Compounds and compositions as sppl2a inhibitors

Abstract

The present invention relates to tricyclic compounds comprising a diazepinone moiety that effectively inhibit Sppl2a (signal peptide peptidase-like protease 2a), pharmaceutical compositions containing such inhibitors, and methods of using such inhibitors and compositions.

Description

[0001] This application is a divisional application of Chinese patent application No. 202180074962.X (filed on September 15, 2021, entitled "Compounds and Compositions as Sppl2a Inhibitors"). Technical Field

[0002] This invention relates to a dinitrate-containing method for effectively inhibiting signal peptidase-like protease 2a (Sppl2a). Tricyclic compounds with a ketone moiety, pharmaceutical compositions containing such inhibitors, methods for synthesizing the novel derivatives, and methods for using such inhibitors and compositions. Background Technology

[0003] The protein Sppl2a appears to affect the function of a variety of immune cells by cleaving different transmembrane anchoring proteins, thereby playing a role in both innate and adaptive immunity.

[0004] Sppl2a was initially described as a protease that controls the release of IL-12 from dendritic cells by partially cleaving the transmembrane portion of TNF-α. Recent observations suggest that Sppl2a may be involved in the processing of CD74, also known as the invariant chain, a crucial mediator of antigen presentation via class II molecules, allowing the differentiation between foreign and autoantigens. Many autoimmune diseases may evolve when the immune system loses its ability to distinguish between "self" and "non-self" antigens. A recent publication by D. Beisner et al., "The intramembrane protease Sppl2a is required for B cell and DC development and survival via cleavage of the invariant chain," J. Exp. Med. 210, pp. 23-39, 2013, describes the cleavage of CD74 by Sppl2a. Inhibition of this process in mice resulted in a significant reduction in the number of mature B cells and myeloid dendritic cells. Scientific literature further indicates that inhibition of Sppl2a leads to the accumulation of the N-terminal fragment of CD74 (p8) in intracellular compartments, thereby inducing B cell and myeloid dendritic cell death. Although little is known about the molecular details of Sppl2a processing and B cell / myeloid dendritic cell disappearance, the accumulation of unprocessed CD74 appears to impair T cell-dependent antibody responses in mice. Inhibition of this protease may be associated with suppressing harmful, uncontrolled immune responses, such as autoantibodies, which may be crucial pathological conditions in autoimmune diseases. Sppl2a inhibition may also affect the proliferation of B-cell lymphomas, which appears to be associated with high levels of CD74 expression.

[0005] Therefore, potent and generally selective inhibitors of Sppl2a may represent a novel and attractive mechanistic pathway for treating diseases and / or disorders, particularly those of the immune system. Summary of the Invention

[0006] In one aspect, the present invention therefore provides compounds of formula (I) or pharmaceutically acceptable salts thereof.

[0007] (I)

[0008] in:

[0009] Y is CH2 or C=O;

[0010] Y is CH2 or C=O;

[0011] R1 is H, C1-C6 alkyl, or halogen;

[0012] R2 is H or a halogen;

[0013] R3 is H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkyl-phenyl or C1-C6 alkyl substituted with C1-C6 alkoxy;

[0014] R4 is H, C1-C6 alkyl, or C1-C6 alkyl-phenyl;

[0015] R 10 It is -NHC(=O)R5, -C(=O)NHR5 or a 9- or 10-membered bicyclic heteroaryl group having 1 to 4 heteroatoms each independently selected from N, O and S as ring members, wherein the bicyclic heteroaryl group is unsubstituted or the bicyclic heteroaryl group is substituted by one or more R6 groups.

[0016] R5 is a 5-membered heteroaryl group having one, two, or three heteroatoms, each independently selected from N, O, and S, as ring members, wherein the 5-membered heteroaryl group is unsubstituted or substituted by one or more substituents independently selected from:

[0017] i) Halogens;

[0018] ii) Amino;

[0019] iii) C3-C6 cycloalkyl groups optionally substituted with one or more halogens;

[0020] iv) C3-C6 cycloalkenyl;

[0021] v) C1-C6 alkyl groups optionally substituted with C1-C6 alkoxy, C3-C6 cycloalkyl, or phenyl groups;

[0022] vi) C1-C6 haloalkyl groups;

[0023] vii) -NHC(=O)C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with a C1-C6 alkoxy group;

[0024] viii) -NHC(=O)-C1-C6 haloalkyl;

[0025] ix) -NHC(=O)-C3-C6 cycloalkyl;

[0026] x)-C(=O)NH-C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with a C1-C6 alkoxy group;

[0027] xi) -C(=O)NH-C1-C6 haloalkyl;

[0028] xii) -C(=O)NH-C3-C6 cycloalkyl;

[0029] xiii) -NHC(=O)phenyl, wherein the phenyl group is optionally substituted with one or more substituents independently selected from halogens and C1-C6 alkyl groups;

[0030] xiv) -C(=O)NHphenyl, wherein the phenyl group is optionally substituted with one or more substituents independently selected from halogens and C1-C6 alkyl groups;

[0031] xv) C1-C6 alkoxy or C1-C6 haloalkoxy;

[0032] xvi) phenoxy group optionally substituted with one or more halogens;

[0033] xvii) Phenyl group optionally substituted with one or more substituents independently selected from halogen, -CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy and C1-C6 haloalkyl;

[0034] xviii) A 4- to 6-membered heterocyclic group optionally substituted with an oxo group, a -C(=O)OC1-C6 alkyl group or a -C(=O)OC1-C6 cycloalkyl group;

[0035] xix) a 5- or 6-membered heteroaryl group having one or two heteroatoms, each independently selected from N, O, and S, as ring members, wherein the heteroaryl group is unsubstituted or substituted by one or more substituents independently selected from: C1-C6 alkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, 4- to 6-membered heterocyclic group, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, and C1-C6 alkyl groups optionally substituted with -OH, C1-C6 alkoxy, or optionally substituted with an oxo group; and

[0036] xx) A 9- or 10-membered bicyclic heteroaryl group having 1 to 4 heteroatoms, each independently selected from N, O and S, as ring members, wherein the heteroaryl group is unsubstituted or substituted by one or more substituents independently selected from: C1-C6 alkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, 4- to 6-membered heterocyclic group, C3-C6 cycloalkyl, C3-C6 cycloalkenyl and C1-C6 alkyl optionally substituted with C1-C6 alkoxy;

[0037] Each R6 is independently selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, cyano, and halogen;

[0038] R 11 It is H, C1-C6 alkyl, or halogen;

[0039] or

[0040] R1 and R 11 Together with the carbon atoms they are attached to, they can form 3- to 6-membered carbon rings.

[0041] As used herein, the serpentine lines in the compound of formula (I) characterizing the chemical bond to substituent R4 indicate two (2) stereochemical options. In one embodiment, the stereochemistry of the carbon atom to which R4 is attached is (S), in another embodiment, the stereochemistry is (R), or in yet another embodiment, the stereochemistry is a mixture of both.

[0042] As used herein, the serpentine lines in the compound of formula (I) characterizing the chemical bond to substituent R3 indicate two (2) stereochemical options. In one embodiment, the stereochemistry of the carbon atom to which R3 is attached is (S), in another embodiment, the stereochemistry is (R), or in yet another embodiment, the stereochemistry is a mixture of both.

[0043] Another aspect of the invention is a pharmaceutical composition comprising a therapeutically effective amount of the compound of the invention or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

[0044] Another aspect of the invention is a pharmaceutical composition comprising a compound or pharmaceutically acceptable salt of the invention and one or more pharmaceutically acceptable carriers.

[0045] In another aspect, the present invention provides a method for treating or preventing a disease or condition mediated by the activity of signal peptidase-like protease 2a (Sppl2a), wherein the method comprises administering to a subject in need of treatment a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof.

[0046] In another aspect, the present invention provides a method for treating or preventing diseases or conditions mediated by the activity of signal peptidase-like protease 2a (Sppl2a), wherein the method comprises administering a compound of the present invention or a pharmaceutically acceptable salt to a subject in need of treatment.

[0047] In another aspect, the present invention provides a method for treating an autoimmune disease in a subject in need, wherein the method comprises administering to the subject a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof.

[0048] In another aspect, the present invention provides a method for treating an autoimmune disease in a subject in need, wherein the method comprises administering to the subject a compound of the present invention or a pharmaceutically acceptable salt thereof.

[0049] In another aspect, the present invention provides a method for treating an autoimmune disease in a subject of need, wherein the method comprises administering to the subject a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, and wherein the autoimmune disease is Sjoegren's disease, systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), lupus nephritis, systemic sclerosis, multiple sclerosis (MS), autoimmune hepatitis, uveitis, pemphigus vulgaris, pemphigus foliaceus, myasthenia gravis, Hashimoto's thyroiditis, thrombocytopenic purpura, myocarditis, atopic dermatitis, Goodpasture syndrome, or type I diabetes.

[0050] In another aspect, the present invention provides a method for treating an autoimmune disease in a subject of need, wherein the method comprises administering to the subject a compound of the present invention or a pharmaceutically acceptable salt thereof, and wherein the autoimmune disease is Sjögren's disease, systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), lupus nephritis, systemic sclerosis, multiple sclerosis (MS), autoimmune hepatitis, uveitis, pemphigus vulgaris, pemphigus foliaceus, myasthenia gravis, Hashimoto's thyroiditis, thrombocytopenic purpura, myocarditis, atopic dermatitis, Goodpassuia syndrome, or type I diabetes.

[0051] In another aspect, the present invention provides a method for treating graft-versus-host disease (GvHD) in a subject, wherein the method comprises administering to the subject a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof. In some embodiments, the graft-versus-host disease (GvHD) is acute graft-versus-host disease, while in other embodiments, the graft-versus-host disease (GvHD) is chronic graft-versus-host disease.

[0052] In another aspect, the present invention provides a method for preventing graft-versus-host disease (GvHD) in a subject, wherein the method comprises administering to the subject a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof prior to transplantation. In some embodiments, the graft-versus-host disease (GvHD) is acute graft-versus-host disease, while in other embodiments, the graft-versus-host disease (GvHD) is chronic graft-versus-host disease.

[0053] In another aspect, the present invention provides a method for treating graft-versus-host disease (GvHD) in a subject, wherein the method comprises administering to the subject a compound of the present invention or a pharmaceutically acceptable salt thereof. In some embodiments, the graft-versus-host disease (GvHD) is acute graft-versus-host disease, while in other embodiments, the graft-versus-host disease (GvHD) is chronic graft-versus-host disease.

[0054] In another aspect, the present invention provides a method for preventing graft-versus-host disease (GvHD) in a subject, wherein the method comprises administering to the subject a compound of the present invention or a pharmaceutically acceptable salt thereof prior to transplantation. In some embodiments, graft-versus-host disease (GvHD) is acute graft-versus-host disease, while in other embodiments, graft-versus-host disease (GvHD) is chronic graft-versus-host disease.

[0055] In another aspect, the present invention provides the use of the compounds of the present invention or pharmaceutically acceptable salts thereof for the manufacture of medicaments for treating diseases or conditions associated with or mediated by the activity of signal peptidase-like proteinase 2a (Sppl2a).

[0056] In another aspect, the present invention provides the use of the compounds of the present invention or pharmaceutically acceptable salts thereof for the manufacture of medicaments for the treatment of autoimmune diseases.

[0057] In another aspect, the present invention provides the use of the compounds of the present invention or pharmaceutically acceptable salts thereof for the manufacture of agents for the treatment of autoimmune diseases, wherein said autoimmune diseases are Sjögren's disease, systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), lupus nephritis, systemic sclerosis, multiple sclerosis (MS), autoimmune hepatitis, uveitis, pemphigus vulgaris, pemphigus foliaceus, myasthenia gravis, Hashimoto's thyroiditis, thrombocytopenic purpura, myocarditis, atopic dermatitis, Goodpassuia syndrome, or type I diabetes.

[0058] In another aspect, the present invention provides the use of the compounds of the present invention or pharmaceutically acceptable salts thereof for the manufacture of agents for the treatment or prevention of graft-versus-host disease (GvHD). In some embodiments, graft-versus-host disease (GvHD) is acute graft-versus-host disease, while in other embodiments, graft-versus-host disease (GvHD) is chronic graft-versus-host disease.

[0059] In another aspect, the present invention provides the use of the compounds of the present invention or pharmaceutically acceptable salts thereof for the treatment of diseases or conditions associated with or mediated by the activity of signal peptidase-like protease 2a (Sppl2a).

[0060] In another aspect, the present invention provides the use of the compounds of the present invention or pharmaceutically acceptable salts thereof for the treatment of autoimmune diseases.

[0061] In another aspect, the present invention provides the use of the compounds of the present invention or pharmaceutically acceptable salts thereof for the treatment of autoimmune diseases, said autoimmune diseases being Sjögren's disease, systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), lupus nephritis, systemic sclerosis, multiple sclerosis (MS), autoimmune hepatitis, uveitis, pemphigus vulgaris, pemphigus foliaceus, myasthenia gravis, Hashimoto's thyroiditis, thrombocytopenic purpura, myocarditis, atopic dermatitis, Goodpassuia syndrome, or type I diabetes.

[0062] In another aspect, the present invention provides the use of the compounds of the present invention or pharmaceutically acceptable salts thereof for the treatment or prevention of graft-versus-host disease (GvHD). In some embodiments, GvHD is acute GvHD, while in other embodiments, GvHD is chronic GvHD.

[0063] In another aspect, the present invention provides compounds of the present invention or pharmaceutically acceptable salts thereof for the treatment of diseases or conditions associated with or mediated by the activity of signal peptidase-like protease 2a (Sppl2a).

[0064] In another aspect, the present invention provides compounds of the present invention or pharmaceutically acceptable salts thereof for the treatment of autoimmune diseases.

[0065] In another aspect, the present invention provides compounds of the present invention or pharmaceutically acceptable salts thereof for the treatment of autoimmune diseases, wherein said autoimmune diseases are Sjögren's disease, systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), lupus nephritis, systemic sclerosis, multiple sclerosis (MS), autoimmune hepatitis, uveitis, pemphigus vulgaris, pemphigus foliaceus, myasthenia gravis, Hashimoto's thyroiditis, thrombocytopenic purpura, myocarditis, atopic dermatitis, Goodpassuia syndrome, or type I diabetes.

[0066] In another aspect, the present invention provides compounds of the present invention or pharmaceutically acceptable salts thereof for the treatment or prevention of graft-versus-host disease (GvHD). In some embodiments, GvHD is acute GvHD, while in other embodiments, GvHD is chronic GvHD. Detailed Implementation

[0067] definition

[0068] As used herein, the term "alkyl" refers to a fully saturated branched or straight-chain hydrocarbon having up to 20 carbon atoms. In some embodiments, alkyl is "C1-C2 alkyl", "C1-C3 alkyl", "C1-C4 alkyl", "C1-C5 alkyl", "C1-C6 alkyl", "C1-C7 alkyl", "C1-C8 alkyl", "C1-C9 alkyl", or "C1-C6 alkyl". 10 "alkyl", where, as used herein, the terms "C1-C2 alkyl", "C1-C3 alkyl", "C1-C4 alkyl", "C1-C5 alkyl", "C1-C6 alkyl", "C1-C7 alkyl", "C1-C8 alkyl", "C1-C9 alkyl" and "C1-C 10 "Alkyl" means an alkyl group containing at least one and at most two, three, four, five, six, seven, eight, nine, or ten carbon atoms. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl.

[0069] As used herein, the term "alkoxy" refers to -O-alkyl or -alkyl-O-, where "alkyl" is as defined herein. In some embodiments, the alkoxy group is "C1-C2 alkoxy", "C1-C3 alkoxy", "C1-C4 alkoxy", "C1-C5 alkoxy", "C1-C6 alkoxy", "C1-C7 alkoxy", "C1-C8 alkoxy", "C1-C9 alkoxy" or "C1-C 10 "Alkoxy", where, as used herein, the terms "C1-C3 alkoxy", "C1-C4 alkoxy", "C1-C5 alkoxy", "C1-C6 alkoxy", "C1-C7 alkoxy", "C1-C8 alkoxy", "C1-C9 alkoxy", and "C1-C6 alkoxy" are used. 10 "Alkoxy" refers to -O-C1-C2 alkyl, -O-C1-C3 alkyl, -O-C1-C4 alkyl, -O-C1-C5 alkyl, -O-C1-C6 alkyl, -O-C1-C7 alkyl, -O-C1-C8 alkyl, -O-C1-C9 alkyl, or -O-C1-C 10 Alkyl groups. Non-limiting examples of "alkoxy" groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, isopentoxy, hexoxy, heptoxy, octoxy, nonoxy, and decoxy.

[0070] As used herein, the term "C3-C8 cycloalkyl" refers to a fully saturated monocyclic hydrocarbon ring system having 3 to 8 carbon atoms as ring members. Non-limiting examples of such "C3-C8 cycloalkyl" groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, as used herein, the term "C3-C6 cycloalkyl" refers to a fully saturated monocyclic hydrocarbon ring system having 3 to 6 carbon atoms as ring members. Non-limiting examples of such "C3-C8 cycloalkyl" groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0071] As used herein, the term "3- to 6-membered carbon ring" refers to a 3- to 6-membered saturated or partially saturated hydrocarbon ring. Non-limiting examples of such carbon ring groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.

[0072] As used herein, the term “C3-C6 cycloalkenyl” refers to a partially saturated (but non-aromatic) monocyclic hydrocarbon ring system having 3 to 6 carbon atoms as ring members.

[0073] As used herein, the term "C1-C6 alkyl-phenyl" refers to a C1-C6 alkyl group as defined above that has been substituted with a phenyl group. A non-limiting example of a C1-C6 alkyl-phenyl group is benzyl.

[0074] As used herein, the term "haloalkyl" refers to an alkyl group as defined herein, wherein at least one hydrogen atom of the alkyl group is replaced by a halogen group (as defined herein). A haloalkyl group can be a monohaloalkyl, dihaloalkyl, trihaloalkyl, or polyhaloalkyl, including perhaloalkyl. A monohaloalkyl group may have an iodine, bromine, chlorine, or fluorine atom within the alkyl group. Dihaloalkyl and polyhaloalkyl groups may have two or more identical halogen atoms or combinations of different halogen groups within the alkyl group. Typically, polyhaloalkyl groups contain up to six, four, three, or two halogen groups. Non-limiting examples of haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, and dichloropropyl. A perhaloalkyl group refers to an alkyl group in which all hydrogen atoms are replaced by halogen atoms, for example, trifluoromethyl. Unless otherwise specified, preferred haloalkyl groups include methyl and ethyl groups substituted with monofluoro, difluoro, and trifluoro compounds, such as CF3, CHF2, CH2F, CH2CHF2, and CH2CF3.

[0075] As used herein, the term "C1-C6 haloalkyl" refers to the corresponding "C1-C6 alkyl" as defined herein, wherein at least one hydrogen atom of the "C1-C6 alkyl" is substituted with a halogen group (as defined herein). A C1-C6 haloalkyl can be a mono-C1-C6 haloalkyl, wherein such a C1-C6 haloalkyl has one iodine, one bromine, one chlorine, or one fluorine atom. Alternatively, a C1-C6 haloalkyl can be a di-C1-C6 haloalkyl, wherein such a C1-C6 haloalkyl can have two halogen atoms independently selected from iodine, bromine, chlorine, or fluorine. Furthermore, a C1-C6 haloalkyl can be a poly-C1-C6 haloalkyl, wherein such a C1-C6 haloalkyl can have two or more identical halogen atoms or a combination of two or more different halogen atoms. Such a poly-C1-C6 haloalkyl can be a perhalogenated C1-C6 haloalkyl, wherein all hydrogen atoms of the corresponding C1-C6 alkyl are substituted with halogen atoms and the halogen atoms can be the same halogen atom or a combination of different halogen atoms. Non-limiting examples of “C1-C6 haloalkyl” groups include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, difluoropropyl, dichloroethyl, and dichloropropyl.

[0076] As used herein, the term "haloalkoxy" refers to an -O-haloalkyl group in which at least one hydrogen atom of the alkyl group of the alkoxy group is substituted with a halogen group (as defined herein). A haloalkoxy can be a monohaloalkoxy, dihaloalkoxy, trihaloalkoxy, or polyhaloalkoxy, including perhaloalkoxy. A monohaloalkoxy may have an iodine, bromine, chlorine, or fluorine atom within the alkyl group. Dihaloalkoxy and polyhaloalkoxy may have two or more identical halogen atoms or combinations of different halogen groups within the alkyl group. Typically, polyhaloalkoxy contains at most six, four, three, or two halogen groups. Non-limiting examples of haloalkoxy include fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, trichloromethoxy, pentafluoroethoxy, heptafluoropropoxy, difluorochloromethoxy, dichlorofluoromethoxy, difluoroethoxy, difluoropropoxy, dichloroethoxy, and dichloropropoxy. A perhaloalkoxy is an alkoxy in which all hydrogen atoms are substituted with halogen atoms, for example, trifluoromethoxy. Unless otherwise specified, preferred haloalkoxy groups include methoxy and ethoxy groups substituted with monofluoro, difluoro, and trifluoro groups, such as -OCF3, -OCHF2, -OCH2F, -OCH2CHF2, and -OCH2CF3.

[0077] As used herein, the term "C1-C6 haloalkoxy" refers to a -O-C1-C6 haloalkyl group, wherein at least one hydrogen atom of the "C1-C6 alkyl" group of the "C1-C6 alkoxy" is substituted with a halogen group (as defined herein). A C1-C6 haloalkoxy can be a mono-C1-C6 haloalkoxy, wherein such a C1-C6 haloalkoxy has one iodine, one bromine, one chlorine, or one fluorine atom. Alternatively, a C1-C6 haloalkoxy can be a di-C1-C6 haloalkoxy, wherein such a C1-C6 haloalkoxy can have two halogen atoms independently selected from iodine, bromine, chlorine, or fluorine. Furthermore, a C1-C6 haloalkoxy can be a poly-C1-C6 haloalkoxy, wherein such a C1-C6 haloalkoxy can have two or more identical halogen atoms or combinations of two or more different halogen atoms. Such poly(C1-C6) haloalkoxy groups can be perhaloC1-C6 haloalkoxy groups, wherein all hydrogen atoms of the corresponding C1-C6 alkoxy group are replaced by halogen atoms and the halogen atoms can be the same halogen atom or a combination of different halogen atoms. Non-limiting examples of "C1-C6 haloalkoxy" groups include fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, trichloromethoxy, pentafluoroethoxy, heptafluoropropoxy, difluorochloromethoxy, dichlorofluoromethoxy, fluoroethoxy, difluoroethoxy, trifluoroethoxy, difluoropropoxy, dichloroethoxy, and dichloropropoxy.

[0078] As used herein, the terms “halogen” or “halogen group” refer to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).

[0079] As used in this article, the term "heteroatom" refers to a nitrogen (N), oxygen (O), or sulfur (S) atom.

[0080] As used herein, the term "heteroaryl" refers to an aromatic ring system containing one or more heteroatoms. Heteroaryl rings containing more than one heteroatom may contain different heteroatoms. Heteroaryl rings can be monocyclic or fused bicyclic systems. Monocyclic heteroaryl rings have 5 to 6 ring atoms. Bicyclic heteroaryl rings have 7 to 12 ring member atoms. Bicyclic heteroaryl rings include those ring systems in which the heteroaryl ring is fused to a phenyl ring. As used herein, non-limiting examples of heteroaryl rings include benzofuranyl, benzo[c]thiophenyl, benzothiophenyl, and benzo[c] ... Azolyl, benzothiazolyl, benzimidazolyl, cenyl, furazolyl, furanyl, imidazolyl, indoleyl, indoleazinyl, indoleyl, isoindoleyl, isoquinolinyl, iso azole group, isothiazol group, azole group, Indole, Diazole groups (including 1, 3, 4-) diazole group and 1,2,4- Diazolyl), purine, pyrazolyl, pyrroleyl, phthalazinyl, pyridyl (including 2-pyridyl, 3-pyridyl and 4-pyridyl), pyridazinyl, pyrazinyl, pyrimidinyl, quinyl Linoyl, quinolinyl, quinazolinyl, tetrazinyl, tetrazolyl, tetrazono[1,5-a]pyridyl, thiazolyl, thiadiazolyl (including 1,3,4-thiadiazolyl), thienyl, triazinyl, and triazolyl.

[0081] As used herein, the term "5-membered heteroaryl" refers to an aromatic 5-membered monocyclic system having one, two, or three heteroatoms as ring members, wherein each heteroatom is independently selected from N, O, and S. Non-limiting examples of such 5-membered heteroaryls, as used herein, include furanyl, imidazolyl, and isoaryl groups. azole group, isothiazol group, Azolyl, pyrroleyl, pyrazolyl, thiadiazolyl, thiazolyl, thiopheneyl, and triazolyl. In some embodiments, as used herein, "5-membered heteroaryl" refers to an aromatic 5-membered monocyclic system having one or two heteroatoms as ring members, wherein each heteroatom is independently selected from N, O, and S. Non-limiting examples of such 5-membered heteroaryls as used herein include furanyl, imidazolyl, iso... azole group, isothiazol group, Azolyl, pyrroleyl, pyrazolyl, thiadiazoleyl, thiazolyl, thiophenyl, and triazoleyl.

[0082] As used herein, the term "6-membered heteroaryl" refers to an aromatic 6-membered monocyclic system having one, two, or three heteroatoms as ring members, wherein each heteroatom is independently selected from N, O, and S. Non-limiting examples of such 6-membered heteroaryls, as used herein, include pyridyl, pyrazinyl, pyrazinyl, pyrimidinyl, and triazinyl. In some embodiments, as used herein, the term "6-membered heteroaryl" refers to an aromatic 6-membered monocyclic system having one or two heteroatoms as ring members, wherein each heteroatom is independently selected from N, O, and S. Non-limiting examples of such 6-membered heteroaryls, as used herein, include pyridyl, pyrazinyl, and pyrimidinyl.

[0083] As used herein, the term "9- or 10-membered bicyclic heteroaryl" refers to a 9- or 10-membered fused bicyclic aromatic ring system having 1, 2, 3, or 4 heteroatoms as ring members, wherein each heteroatom is independently selected from N, O, and S. Non-limiting examples of such bicyclic heteroaryl groups, as used herein, include indole, quinolinyl, isoquinolinyl, indazolyl, purine, phthalazinyl, naphthidyl, quinazolinyl, cenolinyl, thieno[2,3-b]furanyl, 1H-pyrazolo[4,3-d]- Azolyl, imidazo[2,1-b]thiazolyl, pyrazino[2,3-d]pyridazinyl, imidazo[1,2-b][1,2,4]triazinyl, benzo[] Azolyl, benzimidazolyl, imidazopyridyl, and benzothiazolyl. In some embodiments, this bicyclic heteroaryl group is 1H-benzo[d]imidazolyl or 1H-imidazo[4,5-c]pyridyl.

[0084] As used herein, the term "4-6 membered heterocyclic group" refers to a 4- to 6-membered saturated or partially saturated hydrocarbon ring containing one to two heteroatoms as ring members, each heteroatom being independently selected from N, NH, NR. A , O or S, where R AIt is an H, C1-C6 alkyl, or C3-C8 cycloalkyl. The heterocyclic group may be attached to another group at the nitrogen or carbon atom. Non-limiting examples of 4-6 membered heterocyclic alkyl groups as used herein include azirrobutane, azirrobutane-1-yl, azirrobutane-2-yl, azirrobutane-3-yl, oxetane, oxetane-2-yl, oxetane-3-yl, oxetane-4-yl, thioheterobutane, thioheterobutane-2-yl, thioheterobutane-3-yl, thioheterobutane-4-yl, pyrrolidinyl, pyrrolidin-1-yl, pyrrolidin-2-yl, and pyrrolidinyl... Alkyl-3-yl, pyrrolidine-4-yl, pyrrolidine-5-yl, tetrahydrofuranyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrofuran-4-yl, tetrahydrofuran-5-yl, tetrahydrothiophenyl, tetrahydrothiophene-2-yl, tetrahydrothiophene-3-yl, tetrahydrothiophene-4-yl, tetrahydrothiophene-5-yl, piperidinyl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperidin-5-yl, piperidin-6-yl, tetrahydropyranyl Tetrahydropyran-2-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, tetrahydropyran-5-yl, tetrahydropyran-6-yl, tetrahydrothiaranyl, tetrahydrothiaran-2-yl, tetrahydrothiaran-3-yl, tetrahydrothiaran-4-yl, tetrahydrothiaran-5-yl, tetrahydrothiaran-6-yl, piperazinyl, piperazin-1-yl, piperazin-2-yl, piperazin-3-yl, piperazin-4-yl, piperazin-5-yl, piperazin-6-yl, morpholinyl, morpholin-2-yl, morpholin-3-yl, morpholin-4-yl, morpholin-5-yl, morpholin-6 -yl, thiomorpholinyl, thiomorpholin-2-yl, thiomorpholin-3-yl, thiomorpholin-4-yl, thiomorpholin-5-yl, thiomorpholin-6-yl, oxothiocyclohexyl, oxothiocyclohexane-2-yl, oxothiocyclohexane-3-yl, oxothiocyclohexane-5-yl, oxothiocyclohexane-6-yl, dithiaalkyl, dithiaalkyl-2-yl, dithiaalkyl-3-yl, dithiaalkyl-5-yl, dithiaalkyl-6-yl, dioxacyclopentyl, dioxacyclopentyl-2-yl, dioxacyclopentyl-4-yl, dioxacyclopentyl-5-yl, thia Alkyl, thia Alkyl-2-yl, thia Alkyl-3-yl, thia Alkyl-4-yl, thia Alkyl-5-yl, dithiacyclopentyl, dithiacyclopentan-2-yl, dithiacyclopentan-4-yl, dithiacyclopentan-5-yl, pyrazolyl, pyrazolidine-1-yl, pyrazolidine-2-yl, pyrazolidine-3-yl, pyrazolidine-4-yl, pyrazolidine-5-yl, 2-azabicyclo[4.2.0]octyl, octahydro-1H-cyclopentadien[b]pyridine, and decahydroquinoline.

[0085] As used herein, the term "isomer" refers to different compounds having the same molecular formula but different atomic arrangements and configurations. Similarly, as used herein, the terms "optical isomer" or "stereoisomer" refer to any of the various stereoisomeric configurations that a given compound of the present invention may exist in, and include geometric isomers. It should be understood that substituents can be attached at the chiral center of a carbon atom. The term "chiral" refers to a molecule having non-overlapping properties on its mirror-image partner, while the term "chiral" refers to a molecule that can overlap on its mirror-image partner. Therefore, the present invention includes enantiomers, diastereomers, or racemates of compounds. An "enantiomer" is a pair of stereoisomers that are non-overlapping mirror images of each other. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. This term is used to specify racemic mixtures where appropriate. A "diastereomer" is a stereoisomer having at least two asymmetric atoms but not being mirror images of each other. Absolute stereochemistry is specified according to the Cahn-Ingold-Prelog RS system. When the compound is a pure enantiomer, the stereochemistry of each chiral carbon can be specified by R or S. Resolved compounds with unknown absolute configuration can be specified as (+) or (-), depending on the direction (dextrorotatory or levorotatory) in which they rotate plane-polarized light at the wavelength of the sodium D line. Based on absolute stereochemistry, some compounds described herein contain one or more asymmetric centers or axes, and thus can produce enantiomers, diastereomers, and other definable stereoisomers such as (R)- or (S)-.

[0086] As used herein, the term "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delay agents, salts, preservatives, pharmaceutical stabilizers, binders, excipients, disintegrants, lubricants, sweeteners, flavorings, dyes, and combinations thereof, as known to those skilled in the art (see, for example, Remington's Pharmaceutical Sciences, 18th edition, Mack Printing Company, 1990, pp. 1289-1329). Unless any conventional carrier is incompatible with the active ingredient, its use in therapeutic or pharmaceutical compositions is contemplated.

[0087] The term "therapeuticly effective amount" for the compounds of the present invention refers to an amount in which the compounds of the present invention will elicit a biological or medical response in a subject (e.g., a reduction or inhibition of enzyme or protein activity), or improve symptoms, alleviate ailments, slow or delay disease progression, or prevent disease, etc. In one non-limiting embodiment, the term "therapeuticly effective amount" refers to an amount in which the compounds of the present invention, when administered to a subject, effectively achieve: (1) at least partially alleviate, inhibit, prevent, and / or improve (i) ailments or conditions mediated by Sppl2a, or (ii) ailments or conditions associated with or mediated by Sppl2a activity, or (iii) ailments or conditions characterized by (normal or abnormal) Sppl2a activity; (2) reduce or inhibit Sppl2a activity; or (3) reduce or inhibit Sppl2a expression. In another non-limiting embodiment, the term "therapeuticly effective amount" refers to an amount in which the compounds of the present invention, when administered to cells or tissues or non-cellular biological materials or media, effectively achieve: at least partially reduce or inhibit Sppl2a activity; or at least partially reduce or inhibit Sppl2a expression.

[0088] As used herein, the term "subject" can refer to an animal. An animal can be a mammal. A subject also refers to, for example, primates (e.g., humans, males or females), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In some embodiments, the subject is a primate. In other embodiments, the subject is a human.

[0089] As used herein, the term “inhibition” refers to a reduction or suppression of a given ailment, symptom, or condition or disease, or a significant decrease in the baseline activity of a biological activity or process.

[0090] As used herein, the term "treatment" for any disease or condition, in one embodiment, means improving the disease or condition (i.e., slowing or halting or reducing the development of the disease or at least one of its clinical symptoms). In another embodiment, "treatment" means reducing or improving at least one bodily parameter, including those that may not be identifiable by the patient. In yet another embodiment, "treatment" means regulating the disease or condition physically (e.g., stabilization of identifiable symptoms), physiologically (e.g., stabilization of bodily parameters), or in both aspects.

[0091] As used in this article, the term "prevention" refers to delaying the onset, development, or progression of a disease or condition.

[0092] As used in this article, a subject “needs” such treatment if the subject will benefit from it biologically, medically, or in terms of quality of life.

[0093] Unless otherwise indicated herein or clearly contradicted by the context, the terms “a,” “an,” “the,” and similar terms used herein, in the context of the invention (especially in the context of the claims), shall be interpreted to cover both the singular and the plural.

[0094] Unless otherwise specified, the term “compound of the present invention” refers to one or more compounds of formula (I), formula (II), formula (III), formula (IV) and their sub-formulas (such as formula (IIA), formula (IIB), formula (IIC), formula (IID), formula (IIIA), formula (IIIB), formula (IIIC) and formula (IIID)), as well as example compounds and salts thereof, and all their stereoisomers (including diastereomers and enantiomers).

[0095] This document describes various enumerated embodiments of the invention. It will be appreciated that the features specified in each embodiment can be combined with other specified features to provide further embodiments of the invention.

[0096] The compounds of the present invention

[0097] This invention provides compounds of formula (I) or pharmaceutically acceptable salts or stereoisomers thereof.

[0098] (I)

[0099] in:

[0100] Y is CH2 or C=O;

[0101] R1 is H, C1-C6 alkyl, or halogen;

[0102] R2 is H or a halogen;

[0103] R3 is H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkyl-phenyl or C1-C6 alkyl substituted with C1-C6 alkoxy;

[0104] R4 is H, C1-C6 alkyl, or C1-C6 alkyl-phenyl;

[0105] R 10 It is a bicyclic 7- to 12-membered heteroaryl ring of -NHC(=O)R5, -C(=O)NHR5, or having 2 to 4 heteroatoms, each independently selected from N, O, and S, as ring members, wherein the bicyclic heteroaryl group is unsubstituted or the bicyclic heteroaryl group is substituted with one or more R6 groups.

[0106] R5 is a 5-membered heteroaryl group having one, two, or three heteroatoms, each independently selected from N, O, and S, as ring members, wherein the 5-membered heteroaryl group is unsubstituted or substituted by one or more substituents independently selected from:

[0107] i) Halogens;

[0108] ii) Amino;

[0109] iii) C3-C6 cycloalkyl groups optionally substituted with one or more halogens;

[0110] iv) C3-C6 cycloalkenyl;

[0111] v) C1-C6 alkyl groups optionally substituted with C1-C6 alkoxy, C3-C6 cycloalkyl, or phenyl groups;

[0112] vi) C1-C6 haloalkyl groups;

[0113] vii) -NHC(=O)C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with a C1-C6 alkoxy group;

[0114] viii) -NHC(=O)-C1-C6 haloalkyl;

[0115] ix) -NHC(=O)-C3-C6 cycloalkyl;

[0116] x)-C(=O)NH-C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with a C1-C6 alkoxy group;

[0117] xi) -C(=O)NH-C1-C6 haloalkyl;

[0118] xii) -C(=O)NH-C3-C6 cycloalkyl;

[0119] xiii) -NHC(=O)phenyl, wherein the phenyl group is optionally substituted with one or more substituents independently selected from halogens and C1-C6 alkyl groups;

[0120] xiv) -C(=O)NHphenyl, wherein the phenyl group is optionally substituted with one or more substituents independently selected from halogens and C1-C6 alkyl groups;

[0121] xv) C1-C6 alkoxy or C1-C6 haloalkoxy;

[0122] xvi) phenoxy group optionally substituted with one or more halogens;

[0123] xvii) Phenyl group optionally substituted with one or more substituents independently selected from halogen, -CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy and C1-C6 haloalkyl;

[0124] xviii) A 4- to 6-membered heterocyclic group optionally substituted with an oxo group, a -C(=O)OC1-C6 alkyl group or a -C(=O)OC1-C6 cycloalkyl group;

[0125] xix) a 5- or 6-membered heteroaryl group having one or two heteroatoms, each independently selected from N, O, and S, as ring members, wherein the heteroaryl group is unsubstituted or substituted by one or more substituents independently selected from: C1-C6 alkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, 4- to 6-membered heterocyclic group, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, and C1-C6 alkyl groups optionally substituted with -OH, C1-C6 alkoxy, or optionally substituted with an oxo group; and

[0126] xx) A 9- or 10-membered bicyclic heteroaryl group having 1 to 4 heteroatoms, each independently selected from N, O and S, as ring members, wherein the heteroaryl group is unsubstituted or substituted by one or more substituents independently selected from: C1-C6 alkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, 4- to 6-membered heterocyclic group, C3-C6 cycloalkyl, C3-C6 cycloalkenyl and C1-C6 alkyl optionally substituted with C1-C6 alkoxy;

[0127] Each R6 is independently selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, cyano, and halogen;

[0128] R 11 It is H, C1-C6 alkyl, or halogen;

[0129] or

[0130] R1 and R 11 Together with the carbon atoms they are attached to, they can form 3- to 6-membered carbon rings.

[0131] This document describes various embodiments of the compounds of the present invention. It will be appreciated that the features specified in each embodiment can be combined with other specified features to provide further embodiments. The embodiments listed below represent compounds of formula (I) of the present invention.

[0132] Implementation Scheme 1. A compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof,

[0133] (I)

[0134] in:

[0135] Y is CH2 or C=O;

[0136] R1 is H, C1-C6 alkyl, or halogen;

[0137] R2 is H or a halogen;

[0138] R3 is H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkyl-phenyl or C1-C6 alkyl substituted with C1-C6 alkoxy;

[0139] R4 is H, C1-C6 alkyl, or C1-C6 alkyl-phenyl;

[0140] R 10 It is -NHC(=O)R5, -C(=O)NHR5 or a 9- or 10-membered bicyclic heteroaryl group having 1 to 4 heteroatoms each independently selected from N, O and S as ring members, wherein the bicyclic heteroaryl group is unsubstituted or the bicyclic heteroaryl group is substituted by one or more R6 groups.

[0141] R5 is a 5-membered heteroaryl group having one, two, or three heteroatoms, each independently selected from N, O, and S, as ring members, wherein the 5-membered heteroaryl group is unsubstituted or substituted by one or more substituents independently selected from:

[0142] i) Halogens;

[0143] ii) Amino;

[0144] iii) C3-C6 cycloalkyl groups optionally substituted with one or more halogens;

[0145] iv) C3-C6 cycloalkenyl;

[0146] v) C1-C6 alkyl groups optionally substituted with C1-C6 alkoxy, C3-C6 cycloalkyl, or phenyl groups;

[0147] vi) C1-C6 haloalkyl groups;

[0148] vii) -NHC(=O)C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with a C1-C6 alkoxy group;

[0149] viii) -NHC(=O)-C1-C6 haloalkyl;

[0150] ix) -NHC(=O)-C3-C6 cycloalkyl;

[0151] x)-C(=O)NH-C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with a C1-C6 alkoxy group;

[0152] xi) -C(=O)NH-C1-C6 haloalkyl;

[0153] xii) -C(=O)NH-C3-C6 cycloalkyl;

[0154] xiii) -NHC(=O)phenyl, wherein the phenyl group is optionally substituted with one or more substituents independently selected from halogens and C1-C6 alkyl groups;

[0155] xiv) -C(=O)NHphenyl, wherein the phenyl group is optionally substituted with one or more substituents independently selected from halogens and C1-C6 alkyl groups;

[0156] xv) C1-C6 alkoxy or C1-C6 haloalkoxy;

[0157] xvi) phenoxy group optionally substituted with one or more halogens;

[0158] xvii) Phenyl group optionally substituted with one or more substituents independently selected from halogen, -CN, C1-C6 alkyl, C1-C6 alkoxy and C1-C6 haloalkyl;

[0159] xviii) A 4- to 6-membered heterocyclic group optionally substituted with an oxo group, a -C(=O)OC1-C6 alkyl group or a -C(=O)OC1-C6 cycloalkyl group;

[0160] xix) a 5- or 6-membered heteroaryl group having one or two heteroatoms, each independently selected from N, O, and S, as ring members, wherein the heteroaryl group is unsubstituted or substituted by one or more substituents independently selected from: C1-C6 alkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, 4- to 6-membered heterocyclic group, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, and C1-C6 alkyl groups optionally substituted with -OH, C1-C6 alkoxy, or optionally substituted with an oxo group; and

[0161] xx) A 9- or 10-membered bicyclic heteroaryl group having 1 to 4 heteroatoms, each independently selected from N, O and S, as ring members, wherein the heteroaryl group is unsubstituted or substituted by one or more substituents independently selected from: C1-C6 alkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, 4- to 6-membered heterocyclic group, C3-C6 cycloalkyl, C3-C6 cycloalkenyl and C1-C6 alkyl optionally substituted with C1-C6 alkoxy;

[0162] Each R6 is independently selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, cyano, and halogen;

[0163] R 11 It is H, C1-C6 alkyl, or halogen;

[0164] or

[0165] R1 and R 11 Together with the carbon atoms they are attached to, they can form 3- to 6-membered carbon rings.

[0166] Implementation Scheme 2. The compound as described in Implementation Scheme 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 10 It is -NHC(=O)R5.

[0167] Implementation Scheme 3. The compound as described in Implementation Scheme 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 10 It is -C(=O)NHR5.

[0168] Implementation Scheme 4. The compound as described in Implementation Scheme 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 10 It is a 9- or 10-membered bicyclic heteroaryl group having 1 to 4 heteroatoms, each independently selected from N, O and S, as ring members, wherein the bicyclic heteroaryl group is unsubstituted or the bicyclic heteroaryl group is substituted with one or more R6 atoms.

[0169] Implementation Scheme 5. The compound as described in Implementation Scheme 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 10 yes

[0170] or ,

[0171] R6 is H, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, cyano, or halogen.

[0172] Implementation Scheme 6. The compound of any one of Implementation Schemes 1 to 4, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R4 is H.

[0173] Implementation Scheme 7. The compound of any one of Implementation Schemes 1 to 4 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R4 is a C1-C6 alkyl group.

[0174] Implementation Scheme 8. The compound of any one of Implementation Schemes 1 to 4 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R4 is a C1-C6 alkyl-phenyl.

[0175] Implementation Scheme 9. The compound as described in Implementation Scheme 1, or a pharmaceutically acceptable salt or stereoisomer thereof, said compound having the structure of formula (II).

[0176] (II).

[0177] Implementation Scheme 10. The compound as described in Implementation Scheme 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound has the structure of formula (III).

[0178] (III).

[0179] Implementation Scheme 11. The compound as described in Implementation Scheme 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound has the structure of formula (IV):

[0180] (IV).

[0181] Implementation Scheme 12. The compound of any one of Implementation Schemes 1 to 11 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R1 is H.

[0182] Implementation Scheme 13. The compound of any one of Implementation Schemes 1 to 11 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R1 is a C1-C6 alkyl group.

[0183] Implementation Scheme 14. The compound of any one of Implementation Schemes 1 to 11 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R1 is a halogen.

[0184] Implementation Scheme 15. The compound of any one of Implementation Schemes 1 to 11, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 11 It is H.

