbocycle, heterocycle optionally further being 0 to 4 groups selected from H, halogen, OH, =o, cyano, NH 2 、C 1-6 Alkyl, halogen substituted C 1-6 Alkyl or C 1-6 Substituted with an alkoxy substituent, said heterocycle containing 1 to 3 heteroatoms selected from O, S, N;
    each p is independently selected from 0, 1 or 2;
    ring a is selected from 5 to 6 membered heteroaryl rings containing 1 to 3 heteroatoms selected from O, S, N;
    ring B is selected from C 3-8 Monocycloalkyl, C 4-10 And cycloalkyl, C 5-12 Spirocycloalkyl, C 5-12 Bridged cycloalkyl radicals, saidCycloalkyl is optionally further substituted with 0 to 3R b Substituted by substituents;
    R b each independently selected from H, halogen, cyano, OH, C 1-6 Alkyl or C 1-6 Alkoxy, said alkyl or alkoxy optionally being further substituted with 0 to 4 groups selected from H, halogen, OH, cyano, NH 2 、C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 Substituted cycloalkyl;
    and when B contains 2R b Substituent, any one R b In the case of OH, the other cannot be OH or-CH 2 OH；
    R 1 Selected from the group consisting of
    Or R is 1 Selected from the group consisting of
    Provided that when R 1 Is thatWhen ring A is not
    R 1a Each independently selected from H, halogen, OH, cyano, NH 2 、-NH(C 1-6 Alkyl), -N (C) 1-6 Alkyl group 2 、-NH(C 3-6 Cycloalkyl group, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl or 3-to 8-membered heterocyclyl, said alkyl, alkoxy, cycloalkyl or heterocyclyl optionally being further substituted with 0 to 4 groups selected from H, halogen, OH, cyano, NH 2 Halogen-substituted C 1-6 Alkyl, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 Substituted cycloalkyl;
    m is independently selected from 0, 1 or 2;
    R 1b selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, said alkyl or cycloalkyl optionally being further substituted with 0 to 4 groups selected from H, halogen, OH, cyano, NH 2 、C 1-6 Alkyl, halogen substituted C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 Substituted cycloalkyl;
    R 2 selected from halogen, cyano, OH, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 Alkoxy, -NH (C) 1-6 Alkyl) - (CH) 2 ) q -C 3-10 Carbocycle or- (CH) 2 ) q -3 to 12 membered heterocycle, said-CH 2 -, alkyl, alkenyl, alkynyl, alkoxy, carbocycle or heterocycle optionally further substituted with 0 to 4 groups selected from H, halogen, OH, cyano, C 1-6 Alkyl, halogen substituted C 1-6 Alkyl-and cyano-substituted C 1-6 Alkyl or C 1-6 Substituted with an alkoxy substituent, said heterocycle containing 1 to 3 heteroatoms selected from O, S, N;
    R a1 、R a2 、R 2a 、R 2b each independently selected from H, C 1-6 Alkyl, C 3-12 Carbocyclyl or 3-to 12-membered heterocyclyl, said alkyl, carbocyclylOr heterocyclic groups optionally further substituted with 0 to 4 groups selected from H, halogen, OH, cyano, NH 2 、-NH(C 1-6 Alkyl), -N (C) 1-6 Alkyl group 2 、-NH(C 3-6 Cycloalkyl group, C 1-6 Alkyl, C 3-12 Carbocyclyl, 3-to 12-membered heterocyclyl, hydroxy-substituted C 1-6 Alkyl, halogen substituted C 1-6 Alkyl-and cyano-substituted C 1-6 Alkyl or C 1-6 Substituted with an alkoxy substituent, said heterocyclyl containing 1 to 3 heteroatoms selected from O, S, N;
    q is each independently selected from 0, 1, 2, 3 or 4;
    provided that the compound is not
  3. The compound of claim 2, or a stereoisomer, tautomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein,
