Compounds and compositions as Sppl2a inhibitors

Abstract

The present invention provides tricyclic compounds containing a diazepinone moiety that are effective in inhibiting signal peptide peptidase-like protease 2a. A medicament comprising a compound of formula (I). JPEG2026041723000192.jpg43164 (Y: CH2, CO. R1: H, C1-C6 alkyl, halogen. R2: H, halogen. R3: H, C1-C6 alkyl, etc. R4: H, C1-C6 alkyl, C1-C6 alkylphenyl. R 10 :NHCOR5, etc. (R5: substituted / unsubstituted 5-membered heteroaryl). 11 :H, C1-C6 alkyl, halogen, etc.)

Description

[Technical Field]

[0001] The present invention relates to tricyclic compounds containing a diazepinone moiety that are effective in inhibiting signal peptide peptidase-like protease 2a (Sppl2a), pharmaceutical compositions containing such inhibitors, methods for synthesizing the novel derivatives, and methods of using such inhibitors and compositions. [Background technology]

[0002] Background of the Invention The protein Sppl2a appears to play a role in innate and adaptive immunity by cleaving various anchored transmembrane proteins, thereby affecting the function of various immune cells.

[0003] Sppl2a was originally described as a protease that cleaves the transmembrane portion of TNF-α, thereby controlling the release of IL-12 from dendritic cells. Recent observations suggest that Sppl2a may be involved in processing CD74, also known as the invariant chain, a key mediator of class II antigen presentation, enabling the differentiation of foreign antigens from self-antigens. Many autoimmune diseases can develop when the immune system loses its ability to distinguish between "self" and "non-self." 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 how CD74 is cleaved by Sppl2a. In mice, inhibition of this process can result in a significant reduction in the number of mature B cells and myeloid dendritic cells. The scientific literature further suggests that inhibition of Sppl2a leads to the accumulation of the N-terminal fragment of CD74(p8) in intracellular compartments, thereby inducing the death of B cells and myeloid dendritic cells. Although the molecular details of Sppl2a processing and B cell / myeloid dendritic cell loss are still not fully understood, the accumulation of unprocessed CD74 appears to impair T cell-dependent antibody responses in mice. Inhibition of this protease may be relevant for suppressing harmful, uncontrolled immune responses, such as those in which autoantibodies may play a key role in autoimmune diseases. Inhibition of Sppl2a may also affect the growth of B cell lymphomas, which appear to be associated with high levels of CD74 expression.

[0004] Potent and generally selective inhibitors of Sppl2a may therefore represent a novel and attractive mechanism for treating diseases and / or conditions, particularly of the immune system. Summary of the Invention

[0005] Thus, in one embodiment, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, Y is CH2 or C=O; Y is CH2 or C=O; R1 is H, C1-C6 alkyl or halogen; R2 is H or halogen; R3 is H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkylphenyl, or C1-C6 alkyl substituted with C1-C6 alkoxy; R4 is H, C1-C6 alkyl or C1-C6 alkylphenyl; R 10 is -NHC(=O)R5, -C(=O)NHR5, or a 9- or 10-membered bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S as ring members, wherein the bicyclic heteroaryl is unsubstituted or the bicyclic heteroaryl is substituted with one or more R6; 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 or has one or more substituents independently selected from: i) halogens, ii) amino, iii) C3-C6 cycloalkyl optionally substituted with one or more halogens; iv) C3-C6 cycloalkenyl, v) C1-C6 alkyl optionally substituted with C1-C6 alkoxy, C3-C6 cycloalkyl or phenyl; vi) C1-C6 haloalkyl, vii) -NHC(=O)C1-C6 alkyl (C1-C6 alkyl optionally substituted with C1-C6 alkoxy); viii) -NHC(=O)-C1-C6 haloalkyl, ix) -NHC(=O)-C3-C6 cycloalkyl, x) —C(═O)NH—C1-C6 alkyl (C1-C6 alkyl optionally substituted with C1-C6 alkoxy); xi) —C(═O)NH—C1-C6 haloalkyl, xii) —C(═O)NH—C3-C6 cycloalkyl, xiii) —NHC(═O)phenyl, wherein phenyl is optionally substituted with one or more substituents independently selected from halogen and C1-C6 alkyl; xiv) —C(═O)NHphenyl, wherein phenyl is optionally substituted with one or more substituents independently selected from halogen and C1-C6 alkyl; xv) C1-C6 alkoxy or C1-C6 haloalkoxy, xvi) phenyloxy optionally substituted with one or more halogens; xvii) phenyl 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) 4-6 membered heterocyclyl optionally substituted with oxo, -C(=O)OC1-C6 alkyl or -C(=O)OC1-C6 cycloalkyl; xix) 5- or 6-membered heteroaryl having 1 or 2 heteroatoms, each independently selected from N, O, and S, as ring members (wherein the heteroaryl is unsubstituted or substituted with one or more substituents independently selected from C1-C6 alkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, 4- to 6-membered heterocyclyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, and C1-C6 alkyl optionally substituted with —OH, C1-C6 alkoxy, or 4- to 6-membered heterocyclyl optionally substituted with oxo); and xx) a 9- or 10-membered bicyclic heteroaryl having 1 to 4 heteroatoms, each independently selected from N, O, and S, as ring members (wherein the heteroaryl is unsubstituted or substituted with one or more substituents independently selected from C1-C6 alkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, 4-6-membered heterocyclyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, and C1-C6 alkyl optionally substituted with C1-C6 alkoxy); is replaced by each R6 is independently selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, cyano, and halogen; R 11 is H, C1-C6 alkyl or halogen, or R1 and R 11 may form a 3- to 6-membered carbocyclic ring together with the carbon atom to which they are attached.

[0006] As used herein, the serpentine line in compounds of formula (I) characterizing the chemical bond leading to substituent R4 indicates two stereochemical options: in one embodiment, the stereochemistry of the carbon atom to which R4 is attached is (S), in another embodiment, said stereochemistry is (R), or in yet another embodiment, a mixture thereof.

[0007] As used herein, the serpentine line in compounds of formula (I) characterizing the chemical bond leading to substituent R3 indicates two stereochemical options: in one embodiment, the stereochemistry of the carbon atom to which R3 is attached is (S), in another embodiment, said stereochemistry is (R), or in yet another embodiment, a mixture thereof.

[0008] Another aspect of the present invention is a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

[0009] Another aspect of the present invention is a pharmaceutical composition comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

[0010] In another aspect, the present invention provides a method for treating or preventing a disease or disorder mediated by the activity of signal peptide peptidase-like protease 2a (Sppl2a), the method comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound or pharmaceutically acceptable salt of the invention.

[0011] In another aspect, the present invention provides a method for treating or preventing a disease or disorder mediated by the activity of signal peptide peptidase-like protease 2a (Sppl2a), the method comprising administering to a subject in need of such treatment a compound or a pharmaceutically acceptable salt of the present invention.

[0012] In another aspect, the present invention provides a method of treating an autoimmune disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof.

[0013] In another aspect, the present invention provides a method of treating an autoimmune disease in a subject in need thereof, the method comprising administering to the subject a compound of the present invention or a pharmaceutically acceptable salt thereof.

[0014] In another aspect, the present invention provides a method of treating an autoimmune disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, wherein the autoimmune disease is Sjogren'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's syndrome, or type 1 diabetes.

[0015] In another aspect, the present invention provides a method of treating an autoimmune disease in a subject in need thereof, the method comprising administering a compound of the present invention or a pharmaceutically acceptable salt thereof to the subject, wherein the autoimmune disease is Sjogren'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's syndrome, or type 1 diabetes.

[0016] In another aspect, the present invention provides a method of treating graft-versus-host disease (GvHD) in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof. In certain embodiments, the graft-versus-host disease (GvHD) is acute graft-versus-host disease, and in other embodiments, the graft-versus-host disease (GvHD) is chronic graft-versus-host disease.

[0017] In another aspect, the present invention provides a method for preventing graft-versus-host disease (GvHD) in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof. In certain embodiments, the graft-versus-host disease (GvHD) is acute graft-versus-host disease, and in other embodiments, the graft-versus-host disease (GvHD) is chronic graft-versus-host disease.

[0018] In another aspect, the present invention provides a method of treating graft-versus-host disease (GvHD) in a subject, the method comprising administering a compound of the present invention or a pharmaceutically acceptable salt thereof to the subject. In certain embodiments, the graft-versus-host disease (GvHD) is acute graft-versus-host disease, and in other embodiments, the graft-versus-host disease (GvHD) is chronic graft-versus-host disease.

[0019] In another aspect, the present invention provides a method for preventing graft-versus-host disease (GvHD) in a subject, the method comprising administering a compound of the present invention or a pharmaceutically acceptable salt thereof to the subject prior to transplant surgery. In certain embodiments, the graft-versus-host disease (GvHD) is acute graft-versus-host disease, and in other embodiments, the graft-versus-host disease (GvHD) is chronic graft-versus-host disease.

[0020] In another aspect, the present invention provides the use of a compound of the present invention, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease or disorder associated with or mediated by the activity of signal peptide peptidase-like protease 2a (Sppl2a).

[0021] In another aspect, the present invention provides the use of a compound of the present invention, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of an autoimmune disease.

[0022] In another aspect, the present invention provides the use of a compound of the present invention or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of an autoimmune disease, wherein the autoimmune disease is Sjogren'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's syndrome, or type 1 diabetes.

[0023] In another aspect, the present invention provides use of a compound of the present invention, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prevention of graft-versus-host disease (GvHD). In certain embodiments, the graft-versus-host disease (GvHD) is acute graft-versus-host disease, and in other embodiments, the graft-versus-host disease (GvHD) is chronic graft-versus-host disease.

[0024] In another aspect, the present invention provides the use of a compound of the present invention, or a pharmaceutically acceptable salt thereof, in the treatment of a disease or disorder associated with or mediated by the activity of signal peptide peptidase-like protease 2a (Sppl2a).

[0025] In another aspect, the present invention provides the use of a compound of the present invention, or a pharmaceutically acceptable salt thereof, in the treatment of an autoimmune disease.

[0026] In another aspect, the present invention provides the use of a compound of the present invention or a pharmaceutically acceptable salt thereof in the treatment of an autoimmune disease, wherein the autoimmune disease is Sjogren'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's syndrome, or type 1 diabetes.

[0027] In another aspect, the present invention provides use of a compound of the present invention, or a pharmaceutically acceptable salt thereof, in the treatment or prevention of graft-versus-host disease (GvHD). In certain embodiments, the graft-versus-host disease (GvHD) is acute graft-versus-host disease, and in other embodiments, the graft-versus-host disease (GvHD) is chronic graft-versus-host disease.

[0028] In another aspect, the present invention provides a compound of the present invention, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or disorder associated with or mediated by the activity of signal peptide peptidase-like protease 2a (Sppl2a).

[0029] In another aspect, the present invention provides a compound of the present invention, or a pharmaceutically acceptable salt thereof, for use in the treatment of an autoimmune disease.

[0030] In another aspect, the present invention provides a compound of the present invention or a pharmaceutically acceptable salt thereof for use in the treatment of an autoimmune disease, wherein the autoimmune disease is Sjogren'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's syndrome, or type 1 diabetes.

[0031] In another aspect, the present invention provides a compound of the present invention or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of graft-versus-host disease (GvHD). In certain embodiments, the graft-versus-host disease (GvHD) is acute graft-versus-host disease, and in other embodiments, the graft-versus-host disease (GvHD) is chronic graft-versus-host disease. DETAILED DESCRIPTION OF THE INVENTION

[0032] definition The term "alkyl," as used herein, refers to a fully saturated branched or straight chain hydrocarbon having up to 20 carbon atoms. In certain embodiments, an alkyl group is defined as "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-C 10 alkyl", and "C1-C2 alkyl", "C1-C3 alkyl", "C1-C4 alkyl", "C1C 5~ alkyl," "C1-C6 alkyl," "C1-C7 alkyl," "C1-C8 alkyl," "C1-C9 alkyl," and "C1-C 10The term "alkyl," as used herein, refers to an alkyl group containing at least 1, and at most 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms, respectively. 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.

[0033] The term "alkoxy," as used herein, refers to -O-alkyl or -alkyl-O-, where "alkyl" is as defined above. In certain embodiments, an alkoxy group is selected from the group consisting of "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", and includes "C1-C3 alkoxy", "C1-C4 alkoxy", "C1-C5 alkoxy", "C1-C6 alkoxy", "C1-C7 alkoxy", "C1-C8 alkoxy", "C1-C9 alkoxy" and "C 10 The term "alkoxy" as used herein means, respectively, -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, -O-C1-C 10 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.

[0034] The term "C3-C8 cycloalkyl," as used herein, refers to a fully saturated, monocyclic hydrocarbon ring system having from 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 certain embodiments, the term "C3-C6 cycloalkyl," as used herein, refers to a fully saturated, monocyclic hydrocarbon ring system having from 3 to 6 carbon atoms as ring members. Non-limiting examples of such "C3-C8 cycloalkyl" groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0035] The term "3- to 6-membered carbocyclic ring" as used herein refers to a 3- to 6-membered saturated or partially saturated hydrocarbon ring. Non-limiting examples of such carbocyclic groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.

[0036] The term "C3-C6 cycloalkenyl" as used herein refers to a partially saturated (but not aromatic) monocyclic hydrocarbon ring system having from 3 to 6 carbon atoms as ring members.

[0037] The term "C1-C6 alkylphenyl" as used herein refers to a C1-C6 alkyl, as defined above, substituted with a phenyl group. A non-limiting example of a C1-C6 alkylphenyl is benzyl.

[0038] The term "haloalkyl," as used herein, refers to an alkyl group, as defined herein, in which at least one of the alkyl's hydrogen atoms has been replaced with a halo group (as defined herein). The haloalkyl can be a monohaloalkyl, dihaloalkyl, trihaloalkyl, or polyhaloalkyl, including perhaloalkyl. A monohaloalkyl can have one iodine, bromine, chlorine, or fluorine atom within the alkyl group. Dihaloalkyl and polyhaloalkyl groups can have two or more of the same halo atoms or a combination of different halo groups within the alkyl. Typically, a polyhaloalkyl contains up to six, or four, or three, or two halo groups. Non-limiting examples of haloalkyl include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, and dichloropropyl. Perhaloalkyl refers to an alkyl in which all hydrogen atoms have been replaced with halo atoms, such as trifluoromethyl. Preferred haloalkyl groups, unless otherwise specified, include monofluoro-, difluoro-, and trifluoro-substituted methyl and ethyl groups, such as CF, CHF, CHF, CHCHF, and CHCF.

[0039] The term "C1-C6 haloalkyl," as used herein, refers to each "C1-C6 alkyl," as defined herein, in which at least one of the hydrogen atoms of the "C1-C6 alkyl" is replaced by a halo group (as defined herein). A C1-C6 haloalkyl group can be a mono-C1-C6 haloalkyl, where such a C1-C6 haloalkyl group has one iodine, one bromine, one chlorine, or one fluorine. Additionally, a C1-C6 haloalkyl group can be a di-C1-C6 haloalkyl, where such a C1-C6 haloalkyl group can have two halo atoms independently selected from iodine, bromine, chlorine, or fluorine. Additionally, a C1-C6 haloalkyl group can be a poly-C1-C6 haloalkyl, where such a C1-C6 haloalkyl group can have two or more of the same halo atoms or a combination of two or more different halo atoms. Such poly C1-C6 haloalkyls may be perhalo C1-C6 haloalkyls, in which all hydrogen atoms of each C1-C6 alkyl are replaced with halo atoms, and the halo atoms may be the same or a combination of different halo 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.

[0040] The term "haloalkoxy," as used herein, refers to an -O-haloalkyl group, in which at least one of the hydrogen atoms in the alkyl group of the alkoxy is replaced by a halo group (as defined herein). The haloalkoxy can be a monohaloalkoxy, dihaloalkoxy, trihaloalkoxy, or polyhaloalkoxy, including perhaloalkoxy. A monohaloalkoxy can have one iodine, bromine, chlorine, or fluorine atom in the alkyl group. Dihaloalkoxy and polyhaloalkoxy groups can have two or more of the same halo atoms or a combination of different halo groups in the alkyl. Typically, a polyhaloalkoxy contains up to six, or four, or three, or two halo groups. Non-limiting examples of haloalkoxy include fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, trichloromethoxy, pentafluoroethoxy, heptafluoropropoxy, difluorochloromethoxy, dichlorofluoromethoxy, difluoroethoxy, difluoropropoxy, dichloroethoxy, and dichloropropoxy. Perhaloalkoxy refers to an alkoxy in which all hydrogen atoms are replaced with halo atoms, such as trifluoromethytoxy. Preferred haloalkoxy groups, unless otherwise specified, include monofluoro-, difluoro-, and trifluoro-substituted methoxy and ethoxy groups, such as -OCF, -OCHF, -OCHF, -OCHCHF, and -OCHCF.

[0041] The term "C1-C6 haloalkoxy," as used herein, refers to an -O-C1-C6 haloalkyl group, wherein at least one of the hydrogen atoms of the "C1-C6 alkyl" of the "C1-C6 alkoxy" is replaced by a halo group (as defined herein). The C1-C6 haloalkyl group can be a mono-C1-6 haloalkyl, where such a C1-C6 haloalkyl group has one iodine, one bromine, one chlorine, or one fluorine. Additionally, the C1-C6 haloalkoxy group can be a di-C1-C6 haloalkoxy, where such a C1-C6 haloalkoxy group can have two halo atoms independently selected from iodine, bromine, chlorine, or fluorine. Furthermore, the C1-C6 haloalkoxy group can be a poly-C1-C6 haloalkoxy, where such a C1-C6 haloalkoxy group can have two or more of the same halo atoms or a combination of two or more different halo atoms. Such a poly C1-C6 haloalkoxy may be a perhalo C1-C6 haloalkoxy, in which all hydrogen atoms of each C1-C6 alkoxy are replaced with halo atoms, and the halo atoms may be the same or a combination of different halo 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.

[0042] The term "halogen" or "halo," as used herein, refers to fluoro (F), chloro (Cl), bromo (Br) and iodo (I).

[0043] The term "heteroatoms," as used herein, refers to nitrogen (N), oxygen (O), or sulfur (S) atoms.

[0044] The term "heteroaryl," as used herein, refers to an aromatic ring system containing one or more heteroatoms. Heteroaryl groups containing two or more heteroatoms may contain different heteroatoms. Heteroaryl groups can be monocyclic or fused bicyclic ring systems. Monocyclic heteroaryl rings have 5 to 6 ring atoms. Bicyclic heteroaryl rings have 7 to 12 ring atoms. Bicyclic heteroaryl rings include ring systems in which a heteroaryl ring is fused to a phenyl ring. Non-limiting examples of heteroaryl groups, as used herein, include benzofuranyl, benzo[c]thiophenyl, benzothiophenyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, cinnolinyl, furazanyl, furyl, imidazolyl, indolyl, indolizinyl, indazolyl, isoindolyl, isoquinolinyl, isoxazolyl, isothiazolyl, oxazolyl, oxindolyl, oxadiazolyl (1,3,4-oxadiazolyl). and 1,2,4-oxadiazolyl), purinyl, pyrazolyl, pyrrolyl, phthalazinyl, pyridinyl (including 2-, 3- and 4-pyridinyl), pyridazinyl, pyrazinyl, pyrimidinyl, quinoxalinyl, quinolinyl, quinazolinyl, tetrazinyl, tetrazolyl, tetrazolo[1,5-a]pyridinyl, thiazolyl, thiadiazolyl (including 1,3,4-thiadiazolyl), thienyl, triazinyl, and triazolyl.

[0045] The term "5-membered heteroaryl," as used herein, refers to an aromatic 5-membered monocyclic ring system having 1, 2, or 3 heteroatoms, each independently selected from N, O, and S, as ring members. Non-limiting examples of such 5-membered heteroaryl groups, as used herein, include furyl, imidazolyl, isoxazolyl, isothiazolyl, oxazolyl, pyrrolyl, pyrazolyl, thiadiazolyl, thiazolyl, thienyl, and triazolyl. In certain embodiments, the term "5-membered heteroaryl," as used herein, refers to an aromatic 5-membered monocyclic ring system having 1 or 2 heteroatoms, each independently selected from N, O, and S, as ring members. Non-limiting examples of such 5-membered heteroaryl groups, as used herein, include furyl, imidazolyl, isoxazolyl, isothiazolyl, oxazolyl, pyrrolyl, pyrazolyl, thiadiazolyl, thiazolyl, thienyl, and triazolyl.

[0046] The term "6-membered heteroaryl," as used herein, refers to an aromatic 6-membered monocyclic ring system having 1, 2, or 3 heteroatoms as ring members, each independently selected from N, O, and S. Non-limiting examples of such 6-membered heteroaryl groups as used herein include pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, and triazinyl. In certain embodiments, the term "6-membered heteroaryl," as used herein, refers to an aromatic 6-membered monocyclic ring system having 1 or 2 heteroatoms as ring members, each independently selected from N, O, and S. Non-limiting examples of such 6-membered heteroaryl groups as used herein include pyridyl, pyridazinyl, pyrazinyl, and pyrimidinyl.

[0047] The term "9- or 10-membered bicyclic heteroaryl," as used herein, refers to a 9- or 10-membered fused bicyclic aromatic ring system having as ring members 1, 2, 3, or 4 heteroatoms, each independently selected from N, O, and S. Non-limiting examples of such bicyclic heteroaryl groups, as used herein, include indolyl, quinolinyl, isoquinolinyl, indazolyl, purinyl, phthalazinyl, naphthyridinyl, quinazolinyl, cinnolinyl, thieno[2,3-b]furanyl, 1H-pyrazolo[4,3-d]-oxazolyl, imidazo[2,1-b]thiazolyl, pyrazino[2,3-d]pyridazinyl, imidazo[1,2-b][1,2,4]triazinyl, benzoxazolyl, benzimidazolyl, imidazopyridinyl, and benzothiazolyl. In certain embodiments, such a bicyclic heteroaryl group is 1H-benzo[d]imidazolyl or 1H-imidazo[4,5-c]pyridinyl.

[0048] As used herein, the term "4- to 6-membered heterocyclyl" refers to a group having N, NH, NR as ring members. A , O, or S, wherein R Ais H, C1-C6 alkyl, or C3-C8 cycloalkyl. Heterocyclyl groups can be attached to another group at a nitrogen atom or a carbon atom. Non-limiting examples of 4-6 membered heterocycloalkyl groups, as used herein, include azetadinyl, azetadin-1-yl, azetadin-2-yl, azetadin-3-yl, oxetanyl, oxetan-2-yl, oxetan-3-yl, oxetan-4-yl, thietanyl, thietan-2-yl, thietan-3-yl, thietan-4-yl, pyrrolidinyl, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, pyrrolidin-4-yl, pyrrolidin-5-yl, tetrahydrofuranyl, tetramethylbenzo ... tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrofuran-4-yl, tetrahydrofuran-5-yl, tetrahydrothienyl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, tetrahydrothien-4-yl, tetrahydrothien-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, tetrahydro tetrahydropyran-3-yl, tetrahydropyran-4-yl, tetrahydropyran-5-yl, tetrahydropyran-6-yl, tetrahydrothiopyranyl, tetrahydrothiopyran-2-yl, tetrahydrothiopyran-3-yl, tetrahydrothiopyran-4-yl, tetrahydrothiopyran-5-yl, tetrahydrothiopyran-6-yl, piperazinyl, piperazin-1-yl, piperazin-2-yl, piperazin-3-yl, piperazin-4-yl, piperazin-5-yl, piperazin-6-yl, morpholinyl yl, 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, oxathianii, oxathian-2-yl, oxathian-3-yl, oxathian-5-yl, oxathian-6-yl, dithianii, dithian-2-yl, dithian-3-yl, dithian-5-yl, dithian-6-yl,Examples include dioxolanyl, dioxolan-2-yl, dioxolan-4-yl, dioxolan-5-yl, thioxanyl, thioxan-2-yl, thioxan-3-yl, thioxan-4-yl, thioxan-5-yl, dithiolanyl, dithiolan-2-yl, dithiolan-4-yl, dithiolan-5-yl, pyrazolidinyl, pyrazolidin-1-yl, pyrazolidin-2-yl, pyrazolidin-3-yl, pyrazolidin-4-yl, pyrazolidin-5-yl, 2-azabicyclo[4.2.0]octanyl, octahydro-1H-cyclopenta[b]pyridine, and decahydroquinoline.

[0049] The term "isomers," as used herein, refers to different compounds having the same molecular formula but differing in the arrangement and configuration of atoms. Also, as used herein, the terms "optical isomer" or "stereoisomer" refer to any of the various stereoisomeric configurations that may exist in a given compound of the present invention and include geometric isomers. It is understood that substituents may be attached to chiral centers of carbon atoms. The term "chiral" refers to molecules that possess the property of non-superimposability on their mirror-image partners, while the term "achiral" refers to molecules that are superimposable on their mirror-image partners. Thus, the present invention encompasses enantiomers, diastereomers, or racemates of a compound. "Enantiomers" are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. This term is used to designate a racemic mixture where appropriate. "Diastereoisomers" are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. Absolute stereochemistry is designated according to the Cahn-Ingold-Prelog RS system. When a compound is a pure enantiomer, the stereochemistry of each asymmetric carbon can be designated by either R or S. Resolved compounds whose absolute configuration is unknown can be designated as (+) or (-) depending on the direction (dextrorotatory or levorotatory) that they rotate plane-polarized light at the sodium D-line wavelength. Certain compounds disclosed herein contain one or more asymmetric centers or axes, and therefore can form enantiomers, diastereomers, and other stereoisomeric forms that can be defined as (R)- or (S)- in terms of absolute stereochemistry.

[0050] The term "pharmaceutically acceptable carrier," as used herein, includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial, antifungal), isotonic agents, absorption delaying agents, salts, preservatives, drug stabilizers, binders, excipients, disintegrants, lubricants, sweeteners, flavoring agents, dyes, and the like, and combinations thereof known to those skilled in the art (see, e.g., Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329). Any conventional carrier is contemplated for use in the therapeutic or pharmaceutical compositions, unless it is incompatible with the active ingredient.

[0051] The term "therapeutically effective amount" of a compound of the present invention refers to an amount of a compound of the present invention that, when administered to a subject, is effective to (1) at least partially alleviate, inhibit, prevent, and / or ameliorate a condition, disease, or disorder that is (i) mediated by Sppl2a, (ii) associated with or mediated by Sppl2a activity, or (iii) characterized by Sppl2a activity (normal or abnormal), or (2) reduce or inhibit the activity of Sppl2a, or (3) reduce or inhibit the expression of Sppl2a. In another non-limiting embodiment, the term "therapeutically effective amount" refers to an amount of a compound of the present invention that, when administered to a cell, tissue, non-cellular biological material, or culture medium, is effective to at least partially reduce or inhibit the activity of Sppl2a or at least partially reduce or inhibit the expression of Sppl2a.

[0052] As used herein, the term "subject" may refer to an animal. An animal may be a mammal. A subject also refers to, for example, a primate (e.g., a human, male or female), cow, sheep, goat, horse, dog, cat, rabbit, rat, mouse, fish, bird, etc. In certain embodiments, the subject is a primate. In yet other embodiments, the subject is a human.

[0053] The terms "inhibit," "inhibition," or "inhibiting," as used herein, refer to the alleviation or suppression of a given condition, symptom, disease, or disorder, or a significant decrease in the underlying activity of a biological activity or process.

[0054] As used herein, the terms "treat," "treating," or "treatment" with respect to any disease or disorder refer, in one embodiment, to ameliorating the disease or disorder (i.e., delaying, arresting, or reducing the onset of the disease or at least one of its clinical symptoms). In other embodiments, "treat," "treating," or "treatment" refers to alleviating or improving at least one physical parameter, including those that may not be discernible by the patient. In yet other embodiments, "treat," "treating," or "treatment" refers to modulating the disease or disorder either physically (e.g., stabilizing a discernible symptom), physiologically (e.g., stabilizing a physical parameter), or both.

[0055] As used herein, the term "preventing" refers to delaying the onset or development or progression of a disease or disorder.

[0056] As used herein, a subject is "in need of" a treatment if the subject would benefit biologically, medically, or in quality of life from such treatment.

[0057] As used herein, the terms "a," "an," "the," and similar terms as used in the context of the present invention (particularly in the context of the claims) are to be construed to encompass both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

[0058] Unless otherwise specified, the term "compound(s) of the invention" refers to the compound(s) of Formula (I), Formula (II), Formula (III), and Formula (IV), and subformulas thereof (e.g., Formula (IIA), Formula (IIB), Formula (IIC), Formula (IID), Formula (IIIA), Formula (IIIB), Formula (IIIC), and Formula (IIID)), and exemplified compounds, and salt(s) thereof, and all stereoisomer(s) thereof (including diastereoisomers and enantiomers).

[0059] Various enumerated embodiments of the present invention are described herein, and it will be understood that the features specified in each embodiment may be combined with other specified features to provide further embodiments of the present invention.

[0060] Compounds of the Invention The present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof or a stereoisomer thereof: [ka] During the ceremony, Y is CH2 or C=O; R1 is H, C1-C6 alkyl or halogen; R2 is H or halogen; R3 is H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkylphenyl, or C1-C6 alkyl substituted with C1-C6 alkoxy; R4 is H, C1-C6 alkyl or C1-C6 alkylphenyl; R 10is -NHC(=O)R5, -C(=O)NHR5, or a 7-12 membered heteroaryl ring having 2-4 heteroatoms independently selected from N, O, and S as ring members, wherein the bicyclic heteroaryl is unsubstituted or the bicyclic heteroaryl is substituted with one or more R6; 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 or the 5-membered heteroaryl has one or more substituents independently selected from: i) halogens, ii) amino, iii) C3-C6 cycloalkyl optionally substituted with one or more halogens; iv) C3-C6 cycloalkenyl, v) C1-C6 alkyl optionally substituted with C1-C6 alkoxy, C3-C6 cycloalkyl, or phenyl; vi) C1-C6 haloalkyl, vii) -NHC(=O)C1-C6 alkyl (C1-C6 alkyl optionally substituted with C1-C6 alkoxy); viii) -NHC(=O)-C1-C6 haloalkyl, ix) -NHC(=O)-C3-C6 cycloalkyl, x) —C(═O)NH—C1-C6 alkyl (C1-C6 alkyl optionally substituted with C1-C6 alkoxy); xi) —C(═O)NH—C1-C6 haloalkyl, xii) —C(═O)NH—C3-C6 cycloalkyl, xiii) —NHC(═O)phenyl, wherein phenyl is optionally substituted with one or more substituents independently selected from halogen and C1-C6 alkyl; xiv) —C(═O)NHphenyl, wherein phenyl is optionally substituted with one or more substituents independently selected from halogen and C1-C6 alkyl; xv) C1-C6 alkoxy or C1-C6 haloalkoxy, xvi) phenyloxy optionally substituted with one or more halogens; xvii) phenyl 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) 4-6 membered heterocyclyl optionally substituted with oxo, -C(=O)OC1-C6 alkyl or -C(=O)OC1-C6 cycloalkyl; xix) 5- or 6-membered heteroaryl having 1 or 2 heteroatoms, each independently selected from N, O, and S, as ring members (wherein the heteroaryl is unsubstituted or substituted with one or more substituents independently selected from C1-C6 alkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, 4- to 6-membered heterocyclyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, and C1-C6 alkyl optionally substituted with -OH, C1-C6 alkoxy, or oxo), and xx) a 9- or 10-membered bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S as ring members (wherein the heteroaryl is unsubstituted or substituted with one or more substituents independently selected from C1-C6 alkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, 4-6-membered heterocyclyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, and C1-C6 alkyl optionally substituted with C1-C6 alkoxy); is replaced by each R6 is independently selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, cyano, and halogen; R 11 is H, C1-C6 alkyl or halogen, or R1 and R 11may form a 3- to 6-membered carbocyclic ring together with the carbon atom to which they are attached.

[0061] Various embodiments of the compounds of the present invention are described herein. It will be understood that the specified features of each embodiment can be combined with other specified features to provide further embodiments of the present invention. The following listed embodiments are representative of the compounds of formula (I) of the present invention.

[0062] Embodiment 1 A compound of formula (I), or a pharmaceutically acceptable salt thereof or a stereoisomer thereof. [ka] (In the formula, Y is CH2 or C=O; R1 is H, C1-C6 alkyl or halogen; R2 is H or halogen; R3 is H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 alkylphenyl, or C1-C6 alkyl substituted with C1-C6 alkoxy; R4 is H, C1-C6 alkyl or C1-C6 alkylphenyl; R 10 is -NHC(=O)R5, -C(=O)NHR5, or a 9- or 10-membered bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S as ring members, wherein the bicyclic heteroaryl is unsubstituted or substituted with one or more R6; R5 is a 5-membered heteroaryl having 1, 2, or 3 heteroatoms each independently selected from N, O, and S as ring members, wherein said 5-membered heteroaryl is unsubstituted or said 5-membered heteroaryl has one or more substituents independently selected from: i) halogens, ii) amino, iii) C3-C6 cycloalkyl optionally substituted with one or more halogens; iv) C3-C6 cycloalkenyl, v) C1-C6 alkyl optionally substituted with C1-C6 alkoxy, C3-C6 cycloalkyl or phenyl; vi) C1-C6 haloalkyl, vii) -NHC(=O)C1-C6 alkyl (wherein the C1-C6 alkyl is optionally substituted with C1-C6 alkoxy); viii) -NHC(=O)-C1-C6 haloalkyl, ix) -NHC(=O)-C3-C6 cycloalkyl, x) —C(═O)NH—C1-C6 alkyl (the C1-C6 alkyl is optionally substituted with C1-C6 alkoxy); xi) —C(═O)NH—C1-C6 haloalkyl, xii) —C(═O)NH—C3-C6 cycloalkyl, xiii) -NHC(=O)phenyl, wherein said phenyl is optionally substituted with one or more substituents independently selected from halogen and C1-C6 alkyl; xiv) —C(═O)NHphenyl, wherein said phenyl is optionally substituted with one or more substituents independently selected from halogen and C1-C6 alkyl; xv) C1-C6 alkoxy or C1-C6 haloalkoxy, xvi) phenyloxy optionally substituted with one or more halogens; xvii) phenyl optionally substituted with one or more substituents independently selected from halogen, —CN, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl; xviii) 4-6 membered heterocyclyl optionally substituted with oxo, -C(=O)OC1-C6 alkyl or -C(=O)OC1-C6 cycloalkyl; xix) 5- or 6-membered heteroaryl having 1 or 2 heteroatoms, each independently selected from N, O, and S, as ring members, wherein the heteroaryl is unsubstituted or substituted with one or more substituents independently selected from C1-C6 alkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, 4- to 6-membered heterocyclyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, and C1-C6 alkyl optionally substituted with -OH, C1-C6 alkoxy, or oxo, and xx) a 9- or 10-membered bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S as ring members, wherein the heteroaryl is unsubstituted or substituted with one or more substituents independently selected from C1-C6 alkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, 4-6-membered heterocyclyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, and C1-C6 alkyl optionally substituted with C1-C6 alkoxy. is replaced by each R6 is independently selected from C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, cyano, and halogen; R 11 is H, C1-C6 alkyl or halogen, or R1 and R 11 may form a 3- to 6-membered carbocyclic ring together with the carbon atom to which they are attached.

