Pyrazolo[3,4-B]pyrazine SHP2 phosphatase inhibitors

Abstract

The present invention provides a novel pyrazine derivative of formula (I): or its tautomer or solvate or pharmaceutically acceptable salt, wherein the substituent is as defined herein. The present invention also provides a pharmaceutical composition comprising the compound and the use of the compound in treating diseases, such as cancer. Formula (I):

Description

Technical Field

[0001] This invention relates to novel pyrazine derivatives, pharmaceutical compositions comprising said compounds, and the use of said compounds in the treatment of diseases, such as cancer.

[0002] Related applications

[0003] This application relates to UK Patent Application No. 1911928.8, filed on 20 August 2019, the contents of which are incorporated herein by reference in their entirety. Background Technology

[0004] Protein tyrosine phosphatase 2 (SHP2), containing the Src homology region 2 (SH2), is a pan-expressed protein tyrosine phosphatase encoded by the PTPN11 gene. SHP2 contains two N-terminal tandem SH2 domains (N-SH2, C-SH2), a catalytic phosphatase (PTP) domain, and a C-terminal tail with two tyrosine phosphorylation sites.

[0005] Due to the self-inhibitory interaction between the N-SH2 and PTP domains, SHP2 can switch between an "open" active form and a "closed" inactive form. This spontaneous self-inhibition is released when the bistyrosine-phosphorylated peptide binds to the N-SH2 domain and SHP2 adopts an "open" conformation, leading to enzyme activation and exposure of the PTP domain for substrate recognition and catalysis.

[0006] PTPN11 mutations have been associated with several human diseases, including cancer. Embryonic PTPN11 mutations are associated with developmental disorders such as Noonan Syndrome and Leopard Syndrome, while somatic mutations occur in several types of hematologic malignancies such as JMML and are even rarer in solid tumors.

[0007] SHP2 is essential for downstream signaling of receptor tyrosine kinases (e.g., EGFR, ALK, PDGFR) and plays an active role in regulating many cellular processes, such as proliferation in response to growth factor and cytokine stimulation. Previous studies have shown that SHP2 acts upstream of Ras and is essential for the complete and sustained activation of the MAPK pathway. RTK dysregulation commonly leads to a wide range of cancers, making SHP2 a valuable target in RTK-activated cancers. SHP2 has also been reported to play a role in regulating immune responses by mediating immune checkpoint pathways (e.g., PD-1) because the immunoreceptor tyrosine-based inhibitory motif (ITIM) binds to the SH2 domain of SHP2 to mediate negative signaling. Several SHP2 inhibitory compounds have been reported to inhibit the proliferation of cancer cells in vitro and the increase in tumor volume in mouse xenograft models (Nature (2016) 535:148-152).

[0008] This invention describes a series of novel compounds that selectively inhibit SHP2 and have anticancer activity. Summary of the Invention

[0009] On the one hand, the present invention provides a compound of formula (I):

[0010]

[0011] Or its tautomers, solvates, or pharmaceutically acceptable salts, wherein:

[0012] R 1 It is hydrogen or hydroxyl;

[0013] R 2 and R 3 Independently selected from hydrogen, halogen, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl groups and -CN;

[0014] X is O or CR 4 R 5 ;

[0015] R 4 and R 5 Independently selected from hydrogen, halogen, hydroxyl, C 1-4 Alkyl, C 1-4 Alkoxy and halogenated C 1-4 alkyl;

[0016] R 6 and R 7 It is hydrogen, C 1-4 Alkyl or halogen (e.g., chlorine or fluorine), or R6 and R 7 Joined to form optionally by one or more (e.g., 1, 2, or 3) R 10 Ring A substituted with a group;

[0017] Ring A is any one of the following:

[0018] (i) a five-membered nitrogen-containing heterocycle (e.g., an aromatic or non-aromatic ring), wherein the heterocycle optionally contains one or two additional heteroatoms selected from N, O, and S; or

[0019] (ii) a six-membered aromatic nitrogen-containing heterocycle, wherein the heterocycle optionally contains one or two additional heteroatoms selected from N, O, and S; or

[0020] (iii) A six-membered non-aromatic nitrogen-containing heterocycle, wherein the heterocycle optionally contains one or two additional heteroatoms selected from N and S;

[0021] R 8 Selected from halogenated C 1-4 Alkyl groups (e.g., -CF3), -CH3, and halogens (e.g., chlorine or fluorine);

[0022] R 9 Selected from hydrogen, C 1-4 Alkyl groups (e.g., -CH3), halogenated C 1-4 Alkyl groups (e.g., -CF3) and halogens (e.g., chlorine);

[0023] R 10 Independently selected from: halogen; cyano; cyano C 1-4 Alkyl (e.g., -CH2-CN); hydroxyl; =O (oxo); C 1-4 Alkyl groups (e.g., -CH3, -CH(CH3)2, or -CH2CH3); halogenated C 1-4 Alkyl group (e.g., -CHF2); C 1-4 Alkyl groups (e.g., -OCH3, -OCH2CH3, and -OCH(CH3)2); hydroxyl groups C 1-4 Alkyl groups (e.g., -CH2C(CH3)2OH, -CH(CH3)CH2OH, -CH(CH3)OH, -CH2CH2OH, or -CH2OH); C 1-4 Alkoxy C 1-4 Alkylene (e.g., -CH2-O-CH3 or -CH2-CH2-O-CH3); C 1-4 Alkyl sulfones (e.g., -SO2CH3); amino groups; single carbon atoms 1-4 Alkylamino; diC 1-4 Alkylamino (e.g., -N(CH3)2); amino C 1-4Alkylene (e.g., -CH2NH2); -C 1-4 Alkylene-C(=O)NH (2-q) (C 1-6 alkyl) q ;-C 0-4 Alkylene-NHC(=O)C 1-6 Alkyl; sulfonamide C 0-4 Alkylenes (e.g., -SO2NR) x 2 or -CH2SO2NR x 2, where R x Independently selected from H and C 1-6 Alkyl); 3- to 6-membered cycloalkyl; containing one, two, three, or four heteroatoms selected from O, N, or S, optionally substituted five- or six-membered unsaturated heterocyclic groups, wherein the optional substituents are selected from C. 1-4 Alkyl; C substituted with 3 to 6-membered cycloalkyl groups 1-4 Alkyl group; C-shaped alkyl group substituted with a optionally substituted five- or six-membered unsaturated heterocyclic group containing one, two, three, or four heteroatoms selected from O, N, or S. 1-4 Alkyl group, wherein optional substituents are selected from C10. 1-4 Alkyl group; C-shaped alkyl group substituted with a optionally substituted four- or six-membered saturated heterocyclic group containing one or two heteroatoms selected from O, N, or S. 1-4 Alkyl group, wherein optional substituents are selected from C10. 1-4 Alkyl group; and optionally substituted four- or six-membered saturated heterocyclic groups containing one or two heteroatoms selected from O, N or S, wherein the optional substituents are selected from C. 1-4 Alkyl; and

[0024] q is selected from 0, 1, and 2.

[0025] In another aspect of the invention, a compound of formula (I) for preventing or treating diseases or symptoms as described herein, a method for preventing or treating diseases or symptoms as described herein, a pharmaceutical composition comprising a compound of formula (I), and a method for synthesizing a compound of formula (I), said method for preventing or treating diseases or symptoms as described herein comprising administering a compound of formula (I) to a patient.

[0026] definition

[0027] Unless the context otherwise requires, references to formula (I) in all parts of this document (including the uses, methods and other aspects of the invention) include references to all other formulas, subgroups, embodiments and examples as defined herein.

[0028] "Efficacy" is a measure of drug activity, expressed as the amount required to produce a given strength of effect. Highly effective drugs induce a large response at low concentrations. Efficacy is proportional to affinity and efficacy. Affinity is the ability of a drug to bind to a receptor. Efficacy is the relationship between receptor occupancy and the ability to initiate a response at the molecular, cellular, tissue, or systemic level.

[0029] The term "inhibitor" refers to an enzyme inhibitor, which is a ligand or drug that blocks or inhibits a biological response mediated by SHP2. Inhibitors mediate their action by binding to an active or allosteric site on the enzyme, or by interacting at a unique binding site that is not normally involved in the biological regulation of enzyme activity. Inhibition can be induced directly or indirectly and can be mediated through any mechanism and at any physiological level. Therefore, inhibition by a ligand or drug may itself manifest itself in functionally different ways under different circumstances. Inhibitory activity can be reversible or irreversible, depending on the lifetime of the inhibitor-enzyme complex, which in turn depends on the nature of the inhibitor-enzyme binding.

[0030] As used herein, the term "mediated," as used, for example, in conjunction with SHP2 as described herein (and applied, for example, to various physiological processes, diseases, states, symptoms, therapies, treatments, or interventions), is intended to operate restrictively such that the various processes, diseases, states, symptoms, treatments, and interventions to which the term is applied are those in which the protein exerts its biological effect. In the case of the application of the term to a disease, state, or symptom, the biological effect exerted by the protein can be direct or indirect, and can be necessary and / or sufficient for the manifestation of symptoms of the disease, state, or symptom (or the cause or progression of said disease, state, or symptom). Therefore, protein function (and specifically, abnormal levels of function, such as overexpression or underexpression) is not necessarily a proximate cause of the disease, state, or symptom; rather, it is considered that mediated diseases, states, or symptom encompass those with multifactorial causes and complex progressions in which the protein in question is only partially involved. When the terminology is applied to treatment, prevention, or intervention, the role played by the protein can be direct or indirect, and can be necessary and / or sufficient for the outcome of the treatment, prevention, or intervention. Therefore, protein-mediated disease states or symptoms include the development of resistance to any particular cancer drug or treatment.

[0031] As used herein in the context of treating a symptom, i.e., a state, condition, or disease, the term "treatment" generally refers to treatments and therapies, whether for humans or animals (e.g., in veterinary applications), some of which have desired therapeutic effects, such as the suppression of the progression of the symptom, and include a reduction in the rate of progression, cessation of the rate of progression, improvement of the symptom, relief or remission of at least one symptom being treated that is related to or caused by the symptom, and cure of the symptom. For example, treatment may be the relief of one or more symptoms of the symptom or the complete eradication of the symptom.

[0032] As used herein in the context of treating a symptom, i.e., a state, condition, or disease, the term "prevention" (i.e., using a compound as a preventative measure) generally refers to prevention (prophylaxis or prevention) whether for humans or animals (e.g., in veterinary applications), some of which are intended to achieve preventative effects, such as preventing the onset of disease or resisting disease. Prevention includes completely and absolutely blocking all symptoms of a symptom for an indefinite period of time, merely alleviating the onset of one or more symptoms of a disease, or reducing the likelihood of the disease occurring.

[0033] References to the prevention or treatment of disease states or symptoms such as cancer are included within its scope to alleviate or reduce the incidence of, for example, cancer.

[0034] Compared to the therapeutic effect of a single compound / drug when applied alone, the combination of the present invention can produce a therapeutically effective effect.

[0035] The term “effective” includes beneficial effects such as additive, synergistic, reduced side effects, decreased toxicity, increased time to disease progression, increased survival, sensitization or resensitization of one agent to another, or improved response rate. Advantageously, an effective effect can allow for the administration of lower doses of each or any of the components to the patient, thereby reducing the toxicity of chemotherapy while producing and / or maintaining the same therapeutic effect. In the context of this invention, a “synergistic” effect means that the therapeutic effect produced by the combination is greater than the sum of the therapeutic effects of the agents in the combination when administered individually. In the context of this invention, an “additive” effect means that the therapeutic effect produced by the combination is greater than the therapeutic effect of any of the agents in the combination when administered individually. As used herein, the term “response rate” in the case of solid tumors refers to the degree of reduction in tumor size at a given time point, such as 12 weeks. Thus, for example, a 50% response rate means a 50% reduction in tumor size. References herein to “clinical response” refer to a response rate of 50% or higher. “Partial response” is defined herein as a response rate of less than 50%.

[0036] As used herein, the term "combination," when applied to two or more compounds and / or pharmaceuticals, is intended to define materials in which two or more pharmaceuticals are combined. The terms "combined" and "combining" in this context should be interpreted accordingly.

[0037] The combination of two or more compounds / agents in a combination can be physical or non-physical. Examples of physically combined compounds / agents include:

[0038] • Compositions of two or more compounds / pharmaceuticals that are mixed (e.g., in the same unit dose) (e.g., a single formulation);

[0039] • A composition comprising materials in which two or more compounds / pharmaceuticals are chemically / physicochemically linked (e.g., by cross-linking, molecular aggregation, or binding with a common mediator portion);

[0040] • Compositions comprising two or more of the following compounds / pharmaceuticals that are chemically / physicochemically co-packaged (e.g., disposed on or within lipid vesicles, particles (e.g., microparticles or nanoparticles) or emulsion droplets);

[0041] • Drug kits, drug packets, or patient packets in which two or more compounds / pharmaceuticals are co-packaged or co-present (e.g., as part of a unit dose array);

[0042] Examples of compounds / pharmaceuticals that are not physically bound include:

[0043] • Includes at least one of two or more compounds / pharmaceuticals and materials describing the physical combination of said at least one compound to form a physical combination of the two or more compounds / pharmaceuticals (e.g., non-single formulation);

[0044] • Materials comprising at least one of two or more compounds / pharmaceuticals and instructions for combination therapy with two or more compounds / pharmaceuticals (e.g., non-single formulations);

[0045] • Includes at least one of two or more compounds / pharmaceuticals and materials indicating administration to a patient population, wherein the other compounds / pharmaceuticals among the two or more compounds / pharmaceuticals have been (or are being) administered;

[0046] • Materials comprising amounts or forms of two or more compounds / pharmaceuticals, particularly suitable for use in combination with other compounds / pharmaceuticals among two or more compounds / pharmaceuticals.

[0047] As used herein, the term "combination therapy" is intended to define a therapy that includes the use of a combination of two or more compounds / pharmaceuticals (as defined above). Therefore, references to "combination therapy," "combination," and "combination" of compounds / pharmaceuticals in this application may refer to the administration of compounds / pharmaceuticals as part of the same overall treatment regimen. Consequently, the dosing of each of the two or more compounds / pharmaceuticals may differ: each compound / pharmaceutical may be administered simultaneously or at different times. Therefore, it should be understood that compounds / pharmaceuticals in a combination may be administered sequentially (e.g., before or after) or simultaneously in the same formulation (i.e., together) or in different formulations (i.e., individually). Simultaneous administration in the same formulation is as a single formulation, while simultaneous administration in different formulations is not single. Regarding the route of administration, the dosing of each of the two or more compounds / pharmaceuticals in a combination therapy may also differ.

[0048] As used herein, the term "drug kit" defines an array of one or more unit doses of a pharmaceutical composition, along with a delivery device (e.g., a measuring device) and / or a delivery device (e.g., an inhaler or syringe), wherein the pharmaceutical composition and the delivery device and / or delivery device are optionally all contained within a common outer package. In a drug kit comprising a combination of two or more compounds / agents, the individual compounds / agents may be single or non-single formulations. A blister pack may contain a unit dose. The drug kit may optionally further include instructions for use.

[0049] As used herein, the term "drug pack" defines a pharmaceutical composition comprising an array of one or more unit doses, optionally contained within a common outer packaging. In a drug pack comprising a combination of two or more compounds / agents, the individual compounds / agents may be single or non-single formulations. A blister pack may contain a unit dose. Drug packs may optionally further include instructions for use.

[0050] As used herein, the term "optionally substituted" refers to a group that may be unsubstituted or may be substituted by substituents as defined herein.

[0051] As used in this article, the prefix "C" x-y "(where x and y are integers) refers to the number of carbon atoms in a given group." Therefore, C 1-6 Alkyl groups contain 1 to 6 carbon atoms, C 3-6 Cycloalkyl groups contain 3 to 6 carbon atoms, C 1-4 Alkoxy groups contain 1 to 4 carbon atoms, and so on.

[0052] As used in this article, the term "amino" refers to the group -NH2.

[0053] As used in this article, the term "halogenated" or "halogen" refers to fluorine, chlorine, bromine, or iodine, specifically fluorine or chlorine.

[0054] Each or every hydrogen in a compound (such as hydrogen in an alkyl group or a position referred to as hydrogen) contains all the isotopes of hydrogen, specifically 1 H and 2 H (deuterium).

[0055] As used in this article, the term "oxo" refers to the =O group.

[0056] As used in this article, the term "C" 1-4 "Alkyl", as a group or part of a group, refers to a straight-chain or branched saturated hydrocarbon group containing 1 to 4 carbon atoms. Examples of such groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, etc.

[0057] As used in this article, the term "C" 2-4 "Alkenyl" or "C" 2-6 "Alkenyl," as a group or part of a group, refers to a straight-chain or branched hydrocarbon group containing 2 to 4 or 2 to 6 carbon atoms and a carbon-carbon double bond, respectively. Examples of such groups include C... 3-4 alkenyl or C 3-6 Alkenyl groups, such as ethenyl, 1-propenyl, 2-propenyl (allyl), isopropenyl, butenyl, but-1,4-dienyl, pentenyl, and hexenyl.

[0058] As used in this article, the term "C" 2-4 "Alkyne" or "C" 2-6 "Alkyne group," as a group or part of a group, refers to a straight-chain or branched hydrocarbon group having 2 to 4 carbon atoms or 2 to 6 carbon atoms and containing a carbon-carbon triple bond, respectively. Examples of such groups include C 3-4 alkynyl or C 3-6 Alkyne groups, such as ethynyl and 2-propynyl (propynyl).

[0059] As used in this article, the term "C" 1-4 "Alkoxy" as a group or as part of a group refers to -OC 1-4 Alkyl, wherein C 1-4 Alkyl groups are defined herein. Examples of such groups include methoxy, ethoxy, propoxy, butoxy, etc.

[0060] As used in this article, the term "C" 3-6 "Cycloalkyl" refers to a saturated monocyclic hydrocarbon ring consisting of 3 to 6 carbon atoms. Examples of such groups include cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0061] As used in this article, the term "C" 3-6"Cycloalkenyl" refers to a partially saturated monocyclic hydrocarbon ring consisting of 3 to 6 carbon atoms, having one or more (usually one) carbon-carbon double bonds. Examples of such groups include cyclopentenyl, cyclohexenyl, and cyclohexadienyl.

[0062] As used in this article, the term "hydroxyl C" 1-4 "Alkyl", as a group or part of a group, refers to a C-aryl group in which one or more (e.g., one, two, or three) hydrogen atoms are replaced by hydroxyl groups, as defined herein. 1-4 Alkyl group. Therefore, the term "hydroxyl C" is used. 1-4 "alkyl" contains a single hydroxyl C 1-4 Alkyl and polyhydroxy C 1-4 Alkyl groups. One, two, three, or more hydrogen atoms can be replaced by a hydroxyl group, therefore the hydroxyl group has a C=0. 1-4 Alkyl groups can have one, two, three, or more hydroxyl groups. Examples of such groups include hydroxymethyl, hydroxyethyl, hydroxypropyl, etc.

[0063] As used in this article, the term "halogenated C" 1-4 "Alkyl", as a group or part of a group, refers to a C-aryl group in which one or more (e.g., one, two, or three) hydrogen atoms are replaced by a halogen. 1-4 Alkyl group. Therefore, the term "halogenated C" is used. 1-4 "alkyl" includes monohalogenated C 1-4 Alkyl and polyhalogenated C 1-4 Alkyl groups. One, two, three, or more hydrogen atoms can be replaced by halogens, thus halogenated C... 1-4 Alkyl groups can have one, two, three or more halogens. Examples of such groups include fluoroethyl, fluoromethyl, difluoromethyl, trifluoromethyl or trifluoroethyl, etc.

[0064] As used in this article, the term "halogenated C" 1-4 "Alkoxy", as a group or part of a group, refers to a -OC group in which one or more (e.g., one, two, or three) hydrogen atoms are replaced by a halogen. 1-4 Alkyl group. Therefore, the term "halogenated C" is used. 1-4 "Alkoxy" contains a monohalogenated C 1-4 Alkoxy and polyhalogenated C 1-4 Alkyl groups. One, two, three, or more hydrogen atoms can be replaced by halogens, thus halogenated C... 1-4 Alkoxy groups can have one, two, three, or more halogens. Examples of such groups include fluoroethoxy, difluoromethoxy, or trifluoromethoxy.

[0065] Unless the context otherwise requires, the term "heterocyclic group" as used herein shall include both aromatic and non-aromatic ring systems. Thus, for example, the term "heterocyclic group" encompasses aromatic, non-aromatic, unsaturated, partially saturated, and saturated heterocyclic ring systems within its scope. Generally, unless the context otherwise requires, such groups may be monocyclic or bicyclic (including fused, spirocyclic, and bridged bicyclic groups) and may contain, for example, 3 to 12 ring members, more typically 5 to 10 ring members. References to 4 to 7 ring members include 4, 5, 6, or 7 atoms in the ring, and references to 4 to 6 ring members include 4, 5, or 6 atoms in the ring. Examples of monocyclic groups are groups containing 3, 4, 5, 6, 7, and 8 ring members, more typically 3 to 7 or 4 to 7, and preferably 5, 6, or 7 ring members, more preferably 5 or 6 ring members. Examples of bicyclic groups are those comprising 8, 9, 10, 11, and 12 ring members, and more typically 9 or 10 ring members. Heterocyclic groups can be heteroaryl groups having 5 to 12 ring members, and more typically 5 to 10 ring members. In the context of heterocyclic groups mentioned herein, unless the context otherwise requires, the heterocyclic ring may optionally be substituted by one or more (e.g., 1, 2, 3, or 4, specifically one or two) substituents as defined herein, i.e., it may be unsubstituted or substituted.

[0066] The heterocyclic group can be, for example, a five- or six-membered monocyclic ring or a bicyclic structure formed by fused five- and six-membered rings, or two fused six-membered rings, or two fused five-membered rings. Each ring may contain up to five heteroatoms specifically selected from nitrogen, sulfur, and oxygen, as well as oxidized forms of nitrogen or sulfur. Specifically, the heterocyclic ring will contain up to four heteroatoms, more specifically up to three heteroatoms, and more typically up to two, such as a single heteroatom. In one embodiment, the heterocyclic ring will contain one or two heteroatoms selected from N, O, S, and oxidized forms of N or S. In one embodiment, the heterocyclic ring contains at least one cyclic nitrogen atom. The nitrogen atom in the heterocyclic ring can be basic, as in the case of imidazole or pyridine, or substantially non-basic, as in the case of indole or pyrrole nitrogen. Typically, the number of basic nitrogen atoms present in the heterocyclic group, including any amino substituents of the ring, will be less than five.

[0067] Heterocyclic groups can be linked by carbon atoms or heteroatoms (e.g., nitrogen). Similarly, heterocyclic groups can be substituted on carbon atoms or heteroatoms (e.g., nitrogen).

[0068] Examples of five-membered aromatic heterocyclic groups include, but are not limited to, pyrrole, furanyl, thiophene, imidazolyl, furanyl, oxazolyl, oxadiazolyl, oxtriazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, pyrazolyl, triazolyl, and tetrazolyl.

[0069] Examples of six-membered aromatic heterocyclic groups include, but are not limited to, pyridinyl, pyrazinyl, pyridinyl, pyrimidinyl, and triazinyl.

[0070] The term "heteroaryl" is used herein to refer to a heterocyclic group having aromatic characteristics. The term "heteroaryl" encompasses polycyclic (e.g., bicyclic) ring systems in which one or more rings are non-aromatic, provided that at least one ring is aromatic. In such polycyclic systems, the group can be linked via an aromatic ring or via a non-aromatic ring.

[0071] Examples of heteroaryl groups are monocyclic and bicyclic groups containing five to twelve ring members, more commonly five to ten ring members.

[0072] Examples of five-membered heteroaryl groups include, but are not limited to, pyrrole, furanyl, thiophene, imidazolyl, furazolidone, oxazolyl, oxadiazolyl, oxtriazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, pyrazolyl, triazolyl, and tetrazolyl.

[0073] Examples of six-membered heteroaryl compounds include, but are not limited to, pyridine, pyrazine, pyridazine, pyrimidine, and triazine.

[0074] The bicyclic heteroaryl group can be, for example, selected from the following groups:

[0075] a) A benzene ring fused with a 5- or 6-membered ring and containing one, two, or three cyclic heteroatoms;

[0076] b) A pyridine ring fused with a 5- or 6-membered ring and containing 0, 1, 2 or 3 cyclic heteroatoms;

[0077] c) A pyrimidine ring fused with a 5- or 6-membered ring and containing 0, 1, or 2 cyclic heteroatoms;

[0078] d) Pyrrole rings fused with 5- or 6-membered rings, containing 0, 1, 2 or 3 cyclic heteroatoms;

[0079] e) A pyrazole ring fused with a 5- or 6-membered ring and containing 0, 1, or 2 cyclic heteroatoms;

[0080] f) Imidazole rings fused with 5- or 6-membered rings containing 0, 1, or 2 cyclic heteroatoms;

[0081] g) An oxazole ring fused with a 5- or 6-membered ring and containing 0, 1 or 2 cyclic heteroatoms;

[0082] h) An isoxazole ring fused with a 5- or 6-membered ring and containing 0, 1 or 2 cyclic heteroatoms;

[0083] i) A thiazole ring fused with a 5- or 6-membered ring and containing 0, 1, or 2 cyclic heteroatoms;

[0084] j) An isothiazole ring fused with a 5- or 6-membered ring and containing 0, 1, or 2 cyclic heteroatoms;

[0085] k) Thiophene rings fused with 5- or 6-membered rings, containing 0, 1, 2 or 3 cyclic heteroatoms;

[0086] l) Furan rings fused with 5- or 6-membered rings containing 0, 1, 2 or 3 cyclic heteroatoms;

[0087] m) A cyclohexyl ring fused with a 5- or 6-membered ring, containing one, two, or three cyclic heteroatoms; and

[0088] n) A cyclopentyl ring fused with a 5- or 6-membered ring and containing 1, 2 or 3 cyclic heteroatoms.

[0089] Specific examples of bicyclic heteroaryl groups containing one five-membered ring fused with another five-membered ring include, but are not limited to, imidazothiazoles (e.g., imidazo[2,1-b]thiazole) and imidazoimidazolazoles (e.g., imidazo[1,2-a]imidazolazole).

[0090] Specific examples of bicyclic heteroaryl groups containing a six-membered ring fused with a five-membered ring include, but are not limited to, benzofuranyl, benzothiophenyl, benzoimidazolyl, benzoxazolyl, isobenzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indazinyl, indololinyl, isoindololinyl, purine (e.g., adenine, guanine), indazole, pyrazolopyrimidinyl (e.g., pyrazolo[1,5-a]pyrimidinyl), triazolopyrimidinyl (e.g., [1,2,4]triazolo[1,5-a]pyrimidinyl), benzo-m-dioxacyclopentenyl, imidazopyridyl, and pyrazolopyridyl (e.g., pyrazolo[1,5-a]pyridyl).

[0091] Specific examples of bicyclic heteroaryl groups containing two fused six-membered rings include, but are not limited to, quinolinyl, isoquinolinyl, chromanyl, thiochromanyl, isochromanyl, chromenyl, isochromenyl, benzodioxane, quinazinyl, benzooxazinyl, pyridinylpyridinyl, quinoxolinyl, quinazolinyl, terolinyl, phthalazinyl, naphthidyl, and pteridylyl.

[0092] Examples of polycyclic heteroaryl groups containing aromatic and non-aromatic rings include tetrahydroisoquinolinyl, tetrahydroquinolinyl, dihydrobenzothiophenyl, dihydrobenzofuranyl, 2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,3]dioxinyl, 4,5,6,7-tetrahydrobenzofuranyl, tetrahydrotriazolylpyrazinyl (e.g., 5,6,7,8-tetrahydro-[1,2,4]triazol[4,3-a]pyrazinyl), chromanyl, thiochromanyl, isochromyl, chromenyl, isochromyl, benzodioxane, benzooxazinyl, benzodiazepine, and indololinyl.

[0093] A nitrogen-containing heteroaryl ring must contain at least one cyclic nitrogen atom. The nitrogen-containing heteroaryl ring can be N-linked or C-linked. Additionally, each ring may contain up to about four other heteroatoms specifically selected from nitrogen, sulfur, and oxygen. Specifically, the heteroaryl ring will contain up to three heteroatoms, such as one, two, or three, and more typically up to two nitrogen atoms, such as a single nitrogen atom. The nitrogen atom in the heteroaryl ring can be basic, as in the case of imidazole or pyridine, or substantially non-basic, as in the case of indole or pyrrole nitrogen. Typically, the number of basic nitrogen atoms present in the heteroaryl ring, including any amino substituents in the ring, will be less than five.

[0094] Examples of nitrogen-containing heteroaryl groups include, but are not limited to, monocyclic groups such as pyridyl, pyrroloyl, imidazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, oxtriazolyl, isoxazolyl, thiazolyl, isothiazolyl, furanyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl (e.g., 1,2,3-triazolyl, 1,2,4-triazolyl), tetrazolyl, and bicyclic groups such as quinolinyl, isoquinolinyl, benzimidazolyl, etc. Benzooxazolyl, benzoisooxazolyl, benzothiazolyl and benzoisothiazolyl, indoleyl, 3H-indoleyl, isoindoleyl, indazinyl, isoindolinyl, purineyl (e.g. adenine [6-aminopurine], guanine [2-amino-6-hydroxypurine]), indazoleyl, quinazinyl, benzooxazinyl, benzodiazepinel, pyridopyridyl, quinoxalinyl, quinazolinyl, terolinyl, phthalazinyl, naphthidyl and pteridinyl.

[0095] Examples of nitrogen-containing polycyclic heteroaryl groups containing aromatic and non-aromatic rings include tetrahydroisoquinolinyl, tetrahydroquinolinyl, and dihydroindolyl.

[0096] Unless the context otherwise requires, the term "non-aromatic" encompasses unsaturated ring systems, partially saturated, and saturated heterocyclic ring systems that do not possess aromatic characteristics. The terms "unsaturated" and "partially saturated" refer to ring structures containing rings sharing more than one valence bond, i.e., the ring contains at least one multiple bond, such as a C=C, C≡C, or N=C bond. The term "saturated" refers to a ring in which there are no multiple bonds between ring atoms. Saturated heterocyclic groups include piperidinyl, morpholinyl, and thiomorpholinyl. Partially saturated heterocyclic groups include pyrazolinyl groups, such as pyrazolin-2-yl and pyrazolin-3-yl.

[0097] Examples of non-aromatic heterocyclic groups are groups having 3 to 12 ring members, more typically 5 to 10 ring members. Such groups can be monocyclic or bicyclic, for example, having 3 to 7 ring members, specifically 4 to 6 ring members. Specifically, such groups have 1 to 5 or 1 to 4 heteroatom ring members (more typically 1, 2, or 3 heteroatom ring members), typically selected from nitrogen, oxygen, and sulfur, and their oxidized forms. The heterocyclic group may contain, for example, a cyclic ether moiety (e.g., as in tetrahydrofuran and dioxane), a cyclic sulfide moiety (e.g., as in tetrahydrothiophene and dithiane), a cyclic amine moiety (e.g., as in pyrrolidine), a cyclic amide moiety (e.g., as in pyrrolidone), a cyclic thioamide, a cyclic thioester, a cyclic urea (e.g., as in imidazoline-2-one), a cyclic ester moiety (e.g., as in butyrolactone), a cyclic sulfone (e.g., as in sulfolane and sulfolane), a cyclic sulfoxide, a cyclic sulfonamide, and combinations thereof (e.g., thiomorpholine).

[0098] Specific examples include morpholino, piperidinyl (e.g., piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, and piperidin-4-yl), piperidinone, pyrrolyl (e.g., pyrrolidine-1-yl, pyrrolidine-2-yl, and pyrrolidine-3-yl), pyrrolidone, azacyclic butyl, pyranyl (2H-pyran or 4H-pyran), dihydrothiophene, dihydropyranyl, dihydrofuranyl, dihydrothiazolyl, tetrahydrofuranyl, tetrahydrothiophene, dioxyl, oxyl (also known as tetrahydropyranyl) (e.g., oxalidine-4-yl), imidazolino, imidazolinone, oxazolino, thiazolino, pyrazolino-2-yl, pyrazolyl, piperazinone, piperazinyl, and N-alkylpiperazine, such as N-methylpiperazinyl. Typically, non-aromatic heterocyclic groups contain saturated groups such as piperidinyl, pyrrolidinyl, azacyclic butyl, morpholinyl, piperazine, and N-alkylpiperazine, N-methylpiperazine.

[0099] In a nitrogen-containing non-aromatic heterocyclic ring, the ring must contain at least one cyclic nitrogen atom. The nitrogen-containing heterocyclic ring can be N-linked or C-linked. The heterocyclic group can contain, for example, a cyclic amine moiety (e.g., as in pyrrolidinyl), a cyclic amide (e.g., pyrrolidinyl, piperidinone, or caprolactam), a cyclic sulfonamide (e.g., isothiazolyl 1,1-dioxide, [1,2]thiazinyl 1,1-dioxide, or [1,2]thiazolidinyl heptyl 1,1-dioxide), and combinations thereof.

[0100] Specific examples of nitrogen-containing non-aromatic heterocyclic groups include aziridinyl, morpholinyl, thiomorpholinyl, piperidinyl (e.g., piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, and piperidin-4-yl), pyrrolyl (e.g., pyrrolidine-1-yl, pyrrolidine-2-yl, and pyrrolidine-3-yl), pyrrolidone, dihydrothiazolyl, imidazolinyl, imidazolinone, oxazolinyl, thiazolinyl, 6H-1,2,5-thiadiazinyl, pyrazolinyl-2-yl, pyrazolinyl-3-yl, pyrazolylyl, piperazinyl, and N-alkylpiperazine, such as N-methylpiperazinyl.

[0101] Heterocyclic groups can be polycyclic fused ring systems or bridging ring systems, such as oxa-analogs and azira-analogs of bicyclic alkanes, tricyclic alkanes (e.g., adamantane and oxadamantane). For an explanation of the distinction between fused ring systems and bridging ring systems, see *Advanced Organic Chemistry*, Jerry March, 4th ed., Wiley Interscience, pp. 131-133, 1992.

[0102] However, in the definition of a cyclic group or ring, it is stated that the cyclic group contains a certain number of heteroatom ring members, for example, as in the phrase "a 5- or 6-membered ring containing 0, 1, or 2 nitrogen ring members," which should be considered to mean that, apart from the specified number of heteroatom ring members, the remaining ring members are carbon atoms.

[0103] Compounds of formula (I) may contain saturated cyclic groups that can be attached to the rest of the molecule by one or more bonds. When a cyclic group is attached to the rest of the molecule by two or more bonds, these bonds (or two of these bonds) can form with the same atom of the ring (typically a carbon atom) or with different atoms of the ring. If the bonds form with the same atom of the ring, a cyclic group is produced in which a single atom (typically a quaternary carbon) is bonded to two groups. In other words, when a compound of formula (I) contains a cyclic group, the group can be attached to the rest of the molecule by bonds, or the cyclic group and the rest of the molecule can share a common atom, such as in spiro compounds.

[0104] Heterocyclic groups can each be unsubstituted or substituted with one or more (e.g., 1, 2, or 3) substituents. For example, a heterocyclic or carbocyclic group can be unsubstituted or substituted with 1, 2, 3, or 4 substituents, and specifically, the heterocyclic or carbocyclic group is unsubstituted or has 1, 2, or 3 substituents as defined herein. In the case where the cyclic group is saturated, two substituents can be attached to the same carbon (where the substituents are the same so-called twin or geminal substituents).

[0105] Such combinations are permitted only if the combination of substituents produces a stable or chemically viable compound (i.e., a compound that remains substantially unchanged when kept at 40°C or lower for at least one week).

[0106] Specifically, the various functional groups and substituents constituting the compounds of the present invention are selected such that the molecular weight of the compounds of the present invention does not exceed 1000. More generally, the molecular weight of the compounds will be less than 750, for example less than 700, or less than 650, or less than 600 or less than 550. More specifically, the molecular weight is less than 525 and, for example, 500 or less. Detailed Implementation

[0107] This invention provides a compound of formula (I):

[0108]

[0109] Or its tautomers or solvates or pharmaceutically acceptable salts, wherein X, R 1 R 2 R 3 R 6 R 7 R 8 and R 9 As defined in this article.

[0110] X

[0111] X is O or CR 4 R 5 .

[0112] When X is CR 4 R 5 At that time, R 4 and R 5 Independently selected from hydrogen, halogen, hydroxyl, C 1-4 Alkyl, C 1-4 Alkoxy and halogenated C 1-4 alkyl.

[0113] In one embodiment, R 4 and R 5 Independently selected from hydrogen, halogen, C 1-4 Alkyl and Halogenated C 1-4 Alkyl (e.g., halo-C1 alkyl).

[0114] In one embodiment, X is O, and the compound of formula (I) is the compound of formula (Ia):

[0115]

[0116] In one embodiment, X is CR 4 R5 And the compound of formula (I) is the same as the compound of formula (Ib):

[0117]

[0118] Where R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 and R 9 As defined in this article.

[0119] Specifically, X is O, and the compound of formula (I) is the compound of formula (Ia).

[0120] In one embodiment, X is CR 4 R 5 And R 4 and R 5 Independently selected from hydrogen, halogens (e.g., fluorine, chlorine, bromine, or iodine, specifically fluorine) and halogenated C 1-4 Alkyl groups (e.g., monohalomethyl, dihalomethyl, and trihalomethyl, wherein the halogen is selected from fluorine, chlorine, bromine, or iodine).

[0121] In one embodiment, X is CR 4 R 5 And R 4 and R 5 It is independently selected from hydrogen, fluorine, and trifluoromethyl.

[0122] In one embodiment, X is CR 4 R 5 And R 4 and R 5 It is hydrogen.

[0123] In one embodiment, X is CR 4 R 5 And R 4 and R 5 It is a halogen (e.g., fluorine).

[0124] In one embodiment, X is CR 4 R 5 And R 4 It is hydrogen and R 5 Selected from halogens (e.g., fluorine, chlorine, bromine, or iodine, specifically fluorine) and halomethyl groups (e.g., monohalomethyl, dihalomethyl, and trihalomethyl groups, wherein the halogen is selected from fluorine, chlorine, bromine, or iodine).

[0125] In one embodiment, X is CR 4R 5 And R 4 It is hydrogen and R 5 It is fluorine or trifluoromethyl.

[0126] In one embodiment, X is CR 4 R 5 And R 4 It is hydrogen and R 5 It's fluorine.

[0127] In one embodiment, X is CR 4 R 5 And R 4 It is hydrogen and R 5 It is trifluoromethyl.

[0128] In one embodiment, X is CR 4 R 5 And R 4 It is hydrogen and R 5 The compounds are selected from halogens (e.g., fluorine, chlorine, bromine, or iodine, specifically fluorine) and halomethyl groups (e.g., monohalomethyl, dihalomethyl, and trihalomethyl groups, wherein the halogen is selected from fluorine, chlorine, bromine, or iodine), and the compound of formula (Ib) is a compound of formula (Ib'):

[0129]

[0130] Where R 1 R 2 R 3 R 5 R 6 R 7 R 8 and R 9 As defined in this article.

