CN115197154A - HPK1 inhibitor and application thereof in medicine - Google Patents

HPK1 inhibitor and application thereof in medicine Download PDF

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CN115197154A
CN115197154A CN202210337967.3A CN202210337967A CN115197154A CN 115197154 A CN115197154 A CN 115197154A CN 202210337967 A CN202210337967 A CN 202210337967A CN 115197154 A CN115197154 A CN 115197154A
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compound
pharmaceutically acceptable
cycloalkyl
aryl
radical
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吴颢
张剑
吴文茂
李波燕
袁丁
刘奇声
兰宏
王家炳
丁列明
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Betta Pharmaceuticals Co Ltd
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    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
    • C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
    • C07D241/40—Benzopyrazines
    • C07D241/44—Benzopyrazines 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 carbon atoms of the hetero ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • 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
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    • C07—ORGANIC CHEMISTRY
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    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07—ORGANIC CHEMISTRY
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    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Abstract

The present invention relates to a novel compound having cancer therapeutic activity. The invention also relates to a preparation method of the compounds and a pharmaceutical composition containing the compounds.

Description

HPK1 inhibitor and application thereof in medicine
Technical Field
The present invention relates to an HPK1 inhibitor having cancer therapeutic activity. The invention also relates to a preparation method of the compounds and a pharmaceutical composition containing the compounds.
Background
The medicine targeting HPK1 becomes one of the current medicine research and development hot spots, and the existing varieties enter the clinical stage. The invention provides a micromolecular HPK1 inhibitor with a novel structure, which has good anti-tumor activity.
Disclosure of Invention
The invention provides a compound shown as a general formula (I), a stereoisomer, a tautomer, a deuteron or a medicinal salt thereof:
Figure BDA0003577312830000011
wherein,
R 1 is selected from C 3-12 CycloalkanesA group, a 3-12 membered heterocyclic group, C 6-12 Aryl, or 5-12 membered heteroaryl, said C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-12 Aryl, or 5-12 membered heteroaryl optionally further substituted with at least one R 1a Substitution;
R 2 selected from H, halogen, cyano, C 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-12 Aryl or 5-12 membered heteroaryl, said C 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-12 Aryl or 5-12 membered heteroaryl optionally further substituted with at least one R 2a Substitution;
or R 1 And R 2 Together with the atom to which they are attached form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, optionally further substituted by one or more R 1b Substituted by a substituent;
R 3 selected from H, halogen, C 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO 2 、-OR b 、-SR b 、-SO 2 R b 、-SO 2 NR b R c 、-COR b 、-CO 2 R b 、-CONR b R c 、-NR b R c 、-NR b COR c 、-NR b CO 2 R c 、-NR b SONR c R d 、-NR b SO 2 NR c R d or-NR b SO 2 R c Said C is 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl optionally further substituted with at least one R 3a Substitution;
R 4 each independently selected from H, halogen, C 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO 2 、-OR b 、-SR b 、-SO 2 R b 、-SO 2 NR b R c 、-COR b 、-CO 2 R b 、-CONR b R c 、-NR b R c 、-NR b COR c 、-NR b CO 2 R c 、-NR b SONR c R d 、-NR b SO 2 NR c R d or-NR b SO 2 R c Said C is 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl optionally further substituted with at least one R 4a Substitution;
R 5 or R 6 Each independently selected from H, halogen, cyano, C 1-8 Alkyl radical, C 2-8 Alkenyl or C 2-8 Alkynyl radical, said C 1-8 Alkyl radical, C 2-8 Alkenyl or C 2-8 Alkynyl is optionally further substituted with at least one R a Substitution;
l is selected from a bond, alkylene, O, S or NR a Said alkylene is optionally further substituted by at least one R a Substitution;
X 1 selected from N or CR 7 ；
X 2 Selected from N or CR 8 ；
X 3 Selected from N or CR 9 ；
X 4 Selected from N or CR 10 ；
X 5 Selected from N or CR 11 ；
X 6 Selected from N or CR 12 ；
R 7 、R 8 、R 9 、R 10 、R 11 Or R 12 Each independently selected from H, halogen, C 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO 2 、-OR b 、-SR b 、-SO 2 R b 、-SO 2 NR b R c 、-COR b 、-CO 2 R b 、-CONR b R c 、-NR b R c 、-NR b COR c 、-NR b CO 2 R c 、-NR b SONR c R d 、-NR b SO 2 NR c R d or-NR b SO 2 R c Said C is 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with at least one R a Substitution;
R 1a 、R 1b 、R 2a 、R 3a 、R 4a or R a Each independently selected from H, halogen, C 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO 2 、-OR b 、-SR b 、-SO 2 R b 、-SO 2 NR b R c 、-COR b 、-CO 2 R b 、-CONR b R c 、-NR b R c 、-NR b COR c 、-NR b CO 2 R c or-NR b SO 2 R c Said C is 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl optionally further substituted by one or more halogen, C 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO 2 、-OR b 、-SR b 、-SO 2 R b 、-SO 2 NR b R c 、-COR b 、-CO 2 R b 、-CONR b R c 、-NR b R c 、-NR b COR c 、-NR b CO 2 R c 、-NR b SONR c R d 、-NR b SO 2 NR c R d or-NR b SO 2 R c Substituted by a substituent;
R b 、R c or R d Each independently selected from hydrogen and C 1-8 Alkyl radical、C 1-8 Hydroxyalkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;
m is selected from 0, 1,2,3 or 4.
And the compound is not:
Figure BDA0003577312830000031
in some embodiments, R in formula (I) 1 Is selected from
Figure BDA0003577312830000032
R 1 Optionally further substituted by 1-4R 1a And (4) substitution.
In some embodiments, R in formula (I) 1a Is selected from H or C 1-3 An alkyl group.
In some embodiments, R in formula (I) 1 Is selected from
Figure BDA0003577312830000033
In some embodiments, R in formula (I) 2 The substituent is selected from H or C 1-3 Alkyl, preferably methyl.
In some embodiments, R in formula (I) 1 And R 2 Together with the atom to which they are attached form a heterocyclic group optionally further substituted by 1-4R 1b Substituted by a substituent.
In some embodiments, R in formula (I) 3 The substituent is selected from H or C 1-3 Alkyl, preferably methyl.
In some embodiments, R in formula (I) 4 Each independently selected from H, halogen, C 1-3 Alkoxy or-NHC 1-3 Hydroxyalkyl, preferably H.
In some embodiments, R in formula (I) 5 Or R 6 Each independently selected from H or C 1-3 Alkyl, preferably R 5 Or R 6 Are all H.
Some embodimentsIn the formula, X in the formula (I) 1 The substituent(s) is selected from N or CH, preferably N.
In some embodiments, X in formula (I) 2 The substituent is selected from N or CR 8 ，R 8 Selected from H, halogen, cyano, C 1-3 Alkoxy radical, C 1-3 Haloalkyl, -NHC 1-3 Hydroxyalkyl, -C (O) N (R) 8a ) 2 or-S (O) 2 R 8a ，R 8a Independently selected from H or C 1-3 An alkyl group.
In some embodiments, X in formula (I) 3 The substituent is selected from N or CR 9 ，R 9 Selected from H, halogen, cyano, C 1-3 Alkoxy radical, C 1-3 Haloalkyl, -NHC 1-3 Hydroxyalkyl, -C (O) N (R) 9a ) 2 or-S (O) 2 R 9a ，R 9a Independently selected from H or C 1-3 An alkyl group.
In some embodiments, X in formula (I) 4 Selected from N or CH, preferably CH. .
In some embodiments, X in formula (I) 5 The substituent(s) is selected from N or CH, preferably CH.
In some embodiments, X in formula (I) 6 The substituent(s) is selected from N or CH, preferably CH.
In some embodiments, the substituent for L in formula (I) is NH.
