Substitutive 4-([1,2,4]triazolo[1,5-a]pyridine-6-yl)thiophene-2-carboxamide derivatives and their use

Abstract

Provided herein are 4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)thiophene-2-carboxamide and 4-([1,2,4]triazolo[1,5-a]]pyridin-7-yl)thiophene-2-carboxamide derivatives. Such compounds are useful for treating and / or preventing neurodegenerative diseases or disorders, such as, for example, ophthalmological neurodegenerative diseases. The present disclosure also provides compositions comprising such compounds, as well as methods of using and making such compounds.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority under U.S. Provisional Patent Application No. 63 / 091,039, filed on 13 October 2020, the entirety of which is incorporated herein by reference.

[0002] This application relates to 4-([1,2,4]triazolo[1,5-a]pyridine-6-yl)thiophene-2-carboxamide derivatives, methods for producing the same, their use alone or in combination in the treatment and / or prevention of diseases, and their use for the manufacture of pharmaceuticals for the treatment and / or prevention of neurodegenerative diseases such as ophthalmic neurodegenerative diseases. Such therapeutic agents can be used as monotherapy or in combination with other agents or further therapeutic means. [Background technology]

[0003] Neuronal cell death in response to axonal injury is a key feature of many neurodegenerative diseases. For example, the atrophic (shriveled) form of age-related macular degeneration (AMD) is a potentially blinding neurodegenerative disease affecting millions worldwide, for which there is no proven or approved treatment. Another example is glaucoma, a neurodegenerative disease affecting millions of people, damaging the optic nerve, and a leading cause of vision loss and blindness worldwide. While elevated intraocular pressure (IOP) is a significant risk factor for retinal ganglion cell (RGC) damage and optic nerve damage, lowering IOP can be difficult in some patients, and RGC damage persists even after IOP reduction. Therefore, the development of effective neuroprotective techniques may complement IOP reduction by mitigating RGC injury, damage, and cell loss. Further examples of neurodegenerative diseases of the eye include retinitis pigmentosa (RP) and related retinal degenerations, which comprise a group of diseases characterized by degeneration of photoreceptor and retinal pigment epithelial (RPE) cells. Since vision loss due to AMD, glaucoma, and RP-like diseases is irreversible once it occurs, it is essential to develop better treatments for these diseases to prevent vision loss. Similarly, there is a need to develop better and safer treatments for many other forms of neurodegenerative diseases for which there are currently no available treatments or only inadequate treatments. [Overview of the project] [Means for solving the problem]

[0004] In one embodiment, the compound of formula (Z) is used herein: [ka] [In the formula, R C , R D , R E , R G , R H [Z, X, and Y are as defined elsewhere in this specification] are disclosed.

[0005] This specification also provides pharmaceutical compositions comprising a compound described herein or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0006] This specification also provides a method for treating a target neurodegenerative disease, comprising administering to a target an effective amount of a compound or pharmaceutical composition described herein.

[0007] This specification also provides a method for treating a subject optic neuropathy, comprising administering to the subject an effective amount of the compound or pharmaceutical composition described herein.

[0008] This specification also provides a method for inhibiting DLK and / or LZK activity in mammalian cells, comprising contacting the mammalian cells with a compound described herein or a pharmaceutically acceptable salt thereof.

[0009] Details of one or more embodiments of this disclosure are described in the accompanying drawings and the following description. Other features, purposes, and advantages of this disclosure will become apparent from the description and drawings, as well as the claims.

[0010] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art to which this disclosure pertains. While methods and materials for use in this disclosure are described herein, other suitable methods and materials well known in the art may also be used. These materials, methods, and examples are illustrative and not intended to be limiting. All publications, patent applications, patents, sequences, database values, and other references referenced herein are to be used by reference in their entirety. In case of any conflict, this specification, including definitions, shall prevail. [Brief explanation of the drawing]

[0011] [Figure 1]DLK, LZK, optic ganglion cell viability assays, and PK data for compounds 4, 19, 94, and 112 are shown. [Figure 2] The in silico ADMET, molecular properties, in vitro physicochemical properties, safety data, and in vitro PK of compound 112 are shown. [Figure 3] The diagram shows a mouse optic nerve compression experiment, as well as a bar graph showing the p-JUN cell population after injection of solvent and compound 112, and a confocal microscope image showing RGC. [Figure 4] This graph shows the percentage retention of visual acuity in mice in the solvent, compound 112, and brimonidine. [Figure 5] This is a series of graphs showing the ORL thickness, A-wave amplitude, and B-wave amplitude of compound 112 in a mouse photodamage model. [Figure 6] The in vivo PK data for compound 112 in male Wistar rats is shown. [Modes for carrying out the invention]

[0012] Double leucine zipper kinase (DLK, MAP3K12) is a key component of the neuronal stress response that modulates neurodegeneration in models of acute nerve injury and chronic neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis (ALS). This kinase, DLK (also known as mitogen-activated protein 3 kinase 12, MAP3K12), is present at high concentrations in nerve cells and represents a presumed drug-potential component of this conserved neurodegenerative pathway. Pharmacological inhibition or gene deletion of DLK is sufficient to reduce the nerve injury response and protect various neuronal populations from degeneration in response to widespread neuronal injury, suggesting that DLK inhibition may be an attractive and potent therapeutic strategy (Mata, M. et al., J. Biol. Chem. 1996, 271, 16888-16896; Watkins, TA et al., Proc. Natl. Acad. Sci., 2013, 110, 4039-4044).

[0013] Leucine zipper-possessing kinase (LZK / MAP3K13) is a member of a mixed-lineage kinase family that shares high sequence identity with double leucine zipper kinase (DLK / MAP3K12) and has been shown to be involved in neuronal survival. In RGC cell death signaling, DLK and LZK appear to be at least partially complementary, reflecting their involvement in a common biochemical complex (Welsbie, DS et al., Neuron, 2017, 94, 1142-1154). Combined inhibition of DLK and LZK is more effective in preventing neuronal cell death than inhibiting either one alone.

[0014] This specification provides low molecular weight compounds capable of inhibiting both DLK and LZK. Such compounds may be suitable for the treatment and / or prevention of neurodegenerative diseases, such as ophthalmic neurodegenerative diseases.

[0015] Compound of formula (Z) The present disclosure relates to a compound of formula (Z): [Chemical formula] [wherein, X is nitrogen and Y is carbon, or or X is carbon and Y is nitrogen, R E is hydrogen, -C(O)-NR A R B C(O)OR 6 -S(O)2NH(C1-C6)-alkyl, (C1-C6)-alkyl, halo, (C6-C 10 )-aryl, or heteroaryl, provided that (C1-C6)-alkyl, (C6-C 10 )-aryl, and heteroaryl may be substituted with one or more independently selected (C1-C4)-alkyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl-(C1-C3)-alkyl, 4-7 membered heterocyclyl, (C1-C4)-alkoxy, (C3-C7)-cycloalkoxy, -SO2R 4 -NR 4 R 5 cyano, hydroxyl, or halo, provided that (C1-C4)-alkyl, (C3-C7)-cycloalkyl, (C1-C4)-alkoxy, (C3-C7)-cycloalkyl-(C1-C3)-alkyl, and (C3-C7)-cycloalkoxy may be substituted with one or more independently selected hydroxyl, cyano, or halo, R A is hydrogen or -CR 1 R 2 R 3 and R B is hydrogen or (C1-C6)-alkyl, R 1 and R 2 are each independently hydrogen or (C1-C3)-alkyl, provided that (C1-C3)-alkyl may be substituted with one or more independently selected halo, R 3is hydrogen, (C1~C6)-alkyl, (C3~C7)-cycloalkyl, or (C3~C7)-cycloalkyl-(C1~C3)-alkyl, wherein (C1~C6)-alkyl, (C3~C7)-cycloalkyl, or (C3~C7)-cycloalkyl-(C1~C3)-alkyl may be substituted with one or more independently selected hydroxyl, (C1~C4)-alkoxy, oxo, cyano, or halo, wherein (C1~C4)-alkoxy may be substituted with one or more independently selected halos. or R 1 is hydrogen, R 2 and R 3 These atoms bond to each other to form a 3- to 7-membered ring containing, together with the bonded carbon atom, up to two heteroatoms selected from the group consisting of O or N, wherein the ring may be substituted with one or more independently selected hydroxyl, (C1-C4)-alkoxy, (C1-C4)-alkyl, oxo, cyano, or halo, wherein (C1-C4)-alkoxy and (C1-C4)-alkyl may be substituted with one or more independently selected hydroxyl or halo. R C is hydrogen, (C6~C 10 )-aryl, or CR 4 R 5 R 7 And, however, (C6~C 10 The )-aryl group may optionally be substituted with one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, or halo groups, and the (C1-C4)-alkyl and (C1-C4)-alkoxy groups may be substituted with one or more independently selected hydroxyl or halo groups. R 4is hydrogen, (C1-C6)-alkyl, (C3-C7)-cycloalkyl, or a 4- to 7-membered heterocycline, wherein the (C1-C6)-alkyl, (C3-C7)-cycloalkyl, or 4- to 7-membered heterocycline may be substituted with one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, hydroxyl, oxo, cyano, or halo, wherein the (C1-C4)-alkoxy and (C1-C4)-alkyl may be substituted with one or more independently selected halos, and any nitrogen of the 4- to 7-membered heterocycline is C(O)OR 6 or C(O)R 6 It can be replaced with, R 5 (C1~C6)-alkyl, (C3~C7)-cycloalkyl, cyanomethyl, (C6~C 10 )-aryl, (C6~C 10 )-aryl-(C1~C4)-alkyl, heteroaryl, or 4- to 7-membered heterocyclyl, however, (i) (C1~C6)-alkyl, (C3~C7)-cycloalkyl, (C6~C 10 )-aryl, (C6~C 10 )-aryl-(C1~C4)-alkyl, heteroaryl, or 4- to 7-membered heterocyclyl is one or more independently selected (C1~C4)-alkyl, (C 1~ C4)-alkoxy, C(O)OR 6 They may be substituted with (C3-C7)-cycloalkoxy, cyano, 4-7 membered heterocyclyl, or halo, provided that (C1-C4)-alkyl and (C1-C4)-alkoxy may be substituted with one or more independently selected 4-7 membered heterocyclyls optionally substituted with oxo, (C1-C4)-alkyl, (C1-C4)-alkoxy, -NR'R'', or halo. (ii) (C3~C7)-cycloalkyl, (C6~C 10 )-aryl, (C6~C 10 )-aryl-(C1~C4)-alkyl, heteroaryl, or 4- to 7-membered heterocyclyl may be condensed with a 4- to 7-membered heterocyclyl or (C3~C7)-cycloalkyl, or R 4 and R 5 These atoms bond to each other to form a 3- to 8-membered monocyclic or bridged bicyclic ring containing up to two heteroatoms selected from the group consisting of O or N, however, (i) The ring is one or more independently selected (C6~C 10 )-aryl-(C1~C4)-alkyl, (C6~C 10 (C1-C4)-aryl, 4- to 7-membered heterocyclyl, (C1-C4)-alkyl, (C1-C4)-alkoxy, oxo, cyano, or halo may be substituted, provided that (C1-C4)-alkyl and (C6-C 10 The )-aryl group may be substituted with one or more independently selected 4- to 7-membered heterocyclines, (C1-C4)-alkoxys, or halos, where each nitrogen of the 4- to 7-membered heterocycline is C(O)OR 6 or C(O)R 6 It can be independently replaced, (ii) Each ring is optionally substituted with one or more independently selected (C1-C4)-alkoxy or halo (C6-C 10 )-aryl, heteroaryl, or 4- to 7-membered heterocyclyl may be condensed with, R 6 is hydrogen or (C1~C4)-alkyl, R 7 These are hydrogen, (C1~C6)-alkyl, (C3~C7)-cycloalkyl, (C6~C 10 )-aryl, or 4-7 member heterocyclyl, provided that (C1-C6)-alkyl, (C3-C7)-cycloalkyl, (C6-C 10 A )-aryl or 4- to 7-membered heterocyclil may be substituted with one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, oxo, cyano, or halo, provided that (C1-C4)-alkoxy and (C1-C4)-alkyl may be substituted with one or more independently selected halos, and the nitrogen of the 4- to 7-membered heterocyclil may be C(O)OR 6 or C(O)R6 It can be replaced with, R D is either hydrogen or (C1~C6)-alkyl, or R C and R D These atoms bond to each other to form a 4- to 10-membered monocyclic or bicyclic ring containing up to 3 heteroatoms selected from the group consisting of O or N, wherein the 4- to 10-membered monocyclic or bicyclic ring may be substituted with one or more independently selected (C1-C6)-alkyl or (C1-C4)-alkoxy atoms. Z is -NHR F or H, R F is hydrogen or (C1~C6)-alkyl, where (C1~C6)-alkyl is optionally substituted with one or more independently selected -NR'R''. The presence of R' and R'' is either selected from hydrogen and (C1-C4)-alkyl, or R' and R'' bond to each other to form a 3-6 member heterocycline with the nitrogen atom to which they are bonded. R G is hydrogen or halo, R H [These are hydrogen, halos, or (C1-C4)-alkyl atoms.] The present invention also provides salts, solvates, and solvates of these salts.

[0016] This disclosure relates to compounds of formula (Y): [ka] [In the formula, Is X nitrogen and Y carbon? or X is carbon, and Y is nitrogen. R E is hydrogen or -C(O)-NR A R B And, R A is hydrogen or -CR 1 R 2 R 3And, R B is hydrogen or (C1~C6)-alkyl, R 1 and R 2 Each of these is independently hydrogen or (C1-C3)-alkyl, where the (C1-C3)-alkyl may be substituted with one or more independently selected halos. R 3 is hydrogen, (C1~C6)-alkyl, (C3~C7)-cycloalkyl, or (C3~C7)-cycloalkyl-(C1~C3)-alkyl, wherein (C1~C6)-alkyl, (C3~C7)-cycloalkyl, or (C3~C7)-cycloalkyl-(C1~C3)-alkyl may be substituted with one or more independently selected hydroxyl, (C1~C4)-alkoxy, oxo, cyano, or halo, wherein (C1~C4)-alkoxy may be substituted with one or more independently selected halos. or R 1 is hydrogen, R 2 and R 3 These atoms bond to each other to form a 3- to 7-membered ring containing, together with the bonded carbon atom, up to two heteroatoms selected from the group consisting of O or N, wherein the ring may be substituted with one or more independently selected hydroxyl, (C1-C4)-alkoxy, (C1-C4)-alkyl, oxo, cyano, or halo, wherein (C1-C4)-alkoxy and (C1-C4)-alkyl may be substituted with one or more independently selected hydroxyl or halo. R C is hydrogen, (C6~C 10 )-aryl, or CR 4 R 5 R 7 And, however, (C6~C 10 The )-aryl group may optionally be substituted with one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, or halo groups, and the (C1-C4)-alkyl and (C1-C4)-alkoxy groups may be substituted with one or more independently selected hydroxyl or halo groups. R4 is hydrogen, (C1-C6)-alkyl, (C3-C7)-cycloalkyl, or a 4- to 7-membered heterocyclyl, provided that (C1-C6)-alkyl, (C3-C7)-cycloalkyl, or a 4- to 7-membered heterocyclyl may be substituted with one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, hydroxyl, oxo, cyano, or halo, provided that (C1-C4)-alkoxy and (C1-C4)-alkyl may be substituted with one or more independently selected halo, and the nitrogen of the 4- to 7-membered heterocyclyl is C(O)OR 6 or C(O)R 6 and may be substituted with, R 5 is (C1-C6)-alkyl, (C3-C7)-cycloalkyl, cyanomethyl, (C6-C 10 )-aryl, (C6-C 10 )-aryl-(C1-C4)-alkyl, heteroaryl, or a 4- to 7-membered heterocyclyl, provided that (i) (C1-C6)-alkyl, (C3-C7)-cycloalkyl, (C6-C 10 )-aryl, (C6-C 10 )-aryl-(C1-C4)-alkyl, heteroaryl, or a 4- to 7-membered heterocyclyl may be substituted with one or more independently selected (C1-C4)-alkyl, (C 1~ C4)-alkoxy, C(O)OR 6 , (C3-C7)-cycloalkoxy, cyano, a 4- to 7-membered heterocyclyl, or halo, provided that (C1-C4)-alkyl and (C1-C4)-alkoxy may be substituted with one or more independently selected 4- to 7-membered heterocyclyls which may optionally be substituted with oxo, (C1-C4)-alkyl, (C1-C4)-alkoxy, -NR’R’’, or halo, (ii) (C3-C7)-cycloalkyl, (C6-C 10 )-aryl, (C6-C 10)-aryl-(C1-C4)-alkyl, heteroaryl, or 4- to 7-membered heterocyclyl may be fused with a 4- to 7-membered heterocyclyl or (C3-C7)-cycloalkyl, or R 4 and R 5 may be joined to each other to form a 3- to 8-membered monocyclic or bridged bicyclic ring containing up to 2 heteroatoms selected from the group consisting of O or N together with the carbon atoms to which they are attached, provided that (i) the ring may be substituted with one or more (C6-C 10 )-aryl-(C1-C4)-alkyl, (C6-C 10 )-aryl, 4- to 7-membered heterocyclyl, (C1-C4)-alkyl, (C1-C4)-alkoxy, oxo, cyano, or halo, provided that the (C1-C4)-alkyl and (C6-C 10 )-aryl substituents may optionally be substituted with one or more independently selected 4- to 7-membered heterocyclyl, (C1-C4)-alkoxy, or halo, and each nitrogen of the 4- to 7-membered heterocyclyl may be independently substituted with C(O)OR 6 or C(O)R 6 (ii) the ring may be fused with phenyl, heteroaryl, or 4- to 7-membered heterocyclyl, each optionally substituted with one or more independently selected (C1-C4)-alkoxy or halo, (iii) R R 6 is hydrogen or (C1-C4)-alkyl, R 7 is hydrogen, (C1-C6)-alkyl, (C3-C7)-cycloalkyl, (C6-C 10 )-aryl, or 4- to 7-membered heterocyclyl, provided that the (C1-C6)-alkyl, (C3-C7)-cycloalkyl, (C6-C 10A )-aryl or 4- to 7-membered heterocyclil may be substituted with one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, oxo, cyano, or halo, provided that (C1-C4)-alkoxy and (C1-C4)-alkyl may be substituted with one or more independently selected halos, and the nitrogen of the 4- to 7-membered heterocyclil may be C(O)OR 6 or C(O)R 6 It can be replaced with, R D is either hydrogen or (C1~C6)-alkyl, or R C and R D These atoms bond to each other to form a 4- to 10-membered monocyclic or bicyclic ring containing up to 3 heteroatoms selected from the group consisting of O or N, wherein the 4- to 10-membered monocyclic or bicyclic ring may be substituted with one or more independently selected (C1-C6)-alkyl or (C1-C4)-alkoxy atoms. R F is hydrogen or (C1~C6)-alkyl, where (C1~C6)-alkyl is optionally substituted with one or more independently selected -NR'R''. The presence of R' and R'' is selected from hydrogen and (C1-C4)-alkyl groups, respectively. R G is hydrogen or halo, R H [These are hydrogen, halos, or (C1-C4)-alkyl groups.]

[0017] This disclosure relates to compounds of formula (X): [ka] [In the formula, Is X nitrogen and Y carbon? or X is carbon, and Y is nitrogen. R A is hydrogen or -CR 1 R 2 R3 And, R B is hydrogen or (C1~C6)-alkyl, R 1 and R 2 Each of these is independently hydrogen or (C1-C3)-alkyl, where the (C1-C3)-alkyl may be substituted with one or more independently selected halos. R 3 is hydrogen, (C1~C6)-alkyl, (C3~C7)-cycloalkyl, or (C3~C7)-cycloalkyl-(C1~C3)-alkyl, wherein (C1~C6)-alkyl, (C3~C7)-cycloalkyl, or (C3~C7)-cycloalkyl-(C1~C3)-alkyl may be substituted with one or more independently selected hydroxyl, (C1~C4)-alkoxy, oxo, cyano, or halo, wherein (C1~C4)-alkoxy may be substituted with one or more independently selected halos. or R 1 is hydrogen, R 2 and R 3 These atoms bond to each other to form a 3- to 7-membered ring containing, together with the bonded carbon atom, up to two heteroatoms selected from the group consisting of O or N, wherein the ring may be substituted with one or more independently selected hydroxyl, (C1-C4)-alkoxy, (C1-C4)-alkyl, oxo, cyano, or halo, wherein (C1-C4)-alkoxy and (C1-C4)-alkyl may be substituted with one or more independently selected hydroxyl or halo. R C is hydrogen or CR 4 R 5 R 7 And, R 4is hydrogen, (C1-C6)-alkyl, (C3-C7)-cycloalkyl, or a 4- to 7-membered heterocycline, wherein the (C1-C6)-alkyl, (C3-C7)-cycloalkyl, or 4- to 7-membered heterocycline may be substituted with one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, oxo, cyano, or halo, wherein the (C1-C4)-alkoxy and (C1-C4)-alkyl may be substituted with one or more independently selected halos, and the nitrogen of the 4- to 7-membered heterocycline is C(O)OR 6 or C(O)R 6 It can be replaced with, R 5 (C3~C7)-cycloalkyl, cyanomethyl, (C6~C 10 )-aryl or heteroaryl, provided that (C3-C7)-cycloalkyl, (C6-C 10 The (C1-C4)-aryl or heteroaryl may be substituted with one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, cyano, 4- to 7-membered heterocyclyl, or halo, provided that the (C1-C4)-alkyl and (C1-C4)-alkoxy may be substituted with one or more independently selected halos. or R 4 and R 5 These atoms bond to each other to form a 3- to 8-membered monocyclic or bridged bicyclic ring containing up to two heteroatoms selected from the group consisting of O or N, however, (i) A ring is one or more (C6~C 10 )-aryl-(C1~C4)-alkyl, (C6~C 10 (C1-C4)-aryl, 4- to 7-membered heterocyclyl, (C1-C4)-alkyl, (C1-C4)-alkoxy, oxo, cyano, or halo may be substituted, provided that (C1-C4)-alkyl and (C6-C 10 The )-aryl substituent may optionally be substituted with one or more independently selected 4- to 7-membered heterocyclines or halos, where each nitrogen of the 4- to 7-membered heterocycline is C(O)OR 6 or C(O)R6 It can be independently replaced, (ii) Each ring may be condensed with one or more independently selected (C1-C4)-alkoxy or optionally substituted phenyl or heteroaryl rings, R 6 It is (C1~C4)-alkyl, R 7 These are hydrogen, (C1~C6)-alkyl, (C3~C7)-cycloalkyl, (C6~C 10 )-aryl, or 4-7 member heterocyclyl, provided that (C1-C6)-alkyl, (C3-C7)-cycloalkyl, (C6-C 10 A )-aryl or 4- to 7-membered heterocyclil may be substituted with one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, oxo, cyano, or halo, provided that (C1-C4)-alkoxy and (C1-C4)-alkyl may be substituted with one or more independently selected halos, and the nitrogen of the 4- to 7-membered heterocyclil may be C(O)OR 6 or C(O)R 6 It can be replaced with, R D The disclosure includes a compound which is hydrogen or (C1-C6)-alkyl.

[0018] This disclosure relates to compounds of formula (A): [ka] [In the formula, Is X nitrogen and Y carbon? or X is carbon, and Y is nitrogen. R 1 and R 2 Each of these is independently a (C1-C3)-alkyl group optionally substituted with hydrogen or one or more fluorocarbons. R 3is (C1~C6)-alkyl, (C3~C7)-cycloalkyl, or (C3~C7)-cycloalkyl-(C1~C3)-alkyl, wherein (C1~C6)-alkyl, (C3~C7)-cycloalkyl, or (C3~C7)-cycloalkyl-(C1~C3)-alkyl may be substituted with one or more independently selected hydroxyl, (C1~C4)-alkoxy, oxo, cyano, or halo, wherein (C1~C4)-alkoxy may be substituted with one or more independently selected halo. or R 1 is hydrogen, R 2 and R 3 These atoms bond to each other to form a 4- to 7-membered ring containing, together with the carbon atom to which they are bonded, up to two heteroatoms selected from the group consisting of O or N, wherein the ring may be substituted with one or more independently selected hydroxyl, (C1-C4)-alkoxy, (C1-C4)-alkyl, oxo, cyano, or halo, wherein (C1-C4)-alkoxy and (C1-C4)-alkyl may be substituted with one or more independently selected halos. R 4 is hydrogen, (C1-C6)-alkyl, (C3-C7)-cycloalkyl, or a 4- to 7-membered heterocycline, wherein the (C1-C6)-alkyl, (C3-C7)-cycloalkyl, or 4- to 7-membered heterocycline may be substituted with one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, oxo, cyano, or halo, wherein the (C1-C4)-alkoxy and (C1-C4)-alkyl may be substituted with one or more independently selected halos, and any nitrogen of the 4- to 7-membered heterocycline is C(O)OR 6 or C(O)R 6 It can be replaced with, R 5 (C3~C7)-cycloalkyl, cyanomethyl, (C6~C 10 )-aryl or heteroaryl, provided that (C3-C7)-cycloalkyl, (C6-C 10The (C1-C4)-aryl or heteroaryl may be substituted with one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, cyano, 4- to 7-membered heterocyclyl, or halo, provided that the (C1-C4)-alkyl and (C1-C4)-alkoxy may be substituted with one or more independently selected halos. or R 4 and R 5 These atoms bond to each other, forming a 4-7 membered ring containing up to two heteroatoms selected from the group consisting of O or N, however, (i) The ring is one or more independently selected (C6~C 10 (C1~C4)-alkyl, 4~7 member heterocyclil, (C1~C4)-alkyl, (C1~C4)-alkoxy, oxo, cyano, or halo may be substituted, provided that (C1~C4)-alkyl may optionally be substituted with one or more independently selected 4~7 member heterocyclil or halo, and each nitrogen of the 4~7 member heterocyclil may be C(O)OR 6 or C(O)R 6 It can be independently replaced, (ii) The ring is (C6~C 10 )-aryl or heteroaryl may condense with R 6 It is (C1~C4)-alkyl, R 7 These are hydrogen, (C1~C6)-alkyl, (C6~C 10 A (C1-C6)-aryl, (C3-C7)-cycloalkyl, or 4-7 membered heterocyclil, wherein the (C1-C6)-alkyl, (C3-C7)-cycloalkyl, or 4-7 membered heterocyclil may be substituted with one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, oxo, cyano, or halo, wherein the (C1-C4)-alkoxy and (C1-C4)-alkyl may be substituted with one or more independently selected halos, and any nitrogen of the 4-7 membered heterocyclil may be C(O)OR 6 or C(O)R 6Provides [which may be replaced by].