[0185] Implementation Scheme 16. The compound of any one of Implementation Schemes 1 to 11, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 11 It is a C1-C6 alkyl group.

[0186] Implementation Scheme 17. The compound of any one of Implementation Schemes 1 to 11, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 11 It is halogen.

[0187] Implementation Scheme 18. The compound of any one of Implementation Schemes 1 to 11, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R1 and R... 11 Together with the carbon atoms they are attached to, they form 3- to 6-membered carbon rings.

[0188] Implementation Scheme 19. The compound of any one of Implementation Schemes 1 to 11, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R1 and R 11 Together with the carbon atoms they are attached to, they form a cyclopropyl ring.

[0189] Implementation Scheme 20. The compound of any one of Implementation Schemes 1 to 19 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R2 is H.

[0190] Implementation Scheme 21. The compound of any one of Implementation Schemes 1 to 19 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R2 is a halogen.

[0191] Implementation Scheme 22. The compound of any one of Implementation Schemes 1 to 19 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R2 is F.

[0192] Implementation Scheme 23. A compound as described in Implementation Scheme 1 or Implementation Scheme 9, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound has the structure of formula (IIA):

[0193] (IIA).

[0194] Implementation Scheme 24. A compound as described in Implementation Scheme 1 or Implementation Scheme 9, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound has the structure of formula (IIB):

[0195] (IIB).

[0196] Implementation Scheme 25. A compound as described in Implementation Scheme 1 or Implementation Scheme 9, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound has the structure of formula (IIC):

[0197] (IIC).

[0198] Implementation Scheme 26. A compound as described in Implementation Scheme 1 or Implementation Scheme 9, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound has the structure of formula (IID):

[0199] (IID).

[0200] Implementation Scheme 27. A compound or a pharmaceutically acceptable salt or stereoisomer thereof as described in Implementation Scheme 1 or Implementation Scheme 9, said compound having a structure of formula (IIA), formula (IIB), formula (IIC), or formula (IID):

[0201]

[0202] (IIA)(IIB)

[0203]

[0204] (IIC)(IID).

[0205] Implementation Scheme 28. A compound as described in Implementation Scheme 1 or Implementation Scheme 10, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound has the structure of formula (IIIA):

[0206] (IIIA).

[0207] Implementation Scheme 29. A compound as described in Implementation Scheme 1 or Implementation Scheme 10, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound has the structure of formula (IIIB):

[0208] (IIIB)

[0209] Implementation Scheme 30. A compound as described in Implementation Scheme 1 or Implementation Scheme 10, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound has the structure of formula (IIIC):

[0210] (IIIC).

[0211] Implementation Scheme 31. A compound as described in Implementation Scheme 1 or Implementation Scheme 10, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound has the structure of formula (IIID):

[0212] (IIID).

[0213] Implementation Scheme 32. A compound as described in Implementation Scheme 1 or Implementation Scheme 10, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound has a structure of formula (IIIA), (IIIB), (IIIC) or (IIID):

[0214]

[0215] (IIIA)(IIIB)

[0216]

[0217] (IIIC)(IIID).

[0218] Implementation Scheme 33. The compound of any one of Implementation Schemes 1 to 32 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3 is H.

[0219] Implementation Scheme 34. The compound of any one of Implementation Schemes 1 to 32 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3 is a C1-C6 alkyl group.

[0220] Implementation Scheme 35. The compound of any one of Implementation Schemes 1 to 32 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3 is methyl, ethyl, propyl or isopropyl.

[0221] Implementation Scheme 36. The compound of any one of Implementation Schemes 1 to 32 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3 is a C1-C6 haloalkyl group.

[0222] Implementation Scheme 37. The compound of any one of Implementation Schemes 1 to 32 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3 is CF3.

[0223] Implementation Scheme 38. The compound of any one of Implementation Schemes 1 to 32 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3 is a C1-C6 alkyl-phenyl.

[0224] Implementation Scheme 39. The compound of any one of Implementation Schemes 1 to 32 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3 is -CH2-phenyl.

[0225] Implementation Scheme 40. The compound of any one of Implementation Schemes 1 to 32 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3 is a C3-C6 cycloalkyl group.

[0226] Implementation Scheme 41. The compound of any one of Implementation Schemes 1 to 32 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3 is cyclopropyl or cyclobutyl.

[0227] Implementation Scheme 42. The compound of any one of Implementation Schemes 1 to 32 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3 is a C1-C6 alkyl group substituted with a C1-C6 alkoxy group.

[0228] Implementation Scheme 43. The compound of any one of Implementation Schemes 1 to 32 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3 is -CH2CH2OCH3.

[0229] Implementation Scheme 44. The compound of any one of Implementation Schemes 1 to 43 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R5 is a 5-membered heteroaryl having 1, 2 or 3 heteroatoms each independently selected from N, O and S as ring members, wherein the 5-membered heteroaryl is unsubstituted.

[0230] Implementation Scheme 45. The compound of any one of embodiments 1 to 43, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R5 is a 5-membered heteroaryl group having one, two, or three heteroatoms, each independently selected from N, O, and S, as ring members, wherein the 5-membered heteroaryl group is substituted by one or more substituents independently selected from:

[0231] i) Halogens;

[0232] ii) Amino;

[0233] iii) C3-C6 cycloalkyl groups optionally substituted with one or more halogens;

[0234] iv) C3-C6 cycloalkenyl;

[0235] v) C1-C6 alkyl groups optionally substituted with C1-C6 alkoxy, C3-C6 cycloalkyl, or phenyl groups;

[0236] vi) C1-C6 haloalkyl groups;

[0237] vii) -NHC(=O)C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with a C1-C6 alkoxy group;

[0238] viii) -NHC(=O)-C1-C6 haloalkyl;

[0239] ix) -NHC(=O)-C3-C6 cycloalkyl;

[0240] x)-C(=O)NH-C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with a C1-C6 alkoxy group;

[0241] xi) -C(=O)NH-C1-C6 haloalkyl;

[0242] xii) -C(=O)NH-C3-C6 cycloalkyl;

[0243] xiii) -NHC(=O)phenyl, wherein the phenyl group is optionally substituted with one or more substituents independently selected from halogens and C1-C6 alkyl groups;

[0244] xiv) -C(=O)NHphenyl, wherein the phenyl group is optionally substituted with one or more substituents independently selected from halogens and C1-C6 alkyl groups;

[0245] xv) C1-C6 alkoxy or C1-C6 haloalkoxy;

[0246] xvi) phenoxy group optionally substituted with one or more halogens;

[0247] xvii) Phenyl group optionally substituted with one or more substituents independently selected from halogen, -CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy and C1-C6 haloalkyl;

[0248] xviii) A 4- to 6-membered heterocyclic group optionally substituted with an oxo group, a -C(=O)OC1-C6 alkyl group, or a -C(=O)OC1-C6 cycloalkyl group; and

[0249] xix) a 5- or 6-membered heteroaryl group having one or two heteroatoms, each independently selected from N, O, and S, as ring members, wherein the heteroaryl group is unsubstituted or substituted by one or more substituents independently selected from: C1-C6 alkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, 4- to 6-membered heterocyclic group, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, and C1-C6 alkyl groups optionally substituted with -OH, C1-C6 alkoxy, or optionally substituted with an oxo group; and

[0250] xx) A 9- or 10-membered bicyclic heteroaryl group having 1 to 4 heteroatoms, each independently selected from N, O and S, as ring members, wherein the heteroaryl group is unsubstituted or substituted by one or more substituents independently selected from: C1-C6 alkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, 4- to 6-membered heterocyclic group, C3-C6 cycloalkyl, C3-C6 cycloalkenyl and C1-C6 alkyl optionally substituted with C1-C6 alkoxy.

[0251] Implementation Scheme 46. The compound or a pharmaceutically acceptable salt thereof as described in any one of Implementation Schemes 1 to 43, wherein R5 is:

[0252] , or ;

[0253] in

[0254] R 5a It is a C1-C6 alkyl, C1-C6 haloalkyl, or halogen;

[0255] R 5bIt is -C(O)-NH-C1-C6 alkyl, -C(O)NH-C1-C6 haloalkyl, -C(O)NHphenyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 4- to 6-membered heterocyclic, 5- or 6-membered cycloheteroaryl; wherein the heteroaryl group is optionally substituted with halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy or C3-C6 cycloalkyl; and wherein the heterocyclic group is optionally substituted with oxo, -C(O)O-C1-C6 alkyl or -C(O)O-C3-C6 cycloalkyl; and wherein the -C(O)NHphenyl group is optionally substituted with halogen or C1-C6 alkyl;

[0256] R 5c It is a 5- or 6-membered cyclic heteroaryl group optionally substituted with halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy or C3-C6 cycloalkyl;

[0257] and

[0258] R 5d It is a C1-C6 alkyl or a C1-C6 haloalkyl.

[0259] Implementation Scheme 47. The compound of any one of Implementation Schemes 1 to 43, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R5 is

[0260] ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; or .

[0261] Implementation Scheme 48. The compound of any one of Implementation Schemes 1 to 43, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R5 is

[0262] ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; .

[0263] Implementation Scheme 49. The compound as described in Implementation Scheme 1, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein said compound is

[0264] N 2 ,4-Dimethyl-N 5 -((R)-2-methyl-3-oxo-3-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)amino)propyl)thiazole-2,5-dicarboxamide;

[0265] N-((R)-2-(((S)-5,11-dioxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)carbamoyl)-3,3,3-trifluoropropyl)-4-methyliso 5-oxazolium-5-carboxamide;

[0266] 2-Isobutamido-4-methyl-N-((R)-3,3,3-trifluoro-2-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazide -10-yl)carbamoyl)propyl)thiazolyl-5-carboxamide;

[0267] 2-Isobutamido-4-methyl-N-((R)-2-methyl-3-oxo-3-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazide -10-yl)amino)propyl)thiazole-5-carboxamide;

[0268] N 2 -(2,2-difluoroethyl)-4-methyl-N 5 -((R)-3,3,3-trifluoro-2-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)carbamoyl)propyl)thiazole-2,5-dicarboxamide;

[0269] N 5 -((R)-2-Cyclopropyl-3-oxo-3-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)amino)propyl)-N 2 -(2,2-difluoroethyl)-4-methylthiazol-2,5-dicarboxamide;

[0270] N 2 -Ethyl-4-methyl-N 5 -((R)-3,3,3-trifluoro-2-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)carbamoyl)propyl)thiazole-2,5-dicarboxamide;

[0271] N 2 -(2,2-difluoroethyl)-4-methyl-N 5 -((R)-2-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazepine -10-yl)carbamoyl)butyl)thiazole-2,5-dicarboxamide;

[0272] N 5 -((R)-2-Cyclopropyl-3-oxo-3-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)amino)propyl)-N 2 4-Dimethylthiazol-2,5-dicarboxamide;

[0273] N 2 -Ethyl-4-methyl-N 5 -((R)-2-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazepine -10-yl)carbamoyl)butyl)thiazole-2,5-dicarboxamide;

[0274] N 2 ,4-Dimethyl-N 5 -((R)-3,3,3-trifluoro-2-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)carbamoyl)propyl)thiazole-2,5-dicarboxamide;

[0275] N 5 -((R)-2-Cyclopropyl-3-oxo-3-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)amino)propyl)-N 2 -Ethyl-4-methylthiazol-2,5-dicarboxamide;

[0276] N 2 ,4-Dimethyl-N 5 -((R)-2-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazepine -10-yl)carbamoyl)butyl)thiazole-2,5-dicarboxamide;

[0277] N 2 -Isopropyl-4-methyl-N 5 -((R)-3,3,3-trifluoro-2-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)carbamoyl)propyl)thiazole-2,5-dicarboxamide;

[0278] 4-Chloro-N-((R)-2-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)carbamoyl)butyl)-2-(6-(trifluoromethyl)pyridin-3-yl)thiazolyl-5-carboxamide;

[0279] N 2 -Ethyl-4-methyl-N 5 -((R)-2-methyl-3-oxo-3-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)amino)propyl)thiazole-2,5-dicarboxamide;

[0280] 3-Methyl-N-((R)-2-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)carbamoyl)butyl)-5-(trifluoromethyl)iso 4-oxazolium-formamide;

[0281] 4-Methyl-N-((R)-2-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)carbamoyl)butyl)-2-(6-(trifluoromethyl)pyridin-3-yl)thiazolyl-5-carboxamide;

[0282] N 2 -Isopropyl-4-methyl-N 5 -((R)-2-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazepine -10-yl)carbamoyl)butyl)thiazole-2,5-dicarboxamide;

[0283] 4-Methyl-2-(3-methylisocyanate) (-((R)-2-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine) -10-yl)carbamoyl)butyl)thiazole-5-carboxamide;

[0284] N 2 -(2,2-difluoroethyl)-4-methyl-N 5 -((R)-2-methyl-3-oxo-3-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)amino)propyl)thiazole-2,5-dicarboxamide;

[0285] 4-Chloro-N 2 -Isopropyl-N 5 -((R)-2-methyl-3-oxo-3-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)amino)propyl)thiazole-2,5-dicarboxamide;

[0286] 4-Methyl-N-((R)-2-methyl-3-oxo-3-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)amino)propyl)-2-(3-methylisocyanate) (Zyr-5-yl)thiazolyl-5-carboxamide;

[0287] N 2 -Isopropyl-4-methyl-N 5 -((R)-2-methyl-3-oxo-3-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)amino)propyl)thiazole-2,5-dicarboxamide;

[0288] 3,4-Dimethyl-N-((R)-2-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazide -10-yl)carbamoyl)butyl)iso 5-oxazolium-5-carboxamide;

[0289] 2-(3,6-dihydro-2H-pyran-4-yl)-4-methyl-N-((R)-2-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza -10-yl)carbamoyl)butyl)thiazole-5-carboxamide;

[0290] N 5 -((R)-2-Cyclopropyl-3-oxo-3-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)amino)propyl)-N 2 -Isopropyl-4-methylthiazol-2,5-dicarboxamide;

[0291] 4-Chloro-2-(cyclopent-1-en-1-yl)-N-((R)-2-(((S)-5,11-dioxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)carbamoyl)butyl)thiazole-5-carboxamide;

[0292] 4-Methyl-N-((R)-2-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)carbamoyl)butyl)thiazole-5-carboxamide;

[0293] 4-Methyl-N-((R)-2-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)carbamoyl)butyl)-2-propoxythiazol-5-carboxamide;

[0294] N-((R)-2-(((S)-5,11-dioxo-10,11-dihydro-1H,3H,5H-spiro[benzo[d]pyrazolo[1,2-a][1,2]diazepine -2,1'-Cyclopropyl]-10-yl)carbamoyl)butyl)-3-methyl-5-(trifluoromethyl)iso 4-oxazolium-formamide;

[0295] 2-(different) (-5-yl)-4-methyl-N-((R)-2-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine) -10-yl)carbamoyl)butyl)thiazole-5-carboxamide;

[0296] 3,4-Dimethyl-N-((R)-2-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazide -10-yl)carbamoyl)pentyl)iso 5-oxazolium-5-carboxamide;

[0297] 4-Chloro-N-((R)-2-(((S)-5,11-dioxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)carbamoyl)butyl)-2-(6-methoxypyridin-3-yl)thiazolyl-5-carboxamide;

[0298] N-((R)-2-(((S)-5,11-dioxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)carbamoyl)butyl)-4-methylisothiazolyl-5-carboxamide;

[0299] N-((R)-2-(((S)-5,11-dioxo-10,11-dihydro-1H,3H,5H-spiro[benzo[d]pyrazolo[1,2-a][1,2]diazepine -2,1'-Cyclopropyl]-10-yl)carbamoyl)butyl)-4-ethyl-1,2,3-thiadiazole-5-carboxamide;

[0300] 4-Chloro-2-(6-(difluoromethoxy)pyridin-3-yl)-N-((R)-2-(((S)-5,11-dioxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)carbamoyl)butyl)thiazole-5-carboxamide;

[0301] N-((R)-2-(((S)-5,11-dioxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)carbamoyl)-3,3,3-trifluoropropyl)-4-methyl-2-(6-(trifluoromethyl)pyridin-3-yl)thiazolyl-5-carboxamide;

[0302] 4-Chloro-N-((R)-2-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)carbamoyl)butyl)thiazole-5-carboxamide;

[0303] 4-Chloro-N-((R)-2-(((S)-5,11-dioxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)carbamoyl)-3,3,3-trifluoropropyl)-2-(6-(trifluoromethyl)pyridin-3-yl)thiazolyl-5-carboxamide;

[0304] N-((R)-2-cyclopropyl-3-(((S)-5,11-dioxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazide -10-yl)amino)-3-oxopropyl)-4-methyl-2-(3-methyliso) (Zyr-5-yl)thiazolyl-5-carboxamide;

[0305] N-((R)-4-methoxy-2-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)carbamoyl)butyl)-4-methyl-2-(3-methyliso (Zyr-5-yl)thiazolyl-5-carboxamide;

[0306] 4-Chloro-2-cyclopropyl-N-((R)-2-methyl-3-oxo-3-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazide -10-yl)amino)propyl)thiazole-5-carboxamide;

[0307] 2-(3,6-dihydro-2H-pyran-4-yl)-4-methyl-N-((R)-3,3,3-trifluoro-2-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazide -10-yl)carbamoyl)propyl)thiazolyl-5-carboxamide;

[0308] 4-Chloro-2-(1-(difluoromethyl)-1H-pyrazol-4-yl)-N-((R)-2-(((S)-5,11-dioxo-10,11-dihydro-1H,3H,5H-spiro[benzo[d]pyrazolo[1,2-a][1,2]diazine) -2,1'-Cyclopropyl]-10-yl)carbamoyl)butyl)thiazole-5-carboxamide;

[0309] 4-Chloro-2-(3,6-dihydro-2H-pyran-4-yl)-N-((R)-2-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)carbamoyl)butyl)thiazole-5-carboxamide;

[0310] 2-Cyclopropyl-4-methyl-N-((R)-2-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazide -10-yl)carbamoyl)butyl)thiazole-5-carboxamide;

[0311] N-((R)-2-(((S)-5,11-dioxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)carbamoyl)-3,3,3-trifluoropropyl)-3,5-dimethylisocyano) 4-oxazolium-formamide;

[0312] 4-Chloro-N-((R)-2-(((S)-5,11-dioxo-10,11-dihydro-1H,3H,5H-spiro[benzo[d]pyrazolo[1,2-a][1,2]diazine -2,1'-Cyclopropyl]-10-yl)carbamoyl)butyl)thiazole-5-carboxamide;

[0313] 4-Methyl-2-(tetrahydro-2H-pyran-4-yl)-N-((R)-3,3,3-trifluoro-2-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazide -10-yl)carbamoyl)propyl)thiazolyl-5-carboxamide;

[0314] 4-Methyl-N-((R)-2-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)carbamoyl)butyl)iso 5-oxazolium-5-carboxamide;

[0315] 2-(methoxymethyl)-4-methyl-N-((R)-3,3,3-trifluoro-2-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)carbamoyl)propyl)thiazolyl-5-carboxamide;

[0316] 2-Ethoxy-4-methyl-N-((R)-2-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)carbamoyl)butyl)thiazole-5-carboxamide;

[0317] 4-Chloro-2-cyclopropyl-N-((R)-2-cyclopropyl-3-(((S)-6-fluoro-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazide -10-yl)amino)-3-oxopropyl)thiazolyl-5-carboxamide;

[0318] 4-Chloro-N-((R)-2-cyclopropyl-3-(((S)-6-fluoro-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)amino)-3-oxopropyl)-2-methylthiazolyl-5-carboxamide;

[0319] 1-(difluoromethyl)-N-((R)-2-(((S)-5,11-dioxo-10,11-dihydro-1H,3H,5H-spiro[benzo[d]pyrazolo[1,2-a][1,2]diazine -2,1'-Cyclopropyl]-10-yl)carbamoyl)butyl)-1H-pyrazole-5-carboxamide;

[0320] N-((R)-2-(((S)-5,11-dioxo-10,11-dihydro-1H,3H,5H-spiro[benzo[d]pyrazolo[1,2-a][1,2]diazepine -2,1'-Cyclopropyl]-10-yl)carbamoyl)butyl)-4-(trifluoromethyl)thiazolyl-5-carboxamide;

[0321] 2-Benzyl-4-methyl-N-((R)-2-methyl-3-oxo-3-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazide -10-yl)amino)propyl)thiazole-5-carboxamide;

[0322] 2-Cyclopropyl-N-((R)-2-(((S)-5,11-dioxo-10,11-dihydro-1H,3H,5H-spiro[benzo[d]pyrazolo[1,2-a][1,2]diazine] -2,1'-Cyclopropyl]-10-yl)carbamoyl)butyl)-4-(trifluoromethyl)thiazolyl-5-carboxamide;

[0323] 1,3-Dimethyl-N-((R)-2-methyl-3-oxo-3-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazide -10-yl)amino)propyl)-1H-pyrrole-2-carboxamide;

[0324] 1-Methyl-N-((R)-2-methyl-3-oxo-3-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza -10-yl)amino)propyl)-1H-pyrazole-5-carboxamide;

[0325] (R)-N 4 -(3-Isobutyramido-1-methyl-1H-pyrazole-5-yl)-2-methyl-N 1 -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)succinamide;

[0326] (S)-2-Cyclobutyl-N 4 -(3-Isobutyramido-1-methyl-1H-pyrazole-5-yl)-N 1 -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)succinamide;

[0327] (R)-N 4 -(4-chloro-2-(isopropylcarbamoyl)thiazo-5-yl)-2-methyl-N 1 -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)succinamide;

[0328] (R)-N 4 -(3-((2,2-difluoroethyl)carbamoyl)-1-methyl-1H-pyrazole-5-yl)-2-methyl-N 1 -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)succinamide;

[0329] (R)-N 4 -(2-(isopropylcarbamoyl)-4-methylthiazolyl-5-yl)-2-methyl-N 1 -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)succinamide;

[0330] (S)-2-Cyclopropyl-N 4 -(3-(isopropylcarbamoyl)-1-methyl-1H-pyrazole-5-yl)-N 1 -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)succinamide;

[0331] (R)-2-methyl-N 4 -(1-Methyl-3-((2,2,2-trifluoroethyl)carbamoyl)-1H-pyrazole-5-yl)-N 1 -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)succinamide;

[0332] (R)-N 4 -(3-(2-fluorobenzoamido)-1-methyl-1H-pyrazole-5-yl)-2-methyl-N 1 -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)succinamide;

[0333] (R)-2-methyl-N 4 -(1-Methyl-3-(2,2,3,3,3-pentafluoropropamido)-1H-pyrazole-5-yl)-N 1 -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)succinamide;

[0334] (R)-N 4 -(3-(3-Cyclopropylisothio (-5-yl)-1-methyl-1H-pyrazol-5-yl)-2-methyl-N 1 -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)succinamide;

[0335] (R)-2-methyl-N 4 -(1-Methyl-3-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazole-5-yl)-N 1-((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)succinamide;

[0336] (R)-N 4 -(4-chloro-2-(1-methyl-1H-pyrazol-3-yl)thiazo-5-yl)-2-methyl-N 1 -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)succinamide;

[0337] (R)-2-methyl-N 4 -(1-Methyl-3-(5-methylpyridin-3-yl)-1H-pyrazole-5-yl)-N 1 -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)succinamide;

[0338] (S)-2-Cyclopropyl-N 4 -(1-Methyl-3-(5-methylpyridin-3-yl)-1H-pyrazole-5-yl)-N 1 -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)succinamide;

[0339] (R)-N 4 -(3-(2,3-difluorobenzamido)-1-methyl-1H-pyrazole-5-yl)-2-methyl-N 1 -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)succinamide;

[0340] (S)-2-Cyclopropyl-N 1 -((S)-6-fluoro-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-base)-N 4 -(3-(isopropylcarbamoyl)-1-methyl-1H-pyrazol-5-yl)succinamide;

[0341] (S)-2-Cyclopropyl-N 4-(3-(((S)-1-fluoroprop-2-yl)carbamoyl)-1-methyl-1H-pyrazole-5-yl)-N 1 -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)succinamide;

[0342] (R)-N 4 -(2-(5-Fluoropyridin-3-yl)-4-methylthiazo-5-yl)-2-methyl-N 1 -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)succinamide;

[0343] (R)-2-methyl-N 4 -(1-Methyl-3-(5-methylisocyanate) (azol-3-yl)-1H-pyrazol-5-yl)-N 1 -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)succinamide;

[0344] (R)-N 4 -(3-(5-ethylisothio) (-3-yl)-1-methyl-1H-pyrazol-5-yl)-2-methyl-N 1 -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)succinamide;

[0345] (S)-2-Cyclobutyl-N 1 -((S)-5,11-dioxo-10,11-dihydro-1H,3H,5H-spiro[benzo[d]pyrazolo[1,2-a][1,2]diazepine -2,1'-Cyclopropyl]-10-yl)-N 4 -(3-Isobutyramido-1-methyl-1H-pyrazole-5-yl)succinamide;

[0346] (R)-N 4 -(1-Ethyl-3-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazole-5-yl)-2-methyl-N 1-((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)succinamide;

[0347] (R)-2-methyl-N 4 -(1-Methyl-3-((3,3,3-trifluoropropyl)carbamoyl)-1H-pyrazole-5-yl)-N 1 -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)succinamide;

[0348] (R)-N 4 -(1-Ethyl-3-(furan-2-yl)-1H-pyrazole-5-yl)-2-methyl-N 1 -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)succinamide;

[0349] (R)-N 4 -(3-(3-ethylisothiazolinone) (-5-yl)-1-methyl-1H-pyrazol-5-yl)-2-methyl-N 1 -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)succinamide;

[0350] (R)-N 4 -(3-(5-Fluoropyridin-2-yl)-1-methyl-1H-pyrazole-5-yl)-2-methyl-N 1 -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)succinamide;

[0351] (R)-N 4 -(3-chloro-1-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-4-yl)-2-methyl-N 1 -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)succinamide;

[0352] (R)-2-methyl-N4 -(1-Methyl-3-pentaventamyl-1H-pyrazole-5-yl)-N 1 -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)succinamide;

[0353] (R)-2-methyl-N 4 -(1-Methyl-3-(3-methylisocyanate) (azol-5-yl)-1H-pyrazol-5-yl)-N 1 -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)succinamide;

[0354] (R)-N 4 -(2-(isopropylcarbamoyl)thiazo-5-yl)-2-methyl-N 1 -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)succinamide;

[0355] (R)-2-methyl-N 4 -(3-Methyl-1-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazole-4-yl)-N 1 -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)succinamide;

[0356] (S)-2-Cyclopropyl-N 1 -((S)-5,11-dioxo-10,11-dihydro-1H,3H,5H-spiro[benzo[d]pyrazolo[1,2-a][1,2]diazepine -2,1'-Cyclopropyl]-10-yl)-N 4 -(3-Isobutyramido-1-methyl-1H-pyrazole-5-yl)succinamide;

[0357] (R)-2-methyl-N 4 -(1-Methyl-3-(pyridin-2-yl)-1H-pyrazole-5-yl)-N 1 -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)succinamide;

[0358] (R)-N 4 -(4-chloro-2-(1-(oxetane-3-yl)-1H-pyrazol-4-yl)thiazo-5-yl)-2-methyl-N 1 -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)succinamide;

[0359] (R)-N 4 -(1-Cyclopropyl-3-(furan-2-yl)-1H-pyrazol-5-yl)-2-methyl-N 1 -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)succinamide;

[0360] (R)-N 4 -(3-(6-methoxypyridin-3-yl)-1-methyl-1H-pyrazole-5-yl)-2-methyl-N 1 -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)succinamide;

[0361] (R)-2-methyl-N 4 -(1-Methyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazole-5-yl)-N 1 -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)succinamide;

[0362] (R)-N 4 -(4-chloro-2-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)thiazo-5-yl)-2-methyl-N 1 -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)succinamide;

[0363] (S)-2-Cyclopropyl-N 1 -((S)-6-fluoro-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-base)-N 4 -(3-(((S)-1-fluoroprop-2-yl)carbamoyl)-1-methyl-1H-pyrazole-5-yl)succinamide;

[0364] (R)-N 4 -(1-Ethyl-3-(3-methylisocyanate) (-5-yl)-1H-pyrazol-5-yl)-2-methyl-N 1 -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)succinamide;

[0365] (R)-N 4 -(3-(cyclopropylcarbamoyl)-1-methyl-1H-pyrazole-5-yl)-2-methyl-N 1 -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)succinamide;

[0366] (S)-2-Cyclopropyl-N 4 -(3-(3-Cyclopropylisothio (-5-yl)-1-methyl-1H-pyrazol-5-yl)-N 1 -((S)-5,11-dioxo-10,11-dihydro-1H,3H,5H-spiro[benzo[d]pyrazolo[1,2-a][1,2]diazepine -2,1'-cyclopropyl]-10-yl)succinamide;

[0367] (S)-N 4 -(4-chloro-2-(1-(difluoromethyl)-1H-pyrazol-4-yl)thiazo-5-yl)-2-cyclopropyl-N 1 -((S)-5,11-dioxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)succinamide;

[0368] (R)-2-methyl-N 4 -(1-Methyl-3-(6-methylpyridin-3-yl)-1H-pyrazole-5-yl)-N 1 -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)succinamide;

[0369] (S)-N 4 -(4-chloro-2-(6-(trifluoromethyl)pyridin-3-yl)thiazo-5-yl)-2-cyclopropyl-N 1 -((S)-5,11-dioxo-10,11-dihydro-1H,3H,5H-spiro[benzo[d]pyrazolo[1,2-a][1,2]diazepine -2,1'-cyclopropyl]-10-yl)succinamide;

[0370] (S)-N 4 -(4-chloro-2-(6-(trifluoromethyl)pyridin-3-yl)thiazo-5-yl)-2-cyclopropyl-N 1 -((S)-5,11-dioxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)succinamide;

[0371] (R)-N 4 -(4-chloro-2-(6-(trifluoromethyl)pyridin-3-yl)thiazo-5-yl)-2-methyl-N 1 -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)succinamide;

[0372] (R)-N 4 -(3-((2-fluorophenyl)carbamoyl)-1-methyl-1H-pyrazole-5-yl)-2-methyl-N 1 -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)succinamide;

[0373] (R)-N 4 -(3-((2,6-dimethylphenyl)carbamoyl)-1-methyl-1H-pyrazole-5-yl)-2-methyl-N 1 -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)succinamide

[0374] (R)-3-(1H-benzo[d]imidazol-2-yl)-2-methyl-N-((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)propionamide;

[0375] (R)-2-methyl-3-(7-methyl-1H-benzo[d]imidazol-2-yl)-N-((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazol -10-yl)propionamide;

[0376] (R)-3-(7-bromo-1H-benzo[d]imidazol-2-yl)-2-methyl-N-((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine) -10-yl)propionamide;

[0377] (R)-2-methyl-N-((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)-3-(7-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)propionamide;

[0378] (R)-3-(4-chloro-1H-benzo[d]imidazol-2-yl)-2-methyl-N-((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine) -10-yl)propionamide;

[0379] (R)-3-(6-fluoro-7-methyl-1H-benzo[d]imidazol-2-yl)-2-methyl-N-((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazol -10-yl)propionamide;

[0380] (R)-3-(5-fluoro-7-methyl-1H-benzo[d]imidazol-2-yl)-2-methyl-N-((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazol -10-yl)propionamide;

[0381] (R)-N-((S)-6-fluoro-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazepine -10-yl)-3-(5-fluoro-7-methyl-1H-benzo[d]imidazol-2-yl)-2-methylpropionamide;

[0382] or

[0383] (R)-2-((5-fluoro-7-methyl-1H-benzo[d]imidazol-2-yl)methyl)-N-((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine) -10-yl)pentanamide.

[0384] Depending on the choice of starting materials and procedures, compounds may exist as one of possible isomers or mixtures thereof, for example, as pure optical isomers or as mixtures of isomers, such as racemic and diastereomeric mixtures, depending on the number of asymmetric carbon atoms. This invention is intended to include all such possible isomers, including racemic mixtures, diastereomeric mixtures, and optically pure forms. Optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent can be E or Z configuration. If the compound contains a disubstituted cycloalkyl group, the cycloalkyl substituent can have a cis or trans configuration. All tautomers are also intended to be included.

[0385] As used herein, the term "salt" refers to an acid addition salt or a base addition salt of the compounds of the present invention. "Salt" particularly includes "pharmaceutically acceptable salts." As used herein, the term "pharmaceutically acceptable salt" refers to one or more salts that retain the bioavailability and properties of the compounds of the present invention and are generally not biologically or otherwise undesirable. In many cases, the compounds of the present invention are capable of forming acid salts and / or base salts due to the presence of amino and / or carboxyl groups or similar groups.

[0386] Pharmaceutically acceptable acid addition salts can be formed from inorganic and organic acids. Organic or inorganic acids used to form pharmaceutically acceptable acid addition salts of the compounds of this invention include, but are not limited to, acetic acid, adipic acid, ascorbic acid, aspartic acid, benzoic acid, benzenesulfonic acid, carbonic acid, camphorsulfonic acid, decanoic acid, theochloroic acid, citric acid, ethanedisulfonic acid, fumaric acid, D-glycerol-D-glucose-heptanoic acid, galactopyric acid, galactopyric acid / mucin, and glucheptahydrate. (acid), glucohepanoic acid, glucuronic acid, glucuronic acid, glutamic acid, glutamate, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxyethylsulfonic acid, lactic acid, lactobionic acid, lauryl sulfate, malic acid, maleic acid, malonic acid, mandelic acid, methanesulfonic acid, methanesulfonic acid, mucilage, naphtholic acid, 1-hydroxy-2-naphthoic acid, naphthalenesulfonic acid, 2-naphthalenesulfonic acid, nicotinic acid, nitric acid, stearic acid, octadecanoic acid, oleic acid, oxalic acid, palmitic acid, dihydroxynaphthic acid, phosphoric acid, polygalacturonic acid, propionic acid, sebacic acid, stearic acid, succinic acid, sulfosalicylic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid, trifluoroacetic acid, and triphenylacetic acid.

[0387] The salt form of the compounds of the present invention can be converted into the free compound by treatment with a suitable alkaline agent.

[0388] Pharmaceutically acceptable acid addition salts of the compounds of this invention include, but are not limited to, acetates, adipates, ascorbic acid salts, aspartates, benzoates, phenylsulfonates, benzenesulfonates, bicarbonates / carbonates, bisulfates / sulfates, bromides / hydrobromates, camphor sulfonates, camphor sulfonates, decanoates, chlorides / hydrochlorides, theochlorophosphates, citrates, ethanedisulfonates, ethanedisulfonates, fumarates, glucono-heptanoates, glucono-heptanoates, gluconates, glucuronates, glutamates, glutamates, glycolates, hippurates, hydroiodates / iodides, hydroxyethyl sulfonates, lactates, lactobionates, and lauryl salts. Sulfates, malates, maleates, malonates, mandelates, methanesulfonates, methanesulfonates, methyl sulfates, mucilages, naphthates, naphthalenesulfonates, 2-naphthalenesulfonates, naphthalenesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, stearates, oleates, oxalates, palmitates, dihydroxynaphthalates, phosphates / hydrogen phosphates / dihydrogen phosphates, polygalacturonic acids, propionates, sebates, stearates, succinates, sulfosalicylates, sulfates, tartrates, toluenesulfonates, p-toluenesulfonates, trifluoroacetates, triphenylacetates, triphenylacetates, and xinafoate forms.

[0389] Pharmaceutically acceptable base addition salts can be formed using inorganic and organic bases. Organic bases used to form pharmaceutically acceptable base addition salts of the compounds of this invention include, but are not limited to, primary, secondary, and tertiary amines; substituted amines, including naturally occurring substituted amines; cyclic amines; basic ion exchange resins, etc. Certain organic amines include isopropylamine, benzathine, bile salts, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine. Inorganic bases used to form pharmaceutically acceptable base addition salts of the compounds of this invention include, but are not limited to, sodium hydroxide, potassium hydroxide, ammonium hydroxide, ammonium salts, and metals from columns I to XII of the periodic table. Pharmaceutically acceptable base addition salts of the compounds of this invention include, but are not limited to, sodium salts, potassium salts, ammonium salts, calcium salts, magnesium salts, iron salts, silver salts, zinc salts, and copper salts; particularly suitable salts include ammonium salts, potassium salts, sodium salts, calcium salts, and magnesium salts.

[0390] The pharmaceutically acceptable salts of the present invention can be synthesized from the basic or acidic fractions using conventional chemical methods. Generally, such salts can be prepared by reacting the free acidic form of these compounds with a stoichiometric amount of a suitable base (such as hydroxides, carbonates, bicarbonates, etc. of Na, Ca, Mg, or K) or by reacting the free basic form of these compounds with a stoichiometric amount of a suitable acid. Such reactions are typically carried out in water, in an organic solvent, or in a mixture of both. Generally, where feasible, the use of non-aqueous media such as diethyl ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is ideal.

[0391] Any formulas given herein are also intended to represent both unlabeled and isotopically labeled forms of the compound. Isotopically labeled compounds have the structures described by the formulas given herein, except that one or more atoms are substituted with atoms having selected atomic masses or mass numbers. Isotopes that may be incorporated into the compounds of this invention include, for example, isotopes of hydrogen.

[0392] Furthermore, certain isotopes, especially deuterium (i.e., 2 The incorporation of deuterium (H or D) can provide certain therapeutic advantages resulting from higher metabolic stability, such as prolonged in vivo half-life, reduced dose requirement, improved therapeutic index, or improved tolerability. It should be understood that in this context, deuterium is considered a substituent for the compounds of the present invention. The concentration of deuterium can be defined by an isotope enrichment factor. As used herein, the term "isotope enrichment factor" refers to the ratio between the isotopic abundance of a specified isotope and its native abundance. If the substituent in the compound of the present invention is deuterium, then the isotope enrichment factor of such compound for each specified deuterium atom is at least 3500 (52.5% deuterium inclusion at each specified deuterium atom), at least 4000 (60% deuterium inclusion), at least 4500 (67.5% deuterium inclusion), at least 5000 (75% deuterium inclusion), at least 5500 (82.5% deuterium inclusion), at least 6000 (90% deuterium inclusion), at least 6333.3 (95% deuterium inclusion), at least 6466.7 (97% deuterium inclusion), at least 6600 (99% deuterium inclusion), or at least 6633.3 (99.5% deuterium inclusion). It should be understood that the term "isotope enrichment factor" can be applied to any isotope in the same manner as described for deuterium.

[0393] Other examples of isotopes that can be incorporated into the compounds of this invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as... 3 H, 11 C 13 C 14 C 15 N、 18 F, 31 P, 32P, 35 S, 36 Cl、 123 I, 124 I, 125 I. Therefore, it should be understood that the present invention includes the incorporation of one or more of the aforementioned isotopes, including, for example, radioactive isotopes, such as 3 H and 14 Compounds of C, or those containing non-radioactive isotopes, such as 2 H and 13 Compounds containing C. These isotope-labeled compounds can be used for metabolic studies (using...) 14 C); Reaction kinetic studies (using, for example) 2 H or 3 H); detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT), including drug or matrix tissue distribution assays; or radiation therapy to patients. Specifically, 18 F-labeled compounds may be particularly ideal for PET or SPECT studies. The isotopically labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by procedures similar to those described in the appended examples and preparations, using appropriate isotopically labeled reagents instead of previously used unlabeled reagents.

[0394] For example, the compounds of the present invention can exist in the following deuterated form:

[0395] , , , , , , , and .

[0396] Pharmaceutically acceptable solvates according to the invention include those in which the crystallization solvent can be substituted with an isotope, such as D2O, d6-acetone, and d6-DMSO.

[0397] Compounds of the present invention containing groups capable of acting as hydrogen bond donors and / or acceptors may be able to form cocrystals with suitable cocrystal forming agents. These cocrystals can be prepared from the compounds of the present invention using known cocrystal forming procedures. Such procedures include grinding, heating, co-sublimation, co-melting, or contacting the compounds of the present invention with a cocrystal forming agent under crystallization conditions in solution and separating the resulting cocrystal. Suitable cocrystal forming agents include those described in WO 2004 / 078163. Therefore, the present invention further provides cocrystals comprising the compounds of the present invention.

[0398] Furthermore, the compounds of the present invention (including their salts) can also be obtained as hydrates or include other solvents for crystallization. The compounds of the present invention can inherently or by design form solvates with pharmaceutically acceptable solvents (including water); therefore, the present invention is intended to include both solvated and non-solvated forms. The term "solvate" refers to a molecular complex of the compounds of the present invention (including their pharmaceutically acceptable salts) with one or more solvent molecules. Such solvent molecules are those commonly used in the pharmaceutical field and known to be harmless to the recipient, such as water, ethanol, etc. The term "hydrate" refers to a complex in which the solvent molecule is water.

[0399] The compounds of the present invention, including their salts, hydrates and solvates, can be inherently or by design to form polymorphs.

[0400] Any asymmetric atom (e.g., carbon, etc.) in one or more compounds of the present invention may exist in a racemic or enantiomer-enriched form, for example, (R)-, (S)-, or (R,S)- configuration. In some embodiments, each asymmetric atom in the (R)- or (S)- configuration has an enantiomer excess of at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99%. Where possible, substituents on atoms having unsaturated double bonds may exist in cis (Z)- or trans (E)- form.

[0401] Therefore, as used herein, the compounds of the present invention may be in the form of one or a mixture of possible isomers, rotational isomers, tautomers, tautomers, or such mixtures, for example, in substantially pure geometric (cis or trans) isomers, diastereomers, optical isomers (enantiomers), racemates, or mixtures thereof.

[0402] Any resulting mixture of isomers can be separated into pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and / or fractional crystallization, based on the physicochemical differences of the components.

[0403] Any resulting racemic mixture of the final product or intermediate can be resolved into its optical enantiomers by known methods, for example, by separating its diastereomer salts obtained with optically active acids or bases and releasing the optically active acidic or basic compounds. In particular, the compounds of the present invention can therefore be resolved into their optical enantiomers using a basic moiety, for example, by fractional crystallization of salts formed with optically active acids, such as tartaric acid, dibenzoyltartaric acid, diacetyltartaric acid, di-O,O'-p-tolyltartaric acid, mandelic acid, malic acid, or camphor-10-sulfonic acid. Racemic products can also be resolved by chiral chromatography, such as high-performance liquid chromatography (HPLC) using chiral adsorbents.

[0404] The process for preparing the compounds of the present invention

[0405] This document describes a general procedure for preparing the compounds of the present invention. In the described reactions, reactive functional groups, such as hydroxyl, amino, imino, or carboxyl groups, may be protected, where these groups are desirable in the final product to prevent their unnecessary participation in the reaction. Within the scope of this document, unless the context otherwise indicates, only easily removable groups that are not components of the specific desired final product of the compounds of the present invention are designated as “protecting groups.” The protection of functional groups by such protecting groups, the protecting groups themselves, and their cleavage reactions are described, for example, in standard references such as JFW McOmie, *Protective Groups in Organic Chemistry*, Plenum Press, London and New York 1973; TW Greene and PGM Wuts, *Protective Groups in Organic Synthesis*, 3rd edition, Wiley, New York 1999.

[0406] Unless otherwise indicated herein or otherwise clearly contradicted by the context, all methods described herein may be performed in any suitable order. The use of any and all instances or exemplary language (e.g., “such as”) provided herein is intended only to better illustrate the invention and does not limit the scope of the otherwise claimed invention.

[0407] Method for synthesizing the compounds of the present invention

[0408] The agents of the present invention can be prepared by the reaction sequence shown in the reaction scheme of the experimental section (see below).

[0409] Typically, the compounds of the present invention can be prepared according to schemes 1-4 provided below. The compounds of the present invention are prepared by the processes described herein and illustrated in the examples. Various combinations of building blocks and intermediates described herein can be applied to produce the compounds of the present invention. Non-limiting examples of synthetic schemes for preparing the compounds of the present invention are illustrated in schemes 1 to 4. Further guidance can be found in the Examples section.

[0410] Compound (II) can be prepared as outlined in Scheme 1.

[0411]

[0412] Option 1

[0413] The amide of Int-1 and the corresponding N-protected amino acid (Int-2) can be obtained using various coupling reagents or conditions (E. Valeur, M. Bradley, Chem. Soc. Rev. 2009, 38, 606-631; A. El-Faham, F. Albericio, Chem. Rev. 2011, 111, 6557-6602). After removing the protecting group (TW Greene and PGM Wuts, "Protective Groups in Organic Synthesis", 3rd ed., Wiley, New York 1999), such as Boc or Cbz in the formed amide, the released amine intermediate can be coupled with various acid building blocks (Int-3) to provide the final compound of formula (II).