In some embodiments, the compound of formula (I), a tautomer, a deutero-or pharmaceutically acceptable salt thereof, is selected from compounds of formula (IA) or (IB),
Figure BDA0003577312830000041
R 1 -R 12 and m is as defined for formula (I).
The invention also provides a compound, tautomer, deuteron or pharmaceutically acceptable salt thereof, selected from,
Figure BDA0003577312830000051
the invention also provides a pharmaceutical composition, which is characterized by comprising at least one compound shown as the formula (I) in a therapeutically effective amount and at least one pharmaceutically acceptable auxiliary material.
The invention further provides a pharmaceutical composition, which is characterized in that the mass percentage of the therapeutically effective amount of at least one compound shown in the formula (I) and pharmaceutically acceptable auxiliary materials is 0.0001.
The invention provides application of a compound or a pharmaceutical composition shown in a structural formula (I) in preparation of a medicament.
The invention further provides a preferable technical scheme of the application:
preferably, the application is the application in preparing a medicament for treating and/or preventing cancer.
Preferably, the use is for the manufacture of a medicament for the treatment of a disease mediated by HPK 1. Preferably, the disease is cancer.
Preferably, the cancer is selected from breast cancer, multiple myeloma, bladder cancer, endometrial cancer, gastric cancer, cervical cancer, rhabdomyosarcoma, non-small cell lung cancer, pleomorphic lung cancer, ovarian cancer, esophageal cancer, melanoma, colorectal cancer, hepatoma, head and neck tumor, hepatobiliary cell carcinoma, myelodysplastic syndrome, glioblastoma, prostate cancer, thyroid cancer, xu Wangshi cell carcinoma, lung squamous cell carcinoma, bryoid keratosis, synovial sarcoma, skin cancer, pancreatic cancer, testicular cancer, or liposarcoma.
The invention also provides a method for treating and/or preventing diseases, which comprises the step of administering at least one compound shown in the structural formula (I) or a pharmaceutical composition containing the compound to a treated object in a therapeutically effective amount.
The invention also provides a method for treating and/or preventing diseases mediated by HPK1, which comprises the step of administering at least one compound shown in the structural formula (I) or a pharmaceutical composition containing the compound to a treated object in an effective amount.
The present invention also provides a method for treating cancer, comprising administering to a subject a therapeutically effective amount of at least any one of the compounds of formula (I) or a pharmaceutical composition comprising the same.
Preferably, in the above method, the HPK1 mediated disease is cancer.
Preferably, in the above method, the cancer is selected from breast cancer, multiple myeloma, bladder cancer, endometrial cancer, gastric cancer, cervical cancer, rhabdomyosarcoma, non-small cell lung cancer, pleomorphic lung cancer, ovarian cancer, esophageal cancer, melanoma, colorectal cancer, hepatoma, head and neck tumors, hepatobiliary cell carcinoma, myelodysplastic syndrome, glioblastoma, prostate cancer, thyroid cancer, xu Wangshi cell tumors, lung squamous cell carcinoma, lichenification keratosis, synovial sarcoma, skin cancer, pancreatic cancer, testicular cancer, or liposarcoma.
Unless otherwise indicated, general chemical terms used in the structural formulae have the usual meanings.
For example, the term "halogen" as used herein, unless otherwise specified, refers to fluorine, chlorine, bromine or iodine.
In the present invention, unless otherwise specified, "alkyl" includes straight or branched chain monovalent saturated hydrocarbon groups. For example, alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3- (2-methyl) butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-methylpentyl and the like. Similarly, "radical 1-8 Alkyl group "of" 1-8 "refers to a group comprising 1,2,3,4, 5, 6, 7, or 8 carbon atoms arranged in a straight or branched chain.
“C 1-3 Alkylene "refers to methylene, 1,2-ethylene, 1,3-propylene or 1,2-isopropylene.
"alkoxy" refers to the oxygen ether form of the straight or branched chain alkyl group previously described, i.e., -O-alkyl.
In the present invention, "a", "an", "the", "at least one" and "one or more" are used interchangeably. Thus, for example, a composition that includes "a" pharmaceutically acceptable excipient may be interpreted to mean that the composition includes "one or more" pharmaceutically acceptable excipients.
The term "aryl", as used herein, unless otherwise specified, refers to an unsubstituted or substituted monocyclic or fused ring aromatic group comprising carbocyclic atoms. Preferably C 6-12 Aryl, more preferably aryl is a 6 to 10 membered monocyclic or bicyclic aromatic ring group. Preferably phenyl or naphthyl. Most preferred is phenyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl group, wherein the ring attached to the parent structure is an aryl ring, non-limiting examples include, but are not limited to, benzocyclopentyl.
The term "heterocyclyl" refers to a ring system having at least one cyclized alkyl or cycloalkenyl group containing a heteroatom selected from N, O and/or S. The heterocyclic group may comprise a single ring or multiple rings (e.g., having 2,3, or 4 fused rings, spiro rings, bridged rings, etc.). The heterocyclic group may be attached to the rest of the compound via a ring-forming carbon atom or a ring-forming heteroatom. Preferably 3-12 membered heterocyclic group, and "3-12 membered" in 3-12 membered heterocyclic group means a heterocyclic group consisting of 3-12 ring-constituting atoms of C, N, O or S. More preferably 3-8 membered heterocyclyl, more preferably 3-6 membered heterocyclyl, wherein the nitrogen or sulphur heteroatom may optionally be oxidised and the nitrogen heteroatom may optionally be quaternised. Examples of such heterocyclyl groups include, but are not limited to, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, tetrahydrofuranyl, dioxolanyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, and tetrahydrooxadiazolyl. The heterocyclyl group may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring to which the parent structure is attached is heterocyclyl.
The term "heteroaryl", in the present invention, unless otherwise indicated, refers to an unsubstituted or substituted stable 5-or 6-membered monocyclic aromatic ring system or an unsubstituted or substituted 9-or 10-membered benzo-fused heteroaromatic ring system or bicyclic heteroaromatic ring system, consisting of carbon atoms and 1 to 4 heteroatoms selected from N, O or S, and wherein said nitrogen or sulfur heteroatoms may be optionally oxidized and said nitrogen heteroatoms may be optionally quaternized. The heteroaryl group may be attached at any heteroatom or carbon atom to form a stable structure. Preferably 5-12 membered heteroaryl, more preferably 5-6 membered heteroaryl, examples of heteroaryl include, but are not limited to, thienyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridazinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuryl, benzothienyl, benzisoxazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl adenine, quinolinyl or isoquinolinyl. The heteroaryl group can be fused to an aryl, heterocyclyl, or cycloalkyl ring, wherein the ring that is attached to the parent structure is a heteroaryl ring.
The term "cycloalkyl" refers to a ring system having at least one cyclized alkyl group. Preferably C 3-12 Cycloalkyl radicals in which "C" is 3-12 By "it is meant that the cycloalkyl group may have 3,4, 5, 6, 7,8,9, 10, 11, or 12 ring-forming atoms. Cycloalkyl groups can include monocyclic and polycyclic (e.g., having 2,3, or 4 fused rings, spiro rings, bridged rings, etc.). Some embodiments cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and the like; the cycloalkyl groups may also be fused to aryl, heterocyclyl, or heteroaryl rings, wherein the ring to which the parent structure is attached is cycloalkyl.