[0063] Embodiment 2 R 10 is —NHC(═O)R 5 , or a pharmaceutically acceptable salt or stereoisomer thereof.

[0064] Embodiment 3 R 10is —C(═O)NHR 5 , or a pharmaceutically acceptable salt or stereoisomer thereof.

[0065] Embodiment 4 R 10 is a 9- or 10-membered bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S as ring members, wherein the bicyclic heteroaryl is unsubstituted or substituted with one or more R6, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof.

[0066] Embodiment 5 R 10 or a pharmaceutically acceptable salt or stereoisomer thereof. [ka] (wherein R6 is H, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, cyano, or halogen.)

[0067] Embodiment 6 The compound of any of Embodiments 1-4, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R4 is H.

[0068] Embodiment 7 A compound of any of Embodiments 1-4, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R4 is C1-C6 alkyl.

[0069] Embodiment 8 The compound of any of Embodiments 1-4, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R4 is C1-C6 alkylphenyl.

[0070] Embodiment 9 The compound of embodiment 1, having the structure of formula (II), or a pharmaceutically acceptable salt or stereoisomer thereof: [ka]

[0071] Embodiment 10: The compound of embodiment 1, having the structure of formula (III), or a pharmaceutically acceptable salt or stereoisomer thereof. [ka]

[0072] Embodiment 11 The compound of embodiment 1 having the structure of formula (IV), or a pharmaceutically acceptable salt or stereoisomer thereof: [ka]

[0073] Embodiment 12 The compound of any of embodiments 1-11, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R1 is H.

[0074] Embodiment 13. A compound of any of embodiments 1 to 11, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R1 is C1-C6 alkyl.

[0075] Embodiment 14 The compound of any of embodiments 1-11, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R1 is halogen.

[0076] Embodiment 15 R 11 The compound of any of embodiments 1-11, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein is H.

[0077] Embodiment 16 R 11 The compound of any of embodiments 1-11, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein is C1-C6 alkyl.

[0078] Embodiment 17 R 11 12. The compound of any of embodiments 1-11, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein is halogen.

[0079] Embodiment 18 R1 and R 11 together with the carbon atom to which they are attached form a 3-6 membered carbocyclic ring, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0080] Embodiment 19 R1 and R 11 together with the carbon atom to which they are attached form a cyclopropyl ring, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0081] Embodiment 20. A compound of any of embodiments 1-19, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R2 is H.

[0082] Embodiment 21. A compound of any of embodiments 1-19, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R2 is halogen.

[0083] Embodiment 22 The compound of any of Embodiments 1-19, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R2 is F.

[0084] Embodiment 23 A compound of Embodiment 1 or Embodiment 9 having the structure of Formula (IIA), or a pharmaceutically acceptable salt or stereoisomer thereof. [ka]

[0085] Embodiment 24 A compound of Embodiment 1 or Embodiment 9 having the structure of Formula (IIB), or a pharmaceutically acceptable salt or stereoisomer thereof. [ka]

[0086] Embodiment 25 A compound of Embodiment 1 or Embodiment 9 having the structure of Formula (IIC), or a pharmaceutically acceptable salt or stereoisomer thereof. [ka]

[0087] Embodiment 26 A compound of embodiment 1 or embodiment 9 having the structure of formula (IID), or a pharmaceutically acceptable salt or stereoisomer thereof. [ka]

[0088] Embodiment 27 A compound of Embodiment 1 or Embodiment 9 having the structure of Formula (IIA), Formula (IIB), Formula (IIC) or Formula (IID), or a pharmaceutically acceptable salt or stereoisomer thereof. [ka]

[0089] Embodiment 28: A compound of embodiment 1 or embodiment 10 having the structure of formula (IIIA), or a pharmaceutically acceptable salt or stereoisomer thereof. [ka]

[0090] Embodiment 29: A compound of embodiment 1 or embodiment 10 having the structure of formula (IIIB), or a pharmaceutically acceptable salt or stereoisomer thereof. [ka]

[0091] Embodiment 30: A compound of embodiment 1 or embodiment 10 having the structure of formula (IIIC), or a pharmaceutically acceptable salt or stereoisomer thereof. [ka]

[0092] Embodiment 31 A compound of Embodiment 1 or Embodiment 10 having the structure of Formula (IIID), or a pharmaceutically acceptable salt or stereoisomer thereof. [ka]

[0093] Embodiment 32 A compound of embodiment 1 or embodiment 10 having the structure of formula (IIIA), formula (IIIB), formula (IIIC), or formula (IIID), or a pharmaceutically acceptable salt or stereoisomer thereof: [ka]

[0094] Embodiment 33. A compound according to any one of embodiments 1 to 32, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3 is H.

[0095] Embodiment 34. A compound of any of Embodiments 1 to 32, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3 is C1-C6 alkyl.

[0096] Embodiment 35. A compound of any of Embodiments 1-32, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3 is methyl, ethyl, propyl, or isopropyl.

[0097] Embodiment 36. A compound of any of Embodiments 1 to 32, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3 is C1-C6 haloalkyl.

[0098] Embodiment 37. A compound of any of Embodiments 1-32, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3 is CF3.

[0099] Embodiment 38. A compound of any of Embodiments 1 to 32, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3 is C1-C6 alkylphenyl.

[0100] Embodiment 39. A compound of any of Embodiments 1-32, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3 is -CH2-phenyl.

[0101] Embodiment 40. A compound of any of Embodiments 1-32, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3 is C1-C6 cycloalkyl.

[0102] Embodiment 41. A compound of any of Embodiments 1-32, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3 is cyclopropyl or cyclobutyl.

[0103] Embodiment 42. A compound of any of Embodiments 1-32, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3 is C1-C6 alkyl substituted with C1-C6 alkoxy.

[0104] Embodiment 43. A compound of any of Embodiments 1-32, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R3 is -CH2CH2OCH3.

[0105] Embodiment 44. The compound of any of embodiments 1-43, 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, and said 5-membered heteroaryl is unsubstituted.

[0106] Embodiment 45 A compound of any of Embodiments 1-43, 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, and said 5-membered heteroaryl is substituted with one or more substituents independently selected from: i) halogens, ii) amino, iii) C3-C6 cycloalkyl optionally substituted with one or more halogens; iv) C3-C6 cycloalkenyl, v) C1-C6 alkyl optionally substituted with C1-C6 alkoxy, C3-C6 cycloalkyl, or phenyl; vi) C1-C6 haloalkyl, vii) -NHC(=O)C1-C6 alkyl (wherein the C1-C6 alkyl is optionally substituted with C1-C6 alkoxy); viii) —NHC(═O)—C1-C6 haloalkyl, ix) -NHC(=O)-C3-C6 cycloalkyl, x) —C(═O)NH—C1-C6 alkyl (the C1-C6 alkyl is optionally substituted with C1-C6 alkoxy); xi) —C(═O)NH—C1-C6 haloalkyl, xii) —C(═O)NH—C3-C6 cycloalkyl, xiii) —NHC(═O)phenyl, wherein said phenyl is optionally substituted with one or more substituents independently selected from halogen and C1-C6 alkyl; xiv) —C(═O)NHphenyl, wherein said phenyl is optionally substituted with one or more substituents independently selected from halogen and C1-C6 alkyl; xv) C1-C6 alkoxy or C1-C6 haloalkoxy, xvi) phenyloxy optionally substituted with one or more halogens; xvii) phenyl 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) 4-6 membered heterocyclyl optionally substituted with oxo, -C(=O)OC1-C6 alkyl or -C(=O)OC1-C6 cycloalkyl, and xix) 5- or 6-membered heteroaryl having 1 or 2 heteroatoms, each independently selected from N, O, and S, as ring members, wherein the heteroaryl is unsubstituted or substituted with one or more substituents independently selected from C1-C6 alkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, 4- to 6-membered heterocyclyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, and C1-C6 alkyl optionally substituted with -OH, C1-C6 alkoxy, or oxo, and xx) a 9- or 10-membered bicyclic heteroaryl having 1 to 4 heteroatoms, each independently selected from N, O, and S, as ring members, wherein the heteroaryl is unsubstituted or substituted with one or more substituents independently selected from C1-C6 alkyl, halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy, C1-C6 alkoxy, 4-6-membered heterocyclyl, C3-C6 cycloalkyl, C3-C6 cycloalkenyl, and C1-C6 alkyl optionally substituted with C1-C6 alkoxy.

[0107] Embodiment 46. A compound of any one of Embodiments 1 to 43, or a pharmaceutically acceptable salt thereof, wherein R5 is: [ka] (In the formula, R 5a is C1-C6 alkyl or C1-C6 haloalkyl or halogen, R 5bis -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 heterocyclyl, 5- or 6-membered heteroaryl, wherein the heteroaryl is optionally substituted with halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy or C3-C6 cycloalkyl, and the heterocyclyl is optionally substituted with oxo, -C(O)OC1-C6 alkyl or -C(O)OC3-C6 cycloalkyl, and the -C(O)NHphenyl is optionally substituted with halogen or C1-C6 alkyl; R 5c is a 5- or 6-membered heteroaryl optionally substituted with halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or C3-C6 cycloalkyl; and R 5d is C1-C6 alkyl or C1-C6 haloalkyl.

[0108] Embodiment 47. A compound of any of Embodiments 1-43, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R5 is: [ka] [ka] [ka] [ka] [ka] [ka]

[0109] Embodiment 48: A compound of any of embodiments 1-43, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R5 is: [ka] [ka] [ka]

[0110] Embodiment 49 The compound of embodiment 1, wherein the compound is: 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]diazepin-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]diazepin-10-yl)carbamoyl)-3,3,3-trifluoropropyl)-4-methylisoxazole-5-carboxamide, 2-isobutyramido-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]diazepin-10-yl)carbamoyl)propyl)thiazole-5-carboxamide, 2-isobutyramido-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]diazepin-10-yl)amino)propyl)thiazole-5-carboxamide, N 2 -(2,2-difluoroethyl)-4-methyl-N5 -((R)-3,3,3-trifluoro-2-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazepin-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]diazepin-10-yl)amino)propyl)-N 2 -(2,2-difluoroethyl)-4-methylthiazole-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]diazepin-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]diazepin-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]diazepin-10-yl)amino)propyl)-N 2 ,4-dimethylthiazole-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]diazepin-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]diazepin-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]diazepin-10-yl)amino)propyl)-N 2 -ethyl-4-methylthiazole-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]diazepin-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]diazepin-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]diazepin-10-yl)carbamoyl)butyl)-2-(6-(trifluoromethyl)pyridin-3-yl)thiazole-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]diazepin-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]diazepin-10-yl)carbamoyl)butyl)-5-(trifluoromethyl)isoxazole-4-carboxamide, 4-methyl-N-((R)-2-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazepin-10-yl)carbamoyl)butyl)-2-(6-(trifluoromethyl)pyridin-3-yl)thiazole-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]diazepin-10-yl)carbamoyl)butyl)thiazole-2,5-dicarboxamide, 4-methyl-2-(3-methylisoxazol-5-yl)-N-((R)-2-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazepin-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]diazepin-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]diazepin-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]diazepin-10-yl)amino)propyl)-2-(3-methylisoxazol-5-yl)thiazole-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]diazepin-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]diazepin-10-yl)carbamoyl)butyl)isoxazole-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]diazepin-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]diazepin-10-yl)amino)propyl)-N 2 -isopropyl-4-methylthiazole-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]diazepin-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]diazepin-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]diazepin-10-yl)carbamoyl)butyl)-2-propoxythiazole-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'-cyclopropan]-10-yl)carbamoyl)butyl)-3-methyl-5-(trifluoromethyl)isoxazole-4-carboxamide, 2-(isoxazol-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]diazepin-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]diazepin-10-yl)carbamoyl)pentyl)isoxazole-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]diazepin-10-yl)carbamoyl)butyl)-2-(6-methoxypyridin-3-yl)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]diazepin-10-yl)carbamoyl)butyl)-4-methylisothiazole-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'-cyclopropan]-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]diazepin-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]diazepin-10-yl)carbamoyl)-3,3,3-trifluoropropyl)-4-methyl-2-(6-(trifluoromethyl)pyridin-3-yl)thiazole-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]diazepin-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]diazepin-10-yl)carbamoyl)-3,3,3-trifluoropropyl)-2-(6-(trifluoromethyl)pyridin-3-yl)thiazole-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]diazepin-10-yl)amino)-3-oxopropyl)-4-methyl-2-(3-methylisoxazol-5-yl)thiazole-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]diazepin-10-yl)carbamoyl)butyl)-4-methyl-2-(3-methylisoxazol-5-yl)thiazole-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]diazepin-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]diazepin-10-yl)carbamoyl)propyl)thiazole-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]diazepine-2,1'-cyclopropan]-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]diazepin-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]diazepin-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]diazepin-10-yl)carbamoyl)-3,3,3-trifluoropropyl)-3,5-dimethylisoxazole-4-carboxamide, 4-chloro-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'-cyclopropan]-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]diazepin-10-yl)carbamoyl)propyl)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]diazepin-10-yl)carbamoyl)butyl)isoxazole-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]diazepin-10-yl)carbamoyl)propyl)thiazole-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]diazepin-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]diazepin-10-yl)amino)-3-oxopropyl)thiazole-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]diazepin-10-yl)amino)-3-oxopropyl)-2-methylthiazole-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]diazepine-2,1'-cyclopropan]-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'-cyclopropan]-10-yl)carbamoyl)butyl)-4-(trifluoromethyl)thiazole-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]diazepin-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]diazepine-2,1'-cyclopropan]-10-yl)carbamoyl)butyl)-4-(trifluoromethyl)thiazole-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]diazepin-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]diazepin-10-yl)amino)propyl)-1H-pyrazole-5-carboxamide, (R)-N 4 -(3-isobutylamido-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]diazepin-10-yl)succinamide, (S)-2-Cyclobutyl-N 4 -(3-isobutylamido-1-methyl-1H-pyrazol-5-yl)-N 1 -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazepin-10-yl)succinamide, (R)-N 4 -(4-chloro-2-(isopropylcarbamoyl)thiazol-5-yl)-2-methyl-N 1 -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazepin-10-yl)succinamide, (R)-N 4 -(3-((2,2-difluoroethyl)carbamoyl)-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]diazepin-10-yl)succinamide, (R)-N 4-(2-(isopropylcarbamoyl)-4-methylthiazol-5-yl)-2-methyl-N 1 -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazepin-10-yl)succinamide, (S)-2-Cyclopropyl-N 4 -(3-(isopropylcarbamoyl)-1-methyl-1H-pyrazol-5-yl)-N 1 -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazepin-10-yl)succinamide, (R)-2-Methyl-N 4 -(1-methyl-3-((2,2,2-trifluoroethyl)carbamoyl)-1H-pyrazol-5-yl)-N 1 -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazepin-10-yl)succinamide, (R)-N 4 -(3-(2-fluorobenzamido)-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]diazepin-10-yl)succinamide; (R)-2-Methyl-N 4 -(1-methyl-3-(2,2,3,3,3-pentafluoropropanamido)-1H-pyrazol-5-yl)-N 1 -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazepin-10-yl)succinamide, (R)-N 4 -(3-(3-cyclopropylisoxazol-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]diazepin-10-yl)succinamide, (R)-2-Methyl-N 4 -(1-methyl-3-(6-(trifluoromethyl)pyridin-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]diazepin-10-yl)succinamide, (R)-N 4 -(4-chloro-2-(1-methyl-1H-pyrazol-3-yl)thiazol-5-yl)-2-methyl-N 1 -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazepin-10-yl)succinamide, (R)-2-Methyl-N 4 -(1-methyl-3-(5-methylpyridin-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]diazepin-10-yl)succinamide, (S)-2-Cyclopropyl-N 4 -(1-methyl-3-(5-methylpyridin-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]diazepin-10-yl)succinamide, (R)-N 4 -(3-(2,3-difluorobenzamido)-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]diazepin-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]diazepin-10-yl)-N 4 -(3-(isopropylcarbamoyl)-1-methyl-1H-pyrazol-5-yl)succinamide, (S)-2-Cyclopropyl-N 4 -(3-(((S)-1-fluoropropan-2-yl)carbamoyl)-1-methyl-1H-pyrazol-5-yl)-N 1 -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazepin-10-yl)succinamide, (R)-N 4 -(2-(5-fluoropyridin-3-yl)-4-methylthiazol-5-yl)-2-methyl-N 1 -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazepin-10-yl)succinamide, (R)-2-Methyl-N 4 -(1-methyl-3-(5-methylisoxazol-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]diazepin-10-yl)succinamide, (R)-N 4 -(3-(5-ethylisoxazol-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]diazepin-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'-cyclopropan]-10-yl)-N 4-(3-isobutyramido-1-methyl-1H-pyrazol-5-yl)succinamide, (R)-N 4 -(1-ethyl-3-(6-(trifluoromethyl)pyridin-3-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]diazepin-10-yl)succinamide, (R)-2-Methyl-N 4 -(1-methyl-3-((3,3,3-trifluoropropyl)carbamoyl)-1H-pyrazol-5-yl)-N 1 -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazepin-10-yl)succinamide, (R)-N 4 -(1-ethyl-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]diazepin-10-yl)succinamide, (R)-N 4 -(3-(3-ethylisoxazol-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]diazepin-10-yl)succinamide, (R)-N 4 -(3-(5-fluoropyridin-2-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]diazepin-10-yl)succinamide, (R)-N 4 -(3-chloro-1-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-4-yl)-2-methyl-N1 -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazepin-10-yl)succinamide, (R)-2-Methyl-N 4 -(1-methyl-3-pivalamido-1H-pyrazol-5-yl)-N 1 -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazepin-10-yl)succinamide, (R)-2-Methyl-N 4 -(1-methyl-3-(3-methylisoxazol-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]diazepin-10-yl)succinamide, (R)-N 4 -(2-(isopropylcarbamoyl)thiazol-5-yl)-2-methyl-N 1 -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazepin-10-yl)succinamide, (R)-2-Methyl-N 4 -(3-methyl-1-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-4-yl)-N 1 -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazepin-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'-cyclopropan]-10-yl)-N 4 -(3-isobutyramido-1-methyl-1H-pyrazol-5-yl)succinamide, (R)-2-Methyl-N 4-(1-methyl-3-(pyridin-2-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]diazepin-10-yl)succinamide, (R)-N 4 -(4-chloro-2-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)thiazol-5-yl)-2-methyl-N 1 -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazepin-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]diazepin-10-yl)succinamide, (R)-N 4 -(3-(6-methoxypyridin-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]diazepin-10-yl)succinamide, (R)-2-Methyl-N 4 -(1-methyl-3-(5-(trifluoromethyl)pyridin-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]diazepin-10-yl)succinamide, (R)-N 4 -(4-chloro-2-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)thiazol-5-yl)-2-methyl-N 1-((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazepin-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]diazepin-10-yl)-N 4 -(3-(((S)-1-fluoropropan-2-yl)carbamoyl)-1-methyl-1H-pyrazol-5-yl)succinamide, (R)-N 4 -(1-ethyl-3-(3-methylisoxazol-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]diazepin-10-yl)succinamide, (R)-N 4 -(3-(cyclopropylcarbamoyl)-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]diazepin-10-yl)succinamide, (S)-2-Cyclopropyl-N 4 -(3-(3-cyclopropylisoxazol-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′-cyclopropan]-10-yl)succinamide, (S)-N 4 -(4-chloro-2-(1-(difluoromethyl)-1H-pyrazol-4-yl)thiazol-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]diazepin-10-yl)succinamide, (R)-2-Methyl-N 4 -(1-methyl-3-(6-methylpyridin-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]diazepin-10-yl)succinamide, (S)-N 4 -(4-chloro-2-(6-(trifluoromethyl)pyridin-3-yl)thiazol-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′-cyclopropan]-10-yl)succinamide, (S)-N 4 -(4-chloro-2-(6-(trifluoromethyl)pyridin-3-yl)thiazol-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]diazepin-10-yl)succinamide, (R)-N 4 -(4-chloro-2-(6-(trifluoromethyl)pyridin-3-yl)thiazol-5-yl)-2-methyl-N 1 -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazepin-10-yl)succinamide, (R)-N 4 -(3-((2-fluorophenyl)carbamoyl)-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]diazepin-10-yl)succinamide, (R)-N4 -(3-((2,6-dimethylphenyl)carbamoyl)-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]diazepin-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]diazepin-10-yl)propanamide, (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]diazepin-10-yl)propanamide, (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]diazepin-10-yl)propanamide, (R)-2-methyl-N-((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazepin-10-yl)-3-(7-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)propanamide, (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]diazepin-10-yl)propanamide, (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]diazepin-10-yl)propanamide, (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]diazepin-10-yl)propanamide, (R)—N-((S)-6-fluoro-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazepin-10-yl)-3-(5-fluoro-7-methyl-1H-benzo[d]imidazol-2-yl)-2-methylpropanamide, or (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]diazepin-10-yl)pentanamide.

[0111] Depending on the selection of starting materials and procedures, the compounds may exist in one of the possible isomeric forms or as a mixture thereof, e.g., as pure optical isomers, or, depending on the number of asymmetric carbon atoms, as isomeric mixtures, such as racemic and diastereomeric mixtures. The present invention is intended to encompass 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. When the compounds contain double bonds, the substituents may be in the E or Z configuration. When the compounds contain a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis or trans configuration. All tautomeric forms are also intended to be included.

[0112] As used herein, the term "salt(s)" refers to acid addition salts or base addition salts of the compounds of the present invention. "Salt" specifically includes "pharmaceutically acceptable salts." The term "pharmaceutically acceptable salt(s)," as used herein, refers to salts that retain the biological effectiveness and properties of the compounds of the present invention and that are typically not biologically or otherwise undesirable. In many cases, the compounds of the present invention are capable of forming acid salts and / or base salts by virtue of the presence of amino and / or carboxyl groups or groups similar thereto.

[0113] Pharmaceutically acceptable acid addition salts can be formed from inorganic and organic acids. Organic or inorganic acids that can be used to form pharmaceutically acceptable acid addition salts of the compounds of the present invention include acetic acid, adipic acid, ascorbic acid, aspartic acid, benzoic acid, benzenesulfonic acid, carbonic acid, camphorsulfonic acid, capric acid, chlorotheophyllic acid, citric acid, ethanedisulfonic acid, fumaric acid, D-glycero-D-gulo-heptonic acid, galactaric acid, galactaric / mucic acid, gluceptic acid, glucoheptonic acid, These include, but are not limited to, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, glucolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, isethionic acid, lactic acid, lactobionic acid, lauryl sulfuric acid, malic acid, maleic acid, malonic acid, mandelic acid, mesylic acid, methanesulfonic acid, mucic acid, naphthoic acid, 1-hydroxy-2-naphthoic acid, naphthalenesulfonic acid, 2-naphthalenesulfonic acid, nicotinic acid, nitric acid, octadecanoic acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, poglacturonic acid, propionic acid, sebacic acid, stearic acid, succinic acid, sulfosalicylic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid, trifluoroacetic acid, and triphenylacetic acid.

[0114] The salt forms of the compounds of the present invention can be converted to the free compounds by treatment with a suitable basic agent.

[0115] Pharmaceutically acceptable acid addition salts of the compounds of the present invention include acetate, adipate, ascorbate, aspartate, benzoate, besylate, benzenesulfonate, bicarbonate / carbonate, bisulfate / sulfate, bromide / hydrobromide, camphorsulfonate, camsylate, caprate, chloride / hydrochloride, chlorotheophylline, citrate, edisylate, ethanedisulfonate, fumarate, gluceptate, glucoheptonate, gluconate, glucuronate, glutamate, glutarate, glycolate, hippurate, hydrogen iodide / iodide, isethionate, lactate, lactobionate, lauryl sulfate, malate, and maleate. , malonate, mandelate, mesylate, methanesulfonate, methylsulfate, mucate, naphthoate, napsylate, 2-napsylate, naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, polygalacturonate, propionate, sebacate, stearate, succinate, sulfosalicylate, sulfate, tartrate, tosylate, p-toluenesulfonate, trifluoroacetate, triphenylacetate, triphenylacetate, and xinafoate salt forms.

[0116] Pharmaceutically acceptable base addition salts can be formed from inorganic and organic bases. Organic bases used to form pharmaceutically acceptable base addition salts of the compounds of the present 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, and the like. Specific organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine. Inorganic bases used to form pharmaceutically acceptable base addition salts of the compounds of the present invention include, but are not limited to, sodium hydroxide, potassium hydroxide, ammonium hydroxide, ammonium salts, and metals from columns I through XII of the periodic table. Pharmaceutically acceptable base addition salts of the compounds of the present invention include, but are not limited to, sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper salts, with particularly suitable salts being ammonium, potassium, sodium, calcium, and magnesium salts.

[0117] The pharmaceutically acceptable salts herein can be synthesized from basic or acidic moieties by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid form of these compounds with a stoichiometric amount of an appropriate base (e.g., hydroxide, carbonate, bicarbonate, etc. of Na, Ca, Mg, or K), or by reacting the free base form of these compounds with a stoichiometric amount of an appropriate acid. Such reactions are typically carried out in water or an organic solvent, or a mixture of the two. Generally, where feasible, the use of non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is desirable.

[0118] Any formula given herein is also intended to represent the unlabeled form of compound as well as the isotopically labeled form.Isotopically labeled compound has the structure shown by the formula given herein, except that one or more atoms are replaced by atoms with selected atomic mass or mass number.The isotope that can be incorporated into the compound of the present invention includes, for example, hydrogen isotopes.

[0119] Additionally, certain isotopes, particularly deuterium (i.e. 2 Incorporation of H or D) may also provide certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life, or reduced dose requirements, or improved therapeutic index or tolerability. In this context, it is understood that deuterium is considered a substituent of the compounds of the present invention. The concentration of deuterium can be defined by the isotopic enrichment factor. As used herein, the term "isotopic enrichment factor" refers to the ratio between the isotopic abundance and the natural abundance of a particular isotope. When a substituent in a compound of the present invention is designated as deuterium, such compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation per designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). It should be understood that the term "isotopic enrichment factor" can be applied to any isotope in the same manner as described for deuterium.

[0120] Other examples of isotopes that may be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphate, fluorine, and chlorine, e.g., 3 H, 11 C. 13 C.14 C. 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl, 123 I, 124 I, 125 Therefore, the present invention provides, for example, 3 H and 14 Compounds incorporating any one or more of the aforementioned isotopes, including radioactive isotopes such as C, or 2 H and 13 It should be understood that this includes compounds incorporating non-radioactive isotopes such as C. Such isotope-labeled compounds may be used in metabolic studies ( 14 C), reaction kinetics tests (e.g., 2 H or 3 H), in detection or imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radiation treatment of patients. 18 F or labeled compounds may be particularly desirable in PET or SPECT studies. Isotopically labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art, or by processes similar to those described in the Examples and Preparations that follow, substituting the appropriate isotopically labeled reagent for the unlabeled reagent previously used.

[0121] By way of example, the compounds of the present invention may exist in deuterated forms as shown below. [ka]

[0122] Pharmaceutically acceptable solvates in accordance with the present invention include those wherein the solvent of crystallization may be isotopically substituted, eg, D2O, d6-acetone, and d6-DMSO.

[0123] Compounds of the present invention that contain groups capable of functioning as hydrogen bond donors and / or acceptors may be capable of forming co-crystals with suitable co-crystal formers. These co-crystals can be prepared from compounds of the present invention by known co-crystal formation procedures. Such procedures include grinding, heating, co-sublimation, co-melting, or contacting a compound of the present invention with a co-former in solution under crystallization conditions and isolating the co-crystal formed thereby. Suitable co-formers include those described in WO 2004 / 078163. Accordingly, the present invention further provides co-crystals comprising compounds of the present invention.

[0124] Furthermore, the compounds of the present invention, including their salts, may be obtained in the form of their hydrates or may include other solvents used in their crystallization. The compounds of the present invention may inherently or intentionally form solvates with pharmaceutically acceptable solvents (including water), and therefore, the present invention is intended to encompass both solvated and unsolvated forms. The term "solvate" refers to a molecular complex of a compound of the present invention (including its pharmaceutically acceptable salts) with one or more solvent molecules. Such solvent molecules are commonly used in the pharmaceutical field, such as water, ethanol, etc., which are known to be harmless to the recipient. The term "hydrate" refers to a complex in which the solvent molecule is water. The compounds of the present invention, including their salts, hydrates, and solvates, may inherently or intentionally form polymorphs.

[0125] Any asymmetric atom (e.g., carbon, etc.) of the compounds of the present invention can be present in racemic or enantiomeric excess, for example, in the (R)-, (S)-, or (R,S)-configuration. In certain embodiments, each asymmetric atom has an enantiomeric excess of at least 50% in the (R)- or (S)-configuration, at least 60% in the enantiomeric excess, at least 70% in the enantiomeric excess, at least 80% in the enantiomeric excess, at least 90% in the enantiomeric excess, at least 95% in the enantiomeric excess, or at least 99% in the enantiomeric excess. Substituents of atoms having unsaturated double bonds may, if possible, be present in cis-(Z)- or trans-(E)-form.

[0126] Thus, as used herein, the compounds of the present invention may be in the form of any isomer, rotamer, atropisomer, tautomer, or mixture thereof, such as a substantially pure geometric (cis or trans) isomer, diastereomer, optical isomer (enantiomer), racemate, or mixture thereof.

[0127] Any resulting isomeric mixtures can be separated on the basis of the physical chemical differences of the components into pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and / or fractional crystallization.

[0128] Any resulting racemic final products or intermediates can be resolved into their optical antipodes by known methods, for example, by separation of their diastereomeric salts obtained with optically active acids or bases to liberate the optically active acidic or basic compounds. In particular, basic moieties may be used in this manner to resolve the compounds of this invention into their optical antipodes by fractional crystallization of salts formed with optically active acids, such as, for example, tartaric acid, dibenzoyltartaric acid, diacetyltartaric acid, di-O,O'-p-toluoyltartaric acid, mandelic acid, malic acid, or camphor-10-sulfonic acid. Racemic products can also be resolved by chiral chromatography, for example, high-pressure liquid chromatography (HPLC) using a chiral adsorbent.

[0129] Method for producing the compounds of the present invention General procedures for preparing compounds of the present invention are described herein. In the reactions described, reactive functional groups, such as hydroxy, amino, imino, or carboxy groups, may be protected to avoid undesired participation in the reaction if desired in the final product. Within the scope of this specification, only easily removable groups that are not constituents of the specific desired final product of the compounds of the present invention are referred to as "protecting groups," unless the context dictates otherwise. Protection of functional groups by such protecting groups, the protecting groups themselves, and their cleavage reactions are described in standard references, such as JFW McOmie, "Protective Groups in Organic Chemistry," Plenum Press, London and New York, 1973, and T.W. Greene and P.G.M. Buts, "Protective Groups in Organic Synthesis," Third Edition, Wiley, New York, 1999.

[0130] All methods described herein can be performed in any suitable order unless otherwise indicated herein or clearly contradicted by context. Any and all examples provided within this specification, or the use of exemplary language (e.g., "etc."), are intended merely to better clarify the invention and do not impose limitations on the scope of the invention as otherwise claimed.

[0131] Methods for synthesizing the compounds of the present invention The agents of the present invention can be prepared by the reaction sequences shown in the reaction schemes in the Examples section (see below).

[0132] Typically, compounds of the present invention can be prepared according to Schemes 1-4 provided below. The compounds of the present invention were produced by the processes described herein and illustrated in the Examples. Combinations of various building blocks and intermediates described herein can be applied to produce compounds of the present invention. Non-limiting examples of synthetic schemes used to prepare compounds of the present invention are shown in Schemes 1-4. Further guidance can be found in the Examples section.

[0133] Compounds of formula (II) can be prepared as outlined in Scheme 1. [ka] The amide of Int-1 (Int-2) bearing the corresponding N-protected β-amino acid can be achieved using a variety of 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 removal of the protecting group, such as Boc or Cbz (T.W. Greene and P.G.M. Buts, "Protective Groups in Organic Synthesis," Third Edition, Wiley, New York 1999), the released amine intermediate can be coupled with various acid building blocks (Int-3) to provide the final compound of formula (II).