[0131] In one embodiment of the compound of formula (Ib'), R 5 It is fluorine or trifluoromethyl, specifically fluorine.

[0132] In one embodiment, X is CR 4 R 5 And R 4 It is hydrogen and R 5 The compounds are selected from halogens (e.g., fluorine, chlorine, bromine, or iodine, specifically fluorine) and halomethyl groups (e.g., monohalomethyl, dihalomethyl, and trihalomethyl groups, wherein the halogen is selected from fluorine, chlorine, bromine, or iodine), and the compound of formula (Ib) is a compound of formula (Ib)":

[0133]

[0134] Where R 1 R 2 R3 R 5 R 6 R 7 R 8 and R 9 As defined in this article.

[0135] In one embodiment of the compound of formula (Ib), R 5 It is fluorine or trifluoromethyl, specifically trifluoromethyl.

[0136] R 1

[0137] R 1 It is hydrogen or hydroxyl.

[0138] In one embodiment, R 1 It is hydrogen, and the compound of formula (I) is the same as the compound of formula (II):

[0139]

[0140] Among them, X and R 2 R 3 R 6 R 7 R 8 and R 9 As defined in this article.

[0141] In one embodiment, R 1 Hydroxyl group, and compound (I) is a compound of formula (III):

[0142]

[0143] Among them, X and R 2 R 3 R 6 R 7 R 8 and R 9 As defined in this article.

[0144] Specifically, R 1 Hydroxyl group, and compound (I) is compound (III).

[0145] Specifically, R 1 A hydroxyl group, and X is O, and the compound of formula (III) is a compound of formula (III'):

[0146]

[0147] Where R 2 R 3 R 6 R 7 R8 and R 9 As defined in this article.

[0148] R 2 and R 3

[0149] R 2 and R 3 Independently selected from hydrogen, halogen, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl groups and -CN.

[0150] In one embodiment, R 2 and R 3 Independently selected from hydrogen, C 1-4 Alkyl, Halogenated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl and -CN. In one embodiment, R 2 and R 3 It is hydrogen.

[0151] In one embodiment, R 2 It is hydrogen, and R 3 Selected from C 1-4 Alkyl, Halogenated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl groups and -CN.

[0152] In one embodiment, R 2 It is hydrogen, and R 3 Selected from C 1-4 Alkyl, Halogenated C 1-4 Alkyl and hydroxy C 1-4 alkyl.

[0153] In one embodiment, R 2 It is hydrogen, and R 3 It is C 1-4 Alkyl groups, such as -CH3.

[0154] In one embodiment, R 2 It is hydrogen, and R 3 It is a halogen, such as -F.

[0155] In one embodiment, R 2 It is a halogen, such as -F, and R 3 It is hydrogen.

[0156] In one embodiment, R 2 and R 3 It is a halogen, such as -F.

[0157] In one embodiment, R 2 It is hydrogen, and R 3Selected from C 1-4 Alkyl, Halogenated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl groups and -CN, and compounds of formula (I) are compounds of formula (IV):

[0158]

[0159] Where X and R 1 R 3 R 6 R 7 R 8 and R 9 As defined in this article.

[0160] In one embodiment, the compound of formula (IV) is a compound of formula (IV'):

[0161]

[0162] Where X and R 1 R 3 R 6 R 7 R 8 and R 9 As defined in this article.

[0163] In one embodiment, the compound of formula (IV) is a compound of formula (IV"):

[0164]

[0165] Where X and R 1 R 3 R 6 R 7 R 8 and R 9 As defined in this article.

[0166] In one embodiment of compounds of formulas (IV), (IV'), and (IV"), R 3 Selected from C 1-4 Alkyl, Halogenated C 1-4 Alkyl and hydroxy C 1-4 alkyl.

[0167] In one embodiment of compounds of formulas (IV), (IV'), and (IV"), R 3 Selected from C 1-4 Alkyl groups, such as -CH3.

[0168] Specifically, compound (IV) is compound (IV"), R 3 Selected from C 1-4 Alkyl groups, such as -CH3.

[0169] In one embodiment of compounds of formulas (IV), (IV'), and (IV"), R 3 Selected from C 1-4 Alkyl, such as -CH3, and X is O.

[0170] Specifically, compound (IV) is compound (IV"), R 3 Selected from C 1-4 Alkyl, such as -CH3, and X is O.

[0171] R 8

[0172] R 8 Selected from halogenated C 1-4 Alkyl groups (e.g., -CF3), -CH3, and halogens (e.g., chlorine or fluorine).

[0173] In one embodiment, R 8 Selected from C 1-4 Alkyl groups (e.g., -CH3), halogenated C 1-4 Alkyl groups (e.g., -CF3) and chlorine.

[0174] In one embodiment, R 8 Selected from -CH3, chlorine, and fluorine.

[0175] In one embodiment, R 8 It is a halogen (e.g., fluorine, chlorine, bromine, or iodine, such as fluorine or chlorine), and the compound of formula (I) is a compound of formula (V) or a tautomer or solvate thereof or a pharmaceutically acceptable salt thereof:

[0176]

[0177] Among them, X and R 1 R 2 R 3 R 6 R 7 and R 9 As defined in this article, and R 8 It is a halogen, specifically R 8 It is chlorine.

[0178] In one embodiment, R 8 Selected from methyl, chlorine and fluorine.

[0179] In one embodiment, R 8 Selected from chlorine and fluorine.

[0180] In one embodiment, R 8 It is a methyl group.

[0181] Specifically, R8 It's fluorine.

[0182] Specifically, R 8 It is chlorine.

[0183] In one embodiment of the compound of formula (V), X is CR 4 R 5 .

[0184] Specifically, in one embodiment of the compound of formula (V), X is O.

[0185] In one embodiment of the compound of formula (V), R 1 It is hydrogen.

[0186] Specifically, in one embodiment of the compound of formula (V), R 1 It is a hydroxyl group.

[0187] Specifically, in one embodiment of the compound of formula (V), X is O, and R 1 It is a hydroxyl group.

[0188] R 9

[0189] R 9 Selected from hydrogen, C 1-4 Alkyl groups (e.g., -CH3), halogenated C 1-4 Alkyl groups (e.g., -CF3) and halogens (e.g., chlorine).

[0190] In one embodiment, R 9 Selected from hydrogen, -CH3, -CF3, chlorine, and fluorine.

[0191] In one embodiment, R 9 Selected from hydrogen, -CH3, -CF3 and chlorine.

[0192] Specifically, R 9 It is hydrogen, and the compound of formula (I) is a compound of formula (VI) or its tautomer, solvate, or pharmaceutically acceptable salt:

[0193]

[0194] Where X and R 1 R 2 R 3 R 6 R 7 and R 8 As defined in this article.

[0195] In one embodiment of the compound of formula (VI), X is CR 4 R 5 .

[0196] Specifically, in one embodiment of the compound of formula (VI), X is O.

[0197] In one embodiment of the compound of formula (VI), R 1 It is hydrogen.

[0198] Specifically, in one embodiment of the compound of formula (VI), R 1 It is a hydroxyl group.

[0199] Specifically, in one embodiment of the compound of formula (VI), R 8 It is a halogen, such as chlorine.

[0200] Specifically, in one embodiment of the compound of formula (VI), X is O, R 1 It is a hydroxyl group, and R 8 It is chlorine.

[0201] R 6 and R 7

[0202] R 6 and R 7 It is hydrogen, C 1-4 Alkyl or halogen (e.g., chlorine or fluorine), or R 6 and R 7 Joined to form optionally by one or more (e.g., 1, 2, or 3) R 10 Ring A substituted with a group.

[0203] In one embodiment, R 6 and R 7 It is hydrogen or halogen (e.g., chlorine or fluorine), or R 6 and R 7 Joined to form optionally by one or more (e.g., 1, 2, or 3) R 10 Ring A substituted with a group;

[0204] Ring A is any one of the following:

[0205] (i) a five-membered nitrogen-containing heterocycle (e.g., an aromatic or non-aromatic ring), wherein the heterocycle optionally contains one or two additional heteroatoms selected from N, O, and S; or

[0206] (ii) a six-membered aromatic nitrogen-containing heterocycle, wherein the heterocycle optionally contains one or two additional heteroatoms selected from N, O, and S; or

[0207] (iii) A six-membered non-aromatic nitrogen-containing heterocycle, wherein the heterocycle optionally contains one or two additional heteroatoms selected from N and S; and

[0208] R 10 Independently selected from: halogen; cyano; cyano C1-4 Alkyl (e.g., -CH2-CN); hydroxyl; =O (oxo); C 1-4 Alkyl groups (e.g., -CH3, -CH(CH3)2, or -CH2CH3); halogenated C 1-4 Alkyl group (e.g., -CHF2); C 1-4 Alkyl groups (e.g., -OCH3, -OCH2CH3, and -OCH(CH3)2); hydroxyl groups C 1-4 Alkyl groups (e.g., -CH2C(CH3)2OH, -CH(CH3)CH2OH, -CH(CH3)OH, -CH2CH2OH, or -CH2OH); C 1-4 Alkoxy C 1-4 Alkylene (e.g., -CH2-O-CH3 or -CH2-CH2-O-CH3); C 1-4 Alkyl sulfones (e.g., -SO2CH3); amino groups; single carbon atoms 1-4 Alkylamino; diC 1-4 Alkylamino (e.g., -N(CH3)2); amino C 1-4 Alkylene (e.g., -CH2NH2); -C 1-4 Alkylene-C(=O)NH (2-q) (C 1-6 alkyl) q ;-C 0-4 Alkylene-NHC(=O)C 1-6 Alkyl; sulfonamide C 0-4 Alkylenes (e.g., -SO2NR) x 2 or -CH2SO2NR x 2, where R x Independently selected from H and C 1-6 Alkyl); 3- to 6-membered cycloalkyl; containing one, two, three, or four heteroatoms selected from O, N, or S, optionally substituted five- or six-membered unsaturated heterocyclic groups, wherein the optional substituents are selected from C. 1-4 Alkyl; C substituted with 3 to 6-membered cycloalkyl groups 1-4 Alkyl group; C-shaped alkyl group substituted with a optionally substituted five- or six-membered unsaturated heterocyclic group containing one, two, three, or four heteroatoms selected from O, N, or S. 1-4 Alkyl group, wherein optional substituents are selected from C10. 1-4 Alkyl group; C-shaped alkyl group substituted with a optionally substituted four- or six-membered saturated heterocyclic group containing one or two heteroatoms selected from O, N, or S. 1-4 Alkyl group, wherein optional substituents are selected from C10. 1-4 Alkyl group; and optionally substituted four- or six-membered saturated heterocyclic groups containing one or two heteroatoms selected from O, N or S, wherein the optional substituents are selected from C. 1-4 Alkyl; and

[0209] q is selected from 0, 1, and 2.

[0210] In one embodiment, R 6 and R 7 It is hydrogen, C 1-4 alkoxy or fluorine, or R 6 and R 7 Joined to form optionally by one or more (e.g., 1, 2, or 3) R 10 Ring A substituted with a group.

[0211] In one embodiment, R 6 and R 7 It is hydrogen or fluorine, or R 6 and R 7 Joined to form optionally by one or more (e.g., 1, 2, or 3) R 10 Ring A substituted with a group;

[0212] Ring A is any one of the following:

[0213] (i) a five-membered nitrogen-containing heterocycle (e.g., an aromatic or non-aromatic ring), wherein the heterocycle optionally contains one or two additional heteroatoms selected from N, O, and S; or

[0214] (ii) a six-membered aromatic nitrogen-containing heterocycle, wherein the heterocycle optionally contains one or two additional heteroatoms selected from N, O, and S; or

[0215] (iii) A six-membered non-aromatic nitrogen-containing heterocycle, wherein the heterocycle optionally contains one or two additional heteroatoms selected from N and S; and

[0216] R 10 Independently selected from: halogen; cyano; cyano C 1-4 Alkyl (e.g., -CH2-CN); hydroxyl; =O (oxo); C 1-4 Alkyl groups (e.g., -CH3, -CH(CH3)2, or -CH2CH3); halogenated C 1-4 Alkyl group (e.g., -CHF2); C 1-4 Alkyl groups (e.g., -OCH3, -OCH2CH3, and -OCH(CH3)2); hydroxyl groups C 1-4 Alkyl groups (e.g., -CH2C(CH3)2OH, -CH(CH3)CH2OH, -CH(CH3)OH, -CH2CH2OH, or -CH2OH); C 1-4 Alkoxy C 1-4 Alkylene (e.g., -CH2-O-CH3 or -CH2-CH2-O-CH3); C 1-4Alkyl sulfones (e.g., -SO2CH3); amino groups; single carbon atoms 1-4 Alkylamino; diC 1-4 Alkylamino (e.g., -N(CH3)2); amino C 1-4 Alkylene (e.g., -CH2NH2); -C 1-4 Alkylene-C(=O)NH (2-q) (C 1-6 alkyl) q ;-C 0-4 Alkylene-NHC(=O)C 1-6 Alkyl; sulfonamide C 0-4 Alkylenes (e.g., -SO2NR) x 2 or -CH2SO2NR x 2, where R x Independently selected from H and C 1-6 Alkyl); 3- to 6-membered cycloalkyl; containing one, two, three, or four heteroatoms selected from O, N, or S, optionally substituted five- or six-membered unsaturated heterocyclic groups, wherein the optional substituents are selected from C. 1-4 Alkyl; C substituted with 3 to 6-membered cycloalkyl groups 1-4 Alkyl group; C-shaped alkyl group substituted with a optionally substituted five- or six-membered unsaturated heterocyclic group containing one, two, three, or four heteroatoms selected from O, N, or S. 1-4 Alkyl group, wherein optional substituents are selected from C10. 1-4 Alkyl group; C-shaped alkyl group substituted with a optionally substituted four- or six-membered saturated heterocyclic group containing one or two heteroatoms selected from O, N, or S. 1-4 Alkyl group, wherein optional substituents are selected from C10. 1-4 Alkyl group; and optionally substituted four- or six-membered saturated heterocyclic groups containing one or two heteroatoms selected from O, N or S, wherein the optional substituents are selected from C. 1-4 Alkyl; and

[0217] q is selected from 0, 1, and 2.

[0218] In one embodiment, R 6 and R 7 It is hydrogen or halogen (e.g., chlorine or fluorine).

[0219] In one embodiment, R 6 and R 7 It is hydrogen, C 1-4 Alkyl groups or fluorine.

[0220] In one embodiment, R 6 and R 7 Is it hydrogen or C? 1-4 Alkyl group.

[0221] In one embodiment, R6 and R 7 It is hydrogen.

[0222] Specifically, R 7 It is hydrogen, and R 6 It is a halogen (e.g., chlorine or fluorine), and the compound of formula (I) is a compound of formula (VII) or its tautomer, solvate, or pharmaceutically acceptable salt:

[0223]

[0224] Specifically, in one embodiment of the compound of formula (VII), R 8 It's fluorine.

[0225] Specifically, in one embodiment of the compound of formula (VII), R 8 It is chlorine.

[0226] In one embodiment of the compound of formula (VII), X is CR 4 R 5 .

[0227] Specifically, in one embodiment of the compound of formula (VII), X is O.

[0228] In one embodiment of the compound of formula (VII), R 1 It is hydrogen.

[0229] Specifically, in one embodiment of the compound of formula (VII), R 1 It is a hydroxyl group.

[0230] Specifically, in one embodiment of the compound of formula (VII), R 8 It is a halogen, such as chlorine or fluorine.

[0231] Specifically, in one embodiment of the compound of formula (VII), R 9 It is hydrogen.

[0232] Specifically, in one embodiment of the compound of formula (VII), X is O, R 1 It is a hydroxyl group, R 9 It is hydrogen, and R 8 It is chlorine or fluorine.

[0233] In one embodiment, R 6 and R 7 Joined to form optionally by one or more (e.g., 1, 2, or 3) R 10 Ring A substituted with a group;

[0234] Ring A is any of the following:

[0235] (i) a five-membered nitrogen-containing heterocycle (e.g., an aromatic or non-aromatic ring), wherein the heterocycle optionally contains one or two additional heteroatoms selected from N, O, and S; or

[0236] (ii) a six-membered aromatic nitrogen-containing heterocycle, wherein the heterocycle optionally contains one or two additional heteroatoms selected from N, O, and S; or

[0237] (iii) A six-membered non-aromatic nitrogen-containing heterocycle, wherein the heterocycle optionally contains one or two additional heteroatoms selected from N and S.

[0238] In one embodiment, ring A is a five-membered nitrogen-containing heterocycle (e.g., an aromatic or non-aromatic ring) or a six-membered aromatic nitrogen-containing heterocycle, wherein the heterocycle optionally contains one or two additional heteroatoms selected from N, O and S.

[0239] In one embodiment, ring A is pyrazolyl, thiazolyl, pyrazinyl, or pyridinyl. This ring then forms an indazole, benzothiazolyl, quinoxalinyl, or quinolinyl group with the fused benzo[a] moiety, respectively.

[0240] In one embodiment, ring A is a five-membered nitrogen-containing heterocycle (e.g., an aromatic or non-aromatic ring), wherein the heterocycle optionally contains one or two additional heteroatoms selected from N, O, and S.

[0241] In one embodiment, ring A is a five-membered nitrogen-containing heterocycle (e.g., an aromatic or non-aromatic ring) or a six-membered aromatic nitrogen-containing heterocycle, wherein the heterocycle optionally contains one or two additional heteroatoms selected from N, O and S.

[0242] In one embodiment, ring A is a five-membered nitrogen-containing heterocycle, wherein the heterocycle optionally contains one or two additional heteroatoms selected from N, O, and S.

[0243] In one embodiment, ring A is a five-membered nitrogen-containing heterocycle, wherein the heterocycle optionally contains an additional heteroatom selected from N, O, and S.

[0244] In one embodiment, ring A is a five-membered nitrogen-containing heterocycle, wherein the heterocycle optionally contains an additional heteroatom, the additional heteroatom being N or S.

[0245] In one embodiment, ring A is a five-membered aromatic nitrogen-containing heterocycle, wherein the heterocycle optionally contains one or two additional heteroatoms selected from N and S.

[0246] In one embodiment, ring A is a five-membered nitrogen-containing heterocycle, wherein the heterocycle contains an additional heteroatom, and the additional heteroatom is N.

[0247] In one embodiment, ring A is a five-membered aromatic nitrogen-containing heterocycle, wherein the heterocycle contains an additional heteroatom, and the additional heteroatom is N.

[0248] In one embodiment, ring A is a five-membered nitrogen-containing heterocycle, wherein the heterocycle contains an additional heteroatom, and the additional heteroatom is S.

[0249] In one embodiment, ring A is a five-membered aromatic nitrogen-containing heterocycle, wherein the heterocycle contains an additional heteroatom, and the additional heteroatom is S.

[0250] In one embodiment, ring A is pyrrole, imidazolyl, oxazolyl, oxadiazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, pyrazolyl, and triazolyl, for example, where ring A is thiazolyl or pyrazolyl.

[0251] In one embodiment, ring A is a five-membered nitrogen-containing heterocycle (e.g., an aromatic or non-aromatic ring), wherein the heterocycle optionally contains one or two additional heteroatoms selected from N, O, and S, and the compound of formula (I) is a compound of formula (VIII) or a tautomer or solvate thereof or a pharmaceutically acceptable salt thereof:

[0252]

[0253] Where X and R 1 R 2 R 3 R 8 R 9 and R 10 As defined herein, and 5-Het is a five-membered nitrogen-containing heterocycle (e.g., an aromatic or non-aromatic ring), wherein the heterocycle optionally contains one or two additional heteroatoms selected from N, O and S.

[0254] In one embodiment, part

[0255]

[0256] Choose from the following options in Table I, where c is 0, 1, 2, or 3:

[0257] Table I

[0258]

[0259]

[0260]

[0261] For example, some

[0262]

[0263] Choose from options A, B, C, D, E, F, G, H, I, O, P, and Q from Table I.

[0264] Specifically, some

[0265]

[0266] Choose from options C, D, E, F, G, H, I, O, P, and Q from Table I.

[0267] Specifically, some

[0268]

[0269] Options D, H, P, and Q are selected from Table I. In one embodiment, a subset is selected from D and H.

[0270] Specifically, some

[0271]

[0272] Selected from:

[0273]

[0274] Where c is 0, 1, 2, or 3, for example

[0275]

[0276] Where c is 0, 1, 2 or 3.

[0277] Specifically, some

[0278]

[0279] Selected from

[0280]

[0281] Specifically, a compound of formula (VIII) is a compound of formula (VIIIa) or its tautomer, solvate, or pharmaceutically acceptable salt:

[0282]

[0283] Among them, X and R 1 R 2 R 3 R 8 R 9 and R 10 As defined in this article, for example, where R 10 It is C 1-4 alkyl.

[0284] Specifically, the compound of formula (VIIIa) is the compound of formula (VIIIb) or its tautomer, solvate, or pharmaceutically acceptable salt:

[0285]

[0286] Where X and R 1 R 2 R 3 R 8 and R 9 As defined in this article.

[0287] Specifically, the compound of formula (VIIIa) is the compound of formula (VIIIc) or its tautomer, solvate, or pharmaceutically acceptable salt:

[0288]

[0289] Where X and R 1 R 2 R 3 R 8 and R 9 As defined in this article.

[0290] Specifically, the compound of formula (VIII) is the compound of formula (IX) or its tautomer, solvate, or pharmaceutically acceptable salt:

[0291]

[0292] Where X and R 1 R 2 R 3 R 8 R 9 and R 10 As defined in this article.

[0293] Specifically, the compound of formula (VIII) is the compound of formula (IXa) or its tautomer, solvate, or pharmaceutically acceptable salt:

[0294]

[0295] Where X and R 1 R 2 R 3 R 8 and R 9 As defined in this article, and R 10 Selected independently from C 1-4 Alkyl groups (e.g., -CH3) and halogens (e.g., chlorine). Specifically, R is present on either a nitrogen or carbon atom. 10 Selected independently from C 1-4Alkyl groups (e.g., -CH3), and when on a carbon atom, selected from halogens (e.g., chlorine).

[0296] Specifically, the compound of formula (VIII) is the compound of formula (IXb) or its tautomer, solvate, or pharmaceutically acceptable salt:

[0297]

[0298] Where X and R 1 R 2 and R 3 As defined in this article.

[0299] Specifically, the compound of formula (VIII) is the compound of formula (X) or its tautomer, solvate, or pharmaceutically acceptable salt:

[0300]

[0301] Where X and R 1 R 2 R 8 R 9 and R 10 As defined in this article.

[0302] Specifically, in one embodiment of compounds of formulas (VIII), (VIIIa), (VIIIb), (VIIIc), (IX), (IXa), and (X), R 8 It is a halogen, such as chlorine or fluorine.

[0303] Specifically, in one embodiment of compounds of formulas (VIII), (VIIIa), (VIIIb), (VIIIc), (IX), (IXa), and (X), R 8 It's fluorine.

[0304] Specifically, in one embodiment of compounds of formulas (VIII), (VIIIa), (VIIIb), (VIIIc), (IX), (IXa), and (X), R 8 It is chlorine.

[0305] In one embodiment of compounds of formulas (VIII), (VIIIa), (VIIIb), (VIIIc), (IX), (IXa), and (X), X is a CR 4 R 5 .

[0306] Specifically, in one embodiment of compounds of formulas (VIII), (VIIIa), (VIIIb), (VIIIc), (IX), (IXa), and (X), X is O.

[0307] In one embodiment of compounds of formulas (VIII), (VIIIa), (VIIIb), (VIIIc), (IX), (IXa), and (X), R 1 It is hydrogen.

[0308] Specifically, in one embodiment of compounds of formulas (VIII), (VIIIa), (VIIIb), (VIIIc), (IX), (IXa), and (X), R 1 It is a hydroxyl group.

[0309] Specifically, in one embodiment of compounds of formulas (VIII), (VIIIa), (VIIIb), (VIIIc), (IX), (IXa), and (X), R 9 It is hydrogen.

[0310] Specifically, in one embodiment of compounds of formulas (VIII), (VIIIa), (VIIIb), (VIIIc), (IX), (IXa), and (X), X is O, R 1 It is a hydroxyl group, R 9 It is hydrogen, and R 8 It is chlorine or fluorine.

[0311] In one embodiment, ring A is any of the following:

[0312] (i) a six-membered aromatic nitrogen-containing heterocycle, wherein the heterocycle optionally contains one or two additional heteroatoms selected from N, O, and S; or

[0313] (ii) A six-membered non-aromatic nitrogen-containing heterocycle, wherein the heterocycle optionally contains one or two additional heteroatoms selected from N and S.

[0314] In one embodiment, ring A is a six-membered aromatic nitrogen-containing heterocycle, and the compound of formula (I) is a compound of formula (XI) or its tautomer, solvate, or pharmaceutically acceptable salt:

[0315]

[0316] Where X and R 1 R 2 R 3 R 8 R 9 and R 10 As defined in this article, and 6-Het is any of the following:

[0317] (i) a six-membered aromatic nitrogen-containing heterocycle, wherein the heterocycle optionally contains one or two additional heteroatoms selected from N, O, and S; or

[0318] (iii) A six-membered non-aromatic nitrogen-containing heterocycle, wherein the heterocycle optionally contains one or two additional heteroatoms selected from N and S.

[0319] When ring A is a six-membered nitrogen-containing ring, if the ring is aromatic, the ring may optionally contain one or two additional heteroatoms selected from N, O, and S. However, if the six-membered nitrogen-containing ring is non-aromatic, the ring may optionally contain one or two additional heteroatoms selected from N and S, meaning the ring may not contain an additional heteroatom of O.

[0320] In one embodiment, 6-Het is a six-membered nitrogen-containing heterocycle, wherein the heterocycle optionally contains one or two additional heteroatoms selected from N and S.

[0321] Specifically, 6-Het is a six-membered nitrogen-containing heterocycle, wherein the heterocycle optionally contains one or two additional heteroatoms selected from N.

[0322] Specifically, 6-Het is a six-membered nitrogen-containing heterocycle, wherein the heterocycle optionally contains an additional heteroatom selected from N.

[0323] Specifically, 6-Het is a six-membered nitrogen-containing heterocycle, wherein the heterocycle contains an additional heteroatom, and the additional heteroatom is N.

[0324] In one embodiment, part

[0325]

[0326] Choose from the following options in Table II, where c is 0, 1, 2, or 3:

[0327] Table II

[0328]

[0329]

[0330] Specifically, some

[0331]

[0332] Choose from options D, E, G, and H in Table II, and more specifically from D, E, and H, such as D.

[0333] Specifically, some

[0334]

[0335] Selected from:

[0336]

[0337] Where c is 0, 1, 2 or 3.

[0338] Specifically, some

[0339]

[0340] yes:

[0341]

[0342] Where c is 0, 1, 2 or 3.

[0343] Specifically, some

[0344]

[0345] Choose from options E and G in Table II, specifically option G.

[0346] Specifically, some

[0347]

[0348] Selected from:

[0349]

[0350] Where c is 0, 1, 2 or 3.

[0351] Specifically, some

[0352] yes:

[0353]

[0354] Where c is 0, 1, 2 or 3.

[0355] In one embodiment, the compound of formula (I) is the compound of formula (XII) or its tautomer, solvate, or pharmaceutically acceptable salt:

[0356]

[0357] Among them, X and R 1 R 2 R 3 R 8 R 9 and R 10 As defined in this article.

[0358] In one embodiment, the compound of formula (XII) is a compound of formula (XIIa) or a tautomer or solvate thereof or a pharmaceutically acceptable salt thereof:

[0359]

[0360] Where X and R 1 R 2 R 3 R 8 and R 9 As defined in this article.

[0361] In one embodiment, the compound of formula (XII) is a compound of formula (XIIb) or its tautomer, solvate, or pharmaceutically acceptable salt:

[0362]

[0363] Where X and R 1 R 2 R 3 R 8 R 9 and R 10 As defined in this article.

[0364] In one embodiment, the compound of formula (XII) is a compound of formula (XIIc) or its tautomer, solvate, or pharmaceutically acceptable salt:

[0365]

[0366] Where X and R 1 R 2 R 3 R 8 R 9 and R 10 As defined in this article.

[0367] In one embodiment of the compound of formula (XIIc), R 10 It is halogen, cyano, C 1-4 Alkyl groups (e.g., -CH3, -CH(CH3)2, or -CH2CH3), halogenated C 1-4 Alkyl groups (e.g., -CHF2), C 1-4 Alkyl groups (e.g., -OCH3, -OCH2CH3 and -OCH(CH3)2), hydroxyl groups C 1-4 Alkyl groups (e.g., -CH2C(CH3)2OH, -CH(CH3)CH2OH, -CH(CH3)OH, -CH2CH2OH, or -CH2OH), amino groups, mono-C groups 1-4 Alkylamino, diC 1-4 Alkylamino (e.g., -N(CH3)2), amino C 1-4 Alkylene (e.g., -CH2NH2) and optionally substituted four- to six-membered saturated heterocyclic groups containing one or two heteroatoms selected from O, N, or S, wherein the optional substituents are selected from C. 1-4 alkyl.

[0368] In one embodiment of the compound of formula (XIIc), R 10 It is 2C 1-4 Alkylamino (e.g., -N(CH3)2), C 1-4 Alkyl groups (e.g., -OCH3, -OCH2CH3 and -OCH(CH3)2), halogenated C 1-4 Alkyl groups (e.g., -CF3) and optionally substituted four- to six-membered saturated heterocyclic groups containing one or two heteroatoms selected from O, N, or S, wherein the optional substituents are selected from C. 1-4 alkyl.

[0369] In one embodiment, ring A comprises a nitrogen atom adjacent to (i.e., directly bonded to) the benzene ring, and the compound of formula (I) is a compound of formula (XIIIa) or (XIIIb) or a tautomer or solvate thereof or a pharmaceutically acceptable salt thereof, i.e.:

[0370]

[0371] Among them, X, Q, R 1 R 2 R 3 R 8 R 9 and R 10 As defined in this article.

[0372] R 10 Independently selected from: halogen; cyano; cyano C 1-4 Alkyl (e.g., -CH2-CN); hydroxyl; =O (oxo); C 1-4 Alkyl groups (e.g., -CH3, -CH(CH3)2, or -CH2CH3); halogenated C 1-4 Alkyl group (e.g., -CHF2); C 1-4 Alkyl groups (e.g., -OCH3, -OCH2CH3, and -OCH(CH3)2); hydroxyl groups C 1-4 Alkyl groups (e.g., -CH2C(CH3)2OH, -CH(CH3)CH2OH, -CH(CH3)OH, -CH2CH2OH, or -CH2OH); C 1-4 Alkoxy C 1-4 Alkylene (e.g., -CH2-O-CH3 or -CH2-CH2-O-CH3); C 1-4 Alkyl sulfones (e.g., -SO2CH3); amino groups; single carbon atoms 1-4 Alkylamino; diC 1-4 Alkylamino (e.g., -N(CH3)2); amino C 1-4 Alkylene (e.g., -CH2NH2); -C 1-4 Alkylene-C(=O)NH(2-q) (C 1-6 alkyl) q ;-C 1-4 Alkylene-NHC(=O)C 1-6 Alkyl; sulfonamide C 0-4 Alkylenes (e.g., -SO2NR) x 2 or -CH2SO2NR x 2, where R x Independently selected from H and C 1-6 Alkyl); 3- to 6-membered cycloalkyl; containing one, two, three, or four heteroatoms selected from O, N, or S, optionally substituted five- or six-membered unsaturated heterocyclic groups, wherein the optional substituents are selected from C. 1-4 Alkyl; C substituted with 3 to 6-membered cycloalkyl groups 1-4 Alkyl group; C-shaped alkyl group substituted with a optionally substituted five- or six-membered unsaturated heterocyclic group containing one, two, three, or four heteroatoms selected from O, N, or S. 1-4 Alkyl group, wherein optional substituents are selected from C10. 1-4 Alkyl group; C-shaped alkyl group substituted with a optionally substituted four- or six-membered saturated heterocyclic group containing one or two heteroatoms selected from O, N, or S. 1-4 Alkyl group, wherein optional substituents are selected from C10. 1-4 Alkyl group; and optionally substituted four- or six-membered saturated heterocyclic groups containing one or two heteroatoms selected from O, N or S, wherein the optional substituents are selected from C. 1-4 Alkyl; and

[0373] q is selected from 0, 1, and 2.

[0374] In one embodiment, R 10 Independently selected from halogen, cyano, cyano C 1-4 Alkyl (e.g., -CH2-CN), hydroxyl, =O (oxo), C 1-4 Alkyl groups (e.g., -CH3 or -CH2CH3), halogenated C 1-4 Alkyl, C 1-4 Alkyl groups (e.g., -OCH3), hydroxyl groups (C) 1-4 Alkyl groups (e.g., -CH2C(CH3)2OH, -CH(CH3)CH2OH, -CH(CH3)OH, -CH2CH2OH or -CH2OH), C 1-4 Alkoxy C 1-4 Methylene (e.g., -CH2-O-CH3 or -CH2-CH2-O-CH3), C 1-4 Alkyl sulfones (e.g., -SO2CH3), amino groups, mono-C 1-4 Alkylamino, diC 1-4 Alkylamino (e.g., -N(CH3)2), amino C1-4 Methylene (e.g., -CH2NH2), -C 1-4 Methylene-C(=O)NH (2-q) (C 1-6 alkyl) q -C 1-4 Methylene-NHC(=O)C 1-6 Alkyl, sulfonamide C 0-4 Methylene (e.g., -SO2NR) x 2 or -CH2SO2NR x 2, where R x Independently selected from H and C 1-6 Alkyl group and optionally substituted four- to six-membered saturated heterocyclic groups containing one or two heteroatoms selected from O, N or S, wherein the optional substituents are selected from C 1-4 Alkyl; and

[0375] q is selected from 0, 1, and 2.

[0376] In one embodiment, R 10 Independently selected from halogen, cyano, cyano C 1-4 Alkyl (e.g., -CH2-CN), hydroxyl, =O (oxo), C 1-4 Alkyl groups (e.g., -CH3 or -CH2CH3), halogenated C 1-4 Alkyl, C 1-4 Alkyl groups (e.g., -OCH3), hydroxyl groups (C) 1-4 Alkyl groups (e.g., -CH2C(CH3)2OH, -CH(CH3)CH2OH, -CH(CH3)OH, -CH2CH2OH, or -CH2OH), -C 1-4 Methylene C 1-4 Alkyl groups (e.g., -CH2-O-CH3 or -CH2-CH2-O-CH3), C 1-4 Alkyl sulfones (e.g., -SO2CH3), amino groups, mono-C 1-4 Alkylamino, diC 1-4 Alkylamino (e.g., -N(CH3)2), -C 1-4 Methylene amino (e.g., -CH2NH2), -C 1-4 Methylene-C(=O)NH (2-q) (C 1-6 alkyl) q -C 1-4 Methylene-NHC(=O)C 1-6 Alkyl, -C 0-4 Methylenesulfonamide (e.g., -SO2NR) x 2 or -CH2SO2NR x 2, where R xIndependently selected from H and C 1-6 Alkyl group and optionally substituted four- to six-membered saturated heterocyclic groups containing one or two heteroatoms selected from O, N or S, wherein the optional substituents are selected from C 1-4 alkyl.

[0377] In one embodiment, there are two substituents R 10 ; An R 10 It is = O (oxo), and an R 10 Independently selected from halogen, cyano, cyano C 1-4 Alkyl (e.g., -CH2-CN), hydroxyl, C 1-4 Alkyl groups (e.g., -CH3 or -CH2CH3), halogenated C 1-4 Alkyl, C 1-4 Alkyl groups (e.g., -OCH3), hydroxyl groups (C) 1-4 Alkyl groups (e.g., -CH2C(CH3)2OH, -CH(CH3)CH2OH, -CH(CH3)OH, -CH2CH2OH or -CH2OH), C 1-4 Alkoxy C 1-4 Methylene (e.g., -CH2-O-CH3 or -CH2-CH2-O-CH3), C 1-4 Alkyl sulfones (e.g., -SO2CH3), amino groups, mono-C 1-4 Alkylamino, diC 1-4 Alkylamino (e.g., -N(CH3)2), amino C 1-4 Methylene (e.g., -CH2NH2), -C 1-4 Methylene-C(=O)NH (2-q) (C 1-6 alkyl) q -C 1-4 Methylene-NHC(=O)C 1-6 Alkyl, sulfonamide C 0-4 Methylene (e.g., -SO2NR) x 2 or -CH2SO2NR x 2, where R x Independently selected from H and C 1-6 Alkyl group and optionally substituted four- to six-membered saturated heterocyclic groups containing one or two heteroatoms selected from O, N or S, wherein the optional substituents are selected from C 1-4 alkyl.

[0378] In one embodiment, q is 0 or 1. Specifically, q is 1. Specifically, q is 2.

[0379] In one embodiment, there are no substituents or there is one substituent R. 10 Specifically, there exists a substituent R.10 .

[0380] Specifically, there are two substituents R 10 Specifically, there is no substituent R. 10 .

[0381] In one embodiment, R 10 Independently selected from halogen, cyano, cyano C 1-4 Alkyl (e.g., -CH2-CN), hydroxyl, =O (oxo), C 1-4 Alkyl groups (e.g., -CH3 or -CH2CH3), halogenated C 1-4 Alkyl, C 1-4 Alkyl groups (e.g., -OCH3), hydroxyl groups (C) 1-4 Alkyl groups (e.g., -CH(CH3)CH2OH, -CH(CH3)OH, -CH2CH2OH, or -CH2OH), di-C 1-4 Alkylamino (e.g., -N(CH3)2) and C 1-4 Alkoxy C 1-4 Methylene (e.g., -CH2-O-CH3), for example, where R 10 Independently selected from halogen, cyano, hydroxyl, =O (oxo) and C 1-4 Alkyl groups (e.g., -CH3 or -CH2CH3).

[0382] In one embodiment, R 10 Independently selected from halogen, cyano, cyano C 1-4 Alkyl (e.g., -CH2-CN), hydroxyl, =O (oxo), C 1-4 Alkyl groups (e.g., -CH3 or -CH2CH3), halogenated C 1-4 Alkyl, C 1-4 Alkyl groups (e.g., -OCH3), hydroxyl groups (C) 1-4 Alkyl groups (e.g., -CH(CH3)CH2OH, -CH(CH3)OH, -CH2CH2OH, or -CH2OH) and C 1-4 Alkoxy C 1-4 Methylene (e.g., -CH2-O-CH3), for example, where R 10 Independently selected from halogen, cyano, hydroxyl, =O (oxo) and C 1-4 Alkyl groups (e.g., -CH3 or -CH2CH3).