The term "substituted" means that one or more hydrogen atoms in a group are replaced by the same or different substituents, respectively. Typical substituents include, but are not limited to, halogen (F, cl, br or I), C 1-8 Alkyl radical, C 3-12 Cycloalkyl, -OR 1 、-SR 1 、＝O、＝S、-C(O)R 1 、-C(S)R 1 、＝NR 1 、-C(O)OR 1 、-C(S)OR 1 、-NR 1 R 2 、-C(O)NR 1 R 2 Cyano, nitro, -S (O) 2 R 1 、-O-S(O 2 )OR 1 、-O-S(O) 2 R 1 、-OP(O)(OR 1 )(OR 2 ) (ii) a Wherein R is 1 And R 2 Independently selected from-H, C 1-6 Alkyl radical, C 1-6 Haloalkyl or C 3-6 A cycloalkyl group. In some embodiments of the present invention, the, the substituents are independently selected from the group consisting of-F, -Cl, -Br, -I, -OH, trifluoromethoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, -SCH 3 、-SC 2 H 5 Formaldehyde group, -C (OCH) 3 ) Cyano, nitro, -CF 3 、-OCF 3 Amino, dimethylamino, methylthio, sulfonyl and acetyl groups.
Examples of substituted alkyl groups include, but are not limited to, 2,3-dihydroxypropyl, 2-aminoethyl, 2-hydroxyethyl, pentachloroethyl, trifluoromethyl, methoxymethyl, pentafluoroethyl, phenylmethyl, dioxolanylmethyl, and piperazinylmethyl.
Examples of substituted alkoxy groups include, but are not limited to, 2-hydroxyethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 2-methoxyethoxy, 2-aminoethoxy, 2,3-dihydroxypropoxy, cyclopropylmethoxy, aminomethoxy, trifluoromethoxy, 2-diethylaminoethoxy, 2-ethoxycarbonylethoxy, 3-hydroxypropoxy.
The term "pharmaceutically acceptable salt" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids.
When the compound provided by the present invention is an acid, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts derived from inorganic bases include salts of aluminum, ammonium, calcium, copper (high and low), ferric, ferrous, lithium, magnesium, manganese (high and low), potassium, sodium, zinc and the like. Particularly preferred are ammonium, calcium, magnesium, potassium and sodium salts. Non-toxic organic bases which can be derivatized to form pharmaceutically acceptable salts include primary, secondary and tertiary amines, as well as cyclic amines and substituted amines, such as naturally occurring and synthetic substituted amines. Other pharmaceutically acceptable non-toxic organic bases capable of forming salts include ion exchange resins and arginine, betaine, caffeine, choline, N' -dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, reduced glucosamine, histidine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, chloroprocaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.
When the compounds provided by the present invention are bases, their corresponding salts can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include, for example, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, formic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, oxalic, propionic, glycolic, hydroiodic, perchloric, cyclohexanesulfonic, salicylic, 2-naphthalenesulfonic, saccharinic, trifluoroacetic, tartaric, and p-toluenesulfonic acids and the like. Preferably citric, hydrobromic, formic, hydrochloric, maleic, phosphoric, sulfuric and tartaric acids. More preferably formic acid and hydrochloric acid.
Since the compounds of formula (I) are intended for pharmaceutical use, it is preferred to use them in a certain purity, for example, at least 60% pure, more suitably at least 75% pure, and especially at least 98% pure (% by weight).
Prodrugs of the compounds of the present invention are included within the scope of the invention. In general, the prodrug refers to a functional derivative that is readily converted in vivo to the desired compound. For example, any pharmaceutically acceptable salt, ester, salt of an ester, or other derivative of a compound of the present application, which upon administration to a subject is capable of providing, directly or indirectly, a compound of the present application or a pharmaceutically active metabolite or residue thereof.
The compounds of the present invention may contain one or more asymmetric centers and may thus give rise to diastereomers and optical isomers. The present invention includes all possible diastereomers and racemic mixtures thereof, substantially pure resolved enantiomers thereof, all possible geometric isomers thereof, and pharmaceutically acceptable salts thereof.
When a tautomer exists for a compound of formula (I), the present invention includes any possible tautomers and pharmaceutically acceptable salts thereof, and mixtures thereof, unless specifically stated otherwise.
Certain therapeutic advantages may be provided when compounds of formula (I) are replaced with heavier isotopes such as deuterium, for example, which may be attributed to greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements.
When solvates or polymorphs exist of the compounds of formula (I) and pharmaceutically acceptable salts thereof, the present invention includes any possible solvates and polymorphs. The type of solvent forming the solvate is not particularly limited as long as the solvent is pharmaceutically acceptable. For example, water, ethanol, propanol, acetone, and the like can be used.
The term "composition", as used herein, is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. Accordingly, pharmaceutical compositions containing the compounds of the invention as active ingredients as well as methods for preparing the compounds of the invention are also part of the invention. In addition, some crystalline forms of the compounds may exist as polymorphs and as such are intended to be included in the present invention. In addition, some compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates also fall within the scope of the present invention.
The pharmaceutical composition provided by the invention comprises a compound (or a medicinal salt thereof) shown as a formula (I) as an active component, a pharmaceutically acceptable excipient and other optional therapeutic components or auxiliary materials. Although the most suitable mode of administration of the active ingredient in any given case will depend on the particular host, host nature and severity of the condition being treated, the pharmaceutical compositions of the present invention include those suitable for oral, rectal, topical and parenteral (including subcutaneous, intramuscular, intravenous) administration. The pharmaceutical compositions of the present invention may be conveniently prepared in unit dosage forms well known in the art and by any of the methods of preparation well known in the pharmaceutical arts.
Detailed Description
In order to make the above-mentioned contents clearer and clearer, the present invention will be further illustrated by the following examples. The following examples are intended only to illustrate specific embodiments of the present invention so as to enable those skilled in the art to understand the present invention, but not to limit the scope of the present invention. In the embodiments of the present invention, technical means or methods not specifically described are conventional in the art.
All parts and percentages herein are by weight and all temperatures are in degrees Celsius, unless otherwise indicated. The following abbreviations are used in the examples:
BrettPhos Pd G3: methanesulfonic acid (2-dicyclohexylphosphine) -3,6-dimethoxy-2 ',4',6 '-triisopropyl-1,1' -biphenyl) (2 '-amino-1,1' -biphenyl-2-yl) palladium (II);
DCM is dichloromethane;
a Dioxane: dioxane;
DMF: n, N-dimethylformamide;
DMSO, DMSO: dimethyl sulfoxide;
EA: ethyl acetate;
EtOH: ethanol;
ESI-MS: electrospray ionization mass spectrometry;
HATU:2- (7-azabenzotriazole) -N, N' -tetramethyluronium hexafluorophosphate;
MeOH: methanol;
PE: petroleum ether;
parkin's catalyst: (dimethyl phosphonic acid) platinum (II) hydride complex
Pre-HPLC, preparing high performance liquid chromatography;
RuPhos Pd G3: methanesulfonic acid (2-dicyclohexylphosphino-2 ',6' -diisopropoxy-1,1 '-biphenyl) (2-amino-1,1' -biphenyl-2-yl) palladium (II);
TEA: triethylamine.
Synthesis of intermediate compound M1
Figure BDA0003577312830000101
Step 1: synthesis of Compound M1
M1-1 (20.00 g) was dissolved in diethylene glycol monomethyl ether (120 mL) at room temperature, and 2-chloro-N- (2-chloroethyl) -N-methyl-ethylamine (15.60 g) was added thereto, and the mixture was heated to 135 ℃ to react for 20 hours. The reaction was cooled to room temperature, diluted with an equal volume of water, washed twice with methyl tert-butyl ether, extracted three times with DCM, and the organic phases were combined, concentrated under reduced pressure, diluted with DCM, washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (DCM: meOH = 13.
ESI-MS m/z:283.6[M+H] + 。
Synthesis of intermediate compound M2
Figure BDA0003577312830000111
Step 1: synthesis of Compound M2-2
M2-1 (5.00 g) was dissolved in MeOH (50 mL) under an ice bath, nickel chloride hexahydrate (0.57 g) and di-tert-butyl dicarbonate (10.39 g) were added, sodium borohydride (10.80 g) was added in portions, and the ice bath was removed to react at room temperature for 20 hours. The reaction solution was quenched with water under ice-bath, stirred for 10 minutes, filtered through celite, the filtrate was concentrated under reduced pressure, diluted with water, extracted three times with EA, the organic layers were combined, washed with saturated brine, concentrated under reduced pressure, the residue was dissolved in a hydrochloric acid methanol solution, stirred for 5 hours, concentrated under reduced pressure, slurried with PE and EA (V/V =1, 20ml), filtered through suction, and dried to obtain compound M2-2 (3.78g, 63% yield).