[0019] This disclosure relates to compounds of formula (I): [ka] [In the formula, Is X nitrogen and Y carbon? or X is carbon, and Y is nitrogen. R 1 and R 2 Each of these is independently a (C1-C3)-alkyl group optionally substituted with hydrogen or one or more fluorocarbons. R 3 is (C1~C6)-alkyl, (C3~C7)-cycloalkyl, or (C3~C7)-cycloalkyl-(C1~C3)-alkyl, wherein (C1~C6)-alkyl, (C3~C7)-cycloalkyl, or (C3~C7)-cycloalkyl-(C1~C3)-alkyl may be substituted with one or more independently selected hydroxyl, (C1~C4)-alkoxy, oxo, cyano, or halo, wherein (C1~C4)-alkoxy may be substituted with one or more independently selected halo. or R 1 is hydrogen, R 2 and R 3 These atoms bond to each other to form a 4- to 7-membered ring containing, together with the carbon atom to which they are bonded, up to two heteroatoms selected from the group consisting of O or N, wherein the ring may be substituted with one or more independently selected hydroxyl, (C1-C4)-alkoxy, (C1-C4)-alkyl, oxo, cyano, or halo, wherein (C1-C4)-alkoxy and (C1-C4)-alkyl may be substituted with one or more independently selected halos. R 4is hydrogen, (C1-C6)-alkyl, (C3-C7)-cycloalkyl, or a 4- to 7-membered heterocycline, wherein the (C1-C6)-alkyl, (C3-C7)-cycloalkyl, or 4- to 7-membered heterocycline may be substituted with one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, oxo, cyano, or halo, wherein the (C1-C4)-alkoxy and (C1-C4)-alkyl may be substituted with one or more independently selected halos, and any nitrogen of the 4- to 7-membered heterocycline is C(O)OR 6 or C(O)R 6 It can be replaced with, R 5 (C3~C7)-cycloalkyl, (C6~C 10 )-aryl or heteroaryl, provided that (C3-C7)-cycloalkyl, (C6-C 10 The )-aryl or heteroaryl may be substituted with one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, cyano, 4- to 7-membered heterocyclyl, or halo, wherein the (C1-C4)-alkyl and (C1-C4)-alkoxy may be substituted with one or more fluoro. or R 4 and R 5 These atoms bond to each other, forming a 4-7 membered ring containing up to two heteroatoms selected from the group consisting of O or N, however, (i) The ring is one or more independently selected (C6~C 10 (C1~C4)-alkyl, 4~7 member heterocyclil, (C1~C4)-alkyl, (C1~C4)-alkoxy, oxo, cyano, or halo may be substituted, provided that (C1~C4)-alkyl may optionally be substituted with one or more independently selected 4~7 member heterocyclil or fluoro, and each nitrogen of the 4~7 member heterocyclil may be C(O)OR 6 or C(O)R 6 It can be independently replaced, (ii) The ring is (C6~C 10)-aryl or heteroaryl may condense with R 6 It provides [(C1~C4)-alkyl].

[0020] In some embodiments, R 1 and R 2 These are, independently, hydrogen or methyl, R 3 is a (C1-C6)-alkyl which may be substituted with one or more independently selected hydroxyl, (C1-C4)-alkoxy, oxo, cyano, or halo, wherein the (C1-C4)-alkoxy may be substituted with one or more fluoro. or R 1 is hydrogen, R 2 and R 3 These combine with each other to form pyrrolidinone, cyclobutyl, or tetrahydrofuranyl with the carbon atoms to which they are bonded. R 4 The (C1-C6)-alkyl, (C3-C7)-cycloalkyl, or 4-7 membered heterocyclil is a (C1-C6)-alkyl, (C3-C7)-cycloalkyl, or 4-7 membered heterocyclil, which may be substituted with one or more independently selected (C1-C4)-alkoxy or halo, and any nitrogen of the 4-7 membered heterocyclil is C(O)OR 6 or C(O)R 6 It can be replaced with, R 5 is phenyl or benzoxazolyl, wherein phenyl or benzoxazolyl may be substituted with one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, cyano, or halo, provided that (C 1~ C4)-alkyl and (C1-C4)-alkoxy groups may be substituted with one or more fluoropolymers. R 6 It is (C1~C4)-alkyl, Also, salts, solvates, and solvates of those salts.

[0021] In some embodiments, X is carbon, and Y is nitrogen. R 1 It is hydrogen, R 2 It is methyl, R 3 is a (C1-C4)-alkyl which may be substituted with one or more independently selected hydroxyl, (C1-C4)-alkoxy, chloro, or fluoro, wherein the (C1-C4)-alkoxy may be substituted with one or more fluoro. or R 1 is hydrogen, R 2 and R 3 These atoms bond to each other to form a 4-7 membered ring containing up to one O or N atom along with the carbon atom to which they are bonded, wherein the ring may be substituted with one or more independently selected hydroxyl, oxo, (C1-C4)-alkoxy, or halo, wherein the (C1-C4)-alkoxy may be substituted with one or more fluoro. R 4 The (C1-C6)-alkyl, (C3-C7)-cycloalkyl, or 4-7 membered heterocyclil is a (C1-C6)-alkyl, (C3-C7)-cycloalkyl, or 4-7 membered heterocyclil, which may be substituted with one or more independently selected halos, and any nitrogen of the 4-7 membered heterocyclil is C(O)OR 6 or C(O)R 6 It can be replaced with, R 5 is phenyl or benzoxazolyl, wherein phenyl or benzoxazolyl may be substituted with one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, cyano, or halo, provided that (C 1~ C4)-alkyl and (C1-C4)-alkoxy groups may be substituted with one or more fluoropolymers. R 6 It is (C1~C4)-alkyl, Also, salts, solvates, and solvates of those salts.

[0022] In some embodiments, R 1 It is hydrogen, R 2 It is methyl, R 3 is a (C1-C4)-alkyl which may be substituted with one or more independently selected hydroxyl, (C1-C4)-alkoxy, chloro, or fluoro, wherein the (C1-C4)-alkoxy may be substituted with one or more fluoro. or R 1 is hydrogen, R 2 and R 3 These combine with each other to form pyrrolidinone, cyclobutyl, or tetrahydrofuranyl with the carbon atoms to which they are bonded. R 4 The (C1-C6)-alkyl, (C3-C7)-cycloalkyl, or 4-7 membered heterocyclil is a (C1-C6)-alkyl, (C3-C7)-cycloalkyl, or 4-7 membered heterocyclil, which may be substituted with one or more independently selected (C1-C4)-alkoxy or halo, and any nitrogen of the 4-7 membered heterocyclil is C(O)OR 6 or C(O)R 6 It can be replaced with, R 5 is phenyl or benzoxazolyl, wherein phenyl or benzoxazolyl may be substituted with one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, cyano, or halo, provided that (C 1~ C4)-alkyl and (C1-C4)-alkoxy groups may be substituted with one or more fluoropolymers. R 6 It is (C1~C4)-alkyl, Also, salts, solvates, and solvates of those salts.

[0023] In some embodiments, the compound is a compound of formula (IA): [ka] [In the formula, R 1 It is hydrogen, R 2 is a methyl group which may be substituted with one or more fluoropolymers, R 3 is a (C1-C3)-alkyl which may be substituted with one or more independently selected hydroxyl, (C1-C4)-alkoxy, chloro, or fluoro, wherein the (C1-C4)-alkoxy may be substituted with one or more fluoro. or R 2 and R 3 These atoms bond to each other to form a 4-7 membered ring containing up to one O or N atom along with the carbon atom to which they are bonded, wherein the ring may be substituted with an oxo atom. R 4 is a hydrogen, (C1-C6)-alkyl, (C3-C7)-cycloalkyl, or 4- to 7-membered heterocycline, where the (C1-C6)-alkyl, (C3-C7)-cycloalkyl, or 4- to 7-membered heterocycline may be substituted with one or more independently selected (C1-C4)-alkoxy or halo, and any nitrogen of the 4- to 7-membered heterocycline is C(O)OR 6 or C(O)R 6 It can be replaced with, R 5 is phenyl or benzoxazolyl, wherein phenyl or benzoxazolyl may be substituted with one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, cyano, or halo, provided that (C 1~ C4)-alkyl and (C1-C4)-alkoxy groups may be substituted with one or more fluoropolymers. R 4 and R 5 These atoms bond to each other, forming a 5-6 membered ring containing up to one oxygen atom along with the carbon atoms to which they are bonded, although the ring may be fused with phenyl. R 6 It is (C1~C4)-alkyl.

[0024] In some embodiments, the compound is a compound of formula (IB): [ka] [In the formula, R 1 It is hydrogen, R 2 This is a methyl molecule that may be substituted with one or more fluoropolymers. R 3 is methyl or ethyl which may be substituted with one or more independently selected hydroxyl, (C1-C4)-alkoxy, chloro, or fluoro, wherein (C1-C4)-alkoxy may be substituted with one or more fluoro. or R 2 and R 3 These combine with each other to form pyrrolidinone, cyclobutyl, or tetrahydrofuranyl with the carbon atoms to which they are bonded. R 4 is hydrogen, (C1-C6)-alkyl, cyclopropyl, cyclobutyl, cyclopentyl, or a 4-7 membered heterocycline, each of which may be substituted with one or more independently selected (C1-C4)-alkoxy or halo, and any nitrogen of the 4-7 membered heterocycline is C(O)OR 6 or C(O)R 6 It can be replaced with, R 5 is phenyl or benzoxazolyl, each of which may be substituted with one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, cyano, or halo, provided that (C 1~ C4)-alkyl and (C1-C4)-alkoxy groups may be substituted with one or more fluoropolymers. R 4 and R 5 These atoms bond to each other, forming a 5-6 membered ring containing up to one oxygen atom along with the carbon atoms to which they are bonded, although the ring may be fused with phenyl. R 6 [It is (C1~C4)-alkyl] Also included are their salts, solvates, and solvates of salts.

[0025] In some embodiments, the compound is a compound of formula (IC): [ka] [In the formula, R 1 It is hydrogen, R 2 This is a methyl molecule that may be substituted with one or more fluoropolymers. R 3 is methyl or ethyl which may be substituted with one or more independently selected hydroxyl, (C1-C4)-alkoxy, chloro, or fluoro, wherein (C1-C4)-alkoxy may be substituted with one or more fluoro. or R 2 and R 3 These combine with each other to form pyrrolidinone, cyclobutyl, or tetrahydrofuranyl with the carbon atoms to which they are bonded. R 4 is hydrogen, (C1-C6)-alkyl, cyclopropyl, cyclobutyl, cyclopentyl, or a 4-7 membered heterocycline, wherein the (C1-C6)-alkyl, cyclopropyl, cyclobutyl, cyclopentyl, or 4-7 membered heterocycline may be substituted with one or more independently selected (C1-C4)-alkoxy or halo, and any nitrogen of the 4-7 membered heterocycline is C(O)OR 6 or C(O)R 6 It can be replaced with, R 5 is phenyl or benzoxazolyl, each of which may be substituted with one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, cyano, or halo, provided that (C 1~ C4)-alkyl and (C1-C4)-alkoxy groups may be substituted with one or more fluoropolymers. R 4 and R 5These atoms bond to each other, forming a 5-6 membered ring containing up to one oxygen atom along with the carbon atoms to which they are bonded, although the ring may be fused with phenyl. R 6 It is (C1~C4)-alkyl.

[0026] In some embodiments, the compound is the compound of formula (ID): [ka] [In the formula, R 1 It is hydrogen, R 2 It is methyl, R 3 is methyl or ethyl which may be substituted with one or more independently selected hydroxyl, (C1-C4)-alkoxy, chloro, or fluoro, wherein (C1-C4)-alkoxy may be substituted with one or more fluoro. R 5 is phenyl or benzoxazolyl, each of which may be substituted with one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, cyano, or halo, provided that (C 1~ C4)-alkyl and (C1-C4)-alkoxy groups may be substituted with one or more fluoropolymers. Also included are their salts, solvates, and solvates of salts.

[0027] Variables Z and R F In some embodiments, Z is H.

[0028] In some embodiments, Z is -NHR F In some embodiments, Z is NH2.

[0029] In some embodiments, R F It is hydrogen.

[0030] In some embodiments, R Fis a (C1-C6)-alkyl group, where the (C1-C6)-alkyl group is optionally substituted with one or more independently selected -NR'R'' groups. In some embodiments, R F is a (C1-C6)-alkyl group, where the (C1-C6)-alkyl group is substituted with one or more independently selected -NR'R'' groups. In some embodiments, R F is a (C1-C3)-alkyl group, where the (C1-C3)-alkyl group is optionally substituted with one or more independently selected -NR'R'' groups. In some embodiments, R F is a (C1-C3)-alkyl group, where the (C1-C3)-alkyl group is optionally substituted with one or more independently selected -NR'R'' groups. In some embodiments, R F is ethyl or propyl, and ethyl or propyl is optionally substituted with one or more independently selected -NR'R''. In some embodiments, R F is ethyl, and ethyl is optionally substituted with one or more independently selected -NR'R'' (e.g., substituted). In some embodiments, R F is propyl, and propyl is optionally substituted with one or more independently selected -NR'R'' (e.g., substituted). In some embodiments, R F Alkyl is unsubstituted.

[0031] In some embodiments, -NR'R'' is -N(CH3)2 or -N(CH2CH3)2.

[0032] In some embodiments, the presence of R' and R'' is selected from hydrogen and (C1-C4)-alkyl. In some embodiments, the presence of one of R' and R'' is hydrogen, and the presence of the other of R' and R'' is (C1-C4)-alkyl. In some embodiments, the presence of one of R' and R'' is hydrogen, and the presence of the other of R' and R'' is methyl, ethyl, or isopropyl (e.g., methyl, e.g., ethyl). In some embodiments, R' and R'' are hydrogen. In some embodiments, R' and R'' are independently selected (C1-C4)-alkyl. In some embodiments, R' and R'' are methyl.

[0033] In some embodiments, R' and R'' bond to each other to form a 3- to 6-membered heterocycline with the nitrogen atom to which they are bonded. In some embodiments, R' and R'' bond to each other to form a 3- to 6-membered morpholinyl with the nitrogen atom to which they are bonded.

[0034] Variables X and Y In some embodiments, X is carbon and Y is nitrogen. In some embodiments, Y is carbon and X is nitrogen.

[0035] Variable R E In some embodiments, R E It is hydrogen.

[0036] In some embodiments, R E is -C(O)-NR A R B That is the case.

[0037] In some embodiments, R E C(O)OR 6 In some embodiments, R E This is C(O)OMe.

[0038] In some embodiments, R E is -S(O)2NH(C 1~It is C6)-alkyl. In some embodiments, R E This is -S(O)2NHMe.

[0039] In some embodiments, R E (C1~C6)-alkyl, where (C1~C6)-alkyl is one or more independently selected (C1~C4)-alkyl, (C3~C7)-cycloalkyl, (C3~C7)-cycloalkyl-(C1~C3)-alkyl, 4-7 member heterocyclyl, (C1~C4)-alkoxy, (C3~C7)-cycloalkoxy, -SO2R 4 , -NR 4 R 5 , may be substituted with cyano, hydroxyl, or halo, provided that (C1~C4)-alkyl, (C3~C7)-cycloalkyl, (C1~C4)-alkoxy, (C3~C7)-cycloalkyl-(C1~C3)-alkyl, and (C3~C7)-cycloalkoxy may be substituted with one or more independently selected cyano, hydroxyl, or halo. In some embodiments, R E (C1~C6)-alkyl, where (C1~C6)-alkyl is one or more independently selected (C1~C4)-alkyl, (C3~C7)-cycloalkyl, (C3~C7)-cycloalkyl-(C1~C3)-alkyl, 4-7 member heterocyclyl, (C1~C4)-alkoxy, (C3~C7)-cycloalkoxy, -SO2R 4 , -NR 4 R 5 , substituted with cyano, hydroxyl, or halo, wherein (C1~C4)-alkyl, (C3~C7)-cycloalkyl, (C1~C4)-alkoxy, (C3~C7)-cycloalkyl-(C1~C3)-alkyl, and (C3~C7)-cycloalkoxy may be substituted with one or more independently selected cyano, hydroxyl, or halo. In some embodiments, R Emethyl is methyl, where methyl is one or more independently selected (C1-C4)-alkyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl-(C1-C3)-alkyl, 4-7 member heterocyclyl, (C1-C4)-alkoxy, (C3-C7)-cycloalkoxy, -SO2R 4 , -NR 4 R 5 , may be substituted with cyano, hydroxyl, or halo, provided that (C1~C4)-alkyl, (C3~C7)-cycloalkyl, (C1~C4)-alkoxy, (C3~C7)-cycloalkyl-(C1~C3)-alkyl, and (C3~C7)-cycloalkoxy may be substituted with one or more independently selected cyano, hydroxyl, or halo. In some embodiments, R E is an unsubstituted (C1-C6)-alkyl group. In some embodiments, R E This is an unsubstituted methyl group.

[0040] In some embodiments, R E This is a halo (for example, a fluoro).

[0041] In some embodiments, R E (C6~C 10 )-aryl, however (C6~C 10 )-aryl is one or more independently selected (C1-C4)-alkyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl-(C1-C3)-alkyl, 4-7 member heterocyclyl, (C1-C4)-alkoxy, (C3-C7)-cycloalkoxy, -SO2R 4 , -NR 4 R 5 , may be substituted with cyano, hydroxyl, or halo, provided that (C1~C4)-alkyl, (C3~C7)-cycloalkyl, (C1~C4)-alkoxy, (C3~C7)-cycloalkyl-(C1~C3)-alkyl, and (C3~C7)-cycloalkoxy may be substituted with one or more independently selected cyano, hydroxyl, or halo. In some embodiments, R E (C6~C10 )-aryl, however (C6~C 10 )-aryl is one or more independently selected (C1-C4)-alkyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl-(C1-C3)-alkyl, 4-7 member heterocyclyl, (C1-C4)-alkoxy, (C3-C7)-cycloalkoxy, -SO2R 4 , -NR 4 R 5 , substituted with cyano, hydroxyl, or halo, wherein (C1~C4)-alkyl, (C3~C7)-cycloalkyl, (C1~C4)-alkoxy, (C3~C7)-cycloalkyl-(C1~C3)-alkyl, and (C3~C7)-cycloalkoxy may be substituted with one or more independently selected cyano, hydroxyl, or halo. In some embodiments, R E is phenyl, where phenyl is one or more independently selected (C1-C4)-alkyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl-(C1-C3)-alkyl, 4-7 member heterocyclyl, (C1-C4)-alkoxy, (C3-C7)-cycloalkoxy, -SO2R 4 , -NR 4 R 5 , may be substituted with cyano, hydroxyl, or halo, provided that (C1~C4)-alkyl, (C3~C7)-cycloalkyl, (C1~C4)-alkoxy, (C3~C7)-cycloalkyl-(C1~C3)-alkyl, and (C3~C7)-cycloalkoxy may be substituted with one or more independently selected cyano, hydroxyl, or halo. In some embodiments, R E is the non-substitutive (C6~C 10 )-aryl. In some embodiments, R E It is an unsubstituted phenyl compound.

[0042] In some embodiments, R Eis a heteroaryl, where the heteroaryl is one or more independently selected (C1-C4)-alkyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl-(C1-C3)-alkyl, 4-7 member heterocyclyl, (C1-C4)-alkoxy, (C3-C7)-cycloalkoxy, -SO2R 4 , -NR 4 R 5 , may be substituted with cyano, hydroxyl, or halo, provided that (C1~C4)-alkyl, (C3~C7)-cycloalkyl, (C1~C4)-alkoxy, (C3~C7)-cycloalkyl-(C1~C3)-alkyl, and (C3~C7)-cycloalkoxy may be substituted with one or more independently selected cyano, hydroxyl, or halo. In some embodiments, R E is a heteroaryl, where the heteroaryl is one or more independently selected (C1-C4)-alkyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl-(C1-C3)-alkyl, 4-7 member heterocyclyl, (C1-C4)-alkoxy, (C3-C7)-cycloalkoxy, -SO2R 4 , -NR 4 R 5 , substituted with cyano, hydroxyl, or halo, however (C1~C4)-alkyl, (C3~C7)-cycloalkyl, (C1~C4)-alkoxy, (C3~C7)-cycloalkyl-(C1~C3)-alkyl, and (C3~C7)-cycloalkoxy may be substituted with one or more independently selected cyano, hydroxyl, or halo. In some embodiments, the heteroaryl is thiadiazolyl, oxadiazolyl, or pyrazolyl. In some embodiments, the heteroaryl is thiadiazolyl. In some embodiments, the heteroaryl is oxadiazolyl. In some embodiments, the heteroaryl is pyrazolyl. In some embodiments, R E Heteroaryls are unsubstituted.

[0043] In some embodiments, R E is -C(O)-NR AR B And -C(O)-NR A R B teeth [ka] However, The wavy line indicates the binding site to the triazolopyridine nucleus. R 2’ is hydrogen or (C1-C3)-alkyl, where (C1-C3)-alkyl may be substituted with one or more independently selected halos. R 3’ is -((C0~C5)-alkyl)-X, where X is hydroxyl, (C1~C4)-alkoxy, oxo, cyano, or halo, and (C1~C4)-alkoxy may be substituted with one or more independently selected halos.

[0044] In some embodiments, X is hydroxyl.

[0045] In some embodiments, X is a (C1-C4)-alkoxy, where the (C1-C4)-alkoxy may be substituted with one or more independently selected halos. For example, X is methoxy.

[0046] In some embodiments, X is an oxo.

[0047] In some embodiments, X is cyanoacrylate.

[0048] In some embodiments, X is a halo (e.g., fluorocarbon).

[0049] In some embodiments, -C(O)-NR A R B teeth, [ka] However, The wavy line indicates the binding site to the triazolopyridine nucleus. R2’ is hydrogen, methyl, or trifluoromethyl, R 3’ These are hydroxyl, methyl, fluoro, or methoxy compounds.

[0050] Variable R A and R B In some embodiments, R A It is hydrogen.

[0051] In some embodiments, R A -CR 1 R 2 R 3 That is the case.

[0052] In some embodiments, R B It is hydrogen.

[0053] In some embodiments, R B is (C1~C6)-alkyl. In some embodiments, R B is methyl. In some embodiments, R B It is ethyl.

[0054] In some embodiments, R A and R B It is hydrogen.

[0055] In some embodiments, R A is hydrogen, R B is (C1~C6)-alkyl. In some embodiments, R A is hydrogen, R B is methyl. In some embodiments, R A is hydrogen, R B is (C1~C6)-alkyl. In some embodiments, R A is hydrogen, R B is ethyl. In some embodiments, R A -CR 1 R 2 R 3 And RB It is hydrogen.

[0056] In some embodiments, R A -CR 1 R 2 R 3 And R B is (C1~C6)-alkyl. In some embodiments, R A -CR 1 R 2 R 3 And R B is methyl. In some embodiments, R A -CR 1 R 2 R 3 And R B It is ethyl.

[0057] In some embodiments, -C(O)-NR A R B teeth, [ka] However, The wavy line indicates the binding site to the triazolopyridine nucleus. R 2’ is hydrogen or (C1-C3)-alkyl, where (C1-C3)-alkyl may be substituted with one or more independently selected halos. R 3 is -((C0~C5)-alkyl)-X, where X is hydroxyl, (C1~C4)-alkoxy, oxo, cyano, or halo, and (C1~C4)-alkoxy may be substituted with one or more independently selected halos.

[0058] In some embodiments, X is hydroxyl.

[0059] In some embodiments, X is a (C1-C4)-alkoxy, where the (C1-C4)-alkoxy may be substituted with one or more independently selected halos. For example, X is methoxy.

[0060] In some embodiments, X is an oxo.

[0061] In some embodiments, X is cyanoacrylate.

[0062] In some embodiments, X is a halo (e.g., fluorocarbon).

[0063] In some embodiments, -C(O)-NR A R B teeth, [ka] However, The wavy line indicates the binding site to the triazolopyridine nucleus. R 2’ is hydrogen, methyl, or trifluoromethyl, R 3’ These are hydroxyl, methyl, fluoro, or methoxy compounds.

[0064] Variable R G In some embodiments, R G It is hydrogen.

[0065] In some embodiments, R G This is a halo (for example, fluoro or chloro, for example fluoro, for example chloro).

[0066] Variable R H In some embodiments, R H It is hydrogen.

[0067] In some embodiments, R H This is a halo (for example, fluoro or chloro, for example fluoro, for example chloro).

[0068] In some embodiments, R H This is an (C1~C4)-alkyl group (for example, methyl).

[0069] Variable R 1 , R 2 , and R 3 In some embodiments, R 1 It is hydrogen.

[0070] In some embodiments, R 1 is a (C1-C3)-alkyl group optionally substituted with one or more fluoropolymers. In some embodiments, R 1 is a (C1-C3)-alkyl group substituted with one or more fluoropolymers. In some embodiments, R 1 is an unsubstituted (C1-C3)-alkyl. In some embodiments, R 1 is methyl. In some embodiments, R 1 is fluoromethyl. In some embodiments, R 1 R is difluorofluoromethyl. In some embodiments, R 1 It is trifluoromethyl.

[0071] In some embodiments, R 2 It is hydrogen.

[0072] In some embodiments, R 2 is a (C1-C3)-alkyl group optionally substituted with one or more fluoropolymers. In some embodiments, R 1 is a (C1-C3)-alkyl group substituted with one or more fluoropolymers. In some embodiments, R 1 is an unsubstituted (C1-C3)-alkyl. In some embodiments, R 2 is methyl. In some embodiments, R 1 is fluoromethyl. In some embodiments, R 1 R is difluorofluoromethyl. In some embodiments, R 1 It is trifluoromethyl.

[0073] In some embodiments, R1 and R 2 These are, independently, hydrogen, methyl, or trifluoromethyl. In some embodiments, R 1 and R 2 Each is independently hydrogen or methyl. In some embodiments, R 1 and R 2 These are, independently, hydrogen or trifluoromethyl.

[0074] In some embodiments, R 3 It is hydrogen.

[0075] In some embodiments, R 3 is hydrogen, (C3-C7)-cycloalkyl, or (C1-C6)-alkyl, wherein (C1-C6)-alkyl may be substituted with one or more independently selected hydroxyl, (C1-C4)-alkoxy, oxo, cyano, or halo, wherein (C1-C4)-alkoxy may be substituted with one or more independently selected halos.

[0076] In some embodiments, R 3 is hydrogen, (C3-C7)-cycloalkyl-(C1-C3)-alkyl, or (C1-C6)-alkyl, wherein (C1-C6)-alkyl may be substituted with one or more independently selected hydroxyl, (C1-C4)-alkoxy, oxo, cyano, or halo, wherein (C1-C4)-alkoxy may be substituted with one or more independently selected halos.

[0077] In some embodiments, R 3 is hydrogen, (C1-C6)-alkyl, wherein the (C1-C6)-alkyl may be substituted with one or more independently selected hydroxyl, (C1-C4)-alkoxy, oxo, cyano, or halo, wherein the (C1-C4)-alkoxy may be substituted with one or more independently selected halos.

[0078] In some embodiments, R 3is (C1~C6)-alkyl, wherein the (C1~C6)-alkyl may be substituted with one or more independently selected hydroxyl, (C1~C4)-alkoxy, oxo, cyano, or halo, wherein the (C1~C4)-alkoxy may be substituted with one or more independently selected halos.

[0079] In some embodiments, R 3 R is a (C1-C3)-alkyl which may be substituted with one or more independently selected hydroxyl, (C1-C4)-alkoxy, or fluoro, wherein the (C1-C4)-alkoxy may be substituted with one or more fluoro. In some embodiments, R 3 R is a (C1-C6)-alkyl which may be substituted with one or more independently selected hydroxyl, (C1-C4)-alkoxy, chloro, or fluoro, wherein the (C1-C4)-alkoxy may be substituted with one or more fluoro. In some embodiments, R 3 R is a (C1-C3)-alkyl which may be substituted with one or more independently selected hydroxyl, (C1-C4)-alkoxy, chloro, or fluoro, wherein the (C1-C4)-alkoxy may be substituted with one or more fluoro. In some embodiments, R 3 is methyl or ethyl, each of which may be substituted with one or more independently selected hydroxyl, (C1-C4)-alkoxy, chloro, or fluoro, wherein the (C1-C4)-alkoxy may be substituted with one or more fluoro. In some embodiments, R 3 is methyl or ethyl, each of which may be substituted with one or more independently selected (C1-C4)-alkoxy, chloro, or fluoro, wherein the (C1-C4)-alkoxy may be substituted with one or more fluoro. In some embodiments, R 3 R is methyl or ethyl, each of which may be substituted with one or more independently selected (C1-C4)-alkoxy or fluoro groups, wherein the (C1-C4)-alkoxy groups may be substituted with one or more fluoro groups. In some embodiments, R3 is methyl or ethyl, each of which may be substituted with one or more fluoropolymers.