[0134] Similarly, compounds of formula (III) can be prepared as outlined in Scheme 2. [ka] Similar to the preparation of compounds of formula (II), compounds of formula (III) can be achieved by amide coupling between amines (Int-1), but in this case, various monoprotected succinates (Int-4) are used as the acid partner. The chiral succinate intermediates (Int-4) can be prepared in enantiopure form by various methods, including asymmetric hydrogenation of α-substituted acrylic acids using chiral catalysts (e.g., PM Donate, D. Frederico, R. da Silva, MG Constantino, G. Del Ponte, PS Bonatto, Tetrahedron: Asymmetry 2003, 14, 3253-3256) or by the Evans method utilizing chiral oxazolidine additives (DA Evans, LD Wu, JJM Wiener, JS Johnson, DHB Ripin, JS Tedrow, J. Org. Chem. 1999, 64, 6411-6417). Alternatively, such chiral acids can be prepared by chiral resolution using chiral amines or enzymes (J.M.Keith, J.F.L.Arrow, E.N. Jacobsen, Adv. Synth. Catal. 2001, 343, 5-26), dynamic kinetic resolution, or chiral separation using preparative chiral chromatography. The formed amide ester intermediate can then be hydrolyzed and the resulting acid intermediate coupled with an aliphatic or aromatic amine to give the final product of formula (III).

[0135] The required chiral amine intermediate Int-1, where Y is CH 2 , can be prepared as outlined in Scheme 3. [ka] The tricyclic core is prepared by cyclization of 2-(2-(halomethyl)phenyl)acetates (prepared from the corresponding isochroman-3-ones: DJ Ritchie, H.S.R. McCann, M.C.H. Standen, R.V.H. Jones, US6048998, 2000; CAN128:75194) with pyrazolidine (E.E. Boros, F. Bouvier, S. Randhawa, M.R. Rabinowitz, J. Heterocycl. Chem. 2001, 38, 613-616). The required primary amine can be introduced into such compounds in several ways. Such molecules can be converted to α-bromo derivatives, which can undergo nucleophilic substitution with azides and then reduced to primary amines (e.g., ZHANG, Xuqing; WALL, Mark; SUI, Zhihua WO2015 / 160772, 2015, A1). Other possibilities for introducing azides include the azidation of the corresponding enolate with 2,4,6-triisopropylbenzenesulfonyl azide (e.g., C.V.C. Prasad et al. Bioorg. Med. Chem. Lett. 2007, 17, 4006-4011) or a one-step sequence utilizing copper-catalyzed azidation (S.-E. Suh, S.-J. Chen, M. Mandal, I.A. Guzei, C.J. Cramer, S.S. Stahl, J. Am. Chem. Soc. 2020, 142, 11388-11393). Alternatively, amines can be introduced via oxime formation and reduction, as shown in Scheme 3 (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 or by the formation of diastereomeric mixtures that can be separated and cleaved (F. Hoffmann-Emery, R. Jakob-Roetne, A. Flohr, F. Bliss, R. Reents, Tet. Lett. 2009, 50, 6380-6382), or by preparative chiral chromatographic methods.

[0136] Intermediate 1 (Int-1) where Y is C(O) can be prepared according to Scheme 4. [ka] Oxotricyclyls can be prepared analogously to the synthesis of tricyclyls described in Scheme 3, when isochroman-1,3-dione is used instead of 2-(2-(halomethyl)phenyl)acetate in the cyclization with pyrazolidine. Alternatively, Int-1 from Scheme 3 can be oxidized with RuO2 (A.G. Schultz, T.J. Guzi, E. Larsson, R. Rahm, K. Thakkar, J.M. Biddlack, J. Org. Chem. 1998, 63, 7795-7804) to directly provide Int-1 where Y is C(O). Chiral separation can also be carried out as described in Scheme 3.

[0137] Administration and Pharmaceutical Compositions For therapeutic use of the compounds of the present invention, such compounds are administered alone or as part of a pharmaceutical composition. Accordingly, in another aspect of the present invention, a pharmaceutical composition is provided comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, and one or more pharmaceutically acceptable carriers. In a further embodiment, the composition comprises at least two pharmaceutically acceptable carriers, such as those described herein. Pharmaceutical compositions 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 can also involve inhalation or intranasal administration. In certain embodiments, pharmaceutical compositions comprising the compounds of the present invention can be formulated for intramuscular, intravenous, subcutaneous, oral, pulmonary, intrathecal, topical, or intranasal administration.

[0138] The pharmaceutical compositions of the present invention may be comprised in a solid form (including, but not limited to, capsules, tablets, pills, granules, powders, or suppositories) or in a liquid form (including, but not limited to, solutions, suspensions, or emulsions). Tablets may be film coated or enteric coated according to methods known in the art.

[0139] Typically, the pharmaceutical composition is a tablet or gelatin capsule containing the active ingredient together with: a) diluents, such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine; b) lubricants, such as silica, talcum, stearic acid, its magnesium or calcium salts and / or polyethylene glycol (also for tablets); c) binders, such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone (if required); d) disintegrating agents, such as starch, agar, alginic acid or its sodium salt, or effervescent mixtures, and / or e) Absorbents, colorants, flavors and sweeteners.

[0140] Suitable compositions for oral administration include the compounds of the present invention in the form of tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use can be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions can contain one or more agents selected from sweeteners, flavorings, coloring agents, and preservatives to provide a pharmaceutically elegant and palatable preparation. Tablets may contain the active ingredient in a mixture with non-toxic pharmaceutically acceptable carriers / excipients suitable for the manufacture of tablets. These carriers / excipients include, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; binders such as starch, gelatin, or acacia; and lubricants such as magnesium stearate, stearic acid, or talc. The tablets may be uncoated, or may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over a longer period. For example, a time-delay material such as glyceryl monostearate or glyceryl distearate may be used. Formulations for oral use may be provided as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate, or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin, or olive oil.

[0141] Parenteral compositions (e.g., intravenous (IV) formulations) are aqueous isotonic solutions or suspensions. Parenteral compositions may be sterilized and / or contain auxiliary substances such as preservatives, stabilizers, wetting or emulsifying agents, solubility enhancers, salts for regulating osmotic pressure and / or buffers. In addition, parenteral compositions may contain other therapeutically valuable substances. The compositions are generally prepared according to conventional mixing, granulating or coating methods, respectively, and contain about 0.1-75%, or about 1-50%, of the active ingredient.

[0142] The compound of the present invention or its pharmaceutical composition for use in a subject (e.g., human) is typically administered orally or parenterally at a therapeutic dose of about 100 mg / kg or less.When administered intravenously via infusion, the dosage can depend on the infusion rate at which the intravenous dosage formulation is administered.Generally, the therapeutically effective dosage of compound, pharmaceutical composition, or their combination depends on the species, body weight, age, and individual condition of the subject, the disorder or disease to be treated, or its severity.

[0143] The above-mentioned dosage properties are demonstrable in vitro and in vivo tests, using advantageously mammals, for example mice, rats, dogs, monkeys, or their isolated organs, tissues, and preparations. The compounds of the invention can be applied in vitro in solution form, for example in aqueous solution, and in vivo enterally, parenterally, advantageously intravenously, for example as a suspension or in aqueous solution.

[0144] Certain specific aspects and examples of pharmaceutical compositions of the present invention are provided in the following list of enumerated embodiments. It will be understood that the features specified in each embodiment may be combined with other specified features to provide further embodiments of the present invention.

[0145] A pharmaceutical composition comprising a compound of formula (I) according to embodiment 50 or any of embodiments 1-49, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, and one or more pharmaceutically acceptable carriers.

[0146] Embodiment 51 A pharmaceutical composition comprising a compound of embodiment 49, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, and one or more pharmaceutically acceptable carriers.

[0147] Embodiment 52. The pharmaceutical composition of embodiment 50 or embodiment 51, comprising one or more additional therapeutic agents.

[0148] Pharmacology and Usefulness The compounds of the present invention, in free form or in the form of pharmaceutically acceptable salts, exhibit beneficial pharmacological properties, e.g., inhibition of cellular levels of Sppl2a, as demonstrated by the in vitro tests provided herein, and therefore find therapeutic application or use as research agents, e.g., as tool compounds.

[0149] Therefore, the compounds of the present invention may generally be useful for treating indications involving, for example, cells expressing high levels of CD74 and / or cells involved in class II-dependent antigen presentation.In addition, the compounds of the present invention may also be useful for treating autoimmune diseases and / or disorders.In particular, the compounds of the present invention may be useful in treating and / or preventing pemphigus vulgaris, pemphigus foliaceus, Sjogren's disease, systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), myasthenia gravis, Hashimoto's thyroiditis, thrombocytopenic purpura, myocarditis, atopic dermatitis, Goodpasture's syndrome, multiple sclerosis (MS) or type 1 diabetes.

[0150] Furthermore, the compounds of the present invention may also be useful in preventing rejection in clinical / surgical transplants of solid organs, tissues, or cell populations, such as stem cells. Furthermore, the compounds of the present invention may also be useful in treating and / or preventing both acute and chronic graft-versus-host disease (GvHD) associated with solid organ, tissue, or cell population transplants. The compounds of the present invention may also be used prophylactically, for example, as induction therapy, to prepare the host before solid organ, tissue, or cell population transplantation, or they may also be used therapeutically after solid organ, tissue, or cell population transplantation. Non-limiting examples of transplants include kidney transplantation, heart transplantation (acute or chronic), and bone marrow transplantation. Furthermore, the compounds of the present invention may also be useful in treating donors prior to organ, tissue, or cell donation.

[0151] In addition, the compounds of the present invention may also be useful in the treatment of lymphomas, such as non-Hodgkin's lymphoma (NHL), Burkitt's lymphoma (BL) and multiple myeloma (MM), specifically those arising from modified B cells that express high levels of CD74.

[0152] Certain specific aspects and examples of the use of the compounds of the invention and pharmaceutical compositions of the invention are provided in the following list of enumerated embodiments. It will be understood that the features specified in each embodiment can be combined with other specified features to provide further embodiments of the invention.

[0153] Embodiment 53. A method of treating a disease or disorder associated with the activity of signal peptide peptidase-like protease 2a (Sppl2a), said method comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of any of embodiments 1-49, or a pharmaceutically acceptable salt thereof.

[0154] Embodiment 54. A method of treating a disease or disorder associated with the activity of signal peptide peptidase-like protease 2a (Sppl2a), said method comprising administering to a subject in need of such treatment a compound of any of Embodiments 1-49 or a pharmaceutically acceptable salt thereof.

[0155] Embodiment 55. Use of a compound of any of Embodiments 1-49, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease or disorder associated with the activity of signal peptide peptidase-like protease 2a (Sppl2a).

[0156] Embodiment 56. Use of a compound of any of embodiments 1-49, or a pharmaceutically acceptable salt thereof, for the treatment of a disease or disorder associated with the activity of signal peptide peptidase-like protease 2a (Sppl2a).

[0157] Embodiment 57. A compound of any of embodiments 1-49 or a pharmaceutically acceptable salt thereof for use in the treatment of a disease or disorder associated with the activity of signal peptide peptidase-like protease 2a (Sppl2a).

[0158] Embodiment 58. A method of treating an autoimmune disease in a subject in need thereof, said method comprising administering to the subject a therapeutically effective amount of a compound of any of embodiments 1-49, or a pharmaceutically acceptable salt thereof.

[0159] Embodiment 59. A method of treating an autoimmune disease in a subject in need thereof, said method comprising administering to said subject a compound of any of embodiments 1-49 or a pharmaceutically acceptable salt thereof.

[0160] Embodiment 60. Use of a compound of any of embodiments 1-49, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of an autoimmune disease.

[0161] Embodiment 61. Use of a compound of any of embodiments 1-49, or a pharmaceutically acceptable salt thereof, in the treatment of an autoimmune disease.

[0162] Embodiment 62. The use of a compound of any of embodiments 1-49, or a pharmaceutically acceptable salt thereof, for use in treating an autoimmune disease.

[0163] Embodiment 63. The method of any of embodiments 53, 54, 58, or 59, the use of any of the compounds of embodiments 55, 56, 60, or 61, or the compound for use of embodiment 57 or 62, wherein the autoimmune disease is Sjogren'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's syndrome, or type 1 diabetes.

[0164] Embodiment 64. The method of any of embodiments 53, 54, 58 or 59, the use of the compound of any of embodiments 55, 56, 60 or 61, or the compound for use of embodiment 57 or 62, wherein the autoimmune disease is multiple sclerosis (MS), Sjogren's disease, systemic rheumatoid arthritis (RA), lupus nephritis or systemic sclerosis.

[0165] Embodiment 65. The method of any of embodiments 53, 54, 58 or 59, the use of the compound of any of embodiments 55, 56, 60 or 61, or the compound for use of embodiment 57 or 62, wherein the autoimmune disease is multiple sclerosis (MS).

[0166] Embodiment 66. A method of treating a disease associated with high levels of CD74 expression in B cells in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of any of embodiments 1-49, or a pharmaceutically acceptable salt thereof.

[0167] Embodiment 67. A method of treating a disease associated with high levels of CD74 expression in B cells in a subject, said method comprising administering to said subject a compound of any of embodiments 1-49 or a pharmaceutically acceptable salt thereof.

[0168] Embodiment 68. Use of a compound of any of embodiments 1-49, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disease associated with high levels of CD74 expression on B cells in a subject.

[0169] Embodiment 69. Use of a compound of any of embodiments 1-49, or a pharmaceutically acceptable salt thereof, in treating a disease associated with high levels of CD74 expression on B cells in a subject.

[0170] Embodiment 70. A compound of any of embodiments 1-49, or a pharmaceutically acceptable salt thereof, for use in treating a disease associated with high levels of CD74 expression on B cells in a subject.

[0171] Embodiment 71 The method of any of embodiments 66 or 67, the use of the compound of any of embodiments 68 or 69, or the compound for use of embodiment 70, wherein the B-cell lymphoma is non-Hodgkin's lymphoma (NHL), Burkitt's lymphoma (BL), and multiple myeloma (MM).

[0172] Embodiment 72. A method of treating B-cell lymphoma in a subject in need thereof, said method comprising administering to the subject a therapeutically effective amount of a compound of any of embodiments 1-49, or a pharmaceutically acceptable salt thereof.

[0173] Embodiment 73. A method of treating B-cell lymphoma in a subject in need thereof, said method comprising administering to the subject a compound of any of Embodiments 1-49 or a pharmaceutically acceptable salt thereof.

[0174] Embodiment 74. Use of a compound of any of embodiments 1-49, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of B-cell lymphoma.

[0175] Embodiment 75. The use of a compound of any of embodiments 1-49, or a pharmaceutically acceptable salt thereof, in the treatment of B-cell lymphoma.

[0176] Embodiment 76. A compound of any of embodiments 1-49, or a pharmaceutically acceptable salt thereof, for use in the treatment of B-cell lymphoma.

[0177] Embodiment 77 The method of any of embodiments 72 or 73, the use of the compound of any of embodiments 74 or 75, or the compound for use of embodiment 76, wherein the cell lymphoma is non-Hodgkin's lymphoma (NHL), Burkitt's lymphoma (BL), and multiple myeloma (MM).

[0178] Embodiment 78. A method of treating graft-versus-host disease (GvHD) in a subject after transplantation, said method comprising administering to said subject a therapeutically effective amount of a compound of any of embodiments 1-49 or a pharmaceutically acceptable salt thereof, wherein said transplant is a transplant of a solid organ, tissue or cell mass.

[0179] Embodiment 79. A method of treating graft-versus-host disease (GvHD) in a subject after transplantation, said method comprising administering to the subject a compound of any of embodiments 1-49 or a pharmaceutically acceptable salt thereof, wherein the transplant is a transplant of a solid organ, tissue, or cell mass.

[0180] Embodiment 80. A method of preventing graft-versus-host disease (GvHD) in a subject after transplantation, said method comprising administering a therapeutically effective amount of a compound of any of embodiments 1-49, or a pharmaceutically acceptable salt thereof, to the subject prior to transplantation, wherein the transplant is a transplant of a solid organ, tissue, or cell mass.

[0181] Embodiment 81 A method of preventing graft-versus-host disease (GvHD) in a subject after transplantation, said method comprising administering to the subject prior to transplantation a compound of any of embodiments 1-49 or a pharmaceutically acceptable salt thereof, wherein the transplant is a transplant of a solid organ, tissue, or cell mass.

[0182] Embodiment 82. Use of a compound of any of embodiments 1-49 for treating graft-versus-host disease (GvHD) in a subject following a transplant, wherein the transplant is a solid organ, tissue, or cell mass transplant.

[0183] Embodiment 83. Use of a compound of any of embodiments 1-49 in the manufacture of a medicament for treating graft-versus-host disease (GvHD) in a subject following a transplant, wherein the transplant is a solid organ, tissue, or cell mass transplant.

[0184] Embodiment 84. The compound of any of embodiments 1-49 for use in treating graft-versus-host disease (GvHD) in a subject following a transplant, wherein the transplant is a solid organ, tissue, or cell mass transplant.

[0185] Embodiment 85 The method of any of embodiments 78 to 81, the use of a compound of any of embodiments 82 or 83, or the compound for use of embodiment 84, wherein the transplant is a solid organ transplant.

[0186] Embodiment 86. The method of any of embodiments 78 to 81, the use of a compound of any of embodiments 82 or 83, or the compound for use of embodiment 84, wherein the transplant is a bone marrow transplant.

[0187] Embodiment 87. The method of any of embodiments 78 to 81, the use of the compound of any of embodiments 82 or 83, or the compound for use of embodiment 84, wherein the transplant is a stem cell transplant.

[0188] Embodiment 88. The method of any of embodiments 78 to 81, the use of the compound of any of embodiments 82 or 83, or the compound for use of embodiment 84, wherein the transplant is a hematopoietic stem cell transplant.

[0189] Embodiment 89. The method of any of embodiments 78 to 81, the use of a compound of any of embodiments 82 or 83, or the compound for use of embodiment 84, wherein the transplant is a tissue transplant.

[0190] Embodiment 90. The method of any of embodiments 78-81 or 85-89, the use of the compound of any of embodiments 82, 83 or 85-89, or the compound for use of embodiments 84-89, wherein the graft-versus-host disease (GvHD) is acute graft-versus-host disease.

[0191] Embodiment 91. The method of any of embodiments 78-81 or 85-89, the use of the compound of any of embodiments 82, 83 or 85-89, or the compound for use of embodiments 84-89, wherein the graft-versus-host disease (GvHD) is chronic graft-versus-host disease.

[0192] Combination therapy In certain cases, it may be advantageous to administer a compound of the invention in combination with one or more additional therapeutic agents, such as compounds, peptides, antibodies, antibody fragments, or nucleic acids, that have a therapeutic effect or enhance therapeutic activity when administered to a patient in combination with a compound of the invention.

[0193] The compounds of the present invention may be administered as the sole active ingredient useful in the treatment of neoplastic and inflammatory diseases or in combination with other drugs useful in the treatment of neoplastic and inflammatory diseases, in immunomodulatory therapy, or in induction therapy to prevent GvHD and graft rejection. For example, the compounds of the invention may be used in combination with, for example, cyclosporine, rapamycin or ascomycin, or immunosuppressive analogues or derivatives thereof, such as cyclosporine A, cyclosporine G, Isa tx247, FK-506, sirolimus or everolimus, in combination with corticosteroids such as prednisone, in combination with cyclophosphamide, in combination with azathioprene, in combination with methotrexate, in combination with gold salts, in combination with sulfasalazine or antimalarials, in combination with leflunomide, in combination with mizoribine, in combination with mycophenolic acid, in combination with mycophenolate mofetil, in combination with 15-deoxyspergualin, in combination with an S1P receptor agonist, such as FTY720 or an analogue thereof, in combination with an immunosuppressive monoclonal antibody, for example a monoclonal antibody against a leukocyte receptor, such as MHC, or in combination with other immunomodulatory compounds, such as CTLA4Ig.

[0194] The compounds of Formula I may be used in combination with other antiproliferative agents, including, but not limited to, aromatase inhibitors, antiestrogens, topoisomerase I inhibitors, topoisomerase II inhibitors, microtubule-active agents, alkylating agents, histone deacetylase inhibitors, farnesyltransferase inhibitors, COX-2 inhibitors, MMP inhibitors, mTOR inhibitors, antineoplastic antimetabolites, platinum compounds, compounds that decrease protein kinase activity, as well as antiangiogenic compounds, gonadorelin agonists, antiandrogens, bengamides, bisphosphonates, antiproliferative antibodies, and temozolomide (TEMODAL). [Example]

[0195] The compounds of the present invention can be prepared as shown in the following examples. The following examples are intended to illustrate the present invention and should not be construed as limiting thereof. Temperatures are given in degrees Celsius. Unless otherwise specified, all evaporations are carried out under reduced pressure, typically at about 15 mmHg to 100 mmHg (= 20 to 133 mbar). The structures of final products, intermediates, and starting materials are confirmed by standard analytical methods, such as microanalysis and spectroscopic characteristics, e.g., MS, IR, NMR. Abbreviations used are those conventional in the art.

[0196] All starting materials, building blocks, reagents, acids, bases, dehydrating agents, solvents, and catalysts utilized to synthesize the compounds of the present invention are either commercially available, can be prepared by organic synthesis methods known to those skilled in the art, or can be produced by organic synthesis methods described herein.

[0197] For illustrative purposes, the general reaction schemes set forth herein provide potential routes for synthesizing the compounds of the present invention as well as key intermediates. For more detailed descriptions of the individual reaction steps, see the Examples section below. While specific starting materials and reagents are shown 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. In addition, many of the compounds prepared by the methods described below can be further modified in light of this disclosure using conventional chemistry well known to those skilled in the art.

[0198] Abbreviation: ACN Acetonitrile abs anhydrous AcOH acetic acid aq. water-based br.s broad singlet Boc2O Di-tert-butyl dicarbonate BuLi n-butyllithium CaCO3 Calcium Carbonate Cs2CO3 Cesium Carbonate CO Carbon monoxide COMU (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)-dimethylamino-morpholinocarbenium hexafluorophosphate CuBr Copper(I) bromide CuCl Copper(I) chloride d doublet DAST Diethylaminosulfur trifluoride DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DCM dichloromethane de diastereomeric excess DIPEA N,N-Diisopropylethylamine DMA Dimethylacetamide DMAP 4-dimethylaminopyridine DME Dimethoxyethane DMF Dimethylformamide DMSO dimethyl sulfoxide DPPA Diphenylphosphoryl azide EDC 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide ee enantiomeric excess Et3N Triethylamine Et2O diethyl ether EtOAc ethyl acetate EtOH ethanol Flow flow rate h time Hex Hexane, isomer mixture HATU O-(7-aza-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate HBTU 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate HCl Hydrochloric acid HPLC High-Performance Liquid Chromatography HV high vacuum IPA Isopropyl Alcohol i-PrOH isopropanol KHMDS Potassium hexamethyldisilazane KHSO4 Potassium hydrogen sulfate L liters LCMS Liquid Chromatography / Mass Spectrometry LDA Lithium diisopropylamine LiAlH4 Lithium Aluminum Hydride LiHMDS Lithium hexamethyldisilazane LiOH Lithium hydroxide M Molar concentration (mol / L) Me methyl MeI methyl iodide MeOH Methanol MnO2 Manganese dioxide MsCl Mesyl chloride min mL milliliter mm millimeters MHz Megahertz MS mass spectrometry MTBE Methyl tert-butyl ether μm micrometer NaBH4 Sodium borohydride NaBH3CN Sodium cyanoborohydride NaCl Sodium chloride NaH sodium hydride NaHCO3 Sodium Bicarbonate NaHMDS Sodium hexamethyldisilazane NaI Sodium iodide NaOAc Sodium Acetate NaOH Sodium hydroxide Na2SO3 Sodium sulfite Na2SO4 Sodium Sulfate NBS N-Bromosuccinimide NH3 ammonia NH4Cl Ammonium chloride Ni Nickel NMM 4-methylmorpholine NMR nuclear magnetic resonance o / n overnight Pd / C Palladium Carbon Pd(dppf)Cl2.CH2Cl2 1,1'-Bis(diphenylphosphino)ferrocene dichloropalladium(II) dichloromethane complex PhMe Toluene Prep PyBOP (benzotriazol-1-yloxy)-tripyrrolidinophosphonium hexafluorophosphate q quartet rt room temperature t R retention time s singlet sat. saturation scCO2 supercritical carbon dioxide SEM-Cl 2-(trimethylsilyl)ethoxymethyl chloride SFC Supercritical Fluid Chromatography t triplet T3P 1-Propanephosphonic anhydride TEA Triethylamine TFA trifluoroacetic acid THF tetrahydrofuran TLC thin layer chromatography TMSCl Trimethylsilyl chloride TMSCN Trimethylsilanecarbonitrile TOTU O-[(ethoxycarbonyl)cyanomethyleneamino]-N,N,N',N'-tetramethyluronium tetrafluoroborate TsOH paratoluenesulfonic acid UPLC Ultra High Performance Liquid Chromatography

[0199] trademark Celite = Celite® (The Celite Corporation) = diatomaceous earth-based filter aid PL thiol cartridge = Stratosphere® SPE, PL-Thiol MP SPE+, 500 mg per 6 mL tube, 1.5 mmol (nominal) NH2Isolute (=Isolute® NH2, Isolute® is a registered trademark of Argonaut Technologies, Inc.) = Silica gel-based ion exchanger with amino groups Nucleosil = Nucleosil®, a trademark of Machery & Nagel, Duren, FRG as an HPLC material PTFE membrane = Chromafil O-45 / 15MS polytetrafluoroethylene, Machery & Nagel)

[0200] Temperatures are measured in degrees Celsius. Unless otherwise stated, reactions are carried out at room temperature.

[0201] Phase separator: Biotage-Isolute Phase Separator (70 mL part number: 120-1908-F and 150 mL part number: 120-1909-J)

[0202] TLC conditions: TLC R f Values ​​are based on a 5 x 10 cm TLC plate, silica gel F 254 , Merck, Darmstadt, Germany.

[0203] Analysis method HPLC conditions: Method a: HPLC equipment: 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 in 3 min, flow rate: 1.4 mL / min Method b: HPLC equipment: Agilent 1100 series, column: Waters, X-Bridge C18, 2.5 μm, 3 × 50 mm, eluent A: water + 0.1% TFA, B: ACN + 0.1% TFA, gradient: 10 to 98% B in 8.6 min, flow rate: 1.4 mL / min Method c: HPLC equipment: 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 in 3 min, flow rate: 1.4 mL / min Method d: HPLC instrument: Agilent 1200 series; column: 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 in 8.6 min; flow rate: 1 mL / min

[0204] UPLC conditions: LCMS Method a: UPLC / MS Instrument: Waters, UPLC Acquity; Column: Acquity HSS T3, 1.8 μm, 2.1 × 50 mm, 50 °C; Eluent A: Water + 0.05% HCOOH + 3.75 mM ammonium acetate; B: ACN + 0.04% HCOOH; Gradient: 2 to 98% B in 1.4 min; Flow Rate: 1.2 mL / min (2 min) LCMS Method b: UPLC / MS Instrument: Waters, UPLC Acquity; Column: Acquity HSS T3, 1.8 μm, 2.1 × 50 mm, 60 °C; Eluent A: Water + 0.05% HCOOH + 3.75 mM ammonium acetate; B: ACN + 0.04% HCOOH; Gradient: 5 to 98% B in 1.4 min; Flow Rate: 1 mL / min (2 min). LCMS Method c: UPLC / MS Instrument: Ascentis Expresse, 2.7 μm, 2.1 × 30 mm, 60 °C, Eluent A: Water + 0.05% HCOOH + 3.75 mM ammonium acetate, B: ACN + 0.04% HCOOH, Gradient: 2 to 98% B in 1.4 min, Flow rate: 1 mL / min (2 min) 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 in 2.5 min, Flow rate: 1.4 mL / min LCMS Method: Waters, UPLC Acquity; Column: Acquity HSS T3, 1.8 μm, 2.1 × 50 mm, 60 °C; Eluent A: Water + 0.05% HCOOH + 3.75 mM ammonium acetate; B: MeCN + 0.04% HCOOH; Gradient: 10 to 95% B in 1.5 min; Flow rate: 1.0 mL / min LCMS Method f: Waters, UPLC Acquity; Column: Acquity HSS T3, 1.8 μm, 2.1 × 50 mm, 60 °C; Eluent A: Water + 0.05% HCOOH + 3.75 mM ammonium acetate; B: MeCN + 0.04% HCOOH; Gradient: 5 to 98% B in 9.4 min, hold 0.4 min; Flow rate: 0.8 mL / min LCMS Method g: Agilent LCMS; Column: Waters, Acquity HSS T3, 1.8 μm, 2.1 × 50 mm, 60 °C, Eluent A: H2O + 0.05% TFA, B: MeCN + 0.035% TFA, Gradient: 10 to 100% B in 1.35 min, Flow rate: 0.9 mL / min, Gradient: 10 to 100% B in 1.35 min, Flow rate: 0.9 mL / min.

[0205] Synthesis of intermediates Type A intermediate Synthesis of (S)-10-amino-2,3,5,10-tetrahydro-1H,11H-benzo[d]pyrazolo[1,2-a][1,2]diazepin-11-one (int-A1) [ka] Step 1: Thionyl chloride (14.8 mL, 202 mmol) was added dropwise to a suspension of isochroman-3-one (15 g, 101 mmol) in methanol (150 mL) at 0 °C. The resulting solution was stirred at 0 °C for 2 h and then at room temperature for 16 h. The reaction mixture was concentrated, and the crude product was dissolved in ethyl acetate and washed with saturated aqueous NaHCO3. The organic layer was dried (Na2SO4) and concentrated to give methyl 2-(2-chloromethyl)phenyl)acetate. 1 H NMR (DMSO-d6,400 MHz): 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).

[0206] 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 h. The reaction mixture was concentrated, and the crude product 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 in toluene) to give 2,3,5,10-tetrahydrobenzo[d]pyrazolo[1,2-a][1,2]diazepin-11(1H)-one. LCMS (Method d) m / z 203.1 [M+H] + ,t R = 1.35 minutes. 1 H 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(quin, J = 7.0 Hz, 2H).

[0207] Step 3: A 1 M solution of LiHMDS in THF (93 mL, 93 mmol) was added dropwise to a solution of 2,3,5,10-tetrahydrobenzo[d]pyrazolo[1,2-a][1,2]diazepin-11(1H)-one (14.0 g, 62 mmol) and isopentyl nitrite (10.8 mL, 81 mmol) in THF (750 mL) at 0 °C, and the solution was stirred for 2 h at 0 °C. The reaction mixture was concentrated, dissolved in ethyl acetate, washed with saturated NaHCO solution, dried (NaSO), concentrated, and purified by column chromatography (10–90% ethyl acetate in toluene with 0.1% EtN) to give (Z) and (E)-10-(hydroxyimino)-2,3,5,10-tetrahydrobenzo[d]pyrazolo[1,2-a][1,2]diazepin-11(1H)-one. LCMS (Method d) m / z 232.0 [M+H] + ,t R = 0.90 min and 1.06 min.

[0208] Step 4: Zinc dust (10.9 g, 166 mmol) was added to a solution of (Z)- and (E)-10-(hydroxyimino)-2,3,5,10-tetrahydrobenzo[d]pyrazolo[1,2-a][1,2]diazepin-11(1H)-one (9.6 g, 42 mmol) in AcOH (300 mL) and 10% aqueous HCl (300 mL) at room temperature, and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give 10-amino-2,3,5,10-tetrahydrobenzo[d]pyrazolo[1,2-a][1,2]diazepin-11(1H)one, which was used in the next step without further purification.

[0209] Step 5: BocO (9.0 g, 41 mmol) and NaCO (13.0 g, 124 mmol) were added to a solution of 10-amino-2,3,5,10-tetrahydrobenzo[d]pyrazolo[1,2-a][1,2]diazepin-11(1H)-one (29.2 g, 41 mmol) in dioxane (400 mL) and water (200 mL) at room temperature, and the resulting mixture was stirred at room temperature for 16 hours. The mixture was concentrated and treated with ethyl acetate and saturated NaHCO solution. The organic layer was dried (MgSO) and concentrated to give the crude product, which was purified by column chromatography (0-80% ethyl acetate in cyclohexane) to give racemic tert-butyl 11-oxo-1,2,3,5,10,11-hexahydrobenzo[d]pyrazolo[1,2-a][1,2]diazepin-10-ylcarbamate.

[0210] Step 6 (chiral separation): Separate the two enantiomers of tert-butyl 11-oxo-1,2,3,5,10,11-hexahydrobenzo[d]pyrazolo[1,2-a][1,2]diazepin-10-ylcarbamate by HPLC for chiral separation (Thar SFC-200 instrument, mobile phase: scCO / EtOH 85:15, column: Chiralcel Separation by OD-H (30 × 250 mm) gave tert-butyl (S)-(11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazepin-10-yl)carbamate (enantiomeric excess ≥ 99.5%) and tert-butyl (R)-(11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazepin-10-yl)carbamate (enantiomeric excess ≥ 99.5%). Analytical data for tert-butyl (S)-(11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazepin-10-yl)carbamate: LCMS (Method b) m / z 318.3 [M+H] + , t R = 1.03 minutes. 1H NMR(400 MHz,DMSO-d6) δ ppm 7.31 (d, J = 7.3 Hz, 1 H), 7.15-7.27 (m, 2 H), 7.05 (d, J = 6.7 Hz, 1 H), 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).

[0211] Step 7: tert-Butyl (S)-(11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazepin-10-yl)carbamate (17.7 g, 56 mmol) was treated with 4 M HCl in dioxane (250 mL), and the mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated to give (S)-10-amino-2,3,5,10-tetrahydro-1H,11H-benzo[d]pyrazolo[1,2-a][1,2]diazepin-11-one (int-A1) as the hydrochloride salt. 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). 1 H NMR(400MHz, 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).