ESI-MS m/z:214.05[M+H] + 。
Step 2: synthesis of Compound M2-3
M2-2 (3.78 g) was dissolved in DCM (30 mL) under an ice bath, TEA (8.39 mL) was added, a solution of trifluoroacetic anhydride in DCM (20 mL) was slowly added dropwise, the ice bath was removed, and the reaction was carried out at room temperature for 12 hours. Quenched with water, extracted three times with DCM, and the combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (PE: EA =10: 1) to give compound M2-3 (3.89g, 83% yield).
ESI-MS m/z:308.01[M-H] - 。
And step 3: synthesis of Compound M2-4
Concentrated sulfuric acid (10 mL) was added dropwise to a solution of M2-3 (3.20 g) in acetic acid (20 mL) under ice-bath conditions, paraformaldehyde (1.39 g) was added in portions, and the ice-bath was removed and the reaction was carried out at room temperature for 17 hours. The reaction solution was added dropwise to ice water, stirred for half an hour, extracted three times with EA, and the organic layers were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (PE: EA =50 1) to obtain compound M2-4 (1.65g, 50% yield.
ESI-MS m/z:322.02[M+H] + 。
And 4, step 4: synthesis of Compound M2-5
M2-4 (1.65 g) was dissolved in EtOH (20 mL) and water (5 mL) at room temperature, potassium carbonate (2.13 g) was added, and the reaction was allowed to warm to 80 ℃ for 1 hour. The reaction was cooled, diluted with water, extracted three times with DCM, the organic layers combined, washed with saturated brine and concentrated under reduced pressure to give compound M2-5 (1.09 g, crude).
ESI-MS m/z:226.04[M+H] + 。
And 5: synthesis of Compound M2
M2-5 (1.09 g) was dissolved in MeOH (10 mL) at room temperature, and 37% aqueous formaldehyde (0.54 mL) and sodium cyanoborohydride (0.45 g) were added in this order to conduct a reaction at room temperature for 2 hours. The reaction was diluted with water, extracted three times with DCM, and the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (DCM: meOH =20, 1) to give compound M2 (1.09g, 94% yield.
ESI-MS m/z:240.05[M+H] + 。
Example 1: synthesis of Compound 1 (3- ((4- (4-methylpiperazin-1-yl) phenyl) amino) quinoline-2-carboxamide) trifluoroacetate
Figure BDA0003577312830000121
Step 1: synthesis of Compound 1-2
A solution of ethyl 3-bromopyruvate (1.00 g) in EtOH (5 mL) was added dropwise to a solution of pyridine (0.41 g) in EtOH (5.00 mL) at room temperature, heated to 60 ℃ and reacted for 1 hour. After cooling to room temperature, compound 1-1 (0.59 g) and pyridine (0.99 mL) were added to the reaction mixture, and the temperature was raised to 78 ℃ to react for 12 hours. After cooling to room temperature, pyrrolidine (1.01 mL) was added to the reaction mixture, and the temperature was raised to 78 ℃ to react for 2 hours. The reaction solution was cooled, concentrated under reduced pressure, and purified by column chromatography (PE: EA = 4:1) to give compound 1-2 (0.65g, 62% yield).
ESI-MS m/z:217.11[M+H] + 。
Step 2: synthesis of Compounds 1-3
BrettPhos Pd G3 (0.08G) was added to a solution of 1-2 (0.20G), 1- (4-bromophenyl) -4-methylpiperazine (0.28G) and cesium carbonate (0.90G) in Dioxane (10 mL) at room temperature, the nitrogen gas was replaced, the temperature was raised to 100 ℃ and the reaction was carried out by microwave reaction for 60 minutes. The reaction solution was cooled, diluted with EA, filtered through celite, and the filtrate was concentrated under reduced pressure and purified by column chromatography (DCM: meOH = 16) to obtain compound 1-3 (0.15g, 40% yield).
ESI-MS m/z:391.29[M+H] + 。
And step 3: synthesis of Compound 1
1-3 (0.14 g) was dissolved in a methanol solution of ammonia (7M/methanol, 2 mL) at room temperature, and the mixture was heated to 100 ℃ for a microwave reaction for 60 minutes. The reaction solution was cooled, concentrated, and purified by Pre-HPLC (mobile phase: acetonitrile/water/0.1% trifluoroacetic acid) to obtain the objective compound 1 (0.10g, 59% yield).
ESI-MS m/z:362.22[M+H] + 。
1 H NMR(500MHz,DMSO-d 6 )δ10.12(s,1H),9.72(s,1H),8.59(d,J＝2.8Hz,1H),7.98(d,J＝2.7Hz,1H),7.94–7.84(m,1H),7.76(s,1H),7.74–7.66(m,1H),7.48(qd,J＝7.0,3.4Hz,2H),7.30–7.25(m,2H),7.11–7.04(m,2H),3.82(d,J＝13.2Hz,2H),3.54(d,J＝12.1Hz,2H),3.18(t,J＝11.1Hz,2H),2.95(t,J＝12.5Hz,2H),2.88(d,J＝3.7Hz,3H).
Example 2: synthesis of compound 2 (3- ((4- (4-methylpiperazin-1-yl) phenyl) amino) -1,7-naphthyridine-2-carboxamide)
Figure BDA0003577312830000131
Synthesis of example 2 referring to the synthesis method of example 1, 3-aminopyridine-4-aldehyde (2-1) was reacted with ethyl bromopyruvate to obtain 2-2, which was then coupled with 1- (4-bromophenyl) -4-methylpiperazine to obtain 2-3, followed by ammonolysis to obtain the target compound 2.
ESI-MS m/z:363.2[M+H] + 。
1 H NMR(500MHz,CDCl 3 -d)δ10.07(s,1H),9.11(s,1H),8.27(d,J＝5.8Hz,1H),8.25–8.19(m,1H),7.33(s,1H),7.20(s,1H),7.15(d,J＝8.4Hz,2H),6.93(d,J＝8.4Hz,2H),3.19(t,J＝5.0Hz,4H),2.55(t,J＝4.9Hz,4H),2.32(s,3H).
Example 3: synthesis of Compound 3 (3- ((3,5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) amino) quinoline-2-carboxamide)
Figure BDA0003577312830000141
Step 1: synthesis of Compound 3-1
BrettPhos Pd G3 (0.06G) was added to a solution of 1-2 (0.15G), M1 (0.20G) and cesium carbonate (0.68G) in Dioxane (5 mL) at room temperature, the nitrogen was replaced, the temperature was raised to 100 ℃ and the reaction was carried out for 90 minutes by microwave. The reaction was cooled, diluted with DCM, filtered through celite, extracted with water and DCM, the organic layers were combined, concentrated under reduced pressure, slurried with PE and EA (V/V =1, 10 ml), filtered through suction, and dried to give compound 3-1 (0.17 g, crude).
ESI-MS m/z:391.37[M+H] + 。
Step 2: synthesis of Compound 3
3-1 (0.15 g) and HATU (0.17 g) were dissolved in DMF (10 mL) at room temperature, followed by addition of TEA (0.16 mL) and a methanol solution of ammonia (7M/methanol, 5 mL) and reaction at room temperature for 5 hours. The reaction solution was diluted with water, and the solid precipitated, filtered off with suction, dried, and purified by Pre-HPLC to give the target compound 3 (0.07g, 45% yield).
