Inhibitors of PCSK9

Abstract

The present disclosure relates to small molecule inhibitors of proprotein convertase subtilisin-like / kexin type 9 (PCSK9), pharmaceutical compositions comprising said compounds, and their use in the prevention and treatment of diseases and disorders associated with PCSK9.

Description

Technical Field

[0001] This disclosure relates to small molecule inhibitors of the proprotein convertase subtilisin-like / kexin 9 (PCSK9) and compositions comprising said compounds. Background Technology

[0002] Coronary artery disease caused by atherosclerosis remains the leading cause of death worldwide. A key risk factor for the development of atherosclerosis is hypercholesterolemia, characterized by elevated levels of low-density lipoprotein (LDL) cholesterol in the bloodstream (Mach et al., 2020). The LDL receptor (LDLR) plays a crucial role in regulating LDL cholesterol metabolism by promoting cellular uptake of LDL particles, thereby reducing circulating LDL cholesterol levels. The importance of LDLR in maintaining cholesterol homeostasis is evident in patients with familial hypercholesterolemia, where LDLR deficiency or impairment has been observed (Brown and Goldstein, 1986). Therefore, upregulating LDLR expression is an effective way to lower LDL cholesterol levels, which is also the main mechanism of action of widely used statins. Statins inhibit cholesterol synthesis while increasing LDLR expression, thereby reducing circulating LDL cholesterol. However, a significant proportion of patients either do not respond to statins or cannot tolerate them due to various side effects. In addition, statins have been found to increase the expression of proprotein convertase subtilisin-like / kexin 9 (PCSK9) (Dubuc et al., 2004), a potent negative regulator of LDLR, which can counteract the beneficial effects of statins on LDL cholesterol levels.

[0003] Targeting PCSK9 has emerged as a promising strategy for reducing plasma LDL cholesterol levels. PCSK9 binds to LDLR, impairing its recycling and promoting its lysosomal degradation, thereby reducing intracellular LDLR levels (reviewed in Hummelgaard et al., 2023). Gain-of-function mutations in PCSK9 lead to increased LDL cholesterol levels (Abifadel et al., 2003), due to enhanced LDLR degradation (Maxwell and Breslow, 2004). Conversely, individuals with loss-of-function mutations in PCSK9 exhibit lower LDL cholesterol levels and a lower incidence of coronary heart disease (Cohen et al., 2006).

[0004] The potential of PCSK9 as a therapeutic target has been demonstrated by two antibody-based PCSK9 inhibitors, alirocumab and evolucumab, both of which have been successfully introduced into clinical use. These inhibitors effectively lower cholesterol levels and reduce the risk of atherosclerotic cardiovascular events, including myocardial infarction, stroke, and death, without any significant adverse effects (Robinson et al., 2015; Sabatine et al., 2015). Furthermore, siRNA-based PCSK9 inhibitors (Raal et al., 2020) have received FDA approval and are currently awaiting cardiovascular outcome data. In addition, cardiovascular disease typically requires lifelong management, unlike infections which may be intermittent. Therefore, ease of administration and delivery is a key factor in patient adherence to maintenance therapy.

[0005] Currently, there are no effective small molecule compounds that can overcome the drawbacks of biologics-based therapies (such as antibodies or nucleic acids), which suffer from low oral bioavailability, potential immunogenicity, and high cost.

[0006] Therefore, there is an unmet need for small molecule PCSK9 inhibitors that are more effective and easier to administer for the treatment of diseases such as cardiovascular diseases and related conditions. Summary of the Invention

[0007] This disclosure relates to novel PCSK9 inhibitors, compositions comprising the disclosed compounds, and uses thereof. In some embodiments, the disclosed compounds modulate PCSK9 activity. In some embodiments, the disclosed compounds have a binding affinity for PCSK9. In some embodiments, the disclosed compounds are used as inhibitors of PCSK9. Therefore, the disclosed compounds provide a solution to the aforementioned problem of the lack of suitable small molecules for binding PCSK9.

[0008] In one aspect, this disclosure provides compounds according to formula (I): Formula (I) Or its tautomers, enantiomers or diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof; in: R 1 It is an H, C1-C5 alkyl or C3-C5 cycloalkyl, each optionally being substituented by one or more identical or different R groups. X1 Replace; where each R X1 It is halogen; Z is a heterocyclic aromatic ring; A is a heterocyclic aromatic ring; R 2 It is an H, C1-C3 alkyl, amide, or sulfonamide, each optionally being substituented by one or more identical or different R groups. X2 Replace; where each R X2 It is a –C1-C3 alkyl or C1-C3 alkoxy; X A It does not exist; it is either carbonyl or sulfone. R A It is absent, or is a 3- to 6-membered heterocycle or heteroaryl, wherein the 3- to 6-membered heterocycle or heteroaryl is optionally replaced by one or more identical or different substituents R. 3 replace; R 3 It is an H, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, -CN, -OH, =O, amide, or 3 to 6-membered heterocycle, each optionally substituent R by one or more identical or different substituents. X3 Replace; or R 3 It is -NH-R X3 ;where R X3 It is -OH, -OCH3, -CN, C3-C5 cycloalkyl, halogen, C1-C3 alkoxy, or amide.

[0009] One aspect of this disclosure provides compositions comprising compounds as described herein.

[0010] In one aspect, this disclosure provides compounds as described herein or pharmaceutically acceptable salts thereof, which are used as medicines.

[0011] In one aspect, this disclosure provides a method for using a compound as described herein or a pharmaceutically acceptable salt thereof to modulate the activity of PCSK9 in a subject, the method comprising administering an effective amount of the compound to the subject.

[0012] In one aspect, this disclosure provides compounds as described herein or pharmaceutically acceptable salts thereof for the treatment, prevention, or relief of lipoprotein metabolism disorders in a subject, the method comprising administering an effective amount of the compound to the subject.

[0013] definition As used herein, the term "alkyl" refers to a straight-chain or branched hydrocarbon moiety having a hydrogen atom removed. For example, C1-C5 alkyl refers to a straight-chain or branched hydrocarbon moiety having 1 to 5 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, propyl, isopropyl, tert-butyl, sec-butyl, etc.

[0014] As used herein, the term "alkoxy" refers to a group of the formula -O-alkyl, wherein the alkyl group is as defined above. Specifically, C1-C3- Alkoxy groups are intended to represent hydrocarbons having 1, 2, or 3 carbon atoms. Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, and isopropoxy.

[0015] As used herein, the term "halogenated alkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by halogen atoms, such as one or more hydrogen atoms being replaced by any one of F, Cl, Br or I.

[0016] As used herein, the terms "cycloalkyl" or "carbocyclic" refer to monocyclic or polycyclic systems. The term "cycloalkyl," also used herein, may optionally contain one or more unsaturated groups or substituents. As used herein, the terms "cycloalkyl" or "carbocyclic" encompass compounds in which the ring atoms may be substituted with functional groups such as carbonyl groups. Examples, but not limited to, those shown below: .

[0017] As used herein, the term "heterocyclic" or "heterocyclic," used alone or in combination, refers to a saturated or unsaturated nonaromatic or polycyclic system in which at least one of the ring atoms is a heteroatom. A saturated or unsaturated nonaromatic or polycyclic system may, for example, contain 3 to 10 ring atoms. As used herein, the term "heterocyclic" or "heterocyclic" encompasses compounds in which the ring atoms may be substituted with functional groups (such as carbonyl or sulfone). Examples, but not limited to, those shown below: .

[0018] The term "aromatic" or "aryl" refers to a cyclic or polycyclic part of a conjugated unsaturated (4η+2)π-electron system (where n is a positive integer), sometimes referred to as a delocalized π-electron system.

[0019] As used herein, the terms “heteroaromatic” or “heteroaryl” used alone or in combination refer to an aromatic ring or a polycyclic aromatic ring system. A heteroaromatic ring or heteroaryl ring may contain 5 to 12 ring atoms, wherein at least one of the ring atoms is a heteroatom.

[0020] "Polycyclic" refers to a system having several closed atomic rings, where these rings share at least one atom. For example, two or more atomic rings sharing at least one atom, or two or more atomic rings sharing two or three atoms. Examples of polycyclic systems include, but are not limited to: As used in this article, “heteroatoms,” especially cyclic heteroatoms, refer to sulfur, oxygen, and nitrogen.

[0021] As used herein, the term "alkenyl" refers to a hydrocarbon moiety having at least one carbon-carbon double bond.

[0022] As used herein, the terms “substituent” or “substituted” used alone or in combination refer to a group that can be used to replace hydrogen. In some embodiments of the invention, the substituted molecule itself may be further substituted. “Substituent derived from” as mentioned herein refers to an atomic group derived from a particular molecule or formula and located at any position of said molecule or formula. In some embodiments, the substituent derived from the molecule is the corresponding molecule in which a hydrogen atom has been removed. For example, a substituent derived from CH4 could be –CH3.

[0023] Some of the compounds disclosed herein may have different hydrogen bonding sites, referred to as "tautomers". For example, compounds containing a carbonyl group (-CH2C(O)-) (keto form) may undergo tautomerism to form a hydroxyl group (-CH=C(OH)-) (enol form). Keto and enol forms, whether alone or in mixtures thereof, should be included where applicable.

[0024] Stereoisomerism refers to the phenomenon of isomerism caused by differences in the spatial arrangement of atoms, while the connection mode or bond multiplicity between isomers remains unchanged. The compounds described herein may contain one or more stereocenters or stereoconformal units, resulting in stereoisomerism, such as chiral carbons. When referring to chiral carbons or positions, as used herein, the term "stereochemical configuration" or "configuration" of an atom refers to the absolute configuration of that center, which can be R or S, as determined by the Cahn-Ingold-Prelog preference rule.

[0025] "Stereoisomer" or "optical isomer" means a stable isomer having at least one chiral atom or restricted rotation, thereby producing a vertically asymmetric plane (e.g., certain biphenyls, propylenes, and spirocyclic compounds) and capable of rotating plane-polarized light. Compounds according to this disclosure may include an asymmetric center or a structure that produces stereoisomerism. This disclosure contemplates all such stereoisomers or mixtures thereof. The compounds of this disclosure and their salts contain asymmetric carbon atoms and therefore may exist as a single stereoisomer, a racemic mixture, and mixtures of enantiomers and / or diastereomers.

[0026] As used herein, the term "enantiomer" refers to isomers that are mirror images of each other but cannot be superimposed. Specific stereoisomers may also be referred to as enantiomers, and mixtures of such isomers are often referred to as enantiomer mixtures. A 50:50 enantiomer mixture is called a racemic mixture or racemate, which may occur in situations where there is no stereoselectivity or stereospecificity in the chemical reaction or process. The terms "racemic mixture" and "racemate" refer to equimolar mixtures of two enantiomer species (e.g., a pair of non-optically active enantiomers). This disclosure includes all stereoisomers of the compounds described herein. For example, compounds obtained or used as mixtures of enantiomers may have the term "rac" preceding the corresponding stereocenter in their name.

[0027] For example:" 3-Methyl-N-[[rac-(1R,3S)-3-[[5-(6-oxopyridazin-1-yl)-2-pyridyl]amino]cyclic [Pentyl]methyl]isoxazole-5-carboxamide This refers to a mixture of the following enantiomers: .

[0028] In some embodiments, the compounds disclosed herein may be racemic. In some embodiments, the compounds disclosed herein may be enriched with one enantiomer. For example, the compounds disclosed herein may have an enantiomer excess (ee) of more than about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or even about 95% or higher. In some embodiments, the compounds disclosed herein may have more than one stereocenter. In some embodiments, the therapeutic formulation may be enriched to provide a major enantiomer of the compound (e.g., formula (I)). The enantiomer-enriched mixture may contain, for example, at least about 60 mol% of one enantiomer, or more preferably at least about 75 mol%, about 90 mol%, about 95 mol%, or even about 99 mol%. In some embodiments, a compound rich in one enantiomer is substantially free of the other enantiomer, where substantially free means that the amount of the substance in question is less than about 10%, or less than about 5%, or less than about 4%, or less than about 3%, or less than about 2%, or less than about 1%, compared to the amount of the other enantiomer in, for example, a composition or mixture of compounds. For example, if a composition or mixture of compounds contains about 98 grams of the first enantiomer and about 2 grams of the second enantiomer, it is said to contain about 98 mol% of the first enantiomer and only about 2% of the second enantiomer.

[0029] As used herein, the term "diastereomer" refers to a stereoisomer that is not called a mirror image. Mixtures of diastereomers can be separated into their individual diastereomers based on their physicochemical differences using methods well known to those skilled in the art, such as chromatography and / or fractional crystallization. Enantiomers can be separated by: converting a mixture of enantiomers into a mixture of diastereomers by reacting it with a suitable optically active compound (e.g., a chiral excipient such as a chiral alcohol or a Mosher acid chloride); separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers into their respective pure enantiomers. Enantiomers can also be separated using a chiral HPLC column.

[0030] dissociation constant (K) D Binding affinity is a measure of the degree of reversible association between two molecular species, such as the affinity of a small molecule PCSK9 inhibitor for PCSK9. The smaller the dissociation constant, the stronger the binding affinity. Complex A x B y The equilibrium dissociation constants for separating the xA and yB elements are given by the following formula: Among them, [A], [B] and [A] x B y [] indicates the concentration of each substance at equilibrium.

[0031] When x = y = 1, the dissociation constant can be expressed by the following formula: Methods for determining dissociation constants are known in the art. These methods can be based on measurements of the concentrations of free and complexed substances at equilibrium, or on measurements of properties directly related to said concentrations. For example, methods for determining dissociation constants include, but are not limited to, microscale thermophoresis (MST), surface plasmon resonance (SPR), fluorescence polarization (FP), and nuclear magnetic resonance (NMR). Detailed Implementation

[0032] A compound In one aspect, this disclosure provides compounds according to formula (I): Formula (I) Or its tautomers, enantiomers or diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof; wherein R 1 It is an H, C1-C5 alkyl or C3-C5 cycloalkyl, each optionally being substituented by one or more identical or different R groups. X1Replace; where each R X1 It is halogen; Z is a heterocyclic aromatic ring; A is a heterocyclic aromatic ring; R 2 It is an H, C1-C3 alkyl, amide, or sulfonamide, each optionally being substituented by one or more identical or different R groups. X2 Replace; where each R X2 It is a –C1-C3 alkyl or C1-C3 alkoxy; X A It does not exist; it is either carbonyl or sulfone. R A It does not exist; it is a 3- to 6-membered heterocycle or heteroaryl group, wherein each of the 3- to 6-membered heterocycles or heteroaryl groups is optionally substituented by one or more identical or different substituents R. 3 replace; R 3 It is an H, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, -CN, -OH, =O, amide, or 3 to 6-membered heterocycle, each optionally substituent R by one or more identical or different substituents. X3 Replace; or R 3 It is -NH-R X3 ;where R X3 It is -OH, -OCH3, -CN, C3-C5 cycloalkyl, halogen, C1-C3 alkoxy, or amide.

[0033] In one embodiment, the compound is according to formula (Ia) or formula (Ib): Formula (Ia) Formula (Ib).

[0034] In one embodiment, the compound is according to formula (Ia). In one embodiment, the compound is according to formula (Ib). In one embodiment, the compound is a mixture of enantiomers of formula (Ia) and formula (Ib).

[0035] In one embodiment, Z is a heteroaromatic ring. In one embodiment, Z is a 5- to 12-membered heteroaromatic ring. In one embodiment, Z is a 5-membered heteroaromatic ring. In one embodiment, Z is a 6-membered heteroaromatic ring. In one embodiment, Z is a 9-membered heteroaromatic ring. In one embodiment, Z is a 12-membered heteroaromatic ring.

[0036] In one implementation, Z is selected from: , , , , , and .

[0037] In one implementation, Z is selected from: , , , , and .

[0038] In one implementation, the compound is provided such that: a) When Z is or When, then A according to , where R A and X A At least one of them is not missing; or b) When Z is or When, then A according to .

[0039] In one implementation, Z is selected from: , and .

[0040] In one implementation scheme, Z is In one implementation, Z is In one implementation, Z is In one implementation, Z is .

[0041] In one implementation scheme, Z is In one implementation, Z is In one implementation, Z is .

[0042] In one embodiment, the compound is according to Formula II: Equation (II).

[0043] In one embodiment, the compound is according to any one of formula IIIa or IIIb: Formula (IIIa) Equation (IIIb), in X A Does not exist, is or ; R A It does not exist; it is a 3- to 6-membered heterocycle or heteroaryl group, wherein each of the 3- to 6-membered heterocycles or heteroaryl groups is optionally substituented by one or more identical or different substituents R. 3 replace; R 3 The group is selected from H, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, -CN, -OH, =O, amide and 3 to 6 membered heterocycles, each of which is optionally substituent R by one or more identical or different substituents. X3 Replace; or R 3 It is -NH-R X3 ;where R X3 It is a group selected from -OH, -OCH3, -CN, C3-C5 cycloalkyl and halogens; R 1 and R 2 As described in this article.

[0044] In one implementation, X A It does not exist, R A It does not exist, and R 2 It is an N-linked amide or sulfonamide.

[0045] In one implementation, X A It does not exist, R A It does not exist, and R 2 Selected from C-linked amides and S-linked sulfonamides.

[0046] In one implementation, X A It does not exist, R A It does not exist, and R 2 Selected from: , , , , and ;where R X2 It is a –C1-C3 alkyl group.

[0047] In one implementation, R X2 It is –CH3.

[0048] In one implementation, R A Selected from , , , , , , and Each of them is optionally replaced.

[0049] In some implementation schemes, R A yes Where B is a 3- to 6-membered heterocyclic ring, and R 3B It is H, -OH or C1-C3 alkyl.

[0050] In some implementation schemes, R A yes , , or , where R 3C The group is selected from H, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, -CN, amide, and 3 to 6-membered heterocycles, each of which is optionally substituent R by one or more identical or different substituents. X3 Replace, or R 3C It is -NH-R X3 ;where R X3 It is a group selected from -OH, -OCH3, -CN, C1-C3 alkyl, C3-C5 cycloalkyl and halogens.

[0051] In one embodiment, the compound is according to formula (IV). Formula (IV), in X A Does not exist, is or ; B is a 3- to 6-membered heterocyclic ring; R 3B Selected from H, -OH and C1-C3 alkyl groups; and R 1 and R 2 As described in this article.

[0052] In one implementation, X A yes or In one implementation, X A It does not exist.

[0053] In one implementation, ring B is selected from: , , and .

[0054] In one implementation, R 3B It is H. In one implementation, R 3B It is –OH.

[0055] In one implementation scheme Selected from , , or .

[0056] In one embodiment, the compound is according to formula (V): Formula (V) in Selected from , , or ; R 3C The group is selected from H, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, -CN, amide, and 3 to 6-membered heterocycles, each of which is optionally substituent R by one or more identical or different substituents. X3 Replace; or R 3C It is -NH-R X3 ;where R X3 It is a group selected from -OH, -OCH3, -CN, C1-C3 alkyl, C3-C5 cycloalkyl, and halogens; and R 1 and R 2 As described in this article.

[0057] In one implementation, R 3C The group is selected from H, C1-C3 alkyl, C1-C3 haloalkyl and -CN; each of which is optionally substituent R by one or more identical or different substituents. X3 Replace; where R X3 It is a group selected from -OH, -OCH3, -CN, C1-C5 cycloalkyl, and halogens. In one embodiment, R 3C It is H. In one implementation, R 3C It is a C1-C3 alkyl group. In one embodiment, R 3C It is a C1-C3 haloalkyl group. In one embodiment, R 3C It is a C1-C3 alkoxy group. In one embodiment, R 3C Yes –CN. In one implementation, R 3C It is -CH2-O-CH3. In one implementation, R 3C It's -O-CH3.

[0058] In one embodiment, the compound is according to formula (Va): Equation (Va) in R 3CThe group is selected from H, C1-C3 alkyl, C1-C3 haloalkyl, -CN, amide, and 3 to 6-membered heterocycles, each of which is optionally substituent R by one or more identical or different substituents. X3 Replace; or R 3C It is -NH-R X3 ;where R X3 It is a group selected from -OH, -OCH3, -CN, C1-C5 cycloalkyl groups and halogens; and R 1 and R 2 As described in this article.

[0059] In one implementation, R 3C Yes – H. In one implementation, R 3C Not H. In one implementation, R 3C It is a –C1-C3 alkyl group. In one embodiment, R 3C It is –CH2-O-CH3. In one implementation, R 3C It is –CH2-OH. In one embodiment, R 3C It is a C1-C3 haloalkyl group. In one embodiment, R 3C Yes –CF3.

[0060] In one implementation, R 3C It is an N-linked amide. In one embodiment, R 3C It is a C-linked amide. In one embodiment, R 3C It is -C(=O)NR L1 R L2 , where R L1 and L2 Each is independently selected from H and C1-C3 alkyl groups. In one embodiment, R 3C It is -C(=O)NH-CH3. In one implementation, R 3C It is a 3- to 6-membered heterocyclic ring, such as a 3-, 4-, 5-, or 6-membered heterocyclic ring. In one embodiment, R 3C It is a 3-membered heterocyclic ring. In one implementation, R 3C It is a 4-membered heterocyclic ring. In one implementation, R 3C It is a 5-membered heterocyclic ring. In one implementation, R 3C It is a 6-membered heterocyclic ring.

[0061] In one implementation, R 3C yes ,in n is 0, 1, or 2; R X3a Each is independently selected from H, -CN, -OH, -OCH3, and -F.

[0062] In one implementation, n is 0. In one implementation, n is 1 or 2. In one implementation, n is 1. In one implementation, n is 2.

[0063] In one implementation, R X3a Yes –CN. In one implementation, one or more R X3a Yes – F. In one implementation, R X3a It is -OH. In one embodiment, R X3a It is -OCH3.

[0064] In one implementation, R 1 Selected from C1-C3 alkyl groups.

[0065] In one implementation, R 1 Selected from –CH3, -CH2-CH3, and CF2H. In one embodiment, R 1 Yes -CH3. In one implementation, R 1 It is -CH2-CH3. In one implementation, R 1 Yes -H. In one implementation, R 1 Yes –CF2H. In one implementation, R 1 It is a C3-C5 cycloalkyl group. In one embodiment, R 1 It is cyclopropyl.

[0066] In one implementation, R 2 Yes – H. In one implementation, R 2 It is –CH3.

[0067] In one embodiment, in formulas (I), (Ia), (Ib), (II), (IIIa), (IIIb), (IV), (V), and (Va), the substituents on the carbons at positions 1 and 2 are in a cis relationship. The cis relationship is defined by substituents on the same side of the plane defined by the pointing ring, as in the following structures: .

[0068] In one embodiment, the carbon atom at position 1 has a configuration of R, and the carbon atom at position 2 has a configuration of S. In another embodiment, the carbon atom at position 1 has a configuration of S, and the carbon atom at position 2 has a configuration of R.

[0069] In one embodiment, the compound is selected from any of the following: the compounds shown in Table A and their enantiomers; or pharmaceutically acceptable salts thereof.

[0070] Table A

[0071] In some embodiments, the compounds disclosed herein are selected from: 3-Methyl-N-[[(1R,3S)-3-[[5-(6-oxopyridazin-1-yl)-2-pyridyl]amino]cyclopentyl]methyl]isoxazole-5-carboxamide (A1); N-[[(1R,3S)-3-[[6-(dimethylcarbamoyl)-1,3-benzothiazol-2-yl]amino]cyclopentyl]methyl]-3-methyl-isoxazole-5-carboxamide (A2); N-[[(1R,3S)-3-[[6-(4-hydroxypiperidin-1-carbonyl)-1,3-benzothiazol-2-yl]amino]cyclopentyl]methyl]-3-methyl-isoxazole-5-carboxamide (A3); N-[[(1R,3S)-3-[[6-(1,1-dioxo-1,2-thiazolidin-2-yl)-1,3-benzothiazolidin-2-yl]amino]cyclopentyl]methyl]-3-methylisoxazole-5-carboxamide (A4); N-[[(1R,3S)-3-[[6-(3-hydroxyazacyclobutane-1-yl)sulfonyl-1,3-benzothiazol-2-yl]amino]cyclopentyl]methyl]-3-methylisoxazole-5-carboxamide (A5); 3-Methyl-N-[[(1R,3S)-3-[(6-morpholinosulfonyl-1,3-benzothiazolyl-2-yl)amino]cyclopentyl]methyl]isoxazole-5-carboxamide (A6); 3-Methyl-N-[[(1R,3S)-3-[[5-(6-oxopyridazin-1-yl)-2-pyridyl]amino]cyclopentyl]methyl]isoxazole-5-carboxamide (A7); 5-Methyl-N-[[(1R,3S)-3-[[5-(6-oxopyridazin-1-yl)-2-pyridyl]amino]cyclopentyl]methyl]isoxazole-3-carboxamide (A8); 1-Methyl-N-[[(1R,3S)-3-[[5-(6-oxopyridazin-1-yl)-2-pyridyl]amino]cyclopentyl]methyl]triazol-4-carboxamide (A9); N-[[(1R,3S)-3-[[5-(3-methoxy-2-pyridyl)-2-pyridyl]amino]cyclopentyl]methyl]-3-methyl-isoxazole-5-carboxamide (A10); 3-Cyclopropyl-N-[[(1R,3S)-3-[[5-(6-oxopyridazin-1-yl)-2-pyridyl]amino]cyclopentyl]methyl]isoxazole-5-carboxamide (A11); 3-Methyl-N-[[(1R,3S)-3-[[5-[6-oxo-3-(trifluoromethyl)pyridazin-1-yl]-2-pyridyl]amino]cyclopentyl]methyl]isoxazole-5-carboxamide (A12); 3-Ethyl-N-[[(1R,3S)-3-[[5-(6-oxopyridazin-1-yl)-2-pyridyl]amino]cyclopentyl]methyl]isoxazole-5-carboxamide (A13); 3-Methyl-N-[[(1R,3S)-3-[[5-(3-methyl-6-oxo-pyridazin-1-yl)-2-pyridyl]amino]cyclopentyl]methyl]isoxazole-5-carboxamide (A14); N-[[(1R,3S)-3-[[5-[3-(3,3-difluoroazacyclobutane-1-yl)-6-oxo-pyridazin-1-yl]-2-pyridinyl]amino]cyclopentyl]methyl]-3-methyl-isoxazol-5-carboxamide (A15); 3-Methyl-N-[[(1R,3S)-3-[[5-(1,2,4-triazol-1-yl)-2-pyridyl]amino]cyclopentyl]methyl]isoxazole-5-carboxamide (A16); 3-Methyl-N-[[(1R,3S)-3-[[3-methyl-5-(6-oxopyridazin-1-yl)-2-pyridyl]amino]cyclopentyl]methyl]isoxazole-5-carboxamide (A17); N-[[(1R,3S)-3-[[5-[3-(cyclobutylamino)-6-oxo-pyridazin-1-yl]-2-pyridyl]amino]cyclopentyl]methyl]-3-methyl-isoxazole-5-carboxamide (A18); 3-Methyl-N-[[(1R,3S)-3-[[5-(2-oxo-1-piperidinyl)-2-pyridinyl]amino]cyclopentyl]methyl]isoxazole-5-carboxamide (A19); 3-Methyl-N-[[(1R,3S)-3-[[6-Methyl-5-(6-oxopyridazin-1-yl)-2-pyridyl]amino]cyclopentyl]methyl]isoxazole-5-carboxamide (A20); 3-Methyl-N-[[(1R,3S)-3-[[4-Methyl-5-(6-oxopyridazin-1-yl)-2-pyridyl]amino]cyclopentyl]methyl]isoxazole-5-carboxamide (A21); N-[[(1R,3S)-3-[[5-[3-(3-methoxyazacyclobutane-1-yl)-6-oxo-pyridazin-1-yl]-2-pyridinyl]amino]cyclopentyl]methyl]-3-methylisoxazole-5-carboxamide (A22); N-[[(1R,3S)-3-[[5-(5-cyano-6-oxo-pyridazin-1-yl)-2-pyridinyl]amino]cyclopentyl]methyl]-3-methyl-isoxazole-5-carboxamide (A23); N-[[(1R,3S)-3-[[5-[6-(methoxymethyl)-2-pyridyl]-2-pyridyl]amino]cyclopentyl]methyl]-3-methyl-isoxazole-5-carboxamide (A24); N-[[(1R,3S)-3-[[5-(3-cyano-6-oxo-pyridazin-1-yl)-2-pyridyl]amino]cyclopentyl]methyl]-3-methylisoxazole-5-carboxamide (A25); N-[[(1R,3S)-3-[[5-[3-(3-hydroxyazacyclobutane-1-yl)-6-oxo-pyridazin-1-yl]-2-pyridinyl]amino]cyclopentyl]methyl]-3-methyl-isoxazole-5-carboxamide (A26); 3-(difluoromethyl)-N-[[(1R,3S)-3-[[5-(6-oxopyridazin-1-yl)-2-pyridyl]amino]cyclopentyl]methyl]isoxazole-5-carboxamide (A27); N-[[(1R,3S)-3-[[5-[3-(methoxymethyl)-6-oxo-pyridazin-1-yl]-2-pyridyl]amino]cyclopentyl]methyl]-3-methyl-isoxazole-5-carboxamide (A28); N-[[(1R,3S)-3-[[5-[3-(azacyclobutane-1-yl)-6-oxo-pyridazin-1-yl]-2-pyridinyl]amino]cyclopentyl]methyl]-3-methyl-isoxazol-5-carboxamide (A29); N-[[(1R,3S)-3-[[5-[3-(hydroxymethyl)-6-oxo-pyridazin-1-yl]-2-pyridyl]amino]cyclopentyl]methyl]-3-methyl-isoxazole-5-carboxamide (A30); 3-Methyl-N-[[(1R,3S)-3-[[5-[3-(methylcarbamoyl)-6-oxo-pyridazin-1-yl]-2-pyridyl]amino]cyclopentyl]methyl]isoxazole-5-carboxamide (A31); N-[[(1R,3S)-3-[[5-[3-(3-cyanozylate-1-yl)-6-oxo-pyridazin-1-yl]-2-pyridinyl]amino]cyclopentyl]methyl]-3-methylisoxazole-5-carboxamide (A32); Or its pharmaceutically acceptable salt.

