Linear substituted oxazepin-5-one krAs-g12d inhibitors

Abstract

Provided herein are straight-chain substituted oxazepin-5-one compounds useful for treating cancer.

Description

[0001] Cross-reference to related applications

[0002] This application claims priority and benefit to U.S. Provisional Application No. 63 / 566,115, filed March 15, 2024, and U.S. Provisional Application No. 63 / 756,730, filed February 10, 2025. The disclosure of each of the foregoing applications is incorporated herein by reference in its entirety. Background Technology

[0003] Ras is a small GTP-binding protein that acts as a nucleotide-dependent switch in central growth signaling pathways. In response to extracellular signals, Ras binds to GDP under the catalysis of guanine nucleotide exchange factors (GEFs), particularly SOS1 protein. GDP The state transitions to GTP binding (Ras) GTP ) State. Active Ras GTP Ras mediates a variety of growth-stimulating functions through direct interactions with effectors, including Raf, PI3K, and Ral guanine nucleotide dissociation stimulants. Ras' intrinsic GTPase activity subsequently hydrolyzes GTP to GDP, thereby terminating Ras signaling. Ras GTPase activity can be further enhanced through its interactions with GTPase-activating proteins (GAPs), including neurofibromin 1 tumor inhibitors.

[0004] Mutant Ras exhibits reduced GTPase activity, which prolongs its activated state, thereby promoting Ras-dependent signaling and the survival or growth of cancer cells. Mutations in Ras that affect its ability to interact with GAP or convert GTP back to GDP lead to prolonged activation of the protein, and consequently, prolonged signals instructing the cell to continue growing and dividing. Because these signals drive cell growth and division, overactivated RAS signaling may ultimately lead to cancer. Mutations in any of the three major genotypes of RAS (HRas, NRas, or KRas) are common events in human tumorigenesis. Among the three Ras subtypes (K, N, and H), KRas is the most frequently mutated.

[0005] The most common KRas mutations occur at residues G12 and G13 of the P ring, as well as residue Q61. G12D is a common mutation in the KRas gene (glycine-12 mutated to aspartic acid). Ras mutations in cancer are associated with poor prognosis. In mice, inactivation of oncogenic Ras leads to tumor shrinkage. Therefore, Ras is widely considered an extremely important tumor target.

[0006] Therefore, there is an urgent need for therapies targeting KRas-mediated cancers with G12D mutations. Summary of the Invention

[0007] This article provides solutions to the above-mentioned problems and other problems in this field.

[0008] In a first aspect, this document provides a compound of formula (I) as described herein, or a stereoisomer, transisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0009] In some embodiments, the compound is a compound as shown in Table 1 or a stereoisomer, transisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0010] In another respect, this article provides a pharmaceutical composition comprising a compound as described herein, a stereoisomer, a transisomer, a tautomer, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0011] On the other hand, this article provides a method for treating cancers containing KRas mutations, which involves administering to a patient with such cancer a compound described herein, its stereoisomers, transtransfer isomers, tautomers, or pharmaceutically acceptable salts.

[0012] On the other hand, this article provides a method for modulating the activity of a KRas mutant protein, which includes reacting the mutant protein with a compound as described herein or a stereoisomer, transtransferase isomer, tautomer, or pharmaceutically acceptable salt thereof.

[0013] On the other hand, this article provides a method for inhibiting cell population proliferation, which includes contacting the cell population with a compound as described herein or a stereoisomer, transtransfer isomer, tautomer, or pharmaceutically acceptable salt thereof.

[0014] On the other hand, this article provides a method for inhibiting tumor metastasis, comprising administering to an individual in need a therapeutically effective amount of a compound as described herein or a stereoisomer, transmetastatic isomer, tautomer, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described herein, to the individual in need.

[0015] On the other hand, this article provides a method for preparing a labeled KRas G12D mutant protein, the method comprising reacting the KRas G12D mutant protein with a labeled compound as described herein, or a stereoisomer, transtransfer isomer, tautomer, or pharmaceutically acceptable salt thereof, to produce the labeled KRas G12D mutant protein. Detailed Implementation

[0016] definition

[0017] This document discloses linear-substituted oxazolidin-5-one compounds or their stereoisomers, transisomers, tautomers, or pharmaceutically acceptable salts, as described herein, and pharmaceutical compositions thereof, which in some embodiments are inhibitors or modulators of mutant KRas. In some cases, such compounds and compositions are inhibitors or modulators of mutant G12D KRas as provided herein. The compounds and compositions described herein can be used to treat mutant KRas (including KRas...) G12D Diseases and disorders mediated by mutations.

[0018] While the disclosure herein provides enumerated embodiments, it should be understood that they are not intended to limit the compounds and methods described herein to those embodiments. Rather, this disclosure is intended to cover all alternatives, modifications, and equivalents that may be included within the scope of this disclosure as defined by the claims.

[0019] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. All publications, patent applications, patents, and other references mentioned herein are incorporated herein by reference in their entirety. Unless otherwise stated, the nomenclature used in this application is based on the IUPAC system of nomenclature.

[0020] The following definitions are provided to aid in understanding certain terms frequently used herein and are not intended to limit the scope of this disclosure. All references cited herein are incorporated herein in their entirety.

[0021] The terms "halogen" and "halo" are used interchangeably and refer to F, Cl, Br, or I. Additionally, terms such as "haloalkyl" indicate a range including monohaloalkyl, polyhaloalkyl, and perhaloalkyl.

[0022] The term "alkyl" refers to a saturated straight-chain or branched monovalent hydrocarbon group. In one instance, an alkyl group has one to eighteen carbon atoms (C1 to C2). 1-18 In other examples, the alkyl group is C1. 1-12 C 1-10 C 1-8C 1-6 C 1-5 C 1-4 Or C 1-3 Examples of alkyl groups include methyl (Me, –CH3), ethyl (Et, –CH2CH3), 1-propyl (n-Pr, n-propyl, –CH2CH2CH3), 2-propyl (i-Pr, isopropyl, –CH(CH3)2), 1-butyl (n-Bu, n-butyl, –CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, isobutyl, –CH2CH(CH3)2), and 2-butyl (s-Bu, sec-butyl, –CH(CH3)CH2). CH3), 2-methyl-2-propyl (t-Bu, tert-butyl, –C(CH3)3), 1-pentyl (n-pentyl, –CH2CH2CH2CH2CH3), 2-pentyl (–CH(CH3)CH2CH2CH3), 3-pentyl (–CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (–CH(CH3)CH(CH3)2), 3-methyl-1-butyl (–CH2C) H2CH(CH3)2), 2-methyl-1-butyl (–CH2CH(CH3)CH2CH3), 1-hexyl (–CH2CH2CH2CH2CH2CH3), 2-hexyl (–CH(CH3)CH2CH2CH2CH3), 3-hexyl (–CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (–C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (–CH(CH3)CH (CH3)CH2CH3), 4-methyl-2-pentyl (–CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (–C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (–CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (–C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (–CH(CH3)C(CH3)3), 1-heptyl and 1-octyl.

[0023] The term "oxo" refers to the =O group, that is, an oxygen atom double-bonded to a second atom other than oxygen. When used as a cyclic substituent, it means that a cyclic atom, such as a carbon atom, is bonded to an oxygen atom other than the cyclic atom via a double bond.

[0024] The term "alkoxy" refers to –O–alkyl.

[0025] The terms "cyano" or "nitrile" refer to –C≡N or –CN.

[0026] The term "haloalkoxy" refers to –O-haloalkyl.

[0027] The terms "hydroxyl" and "hydroxyl group" refer to –OH.

[0028] The term "alkenyl" refers to a straight-chain or branched monovalent hydrocarbon group having at least one carbon-carbon double bond, and includes groups having "cis" and "trans" orientations, or alternatively "E" and "Z" orientations. In one example, an alkenyl group has two to eighteen carbon atoms (C2, C2, C3, C4, C5, C6, C7, C8, C9 ... 2-18 In other examples, the alkenyl group is C. 2-12 C 2-10 C 2-8 C 2-6 Or C 2-3 Examples include, but are not limited to, ethenyl (–CH=CH2), propenyl (–CH=CHCH3), propenyl (–CH2CH=CH2), 2-methylpropenyl, butenyl, butenyl, butenyl, butenyl, butenyl, butenyl, 1,3-dienyl, 2-methylbutenyl, hexenyl, hexenyl, 2-dienyl, hexenyl, 3-dienyl, hexenyl, 4-dienyl, and hexenyl, 1,3-dienyl.

[0029] The term "alkynyl" refers to a straight-chain or branched monovalent hydrocarbon group having at least one carbon-carbon triple bond. In one instance, an alkynyl group has two to eighteen carbon atoms (C2-C4). 2-18 In other instances, the ynyl group is C. 2-12 C 2-10 C 2-8 C 2-6 Or C 2-3 Examples include, but are not limited to, ethynyl (–C≡CH), propynyl (–C≡CCH3), propynyl (propynyl, –CH2C≡CH), butynyl, butynyl, and butynyl.

[0030] The term "alkylene" refers to a saturated, branched, or straight-chain hydrocarbon group having two monovalent radical centers obtained by removing two hydrogen atoms from the same or two different carbon atoms of the parent alkane. In one example, a divalent alkylene group has one to eighteen carbon atoms (C1 to C2). 1-18 In other examples, the divalent alkylene group is C. 1-12 C 1-10 C 1-8 C 1-6 C 1-5 C 1-4 Or C 1-3Examples of alkylene groups include methylene (–CH2–), 1,1-ethyl (–CH(CH3)–), 1,2-ethyl (–CH2CH2–), 1,1-propyl (–CH(CH2CH3)–), 2,2-propyl (–C(CH3)2–), 1,2-propyl (–CH(CH3)CH2–), 1,3-propyl (–CH2CH2CH2–), 1,1-dimethylethyl-1,2-diyl (–C(CH3)2CH2–), 1,4-butyl (–CH2CH2CH2CH2–), etc.

[0031] A cyclic (ring-containing) portion contains atoms bonded together in a ring and has one or more substituents that are non-hydrogen atoms bonded to one or more ring atoms. Each atom in the ring defines a vertex of the polygon. A cyclic ring can be a monocyclic (i.e., having one ring) or a polycyclic (e.g., a bicyclic (i.e., having two rings), a tricyclic (i.e., having three rings)).

[0032] If two ring atoms are bonded to each other in a ring, they are adjacent to each other in that ring. In a ring with four or more ring atoms, adjacent atoms are bonded to each other but not to other atoms in the same ring. In a ternary ring, each atom must be bonded to every other atom in the ring. Two adjacent ring atoms define an "edge" of the ring.

[0033] Two or more ring-shaped portions can be joined together in one of several ways to form a ring system containing more than one ring.

[0034] If two ring atoms in two rings are adjacent to each other in both rings and are shared by both rings, then the two rings are fused together. Such rings are said to share a common "edge".

[0035] A spirocyclic ring system consists of a pair of rings sharing a single vertex. Such a system contains a ring junction at which the two rings share a single ring atom.

[0036] Bridged ring systems contain at least one pair of rings, in which two or more non-adjacent ring atoms are shared by two or more rings. The two non-adjacent ring atoms in question are called "bridgehead" atoms, and the pair of bridgehead atoms are members of three different rings. Examples of carbocyclic groups containing bridged bicyclic rings are norbornyl and adamantyl.

[0037] A chain ring system contains two or more rings connected to each other but sharing no common ring atoms: one ring is a substituent for the other, and vice versa. Each ring in a chain ring system can be independently a carbocyclic or heterocyclic ring, and can be aromatic, saturated, or partially unsaturated. Biphenyl is an example of a chain ring system.

[0038] A ring system may contain pairs of rings that are fused together or chained, screwed together or bridged together, or in the case of three or more rings, joined together in a combination.

[0039] As used herein, the term "carbon ring" refers to a ring with a specified number of carbon atoms (i.e., C atoms). 3-10 A carbocyclic group refers to an aromatic, saturated, or unsaturated cyclic monovalent hydrocarbon group (meaning three to ten carbon atoms). A carbocyclic group has a single ring (“monocyclic”) or more than one ring (more generally, “bicyclic,” “tricyclic,” or polycyclic). Two or more carbocyclic rings can be joined together by fusion, spirocyclic, bridging, or chain linkages, as further described elsewhere in this document.

[0040] The term "carbocyclic" is intended to encompass groups having one or more adjacent pairs of ring atoms bonded together by a double bond, and where, in the presence of more than one such double bond, the double bonds may or may not form a conjugated system within the ring. Thus, carbocyclic groups may be specified more specifically based on whether they are fully saturated ("cycloalkyl"), at least partially unsaturated ("cycloalkenyl"), or fully conjugated ("aromatic" or "aryl"). A cycloalkyl group is a fully saturated group and is obtained by removing a hydrogen atom from a carbon atom of a parent cycloalkane. A specific cycloalkyl group is one having 3 to 12 ring carbon atoms (C12, C23, C24, C25, C26 ... 3-12 The cycloalkyl group is a group having 3 to 8 cyclic carbon atoms (“C”). 3-8 -cycloalkyl) or having 3 to 6 carbon atoms ("C-cycloalkyl") or having 3 to 6 carbon atoms ("C-cycloalkyl") 3-6 A monocyclic hydrocarbon of the form "-cycloalkyl". In other examples, the cycloalkyl group is C10. 3-4 C 3-5 C 3-7 C 3-8 C 3-10 C 3-10 Or C 5-10 In other examples, the cycloalkyl group, which is a monocyclic ring, is C10. 3-4 C 3-8 C 3-6 Or C 5-6 In another example, the cycloalkyl group in the spirocyclic system is C. 5-12 In another example, the cycloalkyl group in the bicyclic ring is C7-C. 12 Monocyclic cycloalkyl groups have the formula C n H 2n−1Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Cycloalkenyl groups have one or more double bonds between adjacent ring carbon atoms. Examples of cycloalkenyl groups include 1-cyclohex-1-enyl and 1-cyclohex-3-enyl. Examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl. Exemplary arrangements of bicyclic cycloalkyl groups having 7 to 12 ring atoms include, but are not limited to, [4,4], [4,5], [5,5], [5,6], or [6,6] ring systems. Exemplary bridged bicyclic cycloalkyl groups include, but are not limited to, bicyclic [2.2.1]heptane, bicyclic [2.2.2]octane, and bicyclic [3.2.2]nonane. Examples of spirocycloalkyl groups include spiro[2.2]pentane, spiro[2.3]hexane, spiro[2.4]heptane, spiro[2.5]octane and spiro[4.5]decane.

[0041] As used herein, "aryl" refers to a carbocyclic group having a single aromatic ring (e.g., phenyl) or multiple fused aromatic rings (e.g., naphthyl). Preferably, the aryl group comprises 6 to 20 carbon atoms, more preferably 6 to 12 carbon atoms. Particularly preferred aryl groups are those having 6 to 14 cyclic carbon atoms ("C"). 6-14 A group consisting of "-aryl". The term aromatic is used in this document in the same way it is usually used in organic chemistry, which means (with a few recognized exceptions) that a ring atom in a ring and a ring system contributes a total of (4n+2) π electrons to a set of delocalized molecular orbitals, where n is a non-zero positive integer.

[0042] Typical aryl groups include, but are not limited to, groups derived from fused ring systems or conjugated ring systems containing one or more aromatic rings, such as, but not limited to, acenaphthene, phenanthrene, anthracene, azulene, benzene, phenanthrene, fluoranthene, heptaphenene, hexaphenylene, hexanthene, asymmetric indole, symmetric indole, indene, naphthalene (hexaphenylene), octaphenylene, octaphenylene, octaphenylene, meta-anthracene tetraphenylene, pentanebenzene, cyclopentadiene, pentaphenylene, perylene, phenanthracene, phenanthrene, dinaphthenebenzene, heptaphenylene, pyrene, pinane, rubidium, tetraphenylene, benzophenanthrene, and trinaphthene.

[0043] The terms “heterocyclic group,” “heterocyclic,” “heterocyclic,” “heterocyclic base,” or “heterocyclic ring” are used interchangeably and refer to any monocyclic, bicyclic, tricyclic, chain, fused, spirocyclic, or bridged, saturated, partially saturated, or unsaturated, non-aromatic ring system having 3 to 20 ring atoms, wherein the ring atoms are carbon, and at least one atom in the ring or ring system is a heteroatom selected from nitrogen, sulfur, or oxygen. If any ring atom in the cyclic system is a heteroatom, the system is heterocyclic, regardless of the connection point between the cyclic system and the rest of the molecule. In one example, a heterocyclic base comprises 3 to 10 ring atoms (“units”) and includes monocyclic, bicyclic, tricyclic, spirocyclic, and bridged ring systems, wherein the ring atoms are carbon, and at least one atom in the ring or ring system is a heteroatom selected from nitrogen, sulfur, or oxygen. In other examples, a heterocyclic base comprises 4 to 10 or 5 to 10 ring atoms. In one example, a heterocyclic base comprises 1 to 4 heteroatoms. In one example, the heterocyclic group comprises 1 to 3 heteroatoms. In another example, the heterocyclic group comprises a 3- to 7-membered monocyclic ring having 1-2, 1-3, or 1-4 heteroatoms selected from nitrogen, sulfur, or oxygen. In another example, the heterocyclic group comprises a 4- to 6-membered monocyclic ring having 1-2, 1-3, or 1-4 heteroatoms selected from nitrogen, sulfur, or oxygen. In another example, the heterocyclic group comprises a 3-membered monocyclic ring. In another example, the heterocyclic group comprises a 4-membered monocyclic ring. In another example, the heterocyclic group comprises a 5- to 6-membered monocyclic ring. In some embodiments, the heterocyclic alkyl group comprises at least one nitrogen atom. In one example, the heterocyclic group comprises 0 to 3 double bonds. Any nitrogen or sulfur heteroatom may optionally be oxidized (e.g., NO, SO, SO2), and any nitrogen heteroatom may optionally be quaternized (e.g., [NR4]). + Cl - [NR4] + OH -Examples of heterocycles include oxetane, aziridinyl, thioheteropropyl, aziridinyl, oxetane, thioheteropropyl, 1,2-dithioheteropropyl, 1,3-dithioheteropropyl, pyrrolidinyl, dihydro-1H-pyrrolidinyl, dihydrofuranyl, tetrahydrofuranyl, dihydrothiopheneyl, tetrahydrothiopheneyl, imidazoalkyl, piperidinyl, piperazinyl, isoquinolinyl, tetrahydroisoquinolinyl, morpholinyl, thiomorpholinyl, 1,1-dioxothiomorpholinyl, dihydropyranyl, tetrahydropyranyl, hexahydrothiopyranyl, hexahydropyrimidinyl, oxazinyl, thiazinyl, thiaxanyl, homopiperazinyl, homopiperidinyl, aziridinyl-heptyl, and oxetane. Heptyl, thioheptyl, oxazolidinyl, oxazolidinyl, diazabinyl, 1,4-diazabinyl, diazadinyl, thioheptyl, thioheptyl, tetrahydrothiopyranyl, oxazolidinyl, thiazolyl, isothiazolidinyl, 1,1-dioxoisothiazolidinone, 1,1-dioxoisothiazolyl, oxazolidinone, imidazolinone, 4,5,6,7-tetrahydro[2H]inzolyl, tetrahydrobenzimidazolyl, 4,5,6,7-tetrahydrobenzimidazolyl, thiazinyl, oxazinyl, thiadiazinyl, oxadiazinyl, dithiazinyl, dioxazinyl, oxthiazinyl, thiatriazinyl, oxatriazinyl, dithiadiazinyl Azinyl, imidazolinyl, dihydropyrimidinyl, tetrahydropyrimidinyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, thiaranyl, 2H-pyranyl, 4H-pyranyl, dioxalyl, 1,3-dioxolanecycloyl, pyrazolinyl, pyrazolylalkyl, dithiaranyl, dithiacyclopentyl, pyrimidinoneyl, pyrimidinedionyl, pyrimidin-2,4-diketoneyl, piperazinoneyl, piperazinedionyl, pyrazolinylimidazolinyl, 3-azabicyclo[3.1.0]hexyl, 3,6-diazabicyclo[3.1.1]heptyl, 6-azabicyclo[3.1.1]heptyl, 3 ... Bicyclo[4.1.0]heptyl, azabicyclo[2.2.2]hexyl, 2-azabicyclo[3.2.1]octyl, 8-azabicyclo[3.2.1]octyl, 2-azabicyclo[2.2.2]octyl, 8-azabicyclo[2.2.2]octyl, 7-oxabicyclo[2.2.1]heptane, azaspiro[3.5]nonyl, azaspiro[2.5]octyl, azaspiro[4.5]decyl, 1-azaspiro[4.5]decane-2-keto, azaspiro[5.5]undecyl, tetrahydroindolyl, octahydroindolyl, tetrahydroisoindolyl, tetrahydroindazoleyl, 1,1-dioxahexahydrothiopyranyl.

[0044] In a particular embodiment, the heterocyclic group or heteroaryl group is attached at the carbon atom of the heterocyclic group or heteroaryl group. By way of example, carbon-bonded heterocyclic groups include the following bonding arrangements: at positions 2, 3, 4, 5, or 6 of the pyridine ring; at positions 3, 4, 5, or 6 of the pyridazine ring; at positions 2, 4, 5, or 6 of the pyrazine ring; at positions 2, 3, 5, or 6 of the furan, tetrahydrofuran, thiofuran, thiophene, pyrrole, or tetrahydropyrrole ring; at positions 2, 4, or 5 of the oxazole, imidazole, or thiazole ring; at positions 3, 4, or 5 of the isoxazole, pyrazole, or isothiazole ring; at positions 2 or 3 of the aziridine ring; at positions 2, 3, or 4 of the azacyclic butane ring; at positions 2, 3, 4, 5, 6, 7, or 8 of the quinoline ring; or at positions 1, 3, 4, 5, 6, 7, or 8 of the isoquinoline ring.

[0045] In some embodiments, the heterocyclic or heteroaryl group is N-linked. By way of example, nitrogen-bonded heterocyclic or heteroaryl groups include the following bonding arrangements: at the 1 position of aziridine, aziridine, pyrrole, pyrrolidine, 2-pyrrololine, 3-pyrrololine, imidazole, imidazoleidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, dihydroindole, 1H-indazole, at the 2 position of isoindole or isodihydroindole, at the 4 position of morpholine, and at the 9 position of carbazole or β-carboline.

[0046] Heterocyclic rings can form fusion, spiral, or bridging connections with one or more other rings, or any combination of such connections.

[0047] As used herein, "heteroaryl" or "heteroaromatic" refers to an aromatic cyclic group having 1 to 14 ring carbon atoms and at least one ring heteroatom (including, but not limited to, heteroatoms such as nitrogen, phosphorus, oxygen, and sulfur). The term refers to a monovalent heteroaromatic group derived by removing a hydrogen atom from a single ring atom of a parent heteroaromatic ring system. Heteroaryl groups can have a monocyclic ring (e.g., pyridyl, furanyl) or multiple fused rings (e.g., indenyl, benzothiophene). Specific heteroaryl groups are 5- to 14-membered rings having 1 to 12 cyclic (i.e., ring) carbon atoms and 1 to 6 cyclic (i.e., ring) heteroatoms independently selected from nitrogen, phosphorus, oxygen, and sulfur; 5- to 10-membered rings having 1 to 8 cyclic carbon atoms and 1 to 4 cyclic heteroatoms independently selected from nitrogen, phosphorus, oxygen, and sulfur; and 5-, 6-, or 7-membered rings having 1 to 5 cyclic carbon atoms and 1 to 4 cyclic heteroatoms independently selected from nitrogen, oxygen, and sulfur. In one variant, the heteroaryl group comprises a monocyclic aromatic 5-, 6-, or 7-membered ring having 1 to 6 cyclic carbon atoms and 1 to 4 cyclic heteroatoms independently selected from nitrogen, oxygen, and sulfur. In another variant, the heteroaryl group comprises a polycyclic aromatic ring having 1 to 12 cyclic carbon atoms and 1 to 6 cyclic heteroatoms independently selected from nitrogen, phosphorus, oxygen, and sulfur.

[0048] Typical heteroaryl groups include, but are not limited to, those derived from the following groups: acridine, arsine, carbazole, p-carboline, chromene, chromene, zoline, furan, imidazole, indazole, indole, indolline, indolizine, isobenzofuran, isochromene, isoindole, isoindolline, isoquinoline, isothiazole, isoxazole, naphthidine, oxadiazole, oxazole, chloridine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrrolizine, quinazoline, quinoline, quinazine, quinoxaline, tetrazolium, thiadiazole, thiazolium, thiophene, triazole, xanthene, etc. Preferred heteroaryl groups are thiophene, pyrrole, benzothiophene, benzofuran, indole, pyridine, quinoline, imidazole, oxazole, and pyrazine, as well as those derived from them.

[0049] Different types of rings can be connected to each other, such as by fusion, helical or bridging, or by combinations thereof. Such ring systems can be called "hybrid" ring systems.

[0050] For example, at least one ring in a multi-ring system may be aromatic, although one or more of the remaining fused rings may not be aromatic. Examples of fused-ring systems containing at least one aromatic ring and at least one partially saturated ring include fluorene, indane, and biphenylene.

[0051] A mixed-ring system having more than one ring (at least one of which is aromatic and at least one of which is non-aromatic) can be attached to another structure by bonding to an aromatic ring atom or a non-aromatic ring atom.

[0052] A heteroaryl group having more than one ring (at least one of which is non-aromatic) can be attached to another structure at an aromatic ring position or at a non-aromatic ring position.

[0053] Similarly, carbocyclic and heterocyclic groups can join each other in one of several ways to form a cyclic system containing more than one ring.

[0054] "Heteroatom" refers to any atom other than carbon or hydrogen. Typical heteroatoms found in small organic molecules are selected from nitrogen, oxygen, fluorine, phosphorus, sulfur, chlorine, and bromine. Those skilled in the art will understand that when the term "heteroatom" is used to refer to a member of a ring (e.g., a heteroaromatic ring), monovalent heteroatoms such as halogens are excluded.

[0055] "Fused" means any ring structure described herein that shares one or more atoms (e.g., carbon or nitrogen atoms) with existing ring structures in the compounds described herein.

[0056] The term "acyl" refers to a carbonyl-containing substituent represented by the formula –C(=O)-R, where R is a substituent such as hydrogen, alkyl, cycloalkyl, aryl, or heterocyclic, wherein alkyl, cycloalkyl, aryl, and heterocyclic are as defined herein. Acyl groups include alkylacyl (e.g., acetyl), aromatic acyl (e.g., benzoyl), and heteroaromatic acyl (e.g., pyridinyl).

[0057] The term "haloalkyl" refers to an alkyl chain in which one or more hydrogen atoms have been substituted with a halogen. The term "haloalkyl" encompasses monohaloalkyl, polyhaloalkyl, and perhaloalkyl. Examples of haloalkyl are trifluoromethyl, difluoromethyl, and fluoromethyl. A substituted haloalkyl is a haloalkyl having a moiety other than a halogen. An unsubstituted haloalkyl is a haloalkyl as described herein that has not undergone partial substitution other than hydrogen or halogen.

[0058] As used in this article, the wavy lines intersecting with bonds in the chemical structure " "" indicates the connection point between an atom and the rest of the molecule or a segment of a molecule, which is connected to a wavy bond in the chemical structure.

[0059] In some embodiments, the divalent group is generally described as not having a specific bonding configuration. It should be understood that, unless otherwise stated, the general description is intended to include both bonding configurations. For example, unless otherwise specified, in group R... 1 -R 2 -R 3 In, if group R2 If described as -CH2C(O)-, it should be understood that this group can act as R. 1 -CH2C(O)-R 3 and R 1 -C(O)CH2-R 3 Bonding.

[0060] The term "pharmaceutical acceptable" means that a molecular entity or composition, when properly administered to animals (such as, for example, humans), does not produce adverse, allergic, or other adverse reactions.

[0061] The compounds described herein may be in the form of salts, such as pharmaceutically acceptable salts. "Pharmaceutically acceptable salts" include acid addition salts and base addition salts. "Pharmaceutically acceptable acid addition salts" refer to those salts that, when formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, and phosphoric acid, retain the bioavailability and properties of the free base and have no adverse effects on biology or otherwise. The organic acids may be selected from aliphatic, alicyclic, aromatic, arylaliphatic, heterocyclic, carboxylic acid, and sulfonic acid organic acids, such as formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, embrittlement acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc.

[0062] The term "pharmaceutically acceptable base addition salt" includes salts derived from inorganic bases, such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Specific base addition salts are ammonium, potassium, sodium, calcium, and magnesium salts. Salts derived from pharmaceutically acceptable non-toxic organic bases include primary, secondary, and tertiary amines. Substituted amines include naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, tromethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrazine, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, and polyamine resins. Specific non-toxic organic alkaloids include isopropylamine, diethylamine, ethanolamine, tromethamine, dicyclohexylamine, choline, and caffeine.

[0063] In some embodiments, the salt is selected from hydrochloride, hydrobromide, trifluoroacetate, sulfate, phosphate, acetate, fumarate, maleate, tartrate, lactate, citrate, pyruvate, succinate, oxalate, methanesulfonate, p-toluenesulfonate, hydrogen sulfate, benzenesulfonate, ethanesulfonate, malonate, sinesulfonate, ascorbate, oleate, nicotinate, saccharin salt, adipate, formate, glycolate, palmitate, L-lactate, D-lactate, aspartate, malate, L-tartrate, D-tartrate, stearate, furoate (e.g., 2-furonate or 3-furonate), naphthalene disulfonate (naphthalene-1,5-disulfonate or naphthalene-1-(sulfonic acid)-5-sulfonate), ethanedisulfonate (ethane-1,2-disulfonate). Salts or ethane-1-(sulfonic acid)-2-sulfonates), hydroxyethanesulfonates (2-hydroxyethylsulfonate), 2-tris(methyl)toluenesulfonate, 2-naphthalenesulfonate, 2,5-dichlorobenzenesulfonate, D-mandelate, L-mandelate, cinnamate, benzoate, adipate, ethanesulfonate, malonate, tris(methyl)toluenesulfonate (2-tris(methyl)toluenesulfonate), naphthalenesulfonate (2-naphthalenesulfonate), camphorsulfonate (camphor-10-sulfonate, e.g., (1S)-(+)-10-camphorsulfonate), glutamate, glutarate, hippurate (2-(benzoylamino)acetate), orotic acid salts, xylene salts (p-xylene-2-sulfonate), and pamoate (2,2'-dihydroxy-1,1'-dinaphthylmethane-3,3'-dicarboxylic acid ester).

[0064] "Sterile" preparations are sterile or free of all living microorganisms and their spores.

[0065] The term "stereoisomer" refers to compounds that have the same chemical composition but differ in the spatial arrangement of atoms or groups. Stereoisomers include diastereomers, enantiomers, transisomers, and conformational isomers.

[0066] The term "chirality" refers to a molecule that has the property of not overlapping with its mirror-image partner, while the term "chirality" refers to a molecule that can overlap with its mirror-image partner.

[0067] The term "diastereomer" refers to a stereoisomer that has two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting point, boiling point, spectral properties, or biological activity. Mixtures of diastereomers can be separated using high-resolution analytical procedures (such as electrophoresis) and chromatographic methods (such as HPLC).

[0068] The term "enantiomer" refers to two stereoisomers of a compound that are non-overlapping mirror images of each other.

[0069] The term "restricted rotation isomer" refers to two conformational isomers produced by restricted rotation around a single bond, where the spatial strain barrier of the rotation can be high enough to allow separation of each conformational isomer.

[0070] The stereochemical definitions and conventions used in this article generally follow those of SP Parker, ed., McGraw-Hill Dictionary of Chemical Terms (1984), McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., “Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., New York, 1994. Many organic compounds exist in an optically active form, meaning they possess the ability to rotate the plane of polarized light. In describing optically active compounds, the prefixes D and L or R and S are used to indicate the absolute configuration of the molecule around its chiral center. The prefixes d and l or (+) and (-) are used to indicate the symbol for the rotation of the compound with respect to plane-polarized light, where (-) or l indicates that the compound is levorotatory. Compounds with the prefix (+) or d are dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. Specific stereoisomers can also be called enantiomers, and mixtures of such isomers are generally referred to as enantiomeric mixtures. A 50:50 mixture of enantiomers is called a racemic mixture or racemate, which may occur in a chemical reaction or process without stereoselectivity or stereospecificity. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two optically inactive enantiomer species.

[0071] The terms "tautomer" or "tautomer form" refer to structural isomers with different energies that interconvert through low-barrier transformations. For example, proton tautomers (also known as proton-transfer tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerization. Valence tautomers include interconversions that occur through the recombination of some bonding electrons.

[0072] Some of the compounds described herein can exist in both non-solvent and solvated forms, including hydrated forms. A “solvent” is an association or complex of one or more solvent molecules with a compound described herein. Examples of solvents that form solvates include water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine. Some of the compounds described herein can exist in a variety of crystalline or amorphous forms. Generally, all physical forms are envisioned herein. The term “hydrate” refers to a complex in which the solvent molecule is water.

[0073] The compounds described herein and their pharmaceutically acceptable salts may contain one or more asymmetric carbon atoms. Therefore, the compounds may exist as diastereomers, enantiomers, or mixtures thereof. The synthesis of the compounds may employ racemic, diastereomer, or enantiomer as starting materials or intermediates. Mixtures of specific diastereomer compounds may be separated or enriched into one or more specific diastereomers by chromatography or crystallization. Similarly, mixtures of enantiomers may be separated or enriched using the same techniques or other techniques known in the art. Each of the asymmetric carbon or nitrogen atoms may be of an R or S configuration, and both of these configurations are contemplated herein.

[0074] In the structures shown herein, where the stereochemistry of any particular chiral atom is not specified, all stereoisomers are contemplated and included. When the stereochemistry is specified by a solid wedge or dashed line indicating a specific configuration, that stereoisomer is designated and defined. Unless otherwise stated, the use of a solid wedge or dashed line signifies relative stereochemistry.

[0075] The terms “subject,” “individual,” or “patient” refer to vertebrates and are used interchangeably herein. In some embodiments, the vertebrate is a mammal. Mammals include, but are not limited to, livestock (such as cattle), locomotives, pets (such as guinea pigs, cats, dogs, rabbits, and horses), primates, mice, and rats. In some embodiments, the mammal is a human. In embodiments that include administration of the compound to a patient, the patient is typically a patient who needs it.

[0076] The terms “inhibition” and “reduction”, or any variations thereof, including any measurable reduction or complete inhibition, to achieve the desired result. For example, compared to normal, activity may be reduced by about, at most about, or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99% or more, or any range derived therefrom.

[0077] The term "treatment" refers to a clinical intervention aimed at altering the natural course of the treated patient or cells during the course of clinicopathological development. Ideal treatment outcomes include slowing disease progression, alleviating or reducing disease conditions, and improving or resolving prognosis. For example, a patient is considered successfully "treated" if one or more symptoms associated with the cancer described herein are reduced or eliminated, including but not limited to reducing cancer cell proliferation (or destroying cancer cells), alleviating symptoms caused by the disease, improving the quality of life of a patient with the disease, reducing the dosage of other medications required to treat the disease, and / or prolonging the patient's survival.

[0078] The term "delayed progression" in the context of a disease refers to the postponement, halting, slowing, stabilizing, and / or delaying of the progression of the cancer described herein. Such delay can vary in length depending on the patient's cancer history and / or the patient's condition. It will be apparent to those skilled in the art that sufficient or significant delay can effectively encompass prevention, as the patient will not develop cancer or experience a recurrence.

[0079] "Mutant KRas-mediated diseases" refers to diseases described herein (e.g., cancers described herein) that have symptoms as described herein or require treatment, and these symptoms are wholly or partially associated with, as a result of, functionally related to, or otherwise related to the mutant KRas activity described herein. In one such embodiment, the mutant KRas is KRas G12D .

[0080] "Effective dose" or "therapeutic effective dose" is the minimum amount required to achieve at least a measurable improvement or prevention of the cancer described herein. The effective dose described herein can vary depending on factors such as the patient's disease state, age, sex, and weight, and the ability of the agent to elicit the expected response in the patient. An effective dose is also the amount in which the beneficial effects of treatment outweigh any toxic or adverse effects of treatment. Beneficial or desired outcomes include, for example: elimination or reduction of risk, reduction of severity, delay of disease onset (including biochemical, histological, and / or behavioral symptoms of the disease that occur during disease development, its complications, and intermediate pathological phenotypes), reduction of one or more symptoms caused by the disease, improvement of the quality of life of patients with the disease, reduction of the dosage of other drugs required to treat the disease, enhancement of the effects of another drug (e.g., by targeting), delay of disease progression, and / or prolongation of survival. In some embodiments, an effective dose of the drug may have the following effects: reduction of the number of cancer cells; reduction of tumor size; inhibition (i.e., slowing or stopping) of the invasion of cancer cells into surrounding organs; inhibition (i.e., slowing or stopping) of tumor metastasis; inhibition (i.e., slowing or stopping) of tumor growth; and / or relief of one or more of the symptoms associated with the disease. The effective dose can be applied once or multiple times.

[0081] As used herein, the terms “co-administration,” “combination administration,” and their grammatical equivalents cover the administration of two or more formulations to an animal (including a human) such that both formulations and / or their metabolites are present in the subject. Co-administration includes simultaneous administration of a single composition, administration of a single composition at different times (i.e., sequential administration), or administration of a composition in which both agents are present.

[0082] The term "packaging insert" is used to refer to instructions that are typically included in the commercial packaging of therapeutic products, which contain information concerning the indications, usage, dosage, administration, contraindications, and / or warnings related to the use of such therapeutic products.

[0083] The terms “antagonist” and “inhibitor” are used interchangeably, and they refer to compounds that have the ability to inhibit the biological function of a target protein, whether by inhibiting the activity or expression of a mutant form of that protein, such as KRas. Therefore, the terms “antagonist” and “inhibitor” are defined in the context of the biological function of the target protein. While the antagonists preferred herein interact specifically with the target (e.g., bind), compounds that inhibit the biological activity of a target protein by interacting with other members of the signal transduction pathway in which the target protein is a member are also specifically included within this definition. Preferred biological activities inhibited by antagonists are associated with tumorigenesis, growth, or metastasis.

[0084] As used herein, the term "agonist" refers to a compound that has the ability to initiate or enhance the biological function of a target protein, whether by inhibiting the activity or expression of that target protein. Therefore, the term "agonist" is defined in the context of the biological action of the target polypeptide. While the preferred agonists herein interact specifically with the target (e.g., bind), compounds that initiate or enhance the biological activity of a target polypeptide by interacting with other members of the signal transduction pathway in which the target polypeptide is a member are also specifically included within this definition.

[0085] The terms “cancer” and “cancerous,” “vesicle” and “tumor,” as well as related terms, are used interchangeably in this document and refer to or describe a physiological condition in mammals typically characterized by uncontrolled cell growth. A “tumor” contains one or more cancer cells. Examples of cancer include carcinomas, germ cell tumors, sarcomas, seminomas, glioblastomas, melanomas, leukemias, and myeloid or lymphoid malignancies. More specific examples of such cancers include squamous cell carcinoma (e.g., epithelial squamous cell carcinoma) and lung cancer (including small cell lung cancer, non-small cell lung cancer (“NSCLC”), lung adenocarcinoma, and lung squamous cell carcinoma). Other cancers include skin, keratoacanthoma, follicular carcinoma, hairy cell leukemia, buccal cavity, pharynx (oral cavity), lips, tongue, mouth, salivary glands, esophagus, larynx, hepatocellular carcinoma, stomach, gastrointestinal tract, small intestine, large intestine, pancreas, cervix, ovary, liver, bladder, hepatocellular carcinoma, breast, colon, rectum, colorectal, genitourinary system, biliary tract, thyroid, papillary, hepatic, endometrium, uterus, salivary glands, kidney or renal, prostate, testis, vulva, peritoneum, anus, penis, bone, multiple myeloma, B-cell lymphoma, diffuse large B-cell lymphoma (DLBCL), central nervous system, brain, head and neck, Hodgkin's disease, and related metastases. Other examples of myeloproliferative disorders include myeloproliferative disorders such as polycythemia vera, essential thrombocythemia, myelofibrosis (such as primary myelofibrosis), and chronic myeloid leukemia (CML).

[0086] A “chemotherapeutic agent” is a preparation that can be used to treat a pre-existing condition, such as cancer or an inflammatory condition. Examples of chemotherapeutic agents are well known in the art. Additionally, chemotherapeutic agents include any pharmaceutically acceptable salt, acid, or derivative of a chemotherapeutic agent, as well as combinations of two or more of them.