    R n2 Selected from H or C 1-4 An alkyl group;
    R a each independently selected from H, halogen, cyano, OH, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Carbocycles, 3-to 6-membered heterocycles, - (CH) 2 ) q -C(＝O)-NR a1 R a2 、-(CH 2 ) q NR a1 C(＝O)-R a2 、-(CH 2 ) q -NR a1 R a2 、-(O-C 1-4 An alkylene group q -C 1-4 Alkoxy, CH 2 -3 to 6 membered heterocycle, -P (=o) (C 1-4 Alkyl group 2 OR-OR a3 said-CH 2 -, alkyl, alkoxy, carbocycle or heterocycle optionally further substituted with 0 to 4 groups selected from H, halogen, OH, =o, cyano, NH 2 、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl or C 1-4 Substituted with an alkoxy substituent, said heterocycle containing 1 to 3 heteroatoms selected from O, S, N;
    R a3 each independently selected from- (CH) 2 ) q -NR a1 R a2 、-(CH 2 ) q -C 3-6 Carbocycle or- (CH) 2 ) q -3 to 6 membered heterocycle, said-CH 2 -, carbocycle, heterocycle optionally further being 0 to 4 groups selected from H, halogen, OH, =o, cyano, NH 2 、C 1-6 Alkyl, halogen substituted C 1-6 Alkyl or C 1-6 Substituted with an alkoxy substituent, said heterocycle containing 1 to 3 heteroatoms selected from O, S, N;
    R b each independently selected from H, halogen, cyano, OH, C 1-4 Alkyl or C 1-4 Alkoxy, said alkyl or alkoxy optionally being further substituted with 0 to 4 groups selected from H, halogen, OH, cyano, NH 2 、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, C 1-4 Alkoxy or C 3-4 Substituted cycloalkyl;
    and when B contains 2R b Substituent, any one R b In the case of OH, the other cannot be OH or-CH 2 OH；
    R 1a Each independently selected from H, halogen, OH, cyano, NH 2 、-NH(C 1-4 Alkyl), -N (C) 1-4 Alkyl group 2 、-NH(C 3-4 Cycloalkyl group, C 1-4 Alkyl or C 1-4 Alkoxy, said alkyl or alkoxy optionally being further substituted with 0 to 4 groups selected from H, halogen, OH, cyano, NH 2 Halogen-substituted C 1-4 Alkyl, C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 Substituted cycloalkyl;
    R 1b selected from C 1-4 Alkyl, C 3-6 Cycloalkyl, said alkyl or cycloalkyl optionally being further substituted with 0 to 4 groups selected from H, halogen, OH, cyano, NH 2 、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 Substituted cycloalkyl;
    R 2 selected from halogen, cyano, OH, C 1-4 Alkyl, C 1-4 Alkoxy, -NH (C) 1-4 Alkyl) - (CH) 2 ) q -C 3-10 Carbocycle or- (CH) 2 ) q -3 to 10 membered heterocycle, said-CH 2 -, alkyl, alkoxy, carbocycle or heterocycle optionally further substituted with 0 to 4 groups selected from H, halogen, OH, cyano, NH 2 、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl-and cyano-substituted C 1-4 Alkyl or C 1-4 Substituted with an alkoxy substituent, said heterocycle containing 1 to 3 heteroatoms selected from O, S, N;
    R a1 、R a2 、R 2a 、R 2b each independently selected from H, C 1-4 Alkyl, C 3-10 Carbocyclyl or 3-to 10-membered heterocyclyl, said alkyl, carbocyclyl or heterocyclyl optionally being further substituted with 0 to 10 4 are selected from H, halogen, OH, cyano, NH 2 、-NH(C 1-4 Alkyl), -N (C) 1-4 Alkyl group 2 、-NH(C 3-6 Cycloalkyl group, C 1-4 Alkyl, C 3-8 Carbocyclyl, 3-to 8-membered heterocyclyl, hydroxy-substituted C 1-4 Alkyl, halogen substituted C 1-4 Alkyl-and cyano-substituted C 1-4 Alkyl or C 1-4 Substituted with an alkoxy substituent, said heterocyclyl containing 1 to 3 heteroatoms selected from O, S, N;
    q is each independently selected from 0, 1 or 2.