[0072] In some embodiments, the compounds disclosed herein are selected from: 3-Methyl-N-[[rac-(1S,3R)-3-[[5-(6-oxopyridazin-1-yl)-2-pyridyl]amino]cyclopentyl]methyl]isoxazole-5-carboxamide; N-[[rac-(1S,3R)-3-[[6-(dimethylcarbamoyl)-1,3-benzothiazolyl-2-yl]amino]cyclopentyl]methyl]-3-methyl-isoxazole-5-carboxamide; N-[[rac-(1S,3R)-3-[[6-(4-hydroxypiperidin-1-carbonyl)-1,3-benzothiazolyl-2-yl]amino]cyclopentyl]methyl]-3-methyl-isoxazol-5-carboxamide; N-[[rac-(1S,3R)-3-[[6-(1,1-dioxo-1,2-thiazolidin-2-yl)-1,3-benzothiazolidin-2-yl]amino]cyclopentyl]methyl]-3-methylisoxazole-5-carboxamide; N-[[rac-(1S,3R)-3-[[6-(3-hydroxyazacyclobutane-1-yl)sulfonyl-1,3-benzothiazo-2-yl]amino]cyclopentyl]methyl]-3-methylisoxazole-5-carboxamide; 3-Methyl-N-[[rac-(1S,3R)-3-[(6-morpholinosulfonyl-1,3-benzothiazolyl-2-yl)amino]cyclopentyl]methyl]isoxazole-5-carboxamide; 3-Methyl-N-[[(1S,3R)-3-[[5-(6-oxopyridazin-1-yl)-2-pyridyl]amino]cyclopentyl]methyl]isoxazole-5-carboxamide; 5-Methyl-N-[[rac-(1S,3R)-3-[[5-(6-oxopyridazin-1-yl)-2-pyridyl]amino]cyclopentyl]methyl]isoxazole-3-carboxamide; 1-Methyl-N-[[rac-(1S,3R)-3-[[5-(6-oxopyridazin-1-yl)-2-pyridyl]amino]cyclopentyl]methyl]triazole-4-carboxamide; N-[[(1S,3R)-3-[[5-(3-methoxy-2-pyridyl)-2-pyridyl]amino]cyclopentyl]methyl]-3-methyl-isoxazole-5-carboxamide; 3-Cyclopropyl-N-[[rac-(1S,3R)-3-[[5-(6-oxopyridazin-1-yl)-2-pyridyl]amino]cyclopentyl]methyl]isoxazole-5-carboxamide; 3-Methyl-N-[[(1S,3R)-3-[[5-[6-oxo-3-(trifluoromethyl)pyridazin-1-yl]-2-pyridyl]amino]cyclopentyl]methyl]isoxazole-5-carboxamide; 3-Ethyl-N-[[(1S,3R)-3-[[5-(6-oxopyridazin-1-yl)-2-pyridyl]amino]cyclopentyl]methyl]isoxazole-5-carboxamide; 3-Methyl-N-[[(1S,3R)-3-[[5-(3-methyl-6-oxo-pyridazin-1-yl)-2-pyridyl]amino]cyclopentyl]methyl]isoxazole-5-carboxamide; N-[[(1S,3R)-3-[[5-[3-(3,3-difluoroazacyclobutane-1-yl)-6-oxo-pyridazin-1-yl]-2-pyridinyl]amino]cyclopentyl]methyl]-3-methyl-isoxazol-5-carboxamide; 3-Methyl-N-[[(1S,3R)-3-[[5-(1,2,4-triazol-1-yl)-2-pyridyl]amino]cyclopentyl]methyl]isoxazole-5-carboxamide; 3-Methyl-N-[[(1S,3R)-3-[[3-methyl-5-(6-oxopyridazin-1-yl)-2-pyridyl]amino]cyclopentyl]methyl]isoxazole-5-carboxamide; N-[[(1S,3R)-3-[[5-[3-(cyclobutylamino)-6-oxo-pyridazin-1-yl]-2-pyridinyl]amino]cyclopentyl]methyl]-3-methyl-isoxazole-5-carboxamide; 3-Methyl-N-[[(1S,3R)-3-[[5-(2-oxo-1-piperidinyl)-2-pyridinyl]amino]cyclopentyl]methyl]isoxazole-5-carboxamide; 3-Methyl-N-[[(1S,3R)-3-[[6-Methyl-5-(6-oxopyridazin-1-yl)-2-pyridyl]amino]cyclopentyl]methyl]isoxazole-5-carboxamide; 3-Methyl-N-[[(1S,3R)-3-[[4-Methyl-5-(6-oxopyridazin-1-yl)-2-pyridyl]amino]cyclopentyl]methyl]isoxazole-5-carboxamide; N-[[(1S,3R)-3-[[5-[3-(3-methoxyazacyclobutane-1-yl)-6-oxo-pyridazin-1-yl]-2-pyridinyl]amino]cyclopentyl]methyl]-3-methylisoxazole-5-carboxamide; N-[[(1S,3R)-3-[[5-(5-cyano-6-oxo-pyridazin-1-yl)-2-pyridinyl]amino]cyclopentyl]methyl]-3-methyl-isoxazole-5-carboxamide; N-[[(1S,3R)-3-[[5-[6-(methoxymethyl)-2-pyridinyl]-2-pyridinyl]amino]cyclopentyl]methyl]-3-methyl-isoxazole-5-carboxamide; N-[[(1S,3R)-3-[[5-(3-cyano-6-oxo-pyridazin-1-yl)-2-pyridinyl]amino]cyclopentyl]methyl]-3-methylisoxazole-5-carboxamide; N-[[(1S,3R)-3-[[5-[3-(3-hydroxyazacyclobutane-1-yl)-6-oxo-pyridazin-1-yl]-2-pyridinyl]amino]cyclopentyl]methyl]-3-methyl-isoxazol-5-carboxamide; 3-(difluoromethyl)-N-[[(1S,3R)-3-[[5-(6-oxopyridazin-1-yl)-2-pyridyl]amino]cyclopentyl]methyl]isoxazole-5-carboxamide; N-[[(1S,3R)-3-[[5-[3-(methoxymethyl)-6-oxo-pyridazin-1-yl]-2-pyridinyl]amino]cyclopentyl]methyl]-3-methyl-isoxazole-5-carboxamide; N-[[(1S,3R)-3-[[5-[3-(azacyclobutane-1-yl)-6-oxo-pyridazin-1-yl]-2-pyridinyl]amino]cyclopentyl]methyl]-3-methyl-isoxazol-5-carboxamide; N-[[(1S,3R)-3-[[5-[3-(hydroxymethyl)-6-oxo-pyridazin-1-yl]-2-pyridinyl]amino]cyclopentyl]methyl]-3-methyl-isoxazole-5-carboxamide; 3-Methyl-N-[[(1S,3R)-3-[[5-[3-(methylcarbamoyl)-6-oxo-pyridazin-1-yl]-2-pyridyl]amino]cyclopentyl]methyl]isoxazole-5-carboxamide; N-[[(1S,3R)-3-[[5-[3-(3-cyanozyne-1-yl)-6-oxo-pyridazin-1-yl]-2-pyridinyl]amino]cyclopentyl]methyl]-3-methylisoxazole-5-carboxamide; Or its pharmaceutically acceptable salt.

[0073] PCSK9 adjustment In one embodiment, the compound is able to modulate the activity of PCSK9.

[0074] In one implementation, the compound is an inhibitor of PCSK9.

[0075] In one implementation, the compound reduces the activity of PCSK9.

[0076] In one embodiment, the compound has a dissociation constant (Ki) of less than 20 µM, such as less than 5 µM, such as less than 1 µM, such as less than 0.5 µM, such as less than 0.05 µM, such as less than 0.01 µM. D Combined with PCSK9.

[0077] In one embodiment, the compound has a dissociation constant (Ki) of about 1 nM to about 20 µM, such as about 1 nM to about 10 µM, such as about 1 nM to about 1 µM, such as about 1 nM to about 0.5 µM, such as 1 nM to about 200 nM, such as about 1 nM to about 100 nM, such as about 1 nM to about 50 nM. D Combined with PCSK9.

[0078] In one embodiment, the compound has a dissociation constant (Ki) of less than 200 nM, such as about 20 nM to about 150 nM. D Combined with PCSK9.

[0079] In one embodiment, the compound has a dissociation constant (Ki) of less than 25 nM, such as about 1 nM to about 20 nM. D Combined with PCSK9.

[0080] Binding to the target protein or PCSK9 can be measured using various methods known to those skilled in the art. For example, microscale thermophoresis (MST) or surface plasmon resonance.

[0081] Pharmaceutical Composition In one aspect, this disclosure provides pharmaceutical compositions comprising compounds as described herein or pharmaceutically acceptable salts thereof.

[0082] In one embodiment, the pharmaceutical composition comprises a single stereoisomer of the compound described herein. In one embodiment, the pharmaceutical composition comprises a mixture of stereoisomers of the compound described herein, such as a mixture of enantiomers and / or diastereomers. In one embodiment, the pharmaceutical composition comprises a racemic mixture of a pair of enantiomers of the compound described herein. In one embodiment, the pharmaceutical composition comprises a mixture of stereoisomers of the compound described herein, the compound having substituents in a cis relationship at positions 1 and 2 of carbons in formulas (I), (Ia), (Ib), (II), (IIIa), (IIIb), (IV), (V), and (Va).

[0083] In one embodiment, the pharmaceutical composition comprises a compound as described herein or a pharmaceutically acceptable salt thereof, and at least one acceptable pharmaceutical excipient.

[0084] Medical use In one aspect, this disclosure provides compounds as described herein or pharmaceutically acceptable salts thereof; or compositions as described herein, which are used as medicines.

[0085] In one aspect, this disclosure provides the use of compounds as described herein or pharmaceutically acceptable salts thereof; or pharmaceutical compositions as described herein, for the manufacture of medicaments for diseases or ailments.

[0086] In one aspect, this disclosure provides a method for treating a disease or ailment of a subject, the method comprising administering to the subject an effective amount of a compound as described herein or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition as described herein.

[0087] In one aspect, this disclosure provides a method for modulating the activity of PCSK9 in a subject using the compounds described herein or pharmaceutically acceptable salts thereof; or compositions as described herein, the method comprising administering an effective amount of the compound to the subject.

[0088] In one aspect, this disclosure provides the compounds described herein or pharmaceutically acceptable salts thereof; or compositions as described herein, for treating, preventing or alleviating lipoprotein metabolism disorders in a subject, the method comprising administering an effective amount of the compound to the subject.

[0089] In one aspect, this disclosure provides the use of compounds as described herein or pharmaceutically acceptable salts thereof; or pharmaceutical compositions as described herein, for the manufacture of a medicament for the treatment, prevention or relief of lipoprotein metabolism disorders in a subject.

[0090] In one aspect, this disclosure provides a method for treating, preventing, or alleviating lipoprotein metabolism disorders in a subject, the method comprising administering to the subject an effective amount of a compound as described herein or a pharmaceutically acceptable salt thereof; or a pharmaceutical composition as described herein.

[0091] In one aspect, this disclosure provides a method for treating, preventing, or alleviating cardiovascular disease or condition in a subject using a compound described herein or a pharmaceutically acceptable salt thereof; or a composition as described herein, comprising administering to the subject a compound disclosed herein or a pharmaceutically acceptable salt thereof.

[0092] In one implementation, the cardiovascular disease is selected from hypercholesterolemia, hyperlipidemia, hyperlipoproteinemia, hypertriglyceridemia, dyslipidemia, dyslipoproteinemia, atherosclerosis, hepatic steatosis, metabolic syndrome, and coronary artery disease. In some implementations, the cardiovascular disease is familial hypercholesterolemia. In some implementations, the cardiovascular disease is autosomal dominant hypercholesterolemia. In some implementations, the subject's circulating serum cholesterol level is decreased. In some implementations, the subject's circulating serum LDL-cholesterol level is decreased. In some implementations, the subject's circulating serum triglyceride level is decreased. In some implementations, the subject's circulating serum lipoprotein A level is decreased. In some implementations, the subject has atherosclerosis. In some implementations, the formation of atherosclerotic plaques in the subject is reduced. In some implementations, the subject has... PCSK9 Its function is mutated.

[0093] In one embodiment, the condition is a lipoprotein metabolism disorder. In a further embodiment, the condition is selected from dyslipidemia, hypercholesterolemia, and coronary artery disease. In one embodiment, the condition is dyslipidemia. In one embodiment, the condition is hypercholesterolemia. In one embodiment, the condition is coronary artery disease.

[0094] In one embodiment, the method includes administering one additional therapeutic agent. In one embodiment, the method includes administering two additional therapeutic agents. In one embodiment, the method includes administering three additional therapeutic agents. In one embodiment, the method includes administering four additional therapeutic agents.

[0095] In one embodiment, the additional therapeutic agent is a drug used to treat cardiovascular disease. In another embodiment, the additional therapeutic agent is a drug used to treat lipoprotein metabolism disorders.

[0096] In one embodiment, the additional therapeutic agent is selected from HMG-CoA reductase inhibitors, HMG-CoA synthase inhibitors, HMG-CoA reductase gene expression inhibitors, HMG-CoA synthase gene expression inhibitors, MTP / Apo B-secretion inhibitors, cholesterol ester transfer protein (CETP) inhibitors, bile acid absorption inhibitors, cholesterol absorption inhibitors, cholesterol synthesis inhibitors, squalene synthase inhibitors, squalene epoxidase inhibitors, squalene cyclase inhibitors, combined squalene epoxidase / squalene cyclase inhibitors, fibrates, niacin, combinations of niacin and lovastatin, ion exchange resins, antioxidants, ACAT inhibitors, bile acid chelators, PCSK9 translation inhibitors, ATP citrate lyase inhibitors, apoC3 inhibitors, ANGPTL3 inhibitors, ω-3 fatty acids, Lp(a) inhibitors, apoB inhibitors, apoA1 inhibitors, low-density lipoprotein receptor inhibitors, low-density lipoprotein inhibitors, diacylglycerol acyltransferase inhibitors, lysosomal acid lipase inhibitors, and lecithin cholesterol acyltransferase inhibitors.

[0097] entry 1. A compound according to formula (I): Formula (I) Or its tautomers, enantiomers or diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof; wherein R 1 It is an H, C1-C5 alkyl or C3-C5 cycloalkyl, each optionally being substituented by one or more identical or different R groups. X1 Replace; where each R X1 It is halogen; Z is a heterocyclic aromatic ring; A is a heterocyclic aromatic ring; R 2 It is an H, C1-C3 alkyl, amide, or sulfonamide, each optionally being substituented by one or more identical or different R groups. X2 Replace; where each R X2 It is a –C1-C3 alkyl or C1-C3 alkoxy; X A It does not exist; it is either carbonyl or sulfone. R A It is absent, or is a 3- to 6-membered heterocycle or heteroaryl, wherein the 3- to 6-membered heterocycle or heteroaryl is optionally replaced by one or more identical or different substituents R. 3 replace; R 3It is an H, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, -CN, -OH, =O, amide, or 3 to 6-membered heterocycle, each optionally substituent R by one or more identical or different substituents. X3 Replace; or R 3 It is -NH-R X3 ;where R X3 It is -OH, -OCH3, -CN, C3-C5 cycloalkyl, halogen, C1-C3 alkoxy, or amide.

[0098] 2. The compound according to item 1, wherein the compound is according to formula (Ia) or formula (Ib): Formula (Ia) Formula (Ib).

[0099] 3. The compound according to any one of items 1 or 2, wherein Z is a 5-membered heteroaromatic ring.

[0100] 4. The compound according to any one of items 1 to 3, wherein Z is selected from: , , , , , and .

[0101] 5. The compound according to any one of items 1 to 4, wherein Z is selected from: , , , , and .

[0102] 6. The compound according to any one of claims 1 to 5, wherein Z is selected from: , and .

[0103] 7. The compound according to any one of items 1 to 6, wherein Z is .

[0104] 8. The compound according to any one of items 1 to 7, wherein the compound is according to formula II: Equation (II).

[0105] 9. The compound according to any one of items 1 to 8, wherein the compound is according to formula (IIIa) or (IIIb): Formula (IIIa) Equation (IIIb), in X A Does not exist, is or ; R A It is absent, or is a 3- to 6-membered heterocycle or heteroaryl, wherein the 3- to 6-membered heterocycle and heteroaryl are each optionally replaced by one or more identical or different substituents R. 3 replace; R 3 The group is selected from H, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, -CN, -OH, =O, amide and 3 to 6 membered heterocycles, each of which is optionally substituent R by one or more identical or different substituents. X3 Replace; or R 3 It is -NH-R x3 ;where R X3 It is a group selected from -OH, -OCH3, -CN, C3-C5 cycloalkyl and halogens.

[0106] 10. The compound according to item 9, wherein X A It does not exist, R A It does not exist, and R 2 It is an N-linked amide or sulfonamide.

[0107] 11. The compound according to any one of entries 9 to 10, wherein X A It does not exist, R A It does not exist and R 2 It is a C-linked amide or an S-linked sulfonamide.

[0108] 12. The compound according to any one of items 9 to 11, wherein X A It does not exist, R A It does not exist, and R 2 Selected from: , , , , and ;where R X2 It is a –C1-C3 alkyl group.

[0109] 13. The compound according to any one of items 9 to 12, wherein RX2 It is –CH3.

[0110] 14. The compound according to any one of items 1 to 8, wherein the compound is according to formula IV. Formula (IV), in X A Does not exist, is or ; B is a 3- to 6-membered heterocyclic ring; and R 3B Selected from H, -OH and C1-C3 alkyl groups.

[0111] 15. The compound according to item 14, wherein X A yes or .

[0112] 16. The compound according to item 14, wherein X A It does not exist.

[0113] 17. The compound according to any one of entries 13 to 15, wherein ring B is selected from: , , and .

[0114] 18. The compound according to any one of entries 14 to 17, wherein R 3B Yes, it's -H.

[0115] 19. The compound according to any one of entries 14 to 17, wherein R 3B It is –OH.

[0116] 20. The compound according to any one of entries 14 to 17, wherein Selected from: , , and .

[0117] 21. The compound according to any one of items 1 to 8, wherein the compound is according to formula (V): Formula (V) in Selected from , , and ; R 3C The group is selected from H, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, -CN, amide, and 3 to 6-membered heterocycles, each of which is optionally substituent R by one or more identical or different substituents. X3 Replace; or R 3C It is -NH-R X3 ;where R X3 It is a group selected from -OH, -OCH3, -CN, C1-C3 alkyl, C3-C5 cycloalkyl and halogens.

[0118] 22. The compound according to item 21, wherein R 3C It's H.

[0119] 23. The compound according to item 21, wherein R 3C It is a C1-C3 alkyl group.

[0120] 24. The compound according to item 21, wherein R 3C It is a C1-C3 haloalkyl group.

[0121] 25. The compound according to item 21, wherein R 3C It is a C1-C3 alkoxy group.

[0122] 26. The compound according to item 21, wherein R 3C Yes –CN.

[0123] 27. The compound according to item 21, wherein R 3C It is -CH2-O-CH3.

[0124] 28. The compound according to item 21, wherein R 3C It's -O-CH3.

[0125] 29. The compound according to any one of items 1 to 8 and 21, wherein the compound is according to formula Va: Equation (Va) in R 3C The group is selected from H, C1-C3 alkyl, C1-C3 haloalkyl, -CN, amide, 3 to 6-membered heterocycles, each of which is optionally substituent R by one or more identical or different substituents. X3 Replace; or R 3C It is -NH-R X3 ;where R X3 It is a group selected from -OH, -OCH3, -CN, C1-C5 cycloalkyl and halogens.

[0126] 30. The compound according to item 29, wherein R 3C It is H, C1-C3 alkyl, C1-C3 haloalkyl, or -CN, each of which is optionally substituent R by one or more identical or different substituents. X3 Replace; where R X3 It is a group selected from -OH, -OCH3, -CN, C1-C5 cycloalkyl and halogens.

[0127] 31. The compound according to item 29, wherein R 3C Yes –H.

[0128] 32. The compound according to item 29, wherein R 3C Not H.

[0129] 33. The compound according to item 29, wherein R 3C It is a –C1-C3 alkyl group.

[0130] 34. The compound according to item 29, wherein R 3C It is –CH2-O-CH3.

[0131] 35. The compound according to item 29, wherein R 3C It is –CH2-OH.

[0132] 36. The compound according to item 29, wherein R 3C It is a C1-C3 haloalkyl group.

[0133] 37. The compound according to item 29, wherein R 3C Yes –CF3.

[0134] 38. The compound according to item 29, wherein R 3C It is -C(=O)NR L1 R L2 , where R L1 and R L2 Each is independently selected from H or C1-C3 alkyl groups.

[0135] 39. The compound according to any one of entries 29 or 38, wherein R 3C It is -C(=O)NH-CH3.

[0136] 40. The compound according to item 29, wherein R 3C It is a 3- to 6-membered heterocycle, such as a 3, 4, 5 or 6-membered heterocycle.

[0137] 41. The compound according to item 29 or 40, wherein R 3C yes ,in n is 0, 1, or 2; and R X3a Each is independently selected from H, -CN, -OH, -OCH3, and -F.

[0138] 42. The compound according to item 41, wherein n is 0.

[0139] 43. The compound according to item 41, wherein n is 1 or 2.

[0140] 44. The compound according to item 41, wherein R X3a Yes –CN.

[0141] 45. The compound according to item 41, wherein one or more R X3a Yes –F.

[0142] 46. ​​The compound according to item 41, wherein R X3a It is -OH.

[0143] 47. The compound according to item 41, wherein R X3a It is -OCH3.

[0144] 48. The compound according to any one of the preceding entries, wherein R 1 Selected from –CH3, -CH2-CH3 and CF2H.

[0145] 49. The compound according to any one of items 1 to 47, wherein R 1 It is -CH3.

[0146] 50. The compound according to any one of items 1 to 47, wherein R 1 It is -CH2-CH3.

[0147] 51. The compound according to any one of items 1 to 47, wherein R 1 Yes, it's -H.

[0148] 52. The compound according to any one of items 1 to 47, wherein R 1 Yes, it is –CF2H.

[0149] 53. The compound according to any one of items 1 to 47, wherein R 1 It is a C3-C5 cycloalkyl group.

[0150] 54. The compound according to any one of items 1 to 47, wherein R 1 It is cyclopropyl.

[0151] 55. The compound according to any one of items 1 to 54, wherein R 2 Is it –H or –CH? 3。

[0152] 56. The compound according to any one of items 1 to 54, wherein R 2 Yes –H.

[0153] 57. The compound according to any one of items 1 to 54, wherein R 2 It is –CH3.

[0154] 58. The compound according to any one of items 1 to 57, wherein in formulas (I), (II), (III) and (IV), the substituents on the carbons at positions 1 and 2 are in a cis relationship.

[0155] 59. The compound according to any one of items 1 to 57, wherein the configuration of the carbon at position 1 is R and the configuration of the carbon at position 2 is S.

[0156] 60. The compound according to any one of entries 1 to 57, wherein the compound is selected from any one of the compounds shown in Table A of the subsection "A compound", as well as its enantiomers, mixtures thereof, or pharmaceutically acceptable salts thereof.