[0087] Unless otherwise stated, the structures described herein are also intended to include compounds that differ only in the presence of one or more isotopically rich atoms. Exemplary isotopes that may be incorporated into the compounds described herein or their pharmaceutically acceptable salts include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as... 2 H, 3 H, 11 C 13 C 14 C 13 N、 15 N、 15 O、 17 O、 18 O、 32 P, 33 P, 35 S, 18 F, 36 Cl、 123 I and125 I. Isotope-labeled compounds (e.g., 3 H and 14 C-labeled compounds can be used for the determination of the tissue distribution of compounds or substrates. Tritium (i.e., 3 H) and carbon-14 (i.e., ... 14 C) Isotopes are available because they are easy to prepare and detectable. Furthermore, heavier isotopes such as deuterium (i.e., 2 H) Substitution can provide certain therapeutic advantages due to greater metabolic stability (e.g., increased half-life in vivo or reduced dosage requirement). In some embodiments, one or more carbon atoms are enriched in the compounds described herein or their pharmaceutically acceptable salts. 13 C or 14 Carbon substitution of C. Positron-emitting isotopes (such as...) 15 O、 13 N、 11 C and 18 F) It can be used in positron emission tomography (PET) studies to examine substrate acceptor occupancy. Isotope-labeled compounds can generally be prepared by replacing non-isotope-labeled reagents with isotope-labeled reagents, following procedures similar to those disclosed in the protocols or examples herein.

[0088] Specifically, it is contemplated that any limitations discussed with respect to one embodiment provided herein may apply to any other embodiment provided herein. Furthermore, any compound described herein, its pharmaceutically acceptable salt, or the composition described herein may be used in any method provided herein, and any method provided herein may be used to produce or utilize any compound described herein, its pharmaceutically acceptable salt, or the composition described herein.

[0089] Throughout this application, the term “about” is used to indicate that a value includes the standard deviation of the error of the means or method used to determine that value.

[0090] The compounds described herein may have the stereochemical structures depicted below:

[0091]

[0092] It should be understood that, as described in this article, all three stereochemical diagrams are equivalent.

[0093] compound

[0094] In one respect, this paper provides a compound having the structure of formula (I):

[0095] (I)

[0096] Or its stereoisomers, transtransfer isomers, tautomers, or pharmaceutically acceptable salts.

[0097] in:

[0098] m is 0 or 1;

[0099] n is 0, 1, or 2;

[0100] q is 0 or 1;

[0101] p is 0, 1, or 2;

[0102] Where n + m + q does not exceed 2, and p and q are not both 1;

[0103] R1 is , where R 01 R 02 R 03 R 04 and R 05 Each of these elements is independently hydrogen, halogen, -CN, -NH2, -N(Me)2, C 1-3 Alkyl, C 1-3 Halogenated alkyl or cyclopropyl;

[0104] R2 can be hydrogen, -CN, halogen, or C. 1-3 Alkyl, C 1-3 Halogenated alkyl or cyclopropyl;

[0105] R 3A For hydrogen, halogen, C 1-3 Alkyl or C 1-3 Halogenated alkyl groups, and R 3B It is hydrogen; or R 3A and R 3B Together they form oxygen;

[0106] R 4A and R 4B Each of them is independently hydrogen, C 1-3 Alkyl or C 1-3 Halogenated alkyl groups;

[0107] Or R 4A and R 4B Together with the atoms they bind to, they form 3- to 6-membered monocyclic rings;

[0108] R 3C For hydrogen, halogen, C 1-3 Alkyl or C 1-3 Halogenated alkyl groups;

[0109] R3D It is hydrogen;

[0110] Z represents hydrogen, C represents... 1-3 Alkyl, -L1–Cy, -L1–NR5R6, –OR6 or –SR6;

[0111] in:

[0112] L1 either does not exist or is –C(=O)–;

[0113] R5 is hydrogen, C 1-6 Alkyl or –NH2;

[0114] R6 is C 1-6 Alkyl, -L2–Cy, –C(=O)–Cy, or –C(=O)C 1-6 alkyl;

[0115] L2 is –(CR) 7A R 7B ) u –;

[0116] u is 1, 2, or 3;

[0117] Each R 7A and R 7B Independently hydrogen or C 1-3 alkyl;

[0118] Cy is a 3- to 11-membered ring portion selected from monocyclic, fused bicyclic, bridged bicyclic, two or three chain rings and spirocyclic rings, wherein Cy optionally contains one or more heteroatoms selected from N, O and S and optionally is substituted by one or more R8 atoms;

[0119] Each R8 is independently selected from: optionally by a hydroxyl group or C 1-6 alkoxy-substituted C 1-6 Alkyl; C 1-3 Halogenated alkyl group; halogen; hydroxyl group; cyano group; –C(=O)NR9R 10 –C(=O)OR 10 ;Optionally coated with hydroxyl-C 1-6 Alkyl-substituted C 3-6 Cycloalkyl; and oxo; wherein R9 and R 10 Independently hydrogen or C 1-6 Alkyl; or

[0120] R5 and R6, together with their bonded nitrogen atoms, form a 3- to 6-membered monocyclic ring optionally substituted with one or more groups independently selected from the following: C 1-6 Alkyl and hydroxyl; or

[0121] Z and R2 together with the carbon atoms they are bonded to form 5- to 6-membered monocyclic aromatic rings;

[0122] X is –NR 11 ;and

[0123] R 11 For hydrogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups.

[0124] In some embodiments, this document provides a compound having the structure of formula (I):

[0125] (I)

[0126] Or its stereoisomers, transtransfer isomers, tautomers, or pharmaceutically acceptable salts.

[0127] in:

[0128] m is 0 or 1;

[0129] n is 0, 1, or 2;

[0130] q is 0 or 1;

[0131] p is 0, 1, or 2;

[0132] Where n + m + q does not exceed 2, and p and q are not both 1;

[0133] R1 is , where R 01 R 02 R 03 R 04 and R 05 Each of these elements is independently hydrogen, halogen, -CN, -NH2, -N(Me)2, C 1-3 Alkyl, C 1-3 Halogenated alkyl or cyclopropyl;

[0134] R2 can be hydrogen, cyano, halogen, or C. 1-3 Alkyl, C 1-3 Halogenated alkyl or cyclopropyl;

[0135] R 3A For hydrogen, halogen, C 1-3 Alkyl or C 1-3 Halogenated alkyl groups, and R 3B It is hydrogen; or R 3A and R 3B Together they form oxygen;

[0136] R 4A and R 4B Each of them is independently hydrogen, C 1-3 Alkyl or C 1-3 Halogenated alkyl groups;

[0137] Or R 4A and R 4B Together with the atoms they bind to, they form 3- to 6-membered monocyclic rings;

[0138] R 3C For hydrogen, halogen, C 1-3 Alkyl or C 1-3 Halogenated alkyl groups;

[0139] R 3D It is hydrogen;

[0140] Z represents hydrogen, C represents... 1-3 Alkyl, -L1–Cy, -L1–NR5R6, –OR6 or –SR6;

[0141] in:

[0142] L1 either does not exist or is –C(=O)–;

[0143] R5 is hydrogen, C 1-6 Alkyl or –NH2;

[0144] R6 is C 1-6 Alkyl, -L2–Cy, –C(=O)–Cy, or –C(=O)C 1-6 alkyl;

[0145] L2 is –(CR) 7A R 7B ) u –;

[0146] u is 1, 2, or 3;

[0147] Each R 7A and R 7B Independently hydrogen or C 1-3 alkyl;

[0148] Cy is a 3- to 10-membered ring portion selected from monocyclic, fused bicyclic, bridged bicyclic, two or three chain rings and spirocyclic rings, wherein Cy optionally contains one or more heteroatoms selected from N, O and S and optionally is substituted by one or more R8 atoms;

[0149] Each R8 is independently selected from: C14 cells optionally substituted with a hydroxyl group. 1-6 Alkyl; C1-3 Halogenated alkyl group; halogen; hydroxyl group; cyano group; –C(=O)NR9R 10 –C(=O)OR 10 C 3-6 Cycloalkyl; and oxo, wherein R9 and R 10 Each of them is independently hydrogen or C. 1-6 Alkyl; or

[0150] R5 and R6, together with their bonded nitrogen atoms, form a 3- to 6-membered monocyclic ring optionally substituted with one or more groups independently selected from the following: C 1-6 Alkyl and hydroxyl; or

[0151] Z and R2 together with the carbon atoms they are bonded to form 5- to 6-membered monocyclic aromatic rings;

[0152] X is –NR 11 ;and

[0153] R 11 For hydrogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups.

[0154] In some embodiments, this document provides a compound of formula (I) or a stereoisomer, transisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein: m is 0; n is 1; p is 1; q is 0; and R 3A and R 3B Both are hydrogen.

[0155] In some embodiments, this document provides a compound of formula (I) or a stereoisomer, transisomer, tautomer or pharmaceutically acceptable salt thereof, wherein: m is 0; n is 0; p is 0; and q is 1.

[0156] In some embodiments, X is -NR 11 And R 11 It is hydrogen.

[0157] In some embodiments, R 01 R 02 R 03 R 04 and R 05 One or more of the components is hydrogen. In some embodiments, R 01 R 02 R 03 R 04 and R 05 No more than two of them are hydrogen. In some embodiments, R01 R 02 R 03 R 04 and R 05 At least one of them is a halogen. In some embodiments, R 01 R 02 R 03 R 04 and R 05 One of them is a halogen. In some embodiments, R 01 R 02 R 03 R 04 and R 05 Both of these are halogens. In some embodiments, R 01 R 02 R 03 R 04 and R 05 One of them is fluorine. In some embodiments, R 01 R 02 R 03 R 04 and R 05 Both of these are fluorine. In some embodiments, R 01 R 02 R 03 R 04 and R 05 One of them is C 1-3 Haloalkyl. In some embodiments, R 01 R 02 R 03 R 04 and R 05 One of them is –CH2CHF2. In some embodiments, R 01 R 02 R 03 R 04 and R 05 One of them is –CF3. In some embodiments, R 01 R 02 R 03 R 04 and R 05 One of them is –NH2. In some embodiments, R 01 R 02 R 03 R 04 and R 05 One of them is C 1-6 Alkyl group. In some embodiments, R 01 R 02R 03 R 04 and R 05 One of them is C 1-3 Alkyl group. In some embodiments, R 01 R 02 R 03 R 04 and R 05 One of them is methyl. In some embodiments, R 01 R 02 R 03 R 04 and R 05 One of them is C 3-6 Cycloalkyl. In some embodiments, R 01 R 02 R 03 R 04 and R 05 Each of these elements is independently hydrogen, halogen, -NH2, C. 1-3 Alkyl or C 1-3 Haloalkyl. In some embodiments, R 01 R 02 R 03 R 04 and R 05 Each of these is independently hydrogen, fluorine, –NH2, methyl, or –CF3. In some embodiments, R 01 R 02 R 03 R 04 and R 05 Each of them is independently hydrogen, fluorine, –NH2, methyl or –CH2CHF2.

[0158] In some embodiments, R1 is:

[0159] , , , , , , , , , , , , , , , , , , , , , , or .

[0160] In some embodiments, R1 is: , , , , , or .

[0161] In some embodiments, R1 is: or .

[0162] In some embodiments, R1 is: , , , or .

[0163] In some embodiments, R1 is In some embodiments, R1 is In some embodiments, R1 is In some embodiments, R1 is In some embodiments, R1 is In some embodiments, R1 is .

[0164] In some embodiments, R2 is a halogen. In some embodiments, R2 is fluorine or chlorine. In some embodiments, R2 is fluorine. In some embodiments, R2 is chlorine.

[0165] In some embodiments, R 3A For hydrogen, halogen, C 1-3 Alkyl or C 1-3 Halogenated alkyl groups, and R 3B It is hydrogen. In some embodiments, R is... 3A It is hydrogen. In some embodiments, R is... 3A It is a halogen. In some embodiments, R 3A C 1-3 Alkyl group. In some embodiments, R 3A methyl. In some embodiments, R 3A C 1-3 Haloalkyl. In some embodiments, R 3A For –CF3. In some embodiments, R 3A and R 3B Together they form oxygen.

[0166] In some embodiments, R 3C It is hydrogen. In some embodiments, R is... 3C It is a halogen. In some embodiments, R 3C C 1-3 Alkyl group. In some embodiments, R 3C methyl. In some embodiments, R 3C C 1-3 Haloalkyl. In some embodiments, R 3C For –CF3.

[0167] In some embodiments, R 3A and R 3C Both are hydrogen.

[0168] In some embodiments, R 4A and R 4B Each of them is independently hydrogen, C 1-3 Alkyl or C 1-3 Halogenated alkyl groups.

[0169] In some embodiments, R 4A It is hydrogen. In some embodiments, R is... 4A C 1-3 Alkyl group. In some embodiments, R 4A methyl. In some embodiments, R 4A It is ethyl. In some embodiments, R 4A C 1-3 Haloalkyl. In some embodiments, R 4A For –CHF2. In some embodiments, R 4A For –CF3. In some embodiments, R 4A For –CD3.

[0170] In some embodiments, R 4B It is hydrogen. In some embodiments, R is... 4B C 1-3 Alkyl group. In some embodiments, R 4B methyl. In some embodiments, R 4B It is ethyl. In some embodiments, R 4B C 1-3 Haloalkyl. In some embodiments, R 4B For –CHF2. In some embodiments, R 4B For -CF3. In some embodiments, R 4B For –CD3.

[0171] In some embodiments, R 4A and R4B All are hydrogen. In some embodiments, R 4A It is hydrogen, and R 4B C 1-3 Alkyl group. In some embodiments, R 4A C 1-3 Alkyl, and R 4B It is hydrogen. In some embodiments, R is... 4A It is hydrogen, and R 4B methyl. In some embodiments, R 4A It is methyl, and R 4B It is hydrogen. In some embodiments, R is... 4A It is hydrogen, and R 4B It is ethyl. In some embodiments, R 4A It is ethyl, and R 4B It is hydrogen. In some embodiments, R is... 4A and R 4B All are methyl. In some embodiments, R 4A It is hydrogen, and R 4B C 1-3 Haloalkyl. In some embodiments, R 4A C 1-3 Halogenated alkyl groups, and R 4B It is hydrogen. In some embodiments, R is... 4A It is hydrogen, and R 4B For –CF3. In some embodiments, R 4A For –CF3, and R 4B It is hydrogen. In some embodiments, R is... 4A It is hydrogen, and R 4B For –CHF2. In some embodiments, R 4A For –CHF2, and R 4B It is hydrogen. In some embodiments, R is... 4A It is hydrogen, and R 4B For –CD3. In some embodiments, R 4A For –CD3, and R 4B It is hydrogen.

[0172] In some embodiments, R 4A and R 4B Together with the atoms they bind to, they form 3- to 6-membered monocyclic rings. In some embodiments, R 4A and R 4B Together with the atoms they bind to, they form 3- to 6-membered monocyclic carbon rings. In some embodiments, R 4A and R4B Together with the atoms bonded to both, they form a 3- to 6-membered monocyclic ring, which optionally contains one or more heteroatoms selected from N, O, and S. In some embodiments, R 4A and R 4B Together with the atoms bonded to both, they form a 3- to 6-membered monocyclic ring, which contains one or more heteroatoms selected from N and O. In some embodiments, R 4A and R 4B Together with the atoms bonded to both, they form a 3- to 6-membered monocyclic ring, which contains one or more heteroatoms selected from N and S. In some embodiments, R 4A and R 4B Together with the atoms bonded to both, they form a 3- to 6-membered monocyclic ring, which contains one or more heteroatoms selected from S and O. In some embodiments, R 4A and R 4B Together with the atoms bonded to both, they form a 3- to 6-membered monocyclic ring, which contains one or more N atoms. In some embodiments, R 4A and R 4B Together with the atoms bonded to both, they form a 3- to 6-membered monocyclic ring, which contains one or more oxygen atoms. In some embodiments, R 4A and R 4B Together with the atoms bonded to both, they form a 3- to 6-membered monocyclic ring, which optionally contains one or more S atoms.

[0173] In some embodiments, R 4A and R 4B Together with the atoms bonded to both, it forms an oxobutane ring.

[0174] In some embodiments, Z is hydrogen. In some embodiments, Z is C. 1-3 Alkyl. In some embodiments, Z is methyl. In some embodiments, Z is -L1–Cy. In some embodiments, Z is -L1–NR5R6. In some embodiments, Z is –OR6. In some embodiments, Z is –SR6.

[0175] In some embodiments, L1 does not exist. In some embodiments, L1 is –C(=O)–.

[0176] In some embodiments, R5 is hydrogen, C 1-6 Alkyl or –NH2; and R6 is C 1-6 Alkyl, -L2–Cy, –C(=O)–Cy, or –C(=O)C1-6 alkyl.

[0177] In some embodiments, R5 is hydrogen. In some embodiments, R5 is C. 1-6 Alkyl group. In some embodiments, R5 is methyl. In some embodiments, R5 is –NH2.

[0178] In some embodiments, R6 is C 1-6 Alkyl group. In some embodiments, R6 is -L2–Cy. In some embodiments, R6 is –C(=O)–Cy. In some embodiments, R6 is –C(=O)C 1-6 alkyl.

[0179] In some embodiments, R5 is hydrogen and R6 is –C(=O)–Cy. In some embodiments, R5 is hydrogen and R6 is –C(=O)–phenyl. In some embodiments, R5 is hydrogen and R6 is –C(=O)C 1-6 Alkyl group. In some embodiments, R5 is hydrogen and R6 is –C(=O)CH2CH3. In some embodiments, R5 is –NH2 and R6 is C 1-6 Alkyl group. In some embodiments, R5 is –NH2 and R6 is methyl. In some embodiments, R5 is hydrogen and R6 is C2. 1-6 Alkyl group. In some embodiments, R5 is hydrogen and R6 is methyl.

[0180] In some embodiments, R5 and R6, together with nitrogen atoms to which they are both bonded, form a 3- to 6-membered monocycle, which is optionally substituted by one or more groups independently selected from: C 1-6 Alkyl and hydroxyl groups. In some embodiments, R5 and R6, together with nitrogen atoms to which they are bonded, form a 3- to 6-membered monocyclic ring. In some embodiments, R5 and R6, together with the nitrogen atoms to which they are bonded, form a 3- to 6-membered monocyclic ring, which optionally contains one or more heteroatoms selected from N, O, and S. In some embodiments, R5 and R6, together with the nitrogen atoms to which they are bonded, form a 3- to 6-membered monocyclic ring, which includes one or more heteroatoms selected from N and O. In some embodiments, R5 and R6, together with the nitrogen atoms to which they are bonded, form a 3- to 6-membered monocyclic ring, which optionally contains one or more heteroatoms selected from S and O.

[0181] In some embodiments, R5 and R6, together with the nitrogen atom to which they are bonded, form a nitrogen-containing heterocyclic butane optionally substituted with one or more groups independently selected from: C 1-6 Alkyl and hydroxyl groups. In some embodiments, R5 and R6, together with the nitrogen atom to which they are bonded, form a C-hydroxyl group. 1-6 Alkyl and hydroxyl-substituted azahexacyclic butanes. In some embodiments, R5 and R6, together with the nitrogen atoms they are bonded to, form methyl and hydroxyl-substituted azahexacyclic butanes. In some embodiments, R5 and R6, together with the nitrogen atoms they are bonded to, form azahexacyclic butanes.

[0182] In some embodiments, R5 and R6, together with the nitrogen atom to which they are bonded, form a 3- to 6-membered monocyclic ring containing one or more N atoms. In some embodiments, R5 and R6, together with the nitrogen atom to which they are bonded, form a pyrazole. In some embodiments, R5 and R6, together with the nitrogen atom to which they are bonded, form a 3- to 6-membered monocyclic ring containing one or more O atoms. In some embodiments, R5 and R6, together with the nitrogen atom to which they are bonded, form a 3- to 6-membered monocyclic carbon ring.

[0183] In some embodiments, each R 7A Independently hydrogen. In some embodiments, each R 7B Independently hydrogen. In some embodiments, each R 7A and R 7B All are hydrogen. In some embodiments, each R 7A and R 7B Independently for C 1-3 Alkyl group. In some embodiments, each R 7A Independently for C 1-3 Alkyl group. In some embodiments, each R 7A Independently methyl. In some embodiments, each R 7B Independently for C 1-3 Alkyl group. In some embodiments, each R 7B Independently methyl. In some embodiments, each R 7A Independently hydrogen, and each R 7B Independently for C 1-3 Alkyl group. In some embodiments, R 7A It is hydrogen, and R 7B It is a methyl group.

[0184] In some embodiments, u is 1. In some embodiments, u is 2. In some embodiments, u is 3.

[0185] In some embodiments, Cy is a ternary to eleven-membered monocyclic ring optionally containing one or more heteroatoms selected from N, O, and S and optionally substituted with one or more R8 atoms. In some embodiments, Cy is a ternary to eleven-membered fused bicyclic ring optionally containing one or more heteroatoms selected from N, O, and S and optionally substituted with one or more R8 atoms. In some embodiments, Cy is a ternary to eleven-membered bridging bicyclic ring optionally containing one or more heteroatoms selected from N, O, and S and optionally substituted with one or more R8 atoms. In some embodiments, Cy is two or three ternary to eleven-membered rings optionally containing one or more heteroatoms selected from N, O, and S and optionally substituted with one or more R8 atoms.

[0186] In some embodiments, Cy is a ternary to elliptic compound optionally containing one or more heteroatoms selected from N, O, and S. Monocyclic ring. In some embodiments, Cy is a ternary to 11-membered ring optionally containing one or more heteroatoms selected from N, O, and S. Cy is a 3- to 11-bridging bicyclic ring. In some embodiments, Cy is a 3- to 11-bridging bicyclic ring optionally containing one or more heteroatoms selected from N, O, and S. In some embodiments, Cy is two or three 3- to 11-bridging bicyclic rings optionally containing one or more heteroatoms selected from N, O, and S. Metachain ring.

[0187] In some embodiments, Cy is a ternary to decacyclic monocyclic ring optionally comprising one or more heteroatoms selected from N, O, and S and optionally substituted with one or more R8 atoms. In some embodiments, Cy is a ternary to decacyclic fused bicyclic ring optionally comprising one or more heteroatoms selected from N, O, and S and optionally substituted with one or more R8 atoms. In some embodiments, Cy is a ternary to decacyclic bridged bicyclic ring optionally comprising one or more heteroatoms selected from N, O, and S and optionally substituted with one or more R8 atoms. In some embodiments, Cy is two or three ternary to decacyclic rings optionally comprising one or more heteroatoms selected from N, O, and S and optionally substituted with one or more R8 atoms.

[0188] In some embodiments, Cy is a ternary to decacyclic monocyclic ring optionally containing one or more heteroatoms selected from N, O, and S. In some embodiments, Cy is a ternary to decacyclic fused bicyclic ring optionally containing one or more heteroatoms selected from N, O, and S. In some embodiments, Cy is a ternary to decacyclic bridging bicyclic ring optionally containing one or more heteroatoms selected from N, O, and S. In some embodiments, Cy is two or three ternary to decacyclic monocyclic rings optionally containing one or more heteroatoms selected from N, O, and S. Metachain ring.

[0189] In some embodiments, Cy is imidazole, phenyl, pyridine, 2-oxabicyclo[2.1.1]hexane, pyrimidine, pyrazole, pyrazine, pyridazine, 1,2,4-triazole, indazole, pyridinone, thiazole, quinoline, pyrrolo[1,2-a]pyrimidine, 1,2,4-thiadiazole, [1,2,4]triazolo[1,5-a]pyridine, pyrazolo[1,5-a]pyrazine, imidazole[1,2]pyrazine, etc. -a]pyrazine, pyrazolo[1,5-a]pyrimidine, pyrazolo[1,5-c]pyrimidine, imidazo[1,2-b]pyridazine, imidazo[1,2-a]pyridine, imidazo[2,1-b]oxazole, 1,2,5-thiadiazole, isothiazole, 1,2,3-thiadiazole, isoxazole, 1,3,4-thiadiazole, 3-(1H-pyrazol-1-yl)pyrazine Pyridine, 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine, pyrrolo[2,1-f][1,2,4]triazine, 5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one, imidazo[1,2-a]pyrimidine, pyrazolo[3,4-b]pyridine, oxazole, 1,2,3-triazole, 2,3-dihydroindoleazine-5(1H)-one, pyridazine-3(2H)-one, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine, 2-(1H-pyrazol-1-yl)pyridine, 1-azabicyclo[3.2.0]heptane, hexahydro-1H-pyrrolo[2,1-c][1,4]oxazine, pyrrolidine, or hexahydro-1H-pyrroloazine; wherein Cy Optionally replaced by one or more R8s.

[0190] In some embodiments, Cy The following compounds are listed: imidazole, phenyl, pyridine, 2-oxabicyclo[2.1.1]hexane, pyrimidine, pyrazole, pyrazine, pyridazine, 1,2,4-triazole, indazole, pyridinone, thiazole, quinoline, pyrrolo[1,2-a]pyrimidine, 1,2,4-thiadiazole, [1,2,4]triazolo[1,5-a]pyridine, pyrazolo[1,5-a]pyrazine, imidazo[1,2-a]pyrazine, pyrazolo[1,5-a]pyrimidine, pyrazolo[1,5-c]pyrimidine, imidazo[1,2-b]pyridazine, imidazo[1,2-a]pyridine, imidazo[2,1-b]oxazole, 1,2,5-thiadiazole, isothiazole, 1,2,3-thiadiazole, isoxazole, 1,3,4-thiadiazole, 3-(1H-pyrazol-1-yl) Pyridine, 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine, pyrrolo[2,1-f][1,2,4]triazine, 5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one, imidazo[1,2-a]pyrimidine, pyrazolo[3,4-b]pyridine, oxazole, 1,2,3-triazole, 2,3-dihydroindoleazine-5(1H)-one, pyridazine-3(2H)-one, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine, 2-(1H-pyrazol-1-yl)pyridine, 1-azabicyclo[3.2.0]heptane, hexahydro-1H-pyrrolo[2,1-c][1,4]oxazine, pyrrolidine, or hexahydro-1H-pyrroloazine.

[0191] In some embodiments, Cy is imidazole, phenyl, pyridine, 2-oxabicyclo[2.1.1]hexane, pyrimidine, pyrazole, pyrazine, pyridazine, 1,2,4-triazole, indazole, pyridinone, thiazole, quinoline, pyrrolo[1,2-a]pyrimidine, 1,2,4-thiadiazole, [1,2,4]triazolo[1,5-a]pyridine, pyrazolo[1,5-a]pyrazine, imidazole[1,2]pyrazine, etc. -a]pyrazine, pyrazolo[1,5-a]pyrimidine, pyrazolo[1,5-c]pyrimidine, imidazo[1,2-b]pyridazine, imidazo[1,2-a]pyridine, imidazo[2,1-b]oxazole, 1,2,5-thiadiazole, isothiazole, 1,2,3-thiadiazole, isoxazole, 1,3,4-thiadiazole, 3-(1H-pyrazol-1-yl)pyrazine Pyridine, 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine, pyrrolo[2,1-f][1,2,4]triazine, 5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one, imidazo[1,2-a]pyrimidine, pyrazolo[3,4-b]pyridine, oxazole, 1,2,3-triazole, 2,3-dihydroindoleazine-5(1H)-one, pyridazine-3(2H)-one, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine, 2-(1H-pyrazol-1-yl)pyridine, 1-azabicyclo[3.2.0]heptane, hexahydro-1H-pyrrolo[2,1-c][1,4]oxazine, pyrrolidine, or hexahydro-1H-pyrroloazine; wherein Cy It is replaced by one or more R8s.

[0192] In some embodiments, Cy is imidazole, phenyl, pyridine, 2-oxabicyclo[2.1.1]hexane, pyrimidine, pyrazole, pyrazine, pyridazine, 1,2,4-triazole, indazole, pyridinone, thiazole, quinoline, pyrrolo[1,2-a]pyrimidine, 1,2,4-thiadiazole, [1,2,4]triazolo[1,5-a]pyridine, pyrazolo[1,5-a]pyrazine, imidazo[1,2-a]pyrazine, pyrazolo[1,5-a]pyrimidine, pyrazolo[1,5-c]pyrimidine, imidazo[1,2-b]pyridazine, imidazo[1,2-a]pyridine, imidazo[2,1-b]oxazole, 1,2,5-thiadiazole, isothiazole, 1,2,3-thiadiazole, isothiazole, etc. Oxazole, 1,3,4-thiadiazole, 3-(1H-pyrazol-1-yl)pyridine, 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine, pyrrolo[2,1-f][1,2,4]triazine, 5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one, imidazo[1,2-a]pyrimidine, pyrazolo[3,4-b]pyridine, oxazole, 1,2,3-triazole, 2,3-dihydroindoleazine-5(1H)-one, pyridazine-3(2H)-one, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine, or 2-(1H-pyrazol-1-yl)pyridine; wherein Cy is optionally substituted with one or more R8.

[0193] In some embodiments, Cy is imidazole, phenyl, pyridine, 2-oxabicyclo[2.1.1]hexane, pyrimidine, pyrazole, pyrazine, pyridazine, 1,2,4-triazole, indazole, pyridinone, thiazole, quinoline, pyrrolo[1,2-a]pyrimidine, 1,2,4-thiadiazole, [1,2,4]triazolo[1,5-a]pyridine, pyrazolo[1,5-a]pyrazine, imidazo[1,2-a]pyrazine, pyrazolo[1,5-a]pyrimidine, pyrazolo[1,5-c]pyrimidine, imidazo[1,2-b]pyridazine, imidazo[1,2-a]pyridine, imidazo[2,1-b]oxazole, 1,2,5-thiadiazole, isothiazole, 1,2,3-thiadiazole Isoxazole, 1,3,4-thiadiazole, 3-(1H-pyrazol-1-yl)pyridine, 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine, pyrrolo[2,1-f][1,2,4]triazine, 5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one, imidazo[1,2-a]pyrimidine, pyrazolo[3,4-b]pyridine, oxazole, 1,2,3-triazole, 2,3-dihydroindoleazine-5(1H)-one, pyridazine-3(2H)-one, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine, or 2-(1H-pyrazol-1-yl)pyridine.

[0194] In some embodiments, Cy is imidazole, phenyl, pyridine, 2-oxabicyclo[2.1.1]hexane, pyrimidine, pyrazole, pyrazine, pyridazine, 1,2,4-triazole, indazole, pyridinone, thiazole, quinoline, pyrrolo[1,2-a]pyrimidine, 1,2,4-thiadiazole, [1,2,4]triazolo[1,5-a]pyridine, pyrazolo[1,5-a]pyrazine, imidazo[1,2-a]pyrazine, pyrazolo[1,5-a]pyrimidine, pyrazolo[1,5-c]pyrimidine, imidazo[1,2-b]pyridazine, imidazo[1,2-a]pyridine, imidazo[2,1-b]oxazole, 1,2,5-thiadiazole, isothiazole, 1,2,3-thiadiazole, isothiazole, etc. Oxazole, 1,3,4-thiadiazole, 3-(1H-pyrazol-1-yl)pyridine, 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine, pyrrolo[2,1-f][1,2,4]triazine, 5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one, imidazo[1,2-a]pyrimidine, pyrazolo[3,4-b]pyridine, oxazole, 1,2,3-triazole, 2,3-dihydroindoleazine-5(1H)-one, pyridazine-3(2H)-one, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine, or 2-(1H-pyrazol-1-yl)pyridine, wherein Cy is substituted by one or more R8.

[0195] In some embodiments, Cy is imidazole, phenyl, pyridine, 2-oxabicyclo[2.1.1]hexane, pyrimidine, pyrazole, pyrazine, pyridazine, 1,2,4-triazole, indazole, pyridinone, thiazole, or quinoline; wherein Cy is optionally substituted with one or more R8.

[0196] In some embodiments, Cy is imidazole, phenyl, pyridine, 2-oxabicyclo[2.1.1]hexane, pyrimidine, pyrazole, pyrazine, pyridazine, 1,2,4-triazole, indazole, pyridinone, thiazole, or quinoline.

[0197] In some embodiments, Cy is imidazole, phenyl, pyridine, 2-oxabicyclo[2.1.1]hexane, pyrimidine, pyrazole, pyrazine, pyridazine, 1,2,4-triazole, indazole, pyridinone, thiazole, or quinoline; wherein Cy is substituted with one or more R8.

[0198] In some embodiments, Cy is phenyl, pyridine, pyrimidine, pyrazole, pyridinone, thiazole, pyrrolo[1,2-a]pyrimidine, 1,2,4-thiadiazole, [1,2,4]triazolo[1,5-a]pyridine, pyrazolo[1,5-a]pyrazine, imidazo[1,2-a]pyrazine, pyrazolo[1,5-a]pyrimidine, pyrazolo[1,5-c]pyrimidine, imidazo[1,2-b]pyridazine, imidazo[1,2-a]pyridine, imidazo[2,1-b]oxazole, 1,2,5-thiadiazole, isothiazole, 1,2,3-thiadiazole, isoxazole, 1,3,4-thiadiazole, 3-(1H-pyridine) Cy is azol-1-yl)pyridine, 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine, pyrrolo[2,1-f][1,2,4]triazine, 5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one, imidazo[1,2-a]pyrimidine, pyrazolo[3,4-b]pyridine, oxazole, 1,2,3-triazole, 2,3-dihydroindoleazine-5(1H)-one, pyridazine-3(2H)-one, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine, or 2-(1H-pyrazol-1-yl)pyridine; wherein Cy is optionally substituted with one or more R8.

[0199] In some embodiments, Cy is phenyl, pyridine, pyrimidine, pyrazole, pyridinone, thiazole, pyrrolo[1,2-a]pyrimidine, 1,2,4-thiadiazole, [1,2,4]triazolo[1,5-a]pyridine, pyrazolo[1,5-a]pyrazine, imidazo[1,2-a]pyrazine, pyrazolo[1,5-a]pyrimidine, pyrazolo[1,5-c]pyrimidine, imidazo[1,2-b]pyridazine, imidazo[1,2-a]pyridine, imidazo[2,1-b]oxazole, 1,2,5-thiadiazole, isothiazole, 1,2,3-thiadiazole, isoxazole, 1,3,4-thiadiazole, 3-(1H -pyrazol-1-yl)pyridine, 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine, pyrrolo[2,1-f][1,2,4]triazine, 5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one, imidazo[1,2-a]pyrimidine, pyrazolo[3,4-b]pyridine, oxazole, 1,2,3-triazole, 2,3-dihydroindoleazine-5(1H)-one, pyridazine-3(2H)-one, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine, or 2-(1H-pyrazol-1-yl)pyridine.

[0200] In some embodiments, Cy is phenyl, pyridine, pyrimidine, pyrazole, pyridinone, thiazole, pyrrolo[1,2-a]pyrimidine, 1,2,4-thiadiazole, [1,2,4]triazolo[1,5-a]pyridine, pyrazolo[1,5-a]pyrazine, imidazo[1,2-a]pyrazine, pyrazolo[1,5-a]pyrimidine, pyrazolo[1,5-c]pyrimidine, imidazo[1,2-b]pyridazine, imidazo[1,2-a]pyridine, imidazo[2,1-b]oxazole, 1,2,5-thiadiazole, isothiazole, 1,2,3-thiadiazole, isoxazole, 1,3,4-thiadiazole, 3-(1H-pyridine) Cy is substituted with one or more R8 radicals.

[0201] In some embodiments, Cy is pyrazole, 1-azabicyclo[3.2.0]heptane, hexahydro-1H-pyrrolo[2,1-c][1,4]oxazine, pyrrolidinyl or hexahydro-1H-pyrroloazine; wherein Cy is optionally substituted with one or more R8.

[0202] In some embodiments, Cy is pyrazole, 1-azabicyclo[3.2.0]heptane, hexahydro-1H-pyrrolo[2,1-c][1,4]oxazine, pyrrolidinane, or hexahydro-1H-pyrrolidinane.

[0203] In some embodiments, Cy is pyrazole, 1-azabicyclo[3.2.0]heptane, hexahydro-1H-pyrrolo[2,1-c][1,4]oxazine, pyrrolidinyl or hexahydro-1H-pyrroloazine; wherein Cy is substituted with one or more R8.

[0204] In some embodiments, each R8 is independently selected from: optionally by a hydroxyl group or C 1-6 alkoxy-substituted C 1-6 Alkyl; C 1-3 Halogenated alkyl group; halogen; hydroxyl group; cyano group; –C(=O)NR9R 10 –C(=O)OR 10 ;Optionally coated with hydroxyl-C 1-6 Alkyl-substituted C 3-6 Cycloalkyl; and oxo; wherein R9 and R 10 Independently hydrogen or C1-6 Alkyl groups. In some embodiments, each R8 is independently selected from: C groups optionally substituted with hydroxyl groups. 1-6 Alkyl; C 1-3 Halogenated alkyl group; halogen; hydroxyl group; cyano group; –C(=O)NR9R 10 –C(=O)OR 10 C 3-6 Cycloalkyl; and oxo; wherein R9 and R 10 Each of them is independently hydrogen or C. 1-6 Alkyl groups. In some embodiments, each R8 is independently selected from: optionally by a hydroxyl group or C. 1-6 alkoxy-substituted C 1-6 Alkyl; C 1-3 Halogenated alkyl group; halogen; cyano group; oxo group; –C(=O)OR 10 ; and optionally hydroxyl-C 1-6 Alkyl-substituted C 3-6 Cycloalkyl groups. In some embodiments, each R8 is independently selected from: C 1-6 Alkyl groups and halogens.

[0205] In some embodiments, Cy is replaced by 1 to 20 independently selected R8s. In some embodiments, Cy is replaced by one R8. In some embodiments, Cy is replaced by two independently selected R8s. In some embodiments, Cy is replaced by three independently selected R8s. In some embodiments, Cy is replaced by four independently selected R8s. In some embodiments, Cy is replaced by five independently selected R8s. In some embodiments, Cy is replaced by six independently selected R8s. In some embodiments, Cy is replaced by seven R8s. In some embodiments, Cy is replaced by eight R8s. In some embodiments, Cy is replaced by nine R8s. In some embodiments, Cy is replaced by ten R8s.

[0206] In some embodiments, R9 is hydrogen. In some embodiments, R9 is C. 1-6 Alkyl group. In some embodiments, R9 is methyl. In some embodiments, R 10 It is hydrogen. In some embodiments, R is... 10 C 1-6 Alkyl group. In some embodiments, R 10 It is a methyl group.

[0207] In some embodiments, each R8 is independently C 1-6 Alkyl group. In some embodiments, each R8 is independently a C substituted with a hydroxyl group. 1-6Alkyl group. In some embodiments, each R8 is independently formed by C 1-6 alkoxy-substituted C 1-6 Alkyl group. In some embodiments, each R8 is independently C10. 1-3 Halogenated alkyl group. In some embodiments, each R8 is independently hydroxyl-C 1-6 Alkyl-substituted C 3-6 Cycloalkyl.

[0208] In some embodiments, each R8 is independently –CH2OH, –CH2CH2OH, –CH2OCH3, methyl, ethyl, –CHF2, –CF3, chlorine, fluorine, oxo, –C(=O)N(CH3)2, –C(=O)OH, –C(=O)OCH3, hydroxyl, cyano, cyclopropyl, or cyclopropyl substituted with –CH2OH. In some embodiments, each R8 is independently methyl, –CF3, –CHF2, fluorine, hydroxyl, cyano, –CH2OH, –C(=O)OH, –C(=O)OMe, or –C(=O)N(Me)2. In some embodiments, each R8 is independently –CH2OH, –CH2CH2OH, –CH2OCH3, methyl, ethyl, –CHF2, –CF3, chlorine, fluorine, oxo, –C(=O)OH, cyano, cyclopropyl, or cyclopropyl substituted with –CH2OH. In some embodiments, each R8 is independently methyl, ethyl, –CHF2, –CF3, chlorine, or fluorine.

[0209] In some embodiments, Z is -L1-Cy, L1 is absent, and Cy is an optionally substituted pyrazole or an optionally substituted pyrimidine. In some embodiments, Cy is a pyrazole. In some embodiments, Cy is a pyrimidine. In some embodiments, Cy is a substituted pyrazole. In some embodiments, Cy is a substituted pyrimidine. In some embodiments, Cy is a methyl-substituted pyrazole.

[0210] In some embodiments, Z is -L1–NR5R6, L1 is absent, R5 is hydrogen, and R6 is -L2–Cy.