ESI-MS m/z:390.34[M+H] + 。
1 H NMR(500MHz,DMSO-d 6 )δ10.21(s,1H),8.60(s,1H),7.99(d,J＝13.4Hz,2H),7.93–7.85(m,1H),7.84–7.74(m,1H),7.51(dd,J＝9.7,5.4Hz,2H),6.95(s,2H),3.03(s,4H),2.48(s,4H),2.28(s,9H).
Example 4: synthesis of Compound 4 (3- ((2,5-dimethyl-1,2,3,4-tetrahydroisoquinolin-7-yl) amino) quinoline-2-carboxamide) formate salt
Figure BDA0003577312830000142
Synthesis of example 4 the synthesis of reference example 3, coupling of M2 with 1-2 to give 4-1, followed by amide condensation with ammonia and preparation by Pre-HPLC (mobile phase: acetonitrile/water/0.1% formic acid) gave the title compound 4 (formate salt).
ESI-MS m/z:347.25[M+H] + 。
1 H NMR(500MHz,DMSO-d 6 )δ10.22(s,1H),8.61(s,1H),8.19(s,1H),8.01(s,1H),7.96–7.88(m,2H),7.82–7.75(m,1H),7.50(dq,J＝7.3,5.0,3.7Hz,2H),6.98(s,1H),6.89(s,1H),3.52(s,2H),2.68(s,4H),2.37(s,3H),2.20(s,3H).
Example 5: synthesis of Compound 5 (3- ((3,5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -1,7-naphthyridine-2-carboxamide)
Figure BDA0003577312830000151
Synthesis of example 5 the synthesis from step 2 to step 3 in reference example 1, coupling of 2-2 with M1 gave 5-1, which was then aminolyzed to give the title compound 5.
ESI-MS m/z:196.12[M/2+H] + 。
1 H NMR(500MHz,DMSO-d 6 )δ10.52(s,1H),9.15(s,1H),8.68(d,J＝2.5Hz,1H),8.37(d,J＝5.8Hz,1H),8.16–8.04(m,1H),7.81(s,1H),7.67(d,J＝5.8Hz,1H),6.99(s,2H),3.03(t,J＝4.6Hz,4H),2.42(dd,J＝5.9,3.4Hz,4H),2.30(s,6H),2.24(s,3H).
Example 6: synthesis of compound 6 (3- ((3,5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -1,6-naphthyridine-2-carboxamide)
Figure BDA0003577312830000152
Synthesis of example 6 according to the synthesis method of example 1, 4-amino-3-pyridinecarboxaldehyde (6-1) is reacted with ethyl bromopyruvate to obtain 6-2, which is then coupled with M1 to obtain 6-3, followed by aminolysis to obtain the target compound 6.
ESI-MS m/z:391.34[M+H] + 。
1 H NMR(500MHz,Chloroform-d)δ9.97(s,1H),8.98(s,1H),8.40(d,J＝6.0Hz,1H),8.31–8.21(m,1H),7.80(s,1H),7.60(d,J＝5.9Hz,1H),6.90(s,2H),3.17(s,4H),2.61(s,4H),2.41(s,3H),2.29(s,6H).
Synthesis of example 7,8,9, 10 referring to the synthesis of example 6, a substituted amino compound is reacted with ethyl bromopyruvate to give the corresponding product, which is then coupled with M1 and aminolyzed to give the corresponding target compound. The corresponding starting materials are as follows:
Figure BDA0003577312830000161
Figure BDA0003577312830000162
Figure BDA0003577312830000171
Figure BDA0003577312830000181
Figure BDA0003577312830000191
example 11: synthesis of Compound 11 (7-cyano-3- (((3,5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) amino) quinoline-2-carboxamide)
Figure BDA0003577312830000192
Step 1: synthesis of Compound 11-2
11-1 (1.00 g) was dissolved in a mixed solution of EtOH (15 mL) and water (5 mL) at room temperature, and iron powder (3.17 g) and 5 drops of concentrated hydrochloric acid were added to the solution, and the mixture was heated to 70 ℃ to react for 2 hours. The reaction solution was cooled, diluted with EA, filtered with celite, concentrated under reduced pressure, dissolved with EA, washed with water and saturated brine, concentrated under reduced pressure, and purified by column chromatography (PE: EA =10, 1-6:1) to give compound 11-2 (0.49g, 59% yield).
ESI-MS m/z:147.01[M+H] + 。
Then, referring to the synthesis method of example 6, 11-2 is reacted with ethyl bromopyruvate to obtain a compound 11-3, which is then coupled with M1 and aminolyzed to obtain a target compound 11.
ESI-MS m/z:415.31[M+H] + 。
1 H NMR(500MHz,DMSO-d 6 )δ10.47(s,1H),8.76–8.55(m,1H),8.34(s,1H),8.20–8.08(m,1H),8.02–7.90(m,2H),7.73(d,J＝8.6Hz,1H),6.98(s,2H),3.02(t,J＝4.6Hz,4H),2.41(t,J＝4.6Hz,4H),2.29(s,6H),2.23(s,3H).
Example 12: synthesis of compound 12 (3- ((3,5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) amino) quinoline-2,7-dicarboxamide)
Figure BDA0003577312830000201
Step 1: synthesis of Compound 12
Compound 11 (0.22 g) was dissolved in a mixed solution of EtOH (5 mL) and water (2.00 mL), and Parkin's catalyst (0.02 g) was added, and the reaction was allowed to warm to 80 ℃ overnight. The reaction was cooled, concentrated under reduced pressure, and purified by column chromatography (DCM: meOH = 10).
ESI-MS m/z:433.37[M+H] + 。
1 H NMR(500MHz,DMSO-d 6 )δ10.32(s,1H),8.56(d,J＝2.8Hz,1H),8.45(d,J＝1.7Hz,1H),8.15(s,1H),8.06(d,J＝2.8Hz,1H),7.96(s,1H),7.93(dd,J＝8.7,1.8Hz,1H),7.82(d,J＝8.7Hz,1H),7.45(s,1H),6.98(s,2H),3.03(t,J＝4.5Hz,4H),2.44(s,4H),2.29(s,6H),2.25(s,3H).
Example 13: synthesis of Compound 13 (7-cyano-3- (((4- (4-methylpiperazin-1-yl) phenyl) amino) quinoline-2-carboxamide)
Figure BDA0003577312830000202
Synthesis of example 13 referring to the synthesis method of steps 2 to 3 in example 1, coupling with 11-3 and 1- (4-bromophenyl) -4-methylpiperazine gave compound 13-1, which was then aminolyzed to give the objective compound 13.
Examples 14, 15, 16, 17 Synthesis of reference example 13, coupling of 11-3 with 4- (4-bromophenyl) tetrahydropyran, 4- (4-bromophenyl) morpholine, 4- (4-bromophenyl) -1-methylpiperidine, respectively, and M2 gave the corresponding intermediates, which were then aminolyzed to give the corresponding target compounds 14, 15, 16 and 17.
Synthesis of example 18,19,20,21,22,23,24,25,26 referring to the synthesis of example 11, iron powder is used to reduce different substituted nitro compounds, which are then reacted with ethyl bromopyruvate to obtain the corresponding intermediates, which are then coupled with M1 and aminolyzed to obtain the corresponding target compounds. The corresponding starting materials are as follows:
Figure BDA0003577312830000211
Figure BDA0003577312830000221
Figure BDA0003577312830000222
Figure BDA0003577312830000231
Figure BDA0003577312830000241
Figure BDA0003577312830000251
Figure BDA0003577312830000261
example 27: synthesis of compound 27 (N, N-dimethyl-3- ((4- (4-methylpiperazin-1-yl) phenyl) amino) quinoline-2,6-dicarboxamide) trifluoroacetate
Figure BDA0003577312830000271
Step 1: synthesis of Compound 27-2
Sodium hydroxide (2.87 g) was dissolved in water (20 mL) at room temperature, and then added to a solution of 27-1 (5.00 g) in MeOH (40 mL) and reacted at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, adjusted to acidic pH with 1mol/L hydrochloric acid solution, extracted three times with EA, and the organic layers were combined, washed with saturated brine and concentrated under reduced pressure to give compound 27-2 (6.06 g, crude product).