[0157] 61. The compound according to any one of the preceding entries, wherein the compound is capable of modulating the activity of PCSK9.

[0158] 62. The compound according to any one of the preceding entries, wherein the compound is an inhibitor of PCSK9.

[0159] 63. The compound according to any one of the preceding entries, wherein the compound reduces the activity of PCSK9.

[0160] 64. The compound according to any one of the preceding entries, wherein the compound has a dissociation constant (Ki) of less than 20 µM, such as less than 5 µM, such as less than 1 µM, such as less than 0.5 µM, such as less than 0.05 µM, such as less than 0.01 µM. D Combined with PCSK9.

[0161] 65. The compound according to any one of the preceding entries, wherein the compound has a dissociation constant (Ki) of about 1 nM to about 20 µM, such as about 1 nM to about 10 µM, such as about 1 nM to about 1 µM, such as about 1 nM to about 0.5 µM, such as 1 nM to about 200 nM, such as about 1 nM to about 100 nM, such as about 1 nM to about 50 nM. DCombined with PCSK9.

[0162] 66. A pharmaceutical composition comprising a compound according to any one of the preceding entries.

[0163] 67. The compound according to any one of entries 1 to 65, or the pharmaceutical composition according to entry 66, used as a medicine.

[0164] 68. A method for regulating the activity of PCSK9 in a subject using a compound according to any one of items 1 to 65, or a pharmaceutical composition according to item 66, the method comprising administering an effective amount of the compound to the subject.

[0165] 69. A method of using a compound according to any one of items 1 to 65, or a pharmaceutical composition according to item 66, for treating, preventing, or alleviating a lipoprotein metabolism disorder in a subject, the method comprising administering an effective amount of the compound to the subject.

[0166] 70. The compound or composition used according to Item 69, wherein the condition is a lipoprotein metabolism disorder, and wherein the condition is selected from dyslipidemia, hypercholesterolemia, and coronary heart disease.

[0167] Item A 1. A compound according to formula (I): Formula (I) Or its tautomers, enantiomers or diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof; wherein R 1 Choose from the group consisting of H, C1-C5 alkyl and C3-C5 cycloalkyl, each optionally substituent R by one or more identical or different substituents. X1 Replace; where R X1 Choose from the following groups: halogens; Z is a heteroaromatic ring, selected from the following groups: , , , , , and ; A is a polyarium ring. R 2 Choose from the group consisting of: H, C1-C3 alkyl, amide, and sulfonamide, each optionally being substituented by one or more of the same or different R groups. X2 Replace; where R X2Choose from the group consisting of: –C1-C3 alkyl and C1-C3 alkoxy; X A It is absent or selected from the carbonyl or sulfone group; R A The following groups are absent or selected: 3 to 6-membered heterocycles and heteroaryl groups, each of which is optionally substituent for one or more identical or different R groups. 3 replace; R 3 Selected from H, halogenated C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, -CN, -OH, =O, amide, 3 to 6 membered heterocycles, each optionally substituent R by one or more identical or different substituents. X3 Replace; or R 3 It is -NH-R x3 ;where R X3 It is a group selected from the group consisting of: -OH, C1-C3 alkyl, -OCH3, -CN, C3-C5 cycloalkyl, halogen, C1-C3 alkoxy and amide; The attached conditions are: a) When Z is or When, then A according to , where R A and X A At least one of them is not missing; or b) When Z is or When, then A according to .

[0168] 2. The compound according to entry A1, wherein Z is selected from the group consisting of: , and .

[0169] 3. The compound according to any one of entries A1 to A2, wherein the compound is based on any one of formula IIIa or IIIb: Formula (IIIa) Equation (IIIb), in X A Not present or selected and ; R A The following groups are absent or selected: 3 to 6-membered heterocycles and heteroaryl groups, each of which is optionally substituent for one or more identical or different R groups. 3replace; R 3 The group is selected from H, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, -CN, -OH, =O, amide, and 3 to 6-membered heterocycles, each of which is optionally substituent R by one or more identical or different substituents. X3 Replace; or R 3 It is -NH-R x3 ;where R X3 It is a group selected from the following groups: -OH, -OCH3, -CN, C3-C5 cycloalkyl and halogen.

[0170] 4. The compound according to any one of entries A1 to A3, wherein X A It does not exist, R A It does not exist, and R 2 Choose from the following groups: , , , , and ;where R X2 It is a C1-C3 alkyl group.

[0171] 5. The compound according to any one of entries A1 to A3, wherein the compound is according to formula IV. Formula IV, in X A Not present or selected and ; B is a 3- to 6-membered heterocyclic ring; R 3B Selected from H, -OH and C1-C3 alkyl groups.

[0172] 6. The compound according to item A5, wherein Selected from: , , and .

[0173] 7. The compound according to any one of items 1 to 3, wherein the compound is based on V: Formula V in Selected from , , and ; R 3C The following are selected from the group consisting of: H, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, -CN, amide, 3 to 6-membered heterocycles, each of which is optionally substituent R by one or more identical or different substituents. X3 Replace; or R 3C It is -NH-R X3 ;where R X3 It is a group selected from the following groups: -OH, -OCH3, -CN, C1-C3 alkyl, C3-C5 cycloalkyl and halogen.

[0174] 8. The compound according to any one of entries A1 to A3 and A7, wherein the compound is based on formula Va: Equation (Va) in R 3C Choose from the group consisting of: H, C1-C3 alkyl, C1-C3 haloalkyl, -CN, amide, 3 to 6-membered heterocycles, each optionally substituent R by one or more identical or different substituents. X3 Replace; or R 3C It is -NH-R x3 ;where R X3 It is a group selected from the following groups: -OH, -OCH3, -CN, C1-C5 cycloalkyl and halogen.

[0175] 9. The compound according to any one of entries A7 to A8, wherein: i) R 3C It is H, C1-C3 alkyl, C1-C3 haloalkyl, or -CN, each of which is optionally substituent R by one or more identical or different substituents. X3 Replace; where R X3 It is a group selected from the following groups: -OH, -OCH3, -CN, C1-C5 cycloalkyl groups and halogens; or ii) R 3C yes in n is an integer selected from 0, 1, or 2; R X3a Each can be independently selected from the following groups: H, -CN, -OH, -OCH3, -F.

[0176] 10. The compound according to any one of entries A1 to A9, wherein R 1 Selected from –CH3, -CH2-CH3 and CF2H.

[0177] 11. The compound according to any one of entries A1 to A10, wherein R 1 It is -CH3.

[0178] 12. The compound according to any one of entries A1 to A11, wherein R 2 It is –H or -CH3.

[0179] 13. The compound according to any one of entries A1 to A12, wherein the substituents on the carbons at positions 1 and 2 of formula I, IIIa, IIIb, IV, V or Va are in a cis relationship.

[0180] 14. A compound according to any one of entries A1 to A13, wherein the compound is selected from any one of the following groups: the compound shown in Table A in the subsection "A compound", and its enantiomers; or a pharmaceutically acceptable salt thereof.

[0181] 15. A method of using a compound according to any one of entries A1 to A14, or a pharmaceutical composition comprising a compound according to any one of entries A1 to A14, for treating, preventing or alleviating a lipoprotein metabolism disorder in a subject, the method comprising administering an effective amount of the compound to the subject.

[0182] Example Example 1: Bioactivity Purpose In this embodiment, microscale thermophoresis (MST) was used to measure the equilibrium dissociation constant (KD) describing the binding of the compound of this disclosure to PCSK9.

[0183] Materials and methods Using the LV Mosquito pipetting robot (SPT Labtech), a 12-point titration series of compound solutions was prepared in TTP LVDS 384-well plates (SPT Labtech) with a total volume of 1.2 µL in a buffer consisting of 16.7% DMSO (v / v) and 0.05% Tween20 (v / v).

[0184] Before adding 8.8 µL of 56.8 nM PCSK9 and 14.2 nM RED-tris-NTA (Nanotemper) in 28.4 mM Bis-Tris propane (pH 7), 340.9 mM NaCl, 0.05% Tween20 (v / v) to each well, the plates were centrifuged. The plates were sealed with adhesive strips, placed on an Eppendorf hot mixer, stirred at 600 rpm for 3 min, then rotated on a Fisherbrand plate rotator for 15 s, and further incubated at room temperature for 1 h. MST was measured on a Monolith NT. Automated treatment (Nanotemper) was performed in standard-condition capillaries using 5% LED power and high MST power. Dosage-response was extracted at a 20-second thermal effect time. All experiments were performed in duplicate.

[0185] result The results are shown in Table 1.

[0186] Table 1. Binding affinity of the compounds disclosed herein to PCSK9 (***: 1) <K D ≤20 nM; **: 20 <K D ≤200 nM; *:K D >200 nM).

[0187] a: These samples were tested as mixtures of enantiomers isolated as described in the examples below.

[0188] in conclusion The ability of the compounds disclosed herein to bind to and inhibit PCSK9 has been confirmed by representative compounds of formula (I) in Table 1.

[0189] Example 2: Preparation of the compound Generally, compounds according to formula (I) and related formulas can be prepared from readily available starting materials. If such starting materials are not commercially available, they can be prepared using standard synthetic techniques. Generally, the synthetic route for any individual compound of formula (I) and related formulas will depend on the specific substituents of each molecule, and these factors should be understood by those skilled in the art. The general methods and procedures described in the following examples can be used to prepare compounds of formula (I) and related formulas. The reaction conditions (such as temperature, solvent, or auxiliary reagents) depicted in the following schemes are given by way of example only and are not limiting. It should be understood that, given typical or preferred experimental conditions (i.e., reaction temperature, time, molar amounts of reagents, solvent, etc.), other experimental conditions may be used unless otherwise stated. Optimal reaction conditions may vary depending on the specific reactants or solvents used, but those skilled in the art can determine these conditions using conventional optimization procedures.

[0190] In the following examples, compounds obtained or used as mixtures of enantiomers will have the term "rac" preceding the corresponding stereocenter in their names. For example: 3-Methyl-N-[[rac - (1R,3S)-3-[[5-(6-oxopyridazine- [1-yl)-2-pyridyl]amino]cyclopentyl]methyl]isoxazole-5-carboxamide This refers to a mixture of the following enantiomers: Example S1: 3-Methyl-N-[[rac-(1R,3S)-3-[[5-(6-oxopyridazin-1-yl)-2-pyridyl]amino [Oxyl]cyclopentyl]methyl]isoxazole-5-carboxamide 1. General procedure for the preparation of 2-(6-chloropyridin-3-yl)-2,3-dihydropyridazin-3-one: Under N2, 2-chloro-5-iodopyridine (1 g, 4.18 mmol, 1 equivalent ), 1H-pyridazin-6-one (601.95 mg, 6.26 mmol, 1.5... equivalent ), CuI (79.54 mg, 417.64 µmol, 0.1 equivalent ) and K2CO3 (1.73 g, 12.53 mmol, 3 equivalentThe solution in pyridine (10 mL) was stirred at 120 °C for 12 hours. The reaction mixture was quenched by adding saturated NH4Cl aqueous solution (20 mL) and extracted with EtOAc (10 mL * 3). The combined organic layers were washed with brine (10 mL * 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by rapid silica gel chromatography (ISCO®; 20 g SepaFlash® silica rapid column, 0–50% ethyl acetate / petroleum ether gradient eluent, 100 mL / min) to give 2-(6-chloropyridin-3-yl)-2,3-dihydropyridazin-3-one (290 mg, 1.40 mmol, 33.45% yield) as a yellow solid.

[0191] LCMS (ESI + ): m / z 208.0 (M+H) + 2. General procedure for the preparation of 3-methyl-N-[[rac-(1R,3S)-3-[[5-(6-oxopyridazin-1-yl)-2-pyridyl]amino]cyclopentyl]methyl]isoxazole-5-carboxamide: The following substances were added: N-[(rac-(1R,3S)-3-aminocyclopentyl)methyl]-3-methyl-isoxazole-5-carboxamide (100 mg, 385.01 µmol, 1 equivalent, HCl), 2-(6-chloropyridin-3-yl)-2,3-dihydropyridazin-3-one (79.93 mg, 385.01 µmol, 1 equivalent), [2-(2-aminophenyl)phenyl]-methylsulfonyloxy-palladium di-tert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphine (30.58 mg, 38.50 µmol, 0.1 equivalent), di-tert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphine (16.35 mg, 38.50 µmol, 0.1 equivalent), and t-BuONa (74.00 mg, 770.02 µmol, HCl). The mixture of µmol (2 equivalents) in 2-methylbut-2-ol (3 mL) was degassed and purged three times with N2, and then stirred at 100 °C for 12 hours under N2 atmosphere. The reaction mixture was filtered and the filtrate was concentrated to give the residue. The residue was purified by preparative HPLC (neutral conditions; column: Phenomenex Gemini-NX 80*40mm*3µm; mobile phase: [water (10mM NH4HCO3)-ACN]; B%: 10%-40%, 8 min) to give 3-methyl-N-[[rac-(1R,3S)-3-[[5-(6-oxopyridazin-1-yl)-2-pyridyl]amino]cyclopentyl]methyl]isoxazole-5-carboxamide (24.8 mg, 61.35 µmol, 15.93% yield, 97.57% purity) as a white solid.

[0192] LCMS (ESI + ): m / z 395.2 (M+H) + 1 H NMR (400 MHz, methanol-d4) δ = 8.14 (d, J = 2.5 Hz, 1H), 8.02 (dd, J = 1.4, 3.8 Hz, 1H), 7.59 (dd, J = 2.6, 9.0 Hz, 1H), 7.46 (dd, J = 3.9, 9.5 Hz, 1H), 7.06(dd, J = 1.6, 9.4 Hz, 1H), 6.80 (s, 1H), 6.58 (d, J = 9.0 Hz, 1H), 4.24 - 4.14(m, 1H), 3.40 (d,J = 6.8 Hz, 2H), 2.39 - 2.27 (m, 2H), 2.34 (s, 3H), 2.15 –2.05 (m, 1H), 1.90 – 1.80 (m, 1H), 1.67 – 1.50 (m, 2H), 1.31 – 1.19 (m, 1H).

[0193] The two enantiomers in the prepared mixture are: 3-methyl-N-[[(1R,3S)-3-[[5-(6-oxopyridazin-1-yl)-2-pyridyl]amino]cyclopentyl]methyl]isoxazole-5-carboxamide and 3-methyl-N-[[(1S,3R)-3-[[5-(6-oxopyridazin-1-yl)-2-pyridyl]amino]cyclopentyl]methyl]isoxazole-5-carboxamide Example S2: N-[[rac-(1R,3S)-3-[[6-(dimethylcarbamoyl)-1,3-benzothiazol-2-yl] [Amino]cyclopentyl]methyl]-3-methyl-isoxazole-5-carboxamide 1. General procedure for the preparation of 2-chloro-N,N-dimethyl-1,3-benzothiazole-6-carboxamide: At 0 °C, DIEA (1.21 g, 9.36 mmol, 1 equivalent) and HATU (2.67 g, 7.02 mmol, 1.5 equivalent) were added to a solution of 2-chloro-1,3-benzothiazol-6-carboxylic acid (1 g, 4.68 mmol, 1 equivalent) in DMF (10 mL), and the mixture was stirred at 25 °C for 12 hours. The reaction mixture was diluted with H2O (20 mL) and extracted with ethyl acetate (50 mL * 3). The combined organic layers were washed with brine (50 mL * 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate = 50 / 1 to 3 / 1) to give 2-chloro-N,N-dimethyl-1,3-benzothiazol-6-carboxamide (890 mg, 3.70 mmol, 78.99% yield) as a pale yellow oil.

[0194] LCMS (ESI+): m / z 241.1 (M+H) + 2. General procedure for the preparation of N-[[rac-(1R,3S)-3-[[6-(dimethylcarbamoyl)-1,3-benzothiazol-2-yl]amino]cyclopentyl]methyl]-3-methyl-isoxazole-5-carboxamide: K₂CO₃ (122.93 mg, 889.43 μmol, 3 equivalents) was added to a solution of 2-chloro-N,N-dimethyl-1,3-benzothiazole-6-carboxamide (85.64 mg, 355.77 μmol, 1.2 equivalents) and N-[(rac-(1R,3S)-3-aminocyclopentyl)methyl]-3-methyl-isoxazole-5-carboxamide (100 mg, 296.48 μmol, 1 equivalent, TFA) in DMF (2 mL), and the reaction was stirred at 80 °C for 12 h. The reaction mixture was filtered, and the filtrate was purified by preparative HPLC (alkaline conditions, column: water Xbridge Prep OBD C18 150*40mm*10μm, mobile phase: [water(NH3H2O+NH4HCO3)-ACN]; B%: 15%-45%, 8 min) to obtain N-[[rac-(1R,3S)-3-[[6-(dimethylcarbamoyl)-1,3-benzothiazolyl-2-yl]amino]cyclopentyl]methyl]-3-methyl-isoxazole-5-carboxamide (27.1 mg, 62.21 μmol, 20.98% yield, 98.136% purity), as a pale yellow solid.

[0195] 1 H NMR (400 MHz, methanol-d4) δ = 7.70 (d, J = 1.4 Hz, 1H), 7.48 - 7.43 (m,1H), 7.36 - 7.33 (m, 1H), 6.81 - 6.79 (m, 1H), 4.29 - 4.20 (m, 1H), 3.40 (d,J = 6.1 Hz, 2H), 3.08 (br s, 6H), 2.45 - 2.30 (m, 2H), 2.33 (s, 3H), 2.17 -2.09 (m, 1H), 1.92 - 1.83 (m, 1H), 1.76 - 1.66 (m, 1H), 1.60 – 1.50 (m, 1H), 1.40 - 1.28 (m, 1H) LCMS (ESI+): m / z 428.2 (M+H) + The two compounds in the mixture are: N-[[(1R,3S)-3-[[6-(dimethylcarbamoyl)-1,3-benzothiazol-2-yl]amino]cyclopentyl]methyl]-3-methyl-isoxazole-5-carboxamide and N-[[(1S,3R)-3-[[6-(dimethylcarbamoyl)-1,3-benzothiazol-2-yl]amino]cyclopentyl]methyl]-3-methyl-isoxazole-5-carboxamide Example S3: N-[[rac-(1R,3S)-3-[[6-(4-hydroxypiperidin-1-carbonyl)-1,3-benzothiazol-2-yl] [Amino]cyclopentyl]methyl]-3-methyl-isoxazole-5-carboxamide 1. General procedure for the preparation of tert-butyl 3-oxo-2-azabicyclo[2.2.1]hept-5-ene-2-carboxylate: To a stirred solution of 2-azabicyclo[2.2.1]hepten-5-en-3-one (30 g, 274.91 mmol, 1 equivalent) in THF (600 mL), DMAP (3.36 g, 27.49 mmol, 0.1 equivalent) and TEA (83.45 g, 824.74 mmol, 114.79 mL, 3 equivalent) were added, followed by tert-butoxycarbonyl tert-butyl carbonate (72.00 g, 329.90 mmol, 75.79 mL, 1.2 equivalent). The resulting reaction mixture was stirred at 20 °C for 12 hours. The reaction mixture was concentrated under reduced pressure to remove THF. The residue was diluted with water (100 mL) and the reaction mixture was extracted with EtOAc (100 mL x 3). The organic layer was dried over Na2SO4 and concentrated to give the crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 4:1 to 1:1) to give tert-butyl 3-oxo-2-azabicyclo[2.2.1]hept-5-ene-2-carboxylic acid (57.29 g, 273.80 mmol, 99.59% yield), as a white solid.

[0196] The general procedure for preparing tert-butyl 3-oxo-2-azabicyclo[2.2.1]heptane-2-carboxylate is as follows: Under a nitrogen atmosphere, Pd / C (5 g, 10% purity) was added to a solution of tert-butyl 3-oxo-2-azabicyclo[2.2.1]heptane-5-en-2-carboxylate (53 g, 253.30 mmol, 1 equivalent) in MeOH (700 mL). The suspension was degassed and purged three times with H2. The mixture was stirred at 25 °C under H2 (15 psi) for 2 hours. The catalyst was removed by filtration through diatomaceous earth (Celite) and then washed with EtOAc (300 mL). The filtrate was concentrated to give tert-butyl 3-oxo-2-azabicyclo[2.2.1]heptane-2-carboxylate (54 g, crude), a yellow oil, which was used directly without purification.

[0197] LCMS (ESI + ): m / z 156.0 (M+H-56) + 3. General procedure for preparing N-[rac-(1S, 3R)-3-(hydroxymethyl)cyclopentyl]carbamate tert-butyl ester: Under N2, at 0 °C, tert-butyl 3-oxo-2-azabicyclo[2.2.1]heptane-2-carboxylate (25 g, 118.34 mmol, 1 equivalent) was slowly added to a solution of MeOH (1000 mL) and NaBH4 (8.95 g, 236.68 mmol, 2 equivalents), and the reaction was stirred at 0 °C for 2 h. The reaction mixture was quenched by adding a saturated aqueous solution of NH4Cl (500 mL) and then extracted with EtOAc (200 mL * 3). The combined organic layers were washed with brine (300 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by rapid silica gel chromatography (ISCO®; 220 g SepaFlash® silica rapid column, 0-25% ethyl acetate / petroleum ether gradient eluent, 100 mL / min) to obtain N-[rac-(1S, 3R)-3-(hydroxymethyl)cyclopentyl]carbamate tert-butyl ester (13 g, 60.38 mmol, 51.03% yield) as a colorless oil.

[0198] 4. General procedure for preparing [rac-(1R,3S)-3-(tert-butoxycarbonylamino)cyclopentyl]methylmethane sulfonate: To a solution of N-[rac-(1S,3R)-3-(hydroxymethyl)cyclopentyl]carbamate tert-butyl ester (12.90 g, 59.92 mmol, 1 equivalent) and TEA (18.19 g, 179.76 mmol, 25.02 mL, 3 equivalents) in DCM (150 mL), methanesulfonyl methanesulfonate (15.66 g, 89.88 mmol, 1.5 equivalents) was added, and the reaction was stirred at 20 °C for 12 h. The reaction mixture was diluted with water (100 mL) and extracted with DCM (100 mL * 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give [rac-(1R,3S)-3-(tert-butyloxycarbonylamino)cyclopentyl]methylmethanesulfonate (18 g, crude), an orange oil, which was used directly without purification.

[0199] 5. General procedure for preparing N-[rac-(1S, 3R)-3-(azidomethyl)cyclopentyl]carbamate tert-butyl: To a solution of [rac-(1R,3S)-3-(tert-butyloxycarbonylamino)cyclopentyl]methyl methanesulfonate (18 g, 61.35 mmol, 1 equivalent) in DMF (200 mL), NaN3 (7.98 g, 122.71 mmol, 2 equivalents) was added, and the reaction was stirred at 60 °C for 6 h. The reaction mixture was diluted with aqueous solutions of H2O (200 mL) and NaHCO3 (200 mL), and then extracted with EtOAc (200 mL * 3). The combined organic layers were washed with brine (300 mL * 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give N-[rac-(1S, 3R)-3-(azidomethyl)cyclopentyl]carbamate tert-butyl ester (15 g, crude), a yellow oil, which was used directly without purification.

[0200] 6. General procedure for preparing N-[rac-(1S, 3R)-3-(aminomethyl)cyclopentyl]carbamate tert-butyl ester: Under N2, Pd / C (4 g, 22.39 mmol, 10% purity) was added to a solution of N-[rac-(1S, 3R)-3-(azidomethyl)cyclopentyl]carbamate (15 g, 62.42 mmol, 1 equivalent) in MeOH (200 mL). The suspension was degassed under vacuum and purged several times with H2. The mixture was stirred at 20 °C for 12 hours under H2 (15 psi). The reaction mixture was filtered and the filtrate was concentrated to give N-[rac-(1S, 3R)-3-(aminomethyl)cyclopentyl]carbamate (13 g, crude), a colorless oil that was used directly without purification.

[0201] 7. General procedure for preparing N-[rac-(1S, 3R)-3-[[(3-methylisoxazol-5-carbonyl)amino]methyl]cyclopentyl]carbamate tert-butyl ester: At 0 °C, DIEA (603.08 mg, 4.67 mmol, 812.78 uL, 2 equivalents) and HATU (1.77 g, 4.67 mmol, 2 equivalents) were added to a mixture of 3-methylisoxazole-5-carboxylic acid (299.50 mg, 2.36 mmol, 1 equivalent) in DMF (10 mL), and the reaction was stirred at 15 °C for 12 h. The reaction mixture was diluted with H2O (10 mL) and extracted with ethyl acetate (10 mL * 3). The combined organic layers were washed with brine (20 mL * 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by preparative TLC (SiO2, petroleum ether: ethyl acetate = 2:1) to give N-[rac-(1S, 3R)-3-[[(3-methylisoxazole-5-carbonyl)amino]methyl]cyclopentyl]carbamate tert-butyl ester (280 mg, 865.84 µmol, 37.11% yield) as a yellow solid.

[0202] LCMS (ESI + ): m / z 224.2 (M+H-100) + 8. General procedure for the preparation of N-[(rac-(1R,3S)-3-aminocyclopentyl)methyl]-3-methyl-isoxazole-5-carboxamide: A mixture of N-[rac-(1S, 3R)-3-[[(3-methylisoxazole-5-carbonyl)amino]methyl]cyclopentyl]carbamate tert-butyl ester (280.00 mg, 865.84 µmol, 1 equivalent) in DCM (3 mL) and TFA (924.00 mg, 8.10 mmol, 0.6 mL, 9.36 equivalent) was stirred at 15 °C for 4.5 h. The reaction was concentrated to give N-[(rac-(1R,3S)-3-aminocyclopentyl)methyl]-3-methyl-isoxazole-5-carboxamide (300 mg, crude, TFA), a yellow oil that was used directly without purification.

[0203] LCMS (ESI + ): m / z 224.1 (M+H) + 9. General procedure for preparing (2-chloro-1,3-benzothiazol-6-yl)-(4-hydroxy-1-piperidinyl) methyl ketone: To a solution of 2-chloro-1,3-benzothiazol-6-carboxylic acid (200 mg, 936.15 µmol, 1 equivalent) and piperin-4-ol (94.69 mg, 936.15 µmol, 1 equivalent) in DMF (2 mL), DIEA (241.98 mg, 1.87 mmol, 326.11 μL, 2 equivalents) and HATU (533.93 mg, 1.40 mmol, 1.5 equivalents) were added. The mixture was then stirred at 25 °C for 12 hours. The reaction mixture was diluted with H₂O (5 mL) and extracted with ethyl acetate (10 mL * 3). The combined organic layers were washed with brine (10 mL * 3), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by preparative TLC (SiO2, ethyl acetate:methanol = 3:1) to give (2-chloro-1,3-benzothiazol-6-yl)-(4-hydroxy-1-piperidinyl) methyl ketone (250 mg, 842.40 µmol, 89.99% yield), which was a light yellow oil.