[0212] Synthesis of (S)-10-amino-6-fluoro-2,3,5,10-tetrahydro-1H,11H-benzo[d]pyrazolo[1,2-a][1,2]diazepin-11-one (int-A2) [ka] Step 1: Ethyl acetoacetate (17.7 mL, 140 mmol) was added, followed by 2-bromo-6-fluorobenzoic acid (15.3 g, 70 mmol) and CuBr (10.0 g, 70 mmol), to a solution of NaOEt in EtOH (prepared by dissolving metallic Na (4.83 g, 210 mmol) in anhydrous EtOH (400 mL)) at room temperature. The reaction mixture was stirred at reflux for 2 h, cooled to room temperature, and filtered through a pad of Celite®. The solvent was removed in vacuo, and the residue was partitioned between 2 N HCl and CHCl. ​​The organic layer was then treated with saturated NaHCO until a basic pH was reached. The aqueous layer was washed with CHCl, acidified to pH 1 with 2 N HCl, and extracted with CHCl. 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 minutes. 1 H NMR(400MHz, DMSO-d6) δ ppm 13.40 (br s, 1 H), 7.42-.52 (m, 1 H), 7.17-7.26 (m, 2 H), 4.06 (q, J = 7.1 Hz, 2H), 3.84 (s, 2H), 1.17 (t, J = 7.1Hz, 3H).

[0213] 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 EtN (6.4 mL, 46 mmol) in CHCl (84 mL) at 0 °C. After stirring at room temperature for 2 h, the mixture was quenched by adding 1 N HCl, and the mixture was extracted with CHCl. ​​The organic layer was washed with brine, dried (NaSO), and concentrated. The crude intermediate was dissolved in THF (100 mL), and cooled (0 °C) NaBH (3.2 g, 84 mmol) in H0 (34 mL) was added at −15 °C. After stirring at −15 °C for 1 h, the mixture was quenched by adding 1 N HCl and extracted with Et0. The organic layer was washed with saturated NaHCO3, water, and brine, dried (Na2SO4), and concentrated. The crude intermediate was heated with TsOH·H2O (399 mg, 2.1 mmol) in PhMe (100 mL) at 80 °C for 1 h. 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-fluoroisochroman-3-one. LCMS (Method b) m / z 167.1 [M+H] + ,t R = 0.71 minutes. 1 H NMR (400MHz, DMSO-d6) δ ppm 7.33-7.46 (m, 1H), 7.10-7.23 (m, 2H), 5.43 (s, 2H), 3.87 (s, 2H).

[0214] 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 h and then at room temperature for 16 h. 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 minutes. 1 H NMR ((400MHz, 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).

[0215] Step 4: 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 at 200 °C for 10 min in a microwave oven. After cooling to room temperature, the reaction mixture was treated with ethyl acetate and extracted with saturated NaHCO. The organic layer was washed with brine, dried (NaSO), concentrated, and purified by column chromatography (25-50% ethyl acetate in cyclohexane) to give 6-fluoro-2,3,5,10-tetrahydrobenzo[d]pyrazolo[1,2-a][1,2]diazepin-11(1H)-one. LCMS (method b) m / z 221.2 [M+H] + , t R = 0.78 minutes. 1 H NMR(400MHz, 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).

[0216] Step 5: 1 M LiHMDS in THF (3.4 mL, 3.4 mmol) was added dropwise to a mixture of 6-fluoro-2,3,5,10-tetrahydrobenzo[d]pyrazolo[1,2-a][1,2]diazepin-11(1H)-one (300 mg, 1.4 mmol) and isopentylnitrile (330 μL, 2.5 mmol) in THF (10 mL) at 0 °C. The reaction was stirred at 0 °C for 2 h, then treated with saturated NaHCO solution and extracted with ethyl acetate. The organic layer was dried (NaSO) and evaporated to give (E / Z)-6-fluoro-10-(hydroxyimino)-2,3,5,10-tetrahydrobenzo[d]pyrazolo[1,2-a][1,2]diazepin-11(1H)-one, which was used in the next step without further purification. LCMS (method b) m / z 250.2 [M+H] + ,t R = 0.66 minutes.

[0217] Step 6: A mixture of (E / Z)-6-fluoro-10-(hydroxyimino)-2,3,5,10-tetrahydrobenzo[d]pyrazolo[1,2-a][1,2]diazepin-11(1H)-one (141 g, 566 mmol) was hydrogenated (4 bar) over 10% Pd / C (16 g) in a mixture of ethanol (3.3 L) and 1 M HCl (0.9 L) for 16 hours at room temperature. 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]diazepin-11-one as the HCl salt, which was used in the next step without further purification. LCMS (Method b) m / z 236.2 [M+H] + , t R = 0.43 minutes. 1H NMR(400MHz, 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).

[0218] Step 7: A solution of BocO (151 g, 680 mmol) in CHCl (300 mL) was added to a solution of 10-amino-6-fluoro-2,3,5,10-tetrahydro-1H,11H-benzo[d]pyrazolo[1,2-a][1,2]diazepin-11-one (HCl salt, 154 g, 567 mmol) and DIPEA (352 mL, 1984 mmol) in CHCl (3.4 L) at room temperature. The mixture was stirred at room temperature for 16 hours. It was then treated with water, the aqueous phase was extracted with CHCl, and the combined organic phases were dried (NaSO) and concentrated. The crude product was purified by column chromatography (25% EtOH in heptane) to give racemic tert-butyl (6-fluoro-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazepin-10-yl)carbamate.

[0219] Step 8 (chiral separation): The two enantiomers of tert-butyl (6-fluoro-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazepin-10-yl)carbamate were separated by chiral separation HPLC (Bayer, CC50 SMB instrument, mobile phase: acetonitrile / methanol 1:1, column: Chiralpak Separation on an AD column (8 × 10 × 100 mm) gave tert-butyl (S)-(6-fluoro-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazepin-10-yl)carbamate (enantiomeric excess >99.5%) and tert-butyl (R)-(6-fluoro-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazepin-10-yl)carbamate (enantiomeric excess >99.5%). Analytical data for tert-butyl (S)-(6-fluoro-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazepin-10-yl)carbamate: LCMS (Method b) m / z 336.2 [M+H] + , t R = 1.04 min. [α] 23 D -57.2 (c= 1.0, MeOH). 1 H NMR(400MHz, 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).

[0220] Step 9: A mixture of tert-butyl (S)-(6-fluoro-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazepin-10-yl)carbamate (1.3 g, 4.0 mmol) in CHCl (20 mL) was treated with 4 M HCl in dioxane (20 mL, 80 mmol) at 0 °C, and the reaction mixture was stirred at 0 °C for 2 h. EtO was added, and 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]diazepin-11-one (int-A2) as the HCl salt. 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(400MHz, 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).

[0221] Type B Intermediate [ka] Synthesis of (S)-10-amino-2,3-dihydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazepine-5,11(10H)-dione (int-B1) [ka] Step 1: Sodium periodate (36.8 g, 172 mmol) in water (380 mL) was added over 15 min to a mixture of tert-butyl (S)-(11-oxo-2,3,10,11-tetrahydro)-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazepin-10-yl)carbamate (13.6 g, 43 mmol) and ruthenium(IV) oxide hydrate (650 mg, 4.3 mmol) in ethyl acetate (430 mL) at room temperature. After the addition, the resulting mixture was stirred at room temperature for 15 min and then treated with water and CHCl. ​​The aqueous phase was extracted with CHCl, and the combined organic layers were then treated with activated carbon and filtered through a Celite pad. The filtrate was washed with water and brine, dried (NaSO), and concentrated to give tert-butyl (S)-(5,11-dioxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazepin-10-yl)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(400MHz, 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).

[0222] Step 2: 4 M HCl in dioxane (151 mL, 604 mmol) was added to a solution of tert-butyl (S)-(5,11-dioxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazepin-10-yl)carbamate (10 g, 30 mmol) in CHCl (151 mL), and the mixture was stirred at room temperature for 2 h. The reaction mixture was then concentrated, suspended in EtO, and subsequently evaporated to remove residual HCl. Finally, the crude product was triturated with EtO, filtered, and the resulting solid was dried in vacuo to give (S)-10-amino-2,3-dihydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazepine-5,11(10H)-dione (int-B1) as the HCl salt. 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 ppm 9.24 (s, 3H), 7.87 (dd, J= 7.7, 1.2 Hz, 1 H), 7.75 (t, J= 7.7 Hz, 1 H), 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).

[0223] Type C intermediate Synthesis of (S)-10-amino-1H,3H,5H-spiro[benzo[d]pyrazolo[1,2-a][1,2]diazepine-2,1'-cyclopropane]-5,11(10H)-dione (int-C1) [ka] Step 1: A solution of MsCl (57.2 mL, 734 mmol) in CHCl (160 mL) was added dropwise to a solution of cyclopropane-1,1-diyldimethanol (25.0 g, 245 mmol) and EtN (136 mL, 979 mmol) in CHCl (250 mL) at 0 °C. The reaction mixture was stirred at room temperature for 16 h. 1 M HCl (900 mL) was then added, and the mixture was extracted with CHCl. ​​The combined organic layers were washed with brine, dried (NaSO), and concentrated to a volume of 100–150 mL. Hexane was added, and the resulting precipitate was filtered, washed with hexane, and dried under vacuum to give cyclopropane-1,1-diylbis(methylene)dimethanesulfonate. 1 H NMR (400MHz, DMSO-d6) δ ppm 4.14 (s, 4H), 3.19 (s, 6H), 0.77 (s, 4H).

[0224] Step 2: A solution of di-tert-butylhydrazine-1,2-dicarboxylate (18.6 g, 80 mmol) in anhydrous DMF (65 mL) was added dropwise to a suspension of NaH (60% oil dispersion, 6.7 g, 168 mmol) in anhydrous DFM (40 mL) at 0 °C, and the suspension was stirred at room temperature for 1 h. After the addition of cyclopropane-1,1-diylbis(methylene)dimethanesulfonate (20.7 g, 80 mmol), the reaction mixture was stirred at room temperature for 16 h. It was then poured into ice-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 minutes. 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).

[0225] Step 3: A solution of hydrobromic acid (33 wt% in AcOH, 38.5 mL, 0.22 mol) was slowly added to a solution of di-tert-butyl 5,6-diazaspiro[2.4]heptane-5,6-dicarboxylate (12 g, 40 mmol) in EtO (200 mL) at 0 °C, and the mixture was stirred at room temperature for 16 h. After cooling to 0 °C, the solid was filtered off, washed with EtO, and dried in vacuo to give 5,6-diazaspiro[2,4]heptane dihydrobromide. LCMS (Method g) m / z 99.2 [M+H] + , t R = 0.26 minutes. 1 HNMR (400MHz, DMSO-d6) δ ppm 7.80 (brs, 4H), 3.06 (s, 4H), 0.76 (s, 4H).

[0226] Step 4: 5,6-Diazaspiro[2,4]heptane dihydrobromide (5.2 g, 20 mmol) was added to a solution of homophthalic 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 h. After cooling to room temperature, the mixture was diluted with water and extracted with CHCl. ​​The combined organic layers were washed with 10% HCl, 5% NaHCO, water, and brine, dried (NaSO), and concentrated. The crude product was purified by column chromatography (20-50% ethyl acetate in hexanes) to give 1H-spiro[benzo[d]pyrazolo[1,2-a][1,2]diazepine-2,1'-cyclopropane]-5,11(3H,10H)-dione. LCMS (Method g) m / z 243.2 [M+H] + , t R = 1.11 minutes. 1H NMR(400MHz, 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).

[0227] Step 5: 1M LiHMDS in THF (26 mL, 26 mmol) was added dropwise to a suspension of 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 isopentyl nitrite (3.4 mL, 26 mmol) in THF (34 mL) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. AcOH was added, and the mixture was evaporated twice in vacuo to give a mixture of (Z)- and (E)-10-(hydroxyimino)-1H-spiro[benzo[d]pyrazolo[1,2-a][1,2]diazepine-2,1'-cyclopropane]-5,11(3H,10H)-dione, which was used in the next step without further purification. LCMS (Method g) m / z 272.2 [M+H] + ,t R = 1.10 min and 1.13 min.

[0228] Step 6: 4 M HCl (4.3 mL, 17 mmol) was added to a mixture of crude (Z,E)-10-(hydroxyimino)-1H-spiro[benzo[d]pyrazolo[1,2-a][1,2]diazepine-2,1'-cyclopropane]-5,11(3H,10H)-dione (4.6 g, 17.0 mmol) in AcOH (92 mL) at room temperature. The mixture was then cooled to 0 °C, and Zn powder (4.5 g, 68 mmol) was slowly added. After the addition, the reaction mixture was stirred at room temperature for 1.5 h. The inorganic zinc residue was filtered off and washed with CHCl. ​​The filtrate was concentrated, redissolved in CHCl, washed with 10% NaOH, brine, dried (NaSO), and concentrated. The residue was purified by column chromatography (0-4% MeOH in CH2Cl2(NH3)) to give racemic (rac.) 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 minutes. 1 H NMR(400MHz, 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).

[0229] Step 7: BocO (76 g, 347 mmol) was added to a 1:1 mixture of racemic 10-amino-1H,3H,5H-spiro[benzo[d]pyrazolo[1,2-a][1,2]diazepine-2,1'-cyclopropane]-5,11(10H)-dione (68 g, 231 mmol) and NaCO (110 g, 1.04 mol) in dioxane / water (1.4 L) at room temperature, and the resulting mixture was stirred at room temperature for 2 h. The formed precipitate was filtered off, washed twice with water, and dried under vacuum. The solid was dissolved in dioxane containing 3% formic acid, and the enantiomers were separated by chiral preparative HPLC (Thar SFC-200 instrument, mobile phase: scCO2 / EtOH 70:30, column: Chiralpak IC, 5 μM, 250 × 30 mm) to give the (S)-enantiomer (enantiomeric excess >99.5%) and (R)-enantiomer (enantiomeric excess >99.5%). Analytical data for tert-butyl (S)-(5,11-dioxo-10,11-dihydro-1H,3H,5H-spiro[benzo[d]pyrazolo[1,2-a][1,2]diazepine-2,1'-cyclopropan]-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). 1 H NMR(400MHz, 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).

[0230] Step 8: tert-Butyl (S)-(5,11-dioxo-10,11-dihydro-1H,3H,5H-spiro[benzo[d]pyrazolo[1,2-a][1,2]diazepine-2,1′-cyclopropan]-10-yl)carbamate (2.0 g, 5.6 mmol) was dissolved in CHCl (28 mL) and treated with 4 M HCl in dioxane (28 mL, 112 mmol) at 0° C. After stirring at 0° C. for 1 h, the reaction mixture was concentrated. The residue was treated with CHCl and evaporated. It was then triturated with EtO and the precipitate formed was filtered off and dried under vacuum to give (S)-10-amino-1H,3H,5H-spiro[benzo[d]pyrazolo[1,2-a][1,2]diazepine-2,1'-cyclopropane]-5,11(10H)-dione (int-C1) as the HCl salt. 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(400MHz, DMSO-d6) δ ppm 9.33 (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 = 11.1 Hz, 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).

[0231] Type D intermediate [ka] Synthesis of 10-amino-5,10-dihydro-1H-spiro[benzo[d]pyrazolo[1,2-a][1,2]diazepine-2,1'-cyclopropan]-11(3H)-one (int-C1) [ka] Step 1: To a solution of cyclopropane-1,1-diyldimethanol (25.0 g, 245 mmol) in CHCl (250 mL), EtN (136 mL, 979 mmol) was added and the reaction mixture was cooled to 0 °C. A solution of MsCl (57.2 mL, 734 mmol) in CHCl (160 mL) was added dropwise, and the cooling bath was removed. After stirring at room temperature for 16 h, 1 N HCl (900 mL) was added, the mixture was extracted with CHCl, and the combined organic layers were washed with brine and dried (NaSO). The solution was then concentrated to a volume of 100–150 mL, and hexane was added. The brownish crystals were filtered off, washed with CHCl-hexane, hexane, and dried under high vacuum to give cyclopropane-1,1-diylbis(methylene)dimethanesulfonate. 1 H NMR (400MHz, DMSO-d6) δ ppm 4.14 (s, 4H), 3.19 (s, 6H), 0.77 (s, 4H).

[0232] Step 2: A solution of di-tert-butylhydrazine-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 DFM (40 mL) at 0 °C. After stirring the suspension at room temperature for 1 h, solid cyclopropane-1,1-diylbis(methylene)dimethanesulfonate (20.7 g, 80 mmol) was added, and the resulting mixture was stirred at room temperature for 16 h. The reaction mixture was poured into ice-water (1.3 L), and 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 / z 619 [2M+Na] + , 1 H NMR (400MHz, DMSO-d6) δ ppm 3.56 (d, 2H), 3.17 (d, 2H), 1.41 (s, 18H), 0.66 (m, 4H).

[0233] Step 3: A solution of hydrobromic acid (33 wt% in AcOH, 38.5 mL) was slowly added to a solution of di-tert-butyl 5,6-diazaspiro[2.4]heptane-5,6-dicarboxylate (11.9 g, 40 mmol) in EtO (200 mL) at 0 °C, and the mixture was stirred at room temperature for 16 h. The reaction mixture was then cooled to 0 °C and filtered. The solid was washed with EtO and dried under high vacuum to give 5,6-diazaspiro[2,4]heptanedihydrobutomide. 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).

[0234] 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 h. After cooling to room temperature, the reaction mixture was concentrated, treated with water, and extracted with CHCl. ​​The combined organic phases were dried (NaSO) and concentrated. The residue was purified by column chromatography (0-70% ethyl acetate in hexanes) to give 5,10-dihydro-1H-spiro[benzo[d]pyrazolo[1,2-a][1,2]diazepin-2,1'-cyclopropan]-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).

[0235] Step 5: Isoamyl nitrite (0.646 mL, 4.80 mmol) was added to a solution of 5,10-dihydro-1H-spiro[benzo[d]pyrazolo[1,2-a][1,2]diazepin-2,1'-cyclopropan]-11(3H)-one (913 mg, 4 mmol) in THF (10 mL) at 0 °C, followed by the addition of LiHMDS (1 M in THF, 5.60 mL, 5.60 mmol). The reaction mixture was stirred at 0 °C for 2 h, after which the reaction was quenched with water and the mixture was concentrated. The crude product was triturated with EtO, and the solid was filtered off and washed with EtO. It was then dissolved in ethyl acetate and washed with saturated NaHCO solution. The aqueous phase was extracted with ethyl acetate, and the combined organic layers were dried (Na2SO4) and concentrated to give the crude title compound as a (Z,E) isomeric mixture, (Z,E)-10-(hydroxyimino)-5,10-dihydro-1H-spiro[benzo[d]pyrazolo[1,2-a][1,2]diazepine-2,1'-cyclopropan]-11(3H)-one, m / z 258 [M+H] + , t R = 1.14 min (LCMS condition a), 1 H NMR (400MHz, 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).

[0236] Step 6: Zinc powder (1.0 g, 15.9 mmol) was slowly added to a mixture of 4 N HCl (1 mL) and (Z,E)-10-(hydroxyimino)-5,10-dihydro-1H-spiro[benzo[d]pyrazolo[1,2-a][1,2]diazepin-2,1'-cyclopropan]-11(3H)-one (1.03 g, 3.98 mmol) in AcOH (20 mL) at 0 °C, and the reaction mixture was stirred at room temperature for 2.5 h. The mixture was then filtered to remove zinc, and the solid was washed with CHCl. ​​The filtrate was treated with 1 N NaOH, and the aqueous phase was extracted with CHCl. ​​The combined organic phases were dried and concentrated. The residue was purified by column chromatography (0-10% MeOH in (1% NHOH in CH2Cl2)) to give 10-amino-5,10-dihydro-1H-spiro[benzo[d]pyrazolo[1,2-a][1,2]diazepine-2,1'-cyclopropan]-11(3H)-one. m / z 244 [M+H] + , t R = 0.90 min (LCMS condition a), 1 H NMR(400MHz, 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).

[0237] Chiral separation (by BOC protection, chiral separation and BOC deprotection) as described for Type A and Type C intermediates allows isolation of Type D intermediates.

[0238] Type L intermediate Synthesis of 2-(((tert-butoxycarbonyl)amino)methyl)-3,3,3-trifluoropropanoic acid (int-L1) [ka] To a mixture of 2-(aminomethyl)-3,3,3-trifluoropropanoic acid (15 g, 95 mmol) in dioxane (300 mL) was added water (300 mL), NaCO (45.5 g, 430 mmol), and BocO (33.3 mL, 143 mmol). The reaction was stirred at room temperature for 16 h, then CHCl was added and the mixture was acidified with 1 N HCl. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried (MgSO) and concentrated. The crude product was used without further purification. LCMS (Method e) M / z 256 [M−H] - ;t R = 2.70 minutes. 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).

[0239] Synthesis of (R)-3-((tert-butoxycarbonyl)amino)-2-cyclopropylpropanoic acid (int-L2) [ka] Step 1: EDC (6.5 g, 33.9 mmol) was added to a mixture of (S)-4-benzyloxazolidin-2-one (3.0 g, 5.64 mmol), DMAP (3.1 g, 25.4 mmol), and 2-cyclopropylacetic acid (2.36 mL, 25.4 mmol) in CHCl (20 mL) at room temperature, and the mixture was stirred at room temperature for 16 h. The reaction mixture was then diluted with CHCl and washed with water, 1N HCl, 1N NaOH, and brine, dried (NaSO), and concentrated to give (S)-4-benzyl-3-(2-cyclopropylacetyl)-2-one, which 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(400MHz, 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).

[0240] Step 2: 1 M NaHMDS in THF (8.68 mL, 8.68 mmol) was added dropwise to a solution of (S)-4-benzyl-3-(2-cyclopropylacetyl)oxazolidin-2-one (1.5 g, 5.78 mmol) in THF (8 mL) at −78 °C. After stirring at −78 °C for 1 h, tert-butyl 2-bromoacetate (1.55 mL, 10.41 mmol) was added, and the mixture was stirred at −78 °C for 1 h. It was then quenched by adding saturated NH₄Cl and allowed to warm to room temperature. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and brine, dried (Na₂SO₄), and concentrated to give the crude product, which was purified by chromatography (5–20% ethyl acetate in cyclohexane) to give tert-butyl (S)-4-((S)-4-benzyl-2-oxooxazolidin-3-yl)-3-cyclopropyl-4-oxobutanoate. LCMS (method b) m / z 374.3 [M+H] + , t R =1.29 minutes. 1H NMR(400MHz, CDCl3) δ ppm 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).

[0241] Step 3: TFA (4.54 uL, 58.9 mmol) was added to a solution of tert-butyl (S)-4-((S)-4-benzyl-2-oxooxazolidin-3-yl)-3-cyclopropyl-4-oxobutanoate (1.1 g, 2.95 mmol) in CHCl (25 mL) at room temperature, and the solution was stirred at room temperature for 1 hour. The reaction mixture was then concentrated, and the residue was dissolved in CHCl and concentrated again. This was repeated with EtO to remove residual TFA, yielding (S)-4-((S)-4-benzyl-2-oxooxazolidin-3-yl)-3-cyclopropyl-4-oxobutanoic acid. LCMS (Method b) m / z 318.2 [M+H] + , t R = 0.90 minutes. 1H NMR(400MHz, 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, 3.3 Hz, 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).

[0242] Step 4: Ethyl chloroformate (480 mg, 4.42 mmol) was added to a solution of (S)-4-((S)-4-benzyl-2-oxooxazolidin-3-yl)-3-cyclopropyl-4-oxobutanoic acid (1.275 mg, 4.02 mmol) and triethylamine (672 μL, 4.82 mmol) in acetone (40 mL) at 0 °C, and the reaction mixture was stirred at 0 °C for 1 h. Then, a solution of NaN (522 mg in 10 mL of HO) was added to the reaction mixture at 0 °C, and the mixture was stirred at 0 °C for 1 h. The solvent was removed, and the residue was extracted with EtO. The organic phase was dried (NaSO) and concentrated. Toluene (80 mL) was added to the residue, and 40 mL of solvent was distilled off to remove residual water by azeotropic distillation. tert-Butanol (20 mL) was added to the reaction mixture, which was then stirred at reflux for 16 h. After cooling to room temperature, the solvent was removed and the residue was dissolved in CHCl, washed with 2N HCl, water and brine, dried (NaSO), and concentrated to give tert-butyl ((R)-3-((S)-4-benzyl-2-oxooxazolidin-3-yl)-2-cyclopropyl-3-oxopropyl)carbamate. LCMS (Method b) m / z 389.3 [M+H] + ,t R = 1.16 minutes. 1H NMR(400MHz, 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).

[0243] Step 5: Hydrogen peroxide (1.1 mL, 10.81 mmol) was added at 0 °C to a mixture of tert-butyl ((R)-3-((S)-4-benzyl-2-oxooxazolidin-3-yl)-2-cyclopropyl-3-oxopropyl)carbamate (1.4 g, 3.60 mmol) in THF (8 mL), followed by 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 with saturated NaHSO (4 mL) and saturated NaHCO (10 mL) at 0 °C. THF was removed under reduced pressure, and the aqueous layer (pH 10) was washed with CHCl. ​​The aqueous layer was then cooled to 0 °C and acidified to pH 2 with 4 N HCl and 10% KHSO. It was extracted with ethyl acetate, and the combined organic phases were washed with water and brine, dried (NaSO), and concentrated to give an oil that crystallized overnight and was recrystallized from hexane to give (R)-3-((tert-butoxycarbonyl)amino)-2-cyclopropylpropanoic acid (int-L2). 1H NMR(400MHz, 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, H), 0.89 ~ 0.69 (m, 1H), 0.55 ~ 0.31 (m, 2H), 0.26 ~ 0.08 (m,2H).

[0244] Synthesis of (R)-2-(((tert-butoxycarbonyl)amino)methyl)butanoic acid (int-L3) [ka] (R)-2-(((tert-butoxycarbonyl)amino)methyl)butanoic acid (int-L3) was obtained using a similar method as described for the synthesis of ((tert-butoxycarbonyl)amino)-2-cyclopropylpropanoic acid (int-L2), except that 2-cyclopropylacetic acid was replaced with butyric acid. 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).

[0245] Synthesis of (R)-2-((tert-butoxycarbonyl)amino)methyl)pentanoic acid (int-L4) [ka] 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 CHCl (50 mL) and TEA (3.87 mL, 27.7 mmol) at 0 °C, and the mixture was stirred at 0 °C for 1 h. TEA (5.52 mL, 39.6 mmol) was then added, followed by a solution of (1R,2R)-pseudoephedrine (4.37 g, 26.4 mmol) in CHCl (5 mL), and the mixture was stirred at 20 °C for 16 h. The reaction mixture was concentrated, and the residue was dissolved in a 1:1 mixture of MeOH / HO (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 h. The reaction mixture was concentrated, dissolved in water, and washed with ethyl acetate / cyclohexane (1 / 1). The aqueous phase was made basic (pH 12) with 50% NaOH 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-phenylpropan-2-yl)-N-methylpropanamide. LCMS (Method e) m / z 237.0 [M+H] + ,t R = 0.40 minutes. 1 H 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 + is not permitted).

[0246] Step 2: LiHMDS (29.8 mL, 29.8 mmol) was added dropwise to a mixture of 3-amino-N-((1R,2R)-1-hydroxy-1-phenylpropan-2-yl)-N-methylpropanamide (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 h, 1-iodopropane (1.364 mL, 13.96 mmol) was slowly added, and the mixture was stirred at 0 °C for 6 h. The reaction was quenched by adding water followed by 6 N HCl (until a pH of 3 was reached). The aqueous phase was then washed with ethyl acetate / cyclohexane (1 / 1), made basic (pH 12) with 50% NaOH at 0 °C, and extracted with CHCl. ​​The organic phase was dried (MgSO) and concentrated. The crude product was purified by preparative HPLC (Macherey-Nagel, Nucleosil 100-10 C18, flow rate 40 mL / min, ACN: 5% in 5 min, 100% in 20 min). The product fractions were treated with saturated NaHCO3 and extracted with CHCl2. The combined organic phases were dried (MgSO4) and concentrated to give (R)-2-(aminomethyl)-N-((1R,2R)-1-hydroxy-1-phenylpropan-2-yl)-N-methylpentanamide. LCMS (Method e) m / z 279.4 [M+H] + ,t R = 0.59 minutes. 1 H NMR(400MHz, 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 + is not permitted).

[0247] Step 3: A mixture of (R)-2-(aminomethyl)-N-((1R,2R)-1-hydroxy-1-phenylpropan-2-yl)-N-methylpentanamide in water (10 mL) was stirred at 100° C. for 5 days. After cooling to room temperature, the reaction mixture was washed with CHCl and concentrated. The residue was crystallized from MeOH to give (R)-2-(aminomethyl)pentanoic acid. LCMS (Method b) m / z 132.2 [M+H] + ,t R = 0.17 minutes. 1 H NMR (400 MHz, DMSO-d6): δ ppm 2.80 (dd, J = 12.2, 4.4 Hz, 1 H), 2.69 - 2.56 (m, 1 H), 2.08 - 1.94 (m, 1 H), 1.65 - 1.48 (m, 1 H), 1.39 - 1.16 (m, 3H), 0.85 (t, J = 7.0 Hz, 3H). (NH3 + and COOH are not permitted)

[0248] Step 4: Na2CO3 (415 mg, 3.91 mmol) and Boc2O (0.30 mL, 1.30 mmol) were added to a solution of (R)-2-(aminomethyl)pentanoic acid in dioxane (2 mL) and water (1 mL), and the reaction mixture was stirred at room temperature for 2 days. The reaction mixture was then washed with CHCl2, acidified with 1N HCl, and extracted with ethyl acetate. The organic layer was dried (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 minutes. 1 H NMR (400MHz, 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).

[0249] Synthesis of (R)-2-(((tert-butoxycarbonyl)amino)methyl)-4-methoxybutanoic acid (int-L5) [ka] Step 1: Oxalyl chloride (1.844 mL, 21.07 mmol) was added dropwise to a stirred solution of 4-methoxybutanoic acid (2.37 g, 20.06 mmol) in CHCl (100 mL) at room temperature, followed by the addition of a small amount of DMF. The resulting solution was stirred at room temperature for 1 hour. The reaction mixture was concentrated to give 4-methoxybutanoyl chloride, which was used directly in the next step.

[0250] Step 2: n-Butyllithium (1.6 M in hexanes) (12.54 mL, 20.06 mmol) was added dropwise to a stirred solution of (S)-4-benzyloxazolidin-2-one (3.55 g, 20.06 mmol) in THF (201 mL) at −78 °C, and the resulting solution was stirred at −78 °C for 15 min. 4-Methoxybutanoyl chloride (2.74 g, 20.06 mmol) in THF (5 mL) was then added dropwise at −78 °C, and the reaction mixture was stirred at −78 °C for 1 h before being quenched with saturated NaHCO solution (100 mL). The aqueous phase was separated and extracted with CHCl, and the combined organic fractions were dried (MgSO), and concentrated to give the crude product, which was purified by column chromatography (0-40% ethyl acetate in cyclohexane) to give (S)-4-benzyl-3-(4-methoxybutanoyl)oxazolidin-2-one. LCMS (method b) m / z 278.4 [M+H] + ;t R = 1.01 minutes. 1H NMR(400MHz, 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).

[0251] Step 3: LiHMDS (1 M in PhMe) (3.97 mL, 3.97 mmol) was added to a stirred solution of (S)-4-benzyl-3-(4-methoxybutanoyl)oxazolidin-2-one (1 g, 3.61 mmol) in THF (36.1 mL) at −78 °C, and the resulting solution was warmed to −10 °C and stirred for 15 min. After cooling to −78 °C, N,N-dibenzyl-1-methoxymethanamine (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 the addition of NaHCO solution (50 mL). The aqueous phase was separated and extracted with CHCl, and the combined organic fractions were dried (MgSO) and concentrated. The crude product was purified by column chromatography (0-25% ethyl acetate in cyclohexane) to give (S)-4-benzyl-3-((R)-2-((dibenzylamino)methyl)-4-methoxybutanoyl)oxazolidin-2-one. LCMS (Method b) m / z 487.4 [M+H] + ;t R = 1.48 minutes.

[0252] Step 4: (S)-4-benzyl-3-((R)-2-((dibenzylamino)methyl)-4-methoxybutanoyl)oxazolidin-2-one (1.26 g, 2.59 mmol) in MeOH (25 mL) was hydrogenated at room temperature using H (4 bar) and Pd / C (10 mol%) (0.18 g) for 2 h. The reaction mixture was then treated with BocO (0.9 g, 4.1 mmol) to give tert-butyl ((R)-2-(S)-4-benzyl-2-oxooxazolidine-3-carbonyl)-4-methoxybutyl)carbamate. LCMS (Method b) m / z 407.2 [M+H] + ;t R = 1.13 minutes.

[0253] Step 5: Aqueous hydrogen peroxide (399 mg, 3.52 mmol) followed by LiOH (73.9 mg, 1.761 mmol) in water (2.2 mL) was added at 0 °C to a solution of tert-butyl ((R)-2-((S)-4-benzyl-2-oxooxazolidine-3-carbonyl)-4-methoxybutyl)carbamate (358 g, 0.881 mmol) in THF (6.6 mL), and the reaction mixture was stirred at 0 °C for 2 h. It was then treated with saturated NaSO and saturated NaHCO. The THF was evaporated under reduced pressure, and the aqueous layer was washed with CHCl. ​​The aqueous layer was acidified to pH 2 with 2 M HCl and extracted with CHCl. ​​The organic layer was dried (NaSO) and concentrated to give (R)-2-(((tert-butoxycarbonyl)amino)methyl)-4-methoxybutanoic 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).