[0383] In one embodiment, R 10 Independently selected from halogen, cyano, cyano C 1-4 Alkyl (e.g., -CH2-CN), hydroxyl, =O (oxo), C 1-4 Alkyl groups (e.g., -CH3 or -CH2CH3), halogenated C1-4 Alkyl, C 1-4 Alkyl groups (e.g., -OCH3), hydroxyl groups (C) 1-4 Alkyl groups (e.g., -CH(CH3)CH2OH, -CH(CH3)OH, -CH2CH2OH, or -CH2OH) and C 1-4 Alkoxy C 1-4 Methylene (e.g., -CH2-O-CH3), for example, where R 10 Independently selected from halogen, cyano, hydroxyl, =O (oxo) and C 1-4 Alkyl groups (e.g., -CH3 or -CH2CH3).

[0384] In one embodiment, R 10 Independently selected from halogen, cyano, hydroxyl, =O (oxo) and C 1-4 Alkyl groups (e.g., -CH3 or -CH2CH3), for example, where R 10 Independently selected from hydroxyl, =O (oxo), and C 1-4 Alkyl groups (e.g., -CH3).

[0385] In one embodiment, R 10 Independently selected from halogens (e.g., chlorine or fluorine), =O (oxo), C 1-4 Alkyl groups (e.g., -CH3, -CH2CH3, -CH(CH3)2), C 1-4 Alkyl groups (e.g., -OCH3) and dicarbonyl groups 1-4 Alkylamino (e.g., -N(CH3)2), for example, where R 10 Independently selected from halogens, =O (oxo) and C 1-4 Alkyl groups (e.g., -CH3 or -CH2CH3).

[0386] In one embodiment, R 10 Independently selected from halogens (e.g., chlorine), cyano, cyano C 1-4 Alkyl (e.g., -CH2-CN), C 1-4 Alkyl groups (e.g., -OCH3, -OCH2CH3 and -OCH(CH3)2), =O (oxo), C 1-4 Alkyl groups (e.g., -CH3, -CH2CH3, -CH(CH3)2), hydroxyl groups (C) 1-4 Alkyl groups (e.g., -CH2OH, -CH2CH2OH or -CH2C(CH3)2OH), halogenated C 1-4 Alkyl (e.g., -CHF2), di-C 1-4 Alkylamino (e.g., -N(CH3)2), C 1-4 Alkoxy C 1-4Methylene (e.g., -CH2-O-CH3 or -CH2-CH2-O-CH3), -C 0-4 Methylene-C(=O)NH (2-q) (C 1-6 alkyl) q (e.g., -CO-N(CH3)2, -CH2-CH2-CO-N(CH3)2, -CH2-CO-N(CH3)2, -CH2-CO-NH(C(CH3)3) or -CH2-CO-NH(CH3)), four- or six-membered saturated heterocyclic groups containing O or N (e.g., tetrahydrofuranyl, morpholino, aziridine, or oxetane), and C-membered unsaturated heterocyclic groups (e.g., five-membered heterocyclic groups) optionally substituted with one, two, three, or four heteroatoms selected from O, N, and S (e.g., N or O). 1-4 Alkyl (e.g., C1 alkyl), wherein optional substituents are selected from C1 alkyl. 1-4 Alkyl groups (e.g., -CH3).

[0387] In one embodiment, R 10 It is a halogen (e.g., chlorine), a cyano group, or a C group. 1-4 Alkyl groups (e.g., -CH3, -CH(CH3)2, or -CH2CH3), halogenated C 1-4 Alkyl groups (e.g., -CHF2), C 1-4 Alkyl groups (e.g., -OCH3, -OCH2CH3, or -OCH(CH3)2), C 1-4 Alkoxy C 1-4 Methylene (e.g., -CH2OCH3), dimethyl 1-4 Alkylamino (e.g., -N(CH3)2) or a optionally substituted (e.g., unsubstituted) four- or six-membered saturated heterocyclic group containing one or two heteroatoms selected from O or N, wherein the optional substituents are selected from C 1-4 Alkyl (e.g., morpholino or aziridine).

[0388] In one embodiment, R 10 It is -C 0-4 Methylene-C(=O)NH (2-q) (C 1-6 alkyl) q It is selected from -C 1-4 Methylene-C(=O)NH (2-q) (C 1-6 alkyl) q (For example, -CH2-CH2-CO-N(CH3)2, -CH2-CO-N(CH3)2, -CH2-CO-NH(C(CH3)3) or -CH2-CO-NH(CH3) and -CO-N(CH3)2).

[0389] In one embodiment, R 10 Independently selected from halogen, cyano, hydroxyl, =O (oxo) and C 1-4 Alkyl groups (e.g., -CH3 or -CH2CH3), for example, where R 10 Selected independently from C 1-4 Alkyl (e.g., -CH3), halogen, or oxo.

[0390] In one embodiment, R 10 Independently selected from =O (oxo), hydroxyl and C 1-4 Alkyl groups (e.g., -CH3 or -CH2CH3). Specifically, R 10 It is independently selected from =O (oxo), hydroxyl and -CH3.

[0391] Specifically, there exists a substituent R 10 And R 10 Selected from =O (oxo), hydroxyl and -CH3.

[0392] Specifically, there exists a substituent R 10 And R 10 It is -CH3.

[0393] In one embodiment, there are two substituents R 10 And an R 10 It is = O (oxo) and one R 10 It is C 1-4 Alkyl groups (e.g., -CH3 or -CH2CH3).

[0394] In one embodiment, there are two substituents R 10 And one is a halogen, such as chlorine, and one is an R 10 It is C 1-4 Alkyl groups (e.g., -CH3 or -CH2CH3).

[0395] In one embodiment, R 10 It is C 1-4 Alkyl groups (e.g., -CH3, -CH2CH3 or -CH(CH3)2).

[0396] In one embodiment, R 10 It is a halogen, such as chlorine.

[0397] In one embodiment, R 10 It is a optionally substituted four- or six-membered saturated heterocyclic group containing one or two heteroatoms selected from O, N or S, wherein the optional substituents are selected from C. 1-4 alkyl.

[0398] In one embodiment, R10 It is a optionally substituted four- or six-membered saturated heterocyclic group containing one or two heteroatoms selected from O and N, wherein the optional substituents are selected from C. 1-4 alkyl.

[0399] In one embodiment, R 10 It is a four- or six-membered saturated heterocyclic group (e.g., morpholino or azirrobutane) containing one or two heteroatoms selected from O and N.

[0400] In one embodiment, R 10 Independently selected from halogens (e.g., chlorine), C 1-4 Alkyl groups (e.g., -OCH3), =O (oxo), C 1-4 Alkyl groups (e.g., -CH3 or -CH2CH3), hydroxyl groups (C) 1-4 Alkyl groups (e.g., -CH2CH2OH or -CH2OH), dicarbonyl groups 1-4 Alkylamino (e.g., -N(CH3)2), C 1-4 Alkoxy C 1-4 Methylene groups (e.g., -CH2-O-CH3 or -CH2-CH2-O-CH3) and four- or six-membered saturated heterocyclic groups containing O (e.g., tetrahydrofuran).

[0401] It should be understood that for heterocycles and substituents R 10 The above definition covers all possible tautomer forms of the ring. Therefore, for example, the following compounds can exist in the following tautomer forms and all fall within the scope of formula (I):

[0402]

[0403] Moreover, for example, the following compounds can exist in the following tautomer forms and all fall within the scope of formula (I):

[0404]

[0405] In one embodiment, part

[0406]

[0407] Selected from:

[0408]

[0409] In one embodiment, part

[0410]

[0411] Selected from:

[0412]

[0413] In one embodiment, part

[0414]

[0415] Selected from:

[0416]

[0417] In one embodiment, part

[0418]

[0419] Selected from:

[0420]

[0421] In one embodiment, part

[0422]

[0423] Selected from:

[0424]

[0425]

[0426] Specifically, in one embodiment, part

[0427]

[0428] Selected from:

[0429]

[0430] Specifically, in one embodiment, part

[0431]

[0432] yes:

[0433]

[0434] Specifically, in one embodiment, part

[0435]

[0436] yes:

[0437]

[0438] Combination of substituents

[0439] In one embodiment, the compound of formula (I) is a compound of formula (XIV') or a tautomer or solvate thereof or a pharmaceutically acceptable salt:

[0440]

[0441] Where X and R 2 R 3 R 6 R 7 R 8 and R 9 As defined in this article.

[0442] In one embodiment, the compound of formula (XIV') is a compound of formula (XV) or its tautomer, solvate, or pharmaceutically acceptable salt:

[0443]

[0444] Where R 2 R 3 R 6 R 7 R 8 and R 9 As defined in this article.

[0445] In one embodiment, the compound of formula (XV) is a compound of formula (XVI) or its tautomer, solvate, or pharmaceutically acceptable salt:

[0446]

[0447] Where R 3 R 6 R 7 R 8 and R 9 As defined in this article.

[0448] In one embodiment, the compound of formula (XVI) is a compound of formula (XVIa) or its tautomer, solvate, or pharmaceutically acceptable salt:

[0449]

[0450] Where R 3 R 6 R 7 R 8 and R 9 As defined in this article.

[0451] In one embodiment, the compound of formula (XVIa) is a compound of formula (XVIb) or its tautomer, solvate, or pharmaceutically acceptable salt:

[0452]

[0453] Where R 6 R 7 R 8 and R 9 As defined in this article.

[0454] In one embodiment, the compound of formula (XVIb) is a compound of formula (XVII) or its tautomer, solvate, or pharmaceutically acceptable salt:

[0455]

[0456] Where R 6 R 7 and R 8 As defined herein. In one embodiment, R 8 It is halogen.

[0457] In one embodiment, the compound of formula (XVII) is a compound of formula (XVIII) or its tautomer, solvate, or pharmaceutically acceptable salt:

[0458]

[0459] Where R 1 R 2 R 3 R 8 R 9 A and R 10 As defined in this article.

[0460] In one embodiment of the compound of formula (XVIII), part

[0461]

[0462] Selected from the following, where R 8 It is halogen:

[0463]

[0464]

[0465] Specifically, in one embodiment of the compound of formula (XVIII), part of

[0466]

[0467] Selected from the following, where R 8 It is halogen:

[0468]

[0469] For example

[0470] Specific compound groups

[0471] On one hand, the present invention provides a compound of formula (I*):

[0472]

[0473] Or its tautomers, solvates, or pharmaceutically acceptable salts, wherein:

[0474] R 1 It is hydrogen or hydroxyl;

[0475] R 2 It is hydrogen;

[0476] R 3 Is it hydrogen or C? 1-4 Alkyl groups (e.g., -CH3);

[0477] X is O or CR 4 R 5 ;

[0478] Where X is CR 4 R 5 At that time, R 4 and R 5 C is independently selected from hydrogen, halogens (e.g., fluorine), and C that is optionally substituted with one or more halogens. 1-4 Alkyl groups (e.g., -CF3);

[0479] R 6 and R 7 Independently selected from hydrogen and halogens (e.g., chlorine or fluorine);

[0480] Or R 6 and R 7 Joined to form optionally by one or more (e.g., 1, 2, or 3) R 10 Ring A substituted with a group;

[0481] Wherein ring A is a five- or six-membered aromatic heterocycle comprising one or two nitrogen atoms (e.g., two nitrogen atoms);

[0482] R 8 It is a halogen (e.g., chlorine or fluorine);

[0483] R 9 It is hydrogen;

[0484] R 10 Independently selected from halogens (e.g., chlorine), C 1-4 Alkyl groups (e.g., -CH3 or -CH2CH3), C 1-4Alkyl groups (e.g., -OCH3), dicarbonyl groups 1-4 Alkylamino (e.g., -N(CH3)2), halogenated C 1-4 Alkyl groups (e.g., -CF3) and optionally substituted four- to six-membered saturated heterocyclic groups containing one or two heteroatoms selected from O, N, or S, wherein the optional substituents are selected from C. 1-4 Alkyl (e.g., morpholino or aziridine).

[0485] In one embodiment of the compound of formula I*, part of

[0486]

[0487] Selected from:

[0488]

[0489] Specifically, in one embodiment of the compound of formula I*, part of

[0490]

[0491] Selected from:

[0492]

[0493] For example

[0494] Specific compounds

[0495] In one embodiment, the present invention provides a compound of formula (I), which is one of Examples 1-27 or a tautomer thereof, an N-oxide, a pharmaceutically acceptable salt or solvate.

[0496] In one embodiment, the present invention provides compounds of formula (I) selected from the following compounds or their tautomers, N-oxides, pharmaceutically acceptable salts or solvates:

[0497] {6-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-3-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl}methanol;

[0498] (3S,4S)-8-{3-[5-chloro-3-(dimethylamino)quinoxalin-6-yl]-5-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl}-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-amine;

[0499] {6-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-3-(2-chlorophenyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl}methanol;

[0500] {6-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-3-(3-chloro-2-fluorophenyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl}methanol; and

[0501] {6-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-3-(5-chloro-3-methoxyquinoxalin-6-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl}methanol.

[0502] In one embodiment, the present invention provides a compound of formula (I) or a tautomer thereof, an N-oxide, a pharmaceutically acceptable salt or solvate thereof, said compound being:

[0503] {6-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-3-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl}methanol.

[0504] In one embodiment, the present invention provides a compound of formula (I) or a tautomer thereof, an N-oxide, a pharmaceutically acceptable salt or solvate thereof, said compound being:

[0505] (3S,4S)-8-{3-[5-chloro-3-(dimethylamino)quinoxalin-6-yl]-5-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl}-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-amine.

[0506] In one embodiment, the present invention provides a compound of formula (I) or a tautomer thereof, an N-oxide, a pharmaceutically acceptable salt or solvate thereof, said compound being:

[0507] {6-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-3-(2-chlorophenyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl}methanol.

[0508] In one embodiment, the present invention provides a compound of formula (I) or a tautomer thereof, an N-oxide, a pharmaceutically acceptable salt or solvate thereof, said compound being:

[0509] {6-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-3-(3-chloro-2-fluorophenyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl}methanol.

[0510] In one embodiment, the present invention provides a compound of formula (I) or a tautomer thereof, an N-oxide, a pharmaceutically acceptable salt or solvate thereof, said compound being:

[0511] {6-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-3-(5-chloro-3-methoxyquinoxalin-6-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl}methanol.

[0512] For the avoidance of doubt, it should be understood that each general and specific embodiment and example of a substituent may be combined with one or more, specifically all other general and specific embodiments and examples of substituents as defined herein, and this application covers all such embodiments.

[0513] In one embodiment, the present invention provides a compound of formula (I) as defined herein, or a tautomer or solvate thereof or a pharmaceutically acceptable salt thereof, wherein X, R 1 R 2 R 3 R 6 R 7 R 8 and R 9 As defined herein, and wherein the compound of formula (I) is not:

[0514]

[0515] That is, it is not 6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)-3-(2,3-dichlorophenyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)methanol.

[0516] In one embodiment, the present invention provides a compound of formula (I) as defined herein, or a tautomer or solvate thereof or a pharmaceutically acceptable salt thereof, wherein X, R 1 R 2 R 3 R 6 R 7 R 8 and R 9 As defined herein, and wherein the compound of formula (I) is not:

[0517] or its salts or tautomers

[0518] That is, it is not 6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)-3-(2,3-dichlorophenyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)methanol or its salts or tautomers.

[0519] In one embodiment, the present invention provides a compound of formula (I) as defined herein, or a tautomer or solvate thereof or a pharmaceutically acceptable salt thereof, wherein X, R 1 R 2 R 3 R 6 R 7 R 8 and R 9 As defined herein, and wherein the compound of formula (I) is not Example 16 of WO2019213318.

[0520] In one embodiment, the present invention provides a compound of formula (I) as defined herein, or a tautomer or solvate thereof or a pharmaceutically acceptable salt thereof, wherein X, R 1 R 2 R 3 R 6 R 7 R 8 and R 9 As defined herein, and wherein the compound of formula (I) is not:

[0521]

[0522] That is, it is not (6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)-3-(2-fluoro-3-chlorophenyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)methanol.

[0523] In one embodiment, the present invention provides a compound of formula (I) as defined herein, or a tautomer or solvate thereof or a pharmaceutically acceptable salt thereof, wherein X, R 1 R 2 R 3 R 6 R 7 R 8 and R 9 As defined herein, and wherein the compound of formula (I) is not:

[0524] or its salts or tautomers

[0525] That is, it is not (6-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)-3-(2-fluoro-3-chlorophenyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)methanol or its pharmaceutically acceptable salt or tautomer.

[0526] In one embodiment, the present invention provides a compound of formula (I) as defined herein, or a tautomer or solvate thereof or a pharmaceutically acceptable salt thereof, wherein X, R 1 R 2 R 3 R 6 R 7 R 8 and R 9 As defined herein, and wherein the compound of formula (I) is not Example 19C of WO2019183364.

[0527] Salts, solvates, tautomers, isomers, N-oxides, esters, prodrugs, and isotopes

[0528] For formula (I), its subgroups (for example, formulas (I), (Ia), (Ib), (Ib'), (Ib"), (II), (III), (III'), (IV), (IV'), (IV"), (V), (VI), (VII), (VIII), ( VIIIa), (VIIIb), (VIIIc), (IX), (IXa), (X), (XI), (XII), (XIIa), (XIIb), (XIIb), (XIIc), (XIIIa), (XIIIb), (XIV) References to compounds (XIV'), (XV), (XVI), (XVIa), (XVIb), (XVII), (XVIII) and (I*) and any instances thereof also include, for example, their ionic forms, salts, solvates, isomers (unless otherwise specified, including geometric and stereochemical isomers), tautomers, N-oxides, esters, prodrugs, isotopes, and protected forms, as discussed below; specifically, their salts or tautomers or isomers or N-oxides or solvates; and more specifically, their salts or tautomers or N-oxides or solvates. In one embodiment, references to compounds of formula (I), its subgroups (e.g., (I), (Ia), (Ib), (Ib'), (Ib"), (II), (III), (III'), (IV), (IV'), (IV"), (V), (VI), (VII), (VIII), (VIIIa), (VIIIb), (VIIIc), (IX), (IXa), (X), (XI), (XII), (XIIa), (XIIb), (XIIb), (XIIc), (XIIIa), (XIIIb), (XIV), (XIV'), (XV), (XVI), (XVIa), (XVIb), (XVII), (XVIII) and (I*)) and any instances thereof also include their salts or tautomers or solvates.

[0529] Salt

[0530] Many compounds of formula (I) may exist as salts, such as acid addition salts, or in some cases as salts of organic and inorganic bases, such as carboxylates, sulfonates, and phosphates. All of these salts are within the scope of this invention, and references to compounds of formula (I) include the salt forms of said compounds.

[0531] The salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing basic or acidic moieties, such as those described in the following literature: *Pharmaceutical Salts: Properties, Selection, and Use*, P. Heinrich Stahl (ed.), Camille G. Wermuth (ed.), ISBN: 3-90639-026-8, hardcover, 388 pages, August 2002. Such salts are typically prepared by reacting the free acidic or basic form of these compounds with a suitable base or acid in water, in an organic solvent, or in a mixture thereof; generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.

[0532] Acid addition salts (monosal or diosal) can be formed from a wide variety of acids (both inorganic and organic). Examples of acid addition salts include monosal or diosal salts formed from acids selected from: acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid (e.g., L-ascorbic acid), L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetaminobenzoic acid, butyric acid, (+)camphoric acid, camphor-sulfonic acid, (+)-(1S)-camphor-10-sulfonic acid, decanoic acid, hexanoic acid, octanoic acid, cinnamic acid, citric acid, cyclohexane, dodecyl sulfate, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, mucilage, gentian acid, glucoheponic acid, D-gluconic acid, glucuronic acid (e.g., D-glucuronic acid), glutamic acid (e.g., L-glutamic acid), α-oxoglutarate, glycolic acid, and malonic acid. Uric acid, hydrohalic acids (e.g., hydrobromic acid, hydrochloric acid, hydroiodic acid), hydroxyethanesulfonic acid, lactic acid (e.g., (+)-L-lactic acid, (±)-DL-lactic acid), lactobionic acid, maleic acid, malic acid, (-)-L-malic acid, malonic acid, (±)-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, dihydroxynaphthoic acid, phosphoric acid, propionic acid, pyruvic acid, L-pyroglutamic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanate, p-toluenesulfonic acid, undecenoic acid and valeric acid, as well as acylated amino acids and cation exchange resins.

[0533] A specific group of salts consists of salts formed from the following: acetic acid, hydrochloric acid, hydroiodic acid, phosphoric acid, nitric acid, sulfuric acid, citric acid, lactic acid, succinic acid, maleic acid, malic acid, ethanesulfonic acid, fumaric acid, benzenesulfonic acid, toluenesulfonic acid, methanesulfonic acid (methanesulfonates), ethanesulfonic acid, naphthalenesulfonic acid, valeric acid, acetic acid, propionic acid, butyric acid, malonic acid, glucuronic acid, and lactobionic acid. A specific salt is a hydrochloride salt.

[0534] In one embodiment, the compound is a sodium salt or a methanesulfonate.

[0535] If the compound is anionic or has a functional group that can be anionic (e.g., -COOH can be -COO-), then the salt can be formed using an organic or inorganic base, thereby producing a suitable cation. Examples of suitable inorganic cations include, but are not limited to, Li. + Na + and K + Alkali metal ions, such as Ca 2+ and Mg 2+ Alkaline earth metal cations and such as Al 3+ or Zn + Other cations. Examples of suitable organic cations include, but are not limited to, ammonium ions (i.e., NH4+). + ) and substituted ammonium ions (e.g., NH3R) + NH2R2 + NHR3 + NR4 + Examples of suitable substituted ammonium ions are derived from: methylamine, ethylamine, diethylamine, propylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, as well as amino acids such as lysine and arginine. A common example of a quaternary ammonium ion is N(CH3)4. + .

[0536] In the case where the compounds of formula (I) contain amine functional groups, these compounds can be reacted with an alkylating agent, for example, according to methods well known to those skilled in the art, to form quaternary ammonium salts. Such quaternary ammonium compounds are within the scope of formula (I) of the present invention.

[0537] The compounds of the present invention can exist as a single salt or a disalt, depending on the pKa of the acid from which the salt is formed.

[0538] The salt forms of the compounds of this invention are generally pharmaceutically acceptable salts, and examples of pharmaceutically acceptable salts are discussed in Berge et al., 1977, “Pharmaceutically Acceptable Salts”, *Journal of Pharmaceutical Science*, Vol. 66, pp. 1-19. However, pharmaceutically unacceptable salts can also be prepared as intermediates, which can then be converted into pharmaceutically acceptable salts. Such non-pharmaceutically acceptable salt forms, for example, that can be used for the purification or isolation of the compounds of this invention, also form part of this invention.

[0539] In one embodiment of the invention, a pharmaceutical composition is provided comprising a solution (e.g., an aqueous solution) containing a compound of formula (I) as described herein and its subgroups and examples in salt form at a concentration greater than 10 mg / ml, typically greater than 15 mg / ml and typically greater than 20 mg / ml.

[0540] N-oxides

[0541] Compounds of formula (I) containing amine functional groups can also form N-oxides. References to compounds of formula (I) containing amine functional groups in this document also include N-oxides.

[0542] When a compound contains several amine functional groups, one or more nitrogen atoms can be oxidized to form N-oxides. Specific examples of N-oxides are tertiary amines containing nitrogen heterocyclic groups or N-oxides of nitrogen atoms.

[0543] N-oxides can be formed by treating the corresponding amines with oxidizing agents, such as hydrogen peroxide or peracids (e.g., peroxycarboxylic acids), see, for example, *Advanced Organic Chemistry*, Jerry March, 4th ed., Wiley International Scientific Press, p. [page number missing]. More specifically, N-oxides can be prepared by the procedure of LWDeady (*Synthetic Communications*, 1977, 7, 509-514), in which the amine compound reacts with m-chloroperoxybenzoic acid (MCPBA), for example, in an inert solvent such as dichloromethane.

[0544] In one embodiment of the invention, the compound is an N-oxide, for example, from R 6 Or R 7 Nitrogen atoms on groups, such as pyridine N-oxide.

[0545] Geometric isomers and tautomers

[0546] Compounds of formula (I) may exist in a variety of different geometric isomers and tautomers, and references to compounds of formula (I) include all of these forms. For the avoidance of doubt, where a compound may exist in one of several geometric isomers or tautomers and only one geometric isomer or tautomer is specifically described or shown, formula (I) still covers all other forms.

[0547] For example, certain heteroaryl rings can exist in two tautomer forms, as shown in A and B below. For the sake of simplicity, the formula may be shown in one form, but it will be considered to cover both tautomer forms.

[0548]

[0549] Other examples of tautomer forms include, for example, ketone, enol, and enol salt forms, such as the following tautomer pairs: ketone / enol (shown below), imine / enamine, amide / imine alcohol, amidine / endiamine, nitroso / oxime, thionone / enthiol, and nitro / acid nitro.

[0550]

[0551] Stereoisomers

[0552] Unless otherwise mentioned or specified, the chemical name of a compound represents a mixture of all possible stereochemical isomers.

[0553] The center of the solid is shown in the usual way, for example, using “dummy” or “solid” wedges.

[0554]

[0555] In cases where the compound is described as a mixture of two diastereomers / epiromers, the configuration of the stereocenter is not specified and is represented by a straight line.

[0556] Where a compound of formula (I) contains one or more chiral centers and may exist in the form of two or more optical isomers, unless the context requires otherwise, references to a compound of formula (I) include all of its optical isomer forms (e.g., enantiomers, epiomers and diastereomers), whether in the form of a single optical isomer or a mixture (e.g., a racemic or non-racemic mixture) or two or more optical isomers.

[0557] Optical isomers can be described and identified by their optical activity (i.e., as + and - isomers or d and l isomers), or they can be characterized by their absolute stereochemistry using the “R and S” nomenclature developed by Cahn, Ingold, and Prelog. See Advanced Organic Chemistry, Jerry March, 4th ed., John Wiley & Sons, New York, 1992, pp. 109-114. See also Cahn, Ingold, and Prelog, Angew. Chem. Int. Ed., 1966, 5, 385-415.

[0558] Optical isomers can be separated by a variety of techniques, including chiral chromatography (chromatography on a chiral support), and such techniques are well known to those skilled in the art.

[0559] As an alternative to chiral chromatography, optical isomers can be separated by forming diastereomeric salts with chiral acids such as (+)-tartaric acid, (-)-pyroglutamic acid, (-)-xyl-L-tartaric acid, (+)-mandelic acid, (-)-malic acid, and (-)-camphorsulfonic acid, separating the diastereomeric isomers by preferential crystallization, and then dissociating the salts to obtain the individual enantiomers of the free base.

[0560] Alternatively, enantiomer separation can be achieved by covalently attaching an enantiomerically pure chiral auxiliary to the compound and then performing diastereomer separation using conventional methods such as chromatography. The covalent bond is then cleaved to yield the appropriately enantiomerically pure product.

[0561] When a compound of formula (I) exists in two or more optical isomers, one of the enantiomers in a pair may exhibit advantages over the other in terms of biological activity, for example. Therefore, in some cases, it may be desirable to use only one of the enantiomers in a pair or only one of the diastereomers as a therapeutic agent.

[0562] Therefore, the present invention provides compositions comprising compounds of formula (I) having one or more chiral centers, wherein at least 55% (e.g., at least 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) of the compound of formula (I) is present in a single optical isomer (e.g., an enantiomer or a diastereomer). In a general embodiment, 99% or more (e.g., substantially all) of the total amount of the compound of formula (I) may be present in a single optical isomer (e.g., an enantiomer or a diastereomer).

[0563] Compounds containing double bonds may have E (opposite-side) or Z (same-side) stereochemistry at the double bond. Substituents on the divalent ring or (partially) saturated group may have cis or trans configurations. The terms cis and trans are used herein according to the Chemical Abstracts Nomenclature (J. Org. Chem. 1970, 35(9), 2849-2867) and refer to the position of the substituent on the ring moiety.

[0564] Of particular interest are those stereochemically pure compounds of formula (I). When a compound of formula (I) is designated, for example, as R, this means that the compound is substantially free of the S isomer. If a compound of formula (I) is designated, for example, as E, this means that the compound is substantially free of the Z isomer. The terms cis, trans, R, S, E, and Z are well known to those skilled in the art.

[0565] Isotope changes

[0566] This invention includes all pharmaceutically acceptable isotopically labeled compounds of the present invention, namely compounds of formula (I), wherein one or more atoms are replaced by atoms having the same atomic number but with an atomic mass or mass number different from those found in nature.

[0567] Examples of isotopes suitable for inclusion in the compounds of the present invention include the following isotopes: such as 2 H(D) and 3 H(T) and other hydrogen, such as 11 C 13 C and 14 Carbon, such as C, etc. 36 Chlorine, such as Cl, etc. 18 F and other fluorine, such as 123 I, 125 I and 131 Iodine grade I, such as 13 N and 15 Nitrogen, such as N, etc. 15 O, such as 17 O and 18 O and other oxygen, such as 32 P and other phosphorus and such 35 S and other sulfur.

[0568] Certain isotope-labeled compounds of formula (I), such as those incorporating radioactive isotopes, can be used in studies of drug and / or substrate tissue distribution. Compounds of formula (I) can also possess valuable diagnostic properties because they can be used to detect or identify the formation of complexes between the labeled compound and other molecules, peptides, proteins, enzymes, or receptors. Detection or identification methods can use compounds labeled with markers such as radioactive isotopes, enzymes, fluorescent substances, and luminescent substances (e.g., luminol, luminol derivatives, luciferin, jellyfish luminescent proteins, and luciferase). The radioactive isotope tritium is... 3 H(T) and the radioactive isotope carbon-14 14 C is particularly useful for this purpose due to its ease of incorporation and readily available detection methods.

[0569] Use heavier isotopes, such as deuterium, i.e. 2 H(D) substitution can provide certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced dose requirements, and therefore can be used in some cases.

[0570] Specifically, every reference to hydrogen in this application should be understood as encompassing 1 H and 2 H, whether hydrogen is explicitly defined or exists implicitly to satisfy the valence of the relevant atom (specifically, carbon).

[0571] Use as11 C 18 F, 15 O and 13 Substitution with positron emission isotopes such as N can be useful in positron emission tomography (PET) studies used to examine target occupancy.

[0572] Isotopically labeled compounds of formula (I) can generally be prepared using conventional techniques known to those skilled in the art or by methods similar to those described in the appended examples and preparations, in place of suitable isotopically labeled reagents instead of previously used unlabeled reagents.

[0573] ester

[0574] Formula (I) also encompasses esters of Formula (I) compounds carrying a carboxylic acid group or a hydroxyl group, such as carboxylic acid esters, acyloxy esters, and phosphate esters. Examples of esters are compounds containing the group -C(=O)OR, where R is an ester substituent, such as C 1-7 Alkyl, C 3-12 Heterocyclic group or C 5-12 Aryl, usually C 1-6 Alkyl groups. Specific examples of ester groups include, but are not limited to, -C(=O)OCH3, -C(=O)OCH2CH3, -C(=O)OC(CH3)3, and -C(=O)OPh. Examples of acyloxy groups (reverse ester groups) are represented by -OC(=O)R, where R is an acyloxy substituent, such as C 1-6 Alkyl, C 3-12 Heterocyclic group or C 5-12 Aryl, usually C 1-6 Alkyl groups. Specific examples of acyl groups include, but are not limited to, -OC(=O)CH3 (acetoxy), -OC(=O)CH2CH3, -OC(=O)C(CH3)3, -OC(=O)Ph, and -OC(=O)CH2Ph. Examples of phosphate esters are those phosphate esters derived from phosphoric acid.

[0575] In one embodiment of the invention, formula (I) includes, within its scope, an ester of a compound of formula (I) carrying a carboxylic acid group or a hydroxyl group. In another embodiment of the invention, formula (I) does not include, within its scope, an ester of a compound of formula (I) carrying a carboxylic acid group or a hydroxyl group.

[0576] solvates and crystal forms

[0577] Formula (I) also covers any polycrystalline form of the compound and solvates such as hydrates and alcohols.

[0578] The compounds of the present invention can, for example, form solvates (i.e., hydrates) with water or with common organic solvents. As used herein, the term "solvent" means the physical combination of the compounds of the present invention with one or more solvent molecules. This physical combination involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In some cases, the solvate will be separable, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. The term "solvent" is intended to cover both the solution phase and the separable solvate. Non-limiting examples of suitable solvates include the compounds of the present invention in combination with water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, or ethanolamine. The compounds of the present invention can exert their biological effects when in solution.

[0579] Solvates are well-known in medicinal chemistry. They can be important for methods used to prepare substances (e.g., related to the purification of said substance), for the storage of said substance (e.g., for the stability of said substance), and for the ease of handling said substance, and are often formed as part of the separation or purification stage of chemical synthesis. Those skilled in the art can determine, using standard and long-established techniques, whether hydrates or other solvates have formed under the separation or purification conditions used to prepare a given compound. Examples of such techniques include thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), X-ray crystallography (e.g., single-crystal X-ray crystallography or X-ray powder diffraction), and solid-state NMR (SS-NMR, also known as magic-angle rotation NMR or MAS-NMR). These techniques, along with NMR, IR, HPLC, and MS, are part of the standard analytical tool kits for skilled chemists.

[0580] Alternatively, a technician may intentionally form a solvate using crystallization conditions that include the amount of solvent required for a particular solvate. Thereafter, the standard methods described herein can be used to determine whether the solvate has formed.

[0581] Furthermore, the compounds of the present invention may have one or more polymorphs or amorphous crystalline forms and are therefore intended to be included within the scope of the present invention.

[0582] complex

[0583] Formula (I) also includes complexes of compounds (e.g., inclusion complexes or inclusion compounds with compounds, such as cyclodextrins, or complexes with metals) within its scope. Inclusion complexes, inclusion compounds, and metal complexes can be formed by methods well known to those skilled in the art.

[0584] prodrug

[0585] Formula (I) also covers any prodrug of a compound of formula (I). For example, "prodrug" means any compound that is converted in vivo into a biologically active compound of formula (I).

[0586] For example, some prodrugs are esters of the active compound (e.g., physiologically acceptable metabolically unstable esters). During metabolism, the ester group (-C(=O)OR) is cleaved to produce the active drug. Such esters can be formed, for example, by esterifying any carboxylic acid group (-C(=O)OH) in the parent compound, pre-protecting any other reactive groups present in the parent compound where appropriate, and then deprotecting if necessary.

[0587] Examples of such metabolically unstable esters include esters of the formula -C(=O)OR, where R is:

[0588] C 1-7 Alkyl groups (e.g., -Me, -Et, -nPr, -iPr, -nBu, -sBu, -iBu, -tBu); C 1-7 Aminoalkyl groups (e.g., aminoethyl; 2-(N,N-diethylamino)ethyl; 2-(4-morpholino)ethyl); and acyloxy-C 1-7 Alkyl groups (e.g., acyloxymethyl; acyloxyethyl; neopentyloxymethyl; acetoxymethyl; 1-acetoxyethyl; 1-(1-methoxy-1-methyl)ethyl-carbonyloxyethyl; 1-(benzoyloxy)ethyl; isopropoxy-carbonyloxymethyl; 1-isopropoxy-carbonyloxyethyl; cyclohexyl-carbonyloxymethyl; 1-cyclohexyl-carbonyloxyethyl; cyclohexyloxy-carbonyloxymethyl; 1-cyclohexyloxy-carbonyloxyethyl; (4-oxalyloxy)carbonyloxymethyl; 1-(4-oxalyloxy)carbonyloxyethyl; (4-oxalyl)carbonyloxymethyl; and 1-(4-tetrahydropyranyl)carbonyloxyethyl).

[0589] Furthermore, some prodrugs are enzymatically activated to produce active compounds or compounds that produce active compounds after undergoing further chemical reactions (e.g., in antigen-directed enzyme prodrug therapy (ADEPT), gene-directed enzyme prodrug therapy (GDEPT), and ligand-directed enzyme prodrug therapy (LIDEPT)). For example, a prodrug can be a sugar derivative or other glycoside conjugate, or it can be an amino acid ester derivative. In one embodiment, formula (I) does not include a prodrug of formula (I) within its scope.

[0590] Method for preparing compound (I)

[0591] In this section, as in all other parts of this application, unless the context otherwise requires, references to formula (I) also include all its other subforms (e.g., formulas (I), (Ia), (Ib), (Ib'), (Ib"), (II), (III), (III'), (IV), (IV'), (IV"), (V), (VI), (VII), (VIII), (VIIIa), (VIIIb), (VIIIc), (IX), (IXa), (X), (XI), (XII), (XIIa), (XIIb), (XIIb), (XIIc), (XIIIa), (XIIIb), (XIV), (XIV'), (XV), (XVI), (XVIa), (XVIb), (XVII), (XVIII) and (I*)) and instances as defined herein, unless the context otherwise requires.

[0592] Compounds of formula (I) can be prepared according to synthetic methods well known to those skilled in the art.

[0593] According to another aspect of the invention, a method is provided for preparing a compound of formula (I) or a tautomer, stereoisomer, N-oxide, pharmaceutically acceptable salt, or solvate thereof, the method comprising:

[0594] (a) To make a compound of formula (A) or a protected derivative thereof:

[0595]

[0596] Among them, X and R 1 R 2 and R 3 As defined above for compounds of formula (I), where P represents a protecting group (e.g., 2-tetrahydropyran; THP or 2-(trimethylsilyl)ethoxymethyl; SEM) or is hydrogen, and Z is a metal residue (e.g., zinc halide, such as zinc chloride) or a leaving group (e.g., halogen, such as iodine or bromine).

[0597] Coupled with a compound of formula (B) or a protected version thereof

[0598]

[0599] Where R 6 R 7 R 8 and R 9 As defined above for compounds of formula (I), and V represents a metal or metalloid residue (such as boric acid, pinacol borate, magnesium halide, or zinc halide, e.g., boric acid, pinacol borate) or a leaving group, such as a halogen.

[0600] Subsequently, a deprotection reaction suitable for removing the protecting group is carried out; and / or

[0601] (b) To make a compound of formula (C) or a protected derivative thereof:

[0602]

[0603] Where R 1 R 6 R 7 R 8 and R 9 As defined above for compounds of formula (I), P represents a protecting group (such as 2-tetrahydropyran; THP or 2-(trimethylsilyl)ethoxymethyl; SEM) or hydrogen, and L is a leaving group (such as chlorine).

[0604] Coupled with a compound of formula (D) or its protected derivative, wherein X, R 2 and R 3 As defined above for the compound of formula (I).

[0605]

[0606] And / or,

[0607] (c) To make a compound of formula (K) or a protected derivative thereof.

[0608]

[0609] Where X and R 2 R 3 R 6 R 7 R 8 and R 9 As defined herein for compounds of formula (I), P represents an amine protecting group (such as 2-tetrahydropyran; THP or 2-(trimethylsilyl)ethoxymethyl; SEM), N,N-dimethylaminosulfonyl or hydrogen, L 3 It is a leaving group (such as halogens, for example, bromine):

[0610] (i) Reaction of an organometallic species of formula CH3M, wherein M is a metal (e.g., CH3-Zn-Hal, where Hal is a halogen, such as chlorine, bromine, or iodine), in the presence of a metal catalyst (e.g., (1,3-diisopropylimidazol-2-ylidene)(3-chloropyridyl)palladium dichloride(II)) to give a compound of formula (I), wherein R 1 It is H; or

[0611] (ii) Reaction with an alkyl borate ester (e.g., potassium 2-(trimethylsilyl)-ethoxymethyltrifluoroborate) in the presence of a photoredox catalyst (e.g., [Ir{dFCF3ppy}2(bpy)]PF6), a metal catalyst (e.g., nickel(II) glycol dimethyl ether complex), a ligand (e.g., 4,4'-di-tert-butyl-2,2'-dipyridyl), a base (e.g., dipotassium phosphate), and a light source (e.g., a blue LED) to yield a compound of formula (I), wherein R 1 It is OH; and / or

[0612] (d) Cycloning of a compound of formula (R) or a protected derivative thereof using hydrazine or a hydrazine derivative thereof.