[0211] In some embodiments, Z is -L1–NR5R6, L1 is absent, R5 is hydrogen, R6 is -L2–Cy, L2 is –CH2–, and Cy is imidazole, phenyl, pyridine, 2-oxabicyclo[2.1.1]hexane, pyrimidine, pyrazole, pyrazine, pyridazine, 1,2,4-triazole, indazole, pyridinone, thiazole, quinoline, pyrrolo[1,2-a]pyrimidine, 1,2,4-thiadiazole, [1,2,4]triazolo[1,5-a]pyridine, pyrazolo[1,5-a]pyrazine, imidazole[1,2] -a]pyrazine, pyrazolo[1,5-a]pyrimidine, pyrazolo[1,5-c]pyrimidine, imidazo[1,2-b]pyridazine, imidazo[1,2-a]pyridine, imidazo[2,1-b]oxazole, 1,2,5-thiadiazole, isothiazole, 1,2,3-thiadiazole, isoxazole, 1,3,4-thiadiazole, 3-(1H-pyrazol-1-yl)pyrazine Pyridine, 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine, pyrrolo[2,1-f][1,2,4]triazine, 5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one, imidazo[1,2-a]pyrimidine, pyrazolo[3,4-b]pyridine, oxazole, 1,2,3-triazole, 2,3-dihydroindoleazine-5(1H)-one, pyridazine-3(2H)-one, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine, 2-(1H-pyrazol-1-yl)pyridine, 1-azabicyclo[3,2,0]heptane, hexahydro-1H-pyrrolo[2,1-c][1,4]oxazine, pyrrolidine, or hexahydro-1H-pyrroloazine, wherein Cy Optionally substituted with one or more R8 radicals independently selected from: optionally substituted with a hydroxyl group or C 1-6 alkoxy-substituted C 1-6 Alkyl; C 1-3 Halogenated alkyl group; halogen; hydroxyl group; cyano group; –C(=O)NR9R 10 –C(=O)OR 10 ;Optionally coated with hydroxyl-C 1-6 Alkyl-substituted C 3-6 Cycloalkyl; and oxo; wherein R9 and R 10 Independently hydrogen or C 1-6 alkyl.

[0212] In some embodiments, Z is -L1–NR5R6, L1 is absent, R5 is hydrogen, R6 is -L2–Cy, L2 is –CH2–, and Cy is imidazole, phenyl, pyridine, 2-oxabicyclo[2.1.1]hexane, pyrimidine, pyrazole, pyrazine, pyridazine, 1,2,4-triazole, indazole, pyridinone, thiazole, quinoline, pyrrolo[1,2-a]pyrimidine, 1,2,4-thiadiazole, [1,2,4]triazolo[1,5-a]pyridine, pyrazolo[1,5-a]pyrazine, imidazole[1,2] -a]pyrazine, pyrazolo[1,5-a]pyrimidine, pyrazolo[1,5-c]pyrimidine, imidazo[1,2-b]pyridazine, imidazo[1,2-a]pyridine, imidazo[2,1-b]oxazole, 1,2,5-thiadiazole, isothiazole, 1,2,3-thiadiazole, isoxazole, 1,3,4-thiadiazole, 3-(1H-pyrazol-1-yl)pyrazine Pyridine, 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine, pyrrolo[2,1-f][1,2,4]triazine, 5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one, imidazo[1,2-a]pyrimidine, pyrazolo[3,4-b]pyridine, oxazole, 1,2,3-triazole, 2,3-dihydroindoleazine-5(1H)-one, pyridazine-3(2H)-one, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine, 2-(1H-pyrazol-1-yl)pyridine, 1-azabicyclo[3,2,0]heptane, hexahydro-1H-pyrrolo[2,1-c][1,4]oxazine, pyrrolidine, or hexahydro-1H-pyrroloazine, wherein Cy Optionally substituted with one or more R8 groups independently selected from the following: –CH2OH, –CH2CH2OH, –CH2OCH3, methyl, ethyl, –CHF2, –CF3, chlorine, fluorine, oxo, –C(=O)N(CH3)2, –C(=O)OH, –C(=O)OCH3, hydroxyl, cyano, cyclopropyl substituted with –CH2OH, and cyclopropyl.

[0213] In some embodiments, Z is -L1–NR5R6, L1 is absent, R5 is hydrogen, R6 is -L2–Cy, L2 is –CH2–, and Cy is imidazole, phenyl, pyridine, 2-oxabicyclo[2.1.1]hexane, pyrimidine, pyrazole, pyrazine, pyridazine, 1,2,4-triazole, indazole, pyridinone, thiazole, quinoline, pyrrolo[1,2-a]pyrimidine, 1,2,4-thiadiazole, [1,2,4]triazolo[1,5-a]pyridine, pyrazolo[1,5-a]pyrazine, imidazole[1,2] -a]pyrazine, pyrazolo[1,5-a]pyrimidine, pyrazolo[1,5-c]pyrimidine, imidazo[1,2-b]pyridazine, imidazo[1,2-a]pyridine, imidazo[2,1-b]oxazole, 1,2,5-thiadiazole, isothiazole, 1,2,3-thiadiazole, isoxazole, 1,3,4-thiadiazole, 3-(1H-pyrazol-1-yl)pyrazine Pyridine, 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine, pyrrolo[2,1-f][1,2,4]triazine, 5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one, imidazo[1,2-a]pyrimidine, pyrazolo[3,4-b]pyridine, oxazole, 1,2,3-triazole, 2,3-dihydroindoleazine-5(1H)-one, pyridazine-3(2H)-one, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine, 2-(1H-pyrazol-1-yl)pyridine, 1-azabicyclo[3,2,0]heptane, hexahydro-1H-pyrrolo[2,1-c][1,4]oxazine, pyrrolidine, or hexahydro-1H-pyrroloazine, wherein Cy Replaced by one or more R8 molecules independently selected from: optionally by a hydroxyl group or C 1-6 alkoxy-substituted C 1-6 Alkyl; C 1-3 Halogenated alkyl group; halogen; hydroxyl group; cyano group; –C(=O)NR9R 10 –C(=O)OR 10 ;Optionally coated with hydroxyl-C 1-6 Alkyl-substituted C 3-6 Cycloalkyl; and oxo; wherein R9 and R 10 Independently hydrogen or C 1-6 alkyl.

[0214] In some embodiments, Z is -L1–NR5R6, L1 is absent, R5 is hydrogen, R6 is -L2–Cy, L2 is –CH2–, and Cy is imidazole, phenyl, pyridine, 2-oxabicyclo[2.1.1]hexane, pyrimidine, pyrazole, pyrazine, pyridazine, 1,2,4-triazole, indazole, pyridinone, thiazole, quinoline, pyrrolo[1,2-a]pyrimidine, 1,2,4-thiadiazole, [1,2,4]triazolo[1,5-a]pyridine, pyrazolo[1,5-a]pyrazine, imidazole[1,2] -a]pyrazine, pyrazolo[1,5-a]pyrimidine, pyrazolo[1,5-c]pyrimidine, imidazo[1,2-b]pyridazine, imidazo[1,2-a]pyridine, imidazo[2,1-b]oxazole, 1,2,5-thiadiazole, isothiazole, 1,2,3-thiadiazole, isoxazole, 1,3,4-thiadiazole, 3-(1H-pyrazol-1-yl)pyrazine Pyridine, 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine, pyrrolo[2,1-f][1,2,4]triazine, 5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one, imidazo[1,2-a]pyrimidine, pyrazolo[3,4-b]pyridine, oxazole, 1,2,3-triazole, 2,3-dihydroindoleazine-5(1H)-one, pyridazine-3(2H)-one, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine, 2-(1H-pyrazol-1-yl)pyridine, 1-azabicyclo[3,2,0]heptane, hexahydro-1H-pyrrolo[2,1-c][1,4]oxazine, pyrrolidine, or hexahydro-1H-pyrroloazine, wherein Cy It is substituted by one or more R8 groups independently selected from the following: –CH2OH, –CH2CH2OH, –CH2OCH3, methyl, ethyl, –CHF2, –CF3, chlorine, fluorine, oxo, –C(=O)N(CH3)2, –C(=O)OH, –C(=O)OCH3, hydroxyl, cyano, cyclopropyl substituted with –CH2OH, and cyclopropyl.

[0215] In some embodiments, Z is -L1–NR5R6, L1 is absent, R5 is hydrogen, R6 is -L2–Cy, L2 is –CH2–, and Cy The following compounds are listed: imidazole, phenyl, pyridine, 2-oxabicyclo[2.1.1]hexane, pyrimidine, pyrazole, pyrazine, pyridazine, 1,2,4-triazole, indazole, pyridinone, thiazole, quinoline, pyrrolo[1,2-a]pyrimidine, 1,2,4-thiadiazole, [1,2,4]triazolo[1,5-a]pyridine, pyrazolo[1,5-a]pyrazine, imidazo[1,2-a]pyrazine, pyrazolo[1,5-a]pyrimidine, pyrazolo[1,5-c]pyrimidine, imidazo[1,2-b]pyridazine, imidazo[1,2-a]pyridine, imidazo[2,1-b]oxazole, 1,2,5-thiadiazole, isothiazole, 1,2,3-thiadiazole, isoxazole, 1,3,4-thiadiazole, 3-(1H-pyrazol-1-yl) Pyridine, 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine, pyrrolo[2,1-f][1,2,4]triazine, 5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one, imidazo[1,2-a]pyrimidine, pyrazolo[3,4-b]pyridine, oxazole, 1,2,3-triazole, 2,3-dihydroindoleazine-5(1H)-one, pyridazine-3(2H)-one, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine, 2-(1H-pyrazol-1-yl)pyridine, 1-azabicyclo[3.2.0]heptane, hexahydro-1H-pyrrolo[2,1-c][1,4]oxazine, pyrrolidine, or hexahydro-1H-pyrroloazine.

[0216] In some embodiments, Z is -L1–NR5R6, L1 is absent, R5 is hydrogen, R6 is -L2–Cy, L2 is –CH2–, and Cy The following compounds are listed: imidazole, phenyl, pyridine, 2-oxabicyclo[2.1.1]hexane, pyrimidine, pyrazole, pyrazine, pyridazine, 1,2,4-triazole, indazole, pyridinone, thiazole, quinoline, pyrrolo[1,2-a]pyrimidine, 1,2,4-thiadiazole, [1,2,4]triazolo[1,5-a]pyridine, pyrazolo[1,5-a]pyrazine, imidazo[1,2-a]pyrazine, pyrazolo[1,5-a]pyrimidine, pyrazolo[1,5-c]pyrimidine, imidazo[1,2-b]pyridazine, imidazo[1,2-a]pyridine, imidazo[2,1-b]oxazole, 1,2,5-thiadiazole, isothiazole, 1,2,3-thiadiazole, and isothiazole. Oxazole, 1,3,4-thiadiazole, 3-(1H-pyrazol-1-yl)pyridine, 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine, pyrrolo[2,1-f][1,2,4]triazine, 5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one, imidazo[1,2-a]pyrimidine, pyrazolo[3,4-b]pyridine, oxazole, 1,2,3-triazole, 2,3-dihydroindoleazine-5(1H)-one, pyridazine-3(2H)-one, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine, or 2-(1H-pyrazol-1-yl)pyridine, wherein Cy is optionally substituted by one or more R8 radicals independently selected from the group consisting of: optionally hydroxyl or C 1-6 alkoxy-substituted C 1-6 Alkyl; C 1-3 Halogenated alkyl group; halogen; hydroxyl group; cyano group; –C(=O)NR9R 10 –C(=O)OR 10 ;Optionally coated with hydroxyl-C 1-6 Alkyl-substituted C 3-6 Cycloalkyl; and oxo; wherein R9 and R 10 Independently hydrogen or C 1-6 alkyl.

[0217] In some embodiments, Z is -L1–NR5R6, L1 is absent, R5 is hydrogen, R6 is -L2–Cy, L2 is –CH2–, and Cy The following compounds are listed: imidazole, phenyl, pyridine, 2-oxabicyclo[2.1.1]hexane, pyrimidine, pyrazole, pyrazine, pyridazine, 1,2,4-triazole, indazole, pyridinone, thiazole, quinoline, pyrrolo[1,2-a]pyrimidine, 1,2,4-thiadiazole, [1,2,4]triazolo[1,5-a]pyridine, pyrazolo[1,5-a]pyrazine, imidazo[1,2-a]pyrazine, pyrazolo[1,5-a]pyrimidine, pyrazolo[1,5-c]pyrimidine, imidazo[1,2-b]pyridazine, imidazo[1,2-a]pyridine, imidazo[2,1-b]oxazole, 1,2,5-thiadiazole, isothiazole, 1,2,3-thiadiazole, and isothiazole. Oxazole, 1,3,4-thiadiazole, 3-(1H-pyrazol-1-yl)pyridine, 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine, pyrrolo[2,1-f][1,2,4]triazine, 5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one, imidazo[1,2-a]pyrimidine, pyrazolo[3,4-b]pyridine, oxazole, 1,2,3-triazole, 2,3-dihydroindoleazine-5(1H)-one, pyridazine-3(2H)-one, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine, or 2-(1H-pyrazol-1-yl)pyridine, wherein Cy Optionally substituted with one or more R8 groups independently selected from the following: –CH2OH, –CH2CH2OH, –CH2OCH3, methyl, ethyl, –CHF2, –CF3, chlorine, fluorine, oxo, –C(=O)N(CH3)2, –C(=O)OH, –C(=O)OCH3, hydroxyl, cyano, cyclopropyl substituted with –CH2OH, and cyclopropyl.

[0218] In some embodiments, Z is -L1–NR5R6, L1 is absent, R5 is hydrogen, R6 is -L2–Cy, L2 is –CH2–, and Cy The following compounds are listed: imidazole, phenyl, pyridine, 2-oxabicyclo[2.1.1]hexane, pyrimidine, pyrazole, pyrazine, pyridazine, 1,2,4-triazole, indazole, pyridinone, thiazole, quinoline, pyrrolo[1,2-a]pyrimidine, 1,2,4-thiadiazole, [1,2,4]triazolo[1,5-a]pyridine, pyrazolo[1,5-a]pyrazine, imidazo[1,2-a]pyrazine, pyrazolo[1,5-a]pyrimidine, pyrazolo[1,5-c]pyrimidine, imidazo[1,2-b]pyridazine, imidazo[1,2-a]pyridine, imidazo[2,1-b]oxazole, 1,2,5-thiadiazole, isothiazole, 1,2,3-thiadiazole, and isothiazole. Oxazole, 1,3,4-thiadiazole, 3-(1H-pyrazol-1-yl)pyridine, 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine, pyrrolo[2,1-f][1,2,4]triazine, 5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one, imidazo[1,2-a]pyrimidine, pyrazolo[3,4-b]pyridine, oxazole, 1,2,3-triazole, 2,3-dihydroindoleazine-5(1H)-one, pyridazine-3(2H)-one, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine, or 2-(1H-pyrazol-1-yl)pyridine, wherein Cy is substituted by one or more R8 radicals independently selected from the following: optionally by a hydroxyl group or C 1-6 alkoxy-substituted C 1-6 Alkyl; C 1-3 Halogenated alkyl group; halogen; hydroxyl group; cyano group; –C(=O)NR9R 10 –C(=O)OR 10 ;Optionally coated with hydroxyl-C 1-6 Alkyl-substituted C 3-6 Cycloalkyl; and oxo; wherein R9 and R 10 Independently hydrogen or C 1-6 alkyl.

[0219] In some embodiments, Z is -L1–NR5R6, L1 is absent, R5 is hydrogen, R6 is -L2–Cy, L2 is –CH2–, and Cy The following compounds are listed: imidazole, phenyl, pyridine, 2-oxabicyclo[2.1.1]hexane, pyrimidine, pyrazole, pyrazine, pyridazine, 1,2,4-triazole, indazole, pyridinone, thiazole, quinoline, pyrrolo[1,2-a]pyrimidine, 1,2,4-thiadiazole, [1,2,4]triazolo[1,5-a]pyridine, pyrazolo[1,5-a]pyrazine, imidazo[1,2-a]pyrazine, pyrazolo[1,5-a]pyrimidine, pyrazolo[1,5-c]pyrimidine, imidazo[1,2-b]pyridazine, imidazo[1,2-a]pyridine, imidazo[2,1-b]oxazole, 1,2,5-thiadiazole, isothiazole, 1,2,3-thiadiazole, and isothiazole. Oxazole, 1,3,4-thiadiazole, 3-(1H-pyrazol-1-yl)pyridine, 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine, pyrrolo[2,1-f][1,2,4]triazine, 5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one, imidazo[1,2-a]pyrimidine, pyrazolo[3,4-b]pyridine, oxazole, 1,2,3-triazole, 2,3-dihydroindoleazine-5(1H)-one, pyridazine-3(2H)-one, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine, or 2-(1H-pyrazol-1-yl)pyridine, wherein Cy It is substituted by one or more R8 groups independently selected from the following: –CH2OH, –CH2CH2OH, –CH2OCH3, methyl, ethyl, –CHF2, –CF3, chlorine, fluorine, oxo, –C(=O)N(CH3)2, –C(=O)OH, –C(=O)OCH3, hydroxyl, cyano, cyclopropyl substituted with –CH2OH, and cyclopropyl.

[0220] In some embodiments, Z is -L1–NR5R6, L1 is absent, R5 is hydrogen, R6 is -L2–Cy, L2 is –CH2–, and Cy The following compounds are listed: imidazole, phenyl, pyridine, 2-oxabicyclo[2.1.1]hexane, pyrimidine, pyrazole, pyrazine, pyridazine, 1,2,4-triazole, indazole, pyridinone, thiazole, quinoline, pyrrolo[1,2-a]pyrimidine, 1,2,4-thiadiazole, [1,2,4]triazolo[1,5-a]pyridine, pyrazolo[1,5-a]pyrazine, imidazo[1,2-a]pyrazine, pyrazolo[1,5-a]pyrimidine, pyrazolo[1,5-c]pyrimidine, imidazo[1,2-b]pyridazine, imidazo[1,2-a]pyridine, imidazo[2,1-b]oxazole, 1,2,5-thiadiazole, isothiazole, 1,2,3-thiadiazole. Isoxazole, 1,3,4-thiadiazole, 3-(1H-pyrazol-1-yl)pyridine, 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine, pyrrolo[2,1-f][1,2,4]triazine, 5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one, imidazo[1,2-a]pyrimidine, pyrazolo[3,4-b]pyridine, oxazole, 1,2,3-triazole, 2,3-dihydroindoleazine-5(1H)-one, pyridazine-3(2H)-one, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine, or 2-(1H-pyrazol-1-yl)pyridine.

[0221] In some embodiments, Z is -L1–NR5R6, L1 is absent, R5 is hydrogen, R6 is -L2–Cy, L2 is –CH2–, and Cy is phenyl, pyridine, imidazole, 2-oxabicyclo[2.1.1]hexane, pyrimidine, pyrazine, pyridazine, triazole, pyrazole, indazole, pyridinone, thiazole, or quinoline, wherein Cy is optionally substituted by one or more R8s independently selected from: C substituted with hydroxyl groups 1-6 Alkyl; C 1-3 Halogenated alkyl group; halogen; hydroxyl group; cyano group; –C(=O)NR9R 10 –C(=O)OR 10 C 3-6 Cycloalkyl; and oxo; wherein R9 and R 10 Each of them is independently hydrogen or C. 1-6Alkyl. In some embodiments, Z is -L1–NR5R6, L1 is absent, R5 is hydrogen, R6 is -L2–Cy, L2 is –CH2–, and Cy is phenyl, pyridine, imidazole, 2-oxabicyclo[2.1.1]hexane, pyrimidine, pyrazine, pyridazine, triazole, pyrazole, indazole, pyridinone, thiazole, or quinoline, wherein Cy is substituted by one or more R8s independently selected from: optionally substituted C-hydroxyl groups. 1-6 Alkyl; C 1-3 Halogenated alkyl group; halogen; hydroxyl group; cyano group; –C(=O)NR9R 10 –C(=O)OR 10 C 3-6 Cycloalkyl; and oxo; wherein R9 and R 10 Each of them is independently hydrogen or C. 1-6 Alkyl. In some embodiments, Z is -L1–NR5R6, L1 is absent, R5 is hydrogen, R6 is -L2–Cy, L2 is –CH2–, and Cy is phenyl, pyridine, imidazole, 2-oxabicyclo[2.1.1]hexane, pyrimidine, pyrazine, pyridazine, triazole, pyrazole, indazole, pyridinone, thiazole, or quinoline, wherein Cy is optionally substituted by one or more R8s independently selected from: methyl, –CF3, –CHF2, fluorine, hydroxyl, cyano, –CH2OH, –C(=O)OH, –C(=O)OMe, and –C(=O)N(Me)2. In some embodiments, Z is -L1–NR5R6, L1 is absent, R5 is hydrogen, R6 is -L2–Cy, L2 is –CH2–, and Cy is phenyl, pyridine, imidazole, 2-oxabicyclo[2.1.1]hexane, pyrimidine, pyrazine, pyridazine, triazole, pyrazole, indazole, pyridinone, thiazole, or quinoline, wherein Cy is substituted by one or more R8s independently selected from: methyl, –CF3, –CHF2, fluorine, hydroxyl, cyano, –CH2OH, –C(=O)OH, –C(=O)OMe, and –C(=O)N(Me)2. In some embodiments, Z is -L1–NR5R6, L1 is absent, R5 is hydrogen, R6 is -L2–Cy, L2 is –CH2–, and Cy is phenyl, pyridine, imidazole, 2-oxabicyclo[2.1.1]hexane, pyrimidine, pyrazine, pyridazine, triazole, pyrazole, indazole, pyridinone, thiazole, or quinoline.

[0222] In some embodiments, Z is -L1–NR5R6, L1 is absent, R5 is hydrogen, R6 is -L2–Cy, L2 is –CH2–, and Cy The compounds are phenyl, pyridine, pyrimidine, pyrazole, pyridone, thiazole, pyrrolo[1,2-a]pyrimidine, 1,2,4-thiadiazole, [1,2,4]triazolo[1,5-a]pyridine, pyrazolo[1,5-a]pyrazine, imidazo[1,2-a]pyrazine, pyrazolo[1,5-a]pyrimidine, pyrazolo[1,5-c]pyrimidine, imidazo[1,2-b]pyridazine, imidazo[1,2-a]pyridine, imidazo[2,1-b]oxazole, 1,2,5-thiadiazole, isothiazole, 1,2,3-thiadiazole, isoxazole, 1,3,4-thiadiazole, 3-(1H-pyridine) Cy is selected from pyrazol-1-yl)pyridine, 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine, pyrrolo[2,1-f][1,2,4]triazine, 5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one, imidazo[1,2-a]pyrimidine, pyrazolo[3,4-b]pyridine, oxazole, 1,2,3-triazole, 2,3-dihydroindoleazine-5(1H)-one, pyridazine-3(2H)-one, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine, or 2-(1H-pyrazol-1-yl)pyridine, wherein Cy is optionally substituted by one or more R8 radicals independently selected from the following: optionally substituted by a hydroxyl group or C 1-6 alkoxy-substituted C 1-6 Alkyl; C 1-3 Halogenated alkyl group; halogen; cyano group; oxo group; –C(=O)OR 10 ; and optionally hydroxyl-C 1-6 Alkyl-substituted C 3-6 Cycloalkyl.

[0223] In some embodiments, Z is -L1–NR5R6, L1 is absent, R5 is hydrogen, R6 is -L2–Cy, L2 is –CH2–, and Cy The compounds are phenyl, pyridine, pyrimidine, pyrazole, pyridone, thiazole, pyrrolo[1,2-a]pyrimidine, 1,2,4-thiadiazole, [1,2,4]triazolo[1,5-a]pyridine, pyrazolo[1,5-a]pyrazine, imidazo[1,2-a]pyrazine, pyrazolo[1,5-a]pyrimidine, pyrazolo[1,5-c]pyrimidine, imidazo[1,2-b]pyridazine, imidazo[1,2-a]pyridine, imidazo[2,1-b]oxazole, 1,2,5-thiadiazole, isothiazole, 1,2,3-thiadiazole, isoxazole, 1,3,4-thiadiazole, 3-(1H-pyridine) Cy is azol-1-yl)pyridine, 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine, pyrrolo[2,1-f][1,2,4]triazine, 5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one, imidazo[1,2-a]pyrimidine, pyrazolo[3,4-b]pyridine, oxazole, 1,2,3-triazole, 2,3-dihydroindoleazine-5(1H)-one, pyridazine-3(2H)-one, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine, or 2-(1H-pyrazol-1-yl)pyridine, wherein Cy is substituted by one or more R8 radicals independently selected from the following: optionally by a hydroxyl group or C 1-6 alkoxy-substituted C 1-6 Alkyl; C 1-3 Halogenated alkyl group; halogen; cyano group; oxo group; –C(=O)OR 10 ; and optionally hydroxyl-C 1-6 Alkyl-substituted C 3-6 Cycloalkyl.

[0224] In some embodiments, Z is -L1–NR5R6, L1 is absent, R5 is hydrogen, R6 is -L2–Cy, L2 is –CH2–, and Cy The compounds are phenyl, pyridine, pyrimidine, pyrazole, pyridone, thiazole, pyrrolo[1,2-a]pyrimidine, 1,2,4-thiadiazole, [1,2,4]triazolo[1,5-a]pyridine, pyrazolo[1,5-a]pyrazine, imidazo[1,2-a]pyrazine, pyrazolo[1,5-a]pyrimidine, pyrazolo[1,5-c]pyrimidine, imidazo[1,2-b]pyridazine, imidazo[1,2-a]pyridine, imidazo[2,1-b]oxazole, 1,2,5-thiadiazole, isothiazole, 1,2,3-thiadiazole, isoxazole, 1,3,4-thiadiazole, 3-(1H-pyridine) Cy Optionally substituted with one or more R8 groups independently selected from the following: –CH2OH, –CH2CH2OH, –CH2OCH3, methyl, ethyl, –CHF2, –CF3, chlorine, fluorine, oxo, –C(=O)OH, cyano, cyclopropyl substituted with –CH2OH, and cyclopropyl.

[0225] In some embodiments, Z is -L1–NR5R6, L1 is absent, R5 is hydrogen, R6 is -L2–Cy, L2 is –CH2–, and Cy The compounds are phenyl, pyridine, pyrimidine, pyrazole, pyridone, thiazole, pyrrolo[1,2-a]pyrimidine, 1,2,4-thiadiazole, [1,2,4]triazolo[1,5-a]pyridine, pyrazolo[1,5-a]pyrazine, imidazo[1,2-a]pyrazine, pyrazolo[1,5-a]pyrimidine, pyrazolo[1,5-c]pyrimidine, imidazo[1,2-b]pyridazine, imidazo[1,2-a]pyridine, imidazo[2,1-b]oxazole, 1,2,5-thiadiazole, isothiazole, 1,2,3-thiadiazole, isoxazole, 1,3,4-thiadiazole, 3-(1H-pyridine) Cy It is substituted by one or more R8 groups independently selected from the following: –CH2OH, –CH2CH2OH, –CH2OCH3, methyl, ethyl, –CHF2, –CF3, chlorine, fluorine, oxo, –C(=O)OH, cyano, cyclopropyl substituted with –CH2OH, and cyclopropyl.

[0226] In some embodiments, Z is -L1–NR5R6, L1 is absent, R5 is hydrogen, R6 is -L2–Cy, L2 is –CH2–, and Cy is phenyl, pyridine, pyrimidine, pyrazole, pyridinone, thiazole, pyrrolo[1,2-a]pyrimidine, 1,2,4-thiadiazole, [1,2,4]triazolo[1,5-a]pyridine, pyrazolo[1,5-a]pyrazine, imidazo[1,2-a]pyrazine, pyrazolo[1,5-a]pyrimidine, pyrazolo[1,5-c]pyrimidine, imidazo[1,2-b]pyridazine, imidazo[1,2-a]pyridine, imidazo[2,1-b]oxazole, 1,2,5-thiadiazole, isothiazole, 1,2,3-thiadiazole, isoxazole, 1,3,4-thiadiazole, 3-(1H -pyrazol-1-yl)pyridine, 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine, pyrrolo[2,1-f][1,2,4]triazine, 5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one, imidazo[1,2-a]pyrimidine, pyrazolo[3,4-b]pyridine, oxazole, 1,2,3-triazole, 2,3-dihydroindoleazine-5(1H)-one, pyridazine-3(2H)-one, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine, or 2-(1H-pyrazol-1-yl)pyridine.

[0227] In some embodiments, Z is -L1–NR5R6, L1 is absent, R5 is hydrogen, R6 is -L2–Cy, L2 is –CH2–, and Cy is pyrazole, 1-azabicyclo[3.2.0]heptane, hexahydro-1H-pyrrolo[2,1-c][1,4]oxazine, pyrrolidine, or hexahydro-1H-pyrroloazine; wherein Cy is optionally substituted by one or more R8s independently selected from: C 1-6 Alkyl groups and halogens.

[0228] In some embodiments, Z is -L1–NR5R6, L1 is absent, R5 is hydrogen, R6 is -L2–Cy, L2 is –CH2–, and Cy is pyrazole, 1-azabicyclo[3.2.0]heptane, hexahydro-1H-pyrrolo[2,1-c][1,4]oxazine, pyrrolidine, or hexahydro-1H-pyrroloazine; wherein Cy is optionally substituted by one or more R8s independently selected from methyl and fluorine.

[0229] In some embodiments, Z is -L1–NR5R6, L1 is absent, R5 is hydrogen, R6 is -L2–Cy, L2 is –CH2–, and Cy is pyrazole, 1-azabicyclo[3.2.0]heptane, hexahydro-1H-pyrrolo[2,1-c][1,4]oxazine, pyrrolidine, or hexahydro-1H-pyrroloazine; wherein Cy is substituted by one or more R8s independently selected from: C 1-6 Alkyl groups and halogens.

[0230] In some embodiments, Z is -L1–NR5R6, L1 is absent, R5 is hydrogen, R6 is -L2–Cy, L2 is –CH2–, and Cy is pyrazole, 1-azabicyclo[3.2.0]heptane, hexahydro-1H-pyrrolo[2,1-c][1,4]oxazine, pyrrolidine, or hexahydro-1H-pyrroloazine; wherein Cy is substituted by one or more R8s independently selected from methyl and fluorine.

[0231] In some embodiments, Z is -L1–NR5R6, L1 is absent, R5 is hydrogen, R6 is -L2–Cy, L2 is –CH2–, and Cy is pyrazole, 1-azabicyclo[3.2.0]heptane, hexahydro-1H-pyrrolo[2,1-c][1,4]oxazine, pyrrolidine, or hexahydro-1H-pyrroloazine.

[0232] In some embodiments, Z is -L1–NR5R6, L1 is absent, R5 is hydrogen, R6 is -L2–Cy, L2 is –CH(CH3)–, and Cy is phenyl.

[0233] In some embodiments, Z is -L1–NR5R6, where L1 is absent, R5 is hydrogen, and R6 is methyl.

[0234] In some embodiments, Z is -L1–NR5R6, L1 is absent, R5 is hydrogen, and R6 is –C(=O)–Cy. In some embodiments, Z is -L1–NR5R6, L1 is absent, R5 is hydrogen, R6 is –C(=O)–Cy, and Cy is phenyl.

[0235] In some embodiments, Z is -L1–NR5R6, L1 is absent, R5 is hydrogen, and R6 is –C(=O)CH2CH3.

[0236] In some embodiments, Z is -L1–NR5R6, L1 is –C(=O)–, R5 is –NH2, and R6 is methyl.

[0237] In some embodiments, Z is -L1–NR5R6, L1 is absent, and R5 and R6, together with the nitrogen atoms they are bonded to, form a 3- to 6-membered monocycle, which is optionally independently selected from C. 1-6 One or more groups of alkyl and hydroxyl are substituted.

[0238] In some embodiments, Z is -L1–NR5R6, L1 is absent, and R5 and R6 together with the nitrogen atoms they are bonded to form a nitrogen-containing heterocyclic butane, which is optionally independently selected from C14. 1-6 One or more alkyl and hydroxyl groups are substituted. In some embodiments, Z is -L1–NR5R6, L1 is absent, and R5 and R6 together with the nitrogen atom to which they are bonded form an aziridine, which is independently selected from C14. 1-6 One or more groups of alkyl and hydroxyl groups are substituted. In some embodiments, Z is -L1–NR5R6, L1 is absent, and R5 and R6 together with the nitrogen atom they are bonded to form a methyl- and hydroxyl-substituted azahexacyclobutane. In some embodiments, Z is -L1–NR5R6, L1 is absent, and R5 and R6 together with the nitrogen atom they are bonded to form azahexacyclobutane. In some embodiments, Z is -L1–NR5R6, L1 is absent, and R5 and R6 together with the nitrogen atom they are bonded to form a pyrazole.

[0239] In some embodiments, Z is -L1–NR5R6, L1 is absent, and R5 and R6, together with the nitrogen atom they are bonded to, form a 3- to 6-membered monocyclic ring, which optionally contains one or more heteroatoms selected from N, O, and S. In some embodiments, Z is -L1–NR5R6, L1 is absent, and R5 and R6, together with the nitrogen atom they are bonded to, form a 3- to 6-membered monocyclic ring, which contains one or more heteroatoms selected from N and O. In some embodiments, Z is -L1–NR5R6, L1 is absent, and R5 and R6, together with the nitrogen atom they are bonded to, form a 3- to 6-membered monocyclic ring, which contains one or more heteroatoms selected from N and S. In some embodiments, Z is -L1–NR5R6, L1 is absent, and R5 and R6, together with the nitrogen atom they are bonded to, form a 3- to 6-membered monocyclic ring, which optionally contains one or more heteroatoms selected from S and O. In some embodiments, Z is -L1–NR5R6, L1 is absent, and R5 and R6, together with the nitrogen atom they are bonded to, form a 3- to 6-membered monocyclic ring, which contains one or more N atoms. In some embodiments, Z is -L1–NR5R6, L1 is absent, and R5 and R6, together with the nitrogen atom they are bonded to, form a 3- to 6-membered monocyclic ring, which contains one or more O atoms. In some embodiments, Z is -L1–NR5R6, L1 is absent, and R5 and R6, together with the nitrogen atom they are bonded to, form a 3- to 6-membered monocyclic ring, which contains one or more S atoms. In some embodiments, Z is -L1–NR5R6, L1 is absent, and R5 and R6 together with the atoms they are bonded to form 3- to 6-membered monocyclic carbon rings.

[0240] In some embodiments, Z is –OR6 and R6 is -L2-Cy. In some embodiments, L2 is –CH2– and Cy is pyridine. In some embodiments, Z is –OR6 and R6 is -L2-Cy, where L2 is –CH2– and Cy is pyridine.

[0241] In some embodiments, Z is –SR6 and R6 is -L2-Cy. In some embodiments, L2 is –CH2– and Cy is pyridine. In some embodiments, Z is –SR6 and R6 is -L2-Cy, where L2 is –CH2– and Cy is pyridine.

[0242] In some embodiments, Z and R2 together with the carbon atoms to which they are bonded form a 5- to 6-membered monocyclic aromatic ring. In some embodiments, Z and R2 together with the carbon atoms to which they are bonded form a 5- to 6-membered monocyclic heteroaromatic ring. In some embodiments, Z and R2 together with the carbon atoms to which they are bonded form a 5- to 6-membered monocyclic aromatic ring, which optionally contains one or more heteroatoms selected from N, O, and S. In some embodiments, Z and R2 together with the carbon atoms to which they are bonded form a 5- to 6-membered monocyclic aromatic ring, which contains one or more heteroatoms selected from N and O. In some embodiments, Z and R2 together with the carbon atoms to which they are bonded form a 5- to 6-membered monocyclic aromatic ring, which contains one or more heteroatoms selected from N and S. In some embodiments, Z and R2, together with the carbon atoms to which they are bonded, form a 5- to 6-membered monocyclic aromatic ring, which optionally comprises one or more heteroatoms selected from O and S. In some embodiments, Z and R2, together with the carbon atoms to which they are bonded, form a 5- to 6-membered monocyclic aromatic ring, which optionally contains one or more N atoms. In some embodiments, Z and R2, together with the carbon atoms to which they are bonded, form a 5- to 6-membered monocyclic aromatic ring, which optionally contains one or more O atoms. In some embodiments, Z and R2, together with the carbon atoms to which they are bonded, form a pyrazole. In some embodiments, Z and R2, together with the atoms to which they are bonded, form a C6 aryl group.

[0243] In some embodiments, the compound is any of the compounds listed in Table 1 or a stereoisomer, transisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0244] Table 1:

[0245]

[0246] In some embodiments, the compounds are selected from the group consisting of compounds 1 to 146 as shown in Table 1, or their stereoisomers, transisomers, tautomers, or pharmaceutically acceptable salts. In some embodiments, the compounds are selected from the group consisting of compounds 1 to 65 as shown in Table 1, or their stereoisomers, transisomers, tautomers, or pharmaceutically acceptable salts. In some embodiments, the compounds are selected from the group consisting of compounds 66 to 135 as shown in Table 1, or their stereoisomers, transisomers, tautomers, or pharmaceutically acceptable salts. In some embodiments, the compounds are selected from the group consisting of compounds 136 to 146 as shown in Table 1, or their stereoisomers, transisomers, tautomers, or pharmaceutically acceptable salts.

[0247] Compound Synthesis

[0248] The compounds disclosed herein, or their stereoisomers, transisomers, tautomers, or pharmaceutically acceptable salts thereof, can be prepared by various methods described below and in the exemplary synthetic reaction schemes described herein. The starting materials and reagents used to prepare these compounds are generally available from commercial suppliers such as Aldrich Chemical Co., or prepared by methods known to those skilled in the art, according to methods described in the references, such as Fieser and Fieser's Reagents for Organic Synthesis; Wiley & Sons: New York, Vols. 1–21; RC LaRock, Comprehensive Organic Transformations, Vol. 2 Wiley-VCH, New York, 1999; Comprehensive Organic Synthesis, B. Trost and I. Fleming (eds.), Vol. 1–9, Pergamon, Oxford, 1991; Comprehensive Heterocyclic Chemistry, A.R. Katritzky and C.W. Rees (eds.), Pergamon, Oxford, 1984, Vol. 1–9; Comprehensive Heterocyclic Chemistry II, A.R. Katritzky and C.W. Rees (eds.), Pergamon, Oxford, 1996, Vol. 1–11; and Organic Reactions, Wiley & Sons: New York, 1991, Vol. 1–40. The following synthetic reaction schemes are merely illustrative of some methods by which the compounds described herein or their pharmaceutically acceptable salts may be synthesized, and various modifications to these synthetic reaction schemes are possible with reference to the disclosure contained herein, and suggestions are provided to those skilled in the art.

[0249] Synthetic chemical transformations and protecting group methodologies (protection and deprotection) that can be used to synthesize the compounds described herein, as well as the necessary reagents and intermediates, include, for example, R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); TW Greene and PGM Wuts, Protective Groups in Organic Synthesis, Vol. 3 The editions mentioned are John Wiley and Sons (1999); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and subsequent editions.

[0250] The compounds described herein, or their stereoisomers, transisomers, tautomers, or pharmaceutically acceptable salts, can be prepared individually or as a compound library comprising at least two, for example, 5 to 1000 compounds or 10 to 100 compounds. Libraries of the compounds described herein, or their stereoisomers, transisomers, tautomers, or pharmaceutically acceptable salts, having the formula described herein, can be prepared by combination resolution and mixing methods or by using multiple parallel syntheses, for example, solution-phase or solid-phase chemistry. Therefore, according to another aspect, this document provides a compound library comprising at least two of the compounds described herein, or their stereoisomers, transisomers, tautomers, or pharmaceutically acceptable salts.

[0251] The examples provide exemplary methods for preparing compounds as described herein, or their stereoisomers, transisomers, tautomers, or pharmaceutically acceptable salts. Those skilled in the art will understand that other synthetic routes can be used to synthesize compounds as described herein, or their stereoisomers, transisomers, tautomers, or pharmaceutically acceptable salts. Although specific starting materials and reagents are described and discussed in the examples, other starting materials and reagents may be substituted to provide a variety of derivatives and / or reaction conditions. Furthermore, in view of this disclosure, many of the exemplary compounds prepared by the methods can be further modified using conventional chemical methods.