[0414] Similarly, compounds of formula (III) can be prepared as outlined in scheme 2.

[0415]

[0416] Option 2

[0417] Similar to the preparation of compounds of formula (II), compounds of formula (III) can be obtained by amide coupling between amines (Int-1), but in this case, various monoprotected succinates (Int-4) are used as acid partners. The chiral succinate intermediate (Int-4) can be prepared in enantiomeric purity by various methods, including asymmetric hydrogenation of α-substituted acrylic acid using chiral catalysts (e.g., PM Donate, D. Frederico, R. daSilva, MGConstantino, G. Del Ponte, PS Bonatto, Tetrahedron: Asymmetry 2003, 14, 3253-3256), or by utilizing chiral... The Evans method for azole auxiliaries (DA Evans, LD Wu, JJM Wiener, JS Johnson, DHB Ripin, JS Tedrow, J. Org.Chem. 1999, 64, 6411-6417). Alternatively, such chiral acids can also be prepared by chiral resolution (JM Keith, JF Larrow, EN Jacobsen, Adv. Synth. Catal. 2001, 343, 5-26) using chiral amines or enzymes, by dynamic kinetic resolution or by chiral separation using preparative chiral chromatography. The resulting amide ester intermediate then undergoes ester hydrolysis, and the obtained acid intermediate can be coupled with an aliphatic or aromatic amine to provide the final product of formula (III).

[0418] The desired chiral amine intermediate Int-1 (where Y is CH2) can be prepared as outlined in Scheme 3.

[0419]

[0420] Option 3

[0421] The tricyclic core is prepared by cyclization of 2-(2-(halomethyl)phenyl)acetate (prepared from the corresponding isochoric-3-one - DJRitchie, HSR McCann, MCH Standen, RVH Jones, US6048998, 2000; CAN128:75194) with pyrazolidine (EE Boros, F. Bouvier, S. Randhawa, MH Rabinowitz, J. Heterocycl. Chem. 2001, 38, 613-616). The desired primary amine can be introduced into such compounds in several ways. These molecules can be converted to α-bromo derivatives, which undergo nucleophilic substitution with an azide, and then can be reduced to a primary amine (e.g., ZHANG, Xuqing; WALL, Mark; SUI, Zhihua WO2015 / 160772, 2015, A1). Another possibility for introducing the azide is to employ a one-step sequence, utilizing the azidation of the corresponding enol with 2,4,6-triisopropylbenzenesulfonyl azide (e.g., CVC Prasad et al., Bioorg. Med. Chem. Lett. 2007, 17, 4006-4011) or copper-catalyzed azidation (S.-E. Suh, S.-J. Chen, M. Mandal, IA Guzei, CJ Cramer, SS Stahl, J. Am. Chem. Soc. 2020, 142, 11388-11393). Alternatively, as shown in scheme 3, the amine can also be introduced by forming an oxime and its reduction (F. Hoffmann-Emery, R. Jakob-Roetne, A. Flohr, F. Bliss, R. Reents, Tet. Lett. 2009, 50, 6380-6382). Enantiomerically pure amines can be obtained by chiral resolution, by forming a mixture of separable and cleavable diastereomers (F. Hoffmann-Emery, R. Jakob-Roetne, A. Flohr, F. Bliss, R. Reents, Tet. Lett. 2009, 50, 6380-6382), or by preparative chiral chromatography.

[0422] Intermediate 1 (Int-1), where Y is C(O), can be prepared according to scheme 4:

[0423]

[0424] Option 4

[0425] If isocyanate-1,3-dione is used instead of 2-(2-(halomethyl)phenyl)acetate in the cyclization with pyrazolidine, then an oxotricyclic compound can be prepared similarly to the tricyclic synthesis described in Scheme 3. Alternatively, Int-1 from Scheme 3 can be oxidized with RuO2 (AG Schultz, TJ Guzi, E. Larsson, R. Rahm, K. Thakkar, JM Bidlack, J. Org. Chem. 1998, 63, 7795-7804) to directly provide Int-1 where Y is C(O). Chiral separation can also be performed as described in Scheme 3.

[0426] Application and pharmaceutical composition

[0427] For therapeutic use of the compounds of the present invention, such compounds are administered alone or as part of a pharmaceutical composition. Therefore, another aspect of the invention provides a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt or stereoisomer thereof, and one or more pharmaceutically acceptable carriers. In yet another embodiment, the composition comprises at least two pharmaceutically acceptable carriers, such as those described herein. The pharmaceutical composition can be formulated for specific routes of administration, such as oral administration, parenteral administration (e.g., by injection, infusion, transdermal or topical administration), and rectal administration. Topical administration may also involve inhalation or intranasal application. In some embodiments, the pharmaceutical composition comprising the compounds of the present invention can be formulated for intramuscular, intravenous, subcutaneous, oral, pulmonary, intrathecal, topical, or intranasal administration.

[0428] The pharmaceutical compositions of the present invention can be formulated in solid form (including but not limited to capsules, tablets, pills, granules, powders, or suppositories) or in liquid form (including but not limited to solutions, suspensions, or emulsions). Tablets may be coated with a film or enteric coating according to methods known in the art.

[0429] Typically, pharmaceutical compositions are tablets or gelatin capsules containing an active ingredient as well as the following components:

[0430] a) Diluents, such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine;

[0431] b) Lubricants, such as silica, talc, stearic acid, its magnesium or calcium salts, and / or polyethylene glycol; for tablets, also...

[0432] c) Adhesives, such as magnesium aluminum silicate, starch paste, gelatin, tragacanth gum, methylcellulose, sodium carboxymethyl cellulose and / or polyvinylpyrrolidone; if necessary,

[0433] d) Disintegrants, such as starch, agar, alginate or its sodium salt, or effervescent mixtures; and / or

[0434] e) Absorbents, colorants, flavorings and sweeteners.

[0435] Compositions suitable for oral administration include compounds of the present invention in the form of tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard capsules or soft capsules, syrups or elixirs. Compositions intended for oral use are prepared according to any method known in the art for manufacturing pharmaceutical compositions, and such compositions may contain one or more agents selected from the group consisting of sweeteners, flavoring agents, coloring agents, and preservatives to provide a pharmaceutically excellent and palatable formulation. Tablets may contain an active ingredient mixed with a non-toxic, pharmaceutically acceptable carrier / excipient suitable for manufacturing tablets. These carriers / excipients are, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrants such as corn starch or alginic acid; binders such as starch, gelatin, or gum arabic; and lubricants such as magnesium stearate, stearic acid, or talc. Tablets are uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained effect over a longer period. For example, delaying materials such as glyceryl monostearate or glyceryl distearate can be used. Formulations for oral use can be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent (e.g., calcium carbonate, calcium phosphate, or kaolin), or as soft gelatin capsules in which the active ingredient is mixed with an aqueous or oily medium (e.g., peanut oil, liquid paraffin, or olive oil).

[0436] Parenteral compositions (e.g., intravenous (IV) formulations) are aqueous isotonic solutions or suspensions. Parenteral compositions may be sterile and / or contain adjuvants such as preservatives, stabilizers, wetting agents or emulsifiers, solution enhancers, salts and / or buffers for regulating osmotic pressure. Additionally, parenteral compositions may contain other therapeutically valuable substances. Compositions are generally prepared according to conventional mixing, granulation, or coating methods and contain approximately 0.1-75% or approximately 1-50% of the active ingredient.

[0437] The compounds of the present invention or pharmaceutical compositions thereof for use in subjects (e.g., humans) are generally administered orally or parenterally at a therapeutic dose of less than or equal to about 100 mg / kg. When administered intravenously via infusion, the dose may depend on the infusion rate of the intravenous preparation. Generally, the therapeutically effective dose of the compound, pharmaceutical composition, or combination thereof depends on the species, weight, age, and individual condition of the subject, the condition or disease being treated, or its severity.

[0438] The above-described dosage characteristics can be demonstrated in in vitro and in vivo tests, which are advantageously performed using mammals, such as mice, rats, dogs, monkeys, or isolated organs, tissues, and their products. The compounds of the present invention can be administered in vitro as a solution (e.g., an aqueous solution) and in vivo via the intestine, parenteral, or advantageously intravenously, for example, as a suspension or in an aqueous solution.

[0439] Certain aspects and examples of the pharmaceutical compositions of the present invention are provided in the following list of enumerated embodiments. It will be appreciated that the features specified in each embodiment may be combined with other specified features to provide further embodiments of the invention.

[0440] Implementation Scheme 50. A pharmaceutical composition comprising a compound of formula (I) as described in any one of Implementation Schemes 1 to 49, or a pharmaceutically acceptable salt or stereoisomer thereof, and one or more pharmaceutically acceptable carriers.

[0441] Implementation Scheme 51. A pharmaceutical composition comprising a compound as described in Implementation Scheme 49 or a pharmaceutically acceptable salt or stereoisomer thereof, and one or more pharmaceutically acceptable carriers.

[0442] Implementation Scheme 52. The pharmaceutical composition as described in Implementation Scheme 50 or Implementation Scheme 51, wherein the pharmaceutical composition comprises one or more additional therapeutic agents.

[0443] Pharmacology and efficacy

[0444] The compounds of the present invention, in their free form or in pharmaceutically acceptable salt form, exhibit valuable pharmacological properties, such as inhibition of cellular levels of Sppl2a as indicated by the in vitro tests provided herein, and are therefore designated for use in therapeutics or as research chemicals, for example, as tool compounds.

[0445] Therefore, the compounds of the present invention can generally be used to treat indications involving, for example, cells expressing high levels of CD74 and / or cells involved in class II-dependent antigen presentation. Additionally, the compounds of the present invention can be used to treat autoimmune diseases and / or conditions. In particular, the compounds of the present invention can be used to treat and / or prevent pemphigus vulgaris, pemphigus foliaceus, Sjögren's disease, systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), myasthenia gravis, Hashimoto's thyroiditis, thrombocytopenic purpura, myocarditis, atopic dermatitis, Goodpassuia syndrome, multiple sclerosis (MS), or type I diabetes.

[0446] Furthermore, the compounds of the present invention can be used to prevent rejection in clinical / surgical transplantation procedures of solid organs, tissues, or cell populations (such as stem cells). Additionally, the compounds of the present invention can be used to treat and / or prevent acute and chronic graft-versus-host disease (GvHD) associated with the transplantation of solid organs, tissues, or cell populations. The compounds of the present invention can be used further prophylactically, for example as an induction therapy to prepare the host prior to the transplantation of solid organs, tissues, or cell populations; or the compounds of the present invention can be used further therapeutically after the transplantation of solid organs, tissues, or cell populations. Non-limiting examples of transplantation are kidney transplantation, heart transplantation (acute or chronic), and bone marrow transplantation. Furthermore, the compounds of the present invention can be used to treat the donor prior to the donation of organs, tissues, or cells.

[0447] In addition, the compounds of the present invention can be used to treat lymphomas, especially lymphomas caused by modified B cells expressing high levels of CD74, such as non-Hodgkin's lymphoma (NHL), Burkitt lymphoma (BL), and multiple myeloma (MM).

[0448] Certain aspects and examples of the use of the compounds and pharmaceutical compositions of the present invention are provided in the following list of enumerated embodiments. It will be appreciated that the features specified in each embodiment may be combined with other specified features to provide further embodiments of the invention.

[0449] Implementation Scheme 53. A method for treating a disease or condition associated with the activity of signal peptidase-like proteinase 2a (Sppl2a), wherein the method comprises administering to a subject in need of treatment a therapeutically effective amount of a compound or pharmaceutically acceptable salt as described in any one of Implementation Schemes 1 to 49.

[0450] Implementation Scheme 54. A method for treating a disease or condition associated with the activity of signal peptidase-like proteinase 2a (Sppl2a), wherein the method comprises administering to a subject in need of treatment a compound or a pharmaceutically acceptable salt as described in any one of Implementation Schemes 1 to 49.

[0451] Implementation Scheme 55. Use of the compound or a pharmaceutically acceptable salt thereof as described in any one of Implementation Schemes 1 to 49 for the manufacture of an agent for the treatment of a disease or condition associated with the activity of the signal peptidase-like protease 2a (Sppl2a).

[0452] Implementation Scheme 56. Use of the compound or a pharmaceutically acceptable salt thereof as described in any one of Implementation Schemes 1 to 49 for the treatment of diseases or conditions associated with the activity of signal peptidase-like protease 2a (Sppl2a).

[0453] Implementation Scheme 57. The compound or a pharmaceutically acceptable salt thereof as described in any one of Implementation Schemes 1 to 49, for the treatment of diseases or conditions associated with the activity of signal peptidase-like protease 2a (Sppl2a).

[0454] Implementation Scheme 58. A method for treating an autoimmune disease in a subject of need, wherein the method comprises administering to the subject a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof as described in any one of Implementation Schemes 1 to 49.

[0455] Implementation Scheme 59. A method for treating an autoimmune disease in a subject of need, wherein the method comprises administering to the subject a compound as described in any one of Implementation Schemes 1 to 49 or a pharmaceutically acceptable salt thereof.

[0456] Implementation Scheme 60. Use of the compound or a pharmaceutically acceptable salt thereof as described in any one of Implementation Schemes 1 to 49 for the manufacture of an agent for the treatment of autoimmune diseases.

[0457] Implementation Scheme 61. The use of the compound or a pharmaceutically acceptable salt thereof as described in any one of Implementation Schemes 1 to 49 for the treatment of autoimmune diseases.

[0458] Implementation Scheme 62. The compound or a pharmaceutically acceptable salt thereof as described in any one of Implementation Schemes 1 to 49, for the treatment of autoimmune diseases.

[0459] Implementation Scheme 63. Use of the method of any one of Implementation Schemes 53, 54, 58 or 59, the compound of any one of Implementation Schemes 55, 56, 60 or 61, or the compound for use as described in Implementation Scheme 57 or 62, wherein the autoimmune disease is Sjögren's disease, systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), lupus nephritis, systemic sclerosis, multiple sclerosis (MS), autoimmune hepatitis, uveitis, pemphigus vulgaris, pemphigus foliaceus, myasthenia gravis, Hashimoto's thyroiditis, thrombocytopenic purpura, myocarditis, atopic dermatitis, Goodpassuia syndrome, or type I diabetes.

[0460] Implementation Scheme 64. Use of the method of any one of Implementation Schemes 53, 54, 58 or 59, the use of the compound of any one of Implementation Schemes 55, 56, 60 or 61, or the compound for use as described in Implementation Scheme 57 or 62, wherein the autoimmune disease is multiple sclerosis (MS), Sjögren's disease, systemic rheumatoid arthritis (RA), lupus nephritis or systemic sclerosis.

[0461] Implementation Scheme 65. Use of the method as described in any one of Implementation Schemes 53, 54, 58 or 59, the use of the compound as described in any one of Implementation Schemes 55, 56, 60 or 61, or the compound for use as described in Implementation Scheme 57 or 62, wherein the autoimmune disease is multiple sclerosis (MS).

[0462] Implementation Scheme 66. A method for treating a subject with a disease associated with high levels of CD74 expression in B cells, wherein the method comprises administering to the subject a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof as described in any one of Implementation Schemes 1 to 49.

[0463] Implementation Scheme 67. A method for treating a subject with a disease associated with high levels of CD74 expression in B cells, wherein the method comprises administering to the subject a compound as described in any one of Implementation Schemes 1 to 49 or a pharmaceutically acceptable salt thereof.

[0464] Implementation Scheme 68. Use of the compound or a pharmaceutically acceptable salt thereof as described in any one of Implementation Schemes 1 to 49 for the manufacture of an agent for treating a subject for a disease associated with high levels of CD74 expression in B cells.

[0465] Implementation Scheme 69. Use of the compound or a pharmaceutically acceptable salt thereof as described in any one of Implementation Schemes 1 to 49 for the treatment of a subject with a disease associated with high levels of CD74 expression in B cells.

[0466] Implementation Scheme 70. The compound or a pharmaceutically acceptable salt thereof as described in any one of Implementation Schemes 1 to 49, for the treatment of a subject with a disease associated with high levels of CD74 expression in B cells.

[0467] Implementation Scheme 71. The use of the method as described in any one of Implementation Schemes 66 or 67, the use of the compound as described in any one of Implementation Schemes 68 or 69, or the compound for use as described in Implementation Scheme 70, wherein the B-cell lymphoma is non-Hodgkin's lymphoma (NHL), Burkitt lymphoma (BL), or multiple myeloma (MM).

[0468] Implementation Scheme 72. A method of treating a subject with B-cell lymphoma, wherein the method comprises administering to the subject a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof as described in any one of Implementation Schemes 1 to 49.

[0469] Implementation Scheme 73. A method for treating a subject with B-cell lymphoma, wherein the method comprises administering to the subject a compound as described in any one of Implementation Schemes 1 to 49 or a pharmaceutically acceptable salt thereof.

[0470] Implementation Scheme 74. Use of the compound or a pharmaceutically acceptable salt thereof as described in any one of Implementation Schemes 1 to 49 for the manufacture of an agent for the treatment of B-cell lymphoma.

[0471] Implementation Scheme 75. The use of the compound or a pharmaceutically acceptable salt thereof as described in any one of Implementation Schemes 1 to 49 for the treatment of B-cell lymphoma.

[0472] Implementation Scheme 76. The compound or a pharmaceutically acceptable salt thereof as described in any one of Implementation Schemes 1 to 49, for the treatment of B-cell lymphoma.

[0473] Implementation Scheme 77. The use of the method as described in any one of Implementation Schemes 72 or 73, the use of the compound as described in any one of Implementation Schemes 74 or 75, or the compound for use as described in Implementation Scheme 76, wherein the B-cell lymphoma is non-Hodgkin's lymphoma (NHL), Burkitt lymphoma (BL), or multiple myeloma (MM).

[0474] Implementation Scheme 78. A method for treating graft-versus-host disease (GvHD) in a post-transplant subject, wherein the method comprises administering to the subject a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof as described in any one of Implementation Schemes 1 to 49, wherein the transplant is a transplantation of a solid organ, tissue, or cell population.

[0475] Implementation Scheme 79. A method for treating graft-versus-host disease (GvHD) in a post-transplant subject, wherein the method comprises administering to the subject a compound as described in any one of Implementation Schemes 1 to 49 or a pharmaceutically acceptable salt thereof, wherein the transplant is a transplantation of a solid organ, tissue, or cell population.

[0476] Implementation Scheme 80. A method for preventing graft-versus-host disease (GvHD) in a subject after transplantation, wherein the method comprises administering to the subject a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof, as described in any one of Implementation Schemes 1 to 49, prior to transplantation, wherein the transplantation is a transplantation of a solid organ, tissue, or cell population.

[0477] Implementation Scheme 81. A method for preventing graft-versus-host disease (GvHD) in a subject after transplantation, wherein the method comprises administering to the subject a compound or a pharmaceutically acceptable salt thereof as described in any one of Implementation Schemes 1 to 49 prior to transplantation, wherein the transplantation is a transplantation of a solid organ, tissue, or cell population.

[0478] Implementation Scheme 82. Use of the compound as described in any one of Implementation Schemes 1 to 49 for the treatment of graft-versus-host disease (GvHD) in a post-transplant subject, wherein the transplant is a transplantation of a solid organ, tissue, or cell population.

[0479] Implementation Scheme 83. Use of the compound as described in any one of Schemes 1 to 49, for the manufacture of an agent for treating graft-versus-host disease (GvHD) in a post-transplant subject, wherein the transplant is a transplantation of a solid organ, tissue, or cell population.

[0480] Implementation Scheme 84. The compound of any one of Implementation Schemes 1 to 49, for treating graft-versus-host disease (GvHD) in a post-transplant subject, wherein the transplant is a transplantation of a solid organ, tissue, or cell population.

[0481] Implementation Scheme 85. The method of any one of Implementation Schemes 78 to 81, the use of the compound of any one of Implementation Schemes 82 or 83, or the compound for use as described in Implementation Scheme 84, wherein the transplantation is a solid organ transplantation.

[0482] Implementation Scheme 86. The method of any one of Implementation Schemes 78 to 81, the use of the compound of any one of Implementation Schemes 82 or 83, or the compound for use as described in Implementation Scheme 84, wherein the transplantation is a bone marrow transplantation.

[0483] Implementation Scheme 87. The method of any one of Implementation Schemes 78 to 81, the use of the compound of any one of Implementation Schemes 82 or 83, or the compound for use as described in Implementation Scheme 84, wherein the transplantation is a stem cell transplantation.

[0484] Implementation Scheme 88. The method of any one of Implementation Schemes 78 to 81, the use of the compound of any one of Implementation Schemes 82 or 83, or the compound for use as described in Implementation Scheme 84, wherein the transplantation is a hematopoietic stem cell transplantation.

[0485] Implementation Scheme 89. The method of any one of Implementation Schemes 78 to 81, the use of the compound of any one of Implementation Schemes 82 or 83, or the compound for use as described in Implementation Scheme 84, wherein the transplantation is a transplantation of tissue.

[0486] Implementation Scheme 90. The use of the method of any one of Implementation Schemes 78 to 81 or 85 to 89, the use of the compound of any one of Implementation Schemes 82, 83 or 85 to 89, or the compound for use as described in Implementation Schemes 84 to 89, wherein the graft-versus-host disease (GvHD) is acute graft-versus-host disease.

[0487] Implementation Scheme 91. The use of the method as described in any one of Implementation Schemes 78 to 81 or 85 to 89, the use of the compound as described in any one of Implementation Schemes 82, 83 or 85 to 89, or the compound for use as described in Implementation Schemes 84 to 89, wherein the graft-versus-host disease (GvHD) is chronic graft-versus-host disease.

[0488] Combination therapy

[0489] In some cases, it may be advantageous to administer the compounds of the present invention in combination with one or more additional therapeutic agents. Therapeutic agents are, for example, chemical compounds, peptides, antibodies, antibody fragments, or nucleic acids that have therapeutic activity or enhance therapeutic activity when administered to a patient in combination with the compounds of the present invention.

[0490] The compounds of this invention can be administered as the sole active ingredient or in combination with other drugs useful for tumor diseases and inflammatory conditions in immunomodulatory regimens or induction therapies to prevent GvHD and transplant rejection. For example, the compounds of this invention can be used in combination with substances such as cyclosporin, rapamycin, or ascomycin or their immunosuppressive analogs or derivatives, such as cyclosporin A, cyclosporin G, Isa TX247, FK-506, sirolimus, or everolimus; corticosteroids such as prednisone; cyclophosphamide; azathioprene; methotrexate; gold salts; sulfasalazine; antimalarial drugs; leflunomide; mizoribine; and mycophenolic acid. Mycophenolate mofetil; 15-deoxyspergualine; S1P receptor agonists, such as FTY720 or its analogues; immunosuppressive monoclonal antibodies, such as monoclonal antibodies against leukocyte receptors, such as MHC, or other immunomodulatory compounds, such as CTLA4Ig.

[0491] Compounds of Formula I can also be used in combination with other antiproliferative agents. These antiproliferative agents include, but are not limited to, aromatase inhibitors, antiestrogens, topoisomerase I inhibitors, topoisomerase II inhibitors, microtubule activators, alkylating agents, histone deacetylase inhibitors, farnesyltransferase inhibitors, COX-2 inhibitors, MMP inhibitors, mTOR inhibitors, antitumor antimetabolites, platinum compounds, compounds that reduce protein kinase activity and further antiangiogenic compounds, gonadorelin agonists, antiandrogens, benzamide, bisphosphonates, antiproliferative antibodies, and temozolomide (TEMODAL).

[0492] Example

[0493] The compounds of the present invention can be produced as shown in the following examples. The following examples are intended to illustrate the invention and should not be construed as limiting the invention. Temperatures are given in degrees Celsius. Unless otherwise specified, all evaporation was carried out under reduced pressure, typically between about 15 mm Hg and 100 mm Hg (= 20–133 mbar). The structures of the final products, intermediates, and starting materials were confirmed by standard analytical methods, such as trace analysis and spectroscopic characterization, such as MS, IR, and NMR. The abbreviations used are conventional abbreviations in the art.

[0494] All starting materials, building blocks, reagents, acids, bases, dehydrating agents, solvents, and catalysts used to synthesize the compounds of the present invention are commercially available or can be produced by organic synthesis methods known to those skilled in the art, or by organic synthesis methods as described herein.

[0495] For illustrative purposes, the general reaction schemes described herein provide potential pathways for the synthesis of the compounds of this invention and key intermediates. For a more detailed description of individual reaction steps, see the Examples section below. Although specific starting materials and reagents are depicted in the schemes and discussed below, other starting materials and reagents can be readily substituted to provide a variety of derivatives and / or reaction conditions. Furthermore, many compounds prepared by the methods described below can be further modified using conventional chemistry well known to those skilled in the art in light of this disclosure.

[0496] abbreviation:

[0497] ACN Acetonitrile

[0498] Abs Absolute

[0499] AcOH (acetic acid)

[0500] aq. water-based

[0501] br. s broad single peak

[0502] Boc2O ditert-butyl dicarbonate

[0503] BuLi n-Butyllithium

[0504] CaCO3 (calcium carbonate)

[0505] Cs2CO3 (cesium carbonate)

[0506] CO and carbon monoxide

[0507] COMU (1-cyano-2-ethoxy-2-oxoethyleneaminooxy)-dimethylamino-morpholinylcarbomonyhexafluorophosphate

[0508] CuBr (copper bromide I)

[0509] CuCl (copper chloride I)

[0510] d Double peak

[0511] DAST (diethylamino) sulfur trifluoride

[0512] DBU 1,8-diazabicyclo[5.4.0]undec-7-ene

[0513] DCM dichloromethane

[0514] de diastereomer excess

[0515] DIPEA N,N-Diisopropylethylamine

[0516] DMA dimethylacetamide

[0517] DMAP 4-(dimethylamino)pyridine

[0518] DME dimethoxyethane

[0519] DMF (dimethylformamide)

[0520] DMSO (dimethyl sulfoxide)

[0521] DPPA (diphenyl azidophosphate)

[0522] EDC 1-Ethyl-3-(3-Dimethylaminopropyl)carbodiimide

[0523] ee enantiomer excess

[0524] Et3N Triethylamine

[0525] Et2O diethyl ether

[0526] EtOAc (ethyl acetate)

[0527] EtOH (ethanol)

[0528] Flow rate

[0529] h hours

[0530] Hex, a mixture of isomers

[0531] HATU O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylureonium hexafluorophosphate

[0532] HBTU 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylureon tetrafluoroborate

[0533] HCl hydrochloric acid

[0534] HPLC (High Performance Liquid Chromatography)

[0535] HV High Vacuum

[0536] IPA isopropanol

[0537] i-PrOH isopropanol

[0538] KHMDS (Potassium Hexamethyldisilazane)

[0539] KHSO4 Potassium hydrogen sulfate

[0540] L rise

[0541] LCMS (Liquid Chromatography / Mass Spectrometry)

[0542] LDA (Lithium diisopropylamino)

[0543] LiAlH4 lithium aluminum hydride

[0544] LiHMDS (Lithium Hexamethyldisilazane)

[0545] LiOH (Lithium hydroxide)

[0546] M is the molar concentration (mol / L).

[0547] Me methyl

[0548] MeI methyl iodine

[0549] MeOH (methanol)

[0550] Manganese dioxide (MnO2)

[0551] MsCl methanesulfonyl chloride

[0552] min minutes

[0553] mL

[0554] mm

[0555] MHz

[0556] MS mass spectrometry

[0557] MTBE (methyl tert-butyl ether)

[0558] µm

[0559] NaBH4 sodium borohydride

[0560] NaBH3CN Sodium cyanoborohydride

[0561] NaCl (Sodium Chloride)

[0562] Sodium hydride (NaH)

[0563] NaHCO3 (Sodium bicarbonate)

[0564] Sodium hexamethyldisilazane (NaHMDS)

[0565] Sodium iodide (NaI)

[0566] NaOAc (sodium acetate)

[0567] NaOH (sodium hydroxide)

[0568] Na2SO3 Sodium sulfite

[0569] Na2SO4 Sodium sulfate

[0570] NBS N-bromosuccinimide

[0571] NH3 ammonia

[0572] NH4Cl ammonium chloride

[0573] Nickel

[0574] NMM 4-methylmorpholine

[0575] NMR (Nuclear Magnetic Resonance)

[0576] o / n overnight

[0577] Pd / C Palladium on Carbon

[0578] Pd(dppf)Cl2.CH2Cl2 1,1'-bis(diphenylphosphino)ferrocene dichloropalladium(II) dichloromethane complex

[0579] PhMe Toluene

[0580] Prep preparation type

[0581] PyBOP (benzotriazol-1-yloxy)-tripyrrolidinylphosphonium hexafluorophosphate

[0582] q Quadruple Peak

[0583] rt room temperature

[0584] t R Retention time

[0585] s Single peak

[0586] sat. saturated

[0587] scCO2 (supercritical carbon dioxide)

[0588] SEM-Cl 2-(trimethylsilyl)ethoxymethyl chloride

[0589] SFC Supercritical Fluid Chromatography

[0590] t triple peak

[0591] T3P 1-Propionidic Anhydride

[0592] TEA Triethylamine

[0593] TFA (trifluoroacetic acid)

[0594] THF Tetrahydrofuran

[0595] TLC (Thin Layer Chromatography)

[0596] TMSCl trimethylsilyl chloride

[0597] TMSCN Trimethylsilane Nitrile

[0598] TOTU O-[(ethoxycarbonyl)cyanomethyleneamino]-N,N,N',N'-tetramethylureon tetrafluoroborate

[0599] TsOH p-Toluenesulfonic acid

[0600] UPLC (Ultra-High Performance Liquid Chromatography)

[0601] trademark

[0602] Diatomaceous earth = Celite ® (The Celite Corporation) = Diatomaceous earth-based filter aid

[0603] PL Thiol Cylinder = Stratosphere ® SPE, PL-Thiol MP SPE+, 500 mg per 6 mL tube, 1.5 mmol (nominal).

[0604] NH2 Isolute (= Isolute ® NH2, Isolute ® Registered for use in Argonaut Technologies, Inc.) = Amino-based ion exchange based on silica gel

[0605] Nucleosil = Nucleosil ® Maccherry & Nagel's trademark, Düren, FRG for HPLC materials

[0606] PTFE membrane = Chromafil O-45 / 15MS polytetrafluoroethylene (Machereynagel)

[0607] Temperature is measured in degrees Celsius. Unless otherwise indicated, the reaction proceeds at room temperature.

[0608] Phase separator Biotage - Isolute phase separator (part number: 120-1908-F for 70 mL, and part number: 120-1909-J for 150 mL)

[0609] TLC conditions TLC's R f Values ​​were measured on a 5 x 10 cm TLC plate, silicone F 254 , Merck, Darmstadt, Germany.

[0610] Analytical methods

[0611] HPLC conditions :

[0612] Method a: HPLC instrument: Agilent 1100 series; column: Waters X-Bridge C18 2.5 μm 3*30 mm; eluent A: water + 0.1% TFA, B: ACN + 0.1% TFA; gradient: 10% to 98% B over 3 minutes; flow rate: 1.4 mL / min

[0613] Method b: HPLC instrument: Agilent 1100 series; column: Waters X-Bridge C18 2.5 μm 3*50 mm; eluent A: water + 0.1% TFA, eluent B: ACN + 0.1% TFA; gradient: 10% to 98% B over 8.6 minutes; flow rate: 1.4 mL / min

[0614] Method c: HPLC instrument: Agilent 1200 series; column: Waters Eclipse XDB-C18 1.8 μm 2.1*30 mm; eluent A: water + 0.1% TFA, B: ACN + 0.1% TFA; gradient: 5% to 100% B over 3 minutes; flow rate: 1.4 mL / min

[0615] Method d: HPLC instrument: Agilent 1200 series; Waters X-Bridge C18, 2.5 μm, 3*30 mm; eluent A: water + 7.3 mM NH4OH; B: ACN + 7.3 mM NH4OH. Gradient: 10% to 98% B over 8.6 min; flow rate: 1 mL / min.

[0616] UPLC conditions :

[0617] LCMS Method a: UPLC / MS Instrument: Waters UPLC Acquity; Column: Acquity HSS T3 1.8 μm 2.1* 50 mm, 50℃, Eluent A: Water + 0.05% HCOOH + 3.75 mM ammonium acetate, Eluent B: ACN + 0.04% HCOOH, Gradient: 2% to 98% B over 1.4 min, Flow rate: 1.2 mL / min (2 min)

[0618] LCMS Method b: UPLC / MS Instrument: Waters UPLC Acquity; Column: Acquity HSS T3 1.8 μm 2.1* 50 mm, 60℃, Eluent A: Water + 0.05% HCOOH + 3.75 mM ammonium acetate, Eluent B: ACN + 0.04% HCOOH, Gradient: 5% to 98% B over 1.4 min, Flow rate: 1 mL / min (2 min)

[0619] LCMS method c: Agilent HPLC-MS; column: Ascentis Expresse 2.7 μm 2.1*30 mm, 60℃, eluent A: water + 0.05% HCOOH + 3.75 mM ammonium acetate, B: ACN + 0.04% HCOOH, gradient: 2% to 98% B over 1.4 min, flow rate: 1 mL / min (2 min)

[0620] LCMS Method d: Agilent LCMS: Waters SunFire C18, 2.5 μm, 3*30 mm, eluent A: water + 0.1% HCOOH; B: ACN + 0.1% HCOOH. Gradient: 10% to 98% B over 2.5 min, flow rate: 1.4 mL / min

[0621] LCMS method e: Waters UPLC Acquity; Column: Acquity HSS T3 1.8 µm, 2.1 x 50 mm, 60 °C; Eluent A: Water + 0.05% HCOOH + 3.75 mM ammonium acetate, Eluent B: MeCN + 0.04% HCOOH; Gradient: 10% to 95% B over 1.5 min; Flow rate: 1.0 mL / min

[0622] LCMS method f: Waters UPLC Acquity; Column: Acquity HSS T3, 1.8 µm, 2.1 x 50 mm, 60 °C; Eluent A: Water + 0.05% HCOOH + 3.75 mM ammonium acetate, Eluent B: MeCN + 0.04% HCOOH; Gradient: 5% to 98% B over 9.4 min, hold for 0.4 min; Flow rate: 0.8 mL / min

[0623] LCMS method g: Agilent LCMS; Column: Waters Acquity HSS T3, 1.8 µm, 2.1 x 50 mm, 60 °C; Eluent A: H₂O + 0.05% TFA; Eluent B: MeCN + 0.035% TFA. Gradient: 10% to 100% B over 1.35 min; Flow rate: 0.9 mL / min.

[0624] Synthesis of intermediates

[0625] Type A intermediate

[0626] Synthesis of (S)-10-amino-2,3,5,10-tetrahydro-1H,11H-benzo[d]pyrazolo[1,2-a][1,2]diazine - 11-keto (int-A1)

[0627]

[0628] Step 1: Thionyl chloride (14.8 mL, 202 mmol) was added dropwise to a suspension of isochorium-3-one (15 g, 101 mmol) in methanol (150 mL) at 0 °C. The resulting solution was stirred at 0 °C for 2 hours, followed by stirring at room temperature for 16 hours. The reaction mixture was concentrated, the crude material was dissolved in ethyl acetate and washed with a saturated aqueous solution of NaHCO3. The organic layer was dried (Na2SO4) and concentrated to give methyl 2-(2-(chloromethyl)phenyl)acetate. 1 H NMR (DMSO-d6, 400MHz): δ 7.44-7.47 (m, 1H), 7.27-7.36 (m, 3H), 4.80 (s, 2H), 3.85 (s, 2H), 3.63 (s, 3H).

[0629] Step 2: Pyrazolidine dihydrochloride (14.2 g, 98 mmol) was added to a solution of methyl 2-(2-(chloromethyl)phenyl)acetate (19.4 g, 98 mmol) in DMF (500 mL) at room temperature, followed by the addition of DIPEA (85 mL, 488 mmol), sodium iodide (14.6 g, 98 mmol), and sodium acetate (32.0 g, 391 mmol). The suspension was stirred at room temperature for 16 hours. The reaction mixture was concentrated, the crude material was dissolved in ethyl acetate and washed with saturated NaHCO3 solution. The organic phase was dried (Na2SO4), concentrated, and purified by column chromatography (10-20% ethyl acetate / toluene) to give 2,3,5,10-tetrahydrobenzo[d]pyrazol[1,2-a][1,2]diazide. -11(1H)-ketone. LCMS (method d) m / z 203.1 [M+H] + , t R =1.35 min. 1 ¹H NMR (DMSO-d⁶, 400 MHz): δ 7.14–7.26 (m, 3H), 7.03 (d, J = 7.3 Hz, 1H), 4.15 (s, 2H), 3.84 (br s, 2H), 3.48 (t, J = 7.2 Hz, 2H), 3.19 (t, J = 6.7 Hz, 2H), 2.19 (quintet, J = 7.0 Hz, 2H).

[0630] Step 3: At 0°C, add dropwise 93 mL (93 mmol) of 1 M LiHMDS in THF solution to 2,3,5,10-tetrahydrobenzo[d]pyrazolo[1,2-a][1,2]diazide. -11(1H)-one (14.0 g, 62 mmol) and isoamyl nitrite (10.8 mL, 81 mmol) were added to a solution of THF (750 mL), and the solution was stirred at 0 °C for 2 hours. The reaction mixture was concentrated and dissolved in ethyl acetate, washed with saturated NaHCO3 solution, dried (Na2SO4), concentrated, and purified by column chromatography (10-90% ethyl acetate / toluene containing 0.1% Et3N) to give (Z) and (E)-10-(hydroxyimino)-2,3,5,10-tetrahydrobenzo[d]pyrazolo[1,2-a][1,2]diazide. A mixture of -11(1H)-ketones. LCMS (Method d) m / z 232.0 [M+H] + , t R= 0.90 and 1.06 min.

[0631] Step 4: Add zinc powder (10.9 g, 166 mmol) to (Z) and (E)-10-(hydroxyimino)-2,3,5,10-tetrahydrobenzo[d]pyrazolo[1,2-a][1,2]diazide at room temperature. -11(1H)-one (9.6 g, 42 mmol) was added to a solution of AcOH (300 mL) and 10% HCl aqueous solution (300 mL), and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered and the filtrate was concentrated under vacuum to give 10-amino-2,3,5,10-tetrahydrobenzo[d]pyrazolo[1,2-a][1,2]diazid. -11(1H)-one, which was used in the next step without further purification.

[0632] Step 5: Add Boc2O (9.0 g, 41 mmol) and Na2CO3 (13.0 g, 124 mmol) to 10-amino-2,3,5,10-tetrahydrobenzo[d]pyrazolo[1,2-a][1,2]diazide at room temperature. -11(1H)-ketone (29.2 g, 41 mmol) in di The mixture was stirred in a solution of alkyl (400 mL) and water (200 mL) at room temperature for 16 hours. The mixture was concentrated and treated with ethyl acetate and saturated NaHCO3 solution. The organic layer was dried (MgSO4) and concentrated to give a crude product, which was purified by column chromatography (0-80% ethyl acetate / cyclohexane) to give racemic 11-oxo-1,2,3,5,10,11-hexahydrobenzo[d]pyrazolo[1,2-a][1,2]diazide. -10-ylcarbamate tert-butyl ester.

[0633] Step 6 (Chiral Separation); 11-oxo-1,2,3,5,10,11-hexahydrobenzo[d]pyrazolo[1,2-a][1,2]diazide was separated by chiral HPLC (Thar SFC-200 instrument, mobile phase: scCO2 / EtOH 85:15, column: Chiralcel OD-H, 30 x 250 mm). Two enantiomers of tert-butyl 10-ylcarbamate yield (S)-(11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazide). -10-yl)tert-butyl carbamate (enantiomer excess ≥ 99.5%) and (R)-(11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazide) -10-yl) tert-butyl carbamate (enantiomer excess ≥ 99.5%). (S)-(11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazide) Analytical data for tert-butyl carbamate (-10-yl): LCMS (Method b) m / z 318.3 [M+H] + , t R = 1.03 min. 1 H NMR (400 MHz, DMSO-d6) δppm 7.31 (d, J = 7.3 Hz, 1H), 7.15-7.27 (m, 2H), 7.05 (d, J = 6.7 Hz, 1H), 7.00 (d, J = 9.1 Hz, 1H), 6.42 (d, J = 9.1 Hz, 1H), 4.22 (s, 2H), 3.42-3.60(m, 2H), 3.22-3.30 (m, 1H), 3.13-3.21 (m, 1H), 2.27-2.41 (m, 1H), 2.04-2.16(m, 1H), 1.43 (s, 9H).

[0634] Step 7: Use distillate containing 4M HCl Alkane (250 mL) treatment (S)-(11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine) (S)-10-amino-2,3,5,10-tetrahydro-1H,11H-benzo[d]pyrazolo[1,2-a][1,2]diazide in the form of an HCl salt. -11-Keto (int-A1). LCMS (Method b) m / z 218.3 [M+H] + , t R = 0.40 min. Stereochemistry confirmed by X-ray analysis: [α] 23 D -105.7 (c = 1.0, MeOH). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.89 (br s, 3H), 7.29-7.39 (m, 2H), 7.24(d, J = 7.6 Hz, 1H), 7.16 (d, J=7.1 Hz, 1H), 5.98 (s, 1H), 4.28 (s, 2H), 3.55-3.62 (m, 2H), 3.18-3.29 (m, 2H), 2.29-2.44 (m, 1H), 2.12-2.19 (m, 1H).

[0635] Synthesis of (S)-10-amino-6-fluoro-2,3,5,10-tetrahydro-1H,11H-benzo[d]pyrazolo[1,2-a][1,2]di nitrogen -11-keto (int-A2)

[0636]

[0637] Step 1: Ethyl acetoacetate (17.7 mL, 140 mmol) was added to a solution of NaOEt in EtOH (prepared by dissolving Na metal (4.83 g, 210 mmol) in absolute EtOH (400 mL) at room temperature. The reaction mixture was stirred under reflux for 2 hours and, after cooling to room temperature, was subjected to a celestial reaction. ® The mixture was filtered through a pad. The solvent was removed under vacuum, and the residue was partitioned between 2NHCl and CH₂Cl₂. The organic layer was then treated with saturated NaHCO₃ until an alkaline pH was reached. The aqueous layer was washed with CH₂Cl₂, acidified to pH 1 with 2NHCl, and extracted with CH₂Cl₂. The organic layer was washed with brine, dried (Na₂SO₄), and concentrated to give 2-(2-ethoxy-2-oxoethyl)-6-fluorobenzoic acid. LCMS (Method b) m / z 226.5 [M+H] + , t R = 0.65 min. 1 HNMR (400 MHz, DMSO-d6) δ ppm 13.40 (br s, 1H), 7.42-7.52 (m, 1H), 7.17-7.26(m, 2H), 4.06 (q, J = 7.1 Hz, 2H), 3.84 (s, 2H), 1.17 (t, J = 7.1 Hz, 3H).

[0638] Step 2. Ethyl chlorocarbonate (4.4 mL, 46 mmol) was added to a solution of 2-(2-ethoxy-2-oxoethyl)-6-fluorobenzoic acid (9.5 g, 42 mmol) and Et3N (6.4 mL, 46 mmol) in CH2Cl2 (84 mL) at 0 °C. After stirring at room temperature for 2 hours, the mixture was quenched by adding 1N HCl and extracted with CH2Cl2. The organic layer was washed with brine, dried (Na2SO4), and concentrated. The crude intermediate was dissolved in THF (100 mL) and H2O (34 mL) containing cold (0 °C) NaBH4 (3.2 g, 84 mmol) was added at -15 °C. After stirring at -15 °C for 1 hour, the mixture was quenched by adding 1N HCl and extracted with Et2O. The organic layer was washed with saturated NaHCO3, water, and brine, dried (Na2SO4), and concentrated. The crude intermediate was heated at 80 °C with 100 mL of PhMe containing TsOH·H₂O (399 mg, 2.1 mmol) for 1 hour. After cooling to room temperature, the mixture was concentrated, diluted with Et₂O, washed with saturated NaHCO₃, water, and brine, dried (Na₂SO₄), and concentrated to give 8-fluoroisochromo-3-one. LCMS (Method b) m / z 167.1 [M+H] + , t R = 0.71 min. 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.33-7.46 (m, 1H), 7.10-7.23 (m, 2H), 5.43 (s, 2H), 3.87 (s, 2H).