Step 2: synthesis of Compound 27-3
27-2 (2.07 g) was dissolved in toluene (20 mL) at room temperature, and thionyl chloride (0.92 mL) and 3 drops of DMF were added, and the temperature was raised to 100 ℃ to react for 3 hours. The reaction mixture was cooled, concentrated under reduced pressure to give an acid chloride intermediate, dimethylamine hydrochloride (1.04 g) was dissolved in DCM (15 mL) under ice-bath conditions, TEA (4.42 mL) was added, and a solution of acid chloride in DCM (15 mL) was added dropwise and reacted at room temperature for 3 hours. The reaction mixture was washed with water and saturated brine, and concentrated under reduced pressure to give compound 27-3 (1.73 g, crude product).
ESI-MS m/z:223.11[M+H] + 。
Then, referring to the synthesis method of example 11, 27-3 was reduced with iron powder, and then reacted with ethyl bromopyruvate to obtain the corresponding intermediate, which was then coupled with 1- (4-bromophenyl) -4-methylpiperazine, aminolyzed, and finally prepared by Pre-HPLC (mobile phase: acetonitrile/water/0.1% trifluoroacetic acid) to obtain the objective compound 27.
ESI-MS m/z:433.27[M+H] + 。
1 H NMR(500MHz,DMSO-d 6 )δ10.18(s,1H),9.68(s,1H),8.64(s,1H),8.03(s,1H),7.92(d,J＝8.7Hz,1H),7.83(s,1H),7.77(s,1H),7.45(d,J＝8.7Hz,1H),7.28(d,J＝8.3Hz,2H),7.07(d,J＝8.4Hz,2H),3.82(d,J＝13.1Hz,2H),3.54(d,J＝12.1Hz,2H),3.19(d,J＝11.2Hz,2H),3.01(s,3H),2.96(d,J＝13.5Hz,5H),2.88(s,3H).
Example 28: synthesis of compound 28 (3- ((3,5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) amino) -N, N-dimethylquinoline-2,7-dicarboxamide)
Figure BDA0003577312830000281
Step 1: synthesis of Compound 28-2
28-1 (5.00 g) was dissolved in concentrated sulfuric acid (25 mL) while cooling on ice, and a solution of nitric acid (1.77 mL) in concentrated sulfuric acid (2 mL) was added dropwise to the solution to conduct a reaction at room temperature for 30 minutes. The reaction was added dropwise to ice water (50 mL) and a white solid precipitated, which was filtered off with suction and dried to give compound 28-2 (0.68 g, crude).
Then, referring to the synthesis methods of example 27 and example 3, 28-2 and dimethylamine hydrochloride were subjected to amide condensation to obtain 28-3, 28-3 was reduced with iron powder, and then reacted with ethyl bromopyruvate to obtain 28-5, which was then coupled with M2, and further subjected to amide condensation with ammonia to obtain the corresponding target compound 28.
ESI-MS m/z:461.40[M+H] + 。
1 H NMR(500MHz,Chloroform-d)δ9.94(s,1H),8.24(d,J＝4.7Hz,1H),7.86(s,1H),7.72(s,1H),7.50(d,J＝8.5Hz,1H),7.43(dd,J＝8.5,1.6Hz,1H),6.90(s,2H),3.15(s,4H),3.05(d,J＝34.0Hz,6H),2.58(s,4H),2.39(s,3H),2.27(s,6H).
Example 29: synthesis of compound 29 (3- ((4- (4-methylpiperazin-1-yl) phenyl) amino) quinoxaline-2-carboxamide)
Figure BDA0003577312830000291
Step 1: synthesis of Compound 29-2
29-1 (0.50 g) was dissolved in phosphorus oxychloride (6 mL) at room temperature, heated to 100 ℃ and reacted for 1 hour. The reaction solution was cooled, concentrated under reduced pressure, added with water and EA for extraction, and the organic layers were combined and concentrated under reduced pressure to give compound 29-2 (0.50 g, crude product).
ESI-MS m/z:237.16[M+H] + 。
Step 2: synthesis of Compound 29-3
RuPhos Pd G3 (0.11G) was added to 29-2 (0.50G), 1- (4-bromophenyl) -4-methylpiperazine (0.27G) and cesium carbonate (1.38G) in xylene (5 mL) at room temperature, while replacing nitrogen, and the temperature was raised to 150 ℃ for 3 hours. The reaction was cooled, diluted with EA, filtered through celite, and the filtrate was concentrated under reduced pressure and purified by column chromatography (DCM: meOH =10: 1) to give compound 29-3 (0.35g, 63% yield).
ESI-MS m/z:392.35[M+H] + 。
And step 3: synthesis of Compound 29
29-3 (0.35 g) was dissolved in a methanol solution of ammonia (7M in methanol, 15mL) at room temperature, and the reaction was carried out at 100 ℃ for 2.5 hours. The reaction solution was cooled, concentrated under reduced pressure, slurried with DCM (2 mL), filtered with suction, and dried to give the title compound 29 (0.21g, 66% yield).
ESI-MS m/z:363.29[M+H] + 。
1 H NMR(500MHz,DMSO-d 6 )δ11.43–11.21(m,1H),8.71(s,1H),8.22(s,1H),7.89(t,J＝7.9Hz,1H),7.73(dt,J＝27.4,7.7Hz,4H),7.57–7.44(m,1H),7.08–6.86(m,2H),3.23–2.93(m,4H),2.29–2.13(m,3H).
Example 30: synthesis of compound 30 (3- ((3,5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) amino) quinoxaline-2-carboxamide)
Figure BDA0003577312830000301
Synthesis of example 30 the synthesis of steps 2 to 3 in reference example 29, coupling with 17-2 and M1 gave 30-1, which was then subjected to aminolysis to give the title compound 30.
ESI-MS m/z:391.39[M+H] + ；
1 H NMR(500MHz,DMSO-d 6 )δ11.38(s,1H),8.73(s,1H),8.24(s,1H),7.92(d,J＝8.0Hz,1H),7.76(d,J＝3.9Hz,2H),7.55(s,2H),7.55–7.51(m,1H),3.02(t,J＝4.7Hz,4H),2.43–2.40(m,4H),2.32(s,6H),2.23(s,3H).
Figure BDA0003577312830000302
Figure BDA0003577312830000311
Example 31: synthesis of Compound 31 (7-cyano-3- (((3,5-dimethyl-4- (4-methylpiperazin-1-yl) phenyl) amino) quinoxaline-2-carboxamide)
Figure BDA0003577312830000321
Step 1: synthesis of Compound 31-2
Ethyl bromopyruvate (4.24 mL) was added dropwise to a 31-1 (5.0 g) toluene (30 mL) solution in an ice bath, and the reaction was carried out at 100 ℃ for 5 hours. The reaction solution was cooled, concentrated under reduced pressure, slurried with PE/EA (PE: EA =1:1, 50 mL), suction filtered, and dried to give compound 31-2 (7.02g, 83% yield).
ESI-MS m/z:276.16[M-H] - 。
Step 2: synthesis of Compound 31-3
A solution of potassium tert-butoxide (5.59 g) in DMF (20 mL) was added in one portion to a solution of 31-2 (6.90 g) in DMF (30 mL) while cooling on ice, stirring was continued for 30 minutes and the reaction was allowed to warm to room temperature for 1 hour. After dilution with water in ice bath, the solution was adjusted to pH 2 with 6mol/L hydrochloric acid solution, extracted three times with EA, and the organic layers were combined, washed with water and saturated brine, and concentrated under reduced pressure to give compound 31-3 (5.23g, 81.07% yield).