[0613]

[0614] Where X and R 1 R 2 R 3 R 6 R 7 R 8 and R 9 As defined above for the compound of formula (I), and L 1 Indicate a suitable leaving group, such as a halogen; and / or

[0615] In each case, a deprotection step may optionally follow; or

[0616] (e) Deprotecting the protected derivative of the compound of formula (I); and / or

[0617] (f) Interconverting a compound of formula (I) or a protected derivative thereof with another compound of formula (I) or a protected derivative thereof; and / or

[0618] (g) optionally forming a pharmaceutically acceptable salt of a compound of formula (I).

[0619] In one embodiment, a method for preparing a compound of formula (I) or a tautomer, stereoisomer, N-oxide, pharmaceutically acceptable salt, or solvate thereof comprises:

[0620] (a) To make a compound of formula (A) or a protected derivative thereof:

[0621]

[0622] Where X and R 1 R 2 and R 3As defined above for compounds of formula (I), where P represents a protecting group (e.g., 2-(trimethylsilyl)ethoxymethyl; SEM or THP) or is hydrogen, and Z is a leaving group (e.g., a halogen, such as iodine or bromine).

[0623] Coupled with a compound of formula (B) or a protected version thereof

[0624]

[0625] Where R 6 R 7 R 8 and R 9 As defined above for compounds of formula (I), and V represents a metal or metalloid residue (such as boric acid, pinacol borate, magnesium halide, or zinc halide, e.g., boric acid, pinacol borate) or a leaving group, such as a halogen, and / or

[0626] (b) Deprotecting the protected derivative of the compound of formula (I); and / or

[0627] (c) Interconverting a compound of formula (I) or a protected derivative thereof with another compound of formula (I) or a protected derivative thereof; and / or

[0628] (d) Optionally form a pharmaceutically acceptable salt of a compound of formula (I).

[0629] Preparation methods (a), (b), (c), and (d)

[0630] Compounds of formula (B) are commercially available or can be prepared using methods similar to those described in the examples.

[0631] Method (a) typically involves reacting compound (A) with compound (B) at a suitable temperature in a suitable solvent, a suitable base, and a suitable catalyst. Examples of a suitable base are potassium carbonate or potassium phosphate. Examples of a suitable catalyst are [1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride. Examples of a suitable solvent are 1,2-dimethoxyethane or tetrahydrofuran.

[0632] When Z is a metal residue such as zinc halide, the method typically involves reacting a compound of formula (A) with a compound of formula (B), where V is a leaving group, such as a halogen. Typically, the compound of formula (A), where Z is a leaving group, such as a halogen, dissolved in a suitable solvent, such as tetrahydrofuran, is treated with a reagent such as a solution of a magnesium chloride-lithium chloride complex, for a suitable time, such as 35 minutes, to achieve complete metallization. The newly formed organomagnesium species is then treated with a suitable metal salt, such as zinc chloride, to achieve transfer metallization, and optionally stirred for a suitable time, such as 10 minutes, and then warmed to a suitable temperature, such as room temperature, for a period of time, such as 40 minutes. The resulting heteroaryl zinc reagent was directly used in a cross-coupling reaction with formula (B) at a suitable temperature, such as room temperature, for a suitable duration, such as 18 hours, with a suitable catalyst such as methanesulfonic acid (2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl)(2'-methylamino-1,1'-biphenyl-2-yl)palladium(II) (SPhos G4 palladacycle).

[0633] Compounds of formula (D) or their protected derivatives are obtained from commercially available starting materials, prepared by a documented procedure, or prepared using the methods indicated in the examples outlined in this application or similar methods.

[0634] Compounds of formula (C) or their protected derivatives, specifically wherein R 1 It is hydrogen, which can be obtained by making compounds of formula (E):

[0635]

[0636] Where P represents a suitable amine protecting group (e.g., 2-(trimethylsilyl)ethoxymethyl; SEM) or is hydrogen, and L 1 and L 2 Independently representing a leaving group (such as a halide, for example chlorine, bromine or iodine), reacting with a compound of formula (B) or its protected derivative, the reaction being carried out using a method similar to that of method (a).

[0637] Compounds of formula (E) are obtained from commercially available starting materials, prepared by a documented procedure, or prepared using the method indicated in the examples outlined in this patent or a similar method.

[0638] Compounds of formula (A) or their protected derivatives can be obtained by using a suitable base, such as diisopropylethylamine, to form a compound of formula (E), wherein R 1 H is reacted with a compound of formula (D) or its protected derivative in a suitable solvent, such as dimethyl sulfoxide or N-methyl-2-pyrrolidone, at a suitable temperature, such as 80°C to 150°C.

[0639] Compounds of formula (A) or their protected derivatives can be obtained from compounds of formula (F) or their protected derivatives.

[0640]

[0641] Where X and R 2 and R 3 As defined above for compounds of formula (I), and where P represents a suitable amine protecting group (e.g., 2-tetrahydropyran; THP or 2-(trimethylsilyl)ethoxymethyl; SEM) or hydrogen,

[0642] A suitable leaving group Z, such as a halogen, is introduced, for example, by using a suitable halogenating agent (such as N-iodosuccinimide), followed by an optional deprotection step to introduce an amine protecting group P (such as 2-tetrahydropyran; THP or 2-(trimethylsilyl)ethoxymethyl; SEM).

[0643] Compound of formula (A) or its protected derivatives, specifically wherein R 1 It is H or -OH, which can be obtained by making a compound of formula (X') or its protected derivative:

[0644]

[0645] Where R 1 It is hydrogen or hydroxyl, P represents a protecting group (such as 2-tetrahydropyran; THP or 2-(trimethylsilyl)ethoxymethyl; SEM) or is hydrogen, and L is hydrogen. 1 and L 2 Independently represents the leaving group (such as a halide, for example chlorine, bromine or iodine) that reacts with a compound of formula (D) or its protected derivative.

[0646] Compound of formula (X'), specifically wherein R 1 It is OH, or its protected derivatives can be obtained by making a compound of formula (Y) or its protected derivatives:

[0647]

[0648] Where P represents a protecting group (such as 2-tetrahydropyran; THP or 2-(trimethylsilyl)ethoxymethyl; SEM) or is hydrogen, and L 1 and L 2The leaving group (e.g., a halide, such as chlorine, bromine, or iodine) is independently represented by methanol reacting with methanol in a solvent such as DMSO in the presence of a photoredox catalyst (e.g., 2,4,5,6-tetrakis(9H-carbazole-9-yl)isophthalonitrile), a peroxide reagent such as tert-butyl peracetate solution, an acid (e.g., TFA), and a light source (e.g., a blue LED). Alternatively, the reaction can be carried out with an excess of alcohol, such as methanol, in the presence of a metal salt such as silver(II) nitrate, an oxidant such as ammonium persulfate, an acid (e.g., TFA), in a solvent such as DMSO, or with water and a heat source (30-150°C).

[0649] Alternatively, a compound of formula (X') or a protected derivative thereof can be obtained by making a compound of formula (W') or a protected derivative thereof:

[0650]

[0651] Where P represents a protecting group (such as 2-tetrahydropyran; THP or 2-(trimethylsilyl)ethoxymethyl; SEM) or is hydrogen, and L 1 It is a leaving group (such as halogen, e.g., iodine or bromine) that reacts with a suitable halogenating agent (such as N-bromosuccinimide or N-iodosuccinimide) to introduce a leaving group, such as halogen (e.g., bromine or iodine).

[0652] Compounds of formula (W') or their protected derivatives, specifically wherein R 1 It is hydrogen, which can be obtained by making a compound of formula (Y') or its protected derivatives:

[0653]

[0654] Where P represents a protecting group (such as 2-tetrahydropyran; THP or 2-(trimethylsilyl)ethoxymethyl; SEM) or is hydrogen, and L 1 It is a leaving group (such as halogens, for example iodine or bromine) that reacts with organometallic residues (such as organomagnesium species, for example methylmagnesium chloride).

[0655] Compound of formula (Y') or its protected derivative can be obtained by making compound of formula (Z) or its protected derivative:

[0656]

[0657] Where P represents a protecting group (such as 2-tetrahydropyran; THP or 2-(trimethylsilyl)ethoxymethyl; SEM) or is hydrogen, and L 1 It is a leaving group (such as halogens, for example iodine or bromine) that reacts with an oxidizing agent (such as a peracid reagent, for example trifluoroperacetic acid).

[0658] Compounds of formula (F) or their protected derivatives can be obtained by reacting a compound of formula (G) or (G') or a mixture of (G) and (G') with its protected derivatives.

[0659]

[0660] Among them, X and R 1 R 2 and R 3 As defined above for compounds of formula (I), alkoxyvinyl ethers and amines are cyclized intramolecularly using a suitable acid (such as TFA). Under such conditions, one or more protecting groups may also be removed, and therefore a reprotection step may optionally be performed after the cyclization step, for example with di-tert-butyl dicarbonate, to obtain an N-Boc derivative.

[0661] Compounds of formula (G) and (G') or their protected derivatives can be obtained by making a compound of formula (H) or its protected derivative.

[0662]

[0663] Among them, X and R 1 R 2 and R 3 As defined above for compounds of formula (I), where Z is a leaving group (e.g., a halogen).

[0664] It reacts with alkoxyvinyl derivatives, such as (E)-1-ethoxyethylene-2-boronic acid pinacol ester, via a metal catalyst (e.g., using palladium acetate and suitable ligands, such as 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, i.e., Sphos, and a base such as potassium phosphate). The reaction can be carried out in a suitable solvent or combination of solvents, such as acetonitrile and water, and at a suitable temperature, such as 70 °C.

[0665] Compounds of formula (H) or their protected derivatives can be obtained by making compounds of formula (J):

[0666]

[0667] The reaction is carried out with a compound of formula (D) or its protected derivative, wherein Z is a leaving group (e.g., halogen) and V is a leaving group (e.g., halogen), and the reaction is carried out with a suitable base (e.g., N,N-diisopropylethylamine) in a suitable solvent (e.g., N-methyl-2-pyrrolidone) at a suitable temperature (e.g., 120°C).

[0668] Compounds of formula (K) or their protected derivatives can be obtained by making compounds of formula (L) or their protected derivatives:

[0669]

[0670] Where X and R 2 and R 3 As defined above for compounds of formula (I), P represents an amine protecting group (such as 2-(trimethylsilyl)ethoxymethyl; SEM), N,N-dimethylaminesulfonyl, or hydrogen, L 2 It is a leaving group (such as halogens, for example, iodine), L 3 It is a leaving group (such as halogen, for example bromine) that reacts with a compound of formula (B), said reaction being carried out using a procedure such as that outlined for (a).

[0671] Compounds of formula (L) or their protected derivatives can be obtained by making compounds of formula (M):

[0672]

[0673] Where P represents a suitable protecting group, such as 2-(trimethylsilyl)ethoxymethyl (SEM) or N,N-dimethylaminesulfonyl, L 1 It is a leaving group, such as chlorine, L 2 It is a leaving group, such as iodine, and L 3 It is a leaving group, such as bromine, that reacts with a compound of formula (D), said reaction being carried out using a procedure such as that outlined in (b).

[0674] Compounds of formula (M) or their protected derivatives may be obtained from commercially available starting materials, prepared by a documented procedure, or prepared using the methods or similar methods indicated in the examples outlined in this patent.

[0675] Alternatively, a compound of formula (L) or a protected derivative thereof can be obtained by making a compound of formula (N) or a protected derivative thereof:

[0676]

[0677] Where R 2 and R 3 As defined above for compounds of formula (I), P represents an amine protecting group (such as 2-(trimethylsilyl)ethoxymethyl; SEM) or hydrogen, which reacts with a suitable halogenating agent (such as N-bromosuccinimide or N-iodosuccinimide) to introduce a leaving group, such as a halogen (e.g., bromine or iodine).

[0678] Compounds of formula (N) or their protected derivatives can be obtained by making compounds of formula (O) or their protected derivatives:

[0679]

[0680] Where R 2 and R 3 As defined above for compounds of formula (I), they react with a suitable halogenating agent, such as N-iodosuccinimide, to introduce a leaving group, such as a halogen, and react under suitable conditions to introduce a protecting group.

[0681] Compounds of formula (O) or their protected derivatives, wherein X is nitrogen, can be obtained by making compounds of formula (P):

[0682]

[0683] Where R 2 and R 3 As defined above for the compound of formula (I), L 2 It is a leaving group, such as chlorine, that reacts with suitable hydrazine derivatives, such as hydrazine hydrate.

[0684] Compounds of formula (P) or their protected derivatives can be obtained by making compounds of formula (Q):

[0685]

[0686] Reaction with a compound of formula (D) or its protected derivative, wherein L 1 and L 2 It is a leaving group, such as chlorine.

[0687] Compounds of formula (Q) or their protected derivatives are obtained from commercially available starting materials, or prepared by a documented procedure or by the method or similar method indicated in the examples outlined in this patent.

[0688] Compounds of formula (R) or their protected derivatives can be obtained by making compounds of formula (S) or their protected derivatives:

[0689]

[0690] Where R 1 R 6 R 7 R 8 and R 9 As defined above for the compound of formula (I), and L 1 and L 2 Both represent suitable leaving groups, such as halogens, that react with compounds of formula (D).

[0691] Compounds of formula (S) or their protected derivatives can be obtained by making compounds of formula (T) or their protected derivatives:

[0692]

[0693] Where R 1 R 6 R 7 R 8 and R 9 As defined above for the compound of formula (I), and L 1 and L 2 Both represent suitable leaving groups, such as halogens, reacting with suitable oxidizing agents, such as magnesium oxide (IV).

[0694] Compounds of formula (T) or their protected derivatives can be obtained by making compounds of formula (U) or their protected derivatives:

[0695]

[0696] Where R 1 As defined above for the compound of formula (I), and L 1 and L 2 Both represent suitable leaving groups, such as halogens, that react with compounds of formula (B), where V is a metal or metalloid residue (such as magnesium halide).

[0697] Compounds of formula (U) or their protected derivatives can be obtained by making compounds of formula (V') or their protected derivatives:

[0698]

[0699] Where R 1 As defined above for the compound of formula (I), and L 1 and L 2 Both indicate a suitable leaving group, such as a halogen, reacting with a suitable oxidizing agent, such as Dess-Martin periodinane.

[0700] Compounds of formula (V) or their protected derivatives can be obtained by making compounds of formula (W) or their protected derivatives:

[0701]

[0702] Where R 1 As defined above for the compound of formula (I), and L 1 and L 2 Independently representing a suitable leaving group, such as a halogen, reacts with an alcohol, such as methanol, in the presence of a photoredox catalyst (such as 2,4,5,6-tetrakis(9H-carbazole-9-yl)isophthalonitrile), an oxidant such as tert-butyl peracetate solution, an acid (such as TFA), and a light source (such as a blue LED) in a solvent such as DMSO.

[0703] The compound of formula (W) or its protected derivatives are obtained from commercially available starting materials, or prepared by a documented procedure or by the method or similar method indicated in the examples outlined in this patent.

[0704] Compounds of formula (T) or their protected derivatives can also be obtained by making compounds of formula (Z') or their protected derivatives:

[0705]

[0706] Where R 6 R 7 R 8 and R 9 As defined above for compound (I), it reacts with compound (W). The method typically involves reacting compound (W) with a reagent such as a solution of a 2,2,6,6-tetramethylpiperidinyl magnesium chloride-lithium chloride complex for a suitable time, such as 2.5 hours, to achieve complete metallization. The newly formed organomagnesium species is then treated with compound (Z') and heated to, for example, room temperature, and stirred for a suitable time, such as 18 hours.

[0707] Compounds of formula (Z') or their protected derivatives are prepared using the methods indicated in the examples outlined in this patent or similar methods.

[0708] Deprotection of the protected derivative of compound (I)

[0709] Method (e) typically includes any suitable deprotection reaction, the conditions of which will depend on the nature of the protecting group.

[0710] When the protecting group P represents SEM, this deprotection reaction typically involves using a suitable acid in a suitable solvent, followed by removal of the hydroxymethyl adduct formed during acid deprotection of the SEM protecting group with ethylenediamine. For example, the acid may suitably include trifluoroacetic acid or hydrogen chloride, and the solvent may suitably include dichloromethane, DMF, or methanol. Optionally, a mixture of solvents, such as water and methanol, may be used. The second step involves concentration under vacuum, followed by dissolution of the crude material in a suitable solvent, such as methanol, and treatment in a suitable solvent, such as methanol, with a suitable scavenger, such as ethylenediamine.

[0711] When the protecting group is N,N-dimethylaminesulfonyl (SO2NMe2), stronger acids, such as trifluoromethanesulfonic acid, can be used at suitable temperatures.

[0712] When R 1When the =OH group and the protecting group P represents SEM, this deprotection reaction is typically carried out using a suitable acid (e.g., methanesulfonic acid or TFA) in a suitable solvent (e.g., DCM, with or without water), followed by removal of the hydroxymethyl adduct formed during acid deprotection of the SEM protecting group with ethylenediamine or ammonia in a suitable solvent (e.g., DCM, CHCl3, IPA, MeOH, water, or mixtures thereof). For example, the deprotection reaction involves the use of methanesulfonic acid in a DCM / water mixture at room temperature, and a second step involves treating the crude product with ethylenediamine and / or ammonia in a mixture of DCM and water.

[0713] When R 1 When the =H and the protecting group P represents THP, this deprotection reaction will typically involve the use of a suitable acid (e.g., HCl) in a suitable solvent (e.g., dioxane, MeOH) at a temperature between room temperature and 40°C.

[0714] In other cases, when R 1 When the compound is H and protected only by Boc, this deprotection reaction will typically involve the use of a suitable acid (e.g., TFA or HCl) in a suitable solvent (DCM, MeOH, dioxane).

[0715] Deprotection can be performed according to procedures and methods 1-5, which are general procedures for preparing compounds of formula (I) as described herein.

[0716] Formation of pharmaceutically acceptable salts of compounds of formula (I)

[0717] Salt formation can be achieved by treating a compound of formula (I) in the form of a free base dissolved in a suitable solvent with a stoichiometric or excess of a pharmaceutically acceptable organic or inorganic acid, and then separating the resulting salt by methods well known in the art, such as evaporation of the solvent or crystallization.

[0718] Overview

[0719] If appropriate, one or more reactions known to those skilled in the art, either following or preceding the reactions previously described in methods (a), (b), and (c), are carried out in a suitable order to achieve the necessary substitutions as defined above to obtain other compounds of formula (I). Non-limiting examples of such reactions, whose conditions can be found in the literature, include:

[0720] Protection of reactive functional groups;

[0721] Deprotection of reactive functional groups;

[0722] Halogenation;

[0723] Dehalogenation;

[0724] Dealkylation;

[0725] Alkylation and arylation of amines, anilines, alcohols, and phenols;

[0726] Photoelectrophoresis on the hydroxyl group;

[0727] Cycloaddition reactions on appropriate functional groups;

[0728] Reduction of nitro, ester, cyano, and aldehyde groups;

[0729] Transition metal-catalyzed coupling reactions;

[0730] Acylation;

[0731] Sulfonation / Introduction of sulfonyl group;

[0732] Saponification / ester hydrolysis;

[0733] Amide or transesterification of ester groups;

[0734] Esterification or amidation of carboxyl groups;

[0735] Halogen exchange;

[0736] Nucleophilic substitution with amines, thiols, or alcohols;

[0737] Reductive amination;

[0738] Oximes are formed on the carbonyl and hydroxyl groups;

[0739] S-oxidation;

[0740] N-oxidation; and

[0741] Saltification.

[0742] Those skilled in the art are familiar with a range of well-known functional group interconversions for converting precursor compounds into compounds of formula I, as described in *Advanced Organic Chemistry*, Jerry March, 4th edition, John Wiley & Sons, 1992. For example, possible metal-catalyzed functionalizations, such as those using organotin reagents (Stille reaction), Grignard reagents, and reactions with nitrogenophiles, are described in "Palladium Reagents and Catalysts" [Jiro Tsuji, Wiley, ISBN 0-470-85032-9] and *Handbook of OrganoPalladium Chemistry for Organic Synthesis* [Volume 1, edited by Ei-ichi Negishi, Wiley, ISBN 0-471-31506-0].

[0743] Protecting groups:

[0744] In many of the reactions described above, it may be necessary to protect one or more groups to prevent the reaction from occurring at undesirable positions on the molecule. Examples of protecting groups and methods for protecting and deprotecting functional groups can be found in *Protective Groups in Organic Synthesis* (T. Green and P. Wuts; 3rd ed.; John Wiley & Son, 1999).

[0745] The hydroxyl group can be protected, for example, as an ether (-OR) or an ester (-OC(=O)R), such as as: tert-butyl ether; tetrahydropyranyl (THP) ether; benzyl, benzhydryl (diphenylmethyl) or triphenylmethyl (triphenylmethyl) ether; trimethylsilyl or tert-butyldimethylsilyl ether; or acetyl ester (-OC(=O)CH3).

[0746] The aldehyde or ketone group can be protected, for example, as an acetal (R-CH(OR)2) or a ketal (R2C(OR)2), wherein the carbonyl group (>C=O) is treated with, for example, a primary alcohol. The aldehyde or ketone group can be readily regenerated by hydrolysis with a large excess of water in the presence of an acid.

[0747] The amino group can be protected, for example, as an amine (-NRCO-R) or a carbamate (-NRCO-OR), such as as: methylamide (-NHCO-CH3); benzyl carbamate (-NHCO-OCH2C6H5, -NH-Cbz, or NH-Z); as tert-butyl carbamate (-NHCO-OC(CH3)3, -NH-Boc); 2-biphenyl-2-propyl carbamate (-NHCO-OC(CH3)2C6H4C6). H5, -NH-Bpoc); as 9-fluorenylmethyl carbamate (-NH-Fmoc); as 6-nitroveratrol carbamate (-NH-Nvoc); as 2-trimethylsilane carbamate (-NH-Teoc); as 2,2,2-trichloroethyl carbamate (-NH-Troc); as allyl carbamate (-NH-Alloc); or as 2(-phenylsulfonyl)ethyl carbamate (-NH-Psec).

[0748] For example, a compound of formula I contains an amino group, which can be protected by a protecting group as defined above, a preferred group being tert-butoxycarbonyl (Boc), while introducing further functionalization. When subsequent modification of the amino group is not required, the protecting group can be carried through a reaction sequence to obtain the N-protected form of the compound of formula (I), which can then be deprotected by standard methods (e.g., acid treatment in the case of the Boc group) to obtain the compound of formula (I).

[0749] Other protecting groups of amines, such as cyclic amines and heterocyclic NH groups, include toluenesulfonyl (tosyl) and methanesulfonyl (mesyl), benzyl groups such as p-methoxybenzyl (PMB), and tetrahydropyran (THP) groups.

[0750] The carboxylic acid group can be protected as an ester, for example as: C 1-7 Alkyl esters (e.g., methyl esters, tert-butyl esters); C 1-7 Haloalkyl esters (e.g., C10) 1-7 Halogenated alkyl esters); Three C 1-7 Alkylsilyl-C 1-7 Alkyl ester; C 5-20 Aryl-C 1-7 Alkyl esters (e.g., benzyl esters; nitrobenzyl esters; p-methoxybenzyl esters. The thio group is protected, for example as a thioether (-SR), such as: benzyl thioether; acetaminomethyl ether (-S-CH2NHC(=O)CH3).

[0751] Isolation and purification of compounds of the present invention

[0752] The compounds of the present invention can be separated and purified according to standard techniques well known to those skilled in the art. Examples of such methods include chromatographic techniques such as column chromatography (e.g., rapid chromatography) and HPLC. One technique particularly useful in the purification of compounds is preparative liquid chromatography, which uses mass spectrometry as a means of detecting the purified compounds emerging from the chromatographic column.

[0753] Preparative LC-MS is a standard and effective method for purifying small organic molecules, such as those described herein. Methods used in liquid chromatography (LC) and mass spectrometry (MS) can be modified to better separate crude materials and improve MS detection of samples. Optimization of preparative gradient LC methods will involve different columns, volatile eluents and modifiers, and gradients. Methods for optimizing preparative LC-MS methods and then using these methods to purify compounds are well known in the art. Such methods are described in Rosentreter U, Huber U.; Optimal fraction collecting in preparative LC / MS; J Comb Chem. 2004; 6(2), 159-64 and Leister W, Strauss K, Wisnoski D, Zhao Z, Lindsley C., Development of a custom high-throughput preparative liquid chromatography / mass spectrometer platform for the preparative purification and analytical analysis of compound libraries; J Comb Chem. 2003; 5(3); 322-9. Examples of such systems for the purification of compounds by preparative LC-MS are described below in the Examples section of this application (under the title “Quality-Directed Purification LC-MS System”).

[0754] Recrystallization of compounds of formula (I) and their salts can be carried out by methods well known to those skilled in the art—see, for example (P. Heinrich Stahl (ed.), Camille G. Wermuth (ed.), ISBN: 3-90639-026-8, Handbook of Pharmaceutical Salts: Properties, Selection, and Use, Chapter 8, Publisher Wiley-VCH). Products obtained from organic reactions are rarely pure when separated directly from the reaction mixture. If the compound (or its salt) is a solid, it can be purified and / or crystallized by recrystallization from a suitable solvent. A good recrystallization solvent should dissolve a suitable amount of the substance to be purified at elevated temperatures but only a small amount at lower temperatures. The good recrystallization solvent should readily dissolve impurities or not at all at low temperatures. Finally, the solvent should be readily removed from the purified product. This generally means that the solvent has a relatively low boiling point, and those skilled in the art will understand the appropriate recrystallization solvent for a particular substance, or, if such information is not available, several solvents will be tested. To obtain a good yield of the purified material, a minimal amount of hot solvent is used to dissolve all impurities. In practice, 3-5% more solvent than needed is used so that the solution does not become saturated. If the impure compound contains impurities insoluble in the solvent, these impurities can be removed by filtration followed by crystallization of the solution. Additionally, if the impure compound contains trace amounts of non-naturally colored materials, these can be removed by adding a small amount of a decolorizing agent, such as activated carbon, to the hot solution, filtering the colored material, and then crystallizing it. Crystallization typically occurs spontaneously upon cooling the solution. If crystallization does not occur, it can be induced by cooling the solution below room temperature or by adding a single crystal (seed) of the pure material. Recrystallization and / or yield optimization can also be achieved by using an antisolvent or co-solvent. In this case, the compound is dissolved in a suitable solvent at an elevated temperature, filtered, and then an additional solvent in which the desired compound has low solubility is added to aid crystallization. The crystals are then typically separated using vacuum filtration, washed, and then dried, for example, in an oven or by drying.

[0755] Other examples of purification methods include sublimation, which involves, for example, a heating step under vacuum using a finger freezer and crystallization from the melt (Crystallization Technology Handbook, 2nd edition, edited by A. Mersmann, 2001).

[0756] biological effects

[0757] It is envisioned that the compounds of the present invention will be used in pharmaceuticals or therapies. Compounds, subgroups, and examples of the present invention have been shown to inhibit SHP2. This inhibition leads to suppression of tumor cell proliferation and activation of T-cell immune responses against cancer cells, which can be used to prevent or treat disease states or conditions described herein, such as those discussed below and those in which SHP2 plays a role, as described above in the "Background" section. Therefore, it is envisioned, for example, that the compounds of the present invention will be used to alleviate cancer or reduce cancer incidence, prevent or treat SHP2-mediated diseases or conditions, such as cancers with activating mutations in upstream components of the MAPK pathway (such as RAS, KRAS, and NRAS) or cancers with activated receptor tyrosine kinase (RTK). The compounds of the present invention can be used to treat adult populations. The compounds of the present invention can be used to treat pediatric populations.

[0758] The compounds of the present invention have been shown to be good inhibitors of SHP2. Compounds of formula (I) are capable of binding to SHP2 and exhibit efficacy against it. The efficacy of the compounds of the present invention against SHP2 has been determined using the assays described herein and other methods known in the art. More specifically, compounds of formula (I) and their subgroups are effective against SHP2.

[0759] Some of the compounds in this invention are IC 50 Compounds with values ​​less than 0.1 μM, specifically less than 0.01 or 0.001 μM.

[0760] Because SHP2 plays a role in cell survival and proliferation, and in tumorigenesis, primarily through activating the RAS-ERK signaling pathway, its function has been involved in many diseases. Due to the affinity of the compounds for SHP2, it is anticipated that these compounds could be demonstrated for the treatment or prevention of a range of diseases or conditions, including those associated with cell accumulation (e.g., cancer, autoimmune diseases, inflammation, and restenosis), those resulting from excessive apoptosis leading to cell loss (e.g., stroke, heart failure, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, AIDS, ischemic attacks (stroke, myocardial infarction), and osteoporosis), or for the treatment of autoimmune diseases such as multiple sclerosis (MS).

[0761] Therefore, it is also envisioned that the compounds of the present invention as defined herein can be used to treat other conditions, such as inflammation, hepatitis, ulcerative colitis, gastritis, autoimmune diseases, restenosis, stroke, heart failure, neurodegenerative conditions such as Alzheimer's disease, Parkinson's disease, Huntington's disease, myotonic dystrophy and amyotrophic lateral sclerosis, AIDS, local ischemia such as traumatic brain injury, spinal cord injury, cerebral ischemia, cerebral ischemia / reperfusion (I / R) injury, acute and chronic CNS injury, stroke or myocardial infarction, musculoskeletal degenerative diseases such as osteoporosis, autoimmune diseases such as multiple sclerosis (MS) and type 1 diabetes, and eye diseases such as retinal degeneration due to uncontrolled programmed cell death.

[0762] Since the compound is active against SHP2, it is anticipated that the compound could be demonstrated for the treatment or prevention of proliferative diseases, such as cancer.

[0763] Examples of cancers (and their benign counterparts) that can be treated (or suppressed) include, but are not limited to: tumors of epithelial origin (adenomas and various types of carcinoma, including adenocarcinoma, squamous cell carcinoma, transitional cell carcinoma, and other cancers), such as bladder and urinary tract cancers, breast cancers, gastrointestinal cancers (including esophageal cancer, stomach cancer, small bowel cancer, colon cancer, intestinal cancer, colorectal cancer, rectal cancer, and anal cancer), liver cancer (hepatocellular carcinoma), gallbladder and biliary system cancers, exocrine pancreatic cancers, kidney cancers (e.g., renal cell carcinoma), lung cancers (e.g., adenocarcinoma, small cell lung cancer, non-small cell lung cancer, bronchioloalveolar carcinoma, and mesothelioma), head and neck cancers (e.g., tongue cancer, oral cavity cancer, laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, tonsil cancer, salivary gland cancer, nasal cavity cancer, and sinus cancer), ovarian cancer, fallopian tube cancer, abdominal cancers, etc. Cancer of the menstrual periodontium, vagina, vulva, penis, testis, cervix, myometrium, endometrium, thyroid (e.g., follicular thyroid carcinoma), brain, adrenal, prostate, skin, and adnexal cancers (e.g., melanoma, basal cell carcinoma, squamous cell carcinoma, keratoacanthoma, nevus dysplasia); hematologic malignancies (i.e., leukemia, lymphoma) and precancerous hematologic disorders and borderline malignancies, including hematologic malignancies and related lymphoid disorders (e.g., acute lymphoblastic leukemia [ALL], chronic lymphocytic leukemia [CLL], B-cell lymphomas such as diffuse large B-cell lymphoma [DLBCL], follicular lymphoma, Burkitt's lymphoma). Lymphoma, mantle cell lymphoma, T-cell lymphoma and leukemia, natural killer [NK] cell lymphoma, Hodgkin's lymphoma, hairy cell leukemia, monoclonal gammopathy of undetermined significance, plasmacytoma, multiple myeloma and post-transplant lymphoproliferative disorders, as well as hematologic malignancies and related bone marrow population conditions (e.g., acute myeloid leukemia [AML], chronic myeloid leukemia [CML], chronic... Myelomonocytic leukemia [CMML], hypereosinophilic syndrome, myeloproliferative disorders such as polycythemia vera, essential thrombocythemia, and primary myelofibrosis, myelodysplastic syndrome, myelodysplastic syndrome, and promyelocytic leukemia; tumors of stromal origin, such as sarcomas of soft tissue, bone, or cartilage, such as osteosarcoma, fibrosarcoma, chondrosarcoma, rhabdomyosarcoma, leiomyosarcoma, liposarcoma, angiosarcoma, Kaposi's sarcoma, Ewing's sarcoma, synovial sarcoma, epithelioid sarcoma, gastrointestinal stromal tumors, benign and malignant histiocytomas, and dermatofibrosarcoma protuberans; tumors of the central or peripheral nervous system (e.g., astrocytomas (e.g., gliomas), neuromas and malignant gliomas, meningiomas, ependymomas, pineal tumors, and schwannomas);Endocrine tumors (e.g., pituitary adenoma, adrenal adenoma, islet cell tumor, parathyroid adenoma, carcinoid tumor, and medullary thyroid carcinoma); ocular and adnexal tumors (e.g., retinoblastoma); germ cell tumors and trophoblastic tumors (e.g., teratoma, seminoma, dysgerminoma, hydatidiform mole, and choriocarcinoma); and pediatric and embryonal tumors (e.g., medulloblastoma, neuroblastoma, Wilms' tumor, and primitive neuroectodermal tumor); or congenital or other syndromes that predispose said patients to malignant tumors (e.g., xeroderma pigmentosum).

[0764] Cell growth is a tightly controlled function. Cancer is a condition of abnormal cell growth that occurs when cells replicate uncontrollably (increase in number), grow uncontrollably (get larger), and / or undergo reduced cell death through apoptosis (programmed cell death), necrosis, or anoikis. In one embodiment, abnormal cell growth is selected from uncontrolled cell proliferation, excessive cell growth, or reduced programmed cell death. Specifically, the symptom or disease of abnormal cell growth is cancer.

[0765] Therefore, in the pharmaceutical compositions, uses, or methods of the present invention for treating diseases or conditions including abnormal cell growth (i.e., uncontrolled and / or rapid cell growth), in one embodiment, the disease or condition including abnormal cell growth is cancer.

[0766] The compounds of the present invention can be used to treat metastatic and metastatic cancers. Metastatic or metastatic disease is the spread of disease from one organ or part to another non-adjacent organ or part. Cancers that can be treated with the compounds of the present invention include primary tumors (i.e., cancer cells at the site of origin), locally invasive tumors (cancer cells penetrating and infiltrating the surrounding normal tissue in a local area), and metastatic (or secondary) tumors, i.e., tumors formed by malignant cells that circulate through the bloodstream (hematogenous spread) or through the lymphatic system or across body cavities (implantation). Specifically, the compounds of the present invention can be used to treat metastatic and metastatic cancers.

[0767] In one embodiment, the hematologic malignancy is leukemia. In another embodiment, the hematologic malignancy is lymphoma. In one embodiment, the cancer is AML. In another embodiment, the cancer is CLL.

[0768] In one embodiment, the compounds of the present invention are used for the prevention or treatment of leukemia, such as acute or chronic leukemia, specifically acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), or chronic myeloid leukemia (CML). In one embodiment, the compounds of the present invention are used for the prevention or treatment of lymphoma, such as acute or chronic lymphoma, specifically Burkitt lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, or diffuse large B-cell lymphoma.

[0769] In one embodiment, the compounds of the present invention are used for the prevention or treatment of acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL).

[0770] The cancer can be a cancer that is sensitive to treatment with an SHP2 inhibitor. The cancer can be a cancer that overexpresses SHP2. The cancer can be a cancer belonging to the wild-type SHP2. The cancer can be a cancer belonging to the mutant SHP2. In one embodiment, the cancer has an activating mutation in SHP2.

[0771] Specific cancers include hepatocellular carcinoma, melanoma, esophageal cancer, kidney cancer, colon cancer, colorectal cancer, lung cancer such as NSCLC, mesothelioma or lung adenocarcinoma, breast cancer, bladder cancer, gastrointestinal cancer, ovarian cancer, and prostate cancer.

[0772] Specific cancers include those with activated SHP2 (activated mutations, amplified and / or SHP2 wild-type overexpression), such as hepatocellular carcinoma, breast cancer, lung cancer, colorectal cancer and neuroblastoma.

[0773] Specific cancers include those with oncogenic alterations in the RAS-RAF-MEK-ERK pathway, including mutant forms of KRAS.

[0774] Specific cancers include those that are caused by RTK activity or that are resistant to cancer therapies.

[0775] The compounds of the present invention will be particularly useful for the treatment or prevention of cancers of a type associated with or characterized by elevated Ras, BRAF and / or MEK signaling.

[0776] Elevated levels of Ras, BRAF, or MEK signaling have been found in many cancers and are associated with poor prognosis. Additionally, cancers with activating Ras mutations may also be sensitive to SHP2 inhibitors. Elevated Ras signaling and Ras mutation levels can be identified using the techniques outlined in this article.

[0777] The other cancer subset consists of NRas melanoma and NRas AML.

[0778] Another subset of cancers consists of KRas lung cancer, KRas pancreatic cancer, and KRas colorectal cancer (CRC).

[0779] In one embodiment, the cancer is in the colorectal region, breast, lung, and brain.

[0780] In one embodiment, the cancer is childhood cancer.

[0781] In one embodiment, the cancer is breast cancer, leukemia, lung cancer, liver cancer, stomach cancer, laryngeal cancer, or oral cancer.

[0782] Whether a particular cancer is sensitive to SHP2 inhibitors can be determined using the methods described in the section entitled "Diagnostic Methods".

[0783] Another aspect provides the use of the compound in the preparation of a medicament for treating diseases or conditions as described herein, specifically cancer.

[0784] Some cancers develop resistance to specific drug treatments. This may be due to the type of tumor (the most common epithelial malignancies are inherently chemoresistant, while the prostate is relatively resistant to currently available chemotherapy or radiation therapy regimens), or resistance may develop spontaneously as the disease progresses or as a result of treatment. In this regard, references to the prostate include prostate resistant to anti-androgen therapy, specifically abiraterone or enzalutamide, or castration-resistant prostate. Similarly, references to multiple myeloma include bortezomib-insensitive or refractory multiple myeloma, and references to chronic myeloid leukemia include imitanib-insensitive and refractory chronic myeloid leukemia. In this regard, references to mesothelioma include mesothelioma resistant to topoisomerase toxins, alkylating agents, anti-tubulin agents, antifolate agents, platinum compounds, and radiotherapy, particularly mesothelioma resistant to cisplatin. References to melanoma include melanoma resistant to treatment with BRAF and / or MEK inhibitors.