[0639] Step 3: Thionyl chloride (0.88 mL, 12.0 mmol) was added dropwise to a suspension of 8-fluoroisochroman-3-one (1.0 g, 6.0 mmol) in MeOH (10 mL) at 0 °C. The solution was stirred at 0 °C for 1 hour, then at room temperature for 16 hours. The reaction mixture was treated with toluene and washed with water followed by saturated NaHCO3 until pH 6–7. The combined organic layers were washed with brine, dried (Na2SO4), and concentrated to give methyl 2-(2-(chloromethyl)-3-fluorophenyl)acetate, which was used directly in the next step. LCMS (Method b) m / z 240.1 [M + Na] + , t R = 1.01 min. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.33-7.50 (m, 1H), 7.10-7.27 (m, 2H), 4.79 (s, 2H), 3.89 (s, 2H), 3.63 (s, 3H).

[0640] Step 4: In a microwave oven at 200 °C, a mixture of methyl 2-(2-(chloromethyl)-3-fluorophenyl)acetate (1.0 g, 4.6 mmol), pyrazolidine dihydrochloride (0.67 g, 4.6 mmol), DIPEA (4.0 mL, 23 mmol), NaI (0.69 g, 4.6 mmol), and NaOAc (1.52 g, 18.5 mmol) in DMF (45 mL) was stirred for 10 minutes. After cooling to room temperature, the reaction mixture was treated with ethyl acetate and extracted with saturated NaHCO3. The organic layer was washed with brine, dried (Na2SO4), concentrated, and purified by column chromatography (25-50% ethyl acetate / cyclohexane) to give 6-fluoro-2,3,5,10-tetrahydrobenzo[d]pyrazol[1,2-a][1,2]diazide. -11(1H)-ketone. LCMS (Method b) m / z 221.2 [M+H] + , t R = 0.78 min. 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.20 (dd, J = 7.3, 6.6 Hz,1H), 7.02-7.09 (m, 2H), 4.10 (s, 2H), 3.49 (t, J = 7.3 Hz, 2H), 3.32 (s, 2H),3.24 (t, J = 6.7 Hz, 2H), 2.18-2.22 (m, 2H).

[0641] Step 5: At 0°C, add THF (3.4 mL, 3.4 mmol) containing 1 M LiHMDS dropwise to 6-fluoro-2,3,5,10-tetrahydrobenzo[d]pyrazolo[1,2-a][1,2]diazide. -11(1H)-one (300 mg, 1.4 mmol) and isoamyl nitrite (330 µL, 2.5 mmol) were mixed in THF (10 mL). The reaction mixture was stirred at 0 °C for 2 h, followed by treatment with saturated NaHCO3 solution and extraction with ethyl acetate. The organic layer was dried (Na2SO4) and evaporated to give (E / Z)-6-fluoro-10-(hydroxyimino)-2,3,5,10-tetrahydrobenzo[d]pyrazolo[1,2-a][1,2]diazide. -11(1H)-ketone, which was used in the next step without further purification. LCMS (Method b) m / z 250.2 [M+H] + , t R = 0.66 min.

[0642] Step 6: At room temperature, react (E / Z)-6-fluoro-10-(hydroxyimino)-2,3,5,10-tetrahydrobenzo[d]pyrazolo[1,2-a][1,2]diazide. A mixture of -11(1H)-ones (141 g, 566 mmol) was hydrogenated (4 bar) for 16 h in a mixture of 10% Pd / C (16 g) and 3.3 L and 1 M HCl (0.9 L). The reaction mixture was concentrated to give 10-amino-6-fluoro-2,3,5,10-tetrahydro-1H,11H-benzo[d]pyrazolo[1,2-a][1,2]diazid as an HCl salt. -11-keto, which was used in the next step without further purification. LCMS (Method b) m / z 236.2 [M+H] + , t R = 0.43min. 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.03 (s, 3H), 7.42 (q, J = 8.0 Hz, 1H), 7.26-7.29 (m, 1H), 7.13 (d, J = 7.9 Hz, 1H), 6.04 (s, 1H), 4.22 (s, 2H), 3.56-3.64 (m, 2H), 3.23-3.32 (m, 2H), 2.34-2.44 (m, 1H), 2.11-2.19 (m, 1H).

[0643] Step 7: Add the solution of Boc2O (151 g, 680 mmol) in CH2Cl2 (300 mL) to the solution at room temperature until the solution of 10-amino-6-fluoro-2,3,5,10-tetrahydro-1H,11H-benzo[d]pyrazolo[1,2-a][1,2]diazide is added. -11-one (HCl salt, 154 g, 567 mmol) and DIPEA (352 mL, 1984 mmol) were in a solution of CH2Cl2 (3.4 L). The mixture was stirred at room temperature for 16 hours. It was then treated with water, the aqueous phase was extracted with CH2Cl2, and the combined organic phases were dried (Na2SO4) and concentrated. The crude product was purified by column chromatography (25% EtOH / heptane) to give racemic (6-fluoro-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazide). -10-yl) tert-butyl carbamate.

[0644] Step 8 (Chiral Separation); Separation of (6-fluoro-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazide) by chiral HPLC (Bayer CC50 SMB unit, mobile phase: acetonitrile / methanol 1:1, column: Chiralpak AD, 8 x (10 x 100 mm)). Two enantiomers of tert-butyl carbamate (-10-yl)carbamate were obtained to yield (S)-(6-fluoro-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazide). -10-yl) tert-butyl carbamate (enantiomer excess > 99.5%) and (R)-(6-fluoro-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazide) -10-yl) tert-butyl carbamate (enantiomer excess > 99.5%). (S)-(6-fluoro-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazide) Analytical data for tert-butyl carbamate (-10-yl): LCMS (Method b) m / z 336.2 [M+H] + , t R = 1.04 min. [α] 23 D -57.2 (c = 1.0, MeOH). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.25-7.30 (m, 1H), 7.19(d, J = 8.0 Hz, 1H), 7.09-7.15 (m, 2H), 6.45 (d, J = 9.2 Hz, 1H), 4.12 (s,2H), 3.51-3.56 (m, 2H), 3.25-3.30 (m, 2H), 2.33-2.42 (m, 1H), 2.07-2.14 (m,1H), 1.43 (s, 9H).

[0645] Step 9: At 0°C, use a solution containing 4M HCl... Treatment with alkyl (20 mL, 80 mmol) of (S)-(6-fluoro-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazide) A mixture of (S)-10-amino-6-fluoro-2,3,5,10-tetrahydro-1H,11H-benzo[d]pyrazolo[1,2-a][1,2]diazide in CH2Cl2 (20 mL) was stirred at 0 °C for 2 hours. Et2O was added, the resulting precipitate was filtered off and dried under vacuum to give (S)-10-amino-6-fluoro-2,3,5,10-tetrahydro-1H,11H-benzo[d]pyrazolo[1,2-a][1,2]diazide as an HCl salt. -11-Keto (int-A2). LCMS (Method b) m / z 236.2 [M+H] + , t R = 0.44 min. [α] 23 D -99.0 (c = 1.0, MeOH). 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.03 (s, 3H), 7.42 (q, J = 8.0 Hz, 1H), 7.26-7.29 (m, 1H), 7.13 (d, J = 7.9 Hz, 1H), 6.04 (s, 1H), 4.22 (s, 2H), 3.56-3.64 (m, 2H), 3.23-3.32 (m, 2H), 2.34-2.44 (m, 1H), 2.11-2.19 (m, 1H).

[0646] Type B intermediate

[0647]

[0648] Synthesis of (S)-10-amino-2,3-dihydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza -5,11(10H)-dione (int-B1)

[0649]

[0650] Step 1: Add 380 mL of water containing sodium periodate (36.8 g, 172 mmol) to (S)-(11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazide) over 15 minutes at room temperature. A mixture of tert-butyl 1,0-yl)carbamate (13.6 g, 43 mmol) and hydrated ruthenium oxide (IV) (650 mg, 4.3 mmol) in ethyl acetate (430 mL) was added. The mixture was stirred at room temperature for 15 minutes, followed by treatment with water and CH2Cl2. The aqueous phase was extracted with CH2Cl2, and the combined organic layers were treated with charcoal and filtered through a diatomaceous earth stopper. The filtrate was washed with water and brine, dried (Na2SO4), and concentrated to give (S)-(5,11-dioxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazide). 10-yl) tert-butyl carbamate. LCMS (Method b) m / z 332.3 [M+H] + , t R =0.90 min. [α] 23 D -102.3 (c = 1.0, MeOH). 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.78 (d,J = 7.6 Hz, 1H), 7.54-7.68 (m, 2H), 7.40-7.52 (m, 2H), 5.67 (d, J = 8.6 Hz,1H), 4.27 (dt, J = 10.8, 7.2 Hz, 1H), 3.99-4.09 (m, 1H), 3.61 (dt, J = 10.4,7.3 Hz, 1H), 3.12-3.27 (m, 1H), 2.08-2.18 (m, 2H), 1.42 (s, 9H).

[0651] Step 2: Add dimethyl HCl containing 4M HCl Alkane (151 mL, 604 mmol) was added to (S)-(5,11-dioxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazide) (S)-10-amino-2,3-dihydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazocarbamate (10 g, 30 mmol) was added to a solution in CH2Cl2 (151 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was then concentrated and suspended in Et2O, followed by evaporation to remove residual HCl. Finally, the coarse material was wet-milled with Et2O, filtered, and the obtained solid was dried under vacuum to give (S)-10-amino-2,3-dihydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazocarbamate in the form of an HCl salt. -5,11(10H)-dione (int-B1). LCMS (Method b) m / z 232.2 [M+H] + ,t R = 0.32 min. [α] 23 D -145.0 (c = 1.0, MeOH). 1 H NMR (400 MHz, DMSO-d6) δ ppm9.24 (s, 3H), 7.87 (dd, J = 7.7, 1.2 Hz, 1H), 7.75 (t, J = 7.7 Hz, 1H), 7.58(t, J = 7.6 Hz, 1H), 7.43 (d, J = 7.8 Hz, 1H), 5.74 (s, 1H), 4.30 (dt, J =11.0, 7.5 Hz, 1H), 4.09 (ddd, J = 10.9, 7.9, 4.8 Hz, 1H), 3.55-3.61 (m, 1H), 3.28-3.33 (m, 1H), 2.01-2.26 (m, 2H).

[0652] C-type intermediate

[0653] Synthesis of (S)-10-amino-1H,3H,5H-spiro[benzo[d]pyrazolo[1,2-a][1,2]diazine [-2,1'-cyclopropane]-5,11(10H)-dione (int-C1)

[0654]

[0655] Step 1: A solution of MsCl (57.2 mL, 734 mmol) in CH₂Cl₂ (160 mL) was added dropwise to a solution of cyclopropane-1,1-dimethyldiethanol (25.0 g, 245 mmol) and Et₃N (136 mL, 979 mmol) in CH₂Cl₂ (250 mL) at 0 °C. The reaction mixture was stirred at room temperature for 16 hours. Then 1 M HCl (900 mL) was added and the mixture was extracted with CH₂Cl₂. The combined organic layers were washed with brine, dried (Na₂SO₄), and concentrated to a volume of 100–150 mL. Hexane was added and the resulting precipitate was filtered off, washed with hexane, and dried under vacuum to give cyclopropane-1,1-dimethylbis(methylene) dimethanesulfonate. 1 H NMR (400 MHz, DMSO-d6) δ ppm 4.14 (s, 4H), 3.19 (s,6H), 0.77 (s, 4H).

[0656] Step 2: A solution of di-tert-butyl hydrazine-1,2-dicarboxylate (18.6 g, 80 mmol) in anhydrous DMF (65 mL) was added dropwise to a suspension of NaH (60% dispersion in oil, 6.7 g, 168 mmol) in anhydrous DMF (40 mL) at 0 °C, and the suspension was stirred at room temperature for 1 hour. After adding cyclopropane-1,1-dimethylbis(methylene) dimethanesulfonate (20.7 g, 80 mmol), the reaction mixture was stirred at room temperature for 16 hours. It was then poured onto ice and water (1.3 L). The precipitate formed was filtered off, washed with water, and dried under vacuum to give di-tert-butyl 5,6-diazaspiro[2,4]heptane-5,6-dicarboxylate. LCMS (method g) m / z 619.4 [2M + Na] + , t R = 1.57 min. 1 H NMR (400MHz, DMSO-d6) δ ppm 3.56 (d, J = 10.6 Hz, 2H), 3.17 (d, J = 10.6 Hz, 2H), 1.41 (s, 18H), 0.63-0.68 (m, 4H).

[0657] Step 3: A hydrobromic acid solution (33 wt%, in AcOH, 38.5 mL, 0.22 mol) was slowly added to a solution of 5,6-diazaspiro[2,4]heptane-5,6-dicarboxylic acid di-tert-butyl ester (12 g, 40 mmol) in Et₂O (200 mL) at 0 °C, and the mixture was stirred at room temperature for 16 hours. After cooling to 0 °C, the solid was filtered off, washed with Et₂O, and dried under vacuum to give 5,6-diazaspiro[2,4]heptane dihydrobromide. LCMS (method g) m / z 99.2 [M+H] + , t R = 0.26min. 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.80 (br s, 4H), 3.06 (s, 4H), 0.76 (s, 4H).

[0658] Step 4: 5,6-diazaspiro[2,4]heptane dihydrobromide (5.2 g, 20 mmol) was added to a solution of high phthalic anhydride (3.3 g, 20 mmol) in AcOH (35 mL) and pyridine (18 mL) at room temperature. The solution was then stirred at 130 °C for 20 hours. After cooling to room temperature, the mixture was diluted with water and extracted with CH2Cl2. The combined organic layers were washed with 10% HCl, 5% NaHCO3, water, and brine, dried (Na2SO4), and concentrated. The crude product was purified by column chromatography (20-50% ethyl acetate / hexane) to give 1H-spiro[benzo[d]pyrazolo[1,2-a][1,2]diazaspiro[2,4]heptane. [-2,1'-cyclopropane]-5,11(3H,10H)-dione. LCMS (method g) m / z 243.2 [M+H] + , t R = 1.11 min. 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.79 (dd, J = 7.7 Hz, 1.4, 1H), 7.54-7.58 (m, 1H), 7.41-7.47(m, 2H), 4.20 (d, J = 11.0 Hz, 1H), 4.14 (d, J = 13.4 Hz, 1H), 3.88 (d, J =10.6 Hz, 1H), 3.46-3.57 (m, 2H), 3.23 (d, J = 10.5 Hz, 1H), 0.75-0.79 (m,4H).

[0659] Step 5: At 0°C, add THF (26 mL, 26 mmol) containing 1 M LiHMDS dropwise to 1H-spiro[benzo[d]pyrazolo[1,2-a][1,2]diazepine [-2,1'-cyclopropane]-5,11(3H,10H)-dione (4.1 g, 17 mmol) and isoamyl nitrite (3.4 mL, 26 mmol) were in suspension in THF (34 mL). The reaction mixture was stirred at room temperature for 2 hours. AcOH was added and the mixture was evaporated twice under vacuum to give (Z) and (E)-10-(hydroxyimino)-1H-spiro[benzo[d]pyrazolo[1,2-a][1,2]diazepine A mixture of [-2,1'-cyclopropane]-5,11(3H,10H)-diones, used in the next step without further purification. LCMS (method g) m / z 272.2 [M+H] + , t R = 1.10 and 1.13 min.

[0660] Step 6: Add 4M HCl (4.3 mL, 17 mmol) to the crude (Z,E)-10-(hydroxyimino)-1H-spiro[benzo[d]pyrazolo[1,2-a][1,2]diazide at room temperature. [-2,1'-cyclopropane]-5,11(3H,10H)-dione (4.6 g, 17.0 mmol) was added to a mixture in AcOH (92 mL). The mixture was then cooled to 0 °C and zinc powder (4.5 g, 68 mmol) was slowly added. After addition, the reaction mixture was stirred at room temperature for 1.5 hours. The inorganic zinc residue was filtered off and washed with CH2Cl2. The filtrate was concentrated, dissolved again in CH2Cl2, washed with 10% NaOH and brine, dried (Na2SO4), and concentrated. The residue was purified by column chromatography (0-4% MeOH / CH2Cl2 (NH3)) to give racemic 10-amino-1H,3H,5H-spiro[benzo[d]pyrazolo[1,2-a][1,2]diazepine [-2,1'-cyclopropane]-5,11(10H)-dione. LCMS (method g) m / z 258.2 [M+H] + , t R = 0.79 min. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.73-7.78 (m, 2H),7.62 (td, J = 7.6, 1.4, 1H), 7.40-7.45 (m, 1H), 4.97 (s, 1H), 4.21 (d, J =11.2 Hz, 1H), 3.88 (d, J = 10.8 Hz, 1H), 3.54 (d, J = 11.2 Hz, 1H), 3.27 (d,J = 10.8 Hz, 1H), 2.28 (s, 2H), 0.70-0.85 (m, 4H).

[0661] Step 7. Add Boc2O (76 g, 347 mmol) to a mixture containing racemic 10-amino-1H,3H,5H-spiro[benzo[d]pyrazolo[1,2-a][1,2]diazide at room temperature. The di-2,1'-cyclopropane]-5,11(10H)-dione (68 g, 231 mmol) and Na2CO3 (110 g, 1.04 mol) The mixture was stirred in a 1:1 mixture of alkylene and water (1.4 L) at room temperature for 2 hours. The resulting precipitate was filtered off, washed twice with water, and dried under vacuum. The solid was dissolved in a solution containing 3% formic acid. In alkanes, and by preparative chiral HPLC (Thhar SFC-200 instrument, mobile phase: scCO2 / EtOH 70:30, column: Chiralpak IC, 5 uM, 250 x 30 mm), the enantiomers were separated to give (S)-enantiomers (>99.5% ee) and (R)-enantiomers (>99.5% ee). (S)-(5,11-dioxo-10,11-dihydro-1H,3H,5H-spiro[benzo[d]pyrazolo[1,2-a][1,2]diazide) Analytical data for tert-butyl 2,1'-cyclopropyl]-10-yl)carbamate. LCMS (Method e) m / z 358.2 [M+H] + , t R = 1.05 min. [α] 23 D -125.0 (c = 1.0, MeOH). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.81 (d, J = 7.5 Hz, 1H), 7.61-7.71 (m, 2H), 7.45-7.51 (m, 2H), 5.74 (d, J = 8.9 Hz, 1H), 4.21 (d, J = 11.1 Hz, 1H), 3.90(d, J = 10.7 Hz, 1H), 3.62 (d, J = 11.1 Hz, 1H), 3.27 (d, J = 10.7 Hz, 1H), 1.42 (s, 9H), 0.71-0.82 (m, 4H).

[0662] Step 8. Add (S)-(5,11-dioxo-10,11-dihydro-1H,3H,5H-spiro[benzo[d]pyrazolo[1,2-a][1,2]diazepine) 2,1'-Cyclopropyl]-10-yl)tert-butyl carbamate (2.0 g, 5.6 mmol) was dissolved in CH2Cl2 (28 mL) and tested at 0 °C using a dihydrochloric acid solution containing 4 M HCl. The mixture was treated with alkylene (28 mL, 112 mmol). After stirring at 0 °C for 1 hour, the reaction mixture was concentrated. The residue was treated with CH2Cl2 and evaporated. It was then wet-milled with Et2O, the precipitate was filtered off and dried under vacuum to give (S)-10-amino-1H,3H,5H-spiro[benzo[d]pyrazolo[1,2-a][1,2]diazide as an HCl salt. [-2,1'-cyclopropane]-5,11(10H)-dione (int-C1). LCMS (Method b) m / z 258.2 [M+H] + , t R = 0.46 min. [α] 23 D -160.4 (c = 1.0, MeOH). 1H NMR (400 MHz, DMSO-d6) δ ppm9.33 (br s, 3H), 7.89 (d, J = 7.4 Hz, 1H), 7.75 (t, J = 7.2 Hz, 1H), 7.60 (t,J = 7.3 Hz, 1H), 7.46 (d, J = 7.9 Hz, 1H), 5.83 (s, 1H), 4.26 (d, J = 11.1Hz, 1H), 3.91 (d, J = 10.9 Hz, 1H), 3.53 (d, J = 11.1 Hz, 1H), 3.42 (d, J =10.3 Hz, 1H), 0.74-0.89 (m, 4H).

[0663] D-type intermediate

[0664]

[0665] synthesis 10-Amino-5,10-dihydro-1H-spiro[benzo[d]pyrazolo[1,2-a][1,2]diazine -2,1'-ring [Propyl]-11(3H)-one(int-C1)

[0666]

[0667] Step 1: Add Et3N (136 mL, 979 mmol) to a solution of cyclopropane-1,1-dimethyldiethanol (25.0 g, 245 mmol) in CH2Cl2 (250 mL) and cool the reaction mixture to 0 °C. Add MsCl (57.2 mL, 734 mmol) dropwise to a solution of CH2Cl2 (160 mL) and remove the cooling bath. After stirring at room temperature for 16 hours, add 1N HCl (900 mL) and extract the mixture with CH2Cl2. Wash the combined organic layers with brine and dry (Na2SO4). Then concentrate the solution to 100–150 mL and add hexane. Filter out the slightly brown crystals, wash with CH2Cl2-hexane, hexane, and dry under high vacuum to give cyclopropane-1,1-dimethylbis(methylene) dimethanesulfonate. 1 H NMR (400 MHz, DMSO-d6) δ ppm 4.14 (s, 4H), 3.19 (s, 6H), 0.77 (s, 4H).

[0668] Step 2: A solution of di-tert-butyl hydrazine-1,2-dicarboxylate (18.6 g, 80 mmol) in anhydrous DMF (65 mL) was added to a suspension of NaH (6.72 g, 168 mmol) in anhydrous DMF (40 mL) at 0 °C. The suspension was stirred at room temperature for 1 hour, followed by the addition of solid cyclopropane-1,1-dimethylbis(methylene) dimethanesulfonate (20.7 g, 80 mmol), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into ice and water (1.3 L), the solid was filtered off, washed with water, and dried under high vacuum to give di-tert-butyl 5,6-diazaspiro[2,4]heptane-5,6-dicarboxylate. m / z619 [2M+Na] + , 1 H NMR (400 MHz, DMSO-d6) δ ppm 3.56 (d, 2H), 3.17 (d, 2H), 1.41 (s, 18H), 0.66 (m, 4H).

[0669] Step 3: A hydrobromic acid solution (33 wt%, in AcOH, 38.5 mL) was slowly added to a solution of 5,6-diazaspiro[2,4]heptane-5,6-dicarboxylic acid di-tert-butyl ester (11.9 g, 40 mmol) in Et₂O (200 mL) at 0 °C, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was then cooled to 0 °C and filtered. The solid was washed with Et₂O and dried under high vacuum to give 5,6-diazaspiro[2,4]heptane dihydrobromide. m / z 99 [M+H] + , 1 H NMR (400MHz, DMSO-d6) δ ppm 7.80 (bs, 4H), 3.06 (s, 4H), 0.76 (s, 4H).

[0670] Step 4: A mixture of methyl 2-(2-(chloromethyl)phenyl)acetate (2.38 g, 12 mmol), 5,6-diazaspiro[2,4]heptane dihydrobromide (3.74 g, 14.4 mmol), anhydrous MeOH (30 mL), and DIPEA (10.5 mL, 60 mmol) was heated in a microwave oven at 150 °C for 5 hours. After cooling to room temperature, the reaction mixture was concentrated, treated with water, and extracted with CH2Cl2. The collected organic phase was dried (Na2SO4) and concentrated. The residue was purified by column chromatography (0-70% ethyl acetate / hexane) to give 5,10-dihydro-1H-spiro[benzo[d]pyrazolo[1,2-a][1,2]diazaspiro[2,4]heptane. -2,1'-cyclopropyl]-11(3H)-one. m / z 229 [M+H] + , t R = 1.26 min (LCMS condition a), 1 H NMR (600 MHz, DMSO-d6) δ ppm 7.20 (m, 1H), 7.18 (m, 2H), 7.07 (m, 1H), 4.35 (s, 2H), 3.86 (bs, 2H), 3.47 (s, 2H), 3.23 (bs, 2H), 0.76 (m, 4H).

[0671] Step 5: Amyl nitrite (0.646 mL, 4.80 mmol) was added to 5,10-dihydro-1H-spiro[benzo[d]pyrazolo[1,2-a][1,2]diazepine at 0 °C. -2,1'-cyclopropyl]-11(3H)-one (913 mg, 4 mmol) was added to a solution of THF (10 mL), followed by the addition of LiHMDS (1 M, in THF, 5.60 mL, 5.60 mmol). After the reaction mixture was incubated at 0 °C for 2 hours, the reactants were quenched by adding water and the mixture was concentrated. The crude product was wet-milled with Et2O, the solid was filtered off and washed with Et2O. It was then dissolved in ethyl acetate and washed with saturated NaHCO3 solution. The aqueous phase was extracted with ethyl acetate, the collected organic layer was dried (Na2SO4) and concentrated to give the crude title compound as a mixture of (Z, E) isomers: (Z,E)-10-(hydroxyimino)-5,10-dihydro-1H-spiro[benzo[d]pyrazolo[1,2-a][1,2]diazide -2,1'-cyclopropyl]-11(3H)-one. m / z 258 [M+H] + , t R = 1.14 min (LCMS condition a), 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.49 + 11.46 (s, 1H), 7.64 and 7.30 (m, 4H), 4.34 (bs, 2H), 3.52 (s, 2H), 3.14 (bs, 2H), 0.78 (m, 4H).

[0672] Step 6: Slowly add zinc powder (1.0 g, 15.9 mmol) to 4N HCl (1 mL) and (Z,E)-10-(hydroxyimino)-5,10-dihydro-1H-spiro[benzo[d]pyrazolo[1,2-a][1,2]diazide at 0°C. -2,1'-cyclopropane]-11(3H)-one (1.03 g, 3.98 mmol) was added to a mixture in AcOH (20 mL), and the reaction mixture was stirred at room temperature for 2.5 hours. The mixture was then filtered to remove zinc, and the solid was washed with CH2Cl2. The filtrate was treated with 1N NaOH and the aqueous phase was extracted with CH2Cl2. The combined organic phases were dried and concentrated. The residue was purified by column chromatography (0-10% MeOH / (CH2Cl2 containing 1% NH4OH)) to give 10-amino-5,10-dihydro-1H-spiro[benzo[d]pyrazolo[1,2-a][1,2]diazide -2,1'-Cyclopropyl]-11(3H)-one. m / z 244 [M+H] + , t R = 0.90 min (LCMS condition a), 1 H NMR(400 MHz, DMSO-d6) δ ppm 7.80 (m, 1H), 7.19 (m, 2H), 7.03 (m, 1H), 5.53 (s,1H), 4.50 (d, 1H), 4.30 (d, 1H), 3.64 (d, 1H), 3.42 (d, 1H), 3.36 (d, 1H), 2.86 (d, 1H), 2.05 (s, 2H), 0.85 (m, 2H), 0.74 (m, 1H), 0.66 (m, 1H).

[0673] Chiral separation (via BOC protection, chiral separation, and BOC deprotection) as described for type A and type C intermediates allows for the separation of type D intermediates.

[0674] L-shaped intermediate

[0675] Synthesis of 2-(((tert-Butoxycarbonyl)amino)methyl)-3,3,3-trifluoropropionic acid (int-L1)

[0676]

[0677] 2-(aminomethyl)-3,3,3-trifluoropropionic acid (15 g, 95 mmol) was added to dihydrogen phosphate. Water (300 mL), Na₂CO₃ (45.5 g, 430 mmol), and Boc₂O (33.3 mL, 143 mmol) were added to the mixture in alkane (300 mL). The reaction mixture was stirred at room temperature for 16 hours, then CH₂Cl₂ was added and the mixture was acidified with 1N HCl. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried (MgSO₄) and concentrated. The crude product was used without further purification. LCMS (Method e) M / z 256 [MH] - ; t R = 2.70 min. 1 H NMR (400 MHz, DMSO-d6) δ ppm 13.5 (s, 1H), 7.17 (m,1H), 3.49 (m, 1H), 3.37 (m, 2H), 1.38 (s, 9H).

[0678] Synthesis of (R)-3-((tert-butoxycarbonyl)amino)-2-cyclopropylpropionic acid (int-L2)

[0679]

[0680] Step 1: Then, EDC (6.5 g, 33.9 mmol) was added to (S)-4-benzyl group at room temperature. A mixture of 3.0 g (5.64 mmol), DMAP (3.1 g, 25.4 mmol), and 2-cyclopropylacetic acid (2.36 mL, 25.4 mmol) in CH₂Cl₂ (20 mL) was stirred at room temperature for 16 hours. The reaction mixture was then diluted with CH₂Cl₂, washed with water, 1N HCl, 1N NaOH, and brine, dried over (Na₂SO₄), and concentrated to give (S)-4-benzyl-3-(2-cyclopropylacetyl) Zolpidem-2-one was used in the next step without further purification. LCMS (Method b) m / z 260.2 [M+H] + , t R = 1.05 min. [α] 23 D +90.6 (c = 1.0, MeOH); 1H NMR (400 MHz, CDCl3) δ ppm 7.38 - 7.32 (m, 2H), 7.32 - 7.28 (m, 1H), 7.25 -7.23 (m, 2H), 4.78 - 4.70 (m, 1H), 4.28 - 4.19 (m, 2H), 3.36 (dd, J = 13.4, 3.2 Hz, 1H),2.97 (dd, J = 17.0, 6.7 Hz, 1H), 2.89 - 2.75 (m, 2H), 1.31 - 1.14 (m, 1H),0.69 - 0.59 (m, 2H), 0.31 - 0.22 (m, 2H).

[0681] Step 2: Add THF (8.68 mL, 8.68 mmol) containing 1 M NaHMDS dropwise to (S)-4-benzyl-3-(2-cyclopropylacetyl) at -78°C. A solution of 1.5 g (5.78 mmol) of 2-oxazolidin-2-one in 8 mL of THF was added. After stirring at -78 °C for 1 hour, 1.55 mL (10.41 mmol) of 2-bromoacetic acid tert-butyl ester was added and the mixture was stirred at -78 °C for 1 hour. The mixture was then quenched by adding saturated NH4Cl and heated to room temperature. The mixture was extracted with ethyl acetate, the organic layer was washed with water and brine, dried (Na2SO4), and concentrated to give a crude product, which was purified by chromatography (5-20% ethyl acetate / cyclohexane) to give (S)-4-((S)-4-benzyl-2-oxo tert-butyl oxazolidinyl (3-yl)-3-cyclopropyl-4-oxobutyrate. LCMS (Method b) m / z 374.3 [M+H] + , t R = 1.29 min. 1H NMR (400 MHz, CDCl3) δppm 7.38 - 7.27 (m, 5H), 4.71 (td, J = 6.7, 3.3 Hz, 1H), 4.22 - 4.13 (m, 2H), 3.79 - 3.70 (m, 1H), 3.39 (dd, J = 13.4, 3.2 Hz, 1H), 2.97 (dd, J = 16.8,10.8 Hz, 1H), 2.73 (dd, J = 13.4, 10.3 Hz, 1H), 2.59 (dd, J = 16.8, 4.3 Hz,1H), 1.43 (s, 9H), 1.01 - 0.89 (m, 1H), 0.61 - 0.48 (m, 2H), 0.48 - 0.40 (m, 1H), 0.35 -0.18 (m, 1H).

[0682] Step 3: Add TFA (4.54 μL, 58.9 mmol) to (S)-4-((S)-4-benzyl-2-oxo) at room temperature. (S)-4-(S)-3-yl)-3-cyclopropyl-4-oxobutyrate tert-butyl ester (1.1 g, 2.95 mmol) was dissolved in CH2Cl2 (25 mL) and the solution was stirred at room temperature for 1 hour. The reaction mixture was then concentrated, and the residue was dissolved in CH2Cl2 and concentrated again. This process was repeated using Et2O to remove residual TFA and to give (S)-4-((S)-4-benzyl-2-oxobutyrate tert-butyl ester (1.1 g, 2.95 mmol) in CH2Cl2 (25 mL) and the solution was stirred at room temperature for 1 hour. (3-yl)-3-cyclopropyl-4-oxobutyric acid. LCMS (Method b) m / z 318.2 [M+H] + , t R = 0.90 min. 1HNMR (400 MHz, DMSO-d6) δ ppm 12.31 (s, 1H), 7.34 - 7.29 (m, 4H), 7.29 - 7.22(m, 1H), 4.75 - 4.64 (m, 1H), 4.34 (t, J = 8.4 Hz, 1H), 4.15 (dd, J = 8.9, 2.3 Hz, 1H), 3.70 (ddd, J = 10.2, 8.9, 4.6 Hz, 1H), 2.99 (dd, J = 13.6, 3.3Hz, 1H), 2.90 - 2.73 (m, 2H), 2.55 (dd, J = 16.9, 4.7 Hz, 1H), 0.95 - 0.84(m, 1H), 0.51 - 0.41 (m, 1H), 0.41 - 0.31 (m, 2H), 0.26 - 0.16 (m, 1H).

[0683] Step 4: Ethyl chloroformate (480 mg, 4.42 mmol) was added to (S)-4-((S)-4-benzyl-2-oxo) at 0°C. A solution of 3-oxobutyric acid (1.275 mg, 4.02 mmol) and triethylamine (672 µL, 4.82 mmol) in acetone (40 mL) was added, and the reaction mixture was stirred at 0 °C for 1 hour. Then, NaN3 (522 mg, in 10 mL H2O) was added to the reaction mixture at 0 °C, and the mixture was stirred at 0 °C for 1 hour. The solvent was removed, and the residue was extracted with Et2O. The organic phase was dried (Na2SO4) and concentrated. Toluene (80 mL) was added to the residue, and 40 mL of solvent was distilled off to remove residual water via azeotropic extraction. Tert-butanol (20 mL) was added to the reaction mixture, and the mixture was stirred under reflux for 16 hours. After cooling to room temperature, the solvent was removed and the residue was dissolved in CH2Cl2. The mixture was washed with 2NHCl, water, and brine, dried over Na2SO4, and concentrated to give ((R)-3-((S)-4-benzyl-2-oxo) (-3-yl)-2-cyclopropyl-3-oxopropyl)tert-butyl carbamate. LCMS (Method b) m / z 389.3 [M+H] + , t R =1.16 min. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.36 - 7.28 (m, 2H), 7.28 - 7.19 (m,3H), 6.95 (t, J = 5.5 Hz, 1H), 4.72 - 4.60 (m, 1H), 4.36 - 4.27 (m, 1H), 4.19- 4.11 (m, 1H), 3.46 - 3.36 (m, 1H), 3.30 - 3.18 (m, 2H), 3.14 - 3.05 (m,1H), 2.86 - 2.76 (m, 1H), 1.35 (s, 9H), 1.10 - 0.93 (m, 1H), 0.56 - 0.44 (m,1H), 0.42 - 0.31 (m, 1H), 0.26 - 0.11 (m, 2H).

[0684] Step 5: Hydrogen peroxide (1.1 mL, 10.81 mmol) was added to ((R)-3-((S)-4-benzyl-2-oxo) at 0 °C. A mixture of tert-butyl (-3-yl)-2-cyclopropyl-3-oxopropyl)carbamate (1.4 g, 3.60 mmol) in THF (8 mL) was added, followed by the addition of LiOH (302 mg, 7.21 mmol) and water (0.7 mL), and the reaction mixture was stirred at 0 °C for 2.5 h. The reaction mixture was then treated at 0 °C with saturated NaHSO3 (4 mL) and saturated NaHCO3 (10 mL). THF was removed under reduced pressure and the aqueous layer was washed with CH2Cl2 (pH 10). The aqueous layer was then cooled to 0 °C and acidified to pH 2 with 4NHCl and 10% KHSO4. It was extracted with ethyl acetate, the combined organic phases were washed with water and brine, dried (Na2SO4) and concentrated to give an oil, which was allowed to crystallize overnight. Recrystallization from hexane gave (R)-3-((tert-butyloxycarbonyl)amino)-2-cyclopropylpropionic acid (int-L2). 1 H NMR (400 MHz, DMSO-d6) δ ppm 12.12 (s, 1H), 6.78 (t, J = 6.0 Hz, 1H), 3.21 - 2.96 (m, 2H), 1.81 - 1.62 (m, 1H), 1.36 (s, 9H),0.89 - 0.69 (m, 1H), 0.55 - 0.31 (m, 2H), 0.26 - 0.08 (m, 2H).

[0685] Synthesis of (R)-2-(((tert-butoxycarbonyl)amino)methyl)butyric acid(int-L3)

[0686]

[0687] The method described for the synthesis of ((tert-butoxycarbonyl)amino)-2-cyclopropylpropionic acid (int-L2) was used, but but butyric acid was used instead of 2-cyclopropylacetic acid to obtain (R)-2-(((tert-butoxycarbonyl)amino)methyl)butyric acid (int-L3). 1 H NMR (400 MHz, DMSO-d6) δ ppm 12.12 (s, 1H), 6.80 (t, J = 4.7 Hz, 1H), 3.15 - 3.04 (m, 1H), 3.04 - 2.92 (m, 1H), 2.39 - 2.28 (m, 1H), 1.54 - 1.40 (m, 2H), 1.37 (s, 9H), 0.84 (t, J = 7.4 Hz, 3H).

[0688] Synthesis of (R)-2-(((tert-Butoxycarbonyl)amino)methyl)valeric acid (int-L4)

[0689]

[0690] Step 1: Pivaloyl chloride (3.25 mL, 26.4 mmol) was added to a solution of Boc-β-alanine (5 g, 26.4 mmol) in CH₂Cl₂ (50 mL) and TEA (3.87 mL, 27.7 mmol) at 0 °C, and the mixture was stirred at 0 °C for 1 hour. Then, TEA (5.52 mL, 39.6 mmol) was added, followed by a solution of (1R, 2R)-pseudoephedrine (4.37 g, 26.4 mmol) in CH₂Cl₂ (5 mL), and the mixture was stirred at 20 °C for 16 hours. The reaction mixture was concentrated, and the residue was dissolved in a 1:1 mixture of MeOH / H₂O (30 mL). Concentrated HCl (22.5 mL) was added to the solution at 0 °C, and the mixture was stirred at 20 °C for 3 hours. The reaction mixture was concentrated, dissolved in water, and washed with ethyl acetate / cyclohexane (1 / 1). The aqueous phase was prepared with 50% NaOH to make it alkaline (pH 12) and extracted with CH2Cl2. The combined organic phases were dried (Na2SO4) and concentrated. The colorless oil was crystallized from toluene to give 3-amino-N-((1R,2R)-1-hydroxy-1-phenylprop-2-yl)-N-methylpropionamide. LCMS (Method e) m / z 237.0 [M+H] + , t R = 0.40 min. 1¹H NMR (400MHz, DMSO-d⁶): δ ppm 7.41 - 7.20 (m, 5H), 4.55 - 4.40 (m, 1H), 4.03 - 3.85 (m, 1H), 2.83 + 2.75 (s, 3H), 2.73 - 2.61 (m, 2H), 2.46 - 2.25 (m, 2H), 1.49 (s, 1H), 0.88 +0.82 (d, J = 6.7 Hz, 3H) (NH₃ not observed) + ).

[0691] Step 2: LiHMDS (29.8 mL, 29.8 mmol) was added dropwise to a mixture of 3-amino-N-((1R,2R)-1-hydroxy-1-phenylprop-2-yl)-N-methylpropionamide (2.2 g, 9.31 mmol) and LiCl (1.579 g, 37.2 mmol) in THF (44 mL) at 0 °C. After stirring at 0 °C for 1 hour, 1-iodopropane (1.364 mL, 13.96 mmol) was slowly added and the mixture was stirred at 0 °C for 6 hours. The reaction mixture was quenched by adding water followed by 6N HCl (until pH 3 was reached), and the aqueous phase was washed with ethyl acetate / cyclohexane (1 / 1). The mixture was then brought to alkalinity (pH 12) with 50% NaOH at 0 °C and extracted with CH2Cl2. The organic phase was dried (MgSO4) and concentrated. The crude material was purified by preparative HPLC (Macherey-Nagel Nucleosil 100-10 C18, flow rate 40 mL / min, ACN: 5 min to 5%, 20 min to 100%). The product fraction was treated with saturated NaHCO3 and extracted with CH2Cl2. The combined organic phases were dried (MgSO4) and concentrated to give (R)-2-(aminomethyl)-N-((1R,2R)-1-hydroxy-1-phenylpropyl-2-yl)-N-methylpentanamide. LCMS (Method e) m / z 279.4 [M+H] + ,t R = 0.59 min. 1¹H NMR (400 MHz, DMSO-d6): δ ppm 7.39 - 7.19 (m, 5H), 4.85 -4.72 +4.17 - 4.06 (m, 1H), 4.55 - 4.47 (m, 1H), 3.00 - 2.55 (m, 4H), 2.49 -2.42 (m, 2H), 1.73 - 1.11 (m, 5H), 1.03 - 0.59 (m, 6H). (NH₃ not observed) + ).

[0692] Step 3: The mixture of (R)-2-(aminomethyl)-N-((1R,2R)-1-hydroxy-1-phenylprop-2-yl)-N-methylpentanamide in water (10 mL) was stirred for 5 days at 100 °C. After cooling to room temperature, the reaction mixture was washed with CH2Cl2 and concentrated. The residue was crystallized from MeOH to give (R)-2-(aminomethyl)pentanic acid. LCMS (Method b) m / z 132.2 [M+H] + ,t R = 0.17 min. 1 ¹H NMR (400 MHz, DMSO-d⁶): δ ppm 2.80 (dd, J = 12.2, 4.4 Hz, 1H), 2.69 - 2.56 (m, 1H), 2.08 - 1.94 (m, 1H), 1.65 - 1.48 (m, 1H), 1.39 - 1.16 (m, 3H), 0.85 (t, J = 7.0 Hz, 3H). (NH₃⁺ and COOH were not observed.)

[0693] Step 4: Add Na₂CO₃ (415 mg, 3.91 mmol) and Boc₂O (0.30 mL, 1.30 mmol) to (R)-2-(aminomethyl)valerate in diethylcarboxylic acid. The reaction mixture was placed in a solution of alkane (2 mL) and water (1 mL) and stirred at room temperature for 2 days. The reaction mixture was then washed with CH₂Cl₂, acidified with 1N HCl, and extracted with ethyl acetate. The organic layer was dried over (MgSO₄) and concentrated to give (R)-2-(((tert-butoxycarbonyl)amino)methyl)pentanoic acid (int-L4). LCMS (Method b) m / z 232.2 [M+H] + , t R = 1.22 min. 1H NMR (400 MHz, DMSO-d6): δ ppm 12.15 (s, 1H), 6.86 (t, J = 5.9 Hz, 1H), 3.14 - 3.04 (m, 1H), 3.02 - 2.90 (m, 1H), 2.46 -2.34 (m, 1H), 1.46 - 1.39 (m, 1H), 1.36 (s, 9H), 1.34 - 1.14 (m, 3H), 0.85 (t, J = 7.1 Hz, 3H).

[0694] Synthesis of (R)-2-(((tert-butoxycarbonyl)amino)methyl)-4-methoxybutyric acid (int-L5)

[0695]

[0696] Step 1: Oxaloyl chloride (1.844 mL, 21.07 mmol) was added dropwise to a stirred solution of 4-methoxybutyric acid (2.37 g, 20.06 mmol) in CH₂Cl₂ (100 mL) at room temperature, followed by the addition of one drop of DMF. The resulting solution was stirred at room temperature for 1 hour. The reaction mixture was concentrated to obtain 4-methoxybutyryl chloride, which was used directly in the next step.

[0697] Step 2: Add n-butyllithium (1.6 M, in hexane) (12.54 mL, 20.06 mmol) dropwise to (S)-4-benzylmethyl at -78 °C. Azoxyl-2-one (3.55 g, 20.06 mmol) was added to a stirred solution of THF (201 mL) at -78 °C for 15 min. Then, THF (5 mL) containing 4-methoxybutyryl chloride (2.74 g, 20.06 mmol) was added dropwise at -78 °C, and the reaction mixture was stirred at -78 °C for 1 h, followed by quenching with saturated NaHCO3 solution (100 mL). The aqueous phase was separated and extracted with CH2Cl2, and the combined organic fractions were dried (MgSO4) and concentrated to give a crude product, which was purified by column chromatography (0-40% ethyl acetate / cyclohexane) to give (S)-4-benzyl-3-(4-methoxybutyryl). Zolpidem-2-one. LCMS (Method b) m / z 278.4 [M+H] + ; t R = 1.01 min. 1HNMR (400 MHz, DMSO-d6): δ ppm 7.44 - 7.04 (m, 5H), 4.75 - 4.57 (m, 1H), 4.31(t, J = 8.5 Hz, 1H), 4.17 (dd, J = 8.8, 2.8 Hz, 1H), 3.36 (t, J = 6.3 Hz, 2H), 3.23 (s, 3H), 3.00 (dd, J = 13.5, 3.4 Hz, 1H), 2.95 - 2.75 (m, 3H), 1.88- 1.72 (m, 2H).