[0204] LCMS (ESI + ): m / z 297.1 (M+H) + 10. General procedure for the preparation of N-[[rac-(1R,3S)-3-[[6-(4-hydroxypiperidin-1-carbonyl)-1,3-benzothiazol-2-yl]amino]cyclopentyl]methyl]-3-methyl-isoxazole-5-carboxamide: K₂CO₃ (110.64 mg, 800.49 µmol, 3 equivalents) was added to a solution of (2-chloro-1,3-benzothiazolyl-6-yl)-(4-hydroxy-1-piperidinyl) methyl ketone (95.03 mg, 320.20 µmol, 1.2 equivalents) and N-[(rac-(1R,3S)-(3-aminocyclopentyl)methyl]-3-methyl-isoxazole-5-carboxamide (90 mg, 266.83 µmol, 1 equivalent, TFA) in DMF (2 mL), and the reaction was stirred at 80 °C for 12 h. The reaction mixture was filtered and the filtrate was passed through a preparative HPLC (alkaline conditions, column: Waters Xbridge Prep OBD C18). 150*40mm*10um; mobile phase: [water(NH3H2O+NH4HCO3)-ACN]; B%: 10%-40%, 8min) purification yielded N-[[rac-(1R,3S)-3-[[6-(4-hydroxypiperidin-1-carbonyl)-1,3-benzothiazol-2-yl]amino]cyclopentyl]methyl]-3-methyl-isoxazole-5-carboxamide (16.8 mg, 34.74µmol, 13.02% yield, 100% purity), a pale yellow solid.

[0205] LCMS (ESI + ): m / z 484.2 (M+H) + 1H NMR (400 MHz, chloroform-d) δ = 7.69 (s, 1H), 7.52 (d, J = 8.3 Hz, 1H), 7.35 (dd, J = 1.5, 8.3 Hz, 1H), 6.76 (s, 1H), 6.70 (br s, 1H), 4.21 - 4.11(m, 1H), 3.99 (dt, J = 4.0, 7.9 Hz, 2H), 3.59 - 3.51 (m, 1H), 3.47 - 3.37 (m,1H), 3.38 - 3.26 (m, 2H), 2.46 - 2.30 (m, 2H), 2.38 (s, 3H), 2.30 - 2.20 (m,1H), 1.98 – 1.88 (m, 3H), 1.85 – 1.50 (m, 5H), 1.44 – 1.34 (m, 1H).

[0206] The two compounds in the mixture are: N-[[(1R,3S)-3-[[6-(4-hydroxypiperidin-1-carbonyl)-1,3-benzothiazol-2-yl]amino]cyclopentyl]methyl]-3-methyl-isoxazole-5-carboxamide and N-[[(1S,3R)-3-[[6-(4-hydroxypiperidin-1-carbonyl)-1,3-benzothiazol-2-yl]amino]cyclopentyl]methyl]-3-methyl-isoxazole-5-carboxamide Example S4: N-[[rac-(1R,3S)-3-[[6-(1,1-dioxo-1,2-thiazolidin-2-yl)-1,3-benzo[] [Thiazol-2-yl]amino]cyclopentyl]methyl]-3-methylisoxazole-5-carboxamide 1. General procedure for the preparation of 3-chloro-N-(2-chloro-1,3-benzothiazol-6-yl)propane-1-sulfonamide: TEA (1.10 g, 10.83 mmol, 1.51 mL) and 3-chloropropane-1-sulfonyl chloride (479.43 mg, 2.71 mmol, 328.38 μL) were added to a solution of 2-chloro-1,3-benzothiazol-6-amine (0.5 g, 2.71 mmol, 328.38 μL) in DCM (5 mL * 2). The mixture was stirred at 15 °C for 2 h. LC-MS showed detection of the desired compound. The reaction mixture was partitioned between water (10 mL) and DCM (5 mL * 2). The organic phase was separated, washed with brine (5 mL * 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by preparative TLC (SiO2, petroleum ether / ethyl acetate = 1 / 1) to give 3-chloro-N-(2-chloro-1,3-benzothiazol-6-yl)propane-1-sulfonamide (360 mg, 1.11 mmol, 40.88% yield) as a yellow solid.

[0207] LCMS (ESI+): m / z 325.1 (M+H) + General procedure for 2,2-(2-chloro-1,3-benzothiazol-6-yl)-1,2-thiazolidinyl 1,1-dioxide: K₂CO₃ (424.94 mg, 3.07 mmol) was added to a solution of 3-chloro-N-(2-chloro-1,3-benzothiazol-6-yl)propane-1-sulfonamide (400 mg, 1.23 mmol) in ACN (5 mL). The mixture was stirred at 50 °C for 2 hours. The reaction mixture was partitioned between water (10 mL) and ethyl acetate (5 mL * 2). The organic phase was separated, washed with brine (5 mL * 2), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC (SiO₂, petroleum ether / ethyl acetate = 1 / 1) to give 2-(2-chloro-1,3-benzothiazol-6-yl)-1,2-thiazoline 1,1-dioxide (200 mg, 692.58 µmol, 56.31% yield) as a yellow solid.

[0208] LCMS (ESI+): m / z 289.1(M+H) + 3. General procedure for the preparation of N-[[rac-(1R,3S)-3-[[6-(1,1-dioxo-1,2-thiazolidin-2-yl)-1,3-benzothiazolidin-2-yl]amino]cyclopentyl]methyl]-3-methylisoxazole-5-carboxamide: To a solution of 2-(2-chloro-1,3-benzothiazol-6-yl)-1,2-thiazolidinyl 1,1-dioxide (50 mg, 173.15 µmol) and N-[(rac-(1R,3S)-3-aminocyclopentyl)methyl]-3-methyl-isoxazol-5-carboxamide (86.83 mg, 192.38 µmol, 2TFA) in DMF (0.5 mL), K₂CO₃ (53.18 mg, 384.77 µmol) and TEA (38.93 mg, 384.77 µmol, 53.55 μL) were added. The mixture was stirred at 80 °C for 12 hours. LC-MS showed detection of the desired compound. The mixture was added to MeOH (2 mL), and the residue was purified by preparative HPLC (alkaline conditions; column: Waters Xbridge Prep OBD C18 150*40mm*10um; mobile phase: [water(NH3H2O+NH4HCO3)-ACN]; B%: 15%-45%, 8 min) to obtain N-[[rac-(1R,3S)-3-[[6-(1,1-dioxo-1,2-thiazolidin-2-yl)-1,3-benzothiazolidin-2-yl]amino]cyclopentyl]methyl]-3-methylisoxazole-5-carboxamide (13.1 mg, 27.55 µmol, 14.32% yield, 100% purity), as a white solid.

[0209] LCMS (ESI+): m / z 476.2 (M+H) + 1 H NMR (400MHz, methanol-d4) δ = 7.55 (d, J=2.0 Hz, 1H), 7.45 - 7.37 (m,1H), 7.26 - 7.19 (m, 1H), 6.83 - 6.79 (m, 1H), 4.21 (quin, J=6.9 Hz, 1H),3.78 (t, J=6.5 Hz, 2H), 3.46 - 3.38 (m, 4H), 2.50 (quin, J=7.0 Hz, 2H), 2.42- 2.30 (m, 2H), 2.33 (s, 3H), 2.18 - 2.08 (m, 1H), 1.93 - 1.83 (m, 1H), 1.75- 1.65 (m, 1H), 1.60 - 1.46 (m, 1H), 1.38 - 1.28 (m, 1H) The two compounds in the mixture are: N-[[(1R,3S)-3-[[6-(1,1-dioxo-1,2-thiazolidin-2-yl)-1,3-benzothiazolidin-2-yl]amino]cyclopentyl]methyl]-3-methylisoxazole-5-carboxamide and N-[[(1S,3R)-3-[[6-(1,1-dioxo-1,2-thiazolidin-2-yl)-1,3-benzothiazolidin-2-yl]amino]cyclopentyl]methyl]-3-methylisoxazole-5-carboxamide Example S5: N-[[rac-(1R,3S)-3-[[6-(3-hydroxyazacyclobutane-1-yl)sulfonyl-1,3-benzo[] [Thiazol-2-yl]amino]cyclopentyl]methyl]-3-methylisoxazole-5-carboxamide 1. General procedure for preparing 1-[(2-chloro-1,3-benzothiazol-6-yl)sulfonyl]azacyclobutane-3-ol: TEA (150.95 mg, 1.49 mmol, 207.63 μL) and aziridine-3-ol (40.86 mg, 372.94 µmol, HCl) were added to a solution of 2-chloro-1,3-benzothiazol-6-sulfonyl chloride (100 mg, 372.94 µmol) in THF (1 mL). The mixture was stirred at 0 °C for 1 h. LC-MS showed a main peak with the desired mass. The reaction mixture was concentrated under reduced pressure to remove THF, giving 1-[(2-chloro-1,3-benzothiazol-6-yl)sulfonyl]aziridine-3-ol (90 mg, crude) as a yellow solid.

[0210] data: LCMS (ESI+): m / z 305.6 (M+H) + 2. General procedure for the preparation of N-[[rac-(1R,3S)-3-[[6-(3-hydroxyazacyclobutane-1-yl)sulfonyl-1,3-benzothiazol-2-yl]amino]cyclopentyl]methyl]-3-methylisoxazole-5-carboxamide: To a solution of 1-[(2-chloro-1,3-benzothiazol-6-yl)sulfonyl]azacyclobutane-3-ol (70 mg, 229.68 µmol) and N-[(rac-(1R,3S)-3-aminocyclopentyl)methyl]-3-methyl-isoxazole-5-carboxamide (115.18 mg, 255.20 µmol, 2TFA) in DMF (1 mL), TEA (51.65 mg, 510.40 µmol, 71.04 μL) and K2CO3 (70.54 mg, 510.40 µmol) were added. The mixture was stirred at 80 °C for 6 hours. MeOH (2 mL) was added to the mixture, and the residue was purified by preparative HPLC (alkaline conditions; column: Waters Xbridge Prep OBD C18 150*40mm*10um; mobile phase: [water (NH3H2O+NH4HCO3)-ACN]; B%: 15%-45%, 8 min) to obtain N-[[rac-(1R,3S)-3-[[6-(3-hydroxyazacyclobutane-1-yl)sulfonyl-1,3-benzothiazolyl-2-yl]amino]cyclopentyl]methyl]-3-methylisoxazole-5-carboxamide (14.2 mg, 28.89 µmol, 11.32% yield, 100% purity), as a white solid.

[0211] data: LCMS (ESI+): m / z 492.2 (M+H) + 1 H NMR (400MHz, methanol-d4) δ = 8.10 (s, 1H), 7.74 - 7.68 (m, 1H), 7.61 -7.54 (m, 1H), 6.83 - 6.77 (m, 1H), 4.31 - 4.21 (m, 1H), 3.93 (t, J=7.7 Hz,2H), 3.52 - 3.44 (m, 3H), 3.41 (br d, J=6.6 Hz, 2H), 2.45 - 2.34 (m, 2H),2.34 (s, 3H), 2.20 - 2.10 (m, 1H), 1.95 - 1.85 (m, 1H), 1.78 - 1.68 (m, 1H),1.61 - 1.51 (m, 1H), 1.39 - 1.29 (m, 1H) The two compounds in the mixture are: N-[[(1R,3S)-3-[[6-(3-hydroxyazacyclobutane-1-yl)sulfonyl-1,3-benzothiazol-2-yl]amino]cyclopentyl]methyl]-3-methylisoxazole-5-carboxamide and N-[[(1S,3R)-3-[[6-(3-hydroxyazacyclobutane-1-yl)sulfonyl-1,3-benzothiazol-2-yl]amino]cyclopentyl]methyl]-3-methylisoxazole-5-carboxamide Example S6: 3-Methyl-N-[[rac-(1R,3S)-3-[(6-morpholinosulfonyl-1,3-benzothiazo-2-yl) [Amino]cyclopentyl]methyl]isoxazole-5-carboxamide 1. General procedure for the preparation of 2-chloro-1,3-benzothiazole-6-sulfonyl chloride: The following procedure was performed using two flasks. In the first flask, 2-chloro-1,3-benzothiazol-6-amine (1 g, 5.42 mmol, 1 equivalent) was dissolved in concentrated HCl (5 mL), and the resulting solution was cooled to -5°C using an ice / NaCl bath. A solution of sodium nitrite (422.24 mg, 6.12 mmol, 1.13 equivalent) in H₂O (5 mL) was added in portions with stirring, while maintaining the temperature below 0°C, and the mixture was stirred for 10 minutes. In the second flask, SOCl₂ (2.96 g, 24.91 mmol, 1.81 mL, 4.6 equivalent) was added dropwise to H₂O (10 mL), which had been pre-cooled to -5°C using an ice / NaCl bath. The resulting solution was heated to 25°C, and CuCl (27.51 mg, 277.83 μmol, 6.64 μL, 0.0513 equivalents) was added. The reaction mixture was then cooled again to -5°C. While continuing to cool and stir, the contents of the first flask were added in two portions to the contents of the second flask, and the mixture was stirred for 30 minutes, during which time a precipitate formed. The reaction mixture was quenched by adding H₂O (5 mL) and extracted with DCM (10 mL * 3). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO₂, petroleum ether / ethyl acetate = 1 / 0 to 10 / 1, petroleum ether:ethyl acetate = 3:1) to give 2-chloro-1,3-benzothiazol-6-sulfonyl chloride (612 mg, 2.28 mmol, 21.07% yield) as a yellow solid.

[0212] 2. General procedure for preparing 4-[(2-chloro-1,3-benzothiazo-6-yl)sulfonyl]morpholine: TEA (150.95 mg, 1.49 mmol, 207.63 μL, 4 equivalents) and morpholine (32.49 mg, 372.94 μmol, 32.82 μL, 1 equivalent) were added to a solution of 2-chloro-1,3-benzothiazol-6-sulfonyl chloride (100 mg, 372.94 μmol, 1 equivalent) in THF (1 mL). The mixture was stirred at 0 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to remove THF, yielding 4-[(2-chloro-1,3-benzothiazol-6-yl)sulfonyl]morpholine (110 mg, crude) as a yellow solid.

[0213] data: LCMS (ESI+): m / z 319.1 (M+H) + 3. General procedure for the preparation of 3-methyl-N-[[rac-(1R,3S)-3-[(6-morpholinosulfonyl-1,3-benzothiazol-2-yl)amino]cyclopentyl]methyl]isoxazole-5-carboxamide: Add TEA (42.32 mg, 418.24 μmol, 58.21 μL, 2 equivalents) and K2CO3 (57.80 mg, 418.24 μmol, 2 equivalents) to a solution of 4-[(2-chloro-1,3-benzothiazol-6-yl)sulfonyl]morpholine (60 mg, 188.21 μmol, 0.9 equivalents) and N-[(rac-(1R,3S)-3-aminocyclopentyl)methyl]-3-methyl-isoxazole-5-carboxamide (94.38 mg, 209.12 μmol, 1 equivalent, 2 TFA) in DMF (1 mL). Stir the mixture at 80 °C for 6 hours. Add MeOH (2 mL) to the mixture. The residue was purified by preparative HPLC (alkaline conditions, column: Waters Xbridge Prep OBDC18 150*40mm*10μm; mobile phase: [water(NH3H2O+NH4HCO3)-ACN]; B%: 20%-50%, 8min) to give 3-methyl-N-[[rac-(1R,3S)-3-[(6-morpholinosulfonyl-1,3-benzothiazolyl-2-yl)amino]cyclopentyl]methyl]isoxazole-5-carboxamide (29.3 mg, 57.95 μmol, 27.71% yield, 100% purity), as a white solid.

[0214] LCMS (ESI+): m / z 506.2 (M+H) + 1H NMR (400MHz, methanol-d4) δ = 8.04 (d, J=1.8 Hz, 1H), 7.64 (dd, J=1.9,8.5 Hz, 1H), 7.57 - 7.53 (m, 1H), 6.81 - 6.80 (m, 1H), 4.31 - 4.21 (m, 1H),3.72 - 3.68 (m, 4H), 3.43 - 3.39 (m, 2H), 2.97 (br d, J=4.4 Hz, 4H), 2.44 -2.36 (m, 2H), 2.33 (s, 3H), 2.20 - 2.09 (m, 1H), 1.94 - 1.83 (m, 1H), 1.78 -1.65 (m, 1H), 1.62 - 1.48 (m, 1H), 1.42 - 1.25 (m, 1H) The two compounds in the mixture are: 3-methyl-N-[[(1R,3S)-3-[(6-morpholinosulfonyl-1,3-benzothiazol-2-yl)amino]cyclopentyl]methyl]isoxazole-5-carboxamide and 3-methyl-N-[[(1S,3R)-3-[(6-morpholinosulfonyl-1,3-benzothiazol-2-yl)amino]cyclopentyl]methyl]isoxazole-5-carboxamide Example S7: 3-Methyl-N-[[(1R,3S)-3-[[5-(6-oxopyridazin-1-yl)-2-pyridyl]amino] ring [Pentyl]methyl]isoxazole-5-carboxamide 1. General procedure for the preparation of (1R,4S)-3-oxo-2-azabicyclo[2.2.1]hept-5-ene-2-carboxylic acid tert-butyl ester: To (1R,4S)-2-azabicyclo[2.2.1]hepten-5-en-3-one (5 g, 45.82 mmol, 1 equivalent Add TEA (9.27 g, 91.64 mmol, 12.75 mL, 2 mg) to a THF (60 mL) solution. equivalent ), Boc2O (12.00 g, 54.98 mmol, 12.63 mL, 1.2 equivalent ) and DMAP (559.76 mg, 4.58 mmol, 0.1 equivalentThe mixture was stirred at 20 °C for 12 hours. The reaction mixture was quenched by adding saturated NH4Cl aqueous solution (50 mL) and then extracted with EtOAc (50 mL). The combined organic layers were washed with saturated NaCl aqueous solution (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give (1R,4S)-3-oxo-2-azabicyclo[2.2.1]hept-5-en-2-carboxylic acid tert-butyl ester (9 g, 43.01 mmol, 93.88% yield) as a black oil.

[0215] 2. General procedure for the preparation of (1S, 4R)-3-oxo-2-azabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester Under a N2 atmosphere, tert-butyl (9 g, 43.01 mmol, 1...) of (1R,4S)-3-oxo-2-azabicyclo[2.2.1]hept-5-ene-2-carboxylic acid was reacted with nitrogen. equivalent Pd / C (3 g, 10% purity) was added to a solution of MeOH (100 mL). The suspension was degassed and purged three times with H2. The mixture was stirred at 20 °C for 12 hours under H2 (15 psi). The reaction mixture was filtered and the filtrate was concentrated to give (1S, 4R)-3-oxo-2-azabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (10 g, crude) as an orange oil.

[0216] data: LCMS (ESI + ): m / z 212 (M+H) + 3. General procedure for preparing N-[(1S, 3R)-3-(hydroxymethyl)cyclopentyl]carbamate tert-butyl ester: Under N2, at 0°C, tert-butyl (1S, 4R)-3-oxo-2-azabicyclo[2.2.1]heptane-2-carboxylate (9 g, 42.60 mmol, 1 equivalent Slowly add NaBH4 (3.22 g, 85.20 mmol, 2 mmol) to a solution of MeOH (100 mL). equivalentThe reaction was then stirred at 0°C for 2 hours. The reaction mixture was quenched by adding 100 mL of saturated NH4Cl aqueous solution and then extracted with EtOAc (100 mL * 3). The combined organic layers were washed with brine (300 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by rapid silica gel chromatography (ISCO®; 120 g SepaFlash® silica rapid column, 0–30% ethyl acetate / petroleum ether gradient eluent, 100 mL / min) to give N-[(1S, 3R)-3-(hydroxymethyl)cyclopentyl]carbamate tert-butyl ester (4 g, 18.58 mmol, 43.61% yield) as a white solid.

[0217] 4. General procedure for preparing methyl [(1R, 3S)-3-(tert-butoxycarbonylamino)cyclopentyl]methanesulfonate: To N-[(1S, 3R)-3-(hydroxymethyl)cyclopentyl]carbamate tert-butyl ester (4.30 g, 19.97 mmol, 1 when quantity ) and TEA (6.06 g, 59.92 mmol, 8.34 mL, 3 equivalent Add methanesulfonyl methanesulfonate (5.22 g, 29.96 mmol, 1.5 μL) to the solution in DCM (50 mL). equivalent The reaction mixture was then stirred at 20 °C for 12 hours. The reaction mixture was diluted with water (100 mL) and extracted with DCM (50 mL * 2). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give methyl [(1R, 3S)-3-(tert-butoxycarbonylamino)cyclopentyl]methanesulfonate (6 g, crude) as a white solid.

[0218] 5. General procedure for preparing N-[(1S, 3R)-3-(azidomethyl)cyclopentyl]carbamate tert-butyl: Methyl [(1R, 3S)-3-(tert-Butoxycarbonylamino)cyclopentyl]methanesulfonate (6 g, 20.45 mmol, 1 equivalent Add NaN3 (2.66 g, 40.90 mmol, 2) to the DMF (120 mL) solution. equivalentThe reaction was then stirred at 60 °C for 6 hours. The reaction mixture was quenched by adding H2O (100 mL), diluted with an aqueous solution of NaHCO3 (100 mL), and extracted with EtOAc (100 mL * 3). The combined organic layers were washed with brine (100 mL * 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give N-[(1S, 3R)-3-(azidomethyl)cyclopentyl]carbamate tert-butyl ester (4.5 g, crude) as an orange oil.

[0219] 6. General procedure for preparing N-[(1S, 3R)-3-(aminomethyl)cyclopentyl]carbamate tert-butyl ester: Under a nitrogen atmosphere, tert-butyl N-[(1S, 3R)-3-(azidomethyl)cyclopentyl]carbamate (4.5 g, 18.73 mmol, 1 equivalent Pd / C (1 g, 10% purity) was added to a solution of MeOH (100 mL) and NH3·H2O (3 mL, 25% purity). The suspension was degassed and purged three times with H2. The mixture was stirred at 20 °C under H2 (15 psi) for 2 hours. The reaction mixture was filtered and the filtrate was concentrated to give N-[(1S, 3R)-3-(aminomethyl)cyclopentyl]carbamate tert-butyl ester (6.4 g, crude product) as a yellow oil.

[0220] 7. General procedure for preparing N-[(1S, 3R)-3-[[(3-methylisoxazol-5-carbonyl)amino]methyl]cyclopentyl]carbamate tert-butyl: Under N2, at 0°C, N-[(1S,3R)-3-(aminomethyl)cyclopentyl]carbamate tert-butyl ester (1.00 g, 4.67 mmol, 1 equivalent ), 3-methylisoxazole-5-carboxylic acid (711.69 mg, 5.60 mmol, 1.2... equivalent ) and DIEA (1.21g, 9.33 mmol, 1.63 mL, 2 equivalent Slowly add HATU (2.13 g, 5.60 mmol, 1.2 mg) to a solution of DMF (10 mL). equivalentThe reaction was then stirred at 20°C for 2 hours. The reaction mixture was quenched by adding 20 mL of saturated NH4Cl aqueous solution and extracted with EtOAc (10 mL * 3). The combined organic layers were washed with brine (25 mL * 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by rapid silica gel chromatography (ISCO®; 40 g SepaFlash® silica rapid column, 0–33% ethyl acetate / petroleum ether gradient eluent, 100 mL / min) to give N-[(1S,3R)-3-[[(3-methylisoxazole-5-carbonyl)amino]methyl]cyclopentyl]tert-butyl carbamate (650 mg, 2.01 mmol, 43.07% yield) as a pale yellow solid.

[0221] data: LCMS (ESI + ): m / z 324 (M+H) + 8. General procedure for the preparation of N-[[(1R,3S)-3-aminocyclopentyl]methyl]-3-methyl-isoxazole-5-carboxamide: N-[(1S, 3R)-3-[[(3-methylisoxazole-5-carbonyl)amino]methyl]cyclopentyl]tert-butyl carbamate (650 mg, 2.01 mmol, 1 equivalent The solution in HCl / EtOAc (4 M, 5 mL) was stirred at 20 °C for 1 hour. The reaction mixture was concentrated to give N-[[(1R, 3S)-3-aminocyclopentyl]methyl]-3-methyl-isoxazole-5-carboxamide (400 mg, crude, HCl) as a yellow solid. SFC method: AD_EtOH_IPAm_10_50_25_35_5min, t=2.982.

[0222] data: LCMS (ESI + ): m / z 224 (M+H) + 9. General procedure for the preparation of 3-methyl-N-[[(1R,3S)-3-[[5-(6-oxopyridazin-1-yl)-2-pyridyl]amino]cyclopentyl]methyl]isoxazole-5-carboxamide: N-[[(1R,3S)-3-aminocyclopentyl]methyl]-3-methyl-isoxazole-5-carboxamide (400 mg, 1.54 mmol, 1 equivalent ,HCl), 2-(6-chloro-3-pyridyl)pyridazin-3-one (415.66 mg, 2.00 mmol, 1.3 equivalent [2-(2-aminophenyl)phenyl]-methylsulfonyloxy-palladium di-tert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphine (122.34 mg, 154.00 µmol, 0.1) equivalent ), di-tert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphine (130.79 mg, 308.01 µmol, 0.2 equivalent ) and t-BuONa (444.00 mg, 4.62 mmol, 3 equivalent The mixture in 2-methylbut-2-ol (5 mL) was degassed and purged three times with N2, then stirred at 80 °C for 2.5 h under N2 atmosphere. The reaction mixture was filtered and the filtrate was concentrated to give the residue. The residue was purified by preparative HPLC (neutral conditions; column: Phenomenex Gemini-NX 80*40mm*3µm; mobile phase: [water (10mM NH4HCO3)-ACN]; B%: 10%-40%, 8 min) to give 3-methyl-N-[[(1R,3S)-3-[[5-(6-oxopyridazin-1-yl)-2-pyridyl]amino]cyclopentyl]methyl]isoxazole-5-carboxamide (43.7 mg, 110.12 µmol, 7.15% yield, 99.391% purity) as a white solid.