[0785] The compounds can also be used to treat tumor growth, pathogens, and resistance to chemotherapy and radiotherapy by sensitizing cells to chemotherapy and acting as anti-metastatic agents.

[0786] All types of therapeutic anticancer interventions inevitably increase the pressure exerted on target tumor cells. SHP2 inhibitors represent a class of chemotherapeutic agents with the following efficacies: (i) sensitizing malignant cells to anticancer drugs and / or treatments; (ii) alleviating or reducing the incidence of resistance to anticancer drugs and / or treatments; (iii) reversing resistance to anticancer drugs and / or treatments; (iv) enhancing the activity of anticancer drugs and / or treatments; and (v) delaying or preventing the development of resistance to anticancer drugs and / or treatments.

[0787] In one embodiment, the present invention provides a compound for treating SHP2-mediated diseases or symptoms. In another embodiment, the SHP2-mediated disease is cancer characterized by SHP2 overexpression and / or increased activity.

[0788] Another aspect provides the use of the compound in the preparation of a medicament for treating diseases or conditions as described herein, specifically cancer.

[0789] In one embodiment, a compound is provided for the prevention or treatment of diseases or symptoms mediated by SHP2.

[0790] In one embodiment, a pharmaceutical composition comprising an effective amount of at least one compound as defined is provided. In another aspect of the invention, compounds as defined herein are provided.

[0791] In one embodiment, a method for preventing or treating cancer is provided, the method comprising the step of administering a drug comprising at least one compound as defined to a mammal.

[0792] Diagnostic methods

[0793] Prior to administering a compound of formula (I), patients may be screened to determine whether the disease or symptom the patient is experiencing or may experience is one that is easily treatable with a compound that inhibits SHP2. The term “patient” includes human and veterinary subjects, such as primates, specifically human patients.

[0794] For example, biological samples obtained from patients can be analyzed to determine whether the patient is experiencing or may be suffering from a condition or disease, such as cancer, which is characterized by genetic abnormalities or abnormal protein expression leading to upregulation of SHP2 levels or downstream biochemical pathways of SHP2.

[0795] Examples of such abnormalities leading to SHP2 activation or sensitization include: loss or inhibition of regulatory pathways affecting SHP2 expression; upregulation of the receptor or its ligand; cytogenetic aberrations; or the presence of mutants of the receptor or ligand. SHP2 upregulation, specifically SHP2 overexpression or the presence of its activating mutant or tumors containing activating mutations in Ras isotypes, such as KRAS, may make them particularly sensitive to SHP2 inhibitors.

[0796] Ras mutations have been detected in cell lines and primary tumors, including but not limited to melanoma, colorectal cancer, non-small cell lung cancer, as well as pancreatic cancer, prostate cancer, thyroid cancer, urinary tract cancer, and upper respiratory tract cancer (Cancer Research 2012; 72:2457–2467).

[0797] The term upregulation encompasses elevated or overexpression, including gene amplification (i.e., multiple gene copies), cytogenetic aberrations, and increased expression through transcriptional or post-translational effects. Therefore, diagnostic tests can be performed on patients to detect biomarker characteristics of SHP2 upregulation. The term diagnosis includes screening. Biomarkers include genetic biomarkers, such as measurements of DNA composition to identify SHP2 amplification or the presence of SHP2 mutations or the presence of Ras mutations (e.g., KRAS). Biomarkers also include biomarkers exhibiting characteristics of SHP2 upregulation, including protein levels, protein states, and mRNA levels of the aforementioned proteins. Gene amplification includes increases of more than 7 copies and increases between 2 and 7 copies.

[0798] Diagnostic assays for detecting KRAS mutations are described in de Castro et al., Br.J.Cancer., July 10, 2012; 107(2):345-51. doi:10.1038 / bjc.2012.259.Epub, June 19, 2012, “A comparison of three methods for detecting KRAS mutations in formalin-fixed colorectal cancer specimens” and the references cited therein.

[0799] Diagnostic tests and screenings are typically performed on biological samples (i.e., body tissues or fluids) selected from the following: tumor biopsy samples, blood samples (isolation and enrichment of exfoliated tumor cells), cerebrospinal fluid, plasma, serum, saliva, fecal biopsy, sputum, chromosome analysis, pleural effusion, peritoneal fluid, oral smears, skin biopsy, or urine.

[0800] Methods for identifying and analyzing cytogenetic aberrations, gene amplifications, mutations, and protein upregulation are known to those skilled in the art. Screening methods may include, but are not limited to, standard methods, such as DNA sequence analysis using conventional Sanger or next-generation sequencing methods, reverse transcriptase polymerase chain reaction (RT-PCR), RNA sequencing (RNAseq), nanostring hybridization proximity RNA nCounter assay, or in situ hybridization, such as fluorescence in situ hybridization (FISH) or allele-specific polymerase chain reaction (PCR). Newer next-generation sequencing (NGS) technologies, such as massively parallel sequencing, allow for whole-exome sequencing or whole-genome sequencing.

[0801] In screening by RT-PCR, mRNA levels in tumors are assessed by creating cDNA copies of mRNA and then amplifying the cDNA by PCR. The methods of PCR amplification, primer selection, and conditions used for amplification are known to those skilled in the art. Nucleic acid manipulation and PCR are performed using standard methods, as described in, for example, the following literature: Ausubel, FM et al. (2004), *Current Protocols in Molecular Biology*, or John Willie & Sons, or Innis, MA et al. (1990), *PCR Protocols: a guide to methods and applications*, Academic Press, San Diego. Reactions and manipulations involving nucleic acid techniques are also described in Sambrook et al. (2001), 3rd edition, *Molecular Cloning: A Laboratory Manual*, Cold Spring Harbor Laboratory Press. Alternatively, commercially available RT-PCR kits (e.g., Roche Molecular Biochemicals) or methods as described in the following U.S. patents: 4,666,828; 4,683,202; 4,801,531; 5,192,659, 5,272,057, 5,882,864, and 6,218,529, which are incorporated herein by reference. An example of an in situ hybridization technique for assessing mRNA expression is fluorescence in situ hybridization (FISH) (see Angerer (1987), Meth. Enzymol., 152:649).

[0802] Typically, in situ hybridization involves the following main steps: (1) fixing the tissue to be analyzed; (2) pre-hybridizing the sample to increase the accessibility of the target nucleic acid and reduce non-specific binding; (3) hybridizing the nucleic acid mixture with the nucleic acid in the biological structure or tissue; (4) washing after hybridization to remove unbound nucleic acid fragments; and (5) detecting the hybridized nucleic acid fragments. Probes used in such applications are typically labeled with, for example, radioisotopes or fluorescent reporter genes. Some probes are long enough, for example, from about 50, 100, or 200 nucleotides to about 1000 or more nucleotides, to specifically hybridize with the target nucleic acid under stringent conditions. Standard methods for performing FISH are described in, for example, the following literature: Ausubel, FM et al. (2004), *Experimental Guide to Contemporary Molecular Biology*; John Wiley & Sons and Fluorescence In Situ Hybridization: Technical Overview; John M.S. Bartlett, *Molecular Diagnosis of Cancer, Methods and Protocols*, 2nd Edition; ISBN: 1-59259-760-2; March 2004, pp. 077-088; *Series: Methods in Molecular Medicine*.

[0803] The method for gene expression profiling is described by (DePrimo et al. (2003), BMC Cancer, 3:3). In brief, the protocol is as follows: first-strand cDNA synthesis is initiated from polyadenylated mRNA using (dT)24 oligomers, followed by second-strand cDNA synthesis from total RNA using random hexamer primers. The double-stranded cDNA is used as a template for in vitro transcription of cRNA using biotinylated ribonucleotides. The cRNA is chemically fragmented according to a protocol described by Affymetrix (Santa Clara, CA, USA) and then hybridized overnight on a human genome array with gene-specific oligonucleotide probes. Alternatively, a single nucleotide polymorphism (SNP) array is a DNA microarray that can be used to detect polymorphisms within a population.

[0804] Alternatively, protein products expressed from mRNA can be evaluated by: immunohistochemistry of tumor samples, solid-phase immunoassay using microplates, Western blotting, 2D SDS-polyacrylamide gel electrophoresis, ELISA, flow cytometry, and other methods known in the art for detecting specific proteins, such as capillary electrophoresis. The detection method will involve the use of site-specific antibodies. Those skilled in the art will recognize that all these well-known techniques can be used to detect the upregulation of SHP2, the loss of SHP2 or SHP2 variants or mutants, or the negative regulator of SHP2 in this invention.

[0805] Abnormal levels of proteins such as SHP2 can be measured using standard protein assays, such as those described herein. Elevated levels or overexpression in tissue samples, such as tumor tissue, can also be detected, for example, by using assays from Chemicon International. The protein of interest is immunoprecipitated from sample lysates, and its level is measured. Assay methods may also involve the use of biomarkers.

[0806] In other words, SHP2 overexpression or mutant SHP2 can be measured through tumors.

[0807] Methods for assessing gene copy number changes include techniques commonly used in cytogenetics laboratories, such as MLPA (multiplex linkage-dependent probe amplification), multiplex PCR methods for detecting abnormal copy numbers, or other PCR techniques that can detect gene amplification, gain, and deletion.

[0808] In appropriate circumstances, pre-functional assays, such as measuring circulating leukemia cells in cancer patients, can also be used to assess the response to stimulation with SHP2 inhibitors.

[0809] Therefore, all these techniques can also be used to identify tumors that are particularly suitable for treatment with the compounds of the present invention.

[0810] Therefore, another aspect of the invention includes the use of the compounds according to the invention in the preparation of a medicament for treating or preventing a disease state or condition in a patient who has been screened and identified as having or at risk of having a disease or condition that is readily treatable with an SHP2 inhibitor.

[0811] Another aspect of the invention includes compounds of the invention for the prevention or treatment of cancers in patients selected from subpopulations with SHP2 amplification.

[0812] Another aspect of the invention comprises compounds of the invention for the prevention or treatment of cancer in patients with loss of the SHP2 negative regulatory factor.

[0813] Another aspect of the invention comprises compounds of the invention for the prevention or treatment of cancer in patients selected from a subgroup having RTK-driven MAPK signaling pathway activation.

[0814] MRI determinations of vascular normalization (e.g., using MRI gradient echo, spin echo, and contrast enhancement to measure blood volume, relative vessel size, and vascular permeability) in combination with circulating biomarkers can also be used to identify patients suitable for treatment with the compounds of the present invention.

[0815] Therefore, another aspect of the invention is a method for diagnosing and treating a disease state or symptom mediated by SHP2, the method comprising (i) screening a patient to determine whether the disease or symptom the patient is experiencing or may experience is a disease or symptom that is susceptible to treatment with an SHP2 inhibitor; and (ii) in the case of indicating a disease or symptom that the patient is therefore susceptible to, subsequently administering to the patient a compound of formula (I) and a subgroup or instance thereof as defined herein.

[0816] Advantages of the compounds of this invention

[0817] The compounds of formula (I) have many advantages compared to prior art compounds. The compounds of the present invention may have particular advantages in one or more of the following aspects:

[0818] (i) Superior efficacy;

[0819] (ii) Superior internal efficacy;

[0820] (iii) Superior PK;

[0821] (iv) Superior metabolic stability;

[0822] (v) Excellent oral bioavailability;

[0823] (vi) Superior physicochemical properties; and / or

[0824] (vii) Superior safety features or therapeutic index (TI).

[0825] Superior efficacy and internal effects

[0826] Compounds of formula (I) have increased affinity for SHP2, and specifically, increased cellular efficacy against cell lines known to be sensitive to SHP2 antagonists.

[0827] Enhanced target engagement is a highly desirable property in drug compounds because it allows for reduced drug dosage and a good separation between SHP2 activity and toxic effects (“therapeutic window”).

[0828] Compounds of formula (I) exhibit enhanced cellular potency and / or improved selectivity against SHP2 cell lines. Due to the enhanced potency against SHP2, the compounds of this invention exhibit enhanced in vivo efficacy in cancer cell lines and in vivo models.

[0829] Superior PK and metabolic stability

[0830] Compounds of formula (I) may possess favorable ADMET properties, such as better metabolic stability (e.g., as determined by mouse liver microsomes), better P450 profiles, shorter half-lives, and / or beneficial clearance rates (e.g., low or high clearance rates). Many compounds of formula (I) have also been found to have improved PK profiles.

[0831] These characteristics can provide the advantage of having more available drugs circulating in the body reaching the appropriate site of action to exert their therapeutic effect. Increasing drug concentration to exert pharmacological effects in tumors potentially leads to enhanced efficacy, which in turn allows for a reduction in the dosage to be administered. Therefore, compounds of formula (I) should exhibit reduced dosage requirements and should be easier to formulate and administer.

[0832] This allows for a good separation between SHP2 activity and toxicity (“therapeutic window”). The Cmax required for the efficacy of many formula (I) compounds is reduced (due to better SHP2 potency and / or PK).

[0833] Excellent oral bioavailability

[0834] Potentially, the compounds of the present invention have physicochemical properties suitable for oral exposure (oral exposure or AUC). Specifically, compounds of formula (I) may exhibit improved oral bioavailability or improved oral absorption reproducibility. Oral bioavailability may be defined as the ratio (F) of the plasma exposure of the compound when administered orally to the plasma exposure of the compound when administered intravenously (iv), expressed as a percentage.

[0835] Compounds with oral bioavailability (F value) greater than 10%, 20%, or 30%, and more particularly greater than 40%, are particularly advantageous because they can be administered orally rather than parenterally, or may also be administered parenterally.

[0836] Superior physicochemical properties

[0837] Compounds of formula (I) can have favorable physicochemical properties, particularly chemical stability under acidic conditions and reduced lipophilicity.

[0838] Lipophilicity can be measured using the partition coefficient (logP) or the distribution coefficient (logD). The partition coefficient is the ratio of the concentrations of unionized compounds between two immiscible phases (n-octanol and water) at equilibrium, while the distribution coefficient is the ratio of the sum of the concentrations of all forms of the compound (ionized plus unionized) in each of the two phases. High lipophilicity is associated with poorer drug-like properties, such as low water solubility, poor pharmacokinetic properties (low oral bioavailability), undesirable drug metabolism, and high impurities. Compounds with optimal lipophilicity may have a greater chance of success in drug development. However, achieving reduced logP (or calculated logP, clogP) while maintaining acceptable levels of protein-protein interaction (PPI) inhibition efficacy can be challenging due to the lipophilicity of the targets involved.

[0839] Superior safety profile or therapeutic index (TI)

[0840] In the late 1990s, many FDA-approved drugs had to be withdrawn from sale in the United States after they were found to be associated with death from heart failure. It was subsequently discovered that the side effects of these drugs were caused by arrhythmias resulting from the blockage of hERG channels in heart cells. hERG channels are members of the potassium ion channel family, the first member of which was identified in the late 1980s in the mutant *Drosophila melanogaster* (see Jan, LY and Jan, YN (1990). Superfamily of Ion Channels. *Nature*, 345(6277):672). The biophysical properties of the hERG potassium channel were investigated in Sanguinetti, MC, Jiang, C., Curran, ME, and Keating, MT (1995). Mechanistic Link Between an Inherited and an Acquired Cardiac Arrhythmia: HERG encodes the Ikr potassium channel. Cell, 81:299-307 and Trudeau, MC, Warmke, JW, Ganezky, B., and Robertson, GA (1995). HERG, a Human Inward Rectifier in the Voltage-Gated Potassium Channel Family. Science, 269:92-95. Therefore, eliminating hERG blocking activity remains an important consideration in the development of any new drug.

[0841] Compounds exhibiting reduced hERG activity and / or a good separation between activity and hERG activity have a larger “therapeutic window” or “therapeutic index.” One method for measuring hERG activity is the patch-clamp electrophysiological approach. Alternative methods for measuring functional hERG activity include hERG binding assays, which can use commercially available membranes isolated from cells stably expressing hERG channels or from commercially available cell lines expressing hERG channels.

[0842] Compounds may also exhibit improved cardiac safety index (CSI) [CSI = hERG IC50 / Cmax (unbound)] (Shultz et al., *Journal of Medicinal Chemistry*, 2011; Redfern et al., *Cardiovasc. Res.*, 2003). This may be due to an increase in hERG IC50 or a decrease in Cmax required for efficacy (due to better potency and / or pharmacokinetics). Certain compounds may demonstrate CV advantages in vivo.

[0843] Specific compounds exhibit reduced hERG ion channel blocking activity. The average IC50 of the compounds against hERG is [data missing]. 50 The value can be compared with the IC50 value of the compound in cell proliferation assays. 50 The value is 30 times, 40 times, or 50 times greater.

[0844] Drug formulation

[0845] While it is possible to administer the active compound alone, the active compound is usually present in the form of a pharmaceutical composition (e.g., a formulation).

[0846] Therefore, the present invention further provides pharmaceutical compositions as defined above and methods for preparing pharmaceutical compositions, said pharmaceutical compositions comprising (e.g., a mixture) at least one compound of formula (I) (and its subgroups as defined herein) and one or more pharmaceutically acceptable excipients and optionally other therapeutic or preventative agents as described herein.

[0847] Pharmaceutically acceptable excipients may be selected from, for example, carriers (e.g., solid, liquid, or semi-solid carriers), adjuvants, diluents, fillers or swelling agents, granulators, coating agents, release control agents, binders, disintegrants, lubricants, preservatives, antioxidants, buffers, suspending agents, thickeners, flavoring agents, sweeteners, masking agents, stabilizers, or any other excipients conventionally used in pharmaceutical compositions. Examples of excipients used in various types of pharmaceutical compositions are described in more detail below.

[0848] As used herein, the term "pharmaceutically acceptable" means a compound, material, composition, and / or dosage form that, to the extent of reasonable medical judgment, is suitable for contact with the tissues of a subject (e.g., a human subject) without excessive toxicity, irritation, allergic response, or other problems or complications, and is commensurate with a reasonable benefit / risk ratio. Each excipient must also be "acceptable" in the sense of compatibility with the other components of the formulation.

[0849] Pharmaceutical compositions containing compounds of formula (I) can be formulated using known techniques, see, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania, USA.

[0850] The pharmaceutical composition may be in any form suitable for oral, parenteral, topical, intranasal, intrabronchial, sublingual, ocular, ocular, rectal, vaginal, or percutaneous administration. When the composition is intended for parenteral administration, it may be formulated for intravenous, intramuscular, intraperitoneal, subcutaneous administration, or direct delivery to the target organ or tissue by injection, infusion, or other means of delivery. Delivery may be by bolus injection, short-term infusion, or long-term infusion and may be achieved by passive delivery or by using a suitable infusion pump or syringe driver.

[0851] Suitable parenteral drug formulations include aqueous and non-aqueous sterile injectable solutions, which may contain antioxidants, buffers, bactericides, cosolvents, surfactants, organic solvent mixtures, cyclodextrin complexes, emulsifiers (for forming and stabilizing emulsion formulations), liposome components for forming liposomes, gelling polymers for forming polymeric gels, lyophilization protectants, and combinations of agents for stabilizing the active ingredient in a soluble form and making the formulation isotonic with the blood of the intended recipient. Parenteral drug formulations may also be in the form of aqueous and non-aqueous sterile suspensions, which may contain suspending agents and thickeners (RGStrickly, Solubilizing Excipients in oral and injectable formulations, Pharmaceutical Research, 2004, Vol. 21(2), pp. 201-230).

[0852] The formulation can be present in single-dose or multi-dose containers, such as sealed ampoules, vials, and pre-filled syringes, and can be stored under lyophilized (freeze-dried) conditions where a sterile liquid carrier, such as water for injection, only needs to be added just before use. In one embodiment, the formulation is provided in a vial as an active pharmaceutical ingredient for subsequent reconstitution using an appropriate diluent.

[0853] Pharmaceutical formulations can be prepared by lyophilizing compounds of formula (I) or their subgroups. Lyophilization refers to the process of freezing a composition. Therefore, lyophilization and freeze-drying are used as synonyms in this document.

[0854] Temporary injection solutions and suspensions can be prepared from sterile powders, granules, and tablets.

[0855] The pharmaceutical compositions of the present invention for parenteral injection may also comprise pharmaceutically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, as well as sterile powders for recombination into sterile injectable solutions or dispersions prior to use. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents, or mediators include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.), carboxymethyl cellulose and suitable mixtures thereof, vegetable oils (such as sunflower oil, safflower oil, corn oil, or olive oil), and injectable organic esters, such as ethyl oleate. Appropriate flowability can be maintained, for example, by using thickening materials such as lecithin, by maintaining the desired particle size in the case of dispersions, and by using surfactants.

[0856] The compositions of the present invention may also contain adjuvants, such as preservatives, wetting agents, emulsifiers, and dispersants. Prevention of microbial action can be ensured by including various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, etc. It is also desirable to include agents that regulate the drug's viscosity, such as sugars, sodium chloride, etc. Prolonged absorption of injectable drugs can be achieved by including agents that delay absorption, such as aluminum monostearate and gelatin.

[0857] In a typical embodiment of the invention, the pharmaceutical composition is in a form suitable for intravenous administration, for example, by injection or infusion. For intravenous administration, the solution may be administered as is or may be injected into an infusion bag (containing pharmaceutically acceptable excipients, such as 0.9% saline or 5% dextrose) prior to administration.

[0858] In another typical embodiment, the pharmaceutical composition is in a form suitable for subcutaneous (sc) administration.

[0859] Suitable dosage forms for oral administration include tablets (coated or uncoated), capsules (hard or soft shell), capsules, pills, lozenges, syrups, solutions, powders, granules, elixirs and suspensions, sublingual tablets, sheets or patches, such as oral patches.

[0860] Therefore, tablet compositions may contain a unit dose of the active compound and an inert diluent or carrier, such as sugars or sugar alcohols, such as lactose, sucrose, sorbitol, or mannitol, and / or non-sugar-derived diluents, such as sodium carbonate, calcium phosphate, calcium carbonate, or cellulose or its derivatives, such as microcrystalline cellulose (MCC), methylcellulose, ethylcellulose, hydroxypropyl methylcellulose, and starch, such as corn starch. Tablets may also contain standard ingredients, such as binders and granulators, such as polyvinylpyrrolidone, disintegrants (e.g., swelling crosslinking polymers, such as crosslinked carboxymethyl cellulose), lubricants (e.g., stearates), preservatives (e.g., parabens), antioxidants (e.g., BHT), buffers (e.g., phosphate or citrate buffers), and effervescent agents, such as citrate / bicarbonate mixtures. Such excipients are well known and need not be discussed in detail here.

[0861] Tablets can be designed to release the drug upon contact with gastric fluid (immediate-release tablets) or to release it in a controlled manner over a prolonged period of time or in a specific region of the GI tract (controlled-release tablets).

[0862] Capsule formulations can be either hard or soft gelatin and can contain active ingredients in solid, semi-solid, or liquid form. Gelatin capsules can be formed from animal gelatin or its synthetic or plant-derived equivalents.

[0863] Solid dosage forms (e.g., tablets, capsules, etc.) can be coated or uncoated. Coating can serve as a protective film (e.g., polymer, wax, or varnish) or as a mechanism for controlling drug release or for aesthetic or identification purposes. Coating (e.g., Eudragit) TM The coating (often a polymer) can be designed to release the active component at a desired location within the gastrointestinal tract. Therefore, the coating can be selected to degrade under certain pH conditions within the gastrointestinal tract, thereby selectively releasing the compound in the stomach or in the ileum, duodenum, jejunum, or colon.

[0864] As an alternative to or in addition to coating, the drug may be contained in a solid matrix comprising a release controller, such as a release delay agent, suitable for releasing the compound in a controlled manner in the gastrointestinal tract. Alternatively, the drug may be contained in a polymer coating, such as a polymethacrylate polymer coating, suitable for selectively releasing the compound in the gastrointestinal tract under varying acidity or alkalinity conditions. Alternatively, the matrix material or sustained-release coating may be in the form of an erosive polymer (e.g., a maleic anhydride polymer) that is substantially continuously eroded as the dosage form passes through the gastrointestinal tract. In another alternative, the coating may be designed to disintegrate in the intestine under the action of microorganisms. As yet another alternative, the active compound may be formulated in a delivery system that provides permeability control over the release of the compound. Permeable-release and other delayed-release or sustained-release formulations (e.g., ion-exchange resin-based formulations) may be prepared according to methods well known to those skilled in the art.

[0865] Compounds of formula (I) can be formulated with a carrier and administered in the form of nanoparticles, the increased surface area of ​​which facilitates absorption. Additionally, nanoparticles offer the possibility of direct penetration into cells. Nanoparticle drug delivery systems are described in "Nanoparticle Technology for Drug Delivery," edited by Ram B Gupta and Uday B. Kompella, Informa Healthcare, ISBN 9781574448573, March 13, 2006. Nanoparticles for drug delivery are also described in the *Journal of Controlled Release*, 2003, 91(1-2), 167-172, and in Sinha et al., *Molecular Cancer Ther.*, August 1, (2006) 5, 1909.

[0866] Pharmaceutical compositions typically comprise from about 1% (w / w) to about 95% of the active ingredient and from 99% (w / w) to 5% (w / w) of pharmaceutically acceptable excipients or combinations of excipients. Typically, pharmaceutical compositions comprise from about 20% (w / w) to about 90% of the active ingredient and from 80% (w / w) to 10% (w / w) of pharmaceutically acceptable excipients or combinations of excipients. Pharmaceutical compositions according to the invention may be in, for example, unit-dose form, such as ampoules, vials, suppositories, pre-filled syringes, sugar-coated pills, tablets, or capsules.

[0867] Pharmaceutically acceptable excipients can be selected based on the desired physical form of the formulation and can be selected, for example, from diluents (e.g., solid diluents, such as fillers or swelling agents; and liquid diluents, such as solvents and cosolvents), disintegrants, buffers, lubricants, flow aids, release control agents (e.g., sustained-release agents or delayed polymers or waxes), binders, granulators, pigments, plasticizers, antioxidants, preservatives, flavoring agents, taste masking agents, tension modifiers, and coating agents.

[0868] Technicians will possess the expertise to select appropriate amounts of ingredients for formulations. For example, tablets and capsules typically contain 0-20% disintegrants, 0-5% lubricants, 0-5% glidants, and / or 0-99% (w / w) fillers / or swelling agents (depending on the drug dosage). The tablets and capsules may also contain 0-10% (w / w) polymer binders, 0-5% (w / w) antioxidants, and 0-5% (w / w) pigments. Extended-release tablets will additionally contain 0-99% (w / w) polymers (depending on the dosage). Film coatings of tablets or capsules typically contain 0-10% (w / w) controlled-release (e.g., delayed-release) polymers, 0-3% (w / w) pigments, and / or 0-2% (w / w) plasticizers.

[0869] Parenteral formulations typically contain 0-20% (w / w) buffer, 0-50% (w / w) solubilizer, and / or 0-99% (w / w) water for injection (WFI) (depending on dosage and whether lyophilized). Formulations intended for intramuscular storage may also contain 0-99% (w / w) oil.

[0870] Pharmaceutical compositions for oral administration can be obtained by combining an active ingredient with a solid carrier; granulating the resulting mixture if necessary; and, if necessary or required, processing the mixture into tablets, sugar-coated cores, or capsules after adding appropriate excipients. The pharmaceutical composition may also be incorporated into a polymer or wax matrix that allows the active ingredient to diffuse or be released in a measured amount.

[0871] The compounds of this invention can also be formulated as solid dispersions. A solid dispersion is a homogeneous, extremely finely dispersed phase of two or more solids. A solid solution (molecular dispersion system) is a type of solid dispersion, well known for its use in pharmaceutical technology (see Chiou and Riegelman, Journal of Pharmaceutical Sciences (J. Pharm. Sci., 60, 1281-1300 (1971)) and for improving dissolution rates and increasing the bioavailability of poorly water-soluble drugs.

[0872] This invention also provides solid dosage forms comprising the solid solutions described herein. Solid dosage forms include tablets, capsules, chewable tablets, and dispersible or effervescent tablets. Known excipients can be blended with solid solutions to provide the desired dosage form. For example, capsules may contain a solid solution blended with (a) a disintegrant and a lubricant or (b) a disintegrant, a lubricant, and a surfactant. Additionally, capsules may contain a swelling agent, such as lactose or microcrystalline cellulose. Tablets may contain a solid solution blended with at least one disintegrant, a lubricant, a surfactant, a swelling agent, and a slip agent. Chewable tablets may contain a solid solution blended with a swelling agent, a lubricant, and, if desired, an additional sweetener (such as an artificial sweetener) and a suitable flavoring agent. Solid solutions can also be formed by spraying a solution of a drug and a suitable polymer onto the surface of an inert carrier, such as sugar beads (“non-pareil”). These beads can then be filled into capsules or compressed into tablets.

[0873] Medication preparations can be delivered to patients in the form of a "patient kit," typically a blister pack containing the entire course of treatment. Patient kits offer advantages over traditional prescriptions, where pharmacists separate medication delivery from bulk delivery, because patients always have access to the package insert containing instructions typically missing from their prescriptions. Including package inserts has been shown to improve patient adherence to physician instructions.

[0874] Compositions for topical application and nasal delivery include ointments, creams, sprays, patches, gels, drops, and inserts (e.g., intraocular inserts). Such compositions can be formulated according to known methods.

[0875] Examples of formulations for rectal or vaginal administration include pessaries and suppositories, which may be formed, for example, from molded, malleable or wax-based materials containing an active compound. Solutions of the active compound can also be used for rectal administration.

[0876] Compositions intended for inhalation administration can be in the form of inhalable powder compositions, liquids, or powder sprays, and can be administered in standard form using powder inhaler devices or aerosol dispensing devices. Such devices are well known. For inhalation administration, powder formulations typically include an active compound along with an inert solid powder diluent, such as lactose.

[0877] Compounds of formula (I) will typically be present in unit dosage forms and will therefore typically contain sufficient amounts of the compound to provide the desired level of bioactivity. For example, a formulation may contain 1 nanogram to 2 grams of active ingredient, such as 1 nanogram to 2 milligrams of active ingredient. Within these ranges, specific subranges of the compound are 0.1 milligrams to 2 grams of active ingredient (more typically 10 milligrams to 1 gram, such as 50 milligrams to 500 milligrams), or 1 microgram to 20 milligrams (such as 1 microgram to 10 milligrams, such as 0.1 milligrams to 2 milligrams of active ingredient).

[0878] For oral compositions, the unit dosage form may contain 1 mg to 2 g, more typically 10 mg to 1 g, such as 50 mg to 1 g, or 100 mg to 1 g of active compound.

[0879] The active compound will be administered to patients in need (e.g., human or animal patients) in an amount sufficient to achieve the desired therapeutic effect.

[0880] Treatment

[0881] Compounds and subgroups of formula (I) as defined herein can be used to prevent or treat a range of disease states or symptoms mediated by SHP2. Examples of such disease states and symptoms have been described above.

[0882] The compound is typically administered to subjects who require such administration, such as human or animal patients, usually humans.

[0883] The compound will generally be administered in a dose that is useful for treatment or prevention and is generally non-toxic. However, in certain situations (e.g., in cases of life-threatening illness), the benefits of administering a compound of formula (I) may outweigh any disadvantages of toxicity or side effects, in which case it may be considered desirable to administer the compound in a dose that is related to the degree of toxicity.

[0884] The compound can be administered over an extended period to maintain a beneficial therapeutic effect, or it can be administered for a shorter duration. Alternatively, the compound can be administered continuously or in a manner that provides intermittent dosing (e.g., pulsatile dosing).

[0885] Typical daily doses of compounds of formula (I) can range from 100 picograms to 100 milligrams per kilogram of body weight. The compounds of the present invention can also be administered by bolus injection or continuous infusion.

[0886] The amount of compound applied and the type of composition used will be proportionate to the nature of the disease or physiological condition being treated and will be determined by the physician.

[0887] It may be advantageous to use the compounds of the present invention as a single agent or to combine the compounds of the present invention with two of the characteristic features of treating cancer development through a different mechanism of action to regulate cell growth. Combination experiments can be performed, for example, as described in Chou TC, Talalay P. Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv. Enzyme Regulation, 1984; 22:27–55.

[0888] The compounds as defined herein may be administered as the sole therapeutic agent, or the compounds may be administered in combination with one or more other compounds (or therapies) for treating specific disease states, such as neoplastic diseases, such as cancer as defined above. In one embodiment, the combination therapy comprises a compound of formula I and one or more other anticancer compounds (or therapies) for treating cancer. For treating the aforementioned conditions, the compounds of the present invention may advantageously be combined with one or more other pharmaceutical agents, more specifically with other anticancer agents or adjuvants (supportive agents in the therapy) for cancer therapy.

[0889] Examples of other therapeutic agents or treatments that can be administered together with compounds of formula (I) (whether simultaneously or at different time intervals) include, but are not limited to:

[0890] 1. Topoisomerase I inhibitors;

[0891] 2. Antimetabolites and nucleoside derivatives;

[0892] 3. Tubulin targeting agents, including vinca alkaloid, epothilone, tubulin binders, and taxane;

[0893] 4. DNA binding agents, such as platinum-based agents and anthracyclines, as well as topoisomerase II inhibitors;

[0894] 5. Alkylating agent;

[0895] 6. Monoclonal antibodies;

[0896] 7. Anti-hormonal agents, such as GnRA, estrogen receptor antagonists, selective estrogen receptor modulators (SERMs), aromatase inhibitors, and anti-androgens;

[0897] 8. Signal transduction inhibitors;

[0898] 9. Proteasome inhibitors;

[0899] 10. DNA methyltransferase inhibitors;

[0900] 11. Recombinant interferon and retinoids;

[0901] 12. Chromatin-targeted therapy;

[0902] 13. Radiation therapy; and / or

[0903] 14. Other treatments or preventative agents.

[0904] Examples of other therapeutic agents or treatments that can be administered together with compounds of formula (I) (whether simultaneously or at different time intervals) include, but are not limited to:

[0905] I. Platinum compounds;

[0906] II. Taxane compounds;

[0907] III. Topoisomerase I inhibitors;

[0908] IV. Topoisomerase II inhibitors;

[0909] V. Vinca minor alkaloids;

[0910] VI. Nucleoside derivatives;

[0911] VII. Antimetabolites;

[0912] VIII. Alkylating agents;

[0913] IX. Other cytotoxic agents;

[0914] X. Anthracyclines, anthraquinones, and related drugs;

[0915] XI. Epomycin;

[0916] XII. DNA methyltransferase inhibitor;

[0917] XIII. Histone methyltransferase inhibitors;

[0918] XIV. Anti-folic acid agents;

[0919] XV. Cytotoxic antibiotics;

[0920] XVI. Microtubule-binding agents;

[0921] XVII. Signal transduction inhibitors;

[0922] XVIII. Mitotic kinase inhibitors:

[0923] XIX.CDK inhibitors;

[0924] XX.PI3K / AKT pathway inhibitors;

[0925] XXI.ERK inhibitors;

[0926] XXII.Hsp90 inhibitor;

[0927] XXIII. Monoclonal antibodies, antibody derivatives, bispecific antibodies, and "antibody-like" therapeutic proteins or other therapeutic proteins and related agents;

[0928] XXIV. Estrogen receptor antagonists or selective estrogen receptor modulators (SERMs) or estrogen synthesis inhibitors;

[0929] XXV. Aromatase inhibitors and related drugs;

[0930] XXVI. Antiandrogens (i.e., androgen receptor antagonists) and related drugs;

[0931] XXVII. Hormones and their analogues;

[0932] XXVIII. Steroids;

[0933] XXIX. Steroidal cytochrome P450 17α-hydroxylase-17,20-lyase inhibitor (CYP17);

[0934] XXX. Gonadotropin-releasing hormone agonists or antagonists (GnRAs);

[0935] XXXI. Glucocorticoids;

[0936] XXXII. Differentiating agent;

[0937] XXXIII. Hedgehog pathway inhibitor;

[0938] XXXIV. Dehydrogenase inhibitor;

[0939] XXXV. Inhibitor of protein 1 export;

[0940] XXXVI. Polymerase inhibitor;

[0941] XXXVII. Farnesyltransferase inhibitor;

[0942] XXXVIII. Chromatin-Targeted Therapy;

[0943] XXXIX. Drugs that target the ubiquitin-proteasome pathway, including proteasome inhibitors;

[0944] XL. Photodynamic drugs;

[0945] XLI. An anticancer agent derived from marine organisms;

[0946] XLII. Radiolabeled drugs used in radioimmunotherapy;

[0947] XLIII. Telomerase inhibitor;

[0948] XLIV. Inhibitors of matrix metalloproteinases;

[0949] XLV. Recombinant interferon and interleukin;

[0950] XLVI. Selective immune response modulator;

[0951] XLVII. Therapeutic vaccines;

[0952] XLVIII. Cytokine activator;

[0953] XLIX. Cytokine conjugates;

[0954] L. Arsenic trioxide;

[0955] L1. G protein-coupled receptor (GPCR) inhibitors;

[0956] LII. enzyme;

[0957] LIII. DNA repair inhibitor;

[0958] LIV. Death receptor agonists;

[0959] LV. Other immunotherapies;

[0960] LVI. A regulator of cell death (apoptosis);

[0961] LVII. Gene modifier or editor;

[0962] LVIII. Bromine domain inhibitor;

[0963] LIX. Radiation therapy for radical, palliative, or prophylactic purposes (or for adjuvant or neoadjuvant purposes); and / or

[0964] LX. Preventive agents (adjuvants); that is, agents that reduce or alleviate some of the side effects associated with chemotherapy drugs.

[0965] In one embodiment, the combination therapy comprises a compound of formula I and one or more other anticancer compounds (or therapies) for treating cancer, optionally combined with radiotherapy and / or a prophylactic agent. In another embodiment, the combination therapy comprises a compound of formula I combined with radiotherapy and / or a prophylactic agent.