[0252] In the preparation of compounds as described herein, or their stereoisomers, transisomers, tautomers, or pharmaceutically acceptable salts, it may be necessary to protect the distal functional groups (e.g., primary or secondary amines) of intermediates. The need for such protection will vary depending on the nature of the distal functionality and the conditions of the preparation method. Suitable amino protecting groups include acetyl, trifluoroacetyl, tert-butyloxycarbonyl (BOC), benzyloxycarbonyl (CBz), and 9-fluorenylmethyleneoxycarbonyl (Fmoc). The need for such protection can be readily determined. For a general description of protecting groups and their uses, see TW Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.

[0253] In methods for preparing compounds as described herein, or their stereoisomers, transisomers, tautomers, or pharmaceutically acceptable salts, it is advantageous to separate the reaction products from each other and / or from the starting material. The desired products of each step or series of steps are separated and / or purified to the desired homogeneity using techniques common in the art. Typically, such separations involve multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography can involve any method, including, for example: reversed-phase and normal-phase chromatography; size exclusion chromatography; ion exchange chromatography; high-pressure, medium-pressure, and low-pressure liquid chromatography methods and apparatus; small-scale analytical chromatography; simulated moving bed (SMB) and preparative thin-layer or thick-layer chromatography; and small-scale thin-layer and rapid chromatographic techniques.

[0254] Another type of separation method involves treating the mixture with a reagent selected to bind with or otherwise separate the desired product, unreacted starting material, reaction byproducts, etc. Such reagents include adsorbents or absorbents, such as activated carbon, molecular sieves, ion exchange media, etc. Alternatively, the reagent can be an acid (in the case of basic materials); a base (in the case of acidic materials); a binding agent such as an antibody, binding protein; a selective chelating agent such as a crown ether; a liquid / liquid ion extraction reagent (LIX), etc. The choice of a suitable separation method depends on the properties of the materials involved, such as the boiling point and molecular weight of distillation and sublimation, the presence or absence of polar functional groups in chromatography, and the stability of the materials in acidic and basic media during multiphase extraction.

[0255] A mixture of diastereomers can be separated into its individual diastereomers based on differences in their physicochemical properties, using methods such as chromatography and / or fractional crystallization. Enantiomers can be separated by reacting the enantiomer mixture with a suitable optically active compound (e.g., a chiral auxiliary agent, such as a chiral alcohol or Mosher acyl chloride), converting the enantiomer mixture into a mixture of diastereomers, separating the diastereomers, and converting (e.g., hydrolyzing) each diastereomer into its corresponding pure enantiomer. Additionally, some compounds described herein, or their stereoisomers, transisomers, tautomers, or pharmaceutically acceptable salts, can be transisomers (e.g., substituted biaryl groups). Enantiomers can also be separated using chiral HPLC columns.

[0256] A single stereoisomer, such as an enantiomer that is substantially free of its stereoisomers, can be obtained by resolving racemic mixtures using optically active resolving agents by methods such as forming diastereomers (Eliel, E. and Wilen, S. "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994; Lochmuller, CH, (1975) J. Chromatogr., 113(3):283-302). Racemic mixtures of the chiral compounds described herein or their pharmaceutically acceptable salts can be separated and isolated by any suitable method comprising: (1) forming an ionic diastereomer salt with the chiral compound and separating it by fractional crystallization or other methods; (2) forming a diastereomer compound with a chiral derivatizing agent, separating the diastereomer and converting it to a pure stereoisomer; and (3) directly separating substantially pure or enriched stereoisomers under chiral conditions. See: "Drug Stereochemistry, Analytical Methods andPharmacology," Irving W. Wainer, ed., Marcel Dekker, Inc., New York (1993).

[0257] According to method (1), diastereomer salts can be formed by reacting enantiomerically pure chiral bases such as brucine, quinine, ephedrine, strychnine, and α-methyl-β-phenylethylamine (amphetamine) with asymmetric compounds containing acidic functional groups such as carboxylic acids and sulfonic acids. The diastereomer salts can be separated by fractional crystallization or ion chromatography. For the separation of optical isomers of amino compounds, the addition of chiral carboxylic acids or sulfonic acids such as camphorsulfonic acid, tartaric acid, mandelic acid, or lactic acid can induce the formation of diastereomer salts.

[0258] Alternatively, by method (2), the substrate to be resolved is reacted with an enantiomer of a chiral compound to form a diastereomer pair (E. and Wilen, S. “Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., 1994, p. 322). The diastereomer can be formed by reacting the asymmetric compound with an enantiomerically pure chiral derivatizing agent, such as a menthyl derivative, followed by separation of the diastereomer and hydrolysis to obtain a pure or enriched enantiomer. Methods for determining optical purity involve preparing a racemic mixture of chiral esters, such as menthyl esters, for example, the preparation of (-)-chloroformate menthyl ester, or Mosher ester, α-methoxy-α-(trifluoromethyl)phenylacetic acid ester (Jacob III. J. Org. Chem. (1982) 47:4165), and analyzing... 1 ¹H NMR spectroscopy is used to determine the presence of either the enantiomers or diastereomers of the two transisomers. Stable diastereomers of the transisomers can be separated and isolated by normal-phase and reversed-phase chromatography, following the method for separating transisomers of naphthyl-isoquinoline (WO 96 / 15111). By method (3), a racemic mixture of the two enantiomers can be separated by chromatography using a chiral stationary phase (“Chiral Liquid Chromatography” (1989) WJ Lough, ed., Chapman and Hall, New York; Okamoto, J. Chromatogr., (1990) 513:375-378). The enriched or purified enantiomers can be identified by methods used to distinguish other chiral molecules with asymmetric carbon atoms, such as optical rotation or circular dichroism.

[0259] The chemical reactions described herein are readily applicable to the preparation of other compounds described herein and their pharmaceutically acceptable salts. For example, the synthesis of non-exemplary compounds and their pharmaceutically acceptable salts according to this document can be successfully achieved with modifications obvious to those skilled in the art, such as by appropriately protecting interfering groups, utilizing other suitable reagents known in the art, or by conventional modifications to the reaction conditions. Alternatively, other reactions disclosed herein or known in the art will be considered suitable for the preparation of other compounds described herein and their pharmaceutically acceptable salts.

[0260] pharmaceutical preparations

[0261] This article also provides pharmaceutical compositions comprising a compound as described herein, or a stereoisomer, transtransfer isomer, tautomer, or pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0262] The compounds described herein, or their stereoisomers, transisomers, tautomers, or pharmaceutically acceptable salts thereof, can be formulated into pharmaceutical compositions according to standard pharmaceutical practice. Therefore, this document further provides a pharmaceutical composition comprising the compounds described herein, or their stereoisomers, transisomers, tautomers, or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable excipients.

[0263] Typical formulations are prepared by mixing a compound as described herein or a pharmaceutically acceptable salt thereof with an excipient. Suitable carriers, diluents, and excipients include, but are not limited to, materials such as carbohydrates, waxes, water-soluble and / or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc. The specific excipient used will depend on the manner and purpose of administration of the compound as described herein or a pharmaceutically acceptable salt thereof. Generally, solvents are selected based on generally recognized safe solvents (GRAS) for use in mammals. Typically, safe solvents are non-toxic aqueous solvents, such as water and other non-toxic solvents that are soluble in or miscible with water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycol (e.g., PEG 400, PEG 300), and mixtures thereof. The formulation may also contain one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, flow aids, processing aids, colorants, sweeteners, flavorings, flavorings, and other known additives to provide an aesthetically pleasing presentation of the medicine (i.e., the compound or pharmaceutical composition thereof described herein) or to facilitate the preparation of the pharmaceutical product (i.e., the drug).

[0264] Formulations can be prepared using conventional dissolution and mixing procedures. For example, in the presence of one or more of the excipients described above, the active pharmaceutical ingredient (i.e., the compound as described herein or its pharmaceutically acceptable salt, or its stable form (e.g., a complex with a cyclodextrin derivative or other known complexing agent)) is dissolved in a suitable solvent. The compound as described herein, or its stereoisomers, transisomers, tautomers, or pharmaceutically acceptable salts, are typically formulated into pharmaceutical dosage forms to provide easily controlled drug dosages and enable patient adherence to the prescription regimen.

[0265] Depending on the method of administration, pharmaceutical compositions (or formulations) for administration can be packaged in various ways. Typically, the dispensing material includes a container in which the pharmaceutical formulation is deposited in a suitable form. Suitable containers include materials such as bottles (plastic and glass), capsules, ampoules, plastic bags, metal cylinders, etc. Containers may also include tamper-proof components to prevent accidental contact with the packaged contents. Additionally, the container is labeled with a description of its contents. Appropriate warnings may also be included on the label.

[0266] Pharmaceutical formulations of compounds as described herein, or their stereoisomers, transisomers, tautomers, or pharmaceutically acceptable salts, can be prepared for various routes and types of administration. For example, compounds of desired purity, or their stereoisomers, transisomers, tautomers, or pharmaceutically acceptable salts, may optionally be combined with one or more pharmaceutically acceptable excipients (Remington's Pharmaceutical Sciences (1980) p. 16). The compound (Osol, A.) is prepared as a lyophilized formulation, a ground powder, or an aqueous solution. It can be formulated by mixing with a physiologically acceptable carrier (i.e., a carrier that is non-toxic to the receptor at the dose and concentration used) at ambient temperature, with an appropriate pH and desired purity. The pH of the formulation depends primarily on the specific use and concentration of the compound, but can be in the range of about 3 to about 8. For example, formulation in an acetate buffer at pH 5 is a suitable example.

[0267] Pharmaceutical compositions are typically stored as solid compositions, lyophilized formulations, or as aqueous solutions.

[0268] The pharmaceutical compositions described herein can be formulated, administered, and applied in accordance with good medical practice, i.e., dosage, concentration, schedule, duration, medium, and route of administration. Factors considered in this context include the specific condition being treated, the specific mammal being treated, the individual patient's clinical symptoms, the cause of the condition, the site of delivery, the method of administration, the timing of administration, and other factors known to the medical practitioner. The effective amount of the compound to be administered, or its stereoisomers, transisomers, tautomers, or pharmaceutically acceptable salts thereof, will be influenced by these considerations and is the minimum amount necessary to improve or treat the hyperproliferative disorder.

[0269] Generally, the initial effective dose of a parenteral compound or its stereoisomers, transtransfer isomers, tautomers, or pharmaceutically acceptable salts will be in the range of about 0.01 mg / kg to 100 mg / kg per day (i.e., about 0.1 mg / kg of patient body weight to 20 mg / kg of patient body weight), and the typical initial range of the compound used is 0.3 mg / kg / day to 15 mg / kg / day. In another embodiment, the pharmaceutical composition described herein comprises an effective amount of the compound described herein or its stereoisomers, transisomers, tautomers, or pharmaceutically acceptable salts, in an amount of about: 1 mg-10 mg; 10 mg-25 mg; 20 mg-50 mg; 50 mg-75 mg; 70 mg-100 mg; 100 mg-150 mg; 100 mg-200 mg; 100 mg-500 mg; 200 mg-500 mg; 250 mg-500 mg; 500 mg-1000 mg; or 750 mg-1000 mg.

[0270] Acceptable pharmaceutically acceptable excipients are non-toxic to the receptor at the doses and concentrations used and include buffers such as phosphates, citrates, and other organic acids; antioxidants, including ascorbic acid and methionine; preservatives (such as octadecyl dimethyl benzyl ammonium chloride; hexamethyl diammonium chloride; benzalkonium chloride; benzyl chloride; phenol, butanol, or benzyl alcohol; alkyl esters of p-hydroxybenzoate, such as methylparaben or propylparaben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight excipients (less than about 10). (1 residue) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers, such as polyvinylpyrrolidone; amino acids, such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates, including glucose, mannose, or dextrin; chelating agents, such as EDTA; sugars, such as sucrose, mannitol, trehalose, or sorbitol; salt-forming counterions, such as sodium; metal complexes (e.g., zinc protein complexes); and / or nonionic surfactants, such as TWEEN®, PLURONICS®, or polyethylene glycol (PEG). The active pharmaceutical ingredient may also be encapsulated in microcapsules (e.g., hydroxymethyl cellulose or gelatin microcapsules and poly(methyl methacrylate) microcapsules, respectively), prepared by, for example, cohesive drug delivery systems (e.g., liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules), or in coarse droplet emulsions, prepared by, for example, cohesive techniques or by interfacial polymerization. Such techniques are disclosed in Remington's Pharmaceutical Sciences, Issue 16. Edition, Osol, A. (1980).

[0271] Sustained-release formulations of the compounds described herein or their pharmaceutically acceptable salts can be prepared. Suitable examples of sustained-release formulations include semi-permeable matrices containing solid hydrophobic polymers of the compounds described herein or their pharmaceutically acceptable salts, in the form of molded articles such as membranes or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (e.g., poly(2-hydroxyethyl-methacrylate) or poly(vinyl alcohol)), polylactic acid (US 3773919), copolymers of L-glutamic acid and γ-ethyl-L-glutamic acid, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as LUPRON DEPOT™ (injectable microspheres composed of lactic acid-glycolic acid copolymers and leuprolide acetate), and poly-D-(-)-3-hydroxybutyric acid.

[0272] This formulation includes formulations suitable for the routes of administration detailed herein. Formulations are readily available in unit dose form and can be prepared by any method. Techniques and formulations are generally contained in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA). Such methods involve the steps of associating the active ingredient with a carrier constituting one or more excipients. Generally, formulations are prepared by uniformly and tightly binding the active ingredient with a liquid carrier or a subdivided solid carrier, or both, and then, if necessary, shaping the product.

[0273] Formulations of compounds suitable for oral administration, as described herein, or their stereoisomers, transisomers, tautomers, or pharmaceutically acceptable salts, can be prepared into discrete units, such as pills, capsules, pouches, or tablets, each unit containing a predetermined amount of such compound or its stereoisomers, transisomers, tautomers, or pharmaceutically acceptable salts. Compressed tablets can be prepared by compressing the active ingredient in a free-flowing form (e.g., powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surfactant, or dispersant) in a suitable machine. Molded tablets can be prepared by molding a mixture of powdered active ingredients moistened with an inert liquid diluent in a suitable machine. Tablets can optionally be coated or scored and can optionally be formulated to provide a slow or controlled release of the active ingredient therefrom. Tablets, lozenges, tablets, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules (e.g., gelatin capsules), syrups, or elixirs can be prepared for oral administration. Formulations of compounds for oral administration, or pharmaceutically acceptable salts thereof, as described herein, may be prepared according to any method used for preparing pharmaceutical compositions, and such compositions may contain one or more agents, including sweeteners, flavoring agents, coloring agents, and preservatives, to provide a palatable formulation. Tablets containing an active ingredient mixed with non-toxic pharmaceutical excipients suitable for tablet preparation are acceptable. These excipients may be, for example, inert diluents such as calcium carbonate or sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrants such as corn starch or alginate; binders such as starch, gelatin, or gum arabic; and lubricants such as magnesium stearate, stearic acid, or talc. Tablets may be uncoated or coated using known techniques, including microencapsulation, to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained effect over a longer period. For example, delaying materials, such as glyceryl monostearate or glyceryl distearate alone or in combination with waxes, may be used.

[0274] For the treatment of the eyes or other external tissues (e.g., the mouth and skin), the formulation is preferably applied as a topical ointment or cream containing, for example, an active ingredient at a concentration of 0.075% w / w to 20% w / w. When formulated as an ointment, the active ingredient may be used with a paraffin or a water-miscible ointment base. Alternatively, the active ingredient may be formulated as a cream with an oil-in-water cream base. If desired, the aqueous phase of the cream base may include polyols, i.e., alcohols having two or more hydroxyl groups, such as propylene glycol, 1,3-butanediol, mannitol, sorbitol, glycerin, and polyethylene glycol (including PEG400) and mixtures thereof. Topical formulations may desirably include compounds that enhance the absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such skin penetration enhancers include dimethyl sulfoxide and related analogues. The oil phase of the emulsion of the compositions provided herein may be composed of known ingredients in a known manner. Although this phase may contain only emulsifiers, it is desirable to include at least one emulsifier with fats or oils or with a mixture of both fats and oils. Preferably, the hydrophilic emulsifier is included together with the lipophilic emulsifier used as a stabilizer. It is also preferred that both oils and fats are included simultaneously. The emulsifiers, with or without stabilizers, together constitute a so-called emulsified wax, and the wax, together with the oils and fats, constitutes a so-called emulsified ointment matrix, forming an oily dispersed phase of the cream formulation. Emulsifiers and emulsion stabilizers suitable for the formulations described herein include Tween® 60, Span® 80, cetearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl monostearate, and sodium lauryl sulfate.

[0275] Aqueous suspensions containing compounds as described herein, or their stereoisomers, transisomers, tautomers, or pharmaceutically acceptable salts, may contain an active substance mixed with excipients suitable for manufacturing aqueous suspensions. Such excipients include suspending agents such as sodium carboxymethyl cellulose, croscarmellose, povidone, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, astragalus gum, and gum arabic, as well as dispersants or wetting agents such as naturally occurring phospholipids (e.g., lecithin), condensation products of alkyl oxidases and fatty acids (e.g., polyoxyethylene stearate), condensation products of ethylene oxides and long-chain aliphatic alcohols (e.g., heptadecanethoxycetyl alcohol), and condensation products of ethylene oxides and fatty acid-derived metaesters and hexitanic anhydrides (e.g., polyoxyethylene sorbitan monooleate). Aqueous suspensions may also contain one or more preservatives such as ethylparaben or n-propylparaben, one or more colorants, one or more flavorings, and one or more sweeteners such as sucrose or saccharin.

[0276] Pharmaceutical compositions of compounds described herein, or their stereoisomers, transisomers, tautomers, or pharmaceutically acceptable salts, may be in the form of sterile injectable formulations, such as sterile injectable aqueous or oily suspensions. These suspensions may be formulated using suitable dispersants or wetting agents and suspending agents already mentioned above. Sterile injectable formulations may also be sterile injectable solutions or suspensions in non-toxic, parenteral-acceptable diluents or solvents, such as solutions in 1,3-butanediol, or prepared as lyophilized powders. Acceptable media and solvents that may be used are water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile non-volatile oils may conventionally be used as solvents or suspension media. For this purpose, any mild non-volatile oil may be used, including synthetic monoglycerides or diglycerides. Furthermore, fatty acids such as oleic acid may also be used in the preparation of injectable formulations.

[0277] The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending on the host being treated and the specific route of administration. For example, a delayed-release formulation for oral administration to humans may contain about 1 to 1000 mg of the active ingredient compounded with an appropriate and convenient amount of a carrier substance, which may comprise about 5% to about 95% (w / w) of the total composition. Pharmaceutical compositions can be prepared to provide easily measurable dosages. For example, an aqueous solution for intravenous infusion may contain about 3 to 500 μg of the active ingredient per milliliter of solution so that a suitable volume can be infused at a rate of about 30 mL / hr.

[0278] Preparations suitable for parenteral administration include aqueous and non-aqueous sterile injectable solutions that may contain antioxidants, buffers, antibacterial agents and solutes, thereby making the preparation isotonic with the blood of the intended recipient, as well as aqueous and non-aqueous sterile suspensions that may include suspending agents and thickeners.

[0279] Formulations suitable for topical application to the eyes also include eye drops, wherein the active ingredient is dissolved or suspended in a suitable carrier, particularly in an aqueous solvent of the active ingredient. The active ingredient is preferably present in such formulations at a concentration of about 0.5% w / w to 20% w / w, for example, about 0.5% w / w to 10% w / w, for example, about 1.5% w / w.

[0280] Formulations suitable for topical application in the oral cavity include lozenges containing active ingredients in a flavoring base (typically sucrose and gum arabic or astragalus gum); lozenges containing active ingredients in an inert base (e.g., gelatin and glycerin, or sucrose and gum arabic); and mouthwashes containing active ingredients in a suitable liquid carrier.

[0281] Rectal formulations can be presented as suppositories using a suitable matrix containing, for example, cocoa butter or salicylates.

[0282] Formulations suitable for intrapulmonary or nasal administration have particle sizes ranging from, for example, 0.1 to 500 micrometers (including particle sizes ranging from 0.1 to 500 micrometers in increments of 0.5 micrometers, 1 micrometer, 30 micrometers, 35 micrometers, etc.), and can be rapidly inhaled through the nasal cavity or inhaled through the mouth to reach the alveolar sacs. Suitable formulations include aqueous or oily solutions of the active ingredient. Formulations suitable for aerosol or dry powder administration can be prepared according to conventional methods and can be delivered together with other therapeutic agents, such as compounds described to date for the treatment or prevention of diseases.

[0283] Preparations suitable for vaginal application may be in the form of vaginal suppositories, tampons, creams, gels, pastes, foams, or sprays, and contain a carrier deemed appropriate in addition to the active ingredient.

[0284] Formulations can be packaged in single-dose or multi-dose containers, such as sealed ampoules and vials, and can be stored under freeze-dried (lyophilized) conditions, requiring only the addition of a sterile injectable liquid carrier, such as water, before use. Temporary injectable solutions and suspensions are prepared from sterile powders, granules, and tablets of the aforementioned types. Preferred single-dose formulations are those containing the active ingredient at the daily dose or a unit daily sub-dose, or an appropriate fraction thereof, as described above herein.

[0285] In one embodiment, a compound or its stereoisomer, transisomer, tautomer, or pharmaceutically acceptable salt thereof is formulated as a prodrug. As used herein, the term prodrug refers to a derivative of a compound that can be hydrolyzed, oxidized, or cleaved under biological conditions to provide the compound or its stereoisomer, transisomer, tautomer, or pharmaceutically acceptable salt thereof. As defined herein, a prodrug includes a derivative comprising one or more portions that modulate or improve one or more physical, physiological, or pharmaceutical properties (such as, but not limited to, solubility, permeability, uptake, biodistribution, metabolic stability, onset of action, or some other pharmacological property) and are converted into a biologically active substance or a more biologically active substance as provided herein. In one embodiment, the prodrug herein is not biologically active prior to the release of the compound or its pharmaceutically acceptable salt.

[0286] Application method

[0287] The compounds described herein, or their stereoisomers, transisomers, tautomers, or pharmaceutically acceptable salts, may be administered via any route suitable for the condition to be treated. Suitable routes include oral, parenteral (including subcutaneous, intramuscular, intravenous (IV), intraarterial, intradermal, intrathecal, and epidural), transdermal, rectal, nasal, local (including buccal and sublingual), vaginal, intraperitoneal, intrapulmonary, and intranasal administration. In one embodiment, the compounds described herein, or their stereoisomers, transisomers, tautomers, or pharmaceutically acceptable salts, may be administered orally or via IV. For local immunosuppressive therapy, the compounds may be administered via intralesional administration, including pre-transplant perfusion or otherwise exposing the graft to the inhibitor. It should be understood that preferred routes may vary depending on, for example, the recipient's condition. When administering a compound or its stereoisomers, transisomers, tautomers, or pharmaceutically acceptable salts orally, the compound or its stereoisomers, transisomers, tautomers, or pharmaceutically acceptable salts orally may be formulated with a pharmaceutically acceptable carrier or excipient into pills, capsules, tablets, etc. When administering a compound or its stereoisomers, transisomers, tautomers, or pharmaceutically acceptable salts parenterally, the compound or its stereoisomers, transisomers, tautomers, or pharmaceutically acceptable salts orally may be formulated with a pharmaceutically acceptable parenteral medium in unit dose injection form, as detailed below.

[0288] Therefore, in one aspect, this document provides a pharmaceutical composition comprising a compound as described herein or a pharmaceutically acceptable salt thereof, and one or more pharmaceutical excipients. In one embodiment, the compound as described herein, or a stereoisomer, transisomer, tautomer, or pharmaceutically acceptable salt thereof, is administered as a pharmaceutical composition capable of oral or parenteral administration to a subject. The compound as described herein, or a stereoisomer, transisomer, tautomer, or pharmaceutically acceptable salt thereof, may be formulated for topical or parenteral use, wherein the compound, or a stereoisomer, transisomer, tautomer, or pharmaceutically acceptable salt thereof, is dissolved or otherwise suspended in a solution suitable for injections, suspensions, syrups, creams, ointments, gels, sprays, solutions, and emulsions.

[0289] Oral administration can improve patient adherence to taking compounds (e.g., formulated into pharmaceutical compositions), thereby increasing adherence and efficacy. Oral pharmaceutical compositions containing the compounds described herein include, but are not limited to, (e.g., coated, uncoated, and chewable) tablets and capsules (e.g., hard gelatin capsules, soft gelatin capsules, enteric-coated capsules, and sustained-release capsules). Tablets can be prepared by direct compression, wet granulation, or dry granulation. Oral pharmaceutical compositions containing the compounds described herein can be formulated to delay or prolong release.

[0290] The dosage range for treating human patients can be from about 10 mg to about 1000 mg of the compounds described herein. Typical dosages of the compounds can be from about 100 mg to about 300 mg. A dosage can be administered once daily (QID), twice daily (BID), or more frequently, depending on the pharmacokinetic and pharmacodynamic characteristics, including the absorption, distribution, metabolism, and excretion of the specific compound. As used herein, administration refers to the frequency of dosing, not the number of individual units a patient must take in one dose, as described herein. Therefore, in some embodiments, a patient may take two or more dose units (e.g., two or more pills / tablets / capsules) QD. Additionally, toxicity factors may influence dosage and administration regimens. When administered orally, pills, capsules, or tablets may be taken daily or at a lower frequency over a specified time period. This regimen can be repeated for multiple treatment cycles.

[0291] Treatment methods and uses

[0292] The compounds described herein, or their stereoisomers, transisomers, tautomers, or pharmaceutically acceptable salts, can be used as Ras inhibitors. In one aspect, the compounds described herein, or their stereoisomers, transisomers, tautomers, or pharmaceutically acceptable salts, can be used as KRas inhibitors. In another aspect, the compounds described herein, or their stereoisomers, transisomers, tautomers, or pharmaceutically acceptable salts, can be used as NRas inhibitors. In yet another aspect, the compounds described herein, or their stereoisomers, transisomers, tautomers, or pharmaceutically acceptable salts, can be used as HRas inhibitors. In one embodiment, the compounds described herein, or their stereoisomers, transisomers, tautomers, or pharmaceutically acceptable salts, can be used as G12D Ras inhibitors and G12D KRas inhibitors.

[0293] This document provides a method for contacting cells, such as isolated cells, with the compounds described herein or their stereoisomers, transtransferase isomers, tautomers, or pharmaceutically acceptable salts to inhibit Ras activity (e.g., KRas activity) in the cells. In another embodiment, the activity is mutant G12D KRas activity.

[0294] This article further provides a method for treating cancers containing KRas mutations, comprising administering to a patient with such cancer an effective amount of a compound as described herein, or a stereoisomer, transtransferase isomer, tautomer, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In one embodiment, the KRas mutation is KRas G12D mutation.

[0295] In one embodiment, the method further includes testing a sample from a patient (e.g., as described herein) for the presence of KRas prior to administration of the compound described herein or a pharmaceutically acceptable salt thereof. G12D Mutation. In one such embodiment, after identifying the patient sample as KRas G12D After a mutation is confirmed to be positive (e.g., present), the patient is given the compound described herein or its stereoisomer, transtransferase isomer, tautomer, or pharmaceutically acceptable salt, or a pharmaceutical composition thereof.

[0296] The methods for treating cancer described in this article involve the treatment of cancers such as acute myeloid leukemia, adolescent cancer, childhood adrenocortical carcinoma, AIDS-related cancers (e.g., lymphoma and Kaposi's sarcoma), anal cancer, appendiceal cancer, astrocytoma, atypical teratoma, rhabdomyosarcoma, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brainstem glioma, brain tumors, breast cancer, bronchial tumors, Burkitt lymphoma, carcinoid tumors, embryonal tumors, germ cell tumors, primary lymphoma, cervical cancer, childhood cancer, chordoma, cardiac tumors, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myeloproliferative disorders, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, extrahepatic ductal carcinoma in situ (DCIS), embryonal tumors, and CNS. Cancer, endometrial cancer, ependymoma, esophageal cancer, sensory neuroblastoma, Ewing sarcoma, extracranial germ cell tumors, gonadal germ cell tumors, ocular cancer, osteofibrous histiocytoma, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors (GIST), germ cell tumors, gestational trophoblastic tumors, hairy cell leukemia, head and neck cancer, heart cancer, liver cancer, Hodgkin's lymphoma. Lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumors, pancreatic neuroendocrine tumors, kidney cancer, laryngeal cancer, lip and oral cancer, lobular carcinoma in situ (LCIS), lung cancer, lymphoma, occult primary metastatic squamous cell carcinoma of the neck, midline carcinoma, oral cancer, multiple endocrine neoplasia syndrome, multiple myeloma / plasma cell tumor, mycosis fungoides, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasms, multiple myeloma, Merkel cell carcinoma, malignant mesothelioma, malignant fibrous histiocytoma and osteosarcoma, nasal cavity and sinus cancer, nasopharyngeal carcinoma, neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer (NSCLC), oral cancer, oropharyngeal cancer, ovarian cancer, pancreatic cancer, papilloma, paraganglioma, parathyroid cancer, penile cancer, pharyngeal cancer, pleural pulmonary blastoma, primary central nervous system (CNS) cancer. Lymphoma, prostate cancer, rectal cancer, transitional cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, small cell lung cancer, small bowel cancer, soft tissue sarcoma, T-cell lymphoma, testicular cancer, laryngeal cancer, thymoma and thymic carcinoma, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, trophoblastic tumors, cancers uncommon in children, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, or virus-induced cancer.

[0297] In some embodiments, the cancer is a hematologic malignancy, pancreatic cancer, MYH-associated polyposis, colorectal cancer, or lung cancer. In one embodiment, the cancer is lung cancer, colorectal cancer, appendiceal cancer, or pancreatic cancer. In one embodiment, the cancer is pancreatic cancer, lung cancer, or colon cancer. In one embodiment, the cancer is lung cancer. Lung cancer may be adenocarcinoma, non-small cell lung cancer (NSCLC), or small cell lung cancer (SCLC). In one embodiment, the cancer is colorectal cancer. In another embodiment, the cancer is pancreatic cancer. In one embodiment, the cancer is lung adenocarcinoma.

[0298] The methods described herein may also include testing a patient sample for the presence or absence of KRas prior to administration of the compound described herein or its stereoisomers, transtransfer isomers, tautomers, or pharmaceutically acceptable salts. G12D Mutation. In one embodiment, KRas was found to be present in a patient sample. G12D Following the mutation, the patient is administered a compound, its stereoisomer, transtransfer inhibitor, tautomer, or pharmaceutically acceptable salt, or a pharmaceutical composition. In one embodiment, unless the patient sample contains KRas G12D Mutation, or otherwise do not administer the compound described herein or its stereoisomers, transtransfer isomers, tautomers or pharmaceutically acceptable salts.

[0299] In one embodiment, the cancer is pancreatic cancer, lung cancer, or colorectal cancer. In another embodiment, the cancer is histologically undetermined (including KRas). G12D (Mutation). In one such embodiment, pancreatic cancer, lung cancer, or colorectal cancer contains KRas. G12D mutation.

[0300] This article further provides treatment options including KRas in patients with this type of lung cancer. G12D A method for treating lung cancer containing KRas. In one such embodiment, a treatment for lung cancer containing KRas... G12DA method (M1) for treating such lung cancer in a patient with mutated lung cancer, comprising administering to the patient an effective amount of the compound described herein or a stereoisomer, transisomer, tautomer, or pharmaceutically acceptable salt thereof (or a pharmaceutical composition comprising the compound or a stereoisomer, transisomer, tautomer, or pharmaceutically acceptable salt thereof). In one embodiment, the lung cancer is non-small cell lung cancer (NSCLC). In one embodiment, the lung cancer is adenocarcinoma, NSCLC, squamous cell lung cancer (SCLC), or large cell lung cancer. In another embodiment, the lung cancer is adenocarcinoma, NSCLC, or SCLC. In yet another embodiment, the lung cancer is adenomatous tumor, carcinoid tumor, or undifferentiated carcinoma. The lung cancer may be stage I or stage II lung cancer. In one embodiment, the lung cancer is stage III or stage IV lung cancer. The method provided herein includes administering the compound as a 1L therapy.

[0301] This article further provides information on the treatment of patients with this type of pancreatic cancer, including those with KRas. G12D A method for treating pancreatic cancer with mutations. In one such embodiment, a treatment for patients with KRas-containing... G12D A method for treating pancreatic lung cancer in a patient with mutated pancreatic cancer (M2), comprising administering to the patient an effective amount of the compound described herein or a stereoisomer, transtransferase isomer, tautomer, or pharmaceutically acceptable salt thereof. In one embodiment, the patient has previously received radiation therapy and one or more chemotherapy agents. In one embodiment, the pancreatic cancer is stage 0, I, or II. In another embodiment, the pancreatic cancer is stage III or IV.

[0302] This article further provides information on treatments involving KRas in patients with this type of colon cancer. G12D A method for treating mutated colon cancer. In one such embodiment, a treatment for patients with KRas-containing colon cancer... G12D A method (M3) for treating such colon cancer in a patient with mutated colon cancer, comprising administering to the patient an effective amount of the compound described herein or a stereoisomer, transtransfer inhibitor, tautomer, or pharmaceutically acceptable salt thereof. In one embodiment, the colon cancer is in stage I or II. In another embodiment, the colon cancer is in stage III or IV.

[0303] In one embodiment of the methods M1, M2, and M3 described herein, the method further includes:

[0304] (a) Determine the presence of KRas in samples taken from patients suspected of having cancer. G12D Mutation; and

[0305] (b) Administer to the patient an effective amount of the compound described herein or its stereoisomers, transtransfer isomers, tautomers or pharmaceutically acceptable salts.

[0306] This article further provides treatments containing KRas. G12D A method for treating undetermined carcinoma of mutated tissue. In one embodiment of such a method, the method includes:

[0307] (a) Determine the presence of KRas in samples taken from patients suspected of having cancer. G12D Mutation; and

[0308] (b) Administer to the patient an effective amount of the compound described herein or its stereoisomers, transtransfer isomers, tautomers or pharmaceutically acceptable salts.

[0309] In one embodiment of such a method, the patient is diagnosed with the cancer described herein. In another embodiment of such a method, the sample is a tumor sample taken from the subject. In one such embodiment, the sample is collected before any therapy is administered. In another such embodiment, the sample is collected before administration of the compound described herein or its stereoisomers, transisomers, tautomers, or pharmaceutically acceptable salts, and after administration of another chemotherapeutic agent. In another embodiment of such a method, the compound described herein or its stereoisomers, transisomers, tautomers, or pharmaceutically acceptable salts are administered as provided herein (e.g., orally or intravenously).

[0310] This document also provides compounds, or stereoisomers, transisomers, tautomers, or pharmaceutically acceptable salts thereof, for use as therapeutically active substances. In one such embodiment, the compound, or stereoisomer, transisomer, tautomer, or pharmaceutically acceptable salt thereof, may be used in the presence of Kras. G12D Therapeutic treatments for mutated cancers.

[0311] This article further provides information on the use of KRas in therapeutic and / or preventative treatments. G12DCompounds for mutated cancers, or their stereoisomers, transtransfer isomers, tautomers, or pharmaceutically acceptable salts thereof. In some embodiments, this document provides compounds for treating cancers as disclosed herein, or their stereoisomers, transtransfer isomers, tautomers, or pharmaceutically acceptable salts thereof, as described herein. In some embodiments, this document provides compounds for preventing cancers as disclosed herein, or their stereoisomers, transtransfer isomers, tautomers, or pharmaceutically acceptable salts thereof, as described herein. In some embodiments, this document provides compounds for inhibiting tumor metastasis, or their stereoisomers, transtransfer isomers, tautomers, or pharmaceutically acceptable salts thereof. In one embodiment, the compound, or its stereoisomer, transtransfer isomer, tautomer, or pharmaceutically acceptable salt, is used to prepare a medicament for therapeutic treatment of cancers containing KRas. G12D Mutated cancers. In some embodiments, this document provides the use of compounds as disclosed herein, or their stereoisomers, transisomers, tautomers, or pharmaceutically acceptable salts thereof, in the manufacture of a medicament for treating cancers as disclosed herein. In some embodiments, this document provides the use of compounds as disclosed herein, or their stereoisomers, transisomers, tautomers, or pharmaceutically acceptable salts thereof, in the manufacture of a medicament for preventing cancers as disclosed herein. This document further provides the use of compounds as described herein, or their stereoisomers, transisomers, tautomers, or pharmaceutically acceptable salts thereof, in the manufacture of a medicament for inhibiting tumor metastasis.

[0312] This document further provides a method for inhibiting tumor metastasis, the method comprising administering to a patient with a tumor a therapeutically effective amount of the compound described herein or a stereoisomer, transtransfer inhibitor, tautomer, or pharmaceutically acceptable salt thereof. In one embodiment, inhibition is against a compound containing KRas. G12D Mutated tumors. In another embodiment, inhibiting tumor metastasis in the patient described herein results in a reduction in tumor size. In another embodiment, inhibiting tumor metastasis in the patient described herein results in a stable tumor size (e.g., no further growth). In yet another embodiment, inhibiting tumor metastasis in the patient described herein results in a reduction of cancer and / or its symptoms.

[0313] This document further provides a method for inhibiting cell population proliferation, the method comprising contacting the cell population with the compound described herein or its stereoisomers, transtransfer isomers, tautomers, or pharmaceutically acceptable salts. In one embodiment, the cell population is in a human patient. In another embodiment, the cell population comprises KRas G12D mutation.

[0314] This article further provides a method for inhibiting KRas in a patient requiring treatment, the method comprising administering to the patient a therapeutically effective amount of the compound described herein or a stereoisomer, transtransferase isomer, tautomer, or pharmaceutically acceptable salt thereof. In one embodiment, the inhibited KRas is KRas G12D In another embodiment, inhibition of KRas leads to a reduction in tumor size. In yet another embodiment, inhibition of KRas leads to relief of cancer and / or its symptoms.

[0315] This document further provides a method for modulating the activity of a KRas mutant protein, comprising reacting the mutant protein with a compound described herein or a stereoisomer, transtransferase isomer, tautomer, or pharmaceutically acceptable salt thereof. In one embodiment, the mutant protein comprises KRas G12D Mutation. In one embodiment, KRas activity is reduced upon contact with the compound described herein or its stereoisomers, transtransferases, tautomers, or pharmaceutically acceptable salts. In another embodiment, downregulation of KRas mutant protein activity treats the cancer described herein in a patient. In another embodiment, downregulation of KRas mutant protein activity results in a reduction in tumor size. In yet another embodiment, downregulation of KRas mutant protein activity results in relief of the cancer and / or its symptoms described herein.

[0316] In some embodiments, the methods provided herein include making cells react with an amount sufficient to inhibit Kras in the cells. G12D Active amounts of the compound described herein, or its stereoisomers, transtransfer isomers, tautomers, or pharmaceutically acceptable salts thereof, are used to inhibit KRas in said cells. G12D Activity. In some embodiments, the methods provided herein include reacting tissue with an agent sufficient to inhibit KRas activity in said tissue. G12D Active amounts of the compound described herein, or its stereoisomers, transtransfer isomers, tautomers, or pharmaceutically acceptable salts thereof, are used to inhibit KRas in the tissue. G12D Activity. In some embodiments, the method provided herein includes subjecting the patient described herein to KRas activity sufficient to inhibit KRas in the patient. G12D Active amounts of the compound described herein, or its stereoisomers, transtransfer isomers, tautomers, or pharmaceutically acceptable salts thereof, are used to inhibit KRas in the patients. G12D active.

[0317] This article further provides methods for preparing labeled KRas G12D A method for mutating proteins, which includes making KRas G12DThe mutant protein reacts with a labeled compound described herein, or its stereoisomers, transtransfer isomers, tautomers, or pharmaceutically acceptable salts, to produce labeled KRas. G12D Mutant protein. In one embodiment, the marker is an imaging agent. In another embodiment, the labeled KRas G12D It can be used to detect whether G12D mutated KRas are present or absent in patient samples, thereby detecting whether cancer mediated by mutated KRas is present or absent.

[0318] This document further provides methods for inhibiting Ras-mediated cell signaling. In one embodiment, the method includes contacting cells with an effective amount of one or more compounds disclosed herein, or their stereoisomers, transtransferase isomers, tautomers, or pharmaceutically acceptable salts. Inhibition of Ras-mediated signal transduction can be evaluated and demonstrated in a variety of ways known in the art. Non-limiting examples include showing (a) decreased GTPase activity of Ras; (b) decreased GTP-binding affinity or increased GDP-binding affinity; (c) increased K-off of GTP or decreased K-off of GDP; (d) decreased levels of downstream signaling molecules in the Ras pathway, such as decreased pMEK levels; and / or (e) decreased binding of the Ras complex to downstream signaling molecules (including, but not limited to, Raf). Kits and commercially available assays can be used to determine one or more of the above.