[0223] data: LCMS (ESI + ): m / z 395.2 (M+H) + 1 H NMR (400 MHz, methanol-d4) δ = 8.14 (d, J = 2.4 Hz, 1H), 8.06 – 8.00 (m,1H), 7.59 (dd, J = 2.5, 9.0 Hz, 1H), 7.46 (dd, J = 3.8, 9.4 Hz, 1H), 7.06 (dd, J =1.2, 9.4 Hz, 1H), 6.80 (s, 1H), 6.58 (d, J = 9.0 Hz, 1H), 4.23 - 4.13 (m, 1H), 3.40 (br d, J= 6.6 Hz, 2H), 2.41 - 2.30 (m, 2H), 2.34 (s, 3H), 2.16 - 2.06 (m,1H), 1.90 - 1.80 (m, 1H), 1.65 - 1.51 (m, 2H), 1.30 - 1.20 (m, 1H) Examples S8, S9 and S11: Example S8: 5-Methyl-N-[[rac-(1R,3S)-3-[[5-(6-oxopyridazin-1-yl)-2-pyridyl]amino [Oxyl]cyclopentyl]methyl]isoxazole-3-carboxamide 1. General procedure for preparing N-[rac-(1S,3R)-3-(benzyloxycarbonylaminomethyl)cyclopentyl]carbamate tert-butyl ester: At 0 °C, CbzCl (6.69 g, 39.20 mmol, 5.57 mL, 1.2 equivalent) was added dropwise to a solution of N-[rac-(1S,3R)-3-(aminomethyl)cyclopentyl]carbamate tert-butyl ester (7 g, 32.66 mmol, 1 equivalent) and DIEA (8.44 g, 65.33 mmol, 11.38 mL, 2 equivalent) in DCM (80 mL), and the reaction was stirred at 20 °C for 3 hours. The reaction mixture was concentrated to give the residue. The residue was purified by rapid silica gel chromatography (ISCO®; 220 g SepaFlash® silica rapid column, 0–18% ethyl acetate / petroleum ether gradient eluent, 100 mL / min) to give N-[rac-(1S,3R)-3-(benzyloxycarbonylaminomethyl)cyclopentyl]carbamate tert-butyl ester (6.14 g, 17.62 mmol, 53.95% yield) as a white solid.

[0224] 2. General procedure for the preparation of N-[(rac-(1R,3S)-3-aminocyclopentyl)methyl]carbamate: A solution of N-[rac-(1S,3R)-3-(benzyloxycarbonylaminomethyl)cyclopentyl]carbamate tert-butyl ester (6.09 g, 17.48 mmol, 1 equivalent) in HCl / EtOAc (4 M, 65 mL) was stirred at 20 °C for 1 hour. The reaction solution was concentrated to give N-[(rac-(1R,3S)-3-aminocyclopentyl)methyl]carbamate benzyl ester (4.9 g, crude product, HCl), as an orange solid.

[0225] 3. General procedure for the preparation of N-[[rac-(1R,3S)-3-[(5-iodo-2-pyridyl)amino]cyclopentyl]methyl]carbamate: To a solution of N-[(rac-(1R,3S)-3-aminocyclopentyl)methyl]carbamate (1.5 g, 5.27 mmol, 1 equivalent, HCl) in DMSO (15 mL), K₂CO₃ (2.18 g, 15.80 mmol, 3 equivalents) and 2-fluoro-5-iodopyridine (1.41 g, 6.32 mmol, 1.2 equivalents) were added. The mixture was stirred at 80 °C for 1 hour. The reaction mixture was quenched by adding H₂O (10 mL) and extracted with EtOAc (30 mL * 3). The combined organic layers were washed with brine (100 mL * 2), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 3 / 1) to give compound N-[[rac-(1R,3S)-3-[(5-iodo-2-pyridyl)amino]cyclopentyl]methyl]carbamate (1.27 g, 2.81 mmol, 53.43% yield), as a pale yellow oil.

[0226] data: LCMS (ESI+): m / z 452.2 (M+H) + 4. General procedure for the preparation of N-[[rac-(1R,3S)-3-[[5-(6-oxopyridazin-1-yl)-2-pyridyl]amino]cyclopentyl]methyl]carbamate: The mixture of N-[[rac-(1R,3S)-3-[(5-iodo-2-pyridyl)amino]cyclopentyl]methyl]carbamate (1 g, 2.22 mmol, 1 equivalent), 1H-pyridazin-6-one (425.82 mg, 4.43 mmol, 2 equivalent), CuI (42.20 mg, 221.58 μmol, 0.1 equivalent), K2CO3 (612.48 mg, 4.43 mmol, 2 equivalent) and (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (47.28 mg, 332.37 μmol, 0.15 equivalent) in DMSO (10 mL) was degassed and purged three times with N2. The mixture was then stirred at 120 °C for 12 hours under N2 atmosphere. The reaction mixture was quenched by adding H2O (10 mL) and extracted with EtOAc (20 mL * 3). The combined organic layers were washed with brine (50 mL * 2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (alkaline conditions; column: Waters Xbridge Prep OBD C18 150*40mm*10μm; mobile phase: [water (NH3H2O+NH4HCO3)-ACN]; B%: 20%-55%, 8 min) to give N-[[rac-(1R,3S)-3-[[5-(6-oxopyridazin-1-yl)-2-pyridyl]amino]cyclopentyl]methyl]carbamate (290 mg, 691.34 μmol, 31.20% yield) as a yellow oil.

[0227] data: LCMS (ESI+): m / z 420.1 (M+H) + 5. General procedure for the preparation of 2-[6-[[rac-(1S,3R)-3-(aminomethyl)cyclopentyl]amino]-3-pyridyl]pyridazin-3-one: Under a nitrogen atmosphere, Pd / C (2 mg, 10% purity) was added to a solution of N-[[rac-(1R,3S)-3-[[5-(6-oxopyridazin-1-yl)-2-pyridyl]amino]cyclopentyl]methyl]carbamate (270 mg, 643.66 μmol, 1 equivalent) in MeOH (6 mL). The suspension was degassed and purged three times with H2. The mixture was stirred at 25 °C under H2 (15 psi) for 1 hour. The suspension was filtered through a diatomaceous earth mat and the filter cake was washed with MeOH (10 mL). The combined filtrates were concentrated to dryness to give 2-[6-[[rac-(1S,3R)-3-(aminomethyl)cyclopentyl]amino]-3-pyridyl]pyridazin-3-one (180 mg, crude) as a yellow oil.

[0228] data: LCMS (ESI+): m / z 286.0 (M+H) + 6. General procedure for the preparation of 5-methyl-N-[[rac-(1R,3S)-3-[[5-(6-oxopyridazin-1-yl)-2-pyridyl]amino]cyclopentyl]methyl]isoxazole-3-carboxamide: To a solution of 2-[6-[[rac-(1S,3R)-3-(aminomethyl)cyclopentyl]amino]-3-pyridyl]pyridazin-3-one (18.00 mg, 63.08 μmol, 1 equivalent) and 5-methylisoxazol-3-carboxylic acid (8.02 mg, 63.08 μmol, 1 equivalent) in DMF (1 mL), HATU (47.97 mg, 126.16 μmol, 2 equivalent) and DIEA (16.31 mg, 126.16 μmol, 21.97 μL, 2 equivalent) were added. The mixture was stirred at 25 °C for 2 h. LC-MS showed detection of the desired substance. The reaction mixture was quenched by adding H2O (1 mL) and extracted with EtOAc (5 mL * 3). The combined organic layers were washed with brine (15 mL * 2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (alkaline conditions; column: Phenomenex C18 75*30mm*3μm; mobile phase: [water (NH3H2O+NH4HCO3)-ACN]; B%: 10%-40%, 8 min) to give 5-methyl-N-[[rac-(1R,3S)-3-[[5-(6-oxopyridazin-1-yl)-2-pyridyl]amino]cyclopentyl]methyl]isoxazole-3-carboxamide (5.9 mg, 14.55 μmol, 23.07% yield, 97.271% purity), as a white solid.

[0229] LCMS (ESI+): m / z 395.1 (M+H) + 1 H NMR (400 MHz, methanol-d4) δ = 8.14 (d, J = 2.5 Hz, 1H), 8.04 – 8.01 (m,1H), 7.59 (dd, J = 2.6, 9.0 Hz, 1H), 7.46 (dd, J = 3.9, 9.4 Hz, 1H), 7.06(dd, J = 1.1, 9.4 Hz, 1H), 6.58 (d, J = 9.1 Hz, 1H), 6.44 (s, 1H), 4.23 -4.13 (m, 1H), 3.40 (br d, J = 6.6 Hz, 3H), 2.47 (s, 3H), 2.38 - 2.26 (m, 2H),2.17 - 2.06 (m, 1H), 1.90 - 1.80 (m, 1H), 1.65 - 1.50 (m, 2H), 1.30 - 1.20(m, 1H) The two compounds in the mixture are: 5-methyl-N-[[(1R,3S)-3-[[5-(6-oxopyridazin-1-yl)-2-pyridyl]amino]cyclopentyl]methyl]isoxazole-3-carboxamide and 5-methyl-N-[[(1S,3R)-3-[[5-(6-oxopyridazin-1-yl)-2-pyridyl]amino]cyclopentyl]methyl]isoxazole-3-carboxamide The following compounds were prepared according to the general procedure of step 6. The starting materials were either commercially available or prepared from commercially available reagents using conventional reactions well known in the art.

[0230] Example S9: 1-Methyl-N-[[rac-(1R,3S)-3-[[5-(6-oxopyridazin-1-yl)-2-pyridyl]amino [Cyclopentyl]methyl]triazole-4-carboxamide LC / MS[M+1]: 395.1 1H NMR (400 MHz, methanol-d4) δ = 8.28 (s, 1H), 8.13 (d, J = 2.4 Hz, 1H), 8.02 (dd, J = 1.6, 3.8 Hz, 1H), 7.59 (dd, J = 2.6, 9.1 Hz, 1H), 7.46 (dd, J =3.9, 9.4 Hz, 1H), 7.06 (dd, J = 1.6, 9.4 Hz, 1H), 6.58 (d, J = 9.0 Hz, 1H), 4.22 - 4.17 (m, 1H), 4.14 (s, 3H), 3.43 (br d, J = 6.6 Hz, 2H), 2.42 - 2.27(m, 2H), 2.14 - 2.07 (m, 1H), 1.90 - 1.80 (m, 1H), 1.68 - 1.3 (m, 2H), 1.35 –1.25 (m, 1H) The two compounds in the mixture are: 1-methyl-N-[[(1R,3S)-3-[[5-(6-oxopyridazin-1-yl)-2-pyridyl]amino]cyclopentyl]methyl]triazole-4-carboxamide and 1-methyl-N-[[(1S,3R)-3-[[5-(6-oxopyridazin-1-yl)-2-pyridyl]amino]cyclopentyl]methyl]triazole-4-carboxamide Example S11: 3-Cyclopropyl-N-[[rac-(1R,3S)-3-[[5-(6-oxopyridazin-1-yl)-2-pyridyl] [Amino]cyclopentyl]methyl]isoxazole-5-carboxamide LC / MS[M+1]: 421.1 1H NMR (400 MHz, methanol-d4) δ = 8.14 (d, J = 2.6 Hz, 1H), 8.02 (dd, J =1.6, 3.9 Hz, 1H), 7.59 (dd, J = 2.7, 9.1 Hz, 1H), 7.46 (dd, J = 3.9, 9.5 Hz,1H), 7.06 (dd, J = 1.6, 9.4 Hz, 1H), 6.67 (s, 1H), 6.58 (d, J = 9.1 Hz, 1H), 4.18 (quin, J = 7.0 Hz, 1H), 3.39 (d, J = 6.6 Hz, 2H), 2.38 - 2.26 (m, 2H),2.14 - 2.02 (m, 2H), 1.90 - 1.80 (m, 1H), 1.66 - 1.49 (m, 2H), 1.29 - 1.19(m, 1H), 1.15 - 1.06 (m, 2H), 0.87 - 0.83 (m, 2H) The two compounds in the mixture are: 3-cyclopropyl-N-[[(1R,3S)-3-[[5-(6-oxopyridazin-1-yl)-2-pyridyl]amino]cyclopentyl]methyl]isoxazole-5-carboxamide and 3-cyclopropyl-N-[[(1S,3R)-3-[[5-(6-oxopyridazin-1-yl)-2-pyridyl]amino]cyclopentyl]methyl]isoxazole-5-carboxamide Examples S10, S12, S14, S16 and S19: Example S10: N-[[(1R,3S)-3-[[5-(3-methoxy-2-pyridyl)-2-pyridyl]amino]cyclopentyl]methyl]-3-methyl-isoxazole-5-carboxamide 1. General procedure for the preparation of N-[[(1R,3S)-3-[[5-(3-methoxy-2-pyridyl)-2-pyridyl]amino]cyclopentyl]methyl]-3-methyl-isoxazole-5-carboxamide: The mixture of N-[[(1R,3S)-3-[(5-iodo-2-pyridinyl)amino]cyclopentyl]methyl]-3-methyl-isoxazole-5-carboxamide (100 mg, 234.60 μmol, 1 equivalent), tributyl-(3-methoxy-2-pyridinyl)stanane (112.09 mg, 281.52 μmol, 1.2 equivalent) and tri-tert-butylphosphine palladium (47.96 mg, 93.84 μmol, 0.4 equivalent) in dioxane (2 mL) was degassed and purged three times with N2. The mixture was then stirred at 100 °C for 12 hours under N2 atmosphere. The reaction mixture was filtered, and the filtrate was purified by preparative HPLC (HCl conditions, column: Phenomenex Luna 80*30mm*3μm; mobile phase: [water(HCl)-ACN]; B%: 1%-20%, 8 min) to give compound N-[[(1R,3S)-3-[[5-(3-methoxy-2-pyridinyl)-2-pyridinyl]amino]cyclopentyl]methyl]-3-methyl-isoxazole-5-carboxamide (39.8 mg, 82.85 μmol, 35.31% yield, 100% purity, 2 HCl), as a yellow solid.

[0231] LCMS (ESI+): m / z 408.2 (M+H) + 1 H NMR (400 MHz, methanol-d4) δ = 8.48 (d, J = 5.6 Hz, 1H), 8.45 (br s,1H), 8.37 (d, J = 8.6 Hz, 1H), 8.26 (br d, J = 7.0 Hz, 1H), 8.04 (dd, J =5.7, 8.8 Hz, 1H), 7.25 (br d, J = 8.3 Hz, 1H), 6.83 (s, 1H), 4.26 - 4.18 (m,1H), 4.12 (s, 3H), 3.48 - 3.38 (m, 2H), 2.50 - 2.38 (m, 2H), 2.34 (s, 3H),2.32 - 2.20 (m, 1H), 2.03 – 1.93 (m, 1H), 1.87 – 1.78 (m, 1H), 1.70 – 1.61(m, 1H), 1.53 – 1.46 (m, 1H) Example S14: 3-Methyl-N-[[(1R,3S)-3-[[5-(3-methyl-6-oxo-pyridazin-1-yl)-2-pyridine [By]amino]cyclopentyl]methyl]isoxazole-5-carboxamide 1. General procedure for the preparation of 3-methyl-N-[[(1R,3S)-3-[[5-(3-methyl-6-oxo-pyridazin-1-yl)-2-pyridyl]amino]cyclopentyl]methyl]isoxazole-5-carboxamide: A mixture of N-[[(1R,3S)-3-[(5-iodo-2-pyridyl)amino]cyclopentyl]methyl]-3-methyl-isoxazole-5-carboxamide (100 mg, 234.60 μmol, 1 equivalent), 3-methyl-1H-pyridazin-6-one (51.67 mg, 469.21 μmol, 2 equivalents), CuI (22.34 mg, 117.30 μmol, 0.5 equivalents), K₂CO₃ (64.85 mg, 469.21 μmol, 2 equivalents) and (1S,2S)-N₁,N₂-dimethylcyclohexane-1,2-diamine (6.67 mg, 46.92 μmol, 0.2 equivalents) in DMSO (3 mL) was degassed and purged three times with N₂. The mixture was then stirred at 60 °C for 12 hours under N₂ atmosphere. The reaction mixture was concentrated under reduced pressure to give the residue. The residue was purified by preparative HPLC (HCl conditions; column: Phenomenex Luna 80*30mm*3μm; mobile phase: [water(HCl)-ACN]; B%: 10%-25%, 8 min) to give 3-methyl-N-[[(1R,3S)-3-[[5-(3-methyl-6-oxo-pyridazin-1-yl)-2-pyridinyl]amino]cyclopentyl]methyl]isoxazole-5-carboxamide (17.4 mg, 39.11 μmol, 16.67% yield, 100% purity, HCl), as a brown solid.

[0232] data: LCMS (ESI+): m / z 409.1 (M+H) + 1H NMR (400 MHz, methanol-d4) δ = 8.36 (d, J = 2.3 Hz, 1H), 8.22 (dd, J =2.1, 9.8 Hz, 1H), 7.44 (d, J = 9.6 Hz, 1H), 7.13 (d, J = 9.8 Hz, 1H), 7.02(d, J = 9.6 Hz, 1H), 6.82 (s, 1H), 4.13 – 4.06 (m, 1H), 3.43 (d, J = 6.1 Hz,2H), 2.47 – 2.41 (m, 2H), 2.40 (s, 3H), 2.34 (s, 3H), 2.25 - 2.15 (m, 1H),2.00 - 1.90 (m, 1H), 1.85 - 1.75 (m, 1H), 1.70 - 1.60 (m, 1H), 1.48 - 1.40(m, 1H) The following compounds were prepared according to the general procedure described for Example S14. The starting materials were either commercially available or prepared from commercially available reagents using conventional reactions well known in the art.

[0233] Example S12: 3-Methyl-N-[[(1R,3S)-3-[[5-[6-oxo-3-(trifluoromethyl)pyridazin-1-yl]-2- [pyridyl]amino]cyclopentyl]methyl]isoxazole-5-carboxamide LC / MS [M+1] 463.1 1H NMR (400 MHz, methanol-d4) δ = 8.16 (br s, 1H), 7.76 (d, J = 9.8 Hz,1H), 7.61 (dd, J = 2.6, 9.1 Hz,1H), 7.20 (d, J = 9.9 Hz, 1H), 6.80 (s, 1H),6.59 (br d, J = 9.1 Hz, 1H), 4.25 - 4.15 (m, 1H), 3.40 (br d, J = 6.6 Hz,2H), 2.38 - 2.27 (m, 2H), 2.34 (s, 3H), 2.13 - 2.06 (m, 1H), 1.91 - 1.81 (m,1H), 1.67 - 1.51 (m, 2H), 1.31 - 1.23 (m, 1H) Example S16: 3-Methyl-N-[[(1R,3S)-3-[[5-(1,2,4-triazol-1-yl)-2-pyridyl]amino] ring [Pentyl]methyl]isoxazole-5-carboxamide LC / MS [M+1] 368.0 1H NMR (400 MHz, methanol-d4) δ = 8.86 (s, 1H), 8.30 (d, J = 2.6 Hz, 1H), 8.13 (s, 1H), 7.73 (dd, J = 2.8, 9.0 Hz, 1H), 6.80 (s, 1H), 6.62 (d, J = 9.1Hz, 1H), 4.20 (quin, J = 7.0 Hz, 1H), 3.42 – 3.38 (d, 2H), 2.38 – 2.27 (m,2H), 2.34 (s, 3H), 2.14 – 2.07 (m, 1H), 1.91 – 1.81 (m, 1H), 1.65 - 1.50 (m,2H), 1.30 - 1.20 (m, 1H).

[0234] Example S19: 3-Methyl-N-[[(1R,3S)-3-[[5-(2-oxo-1-piperidinyl)-2-pyridinyl]amino] ring [Pentyl]methyl]isoxazole-5-carboxamide LC / MS [M+1] 398.1 ¹H NMR (400 MHz, methanol-d⁴) δ = 7.81 (br s, 1H), 7.30 (dd, J = 2.6, 8.9 Hz, 1H), 6.80 (s, 1H), 6.54 (d, J = 8.9 Hz, 1H), 4.12 (quintet, J = 7.0 Hz, 1H), 3.60 (br t, J = 5.3 Hz, 2H), 3.38 (br d, J = 6.6 Hz, 2H), 2.49 (br t, J = 6.0 Hz, 2H), 2.34 (s, 3H), 2.34 - 2.27 (s, 2H), 2.11 - 2.03 (m, 1H), 2.01 -1.90 (m, 4H), 1.89 - 1.80 (m, 1H), 1.64 - 1.48 (m, 2H), 1.25 -1.15 (m, 1H) Example S13: 3-Ethyl-N-[[(1R,3S)-3-[[5-(6-oxopyridazin-1-yl)-2-pyridyl]amino] ring [Pentyl]methyl]isoxazole-5-carboxamide 1. General procedure for the preparation of (1E)-propionaldehyde oxime: A mixture of Na₂CO₃ (1.09 g, 10.33 mmol, 0.6 equivalent) and propionaldehyde (1 g, 17.22 mmol, 1.25 mL, 1 equivalent) in EtOH (4.5 mL) was added to a solution of hydroxylamine hydrochloride (1.79 g, 25.83 mmol, 1.5 equivalent) in H₂O (5 mL). The mixture was stirred at 15 °C for 2 hours. The reaction mixture was extracted with ethyl acetate (10 mL * 2). The organic phase was separated, washed with brine (10 mL * 2), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give (1E)-propionaldehyde oxime (728 mg, crude), as a yellow oil.

[0235] data: 1 ¹H NMR (400 MHz, chloroform-d) δ = 9.32 (br s, 1H), 7.46 (t, J = 5.7 Hz, 1H), 2.41 (dq, J = 5.5, 7.7 Hz, 1H), 2.24 (dq, J = 5.8, 7.5 Hz, 1H), 1.09 (t, J = 7.5 Hz, 3H) 2. General procedure for the preparation of ethyl 3-ethylisoxazole-5-carboxylate: NCS (1.60 g, 11.95 mmol, 1 equivalent) was added dropwise to a solution of (1E)-propionaldehyde oxime (728 mg, 9.96 mmol, 1 equivalent) in DMF (7 mL). After addition, the mixture was stirred at 15 °C for 2 hours, followed by the dropwise addition of TEA (1.51 g, 14.94 mmol, 2.08 mL, 1.5 equivalent) and ethyl propionate-2-acetylacetate (1.47 g, 14.94 mmol, 1.47 mL, 1.5 equivalent) at 0 °C. The resulting mixture was stirred at 15 °C for 3 hours. The reaction mixture was then partitioned between water (20 mL) and ethyl acetate (20 mL * 2). The organic phase was separated, washed with brine (30 mL * 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain ethyl 3-ethylisoxazole-5-carboxylate (1.33 g, crude product), which was a brown oily substance.

[0236] data: LCMS (ESI + ): m / z 170.1 (M+H) 3. General procedure for the preparation of 3-ethylisoxazole-5-carboxylic acid: LiOH·H2O (659.74 mg, 15.72 mmol, 2 equivalents) was added to a solution of ethyl 3-ethylisoxazole-5-carboxylate (1.33 g, 7.86 mmol, 1 equivalent) in THF (15 mL) and H2O (3 mL). The mixture was stirred at 15 °C for 2 hours. The reaction mixture was concentrated under reduced pressure to remove THF. The residue was diluted with water (30 mL) and extracted with ethyl acetate (10 mL * 2). 1N HCl was added to the aqueous layer until pH < 1, and then it was extracted with ethyl acetate (20 mL * 2). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by preparative HPLC (HCl conditions, column: Phenomenex luna C18 250*50mm*10 um; mobile phase: [water (HCl)-ACN]; B%: 1%-40%, 10 min) to give 3-ethylisoxazole-5-carboxylic acid (170 mg, 1.20 mmol, 15.32% yield) as a white solid.

[0237] data: LCMS (ESI+): m / z 142.0 (M+H) 1 ¹H NMR (400 MHz, chloroform-d) δ = 6.95 (s, 1H), 2.80 (q, J = 7.6 Hz, 2H), 1.33 (t, J = 7.6 Hz, 3H) 4. General procedure for the preparation of 3-ethyl-N-[[(1R,3S)-3-[[5-(6-oxopyridazin-1-yl)-2-pyridyl]amino]cyclopentyl]methyl]isoxazole-5-carboxamide: At 0 °C, DIEA (183.16 mg, 1.42 mmol, 246.85 uL, 4 equivalents) was added to a solution of 3-ethylisoxazole-5-carboxylic acid (50 mg, 354.30 µmol, 1 equivalent, HBr) in DMF (1 mL), followed by dropwise addition of HATU (202.07 mg, 531.45 µmol, 1.5 equivalents). The resulting mixture was stirred at 15 °C for 2 hours. MeOH (2 mL) was added to the mixture, and the residue was purified by preparative HPLC (alkaline conditions, column: Waters Xbridge Prep OBDC18 150*40mm*10um; mobile phase: [water(NH3H2O+NH4HCO3)-ACN]; B%: 10%-40%, 8 min) to give 3-ethyl-N-[[(1R,3S)-3-[[5-(6-oxopyridazin-1-yl)-2-pyridyl]amino]cyclopentyl]methyl]isoxazole-5-carboxamide (17.1 mg, 41.87 µmol, 11.82% yield, 100% purity), as a white solid.

[0238] data: LCMS (ESI + ): m / z 409.1 (M+H) 1 H NMR (400 MHz, methanol-d4) δ = 8.14 (d, J = 2.1 Hz, 1H), 8.05 - 8.01(m, 1H), 7.59 (dd, J = 2.6, 8.9 Hz, 1H), 7.46 (dd, J = 3.8, 9.4 Hz, 1H), 7.08- 7.04 (m, 1H), 6.85 (s, 1H), 6.58 (d, J = 9.3 Hz, 1H), 4.24 - 4.15 (m, 1H), 3.40 (br d, J = 6.6 Hz, 2H), 2.74 (q, J = 7.6 Hz, 2H), 2.40 - 2.28 (m, 2H),2.16 - 2.02 (m, 1H), 1.90 – 1.80 (m, 1H), 1.69 – 1.49 (m, 2H), 1.29 (t, J =7.6 Hz, 3H), 1.29 – 1.22 (m, 1H) Example S15: N-[[(1R,3S)-3-[[5-[3-(3,3-difluoroazacyclobutane-1-yl)-6-oxo-pyridazine- [1-yl]-2-pyridyl]amino]cyclopentyl]methyl]-3-methyl-isoxazole-5-carboxamide 1. General procedure for the preparation of 3-chloro-6-(3,3-difluoroazacyclobutan-1-yl)pyridazine: To a solution of 3,6-dichloropyridazine (2 g, 13.25 mmol, 1 equivalent) in DMF (20 mL), 3,3-difluorozacriane (2.06 g, 15.89 mmol, 1.2 equivalent, HCl) and K₂CO₃ (5.49 g, 39.74 mmol, 3 equivalent) were added. The mixture was stirred at 80 °C for 5 hours. The mixture was diluted with water (20 mL) and then extracted with EtOAc (10 mL * 3). The combined organic layers were washed with a saturated aqueous solution of NaCl (20 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give the residue. o The crude product was ground together with DCM (4 mL) for 30 minutes at C, and the mixture was then filtered under reduced pressure to give compound 3-chloro-6-(3,3-difluoroazacyclobutane-1-yl)pyridazine (1.3 g, 6.26 mmol, 47.26% yield) as a pale yellow solid.