[0080] In some embodiments, R 3 R is a methyl molecule which may be substituted with one or more independently selected hydroxyl, (C1-C4)-alkoxy, chloro, or fluoro, wherein the (C1-C4)-alkoxy may be substituted with one or more fluoro. In some embodiments, R 3 R is a methyl molecule which may be substituted with one or more independently selected (C1-C4)-alkoxy, chloro, or fluoro molecules, wherein the (C1-C4)-alkoxy molecules may be substituted with one or more fluoro molecules. In some embodiments, R 3 R is a methyl molecule which may be substituted with one or more independently selected (C1-C4)-alkoxy molecules, where the (C1-C4)-alkoxy molecules may be substituted with one or more fluoro molecules. In some embodiments, R 3 R is a methyl group which may be substituted with one or more fluoro groups. In some embodiments, R 3 This is an unsubstituted methyl group.

[0081] In some embodiments, R 3 R is ethyl which may be substituted with one or more independently selected hydroxyl, (C1-C4)-alkoxy, chloro, or fluoro, wherein (C1-C4)-alkoxy may be substituted with one or more fluoro. In some embodiments, R 3 R is an ethyl molecule which may be substituted with one or more independently selected (C1-C4)-alkoxy, chloro, or fluoro molecules, wherein the (C1-C4)-alkoxy molecules may be substituted with one or more fluoro molecules. In some embodiments, R 3 R is ethyl which may be substituted with one or more independently selected (C1-C4)-alkoxys, where the (C1-C4)-alkoxys may be substituted with one or more fluoros. In some embodiments, R 3 is an ethyl compound that may be substituted with one or more fluorocarbons.

[0082] In some embodiments, R 3 R is methyl or ethyl, each of which may be substituted with one or more independently selected hydroxyl or fluoro atoms. In some embodiments, R 3 R is methyl or ethyl, each of which may be substituted with one or more hydroxyls. For example, R 3 It is hydroxymethyl. For example, R 3 is unsubstituted ethyl. For example, R 3 This is an unsubstituted methyl group.

[0083] In some embodiments, R 3 is a (C3-C7)-cycloalkyl group, wherein the (C3-C7)-cycloalkyl group may be substituted with one or more independently selected hydroxyl groups, (C1-C4)-alkoxy groups, oxo groups, cyano groups, or halos, wherein the (C1-C4)-alkoxy groups may be substituted with one or more independently selected halos.

[0084] In some embodiments, R 3 is (C3~C7)-cycloalkyl-(C1~C3)-alkyl, where (C3~C7)-cycloalkyl-(C1~C3)-alkyl may be substituted with one or more independently selected hydroxyl, (C1~C4)-alkoxy, oxo, cyano, or halo, where (C1~C4)-alkoxy may be substituted with one or more independently selected halos.

[0085] In some embodiments, R 1 is hydrogen, R 2 and R 3These atoms bond to each other to form a 4- to 7-membered ring containing, together with the carbon atom to which they are bonded, up to two heteroatoms selected from the group consisting of O or N, wherein the ring may be substituted with one or more independently selected hydroxyl, (C1-C4)-alkoxy, (C1-C4)-alkyl, oxo, cyano, or halo, wherein (C1-C4)-alkoxy and (C1-C4)-alkyl may be substituted with one or more independently selected halos. In some embodiments, R 1 is hydrogen, R 2 and R 3 These atoms bond to each other to form a 4- to 7-membered ring containing, together with the carbon atom to which they are bonded, up to two heteroatoms selected from the group consisting of O or N, wherein the ring may be substituted with one or more independently selected hydroxyl, (C1-C4)-alkoxy, (C1-C4)-alkyl, oxo, cyano, or halo, wherein (C1-C4)-alkoxy and (C1-C4)-alkyl are substituted with one or more independently selected halos. In some embodiments, R 1 is hydrogen, R 2 and R 3 These atoms bond to each other to form a 3- to 7-membered ring containing, together with the bonded carbon atom, up to two heteroatoms selected from the group consisting of O or N, wherein the ring may be substituted with one or more independently selected hydroxyl, (C1-C4)-alkyl, oxo, or halo atoms. In some embodiments, R 1 is hydrogen, R 2 and R 3 These atoms bond to each other, forming an unsubstituted 4- to 7-membered ring containing up to two heteroatoms selected from the group consisting of O or N, along with the carbon atom to which they are bonded.

[0086] In some embodiments, R 2 and R 3 These atoms bond to each other to form a 4-7 membered ring containing up to one O or N atom along with the bonded carbon atom, wherein the ring may be substituted with an oxo. In some embodiments, R 2 and R 3These combine with each other to form pyrrolidinone, cyclobutyl, or tetrahydrofuranyl with the carbon atoms to which they are bonded. In some embodiments, R 2 and R 3 These combine with each other to form pyrrolidinone together with the carbon atoms to which they are bonded. In some embodiments, R 2 and R 3 These combine with each other to form cyclobutyl with the carbon atoms to which they are bonded. In some embodiments, R 2 and R 3 These atoms bond with each other, forming tetrahydrofuranyl with the carbon atoms to which they are bonded.

[0087] In some embodiments, R 1 It is hydrogen, R 2 is hydrogen or (C1-C3)-alkyl, where (C1-C3)-alkyl may be substituted with one or more independently selected halos. R 3 is -CH2-R 3’ The compound is -((C0~C5)-alkyl)-X, where X is hydroxyl, (C1~C4)-alkoxy, oxo, cyano, or halo, and the (C1~C4)-alkoxy may be substituted with one or more independently selected halos.

[0088] In some embodiments, X is hydroxyl.

[0089] In some embodiments, X is a (C1-C4)-alkoxy, where the (C1-C4)-alkoxy may be substituted with one or more independently selected halos. For example, X is methoxy.

[0090] In some embodiments, X is an oxo.

[0091] In some embodiments, X is cyanoacrylate.

[0092] In some embodiments, X is a halo (e.g., fluorocarbon).

[0093] In some embodiments, R 1 It is hydrogen, R 2 is hydrogen, methyl, or trifluoromethyl, R 3 It is -CH2- and R 3’ These are hydroxyl, methyl, fluoro, or methoxy compounds.

[0094] In some embodiments, R 1 , R 2 , and R 3 The stereochemistry of the bonded atoms is (S). In some embodiments, R 1 , R 2 , and R 3 The stereochemistry of the bonded atoms is (R).

[0095] Variable R C and R D In some embodiments, R C It is hydrogen.

[0096] In some embodiments, R C CR 4 R 5 R 7 That is the case.

[0097] In some embodiments, R C (C6~C 10 )-aryl, however (C6~C 10 The )-aryl may optionally be substituted with one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, or halo, and the (C1-C4)-alkyl and (C1-C4)-alkoxy may be substituted with one or more independently selected hydroxyl or halo. In some embodiments, R Cis phenyl, wherein phenyl is optionally substituted with one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, or halo, except (C 1~ The (C4)-alkyl and (C1-C4)-alkoxy groups may be substituted with one or more independently selected hydroxyls or halos.

[0098] In some embodiments, R D It is hydrogen.

[0099] In some embodiments, R D is (C1~C6)-alkyl. In some embodiments, R D It is methyl.

[0100] In some embodiments, R C and R D These atoms bond to each other to form a 4- to 10-membered monocyclic or bicyclic ring containing, together with the bonded carbon atom, up to three heteroatoms selected from the group consisting of O or N, wherein the 4- to 10-membered monocyclic or bicyclic ring may be optionally substituted with one or more independently selected (C1-C6)-alkyl or (C1-C4)-alkoxy atoms.

[0101] In some embodiments, R C and R D These atoms bond to each other to form a 4- to 10-membered monocyclic or bicyclic ring containing up to three heteroatoms selected from the group consisting of O or N, wherein the 4- to 10-membered monocyclic or bicyclic ring may be substituted with one or more independently selected (C1-C6)-alkyl or (C1-C4)-alkoxy atoms. C and R D These atoms bond to each other to form a 4- to 7-membered monocyclic ring containing up to 3 heteroatoms selected from the group consisting of O or N, together with the carbon atoms to which they are bonded, wherein the 4- to 10-membered monocyclic or bicyclic rings are optionally substituted with one or more independently selected (C1-C6)-alkyl or (C1-C4)-alkoxy atoms. In some embodiments, RC and R D These atoms bond to each other to form a 4- to 6-membered monocyclic or bicyclic ring containing, together with the bonded carbon atom, up to two heteroatoms selected from the group consisting of O or N, wherein the 4- to 10-membered monocyclic or bicyclic rings may be optionally substituted with one or more independently selected methyl or methoxy atoms.

[0102] In some embodiments, R C CR 4 R 5 R 7 And R D It is hydrogen.

[0103] In some embodiments, R C CR 4 R 5 R 7 And R D It is (C1~C6)-alkyl.

[0104] In some embodiments, R C (C6~C 10 )-aryl, however (C6~C 10 )-aryl is optionally substituted with one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, or halo, wherein (C1-C4)-alkyl and (C1-C4)-alkoxy may be substituted with one or more independently selected hydroxyl or halo, R D It is hydrogen.

[0105] In some embodiments, R C (C6~C 10 )-aryl, however (C6~C 10 )-aryl may optionally be substituted with one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, or halo, and (C1-C4)-alkyl and (C1-C4)-alkoxy may be substituted with one or more independently selected hydroxyl or halo, R D It is (C1~C6)-alkyl.

[0106] In some embodiments, -C(O)NR C R D teeth, [ka] However, The wavy line indicates the binding point to thiophene. R 4 is hydrogen, (C1-C6)-alkyl, (C3-C7)-cycloalkyl, or a 4- to 7-membered heterocycline, wherein the (C1-C6)-alkyl, (C3-C7)-cycloalkyl, or 4- to 7-membered heterocycline may be substituted with one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, hydroxyl, oxo, cyano, or halo, wherein the (C1-C4)-alkoxy and (C1-C4)-alkyl may be substituted with one or more independently selected halos, and any nitrogen of the 4- to 7-membered heterocycline is C(O)OR 6 or C(O)R 6 It can be replaced with, R 5’ (C1~C4)-alkyl, (C1~C4)-alkoxy, C(O)OR 6 The (C3-C7)-cycloalkoxy, cyano, 4-7 membered heterocyclyl, or halo, wherein the (C1-C4)-alkyl and (C1-C4)-alkoxy may be substituted with one or more independently selected 4-7 membered heterocyclyls, optionally substituted with oxo or (C1-C4)-alkyl, (C1-C4)-alkoxy, -NR'R'', or halo.

[0107] In some embodiments, R 5’ is a (C1-C4)-alkyl, where the (C1-C4)-alkyl may be substituted with one or more independently selected 4- to 7-membered heterocyclines, optionally substituted with oxo, (C1-C4)-alkyl, (C1-C4)-alkoxy, -NR'R'', or halo. For example, R 5’ It is methyl or ethyl (for example, methyl).

[0108] In some embodiments, R 5’ is a (C1-C4)-alkoxy, where the (C1-C4)-alkoxy may be substituted with one or more independently selected 4- to 7-membered heterocyclines, optionally substituted with oxo or (C1-C4)-alkyl, (C1-C4)-alkoxy, -NR'R'', or halo. For example, R 5’ It is methoxy.

[0109] In some embodiments, R 5’ C(O)OR 6 For example, R 5’ This is C(O)OMe.

[0110] In some embodiments, R 5’ is a (C3-C7)-cycloalkoxy. In some embodiments, R 5’ It is a (C5~C6)-cycloalkoxy.

[0111] In some embodiments, R 5’ It is cyano.

[0112] In some embodiments, R 5’ These are heterocyclines with 4 to 7 members.

[0113] In some embodiments, R 5’ This is a halo (for example, a fluoro).

[0114] In some embodiments, -C(O)NR C R D teeth, [ka] However, The wavy line indicates the binding point to thiophene. R 4is hydrogen, methyl, or ethyl, wherein methyl or ethyl may be substituted with one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, hydroxyl, oxo, cyano, or halo, wherein (C1-C4)-alkoxy and (C1-C4)-alkyl may be substituted with one or more independently selected halo, and any nitrogen of the 4-7 membered heterocyclil is C(O)OR 6 or C(O)R 6 It can be replaced with this.

[0115] R 5’ These are methyl, methoxy, or fluoro compounds.

[0116] Variable R 4 , R 5 , and R 7 In some embodiments, R 4 It is hydrogen.

[0117] In some embodiments, R 4 is (C1~C6)-alkyl, wherein the (C1~C6)-alkyl may be substituted with one or more independently selected (C1~C4)-alkyl, (C1~C4)-alkoxy, oxo, cyano, or halo, wherein the (C1~C4)-alkoxy and (C1~C4)-alkyl may be substituted with one or more independently selected halos.

[0118] In some embodiments, R 4 is a (C3-C7)-cycloalkyl group, wherein the (C3-C7)-cycloalkyl group may be substituted with one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, oxo, cyano, or halo groups, wherein the (C1-C4)-alkoxy and (C1-C4)-alkyl groups may be substituted with one or more independently selected halo groups.

[0119] In some embodiments, R 4The 4-7 member heterocycline is a 4- to 7 member heterocycline, which may be substituted with one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, oxo, cyano, or halo, wherein the (C1-C4)-alkoxy and (C1-C4)-alkyl may be substituted with one or more independently selected halo, and any nitrogen of the 4- to 7 member heterocycline is C(O)OR 6 or C(O)R 6 It can be replaced with this.

[0120] In some embodiments, R 4 R is hydrogen, (C1-C6)-alkyl, cyclopropyl, cyclobutyl, or cyclopentyl, where (C1-C6)-alkyl, cyclopropyl, cyclobutyl, or cyclopentyl may be substituted with one or more independently selected (C1-C4)-alkoxy or halo. In some embodiments, R 4 is (C1-C6)-alkyl, cyclopropyl, cyclobutyl, or cyclopentyl, where (C1-C6)-alkyl, cyclopropyl, cyclobutyl, or cyclopentyl may be substituted with one or more (C1-C4)-alkoxy or fluoro groups. In some embodiments, R 4 is (C1-C6)-alkyl, cyclopropyl, cyclobutyl, or cyclopentyl, where (C1-C6)-alkyl, cyclopropyl, cyclobutyl, and cyclopentyl may be substituted with one fluoropolymer. In some embodiments, R 4 is a (C1-C6)-alkyl group, where the (C1-C6)-alkyl group may be substituted with one or more independently selected halos. In some embodiments, R 4 is a (C1-C3)-alkyl group, where the (C1-C3)-alkyl group may be substituted with one or more independently selected halos. In some embodiments, R 4 is a (C1-C3)-alkyl group, where the (C1-C3)-alkyl group may be substituted with one fluoropolymer. In some embodiments, R 4is methyl or ethyl, where methyl or ethyl may be substituted with one fluoropolymer. In some embodiments, R 4 is methyl or ethyl. For example, R 4 It is methyl. For example, R 4 It is ethyl.

[0121] In some embodiments, R 4 R is hydrogen, (C1-C6)-alkyl, cyclopropyl, cyclobutyl, or cyclopentyl, where (C1-C6)-alkyl, cyclopropyl, cyclobutyl, or cyclopentyl may be substituted with one or more (C1-C4)-alkoxy or fluoro groups. In some embodiments, R 4 R is hydrogen, (C1-C6)-alkyl, cyclopropyl, cyclobutyl, or cyclopentyl, where (C1-C6)-alkyl, cyclopropyl, cyclobutyl, and cyclopentyl may be substituted with one methoxy or one fluoro. In some embodiments, R 4 R is hydrogen or (C1-C6)-alkyl, where (C1-C6)-alkyl may be substituted with one or more independently selected (C1-C4)-alkoxy or halo. In some embodiments, R 4 R is hydrogen or (C1-C3)-alkyl, where (C1-C3)-alkyl may be substituted with one or more independently selected halos. In some embodiments, R 4 R is hydrogen or (C1-C3)-alkyl, where the (C1-C3)-alkyl may be substituted with one halo. In some embodiments, R 4 is hydrogen or an unsubstituted (C1-C3)-alkyl. In some embodiments, R 4 is hydrogen or methyl. In some embodiments, R 4 It is hydrogen.

[0122] In some embodiments, R 4is a (C1-C6)-alkyl or 4-7 membered heterocycline, wherein the (C1-C6)-alkyl or 4-7 membered heterocycline may be substituted with one or more independently selected (C1-C4)-alkoxy or halo, and any nitrogen of the 4-7 membered heterocycline is C(O)OR 6 or C(O)R 6 It may be replaced with R. In some embodiments, 4 is hydrogen or (C1-C6)-alkyl, where (C1-C6)-alkyl may be substituted with one or more independently selected (C1-C4)-alkoxy or halo.

[0123] In some embodiments, R 4 is hydrogen, methyl, or methoxymethyl.

[0124] In some embodiments, R 4 The (C3-C7)-cycloalkyl or 4-7 membered heterocycline is a (C3-C7)-cycloalkyl or 4-7 membered heterocycline, each of which may be substituted with one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, oxo, cyano, or halo, wherein the (C1-C4)-alkoxy and (C1-C4)-alkyl may be substituted with one or more fluoro, and any nitrogen of the 4-7 membered heterocycline is C(O)OR 6 or C(O)R 6 It may be replaced with R. In some embodiments, 4 is cyclobutyl, cyclopentyl, or a 4- to 7-membered heterocycline, each of which may be substituted with one or more independently selected halos, and any nitrogen of the 4- to 7-membered heterocycline is C(O)OR 6 or C(O)R 6 It may be replaced with R. In some embodiments, 4 is a piperidinyl which may be substituted by one or more independently selected halos, and the nitrogen of piperidinyl is C(O)OR 6 or C(O)R 6 It can be replaced with this.

[0125] In some embodiments, R6 is methyl or t-butyl. For example, R 6 It is methyl. For example, R 6 It is t-butyl.

[0126] In some embodiments, R 5 This is one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, C(O)OR 6 , (C1~C6)-alkyl which may be substituted with (C3~C7)-cycloalkoxy, cyano, 4~7-membered heterocyclyl, or halo, wherein (C1~C4)-alkyl and (C1~C4)-alkoxy may be substituted with one or more independently selected 4~7-membered heterocyclyl which may optionally be substituted with oxo or (C1~C4)-alkyl, (C1~C4)-alkoxy, -NR'R'', or halo. In some embodiments, R 5 This is one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, C(O)OR 6 , (C1-C3)-alkyl which may be substituted with (C3-C7)-cycloalkoxy, cyano, 4- to 7-membered heterocyclyl, or halo, wherein (C1-C4)-alkyl and (C1-C4)-alkoxy may be substituted with one or more independently selected 4- to 7-membered heterocyclyl which may optionally be substituted with oxo or (C1-C4)-alkyl, (C1-C4)-alkoxy, -NR'R'', or halo. In some embodiments, R 5 (C1~C6)-alkyl is methyl, ethyl, or propyl (e.g., isopropyl). In some embodiments, R 5 (C1-C6)-alkyl is methyl.

[0127] In some embodiments, R 5is a (C3-C7)-cycloalkyl, wherein the (C3-C7)-cycloalkyl may be substituted with one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, cyano, 4- to 7-membered heterocyclyl, or halo, wherein the (C1-C4)-alkyl and (C1-C4)-alkoxy may be substituted with one or more fluoro, wherein the (C3-C7)-cycloalkyl may be condensed with a 4- to 7-membered heterocyclyl or (C3-C7)-cycloalkyl. In some embodiments, R 5 is a (C3-C7)-alkyl group, where the (C3-C7)-alkyl group may be substituted with one or more independently selected (C1-C4)-alkyl groups, (C1-C4)-alkoxy groups, cyano groups, 4-7 membered heterocyclyl groups, or halos, where the (C1-C4)-alkyl and (C1-C4)-alkoxy groups may be substituted with one or more fluoro groups. In some embodiments, R 5 is a (C3-C7)-alkyl group, where the (C3-C7)-alkyl group may be substituted with one or more independently selected (C1-C4)-alkyl groups, methoxy groups, 4-7 member heterocyclyl groups, or halos, where the (C1-C4)-alkyl and (C1-C4)-alkoxy groups may be substituted with one or more fluoro groups. In some embodiments, R 5 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, wherein cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl is one or more independently selected (C1-C4)-alkyl, methoxy, 4-7 membered heterocyclyl, or halo, wherein (C1-C4)-alkyl and (C1-C4)-alkoxy may be substituted with one or more fluoro. In some embodiments, R 5 R is a cyclohexyl, wherein the cyclohexyl is one or more independently selected (C1-C4)-alkyl, methoxy, 4-7 membered heterocyclyl, or halo, wherein the (C1-C4)-alkyl and (C1-C4)-alkoxy may be substituted with one or more fluoros. In some embodiments, R 5is an unsubstituted (C3-C7)-cycloalkyl. In some embodiments, R 5 It is an unsubstituted cyclohexyl.

[0128] In some embodiments, R 5 It is cyanomethyl.

[0129] In some embodiments, R 5 (C6~C 10 )-aryl, however (C6~C 10 The )-aryl may be substituted with one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, cyano, 4-7 membered heterocyclyl, or halo, provided that (C1-C4)-alkyl and (C1-C4)-alkoxy may be substituted with one or more fluoro, provided that (C6-C 10 )-aryl may be condensed with a 4- to 7-membered heterocyclyl or (C3-C7)-cycloalkyl. In some embodiments, R 5 (C6~C 10 )-aryl, however (C6~C 10 The )-aryl may be substituted with one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, cyano, 4-7 membered heterocyclyl, or halo, wherein the (C1-C4)-alkyl and (C1-C4)-alkoxy may be substituted with one or more fluoro. In some embodiments, R 5 R is phenyl, wherein phenyl may be substituted with one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, cyano, 4- to 7-membered heterocyclyl, or halo, wherein (C1-C4)-alkyl and (C1-C4)-alkoxy may be substituted with one or more fluoro. In some embodiments, R 5 is phenyl, wherein phenyl may be substituted with one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, or halo, provided that (C 1~C4)-alkyl and (C1-C4)-alkoxy may be substituted with one or more fluoropolymers. In some embodiments, R 5 is phenyl, however phenyl may be substituted with one or more independently selected methyl, ethyl, methoxy, or fluoro compounds, and methyl, ethyl, and methoxy compounds may be substituted with one or more fluoro compounds.

[0130] In some embodiments, R 5 This is one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, C(O)OR 6 (C3~C7)-cycloalkoxy, cyano, 4~7 member heterocyclyl, or halo may be substituted (C6~C 10 )-aryl-(C1~C4)-alkyl, wherein (C1~C4)-alkyl and (C1~C4)-alkoxy may optionally be substituted with oxo or (C1~C4)-alkyl, (C1~C4)-alkoxy, -NR'R'' or halo, one or more independently selected 4- to 7-membered heterocyclines, except (C6~C 10 )-aryl-(C1~C4)-alkyl(C6~C 10 )-aryl may be condensed with a 4- to 7-membered heterocyclyl or (C3-C7)-cycloalkyl. In some embodiments, R 5 This is one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, C(O)OR 6 (C3~C7)-cycloalkoxy, cyano, 4~7 member heterocyclyl, or halo may be substituted (C6~C 10 )-aryl-(C1~C4)-alkyl, wherein the (C1~C4)-alkyl and (C1~C4)-alkoxy may be substituted with one or more independently selected 4- to 7-membered heterocyclines, optionally substituted with oxo or (C1~C4)-alkyl, (C1~C4)-alkoxy, -NR'R'', or halo. In some embodiments, R 5 This is one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, C(O)OR6 , a phenyl-(C1-C4)-alkyl which may be substituted with (C3-C7)-cycloalkoxy, cyano, 4-7 membered heterocyclyl, or halo, wherein (C1-C4)-alkyl and (C1-C4)-alkoxy may be substituted with one or more independently selected 4-7 membered heterocyclyl which may optionally be substituted with oxo or (C1-C4)-alkyl, (C1-C4)-alkoxy, -NR'R'', or halo. In some embodiments, R 5 This is one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, C(O)OR 6 , a phenyl-(C1-C2)-alkyl which may be substituted with (C3-C7)-cycloalkoxy, cyano, 4-7 member heterocyclyl, or halo, wherein (C1-C4)-alkyl and (C1-C4)-alkoxy may be substituted with one or more independently selected 4-7 member heterocyclyl which may optionally be substituted with oxo or (C1-C4)-alkyl, (C1-C4)-alkoxy, -NR'R'', or halo. In some embodiments, R 5 This is one or more independently selected (C1-C2)-alkyl, (C1-C2)-alkoxy, C(O)OR 6 , (C3~C7)-cycloalkoxy, or fluoro-(C1~C2)-alkyl which may be substituted. In some embodiments, R 5 This is one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, C(O)OR 6 , benzyl which may be substituted with (C3~C7)-cycloalkoxy, cyano, 4~7 member heterocyclyl, or halo, wherein (C1~C4)-alkyl and (C1~C4)-alkoxy may be substituted with one or more independently selected 4~7 member heterocyclyl which may optionally be substituted with oxo or (C1~C4)-alkyl, (C1~C4)-alkoxy, -NR'R'', or halo. In some embodiments, R 5 This is one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, C(O)OR 6, phenethyl which may be substituted with (C3~C7)-cycloalkoxy, cyano, 4~7 member heterocyclyl, or halo, wherein (C1~C4)-alkyl and (C1~C4)-alkoxy may be substituted with one or more independently selected 4~7 member heterocyclyl which may optionally be substituted with oxo or (C1~C4)-alkyl, (C1~C4)-alkoxy, -NR'R'', or halo.

[0131] In some embodiments, R 5 R is a heteroaryl, wherein the heteroaryl may be substituted with one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, cyano, 4-7 membered heterocyclyl, or halo, wherein the (C1-C4)-alkyl and (C1-C4)-alkoxy may be substituted with one or more fluoro. In some embodiments, R 5 is an unsubstituted heteroaryl. In some embodiments, R 5 The heteroaryl is a monocyclic heteroaryl. In some embodiments, R 5 The heteroaryl is a bicyclic heteroaryl. In some embodiments, R 5 The heteroaryl is thiophene, furan, benzoxazole, pyrazolyl, or imidazolyl. In some embodiments, R 5 is a benzoxazole, wherein the benzoxazole may be substituted with one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, cyano, 4-7 membered heterocyclyl, or halo, wherein the (C1-C4)-alkyl and (C1-C4)-alkoxy may be substituted with one or more fluoro. In some embodiments, R 5 This is an unsubstituted benzoxazole.

[0132] In some embodiments, R 5 This is one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, C(O)OR 6, a 4-7 membered heterocycline which may be substituted with (C3-C7)-cycloalkoxy, cyano, 4-7 membered heterocycline, or halo, wherein (C1-C4)-alkyl and (C1-C4)-alkoxy may be substituted with one or more independently selected 4-7 membered heterocyclines which may optionally be substituted with oxo or (C1-C4)-alkyl, (C1-C4)-alkoxy, -NR'R'', or halo, wherein the 4-7 membered heterocycline may be condensed with a 4-7 membered heterocycline or (C3-C7)-cycloalkyl. In some embodiments, R 5 This is one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, C(O)OR 6 , a 4-7 membered heterocycline which may be substituted with (C3-C7)-cycloalkoxy, cyano, 4-7 membered heterocycline, or halo, wherein (C1-C4)-alkyl and (C1-C4)-alkoxy may be substituted with one or more independently selected 4-7 membered heterocyclines which may be optionally substituted with oxo or (C1-C4)-alkyl, (C1-C4)-alkoxy, -NR'R'', or halo. In some embodiments, R 5 This is one or more independently selected (C1-C2)-alkyl, (C1-C2)-alkoxy, C(O)OR 6 , a 4-6 member heterocycline which may be substituted with (C3-C7)-cycloalkoxy, cyano, 4-7 member heterocycline, or halo, wherein (C1-C4)-alkyl and (C1-C4)-alkoxy may be substituted with one or more independently selected 4-7 member heterocyclines which may be optionally substituted with oxo or (C1-C4)-alkyl, (C1-C4)-alkoxy, -NR'R'', or halo. In some embodiments, R 5 A heterocyclyl contains one O-ring atom. In some embodiments, R 5 The heterocyclyl is oxetanil, tetrahydrofuranil, or tetrahydropyranil. In some embodiments, R 5 A heterocyclyl contains one N ring atom. In some embodiments, R 5The heterocyclyl is piperidinyl. In some embodiments, R 5 A heterocyclyl contains one O-ring atom and one N-ring atom. In some embodiments, R 5 Heterocyclines are, [ka] In some embodiments, R 5 These are unsubstituted 4- to 7-membered heterocyclines.