[0966] Specific examples of anticancer agents or adjuvants (or salts thereof) include, but are not limited to, any agent selected from the following groups (I)-(LIX) and optionally group (LX):

[0967] I. Platinum compounds, such as cisplatin (optionally in combination with amifostine), carboplatin, oxaliplatin, dicycloplatin, heptaplatin, lobaplatin, nedaplatin, satraplatin, or triplatintetranitrate, specifically cisplatin, carboplatin, or oxaliplatin;

[0968] II. Taxane compounds, such as paclitaxel and paclitaxel protein-bound particles (Abraxane). TM Docetaxel, cabazitaxel, larotaxel; ortataxel, tesetaxel, or simotaxel, specifically paclitaxel, paclitaxel protein-binding particles (Abraxane), etc. TM Or Dorsetas;

[0969] III. Topoisomerase I inhibitors, such as camptothecin compounds, such as camptothecin, irinotecan (CPT11), SN-38, topotecan, bryostatin, callystatin, nogitecan, belootecan, exatecan, rubitecan, or lurtotecan, specifically camptothecin, irinotecan, or topotecan;

[0970] IV. Topoisomerase II inhibitors, such as antitumor epipodophyllotoxin or podophyllotoxin derivatives, such as etoposide, teniposide, sobuzoxane, edotecarin, amonafide, amrubicin, or pixantrone, specifically etoposide or teniposide;

[0971] V. Vinca alkaloids, such as vincristine, vincristine, liposomal vincristine (Onco-TCS), vinorelbine, vindesine, vinflunine, vinvesir, eribulin, or thaliblastine; specifically vincristine, vincristine, or vinorelbine;

[0972] VI. Nucleoside derivatives, such as 5-fluorouracil (5-FU, optionally in combination with leucovorin, such as LV5FU2), gemcitabine, capecitabine, tegafur (optionally in combination with uracil known as UFT, or with gimeracil and oteracilpotassium known as TS-1 or S1), cladribine, cytarabine (Ara-C, cytosine arabinoside), fludarabine, clofarabine, nelarabine; forodesine, doxifluridine, galocitabine, sapacitabine, emitefur, or troxacitabine;

[0973] VII. Antimetabolites, such as clofarabine, aminopterin or methotrexate, azacitidine, cytarabine, fluxuridine, pentostatin, thioguanine, thiopurine, 6-mercaptopurine, hydroxyurea, or trifluridine (optionally in combination with tipiracil);

[0974] VIII. Alkylating agents, such as nitrogen mustard or nitrosourea, including cyclophosphamide, chlorambucil, chlorambucil (BCNU), ambamustine, bendamustine, thiotepa, melphalan, treosulfan, lomustine (CCNU), busulfan, dacarbazine, estramustine, fotemustine, ifosfamide (optionally in combination with mesna), pipebroman, procarbazine (proc... arbazine), streptozocin, temozolomide, uracil, methyl chloroethylamine, methyl chloroethylamine hydrochloride, methylcyclohexylchloroethylnitrosourea, nimustine (ACNU), prednimustine, methyl chloroethylamine, etoglucid; streptozotocin, irofulven, mitolactal, glufosfamide, evofosfamide, ethyleneimine or methylmelamine, including hexamethylmelamine, triethylenemelamine, trimethylolmelamine, triethylenephosphoramide, triethylenethiophosphoramide or trimethylolmelamine;

[0975] IX. Other cytotoxic agents, such as dolastatin, eleutherobin, pancratistatin, sarcodictyin A, or spongistatin;

[0976] X. Anthracyclines, anthraquinones, and related drugs, such as daunorubicin, doxorubicin (optionally in combination with dexrazoxane), and liposomal formulations of doxorubicin (e.g., Caelyx). TM Myocet TM Doxil TM), idarubicin, mitoxantrone, epirubicin, amsacrine, or valrubicin;

[0977] XI. Epomycins, such as ixabepilone, patupilone, BMS-310705, epomomycin A, epomomycin B, deoxyepomomycin B (also known as epomomycin D or KOS-862), azaeepomomycin B (also known as BMS-247550), aulimalide, isolaulimalide, or luetherobin;

[0978] XII. DNA methyltransferase inhibitors, such as temozolomide, azacytidine, decitabine (alone or in combination with cytidine deaminase inhibitors, such as cedazurdine), or guadecitabine (SGI-110).

[0979] XIII. Histone methyltransferase inhibitors, such as EZH2 inhibitors, such as tazemetostat, PF-06821497, CPI-1205 or CPI-0209;

[0980] XIV. Antifolate, such as methotrexate, pemetrexed disodium, raltitrexed, pralatrexate, edatrexate, or trimetrexate;

[0981] XV. Cytotoxic antibiotics, such as antinomycin D, bleomycin, mitomycin C, dactinomycin, carminomycin, daunomycin, levamisole, plicamycin, mithramycin, aclarubicin, pirarubicin, anthramycin, azaserine, cactinomycin, calicheamicin, carabicin, carzinophilin, chromomycin, esoubicin, esperamicin, geldanamycin, marcellomycin. In), olivomycin, peplomycin, puromycin, quelamycin, rebeccamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, dynemicin (including dynemicin A), centanamycin (CC-1065) (including its synthetic analogs adozelesin, carzelesin, and bizelesin), duocarmycin (including its synthetic analogs pibrozelesin (KW-2189) or zinostatin;

[0982] XVI. Microtubule-binding agents, such as combrestatin, colchicine, demecolcine, noscapine, or nocodazole;

[0983] XVII. Signal transduction inhibitors, such as kinase inhibitors, including receptor tyrosine kinase inhibitors (e.g., EGFR (epidermal growth factor receptor (Erbb1) inhibitors), VEGFR (vascular endothelial growth factor receptor) inhibitors, PDGFR (platelet-derived growth factor receptor) inhibitors, FGFR (fibroblast growth factor receptor) inhibitors, Axl inhibitors, MTKI (multi-target kinase inhibitors), c-Kit inhibitors, other Erbb inhibitors such as Errb2 (HER2), Errb3 (HER3), or Errb4 (HER4), Trk inhibitors, Flt3 inhibitors, JAK inhibitors, RET inhibitors, MET inhibitors, Btk inhibitors, ALK inhibitors, ROS1 inhibitors, FYN inhibitors, Src inhibitors, Bcr-Abl inhibitors, hexokinase inhibitors, Raf inhibitors, ROCK inhibitors, MEK inhibitors, or PI3K inhibitors, such as imatinib, erlotinib. Erlotinib, Gefitinib, Afatinib (dual EGFR / HER2), Brigatinib (ALK / EGFR), Osimertinib (EGFR), Almonertinib (EGFR), Olmutinib (EGFR), Icotinib (EGFR), Alflutinib (EGFR), Lazertinib (EGFR), Zorifertinib (EGFR), Mefatinib (EGFR), Sutetinib (EGFR), Dasatinib, Lapatinib, Dovitinib (CHIR) 258), axitinib (AG-13736), nilotinib, vandetanib, vatalinib, saracatinib (AZD-0530), bosutinib, bafetinib (NS-187), abivertinib (EGFR, Btk), mobocertinib (EGFR, Erbb2), anlotinib (multiple kinase inhibitors), avapritinib (KIT, PDGF), lenvatinib (E-7080) (multiple kinase inhibitors), pyrotinib (multiple kinase inhibitors).Lonidamine (hexokinase), BMS-690514, nintedanib (tyrosine kinase), ponatinib (multiple kinases), tivozanib (KRN-951) (multiple kinases), R-1530 (multiple kinases), vatalanib (PDGF, VEGF), PF-337210 (VEGF), AEE-788 (multiple kinases), tevatinib (XL-647) (multiple kinases), K-0706, ripretinib (KIT, PDGF), dacomitinib (EGFR, Erbb2 / Erbb4), neratinib (EGFR, Erbb2 / Erbb4), varitinib (varlitinib)(EGFR, Erbb2 / Erbb4), tucatinib (Erbb2), larotrectinib (Trk), erdafitinib (FGFR), infigratinib (FGFR), pemigatinib (FGFR), rogaratinib (FGFR), derazantinib (FGFR), E-7090 (FGFR), HMPL-453 (FGFR), zoligratinib (FGFR), futibatinib (FGFR), brivanib (FGFR, VEGFR), Ki 23057 (FGFR), Surufatinib (FGFR, VEGFR), Pazopanib (GW 786034), Cediranib (KIT, VEGFR, PDGFR), Orantinib (FGF, PDGF, VEGF), H3B-6527, MAX-40279, ICP-105, Telatinib (BAY-57-9352) (KIT, PDGFR, VEGFR), Pegaptanib (VEGFR), Semaxanib (MAPK, VEGFR), Quizartinib (AC-220) (Flt3, KIT, PDGFR), Crenolanib (CP 868596) (Flt3, PDGFR), Lestaurtinib (Multiple Kinases)Cabozantinib (XL-184) (VEGFR2, Axl, MET, RET), selpercatinib (RET), capmatinib (MET), MK-2461 (MET), SU-11274 (MET), PHA-665752 (MET), ibrutinib (Btk), acalabrutinib (Btk), acininib (Bcr-Abl), flumatinib (Abl), zanubrutinib (Btk), ruxo Ruxolitinib (JAK), Itacitinib (JAK), Paquitinib (JAK), Momelotinib (JAK), INCB-52793 (JAK), Gusacitinib (JAK / SYK), Ilginatinib (JAK), Cerdulatinib (Syk, JAK), Fedratinib (TG-101348) (Flt3, Jak2, RET), Tandutinib (Flt3) KIT, PDGF), pexidartinib (KIT, Flt3), midostaurin (Flt3, KIT, PKC), zotiraciclib (FLT3), alectinib (ALK), crizotinib (ALK), ceritinib (ALK), lorlatinib (ALK, Ros1), entrectinib (ALK, Ros1, TRK), masitinib (multiple kinase inhibitors), sorafenib (sorafenib), sunitinib, vemurafenib (PLX4032 or RG7204), dabrafenib, encorafenib, regorafenib (BAY-73-4506) (FGFR3, KIT), selumetinib (AZD6244), trametinib (GSK121120212), binimetinib (BRAF, MEK), cobimetinib (MEK)Midatinib (PD325901) (MEK), refametinib (MEK), uprosertib (AKT, MEK), pimasertib (MEK), dactolisib (BEZ235), buparlisib (BKM-120; NVP-BKM-120), alpelisib (BYL719) (PI3), copanlisib (BAY-80-6946), paxalisi b) (PI3K / mTOR / AKT pathway), S-49076 (multiplex kinase), rigosertib (multiplex kinase), rebastinib (multiplex kinase), ZSTK-474, fimepinostat (CUDC-907) (PI3K and HDAC), apitolisib (GDC-0980; RG-7422), pictilisib (GDC-0941, RG-7321, GNE-477), idelalisib (formerly known as CAL-101, GS) 1101, GS-1101, IC87114), serabelisib (MLN1117, INK1117) (PI3K), sapanisertib (MLN0128 (INK128)), duvelisib (IPI-145, INK1197) (PI3K), ipatasertib (GDC-0068), afuresertib, MK-2206, MK-8156, SKLB-1 028, LY294002, SF1126 or PI-103, sonolisib (PX-866), GSK1059615 (PI3K), pilaralisib (XL147) (PI3K); SF-1126 (multiplex kinase) or AT13148 or pan-Raf inhibitors, such as PLX8394, RAF-265, or other signal transduction inhibitors, such as mTOR inhibitors, including sirolimus, everolimus (RAD 001), and RAS inhibitors, such as AMG-510, LY-3499446, MRTX-849 or ARS-3248, or isoprenyltransferase inhibitors, such as antroquinonol;

[0984] XVIII. Mitotic kinase inhibitors, such as aurora kinase inhibitors, such as AT9283, barasertib (AZD1152), danusertib (PHA-739358), alisertib (MLN-8237), or CYC-116, or PLK (polo-like kinase inhibitors), such as PLK-1 or PLK-4, including regoraertib, onvansertib, CYC-140, GSK-461364, CFI-400945, or volasertib;

[0985] XIX.CDK inhibitors, such as AT7519, roscovitine, seliciclib, alvocidib (flavopiridol), abemaciclib, dinascilib (SCH-727965), 7-hydroxyastrosporin (UCN-01), JNJ-7706621, PHA533533, ZK-304709, coulitracalceli, or AZD-5438, contain CDK4 inhibitors such as palbociclib (PD332991), abemaciclib, dinascilib, lerociclib, trilaciclib, or ribociclib (LEE-011);

[0986] XX. PI3K / AKT pathway inhibitors, including PKA / B and / or PKB(akt) inhibitors, PI3K inhibitors, mTOR inhibitors, and / or calmodulin inhibitors (forkhead translocation inhibitors), such as PI3K inhibitors like apitolisib, buparlisib, copanlisib, pictilisib, dactolisib, idelalisib, serabelisib, and duvelisib. Eptarseti, alpelisib, afraxetine, passaris, seros, pilaralisib, femesta (CUDC-907), SKLB-1028, GSK1059615 (PI3K), ZSTK-474, GSK-2636771, samotolisib (LY-3023414), LY294002, SF1126, and PI-103; mTOR inhibitors such as sirolimus (originally called rapamycin) and rapamycin analogues such as RAD. 001 (everolimus), CCI779 (temsirolemus), AP23573 and ridaforolimus, or sapanisertib (MLN0128 (INK128), dual inhibitors of mTOR complex I (mTORCI) and mTORC2, PKA / B (or C) inhibitors such as perifosine, epataxetine, euprexetine, afraxetine, MK-2206, MK-8156, AT13148, carpicaxetine (AZD5363), triciribine, enzastaurin, XL-418, GSK-690693 or RX-0201;

[0987] XXI.ERK inhibitors include ulixertinib, ASTX029, LY3214996, LTT462, MK-8353, SCH772984, AZD-0364, ASN-007, or KO-947.

[0988] XXII.Hsp90 inhibitors, such as onalespib (AT13387), herbimycin, herbimycin (GA), 17-allylamino-17-demethoxygerdmycin (17-AAG), such as NSC-330507, Kos-953 and CNF-1010, 17-dimethylaminoethyl hydrochloride-17-demethoxygerdmycin hydrochloride (17-DMAG) For example, NSC-707545 and Kos-1022, NVP-AUY922 (VER-52296), NVP-BEP800, CNF-2024 (BIIB-021, oral purine), allvespimycin, ganetospib (STA-9090), SNX-5422 (SC-102112), or IPI-504 or pimitespib;

[0989] XXIII. Monoclonal antibodies (unconjugated or conjugated with radioactive isotopes, toxins, or other agents, such as cytotoxic anticancer agents, like antibody-drug conjugates), antibody derivatives, bispecific antibodies, and "antibody-like" therapeutic proteins (such as... Or Fab derivatives) or other therapeutic proteins and related agents, such as anti-CD, anti-VEGFR, anti-HER2 or anti-EGFR antibodies, such as rituximab (CD20), ofatumumab (CD20), ibritumomab tiuxetan (CD20), GA101 (CD20), tositumomab (CD20), veltuzumab (CD20), epratuzumab (CD22), lintuzumab (CD33), gemtuzumab bozogamicin (CD33), alemtuzumab (CD52), galiximab (CD80), trastuzumab (HER2 antibody), pertuzumab (HER2), trastuzumab-DM1 (HER2), ado-trastuzumab emtansine, fam-trastuzumab emtansine deruxtecan), ertumaxomab (HER2 and CD3), cetuximab (EGFR), matuzumab (EGFR), panitumumab (EGFR), necitumumab (EGFR), nimotuzumab (EGFR), zalutumumab (EGFR), bevacizumab (VEGF), ramucirumab (VEGFR), catumumab axumab (EpCAM and CD3), abagovomab (CA125), farletuzumab (folate receptor), elotuzumab (CS1), denosumab (RANK ligand), figitumumab (IGF1R), CP751,871 (IGF1R), mapatumumab (TRAIL receptor), metMAB (met), mitumomab (GD3 ganglioside), naptumomab (stifampin).estafenatox (5T4), siltuximab (IL6), zanomizumab (CD4), SGN40 (CD40), ficlatuzumab (anti-HGF), blinatumomab (CD3 modulator; B lymphocyte antigen CD19 modulator), tafasitamab-cxix (CD19), brentuximab vedotin (CD30), daratumumab (IgG1κ antibody), moxetumomab, ranibizumab (anti-VEGF), enfortumab vedotin, sacituzumab govitecan, obinutuzumab (CD20), inotuzumab ozogamicin (CD22), belantamab mafodotin, brentuximab vedotin (CD30), obinutuzumab (CD20), mogamulizumab (CCR4), polatuzumab vedotin (CD79b), isatuximab (CD38), dinutuximab (GD2), olaratumab (IMC 3G3, PDGF mAb), margetuximab, anti-FGFRMAb (IMC-D11), anti-PDGF receptor-βmAb (1B3), aflibercept (AVE-0005) (VEGF trap), or immunomodulatory antibodies containing checkpoint inhibitors or agents, such as CTLA-4 blocking antibodies and / or antibodies against PD-1 and PD-L1 and / or PD-L2, such as ipilimumab (CTLA4), MK-3475 (pembrolizumab, formerly known as Lambda), etc. Lambrolizumab (anti-PD-1), nivolumab (anti-PD-1), BMS-936559 (anti-PD-L1), MPDL320A, AMP-514, or MEDI4736 (anti-PD-L1), or tremelimumab (formerly ticilimumab, CP-675,206, anti-CTLA-4); atezolizumab b) (anti-PD-L1), durvalumab (anti-PD-L1), avelumab (anti-PD-L1), cemiplimab (anti-PD-1), pidilizumab (anti-PD-1); PDR-001 (anti-PD-1), spartalizumab (anti-PD-1), ipsilumab (anti-CTLA-4), abamectin Abatacept (antibody fragments and conjugates with CTLA-4), anti-LAG3 such as relatlimab, LAG-525, TSR-033, IBI-110 or FS-118, and anti-OX40 (CD134) agents such as MOXR0916, MEDI6469, PF-04518600, MEDI0562, BMS986178, ISB-830, KY-1005 or INCAGN-1949;

[0990] XXIV. Estrogen receptor antagonists or selective estrogen receptor modulators (SERMs) or estrogen synthesis inhibitors, such as tamoxifen, fulvestrant, toremifene, droloxifene, faslodex, raloxifene, or keoxifene.

[0991] XXV. Aromatase inhibitors and related drugs, such as exemestane, anastrozole, letrozole, testolactone aminoglutethimide, mitotaneor, or vorozole; fadrozole, liarozole, atamestane, formestane, dexaminoglutethimide, or trilostane;

[0992] XXVI. Antiandrogens (i.e., androgen receptor antagonists) and related agents, such as bicalutamide, nilutamide, flutamide, cyproterone, ketoconazole, apalutamide, darolutamide, or enzalutamide;

[0993] XXVII. Hormones and their analogues, such as medroxyprogesterone, diethylstilbestrol (also known as ethastilbestrol) or octreotide; finasteride, fludrocortisone, fluoxymesterone, azoxifene, pasireotide or vapreotide;

[0994] XXVIII. Steroids, such as dromostanolone propionate, megestrol acetate, nandrolone (decanoate, phenylpropionate), fluoxymestrone, gossypol, calusterone, epistanol, or mepitiostane;

[0995] XXIX. Steroidal cytochrome P450 17α-hydroxylase-17,20-lyase inhibitors (CYP17), such as abiraterone; or fadrozole;

[0996] XXX. Gonadotropin-releasing hormone agonists or antagonists (GnRAs), such as abalex, goserelin acetate, histrelin acetate, leuprolide acetate, triptorelin, buserelin, deslorelin; leuprorelin or nafarelin;

[0997] XXXI. Glucocorticoids, such as prednisone, prednisolone, or dexamethasone;

[0998] XXXII. Differentiating agents, such as retinoids, retinoic acid, vitamin D, or retinoic acid, and retinoic acid metabolism blockers (RAMBAs), such as accutane, alitretinoin, bexarotene, or tretinoin; fenretinide, isotretinoin, or RII retinamide;

[0999] XXXIII. Hedgehog signaling pathway inhibitors, such as glasdegib, vismodegib, or sonidegib;

[1000] XXXIV. Dehydrogenase inhibitors, such as isocitrate dehydrogenase inhibitors, including enasidenib, ivosidenib, vorasidenib, IDH-305, olutasidenib, DS-1001b, and enfludenib; dihydrogen hydracid dehydrogenase inhibitors, including laflunimus, brequinar, ASLAN-003, AG-636, BAY-2402234, or PTC-299; or pyruvate dehydrogenase inhibitors, such as devimistat or KULA-18;

[1001] XXXV. Export protein 1 inhibitors, such as selinexor, eltanexor, verdinexor, or felezonexor; polymerase inhibitors, such as DNA or RNA polymerase inhibitors, including lurbinectedin;

[1002] XXXVI. Farnesyltransferase inhibitors), such as tibifab;

[1003] XXXVII. Chromatin-targeted therapies, such as histone deacetylase (HDAC) inhibitors, including sodium butyrate, succinyl aniline isohydroxyamino acid (SAHA), phenolic peptide (FR 901228), dacinostat (NVP-LAQ824), R306465 / JNJ-16241199, JNJ-26481585, and trichostatin A. A) Vorinostat, Chlamydocin, A-173, JNJ-MGCD-0103, PXD-101, apicidin; belinostat, panobinostat, romidepsin, resminostat, abexinostat, entinostat, quisinostat, pracinostat, tefinostat, mocetinostat, givinostat, or fimepinostat;

[1004] XXXVIII. Drugs targeting the ubiquitin-proteasome pathway, including proteasome inhibitors such as bortezomib, carfilzomib, ixazomib, marizomib (Salinomycin A), oprozomib, ubenimex, CEP-18770MLN-9708, or ONX-0912; NEDD8 inhibitors; HDM2 antagonists, idasanutlin (RG7388), HDM-201, KRT-232 (AMG-232), and nutlin. 3a, RG7112, CGM-097, ALRN-6924, Debio-0123, LY-3143921, MI-773 (SAR405838), milademetan (DS-3032b), APG-115 or BI-907828 or ASTX295 or UBX0101; deubiquitinase inhibitors (DUB); ubiquitin-specific protease inhibitors, such as HBX-41108;

[1005] XXXIX. Photodynamic drugs, such as porfimer sodium or temoporfin;

[1006] XL. Marine organism-derived anticancer agents, such as trabectidin;

[1007] XLI. Radiolabeled drugs used in radioimmunotherapy, such as those using beta-particle emitting isotopes (e.g., iodine-131, yttrium-90) or alpha-particle emitting isotopes (e.g., bismuth-213 or actinium-225), such as ibritumomab, iodine tositumomab, alpha radium-223; iobenguane or dlutriium-177 dotastat;

[1008] XLII. Telomerase inhibitors, such as telomerostigmine;

[1009] XLIII. Matrix metalloproteinase inhibitors, such as batimastat, marimastat, prinostat, or metastat;

[1010] XLIV. Recombinant interferons (such as interferon-γ and interferon-α) and interleukins (e.g., interleukin 2), such as aldesleukin, denileukin diftitox, interferon α2a, interferon α2b or polyethylene glycol interferon α2b.

[1011] XLV. Selective immunomodulators, such as thalidomide or thalidomide derivatives, such as lenalidomide; or pomalidomide (ENMD 0995, CC-4047);

[1012] XLVI. Therapeutic vaccines, such as Ciprox-T (Proveng) OncoVex, spectral BCG live vaccine, mDC3 vaccine, PEPIDH1M vaccine, T-VEC or IDH1 targeted vaccine;

[1013] XLVII. Cytokine activators, including picibanil, romurtide, sizofiran, virulizin, or thymosin;

[1014] XLVIII. Cytokine conjugates, such as cytokine-toxin conjugates, including Tagraxofusp;

[1015] XLIX. Arsenic trioxide;

[1016] LG-protein-coupled receptor (GPCR) inhibitors, such as atrasentan;

[1017] L1. Enzymes, such as L-asparaginase, polyethylene glycolase, rubricase, or polyethylene glycolase;

[1018] LII. DNA repair inhibitors, such as PARP inhibitors, including olaparib, rucaparib, veliparib, iniparib, INO-1001, AG-014699, ONO-2231; or talazoparib.

[1019] LIII. Death receptor agonists (e.g., TNF-associated apoptosis-inducing ligand (TRAIL) receptors), such as mapatumumab (formerly HGS-ETR1), conatumumab (formerly AMG 655), PRO95780, lexatumumab, dulanermin, CS-1008, apomab, or recombinant TRAIL ligands, such as recombinant human TRAIL / Apo2 ligand;

[1020] LIV. Other immunotherapies, such as oncolytic viruses, such as talimogenelaherparepvec (T-VEC); CAR-T cell therapies, such as anti-CD19 CAR T-cell therapy, for example tisagen lecleucel and axicabtagene. ciloleucel), lisocabtagene, idecabtagene, brexucabtagene autoleucel (KTE-X19); engineered T-cell receptor (TCR-T) therapy; TLR agonists, such as motolimod, imiquimod, rintatolimod, or resiquimod; or immune checkpoint inhibitors, such as PD-1 / PD-L1 inhibitors, such as lazertinib, CA-170, CCX-4503, PCC0208025 (BMS202), GS-4224, INCB-086550, or RRx-001;

[1021] LV. Cell death (apoptosis) regulators, including Bcl-2 (B-cell lymphoma 2) antagonists such as venetoclax (ABT-199 or GDC-0199), ABT-737, ABT-263, TW-37, sabutoclax, obatoclax, and MIM1 and IAP antagonists, including LCL-161 (Novartis), Debio-1143 (Debiopharma / Ascenta), AZD5582, and bilinapanth. (Birinapant) / TL-32711 (TetraLogic), CUDC-427 / GDC-0917 / RG-7459 (Genentech), JP1201 (Joyant), T-3256336 (Takeda), GDC-0152 (Genentech), ASTX660 or HGS-1029 / AEG-40826 (HGS / Aegera); and myeloid leukemia-1 (MCL-1 is a member of the BCL2 family) inhibitors, including AMG-176, MIK665 and S63845;

[1022] LVI. Gene modifiers or editors, such as CRISPR / Cas9, zinc finger nucleases or synthetic nucleases or TALENs;

[1023] LVII. Bromodomain inhibitors, including BET inhibitors such as GSK525762, GSK2820151, OTX-015 / MK-8628, BMS-986158, CPI-0610, RO6870810 / TEN-010, RVX000222, FT-1101, ABBV-075, BAY1238097, INCB054329, INCB057643, PLX51107, or ZEN003694;

[1024] LVIII. Radiation therapy for radical, palliative, or prophylactic purposes (or for adjuvant or neoadjuvant purposes); and / or

[1025] LIX. Preventive agents (adjuvants); that is, agents that reduce or alleviate some of the side effects associated with chemotherapy drugs, such as...

[1026] a) Antiemetics;

[1027] b) Agents that prevent or shorten the duration of chemotherapy-related neutropenia and prevent complications caused by decreased platelet, red blood cell, or white blood cell levels, such as interleukin-11 (e.g., epoetin alfa, epoetin beta) or analogues thereof (e.g., dabepoetin alfa), colony-stimulating factor analogues such as granulocyte-macrophage colony-stimulating factor (GM-CSF) (e.g., sargramostim) or granulocyte colony-stimulating factor (G-CSF) or analogues thereof (e.g., filgrastim, pegfilgrastim, lenograstim, leridistim, mirimostim, molgramostim, nartograstim).

[1028] c) Agents that inhibit bone resorption, such as denosumab or bisphosphonates, such as zoledronate, zoledronic acid, pamidronate, or ibandronate.

[1029] d) Medications that suppress the inflammatory response, such as dexamethasone, prednisone, or prednisolone;

[1030] e) Agents used to reduce blood levels of growth hormone and IGF-I (and other hormones) in patients with acromegaly or other rare hormone-producing tumors, such as synthetic forms of the hormone somatostatin, such as octreotide acetate lanreotide.

[1031] f) Antidotes for drugs that lower folic acid levels, such as leucovorin or folinic acid.

[1032] g) Analgesics, such as opioids, such as morphine, diamorphine, or fentanyl;

[1033] h) Nonsteroidal anti-inflammatory drugs (NSAIDs), such as COX-2 inhibitors, such as celecoxib, etoricoxib, or lumiracoxib;

[1034] i) Medications used for mucositis, such as palifermin;

[1035] j) Agents that modulate the metabolism of anticancer drugs, i.e., PK enhancers, such as P450 (e.g., 3A4 inhibitors), such as cobicistat, or cytidine deaminase inhibitors (e.g., zebularine, tetrahydrouracil, or chidamide) or thymine phosphorylase inhibitors (e.g., tipiracil); and / or

[1036] k) Medications used to treat side effects, including anorexia, cachexia, edema, or thromboembolic events, such as medroxyprogesterone acetate.

[1037] In one embodiment, the compound of Formula I is combined with a RAS-MAPK pathway inhibitor as described above, such as a BRAF inhibitor, RAF inhibitor, MEK inhibitor, or ERK inhibitor.

[1038] Each compound present in the combination of the present invention can be administered separately with different dosage regimens and via different routes. Therefore, the dossimetry of each of the two or more agents can be different: each agent can be administered simultaneously or at different times. Those skilled in the art will understand the dosing regimens and combination therapies to be used through their common general knowledge. For example, the compounds of the present invention can be used in combination with one or more other agents administered according to their existing combination regimens. Examples of standard combination regimens are provided below.

[1039] When a compound of formula (I) is administered in combination with one, two, three, four, or more other therapeutic agents (usually one or two therapeutic agents, more usually one therapeutic agent), the compound may be administered simultaneously or sequentially. In the latter case, the two or more compounds will be administered over a period of time in an amount and manner sufficient to ensure a beneficial or synergistic effect. In one embodiment, a compound of formula (I) is administered to a patient who has been treated with one or more therapeutic compounds. It should be understood that typical methods and sequences of administration, as well as the corresponding dosages and regimens of each component of the combination, will depend on the specific other agents and compounds of the invention being administered, their route of administration, the specific tumor being treated, and the specific host being treated.

[1040] Those skilled in the art can determine the weight ratio of the compound according to the invention and one or more other anticancer agents when administered in combination. The ratio, as well as the exact dosage and frequency of administration, depend on the specific compound according to the invention and the other anticancer agents used, the specific condition being treated, the severity of the condition, age, weight, sex, diet, time of administration, the general physical condition of the specific patient, the method of administration, and other medications the individual may be taking, as is well known to those skilled in the art. Furthermore, it is apparent that the effective daily dose can be decreased or increased depending on the response of the treated subject and / or on the evaluation of the physician prescribing the compound of the invention.

[1041] The compounds of the present invention can also be administered in combination with suitable standard chemotherapy regimens, which can be determined by those skilled in the art (e.g., as described in JCO Clin Cancer Inform 4:60-70), comprising, for example, PC (paclitaxel and carboplatin), FR (fludarabine and rituximab), CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone), CVP (cyclophosphamide, vincristine and prednisone), FCM (fludarabine, cyclophosphamide and mitoxantrone), FCR (fludarabine, cyclophosphamide, rituximab), hyperCVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate and... Cytarabine, ICE (isophosphoramide, carboplatin and etoposide), MCP (mitoxantrone, chlorambucil and prednisolone), R-CHOP (rituximab plus CHOP), RCVP (rituximab plus CVP), R-FCM (rituximab plus FCM), R-ICE (rituximab-ICE), ICE-V (ICE plus vincristine), R-MCP (rituximab-MCP), or FOLFOX or FLOX (leucovorin, fluorouracil and oxaliplatin).

[1042] The compounds of this invention can also be used in combination with non-chemical therapies, such as radiotherapy, photodynamic therapy, gene therapy, surgery, and dietary control. Radiotherapy can be used for radical, palliative, adjuvant, neoadjuvant, or preventative purposes.

[1043] The compounds of the present invention also have therapeutic applications for sensitizing tumor cells in radiotherapy and chemotherapy. Therefore, the compounds of the present invention can be administered as "radiosensitizers" and / or "chemosensitizers" or in combination with another "radiosensitizer" and / or "chemosensitizer". In one embodiment, the compounds of the present invention are used as chemosensitizers.

[1044] The term "radiosensitizer" is defined as a molecule administered to a patient in a therapeutically effective amount to increase the sensitivity of cells to ionizing radiation and / or to promote the treatment of diseases that can be treated with ionizing radiation.

[1045] The term "chemosensitizer" is defined as a molecule administered to a patient in a therapeutically effective amount to increase the sensitivity of cells to chemotherapy and / or to promote the treatment of diseases that can be treated with chemotherapy.

[1046] Many cancer treatment regimens currently utilize a combination of radiosensitizers and X-ray radiation. Examples of X-ray-activated radiosensitizers include, but are not limited to, the following: metronidazole, misotronidazole, desmethylmisotronidazole, pipemnidazole, ethamnidazole, nimozolomide, mitomycin C, RSU 1069, SR 4233, EO9, RB 6145, nicotinamide, 5-bromodeoxyuridine (BUdR), 5-iododeoxyuridine (IUdR), bromodeoxycytidine, fluorodeoxyuridine (FudR), hydroxyurea, cisplatin, and their therapeutically effective analogues and derivatives.

[1047] Photodynamic therapy (PDT) for cancer uses visible light as a radioactive activator of the sensitizer. Examples of photodynamic radiosensitizers include, but are not limited to, the following: hematoporphyrin derivatives, photosensitizing proteins, benzoporphyrin derivatives, tin porphyrin, demagnesiboride-a, bacterial chlorophyll-a, naphthalenephthalocyanine, phthalocyanine, zinc phthalocyanine, and their therapeutically effective analogues and derivatives.

[1048] Radiosensitizers may be used in combination with therapeutically effective amounts of one or more other compounds, including but not limited to: compounds that promote the incorporation of radiosensitizers into target cells; compounds that control the flow of therapeutic agents, nutrients, and / or oxygen to target cells; chemotherapeutic agents that act on tumors with or without additional radiation; or other therapeutically effective compounds used to treat cancer or other diseases.

[1049] Chemosensitizers can be used in combination with therapeutically effective amounts of one or more other compounds, including but not limited to: compounds that promote the incorporation of chemosensitizers into target cells; compounds that control the flow of therapeutic agents, nutrients, and / or oxygen to target cells; chemotherapeutic agents that act on tumors; or other therapeutically effective compounds used to treat cancer or other diseases. Calcium antagonists, such as verapamil, have been found to be used in combination with antitumor agents to establish chemosensitivity in tumor cells resistant to received chemotherapeutic agents and to enhance the efficacy of such compounds in drug-sensitive malignancies.

[1050] For use in combination therapy with another chemotherapeutic agent, the compound of formula (I) and one, two, three, four or more other therapeutic agents may, for example, be formulated together into a dosage form containing two, three, four or more therapeutic agents, i.e., a single pharmaceutical composition containing all components. Alternatively, the individual therapeutic agents may be formulated separately and present together in the form of a kit, optionally accompanied by instructions for use of the kit.

[1051] In one embodiment, the invention further provides a combination drug in which a compound of formula (I) and at least one or more therapeutic agents are physically combined. In one embodiment, the compound of formula (I) and at least one or more therapeutic agents are: (a) mixed; (b) chemically / physicochemically linked; (c) chemically / physicochemically co-packaged; or (d) unmixed but co-packaged or coexisting.

[1052] In another embodiment, the compound of formula (I) and at least one or more therapeutic agents are not physically bound. In another embodiment, this optionally further includes (a) a description of the temporary binding of the compound of formula (I) with at least one or more therapeutic agents to form a physical binding of two or more compounds; (b) a description of combination therapy with the compound of formula (I) and at least one or more therapeutic agents; or (c) a description of administration to a patient population.

[1053] When individual pharmaceutical agents are available in the form of a kit, the kit may include two or more separate pharmaceutical compositions: a compound of formula (I) and one or more additional pharmaceutical compounds. The kit may include containers for containing the individual compositions, such as separate bottles or separate foil packs. Additional examples of containers include syringes, boxes, and bags. In some embodiments, the kit includes instructions for using the individual components. The kit format is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral), at different dose intervals, or when the prescribing healthcare professional needs to titrate the individual components of the combination.

[1054] In other embodiments, the present invention provides combinations of compounds as defined herein and another therapeutic agent, such as another therapeutic agent as defined above.

[1055] In another embodiment, the present invention provides a pharmaceutical composition comprising a compound as defined herein, a pharmaceutically acceptable carrier, and one or more therapeutic agents as defined above.

[1056] In one embodiment, the pharmaceutical composition comprises a compound of formula I, a pharmaceutically acceptable carrier, and optionally one or more therapeutic agents.

[1057] In another embodiment, the present invention relates to the use of the combination according to the invention in the preparation of a pharmaceutical composition for inhibiting tumor cell growth.

[1058] In another embodiment, the present invention relates to a product containing a compound of formula I and one or more anticancer agents as a combination preparation for simultaneous, separate or sequential treatment of a patient with cancer.

[1059] In another embodiment, the present invention relates to a compound of formula (I) for treating a disease or symptom as defined herein, wherein a patient is receiving treatment with one or more other therapeutic compounds.

[1060] Example

[1061] The invention will now be illustrated, but not limited, by reference to specific embodiments described in the following examples. For example, compounds may be named using IUPAC rules, using an automatic naming package such as AutoNom (MDL), or by a chemical supplier. In the examples, the following abbreviations are used.

[1062] AcOH (acetic acid)

[1063] Aq. Aqueous solution

[1064] B2pin2 bis(pinacol)diboron

[1065] Boc tert-butoxycarbonyl

[1066] Butyllithium (BuLi)

[1067] Cbz carboxybenzyl

[1068] DCE 1,2-Dichloroethane

[1069] DCM dichloromethane

[1070] DIPEA N,N-Diisopropylethylamine

[1071] DMF N,N-dimethylformamide

[1072] DMP Des Martin periodane

[1073] DMSO (dimethyl sulfoxide)

[1074] Et3N Triethylamine

[1075] EtOAc (ethyl acetate)

[1076] EtOH (ethanol)

[1077] Et2O diethyl ether

[1078] Et3SiH Trimethylsilyl

[1079] HOAt 1-hydroxyazabenzotriazole

[1080] HPLC (High-Performance Liquid Chromatography)

[1081] IPA isopropanol

[1082] KO t Potassium tert-butoxide

[1083] LED Light Emitting Diode

[1084] MeCN Acetonitrile

[1085] MeOH (methanol)

[1086] Min minutes

[1087] MS mass spectrometry analysis

[1088] NaBH(OAc)3 sodium triacetoxyborohydride

[1089] Sodium ethanol (NaOEt)

[1090] NaO t Sodium tert-butoxide

[1091] NBS N-bromosuccinimide

[1092] NMP (N-methyl-2-pyrrolidone)

[1093] NMR (Nuclear Magnetic Resonance Spectroscopy)

[1094] Pd / C carbon-supported palladium

[1095] Pd2(dba)3 tris(dibenzylacetone)dipalladium(0)

[1096] Pd(OAc)₂ Palladium(II) acetate

[1097] Pd(PPh3)4 tetrakis(triphenylphosphine)palladium(0)

[1098] Petroleum ether fraction with a boiling point range of 40-60℃

[1099] RT room temperature

[1100] Sat saturated

[1101] SEM 2-(trimethylsilyl)ethoxymethyl

[1102] SiO2 (silicon dioxide)

[1103] TBAF Tetrabutylammonium Fluoride

[1104] TFA (trifluoroacetic acid)

[1105] THF Tetrahydrofuran

[1106] TMBE tert-butyl methyl ether

[1107] TLC (Thin Layer Chromatography)

[1108] TMSOTf trimethylsilyl trifluoromethanesulfonate

[1109] Synthesis method

[1110] All starting materials and solvents were obtained from commercial sources or prepared according to literature citations. All reactions were stirred unless otherwise specified. Organic solutions were routinely dried over anhydrous magnesium sulfate. Hydrogenation was carried out under the stated conditions in a Parr hydrogenator, a Thales H-legislative flow reactor, or under a hydrogen balloon. Microwave reactions were carried out in CEM Discover and Smithcreator microwave reactors, heated to a constant temperature using variable power microwave radiation. Normal-phase column chromatography was routinely performed using pre-packaged silica (230-400 mesh, 40-63 μm) cartridges in an automated rapid chromatography system such as the CombiFlash Companion or CombiFlash RF system. SCX was purchased from Supelco and treated with 1M hydrochloric acid before use. Unless otherwise specified, the reaction mixture to be purified was first diluted with MeOH and acidified with a few drops of AcOH. This solution was loaded directly onto the SCX and washed with MeOH. The desired material was then eluted by washing with a solvent, such as MeOH containing 1% NH3. Strata NH2 (55 μm, NH2 ion-exchange silica gel purification is performed on an NH2 column, which is directly loaded onto the NH2 column and eluted with a solvent such as methanol. KP-NH SNAP silicone pillars were purchased from [source missing]. Purchased from of Reverse-phase purification was performed using SNAP Ultra C18 silica columns.