[0698] Step 3: Add LiHMDS (1M, in PhMe) (3.97 mL, 3.97 mmol) to (S)-4-benzyl-3-(4-methoxybutyryl) at -78°C. Azoxyl-2-one (1 g, 3.61 mmol) was added to a stirred solution in THF (36.1 mL), and the resulting solution was heated to -10 °C and stirred for 15 min. After cooling to -78 °C, N,N-diphenylmethyl-1-methoxymethylamine (1.74 g, 7.21 mmol) was added, followed by titanium(IV) chloride (0.080 mL, 0.721 mmol). The resulting solution was stirred at -78 °C for 1 h. The reaction mixture was quenched by adding saturated NaHCO3 solution (50 mL). The aqueous phase was separated and extracted with CH2Cl2, and the combined organic fractions were dried (MgSO4) and concentrated. The crude product was purified by column chromatography (0-25% ethyl acetate / cyclohexane) to give (S)-4-phenylmethyl-3-((R)-2-((diphenylmethylamino)methyl)-4-methoxybutyryl) Zolpidem-2-one. LCMS (Method b) m / z 487.4 [M+H] + ; t R = 1.48 min.

[0699] Step 4: At room temperature, use H2 (4 bar) and Pd / C (10 mol%) to prepare (S)-4-benzyl-3-((R)-2-((diphenylmethylamino)methyl)-4-methoxybutyryl) The 2-oxazolidinone (1.26 g, 2.59 mmol) was hydrogenated in MeOH (25 mL) for 2 hours (0.18 g). The reaction mixture was then treated with Boc₂O (0.9 g, 4.1 mmol) to give ((R)-2-((S)-4-benzyl-2-oxo) tert-butyl azolidinyl (3-carbonyl)-4-methoxybutyl)carbamate. LCMS (Method b) m / z 407.2 [M+H] + ; t R = 1.13 min.

[0700] Step 5: At 0°C, add water containing 30% hydrogen peroxide (399 mg, 3.52 mmol) followed by water containing LiOH (73.9 mg, 1.761 mmol) (2.2 mL) to (R)-2-((S)-4-benzyl-2-oxo (R)-2-(((tert-Butoxycarbonyl)amino)carbamate tert-butyl ester (358 mg, 0.881 mmol) was added to a solution of THF (6.6 mL), and the reaction mixture was stirred at 0 °C for 2 hours. The mixture was then treated with saturated Na₂SO₃ and saturated NaHCO₃. THF was distilled off under reduced pressure, and the aqueous layer was washed with CH₂Cl₂. The aqueous layer was acidified to pH 2 with 2 M HCl and extracted with CH₂Cl₂. The organic layer was dried (with Na₂SO₄) and concentrated to give (R)-2-(((tert-Butoxycarbonyl)amino)methyl)-4-methoxybutyric acid (int-L5). 1 H NMR(DMSO-d6, 400 MHz): δ ppm 12.19 (s, 1H), 6.85 (t, J = 5.9 Hz, 1H), 3.31 -3.22 (m, 2H), 3.19 (s, 3H), 3.16 - 3.06 (m, 1H), 3.05 - 2.95 (m, 1H), 2.49 -2.42 (m, 1H), 1.72 - 1.58 (m, 2H), 1.37 (s, 9H).

[0701] Note: Use the following procedure to obtain N,N-diphenylmethyl-1-methoxymethylamine (Bn2NCH2OMe).

[0702]

[0703] Potassium carbonate (21.0 g, 152 mmol) and formaldehyde (3.81 g, 127 mmol) were added to a solution of diphenylmethylamine (10.0 g, 50.7 mmol) in MeOH (10 mL), and the reaction mixture was stirred at room temperature for 4 hours. Then, K₂CO₃ (21.0 g, 152 mmol) was added, and the mixture was stirred at room temperature for 16 hours. After filtration and concentration, the reaction mixture was purified by Kugelrohr distillation (100 °C, 0.3 mbar) to give N,N-diphenylmethyl-1-methoxymethylamine.

[0704] Synthesis of (R)-4-(tert-butoxy)-2-methyl-4-oxobutyric acid (int-L6)

[0705]

[0706] Step 1: THF (37.7 mL, 37.7 mmol) containing 1 M NaHMDS was added dropwise to (S)-4-benzyl-3-propionyl group at -78°C. A solution of 2-oxazolidinone (8 g, 34.3 mmol) in THF (200 mL) was added. After stirring at -78 °C for 1 hour, tert-butyl 2-bromoacetate (15.5 mL, 103 mmol) was added and the solution was stirred at -78 °C for 2.5 hours. The reaction mixture was treated with a saturated aqueous NH4Cl solution and THF was removed under reduced pressure. The residue was extracted with ethyl acetate, and the combined organic layers were dried (MgSO4) and concentrated. Crystallization from Et2O gave (R)-4-((S)-4-benzyl-2-oxo tert-butyl oxobutyrate (3-yl)-3-methyl-4-oxobutyrate. 1 H NMR (400 MHz, CDCl3): δ ppm 7.24-7.36 (m,5H), 4.66 (td, J = 6.7, 3.5 Hz, 1H), 4.11-4.21 (m, 3H), 3.34 (dd, J = 13.4,3.3 Hz, 1H), 2.85 (dd, J = 16.8, 10.0 Hz, 1H), 2.75 (dd, J = 13.4, 9.9 Hz, 1H), 2.38 (dd, J = 16.8, 4.8 Hz, 1H), 1.43 (s, 9H), 1.20 (d, J = 7.0 Hz, 3H). LCMS (method b) m / z 348.1 [M+H] + ; t R = 1.21 min. [α]23 D +78.9 (c = 1.0, MeOH)

[0707] Step 2: At 0°C, add 2.7 mL (26.5 mmol) of water containing 30% hydrogen peroxide followed by 26.5 mL (13.2 mmol) of 0.5 M LiOH aqueous solution to (R)-4-((S)-4-benzyl-2-oxo 2.3 g (6.6 mmol) of tert-butyl (3-yl)-3-methyl-4-oxobutyrate was added to a solution of THF (66 mL), and the reaction mixture was stirred at 0 °C for 2 hours. The mixture was then treated with saturated aqueous solutions of Na₂SO₃ and NaHCO₃. THF was distilled off under reduced pressure, and the aqueous layer was extracted with CH₂Cl₂. The aqueous layer was acidified to pH 2 with 2 M HCl and extracted with CH₂Cl₂. The organic layer was dried (with Na₂SO₄) and concentrated to give (R)-4-(tert-butoxy)-2-methyl-4-oxobutyric acid (int-L6). 1 ¹H NMR (400 MHz, CDCl₃): δppm 2.90 (dq, J = 14.1, 7.2 Hz, 1H), 2.65 (dd, J = 16.4, 8.1 Hz, 1H), 2.37 (dd, J = 16.4, 5.9 Hz, 1H), 1.45 (s, 9H), 1.25 (d, J = 7.2 Hz, 3H). No signal of acidic protons was observed. [α] 23 D +2.6 (c = 1.0, MeOH).

[0708] Synthesis of (S)-4-(tert-butoxy)-2-cyclopropyl-4-oxobutyric acid (int-L7)

[0709]

[0710] Step 1: Add EDC (1.7 g, 8.9 mmol) to (S)-4-benzyl group at room temperature. A mixture of 2-oxazolidinone (800 mg, 4.5 mmol), 2-cyclopropylacetic acid (600 mg, 6.0 mmol), and DMAP (565 mg, 4.6 mmol) in CH₂Cl₂ (5 mL) was stirred at room temperature for 16 hours. The mixture was diluted with CH₂Cl₂ and washed with water, 1 M HCl, saturated aqueous NaHCO₃ solution, saturated aqueous NH₄Cl solution, water, and brine. The mixture was dried over (Na₂SO₄) and concentrated to give (S)-4-benzyl-3-(2-cyclopropylacetyl) Zolpidem-2-one. LCMS (Method b) m / z 260.2 [M+H] + , t R =1.05 min. [α] 23 D +90.6 (c = 1.0, MeOH); 1 H NMR (400 MHz, CDCl3) δ ppm 7.38 -7.32 (m, 2H), 7.32 - 7.28 (m, 1H), 7.25 -7.23 (m, 2H), 4.78 - 4.70 (m, 1H),4.28 - 4.19 (m, 2H), 3.36 (dd, J = 13.4, 3.2 Hz, 1H), 2.97 (dd, J = 17.0, 6.7Hz, 1H), 2.89 - 2.75 (m, 2H), 1.31 - 1.14 (m, 1H), 0.69 - 0.59 (m, 2H), 0.31- 0.22 (m, 2H).

[0711] Step 2: Add THF (5.9 mL, 5.9 mmol) containing 1 M NaHMDS dropwise to (S)-4-benzyl-3-(2-cyclopropylacetyl) at -78°C. A solution of 2-oxazolidinone (1.0 g, 3.9 mmol) in THF (30 mL) was added. After stirring at -78 °C for 1 hour, tert-butyl 2-bromoacetate (1.2 mL, 7.8 mmol) was added, and the solution was stirred at -78 °C for another 1 hour. The reaction mixture was treated with saturated aqueous NH4Cl solution (2 mL) and heated to room temperature, then dried (Na2SO4) and concentrated. The crude product was purified by column chromatography (0-50% ethyl acetate / hexane) to give (S)-4-((S)-4-benzyl-2-oxo tert-butyl oxazolidinyl (3-yl)-3-cyclopropyl-4-oxobutyrate. LCMS (Method b) m / z 374.3 [M+H] + , t R = 1.29 min. [α] 23 D +69.0 (c = 1.0, MeOH); 1H NMR (400 MHz, CDCl3): δ ppm7.38 - 7.27 (m, 5H), 4.71 (td, J = 6.7, 3.3 Hz, 1H), 4.22 - 4.13 (m, 2H), 3.79 - 3.70 (m, 1H), 3.39 (dd, J = 13.4, 3.2 Hz, 1H), 2.97 (dd, J = 16.8,10.8 Hz, 1H), 2.73 (dd, J = 13.4, 10.3 Hz, 1H), 2.59 (dd, J = 16.8, 4.3 Hz,1H), 1.43 (s, 9H), 1.01 - 0.89 (m, 1H), 0.61 - 0.48 (m, 2H), 0.48 -0.40 (m,1H), 0.35 -0.18 (m, 1H).

[0712] Step 3: At 0°C, hydrogen peroxide (30%, in water; 0.88 mL, 8.6 mmol) was followed by 1 mL of water containing LiOH (0.18 g, 4.3 mmol) to (S)-4-((S)-4-benzyl-2-oxo) 0.8 g (2.1 mmol) of tert-butyl (S)-4-(tert-butoxy)-2-cyclopropyl-4-oxobutyric acid was added to a solution of THF (20 mL), and the reaction mixture was stirred at 0 °C for 2 hours. The mixture was then treated at 0 °C with 20 mL of saturated NaHSO3 and 50 mL of saturated NaHCO3. THF was distilled off under reduced pressure, and the aqueous layer was washed with CH2Cl2. The mixture was then cooled to 0 °C, acidified to pH 2 with 4 M HCl, and extracted with CH2Cl2. The combined organic extracts were dried (Na2SO4) and concentrated to give (S)-4-(tert-butoxy)-2-cyclopropyl-4-oxobutyric acid (int-L7). LCMS (Method b) m / z 213.2 [M - H] - ; t R = 0.90 min. [α] 23 D +51.2 (c = 1.0, MeOH); 1H NMR (400 MHz, DMSO-d6): δ ppm 12.12 (s, 1H), 2.53 (dd, J = 16.3, 9.8 Hz, 1H), 2.40 (dd, J = 16.0, 5.3 Hz, 1H), 1.87-1.95 (m,1H), 1.37 (s, 9H), 0.75-0.87 (m, 1H), 0.38-0.49 (m, 2H), 0.29-0.36 (m, 1H), 0.12-0.21 (m, 1H).

[0713] Synthesis of (S)-4-(tert-butoxy)-2-cyclobutyl-4-oxobutyric acid (int-L8)

[0714]

[0715] A method similar to that described for the synthesis of (S)-4-(tert-butoxy)-2-cyclopropyl-4-oxobutyric acid (int-L7) was used, but 2-cyclobutylacetic acid was substituted for 2-cyclopropylacetic acid to obtain (S)-4-(tert-butoxy)-2-cyclobutyl-4-oxobutyric acid (int-L8). LCMS (Method b) m / z 229.3 [M+H] + t R = 0.99 min. 1 H NMR (400MHz, DMSO-d6): δ ppm 12.07 (s, 1H), 2.59 - 2.51 (m, 1H), 2.39 - 2.15 (m, 3H), 2.00 - 1.62 (m, 6H), 1.37 (s, 9H).

[0716] The table below lists the L intermediates purchased.

[0717]

[0718] EC type intermediates

[0719] Synthesis of 2-isobutyramido-4-methylthiazolyl-5-carboxylic acid (int-EC1)

[0720]

[0721] Step 1: Methyl 2-amino-4-methylthiazolyl-5-carboxylate (Combi blocks, CAS: 3829.80-9) (500 mg, 2.90 mmol), isobutyric acid (285 µL, 3.05 mmol), and pyridine (1.2 mL, 14.5 mmol) were dissolved in acetonitrile (29 mL), and EDC (1.1 g, 5.8 mmol) was added. The mixture was stirred overnight at room temperature (white suspension). Anhydrous DMF (10 mL), isobutyric acid (50 µL, 0.581 mmol), and HOBt (736 mg, 4.36 mmol) were added, and the fine suspension was stirred for another 22 hours at room temperature. The reaction mixture was concentrated, quenched with H2O, and extracted twice with ethyl acetate. The organic layers were combined, washed with water and brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give a crude solid. The crude product was dissolved in CH₂Cl₂ / MeOH (9 / 1), loaded onto an isolute pre-column, and purified by column chromatography (10-30% ethyl acetate / cyclohexane) to give methyl 2-isobutyramido-4-methylthiazolyl-5-carboxylate. LCMS (Method b) m / z 243.1 [M+H] + , t R = 0.86 min. 1 H NMR (400 MHz, DMSO-d6) δ ppm 12.42 (s,1H), 3.78 (s, 3H), 2.74 (h, J = 6.9 Hz, 1H), 2.54 (s, 3H), 1.12 (d, J = 6.8Hz, 6H).

[0722] Step 2: 1 M LiOH aqueous solution (16.5 mL, 16.5 mmol) was added to a solution of methyl 2-isobutyramido-4-methylthiazolyl-5-carboxylate (400 mg, 1.65 mmol) in THF (16 mL). The mixture was stirred at room temperature for 16 hours. THF was removed under reduced pressure and the residue was washed with Et₂O. The aqueous phase was acidified with HCl, and the resulting white suspension was stirred for 30 minutes. The suspension was then filtered while cold and dried under high vacuum to give 2-isobutyramido-4-methylthiazolyl-5-carboxylic acid (int-ECI). LCMS (Method b) m / z 229.2 [M+H] + , t R = 0.62 min. 1H NMR (400 MHz, DMSO-d6) δppm 12.79 (s, 1H), 12.31 (s, 1H), 2.72 (h, J = 7.0 Hz, 1H), 2.52 (s, 3H), 1.11 (d, J = 6.8 Hz, 6H).

[0723] Synthesis of 2-(ethylcarbamoyl)-4-methylthiazolyl-5-carboxylic acid (int-EC2)

[0724]

[0725] Step 1: Ethyl 2-amino-2-thioethyl (1.7 g, 12.8 mmol) was added to a solution of tert-butyl 2-chloro-3-oxobutyrate (2.46 g, 12.8 mmol) in DMF (10 mL), and the solution was stirred at 90 °C for 3 days. After cooling to room temperature, the reaction mixture was concentrated, and the residue was purified by column chromatography (0-50% ethyl acetate / cyclohexane) to give 2-ethyl 5-(tert-butyl) 4-methylthiazolium-2,5-dicarboxylic acid. LCMS (Method e) m / z 272.1 [M+H] + , t R = 1.23min. 1 H NMR (400 MHz, DMSO-d6) δ ppm 4.38 (d, J = 7.1 Hz, 2H), 2.67 (s, 3H), 1.54 (s, 9H), 1.33 (t, J = 7.0 Hz, 3H).

[0726] Step 2: A solution of 2-ethyl 5-(tert-butyl) 4-methylthiazolyl-2,5-dicarboxylic acid (500 mg, 1.84 mmol) in 2M ethylamine in EtOH solution (27.6 mL, 55.2 mmol) was stirred for 16 hours at room temperature. The reaction mixture was treated with ethyl acetate and washed with saturated NaHCO3 and 1N HCl. The organic phase was dried (MgSO4) and concentrated to give tert-butyl 2-(ethylcarbamoyl)-4-methylthiazolyl-5-carboxylic acid. LCMS (Method b) m / z 271.1 [M+H] + , t R = 1.14 min. 1HNMR (400 MHz, DMSO-d6) δ ppm 8.97 (t, J = 6.1 Hz, 1H), 3.30 - 3.23 (m, 2H), 2.66 (s, 3H), 1.53 (s, 9H), 1.11 (t, J = 7.3 Hz, 3H).

[0727] Step 3: A solution of tert-butyl 2-(ethylcarbamoyl)-4-methylthiazol-5-carboxylate (540 mg, 1.8 mmol) in TFA (15 mL) and CH2Cl2 (30 mL) was stirred for 16 hours at room temperature. The reaction mixture was concentrated and treated with Et2O. The precipitate was filtered off, washed with cold Et2O, and dried under vacuum to give 2-(ethylcarbamoyl)-4-methylthiazol-5-carboxylic acid (int-EC2). LCMS (Method b) m / z 215.1 [M+H] + , t R = 0.54 min. 1 ¹H NMR (400 MHz, DMSO-d⁶) δ ppm 8.97 (t, J = 6.0 Hz, 1H), 3.30 - 3.26 (m, 2H), 2.67 (s, 3H), 1.12 (q, J = 7.4 Hz, 3H) (no acid protons detected).

[0728] Synthesis of 2-((2,2-difluoroethyl)carbamoyl)-4-methylthiazolyl-5-carboxylic acid (int-EC3)

[0729]

[0730] A method similar to that described for the synthesis of 2-(ethylcarbamoyl)-4-methylthiazol-5-carboxylic acid (int-EC2) was used, but in step 2, ethanol containing 2,2-difluoroethyl-1-amine was used instead of THF containing ethylamine to obtain 2-((2,2-difluoroethyl)carbamoyl)-4-methylthiazol-5-carboxylic acid (int-EC3). LCMS (Method b) m / z 251.1 [M+H] + ,t R = 0.55 min. 1 ¹H NMR (400 MHz, DMSO-d6) δ ppm 9.24 (t, J = 6.3 Hz, 1H), 6.14 (tt, J = 55.8, 4.0 Hz, 1H), 3.66 (tdd, J = 15.3, 6.2, 4.0 Hz, 2H), 2.69 (s, 3H) (no acid protons observed).

[0731] Synthesis of 4-methyl-2-(methylcarbamoyl)thiazolyl-5-carboxylic acid (int-EC4)

[0732]

[0733] A method similar to that described for the synthesis of 2-(ethylcarbamoyl)-4-methylthiazol-5-carboxylic acid (int-EC2) was used, but in step 2, ethanol containing methylamine was used instead of THF containing ethylamine to obtain 4-methyl-2-(methylcarbamoyl)thiazol-5-carboxylic acid (int-EC4). LCMS (Method a) m / z 201.1 [M+H] + , t R = 0.45 min.

[0734] Synthesis of 2-(isopropylcarbamoyl)-4-methylthiazolyl-5-carboxylic acid (int-EC5)

[0735]

[0736] A method similar to that described for the synthesis of 2-(ethylcarbamoyl)-4-methylthiazol-5-carboxylic acid (int-EC2) was used, but in step 2, ethanol containing propan-2-amine was used instead of THF containing ethylamine to obtain 2-(isopropylcarbamoyl)-4-methylthiazol-5-carboxylic acid (int-EC5). LCMS (Method b) m / z 229.2 [M+H] + , t R = 0.61 min. 1 HNMR (400 MHz, DMSO-d6) δ ppm 8.73 (d, J = 8.5 Hz, 1H), 4.20 - 3.96 (m, 1H), 2.68 (s, 3H), 1.18 (d, J = 6.6 Hz, 6H).

[0737] Synthesis of 4-chloro-2-(6-(trifluoromethyl)pyridin-3-yl)thiazolyl-5-carboxylic acid (int-EC6)

[0738]

[0739] Step 1: Add 1N LiOH aqueous solution (235 mL, 235 mmol) to a solution of methyl 2,4-dichlorothiazol-5-carboxylate (10 g, 47.2 mmol) in THF (150 mL). Stir the reaction mixture at room temperature for 1 hour. Add 0.1 M NaOH aqueous solution to the reaction mixture and extract with Et₂O. Acidify the aqueous phase with HCl, concentrate, and extract with Et₂O. Wash the organic layer with brine, dry (Na₂SO₄), and concentrate to give 2,4-dichlorothiazol-5-carboxylic acid. LCMS (Method b) m / z 195.9+ 197.9 [MH] - , t R = 0.46 min.

[0740] Step 2: (6-(trifluoromethyl)pyridin-3-yl)boronic acid (4.24 g, 22.2 mmol), Pd(PPh3)4 (1.17 g, 1.0 mmol), and 2M Na2CO3 aqueous solution (25 mL, 1.88 mmol) were added to a mixture of 2,4-dichlorothiazol-5-carboxylic acid (4 g, 20.20 mmol) and DME (150 mL). The reaction mixture was stirred in a microwave oven at 80 °C for 7 hours. The reaction mixture was quenched with water and extracted with ethyl acetate. The aqueous phase was acidified with concentrated HCl and extracted with ethyl acetate. The combined organic layers were washed with brine, dried (Na2SO4), and concentrated. The crude material was wet-milled in a ultrasonic bath with water / isopropanol (3 / 1), and the solid was filtered and dried under high vacuum to give 4-chloro-2-(6-(trifluoromethyl)pyridin-3-yl)thiazol-5-carboxylic acid (int-EC6). LCMS (Method b) m / z 309.0 + 311.0 [M+H] + , t R = 0.76 min. 1 H NMR (400 MHz, DMSO-d6) δ ppm: 14.13 (s, 1H), 9.36 (s, 1H), 8.66 (d, J = 8.5 Hz, 1H), 8.09 (d, J = 8.3 Hz, 1H).

[0741] Synthesis of 4-methyl-2-(6-(trifluoromethyl)pyridin-3-yl)thiazolyl-5-carboxylic acid (int-EC7)

[0742]

[0743] Step 1: Ethyl 2-chloroacetate (4.77 mL, 32.7 mmol) was added to a solution of 6-(trifluoromethyl)pyridin-3-thiocarboxamide (5.0 g, 24.25 mmol) in ethanol (80 mL), and the mixture was heated to reflux at 95 °C for 36 hours. After cooling to room temperature, the resulting suspension was filtered off and dried under vacuum to give ethyl 4-methyl-2-(6-(trifluoromethyl)pyridin-3-yl)thiazolyl-5-carboxylate. The filtrate was concentrated, then wet-milled with a small amount of EtOH, filtered off while cold, and dried under vacuum to give more ethyl 4-methyl-2-(6-(trifluoromethyl)pyridin-3-yl)thiazolyl-5-carboxylate. LCMS (Method b) m / z 317.1 [M+H] + , t R = 1.25 min. 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.35 (s,1H), 8.64 (d, J = 7.4 Hz, 1H), 8.06 (d, J = 8.3 Hz, 1H), 4.33 (q, J = 7.2 Hz,2H), 2.74 (s, 3H), 1.32 (t, J = 7.1 Hz, 3H).

[0744] Step 2: H₂O containing LiOH (24.66 mL, 24.66 mmol) was added to a mixture of ethyl 4-methyl-2-(6-(trifluoromethyl)pyridin-3-yl)thiazolyl-5-carboxylate (5.2 g, 16.44 mmol) in ethanol (110 mL) at room temperature, and the mixture was stirred for 1.5 hours at room temperature. The solvent was removed, and the residue was treated with water, followed by acidification with 2N HCl. The resulting suspension was filtered off and the solid was dried under vacuum to give 4-methyl-2-(6-(trifluoromethyl)pyridin-3-yl)thiazolyl-5-carboxylic acid (int-EC7). LCMS (Method b) m / z 289.1 [M+H] + , t R = 0.86 min. 1 H NMR (400MHz, DMSO-d6) δ ppm 13.67 (s, 1H), 9.31 (s, 1H), 8.60 (d, J = 8.3 Hz, 1H), 8.04 (d, J = 8.3 Hz, 1H), 2.71 (s, 3H).

[0745] Synthesis of 4-methyl-2-(3-methylisocyanate) (zol-5-yl)thiazolyl-5-carboxylic acid (int-EC8)

[0746]

[0747] Step 1: Add 3-methylisocyanate to the solution. Azoxyl-5-carboxynitrile (1 g, 9.25 mmol) was added to a solution of sodium hydrosulfide (70%, in H2O) (1.48 g, 18.50 mmol) and MgCl2 (0.88 g, 9.25 mmol) in DMF (10 mL), and the solution was stirred at 20 °C for 1 hour. Ethyl acetate and water were added to the reaction mixture, and the aqueous phase was washed with ethyl acetate. The organic layer was dried (MgSO4) and concentrated to give 3-methylisocyanate. Azole-5-thiocarboxamide. LCMS (Method e) m / z 143.1 [M+H] + , t R = 0.52 min. 1 H NMR (400 MHz, DMSO-d6) δ ppm 10.21 (s, 1H), 9.83 (s,1H), 6.95 (s, 1H), 2.27 (s, 3H).

[0748] Step 2: Add 3-methylisocyanate Azoxyl-5-thiocarboxamide (0.858 g, 5.19 mmol) was added to a solution of tert-butyl 2-chloro-3-oxobutyrate (1 g, 5.19 mmol) in t-BuOH (20 mL), and the reaction mixture was stirred at 90 °C for 16 hours. After cooling to room temperature, the reaction mixture was concentrated, and the crude product was purified by column chromatography (0-40% ethyl acetate / cyclohexane) to give 4-methyl-2-(3-methylisothiocarboxamide). tert-butyl 5-(zol-5-yl)thiazolyl-5-carboxylate. LCMS (Method e) m / z 281.2 [M+H] + , t R = 1.35 min. 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.15 (s, 1H), 2.68 (s, 3H), 2.33 (s, 3H), 1.55 (s, 9H).

[0749] Step 3: Add TFA (5 mL) to 4-methyl-2-(3-methylisocyanate) 440 mg (1.57 mmol) of tert-butyl 5-(2-(3-methylisothiazolyl)-5-carboxylate was added to a solution of CH₂Cl₂ (10 mL). The solution was then stirred at room temperature for 2 hours. The reaction mixture was concentrated to give 4-methyl-2-(3-methylisothiazolyl)-5-carboxylate. (Azol-5-yl)thiazolyl-5-carboxylic acid (int-EC8). LCMS (Method e) m / z 225.1 [M+H] + , t R = 0.62 min. 1 H NMR (400 MHz, DMSO-d6) δ ppm 13.76 (s, 1H), 7.14 (s, 1H), 2.69 (s, 3H), 2.33 (s, 3H).

[0750] Synthesis of 4-chloro-2-(isopropylcarbamoyl)thiazolyl-5-carboxylic acid (int-EC9)

[0751]

[0752] Step 1: Ethylene glycol (4.6 mL, 82 mmol) and p-TsOH (260 mg, 1.37 mmol) were added to a solution of 2,4-dichlorothiazol-5-carboxaldehyde (5.0 g, 27.5 mmol) in toluene (60 mL), and the mixture was stirred under reflux for 5 hours. The reaction mixture was cooled to room temperature, poured into 20% Na₂CO₃ (120 mL), and extracted twice with ethyl acetate. The combined organic phases were washed with H₂O and brine, dried (Na₂SO₄), and concentrated. The residue was purified by column chromatography (10% ethyl acetate / cyclohexane) to give 2,4-dichloro-5-(1,3-dioxane-2-yl)thiazolium. LCMS (Method b) m / z 228.0 [M+H] + , t R = 0.96 min. 1 H NMR (400 MHz, DMSO-d6) δ ppm 6.05 (s, 1H), 4.08- 4.01 (m, 2H), 4.00 - 3.93 (m, 2H).

[0753] Step 2: Butyllithium (1.6 M hexane solution, 8.7 mL, 13.9 mmol) was added to a solution of 2,4-dichloro-5-(1,3-dioxacyclopentan-2-yl)thiazole (3.0 g, 13.27 mmol) in THF (20 mL) at -78 °C, and the mixture was stirred at -78 °C for 20 min. Solid carbon dioxide (20 g) was then introduced, and the reaction mixture was gradually heated to room temperature and stirred at room temperature for 16 h. The resulting suspension was concentrated, and the crude product was suspended in ethyl acetate. The solid was collected by filtration to obtain 4-chloro-5-(1,3-dioxacyclopentan-2-yl)thiazole-2-carboxylic acid. LCMS (Method b) m / / z = 236.2 [M+H] + , t R = 0.39 min. 1 ¹H NMR (400 MHz, DMSO-d6) δ ppm 5.98 (s, 1H), 4.09 - 4.00 (m, 2H), 4.00 - 3.90 (m, 2H) (no COOH protons observed).

[0754] Step 3: Propyl-2-amine (1.2 mL, 14.0 mmol) and EDC (3.65 g, 19.10 mmol) were added to a mixture of 4-chloro-5-(1,3-dioxacyclopentan-2-yl)thiazolyl-2-carboxylic acid (3.0 g, 12.73 mmol), HOBt (2.43 mg, 15.28 mmol), and Et3N (2.3 mL, 16.55 mmol) in CH2Cl2 (120 mL), and the suspension was stirred overnight at room temperature. The reaction mixture was concentrated and treated with ethyl acetate and 1N HCl. The combined organic layers were washed with saturated NaHCO3 and brine, dried (Na2SO4), and concentrated to give 4-chloro-5-(1,3-dioxacyclopentan-2-yl)-N-isopropylthiazolyl-2-carboxamide. LCMS (Method b) m / z 277.1 [M+H] + , t R = 0.94 min. 1 H NMR (400 MHz, DMSO-d6)δ ppm 8.84 (d, J = 8.3 Hz, 1H), 6.12 (s, 1H), 4.15 - 3.94 (m, 5H), 1.17 (d, J = 6.6 Hz, 6H).

[0755] Step 4: 6M HCl (3.0 mL, 18.07 mmol) was added to a solution of 4-chloro-5-(1,3-dioxacyclopentan-2-yl)-N-isopropylthiazol-2-carboxamide (1.0 g, 3.61 mmol) in Et₂O (36.0 mL) at room temperature, and the solution was stirred for 16 hours at room temperature. The pH of the mixture was then adjusted to 7–8 with saturated NaHCO₃, and the organic layer was separated. The aqueous layer was extracted with Et₂O, and the combined organic extracts were washed with brine, dried (Na₂SO₄), and concentrated to give 4-chloro-5-formyl-N-isopropylthiazol-2-carboxamide. LCMS (Method b) m / / z = 233.2 [M+H] + , t R = 0.86 min. 1 H NMR (400 MHz, DMSO-d6) δ ppm 10.01 (s, 1H), 9.09 (d, J = 8.4 Hz, 1H), 4.24- 3.94 (m, 1H), 1.19 (d, J = 6.6 Hz, 6H).

[0756] Step 5: A mixture of sulfamic acid (815 mg, 8.38 mmol) and NaClO2 (947 mg, 8.38 mmol) in water (5 mL) was added to a solution of 4-chloro-5-formyl-N-isopropylthiazol-2-carboxamide (1.3 g, 2.15 mmol) in THF (33 mL) and water (18 mL), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with H2O and extracted twice with Et2O. The organic layers were combined and washed with 0.5 M NaOH. The aqueous phase containing the product was acidified with concentrated HCl, and the resulting fine suspension was stirred in an ice bath for 30 minutes. The solid was then filtered off and dried under high vacuum to give 4-chloro-2-(isopropylcarbamoyl)thiazol-5-carboxylic acid (int-EC9). LCMS (Method b) m / / z = 249.1 [M+H] + , t R =0.52 min. 1 H NMR (400 MHz, DMSO-d6) δ ppm 14.14 (s, 1H), 8.97 (d, J = 8.3 Hz,1H), 4.28 - 3.95 (m, 1H), 1.18 (d, J = 6.6 Hz, 6H)

[0757] Synthesis of 2-(3,6-dihydro-2H-pyran-4-yl)-4-methylthiazolyl-5-carboxylic acid (int-EC10)

[0758]

[0759] A mixture of cesium carbonate (550 mg, 1.689 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (130 mg, 0.619 mmol), and 2-chloro-4-methylthiazolyl-5-carboxylic acid (100 mg, 0.563 mmol) in THF (2.6 mL) and water (1.1 mL) was purged with argon for 5 min. Pd(dppf)Cl₂·CH₂Cl₂ (46.0 mg, 0.056 mmol) was added, and the resulting solution was heated in a microwave oven at 80 °C for 1 h. After cooling to room temperature, the reaction mixture was concentrated, and the residue was purified by preparative HPLC to obtain a solid, which was dissolved in CH₂Cl₂ (10 mL) and treated with saturated NaHCO₃ (10 mL). The aqueous phase was extracted with CH₂Cl₂, and the combined organic phases were dried (MgSO₄) and concentrated to give 2-(3,6-dihydro-2H-pyran-4-yl)-4-methylthiazolyl-5-carboxylic acid (int-EC10). LCMS (Method b) m / z 226.1 [M+H] + ; t R = 0.63 min, 1 H NMR (400 MHz, DMSO-d6) δ ppm 13.29(s, 1H), 6.84 - 6.77 (m, 1H), 4.25 (d, J = 2.9 Hz, 2H), 3.80 (t, J = 5.4 Hz,2H), 2.60 (s, 3H), 2.59 - 2.55 (m, 2H).

[0760] Synthesis of 4-chloro-2-(cyclopent-1-en-1-yl)thiazolyl-5-carboxylic acid (int-EC11)

[0761]

[0762] Step 1: A mixture of cesium carbonate (615 mg, 1.89 mmol), cyclopent-1-en-1-ylboronic acid (116 mg, 1.04 mmol), and methyl 2,4-dichlorothiazolium-5-carboxylate (200 mg, 0.94 mmol) in THF (2.4 mL) and water (2.4 mL) was purged with argon for 5 min, followed by the addition of Pd(dppf)Cl2·CH2Cl2 (77 mg, 0.094 mmol), and the resulting mixture was heated in a microwave at 80 °C for 1 h. After cooling to room temperature, the reaction mixture was concentrated, and the residue was purified using preparative HPLC. The obtained solid was dissolved in CH2Cl2 (10 mL) and treated with a saturated aqueous solution of sodium bicarbonate (10 mL). The aqueous phase was extracted with CH₂Cl₂, and the combined organic phases were dried (MgSO₄) and concentrated to give methyl 4-chloro-2-(cyclopent-1-en-1-yl)thiazolyl-5-carboxylate. M / z 244.1 [M+H] + ; t R = 1.23 min (LCMS condition b), 1 H NMR (400MHz, DMSO-d6) δ ppm 6.91 - 6.82 (m, 1H), 3.83 (s, 3H), 2.77 - 2.68 (m, 2H), 2.62 - 2.54 (m, 2H), 2.06 - 1.94 (m, 2H).

[0763] Step 2: 2M LiOH (aqueous solution) (0.42 mL, 0.84 mmol) was added to a mixture of methyl 4-chloro-2-(cyclopent-1-en-1-yl)thiazolyl-5-carboxylate (195 mg, 0.80 mmol) and MeOH / THF / H2O in 1:1:1 ratio (8 mL), and the mixture was stirred at room temperature for 20 hours. The mixture was then concentrated and used in the next step without further purification.

[0764] Step 3: NaBH4 (153 mg, 4.03 mmol) was added in a single addition to a stirred solution of 4-chloro-2-(cyclopent-1-en-1-yl)thiazolyl-5-carboxylate (190 mg, 0.81 mmol) in MeOH (8.064 m) at room temperature, and the resulting solution was stirred at room temperature for 1 hour. The reaction mixture was concentrated, and the residue was dissolved in CH2Cl2 (20 mL) and treated with 1N HCl (10 mL). The aqueous phase was extracted with CH2Cl2, and the combined organic phases were dried (MgSO4) and concentrated to give a 2:1 mixture of inseparable cyclopentenyl and cyclopentyl compounds. Cyclopentenyl: M / z 230.1 [M+H] + ; t R = 0.81 min LCMS (Method b), cyclopentyl: M / z 232.1 [M+H] + ; t R = 0.83 min LCMS (method b).

[0765] Synthetic 2-(iso) (-5-yl)-4-methylthiazolyl-5-carboxylic acid (int-EC12)

[0766]

[0767] Step 1: Remove the foreign object Azoxyl-5-thiocarboxamide (0.665 g, 5.19 mmol) was added to a solution of tert-butyl 2-chloro-3-oxobutyrate (1 g, 5.19 mmol) in t-BuOH (10 mL), and the mixture was stirred at 90 °C for 16 hours. After cooling to room temperature, the reaction mixture was concentrated and the crude product was purified by column chromatography (0-50% ethyl acetate / cyclohexane) to give 2-(isothiocarboxamide) tert-butyl 5-(-5-yl)-4-methylthiazolyl-5-carboxylate. LCMS (Method a) m / z 267.3 [M+H] + , t R =1.28 min. 1 H NMR (400 MHz, DMSO-d6): δ ppm 8.85 (d, J = 2.0 Hz, 1H), 7.29 (d, J= 2.0 Hz, 1H), 2.69 (s, 3H), 1.55 (s, 9H).

[0768] Step 2: Add TFA (3 mL) to 2-(isocyanate) tert-butyl 5-(5-yl)-4-methylthiazolyl-5-carboxylate (300 mg, 1.126 mmol) was added to a solution of CH2Cl2 (6 mL), and the solution was stirred at room temperature for 16 hours. The reaction mixture was then concentrated to give 2-(isobutyl)-4-methylthiazolyl-5-carboxylate. (-5-yl)-4-methylthiazolyl-5-carboxylic acid (int-EC12). LCMS (Method a) m / z 211.2 [M+H] + , t R = 0.52 min. 1 H NMR (400 MHz, DMSO-d6): δ ppm 13.78 (s, 1H), 8.85 (d, J = 2.0 Hz, 1H), 7.28 (d, J = 2.0 Hz, 1H), 2.70 (s, 3H).

[0769] Synthesis of 4-chloro-2-(6-methoxypyridin-3-yl)thiazolyl-5-carboxylic acid (int-EC13)

[0770]

[0771] Step 1: A mixture of aminosulfonic acid (4.0 g, 41.2 mmol) and NaClO2 (4.66 g, 4.66 mmol) in water (2 mL) was added to a solution of 2,4-dichlorothiazol-5-carboxaldehyde (5 g, 27.5 mmol) in THF (150 mL) and water (100 mL), and the mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with H2O and extracted with Et2O. The combined organic layers were washed with 0.5 M NaOH. The aqueous phase was then acidified with concentrated HCl and the extract was extracted with Et2O, washed with brine, dried (Na2SO4), and concentrated. The residue was dried under high vacuum to give 2,4-dichlorothiazol-5-carboxylic acid, which was used in the next step without further purification. LCMS (Method b) m / z 196.0 [M+H] + , t R = 0.46 min. 1 H NMR (400 MHz, DMSO-d6): δ ppm 14.20 (s, 1H).

[0772] Step 2: Pd(PPh3)4 (146 mg, 0.126 mmol) was added to a degassed mixture of (6-methoxypyridin-3-yl)boronic acid (427 mg, 2.65 mmol), 2M Na2CO3 (4.4 mL, 8.8 mmol), and 2,4-dichlorothiazol-5-carboxylic acid (500 mg, 2.52 mmol) in DME (13 mL) at room temperature, and the mixture was heated at 80 °C for 5 hours. After cooling, the reaction mixture was treated with water and washed with ethyl acetate. The aqueous phase was acidified with concentrated HCl and the white precipitate was filtered off while cold to give 4-chloro-2-(6-methoxypyridin-3-yl)thiazol-5-carboxylic acid (int-EC13). LCMS (Method b) m / z 271.2 [M+H] + , t R = 0.71 min. 1 H NMR (400 MHz, DMSO-d6): δ ppm 13.88 (s, 1H), 8.83 (d,J = 2.5 Hz, 1H), 8.26 (dd, J = 8.7, 2.6 Hz, 1H), 6.99 (d, J = 8.8 Hz, 1H), 3.95 (s, 3H).

[0773] Synthesis of 4-chloro-2-(6-(difluoromethoxy)pyridin-3-yl)thiazolyl-5-carboxylic acid (int-EC14)

[0774]

[0775] A method similar to that described for the synthesis of 4-chloro-2-(6-methoxypyridin-3-yl)thiazolyl-5-carboxylic acid (int-EC13) was used, but (6-methoxypyridin-3-yl)boronic acid was replaced with 2-(difluoromethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyridine to obtain 4-chloro-2-(6-(difluoromethoxy)pyridin-3-yl)thiazolyl-5-carboxylic acid (int-EC14). LCMS (Method b) m / z 307.0 [M+H] + , t R = 0.77 min. 1 H NMR (400 MHz, DMSO-d6) δ ppm 14.02 (s, 1H), 8.90 (d, J = 2.5 Hz, 1H), 8.49 (dd, J = 8.6,2.5 Hz, 1H), 7.79 (t, J = 72.2 Hz, 1H), 7.27 (d, J = 8.7 Hz, 1H).

[0776] Synthesis of 4-chloro-2-cyclopropylthiazol-5-carboxylic acid (int-EC15)

[0777]

[0778] NaOH (13.78 mL, 13.78 mmol) was added to a solution of methyl 4-chloro-2-cyclopropylthiazol-5-carboxylate (1 g, 4.59 mmol) in MeOH (20 mL), and the solution was stirred at room temperature for 1 hour. MeOH was removed under reduced pressure, and the remaining solution was washed with CH₂Cl₂. The aqueous phase was acidified with 1N HCl and extracted with ethyl acetate. The combined organic layers were dried (MgSO₄) and concentrated to give 4-chloro-2-cyclopropylthiazol-5-carboxylic acid (int-EC15). LCMS (Method e) m / z 204.0 [M+H] + , t R = 0.57 min. 1 H NMR (400 MHz, DMSO-d6): δ ppm 13.62 (s, 1H), 2.49 -2.40 (m, 1H), 1.28 - 1.15 (m, 2H), 1.11 - 0.97 (m, 2H).

[0779] Synthesis of 4-chloro-2-(1-(difluoromethyl)-1H-pyrazol-4-yl)thiazolyl-5-carboxylic acid (int-EC16)

[0780]

[0781] A method similar to that described for the synthesis of 4-chloro-2-(6-methoxypyridin-3-yl)thiazolyl-5-carboxylic acid (int-EC13) was used, but 1-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole was used instead of (6-methoxypyridin-3-yl)boronic acid to obtain 4-chloro-2-(1-(difluoromethyl)-1H-pyrazole-4-yl)thiazolyl-5-carboxylic acid (int-EC16). LCMS (Method b) m / z 279.9 [M+H] + , t R = 0.61 min. 1 H NMR (400 MHz, DMSO-d6): δ ppm 8.87 (s, 1H), 8.26 (s, 1H), 7.85 (t, J = 58.8 Hz, 1H).

[0782] Synthesis of 4-chloro-2-(3,6-dihydro-2H-pyran-4-yl)thiazolyl-5-carboxylic acid (int-EC17)

[0783]

[0784] Pd(dppf)Cl2.CH2Cl2 (124 mg, 0.151 mmol) was added to a degassed mixture of cesium carbonate (1.48 g, 4.54 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (350 mg, 1.666 mmol), and 2,4-dichlorothiazol-5-carboxylic acid (300 mg, 1.515 mmol) in THF (7.07 mL) and water (3.03 mL) at room temperature. The resulting suspension was then heated in a microwave oven at 80 °C for 1 hour. After cooling to room temperature, the reaction mixture was concentrated and the crude product was purified by preparative HPLC. The HPLC fraction was concentrated under reduced pressure to give a white solid, which was dissolved in CH2Cl2 (10 mL) and diluted with saturated NaHCO3 solution (10 mL). The aqueous phase was separated and extracted with CH₂Cl₂, and the combined organic fractions were dried (MgSO₄) and then concentrated under reduced pressure to give 4-chloro-2-(3,6-dihydro-2H-pyran-4-yl)thiazolyl-5-carboxylic acid (int-EC17). LCMS (Method b) m / z 246.1 [M+H] + , t R = 0.59min.