[0133] In some embodiments, R 5 is a (C3-C7)-cycloalkyl, phenyl, or heteroaryl, wherein the (C3-C7)-cycloalkyl, phenyl, or heteroaryl may be substituted with one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, cyano, 4- to 7-membered heterocyclyl, or halo, wherein the (C1-C4)-alkyl and (C1-C4)-alkoxy may be substituted with one or more fluoro. In some embodiments, R 5 R is a phenyl or heteroaryl, wherein the phenyl or heteroaryl may be substituted with one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, cyano, 4-7 membered heterocyclyl, or halo, wherein the (C1-C4)-alkyl and (C1-C4)-alkoxy may be substituted with one or more fluoro. In some embodiments, R 5 R is a (C3-C7)-cycloalkyl, phenyl, or heteroaryl group, where the (C3-C7)-cycloalkyl, phenyl, or heteroaryl group may be substituted with one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, 4- to 7-membered heterocyclyl, or fluoro group. In some embodiments, R 5 is a phenyl or heteroaryl, wherein the phenyl or heteroaryl may be substituted with one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, 4- to 7-membered heterocyclyl, or fluoro.

[0134] In some embodiments, R 5 is phenyl or benzoxazolyl, each of which may be substituted with one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, cyano, or halo, provided that (C 1~ C4)-alkyl and (C1-C4)-alkoxy may be substituted with one or more fluoropolymers. In some embodiments, R 5 is phenyl or benzoxazolyl, each of which may be substituted with one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, cyano, chloro or fluoro, provided that (C 1~ C4)-alkyl and (C1-C4)-alkoxy may be substituted with one or more fluoropolymers. In some embodiments, R 5 R is phenyl or benzoxazolyl, each of which may be substituted with one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, cyano, or fluoro. In some embodiments, R 5 R is phenyl or benzoxazolyl, each of which may be substituted with one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, or fluoro groups. In some embodiments, R 5 is phenyl or benzoxazolyl, each of which may be substituted with one or more fluoropolymers. In some embodiments, R 5 is benzoxazolyl, which may be substituted with one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, cyano, or halo, provided that (C 1~ C4)-alkyl and (C1-C4)-alkoxy groups may be substituted with one or more fluoropolymers.

[0135] In some embodiments, R 5 is phenyl, which may be substituted with one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, cyano, or halo, provided that (C 1~C4)-alkyl and (C1-C4)-alkoxy groups may be substituted with one or more fluoropolymers. In some embodiments, R 5 R is a phenyl which may optionally be substituted with one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, cyano, 4- to 7-membered heterocyclyl, or halo, wherein (C1-C4)-alkyl and (C1-C4)-alkoxy may be substituted with one or more fluoro. In some embodiments, R 5 R is a phenyl which may optionally be substituted with one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, cyano, or fluoro, wherein (C1-C4)-alkyl and (C1-C4)-alkoxy may be substituted with one or more fluoro. In some embodiments, R 5 R is a phenyl which may optionally be substituted with one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, or fluoro groups, wherein the (C1-C4)-alkyl groups may be substituted with one or more fluoro groups. In some embodiments, R 5 R is a phenyl which may optionally be substituted with one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, or fluoro groups, wherein the (C1-C4)-alkyl groups may be substituted with one or more fluoro groups. In some embodiments, R 5 R is phenyl and may be substituted with one or more independently selected (C1-C4)-alkoxy or halo. In some embodiments, R 5 R is a phenyl which may be substituted with one or more independently selected (C1-C4)-alkoxy or fluoro groups. In some embodiments, R 5 R is a phenyl which may be substituted with one or more fluoro or methoxy groups. For example, R 5 It is phenyl. For example, R 5 It is fluorophenyl. For example, R 5 is methoxyphenyl. For example, R 5 It is 4-fluorophenyl. For example, R 5 It is 3-methoxyphenyl.

[0136] In some embodiments, R 5 is phenyl, 3-pyridinyl, or 4-pyridinyl, each of which may be substituted with one or more independently selected (C1-C4)-alkyl or (C1-C4)-alkoxy compounds, provided that (C 1~ C4)-alkyl and (C1-C4)-alkoxy groups may be substituted with one or more fluoropolymers.

[0137] In some embodiments, R 4 and R 5 These atoms bond to each other, forming a 4-7 membered ring containing up to two heteroatoms selected from the group consisting of O or N, however, (i) The ring is one or more independently selected (C6~C 10 (C1~C4)-alkyl, 4~7 member heterocyclil, (C1~C4)-alkyl, (C1~C4)-alkoxy, oxo, cyano, or halo may be substituted, provided that (C1~C4)-alkyl may optionally be substituted with one or more independently selected 4~7 member heterocyclil or fluoro, and each nitrogen of the 4~7 member heterocyclil may be C(O)OR 6 or C(O)R 6 It can be independently replaced, (ii) The ring is (C6~C 10 It may be condensed with )-aryl or heteroaryl.

[0138] In some embodiments, R 4 and R 5 These atoms bond to each other, forming a 5-6 membered ring containing up to two heteroatoms selected from the group consisting of O or N, however, (i) The ring is one or more independently selected (C6~C 10(C1~C4)-alkyl, 4~7 member heterocyclil, (C1~C4)-alkyl, (C1~C4)-alkoxy, oxo, cyano, or halo may be substituted, provided that (C1~C4)-alkyl may optionally be substituted with one or more independently selected 4~7 member heterocyclil or fluoro, and each nitrogen of the 4~7 member heterocyclil may be C(O)OR 6 or C(O)R 6 It can be independently replaced, (ii) The ring is (C6~C 10 It may be condensed with )-aryl or heteroaryl.

[0139] In some embodiments, R 4 and R 5 These atoms bond to each other, forming a 5-6 membered ring containing up to two heteroatoms selected from the group consisting of O or N, however, (i) The ring is one or more independently selected (C6~C 10 (C1~C4)-alkyl, 4~7 member heterocyclil, (C1~C4)-alkyl, (C1~C4)-alkoxy, oxo, cyano, or halo may be substituted, provided that (C1~C4)-alkyl may optionally be substituted with one or more independently selected 4~7 member heterocyclil or fluoro, and each nitrogen of the 4~7 member heterocyclil may be C(O)OR 6 or C(O)R 6 It can be independently replaced, (ii) The ring may be condensed with phenyl.

[0140] In some embodiments, R 4 and R 5 These atoms bond to each other, forming a 5-6 membered ring containing, together with the bonded carbon atom, up to one heteroatom selected from the group consisting of O or N, however, (i) The ring is one or more independently selected (C6~C 10(C1~C4)-alkyl, 4~7 member heterocyclil, (C1~C4)-alkyl, (C1~C4)-alkoxy, oxo, cyano, or fluoro may be substituted, provided that (C1~C4)-alkyl may optionally be substituted with one or more independently selected 4~7 member heterocyclil or fluoro, and each nitrogen of the 4~7 member heterocyclil may be C(O)OR 6 or C(O)R 6 It can be independently replaced, (ii) The ring may be condensed with phenyl.

[0141] In some embodiments, R 4 and R 5 These atoms bond to each other, forming a 5-6 membered ring containing, together with the bonded carbon atom, up to one heteroatom selected from the group consisting of O or N, however, (i) The ring may be substituted with one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, oxo, cyano, or fluoro groups, wherein the (C1-C4)-alkyl group may be substituted with one or more fluoro groups. (ii) The ring may be condensed with phenyl.

[0142] In some embodiments, R 4 and R 5 These atoms bond to each other, forming a 5-6 membered ring containing one heteroatom selected from the group consisting of O or N, however, (i) The ring may be substituted with one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, oxo, cyano, or fluoro groups, wherein the (C1-C4)-alkyl group may be substituted with one or more fluoro groups. (ii) The ring may be condensed with phenyl.

[0143] In some embodiments, R 4 and R 5These atoms bond to each other, forming a 5-6 membered ring containing one heteroatom selected from the group consisting of O or N, however, (i) The ring may be substituted with one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, oxo, cyano, or fluoro groups, wherein the (C1-C4)-alkyl group may be substituted with one or more fluoro groups. (ii) The ring may be condensed with phenyl, R 7 (C1-C4) may be substituted with hydrogen and one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, oxo, cyano, or halo (C6-C 10 Selected from )-aryl, where (C1-C4)-alkoxy and (C1-C4)-alkyl may be substituted with one or more independently selected halos, and the nitrogen of the 4-7 membered heterocycline is C(O)OR 6 or C(O)R 6 It can be replaced with this.

[0144] In some embodiments, R 4 and R 5 These atoms bond with each other, forming a 5-6 membered ring that does not contain heteroatoms, however, (i) The ring may be substituted with one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, oxo, cyano, or fluoro groups, wherein the (C1-C4)-alkyl group may be substituted with one or more fluoro groups. (ii) The ring may be condensed with phenyl.

[0145] In some embodiments, R 4 and R 5 These atoms bond with each other to form a 5-6 membered ring containing up to one oxygen atom, although the ring may be fused with phenyl.

[0146] In some embodiments, R 4 and R 5These atoms bond with each other, forming cyclopentyl atoms together with the carbon atoms to which they are bonded.

[0147] In some embodiments, R 4 and R 5 These bond with each other to form cyclopentyl with the carbon atoms to which they are bonded, R 7 is a phenyl which may be substituted with one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, oxo, cyano, or halo, wherein (C1-C4)-alkoxy and (C1-C4)-alkyl may be substituted with one or more independently selected halo, and the nitrogen of a 4-7 membered heterocyclil is C(O)OR 6 or C(O)R 6 It can be replaced with this.

[0148] In some embodiments, R 4 and R 5 These atoms bond to each other to form a six-membered ring containing up to one oxygen atom along with the carbon atoms to which they are bonded, wherein the ring is condensed with phenyl. In some embodiments, R 4 and R 5 These atoms bond with each other, forming 1,2,3,4-tetrahydronaphthalenyl or chromanyl together with the carbon atoms to which they are bonded.

[0149] In some embodiments, R 7 It is hydrogen.

[0150] In some embodiments, R 7 R is (C1~C6)-alkyl, where (C1~C6)-alkyl may be substituted with one or more independently selected (C1~C4)-alkyl, (C1~C4)-alkoxy, oxo, cyano, or halo, where (C1~C4)-alkoxy and (C1~C4)-alkyl may be substituted with one or more independently selected halo. In some embodiments, R 7is (C1~C3)-alkyl, wherein (C1~C6)-alkyl may be substituted with one or more independently selected (C1~C4)-alkyl, (C1~C4)-alkoxy, oxo, cyano, or halo, wherein (C1~C4)-alkoxy and (C1~C4)-alkyl may be substituted with one or more independently selected halos.

[0151] In some embodiments, R 7 is a (C3-C7)-cycloalkyl group, wherein the (C3-C7)-cycloalkyl group may be substituted with one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, oxo, cyano, or halo groups, wherein the (C1-C4)-alkoxy and (C1-C4)-alkyl groups may be substituted with one or more independently selected halo groups.

[0152] In some embodiments, R 7 The 4-7 member heterocycline is a 4- to 7 member heterocycline, which may be substituted with one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, oxo, cyano, or halo, wherein the (C1-C4)-alkoxy and (C1-C4)-alkyl may be substituted with one or more independently selected halo, and any nitrogen of the 4- to 7 member heterocycline is C(O)OR 6 or C(O)R 6 It can be replaced with this.

[0153] In some embodiments, R 7 (C6~C 10 )-aryl, however (C6~C 10 The )-aryl group may be substituted with one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, oxo, cyano, or halo groups, wherein the (C1-C4)-alkoxy and (C1-C4)-alkyl groups may be substituted with one or more independently selected halo groups.

[0154] In some embodiments, R 7R is phenyl, wherein phenyl may be substituted with one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, oxo, cyano, or halo, wherein (C1-C4)-alkoxy and (C1-C4)-alkyl may be substituted with one or more independently selected halos. In some embodiments, R 7 R is phenyl, where phenyl may be substituted with one or more independently selected halos. In some embodiments, R 7 (C6~C 10 )-aryl, however (C6~C 10 )-aryl may be substituted with one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, oxo, cyano, or halo, provided that (C1-C4)-alkoxy and (C1-C4)-alkyl may be substituted with one or more independently selected halo, and the nitrogen of the 4-7 membered heterocyclil may be C(O)OR 6 or C(O)R 6 It may be replaced with R. In some embodiments, 7 R is phenyl, where phenyl may be substituted with one or more independently selected halos. In some embodiments, R 7 R is phenyl, where phenyl may be substituted with one or more independently selected fluoropolymers. In some embodiments, R 7 It is 4-fluorophenyl.

[0155] In some embodiments, R 4 and R 5 These atoms bond to each other, forming a 5-6 membered ring containing one heteroatom selected from the group consisting of O or N, however, (i) The ring may be substituted with one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, oxo, cyano, or fluoro groups, wherein the (C1-C4)-alkyl group may be substituted with one or more fluoro groups. (ii) The ring may be condensed with phenyl, R7 It is hydrogen.

[0156] In some embodiments, R 4 and R 5 These bond with each other to form cyclopentyl with the carbon atoms to which they are bonded, R 7 is phenyl, and phenyl may be substituted with one or more independently selected halos.

[0157] In some embodiments, R 6 It is hydrogen.

[0158] In some embodiments, R 6 is (C1~C4)-alkyl. In some embodiments, R 6 is methyl, ethyl, isopropyl, or t-butyl. For example, R 6 It is methyl. For example, R 6 It is t-butyl.

[0159] In some embodiments (for example, when the compound is a compound of formula (A)), -C(O)NHCH(R 4 )R 7 R 5 teeth, [ka] However, The wavy line indicates the binding point to thiophene. R 4 is hydrogen, (C1-C6)-alkyl, (C3-C7)-cycloalkyl, or a 4- to 7-membered heterocycline, wherein the (C1-C6)-alkyl, (C3-C7)-cycloalkyl, or 4- to 7-membered heterocycline may be substituted with one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, hydroxyl, oxo, cyano, or halo, wherein the (C1-C4)-alkoxy and (C1-C4)-alkyl may be substituted with one or more independently selected halos, and any nitrogen of the 4- to 7-membered heterocycline is C(O)OR 6 or C(O)R6 It can be replaced with, R 5’ (C1~C4)-alkyl, (C1~C4)-alkoxy, C(O)OR 6 The (C3-C7)-cycloalkoxy, cyano, 4-7 membered heterocyclyl, or halo, wherein the (C1-C4)-alkyl and (C1-C4)-alkoxy may be substituted with one or more independently selected 4-7 membered heterocyclyls, optionally substituted with oxo or (C1-C4)-alkyl, (C1-C4)-alkoxy, -NR'R'', or halo.

[0160] In some embodiments, R 5’ is a (C1-C4)-alkyl, where the (C1-C4)-alkyl may be substituted with one or more independently selected 4- to 7-membered heterocyclines, optionally substituted with oxo, (C1-C4)-alkyl, (C1-C4)-alkoxy, -NR'R'', or halo. For example, R 5’ It is methyl or ethyl (for example, methyl).

[0161] In some embodiments, R 5’ is a (C1-C4)-alkoxy, where the (C1-C4)-alkoxy may be substituted with one or more independently selected 4- to 7-membered heterocyclines, optionally substituted with oxo or (C1-C4)-alkyl, (C1-C4)-alkoxy, -NR'R'', or halo. For example, R 5’ It is methoxy.

[0162] In some embodiments, R 5’ C(O)OR 6 For example, R 5’ This is C(O)OMe.

[0163] In some embodiments, R 5’ is a (C3-C7)-cycloalkoxy. In some embodiments, R 5’ It is a (C5~C6)-cycloalkoxy.

[0164] In some embodiments, R 5’ It is cyano.

[0165] In some embodiments, R 5’ These are heterocyclines with 4 to 7 members.

[0166] In some embodiments, R 5’ This is a halo (for example, a fluoro).

[0167] In some embodiments (for example, when the compound is a compound of formula (A)), -C(O)NHCH(R 4 ) R 7 R 5 teeth, [ka] However, The wavy line indicates the binding point to thiophene. R 4 is hydrogen, methyl, or ethyl, wherein methyl or ethyl may be substituted with one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, hydroxyl, oxo, cyano, or halo, wherein (C1-C4)-alkoxy and (C1-C4)-alkyl may be substituted with one or more independently selected halo, and any nitrogen of the 4-7 membered heterocyclil is C(O)OR 6 or C(O)R 6 It can be replaced with, R 5’ These are methyl, methoxy, or fluoro compounds.

[0168] In some embodiments, R 4 and R 5 The stereochemistry of the bonded atoms is (S). In some embodiments, R 4 and R 5 The stereochemistry of the bonded atoms is (R).

[0169] In some embodiments (for example, when the compound is a compound of formula (A), (IA), or (IB)), -C(O)NHCH(R 4 )R 7 R 5 teeth, [ka] However, The wavy line indicates the binding point to thiophene. R 4 is hydrogen, (C1-C6)-alkyl, (C3-C7)-cycloalkyl, or a 4- to 7-membered heterocycline, wherein the (C1-C6)-alkyl, (C3-C7)-cycloalkyl, or 4- to 7-membered heterocycline may be substituted with one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, hydroxyl, oxo, cyano, or halo, wherein the (C1-C4)-alkoxy and (C1-C4)-alkyl may be substituted with one or more independently selected halos, and any nitrogen of the 4- to 7-membered heterocycline is C(O)OR 6 or C(O)R 6 It can be replaced with, R 5’ (C1~C4)-alkyl, (C1~C4)-alkoxy, C(O)OR 6 The (C3-C7)-cycloalkoxy, cyano, 4-7 membered heterocyclyl, or halo, wherein the (C1-C4)-alkyl and (C1-C4)-alkoxy may be substituted with one or more independently selected 4-7 membered heterocyclyls, optionally substituted with oxo or (C1-C4)-alkyl, (C1-C4)-alkoxy, -NR'R'', or halo.

[0170] In some embodiments, R 5’ is a (C1-C4)-alkyl, where the (C1-C4)-alkyl may be substituted with one or more independently selected 4- to 7-membered heterocyclines, optionally substituted with oxo, (C1-C4)-alkyl, (C1-C4)-alkoxy, -NR'R'', or halo. For example, R 5’It is methyl or ethyl (for example, methyl).

[0171] In some embodiments, R 5’ is a (C1-C4)-alkoxy, where the (C1-C4)-alkoxy may be substituted with one or more independently selected 4- to 7-membered heterocyclines, optionally substituted with oxo or (C1-C4)-alkyl, (C1-C4)-alkoxy, -NR'R'', or halo. For example, R 5’ It is methoxy.

[0172] In some embodiments, R 5’ C(O)OR 6 For example, R 5’ This is C(O)OMe.

[0173] In some embodiments, R 5’ is a (C3-C7)-cycloalkoxy. In some embodiments, R 5’ It is a (C5~C6)-cycloalkoxy.

[0174] In some embodiments, R 5’ It is cyano.

[0175] In some embodiments, R 5’ These are heterocyclines with 4 to 7 members.

[0176] In some embodiments, R 5’ This is a halo (for example, a fluoro).

[0177] In some embodiments (for example, when the compound is a compound of formula (A), (IA), or (IB)), -C(O)NHCH(R 4 )R 7 R 5 teeth, [ka] However, The wavy line indicates the binding point to thiophene. R 4 is hydrogen, methyl, or ethyl, wherein methyl or ethyl may be substituted with one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, hydroxyl, oxo, cyano, or halo, wherein (C1-C4)-alkoxy and (C1-C4)-alkyl may be substituted with one or more independently selected halo, and any nitrogen of the 4-7 membered heterocyclil is C(O)OR 6 or C(O)R 6 It can be replaced with, R 5’ These are methyl, methoxy, or fluoro compounds.

[0178] In some embodiments, R 4 and R 5 The stereochemistry of the bonded atoms is (S). In some embodiments, R 4 and R 5 The stereochemistry of the bonded atoms is (R).

[0179] Non-limited combinations In some embodiments, R E is -C(O)-NR A R B And, R A -CR 1 R 2 R 3 And, R B It is hydrogen.

[0180] In some embodiments, Z is NH2, R E is -C(O)-NR A R B And, R A -CR 1 R 2 R 3 And, R B It is hydrogen, R CCR 4 R 5 R 7 And, R D It is hydrogen.

[0181] In some embodiments, R E is -C(O)-NR A R B And, R A -CR 1 R 2 R 3 And, R B It is hydrogen, R 1 and R 2 These are, independently, hydrogen or methyl, R 3 is methyl or ethyl, each of which may be substituted with one or more independently selected hydroxyl, (C1-C4)-alkoxy, chloro, or fluoro, wherein (C1-C4)-alkoxy may be substituted with one or more fluoro, or R 1 is hydrogen, R 2 and R 3 These atoms bond to each other to form a 3- to 7-membered ring containing up to two heteroatoms selected from the group consisting of O or N, together with the carbon atom to which they are bonded, wherein the ring contains one or more independently selected hydroxyls. ( C 1~ It may be substituted with C4)-alkyl, oxo, or halo.

[0182] In some embodiments, R E is -C(O)-NR A R B And, R A -CR 1 R 2 R 3 And, R B It is hydrogen, R 1 and R2 is independently hydrogen or methyl, R 3 is methyl or ethyl, each of which may be substituted with one or more independently selected hydroxyl, (C1-C4)-alkoxy, chloro, or fluoro, provided that (C1-C4)-alkoxy may be substituted with one or more fluoro.

[0183] In some embodiments, Z is NH2, R E is -C(O)-NR A R B is, R A is -CR 1 R 2 R 3 is, R B is hydrogen, R C is CR 4 R 5 R 7 is, R D is hydrogen.

[0184] X is carbon and Y is nitrogen, R 1 and R 2 are independently hydrogen or methyl, R 3 is methyl or ethyl, each of which may be substituted with one or more independently selected hydroxyl, (C1-C4)-alkoxy, chloro, or fluoro, provided that (C1-C4)-alkoxy may be substituted with one or more fluoro, R 4is hydrogen, (C1-C6)-cycloalkyl, (C3-C7)-cycloalkyl, or 4-7 member heterocyclyl, each of which may be substituted with one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, oxo, cyano, or halo, provided that (C1-C4)-alkoxy and (C1-C4)-alkyl may be substituted with one or more fluoro, and any nitrogen of the 4-7 member heterocyclyl is C(O)OR 6 or C(O)R 6 and may be substituted with R 5 is (C3-C7)-cycloalkyl, phenyl, or heteroaryl, provided that (C3-C7)-cycloalkyl, phenyl, or heteroaryl may be substituted with one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, cyano, 4-7 member heterocyclyl, or halo, provided that (C1-C4)-alkyl and (C1-C4)-alkoxy may be substituted with one or more fluoro R 6 is methyl or t-butyl.

[0185] In some embodiments Z is NH2 R E is -C(O)-NR A R B and R A is -CR 1 R 2 R 3 and R B is hydrogen R C is CR 4 R 5 R 7 and R D is hydrogen.

[0186] X is nitrogen and Y is carbon R 1 and R 2 are each independently hydrogen or methyl R 3 is methyl or ethyl, each of which may be substituted with one or more independently selected hydroxyl, (C1-C4)-alkoxy, chloro, or fluoro, wherein (C1-C4)-alkoxy may be substituted with one or more fluoro. R 4 is hydrogen, (C1-C6)-cycloalkyl, (C3-C7)-cycloalkyl, or a 4-7 membered heterocycline, each of which may be substituted with one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, oxo, cyano, or halo, wherein (C1-C4)-alkoxy and (C1-C4)-alkyl may be substituted with one or more fluoro, and any nitrogen of the 4-7 membered heterocycline is C(O)OR 6 or C(O)R 6 It can be replaced with, R 5 is a (C3-C7)-cycloalkyl, phenyl, or heteroaryl group, wherein the (C3-C7)-cycloalkyl, phenyl, or heteroaryl group may be substituted with one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, cyano, 4- to 7-membered heterocyclyl, or halo group, wherein the (C1-C4)-alkyl and (C1-C4)-alkoxy groups may be substituted with one or more fluoro groups. R 6 It is methyl or t-butyl.

[0187] In some embodiments, Z is -NHR F And R F is hydrogen or (C1~C6)-alkyl, where (C1~C6)-alkyl is optionally substituted with one or more independently selected -NR'R''. R E is -C(O)-NR A R B And, R A -CR 1 R 2 R 3 And, R B It is hydrogen, R C CR 4 R 5 R 7 And, R D It is hydrogen.

[0188] Is X nitrogen and Y carbon? R 1 and R 2 These are, independently, hydrogen or methyl, R 3 is methyl or ethyl, each of which may be substituted with one or more independently selected hydroxyl, (C1-C4)-alkoxy, chloro, or fluoro, wherein (C1-C4)-alkoxy may be substituted with one or more fluoro. R 4 is hydrogen, (C1-C6)-cycloalkyl, (C3-C7)-cycloalkyl, or a 4-7 membered heterocycline, each of which may be substituted with one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, oxo, cyano, or halo, wherein (C1-C4)-alkoxy and (C1-C4)-alkyl may be substituted with one or more fluoro, and any nitrogen of the 4-7 membered heterocycline is C(O)OR 6 or C(O)R 6 It can be replaced with, R 5 is a (C3-C7)-cycloalkyl, phenyl, or heteroaryl group, wherein the (C3-C7)-cycloalkyl, phenyl, or heteroaryl group may be substituted with one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, cyano, 4- to 7-membered heterocyclyl, or halo group, wherein the (C1-C4)-alkyl and (C1-C4)-alkoxy groups may be substituted with one or more fluoro groups. R 6 It is methyl or t-butyl.

[0189] In some embodiments, Z is H, R E is -C(O)-NR A R B And, R A -CR 1 R 2 R 3 And, R B It is hydrogen, R C CR 4 R 5 R 7 And, R D It is hydrogen.

[0190] X is nitrogen, and Y is carbon. R 1 and R 2 These are, independently, hydrogen or methyl, R 3 is methyl or ethyl, each of which may be substituted with one or more independently selected hydroxyl, (C1-C4)-alkoxy, chloro, or fluoro, wherein (C1-C4)-alkoxy may be substituted with one or more fluoro. R 4 is hydrogen, (C1-C6)-cycloalkyl, (C3-C7)-cycloalkyl, or a 4-7 membered heterocycline, each of which may be substituted with one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, oxo, cyano, or halo, wherein (C1-C4)-alkoxy and (C1-C4)-alkyl may be substituted with one or more fluoro, and any nitrogen of the 4-7 membered heterocycline is C(O)OR 6 or C(O)R 6 It can be replaced with, R 5is (C3-C7)-cycloalkyl, phenyl, or heteroaryl, provided that (C3-C7)-cycloalkyl, phenyl, or heteroaryl may be substituted with one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, cyano, 4- to 7-membered heterocyclyl, or halo, provided that (C1-C4)-alkyl and (C1-C4)-alkoxy may be substituted with one or more fluoro, R 6 is methyl or t-butyl.

[0191] In some embodiments, Z is -NH2, R E is H or halo, R C is CR 4 R 5 R 7 and R D is hydrogen.