[0254] NOTE: N,N-Dibenzyl-1-methoxymethanamine (BnNCHOMe) was generated using the following procedure. [ka] Potassium carbonate (21.0 g, 152 mmol) and formaldehyde (3.81 g, 127 mmol) were added to a solution of dibenzylamine (10.0 g, 50.7 mmol) in MeOH (10 mL), and the reaction mixture was stirred at room temperature for 4 h. KCO (21.0 g, 152 mmol) was then added, and the mixture was stirred at room temperature for 16 h. After filtration and concentration, the reaction mixture was purified by Kugelrohr distillation (100 °C, 0.3 mbar) to give N,N-dibenzyl-1-methoxymethanamine.

[0255] Synthesis of (R)-4-(tert-butoxy)-2-methyl-4-oxobutanoic acid (int-L6) [ka] Step 1: 1 M NaHMDS in THF (37.7 mL, 37.7 mmol) was added dropwise to a solution of (S)-4-benzyl-3-propionyloxazolidin-2-one (8 g, 34.3 mmol) in THF (200 mL) at −78 °C. After stirring at −78 °C for 1 h, tert-butyl 2-bromoacetate (15.5 mL, 103 mmol) was added, and the solution was stirred at −78 °C for 2.5 h. The reaction mixture was treated with saturated aqueous NH4Cl, and the 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 tert-butyl (R)-4-((S)-4-benzyl-2-oxooxazolidin-3-yl)-3-methyl-4-oxobutanoate. 1H NMR(400MHz, 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, 9 H),1.20 (d,J = 7.0 Hz, 3 H). LCMS (method b) m / z 348.1 [M+H] + ;t R = 1.21 min. [α] 23 D +78.9 (c= 1.0,MeOH).

[0256] Step 2: 30% aqueous hydrogen peroxide (2.7 mL, 26.5 mmol) followed by 0.5 M aqueous LiOH (26.5 mL, 13.2 mmol) was added to a solution of tert-butyl (R)-4-((S)-4-benzyl-2-oxooxazolidin-3-yl)-3-methyl-4-oxobutanoate (2.3 g, 6.6 mmol) in THF (66 mL) at 0 °C, and the reaction mixture was stirred at 0 °C for 2 h. It was then treated with saturated aqueous NaSO and saturated aqueous NaHCO. The THF was evaporated under reduced pressure, and the aqueous layer was extracted with CHCl. ​​The aqueous layer was acidified to pH 2 with 2 M HCl and extracted with CHCl. ​​The organic layer was dried (NaSO) and concentrated to give (R)-4-(tert-butoxy)-2-methyl-4-oxobutanoic acid (int-L6). 1 H NMR (400 MHz, CDCl3): δ ppm 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 acidic proton signals were observed. [α] 23 D +2.6 (c = 1.0,MeOH).

[0257] Synthesis of (S)-4-(tert-butoxy)-2-cyclopropyl-4-oxobutanoic acid (int-L7) [ka] Step 1: EDC (1.7 g, 8.9 mmol) was added to a mixture of (S)-4-benzyloxazolidin-2-one (800 mg, 4.5 mmol), 2-cyclopropylacetic acid (600 mg, 6.0 mmol), and DMAP (565 mg, 4.6 mmol) in CHCl (5 mL) at room temperature, and the mixture was stirred at room temperature for 16 h. The mixture was diluted with CHCl and washed with water, 1 M HCl, saturated aqueous NaHCO, saturated aqueous NHCl, water, and brine, dried (NaSO), and concentrated to give (S)-4-benzyl-3-(2-cyclopropylacetyl)oxazolidin-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(400MHz, CDCl3) δ ppm 7.38 - 7.32 (m, 2H), 7.32 - 7.28 (m, 1H), 7.25 -7.23 (m,13.16 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).

[0258] Step 2: 1 M NaHMDS in THF (5.9 mL, 5.9 mmol) was added dropwise to a solution of (S)-4-benzyl-3-(2-cyclopropylacetyl)oxazolidin-2-one (1.0 g, 3.9 mmol) in THF (30 mL) at −78 °C. After stirring at −78 °C for 1 h, tert-butyl 2-bromoacetate (1.2 mL, 7.8 mmol) was added, and the solution was stirred at −78 °C for an additional 1 h. The reaction mixture was treated with saturated aqueous NH4Cl (2 mL) and warmed to room temperature, then dried (Na2SO4), and concentrated. The crude product was purified by column chromatography (0-50% ethyl acetate in hexanes) to give tert-butyl (S)-4-((S)-4-benzyl-2-oxooxazolidin-3-yl)-3-cyclopropyl-4-oxobutanoate. LCMS (method b) m / z 374.3 [M+H] + , t R =1.29 minutes. [α] 23 D +69.0 (c = 1.0, MeOH); 1 H NMR(400MHz, CDCl3): δ ppm 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).

[0259] Step 3: Hydrogen peroxide (30% in water, 0.88 mL, 8.6 mmol) followed by LiOH (0.18 g, 4.3 mmol) in water (1 mL) was added to a solution of tert-butyl (S)-4-((S)-4-benzyl-2-oxooxazolidin-3-yl)-3-cyclopropyl-4-oxobutanoate (0.8 g, 2.1 mmol) in THF (20 mL) at 0 °C, and the reaction mixture was stirred at 0 °C for 2 h. It was then treated with saturated aqueous NaHSO (20 mL) and saturated aqueous NaHCO (50 mL) at 0 °C. THF was evaporated under reduced pressure, and the aqueous layer was washed with CHCl, then cooled to 0 °C, acidified to pH 2 with 4 M HCl, and extracted with CHCl. The combined organic extracts were dried (NaSO) and concentrated to give (S)-4-(tert-butoxy)-2-cyclopropyl-4-oxobutanoic 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); 1 H NMR(400MHz, 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).

[0260] Synthesis of (S)-4-(tert-butoxy)-2-cyclopropyl-4-oxobutanoic acid (int-L8) [ka] (S)-4-(tert-butoxy)-2-cyclobutyl-4-oxobutanoic acid (int-L8) was obtained using the same method as described for the synthesis of (S)-4-(tert-butoxy)-2-cyclopropyl-4-oxobutanoic acid (int-L7), except that 2-cyclopropylacetic acid was replaced with 2-cyclobutylacetic acid. LCMS (Method b) m / z 229.3 [M+H] + t R = 0.99 minutes. 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).

[0261] The table below lists the L intermediates purchased. [Table 1]

[0262] Type EC intermediate Synthesis of 2-isobutyramido-4-methylthiazole-5-carboxylic acid (int-EC1) [ka] Step 1: Methyl 2-amino-4-methylthiazole-5-carboxylate (Combiblocks, 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). EDC (1.1 g, 5.8 mmol) was added, and the mixture (white suspension) was stirred at room temperature overnight. 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 at room temperature for an additional 22 h. The reaction mixture was concentrated, quenched with HO, and extracted twice with ethyl acetate. The combined organic layers were washed with water, brine, dried over NaSO, filtered, and the filtrate was concentrated to give a crude solid. The crude product was dissolved in CH2Cl2 / MeOH (9 / 1), loaded onto a precolumn containing isolute, and purified by column chromatography (10-30% ethyl acetate in cyclohexane) to give methyl 2-isobutyramido-4-methylthiazole-5-carboxylate. LCMS (Method b) m / z 243.1 [M+H] + ,t R = 0.86 minutes. 1 H NMR (400MHz, 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 = 6.8 Hz,6H).

[0263] Step 2: 1M aqueous LiOH (16.5 mL, 16.5 mmol) was added to a solution of methyl 2-isobutyramido-4-methylthiazole-5-carboxylate (400 mg, 1.65 mmol) in THF (16 mL). The mixture was stirred at room temperature for 16 h. THF was removed under reduced pressure, and the residue was washed with EtO. The aqueous phase was acidified with HCl, and the resulting white suspension was stirred for 30 min, then filtered at low temperature and dried under high vacuum (HV) to give 2-isobutyramido-4-methylthiazole-5-carboxylic acid (int-EC1). LCMS (Method b) m / z 229.2 [M+H]+ ,t R = 0.62 minutes. 1 H NMR (400MHz, DMSO-d6) δ ppm 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).

[0264] Synthesis of 2-(ethylcarbamoyl)-4-methylthiazole-5-carboxylic acid (int-EC2) [ka] Step 1: Ethyl 2-amino-2-thioxoacetate (1.7 g, 12.8 mmol) was added to a solution of tert-butyl 2-chloro-3-oxobutanoate (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 in cyclohexane) to give 5-(tert-butyl 2-ethyl 4-methylthiazole-2,5-dicarboxylate. LCMS (Method e) m / z 272.1 [M+H] + ,t R = 1.23 minutes. 1 H NMR (400 MHz, DMSO-d6) δ ppm 4.38 (d,J = 7.1 Hz,2 H), 2.67 (s, 3 H),1.54 (s, 9 H),1.33 (t,J = 7.0 Hz,3 H)).

[0265] Step 2: A solution of 5-(tert-butyl 2-ethyl-4-methylthiazole-2,5-dicarboxylate (500 mg, 1.84 mmol) in 2 M ethanamine in EtOH (27.6 mL, 55.2 mmol) was stirred at room temperature for 16 hours. The reaction mixture was treated with ethyl acetate and washed with saturated NaHCO3 and 1 N HCl. The organic phase was dried (MgSO4) and concentrated to give tert-butyl 2-(ethylcarbamoyl)-4-methylthiazole-5-carboxylate. LCMS (Method b) m / z 271.1 [M+H] + ,t R = 1.14 minutes. 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.97 (t,J = 6.1 Hz,1 H),3.30-3.23 (m, 2 H),2.66 (s, 3 H),1.53 (s, 9 H),1.11 (t,J = 7.3 Hz,3 H).

[0266] Step 3: A solution of tert-butyl 2-(ethylcarbamoyl)-4-methylthiazole-5-carboxylate (540 mg, 1.8 mmol) in TFA (15 mL) and CHCl (30 mL) was stirred at room temperature for 16 hours. The reaction mixture was concentrated and treated with EtO. The precipitate was filtered off, washed with cold EtO, and dried under vacuum to give 2-(ethylcarbamoyl)-4-methylthiazole-5-carboxylic acid (int-EC2). LCMS (Method b) m / z 215.1 [M+H] + ,t R = 0.54 minutes. 1 H NMR (400 MHz, DMSO-d) δ ppm 8.97 (t, J = 6.0 Hz, 1 H), 3.30-3.26 (m, 2 H), 2.67 (s, 3 H), 1.12 (q, J = 7.4 Hz, 3 H) (no acidic protons observed).

[0267] Synthesis of 2-((2,2-difluoroethyl)carbamoyl)-4-methylthiazole-5-carboxylic acid (int-EC3) [ka] 2-((2,2-Difluoroethyl)carbamoyl)-4-methylthiazole-5-carboxylic acid (int-EC3) was obtained using a method similar to that described for the synthesis of 2-(ethylcarbamoyl)-4-methylthiazole-5-carboxylic acid (int-EC2), except that ethanamine in THF was replaced with 2,2-difluoroethan-1-amine in ethanol. LCMS (Method b) m / z 251.1 [M+H] + ,t R = 0.55 minutes. 1 H NMR (400 MHz, DMSO-d) δ ppm 9.24 (t, J = 6.3 Hz, 1 H), 6.14 (tt, J = 55.8, 4.0 Hz, 1 H), 3.66 (tdd, J = 15.3, 6.2, 4.0 Hz, 2 H), 2.69 (s, 3 H) (no acid protons observed).

[0268] Synthesis of 4-methyl-2-(ethylcarbamoyl)thiazole-5-carboxylic acid (int-EC4) [ka] 4-Methyl-2-(methylcarbamoyl)thiazole-5-carboxylic acid (int-EC4) was obtained using a similar method to that described for the synthesis of 2-(ethylcarbamoyl)-4-methylthiazole-5-carboxylic acid (int-EC2), except that ethanamine in THF was replaced with methamine in ethanol. LCMS (Method a) m / z 201.1 M+H + , t R = 0.45 minutes.

[0269] Synthesis of 2-(isopropylcarbamoyl)-4-methylthiazole-5-carboxylic acid (int-EC5) [ka] 2-(Isopropylcarbamoyl)-4-methylthiazole-5-carboxylic acid (int-EC5) was obtained using a method similar to that described for the synthesis of 2-(ethylcarbamoyl)-4-methylthiazole-5-carboxylic acid (int-EC2), except that ethanamine in THF was replaced with propan-2-amine in ethanol. LCMS (Method b) m / z 229.2 [M+H] + ,t R = 0.61 minutes. 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.73 (d, J = 8.5 Hz, 1 H), 4.20-3.96 (m, 1 H), 2.68 (s, 3 H), 1.18 (d, J = 6.6 Hz, 6 H).

[0270] Synthesis of 4-chloro-2-(6-(trifluoromethyl)pyridin-3-yl)thiazole-5-carboxylic acid (int-EC6) [ka] Step 1: To a solution of methyl 2,4-dichlorothiazole-5-carboxylate (10 g, 47.2 mmol) in THF (150 mL) was added 1N aqueous LiOH (235 mL, 235 mmol). The reaction mixture was stirred at room temperature for 1 hour. 0.1 M aqueous NaOH was added to the reaction mixture, which was then extracted with EtO. The aqueous phase was acidified with HCl, concentrated, and extracted with EtO. The organic layer was washed with brine, dried (NaSO), and concentrated to give 2,4-dichlorothiazole-5-carboxylic acid. LCMS (Method b) m / z 195.9 + 197.9 [M−H] - , t R =0.46 minutes.

[0271] 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 2 M aqueous Na2CO3 (25 mL, 1.88 mmol) were added to a mixture of 2,4-dichlorothiazole-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 h. 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 product was triturated with water / isopropanol (3 / 1) in an ultrasonic bath, and the solid was filtered and dried under high vacuum to give 4-chloro-2-(6-(trifluoromethyl)pyridin-3-yl)thiazole-5-carboxylic acid (int-EC6). LCMS (Method b) m / z 309.0 + 311.0 [M+H] + , t R = 0.76 minutes. 1 H NMR (400MHz, 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).

[0272] Synthesis of 4-methyl-2-(6-(trifluoromethyl)pyridin-3-yl)thiazole-5-carboxylic acid (int-EC7) [ka] Step 1: Ethyl 2-chloroacetate (4.77 mL, 32.7 mmol) was added to a solution of 6-(trifluoromethyl)pyridine-3-carbothioamide (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 in vacuo to give ethyl 4-methyl-2-(6-(trifluoromethyl)pyridin-3-yl)thiazole-5-carboxylate. The filtrate was concentrated, then triturated with a small amount of EtOH, cooled, filtered off, and dried in vacuo to give ethyl 4-methyl-2-(6-(trifluoromethyl)pyridin-3-yl)thiazole-5-carboxylate. LCMS (Method b) m / z 317.1 [M+H] + ,t R =1.25 minutes. 1 H NMR(400MHz, 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 = 7.1Hz,3H).

[0273] Step 2: LiOH (24.66 mL, 24.66 mmol) in HO was added to a mixture of ethyl 4-methyl-2-(6-(trifluoromethyl)pyridin-3-yl)thiazole-5-carboxylate (5.2 g, 16.44 mmol) in ethanol (110 mL) at room temperature, and the mixture was stirred at room temperature for 1.5 hours. The solvent was removed, the residue was treated with water, and the solution was acidified with 2N HCl. The resulting suspension was filtered, and the solid was dried under vacuum to give 4-methyl-2-(6-(trifluoromethyl)pyridin-3-yl)thiazole-5-carboxylic acid (int-EC7). LCMS (Method b) m / z 289.1 [M+H] + ,t R = 0.86 minutes. 1H 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).

[0274] Synthesis of 4-methyl-2-(3-methylisoxazol-5-yl)thiazole-5-carboxylic acid (int-EC8) [ka] Step 1: 3-Methylisoxazole-5-carbonitrile (1 g, 9.25 mmol) was added to a solution of sodium hydrogen sulfide (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 h. 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-methylisoxazole-5-carbothioamide. LCMS (Method e) m / z 143.1 [M+H] + ,t R = 0.52 minutes. 1 H NMR (400 MHz, DMSO-d6) δppm 10.21 (s, 1H), 9.83 (s, 1H), 6.95 (s, 1H), 2.27 (s, 3H).

[0275] Step 2: 3-Methylisoxazol-5-carbothioamide (0.858 g, 5.19 mmol) was added to a solution of tert-butyl 2-chloro-3-oxobutanoate (1 g, 5.19 mmol) in t-BuOH (20 mL), and the reaction mixture was stirred at 90 °C for 16 h. After cooling to room temperature, the reaction mixture was concentrated, and the crude product was purified by column chromatography (0-40% ethyl acetate in cyclohexane) to give tert-butyl 4-methyl-2-(3-methylisoxazol-5-yl)thiazole-5-carboxylate. LCMS (Method e) m / z 281.2 [M+H] + ,t R = 1.35 minutes.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).

[0276] Step 3: TFA (5 mL) was added to a solution of tert-butyl 4-methyl-2-(3-methylisoxazol-5-yl)thiazole-5-carboxylate (440 mg, 1.57 mmol) in CHCl (10 mL). The solution was then stirred at room temperature for 2 hours. The reaction mixture was concentrated to give 4-methyl-2-(3-methylisoxazol-5-yl)thiazole-5-carboxylic acid (int-EC8). LCMS (Method e) m / z 225.1 [M+H] + ,t R = 0.62 minutes. 1 H NMR (400 MHz, DMSO-d6) δppm 13.76 (s, 1H), 7.14 (s, 1H), 2.69 (s, 3H), 2.33 (s, 3H).

[0277] Synthesis of 4-chloro-2-(isopropylcarbamoyl)thiazole-5-carboxylic acid (int-EC9) [ka] 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-dichlorothiazole-5-carbaldehyde (5.0 g, 27.5 mmol) in toluene (60 mmol), and the mixture was stirred at reflux for 5 h. The reaction was cooled to room temperature, poured into 20% Na2CO3 (120 mL), and the solution was 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 in cyclohexane) to give 2,4-dichloro-5-(1,3-dioxolan-2-yl)thiazole. LCMS (Method b) m / z 228.0 [M+H] + , t R = 0.96 minutes. 1H NMR (400 MHz, DMSO-d6) δ ppm 6.05 (s, 1H), 4.08-4.01 (m, 2H), 4.00-3.93 (m, 2H).

[0278] Step 2: n-Butyllithium (1.6 M in hexane, 8.7 mL, 13.9 mmol) was added to a solution of 2,4-dichloro-5-(1,3-dioxolan-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 minutes. Solid carbon dioxide (20 g) was then introduced, and the reaction mixture was gradually warmed to room temperature and stirred at room temperature for 16 hours. The resulting suspension was concentrated, and the crude product was suspended in ethyl acetate. The solid was collected by filtration to give 4-chloro-5-(1,3-dioxolan-2-yl)thiazole-2-carboxylic acid. LCMS (Method b) m / z = 236.2 [M+H] + ,t R = 0.39 minutes. 1 H NMR (400 MHz, DMSO-d) δ ppm 5.98 (s, 1H), 4.09-4.00 (m, 2H), 4.00-3.90 (m, 2H) (no COOH protons observed).

[0279] Step 3: Propan-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-dioxolan-2-yl)thiazole-2-carboxylic acid (3.0 g, 12.73 mmol), HOBt (2.43 mg, 15.28 mmol), and EtN (2.3 mL, 16.55 mmol) in CHCl (120 mL), and the suspension was stirred at room temperature overnight. The reaction mixture was concentrated and treated with ethyl acetate and 1N HCl. The combined organic layers were washed with saturated NaHCO, brine, dried (NaSO), and concentrated to give 4-chloro-5-(1,3-dioxolan-2-yl)-N-isopropylthiazole-2-carboxamide. LCMS (Method b) m / z 277.1 [M+H] + ,t R = 0.94 minutes. 1H NMR (400MHz, 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 = 6.6Hz,6H).

[0280] Step 4: 6 M HCl (3.0 mL, 18.07 mmol) was added to a solution of 4-chloro-5-(1,3-dioxolan-2-yl)-N-isopropylthiazole-2-carboxamide (1.0 g, 3.61 mmol) in EtO (36.0 mL) at room temperature, and the solution was stirred at room temperature for 16 h. The pH of the mixture was then adjusted to 7-8 with saturated NaHCO, and the organic layer was separated. The aqueous layer was extracted with EtO, and the combined organic extracts were washed with brine, dried (NaSO), and concentrated to give 4-chloro-5-formyl-N-isopropylthiazole-2-carboxamide. LCMS (Method b) m / z = 233.2 [M+H] + ,t R =0.86 minutes. 1 H NMR (400MHz, 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).

[0281] 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-isopropylthiazole-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 h. The reaction was quenched with HO, and the mixture was 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 min. The solid was then filtered off and dried under high vacuum to give 4-chloro-2-(isopropylcarbamoyl)thiazole-5-carboxylic acid (int-EC9). LCMS (Method b) m / z = 249.1 [M+H]+ ,t R = 0.52 minutes. 1 H NMR (400MHz, 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).

[0282] Synthesis of 2-(3,6-dihydro-2H-pyran-4-yl)-4-methylthiazole-5-carboxylic acid (int-EC10) [ka] 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-dioxaborolane (130 mg, 0.619 mmol), and 2-chloro-4-methylthiazole-5-carboxylic acid (100 mg, 0.563 mmol) in THF (2.6 mL) and water (1.1 mL) was purged with argon for 5 minutes. Pd(dppf)Cl·CHCl (46.0 mg, 0.056 mmol) was added, and the resulting solution was heated in a microwave oven at 80 °C for 1 hour. After cooling to room temperature, the reaction mixture was concentrated, and the residue was purified using preparative HPLC to give a solid, which was dissolved in CHCl (10 mL) and treated with saturated NaHCO (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-methylthiazole-5-carboxylic acid (int-EC10). LCMS (Method b) m / z 226.1 [M+H] + ;t R = 0.63 minutes, 1 H NMR(400MHz, 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).

[0283] Synthesis of 4-chloro-2-(cyclopent-1-en-1-yl)thiazole-5-carboxylic acid (int-EC11) [ka] 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-dichlorothiazole-5-carboxylate (200 mg, 0.94 mmol) in THF (2.4 mL) and water (2.4 mL) was purged with argon for 5 minutes. Pd(dppf)Cl. CHCl (77 mg, 0.094 mmol) was added, and the resulting mixture was heated in a microwave oven at 80 °C for 1 hour. After cooling to room temperature, the reaction mixture was concentrated, and the residue was purified using preparative HPLC. The resulting solid was dissolved in CHCl (10 mL) and treated with saturated aqueous 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)thiazole-5-carboxylate. M / z 244.1 [M+H] + ;t R = 1.23 min (LCMS condition b), 1 H NMR (400 MHz, 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).

[0284] Step 2: 2 M LiOH (aq) (0.42 mL, 0.84 mmol) was added to a mixture of methyl 4-chloro-2-(cyclopent-1-en-1-yl)thiazole-5-carboxylate (195 mg, 0.80 mmol) in a 1:1:1 mixture of MeOH / THF / HO (8 mL), and the mixture was stirred at room temperature for 20 h. The mixture was then concentrated and used in the next step without further purification.

[0285] Step 3: To a stirred solution of lithium 4-chloro-2-(cyclopent-1-en-1-yl)thiazole-5-carboxylate (190 mg, 0.81 mmol) in MeOH (8.064 mL) was added NaBH (153 mg, 4.03 mmol) in one portion at room temperature, and the resulting solution was stirred at room temperature for 1 h. The reaction mixture was concentrated, and the residue was dissolved in CHCl (20 mL) and treated with 1 N HCl (10 mL). The aqueous phase was extracted with CHCl, and the combined organic phases were dried (MgSO) and concentrated to give a 2:1 unseparated mixture of 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).

[0286] Synthesis of 2-(isoxazol-5-yl)-4-methylthiazole-5-carboxylic acid (int-EC12) [ka] Step 1: Isoxazol-5-carbothioamide (0.858 g, 5.19 mmol) was added to a solution of tert-butyl 2-chloro-3-oxobutanoate (1 g, 5.19 mmol) in t-BuOH (10 mL), and the mixture was stirred at 90 °C for 16 h. After cooling to room temperature, the reaction mixture was concentrated, and the crude product was purified by column chromatography (0-50% ethyl acetate in cyclohexane) to give tert-butyl 2-(isoxazol-5-yl)-4-methylthiazole-5-carboxylate. LCMS (Method a) m / z 267.3 [M+H] + ,t R = 1.28 minutes. 1 H NMR (400 MHz,DMSO-d6): δ ppm 8.85 (d,J = 2.0 Hz,1 H),7.29 (d,J = 2.0 Hz,1 H),2.69 (s,3 H),1.55 (s ,9H).

[0287] Step 2: TFA (3 mL) was added to a solution of tert-butyl 2-(isoxazol-5-yl)-4-methylthiazole-5-carboxylate (300 mg, 1.126 mmol) in CHCl (6 mL), and the solution was stirred at room temperature for 16 hours. The reaction mixture was then concentrated to give 2-(isoxazol-5-yl)-4-methylthiazole-5-carboxylic acid (int-EC8). LCMS (Method a) m / z 211.2 [M+H] + ,t R = 0.52 minutes. 1 H NMR (400 MHz,DMSO-d6): δ ppm 13.78 (s,1 H),8.85 (d,J = 2.0 Hz,1 H),7.28 (d,J = 2.0 Hz,1 H),2.70 (s,3H).

[0288] Synthesis of 4-chloro-2-(6-methoxypyridin-3-yl)thiazole-5-carboxylic acid (int-EC13) [ka] Step 1: A mixture of sulfamic 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-dichlorothiazole-5-carbaldehyde (5 g, 27.5 mmol) in THF (150 mL) and water (100 mL), and the mixture was stirred at room temperature for 16 h. The reaction was quenched with HO 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 solution was extracted with Et2O, washed with brine, dried (Na2SO4), and concentrated. The residue was dried under high vacuum to give 2,4-dichlorothiazole-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 minutes. 1 H NMR (400 MHz, DMSO-d6): δppm 14.20 (s, 1H).

[0289] 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-dichlorothiazole-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 h. 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 and cooled to give 4-chloro-2-(6-methoxypyridin-3-yl)thiazole-5-carboxylic acid (int-EC13). LCMS (Method b) m / z 271.2 [M+H] + ,t R = 0.71 minutes. 1 H NMR(400MHz,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).

[0290] Synthesis of 4-chloro-2-(6-(difluoromethoxy)pyridin-3-yl)thiazole-5-carboxylic acid (int-EC14) [ka] 4-Chloro-2-(6-(difluoromethoxy)pyridin-3-yl)thiazole-5-carboxylic acid (int-EC14) was obtained using a method similar to that described for the synthesis of 4-chloro-2-(6-methoxypyridin-3-yl)thiazole-5-carboxylic acid (int-EC13), except that (6-methoxypyridin-3-yl)boronic acid was replaced with 2-(difluoromethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine. LCMS (Method b) m / z 307.0 [M+H] + ,t R = 0.77 minutes. 1H NMR(400 MHz,DMSO-d6) δ ppm 14.02 (s,1 H),8.90 (d,J = 2.5 Hz,1 H),8.49 (dd,J = 8.6,2.5 Hz,1 H),7.79 (t,J = 72.2 Hz,1 H),7.27 (d,J = 8.7 Hz,1 H).

[0291] Synthesis of 4-chloro-2-cyclopropylthiazole-5-carboxylic acid (int-EC15) [ka] NaOH (13.78 mL, 13.78 mmol) was added to a solution of methyl 4-chloro-2-cyclopropylthiazole-5-carboxylate (1 g, 4.59 mmol) in MeOH (20 mL), and the solution was stirred at room temperature for 1 h. MeOH was removed under reduced pressure, and the remaining solution was washed with CHCl. ​​The aqueous phase was acidified with 1 N HCl and extracted with ethyl acetate. The combined organic layers were dried (MgSO) and concentrated to give 4-chloro-2-cyclopropylthiazole-5-carboxylic acid (int-EC15). LCMS (Method e) m / z 204.0 [M+H] + , t R = 0.57 minutes. 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).

[0292] Synthesis of 4-chloro-2-(1-(difluoromethyl)-1H-pyrazol-4-yl)thiazole-5-carboxylic acid (int-EC16) [ka] 4-Chloro-2-(1-(difluoromethyl)-1H-pyrazol-4-yl)thiazole-5-carboxylic acid (int-EC16) was obtained using the same method as described for the synthesis of 4-chloro-2-(6-methoxypyridin-3-yl)thiazole-5-carboxylic acid (int-EC13), except that (6-methoxypyridin-3-yl)boronic acid was replaced with 1-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. LCMS (Method b) m / z 279.9 [M+H] + ,t R = 0.61 minutes. 1 H NMR (400MHz, DMSO-d6): δ ppm 8.87 (s, 1H), 8.26 (s, 1H), 7.85 (t, J = 58.8 Hz, 1H).

[0293] Synthesis of 4-chloro-2-(3,6-dihydro-2H-pyran-4-yl)thiazole-5-carboxylic acid (int-EC17) [ka] Pd(dppf)Cl·CHCl (124 mg, 0.151 mmol) was added to a degassed mixture of cesium carbonate (1.48 g, 4.54 mmol), 2-(3,6-dihydro-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (350 mg, 1.666 mmol), and 2,4-dichlorothiazole-5-carboxylic acid (300 mg, 1.515 mmol) in THF (7.07 mL) and water (3.03 mL) at room temperature, and the resulting suspension was heated at 80 °C in a microwave oven for 1 h. After cooling to room temperature, the reaction mixture was concentrated, and the crude product was purified using preparative HPLC. The HPLC fraction was concentrated under reduced pressure to give a white solid, which was dissolved in CHCl (10 mL) and diluted with saturated NaHCO solution (10 mL). The aqueous phase was separated and extracted with CH2Cl2, and the combined organic fractions were dried (MgSO4) and concentrated under reduced pressure to give 4-chloro-2-(3,6-dihydro-2H-pyran-4-yl)thiazole-5-carboxylic acid (int-EC17). LCMS (Method b) m / z 246.1 [M+H] + ,t R =0.59 minutes.

[0294] Synthesis of 4-methyl-2-(tetrahydro-2H-pyran-4-yl)thiazole-5-carboxylic acid (int-EC18) [ka] 4-Methyl-2-(tetrahydro-2H-pyran-4-yl)thiazole-5-carboxylic acid (int-EC18) was obtained using a similar method as described for the synthesis of 4-methyl-2-(6-(trifluoromethyl)pyridin-3-yl)thiazole-5-carboxylic acid (int-EC7), except that 6-(trifluoromethyl)pyridine-3-carbothioamide was replaced with tetrahydro-2H-pyran-4-carbothioamide. LCMS (Method b) m / z 228.1 [M+H] + ,t R = 0.60 minutes.

[0295] Synthesis of 4-chloro-2-methylthiazole-5-carboxylic acid (int-EC19) [ka] 4-Chloro-2-methylthiazole-5-carboxylic acid (int-EC19) was obtained using the same method as described in Step 2 for the synthesis of 4-chloro-2-(6-methoxypyridin-3-yl)thiazole-5-carboxylic acid (int-EC13), except that (6-methoxypyridin-3-yl)boronic acid was replaced with 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane, Pd(PPh) was replaced with Pd(dppf)Cl·CHCl, and dioxane was used as the solvent. LCMS (Method e) m / z 177.9 [M+H] + , t R = 0.38 minutes. 1 H NMR (DMSO-d6, 400 MHz): δ ppm 13.69 (s, 1H), 2.67 (s, 3H).

[0296] The table below lists the carboxylic acid type EC intermediates that we purchased. [Table 2-1] [Table 2-2] [Table 2-3]

[0297] Synthesis of N-(5-amino-1-methyl-1H-pyrazol-3-yl)isobutyramide (int-EC38) [ka] Step 1: Diphenylphosphoryl azidate (DPPA) (9.0 mL, 40.7 mmol) and EtN (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 h. 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 (NaSO), and concentrated to give the crude product, which was purified by column chromatography (20-70% ethyl acetate in cyclohexane) to give methyl 5-((tert-butoxycarbonyl)amino)-1-methyl-1H-pyrazole-3-carboxylate. LCMS (Method b) m / z 256.2 [M+H] + , t R = 0.78 minutes. 1 H NMR (400MHz, DMSO-d6) δ ppm 9.51 (s, 1H), 6.53 (s, 1H), 3.77 (s, 3H), 3.73 (s, 3H), 1.46 (s, 9H).

[0298] Step 2: 1M LiOH in HO (25 mL, 24.14 mmol) was added to a suspension of methyl 5-((tert-butoxycarbonyl)amino)-1-methyl-1H-pyrazole-3-carboxylate (3.0 g, 11.75 mmol) in THF (45 mL), and the mixture was stirred at room temperature for 2 h. 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 min, then filtered at low temperature 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 minutes. 1H NMR (400MHz, DMSO-d6) δ ppm 12.50 (s, 1H), 9.43 (s, 1H), 6.45 (s, 1H), 3.70 (s, 3H), 1.46 (s, 9H).

[0299] Step 3: DPPA (0.95 mL, 4.29 mmol) and EtN (0.44 mL, 3.15 mmol) were added to a solution of 5-((tert-butoxycarbonyl)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 h. 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 (NaSO), and concentrated to give the crude product, which was purified by column chromatography (10-50% ethyl acetate in cyclohexane) to give tert-butyl (1-methyl-1H-pyrazole-3,5-diyl)dicarbamate. LCMS (Method b) m / z 347.3 [M+H] + ,t R = 0.98 minutes. 1 H NMR(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).

[0300] Step 4: Benzyl tert-butyl (1-methyl-1H-pyrazole-3,5-diyl)dicarbamate (480 mg, 1.39 mmol) in MeOH (25 mL) was hydrogenated using H cube (total H, Pd / C cartridge, 30 °C, 1 h). 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 basic with concentrated NaOH and extracted with ethyl acetate. The organic layer was washed with brine, dried (NaSO), and concentrated to give tert-butyl (3-amino-1-methyl-1H-pyrazol-5-yl)carbamate. LCMS (Method b) m / z 213.4 [M+H] + , t R = 0.55 minutes. 1 H NMR (400MHz, DMSO-d6) δ ppm 9.00 (s, 1H), 5.28 (s, 1H), 4.39 (s, 2H), 3.36 (s, 3H), 1.44 (s, 9H).