[0785] Synthesis of 4-methyl-2-(tetrahydro-2H-pyran-4-yl)thiazolyl-5-carboxylic acid (int-EC18)

[0786]

[0787] A method similar to that described for the synthesis of 4-methyl-2-(6-(trifluoromethyl)pyridin-3-yl)thiazolyl-5-carboxylic acid (int-EC7) was used, but 6-(trifluoromethyl)pyridin-3-yl)thiazolyl-5-carboxylic acid (int-EC18) was obtained by replacing 6-(trifluoromethyl)pyridin-3-yl)thiazolyl-5-carboxylic acid with tetrahydro-2H-pyran-4-thiocarboxamide. LCMS (Method b) m / z 228.1 [M+H] + , t R = 0.60 min.

[0788] Synthesis of 4-chloro-2-methylthiazol-5-carboxylic acid (int-EC19)

[0789]

[0790] The method used is similar to that described in step 2 of the synthesis of 4-chloro-2-(6-methoxypyridin-3-yl)thiazolyl-5-carboxylic acid (int-EC13), but with 2,4,6-trimethyl-1,3,5,2,4,6-trioxaborane instead of (6-methoxypyridin-3-yl)boronic acid, Pd(dppf)Cl2.CH2Cl2 instead of Pd(PPh3)4, and di... Alkane was used as a solvent to obtain 4-chloro-2-methylthiazol-5-carboxylic acid (int-EC19). LCMS (method e) m / z 177.9 [M+H] + , t R = 0.38 min. 1 H NMR (DMSO-d6, 400 MHz): δ ppm 13.69 (s, 1H), 2.67 (s, 3H).

[0791] The table below lists the purchased formic acid EC intermediates.

[0792]

[0793]

[0794]

[0795] Synthesis of N-(5-amino-1-methyl-1H-pyrazol-3-yl)isobutyramide (int-EC38)

[0796]

[0797] Step 1: Diphenylphosphoazide (DPPA) (9.0 mL, 40.7 mmol) and Et3N (4.2 mL, 30.0 mmol) were added to a solution of 3-(ethoxycarbonyl)-1-methyl-1H-pyrazole-5-carboxylic acid (5.0 g, 27.2 mmol) in tert-butanol (90 mL), and the reaction mixture was stirred at 95 °C for 3 hours. After cooling, the reaction mixture was concentrated, and the residue was treated with water and ethyl acetate. The aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with brine, dried (Na2SO4), and concentrated to give a crude product, which was purified by column chromatography (20-70% ethyl acetate / cyclohexane) to give methyl 5-((tert-butoxycarbonyl)amino)-1-methyl-1H-pyrazole-3-carboxylic acid. LCMS (Method b) m / z 256.2 [M+H] + , t R =0.78 min. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.51 (s, 1H), 6.53 (s, 1H), 3.77 (s,3H), 3.73 (s, 3H), 1.46 (s, 9H).

[0798] Step 2: H₂O containing 1 M LiOH (25 mL, 24.14 mmol) was added to a suspension of methyl 5-((tert-butoxycarbonyl)amino)-1-methyl-1H-pyrazole-3-carboxylic acid (3.0 g, 11.75 mmol) in THF (45 mL), and the mixture was stirred at room temperature for 2 hours. The THF was evaporated, and the residue was treated with water and ethyl acetate. The aqueous phase was acidified with concentrated HCl, and the resulting white suspension was stirred for 30 minutes. The suspension was then filtered off while cold and dried under high vacuum to give 5-((tert-butoxycarbonyl)amino)-1-methyl-1H-pyrazole-3-carboxylic acid. LCMS (Method b) m / z 242.2 [M+H] + , t R = 0.61 min. 1 H NMR (400 MHz, DMSO-d6) δ ppm 12.50 (s, 1H), 9.43 (s, 1H), 6.45 (s, 1H), 3.70 (s,3H), 1.46 (s, 9H).

[0799] Step 3: DPPA (0.95 mL, 4.29 mmol) and Et3N (0.44 mL, 3.15 mmol) were added to a solution of 5-((tert-butyloxycarbonyl)amino)-1-methyl-1H-pyrazole-3-carboxylic acid (690 mg, 2.86 mmol) in benzyl alcohol (9.0 mL), and the reaction mixture was stirred at 95 °C for 3 hours. After cooling to room temperature, the reaction mixture was treated with water and ethyl acetate, and the aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with brine, dried (Na2SO4), and concentrated to give a crude product, which was purified by column chromatography (10-50% ethyl acetate / cyclohexane) to give tert-butyl benzoate (1-methyl-1H-pyrazole-3,5-diyl)dicarboxylic acid. LCMS (Method b) m / z 347.3 [M+H] + , t R = 0.98 min. 1HNMR (400 MHz, DMSO-d6) δ ppm 9.83 (s, 1H), 9.25 (s, 1H), 7.43 - 7.37 (m, 4H), 7.36 - 7.27 (m, 1H), 6.14 (s, 1H), 5.11 (s, 2H), 3.50 (s, 3H), 1.45 (s, 9H).

[0800] Step 4: Hydrogenation of MeOH (25 mL) containing tert-butyl benzoate (480 mg, 1.39 mmol) using an H cube (all H₂, Pd / C cylinder, 30 °C, 1 h) was performed. The solution was then concentrated to give the crude product, which was treated with 0.5 M HCl and ethyl acetate. The aqueous phase was made alkaline with concentrated NaOH and extracted with ethyl acetate. The organic layer was washed with brine, dried (Na₂SO₄), and concentrated to give tert-butyl benzoate (3-amino-1-methyl-1H-pyrazole-5-yl)carbamate. LCMS (Method b) m / z 213.4 [M+H] + , t R = 0.55 min. 1 H NMR (400 MHz, DMSO-d6) δppm 9.00 (s, 1H), 5.28 (s, 1H), 4.39 (s, 2H), 3.36 (s, 3H), 1.44 (s, 9H).

[0801] Step 5: Pyridine (171 µl, 2.12 mmol) and EDC (162 mg, 0.848 mmol) were added to a solution of (3-amino-1-methyl-1H-pyrazole-5-yl)carbamate tert-butyl ester (90 mg, 0.424 mmol) and isobutyric acid (44 µl, 0.466 mmol) in acetonitrile (4 mL). After stirring at room temperature for 18 hours, the reaction mixture was treated with water, and the mixture was concentrated and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried (Na₂SO₄), and concentrated to give (3-isobutyramamido-1-methyl-1H-pyrazole-5-yl)carbamate tert-butyl ester. LCMS (Method b) m / z 283.5 [M+H] + , t R = 0.77 min. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.10 (s, 1H), 9.23 (s,1H), 6.32 (s, 1H), 3.52 (s, 3H), 2.62 - 2.52 (m, 1H), 1.46 (s, 9H), 1.04 (d,J = 6.8 Hz, 6H).

[0802] Step 6: Add distillate containing 4M HCl Alkane (1.24 mL, 4.96 mmol) was added to a solution of (3-isobutyramido-1-methyl-1H-pyrazole-5-yl)carbamate (70 mg, 0.248 mmol) in CH₂Cl₂ (2.5 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was then concentrated, and the oily residue was dissolved in CH₂Cl₂ and concentrated, dissolved in Et₂O and concentrated to give N-(5-amino-1-methyl-1H-pyrazole-3-yl)isobutyramide (int-EC38). LCMS (Method b) m / z 183.2 [M+H] + , t R = 0.39 min. 1 H NMR (400 MHz, DMSO-d6) δ ppm11.25 (s, 1H), 5.50 (s, 1H), 3.93 (s, 3H), 2.69 - 2.57 (m, 1H), 1.10 (d, J =6.8 Hz, 6H).

[0803] Synthesis of 5-amino-4-chloro-N-isopropylthiazol-2-carboxamide (int-EC39)

[0804]

[0805] Step 1: Diphenylphosphoazide (1.75 mL, 7.84 mmol) and Et3N (0.80 mL, 5.75 mmol) were added to a solution of 4-chloro-2-(isopropylcarbamoyl)thiazol-5-carboxylic acid (int-EC9, 1.30 g, 5.23 mmol) in tert-butanol (17 mL) at room temperature, and the reaction mixture was stirred at 95 °C for 3 hours. After cooling to room temperature, the solvent was evaporated, and the reaction mixture was treated with water and ethyl acetate. The aqueous phase was extracted with ethyl acetate, and the organic phase was washed with brine, dried (Na2SO4), and concentrated. The crude product was purified by column chromatography (10-20% ethyl acetate / cyclohexane) to give tert-butyl (4-chloro-2-(isopropylcarbamoyl)thiazol-5-yl)carbamate. LCMS (Method b) m / z 320.2 [M+H] + ,t R = 1.09 min. 1 H NMR (400 MHz, DMSO-d6) δ ppm 10.60 (s, 1H), 8.51 (d, J = 8.4Hz, 1H), 4.31 - 3.92 (m, 1H), 1.50 (s, 9H), 1.16 (d, J = 6.6 Hz, 6H).

[0806] Step 2: At room temperature, add dimethyl HCl containing 4M HCl... Alkane (19 mL, 78 mmol) was added to a solution of (4-chloro-2-(isopropylcarbamoyl)thiazolyl-5-yl)carbamate (1.25 g, 3.91 mmol) in CH₂Cl₂ (39 mL), and the solution was stirred at room temperature for 16 hours. The reaction mixture was concentrated, and the oily residue was then dissolved in CH₂Cl₂ and concentrated, dissolved in Et₂O and concentrated to give 5-amino-4-chloro-N-isopropylthiazolyl-2-carboxamide (int-EC39). LCMS (Method b) m / z 220.2 [M+H] + , t R = 0.73 min. 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.16 (d, J = 8.4 Hz, 1H), 6.48 (s, 2H), 4.10 - 3.90 (m, 1H), 1.13 (d, J = 6.6 Hz, 6H).

[0807] Synthesis of 5-amino-N-(2,2-difluoroethyl)-1-methyl-1H-pyrazole-3-carboxamide (int-EC40)

[0808]

[0809] Step 1: EDC (574 mg, 3 mmol) was added to a solution of 5-((tert-butyloxycarbonyl)amino)-1-methyl-1H-pyrazole-3-carboxylic acid (see Step 2 in the synthesis of int-EC38) (121 mg, 0.5 mmol), 2,2-difluoroethylamine (0.042 mL, 0.6 mmol), Et3N (0.090 mL, 0.65 mmol), and HOBT (81 mg, 0.6 mmol) in CH2Cl2 (4 mL) at room temperature, and the reaction mixture was stirred for 48 hours at room temperature. The mixture was then washed with saturated NaHCO3 and water, dried (Na2SO4), and concentrated. The crude product was purified by column chromatography (10-50% ethyl acetate / cyclohexane) to give tert-butyl (3-((2,2-difluoroethyl)carbamoyl)-1-methyl-1H-pyrazole-5-yl)carbamate. LCMS (Method b) m / z 305.3 [M+H] + , t R = 0.78 min. 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.03 (t, J = 6.0 Hz, 1H), 6.64 (s, 1H), 6.15 (s, 1H), 5.91 (tt, J = 56.1, 4.2 Hz, 1H), 3.85 - 3.70 (m,5H), 1.50 (s, 9H).

[0810] Step 2: At room temperature, add dimethyl HCl containing 4 M HCl... Alkane (1.3 mL, 5.2 mmol) was added to a solution of tert-butyl carbamate (79 mg, 0.26 mmol) in CH₂Cl₂ (2.6 mmol), and the reaction mixture was stirred at room temperature for 2 hours. The suspension was concentrated to give 5-amino-N-(2,2-difluoroethyl)-1-methyl-1H-pyrazole-3-carboxamide (int-EC40). LCMS (Method b) m / z 205.2 [M+H] + , t R = 0.39 min. 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.23 ​​(t, J = 6.2 Hz, 1H), 6.05 (t, J = 56.3 Hz, 1H), 5.78 (s, 1H), 3.60 - 3.56 (m, 8H).

[0811] Synthesis of 5-amino-N-isopropyl-4-methylthiazol-2-carboxamide (int-EC41)

[0812]

[0813] A method similar to that described for the synthesis of 5-amino-N-(2,2-difluoroethyl)-1-methyl-1H-pyrazole-3-carboxamide (int-EC40) was used, but 5-((tert-butoxycarbonyl)amino)-4-methylthiazol-2-carboxylic acid was substituted for 5-(tert-butoxycarbonyl)amino)-1-methyl-1H-pyrazole-3-carboxylic acid and 2,2-difluoroethylamine was substituted for propyl-2-amine to obtain 5-amino-N-isopropyl-4-methylthiazol-2-carboxamide (int-EC41). LCMS (Method b) m / z 200.2 [M+H] + , t R = 0.62 min. 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.81 (d, J = 8.4 Hz, 1H), 6.51 (s,3H), 4.10 - 3.92 (m, 1H), 2.16 (s, 3H), 1.13 (d, J = 6.6 Hz, 6H).

[0814] Note: Use the following procedure to obtain 5-((tert-butoxycarbonyl)amino)-4-methylthiazolyl-2-carboxylic acid:

[0815] Step 1: TFA (5.1 mL, 66.3 mmol) was added to a solution of 2-ethyl 5-(tert-butyl) 4-methylthiazolyl-2,5-dicarboxylic acid (see Step 1 in the synthesis of int-EC2) (0.9 g, 3.32 mmol) in 33 mL of CH2Cl2 at room temperature, and the mixture was stirred for 2 hours at room temperature. The reaction solution was then concentrated, and the oily residue was dissolved in CH2Cl2, concentrated, dissolved with Et2O, and concentrated under high vacuum to give 2-(ethoxycarbonyl)-4-methylthiazolyl-5-carboxylic acid. LCMS (Method b) m / z 216.1 [M+H] + , t R = 0.55 min. 1 H NMR (400 MHz, DMSO-d6) δ ppm13.87 (s, 1H), 4.38 (q, J = 7.1 Hz, 2H), 2.68 (s, 3H), 1.33 (t, J = 7.1 Hz, 3H).

[0816] Step 2: DPPA (1.10 mL, 5.02 mmol) and triethylamine (513 µl, 3.68 mmol) were added to a solution of 2-(ethoxycarbonyl)-4-methylthiazol-5-carboxylic acid (0.72 g, 3.35 mmol) in tert-butanol (12 mL), and the reaction mixture was stirred at 95 °C for 3 hours. After cooling to room temperature, the solvent was removed, the residue was treated with water, and extracted with ethyl acetate. The combined organic phases were washed with brine, dried (Na₂SO₄), and concentrated. The crude product was purified by column chromatography (20–40% ethyl acetate / cyclohexane) to give ethyl 5-((tert-butoxycarbonyl)amino)-4-methylthiazol-2-carboxylic acid. LCMS (Method b) m / z 287.2 [M+H] + , t R = 1.00 min. 1 H NMR (400 MHz, DMSO-d6) δ ppm 10.49 (s, 1H), 4.30 (q, J = 7.1 Hz, 2H), 2.36 (s, 3H), 1.50 (s, 9H), 1.30 (t, J = 7.1 Hz, 3H).

[0817] Step 3: H₂O containing 1 M LiOH (10 mL, 10 mmol) was added to a suspension of ethyl 5-((tert-Butoxycarbonyl)amino)-4-methylthiazol-2-carboxylate (0.60 g, 2.1 mmol) in THF (20 mL), and the mixture was stirred at room temperature for 7 hours. The THF was then removed, and the residue was treated with water and washed with ethyl acetate. The aqueous phase was acidified with concentrated HCl, and the resulting white suspension was stirred for 30 minutes. This was then filtered off while cold and dried under high vacuum to give 5-((tert-Butoxycarbonyl)amino)-4-methylthiazol-2-carboxylic acid. LCMS (Method b) m / z 259.2 [M+H] + , t R = 0.62 min. 1 H NMR (400 MHz, DMSO-d6) δ ppm 13.37 (s, 1H), 10.35 (s, 1H), 2.34 (s, 3H), 1.50 (s, 9H).

[0818] Synthesis of 5-amino-N-isopropyl-1-methyl-1H-pyrazole-3-carboxamide (int-EC42)

[0819]

[0820] A method similar to that described for the synthesis of 5-amino-N-(2,2-difluoroethyl)-1-methyl-1H-pyrazole-3-carboxamide (int-EC40) was used, but propyl-2-amine was substituted for 2,2-difluoroethylamine to obtain 5-amino-N-isopropyl-1-methyl-1H-pyrazole-3-carboxamide (int-EC42). LCMS (Method b) m / z 183.1 [M+H] + , t R = 0.46min. 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.77 (d, J = 8.2 Hz, 1H), 6.55 (s, 3H), 5.85 (s, 1H), 4.09 - 3.93 (m, 1H), 3.60 (s, 3H), 1.12 (d, J = 6.6 Hz, 6H).

[0821] Synthesis of 5-amino-N-isopropyl-1-methyl-1H-pyrazole-3-carboxamide (int-EC43)

[0822]

[0823] A method similar to that described for the synthesis of 5-amino-N-(2,2-difluoroethyl)-1-methyl-1H-pyrazole-3-carboxamide (int-EC40) was used, but 2,2,2-trifluoroethylamine was substituted for 2,2-difluoroethylamine to obtain 5-amino-N-isopropyl-1-methyl-1H-pyrazole-3-carboxamide (int-EC43). LCMS (Method b) m / z 223.2 [M+H] + , t R =0.48 min. 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.38 (t, J = 6.7 Hz, 1H), 5.72 (s,1H), 3.94 - 3.91 (m, 5H), 3.59 (s, 3H).

[0824] Synthesis of N-(5-amino-1-methyl-1H-pyrazol-3-yl)-2-fluorobenzamide (int-EC44)

[0825]

[0826] A method similar to that described for the synthesis of N-(5-amino-1-methyl-1H-pyrazol-3-yl)isobutyramide (int-EC38) was used, but 2-fluorobenzoic acid was substituted for isobutyric acid (step 5) to obtain N-(5-amino-1-methyl-1H-pyrazol-3-yl)-2-fluorobenzamide (int-EC44). LCMS (Method b) m / z 235.2 [M+H] + , t R = 0.54 min. 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.54 (s, 1H), 8.92 (d, J = 5.6 Hz, 1H), 8.10- 8.02 (m, 1H), 7.73 (t, J = 7.2 Hz, 1H), 7.69 - 7.59 (m, 1H), 5.70 (s, 1H), 3.59 (s, 3H), 3.57 (s, 3H).

[0827] Synthesis of N-(5-amino-1-methyl-1H-pyrazol-3-yl)-2,2,3,3,3-pentafluoropropionamide (int-EC45)

[0828]

[0829] Step 1: Hydrogenate a solution of 1-methyl-3,5-dinitro-1H-pyrazole (1.0 g, 5.81 mmol) in MeOH (110 mL) using H cube (10% Pd / C, all H2 conditions, 30 °C). The solution is then concentrated to give 1-methyl-1H-pyrazole-3,5-diamine, which is used in the next step without further purification. LCMS (Method b) m / z 113.1 [M+H] + , t R =0.68 min. 1 H NMR (400 MHz, DMSO-d6) δ ppm 4.86 (s, 2H), 4.57 (s, 1H), 4.11 (s,2H), 3.25 (s, 3H).

[0830] Step 2: EDC (512 mg, 2.68 mmol) was added to a solution of 1-methyl-1H-pyrazole-3,5-diamine (150 mg, 1.338 mmol), 2,2,3,3,3-pentafluoropropionic acid (139 µL, 1.34 mmol), and pyridine (539 µL, 6.69 mmol) in acetonitrile (10 mL) at room temperature, and the mixture was stirred for 18 hours at room temperature. The reaction mixture was then treated with water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried (Na2SO4), and concentrated. The crude product was purified by column chromatography (40-80% ethyl acetate / cyclohexane) to give N-(5-amino-1-methyl-1H-pyrazole-3-yl)-2,2,3,3,3-pentafluoropropionamide (int-EC45). LCMS (Method b) m / z 259.1 [M+H] + , t R = 0.64 min. 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.66 (s, 1H), 5.64 (s, 1H), 5.35 (s, 2H), 3.47 (s, 3H).

[0831] Synthesis of 3-(3-cyclopropylisocyanate) (-5-yl)-1-methyl-1H-pyrazole-5-amine (int-EC46)

[0832]

[0833] Step 1: In a microwave oven at 100°C, bake 3-cyclopropyl isocyanate... A mixture of 1.0 g (6.53 mmol) of azole-5-carboxylic acid in MeOH (15 mL, 18.75 mmol) containing 1.25 M HCl was heated for 40 minutes. After cooling to room temperature, the solvent was removed, and the residue was dissolved in MeOH and the solvent was removed. This process was repeated three times to obtain 3-cyclopropylisocyanurate. Methyl 5-azole carboxylate. LCMS (Method b) m / z 168.1 [M+H] + , t R = 0.84 min. 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.09 (d, J = 1.2 Hz, 1H), 3.87 (s, 3H), 2.16 - 2.00 (m, 1H), 1.11 -0.99 (m, 2H), 0.90 - 0.77 (m, 2H).

[0834] Step 2: Acetonitrile (0.687 mL, 13.16 mmol) was added to 25 mL of THF containing a hexane solution of 1.6 M n-BuLi (8.23 mL, 13.16 mmol). After stirring the reaction mixture at -78 °C for 20 minutes, 3-cyclopropylisocyanate was added dropwise at -78 °C. A solution of methyl 5-oxazolium-carboxylate (1.1 g, 6.58 mmol) in THF (25 mL) was prepared. The reaction mixture was then stirred at -78 °C for 2 hours, followed by quenching at -78 °C by adding an aqueous solution of 2N HCl. The mixture was then treated with ethyl acetate and 2N HCl, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried (MgSO4), and concentrated to give 3-(3-cyclopropylisocyanate). (Azolium-5-yl)-3-oxopropionitrile. LCMS (Method b) m / z 175.1 [MH] - ,t R = 0.73 min.

[0835] Step 3: 3-(3-cyclopropylisocyanate) under reflux A solution of 1.2 g (6.81 mmol) of azirazol-5-yl)-3-oxopropionitrile and methylhydrazine (1.0 mL, 19.10 mmol) in EtOH (60 mL) was stirred for 16 hours. After cooling to room temperature, the reaction mixture was concentrated and then dissolved in EtOH. It was then evaporated to dryness. The crude product was purified by column chromatography (0-100% ethyl acetate / cyclohexane containing 2% (3.5 MNH3, in methanol) to give 3-(3-cyclopropylisopropionitrile) (-5-yl)-1-methyl-1H-pyrazole-5-amine (int-EC46). LCMS (Method b) m / z 205.1 [M+H] + , t R = 0.65 min. 1 H NMR(400 MHz, DMSO-d6) δ ppm 6.32 (s, 1H), 5.64 (s, 1H), 5.44 (s, 2H), 3.57 (s,3H), 2.05 - 1.92 (m, 1H), 1.06 - 0.96 (m, 2H), 0.85 - 0.75 (m, 2H).

[0836] Synthesis of 1-methyl-3-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazole-5-amine (int-EC47)

[0837]

[0838] Used for the synthesis of 3-(3-cyclopropylisocyanuric acid) The method described in steps 2-3 of (-5-yl)-1-methyl-1H-pyrazole-5-amine (int-EC46) is similar, but 3-cyclopropylisothiocyanate is used instead of methyl 6-(trifluoromethyl)nicotinate. To obtain 1-methyl-3-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-amine (int-EC47), azole-5-carboxylate (step 2). LCMS (method b) m / z 243.1 [M+H] + , t R = 0.75 min. 1 H NMR (400 MHz, DMSO-d6) δ ppm9.04 (d, J = 2.1 Hz, 1H), 8.26 (dd, J = 8.4, 2.1 Hz, 1H), 7.84 (d, J = 8.2Hz, 1H), 5.90 (s, 1H), 5.46 (s, 2H), 3.61 (s, 3H).

[0839] Note that methyl 6-(trifluoromethyl)nicotinic acid is obtained using the following procedure:

[0840] A solution of 2M trimethylsilyldiazomethane in hexane (32.7 mL, 65.4 mmol) was added to a solution of 6-(trifluoromethyl)nicotinic acid (5.0 g, 26.2 mmol) in MeOH (200 mL) at 0 °C. After stirring the reaction mixture at 0 °C for 1 hour, the reaction mixture was concentrated, treated with water, and extracted with ethyl acetate. The combined organic layers were washed with saturated NaHCO3, dried (MgSO4), and concentrated. The crude product was purified by column chromatography (0-50% ethyl acetate / cyclohexane) to give methyl 6-(trifluoromethyl)nicotinic acid. LCMS (Method b) m / z 206.0 [M+H] + , t R = 0.93 min. 1 H NMR (400MHz, DMSO-d6) δ ppm 9.24 (d, J = 2.1 Hz, 1H), 8.57 (dd, J = 8.3, 1.7 Hz, 1H), 8.09 (d, J = 8.2 Hz, 1H), 3.94 (s, 3H).

[0841] Synthesis of 4-chloro-2-(1-methyl-1H-pyrazol-3-yl)thiazolyl-5-amine (int-EC48)

[0842]

[0843] Step 1: A mixture of 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-1H-pyrazole (578 mg, 2.78 mmol), Pd(PPh3)4 (146 mg, 0.126 mmol), 2M Na2CO3 (4.4 mL, 8.8 mmol), and 2,4-dichlorothiazol-5-carboxylic acid (int-EC13, Step 1, 500 mg, 2.52 mmol) in DME (13 mL) was heated to 80 °C for 5 hours. After cooling to room temperature, the reaction mixture was treated with water and washed with ethyl acetate. The aqueous phase was acidified with concentrated HCl and the white precipitate was filtered off while cold to give 4-chloro-2-(1-methyl-1H-pyrazole-3-yl)thiazol-5-carboxylic acid. LCMS (Method b) m / z 243.9 [M+H] + , t R = 0.52 min. 1 H NMR (400 MHz, DMSO-d6) δ ppm 13.84 (s,1H), 7.91 (d, J = 2.4 Hz, 1H), 6.84 (d, J = 2.4 Hz, 1H), 3.94 (s, 3H).

[0844] Step 2: DPPA (515 µL, 2.34 mmol) and triethylamine (261 µL, 1.87 mmol) were added to a solution of 4-chloro-2-(1-methyl-1H-pyrazol-3-yl)thiazolyl-5-carboxylic acid (380 mg, 1.56 mmol) in tert-butanol (12 mL) at room temperature, and the reaction mixture was stirred at 95 °C for 3 hours. After cooling to room temperature, the solvent was removed, and the residue was treated with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried (Na₂SO₄), and concentrated. The crude product was purified by column chromatography (10–30% ethyl acetate / cyclohexane) to give tert-butyl (4-chloro-2-(1-methyl-1H-pyrazol-3-yl)thiazolyl-5-yl)carbamate. LCMS (Method b) m / z 315.2 [M+H] + , t R = 1.01 min. 1 H NMR (400 MHz, DMSO-d6) δ ppm 10.22 (s, 1 H) 7.83 (d, J = 2.2 Hz, 1H) 6.68 (d, J = 2.3 Hz, 1H) 3.90 (s, 3H) 1.49 (s, 9H).

[0845] Step 3: At room temperature, add dimethyl HCl containing 4M HCl... Alkane (7.6 mL, 30.5 mmol) was added to a solution of (4-chloro-2-(1-methyl-1H-pyrazol-3-yl)thiazolyl-5-yl)carbamate (400 mg, 1.27 mmol) in CH₂Cl₂ (25 mL). The reaction mixture was stirred at room temperature for 18 hours, then cooled to 0 °C. The solid was filtered off, washed with Et₂O, and dried under high vacuum to give 4-chloro-2-(1-methyl-1H-pyrazol-3-yl)thiazolyl-5-amine (int-EC48). LCMS (Method b) m / z 215.2 [M+H] + , t R = 0.61 min. 1 H NMR (400 MHz, DMSO-d6): δ ppm 7.75 (d, J = 2.20 Hz, 1H) 6.55 (d, J = 2.20 Hz, 1H) 6.37 (s, 3H) 3.85 (s, 3H).

[0846] Synthesis of 1-methyl-3-(5-methylpyridin-3-yl)-1H-pyrazole-5-amine (int-EC49)

[0847]

[0848] Used for the synthesis of 3-(3-cyclopropylisocyanuric acid) The method described in steps 2-3 of (-5-yl)-1-methyl-1H-pyrazole-5-amine (int-EC46) is similar, but in step 2, methyl 5-methylnicotinate is used instead of 3-cyclopropylisothiocyanate. To obtain 1-methyl-3-(5-methylpyridin-3-yl)-1H-pyrazol-5-amine (int-EC49), azole-5-carboxylate was used. LCMS (Method b) m / z 189.1 [M+H] + , t R = 0.38 min. 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.65 (s,1H), 8.26 (s, 1H), 7.82 (s, 1H), 5.75 (s, 1H), 5.34 (s, 2H), 3.57 (s, 3H), 2.30 (s, 3H).

[0849] Synthesis of N-(5-amino-1-methyl-1H-pyrazol-3-yl)-2,3-difluorobenzamide (int-EC50)

[0850]

[0851] A method similar to that described for the synthesis of N-(5-amino-1-methyl-1H-pyrazol-3-yl)isobutyramide (int-EC38) was used, but 2,3-difluorobenzoic acid was substituted for isobutyric acid (step 5) to obtain N-(5-amino-1-methyl-1H-pyrazol-3-yl)-2,3-difluorobenzoamide (int-EC50). LCMS (Method b) m / z 253.1 [M+H] + , t R =0.58 min. 1 H NMR (400 MHz, DMSO-d6) δ ppm 11.52 (s, 1H), 8.92 (d, J = 5.7 Hz,1H), 8.12 - 7.99 (m, 1H), 7.75 - 7.57 (m, 1H), 5.74 (s, 1H), 3.58 (s, 3H),3.57 (s, 3H).

[0852] Synthesis of (S)-5-amino-N-(1-fluoroprop-2-yl)-1-methyl-1H-pyrazole-3-carboxamide (int-EC51)

[0853]

[0854] A method similar to that described for the synthesis of 5-amino-N-(2,2-difluoroethyl)-1-methyl-1H-pyrazole-3-carboxamide (int-EC40) was used, but 2,2-difluoroethylamine was replaced with (S)-1-fluoroprop-2-amine (step 3) to obtain (S)-5-amino-N-(1-fluoroprop-2-yl)-1-methyl-1H-pyrazole-3-carboxamide (int-EC51). LCMS (Method b) m / z 201.2 [M+H] + , t R = 0.42 min. 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.77 (d, J = 8.5Hz, 1H), 5.74 (s, 1H), 5.16 (s, 3H), 4.53 - 4.10 (m, 3H), 3.58 (s, 3H), 1.12(d, J = 6.8 Hz, 3H).

[0855] Synthesis of 2-(5-fluoropyridin-3-yl)-4-methylthiazolyl-5-amine (int-EC52)

[0856]

[0857] Step 1: A solution of di-tert-butyl dicarbonate (2.237 mL, 9.63 mmol) in methanol (20 mL) was added dropwise to a mixture of 4-methyl-1,3-thiazol-5-amine (1.0 g, 8.76 mmol) and triethylamine (3.66 mL, 26.3 mmol) in methanol (50 mL) at 0 °C, and the reaction mixture was stirred at room temperature for 16 hours. After solvent removal, the residue was dissolved in CH2Cl2, and the solution was washed with water and saturated NaHCO3, dried over (MgSO4), and concentrated. The crude product was purified by column chromatography (5-30% ethyl acetate / cyclohexane) to give tert-butyl (4-methylthiazol-5-yl)carbamate. LCMS (Method b) m / z 215.1 [M+H] + , t R = 0.81 min. 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.74 (s,1H), 8.54 (s, 1H), 2.26 (s, 3H), 1.47 (s, 9H).

[0858] Step 2: NBS (0.640 g, 3.59 mmol) was added to a solution of (4-methylthiazol-5-yl)carbamate tert-butyl ester (0.70 g, 3.27 mmol) in CH₂Cl₂ (35 mL) at room temperature, and the mixture was stirred for 1 hour at room temperature. The reaction mixture was then concentrated and the residue was purified by column chromatography (5-20% ethyl acetate / cyclohexane) to give (2-bromo-4-methylthiazol-5-yl)carbamate tert-butyl ester. LCMS (Method b) m / z 293.0 [M+H] + , t R = 1.08min. 1 H NMR (400 MHz, DMSO-d6) δ ppm 10.23 (s, 1H), 2.24 (s, 3H), 1.47 (s, 9H).

[0859] Step 3: PdCl2dppf (52.4 mg, 0.072 mmol) was added to a degassed mixture of (2-bromo-4-methylthiazolyl-5-yl)carbamate (70 mg, 0.239 mmol), (5-fluoropyridin-3-yl)boronic acid (33.6 mg, 0.239 mmol), and cesium carbonate (389 mg, 1.194 mmol) in DMF (2.5 mL) at room temperature. The mixture was then heated in a microwave oven at 100 °C for 30 minutes. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and filtered through a diatomaceous earth stopper. The crude product was purified by preparative HPLC (Waters X-Bridge C18 OBD, 5 µm, 30*100 mm, eluent A: H2O + 7.3 mM NH4OH, eluent B: CH3CN + 7.3 mM NH4OH, gradient: 20% to 99% B over 12.5 min, hold for 2.5 min, flow rate 45 mL / min) to give tert-butyl (2-(5-fluoropyridin-3-yl)-4-methylthiazolyl-5-yl)carbamate. LCMS (Method b) m / z 310.1 [M+H] + , t R = 1.07 min. 1 H NMR (400 MHz, CDCl3) δ ppm 8.97 -8.92 (m, 1H), 8.50 - 8.44 (m, 1H), 8.21 (d, J = 8.5 Hz, 1H), 6.80 (s, 1H), 2.44 (s, 3H), 1.56 (s, 9H).

[0860] Step 4: Use distillate containing 4M HCl 2-(5-fluoropyridin-3-yl)-4-methylthiazol-5-yl)carbamate tert-butyl ester (20 mg, 0.065 mmol) was treated with alkylene (3 mL, 12 mmol), and the reaction mixture was stirred at room temperature for 16 hours. The mixture was then concentrated to give 2-(5-fluoropyridin-3-yl)-4-methylthiazol-5-amine (int-EC52). LCMS (Method b) m / z 210.0 [M+H] + , t R = 0.67 min.

[0861] Synthesis of 1-methyl-3-(5-methylisocyanate) (-3-yl)-1H-pyrazole-5-amine (int-EC53)

[0862]

[0863] Used for the synthesis of 3-(3-cyclopropylisocyanuric acid) The method described in step 3 of (int-EC46) pyrazol-5-yl)-1-methyl-1H-pyrazol-5-amine is similar, but uses 3-(5-methylisocyanate) 3-(3-cyclopropylisocyanate)-3-oxopropionitrile replaced by 3-(3-cyclopropylisocyanate) to obtain 1-methyl-3-(5-methylisopropionitrile)-3-oxopropionitrile (-3-yl)-1H-pyrazole-5-amine (int-EC53). LCMS (Method b) m / z 179.0 [M+H] + , t R = 0.52 min. 1 H NMR (400 MHz, DMSO-d6) δ ppm 6.38 (s, 1H), 5.64 (s, 1H), 5.37 (s, 2H), 3.57 (s, 3H), 2.40 (s, 3H).

[0864] Synthesis of 3-(5-ethylisothiazolinone) (-3-yl)-1-methyl-1H-pyrazole-5-amine (int-EC54)

[0865]

[0866] Used for the synthesis of 3-(3-cyclopropylisocyanuric acid) The method described in steps 2-3 of (-5-yl)-1-methyl-1H-pyrazole-5-amine (int-EC46) is similar, but uses 5-ethylisothiocyanate. Ethyl 3-oxazolium-3-carboxylate as a substitute for 3-cyclopropylisothiocyanate Methyl 5-azole carboxylate (step 2) to obtain 3-(5-ethylisothiocarboxylate) (-3-yl)-1-methyl-1H-pyrazole-5-amine (int-EC54). LCMS (Method b) m / z 193.1 [M+H] + , t R = 0.64 min. 1 H NMR (400 MHz, DMSO-d6) δppm 6.41 (t, J = 0.9 Hz, 1H), 5.66 (s, 1H), 5.39 (s, 2H), 3.58 (s, 3H), 2.76(qd, J = 7.6, 0.9 Hz, 2H), 1.24 (t, J = 7.6 Hz, 16H).

[0867] Synthesis of 1-ethyl-3-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazole-5-amine(int-EC55)

[0868]

[0869] Used for the synthesis of 3-(3-cyclopropylisocyanuric acid) The method described in steps 2-3 of (-5-yl)-1-methyl-1H-pyrazole-5-amine (int-EC46) is similar, but 3-cyclopropylisothiocyanate is used instead of methyl 6-(trifluoromethyl)nicotinate. Methyl 5-carboxylate (step 2) and ethylhydrazine instead of methylhydrazine (step 3) to obtain 1-ethyl-3-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-amine (int-EC55). LCMS (method b) m / z 257.1 [M+H] + , t R = 0.83 min. 1 H NMR(400 MHz, DMSO-d6) δ ppm 9.03 (s, 1H), 8.26 (d, J = 8.2 Hz, 1H), 7.84 (d, J =8.2 Hz, 1H), 5.89 (s, 1H), 5.44 (s, 2H), 3.97 (q, J = 7.9, 7.2 Hz, 2H), 1.28(t, J = 7.0 Hz, 3H).

[0870] It should be noted that the procedure described for the synthesis of 1-methyl-3-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazole-5-amine (int-EC47) is used to obtain methyl 6-(trifluoromethyl)nicotinic acid.

[0871] Synthesis of 1-ethyl-3-(furan-2-yl)-1H-pyrazole-5-amine (int-EC56)

[0872]

[0873] Used for the synthesis of 3-(3-cyclopropylisocyanuric acid) The method described in steps 2-3 of (-5-yl)-1-methyl-1H-pyrazol-5-amine (int-EC46) is similar, but 3-cyclopropylisothiocyanate is replaced with 3-(furan-2-yl)-3-oxopropionitrile. Methyl 5-carboxylate (step 2) and ethylhydrazine instead of methylhydrazine (step 3) to obtain 1-ethyl-3-(furan-2-yl)-1H-pyrazole-5-amine (int-EC56). LCMS (method b) m / z 178.1 [M+H] + , t R = 0.59 min. 1H NMR (400MHz, DMSO-d6) δ ppm 7.58 (s, 1H), 6.54 - 6.44 (m, 2H), 5.51 (s, 1H), 5.27 (s,2H), 3.89 (q, J = 7.2 Hz, 2H), 1.24 (t, J = 7.1 Hz, 3H).

[0874] Synthesis of 3-(3-ethylisothio) (-5-yl)-1-methyl-1H-pyrazole-5-amine (int-EC57)

[0875]

[0876] Used for the synthesis of 3-(3-cyclopropylisocyanuric acid) The method described is similar to that of (-5-yl)-1-methyl-1H-pyrazole-5-amine (int-EC46), but uses 3-ethylisothiocyanate. Azole-5-carboxylic acid substituted with 3-cyclopropylisocyanate To obtain 3-(3-ethylisothiazolic acid) (step 1) (-5-yl)-1-methyl-1H-pyrazole-5-amine (int-EC57). LCMS (Method b) m / z 193.1 [M+H] + , t R = 0.62 min. 1 H NMR (400 MHz, DMSO-d6) δ ppm 6.50 (s, 1H), 5.67 (s, 1H), 5.44 (s, 2H), 3.58 (s, 3H), 2.62 (q, J = 7.6 Hz, 2H), 1.20 (t, J =7.6 Hz, 3H).

[0877] Synthesis of 3-(5-fluoropyridin-2-yl)-1-methyl-1H-pyrazole-5-amine (int-EC58)

[0878]

[0879] Used for the synthesis of 3-(3-cyclopropylisocyanuric acid) The method described for (-5-yl)-1-methyl-1H-pyrazole-5-amine (int-EC46) is similar, but uses 5-fluoropyridinecarboxylic acid instead of 3-cyclopropylisocyanate. To obtain 3-(5-fluoropyridin-2-yl)-1-methyl-1H-pyrazol-5-amine (int-EC58) by azole-5-carboxylic acid (step 1). LCMS (method b) m / z 193.1 [M+H] + ,tR = 0.54 min. 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.48 (d, J = 2.9 Hz, 1H), 7.84 (dd, J = 8.8, 4.7 Hz, 1H), 7.66 (td, J = 8.8, 3.0 Hz, 1H), 5.82 (s, 1H), 5.32 (s, 2H), 3.58 (s, 3H).

[0880] Synthesis of 3-chloro-1-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazole-4-amine (int-EC59)

[0881]

[0882] Step 1: Concentrated HCl (14.5 mL) was added to a mixture of 4-nitro-1H-pyrazole (2.0 g, 17.7 mmol) and EtOH (24 mL) at room temperature, and the mixture was purged with argon for 10 min while stirring. Pd / alumina (113 mg) was then added, followed by the slow addition of triethylsilane (11.3 mL, 70.7 mmol). The mixture was then stirred at room temperature for 16 h. The mixture was then filtered through a diatomaceous earth stopper to separate the two phases. The lower phase was concentrated by adding acetonitrile to the mixture several times until a solid was obtained. The solid was then suspended in acetonitrile and filtered off. After washing with acetonitrile and drying under high vacuum, 3-chloro-1H-pyrazole-4-amine in the form of an HCl salt was obtained. 1 H NMR (400 MHz, DMSO-d6)δ ppm 10.50 (s, 3H), 8.02 (s, 1H), 7.74 (s, 1H).

[0883] Step 2: Boc₂O (3.74 g, 17.1 mmol) was added to a mixture of 3-chloro-1H-pyrazole-4-amine (2.4 g, 15.6 mmol) and NaHCO₃ (2.88 g, 34.3 mmol) in THF (28 mL) / H₂O (2.8 mL) at room temperature, and the mixture was stirred at room temperature for 16 hours. The mixture was then treated with water and ethyl acetate, and the aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with brine, dried (Na₂SO₄), and concentrated to give an oil. After treatment with cyclohexane and brief heating to form a suspension, the suspension was filtered off, washed with cyclohexane, and dried to give tert-butyl (3-chloro-1H-pyrazole-4-yl)carbamate. LCMS (Method b): m / z 218.2 [M+H] + , t R= 0.75 min. 1H NMR (400 MHz, CDCl3) δ(ppm) 7.89 (s, 1H), 7.64 (s, 1H), 6.25 (s, 1H), 1.42 (s, 9H)

[0884] Step 3: Treat anhydrous acetonitrile (6 mL) containing tert-butyl (3-chloro-1H-pyrazol-4-yl)carbamate (408 mg, 1.5 mmol), 5-iodo-2-(trifluoromethyl)pyridine (491 mg, 1.8 mmol), K3PO4 (637 mg, 3 mmol), and CuCl (30 mg, 0.3 mmol) with N,N'-dimethylethylenediamine (331 mg, 3.75 mmol) and heat the mixture at 75 °C for 1.5 h. After cooling to room temperature, filter the mixture through a diatomaceous earth stopper and wash with acetonitrile. Then concentrate the filtrate, dissolve it in acetonitrile (10 mL), and treat it with water (20 mL) to obtain a solid, filter it, and wash it with water. Then dissolve the solid in ethyl acetate, wash it with brine, dry it (Na2SO4), and concentrate it. The crude product was purified by column chromatography (10-20% ethyl acetate / cyclohexane) to give tert-butyl (3-chloro-1-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-4-yl)carbamate. LCMS (Method b) m / z 363.1 [M+H] + , t R = 1.23 min. 1 H NMR (400 MHz, CDCl3) δ ppm9.05 (s, 1H), 8.42 (s, 1H), 8.14 (d, J = 8.4 Hz, 1H), 7.76 (d, J = 8.6 Hz,1H), 6.38 (s, 1H), 1.55 (s, 9H).

[0885] Step 4: Treat CH₂Cl₂ (0.91 mL) containing tert-butyl (3-chloro-1-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-4-yl)carbamate (330 mg, 0.91 mmol) with TFA (0.91 mL, 11.8 mmol) and stir the mixture at room temperature for 3 hours. Then dilute the reaction mixture with CH₂Cl₂ and treat with saturated NaHCO₃. Extract the aqueous phase with CH₂Cl₂, wash the combined organic layers with brine, dry (Na₂SO₄), and concentrate to give 3-chloro-1-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-4-amine (int-EC59). LCMS (Method b) m / z 263.1 [M+H]+ , t R = 0.90 min. 1 H NMR(400 MHz, DMSO-d6) δ ppm 9.12 (d, J = 2.6 Hz, 1H), 8.31 (dd, J = 8.7, 2.6 Hz,1H), 7.99 (s, 1H), 7.97 (d, J = 8.8 Hz, 1H), 4.56 (s, 2H).