[0192] X is nitrogen and Y is carbon, R 4 is hydrogen, (C1-C6)-cycloalkyl, (C3-C7)-cycloalkyl, or 4- to 7-membered heterocyclyl, each of which may be substituted with one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, oxo, cyano, or halo, provided that (C1-C4)-alkoxy and (C1-C4)-alkyl may be substituted with one or more fluoro, and any nitrogen of 4- to 7-membered heterocyclyl may be substituted with C(O)OR 6 or C(O)R 6 and R 5is a (C3-C7)-cycloalkyl, phenyl, or heteroaryl group, wherein the (C3-C7)-cycloalkyl, phenyl, or heteroaryl group may be substituted with one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, cyano, 4- to 7-membered heterocyclyl, or halo group, wherein the (C1-C4)-alkyl and (C1-C4)-alkoxy groups may be substituted with one or more fluoro groups. R 6 It is methyl or t-butyl.

[0193] In some embodiments, Z is -NH2, R E is -C(O)-NR A R B , C(O)OR 6 -S(O)2NH(C1~C6)-alkyl, (C1~C6)-alkyl, or (C6~C 10 )-aryl, provided that (C1~C6)-alkyl and (C6~C 10 )-aryl is one or more independently selected (C1-C4)-alkyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl-(C1-C3)-alkyl, 4-7 member heterocyclyl, (C1-C4)-alkoxy, (C3-C7)-cycloalkoxy, -SO2R 4 , -NR 4 R 5 They may be substituted with cyano, hydroxyl, or halo, provided that (C1~C4)-alkyl, (C3~C7)-cycloalkyl, (C1~C4)-alkoxy, (C3~C7)-cycloalkyl-(C1~C3)-alkyl, and (C3~C7)-cycloalkoxy may be substituted with one or more independently selected hydroxyl, cyano, or halo. R A -CR 1 R 2 R 3 And, R B It is hydrogen, R C CR 4 R5 R 7 And, R D It is hydrogen.

[0194] X is nitrogen, and Y is carbon. R 1 and R 2 These are, independently, hydrogen or methyl, R 3 is methyl or ethyl, each of which may be substituted with one or more independently selected hydroxyl, (C1-C4)-alkoxy, chloro, or fluoro, wherein (C1-C4)-alkoxy may be substituted with one or more fluoro. R 4 is hydrogen, (C1-C6)-cycloalkyl, (C3-C7)-cycloalkyl, or a 4-7 membered heterocycline, each of which may be substituted with one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, oxo, cyano, or halo, wherein (C1-C4)-alkoxy and (C1-C4)-alkyl may be substituted with one or more fluoro, and any nitrogen of the 4-7 membered heterocycline is C(O)OR 6 or C(O)R 6 It can be replaced with, R 5 is a (C3-C7)-cycloalkyl, phenyl, or heteroaryl group, wherein the (C3-C7)-cycloalkyl, phenyl, or heteroaryl group may be substituted with one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, cyano, 4- to 7-membered heterocyclyl, or halo group, wherein the (C1-C4)-alkyl and (C1-C4)-alkoxy groups may be substituted with one or more fluoro groups. R 6 It is methyl or t-butyl.

[0195] In some embodiments, Z is NH2, R E is -C(O)-NR A R BAnd, R A -CR 1 R 2 R 3 And, R B It is hydrogen, R C CR 4 R 5 R 7 And, R D It is hydrogen.

[0196] X is carbon, and Y is nitrogen. R 1 and R 2 These are, independently, hydrogen or methyl, R 3 is methyl or ethyl, each of which may be substituted with one or more independently selected hydroxyl, (C1-C4)-alkoxy, or fluoro, wherein (C1-C4)-alkoxy may be substituted with one or more fluoro. R 4 is hydrogen or (C1~C6)-alkyl, wherein the (C1~C6)-alkyl may be substituted with one or more independently selected (C1~C4)-alkyl, (C1~C4)-alkoxy, oxo, cyano, or halo, wherein the (C1~C4)-alkoxy and (C1~C4)-alkyl may be substituted with one or more fluoro. R 5 is a phenyl or heteroaryl, wherein the phenyl or heteroaryl may be substituted with one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, cyano, 4- to 7-membered heterocyclyl, or halo, wherein the (C1-C4)-alkyl and (C1-C4)-alkoxy may be substituted with one or more fluoro.

[0197] In some embodiments, Z is NH2, R E is -C(O)-NR A R B And, R A -CR 1 R 2 R 3 And, R B It is hydrogen, R C CR 4 R 5 R 7 And, R D It is hydrogen.

[0198] X is carbon, and Y is nitrogen. R 1 and R 2 Each of these is a methyl atom that may be independently substituted with hydrogen or one or more fluorocarbons. R 3 is methyl or ethyl, each of which may be substituted with one or more independently selected hydroxyl or fluoro groups. R 4 is hydrogen or (C1-C6)-alkyl, where (C1-C6)-alkyl may be substituted with one or more fluorocarbons. R 5 is a phenyl or heteroaryl, wherein the phenyl or heteroaryl may be substituted with one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, cyano, or halo, provided that (C 1~ C4)-alkyl and (C1-C4)-alkoxy groups may be substituted with one or more fluoropolymers.

[0199] In some embodiments, Z is NH2, R E is -C(O)-NR A R B And, R A -CR 1 R 2 R 3 And, R B It is hydrogen, R CCR 4 R 5 R 7 And, R D It is hydrogen.

[0200] X is carbon, and Y is nitrogen. R 1 and R 2 Each of these is a methyl atom that may be independently substituted with hydrogen or one or more fluorocarbons. R 3 is methyl or ethyl, and each may be substituted with a hydroxyl group. R 4 is a (C1-C6)-alkyl group, where the (C1-C6)-alkyl group may be substituted with one or more fluoropolymers. R 5 is a phenyl or heteroaryl, wherein the phenyl or heteroaryl may be substituted with one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, cyano, or halo, provided that (C 1~ C4)-alkyl and (C1-C4)-alkoxy groups may be substituted with one or more fluoropolymers.

[0201] In some embodiments, Z is NH2, R E is -C(O)-NR A R B And, R A -CR 1 R 2 R 3 And, R B It is hydrogen, R C CR 4 R 5 R 7 And, R D It is hydrogen.

[0202] X is nitrogen, and Y is carbon. R 1and R 2 Each of these is a methyl atom that may be independently substituted with hydrogen or one or more fluorocarbons. R 3 is methyl or ethyl, and each may be substituted with a hydroxyl group. R 4 is a (C1-C6)-alkyl group, where the (C1-C6)-alkyl group may be substituted with one or more fluoropolymers. R 5 is a phenyl or heteroaryl, wherein the phenyl or heteroaryl may be substituted with one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, cyano, or halo, provided that (C 1~ C4)-alkyl and (C1-C4)-alkoxy groups may be substituted with one or more fluoropolymers.

[0203] In some embodiments, Z is NH2, R E is -C(O)-NR A R B And, R A -CR 1 R 2 R 3 And, R B It is hydrogen, R C CR 4 R 5 R 7 And, R D It is hydrogen.

[0204] X is carbon, and Y is nitrogen. R 1 and R 2 Each of these is a methyl atom that may be independently substituted with hydrogen or one or more fluorocarbons. R 3 is methyl or ethyl, and each may be substituted with a hydroxyl group. R 4is a (C1-C6)-alkyl which may be substituted with one or more independently selected (C1-C4)-alkoxy or halo. R 5 is phenyl, where phenyl may be substituted with one or more independently selected fluoropolymers.

[0205] In some embodiments, Z is NH2, R E is -C(O)-NR A R B And, R A -CR 1 R 2 R 3 And, R B It is hydrogen, R C CR 4 R 5 R 7 And, R D It is hydrogen.

[0206] X is carbon, and Y is nitrogen. R 1 and R 2 Each of these is a methyl atom that may be independently substituted with hydrogen or one or more fluorocarbons. R 3 is methyl or ethyl, each of which may be substituted with a hydroxyl group. R 4 It is hydrogen, R 5 is a phenyl or heteroaryl, wherein the phenyl or heteroaryl may be substituted with one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, cyano, or halo, provided that (C 1~ C4)-alkyl and (C1-C4)-alkoxy groups may be substituted with one or more fluoropolymers.

[0207] In some embodiments, Z is NH2, R E is -C(O)-NR A R B And, R A -CR 1 R 2 R 3 And, R B It is hydrogen, R C CR 4 R 5 R 7 And, R D It is hydrogen.

[0208] X is carbon, and Y is nitrogen. R 1 and R 2 Each of these is a methyl atom that may be independently substituted with hydrogen or one or more fluorocarbons. R 3 is methyl or ethyl, each of which may be substituted with a hydroxyl group. R 4 It is hydrogen, R 5 is phenyl, where phenyl may be substituted with one or more independently selected fluoropolymers.

[0209] In some embodiments, Z is NH2, R E is -C(O)-NR A R B And, R A -CR 1 R 2 R 3 And, R B It is hydrogen, R C CR 4 R 5 R 7 And, R D It is hydrogen.

[0210] X is carbon, and Y is nitrogen. R 1 and R 2 These are, independently, hydrogen or methyl, R 3 is methyl or ethyl, each of which may be substituted with one or more independently selected hydroxyl, (C1-C4)-alkoxy, chloro, or fluoro, wherein (C1-C4)-alkoxy may be substituted with one or more fluoro. R 4 The (C3-C7)-cycloalkyl or 4-7 membered heterocycline is a (C3-C7)-cycloalkyl or 4-7 membered heterocycline, each of which may be substituted with one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, oxo, cyano, or halo, wherein the (C1-C4)-alkoxy and (C1-C4)-alkyl may be substituted with one or more fluoro, and any nitrogen of the 4-7 membered heterocycline is C(O)OR 6 or C(O)R 6 It can be replaced with, R 5 is a (C3-C7)-cycloalkyl, phenyl, or heteroaryl group, wherein the (C3-C7)-cycloalkyl, phenyl, or heteroaryl group may be substituted with one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, cyano, 4- to 7-membered heterocyclyl, or halo group, wherein the (C1-C4)-alkyl and (C1-C4)-alkoxy groups may be substituted with one or more fluoro groups. R 6 It is methyl or t-butyl.

[0211] In some embodiments, Z is NH2, R E is -C(O)-NR A R B And, R A -CR 1 R 2 R 3 And, R B It is hydrogen, R C CR 4 R 5 R 7 And, R D It is hydrogen.

[0212] X is carbon, and Y is nitrogen. R 1 and R 2 These are, independently, hydrogen or methyl, R 3 is an ethyl compound which may be substituted with one or more independently selected hydroxyl, (C1-C4)-alkoxy, chloro, or fluoro groups. R 4 The (C3-C6)-cycloalkyl or 4-7 membered heterocycline, each of which may be substituted with one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, oxo, cyano, or halo, and any nitrogen of the 4-7 membered heterocycline is C(O)OR 6 or C(O)R 6 It can be replaced with, R 5 is a phenyl or heteroaryl compound, wherein the phenyl or heteroaryl compound may be substituted with one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, cyano, 4-7 membered heterocyclyl, or fluoro compounds. R 6 It is methyl or t-butyl.

[0213] In some embodiments, Z is NH2, R E is -C(O)-NR A R B And, R A -CR 1 R 2 R 3 And, R B It is hydrogen, X is carbon, and Y is nitrogen. R4 is hydrogen, (C1-C6)-cycloalkyl, (C3-C7)-cycloalkyl, or a 4-7 membered heterocycline, each of which may be substituted with one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, oxo, cyano, or halo, wherein (C1-C4)-alkoxy and (C1-C4)-alkyl may be substituted with one or more fluoro, and any nitrogen of the 4-7 membered heterocycline is C(O)OR 6 or C(O)R 6 It can be replaced with, R 5 is a (C3-C7)-cycloalkyl, phenyl, or heteroaryl group, wherein the (C3-C7)-cycloalkyl, phenyl, or heteroaryl group may be substituted with one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, cyano, 4- to 7-membered heterocyclyl, or halo group, wherein the (C1-C4)-alkyl and (C1-C4)-alkoxy groups may be substituted with one or more fluoro groups. R 6 It is methyl or t-butyl.

[0214] In some embodiments, Z is NH2, R E H is, R C CR 4 R 5 R 7 And, R D It is hydrogen, X is carbon, and Y is nitrogen. R 4 is hydrogen, (C1-C6)-cycloalkyl, (C3-C7)-cycloalkyl, or a 4-7 membered heterocycline, each of which may be substituted with one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, oxo, cyano, or halo, wherein (C1-C4)-alkoxy and (C1-C4)-alkyl may be substituted with one or more fluoro, and any nitrogen of the 4-7 membered heterocycline is C(O)OR6 or C(O)R 6 It can be replaced with, R 5 is a (C3-C7)-cycloalkyl, phenyl, or heteroaryl group, wherein the (C3-C7)-cycloalkyl, phenyl, or heteroaryl group may be substituted with one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, cyano, 4- to 7-membered heterocyclyl, or halo group, wherein the (C1-C4)-alkyl and (C1-C4)-alkoxy groups may be substituted with one or more fluoro groups. R 6 It is methyl or t-butyl.

[0215] In some embodiments, Z is NH2, R E H is, R C CR 4 R 5 R 7 And, R D It is hydrogen, X is carbon, and Y is nitrogen. R 1 and R 2 These are, independently, hydrogen or methyl, R 3 is methyl or ethyl, each of which may be substituted with one or more independently selected hydroxyl, (C1-C4)-alkoxy, chloro, or fluoro, wherein (C1-C4)-alkoxy may be substituted with one or more fluoro. R 4 is hydrogen, (C1-C6)-cycloalkyl, (C3-C7)-cycloalkyl, or a 4-7 membered heterocycline, each of which may be substituted with one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, oxo, cyano, or halo, wherein (C1-C4)-alkoxy and (C1-C4)-alkyl may be substituted with one or more fluoro, and any nitrogen of the 4-7 membered heterocycline is C(O)OR 6or C(O)R 6 It can be replaced with, R 5 is a (C3-C7)-cycloalkyl, phenyl, or heteroaryl group, wherein the (C3-C7)-cycloalkyl, phenyl, or heteroaryl group may be substituted with one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, cyano, 4- to 7-membered heterocyclyl, or halo group, wherein the (C1-C4)-alkyl and (C1-C4)-alkoxy groups may be substituted with one or more fluoro groups. R 6 It is methyl or t-butyl.

[0216] In some embodiments, Z is NH2, R E H is, R C CR 4 R 5 R 7 And, R D It is hydrogen.

[0217] X is carbon, and Y is nitrogen. R 4 is hydrogen, (C1-C6)-cycloalkyl, (C3-C7)-cycloalkyl, or a 4-7 membered heterocycline, each of which may be substituted with one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, oxo, cyano, or halo, wherein (C1-C4)-alkoxy and (C1-C4)-alkyl may be substituted with one or more fluoro, and any nitrogen of the 4-7 membered heterocycline is C(O)OR 6 or C(O)R 6 It can be replaced with, R 5is a (C3-C7)-cycloalkyl, phenyl, or heteroaryl group, wherein the (C3-C7)-cycloalkyl, phenyl, or heteroaryl group may be substituted with one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, cyano, 4- to 7-membered heterocyclyl, or halo group, wherein the (C1-C4)-alkyl and (C1-C4)-alkoxy groups may be substituted with one or more fluoro groups. R 6 It is methyl or t-butyl.

[0218] In some embodiments, Z is NH2, R E is -C(O)-NR A R B And, R A -CR 1 R 2 R 3 And, R B It is hydrogen, R C CR 4 R 5 R 7 And, R D It is hydrogen.

[0219] X is carbon, and Y is nitrogen. R 1 and R 2 These are, independently, hydrogen or methyl, R 3 is methyl or ethyl, each of which may be substituted with one or more independently selected hydroxyl, (C1-C4)-alkoxy, chloro, or fluoro, wherein (C1-C4)-alkoxy may be substituted with one or more fluoro. R 4is hydrogen, (C1-C6)-cycloalkyl, (C3-C7)-cycloalkyl, or a 4-7 membered heterocycline, each of which may be substituted with one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, oxo, cyano, or halo, wherein (C1-C4)-alkoxy and (C1-C4)-alkyl may be substituted with one or more fluoro, and any nitrogen of the 4-7 membered heterocycline is C(O)OR 6 or C(O)R 6 It can be replaced with, R 5 is a (C3-C7)-cycloalkyl, phenyl, or heteroaryl group, wherein the (C3-C7)-cycloalkyl, phenyl, or heteroaryl group may be substituted with one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, cyano, 4- to 7-membered heterocyclyl, or halo group, wherein the (C1-C4)-alkyl and (C1-C4)-alkoxy groups may be substituted with one or more fluoro groups. R 6 It is methyl or t-butyl.

[0220] In some embodiments, Z is NH2, R E H is, R C CR 4 R 5 R 7 And, R D It is hydrogen.

[0221] X is nitrogen, and Y is carbon. R 4is hydrogen, (C1-C6)-cycloalkyl, (C3-C7)-cycloalkyl, or a 4-7 membered heterocycline, each of which may be substituted with one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, oxo, cyano, or halo, wherein (C1-C4)-alkoxy and (C1-C4)-alkyl may be substituted with one or more fluoro, and any nitrogen of the 4-7 membered heterocycline is C(O)OR 6 or C(O)R 6 It can be replaced with, R 5 is a (C3-C7)-cycloalkyl, phenyl, or heteroaryl group, wherein the (C3-C7)-cycloalkyl, phenyl, or heteroaryl group may be substituted with one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, cyano, 4- to 7-membered heterocyclyl, or halo group, wherein the (C1-C4)-alkyl and (C1-C4)-alkoxy groups may be substituted with one or more fluoro groups. R 6 It is methyl or t-butyl.

[0222] In some embodiments, Z is NH2, R E H is, R C CR 4 R 5 R 7 And, R D It is hydrogen.

[0223] X is nitrogen, and Y is carbon. R 4is hydrogen, (C1-C6)-cycloalkyl, (C3-C7)-cycloalkyl, or a 4-7 membered heterocycline, each of which may be substituted with one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, oxo, cyano, or halo, wherein (C1-C4)-alkoxy and (C1-C4)-alkyl may be substituted with one or more fluoro, and any nitrogen of the 4-7 membered heterocycline is C(O)OR 6 or C(O)R 6 It can be replaced with, R 5 is a (C3-C7)-cycloalkyl, phenyl, or heteroaryl group, wherein the (C3-C7)-cycloalkyl, phenyl, or heteroaryl group may be substituted with one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, cyano, 4- to 7-membered heterocyclyl, or halo group, wherein the (C1-C4)-alkyl and (C1-C4)-alkoxy groups may be substituted with one or more fluoro groups. R 6 It is methyl or t-butyl.

[0224] In some embodiments, Z is NH2, R E is a heteroaryl, where the heteroaryl is one or more independently selected (C1-C4)-alkyl, (C3-C7)-cycloalkyl, (C3-C7)-cycloalkyl-(C1-C3)-alkyl, 4-7 member heterocyclyl, (C1-C4)-alkoxy, (C3-C7)-cycloalkoxy, -SO2R 4 , -NR 4 R 5 They may be substituted with cyano, hydroxyl, or halo, provided that (C1~C4)-alkyl, (C3~C7)-cycloalkyl, (C1~C4)-alkoxy, (C3~C7)-cycloalkyl-(C1~C3)-alkyl, and (C3~C7)-cycloalkoxy may be substituted with one or more independently selected cyano, hydroxyl, or halo. R C CR4 R 5 R 7 And, R D It is hydrogen.

[0225] X is carbon, and Y is nitrogen. R 4 is hydrogen, (C1-C6)-cycloalkyl, (C3-C7)-cycloalkyl, or a 4-7 membered heterocycline, each of which may be substituted with one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, oxo, cyano, or halo, wherein (C1-C4)-alkoxy and (C1-C4)-alkyl may be substituted with one or more fluoro, and any nitrogen of the 4-7 membered heterocycline is C(O)OR 6 or C(O)R 6 It can be replaced with, R 5 is a (C3-C7)-cycloalkyl, phenyl, or heteroaryl group, wherein the (C3-C7)-cycloalkyl, phenyl, or heteroaryl group may be substituted with one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, cyano, 4- to 7-membered heterocyclyl, or halo group, wherein the (C1-C4)-alkyl and (C1-C4)-alkoxy groups may be substituted with one or more fluoro groups. R 6 It is methyl or t-butyl.

[0226] In some embodiments, Z is NH2, R E is thiadiazolyl or oxadiazolyl, each of which may be substituted with one or more independently selected (C1-C4)-alkyl groups, where the (C1-C4)-alkyl groups may be substituted with one or more independently selected hydroxyl, cyano, or halo groups. R C CR 4 R 5 R 7 And, R DIt is hydrogen.

[0227] X is carbon, and Y is nitrogen. R 4 is a (C1-C6)-alkyl group, where the (C1-C6)-alkyl group may be substituted with one or more fluoropolymers. R 5 is a phenyl or heteroaryl, wherein the phenyl or heteroaryl may be substituted with one or more independently selected (C1-C4)-alkyl, (C1-C4)-alkoxy, cyano, or halo, provided that (C 1~ C4)-alkyl and (C1-C4)-alkoxy groups may be substituted with one or more fluoropolymers.

[0228] In some embodiments, the compound is one of the compounds disclosed in Table 1A below: [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] Table 1-11 Table 1-12 Table 1-13 Table 1-14 Table 1-15 Table 1-16 Table 1-17 Table 1-18 Table 1-19 Table 1-20 Table 1-21 Table 1-22 Table 1-23 Table 1-24 Table 1-25 Table 1-26 Table 1-27 [Table 1-28] [Table 1-29] [Table 1-30] [Table 1-31] [Table 1-32] [Table 1-33] [Table 1-34] [Table 1-35] [Table 1-36] [Table 1-37] [Table 1-38] [Table 1-39] and selected from the group consisting of these pharmaceutically acceptable salts.

[0229] In some embodiments, the compound is one of the compounds disclosed in Table 1B below: [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] and selected from the group consisting of these pharmaceutically acceptable salts.

[0230] In some embodiments, the compound is one of the compounds disclosed in Table 1C below: [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5] [Table 3-6] [Table 3-7] [Table 3-8] [Table 3-9] [Table 3-10] [Table 3-11] [Table 3-12] [Table 3-13] Table 3-14 Table 3-15 Table 3-16 Table 3-17 Table 3-18 Table 3-19 Table 3-20 Table 3-21 Table 3-22 Table 3-23 Table 3-24 Table 3-25 Table 3-26 Table 3-27 Table 3-28 Table 3-29 Table 3-30 Table 3-31 Table 3-32 Table 3-33 Table 3-34 Table 3-35 Table 3-36 Table 3-37 Table 3-38 Table 3-39 Table 3-40 Table 3-41 Table 3-42 Table 3-43 Table 3-44 Table 3-45 Table 3-46 Table 3-47 [Table 3-48] [Table 3-49] [Table 3-50] and selected from the group consisting of these pharmaceutically acceptable salts.

[0231] In some embodiments, the compound is one of the compounds disclosed in Table 1D below: [Table 4-1] [Table 4-2] and selected from the group consisting of these pharmaceutically acceptable salts.

[0232] In some embodiments, the compound is one of the compounds disclosed in Table 1E below: [Table 5-1] [Table 5-2] [Table 5-3] [Table 5-4] [Table 5-5] [Table 5-6] [Table 5-7] [Table 5-8] and selected from the group consisting of these pharmaceutically acceptable salts.

[0233] In some embodiments, the compound is one of the compounds disclosed in Table 1F below: [Table 6-1] [Table 6-2] [Table 6-3] [Table 6-4] and selected from the group consisting of these pharmaceutically acceptable salts.

[0234] In some embodiments, the compound is one of the compounds disclosed in Table 2A below: [Table 7-1] [Table 7-2] [Table 7-3] [Table 7-4] [Table 7-5] [Table 7-6] [Table 7-7] [Table 7-8] [Table 7-9] [Table 7-10] [Table 7-11] [Table 7-12] [Table 7-13] [Table 7-14] and selected from the group consisting of these pharmaceutically acceptable salts.

[0235] Compounds provided herein include compounds of formulas (Z), (Y), (X), (A), and their salts, solvates, and solvates of salts; compounds of formulas (I), (IA), (IB), (IC), and (ID) as encompassed by formulas (Z), (Y), (X), (A), and their salts, solvates, and solvates of salts; and compounds cited below as examples, encompassed by formulas (Z), (Y), (X), (A), and their salts, solvates, and solvates of salts.

[0236] In the context of this disclosure, "salt" refers to physiologically acceptable salts of the compounds of formulas (Z), (Y), (X), (A), (I), (IA), (IB), (IC), and (ID). This also includes salts that are not suitable for pharmaceutical use on their own but can be used, for example, for the isolation, purification, or storage of the compounds of formulas (Z), (Y), (X), (A), (I), (IA), (IB), (IC), and (ID).

[0237] Physiologically acceptable salts of compounds of formulas (Z), (Y), (X), (A), (I), (IA), (IB), (IC), and (ID) include salts of mineral acids, carboxylic acids, and sulfonic acids, such as salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, naphthalenedisulfonic acid, formic acid, acetic acid, trifluoroacetic acid, propionic acid, succinic acid, fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, benzoic acid, and embonic acid.

[0238] Furthermore, physiologically acceptable salts of compounds of formulas (Z), (Y), (X), (A), (I), (IA), (IB), (IC), or (ID) include salts derived from conventional bases, such as alkali metal salts (e.g., sodium and potassium salts), alkaline earth metal salts (e.g., calcium and magnesium salts), zinc salts, and ammonium salts derived from ammonia or organic amines having 1 to 20 carbon atoms, such as ethylamine, diethylamine, triethylamine, N,N-ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dimethylaminoethanol, diethylaminoethanol, tris(hydroxymethyl)aminomethane, choline, benzalkonium, procaine, dibenzylamine, dicyclohexylamine, N-methylmorpholine, N-methylpiperidine, arginine, lysine, and 1,2-ethylenediamine.

[0239] In connection with this disclosure, solvates are described as forms of formulas (Z), (Y), (X), (A), (I), (IA), (IB), (IC), or (ID) that form a solid or liquid complex by coordination with a solvent molecule. Hydrates are specific forms of solvates coordinated with water. Solvates exemplified in connection with this disclosure are hydrates.

[0240] The compounds of formulas (Z), (Y), (X), (A), (I), (IA), (IB), (IC), and (ID) may exist as different stereoisomers, i.e., configuration isomers, or, where appropriate, conformational isomers (enantiomers and / or diastereomers, including those in the case of atropisomers), depending on their structure. Therefore, this disclosure encompasses enantiomers and diastereomers, as well as mixtures thereof. Stereoisomerically homogeneous components can be isolated from mixtures of enantiomers and / or diastereomers by known methods, for which chromatographic processes, particularly HPLC chromatography on achiral or chiral separation phases, can be used. In the case of carboxylic acids as intermediates or final products, separation by diastereomer salts using chiral amine bases is also possible instead of the above.

[0241] If a compound of formula (Z), (Y), (X), (A), (I), (IA), (IB), (IC), or (ID) may exist as a tautomer, this disclosure encompasses all tautomers.

[0242] This disclosure also encompasses all appropriate isotopic variants of compounds of formula (Z), (Y), (X), (A), (I), (IA), (IB), (IC), or (ID). For the purposes of this specification, isotopic variants of compounds of formula (Z), (Y), (X), (A), (I), (IA), (IB), (IC), and (ID) are understood to mean compounds in which at least one atom in the compound of formula (Z), (Y), (X), (A), (I), (IA), (IB), (IC), and (ID) has been replaced with another atom having the same atomic number but a different atomic mass than that which is normally or predominantly present in nature. Examples of isotopes that can be incorporated into compounds of formulas (Z), (Y), (X), (A), (I), (IA), (IB), (IC), and (ID) include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine, for example, 2 H (deuterium), 3 H (tritium), 13 C,14 C, 15 N, 17 O, 18 O, 32 P, 33 P, 33 S, 34 S, 35 S, 36 S, 18 F, 36 Cl, 82 Br, 123 I, 124 I, 129 I and 131 There is I. Certain isotopic variants of the compounds of formulas (Z), (Y), (X), (A), (I), (IA), (IB), (IC), and (ID), especially those incorporating one or more radioactive isotopes, can be useful for investigating the mechanism of action and the distribution of active ingredients in the body because they are relatively easy to prepare and detect, but in particular 3 H, 14 C and / or 18 Compounds labeled with the 1F isotope are suitable for this purpose. Furthermore, the incorporation of an isotope, such as deuterium, can result in certain therapeutic benefits, such as an extension of the half-life in the body or a reduction in the required active dose, as a result of greater metabolic stability of the compound. Thus, such modifications of compounds of formulas (Z), (Y), (X), (A), (I), (IA), (IB), (IC), or (ID) can also constitute exemplary embodiments of the present disclosure. Isotopic variants of compounds of formulas (Z), (Y), (X), (A), (I), (IA), (IB), (IC), and (ID) can be prepared by using the corresponding isotopic modifications of the respective reagents and / or starting compounds by commonly used processes well known to those skilled in the art, for example, by the methods and procedures described further below in the examples.