[0319] KRas mutations, including G12D mutants, have also been identified in hematologic malignancies (e.g., cancers affecting the blood, bone marrow, and / or lymph nodes). Therefore, some embodiments involve administering to a patient requiring treatment for a hematologic malignancy a compound disclosed herein, or a stereoisomer, transtransferase isomer, tautomer, or pharmaceutically acceptable salt thereof (e.g., in the form of a pharmaceutical composition). Such malignancies include, but are not limited to, leukemia and lymphoma. For example, the currently disclosed compounds can be used to treat diseases such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), chronic myeloid leukemia (CML), acute monocytic leukemia (AMoL), and / or other leukemias. In other embodiments, the compounds described herein, or pharmaceutically acceptable salts thereof, can be used to treat lymphomas, such as Hodgkin lymphoma or all subtypes of non-Hodgkin lymphoma.

[0320] Whether a tumor or cancer contains KRas can be determined by evaluating the nucleotide sequence encoding the KRas protein, evaluating the amino acid sequence of the KRas protein, or evaluating the characteristics of hypothetical KRas mutant proteins. G12D Mutation. The sequence of wild-type human KRas (e.g., accession number NP203524) is known in the art.

[0321] Methods for detecting mutations in the KRas nucleotide sequence are known to those skilled in the art. These methods include, but are not limited to, polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay, polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) assay, real-time PCR assay, PCR sequencing, mutant allele-specific PCR amplification (MASA) assay, direct sequencing, primer extension reaction, electrophoresis, oligonucleotide ligation assay, hybridization assay, TaqMan assay, SNP genotyping assay, high-resolution melting assay, and microarray analysis. In some embodiments, the G12d KRas mutation in a sample is assessed by real-time PCR. In real-time PCR, a fluorescent probe specific for the KRas G12D mutation is used. When a mutation is present, the probe binds and fluorescence is detected. In some embodiments, the KRas G12D mutation is identified using direct sequencing of specific regions in the KRas gene (e.g., exon 2 and / or exon 3). This technique will identify all possible mutations in the sequenced region.

[0322] Used to determine whether a tumor or cancer contains KRas. G12D Mutation methods can use a variety of samples. In some embodiments, the sample is taken from a subject with a tumor or cancer. In some embodiments, the sample is a fresh tumor / cancer sample. In some embodiments, the sample is a frozen tumor / cancer sample. In some embodiments, the sample is a formalin-fixed paraffin-embedded sample. In some embodiments, the sample is processed into cell lysate. In some embodiments, the sample is processed into DNA or RNA.

[0323] This document further provides the use of the compounds described herein, or their stereoisomers, transisomers, tautomers, or pharmaceutically acceptable salts, in the manufacture of medicaments for treating cancer. In some embodiments, the medicament is formulated for oral administration. In some embodiments, the medicament is formulated for injection (e.g., IV administration). In some embodiments, the cancer comprises KRas G12DMutation. In some embodiments, the cancer is a hematologic cancer, pancreatic cancer, MYH-associated polyposis, colorectal cancer, or lung cancer. In one embodiment, the cancer is lung cancer, colorectal cancer, or pancreatic cancer. In one embodiment, the cancer is colorectal cancer. In another embodiment, the cancer is pancreatic cancer. In some embodiments, the cancer is lung adenocarcinoma. In some embodiments, the use of the compounds described herein, or stereoisomers, transtransferases, tautomers, or pharmaceutically acceptable salts thereof, is provided in the manufacture of a medicament for inhibiting tumor metastasis.

[0324] Combination therapy

[0325] The compounds described herein, or their stereoisomers, transisomers, tautomers, or pharmaceutically acceptable salts, may be used alone or in combination with other therapeutic agents to treat the diseases or ailments described herein. The second compound in a pharmaceutical combination formulation or dosing regimen preferably has an activity complementary to that of the compounds described herein or their pharmaceutically acceptable salts, such that they do not adversely affect each other. Combination therapies can provide a “synergistic effect” and are demonstrated to be “synergistic,” meaning that the effect achieved when the active ingredients are used together is greater than the sum of the effects produced by using the compounds alone.

[0326] Combination therapy can be administered simultaneously or sequentially. When administered sequentially, the combination can be administered two or more times. Combination administration includes the combined administration of individual formulations or single-drug formulations, as well as sequential administration in any order, wherein preferably, both (or all) of the active agents exert their biological activity simultaneously over a period of time.

[0327] The combination therapy described herein comprises administration of the compound described herein or its stereoisomers, transisomers, tautomers, or pharmaceutically acceptable salts thereof, and the use of at least one other therapeutic method. The amount of the compound described herein or its stereoisomers, transisomers, tautomers, or pharmaceutically acceptable salts, and one or more other pharmaceutically active agents, as well as the relative timing of administration, will be selected to achieve the desired combination therapeutic effect.

[0328] In various embodiments of this method, additional therapeutic agents are epidermal growth factor receptor (EGFR) inhibitors, phosphatidylinositol kinase (PI3K) inhibitors, insulin-like growth factor receptor (IGF1R) inhibitors, Janus kinase (JAK) inhibitors, Met kinase inhibitors, SRC family kinase inhibitors, mitogen-activated protein kinase (MEK) inhibitors, extracellular signal-regulated kinase (ERK) inhibitors, topoisomerase inhibitors (such as irinotecan, or such as etoposide, or such as doxorubicin), taxanes (such as antimicrotubule agents, including paclitaxel and docetaxel), antimetabolites (such as 5-FU or gemcitabine), or alkylating agents (such as cisplatin or cyclophosphamide), or taxanes.

[0329] In some embodiments, additional therapeutic agents are epidermal growth factor receptor (EGFR) inhibitors, such as erlotinib or afatinib. In some embodiments, additional therapeutic agents are gefitinib, osimertinib, or dacomitinib. In some embodiments, additional therapeutic agents are monoclonal antibodies, such as cetuximab (Erbitux) or panitumumab (Vectibix). In some embodiments, the GFR inhibitor is a dual or all-HER inhibitor. In other embodiments, additional therapeutic agents are phosphatidylinositol-3-kinase (PI3K) inhibitors, such as GDC-0077, GDC-0941, MLN1117, BYL719 (alpelisib), or BKM120 (buparlisib). GDC-0941 refers to 2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine or its salts (e.g., dimethylsulfonate).

[0330] In other embodiments, the additional therapeutic agent is an insulin-like growth factor receptor (IGF1R) inhibitor. For example, in some embodiments, the insulin-like growth factor receptor (IGF1R) inhibitor is NVP-AEW541. In other embodiments, the additional therapeutic agent is IGOSI-906 (Linsitinib), BMS-754807, or in other embodiments, the additional therapeutic agent is a neutralizing monoclonal antibody specific to IGF1R, such as AMG-479 (ganitumab), CP-751,871 (figitumumab), IMC-A12 (cixutumumab), MK-0646 (dalotuzumab), or R-1507 (robatumumab).

[0331] In some other embodiments, the additional therapeutic agent is a Janus kinase (JAK) inhibitor. In some embodiments, the additional therapeutic agent is CYT387, GLPG0634, baricitinib, lettaurtinib, momelotinib, paccitinib, ruxolitinib, or TG101348.

[0332] In some other embodiments, an additional therapeutic agent is an anti-glypican 3 antibody. In some embodiments, the anti-glypican 3 antibody is codrituzumab.

[0333] In some other embodiments, the additional therapeutic agent is an antibody-drug conjugate (ADC). In some embodiments, the ADC is polotuzumab vedotin, RG7986, RG7882, RG6109, or RO7172369.

[0334] In some other embodiments, the additional therapeutic agent is an MDM2 antagonist. In some embodiments, the MDM2 antagonist is idasanutlin.

[0335] In some other embodiments, an additional therapeutic agent is an anti-CD40 agonist antibody. In some embodiments, the anti-CD40 agonist antibody is selicrelumab (RG7876).

[0336] In some other embodiments, the additional therapeutic agent is a bispecific antibody. In some embodiments, the bispecific antibody is RG7828 (BTCT4465A), RG7802, RG7386 (FAP-DR5), RG6160, RG6026, ERY974, or anti-HER2 / CD3.

[0337] In some other embodiments, the additional therapeutic agent is a targeted immune cytokine. In some embodiments, the targeted immune cytokine is RG7813 or RG7461.

[0338] In some other embodiments, the additional therapeutic agent is an antibody that targets the colony-stimulating factor-1 receptor (CSF-1R). In some embodiments, the CSF-1R antibody is emactuzumab.

[0339] In some other embodiments, the additional therapeutic agent is a personalized cancer vaccine. In some embodiments, the personalized cancer vaccine is RG6180.

[0340] In some other embodiments, the additional therapeutic agent is an inhibitor of BET (bromodomain and terminal exofamily) proteins (BRD2 / 3 / 4 / T). In some embodiments, the BET inhibitor is RG6146.

[0341] In some other embodiments, the additional therapeutic agent is an antibody designed to bind to TIGIT. In some embodiments, the anti-TIGIT antibody is RG6058 (MTIG7192A).

[0342] In some other embodiments, the additional therapeutic agent is a selective estrogen receptor degrader (SERD). In some other embodiments, the SERD is RG6047 (GDC-0927) or RG6171 (GDC-9545, giredestrant).

[0343] In some other embodiments, additional therapeutic agents are MET kinase inhibitors, such as crizotinib, tivantinib, AMG337, cabozantinib, or foretinib. In other embodiments, additional therapeutic agents are MET-neutralizing monoclonal antibodies, such as onartuzumab.

[0344] In more embodiments, the additional therapeutic agent is an SRC family non-receptor tyrosine kinase inhibitor. For example, in some embodiments, the additional therapeutic agent is an inhibitor of a subfamily of SRC family non-receptor tyrosine kinases. Exemplary inhibitors in this regard include dasatinib. Other examples in this regard include ponatinib, saracatinib, and bosutinib.

[0345] In some other embodiments, the additional therapeutic agent is a mitogen-activated protein kinase (MEK) inhibitor. In some of these embodiments, the MEK inhibitor is trametinib, selumetinib, COTELLIC®, PD0325901, or RO5126766. In other embodiments, the MEK inhibitor is GSK-1120212, also known as trametinib.

[0346] In some other embodiments, the additional therapeutic agent is an extracellular signal-regulated kinase (ERK) inhibitor. In some of these embodiments, the mitogen-activated protein kinase (MEK) inhibitor is SCH722984 or GDC-0994.

[0347] In other embodiments, the protein kinase inhibitor is taselisib, ipatasertib, GDC-0575, GDC-5573 (HM95573), RG6114 (GDC-0077), CKI27, afatinib, axitinib, atezolizumab, bevacizumab, bosutinib, cetuximab, crizotinib, dasatinib, erlotinib, fantatinib, gefitinib, imatinib, lapatinib, lenvatinib, ibrutinib, nilotinib, panitumumab, pazopanib, pilgatanib sodium, ranibumab, ruxotinib, sorafenib, sunitinib, SU6656, trastuzumab, tofacitinib, vandetanib, or vemurafenib. In many other embodiments, an additional therapeutic agent is a topoisomerase inhibitor. In some of these embodiments, the topoisomerase inhibitor is irinotecan. In some other embodiments, the additional therapeutic agent is a taxane. Exemplary taxanes include paclitaxel and docetaxel.

[0348] In addition to the other therapeutic agents described above, other chemotherapeutic agents are known in the art and can be used in combination with the compounds described herein or their pharmaceutically acceptable salts. In some embodiments, the chemotherapeutic agent is selected from the group consisting of mitosis inhibitors, alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antihormones, angiogenesis inhibitors, and antiandrogens.

[0349] Non-limiting examples include chemotherapeutic agents, cytotoxic agents, and non-peptide small molecules such as Gleevec® (imatinib mesylate), Velcade® (bortezomib), Cascade® (bicalutamide), Iressa® (gefitinib), and doxorubicin, as well as a range of chemotherapeutic agents. Non-limiting examples of chemotherapeutic agents include: alkylating agents, such as thiotepa and cyclosphosphamide (CYTOXAN™); alkyl sulfonates, such as busulfan, improsulfan, and piposulfan; aziridines, such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methyl melamines, including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylol melamine; nitrogen mustards. Mustards, such as chlorambucil, chlornaphazine, cyclophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxidehydrochlorid, melphalan, novombhichin, phenesterine, prednimustine, trofosfamide, and uracil mustard; and nitrosoureas, such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine.Antibiotics, such as aclacinomysins, actinomycin, autramycin, azaserine, bleomycins, cactinomycin C, calicheamicin, carabicin, carminomycin, carzinophilin, Casodex™, chromomycins, dactinomycin D, daunorubicin, detorubicin, 6-diazo-5-oxo-L-leucine, doxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins, and mycophenolic acid. (Acid), nogalamycin, olivomycins, peplomycin, porfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; antimetabolites, such as methotrexate. And 5-fluorouracil (5-FU); folic acid analogs, such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs, such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine;Pyrimidine analogues, such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, and fluxuridine; androgens, such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, and testolactone; anti-adrenergic drugs, such as aminoglutethimide, mitotane, and trilostane; folic acid supplements, such as frolinic acid; aceglatone; and aldophosphamide glycosides. glycoside; aminolevulinic acid; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfomithine; elliptinium acetate; etoglucid; gallium nitrate nitrate); hydroxyurea; lentinan; lonidamine; mitoguazone; mitoxantrone; mopidamol; nitraerine; pentostatin; phenamet; pirarubicin; podophyllinic acid; 2-ethylhydrazide; procarbazine; polysaccharide K; razoxane; sizofiran; spirogermanium;Tenuazonic acid; triaziquone; 2,2',2''-trichlorotriethylamine; urethan; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactalol; piperobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxanes, such as paclitaxel (TAXOL); TM (Bristol-Myers Squibb Oncology, Princeton, NJ) and docetaxel (TAXOTERE) TMRhone-PoulencRorer, Antony, France); retinoic acid; esperamicin; capecitabine; and pharmaceutically acceptable salts, acids, or derivatives of any of the above. Also included as suitable chemotherapeutic cell modulators are antihormonal agents that regulate or inhibit hormonal effects on tumors, such as antiestrogens, including, for example, tamoxifen (Nolvadex™), raloxifene, aromatase inhibitor 4(5)-imidazole, 4-hydroxytamoxifen, trioxifene, keoxifene, LY 117018, onapristone, and toremifene; and antiandrogens, such as flutamide, nilutamide, bicalutamide, and leuprolide. And goserelin; chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate; platinum analogs, such as cisplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine; novantrone; teniposide; daunomycin; aminopterin; Xeloda®; ibandronate; camptothecin-11 (CPT-11); topoisomerase inhibitor RFS2000; and difluoromethylornithine (DMFO). Where necessary, compounds described herein, or their pharmaceutically acceptable salts or pharmaceutical compositions, may be used in combination with commonly prescribed anticancer drugs, such as Herceptin®, Avastin®, Gazyva®, Tecentriq®, Alecensa®, Perjeta®, Venclexta™, Erbitux®, Rituxan®, Taxol®, Arimidex®, Taxotere®, ABVD, AVICINE, Abagovomab, Acridine carboxamide, Adecatumumab, 17-N-allylamino-17-demethoxygeldanamycin, Alpharadin, Alvocidib, 3-aminopyridine-2-carboxymethylthiosqualide, and aminonaphthyl filtrate.(Amonafide), anthracenedione, anti-CD22 immunotoxin, anti-tumor drugs, anti-tumor herbal remedies, apaziquone, atipremod, azathioprine, belotecone, bendamustine, BIBW 2992, Biricodar, Brostallicin, Bryostatin, Butylthionine Sulfide, CBV (chemotherapy), Calyculin, Cell Cycle Nonspecific Antitumor Drugs, Dichloroacetic Acid, Discodermolide, Elsamitrucin, Enocitabine, Epothilone, Eribulin, Everolimus, Exatecan, Exisulind, Ferruginol, Forodesine, Fosfestrol, ICE Chemotherapy regimens, IT-101, Imexon, Imiquimod, Indolocarbazole, Irofulven, Laniquidar, Larotaxel, Lenalidomide, Lucanthone, Lurtotecan, Mafosfamide, Mitozolomide, Nafoxidine, Nedaplatin, Olaparib, Ortataxel, PAC-1, Pawpaw, Pixantrone, proteasome inhibitors, Rebeccamycin, Resiquimod, Rubitecan, SN-38, Salinosporamide A, Sapacitabine, Stanford V, Swainsonine, Talaporfin, Tariquidar, Tegafur-uracil, Temodar, Tesetaxel, Triplatinum Tetranitrate, Tri(2-chloroethyl)amine, Trasatabine(Troxacitabine), uramustine, 2,5-hexanone theobromine (Vadimezan), vinflunine, ZD6126, or zosuquidar.

[0350] The exact method of administering the compound and other therapeutic agents will be apparent to those skilled in the art. In some exemplary embodiments, the compound and other therapeutic agents are administered together. In other embodiments, the compound and other therapeutic agents are administered alone.

[0351] In some embodiments, the compound and an additional therapeutic agent are administered simultaneously or separately with a second agent. Such combined administration can include simultaneous administration of two agents in the same dosage form, simultaneous administration in separate dosage forms, and separate administration. That is, the compound described herein and any other therapeutic agent can be formulated together in the same dosage form and administered simultaneously. Alternatively, the compound and any other therapeutic agent described herein can be administered simultaneously, wherein the two agents are present in separate formulations. In another alternative, the compound can be administered immediately following any other therapeutic agent described herein, or vice versa. In some embodiments of the separate administration regimen, the compound described herein and any other therapeutic agent are administered at intervals of minutes, hours, or days.

[0352] Products

[0353] This document also provides articles or "kits" containing materials that can be used to treat the cancers described herein. In one embodiment, a kit includes a container containing a compound described herein or a stereoisomer, transisomer, tautomer, or pharmaceutically acceptable salt thereof. The kit may also include a label or instruction manual on or associated with the container. Suitable containers include, for example, bottles, vials, syringes, blister packs, etc. The container may be formed from a variety of materials such as glass or plastic. The container may contain a compound described herein that is effective in treating the condition, or a pharmaceutically acceptable salt thereof, or a formulation thereof, and may have a sterile access port (e.g., the container may be an intravenous solution bag or a vial with a stopper that can be pierced by a hypodermic needle). At least one active agent in the composition is a compound described herein or a pharmaceutically acceptable salt thereof. Alternatively or additionally, the article may also include a second container containing a pharmaceutical diluent, such as sterile water for injection (BWFI), phosphate-buffered saline, Ringer's solution, or dextran solution. It may further include other materials desired from a commercial and user perspective, including other buffers, diluents, filters, needles, and syringes.

[0354] In another embodiment, the kit is suitable for delivering the compounds described herein or their pharmaceutically acceptable salts in a solid oral form, such as tablets or capsules. Such kits may include a number of unit doses. An example of such kits is blister packaging. Blister packaging is well-known in the packaging industry and is widely used for packaging unit dosage forms of pharmaceuticals.

[0355] Enumerated Examples

[0356] This disclosure also includes the following embodiments:

[0357] Example 1. A compound of formula (I),

[0358] (I)

[0359] Or its stereoisomers, transtransfer isomers, tautomers, or pharmaceutically acceptable salts.

[0360] in:

[0361] m is 0 or 1;

[0362] n is 0, 1, or 2;

[0363] q is 0 or 1;

[0364] p is 0, 1, or 2;

[0365] Where n + m + q does not exceed 2, and p and q are not both 1;

[0366] R1 is , where R 01 R 02 R 03 R 04 and R 05 Each of these elements is independently hydrogen, halogen, -CN, -NH2, -N(Me)2, C 1-3 Alkyl, C 1-3 Halogenated alkyl or cyclopropyl;

[0367] R2 can be hydrogen, -CN, halogen, or C. 1-3 Alkyl, C 1-3 Halogenated alkyl or cyclopropyl;

[0368] R 3A For hydrogen, halogen, C 1-3 Alkyl or C 1-3 Halogenated alkyl groups, and R 3B It is hydrogen; or R 3A and R 3B Together they form oxygen;

[0369] R 4A and R 4B Each of them is independently hydrogen, C 1-3 Alkyl or C 1-3 Halogenated alkyl groups;

[0370] Or R 4A and R 4B Together with the atoms they bind to, they form 3- to 6-membered monocyclic rings;

[0371] R 3C For hydrogen, halogen, C 1-3 Alkyl or C 1-3 Halogenated alkyl groups;

[0372] R 3D It is hydrogen;

[0373] Z represents hydrogen, C represents... 1-3 Alkyl, -L1–Cy, -L1–NR5R6, –OR6 or –SR6;

[0374] in:

[0375] L1 either does not exist or is –C(=O)–;

[0376] R5 is hydrogen, C 1-6 Alkyl group, –NH2;

[0377] R6 is C 1-6 Alkyl, -L2–Cy, –C(=O)–Cy, or –C(=O)C 1-6 alkyl;

[0378] L2 is –(CR) 7A R 7B ) u –;

[0379] u is 1, 2, or 3;

[0380] Each R 7A and R 7B Independently hydrogen or C 1-3 alkyl;

[0381] Cy is a 3- to 10-membered ring portion selected from monocyclic, fused bicyclic, bridged bicyclic, two or three chain rings and spirocyclic rings, wherein Cy optionally contains one or more heteroatoms selected from N, O and S and optionally is substituted by one or more R8 atoms;

[0382] Each R8 is independently selected from: C14 cells optionally substituted with a hydroxyl group. 1-6 Alkyl, C 1-3Halogenated alkyl, halogen, hydroxyl, cyano, –C(=O)NR9R 10 –C(=O)OR 10 C 3-6 Cycloalkyl and oxoalkyl, wherein R9 and R 10 Independently hydrogen or C 1-6 Alkyl; or

[0383] R5 and R6, together with their bonded nitrogen atoms, form a 3- to 6-membered monocyclic ring optionally substituted with one or more groups independently selected from the following: C 1-6 Alkyl and hydroxyl; or

[0384] Z and R2 together with the carbon atoms they are bonded to form 5- to 6-membered monocyclic aromatic rings;

[0385] X is –NR 11 ;and

[0386] R 11 For hydrogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups.

[0387] Example 2. The compound according to Example 1, or its stereoisomer, transisomer, tautomer, or pharmaceutically acceptable salt, wherein:

[0388] m is 0;

[0389] n is 1;

[0390] p is 1;

[0391] q is 0; and

[0392] R 3A and R 3B Both are hydrogen.

[0393] Example 3. The compound according to Example 1, or its stereoisomer, transisomer, tautomer, or pharmaceutically acceptable salt, wherein:

[0394] m is 0;

[0395] n is 0;

[0396] p is 0; and

[0397] q is 1.

[0398] Example 4. The compound according to any one of Examples 1 to 3, or a stereoisomer, transisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein X is -NR.11 And R 11 It is hydrogen.

[0399] Example 5. The compound according to any one of Examples 1 to 4, or a stereoisomer, transisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 01 R 02 R 03 R 04 and R 05 No more than one of them is hydrogen.

[0400] Example 6. The compound according to any one of Examples 1 to 5, or a stereoisomer, transisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 01 R 02 R 03 R 04 and R 05 One of them is halogen.

[0401] Example 7. The compound according to Example 6, or a stereoisomer, transisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 01 R 02 R 03 R 04 and R 05 One of them is fluorine.

[0402] Example 8. The compound according to any one of Examples 1 to 7, or a stereoisomer, transisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 01 R 02 R 03 R 04 and R 05 One of them is C 1-3 Halogenated alkyl groups.

[0403] Example 9. The compound according to any one of Examples 1 to 8, or a stereoisomer, transisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 01 R 02 R 03 R 04 and R 05 One of them is –NH2.

[0404] Example 10. The compound according to any one of Examples 1 to 9, or a stereoisomer, transisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R1 is... .

[0405] Example 11. The compound according to any one of Examples 1 to 10, or a stereoisomer, transisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R2 is a halogen.

[0406] Example 12. The compound according to Example 11 or its stereoisomer, transisomer, tautomer or pharmaceutically acceptable salt, wherein R2 is fluorine or chlorine.

[0407] Example 13. The compound according to Example 1, or its stereoisomer, transisomer, tautomer, or pharmaceutically acceptable salt, wherein R 3A and R 3C All are H.

[0408] Example 14. The compound according to any one of Examples 1 to 13, or a stereoisomer, transisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 4A It is hydrogen, and R 4B It is a methyl group.

[0409] Example 15. The compound according to any one of Examples 1 to 13, or a stereoisomer, transisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 4A It is hydrogen, and R 4B It is an ethyl group.

[0410] Example 16. The compound according to any one of Examples 1 to 13, or a stereoisomer, transisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 4A and R 4B Both are methyl groups.

[0411] Example 17. The compound according to any one of Examples 1 to 13, or a stereoisomer, transisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 4A It is hydrogen, and R 4B It is -CF3.

[0412] Example 18. A compound according to any one of Examples 1 to 13, or a stereoisomer, transisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 4A and R 4B Together with the atoms bonded to both, it forms an oxobutane ring.

[0413] Example 19. The compound according to any one of Examples 1 to 18, or a stereoisomer, transisomer, tautomer or pharmaceutically acceptable salt thereof, wherein Z is hydrogen.

[0414] Example 20. A compound according to any one of Examples 1 to 18, or a stereoisomer, transisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein Z is C 1-3 alkyl.

[0415] Example 21. The compound according to Example 20 or its stereoisomer, transisomer, tautomer or pharmaceutically acceptable salt thereof, wherein Z is methyl.

[0416] Example 22. The compound according to any one of Examples 1 to 18, or a stereoisomer, transisomer, tautomer or pharmaceutically acceptable salt thereof, wherein Z is -L1–Cy.

[0417] Example 23. The compound according to Example 22 or its stereoisomer, transisomer, tautomer or pharmaceutically acceptable salt thereof, wherein L1 is absent and Cy is a pyrazole or pyrimidine, wherein the pyrazole is optionally substituted with a methyl group.

[0418] Example 24. The compound according to any one of Examples 1 to 18, or a stereoisomer, transisomer, tautomer or pharmaceutically acceptable salt thereof, wherein Z is -L1–NR5R6.

[0419] Example 25. The compound according to Example 24 or its stereoisomer, transisomer, tautomer or pharmaceutically acceptable salt, wherein L1 is absent, R5 is hydrogen and R6 is -L2–Cy.

[0420] Example 26. The compound according to Example 25 or its stereoisomer, transisomer, tautomer or pharmaceutically acceptable salt thereof, wherein L2 is –CH2– and Cy is phenyl, pyridine, imidazole, 2-oxabicyclo[2.1.1]hexane, pyrimidine, pyrazine, pyridazine, triazole, pyrazole, indazole, pyridinone, thiazole or quinoline.

[0421] Example 27. The compound according to Example 26 or its stereoisomers, transisomers, tautomers or pharmaceutically acceptable salts thereof, wherein Cy is optionally substituted by one or more R8 groups independently selected from: methyl, –CF3, –CHF2, fluorine, hydroxyl, cyano, –CH2OH, –C(=O)OH, –C(=O)OMe and –C(=O)N(Me)2.

[0422] Example 28. The compound according to Example 25 or its stereoisomer, transisomer, tautomer or pharmaceutically acceptable salt thereof, wherein L2 is –CH(CH3)– and Cy is phenyl.

[0423] Example 29. The compound according to Example 24 or its stereoisomer, transisomer, tautomer or pharmaceutically acceptable salt, wherein L1 is absent, R5 is hydrogen and R6 is methyl.

[0424] Example 30. The compound according to Example 24 or its stereoisomer, transisomer, tautomer or pharmaceutically acceptable salt, wherein L1 is absent, R5 is hydrogen and R6 is –C(=O)–Cy.

[0425] Example 31. The compound according to Example 30 or its stereoisomer, transisomer, tautomer or pharmaceutically acceptable salt thereof, wherein Cy is phenyl.

[0426] Example 32. The compound according to Example 29 or its stereoisomer, transisomer, tautomer or pharmaceutically acceptable salt, wherein L1 is absent, R5 is hydrogen and R6 is –C(=O)CH2CH3.

[0427] Example 33. The compound according to Example 24 or its stereoisomer, transisomer, tautomer or pharmaceutically acceptable salt, wherein L1 is –C(=O)–, R5 is -NH2 and R6 is methyl.

[0428] Example 34. The compound according to Example 24 or its stereoisomers, transisomers, tautomers or pharmaceutically acceptable salts thereof, wherein L1 is absent and R5 and R6 together with the nitrogen atoms to which they are bonded form an azo-heterocyclic butane ring optionally substituted with hydroxyl and methyl groups.

[0429] Example 35. The compound according to any one of Examples 1 to 18, or a stereoisomer, transisomer, tautomer or pharmaceutically acceptable salt thereof, wherein Z is –OR6.

[0430] Example 36. The compound according to Example 35 or its stereoisomer, transisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R6 is -L2–Cy, wherein L2 is –CH2– and Cy is pyridine.

[0431] Example 37. The compound according to any one of Examples 1 to 18, or a stereoisomer, transisomer, tautomer or pharmaceutically acceptable salt thereof, wherein Z is –SR6.

[0432] Example 38. The compound according to Example 37 or its stereoisomer, transisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R6 is -L2–Cy, wherein L2 is –CH2– and Cy is pyridine.

[0433] Example 39. A compound according to any one of Examples 1 to 18, or a stereoisomer, transisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein Z and R2 together with the carbon atoms to which they are bonded form a pyrazole.

[0434] Example 40. A compound selected from any one of compounds 1 to 65 shown in Table 1, or a stereoisomer, transisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0435] Example 41. A pharmaceutical composition comprising: a compound according to any one of Examples 1 to 40, or a stereoisomer, transisomer, tautomer, or pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0436] Example 42. A method of treating cancer, comprising administering an effective amount of the compound according to any one of Examples 1 to 40 or a stereoisomer, transisomer, tautomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to Example 41.

[0437] Example 43. The method according to Example 42, wherein the cancer is characterized by containing a KRas mutation.

[0438] Example 44. The method according to Example 43, wherein the KRas mutation corresponds to KRas G12D mutation.

[0439] Example 45. The method according to any one of Examples 42 to 44, further comprising testing the sample from the subject for the presence of KRas prior to administration. G12D mutation.

[0440] Example 46. The method according to Example 45, wherein KRas is shown in the patient sample. G12D Following the mutation, the patient is given the compound, its stereoisomer, transtransfer isomer, tautomer, or pharmaceutically acceptable salt, or a pharmaceutical composition thereof.

[0441] Example 47. The method according to any one of Examples 42 to 46, wherein the cancer is tissue-agnostic.

[0442] Example 48. The method according to any one of Examples 42 to 46, wherein the cancer is pancreatic cancer, lung cancer, or colorectal cancer.

[0443] Example 49. The method according to Example 48, wherein the lung cancer is lung adenocarcinoma, NSCLC or SCLC.

[0444] Example 50. The method according to Example 48, wherein the cancer is pancreatic cancer.

[0445] Example 51. The method according to Example 48, wherein the cancer is colorectal cancer.

[0446] Example 52. The method according to any one of Examples 42 to 51, further comprising administering at least one additional therapeutic agent.

[0447] Example 53. The method according to Example 52, wherein the additional therapeutic agent comprises an epidermal growth factor receptor (EGFR) inhibitor, a phosphatidylinositol kinase (PI3K) inhibitor, an insulin-like growth factor receptor (IGF1R) inhibitor, a Janus kinase (JAK) inhibitor, a Met kinase inhibitor, an SRC family kinase inhibitor, a mitogen-activated protein kinase (MEK) inhibitor, an extracellular signal-regulated kinase (ERK) inhibitor, a topoisomerase inhibitor, a taxane, an antimetabolite, or an alkylating agent.

[0448] Example 54. The compound or its stereoisomer, transisomer, tautomer or pharmaceutically acceptable salt according to any one of Examples 1 to 40, used as a therapeutically active substance.

[0449] Example 55. The compound according to any one of Examples 1 to 40, or a stereoisomer, transisomer, tautomer, or pharmaceutically acceptable salt thereof, is used to contain KRas. G12D Use of therapeutic treatments for mutated cancers.

[0450] Example 56. Use of the compound according to any one of Examples 1 to 40, or a stereoisomer, transtransfer isomer, tautomer, or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting tumor metastasis.

[0451] Example 57. Use of the compound according to any one of Examples 1 to 40, or a stereoisomer, transisomer, tautomer, or pharmaceutically acceptable salt thereof, for the preparation of a medicament comprising KRas G12D Therapeutic treatments for mutated cancers.

[0452] Example 58. A compound according to any one of Examples 1 to 40, or a stereoisomer, transisomer, tautomer, or pharmaceutically acceptable salt thereof, for therapeutic and / or prophylactic treatment comprising KRas G12D Mutant cancer.

[0453] Example 59. A method for modulating the activity of a KRas mutant protein, the method comprising reacting the mutant protein with a compound according to any one of Examples 1 to 40 or a stereoisomer, transisomer, tautomer or pharmaceutically acceptable salt thereof.

[0454] Example 60. A method for inhibiting the proliferation of a cell population, the method comprising contacting the cell population with a compound according to any one of Examples 1 to 40 or a stereoisomer, transtransfer isomer, tautomer or pharmaceutically acceptable salt thereof.

[0455] Example 61. The method according to Example 60, wherein proliferation inhibition is measured by a decrease in cell viability of the cell population.

[0456] Example 62. A method for inhibiting tumor metastasis, the method comprising administering to an individual in need a therapeutically effective amount of the compound or a stereoisomer, transtransfer isomer, tautomer, or pharmaceutically acceptable salt thereof according to any one of Examples 1 to 40 to the individual in need.

[0457] Example 63. The compound according to any one of Examples 1 to 40, or its stereoisomer, transtransfer isomer, tautomer or pharmaceutically acceptable salt, for modulating the activity of KRas mutant protein.

[0458] Example 64. The compound according to any one of Examples 1 to 40, or its stereoisomer, transtransfer isomer, tautomer or pharmaceutically acceptable salt, for inhibiting the proliferation of cell populations.

[0459] Example 65. The compound, stereoisomer, transtransfer isomer, tautomer, or pharmaceutically acceptable salt used according to Example 64, wherein the inhibition of proliferation is measured by a decrease in cell viability of the cell population.

[0460] Example 66. The compound according to any one of Examples 1 to 40, or its stereoisomer, transtransfer isomer, tautomer or pharmaceutically acceptable salt, for inhibiting tumor metastasis.

[0461] Example 67. Use of the compound according to any one of Examples 1 to 40, or a stereoisomer, transisomer, tautomer, or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for modulating the activity of a KRas mutant protein.

[0462] Example 68. Use of the compound according to any one of Examples 1 to 40, or a stereoisomer, transisomer, tautomer, or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting the proliferation of cell populations.

[0463] Example 69. The use as described in Example 68, wherein the inhibition of proliferation is measured by a decrease in the cell viability of the cell population.

[0464] Example 70. Use of the compound according to any one of Examples 1 to 40, or a stereoisomer, transtransfer isomer, tautomer, or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting tumor metastasis.

[0465] Example I-1. A compound of formula (I),

[0466] (I)

[0467] Or its stereoisomers, transtransfer isomers, tautomers, or pharmaceutically acceptable salts.

[0468] in:

[0469] m is 0 or 1;

[0470] n is 0, 1, or 2;

[0471] q is 0 or 1;

[0472] p is 0, 1, or 2;

[0473] Where n + m + q does not exceed 2, and p and q are not both 1;

[0474] R1 is , where R 01 R 02 R 03 R 04 and R 05 Each of these elements is independently hydrogen, halogen, -CN, -NH2, -N(Me)2, C 1-3 Alkyl, C 1-3 Halogenated alkyl or cyclopropyl;

[0475] R2 can be hydrogen, -CN, halogen, or C. 1-3 Alkyl, C 1-3 Halogenated alkyl or cyclopropyl;

[0476] R 3A For hydrogen, halogen, C 1-3 Alkyl or C 1-3 Halogenated alkyl groups, and R 3B It is hydrogen; or R 3A and R 3B Together they form oxygen;

[0477] R 4A and R 4B Each of them is independently hydrogen, C 1-3 Alkyl or C 1-3 Halogenated alkyl groups;

[0478] Or R 4A and R 4B Together with the atoms they bind to, they form 3- to 6-membered monocyclic rings;

[0479] R 3C For hydrogen, halogen, C 1-3 Alkyl or C 1-3 Halogenated alkyl groups;

[0480] R 3D It is hydrogen;

[0481] Z represents hydrogen, C represents... 1-3 Alkyl, -L1–Cy, -L1–NR5R6, –OR6 or –SR6;

[0482] in:

[0483] L1 either does not exist or is –C(=O)–;

[0484] R5 is hydrogen, C 1-6Alkyl or –NH2;

[0485] R6 is C 1-6 Alkyl, -L2–Cy, –C(=O)–Cy, or –C(=O)C 1-6 alkyl;

[0486] L2 is –(CR) 7A R 7B ) u –;

[0487] u is 1, 2, or 3;

[0488] Each R 7A and R 7B Independently hydrogen or C 1-3 alkyl;

[0489] Cy is a 3- to 11-membered ring portion selected from monocyclic, fused bicyclic, bridged bicyclic, two or three chain rings and spirocyclic rings, wherein Cy optionally contains one or more heteroatoms selected from N, O and S and optionally is substituted by one or more R8 atoms;

[0490] Each R8 is independently selected from: optionally by a hydroxyl group or C 1-6 alkoxy-substituted C 1-6 Alkyl; C 1-3 Halogenated alkyl group; halogen; hydroxyl group; cyano group; –C(=O)NR9R 10 –C(=O)OR 10 ;Optionally coated with hydroxyl-C 1-6 Alkyl-substituted C 3-6 Cycloalkyl; and oxo; wherein R9 and R 10 Independently hydrogen or C 1-6 Alkyl; or

[0491] R5 and R6, together with their bonded nitrogen atoms, form a 3- to 6-membered monocyclic ring optionally substituted with one or more groups independently selected from the following: C 1-6 Alkyl and hydroxyl; or

[0492] Z and R2 together with the carbon atoms they are bonded to form 5- to 6-membered monocyclic aromatic rings;

[0493] X is –NR 11 ;and

[0494] R 11 For hydrogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups.

[0495] Example I-2. The compound according to Example I-1, or its stereoisomer, transisomer, tautomer, or pharmaceutically acceptable salt, wherein:

[0496] Cy is a 3- to 10-membered ring portion selected from monocyclic, fused bicyclic, bridged bicyclic, two or three chain rings and spirocyclic rings, wherein Cy optionally contains one or more heteroatoms selected from N, O and S and optionally is substituted by one or more R8 atoms;

[0497] Each R8 is independently selected from: C14 cells optionally substituted with a hydroxyl group. 1-6 Alkyl; C 1-3 Halogenated alkyl group; halogen; hydroxyl group; cyano group; –C(=O)NR9R 10 –C(=O)OR 10 C 3-6 Cycloalkyl; and oxo; wherein R9 and R 10 Independently hydrogen or C 1-6 alkyl.

[0498] Example I-3. The compound or its stereoisomer, transisomer, tautomer, or pharmaceutically acceptable salt according to Example I-1 or I-2, wherein:

[0499] m is 0;

[0500] n is 1;

[0501] p is 1;

[0502] q is 0; and

[0503] R 3A and R 3B Both are hydrogen.

[0504] Example I-4. The compound or its stereoisomer, transisomer, tautomer, or pharmaceutically acceptable salt according to Example I-1 or I-2, wherein:

[0505] m is 0;

[0506] n is 0;

[0507] p is 0; and

[0508] q is 1.

[0509] Example I-5. The compound according to any one of Examples I-1 to I-4, or a stereoisomer, transisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 11 It is hydrogen.

[0510] Examples I-6. The compound as described in any one of Examples I-1 to I-5, or a stereoisomer, transisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 01 R 02 R 03 R 04 and R 05 The elements in the formula are independently hydrogen, halogen, and carbon. 1-3 Alkyl, C 1-3 Halogenated alkyl groups or -NH2.

[0511] Examples I-7. The compound according to any one of Examples I-1 to I-6, or a stereoisomer, transisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 01 R 02 R 03 R 04 and R 05 No more than one of them is hydrogen.