  4. A compound according to claim 3, or a stereoisomer, tautomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein,
    R n2 selected from H, methyl or ethyl;
    R 1a each independently selected from H, F, OH, cyano, methyl, ethyl, isopropyl, propyl, methoxy or ethoxy, said methyl, ethyl, isopropyl, propyl, methoxy or ethoxy optionally being further substituted with 0, 1 or 2 groups selected from H, halogen, OH, cyano, NH 2 Halogen-substituted C 1-4 Alkyl, C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 Substituted cycloalkyl;
    R 1b selected from methyl, ethyl, isopropyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, said methyl, ethyl, isopropyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl optionally further being 0, 1, or 2 are selected from H, halogen, OH, cyano, NH 2 Halogen-substituted C 1-4 Alkyl, C 1-4 Alkyl, C 1-4 Alkoxy or C 3-6 Substituted cycloalkyl;
    ring B is selected from the group consisting of substituted or unsubstitutedOne of: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl-cyclobutyl, cyclopropyl-cyclopentyl, cyclobutyl-cyclobutyl, cyclobutyl-cyclopentyl, cyclobutyl-cyclohexyl, cyclopentyl-cyclopentyl, cyclopentyl-cyclohexyl, cyclohexyl-cyclohexyl, cyclopropyl-spirocyclobutyl, cyclopropyl-spirocyclopentyl, cyclopropyl-spirocyclohexyl, cyclobutylspirocyclobutyl, cyclobutylspirocyclopentyl, cyclobutylspirocyclohexyl, cyclopentyl-spiropentyl-cyclopentyl, cyclopentyl-spirocyclohexyl, cyclohexyl-spirocyclohexyl-cyclohexyl-bicyclo [ 1.1.1.1 ]]Pentanyl and bicyclo [2.1.1]Hexalkyl and bicyclo [2.2.1]Heptyl and bicyclo [3.3.2]Decyl and bicyclo [2.2.2]Octyl and bicyclo [3.2.1]Octyl and bicyclo [3.3.3]Undecyl or adamantyl, when substituted, optionally further substituted with 0 to 3R b Substitution;
    R b each independently selected from H, halogen, cyano, OH, C 1-4 Alkyl or C 1-4 An alkoxy group;
    and when B contains 2R b Substituent, any one R b In the case of OH, the other cannot be OH;
    Ring a is selected from one of the following groups: pyrimidinyl, pyrazinyl, pyridazinyl, pyridinyl, triazinyl, pyrazolyl, imidazolyl, pyrrolyl, triazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thienyl, thiazolyl, thiadiazolyl;
    R 2 selected from halogen, cyano, OH, C 1-4 Alkyl, C 1-4 Alkoxy, C 3-6 Carbocycle, 3-to 6-membered heterocycle, -CH 2 -C 3-6 Carbocycle, -CH 2 -3 to 6 membered heterocycle or-NH (C 1-4 Alkyl), said-CH 2 -, alkyl, alkoxy, carbocycle or heterocycle optionally further substituted with 0 to 4 groups selected from H, halogen, OH, cyano, NH 2 、C 1-4 Alkyl, halogen substituted C 1-4 Alkyl-and cyano-substituted C 1-4 Alkyl or C 1-4 Substituted by substituents of alkoxy groups, said heterocyclic ring containing 1 to3 heteroatoms selected from O, S, N.