[1111] NMR data

[1112] Acquisitions were obtained using a 400 MHz Bruker Avance III mass spectrometer, an AL400 (400 MHz; manufactured by JEOL), a Mercury400 (400 MHz; manufactured by Agilent Technologies, Inc.), a 500 MHz Bruker Avance III HD NMR mass spectrometer, or a Bruker Avance NEO NMR mass spectrometer (400 MHz). 1 1H NMR spectroscopy. The central peak of internal standards in chloroform-d, dimethyl sulfoxide-d6, or tetramethylsilane is used as a reference. For NMR data, in cases where the specified number of protons is less than the theoretical number of protons in the molecule, it is assumed that the significantly lost signal is obscured by solvent and / or water peaks. Additionally, when mass spectra are obtained in proton NMR solvents, NH and / or OH protons exchange with the solvent, and therefore such signals are generally not observed.

[1113] Analytical and preparative LC-MS systems

[1114] Description of analytical LC-MS systems and methods

[1115] In the following examples, compounds are characterized by mass spectrometry using the system and operating conditions described below. In cases where atoms with different isotopes are present and a single mass is cited, the mass cited for the compound is the monoisotopic mass (i.e., 35 Cl; 79 Br et al.

[1116] Shimadzu Nexera Nexera)

[1117] HPLC system: Shimadzu SIL-30AC autosampler / 2x Shimadzu LC-30AD pumps

[1118] Mass spectrometry detector: Shimadzu LCMS-2020 single quadrupole MS

[1119] Second detector: Shimadzu SPD-M20A diode array detector

[1120] MS operating conditions

[1121]

[1122] Agilent 1290 InfinityII-6130LC-MS System

[1123] HPLC System: Agilent 1290 Infinity II

[1124] Mass spectrometer detector: Agilent 6130 single quadrupole

[1125] Second detector: Agilent 1290 Infinity II diode array detector

[1126] MS operating conditions

[1127]

[1128]

[1129] LCMS mass spectra were measured alternately under the following two conditions using an SQD manufactured by Waters Corporation, and the results are shown as [M+H]. + value.

[1130] MS test: ESI positive

[1131] UV detection: 254nm

[1132] Column flow rate: 0.5 mL / min

[1133] Mobile phase: Water / acetonitrile (0.1% formic acid)

[1134] Injection volume: 1 μL

[1135] method

[1136] Column: Acguity BEH, 2.1×50mm, 1.7μm

[1137] gradient:

[1138]

[1139] Description of preparative LC-MS systems and methods

[1140] Preparative LC-MS is a standard and effective method for purifying small organic molecules, such as compounds described herein. Methods used for liquid chromatography (LC) and mass spectrometry (MS) can be modified to better separate crude materials and improve MS detection of samples. Optimization of preparative gradient LC methods will involve different columns, volatile eluents and modifiers, and gradients. Methods for optimizing preparative LC-MS methods and then using these methods to purify compounds are well known in the art. Such methods are described in Rosentreter U, Huber U.; Optimal fraction collection in preparative LC-MS; Journal of Combinatorial Chemistry 2004; 6(2), 159-64 and Leister W, Strauss K, Wisnoski D, Zhao Z, Lindsley C., Development of a custom high-throughput preparative liquid chromatography / mass spectrometry platform for preparative purification and analytical analysis of compound libraries; Journal of Combinatorial Chemistry 2003; 5(3), 322-9.

[1141] Several systems for purifying compounds by preparative LC-MS are described below; however, those skilled in the art will understand that alternative systems and methods can be used. Based on the information provided herein, or using alternative chromatographic systems, those skilled in the art can purify the compounds described herein by preparative LC-MS.

[1142] Quality-oriented purification LC-MS system

[1143] Preparative LC-MS is a standard and effective method for purifying small organic molecules, such as compounds described herein. Methods used for liquid chromatography (LC) and mass spectrometry (MS) can be modified to better separate crude materials and improve MS detection of samples. Optimization of preparative gradient LC methods will involve different columns, volatile eluents and modifiers, and gradients. Methods for optimizing preparative LC-MS methods and then using these methods to purify compounds are well known in the art. Such methods are described in Rosentreter U, Huber U.; Optimal fraction collection in preparative LC / MS; Journal of Combinatorial Chemistry 2004; 6(2), 159-64 and Leister W, Strauss K, Wisnoski D, Zhao Z, Lindsley C., Development of a custom high-throughput preparative liquid chromatography / mass spectrometry platform for preparative purification and analytical analysis of compound libraries; Journal of Combinatorial Chemistry 2003; 5(3); 322-9.

[1144] The following describes one such system for purifying compounds using preparative LC-MS; however, those skilled in the art will understand that alternative systems and methods can be used. Specifically, normal-phase preparative LC-based methods can be used instead of the reversed-phase methods described herein. Most preparative LC-MS systems use reversed-phase LC and volatile acid modifiers because this method is highly effective for purifying small molecules, and the eluent is compatible with positive ion electrospray mass spectrometry. Alternatively, other chromatographic solutions, such as normal-phase LC, and alternatively, buffered mobile phases, basic modifiers, etc., as outlined in the analytical methods described above, can be used to purify compounds.

[1145] Agilent 1260LC-MS Preparative System

[1146] hardware:

[1147] Automatic Sampler: G2260A Prep ALS

[1148] Pumps: 2x G1361A Prep pumps for preparative flow gradients, G1311C Quat Pump VL for pumping modifiers in preparative flow rates, and G1310B Iso pumps for supplementing pump flow.

[1149] UV detector: G1365C 1260MWD

[1150] MS detector: G6120B quadrupole LC-MS

[1151] Fraction collectors: 2 x G1364B 1260FC-PS

[1152] G1968D Active Splitter

[1153] software:

[1154] Agilent OpenLab C01.06

[1155] Agilent MS operating conditions:

[1156]

[1157] column:

[1158] 1. Waters XBridge Prep C18 5m OBD 100×19mm

[1159] Commonly used in ammonium bicarbonate-based methods

[1160] 2. Waters SunFire Prep C18 OBD 5m 100×19mm

[1161] Typically used in TFA-based methods

[1162] 3. Waters XBridge Prep Phenyl 5m OBD 100×19mm

[1163] Ammonium acetate method typically used based on neutral pH

[1164] 4. Supelco Ascentis RP-amine 5m 100×21.2mm

[1165] Commonly used in formic acid-based methods

[1166] 5.Phenomenex Synergi Fusion-RP 4m 100×21.2mm

[1167] Commonly used in formic acid-based methods

[1168] Elution buffer:

[1169] Solvent A: Water

[1170] Solvent B: Acetonitrile

[1171] Solvent C: Selection of available modifiers:

[1172] Water containing 2.5% trifluoroacetic acid

[1173] The water contains 2.5% formic acid.

[1174] Water containing 250 mM ammonium bicarbonate has a pH of 9.4.

[1175] 250mM ammonium acetate

[1176] Replenish solvent:

[1177] 90:10 methanol:water + 0.2% formic acid (for all chromatographic types)

[1178] method:

[1179] Select the most suitable preparative chromatography type based on the analytical trace. A typical routine is to run the analytical LC-MS using the chromatography type best suited to the compound structure (low or high pH). Once the analytical trace shows good chromatograms, select the appropriate preparative method of the same type. Typical operating conditions for low and high pH chromatography are:

[1180] Flow rate: 25 ml / min

[1181] Gradients: Typically, all gradients have an initial step size of 0.4 minutes, with 95% A + 5% B (in the case of an additional modifier C). A gradient of 6.6 minutes is then selected based on the analytical trace to achieve good separation (e.g., 5% to 50% B for early-retained compounds; 35% to 80% B for intermediate-retained compounds; and so on).

[1182] Washing: Perform a 1.6-minute washing step at the end of the gradient.

[1183] Replenishment flow rate: 0.8 ml / min

[1184] Solvent:

[1185] All compounds are typically dissolved in 100% MeOH or 100% DMSO.

[1186] Based on the information provided, those skilled in the art can purify the compounds described herein using preparative LC-MS.

[1187] Waters Fractionlynx System

[1188] hardware:

[1189] 2767 Dual-Loop Automatic Sampler / Friction Collector

[1190] 2525 Preparative Pump

[1191] CFO (Column Fluid Organizer) for column selection

[1192] RMA (Waters Reagent Manager) as a supplementary pump

[1193] Waters ZQ mass spectrometer

[1194] Waters 2996 photodiode array detector

[1195] Waters ZQ mass spectrometer

[1196] software:

[1197] Masslynx 4.1

[1198] Waters MS operating conditions:

[1199]

[1200] Alternatively, reversed-phase preparative HPLC column chromatography can be performed under the following conditions.

[1201]

[1202] Agilent Infinity LabLC / MSD

[1203] LC-MS analysis was performed using a Waters X-Select CSH C18 (2.5 μm, 4.6 × 30 mm) or Waters X-Bridge BEH C18 (2.5 μm, 4.6 × 30 mm) column maintained at 40 °C and eluted with a linear acetonitrile gradient suitable for the lipophilicity of the compound at a constant flow rate of 2.5 mL / min over 4 or 15 minutes. The aqueous portion of the mobile phase was 0.1% formic acid (CSH C18 column) or 10 mM ammonium bicarbonate (BEH C18 column). LC-UV chromatograms were recorded at 254 nm using an Agilent VWD or DAD detector. Mass spectra were recorded using an Agilent MSD detector with electrospray ionization that switches between positive and negative ion modes. Sample concentrations were adjusted to obtain sufficient UV response.

[1204] Waters AcquityQDa

[1205] UPLC / MS analysis was performed using a Waters Acquity CSH C18 or BEH C18 column (2.1 × 30 mm) maintained at 40 °C and eluted with a linear acetonitrile gradient suitable for the lipophilicity of the compound at a constant flow rate of 0.77 mL / min over 3 or 10 minutes. The aqueous portion of the mobile phase consisted of 0.1% formic acid (CSH C18 column) or 10 mM ammonium bicarbonate (BEHC18 column). LC-UV chromatograms were recorded between 210 nm and 400 nm using a Waters Acquity PDA detector. Mass spectra were recorded using a Waters Acquity QDa detector with electrospray ionization switching between positive and negative ion modes. Sample concentrations were adjusted to obtain a sufficient UV response.

[1206] Chiral preparative chromatography

[1207] The compound examples described have been purified by HPLC, if indicated, using methods developed according to recommendations described in, for example, Snyder LR, Dolan J.W., High-Performance Gradient Elution: The Practical Application of the Linear-Solvent-Strength Model, Wiley & Son Publishing, Hoboken, 2007.

[1208] Chiral preparative chromatography

[1209] Preparative separation using a chiral stationary phase (CSP) is a natural technique applied to the decomposition of enantiomeric mixtures. Similarly, it can be applied to the separation of diastereomers and achiral molecules. Methods for optimizing preparative chiral separation on a CSP and then purifying compounds using this method are well known in the art. Such methods are described in Beesley TE, Scott RPW; *Chiral Chromatography*; Wiley & Son Publishing, Chichester, 1998.

[1210] Preparation of 1:6-chloro-3-iodo-5-methyl-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazine

[1211]

[1212] Step 1: 6-Chloro-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazine

[1213] A solution of 17.85 g (113.7 mmol) of 6-chloro-1H-pyrazolo[3,4-b]pyrazine and 0.1 equivalent of TsOH·H₂O in 150 mL of THF was cooled on ice (internal temperature approximately 10 °C). Dihydropyran (20.6 mL, 227.4 mmol) was slowly added over 5 minutes. The cooling bath was removed, and the reaction mixture was stirred for 90 minutes. EtOAc (250 mL) was added, and the organic phase was washed with saturated NaHCO₃ (150 mL), brine, and then dried (MgSO₄). This process was repeated for another 17.8 g. The organic layers from both runs were evaporated to give approximately 55 g of orange solid. TBME (40 mL) and heptane (400 mL) were added, and the mixture was heated to 90 °C and then cooled. A very small amount of brown precipitate appeared, which was removed by filtration. The filtrate was stirred until the product crystallized. The product was collected by filtration to obtain batch 1 (20 g), a white crystalline solid. The filtrate was concentrated to approximately 30 mL and then diluted with heptane (100 mL) to induce crystallization. Batch 2 (15.8 g, white crystalline solid) was collected by filtration. MS: [M+H] + =239. 1 H NMR (500MHz, DMSO-d6) δ8.79(s,1H),8.61(s,1H),5.95(dd,J=10.2,2.6Hz,1H),3.94(qd,J=13.2,4.1,1.9Hz,1H),3.77 -3.69(m,1H),2.49-2.41(m,1H),2.08-2.01(m,1H),1.95(dq,J=13.0,3.5Hz,1H),1.86-1.72(m,1H),1.62-1.55(m,2H).

[1214] Step 2: 6-Chloro-1-(oxan-2-yl)-1H-4λ 5 -Pyrazolo[3,4-b]pyrazin-4-one

[1215] Dissolve 6-chloro-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazine (18 g, 75.41 mmol) in MeCN (150 mL) and cool on ice. Add urea-hydrogen peroxide complex (14.9 g, 158.4 mmol) in portions. Add trifluoroacetic anhydride (20.9 mL, 150.8 mmol) in 30 mL solution (MeCN) dropwise over 15 minutes, keeping the internal temperature <10 °C. Stir the reaction mixture at 0–5 °C for 30 minutes and then warm it to room temperature over 1 hour. A thick precipitate forms, and add another 50 mL of MeCN to make it flowable. Pour the mixture into a stirred mixture of 4 M sodium thiosulfate (100 mL), NaHCO3 (50 g solid), and ice-cold water (300 mL). Stir the mixture for 10 minutes and then add DCM (300 mL). The DCM layers were separated, and the aqueous layer was extracted with another DCM (2 × 100 mL). The DCM layers were combined, washed with water (200 mL), dried (MgSO4), and evaporated to dryness. The process was repeated with another 18 g of 6-chloro-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazine. The crude products from the two runs were combined and recrystallized from EtOAc (300 mL). The crystalline material was collected by filtration, dissolved in PhMe, and evaporated to give 6-chloro-1-(oxan-2-yl)-1H-4λ as a white crystalline solid. 5 -Pyrazolo[3,4-b]pyrazin-4-one (11 g, 28%, crop 1). The filtrate was concentrated and dissolved in hot EtOAc (40 mL). Heptane (400 mL) was added, and the mixture was heated until all materials were dissolved. The solution was cooled, and the product was crystallized. The product was collected by filtration, dissolved in PhMe, and evaporated to give 6-chloro-1-(oxapan-2-yl)-1H-4λ 5 -Pyrazolo[3,4-b]pyrazin-4-one (18.46 g, 48%, crop 2). MS: [M+H] + =255. 1 HNMR(500MHz,DMSO-d6)δ8.70(s,1H),8.55(s,1H),5.91(dd,J=10.1,2.6Hz,1H),4.01-3.91(m,1H),3.79-3.68( m,1H),2.45-2.34(m,1H),2.08-1.97(m,1H),1.93(dq,J=13.1,3.6Hz,1H),1.86-1.73(m,1H),1.61-1.55(m,2H).

[1216] Step 3: 6-Chloro-5-methyl-1-(oxan-2-yl)1H-pyrazolo[3,4-b]pyrazine

[1217] Magnesium methyl chloride (in diethyl ether, 3.0 M) (163 ml, 489 mmol) was added over 1 hour and 15 minutes to 6-chloro-1-(oxapan-2-yl)-1H-4λ, which was cooled to -60 °C (internal temperature) on a dry ice / acetone bath. 5 A solution of pyrazolo[3,4-b]pyrazin-4-one (41.5 g, 163 mmol) in toluene (833 mL) was prepared. The mixture was stirred at this temperature for 6 hours, then quenched with saturated NH4Cl (400 mL) and diluted with water (300 mL) and EtOAc (300 mL). The phases were separated, and the aqueous phase was extracted with EtOAc (2 × 300 mL). The organic matter was combined, washed with brine (300 mL), dried (MgSO4), and concentrated to give a crude product (38.6 g) as a red solid. The crude residue was dissolved in acetonitrile (50 mL) under reflux. The solution was cooled to room temperature. The precipitate was separated by filtration and washed with isohexane (50 mL) to give a beige solid (about 17 g). The solid (Crop 1) was reheated once in acetonitrile (25 mL) under reflux. The solution was cooled to room temperature, filtered to obtain a pinkish-brown solid, washed with hexane (10 mL), and dried overnight in a vacuum oven at 40 °C to give the title compound (11.92 g) as a pinkish-brown solid. MS: [M+H] + =253,255. 1 H NMR(500MHz,DMSO-d6)δ8.47(s,1H),5.91(dd,J=10.2,2.6Hz,1H),3.97-3.88(m,1H),3.77-3.66(m,1H),2.70(s ,3H),2.49-2.42(m,1H),2.06-2.00(m,1H),1.94(dq,J=13.1,3.5Hz,1H),1.83-1.72(m,1H),1.61-1.55(m,2H).

[1218] Step 4: 6-Chloro-5-methyl-1H-pyrazolo[3,4-b]pyrazine

[1219] A solution of hydrogen chloride (4.0 M in 1,4-dioxane) (128 mL, 513 mmol) was added dropwise to a suspension of 6-chloro-5-methyl-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazine (33.21 g, 131 mmol) in methanol (633 mL). The brown mixture was stirred overnight at room temperature. After concentration, the residue was dissolved in MeOH-CHCl3 (1 / 1 mixture; 400 mL) and then alkalized with an aqueous solution of NaHCO3 (55 g in 400 mL). The separated aqueous layer was extracted with MeOH-CHCl3 (1 / 1 mixture; 4 × 400 mL). The organic matter was combined, washed with brine (300 mL), dried over Na2SO4, filtered, and concentrated under vacuum to give a crude beige solid (28.5 g). The material was suspended in isohexane (3 × 200 mL), collected by filtration, and dried under vacuum overnight at 40 °C to give 6-chloro-5-methyl-1H-pyrazolo[3,4-b]pyrazine (20.73 g, 121 mmol, 92% yield) as a beige solid. MS: [M+H] + =169. 1 H NMR (500MHz, DMSO-d6) δ14.13(s,1H),8.41(s,1H),2.68(s,3H).

[1220] Step 5: 6-Chloro-3-iodo-5-methyl-1H-pyrazolo[3,4-b]pyrazine

[1221] 1-Iodopyrrolidine-2,5-dione (55.3 g, 246 mmol) was added to a solution of 6-chloro-5-methyl-1H-pyrazolo[3,4-b]pyrazine (20.73 g, 123 mmol) in N,N-dimethylformamide (409 mL). The mixture was stirred at 50 °C for 6 hours. The reaction mixture was slowly added to a rapidly stirred mixture of saturated sodium thiosulfate aqueous solution (400 mL) and water (400 mL). The precipitate was collected by filtration and washed with water (3 × 200 mL) and isohexane (100 mL). The solid was dissolved in THF (300 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum to give 6-chloro-3-iodo-5-methyl-1H-pyrazolo[3,4-b]pyrazine (19.42 g, 64.6 mmol, 52.6% yield) as a creamy solid (dried in a vacuum oven at 40 °C). The aqueous layer was extracted with EtOAc (3 × 400 mL). The organic matter was combined, dried over Na₂SO₄, and concentrated under vacuum to give a reddish-brown oil. Water (200 mL) was added. A beige solid was formed, which was filtered and washed with water (2 × 200 mL). The solid was dried in a vacuum oven at 40 °C. 6-chloro-3-iodo-5-methyl-1H-pyrazolo[3,4-b]pyrazine (12.86 g, 41.5 mmol, 33.7% yield) was isolated as a beige solid. MS:[M+H] + =295. 1 H NMR (500MHz, DMSO-d6) δ14.49 (s, 1H), 2.70 (s, 3H).

[1222] Step 6: 6-Chloro-3-iodo-5-methyl-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazine

[1223] 3,4-Dihydro-2H-pyran (50 mL, 547 mmol) and p-toluenesulfonic acid monohydrate (2.085 g, 10.96 mmol) were added to a solution of 6-chloro-3-iodo-5-methyl-1H-pyrazolo[3,4-b]pyrazine (32.28 g, 110 mmol) in THF (647 mL). The mixture was stirred overnight at room temperature. After concentrating the mixture to half its volume under vacuum at 30 °C, the mixture was poured into a solution of NaHCO3 (36.8 g, 438 mmol) in water (300 mL). The aqueous layer was extracted with EtOAc (200 mL). The organic compounds were combined, washed with brine (200 mL), dried on Na₂SO₄, filtered, and concentrated under vacuum to give a pinkish-brown solid. This pinkish-brown solid was dry-loaded onto silica gel and purified by silica gel chromatography (330 g column; gradient elution, 0-100%, DCM / hexane) to give a white solid (33.98 g). The solid was suspended in isohexane (100 mL) and stirred for 1 hour, then filtered, washed with isohexane (50 mL), and dried in a vacuum oven at 40 °C. 6-chloro-3-iodo-5-methyl-1-(oxan-2-yl)-1H-pyrazolo[3,4-b]pyrazine (31.29 g, 81 mmol, 73.9% yield) was isolated as a white solid. MS: [M+H] + =379. 1 H NMR(500MHz,DMSO-d6)δ5.88(dd,J=10.3,2.5Hz,1H),3.97-3.88(m,1H),3.77-3.66(m,1H),2.72(s,3H), 2.47-2.37(m,1H),2.06-1.98(m,1H),1.94(dq,J=13.0,3.4Hz,1H),1.83-1.71(m,1H),1.64-1.52(m,2H).

[1224] Preparation of 2:6-chloro-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyrazine

[1225]

[1226] (2-(chloromethoxy)ethyl)trimethylsilane (56.8 mL, 321 mmol) was added to a solution of 6-chloro-3-iodo-1H-pyrazolo[3,4-b]pyrazine (75 g, 267 mmol) and DIPEA (93 mL, 535 mmol) in THF (1118 mL) over 30 minutes at 0 °C. After stirring for 18 hours, the reaction mixture was concentrated under vacuum to a yellow solution, which was treated with saturated ammonium chloride (500 mL), then with water (300 mL), and extracted with EtOAc (2 × 400 mL). The combined organic phases were concentrated and then purified by silica gel chromatography (1 kg box, 0-10% EtOAc / isohexane) to give 6-chloro-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyrazine as a pale yellow solid (dried in a vacuum oven at 40°C). MS: [M+H] + =411. 1 ¹H NMR (500MHz, chloroform-d) δ 8.58 (s, 1H), 5.79 (s, 2H), 3.74–3.63 (m, 2H), 1.00–0.89 (m, 2H), -0.03 (s, 9H).

[1227] Preparation 3: (6-chloro-3-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazolo[3,4-b]pyrazin-5-yl)methanol

[1228]

[1229] Silver nitrate (14 g, 82 mmol) was added to a solution of 6-chloro-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyrazine (68.5 g, 165 mmol) in methanol (700 mL). The mixture was heated to 40 °C, and then sodium persulfate (110 g, 462 mmol) in water (210 mL) was added over 30 minutes. The mixture was stirred at 40 °C for 1 hour and then cooled. The mixture was carefully diluted with a solution of sodium carbonate (49.0 g, 462 mmol) in water (2 L), and the precipitate was collected by filtration. The filter cake was extracted with dichloromethane:methanol (9:1, 1 L) and then concentrated onto loose silica gel (150 g). The silicate was purified by silica gel chromatography (1 kg, 0–10% EtOAc / DCM) to give (6-chloro-3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyrazin-5-yl)methanol (27.9 g, 60.8 mmol, 36.8% yield) as a white solid. MS: [M+H] + =441.1 H NMR (500MHz, DMSO-d6) δ5.73 (s, 2H), 5.59 (t, J = 6.0 Hz, 1H), 4.80 (d, J = 6.1 Hz, 2H), 3.68-3.53 (m, 2H), 0.91-0.79 (m, 2H), -0.09 (s, 9H).

[1230] Preparation of 4:5-bromo-4-chloro-2-methyl-2H-indazole

[1231]

[1232] A solution of sodium nitrite (58.6 g, 0.85 mol) in water (98 mL) was added to an ice-bath cooled solution of 4-bromo-3-chloro-2-methylaniline (150 g, 0.68 mol) in acetic acid (3 L) under mechanical stirring, and the mixture was aged at ambient temperature for 1 hour. Most of the solvent was evaporated, and the residue was suspended in water (500 mL) and filtered. The residue was washed with water (250 mL × 4) and petroleum (250 mL × 4), and dried under vacuum at 40 °C to obtain 5-bromo-4-chloro-1H-indazole (130 g). 1 HNMR(400MHz, DMSO-d6):13.61(1H,s),8.16(1H,s),7.62(1H,d),7.53(1H,dd).

[1233] Solid trimethyloxonium tetrafluoroborate (258 g, 1.74 mol) was packed into a solution of 5-bromo-4-chloro-1H-indazole (367 g, 1.59 mol) in EtOAc (1.9 L) cooled in an ice bath, and the resulting mixture was stirred at ambient temperature for 4 hours. The reaction mixture was diluted with petroleum (1.9 L) and aged for 10 minutes, then filtered and washed with petroleum (400 mL × 2). The filter cake was combined with saturated sodium bicarbonate (1.5 L) and EtOAc (2 L), and the phases were separated. The organic phase was washed with saturated sodium bicarbonate, dried (MgSO4), and concentrated under vacuum to give the title compound (236 g). 1 H NMR (400MHz, DMSO-d6): 8.53 (1H, s), 7.56 (1H, dd), 7.48 (1H, d), 4.20 (3H, s).

[1234] Preparation of 5:5-bromo-4-chloro-2-ethyl-2H-indazole

[1235]

[1236] Solid triethyloxonium hexafluorophosphate (20 g, 80.6 mmol) was added to 5-bromo-4-chloro-1H-indazole (12.4 g, 53.7 mmol) in EtOAc (186 mL), and the resulting mixture was stirred overnight at ambient temperature. The reaction mixture was quenched with saturated sodium bicarbonate (125 mL), and the phases were separated. The aqueous solution was extracted with EtOAc (70 mL), and the combined organic matter was washed with brine (70 mL), dried (MgSO4), and concentrated under vacuum. The red / brown residue was treated with activated carbon (12.5 g) in ethanol (125 mL) and EtOAc (125 mL). After stirring at ambient temperature, the mixture was filtered and concentrated under vacuum to give the title compound (9.88 g). 1 H NMR (400MHz, DMSO-d6): 8.58(1H,s),7.58(1H,dd),7.48(1H,d),4.49(2H,q),1.52(3H,t).

[1237] Preparation of 6: 5-bromo-3,4-dichloro-2-methyl-2H-indazole

[1238]

[1239] NCS (2.99 g, 22.4 mmol) was added to a solution of 5-bromo-4-chloro-2-methyl-2H-indazole (5 g, 20.3 mmol) in DMF (50 mL) at 0 °C. The mixture was stirred overnight at room temperature. Water (150 mL) was added at room temperature. The mixture was stirred at room temperature for 1 hour. The precipitate was collected, washed with water, and dried at 60 °C under reduced pressure for 3 hours to give the title compound (5.63 g). MS: [M+H] + =279,281.

[1240] Preparation 7: 5-Bromo-4-chloro-2,3-dimethyl-2H-indazole

[1241]

[1242] 2.5 M butyllithium (4 mL, 10.0 mmol in hexane) was added to a solution of diisopropylamine (1.5 mL, 10.5 mmol) in 10 mL of THF that had been cooled (-10 °C). The mixture was stirred for 10 minutes and then cooled to -78 °C. A solution of 5-bromo-4-chloro-2-methyl-2H-indazole (2.0 g, 8.15 mmol) in 10 mL of THF was added to this solution. The mixture was warmed to 0 °C for 10 minutes and then recooled to -78 °C. Iodomethane (0.66 mL, 10.6 mmol) was added and the mixture was stirred at -78 °C for 1 hour. The mixture was quenched with 30 mL of saturated NH4Cl aqueous solution and extracted with EtOAc (3 × 30 mL). The combined organic phases were dried (Na2SO4), filtered, and concentrated. The crude product was purified by silica gel column chromatography (gradient elution, 15-75% EtOAc / isohexane) to give the title compound (1.7 g). MS: [M+H] + =259,261,263.

[1243] Preparation of 8:7-bromo-2,8-dichloroquinoxaline

[1244]

[1245] Step 1: 4-Bromo-3-chloro-2-nitroaniline

[1246] In a 2 L three-necked flask, a solution of 3-chloro-2-nitroaniline (60 g, 348 mmol) in AcOH (600 mL) was treated in portions with NBS (61.9 g, 348 mmol). The resulting orange solution was heated at 80 °C for 1.5 h. The reaction mixture was cooled to room temperature and poured into stirred ice water (800 mL). The resulting orange precipitate was collected by filtration and washed with water (200 mL). The orange residue was collected and dissolved in EtOAc (500 mL). The solution was dried over MgSO4, filtered, and the solvent was concentrated under vacuum to give an orange solid (86.5 g). The residue was recrystallized from 10% EtOAc / isohexane (500 mL). The resulting solid was filtered, washed with isohexane (100 mL), and dried under vacuum to give a pale orange solid (39.88 g, 158.6 mmol, 46%). The filtrate was concentrated under vacuum to give an orange solid. The residue was recrystallized from 10% Ac / isohexane (250 mL). The resulting solid was filtered, washed with isohexane (50 mL), and dried under vacuum to give a pale orange solid (20 g, 79.53 mmol, 23%). 1H NMR in DMSO-d6: (7.55 (1H, d), 6.84 (1H, d), 6.40 (2H, s).

[1247] Step 2: N-(4-bromo-3-chloro-2-nitrophenyl)-N-[(tert-butoxy)carbonyl]tert-butyl carbamate

[1248] In a 2 L three-necked flask, a solution of 4-bromo-3-chloro-2-nitroaniline (59.88 g, 226 mmol) in THF (400 mL) was treated in portions with a solution of di-tert-butyl dicarbonate (99 g, 452 mmol) in THF (200 mL) at <10 °C (internal temperature, ice bath). N,N-dimethylpyridin-4-amine (2.76 g, 22.62 mmol) was added in portions, and the resulting orange solution was stirred at room temperature for 18 hours. The reaction mixture was concentrated under vacuum to give a light brown solid. The residue was ground together with isohexane (300 mL). The resulting solid was filtered, washed with isohexane (50 mL), and dried under vacuum to give the desired product (97.5 g, 214 mmol, 94% yield) as a viscous, colorless solid. 1 H NMR: 7.81(1H,d),7.16(1H,d),1.45(18H,s).

[1249] Step 3: N-(4-bromo-3-chloro-2-nitrophenyl)carbamate tert-butyl ester

[1250] In a 2 L three-necked flask, a solution of N-(4-bromo-3-chloro-2-nitrophenyl)-N-[(tert-butoxy)carbonyl]carbamate tert-butyl ester (97.5 g, 214 mmol) in DCM (600 mL) was treated with a solution of trifluoroacetic acid (32.9 g, 427 mmol) in DCM (250 mL). The resulting orange solution was stirred at room temperature for 0.5 h. The reaction mixture was quenched to neutral pH with saturated aqueous NaHCO3 solution (300 mL). The phases were separated, and the aqueous layer was extracted with DCM (2 × 100 mL). The organic extracts were combined, dried over MgSO4, filtered, and concentrated under vacuum to give N-(4-bromo-3-chloro-2-nitrophenyl)carbamate tert-butyl ester (75 g, 212 mmol, 99% yield) as a pale orange solid. 1 H NMR: 8.06(1H,d),7.72(1H,d),7.12(1H,s),1.53(9H,s).

[1251] Step 4: Ethyl 2-[(4-bromo-3-chloro-2-nitrophenyl)[(tert-butoxy)carbonyl]amino]acetate

[1252] In a 1 L three-necked flask, a suspension of N-(4-bromo-3-chloro-2-nitrophenyl)carbamate (75 g, 211 mmol) and cesium carbonate (138 g, 422 mmol) in DMF (300 mL) was batch-treated with a solution of ethyl 2-bromoacetate (24.59 mL, 222 mmol) in DMF (125 mL) at <10 °C (internal temperature, ice bath). The resulting orange suspension was stirred at <10 °C for 0.5 h. The reaction mixture was partitioned between EtOAc (300 mL) and water (300 mL). The aqueous layer was extracted with EtOAc (2 × 200 mL). The organic extracts were combined, washed with saturated brine (2 × 100 mL), dried over MgSO4, filtered, and concentrated under vacuum to give a deep orange oil (about 100 mL). The deep orange oil was added to stirred water (200 mL). The resulting orange precipitate was collected by filtration, washed with water (50 mL), and dried under vacuum to give an orange solid (107 g, 196 mmol, 93% yield). DMSO-d6 1 H NMR: 8.14(1H,d),7.57(1H,t),4.40-3.98(4H,m),1.41-1.15(12H,m).

[1253] Step 5: Ethyl 2-[(4-bromo-3-chloro-2-nitrophenyl)amino]

[1254] In a 2 L three-necked flask, a solution of ethyl 2-[(4-bromo-3-chloro-2-nitrophenyl)[(tert-butoxy)carbonyl]amino]acetate (107 g, 196 mmol) in DCM (600 mL) was treated participles with a solution of trifluoroacetic acid (75 mL, 978 mmol) in DCM (200 mL). The resulting orange solution was stirred at room temperature for 18 hours. The reaction mixture was quenched with a saturated aqueous solution of NaHCO3 (700 mL), and then solid NaHCO3 (40 g, 476 mmol) was slowly added participles to neutral pH. The phases were separated, and the aqueous layer was extracted with DCM (2 × 250 mL). The organic extracts were combined, washed with saturated brine (1 × 150 mL), dried over MgSO4, filtered, and concentrated under vacuum to give ethyl 2-[(4-bromo-3-chloro-2-nitrophenyl)amino]acetate (77.47 g, 184 mmol, 94% yield) as a pale orange solid. In DMSO-d6 1 HNMR: 7.68(1H,d),6.78(1H,d),6.70(1H,t),4.12(2H,q),4.04(2H,d),1.20(3H,t).

[1255] Step 6: 7-Bromo-8-chloro-1,2,3,4-tetrahydroquinoxalin-2-one

[1256] In a 2L three-necked flask, a solution of ethyl 2-[(4-bromo-3-chloro-2-nitrophenyl)amino]acetate (35.93 g, 96 mmol) in THF (200 mL) and MeOH (200 mL) was prepared in batches with sodium dithionite (71.2 g, 409 mmol) in water (200 mL) at 0 °C (internal temperature, ice bath). The resulting orange suspension was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (50 mL) and sodium carbonate (65 g, 613 mmol) was slowly added in batches until pH 9. MeOH and THF were removed under vacuum, and the aqueous solution was extracted with Me-THF (2 × 250 mL). The organic extracts were combined, washed with saturated brine (1 × 150 mL), dried over MgSO4, filtered, and concentrated under vacuum to give 7-bromo-8-chloro-3,4-tetrahydroquinoxalin-2(1H)-one (26.4 g, 96 mmol, 94% yield) as a viscous green solid. 1 H NMR: 9.93(1H,s),7.14(1H,d),6.63(1H,d),6.40(1H,br s),3.75(2H,s).

[1257] Step 7: 7-Bromo-8-chloroquinoxaline-2-ol

[1258] In a 2 L three-necked flask, a solution of 7-bromo-8-chloro-1,2,3,4-tetrahydroquinoxalin-2-one (60 g, 174 mmol) was prepared in portions with potassium tert-butoxide (39.1 g, 349 mmol) at <10 °C (internal temperature, ice bath) in THF (425 mL) and MeOH (425 mL). The resulting orange suspension was stirred at room temperature under an air stream for 18 hours. Water (200 mL) was added, followed by the slow addition of AcOH (50 mL). The resulting orange precipitate was collected by filtration, washed with water (100 mL), then with TBME (50 mL), and dried under vacuum to give 7-bromo-8-chloroquinoxalin-2-ol (41.81 g, 155 mmol, 89% yield) as a pale orange solid. 1 H NMR: 8.17 (1H, s), 7.69-7.55 (2H, br s).

[1259] Step 8: 7-Bromo-2,8-Dichloroquinoline

[1260] In a 1 L three-necked flask, a suspension of 7-bromo-8-chloroquinoxalin-2-ol (35 g, 129 mmol) in MeCN (300 mL) was treated dropwise under N2 at 50 °C with a solution of phosphorus oxychloride (36.2 mL, 388 mmol) in MeCN (50 mL). The resulting brown suspension was heated at 80 °C for 3 hours and then cooled to room temperature. The dark brown reaction mixture was concentrated under vacuum, and POCl3 was removed by azeotropic mixing with PhMe (250 mL). The brown residue was dissolved in MeCN (500 mL), and the mixture was quenched by slow addition to water (approximately 30 °C). EtOAc (500 mL) was added, and the mixture was filtered to obtain a dark brown solid. The crude solid was dissolved in EtOAc (200 mL) and combined with the filtrate. The phases were separated. The aqueous layer was extracted with EtOAc (3 × 200 mL). The organic extracts were combined, washed with saturated brine (1 × 200 mL), dried over MgSO4, filtered, and concentrated under vacuum to give a deep orange solid (34.52 g, 96%, crude product). The crude product was purified by silica gel chromatography (330 g box, 0–30% DCM / isohexane) to give 7-bromo-2,8-dichloroquinoxaline (27.69 g, 99 mmol, 76% yield) as a pale grayish-white solid. 1 H NMR: 9.13(1H,s),8.23(1H,d),8.08(1H,d).

[1261] Preparation of 9:7-bromo-8-chloro-2-methoxyquinoxaline

[1262]

[1263] 7-Bromo-2,8-dichloroquinoxaline (2 g, 7.12 mmol) and potassium carbonate (3.94 g, 28.5 mmol) were combined in a 100 mL three-necked flask with MeOH (40 mL). The resulting colorless suspension was heated at 65 °C (internal temperature) for 18 hours. The reaction mixture was cooled to room temperature. Water (150 mL) was added, and the precipitate was filtered to give 7-bromo-8-chloro-2-methoxyquinoxaline (1.79 g, 6.48 mmol, 91% yield) as a light, colorless solid. MS: [M+H] + =275. DMSO-d6 1 H NMR: 8.69(1H,s),8.00-7.89(2H,m),4.10(3H,s).