[0512] Example I-8. The compound according to any one of Examples I-1 to I-7, or a stereoisomer, transisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 01 R 02 R 03 R 04 and R 05 One of them is halogen.

[0513] Examples I-9. The compound according to Examples I-8 or its stereoisomers, transisomers, tautomers or pharmaceutically acceptable salts, wherein R 01 R 02 R 03 R 04 and R 05 One of them is fluorine.

[0514] Example I-10. The compound according to any one of Examples I-1 to I-9, or a stereoisomer, transisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 01 R 02 R 03 R 04 and R 05 One of them is C 1-3 Halogenated alkyl groups.

[0515] Example I-11. The compound according to any one of Examples I-1 to I-10, or a stereoisomer, transisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 01 R 02 R 03 R 04 and R 05 One of them is –NH2.

[0516] Example I-12. The compound according to any one of Examples I-1 to I-11, or a stereoisomer, transisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R1 is... , , , or .

[0517] Example I-13. The compound according to any one of Examples I-1 to I-12, or a stereoisomer, transisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R1 is... .

[0518] Example I-14. The compound or its stereoisomer, transisomer, tautomer or pharmaceutically acceptable salt according to any one of Examples I-1 to I-13, wherein R2 is a halogen.

[0519] Example I-15. The compound according to Example I-14 or its stereoisomer, transisomer, tautomer or pharmaceutically acceptable salt, wherein R2 is fluorine or chlorine.

[0520] Example I-16. The compound according to any one of Examples I-1 to I-15, or a stereoisomer, transisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 3A and R 3C Both are hydrogen.

[0521] Example I-17. The compound according to any one of Examples I-1 to I-16, or a stereoisomer, transisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 4A and R 4B Both are hydrogen.

[0522] Example I-18. The compound according to any one of Examples I-1 to I-16, or a stereoisomer, transisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 4AIt is hydrogen, and R 4B It can be methyl, ethyl, -CHF2, or -CF3.

[0523] Example I-19. The compound or its stereoisomer, transisomer, tautomer, or pharmaceutically acceptable salt according to any one of Examples I-1 to I-16 or I-18, wherein R 4A It is hydrogen, and R 4B It is a methyl group.

[0524] Example I-20. The compound or its stereoisomer, transisomer, tautomer, or pharmaceutically acceptable salt according to any one of Examples I-1 to I-16 or I-18, wherein R 4A It is hydrogen, and R 4B It is an ethyl group.

[0525] Example I-21. The compound according to any one of Examples I-1 to I-16, or a stereoisomer, transisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 4A and R 4B Both are methyl groups.

[0526] Example I-22. The compound or its stereoisomer, transisomer, tautomer, or pharmaceutically acceptable salt according to any one of Examples I-1 to I-16 or I-18, wherein R 4A It is hydrogen, and R 4B It is -CHF2.

[0527] Example I-23. The compound or its stereoisomer, transisomer, tautomer, or pharmaceutically acceptable salt according to any one of Examples I-1 to I-16 or I-18, wherein R 4A It is hydrogen, and R 4B It is -CF3.

[0528] Example I-24. The compound according to any one of Examples I-1 to I-16, or a stereoisomer, transisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 4A and R 4B Together with the atoms bonded to both, it forms an oxobutane ring.

[0529] Example I-25. The compound according to any one of Examples I-1 to I-24, or a stereoisomer, transisomer, tautomer or pharmaceutically acceptable salt thereof, wherein Z is hydrogen.

[0530] Example I-26. The compound according to any one of Examples I-1 to I-24, or a stereoisomer, transisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein Z is C 1-3 alkyl.

[0531] Example I-27. The compound of Example I-26 or its stereoisomer, transisomer, tautomer or pharmaceutically acceptable salt thereof, wherein Z is methyl.

[0532] Example I-28. The compound according to any one of Examples I-1 to I-24, or a stereoisomer, transisomer, tautomer or pharmaceutically acceptable salt thereof, wherein Z is -L1–Cy.

[0533] Example I-29. The compound according to Example I-28 or its stereoisomers, transisomers, tautomers or pharmaceutically acceptable salts thereof, wherein Cy is imidazole, phenyl, pyridine, 2-oxabicyclo[2.1.1]hexane, pyrimidine, pyrazole, pyrazine, pyridazine, 1,2,4-triazole, indazole, pyridinone, thiazole, quinoline, pyrrolo[1,2-a]pyrimidine, 1,2,4-thiadiazole, [1,2,4]triazolo[1,5-a]pyridine, pyrazolo[1,5-a]pyrazine, imidazole[1,2]pyrazine, pyrazole[1,2]pyrazine, pyrazolo ... -a]pyrazine, pyrazolo[1,5-a]pyrimidine, pyrazolo[1,5-c]pyrimidine, imidazo[1,2-b]pyridazine, imidazo[1,2-a]pyridine, imidazo[2,1-b]oxazole, 1,2,5-thiadiazole, isothiazole, 1,2,3-thiadiazole, isoxazole, 1,3,4-thiadiazole, 3-(1H-pyrazol-1-yl)pyrazine Pyridine, 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine, pyrrolo[2,1-f][1,2,4]triazine, 5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one, imidazo[1,2-a]pyrimidine, pyrazolo[3,4-b]pyridine, oxazole, 1,2,3-triazole, 2,3-dihydroindoleazine-5(1H)-one, pyridazine-3(2H)-one, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine, 2-(1H-pyrazol-1-yl)pyridine, 1-azabicyclo[3.2.0]heptane, hexahydro-1H-pyrrolo[2,1-c][1,4]oxazine, pyrrolidine, or hexahydro-1H-pyrroloazine; wherein Cy Optionally selected by one or more independently chosen from the following R 8 Substitution: optionally by a hydroxyl group or C 1-6 alkoxy-substituted C 1-6 Alkyl; C 1-3Halogenated alkyl group; halogen; hydroxyl group; cyano group; –C(=O)NR9R 10 –C(=O)OR 10 ;Optionally coated with hydroxyl-C 1-6 Alkyl-substituted C 3-6 Cycloalkyl; and oxo; wherein R9 and R 10 Independently hydrogen or C 1-6 alkyl.

[0534] Example I-30. The compound or its stereoisomers, transisomers, tautomers or pharmaceutically acceptable salts according to Example I-29, wherein Cy The following compounds are listed: imidazole, phenyl, pyridine, 2-oxabicyclo[2.1.1]hexane, pyrimidine, pyrazole, pyrazine, pyridazine, 1,2,4-triazole, indazole, pyridinone, thiazole, quinoline, pyrrolo[1,2-a]pyrimidine, 1,2,4-thiadiazole, [1,2,4]triazolo[1,5-a]pyridine, pyrazolo[1,5-a]pyrazine, imidazo[1,2-a]pyrazine, pyrazolo[1,5-a]pyrimidine, pyrazolo[1,5-c]pyrimidine, imidazo[1,2-b]pyridazine, imidazo[1,2-a]pyridine, imidazo[2,1-b]oxazole, 1,2,5-thiadiazole, isothiazole, 1,2,3-thiadiazole, and isothiazole. Oxazole, 1,3,4-thiadiazole, 3-(1H-pyrazol-1-yl)pyridine, 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine, pyrrolo[2,1-f][1,2,4]triazine, 5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one, imidazo[1,2-a]pyrimidine, pyrazolo[3,4-b]pyridine, oxazole, 1,2,3-triazole, 2,3-dihydroindoleazine-5(1H)-one, pyridazine-3(2H)-one, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine, or 2-(1H-pyrazol-1-yl)pyridine; wherein Cy is optionally selected by one or more R independently selected from the following 8 Substitution: optionally by a hydroxyl group or C 1-6 alkoxy-substituted C 1-6 Alkyl; C 1-3 Halogenated alkyl group; halogen; hydroxyl group; cyano group; –C(=O)NR9R 10 –C(=O)OR 10 ;Optionally coated with hydroxyl-C 1-6 Alkyl-substituted C 3-6 Cycloalkyl; and oxo; wherein R9 and R 10 Independently hydrogen or C 1-6 alkyl.

[0535] Example I-31. The compound according to Example I-30 or its stereoisomers, transisomers, tautomers or pharmaceutically acceptable salts thereof, wherein Cy is pyrrolo[1,2-a]pyrimidine, 1,2,4-thiadiazole, [1,2,4]triazolo[1,5-a]pyridine, pyrazolo[1,5-a]pyrazine, imidazo[1,2-a]pyrazine, pyrazolo[1,5-a]pyrimidine, pyrazolo[1,5-c]pyrimidine, imidazo[1,2-b]pyridazine, imidazo[1,2-a]pyridine, imidazo[2,1-b]oxazole, 1,2,5-thiadiazole, isothiazole, 1,2,3-thiadiazole, isoxazole, 1,3,4-thiadiazole, 3-(1H-pyrazol-1-yl)pyridine, 6 ,7-Dihydro-5H-pyrazolo[5,1-b][1,3]oxazine, pyrrolo[2,1-f][1,2,4]triazine, 5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one, imidazo[1,2-a]pyrimidine, pyrazolo[3,4-b]pyridine, oxazole, 1,2,3-triazole, 2,3-dihydroindoleazine-5(1H)-one, pyridazine-3(2H)-one, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine or 2-(1H-pyrazol-1-yl)pyridine; wherein Cy is optionally selected by one or more R independently selected from the following 8 Substitution: optionally by a hydroxyl group or C 1-6 alkoxy-substituted C 1-6 Alkyl; C 1-3 Halogenated alkyl group; halogen; hydroxyl group; cyano group; –C(=O)NR9R 10 –C(=O)OR 10 ;Optionally coated with hydroxyl-C 1-6 Alkyl-substituted C 3-6 Cycloalkyl; and oxo; wherein R9 and R 10 Independently hydrogen or C 1-6 alkyl.

[0536] Example I-32. The compound according to Example I-30 or its stereoisomer, transisomer, tautomer or pharmaceutically acceptable salt thereof, wherein Cy is imidazole, phenyl, pyridine, 2-oxabicyclo[2.1.1]hexane, pyrimidine, pyrazole, pyrazine, pyridazine, 1,2,4-triazole, indazole, pyridinone, thiazole or quinoline; wherein Cy is optionally substituted by one or more R8s independently selected from the group consisting of: C substituted by a hydroxyl group 1-6 Alkyl; C 1-3 Halogenated alkyl group; halogen; hydroxyl group; cyano group; –C(=O)NR9R 10 –C(=O)OR 10 C 3-6Cycloalkyl; and oxo; wherein R9 and R 10 Independently hydrogen or C 1-6 alkyl.

[0537] Example I-33. The compound according to Example I-30 or its stereoisomer, transisomer, tautomer, or pharmaceutically acceptable salt, wherein Cy is 1-azabicyclo[3.2.0]heptane, hexahydro-1H-pyrrolo[2,1-c][1,4]oxazine, pyrrolidine, or hexahydro-1H-pyrroloazine; wherein Cy is optionally composed of one or more R groups independently selected from the group consisting of ... 8 Substitution: optionally by a hydroxyl group or C 1-6 alkoxy-substituted C 1-6 Alkyl; C 1-3 Halogenated alkyl group; halogen; hydroxyl group; cyano group; –C(=O)NR9R 10 –C(=O)OR 10 ;Optionally coated with hydroxyl-C 1-6 Alkyl-substituted C 3-6 cycloalkyl; and oxo; wherein R9 and R 10 Independently hydrogen or C 1-6 alkyl.

[0538] Example I-34. The compound or its stereoisomer, transisomer, tautomer or pharmaceutically acceptable salt according to Example I-28, wherein L1 is absent and Cy is a pyrazole or pyrimidine, wherein the pyrazole is optionally substituted with a methyl group.

[0539] Example I-35. The compound or its stereoisomer, transisomer, tautomer or pharmaceutically acceptable salt according to any one of Examples I-1 to I-24, wherein Z is -L1–NR5R6.

[0540] Example I-36. The compound or its stereoisomer, transisomer, tautomer or pharmaceutically acceptable salt according to Example I-35, wherein L1 is absent, R5 is hydrogen, and R6 is -L2–Cy.

[0541] Example I-37. The compound according to Example I-36 or its stereoisomers, transisomers, tautomers or pharmaceutically acceptable salts thereof, wherein L2 is –CH2– and wherein Cy is imidazole, phenyl, pyridine, 2-oxabicyclo[2.1.1]hexane, pyrimidine, pyrazole, pyrazine, pyridazine, 1,2,4-triazole, indazole, pyridinone, thiazole, quinoline, pyrrolo[1,2-a]pyrimidine, 1,2,4-thiadiazole, [1,2,4]triazolo[1,5-a]pyridine, pyrazolo[1,5-a]pyrazine, imidazole[1,2]pyrazine, etc. -a]pyrazine, pyrazolo[1,5-a]pyrimidine, pyrazolo[1,5-c]pyrimidine, imidazo[1,2-b]pyridazine, imidazo[1,2-a]pyridine, imidazo[2,1-b]oxazole, 1,2,5-thiadiazole, isothiazole, 1,2,3-thiadiazole, isoxazole, 1,3,4-thiadiazole, 3-(1H-pyrazol-1-yl)pyrazine Pyridine, 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine, pyrrolo[2,1-f][1,2,4]triazine, 5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one, imidazo[1,2-a]pyrimidine, pyrazolo[3,4-b]pyridine, oxazole, 1,2,3-triazole, 2,3-dihydroindoleazine-5(1H)-one, pyridazine-3(2H)-one, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine, 2-(1H-pyrazol-1-yl)pyridine, 1-azabicyclo[3.2.0]heptane, hexahydro-1H-pyrrolo[2,1-c][1,4]oxazine, pyrrolidine, or hexahydro-1H-pyrroloazine; wherein Cy Optionally selected by one or more independently chosen from the following R 8 Substitution: optionally by a hydroxyl group or C 1-6 alkoxy-substituted C 1-6 Alkyl; C 1-3 Halogenated alkyl group; halogen; hydroxyl group; cyano group; –C(=O)NR9R 10 –C(=O)OR 10 ;Optionally coated with hydroxyl-C 1-6 Alkyl-substituted C 3-6 cycloalkyl; and oxo; wherein R9 and R 10 Independently hydrogen or C 1-6 alkyl.

[0542] Example I-38. The compound or its stereoisomer, transisomer, tautomer, or pharmaceutically acceptable salt according to Examples I-36 to I-37, wherein L2 is –CH2– and Cy The following compounds are listed: imidazole, phenyl, pyridine, 2-oxabicyclo[2.1.1]hexane, pyrimidine, pyrazole, pyrazine, pyridazine, 1,2,4-triazole, indazole, pyridinone, thiazole, quinoline, pyrrolo[1,2-a]pyrimidine, 1,2,4-thiadiazole, [1,2,4]triazolo[1,5-a]pyridine, pyrazolo[1,5-a]pyrazine, imidazo[1,2-a]pyrazine, pyrazolo[1,5-a]pyrimidine, pyrazolo[1,5-c]pyrimidine, imidazo[1,2-b]pyridazine, imidazo[1,2-a]pyridine, imidazo[2,1-b]oxazole, 1,2,5-thiadiazole, isothiazole, 1,2,3-thiadiazole, and isothiazole. Oxazole, 1,3,4-thiadiazole, 3-(1H-pyrazol-1-yl)pyridine, 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine, pyrrolo[2,1-f][1,2,4]triazine, 5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one, imidazo[1,2-a]pyrimidine, pyrazolo[3,4-b]pyridine, oxazole, 1,2,3-triazole, 2,3-dihydroindoleazine-5(1H)-one, pyridazine-3(2H)-one, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine, or 2-(1H-pyrazol-1-yl)pyridine; wherein Cy is optionally substituted by one or more R8 radicals independently selected from the group consisting of: optionally hydroxyl or C 1-6 alkoxy-substituted C 1-6 Alkyl; C 1-3 Halogenated alkyl group; halogen; hydroxyl group; cyano group; –C(=O)NR9R 10 –C(=O)OR 10 ;Optionally coated with hydroxyl-C 1-6 Alkyl-substituted C 3-6 Cycloalkyl; and oxo; wherein R9 and R 10 Independently hydrogen or C 1-6 alkyl.

[0543] Example I-39. The compound or its stereoisomers, transisomers, tautomers or pharmaceutically acceptable salts according to Examples I-36-I-38, wherein Cy is pyrrolo[1,2-a]pyrimidine, 1,2,4-thiadiazole, [1,2,4]triazolo[1,5-a]pyridine, pyrazolo[1,5-a]pyrazine, imidazo[1,2-a]pyrazine, pyrazolo[1,5-a]pyrimidine, pyrazolo[1,5-c]pyrimidine, imidazo[1,2-b]pyridazine, imidazo[1,2-a]pyridine, imidazo[2,1-b]oxazole, 1,2,5-thiadiazole, isothiazole, 1,2,3-thiadiazole, isoxazole, 1,3,4-thiadiazole, 3-(1H-pyrazol-1-yl)pyridine, 6 ,7-Dihydro-5H-pyrazolo[5,1-b][1,3]oxazine, pyrrolo[2,1-f][1,2,4]triazine, 5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one, imidazo[1,2-a]pyrimidine, pyrazolo[3,4-b]pyridine, oxazole, 1,2,3-triazole, 2,3-dihydroindoleazine-5(1H)-one, pyridazine-3(2H)-one, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine or 2-(1H-pyrazol-1-yl)pyridine; wherein Cy is optionally selected by one or more R independently selected from the following 8 Substitution: optionally by a hydroxyl group or C 1-6 alkoxy-substituted C 1-6 Alkyl; C 1-3 Halogenated alkyl group; halogen; hydroxyl group; cyano group; –C(=O)NR9R 10 –C(=O)OR 10 ;Optionally coated with hydroxyl-C 1-6 Alkyl-substituted C 3-6 Cycloalkyl; and oxo; wherein R9 and R 10 Independently hydrogen or C 1-6 alkyl.

[0544] Example I-40. The compound or its stereoisomer, transisomer, tautomer, or pharmaceutically acceptable salt according to Examples I-36-I-37, wherein Cy is 1-azabicyclo[3.2.0]heptane, hexahydro-1H-pyrrolo[2,1-c][1,4]oxazine, pyrrolidine, or hexahydro-1H-pyrroloazine; wherein Cy is optionally composed of one or more R groups independently selected from the group consisting of ... 8 Substitution: optionally by a hydroxyl group or C 1-6 alkoxy-substituted C 1-6 Alkyl; C 1-3 Halogenated alkyl group; halogen; hydroxyl group; cyano group; –C(=O)NR9R 10 –C(=O)OR10 ;Optionally coated with hydroxyl-C 1-6 Alkyl-substituted C 3-6 Cycloalkyl; and oxo; wherein R9 and R 10 Independently hydrogen or C 1-6 alkyl.

[0545] Example I-41. The compound according to any one of Examples I-37 to I-40, or a stereoisomer, transisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein each R8 is independently selected from: –CH2OH, –CH2CH2OH, –CH2OCH3, methyl, ethyl, –CHF2, –CF3, chlorine, fluorine, oxo, –C(=O)N(CH3)2, –C(=O)OH, –C(=O)OCH3, hydroxyl, cyano, cyclopropyl substituted with –CH2OH, and cyclopropyl.

[0546] Example I-42. The compound or its stereoisomers, transisomers, tautomers or pharmaceutically acceptable salts according to Examples I-36 to I-37, wherein Cy The following compounds are listed: imidazole, phenyl, pyridine, 2-oxabicyclo[2.1.1]hexane, pyrimidine, pyrazole, pyrazine, pyridazine, 1,2,4-triazole, indazole, pyridinone, thiazole, quinoline, pyrrolo[1,2-a]pyrimidine, 1,2,4-thiadiazole, [1,2,4]triazolo[1,5-a]pyridine, pyrazolo[1,5-a]pyrazine, imidazo[1,2-a]pyrazine, pyrazolo[1,5-a]pyrimidine, pyrazolo[1,5-c]pyrimidine, imidazo[1,2-b]pyridazine, imidazo[1,2-a]pyridine, imidazo[2,1-b]oxazole, 1,2,5-thiadiazole, isothiazole, 1,2,3-thiadiazole, isoxazole, 1,3,4-thiadiazole, 3-(1H-pyrazol-1-yl) Pyridine, 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine, pyrrolo[2,1-f][1,2,4]triazine, 5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one, imidazo[1,2-a]pyrimidine, pyrazolo[3,4-b]pyridine, oxazole, 1,2,3-triazole, 2,3-dihydroindoleazine-5(1H)-one, pyridazine-3(2H)-one, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine, 2-(1H-pyrazol-1-yl)pyridine, 1-azabicyclo[3.2.0]heptane, hexahydro-1H-pyrrolo[2,1-c][1,4]oxazine, pyrrolidine, or hexahydro-1H-pyrroloazine.

[0547] Example I-43. The compound or its stereoisomers, transisomers, tautomers or pharmaceutically acceptable salts according to Examples I-36, I-37 to I-39 or I-42, wherein Cy The following compounds are listed: imidazole, phenyl, pyridine, 2-oxabicyclo[2.1.1]hexane, pyrimidine, pyrazole, pyrazine, pyridazine, 1,2,4-triazole, indazole, pyridinone, thiazole, quinoline, pyrrolo[1,2-a]pyrimidine, 1,2,4-thiadiazole, [1,2,4]triazolo[1,5-a]pyridine, pyrazolo[1,5-a]pyrazine, imidazo[1,2-a]pyrazine, pyrazolo[1,5-a]pyrimidine, pyrazolo[1,5-c]pyrimidine, imidazo[1,2-b]pyridazine, imidazo[1,2-a]pyridine, imidazo[2,1-b]oxazole, 1,2,5-thiadiazole, isothiazole, 1,2,3-thiadiazole. Isoxazole, 1,3,4-thiadiazole, 3-(1H-pyrazol-1-yl)pyridine, 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine, pyrrolo[2,1-f][1,2,4]triazine, 5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one, imidazo[1,2-a]pyrimidine, pyrazolo[3,4-b]pyridine, oxazole, 1,2,3-triazole, 2,3-dihydroindoleazine-5(1H)-one, pyridazine-3(2H)-one, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine, or 2-(1H-pyrazol-1-yl)pyridine.

[0548] Example I-44. The compound or its stereoisomer, transisomer, tautomer, or pharmaceutically acceptable salt according to Examples I-36 to I-37, wherein L2 is –CH2–, and Cy is phenyl, pyridine, imidazole, 2-oxabicyclo[2.1.1]hexane, pyrimidine, pyrazine, pyridazine, triazole, pyrazole, indazole, pyridinone, thiazole, or quinoline; wherein Cy is optionally substituted by one or more R8s independently selected from: C substituted by a hydroxyl group 1-6 Alkyl; C 1-3 Halogenated alkyl group; halogen; hydroxyl group; cyano group; –C(=O)NR9R 10 –C(=O)OR 10 C 3-6 Cycloalkyl; and oxo; wherein R9 and R 10 Each of them is independently hydrogen or C. 1-6 alkyl.

[0549] Example I-45. The compound according to Example I-44 or its stereoisomers, transisomers, tautomers or pharmaceutically acceptable salts thereof, wherein each R8 is independently selected from methyl, –CF3, –CHF2, fluorine, hydroxyl, cyano, –CH2OH, –C(=O)OH, –C(=O)OMe and –C(=O)N(Me)2.

[0550] Example I-46. The compound or its stereoisomer, transisomer, tautomer or pharmaceutically acceptable salt according to Example I-44, wherein Cy is phenyl, pyridine, imidazole, 2-oxabicyclo[2.1.1]hexane, pyrimidine, pyrazine, pyridazine, triazole, pyrazole, indazole, pyridinone, thiazole or quinoline.

[0551] Example I-47. The compound or its stereoisomers, transisomers, tautomers or pharmaceutically acceptable salts according to Examples I-36 to I-37, wherein Cy The compounds are phenyl, pyridine, pyrimidine, pyrazole, pyridone, thiazole, pyrrolo[1,2-a]pyrimidine, 1,2,4-thiadiazole, [1,2,4]triazolo[1,5-a]pyridine, pyrazolo[1,5-a]pyrazine, imidazo[1,2-a]pyrazine, pyrazolo[1,5-a]pyrimidine, pyrazolo[1,5-c]pyrimidine, imidazo[1,2-b]pyridazine, imidazo[1,2-a]pyridine, imidazo[2,1-b]oxazole, 1,2,5-thiadiazole, isothiazole, 1,2,3-thiadiazole, isoxazole, 1,3,4-thiadiazole, 3-(1H-pyridine) Cy is selected from pyrazol-1-yl)pyridine, 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine, pyrrolo[2,1-f][1,2,4]triazine, 5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one, imidazo[1,2-a]pyrimidine, pyrazolo[3,4-b]pyridine, oxazole, 1,2,3-triazole, 2,3-dihydroindoleazine-5(1H)-one, pyridazine-3(2H)-one, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine, or 2-(1H-pyrazol-1-yl)pyridine, wherein Cy is optionally substituted by one or more R8 radicals independently selected from the following: optionally substituted by a hydroxyl group or C 1-6 alkoxy-substituted C 1-6 Alkyl; C 1-3 Halogenated alkyl group; halogen; cyano group; oxo group; –C(=O)OR 10 ; and optionally hydroxyl-C 1-6 Alkyl-substituted C 3-6 Cycloalkyl.

[0552] Example I-48. The compound according to Example I-47 or its stereoisomer, transisomer, tautomer or pharmaceutically acceptable salt thereof, wherein each R8 is independently –CH2OH, –CH2CH2OH, –CH2OCH3, methyl, ethyl, –CHF2, –CF3, chlorine, fluorine, oxo, –C(=O)OH, cyano, cyclopropyl substituted with –CH2OH or cyclopropyl.

[0553] Example I-49. The compound according to Example I-47 or its stereoisomers, transisomers, tautomers or pharmaceutically acceptable salts thereof, wherein Cy is phenyl, pyridine, pyrimidine, pyrazole, pyridinone, thiazole, pyrrolo[1,2-a]pyrimidine, 1,2,4-thiadiazole, [1,2,4]triazolo[1,5-a]pyridine, pyrazolo[1,5-a]pyrazine, imidazo[1,2-a]pyrazine, pyrazolo[1,5-a]pyrimidine, pyrazolo[1,5-c]pyrimidine, imidazo[1,2-b]pyridazine, imidazo[1,2-a]pyridine, imidazo[2,1-b]oxazole, 1,2,5-thiadiazole, isothiazole, 1,2,3-thiadiazole, isoxazole, 1,3,4-thiadiazole, 3-(1H -pyrazol-1-yl)pyridine, 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine, pyrrolo[2,1-f][1,2,4]triazine, 5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one, imidazo[1,2-a]pyrimidine, pyrazolo[3,4-b]pyridine, oxazole, 1,2,3-triazole, 2,3-dihydroindoleazine-5(1H)-one, pyridazine-3(2H)-one, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine, or 2-(1H-pyrazol-1-yl)pyridine.

[0554] Example I-50. The compound or its stereoisomer, transisomer, tautomer or pharmaceutically acceptable salt according to Example I-36, wherein L2 is –CH(CH3)– and Cy is phenyl.

[0555] Example I-51. The compound or its stereoisomer, transisomer, tautomer or pharmaceutically acceptable salt according to Example I-35, wherein L1 is absent, R5 is hydrogen and R6 is methyl.

[0556] Example I-52. The compound or its stereoisomers, transisomers, tautomers or pharmaceutically acceptable salts according to Example I-35, wherein L1 is absent, R5 is hydrogen, and R6 is methyl, –C(=O)–phenyl or –C(=O)CH2CH3.

[0557] Example I-53. The compound or its stereoisomers, transisomers, tautomers or pharmaceutically acceptable salts according to Example I-35, wherein L1 is absent, R5 is hydrogen, and R6 is –C(=O)–Cy.

[0558] Examples I-54. The compound or its stereoisomers, transisomers, tautomers or pharmaceutically acceptable salts according to Examples I-53, wherein Cy is phenyl.

[0559] Example I-55. The compound or its stereoisomer, transisomer, tautomer or pharmaceutically acceptable salt according to Example I-35 or I-52, wherein L1 is absent, R5 is hydrogen and R6 is –C(=O)CH2CH3.

[0560] Example I-56. The compound or its stereoisomer, transisomer, tautomer or pharmaceutically acceptable salt according to Example I-35, wherein L1 is –C(=O)–, R5 is -NH2 and R6 is methyl.

[0561] Example I-57. The compound according to Example I-35 or its stereoisomer, transisomer, tautomer or pharmaceutically acceptable salt, wherein L1 is absent and R5 and R6 together with the nitrogen atom to which they are bonded form an azo-heterocyclic butane ring optionally substituted with hydroxyl and methyl groups.

[0562] Example I-58. The compound according to any one of Examples I-1 to I-24, or a stereoisomer, transisomer, tautomer or pharmaceutically acceptable salt thereof, wherein Z is –OR6 or –SR6.

[0563] Example I-59. The compound or its stereoisomer, transisomer, tautomer or pharmaceutically acceptable salt according to any one of Examples I-1 to I-24 or I-58, wherein Z is –OR6.

[0564] Example I-60. The compound or its stereoisomer, transisomer, tautomer or pharmaceutically acceptable salt according to Example I-59, wherein R6 is -L2–Cy, wherein L2 is –CH2–, and Cy is pyridine.

[0565] Example I-61. The compound or its stereoisomer, transisomer, tautomer or pharmaceutically acceptable salt according to any one of Examples I-1 to I-24 or I-58, wherein Z is –SR6.

[0566] Example I-62. The compound or its stereoisomer, transisomer, tautomer or pharmaceutically acceptable salt according to Example I-61, wherein R6 is -L2–Cy, wherein L2 is –CH2–, and Cy is pyridine.

[0567] Example I-63. The compound or its stereoisomer, transisomer, tautomer or pharmaceutically acceptable salt according to any one of Examples I-1 to I-24, wherein Z and R2 together with the carbon atoms to which they are bonded form a pyrazole.

[0568] Example I-64. A compound selected from any one of compounds 1 to 146 shown in Table 1, or a stereoisomer, transisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0569] Example 1-65. A pharmaceutical composition comprising: a compound according to any one of Examples 1-1 to 1-64 or a stereoisomer, transisomer, tautomer or pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.

[0570] Example 1-66. A method of treating cancer, comprising administering an effective amount of a compound according to any one of Examples 1-1 to 1-64 or a stereoisomer, transisomer, tautomer, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to Example 1-65.

[0571] Example I-67. The method according to Example I-66, wherein the cancer is characterized by containing a KRas mutation.

[0572] Example I-68. The method according to Example I-67, wherein the KRas mutation corresponds to KRas G12D mutation.

[0573] Example I-69. The method according to any one of Examples I-66 to I-68, further comprising detecting the presence of KRas in a sample from the patient prior to administration. G12D mutation.

[0574] Example I-70. The method according to Example I-69, wherein KRas is shown in the patient sample. G12D Following the mutation, the patient is given a compound, its stereoisomer, transtransfer isomer, tautomer, or pharmaceutically acceptable salt, or a pharmaceutical composition thereof.

[0575] Example I-71. The method according to any one of Examples I-66 to I-70, wherein the cancer is tissue-agnostic.

[0576] Example I-72. The method according to any one of Examples I-66 to I-70, wherein the cancer is pancreatic cancer, lung cancer, or colorectal cancer.

[0577] Example I-73. The method according to Example I-72, wherein the lung cancer is lung adenocarcinoma, NSCLC or SCLC.

[0578] Example I-74. The method according to Example I-72, wherein the cancer is pancreatic cancer.

[0579] Example I-75. The method according to Example I-72, wherein the cancer is colorectal cancer.

[0580] Example I-76. The method according to any one of Examples I-66 to I-75, further comprising administering at least one additional therapeutic agent.

[0581] Example I-77. The method according to Example I-76, wherein the additional therapeutic agent includes an epidermal growth factor receptor (EGFR) inhibitor, a phosphatidylinositol kinase (PI3K) inhibitor, an insulin-like growth factor receptor (IGF1R) inhibitor, a Janus kinase (JAK) inhibitor, a Met kinase inhibitor, an SRC family kinase inhibitor, a mitogen-activated protein kinase (MEK) inhibitor, an extracellular signal-regulated kinase (ERK) inhibitor, a topoisomerase inhibitor, a taxane, an antimetabolite, or an alkylating agent.

[0582] Example I-78. The compound or its stereoisomer, transisomer, tautomer or pharmaceutically acceptable salt according to any one of Examples I-1 to I-64, used as a therapeutically active substance.

[0583] Example I-79. The compound or its stereoisomer, transisomer, tautomer or pharmaceutically acceptable salt according to any one of Examples I-1 to I-64, for use in the treatment of cancer.

[0584] Examples I-80. The compounds used according to Examples I-79, wherein the cancer is pancreatic cancer, lung cancer, or colorectal cancer.

[0585] Example I-81. Use of the compound or its stereoisomer, transisomer, tautomer or pharmaceutically acceptable salt according to any one of Examples I-1 to I-64 in the manufacture of a medicament for treating cancer.

[0586] Example I-82. The use according to Example I-81, wherein the cancer is pancreatic cancer, lung cancer, or colorectal cancer.

[0587] Example I-83. The compound or its stereoisomer, transisomer, tautomer, or pharmaceutically acceptable salt according to any one of Examples I-1 to I-64 is used to contain KRas. G12D Use of therapeutic treatments for mutated cancers.

[0588] Example I-84. Use of any compound according to any one of Examples I-1 to I-64, or a stereoisomer, transtransfer isomer, tautomer, or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting tumor metastasis.

[0589] Example I-85. Use of the compound or its stereoisomer, transisomer, tautomer, or pharmaceutically acceptable salt according to any one of Examples I-1 to I-64 for the preparation of a medicament for use in the formulation of a drug containing KRas. G12D Therapeutic treatments for mutated cancers.

[0590] Example I-86. The compound or its stereoisomer, transisomer, tautomer, or pharmaceutically acceptable salt according to any one of Examples I-1 to I-64, used to contain KRas G12D Therapeutic and / or preventative treatments for mutated cancers.

[0591] Example I-87. A method for a) regulating the activity of KRas mutant protein, b) inhibiting cell population proliferation, or c) inhibiting tumor metastasis;

[0592] The method for modulating the activity of the KRas mutant protein includes reacting the mutant protein with any one of the compounds in Examples I-1 to I-64, or a stereoisomer, transisomer, tautomer, or pharmaceutically acceptable salt thereof.

[0593] The method for inhibiting the proliferation of a cell population includes contacting the cell population with the compound described in any one of Examples I-1 to I-64, or a stereoisomer, transtransfer isomer, tautomer, or pharmaceutically acceptable salt thereof; and

[0594] Methods for inhibiting tumor metastasis include administering a therapeutically effective amount of any one of Examples I-1 to I-64, or a stereoisomer, transtransfer isomer, tautomer, or pharmaceutically acceptable salt thereof, to an individual in need.

[0595] Example I-88. A method for modulating the activity of a KRas mutant protein, the method comprising reacting the mutant protein with a compound according to any one of Examples I-1 to I-64 or a stereoisomer, transisomer, tautomer or pharmaceutically acceptable salt thereof.

[0596] Example I-89. A method for inhibiting the proliferation of a cell population, the method comprising contacting the cell population with a compound according to any one of Examples I-1 to I-64 or a stereoisomer, transtransfer isomer, tautomer or pharmaceutically acceptable salt thereof.

[0597] Example I-90. The method according to Example I-87 or I-89, wherein the inhibition of proliferation is measured by a decrease in the cell viability of the cell population.

[0598] Example I-91. A method for inhibiting tumor metastasis, the method comprising administering to an individual in need a therapeutically effective amount of a compound or a stereoisomer, transtransfer isomer, tautomer, or pharmaceutically acceptable salt thereof according to any one of Examples I-1 to I-64 to the individual in need.

[0599] Example I-92. The compound, or stereoisomer, transtransfer isomer, tautomer or pharmaceutically acceptable salt thereof, according to any one of Examples I-1 to I-64, is used for a) regulating the activity of KRas mutant protein, b) inhibiting cell population proliferation or c) inhibiting tumor metastasis.

[0600] Example I-93. The compound or its stereoisomer, transtransfer isomer, tautomer or pharmaceutically acceptable salt according to any one of Examples I-1 to I-64, used to modulate the activity of KRas mutant protein.

[0601] Example I-94. The compound or its stereoisomer, transtransfer isomer, tautomer or pharmaceutically acceptable salt according to any one of Examples I-1 to I-64, used to inhibit the proliferation of cell populations.

[0602] Example I-95. The compound, stereoisomer, transtransfer isomer, tautomer, or pharmaceutically acceptable salt used according to Example I-92 or I-94, wherein the inhibition of proliferation is measured by a decrease in cell viability of the cell population.

[0603] Example I-96. The compound or its stereoisomer, transtransfer isomer, tautomer or pharmaceutically acceptable salt according to any one of Examples I-1 to I-64, used to inhibit tumor metastasis.

[0604] Example I-97. Use of the compound, or stereoisomer, transtransferase isomer, tautomer, or pharmaceutically acceptable salt thereof, according to any one of Examples I-1 to I-64, in the manufacture of a medicament for a) regulating the activity of KRas mutant protein, b) inhibiting cell population proliferation, or c) inhibiting tumor metastasis.

[0605] Example I-98. Use of any compound according to any one of Examples I-1 to I-64, or a stereoisomer, transisomer, tautomer, or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for modulating the activity of a KRas mutant protein.

[0606] Example I-99. Use of the compound or its stereoisomer, transtransfer isomer, tautomer or pharmaceutically acceptable salt according to any one of Examples I-1 to I-64 in the manufacture of a medicament for inhibiting the proliferation of cell populations.

[0607] Example I-100. The use according to Example I-97 or I-99, wherein the inhibition of proliferation is measured by a decrease in the cell viability of the cell population.

[0608] Example I-101. Use of the compound or its stereoisomer, transtransfer isomer, tautomer or pharmaceutically acceptable salt according to any one of Examples I-1 to I-64 in the manufacture of a medicament for inhibiting tumor metastasis.

[0609] Exemplary embodiments

[0610] Exemplary embodiments of the present invention are provided below.

[0611] The abbreviations used in this article are as follows: Ac = Acetyl; HATU = Tetramethylurea hexafluorophosphate azirconazole; DIPEA = N,N-diisopropylethylamine; EtOAc = Ethyl acetate; DMSO = Dimethyl sulfoxide; DCM = Dichloromethane; ACN = Acetonitrile; FA = Formic acid; HEX = Hexane; ETOH = Ethanol; THF = Tetrahydrofuran; TBAF = Tetra-n-butylammonium fluoride; Bn = Benzyl; DCE = 1,2-Dichloroethane; TMEDA = Tetramethylethylenediamine; LDA = Lithium diisopropylaminoamine; DMF = N,N-Dimethylformamide; Ts = Toluenesulfonyl; TFA = Trifluoroacetic acid; LiHMDS = Lithium bis(trimethylsilyl)amide; DAST = Diethylaminosulfur trifluoride; TTMSS = Tris(trimethylsilyl)silane; dtbbpy = 4,4'-Di-tert-butyl-2,2'-dipyridyl; TBS / TBDMS = tert-butyldimethylsilyl; DMAP = 4-dimethylaminopyridine; DPPA = diphenyl azidophosphate; DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene; PMB = p-methoxybenzyl; NIS = N-iodosuccinimide; Pin = pinacol; dppf = 1,1'-bis(diphenylphosphino)ferrocene; DMA = dimethylacetamide; DME = 1,2-dimethoxyethane; Boc = tert-butyloxycarbonyl; BrOP = bromotris(dimethylamino)phosphonium hexafluorophosphate; BINAP = 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl; dba = dibenzylideneacetone; DIAD = diisopropyl azodicarbonate.

[0612] Example

[0613] The following examples are provided for illustrative purposes only and not for limitation.

[0614] Example 1 – Preparation of intermediates:

[0615] Intermediate 1: (1R,2S,5S)-2-((S)-1-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0616]

[0617] Intermediate 1 was prepared as described in WO2023 / 225302A1, the entire disclosure of which is incorporated herein by reference (see Intermediate 4 in WO2023 / 225302A1).

[0618] Intermediate 2: (5-(bis(4-methoxybenzyl)amino)-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl)boronic acid

[0619]

[0620] Intermediate 2 was prepared as described in WO2023 / 225302A1, the entire disclosure of which is incorporated herein by reference (see Intermediate 20 in WO2023 / 225302A1).