[0886] Synthesis of N-(5-amino-1-methyl-1H-pyrazol-3-yl)pentylamide (int-EC60)

[0887]

[0888] A method similar to that described for the synthesis of N-(5-amino-1-methyl-1H-pyrazol-3-yl)isobutyramide (int-EC38) was used, but pentovalinic acid was substituted for isobutyric acid (step 5) to obtain N-(5-amino-1-methyl-1H-pyrazol-3-yl)pentovalinamide (int-EC60). LCMS (Method b) m / z 197.2 [M+H] + , t R = 0.48 min. 1 H NMR (400MHz, DMSO-d6) δ ppm 10.88 (s, 1H), 5.60 (s, 1H), 3.57 (s, 3H), 3.56 (s, 3H), 1.22 (s, 9H).

[0889] Synthesis of 1-methyl-3-(3-methylisocyanate) (-5-yl)-1H-pyrazole-5-amine (int-EC61)

[0890]

[0891] Used for the synthesis of 3-(3-cyclopropylisocyanuric acid) The method described in steps 2-3 of (-5-yl)-1-methyl-1H-pyrazole-5-amine (int-EC46) is similar, but uses 3-methylisocyanate. Methyl 5-azole carboxylate replacing 3-cyclopropyl isopropyl methyl ether Methyl 5-oxazolium carboxylate (step 2) to obtain 1-methyl-3-(3-methylisocyanate) (-5-yl)-1H-pyrazol-5-amine (int-EC61). LCMS (Method b) m / z 179.1 [M+H] + , t R = 0.51 min.1 ¹H NMR (400 MHz, DMSO-d6) δppm 6.46 (s, 1H), 5.69 (s, 1H), 3.59 (s, 3H), 2.24 (s, 3H). (NH₂ not observed).

[0892] Synthesis of 5-amino-N-isopropylthiazol-2-carboxamide (int-EC62)

[0893]

[0894] A method similar to that described for the synthesis of 5-amino-N-(2,2-difluoroethyl)-1-methyl-1H-pyrazole-3-carboxamide (int-EC40) was used, but 5-((tert-butoxycarbonyl)amino)thiazole-2-carboxylic acid was substituted for 5-((tert-butoxycarbonyl)amino)-1-methyl-1H-pyrazole-3-carboxylic acid and 2,2-difluoroethylamine was substituted for propyl-2-amine to obtain 5-amino-N-isopropylthiazole-2-carboxamide (int-EC62). LCMS (Method b) m / z 186.1 [M+H] + , t R = 0.54 min.

[0895] Synthesis of 3-methyl-1-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazole-4-amine (int-EC63)

[0896]

[0897] Step 1: To a solution of 3-methyl-4-nitro-1H-pyrazole (1.0 g, 7.87 mmol) in DMF (100 mL), add (6-(trifluoromethyl)pyridin-3-yl)boronic acid (2.253 g, 11.80 mmol), Cu(OAc)₂ (0.471 g, 2.36 mmol), and pyridine (0.255 mL, 3.15 mmol), and stir the solution at 100 °C under an oxygen atmosphere for 24 hours. After cooling to room temperature, evaporate the DMF, and dilute the residue in ethyl acetate and extract with H₂O. Extract the aqueous layer again with ethyl acetate, and dry the combined organic layers and evaporate to dryness to obtain the crude product, which is purified by column chromatography (0-60% ethyl acetate / cyclohexane) to give 5-(3-methyl-4-nitro-1H-pyrazole-1-yl)-2-(trifluoromethyl)pyridine. LCMS (Method b) m / z 273.0 [M+H] + , t R = 1.08 min. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.82 (s,1H), 9.37 (d, J = 2.6 Hz, 1H), 8.60 (dd, J = 8.5, 2.6 Hz, 1H), 8.14 (d, J =8.9 Hz, 1H), 2.57 (s, 3H).

[0898] Step 2: Hydrogenate a solution of 5-(3-methyl-4-nitro-1H-pyrazol-1-yl)-2-(trifluoromethyl)pyridine (1.12 g, 4.11 mmol) in ethanol (100 mL) using H cube (10% Pd / C, 1 atm, 30 °C). The solution is then concentrated, and the crude product is dissolved in CH₂Cl₂ and washed with 2N HCl. The aqueous layer is alkaline with 2N NaOH and extracted three times with CH₂Cl₂. The combined organic layers are concentrated to give 3-methyl-1-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-4-amine (int-EC63). LCMS (Method b) m / z 243.1 [M+H] + , t R = 0.76 min. 1 H NMR (400 MHz, DMSO-d6) δppm 9.08 (d, J = 2.6 Hz, 1H), 8.23 ​​(dd, J = 8.7, 2.6 Hz, 1H), 7.91 (d, J =8.7 Hz, 1H), 7.79 (s, 1H), 4.32 (s, 2H), 2.18 (s, 3H).

[0899] Synthesis of 1-methyl-3-(pyridin-2-yl)-1H-pyrazole-5-amine (int-EC64)

[0900]

[0901] Used for the synthesis of 3-(3-cyclopropylisocyanuric acid) The method described in step 3 of (int-EC46)-1-methyl-1H-pyrazol-5-amine is similar, but 3-(3-cyclopropylisothio)propionitrile is used instead of 3-oxo-3-(pyridin-2-yl)propionitrile. To obtain 1-methyl-3-(pyridin-2-yl)-1H-pyrazol-5-amine (int-EC64), LCMS (Method b) m / z 175.1 [M+H] + , t R = 0.36 min. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.49 (d,J = 4.5 Hz, 1H), 7.80 (d, J = 7.9 Hz, 1H), 7.72 (t, J = 7.6 Hz, 1H), 7.24 -7.16 (m, 1H), 5.86 (s, 1H), 5.28 (s, 2H), 3.59 (s, 3H).

[0902] Synthesis of 4-chloro-2-(1-(oxetane-3-yl)-1H-pyrazol-4-yl)thiazolyl-5-amine (int-EC65)

[0903]

[0904] A method similar to that described for the synthesis of 4-chloro-2-(1-methyl-1H-pyrazol-3-yl)thiazolyl-5-amine (int-EC48) was used, but 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-1H-pyrazole was substituted for 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-1H-pyrazole (step 2) to obtain 1-methyl-3-(pyridinan-2-yl)-1H-pyrazol-5-amine (int-EC64). LCMS (Method b) m / z 257.0 [M+H] + , t R = 0.56 min. 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.31 (s, 1H), 7.89 (s, 1H), 5.68 (s, 2H), 5.60 - 5.50 (m, 1H), 4.92 - 4.88 (m, 4H).

[0905] Synthesis of 1-cyclopropyl-3-(furan-2-yl)-1H-pyrazole-5-amine (int-EC66)

[0906]

[0907] Used for the synthesis of 3-(3-cyclopropylisocyanuric acid) The method described in step 3 of (int-EC46) is similar to that of (5-yl)-1-methyl-1H-pyrazol-5-amine, but 3-(3-cyclopropylisothiocyanate) is used instead of 3-(furan-2-yl)-3-oxopropionitrile. The 1-cyclopropyl-3-(furan-2-yl)-1H-pyrazol-5-amine (int-EC66) was obtained by replacing methylhydrazine with cyclopropanehydrazine. LCMS (Method b) m / z 190.1 [M+H]+ , t R = 0.64 min. 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.58 (d, J = 1.7 Hz, 1H), 6.50 (d, J = 3.3 Hz, 1H), 6.47 (dd,J = 3.3, 1.8 Hz, 1H), 5.49 (s, 1H), 5.35 (s, 2H), 3.27 - 3.16 (m, 1H), 0.99 -0.86 (m, 4H).

[0908] Synthesis of 3-(6-methoxypyridin-3-yl)-1-methyl-1H-pyrazole-5-amine (int-EC67)

[0909]

[0910] Used for the synthesis of 3-(3-cyclopropylisocyanuric acid) The method described in steps 2-3 of (-5-yl)-1-methyl-1H-pyrazole-5-amine (int-EC46) is similar, but 3-cyclopropylisothiocyanate is used instead of methyl 6-methoxynicotinic acid. Methyl 5-azole carboxylate was used to obtain 3-(6-methoxypyridin-3-yl)-1-methyl-1H-pyrazole-5-amine (int-EC67). LCMS (Method b) m / z 205.1 [M+H] + , t R = 0.57 min. 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.41 (d, J = 2.2Hz, 1H), 7.94 (dd, J = 8.6, 2.3 Hz, 1H), 6.79 (d, J = 8.6 Hz, 1H), 5.66 (s,1H), 5.29 (s, 2H), 3.85 (s, 3H), 3.54 (s, 3H).

[0911] Synthesis of 1-methyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazole-5-amine (int-EC68)

[0912]

[0913] Used for the synthesis of 3-(3-cyclopropylisocyanuric acid) The method described in steps 2-3 of (-5-yl)-1-methyl-1H-pyrazole-5-amine (int-EC46) is similar, but 3-cyclopropylisothiocyanate is used instead of methyl 5-(trifluoromethyl)nicotinate. Methyl pyrazol-5-carboxylate was used to obtain 1-methyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-amine (int-EC68). LCMS (Method b) m / z 243.1 [M+H] + , t R = 0.74 min. 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.15(s, 1H), 8.81 (s, 1H), 8.30 (s, 1H), 5.95 (s, 1H), 5.44 (s, 2H), 3.60 (s,3H).

[0914] Synthesis of 4-chloro-2-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)thiazolyl-5-amine (int-EC69)

[0915]

[0916] The method described for the synthesis of 4-chloro-2-(1-methyl-1H-pyrazol-3-yl)thiazolyl-5-amine (int-EC48) was used, but 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-1H-pyrazol was replaced with 1-(2-methoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-1H-pyrazol (step 2) to obtain 4-chloro-2-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)thiazolyl-5-amine (int-EC69). LCMS (Method b) m / z 259.0 [M+H] + , t R = 0.62 min. 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.11 (s, 1H), 7.74 (s, 1H), 5.11 (s, 3H), 4.26 (t, J = 5.3 Hz, 2H), 3.69 (t, J = 5.3 Hz, 3H), 3.23 (s, 3H).

[0917] Synthesis of 1-ethyl-3-(3-methylisocyanate) (-5-yl)-1H-pyrazole-5-amine int-EC70)

[0918]

[0919] Used for the synthesis of 3-(3-cyclopropylisocyanuric acid) The method described in steps 2-3 of (-5-yl)-1-methyl-1H-pyrazole-5-amine (int-EC46) is similar, but uses 3-methylisocyanate. Methyl 5-azole carboxylate replacing 3-cyclopropyl isopropyl methyl ether Methyl 5-oxazolium carboxylate (step 2) and methyl methazine instead of methyl methazine (step 3) to obtain 1-ethyl-3-(3-methylisocyanate). (-5-yl)-1H-pyrazole-5-amine (int-EC70). LCMS (Method b) m / z 193.1 [M+H] + , t R = 0.58 min. 1 H NMR (400 MHz, DMSO-d6) δ ppm 6.44 (s, 1H), 5.66 (s, 1H), 5.44 (s, 2H), 3.94 (q, J= 7.2 Hz, 2H), 2.23 (s, 3H), 1.25 (t, J = 7.2 Hz, 3H).

[0920] Synthesis of 5-amino-N-cyclopropyl-1-methyl-1H-pyrazole-3-carboxamide (int-EC71)

[0921]

[0922] A method similar to that described for the synthesis of 5-amino-N-(2,2-difluoroethyl)-1-methyl-1H-pyrazole-3-carboxamide (int-EC40) was used, but cyclopropylamine was substituted for 2,2-difluoroethylamine to obtain 5-amino-N-cyclopropyl-1-methyl-1H-pyrazole-3-carboxamide (int-EC71). LCMS (Method b) m / z 181.2 [M+H] + , t R = 0.38min. 1 ¹H NMR (400 MHz, DMSO-d⁶) δ ppm 7.97 (d, J = 4.4 Hz, 1H), 5.76 (s, 1H), 3.57 (s, 3H), 2.81–2.70 (m, 1H), 0.69–0.45 (m, 4H). (NH₃ not observed) + ).

[0923] Synthesis of 4-chloro-2-(1-(difluoromethyl)-1H-pyrazol-4-yl)thiazolyl-5-amine (int-EC72)

[0924]

[0925] A method similar to that described for the synthesis of 4-chloro-2-(1-methyl-1H-pyrazol-3-yl)thiazolyl-5-amine (int-EC48) was used, but 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-1H-pyrazol was substituted for 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)-1H-pyrazol (step 2) to obtain 4-chloro-2-(1-(difluoromethyl)-1H-pyrazol-4-yl)thiazolyl-5-amine (int-EC72). LCMS (Method b) m / z 251.1 [M+H] + , t R = 0.73 min. 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.67 (s, 1H), 8.11 (s,1H), 7.81 (t, J = 58.9 Hz, 1H). (NH3 + (Hidden among the water peaks).

[0926] Synthesis of 1-methyl-3-(6-methylpyridin-3-yl)-1H-pyrazole-5-amine (int-EC73)

[0927]

[0928] Used for the synthesis of 3-(3-cyclopropylisocyanuric acid) The method described in steps 2-3 of (-5-yl)-1-methyl-1H-pyrazole-5-amine (int-EC46) is similar, but 3-cyclopropylisothiocyanate is used instead of methyl 6-methylnicotinate. Methyl 5-oxazolium carboxylate was used to obtain 1-methyl-3-(6-methylpyridin-3-yl)-1H-pyrazol-5-amine (int-EC73). LCMS (Method b) m / z 189.1 [M+H] + , t R = 0.35 min. 1 H NMR (400 MHz, CDCl3) δ ppm 8.79 (s, 1H), 8.16 (d, J = 8.2 Hz, 1H), 7.30 (d, J = 8.2 Hz, 1H), 5.89 (s, 1H), 3.73 (s, 3H), 3.65 (s, 2H), 2.69 (s, 3H).

[0929] Synthesis of methyl 5-amino-1-methyl-1H-pyrazole-3-carboxylate (int-EC74)

[0930]

[0931] A method similar to that described for the synthesis of 5-amino-4-chloro-N-isopropylthiazole-2-carboxamide (int-EC39) was used, but 4-chloro-2-(isopropylcarbamoyl)thiazole-5-carboxylic acid was substituted for 3-(methoxycarbonyl)-1-methyl-1H-pyrazole-5-carboxylic acid to obtain methyl 5-amino-1-methyl-1H-pyrazole-3-carboxylic acid (int-EC74). LCMS (Method b) m / z 156.2 [M+H] + , t R = 0.36 min. 1 H NMR (400 MHz, DMSO-d6) δ ppm 6.89 (s, 3H), 5.74 (s, 1H), 3.72 (s, 3H), 3.59 (s, 3H).

[0932] Synthesis of 4-chloro-2-(6-(trifluoromethyl)pyridin-3-yl)thiazolyl-5-amine (int-EC75)

[0933]

[0934] A method similar to that described for the synthesis of 5-amino-4-chloro-N-isopropylthiazol-2-carboxamide (int-EC39) was used, but 4-chloro-2-(6-(trifluoromethyl)pyridin-3-yl)thiazol-5-carboxylic acid (int-EC6) was used instead of 4-chloro-2-(isopropylcarbamoyl)thiazol-5-carboxylic acid (int-EC9) to obtain 4-chloro-2-(6-(trifluoromethyl)pyridin-3-yl)thiazol-5-amine (int-EC75). LCMS (Method b) m / z 280.0 [M+H] + , t R = 1.00 min. 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.04 (d, J = 2.3 Hz, 1H), 8.27 (dd, J = 8.3, 2.2 Hz, 1H), 7.90 (d, J = 8.3 Hz, 1H), 6.51 (s, 2H).

[0935] The table below lists the purchased amine EC-type intermediates.

[0936]

[0937] Synthesis Examples of Compounds

[0938] Example 1: N 2 ,4-Dimethyl-N 5-((R)-2-methyl-3-oxo-3-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)amino)propyl)thiazole-2,5-dicarboxamide (1)

[0939]

[0940] Step 1: To (S)-10-amino-2,3,5,10-tetrahydro-1H,11H-benzo[d]pyrazolo[1,2-a][1,2]diazide A solution of 11-one (int-A1) (5.0 g, 11.12 mmol) in CH3CN (50 mL) was mixed with (R)-3-((tert-butoxycarbonyl)amino)-2-methylpropionic acid (int-L9) (2.26 g, 11.12 mmol), DIPEA (5.83 mL, 33.4 mmol), and TOTU (3.65 g, 11.12 mmol), and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was then concentrated, and the crude product was dissolved in ethyl acetate, washed with 1N HCl and saturated NaHCO3, dried (MgSO4), and concentrated to give an oily substance, which was then treated with cold Et2O to crystallize the product. The precipitate was collected by filtration and dried under vacuum to give ((R)-2-methyl-3-oxo-3-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazide -10-yl)amino)propyl)tert-butyl carbamate. LCMS (Method a) m / z 403.1 [M+H] + , t R = 0.92 min. 1H NMR (400 MHz, DMSO-d6) δ ppm: 8.21 (d, J = 8.8Hz, 1H), 7.29 (d, J = 7.9 Hz, 1H), 7.23 (t, J = 7.4 Hz, 1H), 7.15 (t, J = 7.6Hz, 1H), 7.06 (d, J = 7.6 Hz, 1H), 6.80 (d, J = 4.0 Hz, 1H), 6.70 (d, J = 8.7Hz, 1H), 4.24 (s, 2H), 3.62 - 3.43 (m, 2H), 3.31 - 3.22 (m, 1H), 3.21 - 3.08(m, 2H), 3.00 - 2.91 (m, 1H), 2.89 - 2.79 (m, 1H), 2.42 - 2.27 (m, 1H), 2.16- 2.07 (m, 1H), 1.40 (s, 9H), 1.01 (d, J = 6.7 Hz, 3H).

[0941] Step 2: Add ((R)-2-methyl-3-oxo-3-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazide) (R)-3-amino-2-methyl-N-((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazo[]carbamate (4.92 g, 11.0 mmol) was dissolved in 4N HCl (50 mL) and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated and then CH3CN / Et2O was added. The resulting precipitate was filtered off, washed with cold Et2O and dried under vacuum to give (R)-3-amino-2-methyl-N-((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazo[] -10-yl)propionamide. LCMS (Method a) m / z 303 [M+H] + , t R = 0.41 min. 1H NMR (400 MHz, DMSO-d6)δ ppm: 8.74 (d, J = 9.2 Hz, 1H), 7.79 (s, 3H), 7.31 (d, J = 7.7 Hz, 1H), 7.24(t, J = 7.0 Hz, 1H), 7.18 (t, J = 7.0 Hz, 1H), 7.07 (d, J = 7.5 Hz, 1H), 6.77(d, J = 9.1 Hz, 1H), 4.25 (s, 2H), 3.56 - 3.49 (m, 2H), 3.33 - 3.24 (m, 1H), 3.22 - 3.14 (m, 1H), 3.11 - 2.98 (m, 2H), 2.94 - 2.79 (m, 1H), 2.43 - 2.30 (m, 1H), 2.18 - 2.03 (m, 1H), 1.20 (d, J = 6.5 Hz, 3H).

[0942] Step 3: Add 4-methyl-2-(methylcarbamoyl)thiazolyl-5-carboxylic acid (int-EC4) (10 mg, 0.04 mmol) and EDC (14.71 mg, 0.077 mmol) to (R)-3-amino-2-methyl-N-((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazide. -10-yl)propionamide (13 mg, 0.038 mmol) was added to a solution of pyridine (2 mL), and the mixture was stirred at room temperature for 16 hours. Ethyl acetate was added to the reaction mixture, and the organic phase was washed with saturated NaHCO3, dried (MgSO4), and concentrated. The crude product was purified by preparative HPLC (Waters SunFirePrep C18 OBD 5 µm, 30*100 mm, flow rate: 40 mL / min, CH3CN: 5 min to 5%, 25 min to 60%) to give N 2 ,4-Dimethyl-N 5 -((R)-2-methyl-3-oxo-3-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)amino)propyl)thiazolyl-2,5-dicarboxamide (1). LCMS (Method b) m / z 485.2 [M+H] + , t R = 0.73 min. 1H NMR (400 MHz, DMSO-d6) δ ppm: 8.84(q, J = 4.0 Hz, 1H), 8.40 (t, J = 5.6 Hz, 1H), 8.36 (d, J = 8.9 Hz, 1H), 7.23(d, J = 7.9 Hz, 1H), 7.19 (t, J = 7.5 Hz, 1H), 7.05 (d, J = 7.6 Hz, 1H), 6.92(t, J = 7.6 Hz, 1H), 6.73 (d, J = 8.8 Hz, 1H), 4.24 (s, 2H), 3.63 - 3.40 (m,3H), 3.29 - 3.24 (m, 1H), 3.23 - 3.14 (m, 1H), 3.13 - 3.01 (m, 1H), 2.80 (d,J = 4.8 Hz, 3H), 2.59 (s, 3H), 2.43 - 2.26 (m, 2H), 2.17 - 2.03 (m, 1H), 1.10(d, J = 6.9 Hz, 3H).

[0943] Alternatively, the product is wet-milled in MTBE (or acetonitrile) and the suspension is filtered to obtain a solid. The solid is then dried under vacuum to obtain the compound of Example 1 in crystalline form.

[0944] Example 2: N-((R)-2-(((S)-5,11-dioxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)carbamoyl)-3,3,3-trifluoropropyl)-4-methyliso Azole-5-carboxamide (2)

[0945]

[0946] Step 1. To (S)-10-amino-2,3-dihydrobenzo[d]pyrazolo[1,2-a][1,2]diazide A mixture of -5,11(1H,10H)-dione (550 mg, 2.1 mmol) in CH3CN (10 mL) was mixed with 2-(((tert-butoxycarbonyl)amino)methyl)-3,3,3-trifluoropropionic acid (int-L1) (528 mg, 2.1 mmol), TOTU (674 mg, 2.1 mmol), and DIPEA (1.1 mL, 6.2 mol), and the mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated, dissolved in ethyl acetate, washed with 1N HCl and saturated NaHCO3 solution, dried (MgSO4), and concentrated to give a mixture of stereoisomers. The crude substance was purified by rapid chromatography (0-30% ethyl acetate / cyclohexane) to obtain the desired isomer ((R)-2-(((S)-5,11-dioxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazide). -10-yl)carbamoyl)-3,3,3-trifluoropropyl)tert-butyl carbamate. LCMS (condition a) m / z 471.2 [M+H] + , t R = 0.99 min; 1 HNMR (400 MHz, DMSO-d6) δ ppm 9.44 (d, J = 7.7 Hz, 1H), 7.79 (d, J = 7.6 Hz,1H), 7.60 - 7.47 (m, 2H), 7.36 (d, J = 7.8 Hz, 1H), 7.08 (t, J = 5.3 Hz, 1H), 5.95 (d, J = 7.8 Hz, 1H), 4.33 - 4.06 (m, 3H), 3.69 - 3.57 (m, 1H), 3.39 -3.32 (m, 2H), 3.27 - 3.17 (m, 1H), 2.18 - 2.07 (m, 2H), 1.42 (s, 9H).

[0947] Step 2. At room temperature, ((R)-2-(((S)-5,11-dioxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazide) -10-yl)carbamoyl)-3,3,3-trifluoropropyl)carbamate tert-butyl ester (360 mg, 0.8 mmol) in dimethyl HCl containing 4M HCl The mixture in alkane (10 mL, 40 mmol) was stirred for 1 hour. The reaction mixture was then concentrated and treated with CH3CN and Et2O. The precipitate was filtered off, washed with cold Et2O, and dried under vacuum to give (R)-2-(aminomethyl)-N-((S)-5,11-dioxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazide as an HCl salt. (-10-yl)-3,3,3-trifluoropropionamide, which was used in the next step without further purification. LCMS (condition a) m / z 371.2 [M+H] + , t R = 0.35 min. 1 H NMR (400 MHz, DMSO-d6) δppm: 9.74 (d, J = 8.2 Hz, 1H), 8.15 (s, 3H), 7.80 (d, J = 7.7 Hz, 1H), 7.62(t, J = 7.6 Hz, 1H), 7.53 - 7.45 (m, 2H), 6.01 (d, J = 8.0 Hz, 1H), 4.34 -4.16 (m, 2H), 4.11 - 3.97 (m, 1H), 3.73 - 3.58 (m, 1H), 3.32 - 3.18 (m, 3H),2.23 - 2.05 (m, 2H).

[0948] Step 3. 4-Methylisothionate at room temperature Azoxyl-5-carboxylic acid (int-EC29) (80 mg, 0.20 mmol) and EDC (75 mg, 0.39 mmol) were added to (R)-2-(aminomethyl)-N-((S)-5,11-dioxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazide. -10-yl)-3,3,3-trifluoropropionamide (50 mg, 0.39 mmol) was added to a mixture of pyridine (2 mL) and the mixture was stirred at room temperature for 16 hours. The reaction mixture was then treated with ethyl acetate and washed with saturated NH4Cl solution, dried (MgSO4), and concentrated. The crude product was purified by preparative HPLC to give N-((R)-2-(((S)-5,11-dioxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazide -10-yl)carbamoyl)-3,3,3-trifluoropropyl)-4-methyliso Azole-5-carboxamide (2). HPLC (condition a) m / z 480.2 [M+H] + , t R = 0.78 min. 1 H NMR (400 MHz, DMSO-d6) δ ppm: 9.47 (d, J = 7.7Hz, 1H), 9.05 (t, J = 5.7 Hz, 1H), 8.70 (s, 1H), 7.76 (d, J = 7.7 Hz, 1H), 7.43 (t, J = 5.2 Hz, 1H), 7.27 - 7.18 (m, 2H), 5.96 (d, J = 7.6 Hz, 1H), 4.42- 4.17 (m, 2H), 4.11 - 3.99 (m, 1H), 3.74 - 3.57 (m, 3H), 3.26 - 3.14 (m,1H), 2.25 (s, 3H), 2.20 - 2.08 (m, 2H).

[0949] Table 1 shows additional example compounds (Examples 3-61) prepared using methods similar to those described in Example 1 or Example 2. Suitable intermediates used in each step, and the coupling conditions for step 3, are listed.

[0950] Table 1

[0951]

[0952]

[0953]

[0954]

[0955]

[0956]

[0957]

[0958]

[0959]

[0960]

[0961]

[0962]

[0963]

[0964]

[0965]

[0966]

[0967]

[0968]

[0969]

[0970]

[0971]

[0972]

[0973]

[0974]

[0975]

[0976]

[0977]

[0978]

[0979]

[0980]

[0981]

[0982]

[0983]

[0984]

[0985] Example 62: (R)-N 4 -(3-Isobutyramido-1-methyl-1H-pyrazole-5-yl)-2-methyl-N 1 -((S)-11- oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)succinamide (62)

[0986]

[0987] Step 1: Add EDC (19.17 g, 100 mmol) to (R)-4-(tert-butoxy)-2-methyl-4-oxobutyric acid (int-L6) (9.41 g, 50.0 mmol) and (S)-10-amino-2,3,5,10-tetrahydro-1H,11H-benzo[d]pyrazolo[1,2-a][1,2]diazide. -11-one (int-A1) (22.48 g, 50.0 mmol) was dissolved in pyridine (300 mL), and the reaction mixture was stirred at room temperature for 18 hours. The solvent was then removed, the residue was dissolved in ethyl acetate and washed with cold 1M HCl. The aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated NaHCO3 and brine, dried (Na2SO4), and concentrated. The resulting oil was crystallized with Et2O to give (R)-3-methyl-4-oxo-4-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazide -10-yl)amino)tert-butyl butyrate. LCMS (Method b) m / z 388 [M+H] + , t R = 0.99 min. 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.33 (d, J = 8.8Hz, 1H), 7.37 (d, J = 7.8 Hz, 1H), 7.21 (t, J = 7.2 Hz, 1H), 7.13 (t, J = 7.5Hz, 1H), 7.05 (d, J = 7.5 Hz, 1H), 6.67 (d, J = 8.7 Hz, 1H), 4.23 (s, 2H), 3.48-3.59 (m, 2H), 3.23-3.29 (m, 1H), 3.06-3.22 (m, 2H), 2.53-2.61 (m, 1H),2.33-2.41 (m, 1H), 2.26 (dd, J = 16.3, 5.3 Hz, 1H), 2.03-2.17 (m, 1H), 1.38(s, 9H), 1.08 (d, J = 7.0 Hz, 3H).

[0988] Step 2: Add TFA (83 mL) to (R)-3-methyl-4-oxo-4-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazide 16.67 g (43 mmol) of tert-butyl (-10-yl)amino)butyrate was added to a solution of CH2Cl2 (215 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water, the organic layer was washed with water, and the collected aqueous layer was extracted with CH2Cl2. The combined organic layers were dried (Na2SO4) and concentrated. The crude product was purified by column chromatography with ethyl acetate to give (R)-3-methyl-4-oxo-4-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazide. -10-yl)amino)butyric acid. LCMS (Method b) m / z 332.2 [M+H] + , t R = 0.62 min. 1 H NMR (400 MHz, DMSO-d6) δ ppm 12.09 (s,1H), 8.34 (d, J = 8.9 Hz, 1H), 7.41 (d, J = 7.8 Hz, 1H), 7.21 (t, J = 7.2 Hz,1H), 7.14 (t, J = 7.3 Hz, 1H), 7.04 (d, J = 7.3 Hz, 1H), 6.68 (d, J = 8.8 Hz, 1H), 4.23 (s, 2H), 3.47-3.59 (m, 2H), 3.24-3.30 (m, 1H), 3.07-3.22 (m, 2H),2.59 (dd, J = 16.6, 9.3 Hz, 1H), 2.31-2.41 (m, 1H), 2.27 (dd, J = 16.8, 5.3Hz, 1H), 2.03-2.15 (m, 1H), 1.09 (d, J = 7.0 Hz, 3H).

[0989] Step 3: Add EDC (156 mg, 0.815 mmol) to (R)-3-methyl-4-oxo-4-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazide. (R)-N-(5-amino-1-methyl-1H-pyrazol-3-yl)isobutyric acid (90 mg, 0.27 mmol) and N-(5-amino-1-methyl-1H-pyrazol-3-yl)isobutyramide (int-EC38) (60 mg, 0.27 mmol) in pyridine (2.5 mL) were mixed and stirred at room temperature for 16 hours. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried (Na2SO4), and concentrated. The crude product was purified by SFC (column: Reprospher PEI 100A, 250 × 30 mm, 5 μm; 36 °C; eluent A: CO2, eluent B: 15-20% MeOH in 9.8 min; flow rate: 100 mL / min; pressure: 130 bar) to give (R)-N 4 -(3-Isobutyramido-1-methyl-1H-pyrazole-5-yl)-2-methyl-N 1 -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)succinamide (62). LCMS (Method b) m / z 496.3 [M+H] + , t R = 0.71min. 1 H-NMR (400 MHz, DMSO-d6) δ ppm 10.12 (s, 1H), 9.88 (s, 1H), 8.32 (d, J =8.8 Hz, 1H), 7.33 (d, J = 7.8 Hz, 1H), 7.18 (t, J = 7.3 Hz, 1H), 7.11 (t, J =7.5 Hz, 1H), 7.06 - 6.99 (m, 1H), 6.68 (d, J = 8.7 Hz, 1H), 6.45 (s, 1H), 4.23 (s, 2H), 3.61 - 3.49 (m, 2H), 3.47 (s, 3H), 3.28 - 3.22 (m, 1H), 3.19 -3.12 (m, 2H), 2.75 (dd, J = 15.3, 8.5 Hz, 1H), 2.62 - 2.53 (m, 1H), 2.45 -2.30 (m, 2H), 2.10 (s, 1H), 1.14 (d, J = 7.0 Hz, 3H), 1.05 (d, J = 6.8 Hz, 6H).

[0990] Table 2 shows additional example compounds (Examples 63-105) prepared using a method similar to that described in Example 62. Suitable intermediates used in each step, and the coupling conditions for step 3, are listed.

[0991] Table 2

[0992]

[0993]

[0994]

[0995]

[0996]

[0997]

[0998]

[0999]

[1000]

[1001]

[1002]

[1003]

[1004]

[1005]

[1006]

[1007]

[1008]

[1009]

[1010]

[1011]

[1012]

[1013]

[1014]

[1015]

[1016]

[1017]

[1018] Example 109: (R)-N 4 -(3-((2-fluorophenyl)carbamoyl)-1-methyl-1H-pyrazole-5-yl)-2-methyl-N 1 -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)succinamide (109)

[1019]

[1020] Step 1: Add EDC (1.15 g, 6.04 mmol) to (R)-3-methyl-4-oxo-4-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazide. -10-yl)amino)butyric acid (see step 2 of Example 62) (1.0 g, 3.02 mmol), methyl 5-amino-1-methyl-1H-pyrazole-3-carboxylate hydrochloride (714 mg, 3.17 mmol) and pyridine (1.2 mL, 15.09 mmol) were in a solution of acetonitrile (30 mL), and the mixture was stirred at room temperature for 18 hours. The reactants were treated with saturated NaHCO3 and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried (Na2SO4) and concentrated to give 1-methyl-5-((R)-3-methyl-4-oxo-4-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazide Methyl 1H-pyrazole-3-carboxylate (-10-yl)amino)butyramido)-1H-pyrazole-3-carboxylate. LCMS (Method b) m / z 469.2 [M+H] + , t R = 0.71 min. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.14 (s, 1H), 8.35 (d, J = 8.9 Hz, 1H), 7.33 (d, J = 7.8 Hz, 1H), 7.20 (t, J = 7.4 Hz, 1H), 7.11 - 7.01 (m, 2H), 6.74 - 6.60 (m, 2H), 4.23(s, 2H), 3.78 (s, 3H), 3.67 (s, 3H), 3.56 - 3.49 (m, 2H), 3.29 - 3.22 (m,2H), 3.20 - 3.11 (m, 1H), 2.77 (dd, J = 15.3, 8.9 Hz, 1H), 2.47 - 2.41 (m,1H), 2.39 - 2.31 (m, 1H), 2.14 - 2.08 (m, 1H), 1.14 (d, J = 6.9 Hz, 3H).

[1021] Step 2: Add 15 mL (15 mmol) of H2O containing 1 M LiOH to 1-methyl-5-((R)-3-methyl-4-oxo-4-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazide. A mixture of methyl 1-(10-yl)amino)butamido)-1H-pyrazole-3-carboxylate in THF (20 mL) was stirred at 0 °C for 2 hours. The mixture was acidified to pH 3 with 2N HCl under ice cooling and extracted with ethyl acetate. The organic layer was dried (Na2SO4) and concentrated. The crude product was purified by column chromatography (using a reversed-phase column eluted with 10% to 40% H2O / CH3CN) to give 1-methyl-5-((R)-3-methyl-4-oxo-4-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazide) -10-yl)amino)butyramido)-1H-pyrazole-3-carboxylic acid. LCMS (Method b) m / z 455.2 [M+H] + , t R = 0.59 min. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.55 (s,1H), 10.09 (s, 1H), 8.34 (d, J = 8.8 Hz, 1H), 7.33 (d, J = 7.8 Hz, 1H), 7.19(t, J = 7.4 Hz, 1H), 7.10 - 6.98 (m, 2H), 6.68 (d, J = 8.7 Hz, 1H), 6.61 (s,1H), 4.23 (s, 2H), 3.66 (s, 3H), 3.59 - 3.47 (m, 2H), 3.28 - 3.23 (m, 2H),3.21 - 3.18 (m, 1H), 2.77 (dd, J = 15.4, 8.8 Hz, 1H), 2.48 - 2.42 (m, 1H), 2.39 - 2.26 (m, 1H), 2.16 - 2.00 (m, 1H), 1.14 (d, J = 6.9 Hz, 3H).

[1022] Step 3: Add EDC (70 mg, 0.363 mmol) to 1-methyl-5-((R)-3-methyl-4-oxo-4-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazide. (R)-1H-pyrazole-3-carboxylic acid (55 mg, 0.121 mmol) and 2-fluoroaniline (int-EC77) (14 µl, 0.133 mmol) were dissolved in pyridine (1.2 mL) and the mixture was stirred at room temperature for 18 hours. The reactants were treated with saturated NaHCO3 and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried (Na2SO4), and concentrated. The crude product was dissolved in methanol, the precipitate was filtered off while cold, and dried under high vacuum to give (R)-N 4 -(3-((2-fluorophenyl)carbamoyl)-1-methyl-1H-pyrazole-5-yl)-2-methyl-N 1 -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)succinamide (109). LCMS (Method b) m / z 548.3 [M+H] + , t R = 0.92 min; 1H NMR (400 MHz, DMSO-d6) δ ppm 10.17 (s, 1H), 9.47 (s,1H), 8.36 (d, J = 8.9 Hz, 1H), 7.98 - 7.78 (m, 1H), 7.35 (d, J = 7.9 Hz, 1H),7.33 - 7.24 (m, 1H), 7.24 - 7.15 (m, 3H), 7.12 - 7.01 (m, 2H), 6.72 (s, 1H), 6.69 (d, J = 8.8 Hz, 1H), 4.23 (s, 2H), 3.72 (s, 3H), 3.61 - 3.45 (m, 2H),3.29 - 3.22 (m, 2H), 3.22 - 3.18 (m, 1H), 2.80 (dd, J = 15.4, 8.8 Hz, 1H), 2.48 - 2.43 (m, 1H), 2.42 - 2.27 (m, 1H), 2.18 - 2.03 (m, 1H), 1.16 (d, J =7.0 Hz, 3H).

[1023] Table 3 shows additional example compounds (Example 107) prepared using a method similar to that described in Example 109. Suitable intermediates used in each step, and the coupling conditions for step 3, are listed.

[1024] Table 3

[1025]

[1026] Example 111: (R)-3-(1H-benzo[d]imidazol-2-yl)-2-methyl-N-((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza -10-yl)propionamide(111)

[1027]

[1028] Step 1: To (R)-3-methyl-4-oxo-4-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazide 20 mg (0.060 mmol) of 1,0-(1,0-yl)amino)butyric acid (see step 2 of Example 62) was added to a solution of DMF (1 mL) containing DIPEA (0.032 mL, 0.18 mmol) and HATU (23 mg, 0.060 mmol). The reaction mixture was stirred for 30 minutes until tert-butyl 2-aminophenylcarbamate (12.6 mg, 0.060 mmol) was added. The reaction mixture was analyzed by preparative HPLC-MS (Waters, X-Bridge C10 column). 18 ODB 5 µm 30*100 mm, flow rate 45 mL / min, water / ACN: 5 -> 99% ACN, 7.3 mM NH3) to purify the reaction mixture to give 2-((R)-3-methyl-4-oxo-4-((S)-11-oxo-1,2,3,5,10,11-hexahydrobenzo[d]pyrazolo[1,2-a][1,2]diazide 10-(10-ylamino)butamido)phenylcarbamate tert-butyl ester. HPLC (Method a) m / z 522 [M+H] + , t R = 2.14min. 1 H NMR (400 MHz, MeOD) δ ppm: 7.61 (d, 1H), 7.39 (m, 2H), 7.23-7.01 (m,5H), 6.83 (s, 1H), 4.30 (dd, 2H), 3.68 (m, 3H), 3.40 (m, 1H), 3.27 (m, 1H), 2.88 (dd, 1H), 2.61 (dd, 1H), 2.47 (m, 1H), 2.22 (m, 1H), 1.49 (s, 9H), 1.34 (d, 3H).

[1029] Step 2: Add 2-((R)-3-methyl-4-oxo-4-((S)-11-oxo-1,2,3,5,10,11-hexahydrobenzo[d]pyrazolo[1,2-a][1,2]diazide to the pyrazolo[1,2-a][1,2]diazide. 10-(10-ylamino)butamido)phenylcarbamate tert-butyl ester (101 mg, 0.19 mmol) was dissolved in 1.25 M HCl in MeOH solution (3 mL, 3.8 mmol). The sample was heated to 150 °C in a microwave for 30 min. The reaction mixture was concentrated under vacuum and co-evaporated three times with 7 N NH3 in MeOH solution. The final product was analyzed by preparative HPLC-MS (column X-Bridge C). 18ODB 5 μm 30*100 mm, flow rate 45 mL / min, water / ACN: 5 -> 99% ACN in 12.5 min, 7.3 mM NH3) purified the reaction mixture to give (R)-3-(1H-benzo[d]imidazol-2-yl)-2-methyl-N-((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazide -10-yl)propionamide (111). HPLC (Method a) m / z 404.3 [M+H) + , t R = 1.47 min (HPLC condition a), 1 H NMR (400MHz, CDCl3) δ ppm: 7.74 (brs, 1H), 7.27 (m, 3H), 7.11 (m, 2H), 6.98 (d, 1H), 6.78-6.59 (m, 3H), 4.23 (s, 2H, 3.78 (m, 2H), 3.64 (m, 1H), 3.42-3.23 (m,4H), 3.13 (m, 1H), 2.41 (m, 1H), 2.23 (m, 1H), 1.45 (d, 3H).

[1030] Table 4 shows additional example compounds (Examples 112 to 119) prepared using a method similar to that described in Example 111. Suitable intermediates used in each step, and the coupling conditions for step 4, are listed.

[1031] Table 4

[1032]

[1033]

[1034]

[1035]

[1036] Analysis and determination:

[1037] abbreviation

[1038] DC dendritic cells

[1039] DNP 2,4-Dinitrophenyl

[1040] Gal4 regulates the protein GAL4, YPL248C

[1041] FCM Flow Cytometry

[1042] KLH Keyhole Cypriniformis Heliocyanin

[1043] IC 50 Concentration that produces 50% maximum inhibition

[1044] IgG Immunoglobulin G

[1045] NT-amino terminus

[1046] PAGE Polyacrylamide gel electrophoresis

[1047] PBS Phosphate-Buffered Hydrochloric Acid

[1048] RGA reporter gene assay

[1049] RT room temperature

[1050] SDS Sodium lauryl sulfate

[1051] Sppl2a signal peptide protease-like 2a

[1052] TL translocation determination

[1053] TNF (tumor necrosis factor)

[1054] Sppl2a RGA (Reporter Gene Assay) :

[1055] Sppl2a is an intracellular aspartic protease similar to senescent protein, the active subunit of the γ-secretase complex. The assay is based on the coupling of the proteolytic degradation of a membrane-bound synthetic substrate (a VP16-Gal4 fusion protein with an N-terminal domain of TNFα), which migrates to the nucleus after cleavage, accompanied by Gal4-driven luciferase expression. Inhibition of Sppl2a reduces nuclear VP16-Gal4 activator and thus reduces luciferase production. Luciferase-dependent luminescence versus compound concentration is plotted to generate a dose-response curve, allowing calculation of the IC50. 50 value.

[1056] DNA vectors encoding human Sppl2a, NT-TNF-VP16-Gal4, and the Gal4 luciferase reporter were transiently transfected into HEK293 cells. In a typical experiment, 5 µg of plasmid for SPPL2a, 10 µg of plasmid encoding the Gal4 luciferase reporter, and 20 µg of plasmid encoding the substrate NT-TF-VP16-Gal4 were mixed together. The DNA mixture was combined with 107 µl of FuGENE® (Promega) and 735 µl of Opti-MEM® (Life Technologies) and incubated at room temperature for 5 minutes. 20 mL of concentrated HEK293 cells were added to this mixture and thoroughly mixed. The cell suspension was aliquoted into white solid 384-well plates. Over 5 hours, 50 nl of DMSO containing the compound was pressed into the wells using an imprinter. The plates were incubated for 24 hours at 37°C and 5% CO2 in a humidified incubator, followed by the addition of 25 µl of Bright Glo. After incubation at room temperature for 5 minutes, the plate was transferred to a photometer and the luminescence was measured. The IC was determined by plotting the compound concentration versus the normalized luminescence value. 50 .

[1057] γ-secretase RGA (reporter gene assay):

[1058] Presenilin is the active subunit of the γ-secretase complex; this complex is a membrane-bound protease that cleaves numerous type I transmembrane substrates. A current assay has been developed to monitor γ-secretase activity against Notch, a key regulator of immune cell development. This assay is based on the coupling of the proteolytic degradation of a membrane-bound synthetic substrate (a VP16-Gal4 fusion protein containing Notch1), which migrates to the nucleus after cleavage, where it activates Gal4-driven luciferase expression. γ-secretase inhibitors reduce nuclear VP16-Gal4 activator and thus reduce luciferase production. A dose-response curve is generated by plotting luciferase-dependent luminescence against compound concentration, allowing for the calculation of the IC50. 50 value.