[0243] Furthermore, this disclosure also encompasses prodrugs of compounds of formula (Z), (Y), (X), (A), (I), (IA), (IB), (IC), or (ID). The term “prodrug” is used herein to mean a compound that may be biologically active or inactive in itself, but which, while present in the body, is converted to compounds of formula (Z), (Y), (X), (A), (I), (IA), (IB), (IC), and (ID) by, for example, a metabolic or hydrolytic pathway.

[0244] For the sake of clarity, if a compound disclosed in any of Tables 1A, 1B, 1C, 1D, 1E, 1F, or 2A contains a single chiral center, the stereochemistry at the chiral center does not need to be specified (i.e., the bond to the chiral center is not represented by a dashed line or wedge notation). In these cases, the compound is assumed to be a mixture of enantiomers unless it is indicated as "Enantiomer 1" or "Enantiomer 2," where the opposite enantiomer is disclosed elsewhere in this specification as "Enantiomer 2" or "Enantiomer 1," respectively.

[0245] For the sake of clarity, if a compound disclosed in any of Tables 1A, 1B, 1C, 1D, 1E, 1F, or 2A contains two chiral centers, the stereochemistry of one of the two chiral centers does not need to be specified (i.e., the bond to the chiral center is not represented by a dashed line or wedge notation). In these cases, (1) if the compound is not explicitly shown or is shown as a “mixture of diastereomers”, the compound is a mixture of two diastereomers whose stereochemistry at the unspecified stereocenter is (R) and (S); and (2) if the compound is shown as “stereoisomer 1” (and “stereoisomer 2” is disclosed elsewhere herein), or as “stereoisomer 2” (and “stereoisomer 1” is disclosed elsewhere herein), “stereoisomer 1” and “stereoisomer 2” are a pair of diastereomers, where the stereochemistry at the unspecified stereocenter of each diastereomer is unspecified and opposite to that of the other diastereomer. In some cases, the stereochemistry at both chiral centers is unspecified, which is understood to mean that the compound is a mixture of all four possible diastereomers. In the structures of compounds 165 and 200, (1) the stereochemistry of the two stereocenters is represented as a "cis" configuration, (2) compound 165 is shown as "stereoisomer 1", and (3) compound 200 is shown as "stereoisomer 2". In this regard, it is understood that each of compounds 165 and 200 is a "cis" diastereomer whose absolute configuration is not specified, and is the other enantiomer of compounds 165 and 200. In the structures of compounds 198 and 199, (1) the stereochemistry of the two stereocenters is represented as a "trans" configuration, (2) compound 198 is shown as "stereoisomer 1", and (3) compound 199 is shown as "stereoisomer 2". In this regard, it is understood that each of compounds 198 and 199 is a "trans" diastereomer whose absolute configuration is not specified, and is the other enantiomer of compounds 198 and 199.

[0246] In relation to this disclosure, unless otherwise specified, the following terms are defined as follows:

[0247] As used herein, when one ring is “condensed” with another, that ring shares two adjacent ring members with the other ring. For example, cyclohexyl condensed with cyclopentyl is octahydro-1H-indene. Another example is cyclohexyl condensed with phenyl, which is 1,2,3,4-tetrahydronaphthalene.

[0248] In the context of this disclosure, “alkyl” refers to a linear or branched alkyl radical having 1 to 10 (e.g., 1 to 6, 1 to 4, or 1 to 3) carbon atoms. Examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, neopentyl, 3-methylbutyl, n-hexyl, 2-hexyl, 3-hexyl, and 4-methylpentyl. Examples include linear or branched alkyl radicals having 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. Examples include linear or branched alkyl radicals having 1 to 3 carbon atoms, such as methyl, ethyl, n-propyl, and isopropyl.

[0249] In the context of this disclosure, “alkoxy” refers to a linear or branched alkoxy radical having 1 to 8 carbon atoms (e.g., 1 to 6, 1 to 4, or 1 to 2). Examples of alkoxy include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, and tert-butoxy. Examples include linear or branched alkoxy groups such as methoxy, ethoxy, n-propoxy, and isopropoxy.

[0250] In the context of this disclosure, "aryl" refers to an aromatic ring containing 1 to 10 carbon ring members. Examples include phenyl, naphthyl, anthracene, and pyrene.

[0251] "Bicyclic ring" includes bicyclic ring systems such as fused bicyclic, bridging bicyclic, or spirocyclic ring systems in which each ring is independently aromatic or non-aromatic. For example, in relation to this disclosure, R C and R D When atoms bond to each other to form a monocyclic or dicyclic ring of 4 to 10 members with the bonded carbon atoms, a bicyclic ring system includes fused bicyclic, bridging bicyclic, or spirocyclic ring systems in which each ring is independently aromatic or aromatic.

[0252] In the context of this disclosure, "cycloalkyl" refers to a monocyclic saturated cycloalkyl group having 3 to 10 ring carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0253] In the context of this disclosure, "cycloalkoxy" refers to a monocyclic saturated cycloalkyl group having 3 to 10 ring carbon atoms bonded to the rest of the molecule via an oxygen linker. Examples include cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexoxy, and cycloheptoxy.

[0254] In the context of this disclosure, "cycloalkyl-alkyl" refers to an alkyl group that is substituted with a cycloalkyl group and bonded to the rest of the molecule via an alkyl group. For example, (C3~C7)-cycloalkyl-(C1~C3)-alkyl is a (C1~C3)-alkyl group that is substituted with a (C3~C7)-cycloalkyl group and bonded to the rest of the molecule via an alkyl group.

[0255] In the context of this disclosure, "aryl-alkyl" refers to an alkyl group that is substituted with an aryl group and bonded to the rest of the molecule via an alkyl group. For example, (C6~C 10 )-aryl-(C1~C4)-alkyl is, in relation to this disclosure, (C6~C 10It is a (C1-C4) alkyl group that is substituted with an aryl group and bonded to the rest of the molecule via a (C1-C4) alkyl group.

[0256] In relation to this disclosure, "halo" refers to fluorine, chlorine, bromine, or iodine substituents.

[0257] In the context of this disclosure, “heterocyclyl” means a monocyclic or bicyclic saturated heterocycle having a total of 4 to 10 ring atoms and containing 1 to 4 identical or different ring heteroatoms from the group N, O, and S, bonded to the rest of the molecule via ring carbon atoms or optionally via ring nitrogen atoms. Examples include azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, tetrahydrofuranyl, thiolanyl, 1,2-oxazolidinyl, 1,3-oxazolidinyl, 1,3-thiazolidinyl, piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,2-oxazinanyl, morpholinyl, thiomorpholinyl, azepanyl, 1,4-diazepanyl, 1,4-oxazepanyl, and 7-azabicyclo[2.2.1]heptyl. If the heterocyclyl is a bicyclic ring, it can be a fused bicyclic, a bridging bicyclic, or a spirocyclic ring.

[0258] In the context of this disclosure, “heteroaryl” means a monocyclic or optionally bicyclic aromatic heterocyclic (heteroaromatic) molecule having a total of 5 to 10 ring atoms, containing 4 or fewer identical or different ring heteroatoms from the group N, O, and S, and bonded to the rest of the molecule via ring carbon atoms or optionally via ring nitrogen atoms. Examples include furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, 1,2-oxazolyl (isoxazolyl), 1,3-oxazolyl, 1,2-thiazolyl (isothiazolyl), 1,3-thiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridyl Examples include dadinyl, pyrazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, indolyl, indolidinyl, indazolyl, quinolinyl, isoquinolinyl, naphthylidinyl, quinazolinyl, quinoxalinyl, sinnolinyl, phthalazinyl, pyrazolo[3,4-b]pyridinyl, prinyl, and pteridinyl.

[0259] In relation to this disclosure, the "oxo" substituent refers to an oxygen atom bonded to a carbon atom via a double bond.

[0260] Unless otherwise specified, all multiple radicals are defined independently of each other. When radicals in compounds of formula (Z), (Y), (X), (A), (I), (IA), (IB), (IC), or (ID) are substituted, the radicals can be monosubstituted or polysubstituted unless otherwise specified. Examples include substitution with one or two identical or different substituents (e.g., one substituent).

[0261] As used herein, the terms “subject,” “individual,” or “patient” are interchangeable and refer to any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, primates, and humans. In some embodiments, the subject is human. In some embodiments, the subject is experiencing and / or exhibiting at least one symptom of the disease or disorder to be treated and / or prevented.

[0262] In connection with this disclosure, the terms “treatment” or “to treat” include inhibiting, delaying, confirming, alleviating, reducing, limiting, reducing, suppressing, repelling, or curing a disease, condition, disorder, injury, or health problem, the course or progression of such condition, and / or the symptoms of such condition. The term “therapy” is understood herein to be synonymous with the term “treatment.”

[0263] The terms “prevention,” “prevention,” and “elimination” are used synonymously in connection with this disclosure and refer to avoiding or reducing the risk of contracting, experiencing, suffering from, or having contracting a disease, condition, disability, injury or health problem, or the onset or progression of such condition, and / or symptoms of such condition.

[0264] How to use This specification provides methods for modulating the DLK and / or LZK signaling pathways, for example, compounds provided herein can modulate DLK and / or LZK. Such compounds may be useful in the treatment of diseases and disorders treatable by DLK and / or LZK modulators. Compounds of formula (Z), (Y), (X), (A), (I), (IA), (IB), (IC), or (ID), or pharmaceutically acceptable salts thereof, may have useful pharmacological properties and can be used for the prevention and / or treatment of diseases in humans and animals. Compounds of formula (Z), (Y), (X), (A), (I), (IA), (IB), (IC), or (ID), which are low molecular weight, potent, and dual-acting inhibitors of the DLK and LZK signaling pathways, may be suitable for the treatment and / or prevention of neurodegenerative diseases, such as ophthalmic neurodegenerative diseases.

[0265] In connection with this disclosure, neurodegenerative ophthalmic diseases that can be treated and / or prevented using compounds of formula (Z), (Y), (X), (A), (I), (IA), (IB), (IC), or (ID) should be understood to include, for example, the following diseases: age-related macular degeneration (AMD), including dry (non-exudative) and wet (exudative, neovascular) AMD; choroidal neovascularization (CNV); choroidal neovascular membrane (CNVM); cystoid macular edema (CME); epiretinal membrane (ERM) and macular perforation; myopia-related choroidal neovascularization, vascular and vascular striae; retinal detachment; diabetic retinopathy; diabetic macular edema (DME); atrophy and hypertrophy of the retinal pigment epithelium. Thickened lesions, retinal vein occlusion, choroidal retinal vein occlusion, macular edema, macular edema associated with renal vein occlusion, retinitis pigmentosa and other hereditary retinal degenerations (such as Stargardt disease), retinopathy of prematurity, glaucoma (including open-angle and narrow-angle / closed-angle glaucoma, primary and secondary glaucoma, normal-tension and high-tension glaucoma), toxic optic neuropathy (e.g., methanol, ethambutol), non-arteritic Ischemic optic neuropathy, arteritis-induced ischemic optic neuropathy / giant cell arteritis, traumatic optic neuropathy (including traumatic brain injury), idiopathic intracranial hypertension / pseudomyelitis, inflammatory optic neuropathy (such as optic neuritis), compressive optic neuropathy (such as pituitary adenoma), infiltrative optic neuropathy (such as sarcoidosis and lymphoma), autoimmune optic neuropathy, lipid storage disorders (such as Tay-Sachs syndrome), trophotrophic optic neuropathy, Leber's hereditary optic neuropathy, dominant optic atrophy, Friedrich's ataxia, radiation-induced optic neuropathy, other optic neuropathy including iatrogenic optic neuropathy, space flight-related neuroophthalmopathy syndrome (SANS), inflammatory diseases of the eye, such as uveitis, scleritis, cataracts, refractive errors, such as myopia, hyperopia, astigmatism or keratoconus, neurotrophic keratopathy, corneal denervation, and promotion of corneal reinnervation and diabetic keratopathy. In connection with this disclosure, neurodegenerative non-ophthalmic diseases that can be treated and / or prevented using compounds of formula (Z), (Y), (X), (A), (I), (IA), (IB), (IC), or (ID) should be understood to mean, for example, the following diseases (but not limited to these):In other words, nerve damage caused by exposure to toxic compounds selected from the group consisting of amyotrophic lateral sclerosis (ALS), Alzheimer's disease, Parkinson's disease, Parkinson's Plus disease, Huntington's disease, peripheral neuropathy, ischemia, stroke, intracranial hemorrhage, cerebral hemorrhage, heavy metals, industrial solvents, drugs and chemotherapeutic agents, nerve damage caused by physical, mechanical or chemical trauma, trigeminal neuralgia, glossopharyngeal neuralgia, Bell's palsy, myasthenia gravis, muscular dystrophy, progressive muscular atrophy, primary lateral sclerosis (PLS), spinal muscular atrophy, hereditary muscular atrophy, intervertebral disc Spondylosis, cervical spondylosis, plexus disorders, thoracic outlet syndrome, porphyria, pseudobulbar palsy, progressive bulbar palsy, multiple system atrophy, progressive supranuclear palsy, corticobasal degeneration, Lewy body dementia, frontotemporal dementia, demyelinating diseases, Guillain-Barré syndrome, multiple sclerosis, Charcot-Marietooth disease, prion diseases, Creutzfeldt-Jakob disease, Gerstmann-Straussler-Scheinker syndrome (GSS), fatal familial insomnia (FFI), bovine spongiform encephalopathy, Pick's disease, epilepsy, sensorineural hearing loss, traumatic brain injury, and AIDS dementia complex. In some embodiments, the disease is, for example, chemotherapy-induced peripheral neuropathy (CIPN), for example, nerve damage due to exposure to chemotherapeutic agents.

[0266] Due to their activity profiles, compounds of formula (Z), (Y), (X), (A), (I), (IA), (IB), (IC), or (ID) may be suitable for the treatment and / or prevention of age-related macular degeneration (AMD), choroidal neovascularization (CMV), myopia-associated choroidal neovascularization, diabetic retinopathy, macular edema, and retinal vein occlusion.

[0267] In some embodiments, compounds of formula (Z), (Y), (X), (A), (I), (IA), (IB), (IC), or (ID) can be used to treat and / or prevent optic neuropathy, including glaucoma, hereditary retinal degeneration, non-exudative AMD / geographic atrophy, ischemic retinal vascular diseases (diabetes, venous occlusion), retinal detachment, and edema-causing diseases (including exudative AMD).

[0268] Another aspect of this disclosure is a cell transplantation-based regenerative approach being developed for the treatment of ocular and other forms of neurodegeneration. These include photoreceptor and / or RPE transplantation for the treatment of macular degeneration and forms of photoreceptor degeneration, and RGC transplantation for the treatment of glaucoma and other forms of optic nerve disease, which unfortunately show evidence of significant transplanted cell death. Compounds of formulas (Z), (Y), (X), (A), (I), (IA), (IB), (IC), or (ID) may be suitable for reducing cell death and dysfunction in transplanted cells for regenerative therapy for ocular degenerative diseases and other forms of neurodegeneration.

[0269] The aforementioned well-characterized diseases in humans may occur in other mammals with similar etiologies and can similarly be treated with the compounds of this disclosure.

[0270] Accordingly, this disclosure further provides the use of compounds of formula (Z), (Y), (X), (A), (I), (IA), (IB), (IC), or (ID), or pharmaceutically acceptable salts thereof, for treating and / or preventing any of the diseases described above.

[0271] In some embodiments, the compounds of formula (Z), (Y), (X), (A), (I), (IA), (IB), (IC), or (ID), or their pharmaceutical compositions, are formulated for intraocular administration. In some embodiments, the compounds of formula (Z), (Y), (X), (A), (I), (IA), (IB), (IC), or (ID), or their pharmaceutical compositions, are formulated as eye drops, eye ointments, eye gels, eye coils, contact lenses, or ophthalmic inserts. In some embodiments, the compounds of formula (Z), (Y), (X), (A), (I), (IA), (IB), (IC), or (ID), or their pharmaceutical compositions, are formulated for intravitreal administration. In some embodiments, the compounds of formula (Z), (Y), (X), (A), (I), (IA), (IB), (IC), or (ID), or their pharmaceutical compositions, form a depot at the injection site.

[0272] In some embodiments, compounds of formula (Z), (Y), (X), (A), (I), (IA), (IB), (IC), or (ID), or pharmaceutical compositions thereof, are formulated for systemic delivery (delivery to the central nervous system).

[0273] Treatment or prevention of disease, condition, disability, injury, or health problem may be partial or complete.

[0274] This disclosure further provides the use of compounds of formula (Z), (Y), (X), (A), (I), (IA), (IB), (IC), or (ID), or pharmaceutically acceptable salts thereof, for the manufacture of agents for the treatment and / or prevention of any of the aforementioned diseases.

[0275] The disclosure further provides pharmaceutical compositions comprising at least one compound of formula (Z), (Y), (X), (A), (I), (IA), (IB), (IC), or (ID), or a pharmaceutically acceptable salt thereof, for treating and / or preventing any of the diseases described herein.

[0276] This disclosure further provides the use of compounds of formula (Z), (Y), (X), (A), (I), (IA), (IB), (IC), or (ID), or pharmaceutically acceptable salts thereof, in methods for treating and / or preventing diseases, such as any of the aforementioned diseases.

[0277] The disclosure further provides a process for treating and / or preventing a disease, such as any of the aforementioned diseases, using at least one compound of formula (Z), (Y), (X), (A), (I), (IA), (IB), (IC), or (ID) in an effective amount, or a pharmaceutically acceptable salt thereof.

[0278] As used herein, the terms “effective dose” or “therapeutic effective dose” refer to the amount of chemical substance administered that is sufficient to alleviate, to some extent, one or more symptoms of the disease or condition being treated. The results include reduction and / or mitigation of the signs, symptoms, or causes of the disease, or any other desired change in the biological system. For example, “effective dose” in therapeutic use is the amount of a composition containing the compounds disclosed herein that is required to produce a clinically significant reduction in disease symptoms. The appropriate “effective” dose in individual cases is determined using any appropriate technique, such as dose escalation studies.

[0279] Also provided are methods for regulating intracellular DLK and / or LZK activity, comprising contacting cells with compounds of formulas (Z), (Y), (X), (A), (I), (IA), (IB), (IC), and (ID). In some embodiments, the compounds provided herein inhibit intracellular DLK and / or LZK. In some embodiments, the contact is in vitro. In some embodiments, the contact is in vivo. In some embodiments, the contact is in vivo, and the method comprises administering an effective amount of a compound of formulas (Z), (Y), (X), (A), (I), (IA), (IB), (IC), and (ID), or a pharmaceutically acceptable salt thereof, to a subject having cells having DLK and / or LZK activity. In some embodiments, the cells are nerve cells.

[0280] As used herein, the term “contact” means bringing together the indicated parts in an in vitro or in vivo system. For example, “contact” DLK and / or LZK with the compounds provided herein includes administering the compounds provided herein to an individual or subject, such as a human, having DLK and / or LZK, and introducing, for example, the compounds provided herein into a sample containing a cell preparation or purified preparation containing DLK and / or LZK.

[0281] In some embodiments, compounds of formula (Z), (Y), (X), (A), (I), (IA), (IB), (IC), or (ID) (or their pharmaceutically acceptable salts) are MNT (micronucleus test) negative. A positive MNT may indicate that the compound is genotoxic. In some embodiments, an in vitro micronucleus test, such as a test that assesses the presence of micronuclei after cell exposure to compounds of formula (Z), (Y), (X), (A), (I), (IA), (IB), (IC), and (ID), can be used to determine whether compounds of formula (Z), (Y), (X), (A), (I), (IA), (IB), (IC), and (ID) are MNT negative.

[0282] In some embodiments of any method described herein, a compound of formula (Z), (Y), (X), (A), (I), (IA), (IB), (IC), or (ID) (or a pharmaceutically acceptable salt thereof) is administered in combination with at least one further therapeutic agent selected from one or more further therapies or therapeutic agents in a therapeutically effective amount. In some embodiments, a compound of formula (Z), (Y), (X), (A), (I), (IA), (IB), (IC), or (ID), or a pharmaceutically acceptable salt thereof, may be used in combination with one or more other pharmacologically active substances, provided that the combination does not result in undesirable or unacceptable side effects. Accordingly, the present disclosure further provides a pharmacopoeia comprising at least one compound of formula (Z), (Y), (X), (A), (I), (IA), (IB), (IC), and (ID), or a pharmaceutically acceptable salt thereof, and one or more further active ingredients for treating and / or preventing the aforementioned diseases. In some embodiments, examples of combination active ingredients suitable for this purpose include combinations of IOP-reducing agents / neuroprotective agents such as prostaglandins / neuroprotective agents (e.g., bimatoprost, tafluprost, latanoprost, travaprost), beta-blockers / neuroprotective agents (e.g., timolol, levobunolol, carteolol, betaxalol), alpha-agonists / neuroprotective agents (e.g., brimonidine, apraclonidine), carbonic anhydrase inhibitors / neuroprotective agents (e.g., dorzolamide, brinzolamide), rho kinase inhibitors / neuroprotective agents (e.g., netaludil), and cholinergic agents (e.g., pilocarpine), as well as combinations of anti-inflammatory agents / neuroprotective agents such as steroids / neuroprotective agents (e.g., prednisolone, dexamethasone, fluoromethalone, loteprednol, fluocinolone, difluprednate, triamcinolone).

[0283] Accordingly, the Specified also provides a method for treating a neurodegenerative disease, comprising administering to a subject in need of treatment for a neurodegenerative disease a pharmaceutically acceptable combination comprising (a) formula (Z), (Y), (X), (A), (I), (IA), (IB), (IC), or (ID), or a pharmaceutically acceptable salt thereof, for use simultaneously, separately, or sequentially for the treatment of the neurodegenerative disease, wherein the amounts of the compound of formula (Z), (Y), (X), (A), (I), (IA), (IB), (IC), or (ID), or a pharmaceutically acceptable salt thereof, and the further therapeutic agent together are effective for the treatment of the neurodegenerative disease.

[0284] These further therapeutic agents, along with one or more doses of compounds of formula (Z), (Y), (X), (A), (I), (IA), (IB), (IC), or (ID), or pharmaceutically acceptable salts thereof, or pharmaceutically acceptable compositions thereof, may be administered as part of the same or separate dosage forms, via the same or different routes of administration, and / or in the same or different administration schedules, in accordance with standard pharmacopoeias well known to those skilled in the art.

[0285] Pharmaceutical composition and administration The disclosure further provides pharmaceutical compositions comprising at least one compound of formula (Z), (Y), (X), (A), (I), (IA), (IB), (IC), or (ID), or a pharmaceutically acceptable salt thereof, typically together with one or more pharmaceutically acceptable excipients.

[0286] Compounds of formulas (Z), (Y), (X), (A), (I), (IA), (IB), (IC), or (ID), or pharmaceutically acceptable salts thereof, can act systemically and / or topically. For this purpose, they can be administered in appropriate forms, for example, by oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, cutaneous, transdermal, extraocular, intraocular, or ocular routes, or as implants or stents.

[0287] In some embodiments, compounds of formula (Z), (Y), (X), (A), (I), (IA), (IB), (IC), or (ID), or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, are suitable for topical and local administration to the eye (e.g., eye drops, eye ointments, eye gels, eye coils, contact lenses, and other ophthalmic inserts). See, for example, Dubald et al. Pharmaceutics. 2018;10(1): 10; Bertens et al. Eur J Pharm Biopharm. 2020 Mar 12. pii: S0939-6411(20)30074-6, Singh et al. Ther Adv Ophthalmol. 2020 Mar 13;12:2515841420905740, and Patel et al. World J Pharmacol. 2013;2(2): 47-64. In some embodiments, the route of administration is topical extraocular or intraocular. More specifically, possible routes of administration include intravitreal injection, intravitreal implant, periorbital injection (sub-Tenon's capsule, subconjunctival, etc.), periorbital reservoir, retrobulbar injection, subconjunctival injection or depot, intraacular injection, intraacular implant, topical administration (eye drops or gel), suprachoroidal injection, subconjunctival insert, subretinal delivery, punctal plug, and suprachoroidal implant. Compounds of formulas (Z), (Y), (X), (A), (I), (IA), (IB), (IC), or (ID) can be administered in a dosage form suitable for these routes of administration.

[0288] Suitable dosage forms for extraocular (topical) administration include those that rapidly and / or modulate or control the release of a compound of formula (Z), (Y), (X), (A), (I), (IA), (IB), (IC), or (ID), or a pharmaceutically acceptable salt thereof, in crystalline and / or amorphous and / or dissolved forms, for example, eye drops, etc. Dosage forms may include sprays or lotions (e.g., solutions, suspensions, vesicle / colloid systems, emulsions, aerosols), eye drops, powders for sprays or lotions (e.g., pulverized active ingredients, mixtures, lyophilized products, precipitated active ingredients), semi-solid ophthalmic formulations (e.g., hydrogels, in-situ hydrogels, creams or ointments), or ophthalmic inserts (solid or semi-solid formulations, e.g., bioadhesives, films / wafers, tablets, contact lenses).

[0289] Intraocular administration methods include, for example, intravitreous, subretinal, subscleral, choroidal, subconjunctival, retrobulbar, and subtenon's capsule administration. Suitable administration forms for intraocular administration include administration forms that rapidly and / or regulate or control the release of the compound of formula (Z), (Y), (X), (A), (I), (IA), (IB), (IC), or (ID), and which contain the compound of formula (Z), (Y), (X), (A), (I), (IA), (IB), (IC), or (ID) in crystalline and / or amorphous and / or dissolved forms, for example, injectable formulations and concentrates of injectable formulations (e.g., solutions, suspensions, vesicle / colloid systems, emulsions), injectable formulation powders (e.g., pulverized active ingredients, mixtures, lyophilized products, precipitated active ingredients), injectable gels (semi-solid formulations, e.g., hydrogels, in-situ hydrogels), or implants (semi-solid formulations, e.g., biodegradable and non-biodegradable implants, implantable pumps).

[0290] In some embodiments, the injectable composition is embedded in a drug release site. The injectable composition may include a polymer delivery vehicle. Such a polymer delivery vehicle can enable sustained release. In some embodiments, the polymer delivery vehicle can extend delivery to surrounding tissues for up to several months. In some embodiments, the injectable composition can form a depot of a compound of formula (Z), (Y), (X), (A), (I), (IA), (IB), (IC), or (ID). In some embodiments, the compound of formula (Z), (Y), (X), (A), (I), (IA), (IB), (IC), or (ID) is released and / or diffused from the depot over a period of time. For example, the compound of formula (Z), (Y), (X), (A), (I), (IA), (IB), (IC), or (ID) may be released over a period of several days to several months.

[0291] Examples of ophthalmic inserts include multilayer drug-impregnating devices placed inside the eye. In some embodiments, the ophthalmic insert is multilayered. In some embodiments, the ophthalmic insert is sterile. In some embodiments, the ophthalmic insert is placed in the sacrum or conjunctival sac or inside the eye. In some embodiments, drug release from the ophthalmic insert is extended. In some embodiments, the ophthalmic insert is a soluble ophthalmic drug insert, a poly(vinyl methyl ether-maleic anhydride) anhydride ophthalmic insert, a collagen shield, Ocusart, MiniDisc, a novel ophthalmic delivery system, or a topical bimatoprost ophthalmic insert. See, for example, Jervis.J.Bioequiv.Availab.2017,9:1.