[0621] Intermediate 3: (8R,11S,11aS,12S)-4-bromo-2-chloro-3-fluoro-12-methyl-5-oxo-8,9,10,11,11a,12-hexahydro-5H,7H-8,11-bridged iminoazapyro[2,1-c]pyrido[3,2-f][1,4]oxazapyro-14-carboxylic acid tert-butyl ester

[0622]

[0623] Step 1: 2-((S)-1-((1S,2S,5R)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]oct-2-yl)ethoxy)-6-chloro-5-fluoronicotinic acid

[0624]

[0625] Under nitrogen atmosphere and at 0 °C, NaH (476 mg, 11.9 mmol, 60% in mineral oil) was added to a solution of (1S,2S,5R)-2-((S)-1-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (610 mg, 2.38 mmol, intermediate 1) in tetrahydrofuran (5.00 mL). The resulting solution was stirred at 0 °C for 30 min. Then, 2,6-dichloro-5-fluoronicotinic acid (500 mg, 2.38 mmol) was added and the solution was stirred overnight at room temperature. The solution was quenched with water and concentrated under vacuum to give 1.28 g (crude) of the title compound as a white solid. LC-MS: (ESI, m / z): [M+H] + = 430. The crude product was used in the next step without further purification.

[0626] Step 2: (8R,11S,11aS,12S)-2-chloro-3-fluoro-12-methyl-5-oxo-8,9,10,11,11a,12-hexahydro-5H,7H-8,11-bridged iminoazapyro[2,1-c]pyrido[3,2-f][1,4]oxazapyro-14-carboxylic acid tert-butyl ester

[0627]

[0628] HATU (1.36 g, 3.57 mmol) was added to a solution of 2-((S)-1-((1S,2S,5R)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]oct-2-yl)ethoxy)-6-chloro-5-fluoronicotinic acid (1.28 g, 2.98 mmol) and DIPEA (1.15 g, 8.93 mmol) in N,N-dimethylacetamide (35.0 mL) at room temperature. The resulting solution was stirred at room temperature for 1 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (gradient: petroleum ether containing 0% to 50% EtOAc) to give 429 mg (35% yield) of the title compound as a yellow solid. LC-MS: (ESI, m / z): [M+H] + = 412.

[0629] Step 3: (8R,11S,11aS,12S)-4-bromo-2-chloro-3-fluoro-12-methyl-5-oxo-8,9,10,11,11a,12-hexahydro-5H,7H-8,11-bridged iminoazapyro[2,1-c]pyrido[3,2-f][1,4]oxazapyro-14-carboxylic acid tert-butyl ester

[0630]

[0631] Under nitrogen atmosphere, at -78°C, MeLi (2.73 mL, 1.6 M, in diethyl ether) was added to a solution of (8R,11S,11aS,12S)-2-chloro-3-fluoro-12-methyl-5-oxo-8,9,10,11,11a,12-hexahydro-5H,7H-8,11-bridged iminoazapyro[2,1-c]pyrido[3,2-f][1,4]oxazapyro-14-carboxylic acid tert-butyl ester (900 mg, 2.19 mmol) in tetrahydrofuran (6.00 mL), and the mixture was stirred at -78°C for 1 h. Then, at -78°C, a solution of 1,2-dibromo-1,1,2,2-tetrachloroethane (1.07 g, 3.28 mmol) in tetrahydrofuran (7.50 mL) was added dropwise. The mixture was gradually warmed to room temperature and stirred at room temperature for an additional 1 hour. The reaction was quenched with aqueous NH4Cl solution, and the mixture was extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (gradient: petroleum ether containing 0% to 40% EtOAc) to give 669 mg (62% yield) of the title compound as a pink solid. LC-MS: (ESI, m / z): [M+H] + = 490.

[0632] Intermediate 4: (8R,11S,11aS,12S)-2-(5-(bis(4-methoxybenzyl)amino)-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl)-4-bromo-3-fluoro-12-methyl-5-oxo-8,9,10,11,11a,12-hexahydro-5H,7H-8,11-bridged iminoazapyro[2,1-c]pyrido[3,2-f][1,4]oxazapyro-14-carboxylic acid tert-butyl ester

[0633]

[0634] Step 1: (8R,11S,11aS,12S)-2-(5-(bis(4-methoxybenzyl)amino)-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl)-3-fluoro-12-methyl-5-oxo-8,9,10,11,11a,12-hexahydro-5H,7H-8,11-bridged iminoazapyro[2,1-c]pyrido[3,2-f][1,4]oxazapyro-14-carboxylic acid tert-butyl ester

[0635]

[0636] Under nitrogen atmosphere, (8R,11S,11aS,12S)-2-chloro-3-fluoro-12-methyl-5-oxo-8,9,10,11,11a,12-hexahydro-5H,7H-8,11-bridged iminoazapyro[2,1-c]pyrido[3,2-f][1,4]oxazapyro-14-carboxylic acid tert-butyl ester (409 mg, 0.990 mmol, intermediate 3, step 2), (5-(bis(4-methoxybenzyl)amino)-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl)boronic acid (948 mg, 1.99 mmol, intermediate 2), CataCXium® A Pd G3 (145 mg, 0.200 mmol) and K3PO4 (1.66 mL, 1.5 M, in water) were reacted in tetrahydrofuran (8.30 mL, 1.5 M, in water) to form tert-butyl ester (409 mg, 0.990 mmol, intermediate 3, step 2), bis(4-methoxybenzyl)amino)-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl)boronic acid (948 mg, 1.99 mmol, intermediate 2), CataCXium® A Pd G3 (145 mg, 0.200 mmol), and K3PO4 (1.66 mL, 1.5 M, in water) to form tert-butyl ester (8.30 mL, 1.5 M, in water). The solution in mL was stirred at 60 °C for 1 h. The solution was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (gradient: petroleum ether containing 0% to 55% EtOAc) to give 698 mg (87% yield) of the title compound as a pale yellow solid. LC-MS: (ESI, m / z): [M+H] + = 809.

[0637] Step 2: (8R,11S,11aS,12S)-2-(5-(bis(4-methoxybenzyl)amino)-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl)-4-bromo-3-fluoro-12-methyl-5-oxo-8,9,10,11,11a,12-hexahydro-5H,7H-8,11-bridged iminoazapyro[2,1-c]pyrido[3,2-f][1,4]oxazapyro-14-carboxylic acid tert-butyl ester (intermediate) (4) and (8R,11S,11aS,12S)-2-(5-(bis(4-methoxybenzyl)amino)-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl)-3-fluoro-4,12-dimethyl-5-oxo-8,9,10,11,11a,12-hexahydro-5H,7H-8,11-bridged iminoazapyro[2,1-c]pyrido[3,2-f][1,4]oxazapyro-14-carboxylic acid tert-butyl ester (byproduct)

[0638]

[0639] Under nitrogen atmosphere, at -78°C, MeLi (0.770 mL, 1.6 M, in diethyl ether) was added to a solution of (8R,11S,11aS,12S)-2-(5-(bis(4-methoxybenzyl)amino)-4-fluoro-3-methyl-2-(trifluoromethyl)phenyl)-3-fluoro-12-methyl-5-oxo-8,9,10,11,11a,12-hexahydro-5H,7H-8,11-bridged iminoazapyro[2,1-c]pyrido[3,2-f][1,4]oxazapyro-14-carboxylic acid tert-butyl ester (500 mg, 0.620 mmol) in tetrahydrofuran (10.0 mL), and the solution was stirred at -78°C for 1 h. Then, a solution of 1,2-dibromo-1,1,2,2-tetrachloroethane in tetrahydrofuran (2.00 mL) was added dropwise at -78 °C. The mixture was warmed to room temperature and stirred for 1 hour. The reaction was quenched with aqueous NH4Cl and extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (gradient: petroleum ether containing 0% to 50% EtOAc) to give 324 mg (59% yield) of the title compound as a yellow solid (containing 12% byproducts), LC-MS: (ESI, m / z): [M+H] + = 887. The mixture can be used for the synthesis of analogues without further purification.

[0640] Intermediate 5: (1R,2S,5S)-2-(hydroxymethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0641]

[0642] Intermediate 5 was prepared as described in WO2023 / 225302A1, the entire disclosure of which is incorporated herein by reference (see Intermediate 3 in WO2023 / 225302A1).

[0643] Intermediate 6: (1R,2S,5S)-2-((R)-2,2,2-trifluoro-1-hydroxyethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0644]

[0645] Intermediate 6 was prepared as described in WO2023 / 225302A1, the entire disclosure of which is incorporated herein by reference (see Intermediate 163 in WO2023 / 225302A1).

[0646] Intermediate 7: (8R,11S,11aS)-2-chloro-12-ethyl-3-fluoro-5-oxo-8,9,10,11,11a,12-hexahydro-5H,7H-8,11-bridged iminoazapyro[2,1-c]pyrido[3,2-f][1,4]oxazapyro-14-carboxylic acid tert-butyl ester (single unknown stereoisomer)

[0647]

[0648] Step 1: (1S,2S,5R)-2-(1-hydroxypropyl)-3,8-diazabicyclo[3.2.1]octane-3,8-dicarboxylic acid 3-benzyl 8-(tert-butyl) ester

[0649]

[0650] Under nitrogen atmosphere and at -78°C, EtMgBr (3 M, in Et2O, 14 mL, 42 mmol) was added to a solution of (1S,2S,5R)-2-formyl-3,8-diazabicyclo[3.2.1]octane-3,8-dicarboxylic acid 3-benzyl 8-(tert-butyl) ester (3.01 g, 8.04 mmol) (intermediate 6, step 2, faster peak) in tetrahydrofuran (45 mL). The solution was then incubated at -78°C. Stir for 1.5 h. Then, incubate the reaction at -78°C with NH4Cl. The reaction mixture was quenched with an aqueous solution and gradually warmed to room temperature. The reaction solution was extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by rapid silica gel chromatography (gradient: 0% to 17% EtOAc / petroleum ether) to give 2.02 g (62% yield) of the title compound (only one isomer was obtained) as a colorless oil. LC-MS: (ESI, m / z): [M+H] + = 405.

[0651] Step 2: (1S,2S,5R)-2-(1-hydroxypropyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0652]

[0653] A solution of (1S,2S,5R)-2-(1-hydroxypropyl)-3,8-diazabicyclo[3.2.1]octane-3,8-dicarboxylic acid 3-benzyl 8-(tert-butyl) ester (2.02 g, 4.99 mmol) and Pd / C (10%, 551 mg) in methanol (50 mL) was stirred at room temperature for 1.5 h. Pd / C was then removed by filtration. The filtrate was concentrated under vacuum to give 1.12 g (crude) of the title compound as a colorless oil. LC-MS: (ESI, m / z): [M+H] + = 271.

[0654] Step 3: 2-(1-((1S,2S,5R)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]oct-2-yl)propoxy)-6-chloro-5-fluoronicotinic acid

[0655]

[0656] Under nitrogen atmosphere and at 0°C, NaH (60%, in mineral oil, 551 mg) was added to a solution of (1S,2S,5R)-2-(1-hydroxypropyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (600 mg, 2.22 mmol) in tetrahydrofuran (20 mL), and the solution was stirred at room temperature. 0.5 hours. Then, at 0°C, 2,6-dichloro-5-fluoronicotinic acid (743 mg, 3.54 mg) was added to the resulting solution. mmol). The solution was stirred at room temperature for 5 h. The reaction was quenched with aqueous NH4Cl and extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by C18 column chromatography (solvent gradient: water containing 0% to 50% ACN (0.1% FA)) to give 410 mg (42% yield) of the title compound as a white solid. LC-MS: (ESI, m / z): [M+H] + = 444.

[0657] Step 4: (8R,11S,11aS)-2-chloro-12-ethyl-3-fluoro-5-oxo-8,9,10,11,11a,12-hexahydro-5H,7H-8,11-bridged iminoazapyro[2,1-c]pyrido[3,2-f][1,4]oxazapyro-14-carboxylic acid tert-butyl ester

[0658]

[0659] A solution of 2-(1-((1S,2S,5R)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]oct-2-yl)propoxy)-6-chloro-5-fluoronicotinic acid (360 mg, 0.811 mmol), HATU (617 mg, 1.62 mmol), and DIPEA (630 mg, 4.88 mmol) in N,N-dimethylacetamide (16 mL) was stirred at room temperature for 16 h. The reaction mixture was then diluted with brine and extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (gradient: 0% to 18% EtOAc / petroleum ether) to give 240 mg (70% yield) of the title compound as a white solid. LC-MS: (ESI, m / z): [M+H] + = 426.

[0660] Intermediate 8: (8R,11S,11aS)-2-chloro-12-ethyl-3-fluoro-5-oxo-8,9,10,11,11a,12-hexahydro-5H,7H-8,11-bridged iminoazapyro[2,1-c]pyrido[3,2-f][1,4]oxazapyro-14-carboxylic acid tert-butyl ester (Intermediate 7, single unknown stereoisomer)

[0661]

[0662] Step 1: (1S,2S,5R)-2-propionyl-3,8-diazabicyclo[3.2.1]octane-3,8-dicarboxylic acid 3-benzyl-8-(tert-butyl) ester

[0663]

[0664] Under nitrogen atmosphere, at -78°C, DMSO (1.22 g, 15.6 mmol) was slowly added dropwise to a solution of oxaloyl chloride (1.17 g, 9.2 mmol) in dichloromethane (20 mL). The solution in the solution. At -78℃ After stirring for 15 min, (1S,2S,5R)-2-(1-hydroxypropyl)-3,8-diazabicyclo[3.2.1]octane-3,8-dicarboxylic acid 3-benzyl was added dropwise at -78℃. A solution of 8-(tert-butyl) ester (1.51 g, 3.73 mmol, intermediate 7, step 1) in dichloromethane (15 mL). At -78°C After stirring for 15 min, Et3N (2.42 g, 24.0 mmol) was added. The resulting solution was then warmed to room temperature and stirred for 1 h. The reaction was quenched with water and extracted with DCM. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (gradient: 0% to 20% EtOAc / petroleum ether) to give 1.24 g (83% yield) of the title compound as a colorless oil. LC-MS: (ESI, m / z): [M+H] + = 403.

[0665] Step 2: (6R,9S,9aS)-1-ethyl-3-oxohexahydro-1H,3H-6,9-bridged iminooxazolo[3,4-a]azinon-10-carboxylic acid tert-butyl ester

[0666]

[0667] NaBH4 (0.37 g, 9.74 mmol) was added to a solution of (1S,2S,5R)-2-propionyl-3,8-diazabicyclo[3.2.1]octane-3,8-dicarboxylic acid 3-benzyl 8-(tert-butyl) ester (1.24 g, 3.08 mmol) in methanol (13 mL), and the mixture was stirred at room temperature for 0.5 h. The solution was then incubated at 60 °C. Stir for 2 h. Concentrate the solution under vacuum. Dilute the residue with brine and extract with EtOAc. The combined organic layers are dried over anhydrous sodium sulfate and concentrated under vacuum. Purify the residue by silica gel rapid chromatography (gradient: 0% to 35% EtOAc / petroleum ether) to give 820 mg (90% yield) of the title compound as a colorless oil. LC-MS: (ESI, m / z): [M+H] + = 297.

[0668] Step 3: (1S,2S,5R)-2-(1-hydroxypropyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0669]

[0670] A solution of NaOH (2.41 g, 60.3 mmol) in water (4 mL) was added to a solution of (6R,9S,9aS)-1-ethyl-3-oxohexahydro-1H,3H-6,9-bridged iminooxazolo[3,4-a]azinon-10-carboxylic acid tert-butyl ester (820 mg, 2.77 mmol) in ethanol (10 mL). The solution was then incubated at 80 °C. Stir for 6 h. Concentrate the solution under vacuum. Then dilute the residue with DCM. Remove the solid by filtration and concentrate the filtrate under vacuum to give 700 mg (crude) of the title compound as a brown oil. LC-MS: (ESI, m / z): [M+H] + = 271. The crude product was used in the next step without further purification.

[0671] Step 4: 2-(1-((1S,2S,5R)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]oct-2-yl)propoxy)-6-chloro-5-fluoronicotinic acid

[0672]

[0673] Under nitrogen atmosphere and at 0°C, a solution of (1S,2S,5R)-2-(1-hydroxypropyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (320 mg, 1.18 mmol) in tetrahydrofuran (15 mL) was added. NaH (60%, in mineral oil, 291 mg), and the solution was stirred at room temperature. 0.5 h. Then 2,6-dichloro-5-fluoronicotinic acid (403 mg, 1.92 mmol) was added at 0 °C. The solution was stirred at room temperature for 5 h. The reaction was quenched with aqueous NH4Cl and extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by reversed-phase chromatography on a C18 column (solvent gradient: water containing 0% to 40% ACN (0.1% FA)) to give 240 mg (46% yield) of the title compound as a white solid. LC-MS: (ESI, m / z): [M+H] + = 444.

[0674] Step 5: (8R,11S,11aS)-2-chloro-12-ethyl-3-fluoro-5-oxo-8,9,10,11,11a,12-hexahydro-5H,7H-8,11-bridged iminoazapyro[2,1-c]pyrido[3,2-f][1,4]oxazapyro-14-carboxylic acid tert-butyl ester

[0675]

[0676] A solution of 2-(1-((1S,2S,5R)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]oct-2-yl)propoxy)-6-chloro-5-fluoronicotinic acid (240 mg, 0.541 mmol), HATU (410 mg, 1.08 mmol), and DIPEA (437 mg, 3.39 mmol) in N,N-dimethylacetamide (6 mL) was stirred at room temperature for 6 h. Brine was then added to the reaction mixture, and the mixture was extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by rapid silica gel chromatography (gradient: 0% to 18% EtOAc / petroleum ether) to obtain a mixture of two diastereomers. The diastereomers were separated by preparative chiral HPLC (column: CHIRALPAK® IF, 2*25cm, 5 μm; mobile phase A: HEX (0.5% 2M NH3-MeOH), mobile phase B: ETOH; flow rate: 20 mL / min; gradient: isocratic 30; wavelength: 220 / 254 nm; RT1 (min): 6.159; RT2 (min): 7.505; sample solvent: EtOH; injection volume: 0.3 mL; runs: 13) to obtain 105 mg (faster peak, intermediate 7) and 27 mg (slower peak, intermediate 8) of the title compound, which were white solids. LC-MS: (ESI, m / z): [M+H] + = 426.

[0677] Intermediate 9: (1R,5S)-2-(2-hydroxypropyl-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0678]

[0679] Step 1: (1R,5S)-8-benzyl-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester

[0680]

[0681] Under nitrogen atmosphere and at 0°C, (1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester (10.0 g, 47.1 mmol) and K2CO3 (13.1 g, 94.9 mmol) were reacted. A solution of N,N-dimethylformamide (70 mL) was supplemented with (bromomethyl)benzene (12.3 g, 71.9 mmol). The solution was stirred at room temperature for 1.5 h. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by rapid silica gel chromatography (gradient: 0% to 20% EtOAc / petroleum ether) to give the title compound (12.8 g, 90% yield) as a pale yellow oil. LC-MS: (ESI, m / z): [M+H] + = 303.

[0682] Step 2: (1R,5S)-8-benzyl-3,8-diazabicyclo[3.2.1]octane-2,3-dicarboxylic acid 3-(tert-butyl)2-isopropyl ester

[0683]

[0684] Under nitrogen atmosphere and at -78°C, N2 was added to a solution of (1R,5S)-8-benzyl-3,8-diazabicyclo[3.2.1]octane-3-carboxylic acid tert-butyl ester (10.0 g, 33.1 mmol) in diethyl ether (150 mL). 1 N 1 N 2 N 2 -Tetramethylethane-1,2-diamine (7.69 g, 66.2 mmol) and s-BuLi (51.2 mL, 66.6 mmol, 1.3 M, in cyclohexane). The solution was incubated at -78 °C. Stir 1 h. Then, isopropyl chloroformate (8.05 g, 65.7 mmol) was added to the resulting solution at -78 °C. The resulting solution was then gradually warmed to room temperature and stirred for an additional 1.5 h. The reaction was quenched with aqueous NH4Cl and extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (gradient: 0% to 15% EtOAc / petroleum ether) to give 8.93 g (70% yield) of the title compound as a colorless oil. LC-MS: (ESI, m / z): [M+H] + = 389.

[0685] Step 3: (6S,9R)-10-benzyl-1,1-dimethylhexahydro-1H,3H-6,9-bridged iminooxazolo[3,4-a]azopon-3-one (two isomers)

[0686]

[0687] Under nitrogen atmosphere and at -20°C, a solution of (1R,5S)-8-benzyl-3,8-diazabicyclo[3.2.1]octane-2,3-dicarboxylic acid 3-(tert-butyl)-2-isopropyl ester (8.93 g, 23.0 mmol) in tetrahydrofuran (150 mL) was added. MeMgBr (1 M, in THF, 80 mL). The solution was gradually warmed to room temperature and stirred for 16 hours. The reaction was quenched with aqueous NH4Cl and extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by rapid silica gel chromatography (gradient: 0% to 40% EtOAc / petroleum ether) to obtain a mixture of two diastereomers. The mixture was separated by a preparative chiral SFC (column: (S, S)-Whelk-O 1 5 μm Kromasil, 3*25 cm, 5 μm; mobile phase A: CO2; mobile phase B: IPA; flow rate: 100 mL / min; gradient (B%): isocratic 30% B; back pressure (bar): 100; wavelength: 220 nm; RT1 (min): 6.2; RT2 (min): 9; sample solvent: MeOH; injection volume: 3 mL) to obtain 2.37 g (faster peak) and 2.33 g (slower peak), which were white solids. LC-MS: (ESI, m / z): [M+H] + = 287.

[0688] Step 4: (6S,9R)-1,1-dimethylhexahydro-1H,3H-6,9-bridged iminooxazolo[3,4-a]azopon-3-one

[0689]

[0690] A solution of (6S,9R)-10-benzyl-1,1-dimethylhexahydro-1H,3H-6,9-bridged iminooxazolo[3,4-a]azopon-3-one (2.31 g, 8.07 mmol) (the faster peak from the previous step) and Pd / C (10%, 652 mg) in methanol (80 mL) was stirred at room temperature for 2 h. Pd / C was then removed by filtration. The filtrate was concentrated under vacuum to give 1.52 g (crude) of the title compound as a white solid. LC-MS: (ESI, m / z): [M+H] + =197.

[0691] Step 5: (6S,9R)-1,1-dimethyl-3-oxohexahydro-1H,3H-6,9-bridged iminooxazolo[3,4-a]azinon-10-carboxylic acid tert-butyl ester

[0692]

[0693] A solution of (6S,9R)-1,1-dimethylhexahydro-1H,3H-6,9-bridged iminooxazolo[3,4-a]azopon-3-one (1.51 g, 7.69 mmol), Boc₂O (3.34 g, 15.3 mmol), and DIPEA (3.97 g, 30.8 mmol) in dichloromethane (40 mL) was stirred at room temperature for 2 h. The solution was diluted with brine and extracted with DCM. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by rapid silica gel chromatography (gradient: 0% to 33% EtOAc / petroleum ether) to give 2.04 g (90% yield) of the title compound as a white solid. LC-MS: (ESI, m / z): [M+H] + = 297.

[0694] Step 6: (1R,5S)-2-(2-hydroxypropyl-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0695]

[0696] A solution of (6S,9R)-1,1-dimethyl-3-oxohexahydro-1H,3H-6,9-bridged iminooxazolo[3,4-a]azinon-10-carboxylic acid tert-butyl ester (1.01 g, 3.41 mmol) and NaOH (2.73 g, 68.3 mmol) in ethanol (12 mL) and water (6 mL) was prepared at 80 °C. Stir for 6 h. Concentrate the solution under vacuum. Dilute the residue with DCM. Remove the solid by filtration, and concentrate the filtrate under vacuum to give 892 mg (crude) of the title compound as a yellow solid. LC-MS: (ESI, m / z): [M+H] + = 271. The crude product was used in the next step without further purification.

[0697] Intermediate 10: (1R,5S)-2-(2-hydroxypropyl-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (enantiomer of intermediate 9)

[0698]

[0699] Similar to the method described for intermediate 9, 920 mg of the title compound was obtained from the slower peak of 2.33 g of intermediate 9 (step 3).

[0700] Intermediate 11: (1S,4S)-6-(2,2,2-trifluoro-1-hydroxyethyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester

[0701]

[0702] Step 1: (2S,4R)-4-hydroxy-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0703]

[0704] Under nitrogen atmosphere and at 0°C, 1-(tert-butyl)-2-methyl ester of (2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylic acid (30.1 g, 123 mmol) was subjected to... A solution of LiAlH4 (58.9 mL, 2.5 M, in THF) was added to a THF solution (500 mL). The resulting solution was stirred at room temperature for 2 h. The reaction was quenched with Na2SO4·10H2O. After filtration, the filtrate was concentrated under reduced pressure to give 15.6 g (crude) of the title compound as a yellow oil. LC-MS: (ESI, m / z): [M+H] + =218. The crude product is used in the next step without further purification.

[0705] Step 2: (2S,4R)-2-(((tert-butyldimethylsilyl)oxy)methyl)-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester

[0706]

[0707] Under nitrogen atmosphere, 2,6-dimethylpyridine (20.1 g, 187 mmol) was added to a solution of (2S,4R)-4-hydroxy-2-(hydroxymethyl)pyrrolidine-1-carboxylic acid tert-butyl ester (40.5 g, 186 mmol) in DCM (300 mL) at room temperature. The reaction system was then cooled to... The reaction was carried out at -78°C with the addition of TBDMSOTf (39.4 g, 149 mmol). Stir for 1 h. Dilute the reaction mixture with water and extract with DCM. Wash the combined organic layers with brine, dry over anhydrous sodium sulfate, and concentrate under vacuum. Purify the residue by silica gel rapid chromatography (gradient: petroleum ether containing 0% to 40% EtOAc) to give 18.9 g (31% yield) of the title compound as a colorless oil. LC-MS: (ESI, m / z): [M+H] + =332.

[0708] Step 3: (2S,4R)-2-(((tert-butyldimethylsilyl)oxy)methyl)-4-(toluenesulfonyloxy)pyrrolidine-1-carboxylic acid tert-butyl ester

[0709]

[0710] TsCl (56.1 g, 295 mmol) was added to a solution of (2S,4R)-2-(((tert-butyldimethylsilyl)oxy)methyl)-4-hydroxypyrrolidine-1-carboxylic acid tert-butyl ester (32.6 g, 98.3 mmol) in pyridine (400 mL) at room temperature, and the mixture was stirred at room temperature for 16 h. The resulting mixture was diluted with ethyl acetate and washed with water. The separated organic layer was concentrated under vacuum. The residue was purified by silica gel rapid chromatography (gradient: petroleum ether containing 0% to 50% EtOAc) to give 36.2 g (76% yield) of the title compound as a yellow oil. LC-MS: (ESI, m / z): [M+H] + = 486.

[0711] Step 4: (2S,4R)-2-(hydroxymethyl)-4-(toluenesulfonyloxy)pyrrolidine-1-carboxylic acid tert-butyl ester

[0712]

[0713] TBAF (212 mL, 1 M, in THF) was added to a solution of (2S,4R)-2-(((tert-butyldimethylsilyl)oxy)methyl)-4-(toluenesulfonyloxy)pyrrolidine-1-carboxylic acid tert-butyl ester (36.2 g, 74.5 mmol) in THF (300 mL) at room temperature, and the mixture was stirred at room temperature for 3 h. The resulting reaction mixture was diluted with EtOAc and washed with water. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by rapid silica gel chromatography (gradient: petroleum ether containing 0% to 80% EtOAc) to give 15.1 g (55% yield) of the title compound as a white solid. LC-MS: (ESI, m / z): [M+H] + = 372.

[0714] Step 5: (2S,4R)-2-formyl-4-(toluenesulfonyloxy)pyrrolidine-1-tert-butyl carboxylate

[0715]

[0716] Under nitrogen atmosphere, at -70°C, a solution of DMSO (16.9 g, 216 mmol) in DCM (500 mL) was added. (COCl)₂ (13.8 g, 10⁸ mmol). The resulting solution was incubated at -70°C. Stir for 0.5 h. Then add (2S,4R)-2-(hydroxymethyl)-4-(toluenesulfonyloxy)pyrrolidine-1-carboxylic acid tert-butyl ester (20.2 g, 54.3 mmol), and stir the mixture at -70 °C. 1 h. Then Et3N (33.1 g, 328 mmol) was added. The reaction system was gradually warmed to room temperature, and the mixture was stirred for an additional 1 h. The solution was diluted with water and extracted with DCM. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum to give 18.2 g (crude) of the title compound as a yellow oil. LC-MS: (ESI, m / z): [M+H] + = 370.

[0717] Step 6: (2S,4R)-2-((S)-(benzylamino)(cyano)methyl)-4-(toluenesulfonyloxy)pyrrolidine-1-carboxylic acid tert-butyl ester

[0718]

[0719] Diethyl cyanophosphate (14.6 g, 89.5 mmol) and BnNH2 (19.9 g, 186 mmol) were added to a solution of (2S,4R)-2-formyl-4-(toluenesulfonyloxy)pyrrolidine-1-carboxylic acid tert-butyl ester (27.6 g, 74.7 mmol) in THF (300 mL). The resulting solution was stirred at room temperature for 16 h. The solution was diluted with water and extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (gradient: petroleum ether containing 0% to 50% EtOAc) to give 22.5 g (62% yield) of the title compound as a white solid. LC-MS: (ESI, m / z): [M+H] + = 486.

[0720] Step 7: (1S,4S)-5-benzyl-6-cyano-2,5-diazabicyclo[2.2.1]heptane-2-tert-butyl carboxylate

[0721]

[0722] A solution of (2S,4R)-2-((S)-(benzylamino)(cyano)methyl)-4-(toluenesulfonyloxy)pyrrolidine-1-carboxylic acid tert-butyl ester (22.3 g, 45.9 mmol) and DIPEA (29.5 g, 228 mmol) in DCE (300 mL) was stirred at 85 °C for 18 h. The solvent was concentrated under vacuum. The residue was purified by rapid silica gel chromatography (gradient: petroleum ether containing 0% to 40% EtOAc) to give a faster peak of 3.71 g (26% yield) and a slower peak of 6.21 g (43% yield), which was a yellow oil. LC-MS: (ESI, m / z): [M+H] + = 314.

[0723] Faster peaks: 1H NMR (500 MHz, DMSO- d6, ppm) δ 7.44 – 7.21 (m, 5H), 4.40(d, J = 16.3 Hz, 1H), 3.88 (d, J = 13.5 Hz, 1H), 3.74 (dd, J = 13.5, 4.4 Hz, 1H), 3.67 – 3.58 (m, 2H), 3.48 (d, J = 9.5 Hz, 1H), 3.10 (dd, J = 16.1, 10.5Hz, 1H), 1.97 (d, J = 10.1 Hz, 1H), 1.89 (dd, J = 15.9, 10.4 Hz, 1H), 1.44(s, 9H).

[0724] Slower peaks: 1 H NMR (500 MHz, DMSO- d6, ppm) δ 7.44 – 7.23 (m, 5H), 4.52(d, J = 42.4 Hz, 1H), 3.88 – 3.79 (m, 2H), 3.69 (d, J = 13.5 Hz, 1H), 3.51(s, 1H), 3.30 – 3.13 (m, 2H), 1.88 (d, J = 10.4 Hz, 1H), 1.85 – 1.70 (m, 1H), 1.41 (s, 9H).

[0725] Step 8: (1S,4S)-5-benzyl-2,5-diazabicyclo[2.2.1]heptane-2,6-dicarboxylic acid 2-(tert-butyl)-6-methyl ester

[0726]

[0727] MeONa (5.66 g, 104 mmol) was added to a solution of (1S,4S)-5-benzyl-6-cyano-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (6.21 g, 19.8 mmol) (the slower peak from the previous step) in MeOH (100 mL), and the solution was stirred at 60 °C for 6 h. Then, HCl (62 mL, 3 N) was added at 0 °C, and the mixture was stirred at 0 °C for 2 h. The reaction was quenched with an aqueous solution of NaHCO3. The solution was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by rapid silica gel chromatography (gradient: petroleum ether containing 0% to 50% EtOAc) to give 3.32 g (48% yield) of the title compound as a yellow oil. LC-MS: (ESI, m / z): [M+H]+ = 347.

[0728] Step 9: (1S,4S)-5-benzyl-6-(hydroxymethyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester

[0729]

[0730] Under nitrogen atmosphere and at 0°C, (1S,4S)-5-benzyl-2,5-diazabicyclo[2.2.1]heptane-2,6-dicarboxylic acid 2-(tert-butyl)-6-methyl ester (3.31 g, 9.55 mmol) was reacted with THF. Add 5.2 mL of LiAlH4 (2.5 M, in THF) to a 100 mL solution. Incubate the resulting solution at 0 °C. Stir for 1 h. Quench the reaction with Na₂SO₄·10H₂O. Filter and concentrate the filtrate under vacuum. Purify the residue by silica gel rapid chromatography (gradient: petroleum ether containing 0% to 90% EtOAc) to give 2.89 g (crude) of the title compound as a colorless oil. LC-MS: (ESI, m / z): [M+H] + = 319. The crude product was used in the next step without further purification.

[0731] Step 10: (1S,4S)-5-benzyl-6-formyl-2,5-diazabicyclo[2.2.1]heptane-2-tert-butyl carboxylate

[0732]

[0733] Under nitrogen atmosphere, at -70°C, a solution of DMSO (2.83 g, 36.2 mmol) in DCM (100 mL) was added. (COCl)₂ (2.31 g, 18.2 mmol). The resulting solution was incubated at -70°C. The mixture was stirred for 0.5 h. Then (1S,4S)-5-benzyl-6-(hydroxymethyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (2.89 g, 9.08 mmol) was added, and the mixture was stirred at -70 °C for 1 h. Then Et3N (5.49 g, 54.3 mmol) was added, and the mixture was stirred at room temperature for 1 h. The solution was diluted with water and extracted with DCM. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum to give 2.81 g (crude) of the title compound as a white solid. LC-MS: (ESI, m / z): [M+H] + = 317. The crude product is used in the next step without further purification.

[0734] Step 11: (1S,4S)-5-benzyl-6-(2,2,2-trifluoro-1-((trimethylsilyl)oxy)ethyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester

[0735]

[0736] Under nitrogen atmosphere, LiOAc (588 mg, 8.91 mmol) and trimethyl(trifluoromethyl)silane (2.52 g, 17.7 mmol) were added to a solution of (1S,4S)-5-benzyl-6-formyl-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (2.81 g, 8.88 mmol) in DMF (80 mL). The solution was stirred at room temperature for 1.5 h. The reaction system was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give 3.81 g (crude) of the title compound as a yellow oil. LC-MS: (ESI, m / z): [M+H] + =459. The crude product was used in the next step without further purification.

[0737] Step 12: (1S,4S)-5-benzyl-6-(2,2,2-trifluoro-1-hydroxyethyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester

[0738]

[0739] TBAF (5.7 mL, 1 M, in THF) was added to a solution of (1S,4S)-5-benzyl-6-(2,2,2-trifluoro-1-((trimethylsilyl)oxy)ethyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (3.81 g, 8.31 mmol) in THF (100 mL), and the mixture was stirred at room temperature for 1 h. The solvent was concentrated under vacuum. The residue was purified by silica gel rapid chromatography (gradient: petroleum ether containing 0% to 50% EtOAc) to give a faster peak of 1.31 g (41% yield) and a slower peak of 1.25 g (39% yield) as a yellow solid. LC-MS: (ESI, m / z): [M+H] + = 387.

[0740] Faster peaks: 1 H NMR (500 MHz, DMSO- d6, ppm) δ 7.32 (m, 4H), 7.23 (t, J =6.6 Hz, 1H), 6.10 (dd, J = 29.5, 6.3 Hz, 1H), 4.53 (s, 1H), 3.57 (t, J = 12.3Hz, 3H), 3.15 (d, J = 25.3 Hz, 2H), 3.02 – 2.70 (m, 2H), 1.88 (t, J = 11.8Hz, 1H), 1.55 – 1.49 (m, 1H), 1.41 (s, 9H).

[0741] Slower peaks: 1 H NMR (500 MHz, DMSO- d6, ppm) 7.46 – 7.21 (m, 5H), 6.33 –5.80 (m, 1H), 4.32 (d, J = 25.4 Hz, 1H), 3.85- 3.80 (m, 2H), 3.58 (dd, J =19.1, 13.2 Hz, 1H), 3.28 – 3.04 (m, 2H), 2.93 (dd, J = 35.7, 9.0 Hz, 2H), 1.95 (d, J = 10.1 Hz, 1H), 1.56 (d, J = 10.2 Hz, 1H), 1.39 (s, 9H).

[0742] Step 13: (1S,4S)-6-(2,2,2-trifluoro-1-hydroxyethyl)-2,5-diazabicyclo[2.2.1]heptane-2-tert-butyl carboxylate

[0743]

[0744] Under H2 (4 atm), Pd(OH)2 / C (1.25 g) was added to a solution of (1S,4S)-5-benzyl-6-(2,2,2-trifluoro-1-hydroxyethyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (1.25 g, 3.23 mmol) (the faster peak from the previous step) in MeOH (10 mL), and the solution was stirred at room temperature for 6 h. After filtration, the filtrate was concentrated under reduced pressure to give 921 mg (crude) of the title compound as a yellow oil. LC-MS: (ESI, m / z): [M+H] + = 297. The crude product was used in the next step without further purification.

[0745] Intermediate 12: (1S,4S)-6-(2,2,2-trifluoro-1-hydroxyethyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (another isomer of intermediate 11)

[0746]

[0747] Similar to the method described above, this heterogeneous system is synthesized from the slower peaks of step 12 and intermediate 11.

[0748] Intermediate 13: 2-(3-hydroxyoxetane-3-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0749]

[0750] Step 1: 10'-Benzylhexahydro-3'H-spiro[oxetane-3,1'-[6,9]bridged iminooxazolo[3,4-a]azopon]-3'-one

[0751]

[0752] Under nitrogen atmosphere, s-BuLi (13.3 mL, 2.5 M, in hexane) was added to a solution of tert-butyl 8-benzyl-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (5.00 g, 16.5 mmol) and TMEDA (3.84 g, 33.1 mmol) in diethyl ether (70 mL) at -78 °C, and the mixture was stirred at -78 °C for 1 h. Then, oxetane (2.38 g, 33.1 mmol) was added at -78 °C, and the mixture was stirred at -78 °C for 10 min. The solution was warmed to room temperature and stirred overnight. The reaction was quenched with aqueous NH4Cl solution and extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (gradient: petroleum ether containing 0% to 20% EtOAc) to give 1.41 g of the mixture product, which was a yellow oil. The mixture was purified by chiral preparative HPLC under the following conditions (column: CHIRALPAK® ID, 3*25 cm, 5 μm; mobile phase A: CO2, mobile phase B: MEOH; flow rate: 100 mL / min; gradient (B%): isocratic 30% B; back pressure (bar): 100; wavelength: 220 nm; R T1 (min): 4.3; R T2 (min): 6.5; Sample solvent: MeOH) Separation was performed to obtain a faster peak at 625 mg (yield 13%) and a slower peak at 637 mg (yield 13%), which were yellow oily substances. LC-MS: (ESI, m / z): [M+H] + = 301.

[0753] Faster peaks: 1 H NMR (300 MHz, DMSO-d6, ppm): δ 7.52 – 7.17 (m, 5H), 4.85 –4.55 (m, 4H), 4.22 – 4.09 (m, 1H), 3.63 – 3.48 (m, 3H), 3.36 (d, 1H), 3.16 –3.06 (m, 1H), 3.01 (d, J = 12.4, 2.3 Hz, 1H), 2.12 – 1.78 (m, 2H), 1.49 –1.28 (m, 1H), 1.11 – 0.93 (m, 1H).

[0754] Slower peaks: 1H NMR (300 MHz, DMSO-d6, ppm): δ 7.52 – 7.18 (m, 5H), 4.85 – 4.57 (m, 4H), 4.22 – 4.11 (m, 1H), 3.63 – 3.47 (m, 3H), 3.43 – 3.37 (m, 1H), 3.18 – 3.07 (m, 1H), 3.06 – 2.97 (m, 1H), 2.11 – 1.82 (m, 2H), 1.48 – 1.31(m, 1H), 1.11 – 0.92 (m, 1H).