[1264] Preparation of 10:7-bromo-8-chloro-N,N-dimethylquinoxaloline-2-amine

[1265]

[1266] In a 100 mL three-necked flask, a solution (22 mL, 44.0 mmol) of 2 M dimethylamine in THF was treated with 7-bromo-2,8-dichloroquinoxaline (2.01 g, 7.16 mmol) at 0 °C (internal temperature, ice bath). The resulting yellow solution was warmed to room temperature and stirred for 3 hours. The reaction mixture was concentrated under vacuum and partitioned between EtOAc (50 mL) and a saturated aqueous solution of NaHCO3 (50 mL). The layers were separated, and the aqueous phase was extracted with EtOAc (2 × 50 mL). The organic extracts were combined, washed with saturated brine (1 × 50 mL), dried over MgSO4, filtered, and concentrated under vacuum to give 7-bromo-8-chloro-N,N-dimethylquinoxaline-2-amine (1.98 g, 6.77 mmol, 95% yield) as a pale yellow solid. MS: [M+H] + =288. 1 H NMR (500MHz, DMSO-d6) δ8.76 (s, 1H), 7.72 (d, J = 8.8Hz, 1H), 7.63 (d, J = 8.8Hz, 1H), 3.29 (s, 6H).

[1267] Preparation of 11:2-(azacyclobutane-1-yl)-7-bromo-8-chloroquinoxaline

[1268]

[1269] Azacyclobutane (0.49 mL, 7.20 mmol) was added to a solution of 7-bromo-2,8-dichloroquinoxaline (1.00 g, 3.60 mmol) and triethylamine (1.00 mL, 7.20 mmol) in THF (5 mL), and the mixture immediately turned yellow. The mixture was stirred at room temperature for 80 hours and then partitioned between EtOAc and a saturated aqueous solution of NaHCO3. The phases were separated, the aqueous phase was extracted with EtOAc, and the combined organic phases were washed with brine, dried (MgSO4 + hydrophobic glass frit), and concentrated to give the title compound (1.05 g). 1 H NMR (400MHz, DMSO-d6): 8.36 (1H, s), 7.71 (1H, d), 7.64 (1H, d), 4.28 (4H, t), 2.49-2.41 (2H, m).

[1270] Preparation of 12:7-bromo-8-chloro-2-(morpholin-4-yl)quinoxaline

[1271]

[1272] 7-Bromo-8-chloro-2-(morpholin-4-yl)quinoxaline was prepared from 7-bromo-2,8-dichloroquinoxaline and morpholine using a procedure similar to that in Preparation 11.

[1273] Preparation of 13: 4-chloro-2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-2H-indazole

[1274]

[1275] Method A

[1276] A mixture of 5-bromo-4-chloro-2-methyl-2H-indazole (12.14 g, 49.45 mmol), bis(pinacol)diboron (18.83 g, 74.18 mmol), and [1,1'-bis(diphenylphosphine)ferrocene]dichloropalladium(II) complex with dichloromethane (4.038 g, 4.945 mmol) and potassium acetate (9.706 g, 98.90 mmol) in 1,4-dioxane (120 mL) was degassed, purged with nitrogen, and stirred at 120 °C for 5 h. The reaction was cooled to room temperature, filtered through a diatomaceous earth pad, and washed with EtOAc. The filtrate was concentrated under vacuum. The residue was purified by NH4Cl column chromatography (gradient elution, 0–70% EtOAc / hexane) to give the title compound (14.36 g). MS: [M+H] + =293,295.

[1277] Method B

[1278] Will i PrMgCl·LiCl (1.3 M in THF, 63 mL, 82.0 mmol) was added to a solution of 5-bromo-4-chloro-2-methyl-2H-indazole (10.00 g, 40.73 mmol) in THF (100 mL) cooled to an internal temperature of <5 °C on ice under nitrogen. The mixture was kept at an internal temperature below 10 °C throughout the addition process and then stirred at <5 °C for 5 hours. The mixture was cooled to an internal temperature of -10 °C, and isopropoxypinacolborane (25.00 mL, 122.6 mmol) was added. The mixture was stirred at this temperature for 1 hour and then quenched with water. A saturated aqueous solution of NH4Cl was added, and the aqueous mixture was extracted with EtOAc. The combined organic phases were washed with water and brine, dried (MgSO4), and concentrated. The residue was dissolved in IPA, and then water was added to induce precipitation. The solid was collected by filtration. The solid was further ground together with petroleum and then collected by filtration to obtain a pale yellow solid (10.18 g, 34.79 mmol, 85%).

[1279] Preparation of 14: 4-chloro-2-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-2H-indazole

[1280]

[1281] The preparation was carried out using 5-bromo-4-chloro-2-ethyl-2H-indazole according to the above preparation method 10. MS: [M+H] + =307.

[1282] Preparation of 15:(3,4-dichloro-2-methyl-2H-indazol-5-yl)boronic acid

[1283]

[1284] A stirred solution of 5-bromo-3,4-dichloro-2-methyl-2H-indazole (36.4 g, 130 mmol) in THF (364 mL) was cooled to 5 °C (internal temperature) under nitrogen. THF (1.3 M) containing a magnesium isopropyl chloride-lithium chloride complex (200 mL, 260 mmol) was added dropwise through a sleeve over 25 minutes. The temperature was maintained at 5 °C for the duration of the addition. The mixture was warmed to room temperature over 1 hour. The mixture was recooled to 5 °C, and then triisopropyl borate (100 mL, 431 mmol) was added through a sleeve over 10 minutes. The mixture was stirred at room temperature for 1 hour, then cooled to 5 °C and quenched with AcOH (145 mL, 2533 mmol). The mixture was added dropwise to stirred water (6 L), and the precipitate was collected by filtration to give the crude product. The product was dissolved in a solution of NaOH (10.5 g, 263 mmol) in water (350 mL), and then washed with TBME (350 mL). The aqueous layer was treated with 1 M HCl (300 mL, 300 mmol), and the precipitate was collected by filtration to give (3,4-dichloro-2-methyl-2H-indazol-5-yl)boronic acid (23.9 g, 88 mmol, 67.6% yield) as a beige solid. MS: [M+H] + =245. 1 H NMR (500MHz, DMSO-d6) δ8.33 (s, 2H), 7.51 (d, J = 8.7Hz, 1H), 7.27 (d, J = 8.6Hz, 1H), 4.12 (s, 3H).

[1285] Preparation of 16:8-chloro-N,N-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)quinoxalin-2-amine

[1286]

[1287] The suspension of diboronol diboron (2.58 g, 10.16 mmol), 7-bromo-8-chloro-N,N-dimethylquinoxaloline-2-amine (1.98 g, 6.77 mmol), and potassium acetate (1.994 g, 20.31 mmol) in 1,4-dioxane (20 mL) was degassed using three evacuation / nitrogen backfill cycles. The reaction mixture was then treated with Pd(dppf)Cl2 (0.495 g, 0.677 mmol), and the degassed cycles were repeated. The resulting red suspension was heated at 100 °C (internal temperature) for 1.5 h. The reaction mixture was cooled to room temperature and then concentrated under vacuum. The crude product was purified by silica gel chromatography (24 g cartridge, 0-100% DCM / isohexane) to give the title compound (790 mg) as a pale yellow solid. MS: [M+H] + =334. 1 H NMR (500MHz, DMSO-d6) δ8.77(s,1H),7.75(d,1H),7.46(d,1H),3.32(s,6H),1.35(s,12H).

[1288] The following borates are prepared in a similar manner:

[1289]

[1290] Preparation of 17:3,4-dichloro-2-methyl-2H-indazole-5-carboxaldehyde

[1291]

[1292] Isopropyl magnesium chloride-lithium chloride complex (1.3 mol / L, 55 mL, 71.4 mmol in THF) was added to a solution of 5-bromo-3,4-dichloro-2-methyl-indazole (10.0 g, 35.7 mmol) in 100 mL of THF at 0 °C, and the mixture was stirred at 0 °C for 1 hour. Then, DMF (11.0 mL, 143 mmol) was added at the same temperature, and the mixture was stirred at 0 °C for 30 minutes, quenched with a saturated aqueous NH4Cl solution, and diluted with water. The mixture was extracted with EtOAc, washed with brine, dried over Na2SO4, filtered, and then concentrated to give a pale orange solid. The crude product was suspended in EtOAc / heptane (1:1, 10 mL) and stirred at room temperature for 1 hour. The precipitate was collected, washed with hexane, and dried under reduced pressure at 50 °C for 3 hours to give the title compound (5.50 g). MS: [M+H] + =229,231

[1293] Preparation of 18:4-chloro-2-methyl-2H-indazole-5-carboxaldehyde

[1294]

[1295] 4-Chloro-2-methyl-2H-indazole-5-carboxaldehyde was prepared from 5-bromo-4-chloro-2-methyl-2H-indazole using a procedure similar to that described in Preparation 17 above. MS: [M+H] + =195.

[1296] Preparation of 19:(3,4-dichloro-2-methyl-2H-indazol-5-yl)(3,5-dichloro-6-methylpyrazine-2-yl)methanol

[1297]

[1298] A solution of 3,5-dichloro-2-methylpyrazine (391 mg, 2.40 mmol) in THF (5 mL) was added at -60 °C to a solution of bromo-3,5-dichloro-2-methylpyrazine (591 mg, 2.40 mmol) in THF (5 mL). After stirring for 45 min, 3,4-dichloro-2-methyl-indazole-5-carboxaldehyde (500 mg, 2.18 mmol) was added to the mixture at the same temperature, and the mixture was stirred at -60 °C for 10 min, followed by stirring at room temperature for 30 min. After quenching with a saturated aqueous NH4Cl solution, the mixture was diluted with water, extracted with EtOAc, washed with brine, dried over Na2SO4, filtered, and then concentrated to give a brown residue. The brown residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (510 mg) as a pale yellow amorphous compound. MS: [M+H]+=391,393.

[1299] Preparation of 20:(4-chloro-2-methyl-2H-indazol-5-yl)(3,5-dichloro-6-methylpyrazine-2-yl)methanol

[1300]

[1301] The title compound was prepared from 4-chloro-2-methyl-indazole-5-carboxaldehyde and 3,5-dichloro-2-methyl-pyrazine using a procedure similar to that described in Preparation 19 above. MS: [M+H]+ = 357.

[1302] Preparation of 21: 3,4-dichloro-5-(3,5-dichloro-6-methylpyrazine-2-carbonyl)-2-methyl-2H-indazole

[1303]

[1304] Manganese oxide (IV) (1.93 g, 19.5 mmol) was added to a solution of (3,4-dichloro-2-methyl-indazole-5-yl)-(3,5-dichloro-6-methyl-pyrazin-2-yl)methanol (510 mg, 1.301 mmol) in chloroform (10.2 mL) at room temperature. The mixture was stirred at room temperature for 6 hours. An additional 1.93 g, 19.5 mmol, of manganese oxide (IV) was added to the reaction mixture. The mixture was stirred at room temperature for 18 hours. After filtration, the filtrate was concentrated to give a pale yellow solid, which was suspended in hexane, collected by filtration, and dried under vacuum at 50 °C to give the title compound (490 mg). MS: [M+H]+ = 389, 391.

[1305] Preparation of 22: 4-chloro-5-(3,5-dichloro-6-methylpyrazine-2-carbonyl)-2-methyl-2H-indazole

[1306]

[1307] At room temperature, manganese oxide (IV) (1.56 g, 17.9 mmol) was added to a stirred solution of (4-chloro-2-methyl-2H-indazol-5-yl)(3,5-dichloro-6-methylpyrazin-2-yl)methanol (0.32 g, 0.895 mmol) in DCM (8.95 mL). The suspension was stirred overnight, then filtered, washed with DCM (3x), and concentrated to give the title compound (0.231 g), which was ready for use without further purification. MS: [M+H] + =355.

[1308] Preparation of 23:(S)-2-oxa-8-azaspiro[4.5]dec-4-amine

[1309]

[1310] At room temperature, a solution of (4S)-4-((tert-butylsulfinyl)amino)-2-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester (0.10 g, 0.28 mmol) prepared by the method described in WO2016203405 in MeOH was added with 1,4-dioxane (0.70 mL, 2.8 mmol) containing 4M HCl. The mixture was stirred at 50 °C for 30 min and cooled to room temperature. The volatiles were removed under reduced pressure, and the residue was azeotropically reacted with toluene. The resulting crude product, (S)-2-oxa-8-azaspiro[4.5]decane-4-amine salt, was ready for use without further purification. MS: [M+H] + =157.

[1311] Preparation of 24:(1R)-8-azaspiro[4.5]dec-1-amine

[1312]

[1313] The (1R)-1-((tert-butylsulfinyl)amino)-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester prepared by the method described in WO2016203405 was deprotected using a procedure similar to that in Preparation 23. The resulting (1R)-8-azaspiro[4.5]dec-1-amine dihydrochloride was ready for use without further purification.

[1314] Preparation of 25:(3S,4S)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-amine hydrochloride

[1315]

[1316] Step 1: Ethyl (2S)-2-[(tert-butyldimethylsilyl)oxy]propionate

[1317] The reaction mixture of ethyl (2S)-2-hydroxypropionate (95.0 g, 0.8 mol) in DCM (1 L) was cooled to 0 °C, and then imidazole (81.6 g, 1.2 mol) and TBSCl (133.3 g, 0.88 mol) were added. The mixture was stirred at ambient temperature for about 1.5 hours. The reaction mixture was poured into water (1.0 L), extracted with DCM (2 × 500 mL), washed with brine, dried over Na2SO4, concentrated under vacuum, and purified by silica column chromatography (petroleum ether / EtOAc = 50 / 1 to 20 / 1) to give a product as a colorless oil (180.0 g, 97%). 1 H NMR (500MHz, CDCl3) δ: 4.33 (s, 1H), 4.22 (s, 2H), 1.44 (d, J = 6.7Hz, 3H), 1.32 (t, J = 7.1Hz, 3H), 0.97 (s, 9H), 0.15 (s, 6H).

[1318] Step 2: (2S)-2-[(tert-butyldimethylsilyl)oxy]propionaldehyde

[1319] A solution of ethyl (2S)-2-[(tert-butyldimethylsilyl)oxy]propionate (131.0 g, 0.56 mol) in toluene (800 mL) was cooled to -60 °C, and DIBAL-H (1.5 M, 560 mL, 0.85 mol) was added dropwise, followed by stirring at 60 °C for 2 hours. The reaction mixture was poured into water (800 mL), extracted with EtOAc (2 × 500 mL), washed with brine, dried over Na₂SO₄, and concentrated under vacuum to obtain the crude product. The crude product was ready for use in the next step without further purification.

[1320] Step 3: 4-[(2S)-2-[(tert-butyldimethylsilyl)oxy]-1-hydroxypropyl]piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester

[1321] A solution of diisopropylamine (65.0 g, 0.64 mol) in THF (400 mL) was cooled to -20 °C. n-BuLi (2.5 M, 224 mL, 0.56 mol) was added dropwise, followed by stirring at -10 °C for 1 hour. THF (200 mL) containing 1-tert-butyl-4-ethyl piperidine-1,4-dicarboxylic acid (110.0 g, 0.43 mol) was added dropwise at -10 °C, followed by stirring at N2 from -10 °C to ambient temperature for 1 hour. THF (200 mL) containing (2S)-2-[(tert-butyldimethylsilyl)oxy]propionaldehyde (120.0 g, 0.64 mol) was added dropwise at -10 °C, followed by stirring at -10 °C to 0 °C for 2 hours. The reaction mixture was poured into saturated NH4Cl (1 L) and extracted with EtOAc (2 × 500 mL). The combined EtOAc phases were washed with brine, dried over Na2SO4, concentrated under vacuum, and purified by silica column chromatography (petroleum ether / EtOAc = 50 / 1 to 30 / 1 to 20 / 1) to give a product as a yellow oil (70.0 g, 37%). 1 H NMR(400MHz, CDCl3)δ:4.29-4.09(m,2H),4.06-3.88(m,2H),3.79(d,1H),3.60-3.48(m,1H),2.78(s,2H),2.66-2.25( m,1H),2.24-1.94(m,2H),1.74(m,2H),1.50-1.37(m,9H),1.34-1.18(m,5H),1.12(d,3H),0.91(s,10H),0.04(s,6H).

[1322] Step 4: 4-[(2S)-2-[(tert-butyldimethylsilyl)oxy]-1-hydroxypropyl]-4-(hydroxymethyl)piperidine-1-carboxylic acid tert-butyl ester

[1323] LiBH4 (2M, 118mL, 0.236mol) was added to a solution of 4-[(2S)-2-[(tert-butyldimethylsilyl)oxy]-1-hydroxypropyl]piperidine-1,4-dicarboxylic acid 1-tert-butyl 4-ethyl ester (70.0g, 0.157mol) in THF (700mL) at 0°C, and the mixture was stirred overnight at ambient temperature. The mixture was poured into water (500mL), stirred at ambient temperature for 20 minutes, extracted with EtOAc (2×300mL), washed with brine, dried over Na2SO4, and concentrated under vacuum to give a crude product (60.0g). The crude product was ready for use in the next step without further purification.

[1324] Step 5: 4-[(2S)-1,2-dihydroxypropyl]-4-(hydroxymethyl)piperidine-1-carboxylic acid tert-butyl ester

[1325] TBAF (1M, 223mL, 0.223mol) was added to a cooled (0°C) solution of 4-[(2S)-2-[(tert-butyldimethylsilyl)oxy]-1-hydroxypropyl]-4-(hydroxymethyl)piperidine-1-carboxylic acid tert-butyl ester (60.0 g, 0.149 mol) in THF (600 mL), and the mixture was stirred at ambient temperature for 2 hours. NaHCO3 (600 mL aqueous solution) was added, and the mixture was stirred at ambient temperature for 10 minutes. Extraction was performed with EtOAc (2 × 300 mL), washed with brine, dried over Na2SO4, concentrated under vacuum, and purified by silica column chromatography (DCM / MeOH = 100 / 1 to 50 / 1 to 30 / 1) to give a product as a yellow oil (37.0 g, 86%). 1 H NMR (400MHz, CDCl3) δ: 4.02-3.87 (m, 1H), 3.74 (m, 4H), 3.36 (d, 4H), 3.10 (s, 2H), 1.66 (s, 3H), 1.40 (s, 10H), 1.31 (s, 3H).

[1326] Step 6: (3S)-4-hydroxy-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester

[1327] NaH (17.8 g, 0.44 mol) was added in portions to an ice-cooled solution of 4-[(2S)-1,2-dihydroxypropyl]-4-(hydroxymethyl)piperidine-1-carboxylic acid tert-butyl ester (37.0 g, 0.127 mol) in THF (400 mL), followed by the addition of TsCl (25.5 g, 0.134 mol) in THF (200 mL). The reaction mixture was stirred at 0 °C for 2 hours. The reaction mixture was poured into ice and NH4Cl (600 mL aqueous solution), extracted with EtOAc (3 × 400 mL), washed with brine, dried over Na2SO4, concentrated under vacuum, and purified by silica column chromatography (DCM / MeOH = 100 / 1 to 50 / 1 to 30 / 1) to give a product as a yellow oil (20.0 g, 58%). 1 H NMR (400MHz, CDCl3) δ: 3.94-3.57 (m, 4H), 3.45 (d, 1H), 2.96 (s, 2H), 1.70 (s, 3H), 1.42 (s, 10H), 1.29 (m, 4H).

[1328] Step 7: (3S)-3-methyl-4-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester

[1329] DMP (37.5 g, 0.088 mol) was added in portions to an ice-cooled solution of (3S)-4-hydroxy-3-methyl-2-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester (20.0 g, 0.074 mol) in DCM (200 mL). The reaction mixture was stirred at ambient temperature for 1 hour, poured into NaHCO3 (aqueous solution), extracted with DCM, washed with brine, dried over Na2SO4, and concentrated under vacuum to give a product as a yellow oil (19.0 g, 95%). The product was used directly in the next step.

[1330] Step 8: (3S,4S)-3-methyl-4-[(2-methylpropane-2-sulfinyl)amino]-2-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester

[1331] To a solution of (3S)-3-methyl-4-oxo-2-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester (11.0 g, 0.04 mol) in THF (250 mL), (R)-2-methylpropane-2-sulfinamide (9.9 g, 0.08 mol) and Ti(OEt)4 (36.5 g, 0.16 mol) were added, and the reaction mixture was stirred overnight at 75 °C. The reaction mixture was cooled to -10 °C, and LiBH4 (2 M, 30 mL, 0.06 mol) was added dropwise, followed by stirring at -10 °C for 1 hour. The reaction mixture was poured into ice and NH4Cl (300 mL aqueous solution) and EtOAc (300 mL), stirred at ambient temperature for 20 minutes, and then filtered through diatomaceous earth. The reaction mixture was extracted with EtOAc (2 × 300 mL), washed with brine, dried over Na2SO4, concentrated under vacuum, and purified by silica column (petroleum ether / EtOAc = 10 / 1 to 5 / 1 to 3 / 1 to 2 / 1) to give the product (7.0 g, 47%). 1 H NMR(400MHz,DMSO-d6)δ:5.07(d,J=11.0Hz,1H),4.06(s,1H),3.74(m,3H),3.37 (d,3H),2.84(s,2H),1.69-1.50(m,2H),1.39(s,11H),1.15(s,9H),1.06(m,3H).

[1332] Step 9: (3S,4S)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-amine hydrochloride

[1333] To a solution of (3S,4S)-3-methyl-4-[(2-methylpropane-2-sulfinyl)amino]-2-oxa-8-azaspiro[4.5]decane-8-carboxylic acid tert-butyl ester (5.8 g, 15.5 mmol) in MeOH (20 mL), HCl / dioxane (4 M, 39 mL, 155 mmol) was added, and the mixture was stirred at 50 °C for 2 h. The reaction mixture was cooled to ambient temperature and concentrated under vacuum. The crude product was dissolved in water (50 mL) and extracted with EtOAc (3 × 40 mL). The aqueous phase was freeze-dried to give an HCl salt of the product as a yellow solid (4.0 g). MS: [M+H] + =171. 1 H NMR(400MHz, DMSO-d6)δ:4.44(m,1H),4.05-3.88(m,2H),3.67(s,1H),3.58-3.39(m,2H),3.22-3.01(m,2H),1.98(m,4H),1.34(s,3H).

[1334] Preparation of 26:1-oxo-8-azaspiro[4.5]dec-2-ene-8-carboxylic acid tert-butyl ester

[1335]

[1336] Step 1: 4-Formyl-4-(prop-2-en-1-yl)piperidin-1-carboxylic acid tert-butyl ester

[1337] The reaction mixture of 4-formylpiperidin-1-carboxylic acid tert-butyl ester (1200.0 g, 5.63 mol) in THF (10 L) was cooled to -25 °C, and then allyl bromide (816.5 g, 6.75 mol) was added, followed by the fractional addition of t-BuOK (757.8 g, 6.75 mol). The reaction mixture was stirred at -25 °C to -15 °C for about 45 min, then poured into ice-cold NH4Cl (8 L of aqueous solution), extracted with EtOAc, washed with brine, dried over Na2SO4, and concentrated under vacuum. The crude product was purified by silica column chromatography (petroleum ether / EtOAc = 50 / 1 to 20 / 1 to 10 / 1) to give the title compound (920.0 g, 64.5%) as a colorless oil. 1 H NMR(CDCl3): 9.49(1H,s),5.63(1H,m),5.09(2H,m),3.79(2H,m),2.96(2H,m),2.23(2H,d),1.93(2H,m),1.44(10H,m).

[1338] Step 2: 4-(1-hydroxypropyl-2-en-1-yl)-4-(propyl-2-en-1-yl)piperidin-1-carboxylic acid tert-butyl ester

[1339] A solution of 4-formyl-4-(prop-2-en-1-yl)piperidin-1-carboxylic acid tert-butyl ester (400.0 g, 1.58 mol) in THF (4 L) was cooled to -60 °C, and vinyl magnesium bromide (1.90 L, 1.90 mol) was added. The mixture was then stirred at room temperature for 1 hour. The mixture was poured into NH4Cl (aqueous solution, 5 L), extracted with EtOAc, washed with brine, dried over Na2SO4, and concentrated under vacuum to give a product as a brown oil (426.0 g, 95.8%).

[1340] 1 H NMR(CDCl3):5.93(2H,m),5.24(2H,m),5.07(2H,t),4.00 91H,d),3.69(2H,m),3.12(2H,m),2.30(1H,m),2.19(1H,m),1.74(1H,m),1.60-1.53(2H,m)1.49(11H,m).

[1341] Step 3: 1-Hydroxy-8-a...

Claims

1. A compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein: R 1 is hydrogen or hydroxyl; R 2 and R 3 are independently selected from hydrogen, halogen, C 1-4 Alkyl, halogenated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl and -CN; X is O or CR 4 R 5 ; R 4 and R 5 are independently selected from hydrogen, halogen, hydroxyl, C 1-4 Alkyl, C 1-4 Alkoxy and halogenated C 1-4 alkyl; R 6 and R 7 joined to form optionally one or more R 10 Ring A substituted with a group; Ring A is any of the following: (i) a five-membered nitrogen-containing heterocyclic ring, wherein the heterocyclic ring optionally contains one or two additional heteroatoms selected from N, O and S; or (ii) a six-membered aromatic nitrogen-containing heterocyclic ring, wherein the heterocyclic ring optionally contains one or two additional heteroatoms selected from N, O and S; or (iii) a six-membered non-aromatic nitrogen-containing heterocyclic ring, wherein the heterocyclic ring optionally contains one or two additional heteroatoms selected from N and S; R 8 Selected from halogenated C 1-4 Alkyl, -CH3 and halogen; R 9 Selected from hydrogen, C 1-4 Alkyl, halogenated C 1-4 Alkyl and halogen; R 10 Independently selected from: halogen; C 1-4 Alkyl; C 1-4 Alkoxy, di-C 1-4 alkylamino; and an optionally substituted four- or six-membered saturated heterocyclic group containing 1 or 2 heteroatoms selected from O and N, wherein the optional substituents are selected from C 1-4 alkyl.

2. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein: Ring A is a five-membered nitrogen-containing aromatic or non-aromatic heterocyclic ring, wherein the heterocyclic ring optionally contains one or two additional heteroatoms selected from N, O and S; and / or R 8 is -CF3, chlorine or fluorine; and / or R 9 is -CH3, -CF3 or chlorine; and / or R 10 Independently selected from: -CH3, -CH(CH3)2, -CH2CH3, -OCH3, -OCH2CH3, -OCH(CH3)2 and -N(CH3)2.

3. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein X is O.

4. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein X is CR 4 R 5 , and R 4 and R 5 independently selected from hydrogen, halogen and C optionally substituted by one or more halogens 1-4 alkyl.

5. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 4, wherein X is CR 4 R 5 , and R 4 and R 5 Independently selected from C1 alkyl optionally substituted with one or more halogens.

6. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein X is CR 4 R 5 , and R 4 is hydrogen and R 5 Selected from halogen and halomethyl.

7. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 6, wherein X is CR 4 R 5 , and R 4 is hydrogen and R 5 is selected from fluorine, chlorine, bromine, iodine, monohalomethyl, dihalomethyl and trihalomethyl, wherein halo is selected from fluorine, chlorine, bromine or iodine.

8. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 7, wherein X is CR 4 R 5 , and R 4 is hydrogen and R 5 It's fluorine.

9. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 1 It's hydroxyl.

10. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 1 It's hydrogen.

11. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 2 is hydrogen, and R 3 Selected from C 1-4 Alkyl, halogenated C 1-4 Alkyl, hydroxyl C 1-4 Alkyl and -CN.

12. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 2 is hydrogen, and R 3 It is C 1-4 alkyl.

13. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 12, wherein R 2 is hydrogen, and R 3 It is -CH3.

14. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 8 Selected from -CH3, chlorine and fluorine.

15. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 8 It's chlorine.

16. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 9 It's hydrogen.

17. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein ring A is a five-membered nitrogen-containing heterocycle or a six-membered aromatic nitrogen-containing heterocycle, wherein the heterocycle optionally contains one or two additional heteroatoms selected from N, O and S.

18. The compound according to claim 17, or a pharmaceutically acceptable salt thereof, wherein Ring A is a five-membered nitrogen-containing heterocycle, wherein the heterocycle optionally contains one or two additional heteroatoms selected from N, O and S.

19. The compound according to claim 17, or a pharmaceutically acceptable salt thereof, wherein Ring A is a five-membered nitrogen-containing aromatic or non-aromatic heterocyclic ring, wherein the heterocyclic ring optionally contains one or two additional heteroatoms selected from N, O and S. 20 . The compound according to claim 18 , or a pharmaceutically acceptable salt thereof, wherein Ring A is a five-membered aromatic nitrogen-containing heterocyclic ring, wherein the heterocyclic ring optionally contains one or two additional heteroatoms selected from N and S.

21. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Ring A is any one of the following: (i) a six-membered aromatic nitrogen-containing heterocyclic ring, wherein the heterocyclic ring optionally contains one or two additional heteroatoms selected from N, O and S; or (ii) a six-membered non-aromatic nitrogen-containing heterocyclic ring, wherein the heterocyclic ring optionally contains one or two additional heteroatoms selected from N and S.

22. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein part Selected from the following Table I or Table II Table I Table II Where c is 0, 1, 2, or 3.

23. The compound according to claim 22 or a pharmaceutically acceptable salt thereof, wherein part Selected from: Or selected from: Where c is 0, 1, 2, or 3.

24. The compound according to claim 23 or a pharmaceutically acceptable salt thereof, wherein part Selected from: Or selected from 25. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 10 independently selected from halogen, C 1-4 Alkoxy, di-C 1-4 Alkylamino and C 1-4 alkyl.

26. The compound according to claim 25 or a pharmaceutically acceptable salt thereof, wherein R 10 Independently selected from -OCH3, -N(CH3)2, -CH3 and -CH2CH3.

27. The compound according to claim 25 or a pharmaceutically acceptable salt thereof, wherein R 10 are independently selected from -CH3.

28. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 are joined to form ring A, and the compound of formula (I) is a compound of formula (XVIII):

29. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: (1R,3R)-8-[3-(4-chloro-2-methyl-2H-indazol-5-yl)-5-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl]-3-(trifluoromethyl)-8-azaspiro[4.5]decan-1-amine; (1R)-8-[3-(4-chloro-2-methyl-2H-indazol-5-yl)-5-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl]-3,3-difluoro-8-azaspiro[4.5]decan-1-amine; (4S)-8-[3-(4-chloro-2-methyl-2H-indazol-5-yl)-5-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl]-2-oxa-8-azaspiro[4.5]decan-4-amine; (4S)-8-[3-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-5-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl]-2-oxa-8-azaspiro[4.5]decan-4-amine; (4S)-8-[3-(4-chloro-2-ethyl-2H-indazol-5-yl)-5-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl]-2-oxa-8-azaspiro[4.5]decan-4-amine; (3S,4S)-8-[3-(4-chloro-2-methyl-2H-indazol-5-yl)-5-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl]-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine; {6-[(1R)-1-amino-3,3-difluoro-8-azaspiro[4.5]dec-8-yl]-3-(4-chloro-2-methyl-2H-indazol-5-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl}methanol; {6-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-3-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl}methanol; (3S,4S)-8-[3-(5-chloro-3-methoxyquinoxalin-6-yl)-5-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl]-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine; (3S,4S)-8-{3-[5-chloro-3-(dimethylamino)quinoxalin-6-yl]-5-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl}-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine; (4S)-8-{3-[5-chloro-3-(dimethylamino)quinoxalin-6-yl]-5-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl}-2-oxa-8-azaspiro[4.5]decan-4-amine; 7-{6-[(1R)-1-amino-8-azaspiro[4.5]dec-8-yl]-5-methyl-1H-pyrazolo[3,4-b]pyrazin-3-yl}-8-chloro-N,N-dimethylquinoxalin-2-amine; (4S)-8-[3-(5-chloro-3-methoxyquinoxalin-6-yl)-5-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl]-2-oxa-8-azaspiro[4.5]decan-4-amine; (1R)-8-[3-(5-chloro-3-methoxyquinoxalin-6-yl)-5-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl]-8-azaspiro[4.5]decan-1-amine; (1R)-8-[3-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-5-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl]-8-azaspiro[4.5]decan-1-amine; {6-[(1R)-1-amino-3,3-difluoro-8-azaspiro[4.5]dec-8-yl]-3-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl}methanol; {6-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-3-[5-chloro-3-(dimethylamino)quinoxalin-6-yl]-1H-pyrazolo[3,4-b]pyrazin-5-yl}methanol; {6-[(1R,3S)-1-amino-3-fluoro-8-azaspiro[4.5]dec-8-yl]-3-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl}methanol; {6-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-3-(4-chloro-2,3-dimethyl-2H-indazol-5-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl}methanol; {6-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-3-(5-chloro-3-methoxyquinoxalin-6-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl}methanol; (3S,4S)-8-{3-[3-(azetidin-1-yl)-5-chloroquinoxalin-6-yl]-5-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl}-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine; and (3S,4S)-8-{3-[5-chloro-3-(morpholin-4-yl)quinoxalin-6-yl]-5-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl}-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine.

30. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is {6-[(1R)-1-amino-3,3-difluoro-8-azaspiro[4.5]dec-8-yl]-3-(4-chloro-2-methyl-2H-indazol-5-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl}methanol.

31. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is {6-[(3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]-3-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl}methanol.

32. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is (3S,4S)-8-[3-(5-chloro-3-methoxyquinoxalin-6-yl)-5-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl]-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine.

33. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is (3S,4S)-8-{3-[5-chloro-3-(dimethylamino)quinoxalin-6-yl]-5-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl}-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine.

34. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is (1R)-8-[3-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-5-methyl-1H-pyrazolo[3,4-b]pyrazin-6-yl]-8-azaspiro[4.5]decan-1-amine.

35. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is {6-[(1R)-1-amino-3,3-difluoro-8-azaspiro[4.5]dec-8-yl]-3-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl}methanol.

36. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is {6-[(1R,3S)-1-amino-3-fluoro-8-azaspiro[4.5]dec-8-yl]-3-(3,4-dichloro-2-methyl-2H-indazol-5-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl}methanol.

37. A combination comprising a compound of formula (I) according to any one of claims 1 to 36, or a pharmaceutically acceptable salt thereof, and one or more other therapeutic agents.

38. A combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 36 and one or two anticancer agents.

39. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 36 or a pharmaceutically acceptable salt thereof, or a combination according to claim 38.

40. Use of a compound according to any one of claims 1 to 36 or a pharmaceutically acceptable salt thereof, a combination according to claim 38 or a pharmaceutical composition according to claim 39 in the preparation of a medicament for preventing or treating hepatocellular carcinoma, melanoma, esophageal cancer, kidney cancer, colon cancer, lung cancer, mesothelioma, breast cancer, bladder cancer, gastrointestinal cancer, ovarian cancer or prostate cancer.

41. Use of a compound according to any one of claims 1 to 36 or a pharmaceutically acceptable salt thereof, a combination according to claim 38 or a pharmaceutical composition according to claim 39 in the preparation of a medicament for preventing or treating colorectal cancer or lung adenocarcinoma.

42. A method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, the method comprising: (a) making a compound of formula (A) or a protected derivative thereof: Among them, X, R 1 , R 2 and R 3 As defined in claim 1 for the compound of formula (I), P represents a protecting group or is hydrogen, and Z is a metal residue or a leaving group Coupling with a compound of formula (B) or a protected version thereof Where R 6 , R 7 , R 8 and R 9 As defined in claim 1 for the compound of formula (I), wherein V represents a metal or metalloid residue or a leaving group, followed by a deprotection reaction suitable for removing the protecting group; or (b) treating a compound of formula (C) or a protected derivative thereof: Where R 1 , R 6 , R 7 , R 8 and R 9 As defined in claim 1 for the compound of formula (I), X is CH, P represents a protecting group or hydrogen, L is a leaving group, Coupled with a compound of formula (D) or a protected derivative thereof, wherein X, R 2 and R 3 As defined in claim 1 for the compound of formula (I) (c) treating a compound of formula (K) or a protected derivative thereof, Among them, X, R 2 , R 3 , R 6 , R 7 , R 8 and R 9 As defined in claim 1 for the compound of formula (I), P represents an amine protecting group, N,N-dimethylsulfamoyl or hydrogen, L 3 is a leaving group: (i) reacting with an organometallic species of formula CH3M, wherein M is a metal, in the presence of a metal catalyst to obtain a compound of formula (I), wherein R 1 is H; or (ii) reacting with an alkyl borate in the presence of a photoredox catalyst, a metal catalyst, a ligand, a base and a light source to obtain a compound of formula (I), wherein R 1 is OH; or (d) cyclizing the compound of formula (R) or a protected derivative thereof using hydrazine or a protected hydrazine derivative thereof, Among them, X, R 1 , R 2 , R 3 , R 6 , R 7 , R 8 and R 9 As defined in claim 1 for the compound of formula (I), and L 1 represents a suitable leaving group; in each case optionally followed by a deprotection step; or (e) deprotecting a protected derivative of a compound of formula (I); or (f) interconverting a compound of formula (I) or a protected derivative thereof with another compound of formula (I) or a protected derivative thereof; or (g) optionally forming a pharmaceutically acceptable salt of the compound of formula (I).

43. A method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 42, wherein: In method (a) P represents 2-tetrahydropyran; THP; 2-(trimethylsilyl)ethoxymethyl; or SEM; and / or Z is zinc chloride, iodine or bromine; and / or V represents boric acid, boric acid pinacol ester, magnesium halide, zinc halide or halogen; and / or In method (b) P represents 2-tetrahydropyran; THP; 2-(trimethylsilyl)ethoxymethyl; or SEM; and / or L is chlorine; and / or In method (c) P represents 2-tetrahydropyran; THP; 2-(trimethylsilyl)ethoxymethyl; or SEM; and / or L 3 is a halogen; and / or M is CH3-Zn-Hal, wherein Hal is a halogen; and / or The metal catalyst is (1,3-diisopropylimidazol-2-ylidene)(3-chloropyridyl)palladium(II) dichloride; and / or The alkyl borate ester is potassium 2-(trimethylsilyl)-ethoxymethyl trifluoroborate; and / or The photoredox catalyst is [Ir{dFCF3ppy}2(bpy)]PF6); and / or The metal catalyst is nickel(II) chloride ethylene glycol dimethyl ether complex; and / or The ligand is 4,4'-di-tert-butyl-2,2'-bipyridyl; and / or The base is dipotassium phosphate; and / or The light source is a blue LED; and / or In method (d) L 1 It's a halogen.

44. A method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 42, wherein the compound of formula (A) Among them, X, R 1 , R 2 , R 3 , Z and P as defined in claim 42, is produced by: making a compound of formula (X') or a protected derivative thereof: Where R 1 As defined in claim 42, P represents a protecting group or is hydrogen, and L 1 and L 2 independently represent a leaving group, Reaction with a compound of formula (D) or a protected derivative thereof: Among them, X, R 2 and R 3 As defined in claim 42.

45. A method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 44, wherein P represents 2-tetrahydropyran, THP, 2-(trimethylsilyl)ethoxymethyl or SEM; and / or L 1 and L 2 independently represents a halide.

Images