ESI-MS m/z:258.17[M-H] - 。
And step 3: synthesis of Compound 31-4
Phosphorus tribromide (5.69 mL) was added dropwise to a solution of 31-3 (5.23 g) in DMF (50 mL) while cooling on ice, and the reaction was carried out at room temperature for 2 hours with the ice bath removed. The reaction solution was added dropwise to ice water, extracted three times with EA, and the organic layers were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 31-4 (4.51g, 92% yield).
ESI-MS m/z:242.16[M-H] - 。
And 4, step 4: synthesis of Compound 31-5
31-4 (2.10 g) was dissolved in phosphorus oxychloride (20 mL) while cooling on ice, and the reaction was carried out at 115 ℃ for 4 hours. Concentration under reduced pressure, dropwise adding the residual liquid into ice water, adjusting pH to about 7 with saturated sodium bicarbonate solution, extracting with EA three times, combining organic layers, washing with saturated sodium bicarbonate solution and saturated brine in turn, concentrating under reduced pressure, and purifying by column chromatography (PE: EA = 4:1) to obtain 31-5 (1.10 g,49% yield).
And 5: synthesis of Compound 31-6
31-5 (0.20 g), 3,5-dimethyl-4- (4-methylpiperazin-1-yl) aniline (0.2 g) was dissolved in acetonitrile (5 mL) at room temperature, N-diisopropylethylamine (0.30 g) was added, and the reaction was carried out at 80 ℃ for 24 hours. Concentrated under reduced pressure and purified by column chromatography (DCM: meOH =25 1) to give compound 31-6 (0.29g, 84% yield).
ESI-MS m/z:445.39[M+H] + ；
Step 6: synthesis of Compound 31
Referring to the synthesis procedure of step 3 in example 1, aminolysis of 31-6 gave the title compound 31.
ESI-MS m/z:416.37[M+H] + 。
1 H NMR(500MHz,CDCl 3 )δ11.22(s,1H),8.20(s,1H),8.10(s,1H),7.80(s,2H),7.53(s,2H),3.21(s,4H),2.67(s,4H),2.47(s,3H),2.38(s,6H).
Example 32: synthesis of Compound 32 (7-cyano-3- (((4- (4-methylpiperazin-1-yl) phenyl) amino) quinoxaline-2-carboxamide)
Figure BDA0003577312830000331
Synthesis of example 32 referring to the synthesis method of steps 5 to 6 in example 31, substitution reaction with 31-5 and 4- (4-methylpiperazin-1-yl) aniline gave 32-1, which was then aminolyzed to give the objective compound 32.
ESI-MS m/z:388.32[M+H] + 。
1 H NMR(500MHz,CDCl 3 )δ11.21(s,1H),8.17(s,1H),8.09(s,1H),7.83–7.66(m,4H),6.99(d,J＝8.5Hz,2H),3.23(s,4H),2.61(s,4H),2.37(s,3H).
Example 33: synthesis of compound 33 (5- ((2-hydroxyethyl) amino) -3- ((4- (4-methylpiperazin-1-yl) phenyl) amino) quinoxaline-2-carboxamide)
Figure BDA0003577312830000341
Synthesis of example 33 referring to the synthesis method of example 31, the starting material 33-1 is amide-condensed with ethyl 3-chloro-3-oxopropionate to give 33-2, which is subjected to ring closure, reduction, and chlorination to give 33-5, which is subjected to substitution reaction with 4- (4-methylpiperazin-1-yl) aniline to give 33-6, which is then aminolyzed to give compound 33-7.
And 7: synthesis of Compound 33
33-7 (0.15 g), ethanolamine (0.21 g), cuprous iodide (0.01 g) and potassium carbonate (0.09 g) were dissolved in DMSO (1.50 mL) at room temperature, and the mixture was heated to 90 ℃ for three hours while replacing nitrogen. The reaction solution was cooled, diluted with water, extracted three times with EA, and purified by column chromatography (DCM: meOH = 10.
ESI-MS m/z:422.36[M+H] + 。
1 H NMR(500MHz,DMSO-d 6 )δ11.27(s,1H),8.64(d,J＝2.2Hz,1H),8.17(d,J＝2.3Hz,1H),7.72(d,J＝8.7Hz,2H),7.32(t,J＝8.0Hz,1H),7.13(d,J＝8.2Hz,1H),6.98(d,J＝8.7Hz,2H),6.75(d,J＝7.7Hz,1H),5.99(t,J＝5.6Hz,1H),4.99(t,J＝4.7Hz,1H),3.75(q,J＝5.2Hz,2H),3.31(d,J＝5.6Hz,2H),3.13(s,4H),2.28(s,4H).
Figure BDA0003577312830000342
Figure BDA0003577312830000351
Pharmacological experiments
Example 1: enzymatic activity assay
(1) Preparation of 4 Xkinase buffer (Promega, cat. No. V9102)
(2) Compound gradient dilution: the test compound was diluted 3-fold, and 11 gradient concentrations were set, each concentration being set for multiple well detection. Solutions were diluted in 384-well formulation plates in steps to the corresponding 100-fold final concentration and then transferred with Echo to 0.1. Mu.L to 384-well reaction plates for assay. 100% DMSO of 0.1. Mu.L transferred in Min and Max wells.
(3) HPK1 enzyme working solution was prepared with 4x kinase buffer.
(4) mu.L of HPK1 enzyme working solution was added to each well, 5. Mu.L of 1 Xkinase buffer was added to Min wells, centrifuged at 1000rpm for 1Min, and incubated at 25 ℃ for 15Min.
(5) During incubation, substrate working solution was prepared with 4x kinase buffer.
(6) mu.L of substrate working solution was added to each well of the reaction plate, centrifuged at 1000rpm for 1min, and incubated at 25 ℃ for 60min.
(7) At the end of incubation, 5 μ L ADP Glo reagent (Promega, cat. No. v9102) was added to each well. Centrifugation was carried out at 1000rpm for 1min and incubation was carried out at 25 ℃ for 60min.
(8) Add 10. Mu.L of assay per well, centrifuge at 1000rpm for 1min, and incubate at 25 ℃ for 60min.
(9) EnVision readings were used.
Inhibition rate calculation formula:
Figure BDA0003577312830000361
signal value _ max: reading of DMSO control wells
Signal value _ min enzyme-free Kong Douzhi
Sample Kong Douzhi Signal value sample
The log value of the concentration is taken as an X axis, the percentage inhibition rate is taken as a Y axis, and an analysis software GraphPad Prism 5 log (inhibitor) vs. response-Variable slope is adopted to fit a dose-effect curve, so that the IC of the compound for inhibiting the combination of the kinase is obtained 50 The value is obtained.
Enzymatic IC of example Compounds on HPK1 50 See table 1 for data.
TABLE 1
Figure BDA0003577312830000362
Figure BDA0003577312830000371
While the present invention has been fully described by way of embodiments thereof, it is to be noted that various changes and modifications will be apparent to those skilled in the art. Such changes and modifications are intended to be included within the scope of the appended claims.