[0301] Step 5: Pyridine (171 μL, 2.12 mmol) and EDC (162 mg, 0.848 mmol) were added to a solution of tert-butyl (3-amino-1-methyl-1H-pyrazol-5-yl)carbamate (90 mg, 0.424 mmol) and isobutyric acid (44 μL, 0.466 mmol) in acetonitrile (4 mL) at room temperature. After stirring for 18 minutes at room temperature, the reaction mixture was diluted with water, concentrated, and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried (NaSO), and concentrated to give tert-butyl (3-isobutylamino-1-methyl-1H-pyrazol-5-yl)carbamate. LCMS (Method b) m / z 283.5 [M+H] + ,t R = 0.77 minutes. 1 H 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).

[0302] Step 6: 4M HCl in dioxane (1.24 mL, 4.96 mmol) was added to a solution of tert-butyl (3-isobutyramido-1-methyl-1H-pyrazol-5-yl)carbamate (70 mg, 0.248 mmol) in CHCl (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 CHCl, concentrated, dissolved in EtO, and concentrated to give N-(5-amino-1-methyl-1H-pyrazol-3-yl)isobutyramide (int-EC38). LCMS (Method b) m / z 183.2 [M+H] + ,t R = 0.39 minutes. 1 H NMR(400 MHz,DMSO-d6) δ ppm 11.25 (s,1H),5.50 (s,1H),3.93 (s,3H),2.69-2.57 (m,1H),1.10 (d,J) = 6.8Hz,6H).

[0303] Synthesis of 5-amino-4-chloro-N-isopropylthiazole-2-carboxamide (int-EC39) [ka] Step 1: Diphenylphosphoryl azide (1.75 mL, 7.84 mmol) and EtN (0.80 mL, 5.75 mmol) were added to a solution of 4-chloro-2-(isopropylcarbamoyl)thiazole-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 h. 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 (NaSO), and concentrated. The crude product was purified by column chromatography (10-20% ethyl acetate in 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 minutes.1 H NMR(400MHz, DMSO-d6) δ ppm 10.60 (s, 1H), 8.51 (d, J = 8.4 Hz, 1H), 4.31-3.92 (m, 1H), 1.50 (s, 9H), 1.16 (d,J = 6.6 Hz,6 H).

[0304] Step 2: 4M HCl in dioxane (19 mL, 78 mmol) was added to a solution of tert-butyl (4-chloro-2-(isopropylcarbamoyl)thiazol-5-yl)carbamate (1.25 g, 3.91 mmol) in CHCl (36 mL) at room temperature, and the solution was stirred at room temperature for 16 hours. The reaction mixture was concentrated, and the oily residue was then dissolved in CHCl, concentrated, dissolved in EtO, and concentrated to give 5-amino-4-chloro-N-isopropylthiazole-2-carboxamide (int-EC39). LCMS (Method b) m / z 220.2 [M+H] + ,t R = 0.73 minutes. 1 H NMR (400 MHz, DMSO-d6) δppm 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).

[0305] Synthesis of 5-amino-N-(2,2-difluoroethyl)-1-methyl-1H-pyrazole-3-carboxamide (int-EC40) [ka] Step 1: EDC (574 mg, 3 mmol) was added to a solution of 5-((tert-butoxycarbonyl)amino)-1-methyl-1H-pyrazole-3-carboxylic acid (see Step 2 of the synthesis of int-EC38) (121 mg, 0.5 mmol), 2,2-difluoroethanamine (0.042 mL, 0.6 mmol), EtN (0.090 mL, 0.65 mmol), and HOBT (81 mg, 0.6 mmol) in CHCl (4 mL) at room temperature, and the reaction mixture was stirred at room temperature for 48 h. The mixture was then washed with saturated NaHCO and water, dried (NaSO), and concentrated. The crude product was purified by column chromatography (10-50% ethyl acetate in cyclohexane) to give tert-butyl (3-((2,2-difluoroethyl)carbamoyl)-1-methyl-1H-pyrazol-5-yl)carbamate. LCMS (Method b) m / z 305.3 [M+H] + ,t R = 0.78 minutes. 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).

[0306] Step 2: 4 M HCl in dioxane (1.3 mL, 5.2 mmol) was added to a solution of tert-butyl (3-((2,2-difluoroethyl)carbamoyl)-1-methyl-1H-pyrazol-5-yl)carbamate (79 mg 0.26 mmol) in CHCl (2.6 mmol) at room temperature, 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-H-pyrazole-3-carboxamide (int-EC40). LCMS (Method b) m / z 205.2 [M+H] + ,t R = 0.39 minutes. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.23 ​​(t, J = 6.2 Hz, 1 H), 6.05 (t, J = 56.3 Hz, 1 H), 5.78 (s, 1 H), 3.60-3.56 (m, 8 H).

[0307] Synthesis of 5-amino-N-isopropyl-4-methylthiazole-2-carboxamide (int-EC41) [ka] 5-Amino-N-isopropyl-4-methylthiazole-2-carboxamide (int-EC41) was obtained using a similar method as described for the synthesis of 5-amino-N-(2,2-difluoroethyl)-1-methyl-1H-pyrazole-3-carboxamide (int-EC40), except that 5-((tert-butoxycarbonyl)amino)-1-methyl-1H-pyrazole-3-carboxylic acid was replaced with 5-((tert-butoxycarbonyl)amino)-4-methylthiazole-2-carboxylic acid and 2,2-difluoroethanamine was replaced with propan-2-amine. LCMS (Method b) m / z 200.2 [M+H] + ,t R = 0.62 minutes. 1 H NMR(400 MHz,DMSO-d6) δ ppm 7.81 (d, J = 8.4 Hz, 1 H), 6.51 (s, 3 H), 4.10-3.92 (m, 1 H), 2.16 (s, 3 H), 1.13 (d, J = 6.6 Hz, 6H).

[0308] NOTE: 5-((tert-butoxycarbonyl)amino)-4-methylthiazole-2-carboxylic acid was obtained using the following procedure. Step 1: TFA (5.1 mL, 66.3 mmol) was added to a solution of 5-(tert-butyl) 2-ethyl 4-methylthiazole-2,5-dicarboxylate (see Step 1 of the synthesis of int-EC2) (0.9 g, 3.32 mmol) in CHCl (33 mL) at room temperature, and the mixture was stirred at room temperature for 2 hours. The reaction solution was then concentrated, and the oily residue was dissolved in CHCl, concentrated, dissolved in EtO, and concentrated under high vacuum to give 2-(ethoxycarbonyl)-4-methylthiazole-5-carboxylic acid. LCMS (Method b) m / z 216.1 [M+H] + , t R = 0.55 minutes. 1 H NMR (400MHz, DMSO-d6) δ ppm 13.87 (s, 1H), 4.38 (q, J = 7.1 Hz, 2H), 2.68 (s, 3H), 1.33 (t, J = 7.1 Hz, 3H).

[0309] 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-methylthiazole-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 h. After cooling to room temperature, the solvent was removed, and the residue was treated with water and extracted with ethyl acetate. The combined organic phases were washed with brine, dried (NaSO), and concentrated. The crude product was purified by column chromatography (20-40% ethyl acetate in cyclohexane) to give ethyl 5-((tert-butoxycarbonyl)amino)-4-methylthiazole-2-carboxylate. LCMS (Method b) m / z 287.2 [M+H] + ,t R = 1.00 minutes. 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 = 7.1Hz, 3H).

[0310] Step 3: 1M LiOH in HO (10 mL, 10 mmol) was added to a suspension of ethyl 5-((tert-butoxycarbonyl)amino)-4-methylthiazole-2-carboxylate (0.60 g, 2.1 mmol) in THF (20 mL), and the mixture was stirred at room temperature for 7 h. 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 min, then filtered at low temperature and dried under high vacuum to give 5-((tert-butoxycarbonyl)amino)-4-methylthiazole-2-carboxylic acid. LCMS (Method b) m / z 259.2 [M+H] + , t R = 0.62 minutes. 1 H NMR (400MHz, DMSO-d6) δ ppm 13.37 (s, 1H), 10.35 (s, 1H), 2.34 (s, 3H), 1.50 (s, 9H).

[0311] Synthesis of 5-amino-N-isopropyl-1-methyl-1H-pyrazole-3-carboxamide (int-EC42) [ka] 5-Amino-N-isopropyl-1-methyl-1H-pyrazole-3-carboxamide (int-EC42) was obtained using a similar method as described for the synthesis of 5-amino-N-(2,2-difluoroethyl)-1-methyl-1H-pyrazole-3-carboxamide (int-EC40), except replacing 2,2-difluoroethanamine with propan-2-amine. LCMS (Method b) m / z 183.1 [M+H] + , t R = 0.46 minutes. 1 H NMR(400 MHz,DMSO-d6) δppm 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).

[0312] Synthesis of 5-amino-N-isopropyl-1-methyl-1H-pyrazole-3-carboxamide (int-EC43) [ka] 5-Amino-N-isopropyl-1-methyl-1H-pyrazole-3-carboxamide (int-EC43) was obtained using a similar method as described for the synthesis of 5-amino-N-(2,2-difluoroethyl)-1-methyl-1H-pyrazole-3-carboxamide (int-EC40), except replacing 2,2-difluoroethanamine with 2,2,2-trifluoroethanamine. LCMS (Method b) m / z 223.2 [M+H] + ,t R = 0.48 minutes. 1 H NMR (400 MHz, DMSO-d6) δppm 8.38 (t, J = 6.7 Hz, 1 H), 5.72 (s, 1 H), 3.94-3.91 (m, 5 H), 3.59 (s, 3 H).

[0313] Synthesis of N-(5-amino-1-methyl-1H-pyrazol-3-yl)-2-fluorobenzamide (int-EC44) [ka] N-(5-amino-1-methyl-1H-pyrazol-3-yl)-2-fluorobenzamide (int-EC44) was obtained using a similar method as described for the synthesis of N-(5-amino-1-methyl-1H-pyrazol-3-yl)isobutyramide (int-EC38), except that isobutyric acid (step 5) was replaced with 2-fluorobenzoic acid. LCMS (method b) m / z 235.2 [M+H] + ,t R = 0.54 minutes. 1H 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).

[0314] Synthesis of N-(5-amino-1-methyl-1H-pyrazol-3-yl)-2,2,3,3,3-pentafluoropropanamide (int-EC45) [ka] Step 1: A solution of 1-methyl-3,5-dinitro-1H-pyrazole (1.0 g, 5.81 mmol) in MeOH (110 mL) was hydrogenated using an H cube (10% Pd / C, total H2 conditions, 30 °C). The solution was then concentrated to give 1-methyl-1H-pyrazole-3,5-diamine, which was used in the next step without further purification. LCMS (Method b) m / z 113.1 [M+H] + , t R = 0.68 minutes. 1 H NMR (400MHz, DMSO-d6) δ ppm 4.86 (s, 2H), 4.57 (s, 1H), 4.11 (s, 2H), 3.25 (s, 3H).

[0315] 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-pentafluoropropanoic 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 at room temperature for 18 hours. The reaction was treated with water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried (NaSO), and concentrated. The crude product was purified by column chromatography (40–80% ethyl acetate in cyclohexane) to give N-(5-amino-1-methyl-1H-pyrazol-3-yl)-2,2,3,3,3-pentafluoropropanamide (int-EC45). LCMS (method b) m / z 259.1 [M+H] + , t R = 0.64 minutes. 1 H NMR (400MHz, DMSO-d6) δ ppm 1.66 (s, 1H), 5.64 (s, 1H), 5.35 (s, 2H), 3.47 (s, 3H).

[0316] Synthesis of 3-(3-cyclopropylisoxazol-5-yl)-1-methyl-1H-pyrazol-5-amine (int-EC46) [ka] Step 1: A mixture of 3-cyclopropylisoxazole-5-carboxylic acid (1.0 g, 6.53 mmol) in 1.25 M HCl in MeOH (15 mL, 18.75 mmol) was heated in a microwave oven at 100° C. for 40 minutes. After cooling to room temperature, the solvent was removed, the residue was dissolved in MeOH, and the solvent was removed. After repeating this step three times, methyl 3-cyclopropylisoxazole-5-carboxylate was obtained. LCMS (Method b) m / z 168.1 [M+H] + ,t R = 0.84 minutes. 1H 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).

[0317] Step 2: Acetonitrile (0.687 mL, 13.16 mmol) was added to a solution of 1.6 M n-BuLi in hexane (8.23 mL, 13.16 mmol) in THF (25 mL) at −78° C. After stirring the reaction mixture at −78° C. for 20 minutes, a solution of methyl 3-cyclopropylisoxazole-5-carboxylate (1.1 g, 6.58 mmol) in THF (25 mL) was added dropwise at −78° C. The reaction mixture was then stirred at −78° C. for 2 hours, after which the reaction mixture was quenched by adding 2 N aqueous HCl at −78° C. It was then treated with ethyl acetate and 2 N 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-cyclopropylisoxazol-5-yl)-3-oxopropanenitrile. LCMS (Method b) m / z 175.1 [M−H], t R = 0.73 minutes.

[0318] Step 3: A solution of 3-(3-cyclopropylisoxazol-5-yl)-3-oxopropanenitrile (1.2 g, 6.81 mmol) and methylhydrazine (1.0 mL, 19.10 mmol) in EtOH (60 mL) was stirred at reflux for 16 h. After cooling to room temperature, the reaction mixture was concentrated and redissolved in EtOH. It was then evaporated to dryness. The crude product was purified by column chromatography (0-100% ethyl acetate in cyclohexane containing 2% (3.5 M NH3 in methanol)) to give 3-(3-cyclopropylisoxazol-5-yl)-1-methyl-1H-pyrazol-5-amine (int-EC46). LCMS (Method b) m / z 205.1 [M+H] + , t R = 0.65 minutes. 1H NMR(400MHz, 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).

[0319] Synthesis of 1-methyl-3-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-amine (int-EC47) [ka] 1-Methyl-3-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-amine (int-EC47) was obtained using the same method as described in steps 2-3 of the synthesis of 3-(3-cyclopropylisoxazol-5-yl)-1-methyl-1H-pyrazol-5-amine (int-EC46), except replacing 3-cyclopropylisoxazole-5-carboxylate (step 2) with methyl 6-(trifluoromethyl)nicotinate. LCMS (Method b) m / z 243.1 [M+H] + ,t R = 0.75 minutes. 1 H NMR(400 MHz,DMSO-d6) δ ppm 9.04 (d, J = 2.1 Hz, 1 H), 8.26 (dd, J = 8.4, 2.1 Hz, 1H), 7.84 (d, J = 8.2 Hz, 1H), 5.90 (s, 1H), 5.46 (s, 2H), 3.61 (s, 3H).

[0320] Note that methyl 6-(trifluoromethyl)nicotinate was obtained using the following procedure: A 2M solution of trimethylsilyldiazomethane in hexanes (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 h, the reaction mixture was concentrated, washed with water, and extracted with ethyl acetate. The combined organics were washed with saturated aqueous NaHCO3, dried (MgSO4), and concentrated. The crude product was purified by column chromatography (0-50% ethyl acetate in cyclohexane) to give methyl 6-(trifluoromethyl)nicotinate. LCMS (Method b) m / z 206.0 [M+H] + , t R = 0.93 minutes. 1 H NMR(400 MHz,DMSO-d6) δ ppm 9.24 (d, J = 2.1 Hz, 1 H), 8.57 (dd, J = 8.3, 1.7 Hz, 1 H), 8.09 (d, J = 8.2 Hz, 1 H), 3.94(s, 3H).

[0321] Synthesis of 4-chloro-2-(1-methyl-1H-pyrazol-3-yl)thiazol-5-amine (int-EC48) [ka] Step 1: A mixture of 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboralon-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-dichlorothiazole-5-carboxylic acid (int-EC13, Step 1, 500 mg, 2.52 mmol) in DME (13 mL) was heated to 80 °C for 5 h. 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 in the cold to give 4-chloro-2-(1-methyl-1H-pyrazol-3-yl)thiazole-5-carboxylic acid. LCMS (Method b) m / z 243.9 [M+H] + ,t R= 0.52 minutes. 1 H NMR (400MHz, 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).

[0322] 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)thiazole-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 h. 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 (Na SO ), and concentrated. The crude product was purified by column chromatography (10-30% ethyl acetate in cyclohexane) to give tert-butyl (4-chloro-2-(1-methyl-1H-pyrazol-3-yl)thiazol-5-yl)carbamate. LCMS (Method b) m / z 315.2 [M+H] + , t R = 1.01 minutes. 1 H NMR(400 MHz,DMSO-d6) δ ppm 10.22 (s, 1H) 7.83 (d, J = 2.2 Hz, 1H) 6.68 (d, J = 2.3 Hz, 1H) 3.90 (s, 3H) 1.49 (s, 9H).

[0323] Step 3: 4M HCl in dioxane (7.6 mL, 30.5 mmol) was added to a solution of tert-butyl (4-chloro-2-(1-methyl-1H-pyrazol-3-yl)thiazol-5-yl)carbamate (400 mg, 1.27 mmol) in CHCl (25 mL) at room temperature. The reaction mixture was stirred at room temperature for 18 hours and then cooled to 0 °C. The solid was filtered off, washed with EtO, and dried under high vacuum to give 4-chloro-2-(1-methyl-1H-pyrazol-3-yl)thiazol-5-amine (int-EC48). LCMS (Method b) m / z 215.2 [M+H] + , t R = 0.61 minutes. 1 H NMR (400 MHz, DMSO-d6): δ ppm 7.75 (d, J = 2.20 Hz, 1 H) 6.55 (d, J = 2.20 Hz, 1 H) 6.37 (s, 3 H) 3.85 (s, 3 H).

[0324] Synthesis of 1-methyl-3-(5-methylpyridin-3-yl)-1H-pyrazol-5-amine (int-EC49) [ka] 1-Methyl-3-(5-methylpyridin-3-yl)-1H-pyrazol-5-amine (int-EC49) was obtained using the same method as described in steps 2-3 for the synthesis of 3-(3-cyclopropylisoxazol-5-yl)-1-methyl-1H-pyrazol-5-amine (int-EC46), except that in step 2, 3-cyclopropylisoxazol-5-carboxylate was replaced with methyl 5-methylnicotinate. LCMS (Method b) m / z 189.1 [M+H] + , t R = 0.38 minutes. 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).

[0325] Synthesis of N-(5-amino-1-methyl-1H-pyrazol-3-yl)-2,3-difluorobenzamide (int-EC50) [ka] N-(5-amino-1-methyl-1H-pyrazol-3-yl)-2,3-difluorobenzamide (int-EC50) was obtained using a similar method as described for the synthesis of N-(5-amino-1-methyl-1H-pyrazol-3-yl)isobutyramide (int-EC38), except that isobutyric acid (step 5) was replaced with 2,3-fluorobenzoic acid. LCMS (method b) m / z 253.1 [M+H] + , t R = 0.58 minutes. 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).

[0326] Synthesis of (S)-5-amino-N-(1-fluoropropan-2-yl)-1-methyl-1H-pyrazole-3-carboxamide (int-EC51) [ka] (S)-5-Amino-N-(1-fluoropropan-2-yl)-1-methyl-1H-pyrazole-3-carboxamide (int-EC51) was obtained using a similar method as described for the synthesis of 5-amino-N-(2,2-difluoroethyl)-1-methyl-1H-pyrazole-3-carboxamide (int-EC40), except that 2,2-difluoroethanamine was replaced with (S)-1-fluoropropan-2-amine (Step 3). LCMS (Method b) m / z 201.2 [M+H] + , t R= 0.42 minutes. 1 H NMR(400 MHz,DMSO-d6) δ ppm 7.77(d, J = 8.5 Hz, 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).

[0327] Synthesis of 2-(5-fluoropyridin-3-yl)-4-methylthiazol-5-amine (int-EC52) [ka] Step 1: A solution of di-tert-butyl dicarbonate (2.237 mL, 9.63 mmol) in methanol (20 mL) was added dropwise to a solution 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 h. After removal of the solvent, the residue was dissolved in CHCl, and the solution was washed with water and saturated NaHCO, dried (MgSO), and concentrated. The crude product was purified by column chromatography (5-30% ethyl acetate in cyclohexane) to give tert-butyl (4-methylthiazol-5-yl)carbamate. LCMS (Method b) m / z 215.1 [M+H] + , t R = 0.81 minutes. 1 H NMR (400MHz, DMSO-d6) δ ppm 9.74 (s, 1H), 8.54 (s, 1H), 2.26 (s, 3H), 1.47 (s, 9H).

[0328] Step 2: NBS (0.640 g, 3.59 mmol) was added to a solution of tert-butyl (4-methylthiazol-5-yl)carbamate (0.70 g, 3.27 mmol) in CHCl (35 mL) at room temperature, and the mixture was stirred at room temperature for 1 h. The reaction mixture was then concentrated, and the residue was purified by column chromatography (5-20% ethyl acetate in cyclohexane) to give tert-butyl (2-bromo-4-methylthiazol-5-yl)carbamate. LCMS (Method b) m / z 293.0 [M+H] + , t R = 1.08 minutes. 1 H NMR (400MHz, DMSO-d6) δ ppm 10.23 (s, 1H), 2.24 (s, 3H), 1.47 (s, 9H).

[0329] Step 3: PdCl2dppf (52.4 mg, 0.072 mmol) was added to a degassed mixture of tert-butyl (2-bromo-4-methylthiazol-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, and the mixture was then heated in a microwave oven at 100° C. for 30 min. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and filtered through a Celite pad. The crude product was purified by preparative HPLC (Waters X-Bridge C18 OBD, 5 μm, 30 × 100 mm, eluent A: HO + 7.3 mM NH4OH, B: CH3CN + 7.3 mM NH4OH, gradient: 20 to 99% B in 12.5 min, hold 2.5 min, flow rate 45 mL / min) to give tert-butyl (2-(5-fluoropyridin-3-yl)-4-methylthiazol-5-yl)carbamate. LCMS (Method b) m / z 310.1 [M+H] + ,t R = 1.07 minutes. 1H 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).

[0330] Step 4: tert-Butyl (2-(5-fluoropyridin-3-yl)-4-methylthiazol-5-yl)carbamate (20 mg, 0.065 mmol) was treated with 4 M HCl in dioxane (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 minutes.

[0331] Synthesis of 1-methyl-3-(5-methylisoxazol-3-yl)-1H-pyrazol-5-amine (int-EC53) [ka] 1-Methyl-3-(5-methylisoxazol-3-yl)-1H-pyrazol-5-amine (int-EC53) was obtained using the same method as described in Step 3 for the synthesis of 3-(3-cyclopropylisoxazol-5-yl)-1-methyl-1H-pyrazol-5-amine (int-EC46), except replacing 3-(3-cyclopropylisoxazol-5-yl)-3-oxopropanenitrile with 3-(5-methylisoxazol-3-yl)-3-oxopropanenitrile. LCMS (Method b) m / z 179.0 [M+H] + ,t R = 0.52 minutes. 1 H NMR (400MHz, DMSO-d6) δ ppm 6.38 (s, 1H), 5.64 (s, 1H), 5.37 (s, 2H), 3.57 (s, 3H), 2.40 (s, 3H).

[0332] Synthesis of 3-(5-ethylisoxazol-3-yl)-1-methyl-1H-pyrazol-5-amine (int-EC54) [ka] 3-(5-Ethylisoxazol-3-yl)-1-methyl-1H-pyrazol-5-amine (int-EC54) was obtained using the same method as described in steps 2-3 for the synthesis of 3-(3-cyclopropylisoxazol-5-yl)-1-methyl-1H-pyrazol-5-amine (int-EC46), except that methyl 3-cyclopropylisoxazol-5-carboxylate (step 2) was replaced with ethyl 5-ethylisoxazol-3-carboxylate. LCMS (method b) m / z 193.1 [M+H] + ,t R = 0.64 minutes. 1 H NMR(400 MHz,DMSO-d6) δ ppm 6.41 (t, J = 0.9 Hz, 1 H), 5.66 (s, 1 H), 5.39 (s, 2 H), 3.58 (s, 3 H), 2.76 (qd, J = 7.6, 0.9 Hz, 2H), 1.24 (t, J = 7.6 Hz, 16H).

[0333] Synthesis of 1-ethyl-3-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-amine (int-EC55) [ka] 1-Ethyl-3-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-amine (int-EC55) was obtained using the same method as described in steps 2-3 for the synthesis of 3-(3-cyclopropylisoxazol-5-yl)-1-methyl-1H-pyrazol-5-amine (int-EC46), except that methyl 3-cyclopropylisoxazol-5-carboxylate (step 2) was replaced with methyl 6-(trifluoromethyl)nicotinate and methylhydrazine (step 3) was replaced with ethylhydrazine. LCMS (Method b) m / z 257.1 [M+H] + ,t R = 0.83 minutes. 1 H NMR(400 MHz,DMSO-d6) δ ppm 9.03 (s, 1 H), 8.26 (d, J = 8.2 Hz, 1 H), 7.84 (d, J = 8.2 Hz, 1 H), 5.89 (s, 1 H), 5.44 (s, 2H), 3.97 (q, J = 7.9, 7.2 Hz, 2 H), 1.28 (t, J = 7.0 Hz, 3 H).

[0334] Note that methyl 6-(trifluoromethyl)nicotinate was obtained using the procedure described for the synthesis of 1-methyl-3-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-amine (int-EC47).

[0335] Synthesis of 1-ethyl-3-(furan-2-yl)-1H-pyrazol-5-amine (int-EC56) [ka] 1-Ethyl-3-(furan-2-yl)-1H-pyrazol-5-amine (int-EC56) was obtained using the same method as described in steps 2-3 for the synthesis of 3-(3-cyclopropylisoxazol-5-yl)-1-methyl-1H-pyrazol-5-amine (int-EC46), except that methyl 3-cyclopropylisoxazole-5-carboxylate (step 2) was replaced with 3-(furan-2-yl)-3-oxopropanenitrile, and methyl hydrazine (step 3) was replaced with ethyl hydrazine. LCMS (method b) m / z 178.1 [M+H] + ,t R = 0.59 minutes. 1 H NMR(400 MHz,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).

[0336] Synthesis of 3-(3-ethylisoxazol-5-yl)-1-methyl-1H-pyrazol-5-amine (int-EC57) [ka] 3-(3-Ethylisoxazol-5-yl)-1-methyl-1H-pyrazol-5-amine (int-EC57) was obtained using the same method as described for the synthesis of 3-(3-cyclopropylisoxazol-5-yl)-1-methyl-1H-pyrazol-5-amine (int-EC46), except that 3-cyclopropylisoxazol-5-carboxylic acid (Step 1) was replaced with 3-ethylisoxazol-5-carboxylic acid. LCMS (Method b) m / z 193.1 [M+H] + ,t R = 0.62 minutes. 1H 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).

[0337] Synthesis of 3-(5-fluoropyridin-2-yl)-1-methyl-1H-pyrazol-5-amine (int-EC58) [ka] 3-(5-Fluoropyridin-2-yl)-1-methyl-1H-pyrazol-5-amine (int-EC58) was obtained using the same method as described for the synthesis of 3-(3-cyclopropylisoxazol-5-yl)-1-methyl-1H-pyrazol-5-amine (int-EC46), except that 3-cyclopropylisoxazol-5-carboxylic acid (step 1) was replaced with 5-fluoropicolinic acid. LCMS (method b) m / z 193.1 [M+H] + , t R = 0.54 minutes. 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).

[0338] Synthesis of 3-chloro-1-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-4-amine (int-EC59) [ka] Step 1: Concentrated HCl (14.5 mL) was added to a mixture of 4-nitro-1H-pyrazole (2.0 g, 17.7 mmol) in EtOH (24 mL) at room temperature, and the mixture was purged with argon for 10 minutes while stirring. Alumina-supported Pd (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 hours. The mixture was then filtered through a Celite pad, and the biphasic mixture was separated. 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-pyrazol-4-amine was obtained as the HCl salt. 1 H NMR (400MHz, DMSO-d6) δ ppm 10.50 (s, 3H), 8.02 (s, 1H), 7.74 (s, 1H).

[0339] Step 2: BoC0 (3.74 g, 17.1 mmol) was added to a mixture of 3-chloro-1H-pyrazol-4-amine (2.4 g, 15.6 mmol) and NaHCO (2.88 g, 34.3 mmol) in THF (28 mL) / HO (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 (NaSO), and concentrated to give an oil. After treatment with cyclohexane and brief heating, a suspension formed, which was filtered off, washed with cyclohexane, and dried to give tert-butyl (3-chloro-1H-pyrazol-4-yl)carbamate. LCMS (Method b): m / z 218.2 [M+H] + ,t R = 0.75 minutes. 1H NMR (400 MHz, CDCl3) δ (ppm) 7.89 (s, 1H), 7.64 (s, 1H), 6.25 (s, 1H), 1.42 (s, 9H).

[0340] Step 3: tert-Butyl (3-chloro-1H-pyrazol-4-yl)carbamate (408 mg, 1.5 mmol), 5-iodo-2-(trifluoromethyl)pyridine (491 mg, 1.8 mmol), KPO (637 mg, 3 mmol), and CuCl (30 mg, 0.3 mmol) in anhydrous acetonitrile (6 mL) were treated with N,N'-dimethylethylenediamine (331 mg, 3.75 mmol), and the mixture was heated at 75 °C for 1 h. After cooling to room temperature, the mixture was filtered through a Celite pad and washed with acetonitrile. The filtrate was then concentrated, redissolved in acetonitrile (10 mL), and treated with water (20 mL) to give a solid, which was filtered off and washed with water. The solid was then dissolved in ethyl acetate, washed with brine, dried (NaSO), and concentrated. The crude product was purified by column chromatography (10-20% ethyl acetate in cyclohexane) to give tert-butyl (3-chloro-1-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazole-4-)carbamate. LCMS (Method b) m / z 363.1 [M+H] + ,t R = 1.23 minutes. 1 H NMR(400MHz, CDCl3) δ ppm 9.05 (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).

[0341] Step 4: tert-Butyl (3-chloro-1-(6-trifluoromethyl)pyridin-3-yl)-1H-pyrazol-4-yl)carbamate (330 mg, 0.91 mmol) in CHCl (0.91 mL) was treated with TFA (0.91 mL, 11.8 mmol), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was then diluted with CHCl and treated with saturated NaHCO. The aqueous phase was extracted with CHCl, and the combined organic layers were washed with brine, dried (NaSO), and concentrated 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 minutes. 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).

[0342] Synthesis of N-(5-amino-1-methyl-1H-pyrazol-3-yl)pivalamide (int-EC60) [ka] N-(5-amino-1-methyl-1H-pyrazol-3-yl)pivalamide (int-EC60) was obtained using a similar method as described for the synthesis of N-(5-amino-1-methyl-1H-pyrazol-3-yl)isobutyramide (int-EC38), except that isobutyric acid (step 5) was replaced with pivalic acid. LCMS (method b) m / z 197.2 [M+H] + ,t R = 0.48 minutes. 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).

[0343] Synthesis of 1-methyl-3-(3-methylisoxazol-5-yl)-1H-pyrazol-5-amine (int-EC61) [ka] 1-Methyl-3-(3-methylisoxazol-5-yl)-1H-pyrazol-5-amine (int-EC61) was obtained using the same method as described in Steps 2-3 for the synthesis of 3-(3-cyclopropylisoxazol-5-yl)-1-methyl-1H-pyrazol-5-amine (int-EC46), except replacing methyl 3-cyclopropylisoxazol-5-carboxylate (Step 2) with methyl 3-methylisoxazol-5-carboxylate. LCMS (Method b) m / z 179.1 [M+H] + ,t R = 0.51 minutes. 1 H NMR (400 MHz, DSMO-d6) δ ppm 6.46 (s, 1H), 5.69 (s, 1H), 3.59 (s, 3H), 2.24 (s, 3H) (NH2 not observed).

[0344] Synthesis of 5-amino-N-isopropylthiazole-2-carboxamide (int-EC62) [ka] 5-Amino-N-isopropylthiazole-2-carboxamide (int-EC62) was obtained using a similar method as described for the synthesis of 5-amino-N-(2,2-difluoroethyl)-1-methyl-1H-pyrazole-3-carboxamide (int-EC40), except for replacing 5-((tert-butoxycarbonyl)amino)-1-methyl-1H-pyrazole-3-carboxylic acid with 5-((tert-butoxycarbonyl)amino)thiazole-2-carboxylic acid and 2,2-difluoroethanamine with propan-2-amine. LCMS (Method b) m / z 186.1 [M+H] + , t R = 0.54 minutes.

[0345] Synthesis of 3-methyl-1-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-4-amine (int-EC63) [ka] Step 1: To a solution of 3-methyl-4-nitro-1H-pyrazole (1.0 g, 7.78 mmol) in DMF (100 mL) were added (6-(trifluoromethyl)pyridin-3-yl)boronic acid (2.253 g, 11.80 mmol), Cu(OAc) (0.471 g, 2.36 mmol), and pyridine (0.255 mL, 3.15 mmol), and the solution was stirred at 100 °C under an oxygen atmosphere for 24 h. After cooling to room temperature, the DMF was evaporated, and the residue was diluted with ethyl acetate and extracted with HO. The aqueous layer was extracted again with ethyl acetate, and the combined organic layers were dried and evaporated to dryness to give the crude product, which was purified by column chromatography (0-60% ethyl acetate in cyclohexane) to give 5-(3-methyl-4-nitro-1H-pyrazol-1-yl)-2-(trifluoromethyl)pyridine. LCMS (method b) m / z 273.0 [M+H] + ,t R = 1.08 minutes. 1 H 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).