[1059] Transiently transfect DNA vectors encoding human Notch1-VP16-Gal4 and the Gal4 luciferase reporter into HEK293 cells that endogenously express γ-secretase components. In a typical experiment, 10 µg of plasmid encoding the Gal4 luciferase reporter and 20 µg of plasmid encoding the Notch1-VP16-Gal4 substrate were mixed together. The DNA mixture was combined with 107 µl of FuGENE® (Promega) and 735 µl of Opti-MEM® (Life Technologies) and incubated at room temperature for 5 minutes. 20 mL of concentrated HEK293 cells were added to this mixture and thoroughly mixed. The cell suspension was aliquoted into white solid 384-well plates. Over 5 hours, 50 nl of DMSO containing the compound was pressed into the wells using an imprinter. The plates were incubated for 24 hours in a humidified incubator at 37 °C and 5% CO2, followed by the addition of 25 µl of Bright Glo. After incubation at room temperature for 5 minutes, the plates were transferred to a photometer and luminescence was measured. IC was determined by plotting the compound concentration relative to the normalized luminescence value. 50 .

[1060] Sppl2a TL determination:

[1061] SPPL2a, TL in U-2 OS cells. A stable U-2 OS cell line constitutively expressing human SPPL2a and expressing EGFP-labeled TNFα(aa1-76) NTF substrate under a doxycycline-regulated promoter was used for imaging assays. Cells were seeded at 3000 cells / 30 μL / 384 wells in DMEM / GlutaMax™-I (Invitrogen) supplemented with 10% FBS (Amimed) with or without tetracycline and incubated at 37°C, 5% CO2 for 3–4 h. Subsequently, 3.3 μL of pre-diluted inhibitor in doxycycline-containing medium for an 11-point concentration response curve was added to each well using a CyBi well liquid handling device (Cybio AG, Jena, Germany) to produce a final inhibitor concentration in the range of 100 μM to 1 nM (final DMSO concentration 0.9% (v / v) and 5 μg / mL doxycycline). Cells were incubated with inhibitors at 37°C and 5% CO2 for 24 hours. Afterward, cells were fixed in 4% PFA / PBS and, in parallel, stained nuclei with Hoechst (Invitrogen) 1:5000 in PBS for 30 minutes. Plate imaging was performed using a CellmicsArrayScan VTI HCS reader (Thermo Fisher Scientific, USA) with 10× / 0.3NA objectives. Six images were acquired per well. Images of the EGFP signal (Ex395, Em509) and Hoechst nuclear stain (Ex350, Em425) were acquired, and image analysis was performed simultaneously using the “Nuclear Translocation” assay algorithm in Cellmics ArrayScan software. Nuclei were detected based on Hoechst staining, with the nuclear masking transferred to the EGFP channel and a 4-pixel wide cytoplasmic ring defined around the nucleus. The intensity of the EGFP signal was measured in the nucleus and cytoplasmic loop of each individual cell (typically 800-1000 individual cells analyzed per well), and the difference between the mean nuclear intensity and the mean cytoplasmic intensity of the EGFP signal was calculated (“CircRingAvgIntenDiffCh2” = “CircAvgIntenCh2” - “RingAvgIntenCh2”). Additionally, the number of cells collected (a feature called “ValidCellCount”) was used to calculate cytotoxicity (CC50). The percentage of inhibition was calculated relative to positive (0.5 μM LY-411,575 = 100% inhibition) and negative (DMSO = 0% inhibition) controls. The IC50 was calculated from a curve of the percentage of inhibition versus the inhibitor concentration using nonlinear regression analysis software such as Origin (OriginLab Corp.). 50value.

[1062] CD74 / p8 mouse whole blood assay: flow cytometry pattern

[1063] Whole blood (sodium citrate) from Balb / c mice was ordered from Bioreclamation LLC; USA. The blood was used the day after receipt (stored at 4°C). 100 µL of blood was transferred to a 96-well plate previously deposited with the 11-point dilution of the compound to be tested to 30 µM. The plate was incubated at 37°C, 5% CO2, under continuous motion for 5 hours. After incubation, the blood was diluted with RBC rehydration buffer (Amined; catalog 3-13F00-H or BD; catalog 555899). The solution was mixed by pipetting and incubated at 37°C for 10 minutes. White blood cells were allowed to settle at 2000 rpm for 3 minutes. After removing the supernatant, the cell clumps were resuspended and washed twice in RCB buffer and held at room temperature for approximately 5 minutes, followed by centrifugation at 2000 rpm for 2 minutes. The cell clumps were then resuspended in D-PBS and centrifuged twice. Finally, cells were dissolved in D-PBS / 0.5% inactivated fetal bovine serum / 2 mM EDTA. Cell suspensions were treated with a live / dead fixative stain (LifeTechnologies, >470 nm model), and B cells were identified by surface staining with an anti-B220 antibody conjugated to APC fluorofor. After staining, cells were washed extensively with PBS. Cells were infiltrated and fixed in FACS rehydration buffer (BD; 349202, diluted 1:10 in water) and labeled with an anti-CD74 FITC-labeled antibody. Cells were washed again with diluted FACS rehydration buffer and spin-down. Cell clumps were washed with D-PBS / 0.5% inactivated fetal bovine serum / 2 mM EDTA and PBS, followed by flow cytometry analysis. A plot of compound concentration versus the intensity (median fluorescence intensity) of the CD74 signal on gated life B cells was constructed, and IC50 was determined by fitting data from 11 dose-response studies. 50 .

[1064] Biological data:

[1065] The compounds described herein were evaluated using the assays described above. Table 5 lists the corresponding IC values ​​obtained for each of the example compounds described above. 50 (µM) value.

[1066] Table 5

[1067]

[1068]

[1069]

[1070] The nd instruction is undetermined.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof, (I) in: Y is CH2 or C=O; R1 is H, C1-C6 alkyl, or halogen; R2 is H or a halogen; R3 is H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkyl-phenyl or C1-C6 alkyl substituted with C1-C6 alkoxy; R4 is H, C1-C6 alkyl, or C1-C6 alkyl-phenyl; R 10 It is -NHC(=O)R5, -C(=O)NHR5 or a 9- or 10-membered bicyclic heteroaryl group having 1 to 4 heteroatoms each independently selected from N, O and S as ring members, wherein the bicyclic heteroaryl group is unsubstituted or the bicyclic heteroaryl group is substituted by one or more R6 groups. R5 is a 5-membered heteroaryl group having one, two, or three heteroatoms, each independently selected from N, O, and S, as ring members, wherein the 5-membered heteroaryl group is substituted by one or more substituents independently selected from: i) Halogens; ii) Amino; iii) C3-C6 cycloalkyl groups optionally substituted with one or more halogens; iv) C3-C6 cycloalkenyl; v) C1-C6 alkyl groups optionally substituted with C1-C6 alkoxy, C3-C6 cycloalkyl, or phenyl groups; vi) C1-C6 haloalkyl groups; vii) -NHC(=O)C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with a C1-C6 alkoxy group; viii) -NHC(=O)-C1-C6 haloalkyl; ix) -NHC(=O)-C3-C6 cycloalkyl; x)-C(=O)NH-C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with a C1-C6 alkoxy group; xi) -C(=O)NH-C1-C6 haloalkyl; xii) -C(=O)NH-C3-C6 cycloalkyl; xiii) -NHC(=O)phenyl, wherein the phenyl group is optionally substituted with one or more substituents independently selected from halogens and C1-C6 alkyl groups; xiv) -C(=O)NHphenyl, wherein the phenyl group is optionally substituted with one or more substituents independently selected from halogens and C1-C6 alkyl groups; xv) C1-C6 alkoxy or C1-C6 haloalkoxy; xvi) phenoxy group optionally substituted with one or more halogens; xvii) Phenyl group optionally substituted with one or more substituents independently selected from halogen, -CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy and C1-C6 haloalkyl; xviii) A 4- to 6-membered heterocyclic group optionally substituted with an oxo group, a -C(=O)OC1-C6 alkyl group or a -C(=O)OC1-C6 cycloalkyl group; xix) a 5- or 6-membered heteroaryl group having one or two heteroatoms, each independently selected from N, O, and S, as ring members, wherein the heteroaryl group is unsubstituted or substituted by one or more substituents independently selected from: halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, 4- to 6-membered heterocyclic group, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, and C1-C6 alkyl groups optionally substituted with -OH, C1-C6 alkoxy, or optionally substituted with an oxo group; and xx) A 9- or 10-membered bicyclic heteroaryl group having 1 to 4 heteroatoms, each independently selected from N, O and S, as ring members, wherein the heteroaryl group is unsubstituted or substituted by one or more substituents independently selected from: halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, 4- to 6-membered heterocyclic group, C3-C6 cycloalkyl, C3-C6 cycloalkenyl and C1-C6 alkyl optionally substituted with C1-C6 alkoxy; Each R6 is independently selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, cyano, and halogen; and R 11 It is H, C1-C6 alkyl, or halogen; or R1 and R 11 Together with the carbon atoms they are attached to, they can form 3- to 6-membered carbon rings; One or more of the hydrogen atoms are deuterium.

2. The compound of claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound has the structure of formula (II). (II) in: Y is CH2 or C=O; R1 is H, C1-C6 alkyl, or halogen; R2 is H or a halogen; R3 is H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkyl-phenyl or C1-C6 alkyl substituted with C1-C6 alkoxy; R5 is a 5-membered heteroaryl group having one, two, or three heteroatoms, each independently selected from N, O, and S, as ring members, wherein the 5-membered heteroaryl group is substituted by one or more substituents independently selected from: i) Halogens; ii) Amino; iii) C3-C6 cycloalkyl groups optionally substituted with one or more halogens; iv) C3-C6 cycloalkenyl; v) C1-C6 alkyl groups optionally substituted with C1-C6 alkoxy, C3-C6 cycloalkyl, or phenyl groups; vi) C1-C6 haloalkyl groups; vii) -NHC(=O)C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with a C1-C6 alkoxy group; viii) -NHC(=O)-C1-C6 haloalkyl; ix) -NHC(=O)-C3-C6 cycloalkyl; x)-C(=O)NH-C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with a C1-C6 alkoxy group; xi) -C(=O)NH-C1-C6 haloalkyl; xii) -C(=O)NH-C3-C6 cycloalkyl; xiii) -NHC(=O)phenyl, wherein the phenyl group is optionally substituted with one or more substituents independently selected from halogens and C1-C6 alkyl groups; xiv) -C(=O)NHphenyl, wherein the phenyl group is optionally substituted with one or more substituents independently selected from halogens and C1-C6 alkyl groups; xv) C1-C6 alkoxy or C1-C6 haloalkoxy; xvi) phenoxy group optionally substituted with one or more halogens; xvii) Phenyl group optionally substituted with one or more substituents independently selected from halogen, -CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy and C1-C6 haloalkyl; xviii) A 4- to 6-membered heterocyclic group optionally substituted with an oxo group, a -C(=O)OC1-C6 alkyl group or a -C(=O)OC1-C6 cycloalkyl group; xix) a 5- or 6-membered heteroaryl group having one or two heteroatoms, each independently selected from N, O, and S, as ring members, wherein the heteroaryl group is unsubstituted or substituted by one or more substituents independently selected from: halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, 4- to 6-membered heterocyclic group, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, and C1-C6 alkyl groups optionally substituted with -OH, C1-C6 alkoxy, or optionally substituted with an oxo group; and xx) A 9- or 10-membered bicyclic heteroaryl group having 1 to 4 heteroatoms, each independently selected from N, O and S, as ring members, wherein the heteroaryl group is unsubstituted or substituted by one or more substituents independently selected from: halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, 4- to 6-membered heterocyclic group, C3-C6 cycloalkyl, C3-C6 cycloalkenyl and C1-C6 alkyl optionally substituted with C1-C6 alkoxy; Each R6 is independently selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, cyano, and halogen; and R 11 It is H, C1-C6 alkyl, or halogen; or R1 and R 11 Together with the carbon atoms they are attached to, they can form 3- to 6-membered carbon rings; One or more of the hydrogen atoms are deuterium.

3. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein the compound has a structure of formula (IIA), (IIB), (IIC), or (IID): (IIA)(IIB) (IIC)(IID) in R3 is H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkyl-phenyl or C1-C6 alkyl substituted with C1-C6 alkoxy; R5 is a 5-membered heteroaryl group having one, two, or three heteroatoms, each independently selected from N, O, and S, as ring members, wherein the 5-membered heteroaryl group is substituted by one or more substituents independently selected from: i) Halogens; ii) Amino; iii) C3-C6 cycloalkyl groups optionally substituted with one or more halogens; iv) C3-C6 cycloalkenyl; v) C1-C6 alkyl groups optionally substituted with C1-C6 alkoxy, C3-C6 cycloalkyl, or phenyl groups; vi) C1-C6 haloalkyl groups; vii) -NHC(=O)C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with a C1-C6 alkoxy group; viii) -NHC(=O)-C1-C6 haloalkyl; ix) -NHC(=O)-C3-C6 cycloalkyl; x)-C(=O)NH-C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with a C1-C6 alkoxy group; xi) -C(=O)NH-C1-C6 haloalkyl; xii) -C(=O)NH-C3-C6 cycloalkyl; xiii) -NHC(=O)phenyl, wherein the phenyl group is optionally substituted with one or more substituents independently selected from halogens and C1-C6 alkyl groups; xiv) -C(=O)NHphenyl, wherein the phenyl group is optionally substituted with one or more substituents independently selected from halogens and C1-C6 alkyl groups; xv) C1-C6 alkoxy or C1-C6 haloalkoxy; xvi) phenoxy group optionally substituted with one or more halogens; xvii) Phenyl group optionally substituted with one or more substituents independently selected from halogen, -CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy and C1-C6 haloalkyl; xviii) A 4- to 6-membered heterocyclic group optionally substituted with an oxo group, a -C(=O)OC1-C6 alkyl group, or a -C(=O)OC1-C6 cycloalkyl group; and xix) A 5- or 6-membered heteroaryl group having one or two heteroatoms, each independently selected from N, O and S, as ring members, wherein the heteroaryl group is unsubstituted or substituted by one or more substituents independently selected from: halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, 4- to 6-membered heterocyclic group, C3-C6 cycloalkyl, C3-C6 cycloalkenyl and C1-C6 alkyl group substituted with a 4- to 6-membered heterocyclic group optionally substituted with -OH, C1-C6 alkoxy or optionally substituted with an oxo group; xx) A 9- or 10-membered bicyclic heteroaryl group having 1 to 4 heteroatoms, each independently selected from N, O and S, as ring members, wherein the heteroaryl group is unsubstituted or substituted by one or more substituents independently selected from: halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, 4- to 6-membered heterocyclic group, C3-C6 cycloalkyl, C3-C6 cycloalkenyl and C1-C6 alkyl optionally substituted with C1-C6 alkoxy; One or more of the hydrogen atoms are deuterium.

4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of formula (III). (III) in: Y is CH2 or C=O; R1 is H, C1-C6 alkyl, or halogen; R2 is H or a halogen; R3 is H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkyl-phenyl or C1-C6 alkyl substituted with C1-C6 alkoxy; R5 is a 5-membered heteroaryl group having one, two, or three heteroatoms, each independently selected from N, O, and S, as ring members, wherein the 5-membered heteroaryl group is substituted by one or more substituents independently selected from: i) Halogens; ii) Amino; iii) C3-C6 cycloalkyl groups optionally substituted with one or more halogens; iv) C3-C6 cycloalkenyl; v) C1-C6 alkyl groups optionally substituted with C1-C6 alkoxy, C3-C6 cycloalkyl, or phenyl groups; vi) C1-C6 haloalkyl groups; vii) -NHC(=O)C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with a C1-C6 alkoxy group; viii) -NHC(=O)-C1-C6 haloalkyl; ix) -NHC(=O)-C3-C6 cycloalkyl; x)-C(=O)NH-C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with a C1-C6 alkoxy group; xi) -C(=O)NH-C1-C6 haloalkyl; xii) -C(=O)NH-C3-C6 cycloalkyl; xiii) -NHC(=O)phenyl, wherein the phenyl group is optionally substituted with one or more substituents independently selected from halogens and C1-C6 alkyl groups; xiv) -C(=O)NHphenyl, wherein the phenyl group is optionally substituted with one or more substituents independently selected from halogens and C1-C6 alkyl groups; xv) C1-C6 alkoxy or C1-C6 haloalkoxy; xvi) phenoxy group optionally substituted with one or more halogens; xvii) Phenyl group optionally substituted with one or more substituents independently selected from halogen, -CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy and C1-C6 haloalkyl; xviii) A 4- to 6-membered heterocyclic group optionally substituted with an oxo group, a -C(=O)OC1-C6 alkyl group or a -C(=O)OC1-C6 cycloalkyl group; xix) a 5- or 6-membered heteroaryl group having one or two heteroatoms, each independently selected from N, O, and S, as ring members, wherein the heteroaryl group is unsubstituted or substituted by one or more substituents independently selected from: halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, 4- to 6-membered heterocyclic group, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, and C1-C6 alkyl groups optionally substituted with -OH, C1-C6 alkoxy, or optionally substituted with an oxo group; and xx) A 9- or 10-membered bicyclic heteroaryl group having 1 to 4 heteroatoms, each independently selected from N, O and S, as ring members, wherein the heteroaryl group is unsubstituted or substituted by one or more substituents independently selected from: halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, 4- to 6-membered heterocyclic group, C3-C6 cycloalkyl, C3-C6 cycloalkenyl and C1-C6 alkyl optionally substituted with C1-C6 alkoxy; Each R6 is independently selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, cyano, and halogen; and R 11 It is H, C1-C6 alkyl, or halogen; or R1 and R 11 Together with the carbon atoms they are attached to, they can form 3- to 6-membered carbon rings; One or more of the hydrogen atoms are deuterium.

5. The compound of claim 1 or claim 4, or a pharmaceutically acceptable salt thereof, wherein the compound has a structure of formula (IIIA), (IIIB), (IIIC), or (IIID): (IIIA)(IIIB) (IIIC)(IIID) in R3 is H, a C1-C6 alkyl, a C1-C6 haloalkyl, a C3-C6 cycloalkyl, a C1-C6 alkyl-phenyl, or a C1-C6 alkyl substituted with a C1-C6 alkoxy; and R5 is a 5-membered heteroaryl group having one, two, or three heteroatoms, each independently selected from N, O, and S, as ring members, wherein the 5-membered heteroaryl group is substituted by one or more substituents independently selected from: i) Halogens; ii) Amino; iii) C3-C6 cycloalkyl groups optionally substituted with one or more halogens; iv) C3-C6 cycloalkenyl; v) C1-C6 alkyl groups optionally substituted with C1-C6 alkoxy, C3-C6 cycloalkyl, or phenyl groups; vi) C1-C6 haloalkyl groups; vii) -NHC(=O)C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with a C1-C6 alkoxy group; viii) -NHC(=O)-C1-C6 haloalkyl; ix) -NHC(=O)-C3-C6 cycloalkyl; x)-C(=O)NH-C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with a C1-C6 alkoxy group; xi) -C(=O)NH-C1-C6 haloalkyl; xii) -C(=O)NH-C3-C6 cycloalkyl; xiii) -NHC(=O)phenyl, wherein the phenyl group is optionally substituted with one or more substituents independently selected from halogens and C1-C6 alkyl groups; xiv) -C(=O)NHphenyl, wherein the phenyl group is optionally substituted with one or more substituents independently selected from halogens and C1-C6 alkyl groups; xv) C1-C6 alkoxy or C1-C6 haloalkoxy; xvi) phenoxy group optionally substituted with one or more halogens; xvii) Phenyl group optionally substituted with one or more substituents independently selected from halogen, -CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy and C1-C6 haloalkyl; xviii) A 4- to 6-membered heterocyclic group optionally substituted with an oxo group, a -C(=O)OC1-C6 alkyl group or a -C(=O)OC1-C6 cycloalkyl group; xix) a 5- or 6-membered heteroaryl group having one or two heteroatoms, each independently selected from N, O, and S, as ring members, wherein the heteroaryl group is unsubstituted or substituted by one or more substituents independently selected from: halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, 4- to 6-membered heterocyclic group, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, and C1-C6 alkyl groups optionally substituted with -OH, C1-C6 alkoxy, or optionally substituted with an oxo group; and xx) A 9- or 10-membered bicyclic heteroaryl group having 1 to 4 heteroatoms, each independently selected from N, O and S, as ring members, wherein the heteroaryl group is unsubstituted or substituted by one or more substituents independently selected from: halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, 4- to 6-membered heterocyclic group, C3-C6 cycloalkyl, C3-C6 cycloalkenyl and C1-C6 alkyl optionally substituted with C1-C6 alkoxy; One or more of the hydrogen atoms are deuterium.

6. The compound of any one of claims 1 to 5 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3 is methyl, ethyl, propyl, isopropyl, CF3, -CH2-phenyl, cyclopropyl, cyclobutyl or -CH2CH2OCH3.

7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R5 is , or ; in R 5a It is a C1-C6 alkyl, C1-C6 haloalkyl, or halogen; R 5b It is -C(O)-NH-C1-C6 alkyl, -C(O)NH-C1-C6 haloalkyl, -C(O)NHphenyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, 4- to 6-membered heterocyclic, 5- or 6-membered cycloheteroaryl; wherein the heteroaryl group is optionally substituted with halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy or C3-C6 cycloalkyl; and wherein the heterocyclic group is optionally substituted with oxo, -C(O)O-C1-C6 alkyl or -C(O)O-C3-C6 cycloalkyl; and wherein the -C(O)NHphenyl group is optionally substituted with halogen or C1-C6 alkyl; R 5c It is a 5- or 6-membered cyclic heteroaryl group optionally substituted with halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy or C3-C6 cycloalkyl; and R 5d It is a C1-C6 alkyl or a C1-C6 haloalkyl.

8. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R5 is: ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ; ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; or .

9. The compound of claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein... R 10 yes or ;and R6 is H, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, cyano, or halogen.

10. The compound of claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound has the structure of formula (IV): (IV) in R1 is H, C1-C6 alkyl, or halogen; R2 is H or a halogen; Y is CH2 or C(O); R3 is H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkyl-phenyl or C1-C6 alkyl substituted with C1-C6 alkoxy; X is CH or N; R6 is H, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, cyano, or halogen; and R 11 It is H, C1-C6 alkyl, or halogen; or R1 and R 11 Together with the carbon atoms they are attached to, they can form 3- to 6-membered carbon rings.

11. The compound of claim 1, wherein the compound of formula I is selected from: , , , , , , , ,as well as .

12. The compound of claim 1, wherein the compound of formula I is selected from: N 2 ,4-Dimethyl-N 5 -((R)-2-methyl-3-oxo-3-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)amino)propyl)thiazole-2,5-dicarboxamide; N-((R)-2-(((S)-5,11-dioxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)carbamoyl)-3,3,3-trifluoropropyl)-4-methyliso 5-oxazolium-5-carboxamide; 2-Isobutamido-4-methyl-N-((R)-3,3,3-trifluoro-2-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazide -10-yl)carbamoyl)propyl)thiazolyl-5-carboxamide; 2-Isobutamido-4-methyl-N-((R)-2-methyl-3-oxo-3-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazide -10-yl)amino)propyl)thiazole-5-carboxamide; N 2 -(2,2-difluoroethyl)-4-methyl-N 5 -((R)-3,3,3-trifluoro-2-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)carbamoyl)propyl)thiazole-2,5-dicarboxamide; N 5 -((R)-2-Cyclopropyl-3-oxo-3-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)amino)propyl)-N 2 -(2,2-difluoroethyl)-4-methylthiazol-2,5-dicarboxamide; N 2 -Ethyl-4-methyl-N 5 -((R)-3,3,3-trifluoro-2-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)carbamoyl)propyl)thiazole-2,5-dicarboxamide; N 2 -(2,2-difluoroethyl)-4-methyl-N 5 -((R)-2-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazepine -10-yl)carbamoyl)butyl)thiazole-2,5-dicarboxamide; N 5 -((R)-2-Cyclopropyl-3-oxo-3-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)amino)propyl)-N 2 4-Dimethylthiazol-2,5-dicarboxamide; N 2 -Ethyl-4-methyl-N 5 -((R)-2-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazepine -10-yl)carbamoyl)butyl)thiazole-2,5-dicarboxamide; N 2 ,4-Dimethyl-N 5 -((R)-3,3,3-trifluoro-2-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)carbamoyl)propyl)thiazole-2,5-dicarboxamide; N 5 -((R)-2-Cyclopropyl-3-oxo-3-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)amino)propyl)-N 2 -Ethyl-4-methylthiazol-2,5-dicarboxamide; N 2 ,4-Dimethyl-N 5 -((R)-2-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazepine -10-yl)carbamoyl)butyl)thiazole-2,5-dicarboxamide; N 2 -Isopropyl-4-methyl-N 5 -((R)-3,3,3-trifluoro-2-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)carbamoyl)propyl)thiazole-2,5-dicarboxamide; 4-Chloro-N-((R)-2-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)carbamoyl)butyl)-2-(6-(trifluoromethyl)pyridin-3-yl)thiazolyl-5-carboxamide; N 2 -Ethyl-4-methyl-N 5 -((R)-2-methyl-3-oxo-3-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)amino)propyl)thiazole-2,5-dicarboxamide; 3-Methyl-N-((R)-2-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)carbamoyl)butyl)-5-(trifluoromethyl)iso 4-oxazolium-formamide; 4-Methyl-N-((R)-2-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)carbamoyl)butyl)-2-(6-(trifluoromethyl)pyridin-3-yl)thiazolyl-5-carboxamide; N 2 -Isopropyl-4-methyl-N 5 -((R)-2-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazepine -10-yl)carbamoyl)butyl)thiazole-2,5-dicarboxamide; 4-Methyl-2-(3-methylisocyanate) (-((R)-2-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine) -10-yl)carbamoyl)butyl)thiazole-5-carboxamide; N 2 -(2,2-difluoroethyl)-4-methyl-N 5 -((R)-2-methyl-3-oxo-3-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)amino)propyl)thiazole-2,5-dicarboxamide; 4-Chloro-N 2 -Isopropyl-N 5 -((R)-2-methyl-3-oxo-3-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)amino)propyl)thiazole-2,5-dicarboxamide; 4-Methyl-N-((R)-2-methyl-3-oxo-3-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)amino)propyl)-2-(3-methylisocyanate) (Zyr-5-yl)thiazolyl-5-carboxamide; N 2 -Isopropyl-4-methyl-N 5 -((R)-2-methyl-3-oxo-3-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)amino)propyl)thiazole-2,5-dicarboxamide; 3,4-Dimethyl-N-((R)-2-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazide -10-yl)carbamoyl)butyl)iso 5-oxazolium-5-carboxamide; 2-(3,6-dihydro-2H-pyran-4-yl)-4-methyl-N-((R)-2-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza -10-yl)carbamoyl)butyl)thiazole-5-carboxamide; N 5 -((R)-2-Cyclopropyl-3-oxo-3-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)amino)propyl)-N 2 -Isopropyl-4-methylthiazol-2,5-dicarboxamide; 4-Chloro-2-(cyclopent-1-en-1-yl)-N-((R)-2-(((S)-5,11-dioxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)carbamoyl)butyl)thiazole-5-carboxamide; 4-Methyl-N-((R)-2-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)carbamoyl)butyl)thiazole-5-carboxamide; 4-Methyl-N-((R)-2-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)carbamoyl)butyl)-2-propoxythiazol-5-carboxamide; N-((R)-2-(((S)-5,11-dioxo-10,11-dihydro-1H,3H,5H-spiro[benzo[d]pyrazolo[1,2-a][1,2]diazepine -2,1'-Cyclopropyl]-10-yl)carbamoyl)butyl)-3-methyl-5-(trifluoromethyl)iso 4-oxazolium-formamide; 2-(different) (-5-yl)-4-methyl-N-((R)-2-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine) -10-yl)carbamoyl)butyl)thiazole-5-carboxamide; 3,4-Dimethyl-N-((R)-2-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazide -10-yl)carbamoyl)pentyl)iso 5-oxazolium-5-carboxamide; 4-Chloro-N-((R)-2-(((S)-5,11-dioxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)carbamoyl)butyl)-2-(6-methoxypyridin-3-yl)thiazolyl-5-carboxamide; N-((R)-2-(((S)-5,11-dioxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)carbamoyl)butyl)-4-methylisothiazolyl-5-carboxamide; N-((R)-2-(((S)-5,11-dioxo-10,11-dihydro-1H,3H,5H-spiro[benzo[d]pyrazolo[1,2-a][1,2]diazepine -2,1'-Cyclopropyl]-10-yl)carbamoyl)butyl)-4-ethyl-1,2,3-thiadiazole-5-carboxamide; 4-Chloro-2-(6-(difluoromethoxy)pyridin-3-yl)-N-((R)-2-(((S)-5,11-dioxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)carbamoyl)butyl)thiazole-5-carboxamide; N-((R)-2-(((S)-5,11-dioxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)carbamoyl)-3,3,3-trifluoropropyl)-4-methyl-2-(6-(trifluoromethyl)pyridin-3-yl)thiazolyl-5-carboxamide; 4-Chloro-N-((R)-2-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)carbamoyl)butyl)thiazole-5-carboxamide; 4-Chloro-N-((R)-2-(((S)-5,11-dioxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)carbamoyl)-3,3,3-trifluoropropyl)-2-(6-(trifluoromethyl)pyridin-3-yl)thiazolyl-5-carboxamide; N-((R)-2-cyclopropyl-3-(((S)-5,11-dioxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazide -10-yl)amino)-3-oxopropyl)-4-methyl-2-(3-methyliso) (Zyr-5-yl)thiazolyl-5-carboxamide; N-((R)-4-methoxy-2-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)carbamoyl)butyl)-4-methyl-2-(3-methyliso (Zyr-5-yl)thiazolyl-5-carboxamide; 4-Chloro-2-cyclopropyl-N-((R)-2-methyl-3-oxo-3-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazide -10-yl)amino)propyl)thiazole-5-carboxamide; 2-(3,6-dihydro-2H-pyran-4-yl)-4-methyl-N-((R)-3,3,3-trifluoro-2-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazide -10-yl)carbamoyl)propyl)thiazolyl-5-carboxamide; 4-Chloro-2-(1-(difluoromethyl)-1H-pyrazol-4-yl)-N-((R)-2-(((S)-5,11-dioxo-10,11-dihydro-1H,3H,5H-spiro[benzo[d]pyrazolo[1,2-a][1,2]diazine) -2,1'-Cyclopropyl]-10-yl)carbamoyl)butyl)thiazole-5-carboxamide; 4-Chloro-2-(3,6-dihydro-2H-pyran-4-yl)-N-((R)-2-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)carbamoyl)butyl)thiazole-5-carboxamide; 2-Cyclopropyl-4-methyl-N-((R)-2-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazide -10-yl)carbamoyl)butyl)thiazole-5-carboxamide; N-((R)-2-(((S)-5,11-dioxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)carbamoyl)-3,3,3-trifluoropropyl)-3,5-dimethylisocyano 4-oxazolium-formamide; 4-Chloro-N-((R)-2-(((S)-5,11-dioxo-10,11-dihydro-1H,3H,5H-spiro[benzo[d]pyrazolo[1,2-a][1,2]diazine -2,1'-Cyclopropyl]-10-yl)carbamoyl)butyl)thiazole-5-carboxamide; 4-Methyl-2-(tetrahydro-2H-pyran-4-yl)-N-((R)-3,3,3-trifluoro-2-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazide -10-yl)carbamoyl)propyl)thiazolyl-5-carboxamide; 4-Methyl-N-((R)-2-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)carbamoyl)butyl)iso 5-oxazolium-5-carboxamide; 2-(methoxymethyl)-4-methyl-N-((R)-3,3,3-trifluoro-2-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)carbamoyl)propyl)thiazolyl-5-carboxamide; 2-Ethoxy-4-methyl-N-((R)-2-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)carbamoyl)butyl)thiazole-5-carboxamide; 4-Chloro-2-cyclopropyl-N-((R)-2-cyclopropyl-3-(((S)-6-fluoro-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazide -10-yl)amino)-3-oxopropyl)thiazolyl-5-carboxamide; 4-Chloro-N-((R)-2-cyclopropyl-3-(((S)-6-fluoro-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)amino)-3-oxopropyl)-2-methylthiazolyl-5-carboxamide; 1-(difluoromethyl)-N-((R)-2-(((S)-5,11-dioxo-10,11-dihydro-1H,3H,5H-spiro[benzo[d]pyrazolo[1,2-a][1,2]diazine -2,1'-Cyclopropyl]-10-yl)carbamoyl)butyl)-1H-pyrazole-5-carboxamide; N-((R)-2-(((S)-5,11-dioxo-10,11-dihydro-1H,3H,5H-spiro[benzo[d]pyrazolo[1,2-a][1,2]diazepine -2,1'-Cyclopropyl]-10-yl)carbamoyl)butyl)-4-(trifluoromethyl)thiazolyl-5-carboxamide; 2-Benzyl-4-methyl-N-((R)-2-methyl-3-oxo-3-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazide -10-yl)amino)propyl)thiazole-5-carboxamide; 2-Cyclopropyl-N-((R)-2-(((S)-5,11-dioxo-10,11-dihydro-1H,3H,5H-spiro[benzo[d]pyrazolo[1,2-a][1,2]diazine] -2,1'-Cyclopropyl]-10-yl)carbamoyl)butyl)-4-(trifluoromethyl)thiazolyl-5-carboxamide; 1,3-Dimethyl-N-((R)-2-methyl-3-oxo-3-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazide -10-yl)amino)propyl)-1H-pyrrole-2-carboxamide; 1-Methyl-N-((R)-2-methyl-3-oxo-3-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diaza -10-yl)amino)propyl)-1H-pyrazole-5-carboxamide; (R)-N 4 -(3-Isobutyramido-1-methyl-1H-pyrazole-5-yl)-2-methyl-N 1 -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)succinamide; (S)-2-Cyclobutyl-N 4 -(3-Isobutyramido-1-methyl-1H-pyrazole-5-yl)-N 1 -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)succinamide; (R)-N 4 -(4-chloro-2-(isopropylcarbamoyl)thiazo-5-yl)-2-methyl-N 1 -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)succinamide; (R)-N 4 -(3-((2,2-difluoroethyl)carbamoyl)-1-methyl-1H-pyrazole-5-yl)-2-methyl-N 1 -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)succinamide; (R)-N 4 -(2-(isopropylcarbamoyl)-4-methylthiazolyl-5-yl)-2-methyl-N 1 -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)succinamide; (S)-2-Cyclopropyl-N 4 -(3-(isopropylcarbamoyl)-1-methyl-1H-pyrazole-5-yl)-N 1 -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)succinamide; (R)-2-methyl-N 4 -(1-Methyl-3-((2,2,2-trifluoroethyl)carbamoyl)-1H-pyrazole-5-yl)-N 1 -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)succinamide; (R)-N 4 -(3-(2-fluorobenzoamido)-1-methyl-1H-pyrazole-5-yl)-2-methyl-N 1 -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)succinamide; (R)-2-methyl-N 4 -(1-Methyl-3-(2,2,3,3,3-pentafluoropropamido)-1H-pyrazole-5-yl)-N 1 -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)succinamide; (R)-N 4 -(3-(3-Cyclopropylisothio (-5-yl)-1-methyl-1H-pyrazol-5-yl)-2-methyl-N 1 -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)succinamide; (R)-2-methyl-N 4 -(1-Methyl-3-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazole-5-yl)-N 1 -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)succinamide; (R)-N 4 -(4-chloro-2-(1-methyl-1H-pyrazol-3-yl)thiazo-5-yl)-2-methyl-N 1 -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)succinamide; (R)-2-methyl-N 4 -(1-Methyl-3-(5-methylpyridin-3-yl)-1H-pyrazole-5-yl)-N 1 -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)succinamide; (S)-2-Cyclopropyl-N 4 -(1-Methyl-3-(5-methylpyridin-3-yl)-1H-pyrazole-5-yl)-N 1 -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)succinamide; (R)-N 4 -(3-(2,3-difluorobenzamido)-1-methyl-1H-pyrazole-5-yl)-2-methyl-N 1 -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)succinamide; (S)-2-Cyclopropyl-N 1 -((S)-6-fluoro-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-base)-N 4 -(3-(isopropylcarbamoyl)-1-methyl-1H-pyrazol-5-yl)succinamide; (S)-2-Cyclopropyl-N 4 -(3-(((S)-1-fluoroprop-2-yl)carbamoyl)-1-methyl-1H-pyrazole-5-yl)-N 1 -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)succinamide; (R)-N 4 -(2-(5-Fluoropyridin-3-yl)-4-methylthiazo-5-yl)-2-methyl-N 1 -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)succinamide; (R)-2-methyl-N 4 -(1-Methyl-3-(5-methylisocyanate) (azol-3-yl)-1H-pyrazol-5-yl)-N 1 -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)succinamide; (R)-N 4 -(3-(5-ethylisothio) (-3-yl)-1-methyl-1H-pyrazol-5-yl)-2-methyl-N 1 -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)succinamide; (S)-2-Cyclobutyl-N 1 -((S)-5,11-dioxo-10,11-dihydro-1H,3H,5H-spiro[benzo[d]pyrazolo[1,2-a][1,2]diazepine -2,1'-Cyclopropyl]-10-yl)-N 4 -(3-Isobutyramido-1-methyl-1H-pyrazole-5-yl)succinamide; (R)-N 4 -(1-Ethyl-3-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazole-5-yl)-2-methyl-N 1 -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)succinamide; (R)-2-methyl-N 4 -(1-Methyl-3-((3,3,3-trifluoropropyl)carbamoyl)-1H-pyrazole-5-yl)-N 1 -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)succinamide; (R)-N 4 -(1-Ethyl-3-(furan-2-yl)-1H-pyrazole-5-yl)-2-methyl-N 1 -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)succinamide; (R)-N 4 -(3-(3-ethylisothiazolinone) (-5-yl)-1-methyl-1H-pyrazol-5-yl)-2-methyl-N 1 -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)succinamide; (R)-N 4 -(3-(5-Fluoropyridin-2-yl)-1-methyl-1H-pyrazole-5-yl)-2-methyl-N 1 -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)succinamide; (R)-N 4 -(3-chloro-1-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-4-yl)-2-methyl-N 1 -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)succinamide; (R)-2-methyl-N 4 -(1-Methyl-3-pentaventamyl-1H-pyrazole-5-yl)-N 1 -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)succinamide; (R)-2-methyl-N 4 -(1-Methyl-3-(3-methylisocyanate) (azol-5-yl)-1H-pyrazol-5-yl)-N 1 -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)succinamide; (R)-N 4 -(2-(isopropylcarbamoyl)thiazo-5-yl)-2-methyl-N 1 -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)succinamide; (R)-2-methyl-N 4 -(3-Methyl-1-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazole-4-yl)-N 1 -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)succinamide; (S)-2-Cyclopropyl-N 1 -((S)-5,11-dioxo-10,11-dihydro-1H,3H,5H-spiro[benzo[d]pyrazolo[1,2-a][1,2]diazepine -2,1'-Cyclopropyl]-10-yl)-N 4 -(3-Isobutyramido-1-methyl-1H-pyrazole-5-yl)succinamide; (R)-2-methyl-N 4 -(1-Methyl-3-(pyridin-2-yl)-1H-pyrazole-5-yl)-N 1 -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)succinamide; (R)-N 4 -(4-chloro-2-(1-(oxetane-3-yl)-1H-pyrazol-4-yl)thiazo-5-yl)-2-methyl-N 1 -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)succinamide; (R)-N 4 -(1-Cyclopropyl-3-(furan-2-yl)-1H-pyrazol-5-yl)-2-methyl-N 1 -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)succinamide; (R)-N 4 -(3-(6-methoxypyridin-3-yl)-1-methyl-1H-pyrazole-5-yl)-2-methyl-N 1 -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)succinamide; (R)-2-methyl-N 4 -(1-Methyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazole-5-yl)-N 1 -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)succinamide; (R)-N 4 -(4-chloro-2-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)thiazo-5-yl)-2-methyl-N 1 -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)succinamide; (S)-2-Cyclopropyl-N 1 -((S)-6-fluoro-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-base)-N 4 -(3-(((S)-1-fluoroprop-2-yl)carbamoyl)-1-methyl-1H-pyrazole-5-yl)succinamide; (R)-N 4 -(1-Ethyl-3-(3-methylisocyanate) (-5-yl)-1H-pyrazol-5-yl)-2-methyl-N 1 -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)succinamide; (R)-N 4 -(3-(cyclopropylcarbamoyl)-1-methyl-1H-pyrazole-5-yl)-2-methyl-N 1 -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)succinamide; (S)-2-Cyclopropyl-N 4 -(3-(3-Cyclopropylisothio (-5-yl)-1-methyl-1H-pyrazol-5-yl)-N 1 -((S)-5,11-dioxo-10,11-dihydro-1H,3H,5H-spiro[benzo[d]pyrazolo[1,2-a][1,2]diazepine -2,1'-cyclopropyl]-10-yl)succinamide; (S)-N 4 -(4-chloro-2-(1-(difluoromethyl)-1H-pyrazol-4-yl)thiazo-5-yl)-2-cyclopropyl-N 1 -((S)-5,11-dioxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)succinamide; (R)-2-methyl-N 4 -(1-Methyl-3-(6-methylpyridin-3-yl)-1H-pyrazole-5-yl)-N 1 -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)succinamide; (S)-N 4 -(4-chloro-2-(6-(trifluoromethyl)pyridin-3-yl)thiazo-5-yl)-2-cyclopropyl-N 1 -((S)-5,11-dioxo-10,11-dihydro-1H,3H,5H-spiro[benzo[d]pyrazolo[1,2-a][1,2]diazepine -2,1'-cyclopropyl]-10-yl)succinamide; (S)-N 4 -(4-chloro-2-(6-(trifluoromethyl)pyridin-3-yl)thiazo-5-yl)-2-cyclopropyl-N 1 -((S)-5,11-dioxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)succinamide; (R)-N 4 -(4-chloro-2-(6-(trifluoromethyl)pyridin-3-yl)thiazo-5-yl)-2-methyl-N 1 -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)succinamide; (R)-N 4 -(3-((2-fluorophenyl)carbamoyl)-1-methyl-1H-pyrazole-5-yl)-2-methyl-N 1 -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)succinamide; (R)-N 4 -(3-((2,6-dimethylphenyl)carbamoyl)-1-methyl-1H-pyrazole-5-yl)-2-methyl-N 1 -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)succinamide; (R)-3-(1H-benzo[d]imidazol-2-yl)-2-methyl-N-((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)propionamide; (R)-2-methyl-3-(7-methyl-1H-benzo[d]imidazol-2-yl)-N-((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazol -10-yl)propionamide; (R)-3-(7-bromo-1H-benzo[d]imidazol-2-yl)-2-methyl-N-((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine) -10-yl)propionamide; (R)-2-methyl-N-((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine -10-yl)-3-(7-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)propionamide; (R)-3-(4-chloro-1H-benzo[d]imidazol-2-yl)-2-methyl-N-((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine) -10-yl)propionamide; (R)-3-(6-fluoro-7-methyl-1H-benzo[d]imidazol-2-yl)-2-methyl-N-((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazol -10-yl)propionamide; (R)-3-(5-fluoro-7-methyl-1H-benzo[d]imidazol-2-yl)-2-methyl-N-((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazol -10-yl)propionamide; (R)-N-((S)-6-fluoro-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazepine -10-yl)-3-(5-fluoro-7-methyl-1H-benzo[d]imidazol-2-yl)-2-methylpropionamide; and (R)-2-((5-fluoro-7-methyl-1H-benzo[d]imidazol-2-yl)methyl)-N-((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazine) -10-yl)pentylamide Or its pharmaceutically acceptable salt. One or more of the hydrogen atoms are deuterium.

13. A pharmaceutical composition comprising a therapeutically effective amount of the compound as described in any one of claims 1 to 12 or a pharmaceutically acceptable salt or stereoisomer thereof, and one or more pharmaceutically acceptable carriers.

14. Use of the compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt or stereoisomer thereof, in the preparation of a medicament for the treatment or prevention of diseases or conditions mediated by Sppl2a activity.

15. The use as described in claim 14, wherein the disease or condition is an autoimmune disease or condition selected from pemphigus vulgaris, pemphigus foliaceus, Sjögren's disease, systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), lupus nephritis, systemic sclerosis, multiple sclerosis (MS), autoimmune hepatitis, uveitis, pemphigus vulgaris, pemphigus foliaceus, myasthenia gravis, Hashimoto's thyroiditis, thrombocytopenic purpura, myocarditis, atopic dermatitis, Goodpassuia syndrome, or type I diabetes.

16. The use as claimed in claim 14, wherein the disease or condition is acute and chronic graft-versus-host disease (GvHD); or prevention of rejection in clinical / surgical transplantation procedures of solid organs or cell populations.

17. The use as described in claim 14, wherein the disease or condition is lymphoma.

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