[0239] 2. General procedure for the preparation of 6-(3,3-difluoroazacyclobutane-1-yl)-2,3-dihydropyridazin-3-one: KOAc (614.55 mg, 6.26 mmol, 1 equivalent) was added to a solution of 3-chloro-6-(3,3-difluoroazacyclobutan-1-yl)pyridazine (1.3 g, 6.26 mmol, 1 equivalent) in AcOH (13 mL). The mixture was stirred at 120 °C for 12 h. The mixture was diluted with water (10 mL) and saturated NaCl aqueous solution (10 mL), and then extracted with EtOAc (10 mL * 3). The combined organic layers were washed with saturated NaCl aqueous solution (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 1 to petroleum ether / ethyl acetate = 0 / 1) to give 6-(3,3-difluoroazacyclobutane-1-yl)-2,3-dihydropyridazin-3-one (600 mg, 3.21 mmol, 51.20% yield) as a yellow solid.

[0240] data: LCMS (ESI +): m / z 188.2 (M+H) 3. General procedure for the preparation of N-[[(1R,3S)-3-[[5-[3-(3,3-difluoroazacyclobutane-1-yl)-6-oxo-pyridazin-1-yl]-2-pyridyl]amino]cyclopentyl]methyl]-3-methyl-isoxazole-5-carboxamide: 6-(3,3-difluoroazacyclobutan-1-yl)-2,3-dihydropyridazin-3-one (175.62 mg, 938.41 µmol, 4 equivalents), N-[[(1R,3S)-3-[(5-iodo-2-pyridyl)amino]cyclopentyl]methyl]-3-methyl-isoxazole-5-carboxamide (100 mg, 234.60 µmol, 1 equivalent), K2CO3 (64.85 mg, 469.21 µmol, 2 equivalents), CuI (22.34 mg, 117.30 µmol, 0.5 equivalents) and N1,N2-dimethylcyclohexane-1,2-diamine (16.69 mg, 117.30 µmol, 0.5 equivalents) were prepared in DMSO (2 The mixture in mL was degassed and purged three times with N2, and then stirred at 60 °C for 8 hours under N2 atmosphere. The mixture was filtered, and the filtrate was purified by preparative HPLC (alkaline conditions, column: Waters XbridgePrep OBD C18 150*40mm*10um; mobile phase: [water(NH3H2O+NH4HCO3)-ACN]; B%: 20%-50%, 8 min) to give N-[[(1R,3S)-3-[[5-[3-(3,3-difluoroazacyclobutane-1-yl)-6-oxo-pyridazin-1-yl]-2-pyridyl]amino]cyclopentyl]methyl]-3-methyl-isoxazole-5-carboxamide (64 mg, 131.83 µmol, 56.19% yield, 100% purity), as a yellow solid.

[0241] LCMS (ESI+): m / z 486.1 (M+H) 1H NMR (400 MHz, methanol-d4) δ = 8.16 (d, J=2.13 Hz, 1H), 7.60 (dd, J=9.01, 2.63 Hz, 1H), 7.21 (d, J=9.76 Hz, 1H), 7.00 (d, J=9.63 Hz, 1H), 6.80(s, 1H), 6.57 (d, J=9.01 Hz, 1H), 4.36 (t, J=12.13 Hz, 4H), 4.22 - 4.12 (m,1H), 3.39 (d, J=6.75 Hz, 2H), 2.38 - 2.27 (m, 2H), 2.33 (s, 3H), 2.14 - 2.05(m, 1H), 1.90 - 1.80 (m, 1H), 1.66 - 1.49 (m, 2H), 1.30 - 1.20 (m, 1H).

[0242] Example S17: 3-Methyl-N-[[(1R,3S)-3-[[3-Methyl-5-(6-oxopyridazin-1-yl)-2-pyridyl] [Amino]cyclopentyl]methyl]isoxazole-5-carboxamide 1. General procedure for N-[[(1R,3S)-3-[(5-iodo-3-methyl-2-pyridyl)amino]cyclopentyl]methyl]-3-methyl-isoxazole-5-carboxamide: K₂CO₃ (957.80 mg, 6.93 mmol, 6 equivalents) was added to a solution of N-[[(1R,3S)-3-aminocyclopentyl]methyl]-3-methyl-isoxazol-5-carboxamide (300 mg, 1.16 mmol, 1 equivalent) and 2-fluoro-5-iodo-3-methyl-pyridine (273.76 mg, 1.16 mmol, 1 equivalent) in DMSO (3 mL). The mixture was stirred at 100 °C for 12 hours. The mixture was filtered, and the reaction mixture was partitioned between H₂O (30 mL) and ethyl acetate (30 mL). The organic phase was separated, washed with brine (20 mL * 3), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by preparative TLC to give N-[[(1R,3S)-3-[(5-iodo-3-methyl-2-pyridyl)amino]cyclopentyl]methyl]-3-methyl-isoxazole-5-carboxamide (90 mg, 204.42 µmol, 17.70% yield) as a white solid.

[0243] data: LCMS (ESI + ): m / z 441.2 (M+H) + 2. General procedure for 3-methyl-N-[[(1R,3S)-3-[[3-methyl-5-(6-oxopyridazin-1-yl)-2-pyridyl]amino]cyclopentyl]methyl]isoxazole-5-carboxamide: The mixture of N-[[(1R,3S)-3-[(5-iodo-3-methyl-2-pyridyl)amino]cyclopentyl]methyl]-3-methyl-isoxazole-5-carboxamide (80 mg, 181.70 µmol, 1 equivalent), 1H-pyridazin-6-one (26.19 mg, 272.56 µmol, 1.5 equivalent), CuI (34.61 mg, 181.70 µmol, 1 equivalent), K2CO3 (75.34 mg, 545.11 µmol, 3 equivalent) and N1,N2-dimethylcyclohexane-1,2-diamine (25.85 mg, 181.70 µmol, 1 equivalent) in DMSO (3 mL) was degassed and purged three times with N2. The mixture was then stirred at 80 °C for 12 hours under N2 atmosphere. The mixture was filtered, and the residue was partitioned between H2O (20 mL) and ethyl acetate (20 mL). The organic phase was separated, washed with brine (10 mL * 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (alkaline conditions; column: Waters Xbridge Prep OBD C18 150*40mm*10um; mobile phase: [water (NH3H2O+NH4HCO3)-ACN]; B%: 15%-30%, 8 min) to give 3-methyl-N-[[(1R, 3S)-3-[[3-methyl-5-(6-oxopyridazin-1-yl)-2-pyridyl]amino]cyclopentyl]methyl]isoxazole-5-carboxamide (25.6 mg, 62.21 µmol, 34.24% yield, 99.260% purity) as a white solid.

[0244] data: LCMS (ESI + ): m / z 409.2 (M+H) + 1¹H NMR (400 MHz, methanol-d⁴) δ = 8.06 - 8.00 (m, 2H), 7.50 - 7.43 (m, 2H), 7.06 (dd, J = 1.6, 9.4 Hz, 1H), 6.80 (s, 1H), 4.40 (quintet, J = 7.3 Hz, 1H), 3.44 - 3.39 (m, 2H), 2.38 - 2.30 (m, 2H), 2.35 (s, 3H), 2.17 (s, 3H), 2.17 - 2.07 (m, 1H), 1.90 - 1.81 (m, 1H), 1.72 - 1.62 (m, 1H), 1.61 - 1.51 (m, 1H). 1.37 – 1.27 (m, 1H).

[0245] Examples S18 and S22: Example S18: N-[[(1R,3S)-3-[[5-[3-(cyclobutylamino)-6-oxo-pyridazin-1-yl]-2-pyridine [3-methyl-isoxazole-5-carboxamide] 1. General procedure for N-[[(1R,3S)-3-[[5-(3-chloro-6-oxo-pyridazin-1-yl)-2-pyridyl]amino]cyclopentyl]methyl]-3-methyl-isoxazole-5-carboxamide: To a solution of N-[[(1R,3S)-3-[(5-iodo-2-pyridyl)amino]cyclopentyl]methyl]-3-methyl-isoxazole-5-carboxamide (100 mg, 234.60 µmol, 1 equivalent), 3-chloro-1H-pyridazin-6-one (45.94 mg, 351.91 µmol, 1.5 equivalent) in DMSO (4 mL), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (16.69 mg, 117.30 µmol, 0.5 equivalent), CuI (22.34 mg, 117.30 µmol, 0.5 equivalent), and K2CO3 (97.27 mg, 703.81 µmol, 3 equivalent) were added. The mixture was stirred at 80 °C for 12 hours. The reaction mixture was partitioned between water (10 mL) and ethyl acetate (10 mL). The organic phase was separated, washed with brine (5 mL * 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative TLC to give N-[[(1R, 3S)-3-[[5-(3-chloro-6-oxo-pyridazin-1-yl)-2-pyridinyl]amino]cyclopentyl]methyl]-3-methyl-isoxazole-5-carboxamide (140 mg, crude), as a brown solid.

[0246] data: LCMS (ESI + ): m / z 429.2 (M+H) + 2. General procedure for N-[[(1R,3S)-3-[[5-[3-(cyclobutylamino)-6-oxo-pyridazin-1-yl]-2-pyridyl]amino]cyclopentyl]methyl]-3-methyl-isoxazole-5-carboxamide: The following were added: N-[[(1R,3S)-3-[[5-(3-chloro-6-oxo-pyridazin-1-yl)-2-pyridyl]amino]cyclopentyl]methyl]-3-methyl-isoxazole-5-carboxamide (100 mg, 233.17 µmol, 1 equivalent), cyclobutamine (25.08 mg, 233.17 µmol, 30.22 uL, 1 equivalent, HCl), di-tert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphine (19.80 mg, 46.63 µmol, 0.2 equivalent), [2-(2-aminophenyl)phenyl]-methylsulfonyloxy-palladium-di-tert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphine (18.52 mg, 23.32 µmol, 0.1 equivalent), and t-BuONa (67.23... The mixture of N-[[(1R,3S)-3-[[5-[3-(cyclobutylamino)-6-oxo-pyridazin-1-yl]-2-pyridyl]amino]cyclopentyl]methyl]-3-methyl-isoxazole-5-carboxamide (22.2 mg, 47.89 µmol, 20.54% yield, 100% purity) in 2-methyl-2-butanol (2 mL) was degassed and purged three times with N2. The mixture was then stirred at 80 °C for 12 h under N2 atmosphere. The mixture was filtered and the residue was purified by preparative HPLC (alkaline conditions; column: Waters Xbridge Prep OBD C18 150*40mm*10um; mobile phase: [water (NH3H2O+NH4HCO3)-ACN]; B%: 20%-50%, 8 min) to give compound N-[[(1R,3S)-3-[[5-[3-(cyclobutylamino)-6-oxo-pyridazin-1-yl]-2-pyridyl]amino]cyclopentyl]methyl]-3-methyl-isoxazole-5-carboxamide (22.2 mg, 47.89 µmol, 20.54% yield, 100% purity) as a white solid.

[0247] data: LCMS (ESI + ): m / z 464.3 (M+H) + 1H NMR (400 MHz, methanol-d4) δ = 8.18 (s, 1H), 7.64 (dd, J = 2.5, 9.0 Hz,1H), 7.01 (d, J = 9.6 Hz, 1H), 6.84 (d, J = 9.8 Hz, 1H), 6.80 (s, 1H), 6.56(d, J = 9.0 Hz, 1H), 4.21 - 4.07 (m, 2H), 3.40 (br d, J = 6.3 Hz, 2H), 2.39 -2.29 (m, 7H), 2.14 - 2.04 (m, 1H), 1.94 - 1.80 (m, 3H), 1.80 - 1.70 (m, 2H),1.67 - 1.50 (m, 2H), 1.30 - 1.19 (m, 1H) The following compounds were prepared according to the general procedure of step 2. The starting materials were either commercially available or prepared from commercially available reagents using conventional reactions well known in the art.

[0248] Example S22: N-[[(1R,3S)-3-[[5-[3-(3-methoxyazine-1-yl)-6-oxo-pyridazine- [1-yl]-2-pyridyl]amino]cyclopentyl]methyl]-3-methylisoxazole-5-carboxamide LC / MS [M+1] 480.1 1H NMR (400 MHz, methanol-d4) δ = 8.15 (d, J=2.50 Hz, 1H), 7.60 (dd, J=9.07, 2.56 Hz, 1H), 7.12 (d, J=9.76 Hz, 1H), 6.94 (d, J=9.76 Hz, 1H), 6.80(s, 1H), 6.56 (d, J=9.13 Hz, 1H), 4.36 - 4.30 (m, 1H), 4.20 - 4.25 (m, 3H), 3.83 (dd, J=8.94, 4.19 Hz, 2H), 3.39 (br d, J=6.50 Hz, 2H), 3.32 (br s, 3H), 2.37 - 2.27 (m, 2H), 2.34 (s, 3H), 2.15 – 2.06 (m, 1H), 1.90 – 1.80 (m, 1H), 1.65 – 1.50 (m, 2H), 1.30 – 1.20 (m, 1H) Example S20: 3-Methyl-N-[[(1R,3S)-3-[[6-Methyl-5-(6-oxopyridazin-1-yl)-2-pyridyl] [Amino]cyclopentyl]methyl]isoxazole-5-carboxamide 1. General procedure for the preparation of 6-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)pyridine: A mixture of 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-1,3,2-dioxacyclopentaborane (642.85 mg, 2.53 mmol, 1.2 equivalents), 6-fluoro-3-iodo-2-methylpyridine (500 mg, 2.11 mmol, 1 equivalent), Pd(dppf)Cl2.CH2Cl2 (172.28 mg, 210.96 μmol, 0.1 equivalents), and AcOK (414.07 mg, 4.22 mmol, 2 equivalents) in DMF (10 mL) was degassed and purged three times with N2. The mixture was then stirred at 90 °C for 1 hour under N2 atmosphere. The reaction mixture was partitioned between saturated aqueous NH4Cl solution (15 mL) and ethyl acetate (10 mL). The organic phase was separated, washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by rapid silica gel chromatography (ISCO®; 12 g SepaFlash® silica rapid column, 0–58% ethyl acetate / petroleum ether gradient eluent, 60 mL / min) to give 6-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)pyridine (221.9 mg, 935.98 μmol, 44.37% yield) as a white solid.

[0249] data: LCMS (ESI+): m / z 238.1 (M+H) + 2. General procedure for the preparation of 2-(6-fluoro-2-methyl-3-pyridyl)pyridazin-3-one: A mixture of 6-fluoro-2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)pyridine (200 mg, 843.61 μmol, 1 equivalent), 1H-pyridazin-6-one (81.06 mg, 843.61 μmol, 1 equivalent), Cu(OAc)₂ (229.84 mg, 1.27 mmol, 1.5 equivalent), and pyridine (200.19 mg, 2.53 mmol, 204.27 μL, 3 equivalent) in DMF (3 mL) was degassed and purged three times with O₂, and then stirred at 90 °C for 3 hours under an O₂ (15 psi) atmosphere. The reaction mixture was partitioned between saturated NH₄Cl aqueous solution (15 mL) and ethyl acetate (10 mL). The organic phase was separated, washed with brine (10 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by preparative TLC (SiO2, ethyl acetate:methanol = 10 / 1) to give 2-(6-fluoro-2-methyl-3-pyridyl)pyridazin-3-one (98.2 mg, 478.59 μmol, 56.73% yield) as a white solid.

[0250] data: LCMS (ESI+): m / z 206.2 (M+H) + 3. General procedure for the preparation of 3-methyl-N-[[(1R,3S)-3-[[6-methyl-5-(6-oxopyridazin-1-yl)-2-pyridyl]amino]cyclopentyl]methyl]isoxazole-5-carboxamide: K₂CO₃ (181.86 mg, 1.32 mmol, 3 equivalents) was added to a solution of 2-(6-fluoro-2-methyl-3-pyridyl)pyridazin-3-one (90 mg, 438.62 μmol, 1 equivalent) and N-[[(1R,3S)-3-aminocyclopentyl]methyl]-3-methyl-isoxazole-5-carboxamide (97.93 mg, 377.05 μmol, 0.86 equivalents, HCl) in DMSO (3 mL). The mixture was stirred at 100 °C for 12 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure to give the product. The residue was purified by preparative HPLC (column: Phenomenex C18 75*30mm*3μm; mobile phase: [water(NH3H2O+NH4HCO3)-ACN]; B%: 15%-35%, 8 min) to obtain 3-methyl-N-[[(1R,3S)-3-[[6-methyl-5-(6-oxopyridazin-1-yl)-2-pyridyl]amino]cyclopentyl]methyl]isoxazole-5-carboxamide (15.8 mg, 38.68 μmol, 8.82% yield, 100% purity), as a white solid.

[0251] data: LCMS (ESI+): m / z 409.3 (M+H) + 1 H NMR (400 MHz, methanol-d4) δ ppm 8.04 (dd, J=3.88, 1.50 Hz, 1H), 7.51 (dd, J=9.38, 3.88 Hz, 1H), 7.29 (d, J=8.75 Hz, 1H), 7.09 (dd, J=9.51, 1.63Hz, 1H), 6.81 (s, 1H), 6.44 (d, J=8.76 Hz, 1H), 4.22 - 4.14 (m, 1H), 3.40 (brd, J=5.88 Hz, 2H), 2.39 - 2.30 (m, 2H), 2.34 (s, 3H), 2.13 – 2.05 (m, 1H),2.10 (s, 3H), 1.90 – 1.80 (m, 1H), 1.65 – 1.50 (m, 2H), 1.30 – 1.20 (m, 1H) Example S21: 3-Methyl-N-[[(1R,3S)-3-[[4-Methyl-5-(6-oxopyridazin-1-yl)-2-pyridyl] [Amino]cyclopentyl]methyl]isoxazole-5-carboxamide 1. General procedure for the preparation of 2-(6-fluoro-4-methyl-3-pyridyl)pyridazin-3-one: A mixture of (6-fluoro-4-methyl-3-pyridyl)boronic acid (5 g, 32.27 mmol, 1 equivalent), 1H-pyridazin-6-one (2.17 g, 22.59 mmol, 0.7 equivalent), copper diacetate (8.79 g, 48.41 mmol, 1.5 equivalent), and pyridine (7.66 g, 96.82 mmol, 7.81 mL, 3 equivalent) in DMF (70 mL) was degassed and purged three times with O2. The mixture was then stirred at 50 °C for 12 hours under an O2 atmosphere (15 psi). The reaction mixture was added to water (70 mL) and extracted with ethyl acetate (70 mL * 3). The organic layer was washed with brine (100 mL * 3), dried over Na2SO4, and concentrated to give the crude product. The residue was purified by column chromatography (SiO2, petroleum ether: ethyl acetate = 5 / 1 to 0 / 1) to give 2-(6-fluoro-4-methyl-3-pyridyl)pyridazin-3-one (3.1 g, 15.11 mmol, 46.82% yield) as a brown solid.

[0252] data: LCMS (ESI + ): m / z 206.1 (M+H) + 2. General procedure for the preparation of 3-methyl-N-[[(1R,3S)-3-[[4-methyl-5-(6-oxopyridazin-1-yl)-2-pyridyl]amino]cyclopentyl]methyl]isoxazole-5-carboxamide: K₂CO₃ (425.69 mg, 3.08 mmol, 4 equivalents) was added to a solution of N-[[(1R,3S)-3-aminocyclopentyl]methyl]-3-methyl-isoxazol-5-carboxamide (200 mg, 770.03 μmol, 1 equivalent, HCl) and 2-(6-fluoro-4-methyl-3-pyridyl)pyridazin-3-one (110.60 mg, 539.02 μmol, 0.7 equivalents) in DMSO (3 mL). The mixture was stirred at 95 °C for 12 h. The mixture was diluted with water (25 mL) and then extracted with ethyl acetate (25 mL * 3). The combined organic layers were washed with saturated aqueous NaCl solution (30 mL * 2) and dried over Na₂SO₄. The mixture was filtered and concentrated under reduced pressure to give the residue. The residue was purified by preparative HPLC (HCl conditions; column: Phenomenex Luna C18 250*50mm*10 μm; mobile phase: [H2O(0.05%HCl)-ACN]; gradient: 5%-35% B for 10.0 min) to obtain 3-methyl-N-[[(1R,3S)-3-[[4-methyl-5-(6-oxopyridazin-1-yl)-2-pyridyl]amino]cyclopentyl] [Methyl]isoxazole-5-carboxamide (216.6 mg, 469.50 μmol, 7.62% yield, 96.439% purity, HCl) is a white solid.

[0253] data: LCMS (ESI + ): m / z 409.2 (M+H) + 1H NMR (400 MHz, methanol-d4) δ = 8.12 (dd, J=3.81, 1.43 Hz, 1H), 8.01 (s,1H), 7.59 (dd, J=9.54, 3.93 Hz, 1H), 7.17 (dd, J=9.54, 1.43 Hz, 1H), 7.02 (s,1H), 6.85 (s, 1H), 4.09 (quin, J=6.68 Hz, 1H), 3.45 (d, J=6.56 Hz, 2H), 2.45- 2.35 (m, 2H), 2.36 (s, 3H), 2.25 - 2.20 (m, 1H), 2.20 (s, 3H), 1.99 - 1.89(m, 1H), 1.84 - 1.74 (m, 1H), 1.69 - 1.59 (m, 1H), 1.48 - 1.38 (m, 1H) Example S23: N-[[(1R,3S)-3-[[5-(5-cyano-6-oxo-pyridazin-1-yl)-2-pyridyl]amino] Cyclopentyl]methyl]-3-methyl-isoxazole-5-carboxamide 1. General procedure for the preparation of N-[[(1R,3S)-3-[[5-(5-cyano-6-oxo-pyridazin-1-yl)-2-pyridyl]amino]cyclopentyl]methyl]-3-methyl-isoxazole-5-carboxamide: The mixture of 6-oxo-1H-pyridazin-5-carboxynitrile (25.33 mg, 209.20 µmol, 1.2 equivalents), [6-[[(1S,3R)-3-[[(3-methylisoxazol-5-carbonyl)amino]methyl]cyclopentyl]amino]-3-pyridyl]boronic acid (60 mg, 174.33 µmol, 1 equivalent), Cu(OAc)2 (31.66 mg, 174.33 µmol, 1 equivalent), and pyridine (27.58 mg, 348.66 µmol, 28.14 uL, 2 equivalents) in DMF (1 mL) was degassed and purged three times with O2. The mixture was then stirred at 90 °C for 2 hours under an O2 atmosphere (15 psi). The mixture was filtered, and the filtrate was purified by preparative HPLC (alkaline conditions: column: Waters Xbridge Prep OBD C18 150*40mm*10um; mobile phase: [water(NH3H2O+NH4HCO3)-ACN]; B%: 15%-45%, 8 min) to obtain N-[[(1R,3S)-3-[[5-(5-cyano-6-oxo-pyridazin-1-yl)-2-pyridinyl]amino]cyclopentyl]methyl]-3-methyl-isoxazole-5-carboxamide (11.3 mg, 26.94 µmol, 15.45% yield, 100.00% purity), as a yellow solid.

[0254] data: LCMS (ESI + ): 420.2 m / z (M+1) + 1 H NMR (400 MHz, methanol-d4) δ = 8.18 (d, J = 2.4 Hz, 1H), 8.12 (d, J =4.2 Hz, 1H), 7.96 (d, J = 4.2 Hz, 1H), 7.62 (dd, J = 2.6, 9.0 Hz, 1H), 6.80(s, 1H), 6.58 (d, J = 9.0 Hz, 1H), 4.23 - 4.15 (m, 1H), 3.43 - 3.37 (m, 2H), 2.38 - 2.28 (m, 2H), 2.35 (s, 3H), 2.15 - 2.07 (m, 1H), 1.90 - 1.80 (m, 1H),1.65 - 1.50 (m, 2H), 1.30 - 1.20 (m, 1H) Example S24: N-[[(1R,3S)-3-[[5-[6-(methoxymethyl)-2-pyridyl]-2-pyridyl]amino] Cyclopentyl]methyl]-3-methyl-isoxazole-5-carboxamide 1. General procedure for preparing [6-(6-fluoro-3-pyridyl)-2-pyridyl]methanol: A mixture of 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)pyridine (1 g, 4.48 mmol, 1 equivalent), (6-bromo-2-pyridyl)methanol (842.95 mg, 4.48 mmol, 1 equivalent), Pd(dppf)Cl2 (328.04 mg, 448.33 µmol, 0.1 equivalent), and K2CO3 (1.24 g, 8.97 mmol, 2 equivalent) in dioxane (10 mL) and H2O (1 mL) was degassed and purged three times with N2. The mixture was then stirred at 80 °C for 12 hours under N2 atmosphere. The mixture was quenched by adding water (15 mL) and then extracted with ethyl acetate (15 mL * 3). The combined organic layers were washed with saturated aqueous NaCl solution (15 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to give [6-(6-fluoro-3-pyridyl)-2-pyridyl]methanol (900 mg, 4.41 mmol, 98.31% yield) as a white solid.

[0255] data: LCMS (ESI + ): m / z 205.2 (M+H) + 2. General procedure for preparing 2-fluoro-5-[6-(methoxymethyl)-2-pyridyl]pyridine: MeI (417.06 mg, 2.94 mmol, 182.92 μL, 2 equivalents) and NaH (88.14 mg, 2.20 mmol, 60% purity, 1.5 equivalents) were added to a solution of [6-(6-fluoro-3-pyridyl)-2-pyridyl]methanol (300 mg, 1.47 mmol, 1 equivalent) in THF (3 mL) at 0 °C. The mixture was stirred at 15 °C for 1 hour. The reaction mixture was quenched by adding saturated aqueous NH4Cl solution (5 mL) and extracted with ethyl acetate (10 mL * 3). The combined organic layers were washed with brine (30 mL * 2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (SiO2, petroleum ether: ethyl acetate = 1:1) to give 2-fluoro-5-[6-(methoxymethyl)-2-pyridyl]pyridine (90 mg, 412.42 µmol, 28.07% yield) as a yellow solid.