[0346] Step 2: 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) was hydrogenated using an H cube (10% Pd / C, 1 atm, 30 °C). The solution was then concentrated, and the crude product was dissolved in CHCl and washed with 2N HCl. The aqueous layer was made basic with 2N NaOH and extracted three times with CHCl. ​​The combined organic layers were 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 minutes. 1 H NMR(400 MHz,DMSO-d6) δ ppm 9.08 (d, J = 2.6 Hz, 1 H), 8.23 ​​(dd, J = 8.7, 2.6 Hz, 1 H), 7.91 (d, J =8.7 Hz, 1H), 7.79 (s, 1H), 4.32 (s, 2H), 2.18 (s, 3H).

[0347] Synthesis of 1-methyl-3-(pyridin-2-yl)-1H-pyrazol-5-amine (int-EC64) [ka] 1-Methyl-3-(pyridin-2-yl)-1H-pyrazol-5-amine (int-EC64) was obtained using a similar method as described for the synthesis of 3-(3-cyclopropylisoxazol-5-yl)-1-methyl-1H-pyrazol-5-amine (int-EC46), except that 3-(3-cyclopropylisoxazol-5-yl)-3-oxopropanenitrile was replaced with 3-oxo-3-(pyridin)-2-yl)propanenitrile. LCMS (Method b) m / z 175.1 [M+H] + ,t R = 0.36 minutes. 1H NMR(400 MHz,DMSO-d6) δ ppm 8.49 (d, J = 4.5 Hz, 1 H), 7.80 (d, J = 7.9 Hz, 1 H), 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).

[0348] Synthesis of 4-chloro-2-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)thiazol-5-amine (int-EC65) [ka] 1-Methyl-3-(pyridin-2-yl)-1H-pyrazol-5-amine (int-EC64) was obtained using the same method as described for the synthesis of 4-chloro-2-(1-methyl-1H-pyrazol-3-yl)thiazol-5-amine (int-EC48), except that 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Step 2) was replaced with 1-(oxetan-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. LCMS (Method b) m / z 257.0 [M+H] + ,t R = 0.56 minutes. 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).

[0349] Synthesis of 1-cyclopropyl-3-(furan-2-yl)-1H-pyrazol-5-amine (int-EC66) [ka] 1-Cyclopropyl-3-(furan-2-yl)-1H-pyrazol-5-amine (int-EC66) was obtained using the same method as described in Step 3 for the synthesis of 3-(3-cyclopropylisoxazol-5-yl)-1-methyl-1H-pyrazol-5-amine (int-EC46), except for replacing 3-(3-cyclopropylisoxazol-5-yl)-3-oxopropanenitrile with 3-(furan-2-yl)-3-oxopropanenitrile and replacing methylhydrazine with cyclopropylhydrazine. LCMS (Method b) m / z 190.1 [M+H] + ,t R = 0.64 minutes. 1 H NMR(400 MHz,DMSO-d6) δ ppm 7.58(d, J = 1.7 Hz, 1 H), 6.50 (d, J = 3.3 Hz,1 H), 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).

[0350] Synthesis of 3-(6-methoxypyridin-3-yl)-1-methyl-1H-pyrazol-5-amine (int-EC67) [ka] 3-(6-Methoxypyridin-3-yl)-1-methyl-1H-pyrazol-5-amine (int-EC67) was obtained using the same method as described in steps 2-3 for the synthesis of 3-(3-cyclopropylisoxazol-5-yl)-1-methyl-1H-pyrazol-5-amine (int-EC46), except replacing methyl 3-cyclopropylisoxazol-5-carboxylate with methyl 6-methoxynicotinate. LCMS (Method b) m / z 205.1 [M+H] + ,t R = 0.57 minutes. 1H NMR(400 MHz,DMSO-d6) δ ppm 8.41 (d, J = 2.2 Hz, 1 H), 7.94 (dd, J = 8.6,2.3 Hz, 1 H), 6.79 (d, 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).

[0351] Synthesis of 1-methyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-amine (int-EC68) [ka] 1-Methyl-3-(5-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-5-amine (int-EC68) was obtained using the same method as described in steps 2-3 for the synthesis of 3-(3-cyclopropylisoxazol-5-yl)-1-methyl-1H-pyrazol-5-amine (int-EC46), except replacing methyl 3-cyclopropylisoxazole-5-carboxylate with methyl 5-(trifluoromethyl)nicotinate. LCMS (Method b) m / z 243.1 [M+H] + ,t R = 0.74 minutes. 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).

[0352] Synthesis of 4-chloro-2-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)thiazol-5-amine (int-EC69) [ka] 4-Chloro-2-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)thiazol-5-amine (int-EC69) was obtained using the same method as described for the synthesis of 4-chloro-2-(1-methyl-1H-pyrazol-3-yl)thiazol-5-amine (int-EC48), except that 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Step 2) was replaced with 1-(2-methoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2)-yl)-1H-pyrazole. LCMS (Method b) m / z 259.0 [M+H] + ,t R = 0.62 minutes. 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).

[0353] Synthesis of 1-ethyl-3-(3-methylisoxazol-5-yl)-1H-pyrazol-5-amine (int-EC70) [ka] 1-Ethyl-3-(3-methylisoxazol-5-yl)-1H-pyrazol-5-amine (int-EC70) was obtained using the same method as described in Steps 2-3 for the synthesis of 3-(3-cyclopropylisoxazol-5-yl)-1-methyl-1H-pyrazol-5-amine (int-EC46), except that methyl 3-cyclopropylisoxazol-5-carboxylate (Step 2) was replaced with methyl 3-methylisoxazol-5-carboxylate and methylhydrazine (Step 3) was replaced with ethylhydrazine. LCMS (Method b) m / z 193.1 [M+H] + ,t R = 0.58 minutes. 1H 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).

[0354] Synthesis of 5-amino-N-cyclopropyl-1-methyl-1H-pyrazole-3-carboxamide (int-EC71) [ka] 5-Amino-N-cyclopropyl-1-methyl-1H-pyrazole-3-carboxamide (int-EC71) was obtained using a similar method as described for the synthesis of 5-amino-N-(2,2-difluoroethyl)-1-methyl-1H-pyrazole-3-carboxamide (int-EC40), except replacing 2,2-difluoroethanamine with cyclopropylamine. LCMS (Method b) m / z 181.2 [M+H] + ,t R = 0.38 minutes. 1 H 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 + is not permitted).

[0355] Synthesis of 4-chloro-2-(1-(difluoromethyl)-1H-pyrazol-4-yl)thiazol-5-amine (int-EC72) [ka] 4-Chloro-2-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)thiazol-5-amine (int-EC72) was obtained using the same method as described for the synthesis of 4-chloro-2-(1-methyl-1H-pyrazol-3-yl)thiazol-5-amine (int-EC48), except that 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (step 2) was replaced with 1-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2)-yl)-1H-pyrazole. LCMS (Method b) m / z 251.1 [M+H] , t R = 0.73 minutes. 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 + is hidden in the water peaks).

[0356] Synthesis of 1-methyl-3-(6-methylpyridin-3-yl)-1H-pyrazol-5-amine (int-EC73) [ka] 1-Methyl-3-(6-methylpyridin-3-yl)-1H-pyrazol-5-amine (int-EC73) was obtained using the same method as described in steps 2-3 for the synthesis of 3-(3-cyclopropylisoxazol-5-yl)-1-methyl-1H-pyrazol-5-amine (int-EC46), except replacing methyl 3-cyclopropylisoxazol-5-carboxylate with methyl 6-methoxynicotinate. LCMS (Method b) m / z 189.1 [M+H] + ,t R = 0.35 minutes. 1H 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).

[0357] Synthesis of methyl 5-amino-1-methyl-1H-pyrazole-3-carboxylate (int-EC74) [ka] Methyl 5-amino-1-methyl-1H-pyrazole-3-carboxylate (int-EC74) was obtained using a similar method as described for the synthesis of 5-amino-4-chloro-N-isopropylthiazole-2-carboxamide (int-EC39), except that 4-chloro-2-(isopropylcarbamoyl)thiazole-5-carboxylic acid was replaced with 3-(methoxycarbonyl)-1-methyl-1H-pyrazole-5-carboxylic acid. LCMS (Method b) m / z 156.2 [M+H] + ,t R = 0.36 minutes. 1 H NMR (400MHz, DMSO-d6) δ ppm 6.89 (s, 3H), 5.74 (s, 1H), 3.72 (s, 3H), 3.59 (s, 3H).

[0358] Synthesis of 4-chloro-2-(6-(trifluoromethyl)pyridin-3-yl)thiazol-5-amine (int-EC75) [ka] 4-Chloro-2-(6-(trifluoromethyl)pyridin-3-yl)thiazol-5-amine (int-EC75) was obtained using the same method as described for the synthesis of 5-amino-4-chloro-N-isopropylthiazole-2-carboxamide (int-EC39), except that 4-chloro-2-(isopropylcarbamoyl)thiazole-5-carboxylic acid (int-EC9) was replaced with 4-chloro-2-(6-(trifluoromethyl)pyridin-3-yl)thiazole-5-carboxylic acid (int-EC6). LCMS (Method b) m / z 280.0 [M+H] + ,t R = 1.00 minutes. 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).

[0359] The table below lists the amine-type EC intermediates that were purchased. [Table 3]

[0360] Synthesis of example compounds 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]diazepin-10-yl)amino)propyl)thiazole-2,5-dicarboxamide (1) [ka] Step 1: To a solution of (S)-10-amino-2,3,5,10-tetrahydro-1H,11H-benzo[d]pyrazolo[1,2-a][1,2]diazepin-11-one (int-A1) (5.0 g, 11.12 mmol) in CHCN (50 mL) was added (R)-3-((tert-butoxycarbonyl)amino)-2-methylpropanoic acid (int-L9) (2.26 g, 11.12 mmol), DIPEA (5.83 mL, 33.4 mmol), and TOTU (3.65 g, 11.12 mmol). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was then concentrated, and the crude product was dissolved in ethyl acetate, washed with 1 N HCl and saturated NaHCO, dried (MgSO), and concentrated to give an oil, which was treated with cold EtO to crystallize the product. The resulting precipitate was collected by filtration and dried under vacuum to give tert-butyl ((R)-2-methyl-3-oxo-3-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazepin-10-yl)amino)propyl)carbamate. LCMS (Method a) m / z 403.1 [M+H] + ,t R = 0.92 minutes. 1 H NMR(400 MHz,DMSO-d6) δ ppm: 8.21 (d, J = 8.8 Hz, 1 H), 7.29 (d, J = 7.9 Hz, 1 H), 7.23 (t, J = 7.4 Hz, 1 H), 7.15 (t, J = 7.6 Hz, 1H), 7.06 (d, J = 7.6 Hz, 1H), 6.80 (d, J = 4.0 Hz, 1H), 6.70 (d, J = 8.7 Hz, 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).

[0361] Step 2: tert-Butyl ((R)-2-methyl-3-oxo-3-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazepin-10-yl)amino)propyl)carbamate (4.92 g, 11.0 mmol) was dissolved in 4 N HCl (50 mL), and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated, and then CHCN / EtO was added. The resulting precipitate was filtered off, washed with cold EtO, 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]diazepin-10-yl)propanamide. LCMS (method a) m / z 303 [M+H] + ,t R = 0.41 minutes. 1 H NMR(400 MHz,DMSO-d6) δ ppm: 8.74 (d, J = 9.2 Hz, 1 H), 7.79 (s, 3 H), 7.31 (d, J = 7.7 Hz, 1 H), 7.24 (t, J = 7.0 Hz, 1 H), 7.18 (t, J = 7.0 Hz, 1 H), 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).

[0362] Step 3: 4-Methyl-2-(methylcarbamoyl)thiazole-5-carboxylic acid (int-EC4) (10 mg, 0.04 mmol) and EDC (14.71 mg, 0.077 mmol) were added to a solution of (R)-3-amino-2-methyl-N-((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazepin-10-yl)propanamide (13 mg, 0.038 mmol) in pyridine (2 mL), and the mixture was stirred at room temperature for 16 h. Ethyl acetate was added to the reaction mixture, and the organic phase was washed with saturated NaHCO, dried (MgSO), and concentrated. The crude product was purified by preparative HPLC (Waters, SunFire Prep C18 OBD, 5 μm, 30 × 100 mm, flow rate: 40 mL / min, CH3CN: 5% in 5 min, 60% in 25 min) to obtain 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]diazepin-10-yl)amino)propyl)thiazole-2,5-dicarboxamide (1) was obtained. LCMS (Method b) m / z 485.2 [M+H] + ,t R = 0.73 minutes. 1H NMR(400 MHz,DMSO-d6) δ ppm: 8.84 (q, J = 4.0 Hz, 1 H), 8.40 (t, J = 5.6 Hz, 1 H), 8.36 (d, J = 8.9 Hz, 1 H), 7.23 (d, J = 7.9 Hz, 1H), 7.19 (t, J = 7.5 Hz, 1 H), 7.05 (d, J = 7.6 Hz, 1 H), 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).

[0363] Alternatively, the resulting product was triturated with MTBE (or acetonitrile), and the suspension was filtered to obtain a solid, which was then dried under vacuum to obtain the compound of Example 1 in crystalline form.

[0364] Example 2: N-((R)-2-(((S)-5,11-dioxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazepin-10-yl)carbamoyl)-3,3,3-trifluoropropyl)-4-methylisoxazole-5-carboxamide (2) [ka] Step 1: To a mixture of (S)-10-amino-2,3-dihydrobenzo[d]pyrazolo[1,2-a][1,2]diazepine-5,11(1H,10H)-dione (550 mg, 2.1 mmol) in CHCN (10 mL) was added 2-(((tert-butoxycarbonyl)amino)methyl)-3,3,3-trifluoropropanoic acid (int-L1) (528 mg, 2.1 mmol), TOTU (674 mg, 2.1 mmol), and DIPEA (1.1 mL, 6.2 mmol), and the mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated, dissolved in ethyl acetate, washed with 1 N HCl and saturated NaHCO solution, dried (MgSO), and concentrated to give a mixture of stereoisomers. The crude product was purified by flash chromatography (0-30% ethyl acetate in cyclohexane) to give the desired isomer tert-butyl ((R)-2-(((S)-5,11-dioxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazepin-10-yl)carbamoyl)3,3,3-trifluoropropyl)carbamate. LCMS (Condition a) m / z 471.2 [M+H] + , t R = 0.99 minutes. 1 H NMR(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).

[0365] Step 2: A mixture of tert-butyl ((R)-2-(((S)-5,11-dioxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazepin-10-yl)carbamoyl)-3,3,3-trifluoropropyl)carbamate (360 mg, 0.8 mmol) in 4 M HCl in dioxane (10 mL, 40 mmol) was stirred at room temperature for 1 h. The reaction mixture was then concentrated and treated with CHCN and EtO. The precipitate was filtered off, washed with cold EtO, 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]diazepin-10-yl)-3,3,3-trifluoropropanamide as the HCl salt, which was used in the next step without further purification. LCMS (Condition a) m / z 371.2 [M+H] + ,t R = 0.35 minutes. 1 H NMR(400 MHz,DMSO-d6) δ ppm: 9.74 (d, J = 8.2 Hz, 1 H), 8.15 (s, 3 H), 7.80 (d, J = 7.7 Hz, 1 H), 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).

[0366] Step 3: 4-Methylisoxazole-5-carboxylic acid (int-EC29) (80 mg, 0.20 mmol) and EDC (75 mg, 0.39 mmol) were added to a mixture of (R)-2-(aminomethyl)-N-((S)-5,11-dioxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazepin-10-yl)-3,3,3-trifluoropropanamide (50 mg, 0.39 mmol) in pyridine (2 mL) at room temperature, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was then treated with ethyl acetate, 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]diazepin-10-yl)carbamoyl)-3,3,3-trifluoropropyl)-4-methylisoxazole-5-carboxamide (2). HPLC (condition a) m / z 480.2 [M+H] + , t R = 0.78 minutes. 1 H NMR(400MHz, DMSO-d6) δ ppm: 9.47 (d, J = 7.7 Hz, 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).

[0367] Table 1 shows additional exemplary compounds (Examples 3-61) prepared using methods similar to those described in Example 1 or Example 2. The appropriate intermediates used in each step are listed along with the coupling conditions for Step 3. [Table 4-1] Table 4-2 Table 4-3 Table 4-4 Table 4-5 Table 4-6 Table 4-7 Table 4-8 Table 4-9 Table 4-10 Table 4-11 Table 4-12 Table 4-13 Table 4-14 Table 4-15 Table 4-16 Table 4-17 Table 4-18 [Table 4-19] [Table 4-20] [Table 4-21] [Table 4-22] [Table 4-23] [Table 4-24] [Table 4-25] [Table 4-26] [Table 4-27] [Table 4-28] [Table 4-29] [Table 4-30]

[0368] Example 62: (R)-N 4 -(3-isobutylamido-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]diazepin-10-yl)succinamide (62) [ka] Step 1: EDC (19.17 g, 100 mmol) was added to a solution of (R)-4-(tert-butoxy)-2-methyl-4-oxobutanoic 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]diazepin-11-one (int-A1) (22.48 g, 50.0 mmol) in pyridine (300 mL), and the reaction mixture was stirred at room temperature for 18 h. The solvent was then removed, and the residue was dissolved in ethyl acetate and washed with cold 1 M HCl. The aqueous phase was extracted with ethyl acetate. The organic layer was washed with saturated NaHCO3 and brine, dried (Na2SO4), and concentrated. The resulting oil was crystallized from EtO to give tert-butyl (R)-3-methyl-4-oxo-4-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazepin-10-yl)amino)butanoate. LCMS (Method b) m / z 388 [M+H] + , t R = 0.99 minutes. 1 H NMR(400MHz, DMSO-d6) δ ppm 8.33 (d, J = 8.8 Hz, 1H), 7.37 (d, J = 7.8 Hz, 1H), 7.21 (t, J = 7.2 Hz, 1H), 7.13 (t, J = 7.5 Hz, 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).

[0369] Step 2: TFA (83 mL) was added to a solution of tert-butyl (R)-3-methyl-4-oxo-4-(((S)-11-oxo-2,3,10,11-tetrahydro)-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazepin-10-yl)amino)butanoate (16.67 g, 43 mmol) in CHCl (215 mL), and the mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with water, the organic layer was washed with water, and the combined aqueous layers were extracted with CHCl. ​​The combined organic layers were dried (NaSO) 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]diazepin-10-yl)amino)butanoic acid. LCMS (Method b) m / z 332.2 [M+H] + , t R = 0.62 minutes. 1 H NMR(400MHz, 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), 3.22 - 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, 5.3 Hz, 1H), 2.03 - 2.15(m, 1H), 1.09 (d, J = 7.0 Hz, 3H).

[0370] Step 3: EDC (156 mg, 0.815 mmol) was added to a solution of (R)-3-methyl-4-oxo-4-(((S)-11-oxo-2,3,10,11-tetrahydro)-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazepin-10-yl)amino)butanoic 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), and the mixture was stirred at room temperature for 16 hours. The reaction was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried (NaSO), and concentrated. The crude product was purified by SFC (column: Reprospher PEI 100A, 250 × 30 mm, 5 μm; 36 °C; eluent A: CO, eluent B: 15–20% MeOH in 9.8 min; flow rate: 100 mL / min; pressure: 130 bar) to give (R)-N 4 -(3-isobutylamido-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]diazepin-10-yl)succinamide (62) was obtained. LCMS (Method b) m / z 496.3 [M+H] + , t R = 0.71 minutes. 1H-NMR(400MHz, DMSO-d6) δ ppm 0.12 (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).

[0371] Table 2 lists additional exemplary compounds (Examples 63-105) prepared using methods similar to those described in Example 62. The appropriate intermediates used at each step are listed along with the coupling conditions for Step 3. [Table 5-1] [Table 5-2] [Table 5-3] [Table 5-4] [Table 5-5] [Table 5-6] [Table 5-7] Table 5-8 Table 5-9 Table 5-10 Table 5-11 Table 5-12 Table 5-13 Table 5-14 Table 5-15 Table 5-16 Table 5-17 Table 5-18 Table 5-19 Table 5-20 Table 5-21 Table 5-22 Table 5-23

[0372] Example 109: (R)-N 4 -(3-((2-fluorophenyl)carbamoyl)-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]diazepin-10-yl)succinamide (109) [ka] Step 1: EDC (1.15 g, 6.04 mmol) was added to a solution of (R)-3-methyl-4-oxo-4-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazepin-10-yl)amino)butanoic 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) in acetonitrile (30 mL), and the mixture was stirred at room temperature for 18 hours. The reaction was treated with saturated NaHCO and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried (Na2SO4), and concentrated to give methyl 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]diazepin-10-yl)amino)butanamide)-1H-pyrazole-3-carboxylate. LCMS (Method b) m / z 469.2 [M+H] + , t R = 0.71 minutes. 1H NMR(400MHz, 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).

[0373] Step 2: 1M LiOH in HO (15 mL, 15 mmol) was added to a mixture of methyl 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]diazepine-10-yl)amino)butanamide)-1H-pyrazole-3-carboxylate in THF (20 mL), and the mixture was stirred at 0° C. for 2 h. The mixture was acidified to pH 3 with 2 N HCl under ice-cooling, and the mixture was extracted with ethyl acetate. The organic layer was dried (NaSO) and concentrated. The crude product was purified by column chromatography (reverse phase column eluted with 10%-0% HO in CHCN) 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]diazepin-10-yl)amino)butanamide)-1H-pyrazole-3-carboxylic acid. LCMS (Method b) m / z 455.2 [M+H] + ,t R = 0.59 minutes. 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).

[0374] Step 3: EDC (70 mg, 0.363 mmol) was added to a solution of 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]diazepin-10-yl)amino)butanamide)-1H-pyrazole-3-carboxylic acid (55 mg, 0.121 mmol) and 2-fluoroaniline (int-EC77) (14 μl, 0.133 mmol) in pyridine (1.2 mL), and the mixture was stirred at room temperature for 18 hours. The reaction was treated with saturated NaHCO and extracted with ethyl acetate. The combined organic layers were washed with water and brine, dried (NaSO), and concentrated. The crude product was dissolved in methanol, and the precipitate was filtered off at low temperature and dried under high vacuum to give (R)-N 4 -(3-((2-fluorophenyl)carbamoyl)-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]diazepin-10-yl)succinamide (109) was obtained. LCMS (Method b) m / z 548.3 [M+H]+ , t R = 0.92 minutes; 1 H NMR(400MHz, 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).

[0375] Table 3 shows an additional exemplary compound (Example 107) prepared using methods similar to those described in Example 109. The appropriate intermediates used at each step are listed along with the coupling conditions in Step 3. [Table 6]

[0376] 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]diazepin-10-yl)propanamide (111) [ka] Step 1: To a solution of (R)-3-methyl-4-oxo-4-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazepin-10-yl)amino)butanoic acid (see Step 2 of Example 62) (20 mg, 0.060 mmol) in DMF (1 mL) was added DIPEA (0.032 mL, 0.18 mmol) and HATU (23 mg, 0.060 mmol). The reaction mixture was stirred for 30 min, and then tert-butyl 2-aminophenylcarbamate (12.6 mg, 0.060 mmol) was added. The reaction mixture was analyzed by preparative HPLC-MS (Waters, column X-Bridge C 18 Purification with ODB, 5 μm, 30 × 100 mm, flow rate 45 mL / min, water / ACN: 5 to 99% ACN in 12.5 min, 7.3 mM NH3) gave tert-butyl 2-((R)-3-methyl-4-oxo-4-((S)-11-oxo-1,2,3,5,10,11-hexahydrobenzo[d]pyrazolo)[1,2-a][1,2]diazepin-10-ylamino)butanamido)phenylcarbamate. HPLC (Method a) m / z 522 [M+H] + ,t R =2.14 minutes. 1 H NMR(400MHz, 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).

[0377] Step 2: tert-Butyl 2-((R)-3-methyl-4-oxo-4-((S)-11-oxo-1,2,3,5,10,11-hexahydrobenzo[d]pyrazolo[1,2-a][1,2]diazepin-10-ylamino)butanamide)phenylcarbamate (101 mg, 0.19 mmol) was dissolved in 1.25 M HCl solution in MeOH (3 mL, 3.8 mmol). The sample was heated to 150 °C in a microwave for 30 min. The reaction mixture was concentrated in vacuo and coevaporated three times with 7 N NH3 solution in MeOH. The reaction mixture was analyzed by preparative HPLC-MS (column X-Bridge C). 18 Purification with ODB, 5 μm, 30 × 100 mm, flow rate 45 mL / min, water / ACN: 5 to 99% ACN in 12.5 min, 7.3 mM NH3) gave (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]diazepin-10-yl)propanamide (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).

[0378] Table 4 lists additional exemplary compounds (Examples 112-119) prepared using methods similar to those described in Example 111. The appropriate intermediates used in each step are listed along with the coupling conditions in Step 4. [Table 7-1] [Table 7-2] [Table 7-3] [Table 7-4] [Table 7-5]

[0379] Biological Assays: Abbreviation DC dendritic cell(s) DNP 2,4-dinitrophenyl Gal4 regulatory protein GAL4, YPL248C FCM flow cytometry KLH Keyhole Limpet Hemacyanin I C 50 Concentration that produces 50% of maximum inhibition IgG immunoglobulin G NT amino terminus PAGE Polyacrylamide gel electrophoresis PBS Phosphate-buffered saline RGA reporter gene assay RT room temperature SDS Sodium dodecyl sulfate Sppl2a Signal peptide protease-like protease 2a TL translocation assay TNF tumor necrosis factor

[0380] Sppl2a RGA (Reporter Gene Assay): Sppl2a is an intramembrane aspartyl protease similar to presenilin, the active subunit of the γ-secretase complex. The assay is based on coupling the proteolysis of a membrane-bound synthetic substrate (a VP16-Gal4 fusion protein containing the N-terminal domain of TNFα), which migrates to the nucleus upon cleavage, to Gal4-driven expression of luciferase. Inhibition of Sppl2a reduces the nuclear VP16-Gal4 activator and, consequently, reduces luciferase production. Dose-response curves were generated by plotting luciferase-dependent luminescence against compound concentration to determine IC 50 The value can be calculated.

[0381] DNA vectors encoding human Sppl2a, NT-TNF-VP16-Gal4, and a Gal4-luciferase reporter were transiently transfected into HEK293 cells. In a typical experiment, 5 μg of SPPL2a plasmid, 10 μg of a plasmid encoding the reporter Gal4-luciferase, and 20 μg of a plasmid encoding the substrate NT-TF-VP16-Gal4 were mixed. The DNA mixture was mixed 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 was added to the mixture and mixed thoroughly. The cell suspension was distributed into a white 384-solid-well plate. Within 5 hours, 50 nL of compound in DMSO was stamped into the wells using a pin tool. Plates were incubated in a humidified incubator at 37°C and 5% CO2 for 24 hours, after which 25 μL of Bright Glo was added. Plates were incubated at room temperature for 5 minutes before being transferred to a luminometer to measure luminescence. IC was determined by plotting compound concentration against normalized luminescence values. 50 It was decided that:

[0382] γ-Secretase RGA (Reporter Gene Assay): Presenilins are the active subunits of the γ-secretase complex, membrane-bound proteases that cleave multiple type 1 transmembrane substrates. This assay was developed to monitor γ-secretase activity against Notch, a key modulator of immune cell development. The assay is based on the coupling of proteolysis of a membrane-bound synthetic substrate, VP16-Gal4 fusion protein, to Notch1, which upon cleavage translocates to the nucleus and activates Gal4-driven expression of luciferase. Inhibition of γ-secretase reduces nuclear VP16-Gal4 activator, resulting in reduced luciferase production. Dose-response curves were generated by plotting luciferase-dependent luminescence versus compound concentration to determine IC 50 The value can be calculated.

[0383] DNA vectors encoding human Notch1-VP16-Gal4 and a Gal4-luciferase reporter were transiently transfected into HEK293 cells, which endogenously express γ-secretase components. In a typical experiment, 10 μg of a plasmid encoding the reporter Gal4-luciferase was mixed with 20 μg of a plasmid encoding the substrate Notch1-VP16-Gal4. The DNA mixture was mixed 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 was added to the mixture and mixed thoroughly. The cell suspension was distributed into a white 384-solid-well plate. Within 5 hours, 50 nL of compound in DMSO was stamped into the wells using a pin tool. Plates were incubated in a humidified incubator at 37°C and 50% CO2 for 24 hours, after which 25 μL of Bright Glo was added. Plates were incubated at room temperature for 5 minutes before being transferred to a luminometer to measure luminescence. IC was determined by plotting compound concentration against normalized luminescence values. 50 It was decided that:

[0384] Sppl2a TL assay: SPPL2a, a TL in U-2 OS cells. A stable U-2 OS cell line constitutively expressing human SPPL2a and the EGFP-tagged TNFα (aa1-76) NTF substrate under a doxycycline-regulated promoter was used for the imaging assay. Cells were seeded at 3000 cells / 30 μL / 384-well in DMEM / GlutaMax™-I (Invitrogen) supplemented with tetracycline-free 10% FBS (Amimed) and incubated at 37°C and 5% CO2 for 3–4 h. Subsequently, 3.3 μL of inhibitor pre-diluted in doxycycline-containing medium for an 11-point concentration-response curve was added to each well using a CyBi Well Liquid Handling System (Cybio AG, Jena, Germany) to achieve final inhibitor concentrations ranging from 100 μM to 1 nM (final DMSO concentration 0.9% (v / v) and doxycycline 5 μg / mL). Cells were incubated with the inhibitors at 37°C and 5% CO2 for 24 hours. Cells were then fixed with 4% PFA / PBS, and nuclei were simultaneously stained with 1:5000 Hoechst (Invitrogen) in PBS for 30 minutes. Plates were imaged using a Cellomics ArrayScan VTI HCS reader (Thermo Fisher Scientific, USA) equipped with a 10x objective with a 0.3 NA. Six images were acquired per well. Images of EGFP signals (Ex395, Em509) and Hoechst nuclear staining dyes (Ex350, Em425) were simultaneously acquired by image analysis using the "Nuclear Translocation" assay algorithm in the Cellomics ArrayScan software. Nuclei were detected based on Hoechst staining, and the nuclear mask was transferred to the EGFP channel, revealing a 4-pixel-wide cytoplasmic ring region surrounding the nucleus. The intensity of the EGFP signal was measured both within the nucleus and within the cytoplasmic ring region of individual cells (generally, 800–1000 individual cells were 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, cell counts were obtained (a function called "ValidCellCount") and used to calculate cytotoxicity (CC50). Percent inhibition was calculated relative to the positive control (0.5 μM LY-411,575 = 100% inhibition) and negative control (DMSO = 0% inhibition). IC. 50 Values ​​were calculated from plots of percent inhibition versus inhibitor concentration using nonlinear regression analysis software such as, for example, Origin (OriginLab Corp.).