  5. The compound of claim 4, or a stereoisomer, tautomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, wherein,
    ring B is selected from Right side and R 2 Directly connecting;
    R 2 selected from F, cyano, OH, -OCH 3 Methyl, ethyl, CF 3 、-CH 2 OH、-CH 2 CH 2 OH、-CH 2 CH 2 CH 2 OH、-CH 2 CN、-CH 2 CH 2 CN、-CH 2 CH 2 CH 2 CN、-CH 2 CH 2 CH 2 CH 2 CN、-NHCH 2 CN、-NHCH 2 CH 2 CN、-NHCH 2 CH 2 CH 2 CN、-NHCH 2 CH 2 CH 2 CH 2 CN、
    R 1 Selected from the group consisting of
    R a Each independently selected from H, F, cyano, OH, CF 3 、CHF 2 、CH 2 F. Methyl, ethyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, pyrazolyl, triazolyl, thiazolyl, imidazolyl, oxazolyl, thienyl, furyl, pyrrolyl, isoxazolyl, isothiazolyl, pyridyl, pyrimidinyl, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, tetrahydrofuranyl, dihydrofuryl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, -P (=o) (CH 3 ) 2 、-P(＝O)(CH 2 CH 3 ) 2 、-P(＝O)(CH 2 CH 2 CH 3 ) 2 、-OCH 2 CH 2 OCH 3 、-OCH 2 CH 2 OCH 2 CH 2 OCH 3 、-CH 2 NHCH 2 CH 2 CN、-CH 2 NHCH 2 CN、-CH 2 NHCH 2 CH 2 CH 2 CN、-CH 2 C(＝O)NH-Ph-CH 2 OH、-CH 2 C(＝O)NH-Ph-CH 2 CN、-CH 2 C(＝O)NH-Ph-CH 2 F、-CH 2 C(＝O)NH-Ph-CHF 2 、-CH 2 C(＝O)NH-Ph-CF 3 、-CH 2 C(＝O)NHCH 2 -cyclopropyl, -CH 2 C(＝O)NHCH 2 -cyclobutyl, -CH 2 C(＝O)NHCH 2 -cyclopentyl, -CH 2 C(＝O)NHCH 2 -cyclohexyl, -CH 2 C(＝O)NHCH 2 CH 2 NH 2 、-CH 2 C(＝O)NHCH 2 CH 2 NHCH 3 、-CH 2 C(＝O)NHCH 2 CH 2 N(CH 3 ) 2 、-CH 2 C(＝O)NHCH 2 CH 2 N(CH 2 CH 3 ) 2 -NH-pyrazolyl, -NH-thiazolyl, -NH-imidazolyl, -NH-oxazolyl, -NH-thienyl, -NH-furanyl, -NH-pyrrolyl, -NH-isoxazolyl, -NH-isothienyl, -NH-pyridinyl, -NH-pyrimidinyl, -NH-phenyl, -NH-cyclopropyl, -NH-cyclobutyl, -NH-cyclopentyl, -NH-cyclohexyl, -C (=o) NH 2 、-C(＝O)NHCH 3 、-C(＝O)NHCH 2 CH 3 -C (=o) NH-cyclopropyl, -C (=o) NH-cyclobutyl, -C (=o) NH-cyclopentyl, -C (=o) NH-cyclohexyl, -C (=o) NH-phenyl, -NHC (=o) H, -NHC (=o) CH 3 、-NHC(＝O)CH 2 CH 3 、-NHC(＝O)CH 2 CH 2 CH 3 -NHC (=o) -cyclopropyl, -NHC (=o) -cyclobutyl, -NHC (=o) -cyclopentyl, -NHC (=o) -cyclohexyl, -NHC (=o) -phenyl OR-OR a3 The methyl, ethyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrazolyl, triazolyl, thiazolyl, imidazolyl, oxazolyl, thienyl, furyl, pyrrolyl, isoxazolyl, isothiazolyl, pyridyl, pyrimidinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, dihydrofuranyl, or phenyl optionally further substituted with 0, 1, 2, 3 or 4 groups selected from H, F, CF 3 OH, =O, cyano, NH 2 A methyl, ethyl, methoxy or ethoxy substituent;
    R a3 each independently selected from-CH 2 N(CH 3 ) 2 、-CH 2 CH 2 N(CH 3 ) 2 、-CH(CH 3 )CH 2 N(CH 3 ) 2 、-CH 2 CH 2 N(CH 2 CH 3 ) 2 、-CH 2 CH 2 NH 2 、-CH 2 CH 2 NHCH 3 Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, oxetanyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, -CH 2 -cyclopropyl, -CH 2 -cyclobutyl, -CH 2 -cyclopentyl, -CH 2 -cyclohexyl, -CH 2 -azetidinyl, -CH 2 Pyrrolidinyl, -CH 2 -piperidinyl, -CH 2 Morpholinyl, -CH 2 Piperazinyl, -CH 2 -oxetanyl, -CH 2 -tetrahydrofuranyl, -CH 2 Tetrahydropyranyl, -CH 2 CH 2 -piperidinyl, -CH 2 CH 2 Pyrrolidinyl, -CH 2 CH 2 -azetidinyl, -CH 2 CH 2 Morpholinyl group,The cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, oxetanyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,Optionally further 0, 1, 2, 3 or 4 are selected from H, F, CF 3 OH, =O, cyano, NH 2 A methyl, ethyl, methoxy or ethoxy substituent.