[0292] In some embodiments, compositions suitable for delivery to the eye include in-situ gelling systems, liposomes, nanoparticles (e.g., chitosan-based polymer nanoparticles, poly(lactic acid-co-glycolic acid) nanoparticles, gelatin nanoparticles, propoxylated glyceryl triacylate nanoparticles, and PGT-ethylene glycol dimethacrylate nanoparticles), niosomes, nanoemulsions, nanospheres, and microemulsions. In some embodiments, the in-situ gelling system is thermosensitive. In some embodiments, the in-situ gelling system comprises the triblock polymer PLGA-PEG-PLGA (poly-(DL-lactic acid-co-glycolic acid)-polyethylene glycol-poly-(DL-lactic acid-co-glycolic acid)).

[0293] The ophthalmic composition may contain, but is not limited to, one or more of the following: viscogen, stabilizers, preservatives, penetration enhancers, and lubricants. Non-limiting examples of viscogen include polyvinyl alcohol (PVA), hydroxymethylcellulose, hydroxyethylcellulose carboxymethylcellulose, glycerin, polyvinylpyrrolidone, and polyethylene glycol. Non-limiting examples of stabilizers include Pluronic® (triblock copolymer) and cyclodextrin. Non-limiting examples of preservatives include benzalkonium chloride, ETDA, SofZia (boric acid, propylene glycol, sorbitol, and zinc chloride; Alcon Laboratories, Inc.), and Purite (stabilized oxychloro complex; Allergan, Inc.). Non-limiting examples of penetration enhancers include polyoxyethylene glycol esters and sodium ethylenediaminetetraacetate. In some embodiments, the ophthalmic delivery composition is isotonic.

[0294] In some embodiments, the ophthalmic ointment contains a non-aqueous excipient. In some embodiments, the ophthalmic ointment has an oily base, an absorbent base, a water-removable base, or a water-soluble base. The oily base can be a lipophilic ointment. For example, the oily base can include petrolatum and white ointment. Adsorbent bases can be used as emollients. For example, adsorbent bases can include lanolin, fatty alcohols, and petrolatum. The water-soluble base can contain only water-soluble excipients such as high molecular weight macrogol. Water-removable bases include compositions that are oil-in-water emulsions.

[0295] In some embodiments, the ophthalmic gel is a hydrogel. For example, it may be a pre-formed gel or a composition that forms a gel in situ. Examples of hydrogels include polymers such as methylcellulose, hydroxyethylcellulose, sodium hyaluronate, sodium alginate, povidone, polyvinyl alcohol, cellulose acetate and its derivatives, carbomer, magrogol, pseudolatex, polymethacrylic acid, sodium alginate, gellan gum (GELRITE®), Pluronics, poly(n-isopropylacrylamide), poly(acrylic acid), polyacrylamide, poloxamer, chitosan, and hydroxypropylmethylcellulose.

[0296] In some embodiments, compounds of formula (Z), (Y), (X), (A), (I), (IA), (IB), (IC), or (ID), or pharmaceutically acceptable salts thereof, are suitable for systemic administration by oral or parenteral administration, such as by intravenous, subcutaneous, or intramuscular injection.

[0297] Suitable dosage forms for oral administration include those that rapidly and / or in a controlled or regulated manner release the compound of formula (Z), (Y), (X), (A), (I), (IA), (IB), (IC), or (ID), or a pharmaceutically acceptable salt thereof, in crystalline and / or amorphous and / or dissolved forms, for example, tablets (coated) Dosage forms include, for example, gastric juice-resistant or delayed-dissolving or insoluble coated tablets that control the release of compounds of formula (Z), (Y), (X), (A), (I), (IA), (IB), (IC), or (ID), tablets or films / oblates that disintegrate rapidly in the oral cavity, films / lyophilized products, capsules (e.g., hard or soft gelatin capsules), sugar-coated tablets, granules, pellets, powders, emulsions, suspensions, aerosols, or solutions.

[0298] In some embodiments, compounds of formula (Z), (Y), (X), (A), (I), (IA), (IB), (IC), or (ID), or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, are suitable for administration to the central nervous system (CNS). Compounds of formula (Z), (Y), (X), (A), (I), (IA), (IB), (IC), or (ID) can be administered in dosage forms suitable for these administration routes. In some embodiments, compositions suitable for CNS delivery include nanoparticles. Non-limiting examples of such nanoparticles include gold nanoparticles, lipid-based nanoparticles (e.g., liposomes), polymer nanoparticles, and dendrimers. See, for example, Spencer et al. Pharmaceutics. 2020 Feb;12(2):192.

[0299] Parenteral administration may involve bypassing the absorption step (e.g., intravenous, intraarterial, intracardiac, intraspinal, or intralumbar) or absorption (e.g., inhalation, intramuscular, subcutaneous, intradermal, transdermal, or intraperitoneal). Suitable dosage forms for parenteral administration include formulations for injection and infusion in the form of solutions, suspensions, emulsions, lyophilized products, or sterile powders.

[0300] Other routes of administration include, but are not limited to, inhalable drug forms (including powder inhalers, nebulizers, and metered aerosols), nasal drops, solutions or sprays, tablets; films / wafers or capsules for tongue, sublingual, or buccal administration; suppositories; ear preparations; vaginal capsules; aqueous suspensions (lotions, shaken mixtures); lipophilic suspensions; ointments; creams; transdermal treatment systems (such as patches); milk; pastes; foams; sprinkling powders; implants or stents.

[0301] In some embodiments, treatment of an ophthalmic disease includes extraocular topical or intraocular administration of a compound of formula (Z), (Y), (X), (A), (I), (IA), (IB), (IC), or (ID). In some embodiments, treatment of other diseases includes oral or intravenous administration of a compound of formula (Z), (Y), (X), (A), (I), (IA), (IB), (IC), or (ID). In some embodiments, treatment of other diseases includes administration of a compound of formula (Z), (Y), (X), (A), (I), (IA), (IB), (IC), or (ID) to the central nervous system of the target.

[0302] Compounds of formulas (Z), (Y), (X), (A), (I), (IA), (IB), (IC), or (ID) can be converted into the dosage forms mentioned. This can be achieved in ways known to the extent of mixing with inert, non-toxic, and pharmaceutically appropriate excipients. These excipients include carriers (e.g., microcrystalline cellulose, lactose, mannitol), solvents (e.g., liquid polyethylene glycol), emulsifiers and dispersants or wetting agents (e.g., sodium dodecyl sulfate, polyoxysorbitan oleate), binders (e.g., polyvinylpyrrolidone), synthetic and natural polymers (e.g., albumin), stabilizers (e.g., antioxidants, e.g., ascorbic acid), colorants (e.g., inorganic pigments, e.g., iron oxides), and flavor and / or odor modifiers.

[0303] In general, for parenteral administration, it has been found that administering a dose of approximately 0.001 to 1 mg per kg of body weight, for example, approximately 0.01 to 0.5 mg, is advantageous for obtaining effective results. For oral administration, the dose is approximately 0.01 to 100 mg per kg of body weight, for example, approximately 0.01 to 20 mg, or approximately 0.1 to 10 mg. For extraocular administration, the dose is approximately 1 to 50 mg / ml in an application volume of 10 to 100 μl.

[0304] However, in some cases, the dosage may need to deviate from the stated amount, particularly depending on body weight, route of administration, individual response to the active ingredient, the nature of the formulation, and the time or time interval at which administration is performed. Therefore, in some cases, it may be sufficient to manage the dosage below the aforementioned minimum amount, while in other cases, it may be necessary to exceed the stated upper limit. When administering larger amounts, it may be recommended to divide them into several individual doses throughout the day. [Examples]

[0305] The present invention will be described in more detail by specific examples. The following examples are provided for illustrative purposes and to illustrate the compositions and methods described herein, and are not intended to limit the disclosure in any way. Many variations are obvious and within the full scope of assumption. Those skilled in the art will readily recognize a variety of less important parameters that can be changed or modified to produce essentially the same results.

[0306] The following sections contain materials, methods, synthesis procedures, and biological data for compounds of formula (Z), (Y), (X), (A), (I), (IA), (IB), (IC), or (ID).

[0307] Part I. Materials, methods, synthesis procedures, and biological data of the compound of formula (I). The compounds disclosed herein can be prepared in a wide range of ways using commercially available starting materials, compounds known in the literature, or readily prepared intermediates, by employing standard synthetic methods and procedures that are well known to those skilled in the art or that take into account the teachings herein. The synthesis of the compounds disclosed herein can be achieved by generally following the following schemes and procedures, including modification of specific desired substituents.

[0308] Standard synthetic methods and procedures for the preparation of organic molecules and the transformation and manipulation of functional groups can be obtained from relevant academic literature or standard textbooks in the art. While not limited to one or more sources, R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); Smith, MB, March, J., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th edition, John Wiley & Sons: New York, 2001; and Greene, TW, Wuts, PGM, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons: New York, 1999 are well-known and recognized reference books for organic synthesis to those skilled in the art. The following description of the synthesis method is designed to illustrate, but is not limited to, the general procedure for preparing the compounds of this disclosure.

[0309] The synthetic processes disclosed herein are accommodating a wide range of functional groups and therefore allow the use of various substituted starting materials. These processes generally yield the desired final compound at or near the end of the overall process, although in some cases it may be desirable to further convert the compound into pharmaceutically acceptable salts thereof.

[0310] LC-MS method LC-MS Method 1: MS Instrument: Thermo Scientific FT-MS; UHPLC+ Instrument: Thermo Scientific UltiMate3000; Column: Waters, HSS T3, C18 1.8 μm, 2.1 x 75 mm; Eluent A: Water + 0.01% Formic Acid; Eluent B: Acetonitrile + 0.01% Formic Acid; Gradient: 10% B / 0.0 to 95% B / 2.5 to 95% B / 3.5; Oven: 50°C; Flow Rate: 0.90 mL / min; UV Detection: 210 nm / Optimal Integration Path 210-300 nm LC-MS Method 2: Apparatus: Waters ACQUITY SQD UPLC system; Column: Waters Acquity UPLC HSS T3, 1.8 μm, 50 x 1 mm; Eluent A: 1 L water + 0.25 mL formic acid; Eluent B: 1 L acetonitrile + 0.25 mL formic acid; Gradient: 90% A / 0.0 to 5% A / 1.2 to 5% A / 2.0; Oven: 50°C; Flow rate: 0.40 mL / min; UV detection: 210 nm.

[0311] LC-MS method 3: Column: CORTECS C18, 2.7 μm, 2.1 x 50 mm. A linear gradient was applied over 1.1 minutes, starting with 90% A (A: 0.1% formic acid in water) and ending with 100% B (B: 0.1% formic acid in acetonitrile), for a total runtime of 2.0 minutes. Oven: 40°C; Flow rate: 1.0 mL / min.

[0312] LC-MS method 4: Column: IntertSustain, 2.1 μm, 3.0 x 50 mm. A linear gradient was applied over 1.3 minutes, starting with 90% A (A: 0.03% NH3·H2O in water) and ending with 95% B (B: acetonitrile), for a total runtime of 2.0 minutes. Oven: 40°C; Flow rate: 1.2 mL / min.

[0313] LC-MS method 5: Column: Poroshell HPH-C18, 2.7 μm, 3.0 x 50 mm. A linear gradient was applied over 2.0 minutes, starting with 90% A (A: water, 0.03% NH3·H2O) and ending with 95% B (B: acetonitrile), for a total runtime of 3.0 minutes. Oven: 40°C; Flow rate: 1.2 mL / min.

[0314] Scheme 1 shows the formation of thiophenecarboxamidoboronic acid (e.g., intermediates 10-12) used in the preparation of the compound of formula (Z).

[0315] Scheme 1 - Preparation of substituted (5-carbamoylthiophen-3-yl)boronic acid [ka] Scheme 2 is R E C(O)NHCR 1 R 2 R 3 The following describes a method for preparing the compound of formula (Z), where X is carbon and Y is nitrogen.

[0316] Preparation of scheme 2-substituted 2-amino-6-(5-carbamoylthiophen-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-8-carboxamide [ka]

[0317] intermediate Intermediate 1 2-amino-5-bromo-N-(propan-2-yl)pyridine-3-carboxamide [ka] A suspension of 2-amino-5-bromopyridine-3-carboxylic acid (20.0 g, 92.2 mmol) in THF (270 mL) was cooled to 0°C. Propan-2-amine (7.8 mL, 92 mmol) was added, followed by diethylcyanophosphonate [CAS-RN2942-58-7] (17 mL, 93% purity, 100 mmol) and triethylamine (27 mL, 190 mmol). After 15 minutes, the mixture was raised to room temperature and stirred for 2 hours. Further addition of propan-2-amine (3.1 mL, 37 mmol) and diethyl cyanophosphonate (6.0 mL, 93% purity, 37 mmol) was added, and stirring was continued for 1.5 hours. Next, the reaction mixture was concentrated under reduced pressure, and the residue was polished with tert-butyl methyl ether:cyclohexane:dichloromethane = 2:1:1 (150 mL). The precipitate was recovered by suction filtration and dried under reduced pressure to obtain 18.6 g (100% purity, 78% yield) of the title compound.

[0318] LC-MS (Method 2):R t =0.67min;MS(ESIpos):m / z=258 / 260[M+H] + 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.14 (d,6 H), 3.98 - 4.11 (m, 1 H), 7.21 (br s, 2 H), 8.09 (d, 1 H), 8.13 (d, 1 H), 8.29(br d, 1 H).

[0319] Intermediate 2 Ethyl ({5-bromo-3-[(propan-2-yl)carbamoyl]pyridine-2-yl}carbamate) [ka]

[0320] 2-amino-5-bromo-N-(propan-2-yl)pyridine-3-carboxamide (18.6 g, 71.9 mmol) was dissolved in 1,4-dioxane (250 mL), and ethyl carboisothiocyanate [CAS-RN16182-04-0] (8.5 mL, 72 mmol) was added dropwise. The mixture was stirred overnight at room temperature, and then concentrated under reduced pressure. The residue was smeared with tert-butyl methyl ether (35 mL), and the precipitate was collected by suction filtration and dried under reduced pressure to obtain 27.2 g (100% purity, 97% yield) of the title compound.

[0321] LC-MS (Method 1):R t =1.71 min;MS(ESIpos):m / z=389 / 391[M+H] + 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.14 (d,6 H), 1.26 (t, 3 H), 3.96 - 4.09 (m, 1 H), 4.21 (q, 2 H), 8.33 (d, 1 H), 8.57 (brd, 1 H), 8.67 (d, 1 H), 12.11 (br s, 1 H), 12.14 (br s, 1 H).

[0322] Intermediate 3 2-amino-6-bromo-N-(propan-2-yl)[1,2,4]triazolo[1,5-a]pyridine-8-carboxamide [ka] Hydroxylamine hydrochloride (1:1) (27.1 g, 390 mmol) and N,N-diisopropylethylamine (63 mL, 360 mmol) were dissolved in methanol / ethanol 1:1 (600 mL) and heated to 60°C. Ethyl ({5-bromo-3-[(propan-2-yl)carbamoyl]pyridine-2-yl}carbamotioyl) carbamate (28.1 g, 72.2 mmol) was added, and the mixture was stirred at this temperature for 1.5 hours. After cooling to room temperature, the pH was adjusted to 6-7 by adding saturated sodium bicarbonate aqueous solution (approximately 100 mL). The mixture was poured into water (1.2 L) and stirred for 10 minutes. The precipitate was collected by suction filtration, washed with water (80 mL), and dried under reduced pressure to obtain 21.1 g (100% purity, 98% yield) of the title compound.

[0323] LC-MS (Method 2): R t = 0.69 min;MS (ESIpos): m / z = 298 / 300 [M+H] + 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.24 (d,6 H), 4.06 - 4.18 (m, 1 H), 6.55 (s, 2 H), 8.05 (d, 1 H), 9.16 (d, 1 H), 9.20 (brd, 1 H).

[0324] Intermediate 4 2-amino-5-bromo-N-[(2S)-1-hydroxypropan-2-yl]pyridine-3-carboxamide [ka] To a solution of 2-amino-5-bromopyridine-3-carboxylic acid (20.0 g, 92.2 mmol) and [(1H-benzotriazole-1-yl)oxy](dimethylamino)-N,N-dimethylmethaneiminium tetrafluoroborate [CAS-RN 125700-67-6] (38.5 g, 120 mmol) in THF (270 mL), (2S)-2-aminopropan-1-ol (8.6 mL, 110 mmol) was added at room temperature, and the reaction mixture was stirred for 3 hours. Subsequently, the mixture was concentrated under reduced pressure, and water was added. This was extracted twice with ethyl acetate, and the combined organic layers were washed with brine, dried over sodium sulfate, and the solvent was removed under reduced pressure. The residue was polished with tert-butyl methyl ether / acetonitrile, and the precipitate was recovered by suction filtration to obtain 17.7 g (100% purity, 70% yield). The mother liquor was concentrated and purified by column chromatography (Biotage® SNAP Ultra 100g cartridge, eluent: cyclohexane / ethyl acetate gradient = 80:20~0:100) to obtain 3.00g (100% purity, 12% yield) of the title compound.

[0325] LC-MS (Method 1):R t =0.83min;MS(ESIpos):m / z=274 / 276[M+H] + 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.10 (d,3H), 3.29 - 3.37 (m, 1H), 3.38 - 3.46 (m, 1H), 3.91 - 4.03 (m, 1H), 4.72 (t, 1H),7.19 (br s, 2H), 8.08 - 8.15 (m, 2H), 8.19 (br d, 1H).

[0326] Intermediate 5 Ethyl [(5-bromo-3-{[(2S)-1-hydroxypropan-2-yl]carbamoyl}pyridine-2-yl)carbamate]carbamate [ka] To a solution of 2-amino-5-bromo-N-[(2S)-1-hydroxypropan-2-yl]pyridine-3-carboxamide (20.7 g, 75.5 mmol) in 1,4-dioxane (250 mL), ethyl carboisothiocyanate (9.8 mL, 83 mmol) was added dropwise at room temperature, and the reaction mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure, and the residue was polished with tert-butyl methyl ether (200 mL). The precipitate was recovered by suction filtration. This was then polished with tert-butyl methyl ether (150 mL) and dichloromethane (20 mL), and recovered again by suction filtration to obtain 29.9 g (purity 93%, yield 90%) of the title compound.

[0327] LC-MS (Method 2):R t =0.71 min;MS(ESIpos):m / z=405 / 407[M+H] + 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.10 (d,3H), 1.26 (t, 3H), 3.28 - 3.36 (m, 1H), 3.43 (dt, 1H), 3.89 - 4.02 (m, 1H), 4.21(q, 2H), 4.75 (t, 1H), 8.39 (d, 1H), 8.53 (br d, 1H), 8.67 (d, 1H), 12.10 - 12.21(m, 2H).

[0328] Intermediate 6 2-amino-6-bromo-N-[(2S)-1-hydroxypropan-2-yl][1,2,4]triazolo[1,5-a]pyridine-8-carboxamide [ka] The reaction was carried out in two batches of equal size. To a methanol / ethanol (1:1, 400 mL) solution of hydroxylamine hydrochloride (25.4 g, 365 mmol), N,N-diisopropylethylamine (59 mL, 340 mmol) was added, and the mixture was heated to 60°C. Ethyl [(5-bromo-3-{[(2S)-1-hydroxypropan-2-yl]carbamoyl}pyridine-2-yl)carbamotioil]carbamate (29.8 g, 92% purity, 67.6 mmol) was added, and the reaction mixture was stirred at 60°C for 30 minutes. The two reaction solutions were cooled to room temperature and added together. The pH was adjusted to 6-7 by adding a saturated sodium bicarbonate solution (approximately 40 mL), and the mixture was poured into water (600 mL). Ethyl acetate was added to separate the phases. The aqueous layer was extracted twice with ethyl acetate, and the combined organic layer was dried over anhydrous sodium sulfate. The solvent was then removed under reduced pressure to obtain 19.5 g of the title compound (100% purity, 92% yield).

[0329] LC-MS (Method 1):R t =0.89min;MS(ESIpos):m / z=314 / 316[M+H] + 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.21 (d,3H), 3.40 - 3.54 (m, 2H), 4.01 - 4.14 (m, 1H), 4.90 (t, 1H), 6.54 (s, 2H), 8.07(d, 1H), 9.16 (d, 1H), 9.24 (d, 1H).

[0330] Intermediate 7 2-amino-5-bromo-N-[(2S)-butan-2-yl]pyridine-3-carboxamide [ka] 2-amino-5-bromopyridine-3-carboxylic acid (24.3 g, 112 mmol) was suspended in THF (400 mL) and cooled to 0°C. (2S)-butane-2-amine (9.00 g, 123 mmol) was added to obtain a clear solution. Diethylcyanophosphonate (21.9 g, 134 mmol) and triethylamine (31 mL, 220 mmol) were added. After 15 minutes, the mixture was raised to room temperature and stirred for a further 1 hour. The THF was then removed under reduced pressure, and the residue was polished with petroleum ether. The precipitate was recovered by suction filtration to obtain 16.0 g (purity 99%, yield 52%) of the title compound.

[0331] LC-MS (Method 3):R t =0.78min;MS(ESIpos):m / z=272 / 274[M+H] + 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.86 (t,3H), 1.12 (d, 3H), 1.49 - 1.56 (m, 2H), 3.84 - 3.91 (m, 1H), 7.21 (s, 2H), 8.10(s, 1H), 8.14 (s, 1H), 8.23 ​​(d, 1H).

[0332] Intermediate 8 Ethyl [(5-bromo-3-{[(2S)-butan-2-yl]carbamoyl}pyridine-2-yl)carbamate]carbamate [ka] To a solution of 2-amino-5-bromo-N-[(2S)-butan-2-yl]pyridine-3-carboxamide (16.0 g, 58.8 mmol) in 1,4-dioxane (300 mL), ethyl carboisothiocyanate (38.6 g, 294 mmol) was gradually added, and the mixture was stirred at room temperature for 3 hours. The solvent was then removed under reduced pressure, and the residue was polished with tert-butyl methyl ether. The precipitate was collected by suction filtration to obtain 23.0 g (purity 99%, yield 96%) of the title compound.

[0333] LC-MS (Method 4):R t =0.67min;MS(ESIpos):m / z=403 / 405[M+H] + 1 H-NMR (300 MHz, DMSO-d6) δ [ppm]: 0.84 (t,3H), 1.11 (d, 3H), 1.23 (t, 3H), 1.41 - 1.51 (m, 2H), 3.79 - 3.88 (m, 1H), 4.19(q, 2H)), 8.31 (s, 1H), 8.46 - 8.52 (m, 1H), 8.66 (s, 1H), 12.06 - 12.13 (m, 2H).

[0334] Intermediate 9 2-amino-6-bromo-N-[(2S)-butan-2-yl][1,2,4]triazolo[1,5-a]pyridine-8-carboxamide [ka] N,N-diisopropylethylamine (57 mL, 340 mmol) was added to a methanol (500 mL) solution of hydroxylamine hydrochloride (23.8 g, 342 mmol) at room temperature. The mixture was heated to 60°C. Ethyl ({5-bromo-3-{[(2S)-butan-2-yl]carbamoyl]pyridine-2-yl}carbamotioyl)carbamate (23.0 g, 57.0 mmol) was added, and the reaction mixture was stirred at 65°C for a further 1 hour. After cooling to room temperature, the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (330 g; eluent: petroleum ether / ethyl acetate = 1:1) to obtain 16.1 g (purity 99%, yield 89%) of the title compound.

[0335] LC-MS (Method 5):R t =1.23min;MS(ESIpos):m / z=312 / 314[M+H] + 1H-NMR (300 MHz, DMSO-d6) δ [ppm]: 0.93 (t,3H), 1.21 (d, 3H), 1.52 - 1.62 (m, 2H), 3.94 - 4.04 (m, 1H), 6.56 (s, 2H), 8.06(s, 1H), 9.16 - 9.21 (m, 2H).

[0336] Intermediate 10 (5-{[(4-fluorophenyl)methyl]carbamoyl}thiophen-3-yl)boronic acid [ka] 4-Boronothiophene-2-carboxylic acid (8.50 g, 49.4 mmol), 1-(4-fluorophenyl)methaneamine (6.2 mL, 54 mmol), [(1H-benzotriazole-1-yl)oxy](dimethylamino)-N,N-dimethylmethaneiminium tetrafluoroborate (17.5 g, 54.4 mmol), and triethylamine (8.3 mL, 59 mmol) were added to DMF (70 mL) and stirred overnight at room temperature. Water was added to the reaction mixture and extracted twice with ethyl acetate. The combined organic layers were washed with saturated sodium bicarbonate aqueous solution, dried over sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by chromatography (2 batches; column: HP-Sphere C18 cartridge, 60g; eluent A: water, eluent B: acetonitrile; gradient from 15% B to 80% over 10 minutes, 254 / 280nm) to obtain 12.4g (purity 95%, yield 85%) of the title compound.

[0337] LC-MS (Method 1):R t =1.19min;MS(ESIpos):m / z=280[M+H] + 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 4.40 (d,2 H), 7.15 (t, 2 H), 7.34 (dd, 2 H), 7.99 (d, 1 H), 8.08 - 8.14 (m, 3 H), 9.02 (t,1 H).

[0338] Intermediate 11 (5-{[(1S)-1-(4-fluorophenyl)ethyl]carbamoyl}thiophen-3-yl)boronic acid [ka] A mixture of 4-boronothiophene-2-carboxylic acid (10.0 g, 58.2 mmol), (1S)-1-(4-fluorophenyl)ethane-1-amine (8.90 g, 64.0 mmol), [(1H-benzotriazole)-1-yl)oxy](dimethylamino)-N,N-dimethylmethaneiminium tetrafluoroborate (20.5 g, 64.0 mmol), and triethylamine (9.7 mL, 70 mmol) was added to DMF (70 mL) and stirred overnight at room temperature. Water was added to the reaction mixture and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by chromatography (2 batches; column: HP-Sphere C18 cartridge, 120 g; eluent A: water, eluent B: acetonitrile; 4.4 minutes with 15% B, then 3.4 minutes with 30% B, then 2.2 minutes with 70% B, then 0.8 minutes with 90% B, 254 / 280 nm) to obtain 11.8 g (purity 95%, yield 66%) of the title compound.

[0339] LC-MS (Method 1): R t = 1.30 min; MS (ESIpos): m / z = 294 [M+H] + 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.45 (d,3 H), 5.06 - 5.14 (m, 1 H), 7.14 (t, 2 H), 7.38 - 7.44 (m, 2 H), 8.04 - 8.15 (m,4 H), 8.84 (d, 1 H).

[0340] Intermediate 12 (5-{[(1S)-1-(4-fluorophenyl)propyl]carbamoyl}thiophen-3-yl)boronic acid [ka] A mixture of 4-boronothiophene-2-carboxylic acid (7.81 g, 45.4 mmol), (1S)-1-(4-fluorophenyl)propan-1-amine (7.65 g, 49.9 mmol), [(1H-benzotriazole)-1-yl)oxy](dimethylamino)-N,N-dimethylmethaneiminium tetrafluoroborate (16.0 g, 49.9 mmol), and triethylamine (7.6 mL, 54 mmol) was added to DMF (100 mL) and stirred at room temperature for 4 hours. Water was added to the reaction mixture and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by chromatography (2 batches; column: HP-Sphere C18 cartridge, 30 g; eluent A: water, eluent B: acetonitrile; 3.5 minutes with 20% B, then 2.5 minutes with 30% B, then 3.5 minutes with 45% B, then 4.8 minutes with 75% B, 254 / 280 nm) to obtain 11.7 g (100% purity, 84% yield) of the title compound.