[0755] Step 2: 3'-oxohexahydro-3'H-spiro[oxetane-3,1'-[6,9]bridged iminooxazolo[3,4-a]azinon]-10'-tert-butyl formate

[0756]

[0757] Under hydrogen (4 atm), Pd / C (288 mg) was added to a solution of 10'-benzylhexahydro-3'H-spiro[oxetane-3,1'-[6,9]bridged iminooxazolo[3,4-a]azopon]-3'-one (575 mg, 1.91 mmol) (the faster peak from the previous step) in MeOH (10 mL). The solution was stirred at room temperature for 2 h. Then Boc2O (581 mg, 2.67 mmol) was added, and the mixture was stirred at room temperature for another 2 h. After filtration, the solution was concentrated under vacuum to give 698 mg (crude) of the title compound as a yellow solid. LC-MS: (ESI, m / z): [M+H] + = 311. The crude product is used in the next step without further purification.

[0758] Step 3: 2-(3-hydroxyoxetane-3-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester

[0759]

[0760] NaOH (355 mg, 8.88 mmol) was added to a solution of 3'-oxohexahydro-3'H-spiro[oxetane-3,1'-[6,9]bridged iminooxazolo[3,4-a]azopon]-10'-carboxylic acid tert-butyl ester (688 mg, 2.22 mmol) in EtOH (7.5 mL) and water (2.5 mL). The solution was stirred at 80 °C for 2 h. The solution was cooled to room temperature and concentrated under vacuum. The solid was washed with DCM, and the organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to give 702 mg (crude) of the title compound as a white solid. LC-MS: (ESI, m / z): [M+H] + = 285. 1 ¹H NMR (400MHz, DMSO-d6, ppm): δ 5.89 (s, 1H), 4.70 – 4.54 (m, 1H), 4.51 – 4.24 (m, 3H), 4.08 – 3.84 (m, 2H), 2.92 (s, 1H), 2.80 (d, J = 12.6 Hz, 1H), 2.63 (d, J = 12.6 Hz, 1H), 2.28 (s, 1H), 2.02 (s, 1H), 1.74 (s, 2H), 1.61 (s, 1H), 1.42 (s, 9H). The crude product was used in the next step without further purification.

[0761] Intermediate 14: 2-(3-hydroxyoxetane-3-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (another isomer of intermediate 13)

[0762]

[0763] Similar to the method described above, this heterogeneous system is synthesized from intermediate 13 and the slower peak of step 1.

[0764] Intermediate 15: 5-(aminomethyl)-N,N-dimethylpyridinecarboxamide

[0765]

[0766] Step 1: 5-(((tert-butoxycarbonyl)amino)methyl)pyridinecarboxylic acid

[0767]

[0768] Di-tert-butyl dicarbonate (1.95 g, 8.94 mmol) was added to a solution of 5-(aminomethyl)pyridine-2-carboxylic acid (680 mg, 4.47 mmol) and DIPEA (2.89 g, 22.4 mmol) in dichloromethane (15 mL). The resulting mixture was incubated at 25 °C. Stir for 1 h. Partition the resulting solution between water and EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by C18 column chromatography (solvent gradient: water containing 0% to 60% acetonitrile (1% formic acid)) to give 350 mg (31% yield) of the title compound as a yellow solid. LC-MS: (ESI, m / z): [M+H] + = 253.

[0769] Step 2: N-[[6-(dimethylaminoformyl)-3-pyridyl]methyl]tert-butyl carbamate

[0770]

[0771] HATU (1.48 mg, 3.88 mmol) and N,N-dimethylamine hydrochloride (317 mg, 3.88 mmol) were added to a solution of 5-[(tert-butoxycarbonylamino)methyl]pyridine-2-carboxylic acid (490 mg, 1.94 mmol) and DIPEA (1.26 g, 9.71 mmol) in N,N-dimethylformamide (6 mL). The resulting mixture was incubated at 25 °C. Stir for 1 h. Partition the resulting solution between water and EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by C18 column chromatography (solvent gradient: water containing 0% to 80% ACN (0.05% NH4HCO3)) to give 170 mg (31% yield) of the title compound as a yellow solid. LC-MS: (ESI, m / z): [M+H] + = 280.

[0772] Step 3: 5-(aminomethyl)-N,N-dimethylpyridinecarboxamide TFA salt

[0773]

[0774] A solution of N-[[6-(dimethylaminoformyl)-3-pyridyl]methyl]carbamate tert-butyl ester (200 mg, 0.720 mmol) in 2,2,2-trifluoroacetic acid (1 mL) was stirred at room temperature for 20 min. The resulting mixture was diluted with CH₂Cl₂ (4 mL) and concentrated under reduced pressure to give 110 mg (crude) of the title compound as a yellow solid. LC-MS: (ESI, m / z): [M+H] + = 180. The crude product is used in the next step without further purification.

[0775] Intermediate 16: (1-Methyl-4-(trifluoromethyl)-1H-pyrazol-3-yl)methylamine

[0776]

[0777] Step 1: 1-Methyl-4-(trifluoromethyl)-1H-pyrazole-3-carboxamide

[0778]

[0779] HATU (940 mg, 2.47 mmol) and NH4Cl (265 mg, 4.95 mmol) were added to a solution of 1-methyl-4-(trifluoromethyl)pyrazole-3-carboxylic acid (240 mg, 1.24 mmol) and DIPEA (799 mg, 6.18 mmol) in N,N-dimethylformamide (5 mL). The resulting mixture was incubated at 25 °C. Stir for 1 h. Partition the resulting solution between water and EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by passing it through a C18 column (solvent gradient: water containing 0% to 80% ACN (0.05% NH4HCO3)) to give 220 mg (92% yield) of the title compound as a yellow solid. LC-MS: (ESI, m / z): [M+H] + =194.

[0780] Step 2: (1-Methyl-4-(trifluoromethyl)-1H-pyrazol-3-yl)methylamine

[0781]

[0782] Add dropwise to a solution of 1-methyl-4-(trifluoromethyl)pyrazole-3-carboxamide (270 mg, 1.40 mmol) in tetrahydrofuran (3 mL) at 0 °C. LiAlH4 (2.8 mL, 1 M, in THF), and the mixture was incubated at 60 °C. Stir for 2 hours. Transfer the reaction mixture to Na₂SO₄. . Quenched in 10H₂O and filtered through diatomaceous earth. The filtrate was concentrated under vacuum to give 210 mg (crude) of the title compound as a white solid. LC-MS (ESI, m / z): [M+H] + =180. The crude product is used in the next step without further purification.

[0783] Intermediate 17: (1-(difluoromethyl)-1H-pyrazol-3-yl)methylamine

[0784]

[0785] Step 1: 1-(difluoromethyl)-1H-pyrazole-3-carboxamide

[0786]

[0787] HATU (2.34 g, 6.17 mmol) and NH4Cl (660 mg, 12.3 mmol) were added to a solution of 1-(difluoromethyl)-1H-pyrazole-3-carboxylic acid (500 mg, 3.08 mmol) and DIPEA (1.99 g, 15.4 mmol) in N,N-dimethylformamide (13 mL). The resulting mixture was incubated at 25 °C. Stir for 1 h. Partition the resulting solution between water and EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by C18 column chromatography (solvent gradient: water containing 0% to 80% ACN (0.05% NH4HCO3)) to give 450 mg (91% yield) of the title compound as a yellow solid. LC-MS: (ESI, m / z): [M+H] + =162.

[0788] Step 2: (1-(difluoromethyl)-1H-pyrazole-3-yl)methylamine

[0789]

[0790] Add dropwise to a solution of 1-(difluoromethyl)pyrazole-3-carboxamide (300 mg, 1.86 mmol) in tetrahydrofuran (3 mL) at 0 °C. LiAlH4 (3.7 mL, 1 M, in THF), and the mixture was incubated at 60 °C. Stir for 2 hours. Then, use Na₂SO₄ to react the reaction mixture. . Quenched in 10H₂O and filtered through diatomaceous earth. The filtrate was concentrated under vacuum to give 180 mg (crude) of the title compound as a white solid. LC-MS (ESI, m / z): [M+H] + =148. The crude product was used in the next step without further purification.

[0791] Intermediate 18: (4-fluoro-1-methyl-1H-pyrazol-3-yl)methylamine

[0792]

[0793] Step 1: 4-Fluoro-1-methyl-1H-pyrazole-3-carboxamide

[0794]

[0795] HATU (1.05 g, 2.78 mmol) and NH4Cl (297 mg, 5.55 mmol) were added to a solution of 4-fluoro-1-methylpyrazol-3-carboxylic acid (200 mg, 1.39 mmol) and DIPEA (897 mg, 6.94 mmol) in N,N-dimethylformamide (5 mL). The resulting mixture was incubated at 25 °C. Stir for 2 h. Partition the resulting solution between water and EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by C18 column chromatography (solvent gradient: water containing 0% to 80% ACN (0.05% NH4HCO3)) to give 180 mg (91% yield) of the title compound as a yellow solid. LC-MS: (ESI, m / z): [M+H] + =144.

[0796] Step 2: (4-Fluoro-1-methyl-1H-pyrazole-3-yl)methylamine

[0797]

[0798] Add dropwise to a solution of 4-fluoro-1-methylpyrazole-3-carboxamide (390 mg, 2.72 mmol) in tetrahydrofuran (6 mL) at 0 °C. LiAlH4 (5.4 mL, 1 M, in THF), and the mixture was incubated at 60 °C. Stir for 2 h. Quench the reaction with Na₂SO₄·10H₂O and filter through diatomaceous earth. Concentrate the filtrate under vacuum to give 210 mg (crude) of the title compound as a white solid. LC-MS: (ESI, m / z): [M+H] + =130. The crude product is used in the next step without further purification.

[0799] Intermediate 19: (1-Cyclopropyl-1H-pyrazole-3-yl)methylamine

[0800]

[0801] Step 1: 1-Cyclopropyl-1H-pyrazole-3-carboxamide

[0802]

[0803] HATU (502 mg, 1.32 mmol) and NH4Cl (106 mg, 1.98 mmol) were added to a solution of 1-cyclopropyl-1H-pyrazole-3-carboxylic acid (100 mg, 0.66 mmol), DIPEA (129 mg, 3.29 mmol), and N,N-dimethylformamide (10 mL). The resulting mixture was stirred at room temperature for 2 h. The solution was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum to give 90.0 mg (crude) of the title compound as a brown solid. LC-MS: (ESI, m / z): [M+H] + = 152.

[0804] Step 2: (1-Cyclopropyl-1H-pyrazole-3-yl)methylamine

[0805]

[0806] 1-Cyclopropyl-1H-pyrazole-3-carboxamide (90.0 mg, 0.60 mmol) was dissolved in tetrahydrofuran (5 mL) at 0 °C. The solution was treated with LiAlH4 (1.20 mL, 1 M, in THF), and the mixture was incubated at 60 °C. Stir for 2 hours. Transfer the reaction mixture to Na₂SO₄. . Quenched in 10H₂O. After filtration, the filtrate was collected and concentrated under vacuum to give 68.0 mg (crude) of the title compound as a white solid. LC-MS: (ESI, m / z): [M+H] + = 138. The crude product was used in the next step without further purification.

[0807] Intermediate 20: (8R,11S,11aS,12S)-2-chloro-3-fluoro-12-methyl-4-(((1-methyl-1H-pyrazol-3-yl)methyl)amino)-5-oxo-8,9,10,11,11a,12-hexahydro-5H,7H-8,11-bridged iminoazapyro[2,1-c]pyrido[3,2-f][1,4]oxazapyro-14-carboxylic acid tert-butyl ester

[0808]

[0809] Step 1: (8R,11S,11aS,12S)-4-bromo-2-chloro-3-fluoro-12-methyl-5-oxo-8,9,10,11,11a,12-hexahydro-5H,7H-8,11-bridged iminoazapyro[2,1-c]pyrido[3,2-f][1,4]oxazapyro-14-carboxylic acid tert-butyl ester

[0810]

[0811] Under nitrogen atmosphere, at -78°C, LDA (10.1 mL, 21.8 mmol) was added to a solution of (8R,11S,11aS,12S)-2-chloro-3-fluoro-12-methyl-5-oxo-8,9,10,11,11a,12-hexahydro-5H,7H-8,11-bridged iminoazapyro[2,1-c]pyrido[3,2-f][1,4]oxazapyro-14-carboxylic acid tert-butyl ester (3.62 g, 8.79 mmol, intermediate 3, step 2) in tetrahydrofuran (70 mL). The resulting solution was stirred at -78°C for 1 h. Then, tetrahydrofuran (7 ml) containing 1,2-dibromo-1,1,2,2-tetrachloroethane (4.29 g, 13.2 mmol) was added at -78 °C, and the mixture was stirred at room temperature for 1 h. The reaction was quenched with aqueous NH4Cl solution and extracted with EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (gradient: 0% to 30% EtOAc / petroleum ether) to give 1.73 g (yield 40.1%) of the title compound as a yellow solid. LC-MS: (ESI, m / z): [M+H] + = 490.

[0812] Step 2: (8R,11S,11aS,12S)-2-chloro-3-fluoro-12-methyl-4-(((1-methyl-1H-pyrazol-3-yl)methyl)amino)-5-oxo-8,9,10,11,11a,12-hexahydro-5H,7H-8,11-bridged iminoazapyro[2,1-c]pyrido[3,2-f][1,4]oxazapyro-14-carboxylic acid tert-butyl ester

[0813]

[0814] (1-Methyl-1H-pyrazol-3-yl)methylamine (768 mg, 6.91 mmol) was added to a solution of (8R,11S,11aS,12S)-4-bromo-2-chloro-3-fluoro-12-methyl-5-oxo-8,9,10,11,11a,12-hexahydro-5H,7H-8,11-bridged iminoazapyro[2,1-c]pyrido[3,2-f][1,4]oxazapyro-14-carboxylic acid tert-butyl ester (1.13 g, 2.30 mmol) and DIPEA (742 mg, 5.76 mmol) in 1,4-dioxane (10 mL). The mixture was stirred at room temperature for 1 h, and the resulting solution was partitioned between water and EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by rapid silica gel chromatography (gradient: 0% to 100% EtOAc / petroleum ether) to give 1.08 g (90% yield) of the title compound as a white solid. LC-MS: (ESI, m / z): [M+H] + = 521.

[0815] Intermediate 21: Pyrazolo[1,5-a]pyrazin-2-ylmethylamine

[0816]

[0817] Step 1: 3-Bromo-N-(2,2-Dimethoxyethyl)-1H-pyrazole-5-carboxamide

[0818]

[0819] A solution of 3-bromo-1H-pyrazole-5-carboxylic acid (3.00 g, 15.7 mmol), 2,2-dimethoxyethyl-1-amine (1.20 g, 18.8 mmol), HATU (8.96 g, 23.6 mmol), and DIPEA (6.09 g, 47.1 mmol) in DMF (35 mL) was stirred at 25 °C for 1 h. The resulting solution was partitioned between water and EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by passing it through a C18 column (solvent gradient: water containing 0% to 17% ACN (0.05% NH4HCO3)) to give 1.80 g (41.2% yield) of the title compound as a yellow solid. LC-MS: (ESI, m / z): [M+H] + = 278.

[0820] Step 2: 2-Bromo-7-hydroxy-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one

[0821]

[0822] A solution of 3-bromo-N-(2,2-dimethoxyethyl)-1H-pyrazole-5-carboxamide (1.80 g, 6.47 mmol) and TsOH (1.67 g, 9.71 mmol) in acetone (30 mL) and water (3 mL) was prepared at 70 °C. Stir for 2 hours. The resulting solution was partitioned between water and EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by passing it through a C18 column (solvent gradient: water containing 0% to 20% ACN (0.05% NH4HCO3)) to give 650 mg (43.3% yield) of the title compound as a yellow solid. LC-MS: (ESI, m / z): [M+H] + = 232.

[0823] Step 3: 2-Bromopyrazolo[1,5-a]pyrazin-4(5H)-one

[0824]

[0825] A solution of 650 mg (2.80 mmol) of 2-bromo-7-hydroxy-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one in TFA (7 mL) was stirred at 80 °C for 2 hours. The resulting mixture was concentrated under reduced pressure to give 580 mg (crude) of the title compound as a yellow oil. LC-MS: (ESI, m / z): [M+H] + = 214. The crude product was used directly in the next step without further purification.

[0826] Step 4: ((4-hydroxypyrazolo[1,5-a]pyrazin-2-yl)methyl)tert-butyl carbamate

[0827]

[0828] Under nitrogen atmosphere, a solution of 2-bromopyrazolo[1,5-a]pyrazin-4(5H)-one (580 mg, 2.71 mmol), potassium trifluoroborate (1.42 g, 5.96 mmol), cataCXium® A Pd G3 (395 mg, 0.542 mmol), and Cs2CO3 (5.30 g, 16.3 mmol) in 1,4-dioxane (25 mL) and water (5 mL) was incubated at 100 °C. Stir overnight. Partition the resulting solution between water and EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (gradient: 0% to 90% EtOAc / petroleum ether) to give 490 mg (68.2% yield) of the title compound as a yellow solid. LC-MS: (ESI, m / z): [M+H] + = 265.

[0829] Step 5: (4-chloropyrazolo[1,5-a]pyrazin-2-yl)methylamine

[0830]

[0831] A solution of ((4-hydroxypyrazolo[1,5-a]pyrazin-2-yl)methyl)carbamate tert-butyl (490 mg, 1.85 mmol) in DCE (4 mL) and POCl3 (2 mL) was incubated at 80 °C. Stir for 3 hours. Concentrate the resulting mixture under reduced pressure to give 200 mg (crude) of the title compound as a yellow oil. LC-MS: (ESI, m / z): [M+H] += 183. The crude product was used directly in the next step without further purification.

[0832] Step 6: ((4-chloropyrazolo[1,5-a]pyrazin-2-yl)methyl)tert-butyl carbamate

[0833]

[0834] At 0°C, a solution of (4-chloropyrazolo[1,5-a]pyrazin-2-yl)methylamine (150 mg, 0.820 mmol) and DIPEA (1.06 g, 8.22 mmol) in DCM (4 mL) was added. (Boc)₂O (358 mg, 1.64 mmol). The solution was stirred at room temperature for 1.5 h. The resulting solution was partitioned between water and EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (gradient: 0% to 25% EtOAc / petroleum ether) to give 50.0 mg (yield 21.5%) of the title compound as a yellow solid. LC-MS: (ESI, m / z): [M+H] + = 283.

[0835] Step 7: (pyrazolo[1,5-a]pyrazin-2-ylmethyl)tert-butyl carbamate

[0836]

[0837] Under nitrogen atmosphere, a solution of ((4-chloropyrazolo[1,5-a]pyrazin-2-yl)methyl)carbamate tert-butyl ester (50.0 mg, 0.177 mmol), sodium formate (18.0 mg, 0.265 mmol), and Pd(PPh3)4 (10.2 mg, 0.009 mmol) in DMF (3 mL) was incubated at 120°C. Stir for 2 hours. Partition the resulting solution between water and EtOAc. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel rapid chromatography (gradient: 0% to 40% EtOAc / petroleum ether) to give 25.0 mg (56.7% yield) of the title compound as a yellow solid. LC-MS: (ESI, m / z): [M+H] + = 249.

[0838] Step 8: Pyrazolo...

Claims

1. A compound of formula (I), (I) Or its stereoisomers, transtransfer isomers, tautomers, or pharmaceutically acceptable salts. in: m is 0 or 1; n is 0, 1, or 2; q is 0 or 1; p is 0, 1, or 2; Where n + m + q does not exceed 2, and p and q are not both 1; R1 is , where R 01 R 02 R 03 R 04 and R 05 Each of these elements is independently hydrogen, halogen, -CN, -NH2, -N(Me)2, C 1-3 Alkyl, C 1-3 Halogenated alkyl or cyclopropyl; R2 can be hydrogen, -CN, halogen, or C. 1-3 Alkyl, C 1-3 Halogenated alkyl or cyclopropyl; R 3A For hydrogen, halogen, C 1-3 Alkyl or C 1-3 Halogenated alkyl groups, and R 3B It is hydrogen; or R 3A and R 3B Together they form oxygen; R 4A and R 4B Each of them is independently hydrogen, C 1-3 Alkyl or C 1-3 Halogenated alkyl groups; Or R 4A and R 4B Together with the atoms they bind to, they form 3- to 6-membered monocyclic rings; R 3C For hydrogen, halogen, C 1-3 Alkyl or C 1-3 Halogenated alkyl groups; R 3D It is hydrogen; Z represents hydrogen, C represents... 1-3 Alkyl, -L1–Cy, -L1–NR5R6, –OR6 or –SR6; in: L1 either does not exist or is –C(=O)–; R5 is hydrogen, C 1-6 Alkyl or –NH2; R6 is C 1-6 Alkyl, -L2–Cy, –C(=O)–Cy, or –C(=O)C 1-6 alkyl; L2 is –(CR) 7A R 7B ) u –; u is 1, 2, or 3; Each R 7A and R 7B Independently hydrogen or C 1-3 alkyl; Cy is a 3- to 11-membered ring portion selected from monocyclic, fused bicyclic, bridged bicyclic, two or three chain rings and spirocyclic rings, wherein Cy optionally contains one or more heteroatoms selected from N, O and S and optionally is substituted by one or more R8 atoms; Each R8 is independently selected from: optionally by a hydroxyl group or C 1-6 alkoxy-substituted C 1-6 Alkyl; C 1-3 Halogenated alkyl group; halogen; hydroxyl group; cyano group; –C(=O)NR9R 10 –C(=O)OR 10 ;Optionally coated with hydroxyl-C 1-6 Alkyl-substituted C 3-6 Cycloalkyl; and oxo; wherein R9 and R 10 Independently hydrogen or C 1-6 Alkyl; or R5 and R6, together with their bonded nitrogen atoms, form a 3- to 6-membered monocyclic ring optionally substituted with one or more groups independently selected from the following: C 1-6 Alkyl and hydroxyl; or Z and R2 together with the carbon atoms they are bonded to form 5- to 6-membered monocyclic aromatic rings; X is –NR 11 ;and R 11 For hydrogen, C 1-6 Alkyl or C 1-6 Halogenated alkyl groups.

2. The compound according to claim 1, or a stereoisomer, transisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein: Cy is a 3- to 10-membered ring portion selected from monocyclic, fused bicyclic, bridged bicyclic, two or three chain rings and spirocyclic rings, wherein Cy optionally contains one or more heteroatoms selected from N, O and S and optionally is substituted by one or more R8 atoms; Each R8 is independently selected from: C14 cells optionally substituted with a hydroxyl group. 1-6 Alkyl; C 1-3 Halogenated alkyl group; halogen; hydroxyl group; cyano group; –C(=O)NR9R 10 –C(=O)OR 10 C 3-6 Cycloalkyl; and oxo; wherein R9 and R 10 Independently hydrogen or C 1-6 alkyl.

3. The compound according to claim 1 or 2, or a stereoisomer, transisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 11 It is hydrogen.

4. The compound according to any one of claims 1 to 3, or a stereoisomer, transisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 01 R 02 R 03 R 04 and R 05 Each of these elements is independently hydrogen, halogen, or carbon. 1-3 Alkyl, C 1-3 Halogenated alkyl groups or -NH2.

5. The compound according to any one of claims 1 to 4, or a stereoisomer, transisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 01 R 02 R 03 R 04 and R 05 No more than one of them is hydrogen.

6. The compound according to any one of claims 1 to 5, or a stereoisomer, transisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R2 is a halogen.

7. The compound according to any one of claims 1 to 6, or a stereoisomer, transisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 3A and R 3C All are H.

8. The compound according to any one of claims 1 to 7, or a stereoisomer, transisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 4A and R 4B Both are hydrogen.

9. The compound according to any one of claims 1 to 7, or a stereoisomer, transisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R 4A It is hydrogen, and R 4B It can be methyl, ethyl, -CHF2, or -CF3.

10. The compound according to any one of claims 1 to 9, or a stereoisomer, transisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein Z is hydrogen.

11. The compound according to any one of claims 1 to 9, or a stereoisomer, transisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein Z is C 1-3 alkyl.

12. The compound according to any one of claims 1 to 9, or a stereoisomer, transisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein Z is -L1–Cy.

13. The compound of claim 12 or a stereoisomer, transisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein Cy is imidazole, phenyl, pyridine, 2-oxabicyclo[2.1.1]hexane, pyrimidine, pyrazole, pyrazine, pyridazine, 1,2,4-triazole, indazole, pyridinone, thiazole, quinoline, pyrrolo[1,2-a]pyrimidine, 1,2,4-thiadiazole, [1,2,4]triazolo[1,5-a]pyridine, pyrazolo[1,5-a]pyrazine, imidazole[1,2]pyrazine, pyrazolo[1,2]pyrimidine, pyrazolo[1,2]pyrazine ... -a]pyrazine, pyrazolo[1,5-a]pyrimidine, pyrazolo[1,5-c]pyrimidine, imidazo[1,2-b]pyridazine, imidazo[1,2-a]pyridine, imidazo[2,1-b]oxazole, 1,2,5-thiadiazole, isothiazole, 1,2,3-thiadiazole, isoxazole, 1,3,4-thiadiazole, 3-(1H-pyrazol-1-yl)pyrazine Pyridine, 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine, pyrrolo[2,1-f][1,2,4]triazine, 5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one, imidazo[1,2-a]pyrimidine, pyrazolo[3,4-b]pyridine, oxazole, 1,2,3-triazole, 2,3-dihydroindoleazine-5(1H)-one, pyridazine-3(2H)-one, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine, 2-(1H-pyrazol-1-yl)pyridine, 1-azabicyclo[3.2.0]heptane, hexahydro-1H-pyrrolo[2,1-c][1,4]oxazine, pyrrolidine, or hexahydro-1H-pyrroloazine; wherein Cy Optionally selected by one or more independently chosen from the following R 8 Substitution: optionally by a hydroxyl group or C 1-6 alkoxy-substituted C 1-6 Alkyl; C 1-3 Halogenated alkyl group; halogen; hydroxyl group; cyano group; –C(=O)NR9R 10 –C(=O)OR 10 ;Optionally coated with hydroxyl-C 1-6 Alkyl-substituted C 3-6 Cycloalkyl; and oxo; wherein R9 and R 10 Independently hydrogen or C 1-6 alkyl.

14. The compound of claim 13 or a stereoisomer, transisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein Cy is pyrrolo[1,2-a]pyrimidine, 1,2,4-thiadiazole, [1,2,4]triazolo[1,5-a]pyridine, pyrazolo[1,5-a]pyrazine, imidazo[1,2-a]pyrazine, pyrazolo[1,5-a]pyrimidine, pyrazolo[1,5-c]pyrimidine, imidazo[1,2-b]pyridazine, imidazo[1,2-a]pyridine, imidazo[2,1-b]oxazole, 1,2,5-thiadiazole, isothiazole, 1,2,3-thiadiazole, isoxazole, 1,3,4-thiadiazole, 3-(1H-pyrazol-1-yl)pyridine, 6,7-Dihydro-5H-pyrazolo[5,1-b][1,3]oxazine, pyrrolo[2,1-f][1,2,4]triazine, 5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one, imidazo[1,2-a]pyrimidine, pyrazolo[3,4-b]pyridine, oxazole, 1,2,3-triazole, 2,3-dihydroindoleazine-5(1H)-one, pyridazine-3(2H)-one, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine or 2-(1H-pyrazol-1-yl)pyridine; wherein Cy is optionally selected by one or more R independently selected from the following 8 Substitution: optionally by a hydroxyl group or C 1-6 alkoxy-substituted C 1-6 Alkyl; C 1-3 Halogenated alkyl group; halogen; hydroxyl group; cyano group; –C(=O)NR9R 10 –C(=O)OR 10 ;Optionally coated with hydroxyl-C 1-6 Alkyl-substituted C 3-6 Cycloalkyl; and oxo; wherein R9 and R 10 Independently hydrogen or C 1-6 alkyl.

15. The compound of claim 13 or a stereoisomer, transisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein Cy is an imidazole, phenyl, pyridine, 2-oxabicyclo[2.1.1]hexane, pyrimidine, pyrazole, pyrazine, pyridazine, 1,2,4-triazole, indazole, pyridinone, thiazole, or quinoline; wherein Cy is optionally substituted by one or more R8s independently selected from the group consisting of: C substituted with a hydroxyl group 1-6 Alkyl; C 1-3 Halogenated alkyl group; halogen; hydroxyl group; cyano group; –C(=O)NR9R 10 –C(=O)OR 10 C 3-6 Cycloalkyl; and oxo; wherein R9 and R 10 Independently hydrogen or C 1-6 alkyl.

16. The compound of claim 12 or a stereoisomer, transisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein L1 is absent and Cy is a pyrazole or pyrimidine, wherein the pyrazole is optionally substituted with a methyl group.

17. The compound according to any one of claims 1 to 9, or a stereoisomer, transisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein Z is -L1–NR5R6.

18. The compound of claim 17 or a stereoisomer, transisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein L1 is absent, R5 is hydrogen, and R6 is -L2–Cy.

19. The compound of claim 18 or a stereoisomer, transisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein L2 is –CH2– and Cy is imidazole, phenyl, pyridine, 2-oxabicyclo[2.1.1]hexane, pyrimidine, pyrazole, pyrazine, pyridazine, 1,2,4-triazole, indazole, pyridinone, thiazole, quinoline, pyrrolo[1,2-a]pyrimidine, 1,2,4-thiadiazole, [1,2,4]triazolo[1,5-a]pyridine, pyrazolo[1,5-a]pyrazine, imidazole[1,2]pyrazine, pyrazolo[1,2]pyrimidine, pyrazolo[1,2]pyrazine ... -a]pyrazine, pyrazolo[1,5-a]pyrimidine, pyrazolo[1,5-c]pyrimidine, imidazo[1,2-b]pyridazine, imidazo[1,2-a]pyridine, imidazo[2,1-b]oxazole, 1,2,5-thiadiazole, isothiazole, 1,2,3-thiadiazole, isoxazole, 1,3,4-thiadiazole, 3-(1H-pyrazol-1-yl)pyrazine Pyridine, 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine, pyrrolo[2,1-f][1,2,4]triazine, 5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one, imidazo[1,2-a]pyrimidine, pyrazolo[3,4-b]pyridine, oxazole, 1,2,3-triazole, 2,3-dihydroindoleazine-5(1H)-one, pyridazine-3(2H)-one, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine, 2-(1H-pyrazol-1-yl)pyridine, 1-azabicyclo[3.2.0]heptane, hexahydro-1H-pyrrolo[2,1-c][1,4]oxazine, pyrrolidine, or hexahydro-1H-pyrroloazine; wherein Cy Optionally substituted with one or more R8 radicals independently selected from: optionally substituted with a hydroxyl group or C 1-6 alkoxy-substituted C 1-6 Alkyl; C 1-3 Halogenated alkyl group; halogen; hydroxyl group; cyano group; –C(=O)NR9R 10 –C(=O)OR 10 ;Optionally coated with hydroxyl-C 1-6 Alkyl-substituted C 3-6 Cycloalkyl; and oxo; wherein R9 and R 10 Independently hydrogen or C 1-6 alkyl.

20. The compound according to claim 18 or 19, or a stereoisomer, transisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein L2 is –CH2–, and Cy The following compounds are listed: imidazole, phenyl, pyridine, 2-oxabicyclo[2.1.1]hexane, pyrimidine, pyrazole, pyrazine, pyridazine, 1,2,4-triazole, indazole, pyridinone, thiazole, quinoline, pyrrolo[1,2-a]pyrimidine, 1,2,4-thiadiazole, [1,2,4]triazolo[1,5-a]pyridine, pyrazolo[1,5-a]pyrazine, imidazo[1,2-a]pyrazine, pyrazolo[1,5-a]pyrimidine, pyrazolo[1,5-c]pyrimidine, imidazo[1,2-b]pyridazine, imidazo[1,2-a]pyridine, imidazo[2,1-b]oxazole, 1,2,5-thiadiazole, isothiazole, 1,2,3-thiadiazole, and isothiazole. Oxazole, 1,3,4-thiadiazole, 3-(1H-pyrazol-1-yl)pyridine, 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine, pyrrolo[2,1-f][1,2,4]triazine, 5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one, imidazo[1,2-a]pyrimidine, pyrazolo[3,4-b]pyridine, oxazole, 1,2,3-triazole, 2,3-dihydroindoleazine-5(1H)-one, pyridazine-3(2H)-one, 6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazine or 2-(1H-pyrazol-1-yl)pyridine; wherein Cy is optionally substituted by one or more R8 radicals independently selected from the group consisting of: optionally hydroxyl or C 1-6 alkoxy-substituted C 1-6 Alkyl; C 1-3 Halogenated alkyl group; halogen; hydroxyl group; cyano group; –C(=O)NR9R 10 –C(=O)OR 10 ;Optionally coated with hydroxyl-C 1-6 Alkyl-substituted C 3-6 Cycloalkyl; and oxo; wherein R9 and R 10 Independently hydrogen or C 1-6 alkyl.

21. The compound according to claim 19 or 20, or a stereoisomer, transisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein each R8 is independently selected from: –CH2OH, –CH2CH2OH, –CH2OCH3, methyl, ethyl, –CHF2, –CF3, chlorine, fluorine, oxo, –C(=O)N(CH3)2, –C(=O)OH, –C(=O)OCH3, hydroxyl, cyano, cyclopropyl substituted with –CH2OH, and cyclopropyl.

22. The compound according to claim 18 or 19, or a stereoisomer, transisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein L2 is –CH2–, and Cy is phenyl, pyridine, imidazole, 2-oxabicyclo[2.1.1]hexane, pyrimidine, pyrazine, pyridazine, triazole, pyrazole, indazole, pyridinone, thiazole, or quinoline; wherein Cy is optionally substituted by one or more R8s independently selected from: C substituted with a hydroxyl group 1-6 Alkyl; C 1-3 Halogenated alkyl group; halogen; hydroxyl group; cyano group; –C(=O)NR9R 10 –C(=O)OR 10 C 3-6 Cycloalkyl; and oxo; wherein R9 and R 10 Each of them is independently hydrogen or C. 1-6 alkyl.

23. The compound of claim 22 or a stereoisomer, transisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein each R8 is independently selected from methyl, –CF3, –CHF2, fluorine, hydroxyl, cyano, –CH2OH, –C(=O)OH, –C(=O)OMe, and –C(=O)N(Me)2.

24. The compound of claim 22 or a stereoisomer, transisomer, tautomer or pharmaceutically acceptable salt thereof, wherein Cy is phenyl, pyridine, imidazole, 2-oxabicyclo[2.1.1]hexane, pyrimidine, pyrazine, pyridazine, triazole, pyrazole, indazole, pyridinone, thiazole or quinoline.

25. The compound of claim 18 or a stereoisomer, transisomer, tautomer or pharmaceutically acceptable salt thereof, wherein L2 is –CH(CH3)– and Cy is phenyl.

26. The compound of claim 17 or a stereoisomer, transisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein L1 is absent, R5 is hydrogen, and R6 is methyl, –C(=O)–phenyl, or –C(=O)CH2CH3.

27. The compound of claim 17 or a stereoisomer, transisomer, tautomer or pharmaceutically acceptable salt thereof, wherein L1 is –C(=O)–, R5 is -NH2, and R6 is methyl.

28. The compound of claim 17 or a stereoisomer, transisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein L1 is absent, and R5 and R6 together with the nitrogen atom to which they are bonded form an azide heterocyclic butane ring optionally substituted with hydroxyl and methyl groups.

29. The compound according to any one of claims 1 to 9, or a stereoisomer, transisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein Z is –OR6 or –SR6.

30. The compound of claim 29 or a stereoisomer, transisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R6 is -L2–Cy, wherein L2 is –CH2– and Cy is pyridine.

31. The compound according to any one of claims 1 to 9, or a stereoisomer, transisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein Z and R2 together with the carbon atoms to which they are bonded form a pyrazole.

32. A compound selected from any one of compounds 1 to 146 shown in Table 1, or a stereoisomer, transisomer, tautomer, or pharmaceutically acceptable salt thereof.

33. A pharmaceutical composition comprising: a compound according to any one of claims 1 to 32 or a stereoisomer, transisomer, tautomer or pharmaceutically acceptable salt thereof; and one or more pharmaceutically acceptable excipients.

34. A method of treating cancer, the method comprising administering an effective amount of the compound according to any one of claims 1 to 32 or a stereoisomer, transisomer, tautomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 33.

35. The method of claim 34, wherein the cancer is characterized by containing a KRas mutation.

36. The method of claim 35, wherein the KRas mutation corresponds to KRas G12D mutation.

37. The method according to any one of claims 34 to 36, further comprising detecting the presence of KRas in a sample from the patient prior to administration. G12D mutation.

38. The method of claim 37, wherein KRas is shown to be present in the patient sample. G12D Following the mutation, the patient is given the compound, its stereoisomer, transtransfer isomer, tautomer, or pharmaceutically acceptable salt, or a pharmaceutical composition thereof.

39. The method according to any one of claims 34 to 38, wherein the cancer is pancreatic cancer, lung cancer, or colorectal cancer.

40. The method according to any one of claims 34 to 39, further comprising administering at least one additional therapeutic agent.

41. The method of claim 40, wherein the additional therapeutic agent comprises an epidermal growth factor receptor (EGFR) inhibitor, a phosphatidylinositol kinase (PI3K) inhibitor, an insulin-like growth factor receptor (IGF1R) inhibitor, a Janus kinase (JAK) inhibitor, a Met kinase inhibitor, an SRC family kinase inhibitor, a mitogen-activated protein kinase (MEK) inhibitor, an extracellular signal-regulated kinase (ERK) inhibitor, a topoisomerase inhibitor, a taxane, an antimetabolite, or an alkylating agent.

42. The compound according to any one of claims 1 to 32, or a stereoisomer, transisomer, tautomer, or pharmaceutically acceptable salt thereof, used as a therapeutically active substance.

43. The compound of any one of claims 1 to 32, or a stereoisomer, transisomer, tautomer, or pharmaceutically acceptable salt thereof, for use in the treatment of cancer.

44. The compound used according to claim 43, wherein the cancer is pancreatic cancer, lung cancer, or colorectal cancer.

45. Use of any compound of claims 1 to 32, or a stereoisomer, transisomer, tautomer, or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating cancer.

46. ​​The use according to claim 45, wherein the cancer is pancreatic cancer, lung cancer, or colorectal cancer.

47. The compound according to any one of claims 1 to 32, or a stereoisomer, transisomer, tautomer, or pharmaceutically acceptable salt thereof, for containing KRas G12D Use of therapeutic treatments for mutated cancers.

48. Use of any compound of claims 1 to 32, or a stereoisomer, transtransfer isomer, tautomer, or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for inhibiting tumor metastasis.

49. Use of any compound according to any one of claims 1 to 32, or a stereoisomer, transisomer, tautomer, or pharmaceutically acceptable salt thereof, for the preparation of a medicament comprising KRas G12D Therapeutic treatments for mutated cancers.

50. The compound according to any one of claims 1 to 32, or a stereoisomer, transisomer, tautomer, or pharmaceutically acceptable salt thereof, for use in containing KRas G12D Therapeutic and / or preventative treatments for mutated cancers.

51. A method for a) regulating the activity of KRas mutant protein, b) inhibiting cell population proliferation, or c) inhibiting tumor metastasis; The method for modulating the activity of the KRas mutant protein includes reacting the mutant protein with a compound according to any one of claims 1 to 32, or a stereoisomer, transisomer, tautomer or pharmaceutically acceptable salt thereof. The method for inhibiting the proliferation of a cell population includes contacting the cell population with a compound according to any one of claims 1 to 32, or a stereoisomer, transtransfer isomer, tautomer, or pharmaceutically acceptable salt thereof; and Methods for inhibiting tumor metastasis include administering a therapeutically effective amount of the compound, or a stereoisomer, transmetabolite, tautomer, or pharmaceutically acceptable salt thereof, according to any one of claims 1 to 32, to an individual in need.

52. The method of claim 51, wherein the inhibition of proliferation is measured by a decrease in the cell viability of the cell population.

53. The compound of any one of claims 1 to 32, or a stereoisomer, transtransferase isomer, tautomer or pharmaceutically acceptable salt thereof, for use in a) regulating the activity of KRas mutant protein, b) inhibiting cell population proliferation or c) inhibiting tumor metastasis.

54. Use of any compound of any one of claims 1 to 32, or a stereoisomer, transtransfer isomer, tautomer, or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for a) regulating the activity of KRas mutant protein, b) inhibiting cell population proliferation, or c) inhibiting tumor metastasis.

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