  6. The compound according to claim 5, wherein the compound is represented by the formula (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg), (IIh) or (IIi),
    Ring a is selected from pyrimidinyl, pyrazinyl, triazolyl or oxadiazolyl;
    A 1 selected from O, S, NH, N (CH) 3 ) Or N (CH) 2 CH 3 )；
    A 2 Selected from CR a Or N;
    R n2 each independently selected from H or methyl;
    R 2 selected from OH, -OCH 3 、-CH 2 CN；
    R 1 Selected from the group consisting of
    R a Are independently selected from H, F and cyanogenRadicals, OH, CF 3 、CHF 2 Methyl, ethyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, pyrazolyl, triazolyl, thiazolyl, imidazolyl, oxazolyl, thienyl, furyl, tetrahydrofuranyl, dihydrofuryl, tetrahydropyranyl, pyrrolyl, isoxazolyl, isothienyl, pyridyl, pyrimidinyl, phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, -O-cyclopropyl, -O-cyclopentyl, -O-cyclobutyl, -O-cyclohexyl, -O-azetidinyl, -O-oxetanyl, -O-tetrahydrofuranyl, -O-tetrahydropyranyl, -O-CH 2 -pyrrolidinyl, -OCH 2 N(CH 3 ) 2 、-OCH 2 CH 2 N(CH 3 ) 2 、-OCH(CH 3 )CH 2 N(CH 3 ) 2 、-OCH 2 CH 2 OCH 3 、-OCH 2 CH 2 OCH 2 CH 2 OCH 3 、-P(＝O)(CH 3 ) 2 、-P(＝O)(CH 2 CH 3 ) 2 、-P(＝O)(CH 2 CH 2 CH 3 ) 2 、-C(＝O)NH 2、 -C (=o) NH-cyclopropyl, -C (=o) NH-cyclobutyl, -C (=o) NH-cyclopentyl, -C (=o) NH-cyclohexyl, -OCH 2 CH 2 -piperidinyl, -OCH 2 CH 2 -pyrrolidinyl, -OCH 2 CH 2 -azetidinyl, -OCH 2 CH 2 Morpholinyl, -OCH 2 -piperidinyl, -OCH 2 -azetidinyl, -OCH 2 Morpholinyl, -OCH 2 Tetrahydrofuran radical,The methyl, ethyl, isopropyl, methoxy, ethoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrazolyl, triazolyl, thiazolyl, imidazolyl, oxazolyl, thienyl, furyl, pyrrolyl, isoxazolyl, isothiazolyl, pyridyl, pyrimidinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, and the like, Or phenyl optionally further substituted with 0, 1, 2, 3 or 4 groups selected from H, F, CF 3 OH, =O, cyano, NH 2 A methyl, ethyl, methoxy or ethoxy substituent;
    p is each independently selected from 0, 1 or 2.
  7. The compound of claim 1, or a stereoisomer, tautomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, wherein the compound is selected from one of the following structures:
  8. a pharmaceutical composition comprising a compound of any one of claims 1-7, or a stereoisomer, tautomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt, or co-crystal thereof, and a pharmaceutically acceptable carrier.
  9. Use of a compound according to any one of claims 1-7, or a stereoisomer, tautomer, deuterate, solvate, prodrug, metabolite, pharmaceutically acceptable salt or co-crystal thereof, for the manufacture of a medicament for the treatment of a disease associated with JAK kinase activity or expression level.
  10. The use according to claim 9, wherein the disease is selected from inflammatory diseases.
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