[0256] data: LCMS (ESI + ): m / z 219.2 (M+H) + 3. General procedure for the preparation of N-[[(1R,3S)-3-[[5-[6-(methoxymethyl)-2-pyridyl]-2-pyridyl]amino]cyclopentyl]methyl]-3-methyl-isoxazole-5-carboxamide: To a solution of 2-fluoro-5-[6-(methoxymethyl)-2-pyridyl]pyridine (90 mg, 412.42 µmol, 1 equivalent) in DMSO (2 mL), K₂CO₃ (170.99 mg, 1.24 mmol, 3 equivalents) and N-[[(1R,3S)-3-aminocyclopentyl]methyl]-3-methyl-isoxazole-5-carboxamide (128.54 mg, 494.90 µmol, 1.20 equivalents, HCl) were added. The mixture was stirred at 100 °C for 12 hours. The mixture was filtered and the filtrate was purified by preparative HPLC (alkaline conditions; column: WatersXbridge Prep OBD C18 150*40mm*10um; mobile phase: [water(NH3H2O+NH4HCO3)-ACN]; B%: 20%-50%, 8 min) to obtain N-[[(1R,3S)-3-[[5-[6-(methoxymethyl)-2-pyridyl]-2-pyridyl]amino]cyclopentyl]methyl]-3-methyl-isoxazole-5-carboxamide (29.3 mg, 67.53 µmol, 16.37% yield, 97.146% purity), as a pale yellow solid.

[0257] data: LCMS (ESI + ): m / z 422.1 (M+H) + 1 H NMR (400 MHz, methanol-d4) δ = 8.57 (d, J=2.00 Hz, 1H), 8.04 (dd, J=8.82, 2.44 Hz, 1H), 7.80 (t, J=7.75 Hz, 1H), 7.61 (d, J=7.88 Hz, 1H), 7.32(d, J=7.50 Hz, 1H), 6.80 (s, 1H), 6.60 (d, J=8.88 Hz, 1H), 4.58 (s, 2H), 4.20(quin, J=6.97 Hz, 1H), 3.48 (s, 3H), 3.40 (d, J=6.75 Hz, 2H), 2.39 - 2.29(m, 2H), 2.31 (s, 3H), 2.17 - 2.07 (m, 1 H), 1.90 - 1.80 (m, 1 H), 1.67 -1.50 (m, 2 H), 1.31 - 1.20 (m, 1 H) Example S25: N-[[(1R,3S)-3-[[5-(3-cyano-6-oxo-pyridazin-1-yl)-2-pyridinyl]amino] Cyclopentyl]methyl]-3-methylisoxazole-5-carboxamide 1. General procedure for the preparation of 6-oxo-1H-pyridazine-3-carbonyl chloride: To a solution of 6-oxo-1H-pyridazin-3-carboxylic acid (5 g, 35.69 mmol, 1 equivalent) in DCM (50 mL), DMF (260.87 mg, 3.57 mmol, 274.60 μL, 0.1 equivalent) and (COCl)₂ (6.79 g, 53.53 mmol, 4.69 mL, 1.5 equivalent) were added. The mixture was stirred at 20 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to give 6-oxo-1H-pyridazin-3-carbonyl chloride (5.6 g, crude) as a white solid, which was used directly without purification.

[0258] 2. General procedure for the preparation of 6-oxo-1H-pyridazine-3-carboxamide: A solution of 6-oxo-1H-pyridazin-3-carbonyl chloride (5.6 g, 35.32 mmol, 1 equivalent) in DCM (20 mL) was added to a solution of NH3·H2O (60 mL, 25% purity). The resulting mixture was stirred at 20 °C for 0.5 h. The reaction mixture was filtered and the filter cake was dried to give 6-oxo-1H-pyridazin-3-carboxamide (3.4 g, crude product), a grayish-white solid, which was used directly without purification.

[0259] 3. General procedure for the preparation of 6-oxo-1H-pyridazine-3-carboxynitrile: Burgess reagent (8.74 g, 36.66 mmol, 1.5 equivalence) was added to a solution of 6-oxo-1H-pyridazin-3-carboxamide (3.4 g, 24.44 mmol, 1 equivalent) in THF (50 mL). The mixture was stirred at 70 °C for 12 hours. The reaction mixture was concentrated to give a residue. The residue was purified by column chromatography to give 6-oxo-1H-pyridazin-3-carboxynitrile (300 mg, 2.48 mmol, 10.14% yield) as a white solid. data: 1 ¹H NMR (400 MHz, methanol-d⁴) δ ppm 7.04 (d, J=9.88 Hz, 1H), 7.66 (d, J=9.88 Hz, 1H) 4. General procedure for the preparation of N-[[(1R,3S)-3-[[5-(3-cyano-6-oxo-pyridazin-1-yl)-2-pyridyl]amino]cyclopentyl]methyl]-3-methylisoxazole-5-carboxamide: A mixture of [6-[[(1S,3R)-3-[[(3-methylisoxazol-5-carbonyl)amino]methyl]cyclopentyl]amino]-3-pyridyl]boronic acid (100 mg, 290.55 µmol, 1 equivalent), 6-oxo-1H-pyridazin-3-carboxynitrile (35.18 mg, 290.55 µmol, 1 equivalent), Cu(OAc)₂ (52.77 mg, 290.55 µmol, 1 equivalent), and pyridine (45.97 mg, 581.10 µmol, 46.90 μL, 2 equivalent) in DMF (2 mL) was degassed and purged three times with O₂. The mixture was then stirred at 90 °C for 2 hours under an O₂ atmosphere (15 psi). The reaction mixture was filtered and the filtrate was concentrated to give the residue. The residue was purified by preparative HPLC (TFA conditions, column: Phenomenex Luna C18 150*30mm*5um; mobile phase: [water (TFA)-ACN]; B%: 10%-40%, 8 min). It was then purified again by preparative HPLC (alkaline conditions, column: Phenomenex C18 75*30mm*3µm; mobile phase: [water (NH3H2O+NH4HCO3)-ACN]; B%: 10%-50%, 8 min) to obtain N-[[(1R,3S)-3-[[5-(3-cyano-6-oxo-pyridazin-1-yl)-2-pyridyl]amino]cyclopentyl]methyl]-3-methylisoxazole-5-carboxamide (33.9 mg, 78.88 µmol, 27.15% yield, 97.601% purity), as a yellow solid.

[0260] data: LCMS (ESI + ): 420.0 m / z (M+1) + 1H NMR (400 MHz, methanol-d4) δ ppm 8.17 (d, J=2.50 Hz, 1H), 7.70 (d, J=9.63 Hz, 1H), 7.60 (dd, J=9.07, 2.69 Hz, 1H), 7.13 (d, J=9.76 Hz, 1H), 6.81(s, 1H), 6.59 (d, J=9.01 Hz, 1H), 4.25 – 4.17 (m, 1H), 3.40 (d, J=6.75 Hz, 2H), 2.40 – 2.30 (m, 2H), 2.34 (s, 3 H), 2.17 – 2.05 (m,1H), 1.90 - 1.80 (m,1H), 1.68 - 1.50 (m, 2 H), 1.32 - 1.20 (m, 1 H).

[0261] Example S26: N-[[(1R,3S)-3-[[5-[3-(3-hydroxyazacyclobutane-1-yl)-6-oxo-pyridazine-1- [2-pyridyl]amino]cyclopentyl]methyl]-3-methyl-isoxazole-5-carboxamide 1. General procedure for the preparation of N-[[(1R,3S)-3-[(5-iodo-2-pyridyl)amino]cyclopentyl]methyl]-3-methyl-isoxazole-5-carboxamide: K₂CO₃ (10.86 g, 78.54 mmol, 4 equivalents) was added to a solution of N-[[(1R,3S)-3-aminocyclopentyl]methyl]-3-methyl-isoxazol-5-carboxamide (5.1 g, 19.64 mmol, 1 equivalent, HCl) and 2-fluoro-5-iodopyridine (6.57 g, 29.45 mmol, 1.5 equivalents) in DMSO (50 mL). The mixture was stirred at 95 °C for 12 h. The reaction mixture was quenched by adding H₂O (40 mL) and extracted with EtOAc (100 mL * 3). The combined organic layers were washed with brine (300 mL * 2), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 1 / 1) to give N-[[(1R,3S)-3-[(5-iodo-2-pyridyl)amino]cyclopentyl]methyl]-3-methyl-isoxazole-5-carboxamide (3.1 g, 7.27 mmol, 37.04% yield) as a white solid.

[0262] data: LCMS (ESI+): m / z 427.0 (M+H) + 2. General procedure for the preparation of N-[[(1R,3S)-3-[[5-(3-chloro-6-oxo-pyridazin-1-yl)-2-pyridyl]amino]cyclopentyl]methyl]-3-methyl-isoxazole-5-carboxamide: To a solution of N-[[(1R,3S)-3-[(5-iodo-2-pyridyl)amino]cyclopentyl]methyl]-3-methyl-isoxazole-5-carboxamide (400 mg, 938.41 μmol, 1 equivalent), 3-chloro-1H-pyridazin-6-one (183.74 mg, 1.41 mmol, 1.5 equivalent) in DMSO (3 mL), (1S,2S)-N1,N2-dimethylcyclohexane-1,2-diamine (66.74 mg, 469.21 μmol, 0.5 equivalent), CuI (89.36 mg, 469.21 μmol, 0.5 equivalent), and K2CO3 (259.40 mg, 1.88 mmol, 2 equivalent) were added, the mixture was then degassed and purged three times with N2. The mixture was stirred at 80 °C for 12 hours under a N2 atmosphere. The catalyst was removed by filtration through diatomaceous earth and then washed with EtOAc (10 mL). The mixture was diluted with water (10 mL) and then extracted with EtOAc (10 mL * 3). The combined organic layers were washed with a saturated aqueous solution of NaCl (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by preparative TLC (SiO2, ethyl acetate:methanol = 10:1) to give N-[[(1R,3S)-3-[[5-(3-chloro-6-oxo-pyridazin-1-yl)-2-pyridyl]amino]cyclopentyl]methyl]-3-methyl-isoxazole-5-carboxamide (210 mg, 489.66 μmol, 52.18% yield) as a yellow solid.

[0263] data: LCMS (ESI+): m / z 429.2 (M+H) + 3. General procedure for the preparation of N-[[(1R,3S)-3-[[5-[3-[3-[tert-butyl(dimethyl)silyl]oxyazinobutane-1-yl]-6-oxo-pyridazin-1-yl]-2-pyridyl]amino]cyclopentyl]methyl]-3-methyl-isoxazole-5-carboxamide: Pd₂(dba)₃ (44.84 mg, 48.97 μmol, 0.1 equivalent) and BINAP (30.49 mg, 48.97 μmol, 0.1 equivalent) and Cs₂CO₃ (319.08 mg, 979.31 μmol, 2 equivalent) were added to a solution of aziridine-3-yloxy-tert-butyl-dimethylsilane (183.48 mg, 979.31 μmol, 2 equivalent), N-[[(1R,3S)-3-[[5-(3-chloro-6-oxo-pyridazin-1-yl)-2-pyridinyl]amino]cyclopentyl]methyl]-3-methyl-isoxazole-5-carboxamide (210 mg, 489.66 μmol, 1 equivalent) in dioxane (3 mL). The mixture was stirred at 100 °C for 12 hours. The insoluble material was removed by filtration through diatomaceous earth and then washed with EtOAc (10 mL). The mixture was diluted with water (10 mL) and then extracted with EtOAc (10 mL * 3). The combined organic layers were washed with a saturated aqueous solution of NaCl (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative TLC (SiO2, ethyl acetate:methanol = 10:1) to give N-[[(1R,3S)-3-[[5-[3-[3-[tert-butyl(dimethyl)silyl]oxyazinobutane-1-yl]-6-oxo-pyridazin-1-yl]-2-pyridyl]amino]cyclopentyl]methyl]-3-methyl-isoxazole-5-carboxamide (40 mg, 68.99 μmol, 14.09% yield) as a yellow oil.

[0264] data: LCMS (ESI+): m / z 580.5 (M+H) + 4. General procedure for the preparation of N-[[(1R,3S)-3-[[5-[3-(3-hydroxyazacyclobutane-1-yl)-6-oxo-pyridazin-1-yl]-2-pyridyl]amino]cyclopentyl]methyl]-3-methyl-isoxazole-5-carboxamide: Add 3HF.TEA (33.37 mg, 206.98 μmol, 33.74 μL, 3 equivalents) to a solution of N-[[(1R,3S)-3-[[5-[3-[3-[tert-butyl(dimethyl)silyl]oxyazacyclobutane-1-yl]-6-oxo-pyridazin-1-yl]-2-pyridinyl]amino]cyclopentyl]methyl]-3-methyl-isoxazole-5-carboxamide (40 mg, 68.99 μmol, 1 equivalent) in THF (1 mL). Stir the mixture at 15 °C for 12 hours. Filter the mixture and purify the filtrate by preparative HPLC. The mixture was purified by preparative HPLC (alkaline conditions; column: Waters Xbridge Prep OBD C18 150*40mm*10μm; mobile phase: [water(NH3H2O+NH4HCO3)-ACN]; B%: 5%-50%, 8 min) to obtain N-[[(1R,3S)-3-[[5-[3-(3-hydroxyazacyclobutane-1-yl)-6-oxo-pyridazin-1-yl]-2-pyridyl]amino]cyclopentyl]methyl]-3-methyl-isoxazole-5-carboxamide (11.5 mg, 24.70 μmol, 35.81% yield, 100% purity), as a yellow solid.

[0265] data: LCMS (ESI+): m / z 466.1 (M+H) + 1 H NMR (400 MHz, methanol-d4) δ = 8.15 (d, J=2.25 Hz, 1H), 7.60 (dd, J=9.01, 2.63 Hz, 1H), 7.12 (d, J=9.76 Hz, 1H), 6.94 (d, J=9.63 Hz, 1H), 6.80(s, 1H), 6.56 (d, J=9.01 Hz, 1H), 4.69 - 4.61 (m, 1H), 4.23 - 4.13 (m, 3H), 3.78 (dd, J=8.88, 4.75 Hz, 2H), 3.40 - 3.37 (m, 2H), 2.38 - 2.28 (m, 2H),2.34 (s, 3H), 2.15 - 2.05 (m, 1H), 1.90 - 1.81 (m, 1H), 1.66 - 1.50 (m, 2H),1.29 - 1.19 (m, 1H) Example S27: 3-(difluoromethyl)-N-[[(1R,3S)-3-[[5-(6-oxopyridazin-1-yl)-2-pyridyl] [Amino]cyclopentyl]methyl]isoxazole-5-carboxamide 1. General procedure for preparing N-[(1S,3R)-3-(benzyloxycarbonylaminomethyl)cyclopentyl]carbamate tert-butyl ester: At 0 °C, DIEA (6.03 g, 46.66 mmol, 8.13 mL, 2 equivalents) and CbzCl (4.78 g, 28.00 mmol, 3.98 mL, 1.2 equivalents) were added to a solution of N-[(1S,3R)-3-(aminomethyl)cyclopentyl]carbamate (5 g, 23.33 mmol, 1 equivalent) in DCM (50 mL). The mixture was stirred at 15 °C for 1 hour. The mixture was concentrated to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to give N-[(1S,3R)-3-(benzyloxycarbonylaminomethyl)cyclopentyl]carbamate (7.4 g, 21.24 mmol, 91.03% yield) as a white solid.

[0266] data: LCMS (ESI+): m / z 349.5 (M+H) + 2. General procedure for the preparation of N-[[(1R,3S)-3-aminocyclopentyl]methyl]carbamate: A mixture of N-[(1S,3R)-3-(benzyloxycarbonylaminomethyl)cyclopentyl]carbamate tert-butyl ester (7 g, 20.09 mmol, 1 equivalent) in HCl / EtOAc (100 mL, 4 M) was stirred at 15 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to give N-[[(1R,3S)-3-aminocyclopentyl]methyl]carbamate benzyl ester (7.5 g, crude product, HCl) as a white solid.

[0267] data: LCMS (ESI+): m / z 249.3 (M+H) + 3. General procedure for the preparation of N-[[(1R,3S)-3-[(5-iodo-2-pyridyl)amino]cyclopentyl]methyl]carbamate: K₂CO₃ (10.92 g, 79.01 mmol, 3 equivalents) was added to a solution of N-[[(1R,3S)-3-aminocyclopentyl]methyl]carbamate (7.5 g, 26.34 mmol, 1 equivalent, HCl) and 2-fluoro-5-iodopyridine (6.17 g, 27.65 mmol, 1.05 equivalents) in DMSO (75 mL). The mixture was stirred at 80 °C for 8 hours. LC-MS showed detection of the desired compound. The reaction mixture was partitioned between water (200 mL) and EtOAc (300 mL). The organic phase was separated, washed with brine (200 mL * 2), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 3 / 1) to give N-[[(1R,3S)-3-[(5-iodo-2-pyridyl)amino]cyclopentyl]methyl]carbamate (2.8 g, 6.20 mmol, 23.56% yield) as a yellow oil.

[0268] data: LCMS (ESI+): m / z 452.3 (M+H) + 4. General procedure for the preparation of N-[[(1R,3S)-3-[[5-(6-oxopyridazin-1-yl)-2-pyridyl]amino]cyclopentyl]methyl]carbamate: A mixture of N-[[(1R,3S)-3-[(5-iodo-2-pyridyl)amino]cyclopentyl]methyl]carbamate (1 g, 2.22 mmol, 1 equivalent), 1H-pyridazin-6-one (425.82 mg, 4.43 mmol, 2 equivalents), CuI (84.40 mg, 443.16 μmol, 0.2 equivalents), (2S)-pyrrolidine-2-carboxylic acid (51.02 mg, 443.16 μmol, 0.2 equivalents) and tripotassium phosphate (940.69 mg, 4.43 mmol, 2 equivalents) in DMSO (10 mL) was degassed and purged three times with N2. The mixture was then stirred at 80 °C for 12 hours under N2 atmosphere. The reaction mixture was partitioned between water (20 mL) and EtOAc (20 mL * 3). The organic phase was separated, washed with brine (40 mL * 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (alkaline conditions, column: Waters Xbridge Prep OBD C18 150*40mm*10μm; mobile phase: [water (NH3H2O+NH4HCO3)-ACN]; B%: 20%-50%, 8 min) to obtain N-[[(1R,3S)-3-[[5-(6-oxopyridazin-1-yl)-2-pyridyl]amino]cyclopentyl]methyl]carbamate (385 mg, 917.81 μmol, 41.42% yield), as a yellow gel.

[0269] data: LCMS (ESI+): m / z 420.2 (M+H) + 1H NMR (400 MHz, methanol-d4) δ = 8.13 (d, J = 2.4 Hz, 1H), 8.03 (dd, J =1.5, 3.9 Hz, 1H), 7.59 (dd, J = 2.6, 9.0 Hz, 1H), 7.46 (dd, J = 3.9, 9.5 Hz,1H), 7.37 - 7.32 (m, 4H), 7.32 - 7.27 (m, 1H), 7.06 (dd, J = 1.5, 9.5 Hz,1H), 6.57 (d, J = 8.9 Hz, 1H), 5.07 (s, 2H), 4.16 (quin, J = 7.3 Hz, 1H),3.14 (d, J = 7.1 Hz, 2H), 2.37 - 2.27 (m, 1H), 2.20 - 2.10 (m, 1H), 2.10 -2.03 (m, 1H), 1.86 - 1.76 (m, 1H), 1.62 - 1.52 (m, 1H), 1.52 - 1.42 (m, 1H),1.20 – 1.10 (m, 1H) 5. General procedure for the preparation of 2-[6-[[(1S,3R)-3-(aminomethyl)cyclopentyl]amino]-3-pyridyl]pyridazin-3-one: HBr (0.8 mL, 33% purity) was added to a solution of N-[[(1R,3S)-3-[[5-(6-oxopyridazin-1-yl)-2-pyridyl]amino]cyclopentyl]methyl]carbamate (370 mg, 882.05 μmol, 1 equivalent) in AcOH (4 mL). The mixture was stirred at 15 °C for 2.5 h. The reaction solution was filtered, the filter cake was collected and dried under reduced pressure to remove AcOH and HBr, yielding 2-[6-[[(1S,3R)-3-(aminomethyl)cyclopentyl]amino]-3-pyridyl]pyridazin-3-one (540 mg, crude, HBr), as a brown solid.

[0270] data: LCMS (ESI+): m / z 286.6 (M+H) + 6. General procedure for the preparation of 3-(difluoromethyl)-N-[[(1R,3S)-3-[[5-(6-oxopyridazin-1-yl)-2-pyridyl]amino]cyclopentyl]methyl]isoxazole-5-carboxamide: At 0 °C, DIEA (158.50 mg, 1.23 mmol, 213.61 μL, 4 equivalents) was added to a solution of 3-(difluoromethyl)isoxazol-5-carboxylic acid (50 mg, 306.60 μmol, 1 equivalent, HBr) in DMF (1 mL), followed by dropwise addition of HATU (174.87 mg, 459.90 μmol, 1.5 equivalents). The resulting mixture was stirred at 15 °C for 8 hours. MeOH (2 mL) was added to the mixture without further treatment. The residue was purified by preparative HPLC (alkaline conditions, column: Waters Xbridge Prep OBD C18 150*40mm*10μm; mobile phase: [water(NH3H2O+NH4HCO3)-ACN]; B%: 20%-50%, 8 min) to give 3-(difluoromethyl)-N-[[(1R,3S)-3-[[5-(6-oxopyridazin-1-yl)-2-pyridyl]amino]cyclopentyl]methyl]isoxazole-5-carboxamide (16.9 mg, 38.66 μmol, 12.61% yield, 98.467% purity), as a yellow solid.

[0271] data: LCMS (ESI+): m / z 431.1 (M+H) + 1 H NMR (400 MHz, methanol-d4) δ = 8.14 (d, J = 2.5 Hz, 1H), 8.03 (dd, J =1.6, 3.8 Hz, 1H), 7.59 (dd, J = 2.6, 9.0 Hz, 1H), 7.46 (dd, J = 3.9, 9.4 Hz,1H), 7.18 - 7.15 (m, 1H), 7.10 - 7.03 (m, 2H), 6.58 (d, J = 9.0 Hz, 1H), 4.23- 4.13 (m, 1H), 3.42 (dd, J = 1.7, 6.8 Hz, 2H), 2.40 - 2.30 (m, 2H), 2.16 -2.06 (m, 1H), 1.93 - 1.83 (m, 1H), 1.67 - 1.50 (m, 2H), 1.37 - 1.21 (m, 1H) Example S28: N-[[(1R,3S)-3-[[5-[3-(methoxymethyl)-6-oxo-pyridazin-1-yl]-2-pyridine [3-methyl-isoxazole-5-carboxamide] 1. General procedure for preparing 3-methoxy-6-(methoxymethyl)pyridazine: Under a nitrogen atmosphere, at 0 °C, NaH (111.32 mg, 2.78 mmol, 60% purity, 1.3 equivalents) was added to a solution of (6-methoxypyridazine-3-yl)methanol (300 mg, 2.14 mmol, 1 equivalent) in THF (10 mL). After stirring for 30 min, MeI (607.70 mg, 4.28 mmol, 266.54 μL, 2 equivalents) was added, and the reaction was stirred at 15 °C for 1 h. The reaction was quenched by adding MeOH (5 mL), and the solution was then concentrated to give a residue. The residue was purified by preparative TLC (SiO2, petroleum ether / ethyl acetate = 1 / 2) to give 3-methoxy-6-(methoxymethyl)pyridazine (260 mg, 1.69 mmol, 78.78% yield) as an orange oil.

[0272] data: LCMS (ESI + ): m / z 155.1 (M+H) + 2. General procedure for the preparation of 6-(methoxymethyl)pyridazine-3-ol: HBr (1.03 g, 4.22 mmol, 693.79 μL, 33% purity, 2.5 equivalence) was added to a solution of 3-methoxy-6-(methoxymethyl)pyridazine (260 mg, 1.69 mmol, 1 equivalent) in THF (6 mL), and the reaction was stirred at 30 °C for 12 h. The reaction was quenched with NH3·H2O (0.1 mL) and concentrated to give a residue. The residue was purified by preparative HPLC (neutral conditions; column: Waters Xbridge Prep OBD C18 150*40mm*10um; mobile phase: [water (NH4HCO3)-ACN]; B%: 1%-15%, 8 min) to give 6-(methoxymethyl)pyridazine-3-ol (180 mg, 1.28 mmol, 76.16% yield) as a white solid.

[0273] data: LCMS (ESI + ): m / z 141.2 (M+H) + 3. General procedure for the preparation of N-[[(1R,3S)-3-[[5-[3-(methoxymethyl)-6-oxo-pyridazin-1-yl]-2-pyridyl]amino]cyclopentyl]methyl]-3-methyl-isoxazole-5-carboxamide: A mixture of 6-(methoxymethyl)pyridazine-3-ol (180 mg, 1.28 mmol, 1 equivalent), N-[[(1R,3S)-3-[(5-iodo-2-pyridyl)amino]cyclopentyl]methyl]-3-methyl-isoxazole-5-carboxamide (547.49 mg, 1.28 mmol, 1 equivalent), K3PO4 (545.29 mg, 2.57 mmol, 2 equivalents), CuI (24.46 mg, 128.44 µmol, 0.1 equivalent), and (2S)-pyrrolidine-2-carboxylic acid (14.79 mg, 128.44 µmol, 0.1 equivalent) in DMSO (4 mL) was degassed and purged three times with N2. The mixture was then stirred at 80 °C for 12 hours under N2 atmosphere. The reaction mixture was quenched by adding water (10 mL) and extracted with EtOAc (10 mL * 3). The combined organic layers were washed with brine (20 mL * 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (alkaline conditions; column: Waters Xbridge Prep OBD C18 150*40mm*10um; mobile phase: [water (NH3H2O+NH4HCO3)-ACN]; B%: 15%-45%, 8 min) to obtain N-[[(1R,3S)-3-[[5-[3-(methoxymethyl)-6-oxo-pyridazin-1-yl]-2-pyridyl]amino]cyclopentyl]methyl]-3-methyl-isoxazole-5-carboxamide (27.1 mg, 60.65 µmol, 4.72% yield, 98.137% purity), as a pale yellow solid.