Claims (21)

1. A compound of formula (I), a stereoisomer, a tautomer, a deutero-compound, or a pharmaceutically acceptable salt thereof:
Figure FDA0003577312820000011
wherein,
R 1 is selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-12 Aryl, or 5-12 membered heteroaryl, said C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-12 Aryl, or 5-12 membered heteroaryl optionally further substituted with at least one R 1a Substitution;
R 2 selected from H, halogen, cyano, C 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-12 Aryl or 5-12 membered heteroaryl, said C 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, C 3-12 Cycloalkyl, 3-12 membered heterocyclyl, C 6-12 Aryl or 5-12 membered heteroaryl optionally further substituted with at least one R 2a Substitution;
or R 1 And R 2 Together with the atom to which they are attached form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, optionally further substituted by one or more R 1b Substituted by a substituent;
R 3 selected from H, halogen, C 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO 2 、-OR b 、-SR b 、-SO 2 R b 、-SO 2 NR b R c 、-COR b 、-CO 2 R b 、-CONR b R c 、-NR b R c 、-NR b COR c 、-NR b CO 2 R c 、-NR b SONR c R d 、-NR b SO 2 NR c R d or-NR b SO 2 R c Said C is 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted with at least one R 3a Substitution;
R 4 each independently selected from H, halogen, C 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO 2 、-OR b 、-SR b 、-SO 2 R b 、-SO 2 NR b R c 、-COR b 、-CO 2 R b 、-CONR b R c 、-NR b R c 、-NR b COR c 、-NR b CO 2 R c 、-NR b SONR c R d 、-NR b SO 2 NR c R d or-NR b SO 2 R c Said C is 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl optionally further substituted with at least one R 4a Substitution;
R 5 or R 6 Each independently selected from H, halogen, cyano, C 1-8 Alkyl radical, C 2-8 Alkenyl or C 2-8 Alkynyl radical, said C 1-8 Alkyl radical, C 2-8 Alkenyl or C 2-8 Alkynyl is optionally further substituted with at least one R a Substitution;
l is selected from the group consisting of a bond, alkylene, O, S or NR a Said alkylene group is optionally further substituted by at least one R a Substitution;
X 1 selected from N or CR 7 ；
X 2 Selected from N or CR 8 ；
X 3 Selected from N or CR 9 ；
X 4 Selected from N or CR 10 ；
X 5 Selected from N or CR 11 ；
X 6 Selected from N or CR 12 ；
R 7 、R 8 、R 9 、R 10 、R 11 Or R 12 Each independently selected from H, halogen, C 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO 2 、-OR b 、-SR b 、-SO 2 R b 、-SO 2 NR b R c 、-COR b 、-CO 2 R b 、-CONR b R c 、-NR b R c 、-NR b COR c 、-NR b CO 2 R c 、-NR b SONR c R d 、-NR b SO 2 NR c R d or-NR b SO 2 R c Said C is 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl optionally further substituted with at least one R a Substitution;
R 1a 、R 1b 、R 2a 、R 3a 、R 4a or R a Each independently selected from H, halogen, C 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO 2 、-OR b 、-SR b 、-SO 2 R b 、-SO 2 NR b R c 、-COR b 、-CO 2 R b 、-CONR b R c 、-NR b R c 、-NR b COR c 、-NR b CO 2 R c or-NR b SO 2 R c Said C is 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally further substituted by one or more halogen, C 1-8 Alkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, oxo, -CN, -NO 2 、-OR b 、-SR b 、-SO 2 R b 、-SO 2 NR b R c 、-COR b 、-CO 2 R b 、-CONR b R c 、-NR b R c 、-NR b COR c 、-NR b CO 2 R c 、-NR b SONR c R d 、-NR b SO 2 NR c R d or-NR b SO 2 R c Substituted by a substituent;
R b 、R c or R d Each independently selected from hydrogen and C 1-8 Alkyl radical, C 1-8 Hydroxyalkyl radical, C 2-8 Alkenyl radical, C 2-8 Alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;
m is selected from 0, 1,2,3 or 4;
and the compound is not:
Figure FDA0003577312820000021
2. the compound, stereoisomer, tautomer, deuterated or pharmaceutically acceptable salt thereof according to claim 1 wherein R is 1 Is selected from
Figure FDA0003577312820000022
R 1 Optionally further substituted with 1-4R 1a And (4) substitution.
3. The compound, its stereoisomers, tautomers, deuterons or pharmaceutically acceptable salts thereof, according to claim 1 or 2, wherein R is 1a Is selected from H or C 1-3 An alkyl group.
4. The compound, its stereoisomers, tautomers, deuterons or pharmaceutically acceptable salts thereof, according to any one of claims 1-3, wherein said R is 1 Is selected from
Figure FDA0003577312820000031
5. The compound, its stereoisomers, tautomers, deuterons or pharmaceutically acceptable salts thereof, according to any one of claims 1-4, wherein said R is 2 The substituent is selected from H or C 1-3 Alkyl, preferably methyl.
6. The compound, its stereoisomers, tautomers, deuterons or pharmaceutically acceptable salts thereof, according to any one of claims 1-5, wherein said R is 1 And R 2 Together with the atom to which they are attached form a heterocyclic group optionally further substituted by 1-4R 1b Substituted by a substituent.
7. The compound, its stereoisomers, tautomers, deuterons or pharmaceutically acceptable salts thereof, according to any one of claims 1-6, wherein said R is 3 The substituent is selected from H or C 1-3 Alkyl, preferably methyl.
8. The compound, its stereoisomers, tautomers, deuterons or pharmaceutically acceptable salts thereof according to any one of claims 1-7, wherein said R 4 Each independently selected from H, halogen, C 1-3 Alkoxy or-NHC 1-3 Hydroxyalkyl, preferably H.
9. The compound, its stereoisomers, tautomers, deuterons or pharmaceutically acceptable salts thereof, according to any one of claims 1-8, wherein said R is 5 Or R 6 Each independently selected from H or C 1-3 Alkyl, preferably R 5 Or R 6 Are all H.
10. The compound, its stereoisomers, tautomers, deuterons or pharmaceutically acceptable salts thereof, according to any one of claims 1-9, wherein X is 1 Is selected fromN or CH, preferably N.
11. The compound, its stereoisomers, tautomers, deuterons or pharmaceutically acceptable salts thereof, according to any one of claims 1-10, wherein X is 2 The substituent is selected from N or CR 8 ，R 8 Selected from H, halogen, cyano, C 1-3 Alkoxy radical, C 1-3 Haloalkyl, -NHC 1-3 Hydroxyalkyl, -C (O) N (R) 8a ) 2 or-S (O) 2 R 8a ，R 8a Independently selected from H or C 1-3 An alkyl group.
12. The compound, its stereoisomers, tautomers, deuterons or pharmaceutically acceptable salts thereof according to any one of claims 1 to 11, wherein X is 3 The substituent is selected from N or CR 9 ，R 9 Selected from H, halogen, cyano, C 1-3 Alkoxy radical, C 1-3 Haloalkyl, -NHC 1-3 Hydroxyalkyl, -C (O) N (R) 9a ) 2 or-S (O) 2 R 9a ，R 9a Independently selected from H or C 1-3 An alkyl group.
13. The compound, its stereoisomers, tautomers, deuterons or pharmaceutically acceptable salts thereof according to any one of claims 1-12, wherein X is 4 Selected from N or CH, preferably CH.
14. The compound, its stereoisomers, tautomers, deuterons or pharmaceutically acceptable salts thereof, according to any one of claims 1-13, wherein X is 5 The substituent(s) of (b) is selected from N or CH, preferably CH.
15. The compound, its stereoisomers, tautomers, deuterons or pharmaceutically acceptable salts thereof, according to any one of claims 1-14, wherein X is 6 The substituent(s) is selected from N or CH, preferably CH.
16. The compound, a stereoisomer, a tautomer, a deuteron, or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 15, wherein the substituent of L is NH.
17. The compound of any one of claims 1-16, a stereoisomer, tautomer, deuterio, or pharmaceutically acceptable salt thereof, selected from a compound of formula (IA) or (IB),
Figure FDA0003577312820000041
R 1 -R 12 and m is as defined for formula (I).
18. A compound, stereoisomer, tautomer, deuteron, or pharmaceutically acceptable salt thereof, selected from,
Figure FDA0003577312820000051
19. a pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of claims 1-18 and at least one pharmaceutically acceptable excipient.
20. Use of a compound according to any one of claims 1 to 18 or a pharmaceutical composition according to claim 19 in the manufacture of a medicament.
21. A method of treating and/or preventing a disease comprising administering to a subject a therapeutically effective amount of a compound of any one of claims 1-18 or a pharmaceutical composition of claim 19.
CN202210337967.3A 2021-04-02 2022-04-01 HPK1 inhibitor and application thereof in medicine Pending CN115197154A (en)

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