[0385] CD74 / p8 Mouse Whole Blood Assay: Flow Cytometry Format Whole mouse blood (sodium citrate) from Balb / c mice was ordered from Bioreclamation LLC, USA. Blood was used the day after receipt (stored at 4°C). 100 μL of blood was transferred to a 96-well plate pre-plated with 11-point dilutions of the test compound starting from 30 μM. The plate was incubated for 5 hours at 37°C in a 5% CO2 incubator with continuous movement. After incubation, the blood was diluted with RBC Lysis Buffer (Amined; Cat. No. 3-13F00-H or BD; Cat. No. 555899). The solution was mixed by pipetting and incubated for 10 minutes in a 37°C incubator. Leukocytes were sedimented at 2000 rpm for 3 minutes. After removing the supernatant, the cell pellet was resuspended and washed twice with RBC buffer. The plate was kept at room temperature for approximately 5 minutes and then centrifuged at 2000 rpm for 2 minutes. The cell pellet was then resuspended in D-PBS and centrifuged twice. Finally, the cells were taken up in D-PBS / 0.5% inactivated fetal bovine serum / 2mM EDTA. The cell suspension was treated with Live / Dead fixative stain (Life Technologies, >470nm version), and B cells were identified by surface staining with anti-B220 antibody conjugated to an APC fluorophore. After staining, the cells were washed extensively with PBS. The cells were permeabilized, fixed with FACS lysis buffer (BD; #349202, diluted 1:10 in water), labeled with FITC-conjugated anti-CD74 antibody, washed again with diluted FACS lysis buffer, and spun down. The cell pellet was washed with D-PBS / 0.5% inactivated fetal bovine serum / 2mM EDTA and PBS before analysis on a flow cytometer. Compound concentration was plotted against CD74 signal intensity (medium fluorescence intensity) in gated live B cells, and IC was calculated by fitting the data for a dose-response of 11 concentrations. 50 It was decided that:

[0386] Biological Data: The compounds described herein were evaluated using the above assays. Table 5 shows the corresponding IC values ​​obtained for each of the above exemplary compounds. 50(μM) values ​​are listed. [Table 8-1] [Table 8-2] [Table 8-3]

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof or a stereoisomer thereof. 【Chemistry 1】 (In the formula, Y is CH ２ or C=O, R １ is H, C １ ~C ６ is alkyl or halogen, R ２ is H or a halogen, R ３ is H, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C ３ ~C ６ Cycloalkyl, C １ ~C ６ Alkylphenyl or C １ ~C ６ Alkoxy-substituted C １ ~C ６ is alkyl, R ４ is H, C １ ~C ６ Alkyl or C １ ~C ６ alkylphenyl, R １０ is -NHC(=O)R ５ , -C(=O)NHR ５ or a 9- or 10-membered bicyclic heteroaryl having 1 to 4 heteroatoms each independently selected from N, O, and S as ring members, wherein said bicyclic heteroaryl is unsubstituted or said bicyclic heteroaryl is selected from one or more R ６ is replaced by R ５ is a 5-membered heteroaryl having 1, 2, or 3 heteroatoms each independently selected from N, O, and S as ring members, wherein said 5-membered heteroaryl is unsubstituted or said 5-membered heteroaryl has one or more substituents independently selected from: i) halogens, ii) amino, iii) C optionally substituted with one or more halogens ３ ~C ６ cycloalkyl, iv) C ３ ~C ６ cycloalkenyl, v) C １ ~ ６ Alkoxy, C ３ ~C ６ C optionally substituted with cycloalkyl or phenyl １ ~C ６ Alkyl, vi) C １ ~C ６ haloalkyl, vii)-NHC(=O)C １ ~C ６ Alkyl (the above C １ ~C ６ The alkyl is C １ ~C ６ optionally substituted with alkoxy); viii)-NHC(=O)-C １ ~C ６ haloalkyl, ix)-NHC(=O)-C ３ ~C ６ cycloalkyl, x) -C(=O)NH-C １ ~C ６ Alkyl (the above C １ -C ６ The alkyl is C １ ~C ６ optionally substituted with alkoxy); xi)-C(=O)NH-C １ ~C ６ haloalkyl, xii)-C(=O)NH-C ３ ~C ６ cycloalkyl, xiii) -NHC(=O)phenyl, wherein the phenyl is selected from the group consisting of halogen and C １ ~C ６ optionally substituted with one or more substituents independently selected from alkyl, xiv) —C(═O)NHphenyl, wherein the phenyl is selected from the group consisting of halogen and C １ ~C ６ optionally substituted with one or more substituents independently selected from alkyl, xv) C １ ~C ６ Alkoxy or C １ ~C ６ haloalkoxy, xvi) phenyloxy optionally substituted with one or more halogens; xvii) halogen, —CN, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, C １ ~C ６ Haloalkoxy and C １ ~C ６ phenyl optionally substituted with one or more substituents independently selected from haloalkyl; xviii) oxo, —C(═O)OC １ ~C ６ Alkyl or -C(=O)OC １ ~C ６ 4-6 membered heterocyclyl optionally substituted with cycloalkyl; xix) a 5- or 6-membered heteroaryl having 1 to 2 heteroatoms independently selected from N, O, and S as ring members, wherein the heteroaryl is unsubstituted or is C １ ~C ６ Alkyl, halogen, C １ ~C ６ Haloalkyl, C １ ~C ６ Haloalkoxy, C １ ~C ６ Alkoxy, 4-6 membered heterocyclyl, C ３ ~C ６ Cycloalkyl, C ３ ~C ６ Cycloalkenyl, and —OH, C １ ~C ６ C optionally substituted with 4-6 membered heterocyclyl optionally substituted with alkoxy or oxo １ ~C ６ substituted with one or more substituents independently selected from alkyl, and xx) a 9- or 10-membered bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S as ring members, wherein the heteroaryl is unsubstituted or is C １ ~C ６ Alkyl, halogen, C １ ~C ６ Haloalkyl, C １ ~C ６ Haloalkoxy, C １ ~C ６ Alkoxy, 4-6 membered heterocyclyl, C ３ ~C ６ Cycloalkyl, C ３ ~C ６ cycloalkenyl, and C １ ~C ６ C optionally substituted with alkoxy １ ~C ６ substituted with one or more substituents independently selected from alkyl is replaced by Each R ６ is C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, C １ ~C ６ independently selected from haloalkyl, cyano, and halogen; R １１ is H, C １ ~C ６ alkyl or halogen; or R １ and R １１ may form, together with the carbon atom to which they are attached, a 3- to 6-membered carbocyclic ring.

2. 10. The compound of claim 1 having the structure of formula (II): or a pharmaceutically acceptable salt thereof or a stereoisomer thereof. 【Chemistry 2】 (In the formula, Y is CH ２ or C=O, R １ is H, C １ ~C ６ is alkyl or halogen, R ２ is H or a halogen, R ３ is H, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C ３ ~C ６ Cycloalkyl, C １ ~C ６ Alkylphenyl or C １ ~C ６ Alkoxy-substituted C １ ~C ６ is alkyl, R ５ is a 5-membered heteroaryl having 1, 2, or 3 heteroatoms each independently selected from N, O, and S as ring members, wherein said 5-membered heteroaryl is unsubstituted or said 5-membered heteroaryl has one or more substituents independently selected from: i) halogens, ii) amino, iii) C optionally substituted with one or more halogens ３ ~C ６ cycloalkyl, iv) C ３ ~C ６ cycloalkenyl, v) C １ ~ ６ Alkoxy, C ３ ~C ６ C optionally substituted with cycloalkyl or phenyl １ ~C ６ Alkyl, vi) C １ ~C ６ haloalkyl, vii)-NHC(=O)C １ ~C ６ Alkyl (the above C １ ~C ６ The alkyl is C １ ~C ６ optionally substituted with alkoxy); viii)-NHC(=O)-C １ ~C ６ haloalkyl, ix)-NHC(=O)-C ３ ~C ６ cycloalkyl, x) -C(=O)NH-C １ ~C ６ Alkyl (the above C １ -C ６ The alkyl is C １ ~C ６ optionally substituted with alkoxy); xi)-C(=O)NH-C １ ~C ６ haloalkyl, xii)-C(=O)NH-C ３ ~C ６ cycloalkyl, xiii) -NHC(=O)phenyl, wherein the phenyl is selected from the group consisting of halogen and C １ ~C ６ optionally substituted with one or more substituents independently selected from alkyl, xiv) —C(═O)NHphenyl, wherein the phenyl is selected from the group consisting of halogen and C １ ~C ６ optionally substituted with one or more substituents independently selected from alkyl, xv) C １ ~C ６ Alkoxy or C １ ~C ６ haloalkoxy, xvi) phenyloxy optionally substituted with one or more halogens; xvii) halogen, —CN, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, C １ ~C ６ Haloalkoxy and C １ ~C ６ phenyl optionally substituted with one or more substituents independently selected from haloalkyl; xviii) oxo, —C(═O)OC １ ~C ６ Alkyl or -C(=O)OC １ ~C ６ 4- to 6-membered heterocyclyl optionally substituted with cycloalkyl, and xix) a 5- or 6-membered heteroaryl having one or two heteroatoms independently selected from N, O, and S as ring members, wherein the heteroaryl is unsubstituted or is C １ ~C ６ Alkyl, halogen, C １ ~C ６ Haloalkyl, C １ ~C ６ Haloalkoxy, C １ ~C ６ Alkoxy, 4-6 membered heterocyclyl, C ３ ~C ６ Cycloalkyl, C ３ ~C ６ Cycloalkenyl, and —OH, C １ ~C ６ C optionally substituted with 4-6 membered heterocyclyl optionally substituted with alkoxy or oxo １ ~C ６ substituted with one or more substituents independently selected from alkyl; xx) a 9- or 10-membered bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S as ring members, wherein the heteroaryl is unsubstituted or is C １ ~C ６ Alkyl, halogen, C １ ~C ６ Haloalkyl, C １ ~C ６ Haloalkoxy, C １ ~C ６ Alkoxy, 4-6 membered heterocyclyl, C ３ ~C ６ Cycloalkyl, C ３ ~C ６ cycloalkenyl, and C １ ~C ６ C optionally substituted with alkoxy １ ~C ６ substituted with one or more substituents independently selected from alkyl ), which is replaced by Each R ６ is C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, C １ ~C ６ independently selected from haloalkyl, cyano, and halogen; R １１ is H, C １ ~C ６ alkyl or halogen; or R １ and R １１ may form, together with the carbon atom to which they are attached, a 3- to 6-membered carbocyclic ring.

3. 3. The compound of claim 1 or 2, having the structure of formula (IIA), formula (IIB), formula (IIC), or formula (IID), or a pharmaceutically acceptable salt thereof. 【Transformation 3】 (In the formula, R ３ is H, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C ３ ~C ６ Cycloalkyl, C １ ~C ６ Alkylphenyl or C １ ~C ６ Alkoxy-substituted C １ ~C ６ is alkyl, R ５ is a 5-membered heteroaryl having 1, 2, or 3 heteroatoms each independently selected from N, O, and S as ring members, wherein said 5-membered heteroaryl is unsubstituted or said 5-membered heteroaryl has one or more substituents independently selected from: i) halogens, ii) amino, iii) C optionally substituted with one or more halogens ３ ~C ６ cycloalkyl, iv) C ３ ~C ６ cycloalkenyl, v) C １ ~ ６ Alkoxy, C ３ ~C ６ C optionally substituted with cycloalkyl or phenyl １ ~C ６ Alkyl, vi) C １ ~C ６ haloalkyl, vii)-NHC(=O)C １ ~C ６ Alkyl (the above C １ ~C ６ The alkyl is C １ ~C ６ optionally substituted with alkoxy); viii)-NHC(=O)-C １ ~C ６ haloalkyl, ix)-NHC(=O)-C ３ ~C ６ cycloalkyl, x)-C(=O)NH-C １ ~C ６ Alkyl (the above C １ ~C ６ The alkyl is C １ ~C ６ optionally substituted with alkoxy); xi)-C(=O)NH-C １ ~C ６ haloalkyl, xii)-C(=O)NH-C ３ ~C ６ cycloalkyl, xiii) -NHC(=O)phenyl, wherein the phenyl is selected from the group consisting of halogen and C １ ~C ６ optionally substituted with one or more substituents independently selected from alkyl, xiv) —C(═O)NHphenyl, wherein the phenyl is selected from the group consisting of halogen and C １ ~C ６ optionally substituted with one or more substituents independently selected from alkyl, xv) C １ ~C ６ Alkoxy or C １ ~C ６ haloalkoxy, xvi) phenyloxy optionally substituted with one or more halogens; xvii) halogen, —CN, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, C １ ~C ６ Haloalkoxy and C １ ~C ６ phenyl optionally substituted with one or more substituents independently selected from haloalkyl; xviii) oxo, —C(═O)OC １ ~C ６ Alkyl or -C(=O)OC １ ~C ６ 4- to 6-membered heterocyclyl optionally substituted with cycloalkyl, and xix) a 5- or 6-membered heteroaryl having one or two heteroatoms independently selected from N, O, and S as ring members, wherein the heteroaryl is unsubstituted or is C １ ~C ６ Alkyl, halogen, C １ ~C ６ Haloalkyl, C １ ~C ６ Haloalkoxy, C １ ~C ６ Alkoxy, 4-6 membered heterocyclyl, C ３ ~C ６ Cycloalkyl, C ３ ~C ６ Cycloalkenyl, and —OH, C １ ~C ６ C optionally substituted with 4-6 membered heterocyclyl optionally substituted with alkoxy or oxo １ ~C ６ substituted with one or more substituents independently selected from alkyl; xx) a 9- or 10-membered bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S as ring members, wherein the heteroaryl is unsubstituted or is C １ ~C ６ Alkyl, halogen, C １ ~C ６ Haloalkyl, C １ ~C ６ Haloalkoxy, C １ ~C ６ Alkoxy, 4-6 membered heterocyclyl, C ３ ~C ６ Cycloalkyl, C ３ ~C ６ cycloalkenyl, and C １ ~C ６ C optionally substituted with alkoxy １ ~C ６ substituted with one or more substituents independently selected from alkyl is replaced by

4. 10. The compound of claim 1 having the structure of formula (III): or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof. 【Chemistry 4】 (In the formula, Y is CH ２ or C=O, R １ is H, C １ ~C ６ is alkyl or halogen, R ２ is H or a halogen, R ３ is H, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C ３ ~C ６ Cycloalkyl, C １ ~C ６ Alkylphenyl or C １ ~C ６ Alkoxy-substituted C １ ~C ６ is alkyl, R ５ is a 5-membered heteroaryl having 1, 2, or 3 heteroatoms each independently selected from N, O, and S as ring members, wherein said 5-membered heteroaryl is unsubstituted or said 5-membered heteroaryl has one or more substituents independently selected from: i) halogens, ii) amino, iii) C optionally substituted with one or more halogens ３ ~C ６ cycloalkyl, iv) C ３ ~C ６ cycloalkenyl, v) C １ ~ ６ Alkoxy, C ３ ~C ６ C optionally substituted with cycloalkyl or phenyl １ ~C ６ Alkyl, vi) C １ ~C ６ haloalkyl, vii)-NHC(=O)C １ ~C ６ Alkyl (the above C １ ~C ６ The alkyl is C １ ~C ６ optionally substituted with alkoxy); viii)-NHC(=O)-C １ ~C ６ haloalkyl, ix)-NHC(=O)-C ３ ~C ６ cycloalkyl, x)-C(=O)NH-C １ ~C ６ Alkyl (the above C １ ~C ６ The alkyl is C １ ~C ６ optionally substituted with alkoxy); xi)-C(=O)NH-C １ ~C ６ haloalkyl, xii)-C(=O)NH-C ３ ~C ６ cycloalkyl, xiii) -NHC(=O)phenyl, wherein the phenyl is selected from the group consisting of halogen and C １ ~C ６ optionally substituted with one or more substituents independently selected from alkyl, xiv) —C(═O)NHphenyl, wherein the phenyl is selected from the group consisting of halogen and C １ ~C ６ optionally substituted with one or more substituents independently selected from alkyl, xv) C １ ~C ６ Alkoxy or C １ ~C ６ haloalkoxy, xvi) phenyloxy optionally substituted with one or more halogens; xvii) halogen, —CN, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, C １ ~C ６ Haloalkoxy and C １ ~C ６ phenyl optionally substituted with one or more substituents independently selected from haloalkyl; xviii) oxo, —C(═O)OC １ ~C ６ Alkyl or -C(=O)OC １ ~C ６ 4- to 6-membered heterocyclyl optionally substituted with cycloalkyl, and xix) a 5- or 6-membered heteroaryl having one or two heteroatoms independently selected from N, O, and S as ring members, wherein the heteroaryl is unsubstituted or is C １ ~C ６ Alkyl, halogen, C １ ~C ６ Haloalkyl, C １ ~C ６ Haloalkoxy, C １ ~C ６ Alkoxy, 4-6 membered heterocyclyl, C ３ ~C ６ Cycloalkyl, C ３ ~C ６ Cycloalkenyl, and —OH, C １ ~C ６ C optionally substituted with 4-6 membered heterocyclyl optionally substituted with alkoxy or oxo １ ~C ６ substituted with one or more substituents independently selected from alkyl; xx) a 9- or 10-membered bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S as ring members, wherein the heteroaryl is unsubstituted or is C １ ~C ６ Alkyl, halogen, C １ ~C ６ Haloalkyl, C １ ~C ６ Haloalkoxy, C １ ~C ６ Alkoxy, 4-6 membered heterocyclyl, C ３ ~C ６ Cycloalkyl, C ３ ~C ６ cycloalkenyl, and C １ ~C ６ C optionally substituted with alkoxy １ ~C ６ substituted with one or more substituents independently selected from alkyl is replaced by Each R ６ is C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, C １ ~C ６ independently selected from haloalkyl, cyano, and halogen; R １１ is H, C １ ~C ６ alkyl or halogen; or R １ and R １１ may form, together with the carbon atom to which they are attached, a 3- to 6-membered carbocyclic ring.

5. 10. The compound of claim 1 or 4, having the structure of Formula (IIIA), Formula (IIIB), Formula (IIIC), or Formula (IIID), or a pharmaceutically acceptable salt thereof: 【Transformation 5】 (In the formula, R ３ is H, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C ３ ~C ６ Cycloalkyl, C １ ~C ６ Alkylphenyl or C １ ~C ６ Alkoxy-substituted C １ ~C ６ is alkyl, R ５ is a 5-membered heteroaryl having 1, 2, or 3 heteroatoms each independently selected from N, O, and S as ring members, wherein said 5-membered heteroaryl is unsubstituted or said 5-membered heteroaryl has one or more substituents independently selected from: i) halogens, ii) amino, iii) C optionally substituted with one or more halogens ３ ~C ６ cycloalkyl, iv) C ３ ~C ６ cycloalkenyl, v) C １ ~ ６ Alkoxy, C ３ ~C ６ C optionally substituted with cycloalkyl or phenyl １ ~C ６ Alkyl, vi) C １ ~C ６ haloalkyl, vii)-NHC(=O)C １ ~C ６ Alkyl (the above C １ ~C ６ The alkyl is C １ ~C ６ optionally substituted with alkoxy); viii)-NHC(=O)-C １ ~C ６ haloalkyl, ix)-NHC(=O)-C ３ ~C ６ cycloalkyl, x)-C(=O)NH-C １ ~C ６ Alkyl (the above C １ ~C ６ The alkyl is C １ ~C ６ optionally substituted with alkoxy); xi)-C(=O)NH-C １ ~C ６ haloalkyl, xii)-C(=O)NH-C ３ ~C ６ cycloalkyl, xiii) -NHC(=O)phenyl, wherein the phenyl is selected from the group consisting of halogen and C １ ~C ６ optionally substituted with one or more substituents independently selected from alkyl, xiv) —C(═O)NHphenyl, wherein the phenyl is selected from the group consisting of halogen and C １ ~C ６ optionally substituted with one or more substituents independently selected from alkyl, xv) C １ ~C ６ Alkoxy or C １ ~C ６ haloalkoxy, xvi) phenyloxy optionally substituted with one or more halogens; xvii) halogen, —CN, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, C １ ~C ６ Haloalkoxy and C １ ~C ６ phenyl optionally substituted with one or more substituents independently selected from haloalkyl; xviii) oxo, —C(═O)OC １ ~C ６ Alkyl or -C(=O)OC １ ~C ６ 4- to 6-membered heterocyclyl optionally substituted with cycloalkyl, and xix) a 5- or 6-membered heteroaryl having one or two heteroatoms independently selected from N, O, and S as ring members, wherein the heteroaryl is unsubstituted or is C １ ~C ６ Alkyl, halogen, C １ ~C ６ Haloalkyl, C １ ~C ６ Haloalkoxy, C １ ~C ６ Alkoxy, 4-6 membered heterocyclyl, C ３ ~C ６ Cycloalkyl, C ３ ~C ６ Cycloalkenyl, and —OH, C １ ~C ６ C optionally substituted with 4-6 membered heterocyclyl optionally substituted with alkoxy or oxo １ ~C ６ substituted with one or more substituents independently selected from alkyl; xx) a 9- or 10-membered bicyclic heteroaryl having 1 to 4 heteroatoms independently selected from N, O, and S as ring members, wherein the heteroaryl is unsubstituted or is C １ ~C ６ Alkyl, halogen, C １ ~C ６ Haloalkyl, C １ ~C ６ Haloalkoxy, C １ ~C ６ Alkoxy, 4-6 membered heterocyclyl, C ３ ~C ６ Cycloalkyl, C ３ ~C ６ cycloalkenyl, and C １ ~C ６ C optionally substituted with alkoxy １ ~C ６ substituted with one or more substituents independently selected from alkyl is replaced by

6. R ３ is methyl, ethyl, propyl or isopropyl, CF ３ , -CH ２ -phenyl, cyclopropyl, cyclobutyl, or -CH ２ CH ２ OCH ３ 6. The compound of any one of claims 1 to 5, wherein:

7. R ５ 7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof or a stereoisomer thereof, wherein: 【Transformation 6】 (In the formula, R ５ａ is C １ ~C ６ Alkyl or C １ ~C ６ haloalkyl or halogen, R ５ｂ is -C(O)-NH-C １ ~C ６ Alkyl, —C(O)NH—C １ ~C ６ haloalkyl, —C(O)NHphenyl, C １ ~C ６ Alkoxy, C １ ~C ６ Haloalkoxy, C ３ ~C ６ Cycloalkyl, C ３ ~C ６ cycloalkenyl, 4- to 6-membered heterocyclyl, 5- or 6-membered heteroaryl, wherein heteroaryl is selected from the group consisting of halogen, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Alkoxy, C １ ~C ６ haloalkoxy or C ３ ~C ６ Optionally substituted cycloalkyl and heterocyclyl include oxo, —C(O)O—C １ ~C ６ Alkyl or —C(O)O—C ３ ~C ６ and -C(O)NHphenyl is optionally substituted with halogen or C １ ~C ６ optionally substituted with alkyl; R ５ｃ is a halogen, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Alkoxy, C １ ~C ６ haloalkoxy, or C ３ ~C ６ a 5- or 6-membered heteroaryl optionally substituted with cycloalkyl; and R ５ｄ is C １ ~C ６ Alkyl or C １ ~C ６ It is haloalkyl.

8. R ５ 7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof or a stereoisomer thereof, wherein: 【Chemistry 7-1】 【Chemistry 7-2】 【Transformation 7-3】 【Chemistry 7-4】 【Transformation 7-5】 【Transformation 7-6】

9. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof. (In the formula, R １０ teeth, 【Transformation 8】 and and R ６ is H, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, C １ ~C ６ haloalkyl, cyano or halogen).

10. 10. The compound of claim 1 having the structure of formula (IV), or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof. 【Chemistry 9】 (In the formula, R １ is H, C １ ~C ６ is alkyl or halogen, R ２ is H or a halogen, Y is CH ２ or C(O), R ３ is H, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C ３ ~C ６ Cycloalkyl, C １ ~C ６ alkylphenyl, or C １ ~C ６ Alkoxy-substituted C １ ~C ６ is alkyl, X is CH or N; R ６ is H, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, C １ ~C ６ haloalkyl, cyano, or halogen; R １１ is H, C １ ~C ６ alkyl or halogen; or R １ and R １１ together with the carbon atoms to which they are attached form a 3- to 6-membered carbocyclic ring.

11. The compound of claim 1 selected from the following: 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]diazepin-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]diazepin-10-yl)carbamoyl)-3,3,3-trifluoropropyl)-4-methylisoxazole-5-carboxamide, 2-isobutyramido-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]diazepin-10-yl)carbamoyl)propyl)thiazole-5-carboxamide, 2-isobutyramido-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]diazepin-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]diazepin-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]diazepin-10-yl)amino)propyl)-N ２ -(2,2-difluoroethyl)-4-methylthiazole-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]diazepin-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]diazepin-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]diazepin-10-yl)amino)propyl)-N ２ , 4-dimethylthiazole-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]diazepin-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]diazepin-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]diazepin-10-yl)amino)propyl)-N ２ -ethyl-4-methylthiazole-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]diazepin-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]diazepin-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]diazepin-10-yl)carbamoyl)butyl)-2-(6-(trifluoromethyl)pyridin-3-yl)thiazole-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]diazepin-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]diazepin-10-yl)carbamoyl)butyl)-5-(trifluoromethyl)isoxazole-4-carboxamide, 4-methyl-N-((R)-2-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazepin-10-yl)carbamoyl)butyl)-2-(6-(trifluoromethyl)pyridin-3-yl)thiazole-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]diazepin-10-yl)carbamoyl)butyl)thiazole-2,5-dicarboxamide, 4-methyl-2-(3-methylisoxazol-5-yl)-N-((R)-2-(((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazepin-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]diazepin-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]diazepin-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]diazepin-10-yl)amino)propyl)-2-(3-methylisoxazol-5-yl)thiazole-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]diazepin-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]diazepin-10-yl)carbamoyl)butyl)isoxazole-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]diazepin-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]diazepin-10-yl)amino)propyl)-N ２ -isopropyl-4-methylthiazole-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]diazepin-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]diazepin-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]diazepin-10-yl)carbamoyl)butyl)-2-propoxythiazole-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′-cyclopropan]-10-yl)carbamoyl)butyl)-3-methyl-5-(trifluoromethyl)isoxazole-4-carboxamide, 2-(isoxazol-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]diazepin-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]diazepin-10-yl)carbamoyl)pentyl)isoxazole-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]diazepin-10-yl)carbamoyl)butyl)-2-(6-methoxypyridin-3-yl)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]diazepin-10-yl)carbamoyl)butyl)-4-methylisothiazole-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′-cyclopropan]-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]diazepin-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]diazepin-10-yl)carbamoyl)-3,3,3-trifluoropropyl)-4-methyl-2-(6-(trifluoromethyl)pyridin-3-yl)thiazole-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]diazepin-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]diazepin-10-yl)carbamoyl)-3,3,3-trifluoropropyl)-2-(6-(trifluoromethyl)pyridin-3-yl)thiazole-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]diazepin-10-yl)amino)-3-oxopropyl)-4-methyl-2-(3-methylisoxazol-5-yl)thiazole-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]diazepin-10-yl)carbamoyl)butyl)-4-methyl-2-(3-methylisoxazol-5-yl)thiazole-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]diazepin-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]diazepin-10-yl)carbamoyl)propyl)thiazole-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]diazepine-2,1′-cyclopropan]-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]diazepin-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]diazepin-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]diazepin-10-yl)carbamoyl)-3,3,3-trifluoropropyl)-3,5-dimethylisoxazole-4-carboxamide, 4-chloro-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′-cyclopropan]-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]diazepin-10-yl)carbamoyl)propyl)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]diazepin-10-yl)carbamoyl)butyl)isoxazole-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]diazepin-10-yl)carbamoyl)propyl)thiazole-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]diazepin-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]diazepin-10-yl)amino)-3-oxopropyl)thiazole-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]diazepin-10-yl)amino)-3-oxopropyl)-2-methylthiazole-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]diazepine-2,1′-cyclopropan]-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′-cyclopropan]-10-yl)carbamoyl)butyl)-4-(trifluoromethyl)thiazole-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]diazepin-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]diazepine-2,1′-cyclopropan]-10-yl)carbamoyl)butyl)-4-(trifluoromethyl)thiazole-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]diazepin-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]diazepin-10-yl)amino)propyl)-1H-pyrazole-5-carboxamide, (R)-N ４ -(3-isobutylamido-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]diazepin-10-yl)succinamide, (S)-2-Cyclobutyl-N ４ -(3-isobutylamido-1-methyl-1H-pyrazol-5-yl)-N １ -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazepin-10-yl)succinamide, (R)-N ４ -(4-chloro-2-(isopropylcarbamoyl)thiazol-5-yl)-2-methyl-N １ -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazepin-10-yl)succinamide, (R)-N ４ -(3-((2,2-difluoroethyl)carbamoyl)-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]diazepin-10-yl)succinamide, (R)-N ４ -(2-(isopropylcarbamoyl)-4-methylthiazol-5-yl)-2-methyl-N １ -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazepin-10-yl)succinamide, (S)-2-Cyclopropyl-N ４ -(3-(isopropylcarbamoyl)-1-methyl-1H-pyrazol-5-yl)-N １ -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazepin-10-yl)succinamide, (R)-2-methyl-N ４ -(1-methyl-3-((2,2,2-trifluoroethyl)carbamoyl)-1H-pyrazol-5-yl)-N １ -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazepin-10-yl)succinamide, (R)-N ４ -(3-(2-fluorobenzamido)-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]diazepin-10-yl)succinamide, (R)-2-methyl-N ４ -(1-methyl-3-(2,2,3,3,3-pentafluoropropanamido)-1H-pyrazol-5-yl)-N １ -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazepin-10-yl)succinamide, (R)-N ４ -(3-(3-cyclopropylisoxazol-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]diazepin-10-yl)succinamide, (R)-2-methyl-N ４ -(1-methyl-3-(6-(trifluoromethyl)pyridin-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]diazepin-10-yl)succinamide, (R)-N ４ -(4-chloro-2-(1-methyl-1H-pyrazol-3-yl)thiazol-5-yl)-2-methyl-N １ -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazepin-10-yl)succinamide, (R)-2-methyl-N ４ -(1-methyl-3-(5-methylpyridin-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]diazepin-10-yl)succinamide, (S)-2-Cyclopropyl-N ４ -(1-methyl-3-(5-methylpyridin-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]diazepin-10-yl)succinamide, (R)-N ４ -(3-(2,3-difluorobenzamido)-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]diazepin-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]diazepin-10-yl)-N ４ -(3-(isopropylcarbamoyl)-1-methyl-1H-pyrazol-5-yl)succinamide, (S)-2-Cyclopropyl-N ４ -(3-(((S)-1-fluoropropan-2-yl)carbamoyl)-1-methyl-1H-pyrazol-5-yl)-N １ -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazepin-10-yl)succinamide, (R)-N ４ -(2-(5-fluoropyridin-3-yl)-4-methylthiazol-5-yl)-2-methyl-N １ -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazepin-10-yl)succinamide, (R)-2-methyl-N ４ -(1-methyl-3-(5-methylisoxazol-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]diazepin-10-yl)succinamide, (R)-N ４ -(3-(5-ethylisoxazol-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]diazepin-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'-cyclopropan]-10-yl)-N ４ -(3-isobutyramido-1-methyl-1H-pyrazol-5-yl)succinamide, (R)-N ４ -(1-ethyl-3-(6-(trifluoromethyl)pyridin-3-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]diazepin-10-yl)succinamide, (R)-2-methyl-N ４ -(1-methyl-3-((3,3,3-trifluoropropyl)carbamoyl)-1H-pyrazol-5-yl)-N １ -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazepin-10-yl)succinamide, (R)-N ４ -(1-ethyl-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]diazepin-10-yl)succinamide, (R)-N ４ -(3-(3-ethylisoxazol-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]diazepin-10-yl)succinamide, (R)-N ４ -(3-(5-fluoropyridin-2-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]diazepin-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]diazepin-10-yl)succinamide, (R)-2-methyl-N ４ -(1-methyl-3-pivalamido-1H-pyrazol-5-yl)-N １ -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazepin-10-yl)succinamide, (R)-2-methyl-N ４ -(1-methyl-3-(3-methylisoxazol-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]diazepin-10-yl)succinamide, (R)-N ４ -(2-(isopropylcarbamoyl)thiazol-5-yl)-2-methyl-N １ -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazepin-10-yl)succinamide, (R)-2-methyl-N ４ -(3-methyl-1-(6-(trifluoromethyl)pyridin-3-yl)-1H-pyrazol-4-yl)-N １ -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazepin-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'-cyclopropan]-10-yl)-N ４ -(3-isobutyramido-1-methyl-1H-pyrazol-5-yl)succinamide, (R)-2-methyl-N ４ -(1-methyl-3-(pyridin-2-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]diazepin-10-yl)succinamide, (R)-N ４ -(4-chloro-2-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)thiazol-5-yl)-2-methyl-N １ -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazepin-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]diazepin-10-yl)succinamide, (R)-N ４ -(3-(6-methoxypyridin-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]diazepin-10-yl)succinamide, (R)-2-methyl-N ４ -(1-methyl-3-(5-(trifluoromethyl)pyridin-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]diazepin-10-yl)succinamide, (R)-N ４ -(4-chloro-2-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)thiazol-5-yl)-2-methyl-N １ -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazepin-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]diazepin-10-yl)-N ４ -(3-(((S)-1-fluoropropan-2-yl)carbamoyl)-1-methyl-1H-pyrazol-5-yl)succinamide, (R)-N ４ -(1-ethyl-3-(3-methylisoxazol-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]diazepin-10-yl)succinamide, (R)-N ４ -(3-(cyclopropylcarbamoyl)-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]diazepin-10-yl)succinamide, (S)-2-Cyclopropyl-N ４ -(3-(3-cyclopropylisoxazol-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′-cyclopropan]-10-yl)succinamide, (S)-N ４ -(4-chloro-2-(1-(difluoromethyl)-1H-pyrazol-4-yl)thiazol-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]diazepin-10-yl)succinamide, (R)-2-methyl-N ４ -(1-methyl-3-(6-methylpyridin-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]diazepin-10-yl)succinamide, (S)-N ４ -(4-chloro-2-(6-(trifluoromethyl)pyridin-3-yl)thiazol-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′-cyclopropan]-10-yl)succinamide, (S)-N ４ -(4-chloro-2-(6-(trifluoromethyl)pyridin-3-yl)thiazol-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]diazepin-10-yl)succinamide, (R)-N ４ -(4-chloro-2-(6-(trifluoromethyl)pyridin-3-yl)thiazol-5-yl)-2-methyl-N １ -((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazepin-10-yl)succinamide, (R)-N ４ -(3-((2-fluorophenyl)carbamoyl)-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]diazepin-10-yl)succinamide, (R)-N ４ -(3-((2,6-dimethylphenyl)carbamoyl)-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]diazepin-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]diazepin-10-yl)propanamide, (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]diazepin-10-yl)propanamide, (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]diazepin-10-yl)propanamide, (R)-2-methyl-N-((S)-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazepin-10-yl)-3-(7-(trifluoromethyl)-1H-benzo[d]imidazol-2-yl)propanamide, (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]diazepin-10-yl)propanamide, (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]diazepin-10-yl)propanamide, (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]diazepin-10-yl)propanamide, (R)—N-((S)-6-fluoro-11-oxo-2,3,10,11-tetrahydro-1H,5H-benzo[d]pyrazolo[1,2-a][1,2]diazepin-10-yl)-3-(5-fluoro-7-methyl-1H-benzo[d]imidazol-2-yl)-2-methylpropanamide, 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]diazepin-10-yl)pentanamide, or a pharmaceutically acceptable salt thereof.

12. 12. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, and one or more pharmaceutically acceptable carriers.

13. A combination comprising a therapeutically effective amount of a compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, and at least one other drug substance.

14. 12. A method of treating a disease or disorder mediated by Sppl2a activity in a subject, said method comprising administering to said subject a therapeutically effective amount of a compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt or stereoisomer thereof.

15. A compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, for use as a pharmaceutical.

16. 12. A compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, for use in the treatment or prevention of a disease or disorder mediated by Sppl2a activity.

17. 17. The method of claim 14 or the compound for use of claim 16, wherein the disease or disorder is an autoimmune disease and is selected from pemphigus vulgaris, pemphigus foliaceus, Sjogren'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's syndrome, or type 1 diabetes.

18. The method of claim 14 or the compound of claim 16 for use in preventing rejection in clinical / surgical transplantation of solid organs or cell masses, wherein the disease or disorder is acute and chronic graft-versus-host disease (GvHD).

19. 17. The method of claim 14 or the compound for use of claim 16, wherein said method or use relates to the treatment of lymphoma.

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