[0274] data: LCMS (ESI + ): m / z 439.2 (M+H) + 1 ¹H NMR (400 MHz, methanol-d⁴) δ = 8.13 (br s, 1H), 7.60 - 7.54 (m, 2H), 7.07 (d, 1H) J = 9.5 Hz, 1H), 6.80 (s, 1H), 6.58 (d, J= 9.0 Hz, 1H), 4.40 (s, 2H),4.24 - 4.14 (m, 1H), 3.43 (s, 3H), 3.42 - 3.38 (d, 2H), 2.38 - 2.28 (m, 2H),2.34 (s, 3H), 2.13 – 2.04 (m, 1H), 1.90 – 1.80 (m, 1H), 1.67 – 1.48 (m, 2H), 1.30 – 1.20 (m, 1H) Example S29: N-[[(1R,3S)-3-[[5-[3-(azacyclobutane-1-yl)-6-oxo-pyridazin-1-yl]-2- [pyridyl]amino]cyclopentyl]methyl]-3-methyl-isoxazole-5-carboxamide 1. General procedure for the preparation of 3-(azacyclobutan-1-yl)-1H-pyridazin-6-one: A mixture of 3-bromo-1H-pyridazin-6-one (500 mg, 2.86 mmol, 1 equivalent), azacyclobutane hydrochloride (400.99 mg, 4.29 mmol, 1.5 equivalent), tBuONa (823.82 mg, 8.58 mmol, 3 equivalent), tBuXPhos Pd G3 (226.98 mg, 286.00 µmol, 0.1 equivalent), and di-tert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphine (121.34 mg, 286.00 µmol, 0.1 equivalent) in t-AmylOH (10 mL) was degassed and purged three times with N2. The mixture was then stirred at 80 °C for 12 hours under N2 atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to remove most of the solvent. The mixture was purified by preparative HPLC (alkaline conditions: P1: RT = 0.44 min, column: Waters Xbridge Prep OBD C18 150*40mm*10um; mobile phase: [water (NH3H2O+NH4HCO3)-ACN]; B%: 1%-20%, 8 min) to give 3-(azacyclobutan-1-yl)-1H-pyridazin-6-one (94 mg, 621.84 µmol, 21.74% yield) as a white solid.

[0275] 2. General procedure for the preparation of N-[[(1R,3S)-3-[[5-[3-(azacyclobutan-1-yl)-6-oxo-pyridazin-1-yl]-2-pyridinyl]amino]cyclopentyl]methyl]-3-methyl-isoxazole-5-carboxamide: A mixture of [6-[[(1S,3R)-3-[[(3-methylisoxazol-5-carbonyl)amino]methyl]cyclopentyl]amino]-3-pyridyl]boronic acid (30 mg, 87.17 µmol, 1 equivalent), 3-(azacyclobutan-1-yl)-1H-pyridazin-6-one (13.18 mg, 87.17 µmol, 1 equivalent), pyridine (13.79 mg, 174.33 µmol, 14.07 uL, 2 equivalent) and Cu(OAc)₂ (15.83 mg, 87.17 µmol, 1 equivalent) in DMF (2 mL) was degassed and purged three times with O₂. The mixture was then stirred at 90 °C for 2 hours under an O₂ (15 psi) atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give the residue. The residue was purified by preparative HPLC (alkaline conditions; column: Phenomenex C18 75*30mm*3µm; mobile phase: [water(NH3H2O+NH4HCO3)-ACN]; B%: 30%-60%, 8 min) to obtain N-[[(1R,3S)-3-[[5-[3-(azacyclobutan-1-yl)-6-oxo-pyridazin-1-yl]-2-pyridinyl]amino]cyclopentyl]methyl]-3-methyl-isoxazole-5-carboxamide (26.2 mg, 58.29 µmol, 33.43% yield, 100% purity), as a yellow solid.

[0276] data: LCMS (ESI + ): m / z 450.3 (M+H) + 1 H NMR (400 MHz, methanol-d4) δ = 8.16 (br s, 1H), 7.60 (dd, J = 2.5, 9.0Hz, 1H), 7.09 (d, J = 9.8 Hz, 1H), 6.93 (d, J = 9.8 Hz, 1H), 6.80 (s, 1H), 6.57 (br d, J = 9.0 Hz, 1H), 4.22 - 4.12 (m, 1H), 4.01 (t, J = 7.4 Hz, 4H), 3.39 (br d, J = 6.6 Hz, 2H), 2.45 - 2.28 (m, 4H), 2.34 (s, 3H), 2.13 - 2.05(m, 1H), 1.90 - 1.80 (m, 1H), 1.65 - 1.48 (m, 2H), 1.30 - 1.18 (m, 1H) Examples S30 and S31: Example S30: N-[[(1R,3S)-3-[[5-[3-(hydroxymethyl)-6-oxo-pyridazin-1-yl]-2-pyridyl]amino]cyclopentyl]methyl]-3-methyl-isoxazole-5-carboxamide 1. General procedure for preparing [6-[[(1S,3R)-3-[[(3-methylisoxazol-5-carbonyl)amino]methyl]cyclopentyl]amino]-3-pyridyl]boronic acid: To a solution of N-[[(1R,3S)-3-aminocyclopentyl]methyl]-3-methyl-isoxazole-5-carboxamide (3 g, 11.55 mmol, 1 equivalent, HCl) in DMSO (60 mL), K₂CO₃ (4.79 g, 34.65 mmol, 3 equivalents) and 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)pyridine (3.09 g, 13.86 mmol, 1.2 equivalents) were added. The mixture was stirred at 90 °C for 12 hours. The mixture was filtered, and the filtrate was purified by preparative HPLC (alkaline conditions; column: Ultimate C18 10u 250mm*80mm; mobile phase: [water(NH3H2O+NH4HCO3)-ACN]; B%: 0%-35%, 30min) to obtain [6-[[(1S,3R)-3-[[(3-methylisoxazole-5-carbonyl)amino]methyl]cyclopentyl]amino]-3-pyridyl]boronic acid (410 mg, 1.19 mmol, 10.31% yield) as a yellow solid.

[0277] data: LCMS (ESI + ): m / z 345.1 (M+H) + 2. General procedure for the preparation of methyl 1-[6-[[(1S,3R)-3-[[(3-methylisoxazol-5-carbonyl)amino]methyl]cyclopentyl]amino]-3-pyridyl]-6-oxo-pyridazine-3-carboxylic acid: A mixture of [6-[[(1S,3R)-3-[[(3-methylisoxazol-5-carbonyl)amino]methyl]cyclopentyl]amino]-3-pyridyl]boronic acid (120 mg, 348.66 µmol, 1 equivalent), methyl 6-oxo-1H-pyridazine-3-carboxylate (64.48 mg, 418.39 µmol, 1.2 equivalent), Cu(OAc)₂ (63.33 mg, 348.66 µmol, 1 equivalent), and pyridine (55.16 mg, 697.32 µmol, 56.28 μL, 2 equivalent) in DMF (3 mL) was degassed and purged three times with O₂. The mixture was then stirred at 90 °C for 1 hour under an O₂ atmosphere (15 psi). The mixture was filtered and the filtrate was concentrated to give a green solid. The green solid was ground with petroleum ether / EtOAc (5 mL, 1:1) for 5 minutes at 15 °C. The mixture was then filtered and the filter cake was dried to give methyl 1-[6-[[(1S,3R)-3-[[(3-methylisoxazol-5-carbonyl)amino]methyl]cyclopentyl]amino]-3-pyridyl]-6-oxo-pyridazine-3-carboxylate (270 mg, 596.73 µmol, 85.57% yield), a yellow solid, which was used directly without purification.

[0278] data: LCMS (ESI + ): m / z 453.2 (M+H) + 3. General procedure for the preparation of N-[[(1R,3S)-3-[[5-[3-(hydroxymethyl)-6-oxo-pyridazin-1-yl]-2-pyridyl]amino]cyclopentyl]methyl]-3-methyl-isoxazole-5-carboxamide: At 0 °C, NaBH4 (15.05 mg, 397.82 µmol, 3 equivalents) was carefully added to a solution of methyl 1-[6-[[(1S,3R)-3-[[(3-methylisoxazol-5-carbonyl)amino]methyl]cyclopentyl]amino]-3-pyridyl]-6-oxo-pyridazine-3-carboxylate (60 mg, 132.61 µmol, 1 equivalent) in MeOH (2 mL). The reaction mixture was then stirred at 0 °C for 1 h and at 15 °C for 12 h. The mixture was then stirred at 30 °C for 12 h. The reaction mixture was quenched by adding 1 M HCl aqueous solution and extracted with EtOAc (5 mL * 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a crude product. This crude product was purified by preparative HPLC (alkaline conditions; column: Waters Xbridge Prep OBDC18 150*40mm*10um; mobile phase: [water(NH3H2O+NH4HCO3)-ACN]; B%: 10%-40%, 8 min) to obtain N-[[(1R,3S)-3-[[5-[3-(hydroxymethyl)-6-oxo-pyridazin-1-yl]-2-pyridyl]amino]cyclopentyl]methyl]-3-methyl-isoxazole-5-carboxamide (5.5 mg, 12.96 µmol, 9.77% yield, 100% purity), as a yellow solid.

[0279] data: LCMS (ESI + ): m / z 425.1 (M+H) + 1 H NMR (400 MHz, methanol-d4) δ = 8.13 (br s, 1H), 7.60 (br t, J = 9.7 Hz, 2H), 7.08 (br d, J = 9.6 Hz, 1H), 6.80 (s, 1H), 6.58 (br d, J = 9.0 Hz, 1H),4.53 (s, 2H), 4.23 - 4.13 (m, 1H), 3.40 (br d, J = 6.3 Hz, 2H), 2.42 - 2.26(m, 2H), 2.34 (s, 3H), 2.13 - 2.05 (m, 1H), 1.90 – 1.80 (m, 1H), 1.65 - 1.49(m, 2H), 1.30 - 1.20 (m, 1H) Example S31: 3-Methyl-N-[[(1R,3S)-3-[[5-[3-(methylcarbamoyl)-6-oxo-pyridazine-1- [2-pyridyl]amino]cyclopentyl]methyl]isoxazole-5-carboxamide 1. General procedure for the preparation of 3-methyl-N-[[(1R,3S)-3-[[5-[3-(methylcarbamoyl)-6-oxo-pyridazin-1-yl]-2-pyridyl]amino]cyclopentyl]methyl]isoxazole-5-carboxamide: A solution of methylamine hydrochloride (11.94 mg, 176.81 µmol, 4 equivalents) and K₂CO₃ (48.87 mg, 353.62 µmol, 8 equivalents) in EtOH (2 mL) was stirred for 0.5 h at 15 °C. The mixture was then filtered, and methyl 1-[6-[[(1S,3R)-3-[[(3-methylisoxazol-5-carbonyl)amino]methyl]cyclopentyl]amino]-3-pyridyl]-6-oxo-pyridazine-3-carboxylate (20 mg, 44.20 µmol, 1 equivalent) was added to the filtrate. The reaction was then stirred at 80 °C for 12 h. LCMS showed detection of the desired substance. The mixture was filtered, and the filtrate was purified by preparative HPLC (alkaline conditions; column: Waters Xbridge Prep OBD C18 150*40mm*10um; mobile phase: [water(NH3H2O+NH4HCO3)-ACN]; B%: 10%-45%, 8 min) to give 3-methyl-N-[[(1R,3S)-3-[[5-[3-(methylcarbamoyl)-6-oxo-pyridazin-1-yl]-2-pyridyl]amino]cyclopentyl]methyl]isoxazole-5-carboxamide (13.5 mg, 29.90 µmol, 67.65% yield, 100% purity), as a yellow solid.

[0280] LCMS (ESI + ): m / z 452.1 (M+H) + 1H NMR (400 MHz, methanol-d4) δ = 8.21 (d, J = 2.1 Hz, 1H), 8.01 (d, J =9.6 Hz, 1H), 7.67 (dd, J = 2.6, 9.1 Hz, 1H), 7.13 (d, J = 9.8 Hz, 1H), 6.80(s, 1H), 6.61 (d, J = 9.0 Hz, 1H), 4.24 - 4.15 (m, 1H), 3.40 (br d, J = 6.8Hz, 2H), 2.89 (s, 3H), 2.39 - 2.30 (m, 2H), 2.34 (s, 3H), 2.15 – 2.05 (m,1H), 1.90 – 1.80 (m, 1H), 1.67 - 1.52 (m, 2H), 1.35 - 1.23 (m, 1H) Example S32: N-[[(1R,3S)-3-[[5-[3-(3-cyanoazonobutane-1-yl)-6-oxo-pyridazine-1- [2-pyridyl]amino]cyclopentyl]methyl]-3-methylisoxazole-5-carboxamide 1. General procedure for the preparation of 1-(6-chloropyridazine-3-yl)azacyclobutane-3-carboxylonitrile: To a solution of 3,6-dichloropyridazine (493.32 mg, 3.31 mmol, 1 equivalent) in DMF (10 mL), K₂CO₃ (1.37 g, 9.93 mmol, 3 equivalents) and aziridine-3-carboxynitrile (471.14 mg, 3.97 mmol, 1.2 equivalents, HCl) were added. The mixture was then heated at 80 °C. o The mixture was stirred at C for 12 hours. The mixture was diluted with water (10 mL) and then extracted with EtOAc (10 mL * 3). The combined organic layers were washed with a saturated aqueous solution of NaCl (10 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (SiO₂, petroleum ether:ethyl acetate = 1:1) to give 1-(6-chloropyridazine-3-yl)azacyclobutane-3-carboxynitrile (300 mg, 1.54 mmol, 46.55% yield) as a yellow solid.

[0281] data: LCMS (ESI + ): m / z 197.2 (M+H) + 2. General procedure for the preparation of 1-(6-oxo-1H-pyridazin-3-yl)azacyclobutane-3-carboxylonitrile: KOAc (124.77 mg, 1.27 mmol, 1 equivalent) was added to a solution of 1-(6-chloropyridazin-3-yl)azacyclobutane-3-carboxynitrile (247.44 mg, 1.27 mmol, 1 equivalent) in AcOH (3 mL). The mixture was stirred at 120 °C for 12 h. The mixture was diluted with water (10 mL) and saturated NaCl aqueous solution (10 mL), and then extracted with EtOAc (10 mL * 3). The combined organic layers were washed with saturated NaCl aqueous solution (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (SiO2, ethyl acetate:methanol = 3:1) to give 1-(6-oxo-1H-pyridazin-3-yl)azacyclobutane-3-carboxynitrile (70 mg, 397.33 µmol, 31.25% yield) as a yellow solid.

[0282] data: LCMS (ESI + ): m / z 177.2 (M+H) + 3. General procedure for the preparation of N-[[(1R,3S)-3-[[5-[3-(3-cyanozylate-1-yl)-6-oxo-pyridazin-1-yl]-2-pyridinyl]amino]cyclopentyl]methyl]-3-methylisoxazole-5-carboxamide: The mixture of [6-[[(1S,3R)-3-[[(3-methylisoxazol-5-carbonyl)amino]methyl]cyclopentyl]amino]-3-pyridyl]boronic acid (60 mg, 174.33 µmol, 1 equivalent), 1-(6-oxo-1H-pyridazin-3-yl)azacyclobutane-3-carboxylonitrile (36.86 mg, 209.20 µmol, 1.2 equivalent), Cu(OAc)2 (31.66 mg, 174.33 µmol, 1 equivalent), and pyridine (2.30 mg, 29.06 µmol, 2.35 uL, 2 equivalent) in DMF (1 mL) was degassed and purged three times with O2. The mixture was then stirred at 90 °C for 2 hours under an O2 atmosphere (15 psi). The mixture was filtered and the filtrate was purified by preparative HPLC (alkaline conditions: Waters Xbridge Prep OBD C18 150*40mm*10um; mobile phase: [water(NH3H2O+NH4HCO3)-ACN]; B%: 20%-50%, 8 min) to obtain N-[[(1R,3S)-3-[[5-[3-(3-cyanozylate-1-yl)-6-oxo-pyridazin-1-yl]-2-pyridinyl]amino]cyclopentyl]methyl]-3-methylisoxazole-5-carboxamide (27.5 mg, 57.95 µmol, 33.24% yield, 100% purity), as a yellow solid.

[0283] data: LCMS (ESI + ): m / z 475.1 (M+H) + 1H NMR (400 MHz, methanol-d4) δ ppm 8.15 (d, J=2.25 Hz, 1H), 7.60 (dd, J=9.07, 2.56 Hz, 1H), 7.14 (d, J=9.76 Hz, 1H), 6.98 (d, J=9.63 Hz, 1H), 6.80(s, 1H), 6.56 (d, J=9.01 Hz, 1H), 4.31 - 4.25 (m, 2H), 4.20 - 4.13 (m, 3H), 3.78 - 3.72 (m, 1H), 3.39 (d, J=6.63 Hz, 2H), 2.37 - 2.26 (m, 2H), 2.34 (s,3H), 2.13 - 2.05 (m, 1H), 1.90 - 1.80 (m, 1H), 1.65 - 1.50 (m, 2H) 1.30 -1.20 (m, 1H) Equivalence and incorporation by reference While aspects of this disclosure have been shown and described with particular reference to certain embodiments and various alternative embodiments, those skilled in the art will understand that various changes in form and detail may be made therein without departing from the spirit and scope of this disclosure.

[0284] All references cited in the text of this specification are incorporated herein by reference in their entirety for all purposes. Specifically, European Patent Application No. 23193545.3, filed on August 25, 2023, is incorporated herein by reference in its entirety.

[0285] References

Claims

1. A compound according to formula (I): Formula (I) Or its tautomers, enantiomers or diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof; wherein R 1 It is an H, C1-C5 alkyl or C3-C5 cycloalkyl, each optionally being substituented by one or more identical or different R groups. X1 Replace; where each R X1 It is halogen; Z is a heteroaryrotic ring, selected from: , , , , , and ; A is a heterocyclic aromatic ring; R 2 It is H, C1-C3 alkyl, amide, or sulfonamide, each optionally being substituent R by one or more identical or different substituents. X2 Replace; where each R X2 It is a –C1-C3 alkyl or C1-C3 alkoxy; X A It does not exist; it is either carbonyl or sulfone. R A It is absent, or is a 3- to 6-membered heterocycle or heteroaryl, wherein each of the 3- to 6-membered heterocycles or heteroaryl groups is optionally replaced by one or more identical or different substituents R. 3 replace; R 3 It is an H, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, -CN, -OH, =O, amide, or 3 to 6-membered heterocycle, each optionally substituent R by one or more identical or different substituents. X3 Replace; or R 3 It is -NH-R X3 ;where R X3 It is -OH, -OCH3, -CN, C3-C5 cycloalkyl, halogen, C1-C3 alkoxy, or amide; The attached conditions are: a) When Z is or When, then A according to , where R A and X A At least one of them is not missing; or b) When Z is or When, then A according to .

2. The compound according to claim 1, wherein the compound is based on formula (Ia) or formula (Ib): Formula (Ia) Formula (Ib).

3. The compound according to any one of claims 1 to 2, wherein Z is selected from: , , , , and .

4. The compound according to any one of claims 1 to 3, wherein Z is selected from: , and .

5. The compound according to any one of claims 1 to 4, wherein Z is .

6. The compound according to any one of claims 1 to 5, wherein the compound is based on formula II: Equation (II).

7. The compound according to any one of claims 1 to 6, wherein the compound is according to formula (IIIa) or (IIIb): Formula (IIIa) Equation (IIIb), in X A Does not exist, is or ; R A It is absent, or is a 3- to 6-membered heterocycle or heteroaryl, wherein the 3- to 6-membered heterocycle and heteroaryl are each optionally replaced by one or more identical or different substituents R. 3 replace; R 3 The group is selected from H, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, -CN, -OH, =O, amide and 3 to 6 membered heterocycles, each of which is optionally substituent R by one or more identical or different substituents. X3 Replace; or R 3 It is -NH-R x3 ;where R X3 It is a group selected from -OH, -OCH3, -CN, C3-C5 cycloalkyl and halogens.

8. The compound according to claim 7, wherein X A It does not exist, R A It does not exist, and R 2 It is an N-linked amide or sulfonamide.

9. The compound according to any one of claims 7 or 8, wherein X A It does not exist, R A It does not exist, and R 2 It is a C-linked amide or an S-linked sulfonamide.

10. The compound according to any one of claims 7 to 9, wherein X A It does not exist, R A It does not exist, and R 2 Selected from: , , , , and ;where R X2 It is a –C1-C3 alkyl group.

11. The compound according to any one of claims 7 to 10, wherein R X2 It is –CH3.

12. The compound according to any one of claims 1 to 6, wherein the compound is according to formula (IV) Formula (IV), in X A Does not exist, is or ; B is a 3- to 6-membered heterocyclic ring; and R 3B Selected from H, -OH and C1-C3 alkyl groups.

13. The compound according to claim 12, wherein X A yes or .

14. The compound according to claim 12, wherein X A It does not exist.

15. The compound according to any one of claims 12 to 14, wherein ring B is selected from: , , and .

16. The compound according to any one of claims 12 to 15, wherein R 3B Yes, it's -H.

17. The compound according to any one of claims 12 to 15, wherein R 3B It is –OH.

18. The compound according to any one of claims 12 to 15, wherein Selected from: , , and .

19. The compound according to any one of claims 1 to 6, wherein the compound is according to formula (V): Formula (V) in Selected from , , and ; R 3C The group is selected from H, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, -CN, amide, and 3 to 6-membered heterocycles, each of which is optionally substituent R by one or more identical or different substituents. X3 Replace; or R 3C It is -NH-R X3 ;where R X3 It is a group selected from -OH, -OCH3, -CN, C1-C3 alkyl, C3-C5 cycloalkyl and halogens.

20. The compound according to claim 19, wherein R 3C It's H.

21. The compound according to claim 19, wherein R 3C It is a C1-C3 alkyl group.

22. The compound according to claim 19, wherein R 3C It is a C1-C3 haloalkyl group.

23. The compound according to claim 19, wherein R 3C It is a C1-C3 alkoxy group.

24. The compound according to claim 19, wherein R 3C Yes –CN.

25. The compound according to claim 19, wherein R 3C It is -CH2-O-CH3.

26. The compound according to claim 19, wherein R 3C It's -O-CH3.

27. The compound according to any one of claims 1 to 6 and 19, wherein the compound is based on formula Va: Expression(Va) in R 3C The group is selected from H, C1-C3 alkyl, C1-C3 haloalkyl, -CN, amide, 3 to 6-membered heterocycles, each of which is optionally substituent R by one or more identical or different substituents. X3 Replace; or R 3C It is -NH-R X3 ;where R X3 It is a group selected from -OH, -OCH3, -CN, C1-C5 cycloalkyl and halogens.

28. The compound according to claim 27, wherein R 3C It is H, C1-C3 alkyl, C1-C3 haloalkyl, or -CN, each of which is optionally substituent R by one or more identical or different substituents. X3 Replace; where R X3 It is a group selected from -OH, -OCH3, -CN, C1-C5 cycloalkyl and halogens.

29. The compound according to claim 27, wherein R 3C Yes –H.

30. The compound according to claim 27, wherein R 3C Not H.

31. The compound according to claim 27, wherein R 3C It is a –C1-C3 alkyl group.

32. The compound according to claim 27, wherein R 3C It is –CH2-O-CH3.

33. The compound according to claim 27, wherein R 3C It is –CH2-OH.

34. The compound according to claim 27, wherein R 3C It is a C1-C3 haloalkyl group.

35. The compound according to claim 27, wherein R 3C Yes –CF3.

36. The compound according to claim 27, wherein R 3C It is -C(=O)NR L1 R L2 , where R L1 and R L2 Each is independently selected from H or C1-C3 alkyl groups.

37. The compound according to any one of claims 27 or 36, wherein R 3C It is -C(=O)NH-CH3.

38. The compound according to claim 27, wherein R 3C It is a 3- to 6-membered heterocycle, such as a 3, 4, 5 or 6-membered heterocycle.

39. The compound according to claim 27 or 38, wherein R 3C yes ,in n is 0, 1, or 2; R X3a Each is independently selected from H, -CN, -OH, -OCH3, and -F.

40. The compound according to claim 39, wherein n is 0.

41. The compound according to claim 39, wherein n is 1 or 2.

42. The compound according to claim 39, wherein R X3a Yes –CN.

43. The compound of claim 39, wherein one or more R X3a Yes –F.

44. The compound according to claim 39, wherein R X3a It is -OH.

45. The compound according to claim 39, wherein R X3a It is -OCH3.

46. ​​The compound according to any one of claims 1 to 45, wherein R 1 Selected from –CH3, -CH2-CH3 and CF2H.

47. The compound according to any one of claims 1 to 45, wherein R 1 It is -CH3.

48. The compound according to any one of claims 1 to 45, wherein R 1 It is -CH2-CH3.

49. The compound according to any one of claims 1 to 45, wherein R 1 Yes, it's -H.

50. The compound according to any one of claims 1 to 45, wherein R 1 Yes, it is –CF2H.

51. The compound according to any one of claims 1 to 45, wherein R 1 It is a C3-C5 cycloalkyl group.

52. The compound according to any one of claims 1 to 45, wherein R 1 It is cyclopropyl.

53. The compound according to any one of claims 1 to 52, wherein R 2 Is it –H or –CH? 3。 54. The compound according to any one of claims 1 to 52, wherein R 2 Yes –H.

55. The compound according to any one of claims 1 to 52, wherein R 2 It is –CH3.

56. The compound according to any one of claims 1 to 55, wherein in formulas (I), (II), (III) and (IV), the substituents on the carbons at positions 1 and 2 are in a cis relationship.

57. The compound according to any one of claims 1 to 55, wherein the carbon at position 1 has a configuration of R and the carbon at position 2 has a configuration of S.

58. The compound according to any one of claims 1 to 55, wherein the compound is selected from the compounds shown in Table A of the subsection "A Compound", its enantiomers, mixtures thereof or pharmaceutically acceptable salts thereof.

59. The compound according to any one of the preceding claims, wherein the compound is capable of modulating the activity of PCSK9.

60. The compound according to any one of the preceding claims, wherein the compound is an inhibitor of PCSK9.

61. The compound according to any one of the preceding claims, wherein the compound is capable of reducing the activity of PCSK9.

62. The compound according to any one of the preceding claims, wherein the compound has a dissociation constant (Ki) of less than 20 µM, such as less than 5 µM, such as less than 1 µM, such as less than 0.5 µM, such as less than 0.05 µM, such as less than 0.01 µM. D Combined with PCSK9.

63. The compound according to any one of the preceding claims, wherein the compound has a dissociation constant (Ki) of about 1 nM to about 20 µM, such as about 1 nM to about 10 µM, such as about 1 nM to about 1 µM, such as about 1 nM to about 0.5 µM, such as 1 nM to about 200 nM, such as about 1 nM to about 100 nM, such as about 1 nM to about 50 nM. D Combined with PCSK9.

64. A pharmaceutical composition comprising a compound according to any one of the preceding claims.

65. The compound according to any one of claims 1 to 63, or the pharmaceutical composition according to claim 64, used as a medicament.

66. A method for modulating the activity of PCSK9 in a subject using a compound according to any one of claims 1 to 63, or a pharmaceutical composition according to claim 64, the method comprising administering an effective amount of the compound to the subject.

67. A method of using the compound according to any one of claims 1 to 63, or the pharmaceutical composition according to claim 66, for treating, preventing, or alleviating lipoprotein metabolism disorders in a subject, the method comprising administering an effective amount of the compound to the subject.

68. The compound or composition used according to claim 67, wherein the condition is a lipoprotein metabolism disorder, wherein the condition is selected from dyslipidemia, hypercholesterolemia, and coronary heart disease.

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