[0341] LC-MS (Method 1): R t = 1.44 min;MS (ESIpos): m / z =308 [M+H] + 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.86 -0.92 (m, 3 H), 1.69 - 1.92 (m, 2 H), 4.79 - 4.93 (m, 1 H), 7.14 (t, 2 H), 7.38 -7.45 (m, 2 H), 7.99 - 8.17 (m, 4 H), 8.77 (d, 1 H).

[0342] compound 4 2-amino-6-(5-{[(4-fluorophenyl)methyl]carbamoyl}thiophen-3-yl)-N-(propan-2-yl)[1,2,4]triazolo[1,5-a]pyridine-8-carboxamide [ka] 2-amino-6-bromo-N-(propan-2-yl)[1,2,4]triazolo[1,5-a]pyridine-8-carboxamide (55.0 mg, 184 μmol), (5-{[(4-fluorophenyl)methyl]carbamoyl}thiophen-3-yl)boronic acid (68.6 mg, 221 μmol), potassium carbonate (76.5 mg, 553 μmol), triphenylphosphine (2.42 mg, 9.22 μmol), and bis(triphenylphosphine)palladium(II) dichloride [CAS-RN 13965-03-2] (12.9 mg, 18.4 μmol) were added to a mixture of degassed n-propanol (1.4 mL) and water (190 μL). This reaction mixture was heated at 110 °C for 2 hours. Water and ethyl acetate were added. Each layer was separated, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine and filtered through a hydrophobic phase separation filter. The solvent was removed under reduced pressure, and the residue was purified by column chromatography (Biotage® SNAP KP-NH 11g cartridge, eluent: dichloromethane / methanol gradient). The product was further purified by preparative HPLC (Chromatorex C18, 10 μm, 125 x 30 mm, eluent: water (0.1% formic acid) / acetonitrile gradient 90:10~5:95) to obtain 51.1 mg (100% purity, 61% yield) of the title compound.

[0343] LC-MS (Method 2):R t =0.89min;MS(ESIpos):m / z=453[M+H] + 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.26 (d,6 H), 4.16 (dq, 1 H), 4.47 (d, 2 H), 6.50 (s, 2 H), 7.18 (t, 2 H), 7.39 (dd, 2 H),8.27 (d, 1 H), 8.38 (t, 2 H), 9.10 - 9.15 (m, 1 H), 9.16 (d, 1 H), 9.29 (d, 1 H).

[0344] compound 19 2-amino-6-(5-{[(1S)-1-(4-fluorophenyl)ethyl]carbamoyl}thiophen-3-yl)-N-(propan-2-yl)[1,2,4]triazolo[1,5-a]pyridine-8-carboxamide [ka] 2-amino-6-bromo-N-(propan-2-yl)[1,2,4]triazolo[1,5-a]pyridine-8-carboxamide (6.50 g, 21.8 mmol) and (5-{[(1S)-1-(4-fluorophenyl)ethyl]carbamoyl}thiophen-3-yl)boronic acid (8.07 g, 26.2 mmol) were reacted in the same manner as in the previous example to obtain 7.97 g (100% purity, 78% yield) of the title compound.

[0345] LC-MS (Method 1): R t = 1.80 min; MS (ESIpos): m / z =467 [M+H] + 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.27 (d,6 H), 1.50 (d, 3 H), 4.10 - 4.24 (m, 1 H), 5.09 - 5.20 (m, 1 H), 6.51 (s, 2 H),7.17 (t, 2 H), 7.44 (dd, 2 H), 8.25 (s, 1 H), 8.40 (m, 1 H), 8.45 (s, 1 H), 8.92(br d, 1 H), 9.17 (s, 1 H), 9.30 (d, 1 H).

[0346] compound 26 2-amino-6-(5-{[(1S)-1-(4-fluorophenyl)ethyl]carbamoyl}thiophen-3-yl)-N-[(2S)-1-hydroxypropan-2-yl][1,2,4]triazolo[1,5-a]pyridine-8-carboxamide [ka] 2-amino-6-bromo-N-[(2S)-1-hydroxypropan-2-yl][1,2,4]triazolo[1,5-a]pyridine-8-carboxamide (80.0 mg, 255 μmol) and (5-{[(1S)-1-(4-fluorophenyl)ethyl]carbamoyl}thiophen-3-yl)boronic acid (99.5 mg, 306 μmol) were reacted in the same manner as in Example 1 to obtain 68.7 mg (100% purity, 56% yield) of the title compound.

[0347] LC-MS (Method 2): R t = 0.82 min;MS (ESIpos): m / z =483 [M+H] + 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.24 (d,3 H), 1.51 (d, 3 H), 3.43 - 3.56 (m, 2 H), 4.07 - 4.18 (m, 1 H), 4.91 (t, 1 H),5.10 - 5.19 (m, 1) H), 6.49 (s, 2 H), 7.17 (t, 2 H), 7.44 (dd, 2 H), 8.26 (d, 1 H),8.41 (d, 1 H), 8.45 (d, 1 H), 8.92 (d, 1 H), 9.17 (d, 1 H), 9.33 (d, 1 H).

[0348] compound 94 2-amino-N-[(2S)-butan-2-yl]-6-(5-{[(1S)-1-(4-fluorophenyl)ethyl]carbamoyl}thiophen-3-yl)[1,2,4]triazolo[1,5-a]pyridine-8-carboxamide [ka] 2-amino-6-bromo-N-[(2S)-butan-2-yl][1,2,4]triazolo[1,5-a]pyridine-8-carboxamide (75.0 mg, 240 μmol) and (5-{[(1S)-1-(4-fluorophenyl)ethyl]carbamoyl}thiophen-3-yl)boronic acid (84.5 mg, 288 μmol) were reacted in the same manner as in Example 1 to obtain 69.0 mg (100% purity, 60% yield) of the title compound.

[0349] LC-MS (Method 2): R t = 0.98 min;MS (ESIpos): m / z =481 [M+H] + 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.95 (t,3 H), 1.23 (d, 3 H), 1.50 (d, 3 H), 1.53 - 1.68 (m, 2 H), 3.98 - 4.10 (m, 1 H),5.10 - 5.19 (m, 1 H), 6.50 (s, 2 H), 7.17 (t, 2 H), 7.44 (dd, 2 H), 8.25 (d, 1 H),8.40 (d, 1 H), 8.45 (d, 1 H), 8.92 (d, 1 H), 9.17 (d, 1 H), 9.28 (d, 1 H).

[0350] compound 112 2-amino-N-[(2S)-butan-2-yl]-6-(5-{[(1S)-1-(4-fluorophenyl)propyl]carbamoyl}thiophen-3-yl)[1,2,4]triazolo[1,5-a]pyridine-8-carboxamide [ka] 2-amino-6-bromo-N-[(2S)-butan-2-yl][1,2,4]triazolo[1,5-a]pyridine-8-carboxamide (10.3 g, 32.9 mmol), (5-{[(1S)-1-(4-fluorophenyl)propyl]carbamoyl}thiophen-3-yl)boronic acid (11.7 g, 36.2 mmol), sodium carbonate (17.4 g, 164 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) 1:1 complex with dichloromethane [CAS-RN 95464-05-4]) (1.34 g, 1.64 mmol) were added to a mixture of degassed 1,4-dioxane (200 mL) and water (66 mL). The mixture was heated at 90°C for 1 hour. Water and ethyl acetate were added, and the organic layer was separated. The aqueous layer was washed twice with ethyl acetate, and the combined organic layer was washed with brine and dried over sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by chromatography (2 batches; column: HP-Sphere 25 μm cartridge, 340 g; eluent: cyclohexane / ethyl acetate gradient). The product was further purified by column chromatography (Biotage® SNAP KP-NH 375 g cartridge, eluent: cyclohexane / ethyl acetate gradient) to obtain 14.0 g (100% purity, 86% yield) of the title compound.

[0351] LC-MS (Method 1): R t = 1.97 min;MS (ESIpos): m / z =495 [M+H] + 1H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.90 -1.00 (m, 6 H), 1.24 (d, 3 H), 1.52 - 1.68 (m, 2 H), 1.76 - 1.93 (m, 2 H), 3.98 -4.11 (m, 1 H), 4.86 - 4.94 (m, 1 H), 6.51 (s, 2 H), 7.17 (t, 2 H), 7.44 (dd, 2 H),8.25 (s, 1 H), 8.41 (d, 1 H), 8.46 (s, 1 H), 8.85 (br d, 1 H), 9.18 (d, 1 H), 9.29(d, 1 H).

[0352] Using a similar procedure, other compounds of formula (Z) shown in Table 1A were prepared by appropriately changing specific desired substituents as understood by those skilled in the art.

[0353] Scheme 3 is R E C(O)NHCR 1 R 2 R 3 The following describes a method for preparing the compound of formula (Z), where Y is carbon and X is nitrogen.

[0354] Preparation of scheme 3-substituted 2-amino-7-(5-carbamoylthiophen-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-5-carboxamide [ka] Representative procedures for intermediates 13-20 related to Scheme 3 are shown below. Using these procedures, as well as those shown elsewhere in this specification, other compounds of formula (Z) shown in Table 1B were prepared by appropriately changing specific desired substituents as understood by those skilled in the art.

[0355] Intermediate 13 N-[(2S)-butan-2-yl]-4-chloro-6-fluoropyridine-2-carboxamide [ka] To a solution of methyl 4-chloro-6-fluoropyridine-2-carboxylate [CAS-RN1256810-49-7] (600 mg, 3.16 mmol) in methanol (7.1 ml), (2S)-butane-2-amine (1.6 ml, 16 mmol) was added, and the mixture was stirred in a sealed container at room temperature for 2 hours. The mixture was then evaporated under reduced pressure, and the residue was purified by column chromatography (Biotage® SNAP Ultra 25 g cartridge, eluent: cyclohexane / ethyl acetate gradient) to obtain 700 mg (purity 95%, yield 91%) of the title compound.

[0356] LC-MS (Method 1): R t = 1.81 min;MS (ESIpos): m / z = 231 [M+H] + 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 0.84 (t, 3H), 1.15 (d, 3H), 1.44 - 1.65 (m, 2H), 3.85 - 3.97 (m, 1H), 7.74 (t, 1H), 7.96(s, 1H), 8.44 (br d, 1H).

[0357] Intermediate 14 6-amino-N-[(2S)-butan-2-yl]-4-chloropyridine-2-carboxamide [ka] The reaction was carried out in four batches of equal size. N-[(2S)-butan-2-yl]-4-chloro-6-fluoropyridine-2-carboxamide (4.50 g, 19.5 mmol) in aqueous ammonia (30%, 30 ml) was heated in a microwave oven at 120°C for 100 minutes. The mixture was then diluted with ethyl acetate and water, and the layers were separated. The aqueous phase was extracted twice with ethyl acetate, and the combined organic layers were filtered through a hydrophobic phase separation filter. The solvent was removed under vacuum to obtain 3.82 g (purity 95%, yield 82%) of the title compound.

[0358] LC-MS (Method 1): R t = 1.45 min; MS (ESIpos): m / z = 228 [M+H] + 1 H-NMR (500 MHz, DMSO-d6) δ [ppm]: 0.86 (t,3H), 1.14 (d, 3H), 1.51 (quadruple, 2H), 3.82 - 3.91 (m, 1H), 6.52 (br s, 2H), 6.68 (d,1H), 7.11 (d, 1H), 7.91 (br d, 1H).

[0359] Intermediate 15 Ethyl [(6-{[(2S)-butan-2-yl]carbamoyl}-4-chloropyridine-2-yl)carbamate]carbamate [ka] To a solution of 6-amino-N-[(2S)-butan-2-yl]-4-chloropyridine-2-carboxamide (4.47 g, 95% purity, 18.6 mmol) in 1,4-dioxane (40 ml), ethyl carboisothiocyanate (2.4 ml, 21 mmol) was added dropwise, and the mixture was stirred overnight at room temperature. The mixture was concentrated under reduced pressure. The residue was smeared with tert-butyl methyl ether (50 ml), and the precipitate was collected by suction filtration. The precipitate was washed twice with tert-butyl methyl ether (5 ml each) to obtain 5.39 g (100% purity, 81% yield) of the title compound.

[0360] LC-MS (Method 1): R t = 2.05 min; MS (ESIpos): m / z = 359 [M+H] + 1H-NMR (500 MHz, DMSO-d6) δ [ppm]: 0.86 (t,3H), 1.17 (d, 3H), 1.28 (t, 3H), 1.47 - 1.63 (m, 2H), 3.86 - 3.97 (m, 1H), 4.25(q, 2H), 7.83 (d, 1H), 8.29 (br d, 1H), 8.80 (br s, 1H), 11.76 (br s, 1H), 12.15(br s, 1H).

[0361] Intermediate 16 2-amino-N-[(2S)-butan-2-yl]-7-chloro[1,2,4]triazolo[1,5-a]pyridine-5-carboxamide [ka] To a methanol / ethanol (1:1, 30 mL) solution of hydroxylamine hydrochloride (3.28 g, 47.3 mmol), N,N-diisopropylethylamine (7.7 mL, 44 mmol) was added, and the mixture was heated to 60°C. Ethyl [(6-{[(2S)-butan-2-yl]carbamoyl}-4-chloropyridine-2-yl)carbamotioyl]carbamate (5.30 g, 14.8 mmol) was added (the generated hydrogen sulfide was introduced into a sodium hydroxide solution), and heating was continued for 1 hour. The mixture was cooled to room temperature, and saturated sodium bicarbonate aqueous solution was added to adjust the pH to 6-7. The mixture was poured into water (50 mL) and extracted with ethyl acetate. The aqueous layer was extracted twice with ethyl acetate, and the combined organic layers were filtered through a hydrophobic phase separation filter. The solvent was evaporated, and the residue was purified by column chromatography (Biotage® SNAP Ultra 50g cartridge, eluent: cyclohexane / ethyl acetate gradient) to obtain 3.66 g (100% purity, 92% yield) of the title compound.

[0362] LC-MS (Method 1): R t = 1.45 min; MS (ESIpos): m / z = 268 [M+H] + 1H-NMR (500 MHz, DMSO-d6) δ [ppm]: 0.94 (t,3H), 1.22 (d, 3H), 1.59 (quadruple, 2H), 3.93 - 4.03 (m, 1H), 6.55 (s, 2H), 7.48 (d, 1H),7.76 (d, 1H), 9.94 (br d, 1H).

[0363] Intermediate 17 4-Chloro-6-fluoro-N-[(3S)-tetrahydrofuran-3-yl]pyridine-2-carboxamide [ka] Methyl 4-chloro-6-fluoropyridine-2-carboxylate (4.70 g, 24.8 mmol) was dissolved in methanol (10 ml). (3S)-tetrahydrofuran-3-amine (6.48 g, 74.4 mmol) was added, and the reaction mixture was stirred overnight at room temperature. Volatile substances were removed under reduced pressure. The crude product was purified by column chromatography (silica gel, 220 g; eluent: petroleum ether / ethyl acetate, 5:1) to obtain 4.10 g of the title compound (purity 99%, yield 67%).

[0364] LC-MS (Method 5): R t = 0.81 min; MS (ESIpos): m / z = 245 [M+H] +

[0365] Intermediate 18 6-amino-4-chloro-N-[(3S)-tetrahydrofuran-3-yl]pyridine-2-carboxamide [ka] 4-chloro-6-fluoro-N-[(3S)-tetrahydrofuran-3-yl]pyridine-2-carboxamide (4.00 g, 16.3 mmol) was dissolved in 1,4-dioxane (30 ml) and then 30 ml of aqueous ammonia was added. The container was sealed and heated overnight at 120°C. The reaction mixture was then diluted with ethyl acetate (80 ml) and water (80 ml). The layers were separated, and the aqueous layer was extracted twice with ethyl acetate (80 ml each time). The combined organic layers were dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The crude product was allowed to crystallize overnight. This was then scrubbed with cyclohexane (20 ml) and tert-butyl methyl ether (1 ml). The precipitate was collected by suction filtration to obtain 2.70 g (purity 99%, yield 68%) of the title compound.

[0366] LC-MS (Method 19): R t = 0.61 min;MS (ESIpos): m / z = 242 [M+H] +

[0367] Intermediate 19 Ethyl ({4-chloro-6-[(3S)-tetrahydrofuran-3-ylcarbamoyl]pyridine-2-yl}carbamate) [ka] To a stirred solution of 6-amino-4-chloro-N-[(3S)-tetrahydrofuran-3-yl]pyridine-2-carboxamide (3.70 g, 15.3 mmol) in 1,4-dioxane (100 ml), ethyl carboisothiocyanate (4.02 g, 30.6 mmol) was added dropwise at room temperature, and the mixture was stirred overnight. Hexane (200 ml) was added, and the precipitate was collected by suction filtration. The precipitate was washed twice with hexane (20 ml each time) to obtain 5.45 g (purity 98%, yield 94%) of the title compound.

[0368] LC-MS (Method 12): R t = 0.89 min;MS (ESIpos): m / z = 373 [M+H] + 1H-NMR (300 MHz, DMSO-d6) δ [ppm]: 1.28 (t,3H), 1.90 - 2.03 (m, 1H), 2.12 - 2.26 (m, 1H), 3.63 (dd, 1H), 3.73 (td, 1H), 3.81- 3.93 (m, 2H), 4.26 (q, 2H), 4.43 - 4.56 (m, 1H), 7.84 (d, 1H), 8.68 (d, 1H), 8.79- 8.88 (m, 1H), 11.81 (br s, 1H), 12.18 (br s, 1H).

[0369] Intermediate 20 2-amino-7-chloro-N-[(3S)-tetrahydrofuran-3-yl][1,2,4]triazolo[1,5-a]pyridine-5-carboxamide [ka] To a methanol (80 mL) solution of hydroxylamine hydrochloride (3.65 g, 52.6 mmol), N,N-diisopropylethylamine (11 mL, 66 mmol) was added at room temperature. The resulting mixture was heated to 60°C. Ethyl ({4-chloro-6-[(3S)-tetrahydrofuran-3-ylcarbamoyl]pyridine-2-yl}carbamotioyl) carbamate (4.90 g, 13.1 mmol) was added, and the reaction mixture was stirred at 65°C for 1.5 hours. This was then cooled to room temperature and diluted with water (150 ml). The precipitate was collected by suction filtration. The filter cake was polished with saturated sodium bicarbonate solution (100 ml) and stirred for 4 hours. The precipitate was collected by suction filtration, washed with water (20 ml), and dried under reduced pressure to obtain 3.30 g of the title compound (purity 98%, yield 87%).

[0370] LC-MS (Method 7): R t = 0.88 min; MS (ESIpos): m / z = 282 [M+H] + 1H-NMR (300 MHz, DMSO-d6) δ [ppm]: 1.86 -1.98 (m, 1H), 2.29 (dq, 1H), 3.69 (dd, 1H), 3.77 (td, 1H), 3.85 - 3.98 (m, 2H),4.49 - 4.61 (m, 1H), 6.59 (s, 2H), 7.47 (d, 1H), 7.78 (d, 1H), 10.23 (br d, 1H). Scheme 4 is R E C(O)NHCR 1 R 2 R 3 Herein lies another method for preparing the compound of formula (Z), where Y is carbon and X is nitrogen.

[0371] Another preparation of scheme 4-substituted 2-amino-7-(5-carbamoylthiophen-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-5-carboxamide [ka]

[0372] Representative procedures for intermediates 21-26 related to Scheme 4 are shown below. Using these procedures, as well as those shown elsewhere in this specification (or with certain modifications), other compounds of formula (Z) shown in Table 1B were prepared by appropriately changing certain desired substituents as understood by those skilled in the art.

[0373] Intermediate 21 4-Bromo-6-[(1-fluoropropan-2-yl)carbamoyl]pyridine-2-carboxylate methyl (mixture of enantiomers) [ka] To a solution of 4-bromo-6-(methoxycarbonyl)pyridine-2-carboxylic acid [CAS-RN 293294-72-1] (4.3 g, 16.54 mmol) in N,N-dimethylformamide (50 ml), HATU (9.43 g, 24.8 mmol), N,N-diisopropylethylamine (6.41 g, 49.6 mmol), and racemic 1-fluoropropan-2-amine hydrochloride (1:1) [CAS-RN 921602-78-0] (2.25 g, 19.8 mmol) were added. After stirring at room temperature for 3 hours, the reaction mixture was diluted with water (150 ml) and extracted three times with ethyl acetate (200 ml each time). The combined organic layers were washed three times with brine (200 ml each time) and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The crude product was purified by column chromatography (silica gel, 220 g; eluent: petroleum ether / ethyl acetate, 1:1) to obtain 3.80 g (purity 82%, yield 59%) of the title compound.

[0374] LC-MS (Method 16):R t =1.01 min;MS(ESIpos):m / z=319,321[M+H] + 1 H-NMR (300 MHz, DMSO-d6) δ [ppm]: 1.15 -1.23 (m, 3H), 3.94 (s, 3H), 4.31 - 4.66 (m, 3H), 8.35 - 8.39 (m, 2H), 8.56 (d, 1H).

[0375] Intermediate 22 4-Bromo-6-[(1-fluoropropan-2-yl)carbamoyl]pyridine-2-carboxylic acid [ka] To a methanol (50 ml) solution of methyl 4-bromo-6-[(1-fluoropropan-2-yl)carbamoyl]pyridine-2-carboxylate (3.8 g, 82% purity, 9.76 mmol), sodium hydroxide (1.56 g, 39.1 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour, then concentrated under reduced pressure and diluted with water (40 ml). The pH was adjusted to 5 with 1N hydrochloric acid. The precipitate was collected by suction filtration, washed with water (20 ml), and dried under reduced pressure to obtain 2.80 g (99% purity, 93% yield) of the title compound.

[0376] LC-MS (Method 7):R t =0.77min;MS(ESIpos):m / z=327,329[M+H] + 1 H-NMR (300 MHz, DMSO-d6) δ [ppm]: 1.23 -1.26 (m, 3H), 4.29 - 4.42 (m, 2H), 4.56 - 4.58 (m, 1H), 8.38 - 8.41 (m, 2H), 9.06(d, 1H).

[0377] Intermediate 23 tert-butyl{4-bromo-6-[(1-fluoropropan-2-yl)carbamoyl]pyridine-2-yl}carbamate (mixture of enantiomers) [ka] To a solution of 4-bromo-6-[(1-fluoropropan-2-yl)carbamoyl]pyridine-2-carboxylic acid (2.30 g, 7.54 mmol) in 1,4-dioxane (30 ml), triethylamine (1.6 ml, 11 mmol), tert-butanol (12.0 ml, 130 mmol), and diphenyl phosphorazidate (3.11 g, 11.3 mmol) were added. The resulting mixture was stirred at 100°C for 4 hours. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography (120 g silica gel, eluent: petroleum ether / ethyl acetate = 5:1) to obtain 1.40 g (purity 92%, yield 45%) of the title compound.

[0378] LC-MS (Method 7):R t =1.16 min;MS(ESIpos):m / z=376,378[M+H] +

[0379] Intermediate 24 6-amino-4-bromo-N-(1-fluoropropan-2-yl)pyridine-2-carboxamide trifluoroacetate (a mixture of enantiomers) [ka] Trifluoroacetic acid (1.3 ml, 17 mmol) was added to a solution of tert-butyl{4-bromo-6-[(1-fluoropropan-2-yl)carbamoyl]pyridine-2-yl}carbamate (1.40 g, 92% purity, 3.42 mmol) in dichloromethane (20 ml). The reaction mixture was stirred at room temperature for 3 hours and then concentrated under reduced pressure. The residue was evaporated three times with dichloromethane (20 ml) to obtain 1.00 g (98% purity, 73% yield) of the title compound.

[0380] LC-MS (Method 16):R t =1.08min;MS(ESIpos):m / z=276,278[M+H] + 1 H-NMR (300 MHz, DMSO-d6) δ [ppm]: 1.18 (d,3H), 4.17 - 4.39 (m, 2H), 4.48 - 4.53 (m, 1H), 6.52 (br s, 2H), 6.85 (s, 1H), 7.23(s, 1H), 8.17 (d, 1H).

[0381] Intermediate 25 Ethyl ({4-bromo-6-[(1-fluoropropan-2-yl)carbamoyl]pyridine-2-yl}carbamotioyl) carbamate (a mixture of enantiomers) [ka] Ethyl carboisothiocyanate (908 mg, 6.92 mmol) was added dropwise to a solution of 6-amino-4-bromo-N-(1-fluoropropan-2-yl)pyridine-2-carboxamide trifluoroacetate (900 mg, 2.31 mmol) in 1,4-dioxane (15 ml) at room temperature. The reaction mixture was stirred overnight at room temperature and then diluted with hexane (50 ml). The precipitate was collected by suction filtration, washed with hexane (20 ml), and dried under reduced pressure to obtain 700 mg (purity 96%, yield 71%) of the title compound.

[0382] LC-MS (Method 8): R t = 1.47 min;MS (ESIpos): m / z = 407, 409 [M+H] + 1 H-NMR (300 MHz, DMSO-d6) δ [ppm]: 1.19 (d,3H), 1.28 (t, 3H), 4.21 - 4.42 (m, 4H), 4.44 - 4.60 (m, 1H), 7.98 (s, 1H), 8.58(d, 1H), 9.00 (s, 1H), 11.79 (s, 1H), 12.18 (s, 1H).

[0383] Intermediate 26 2-amino-7-bromo-N-(1-fluoropropan-2-yl)[1,2,4]triazolo[1,5-a]pyridine-5-carboxamide (a mixture of enantiomers) [ka] To a methanol (15 ml) solution of hydroxylamine hydrochloride (410 mg, 5.89 mmol), N,N-diisopropylethylamine (1.0 ml, 5.9 mmol) was added at room temperature. The solution was heated to 65°C. Ethyl ({4-bromo-6-[(1-fluoropropan-2-yl)carbamoyl]pyridine-2-yl}carbamotioyl)carbamate (800 mg, 1.96 mmol) was added. The resulting mixture was stirred at 65°C for 2 hours. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure. The residue was diluted with water (100 ml). The precipitate was collected by suction filtration. This was mixed with saturated sodium bicarbonate solution (100 ml) and stirred for 4 hours. The precipitate was collected by suction filtration, washed with water (20 ml), and dried under reduced pressure to obtain 507 mg (purity 96%, yield 78%) of the title compound.

[0384] LC-MS (Method 8): R t = 1.04 min;MS (ESIpos): m / z = 316, 318 [M+H] + 1 H-NMR (300 MHz, DMSO-d6) δ [ppm]: 1.30 (d,3H), 4.25 - 4.49 (m, 2H), 4.55 - 4.65 (m, 1H), 6.57 (s, 2H), 7.60 (s, 1H), 7.92(s, 1H), 10.14 (d, 1H). Scheme 5 is R, such as those shown in Tables 1C and 1E (e.g., compounds 371-383 and 387-388). E The present invention provides a method for preparing compounds of formula (Z) such that is H, halo, or (C1-C6)-alkyl, X is carbon, and Y is nitrogen.

[0385] Preparation of Scheme 5-Substitution 4-(2-amino-[1,2,4]triazolo[1,5-a]pyridine-6-yl)thiophene-2-carboxamide [ka] Scheme 6 is R, as shown in Table 1D and certain compounds in Table 1E (e.g., compound 370).E However, H or C(O)OR 6 The following describes a method for preparing a compound of formula (Z) where Y is carbon and X is nitrogen.

[0386] Preparation of Scheme 6-Substituted 4-(2-amino-[1,2,4]triazolo[1,5-a]pyridine-7-yl)thiophene-2-carboxamide [ka] Scheme 7 involves R, such as the specific compounds shown in Table 1E (e.g., compounds 384-386). E The following describes a method for preparing a compound of formula (Z) such that it is S(O)2NH(C1~C6)-alkyl, where X is carbon and Y is nitrogen.

[0387] Preparation of Scheme 7-Substitution 4-(2-amino-8-sulfamoyl-[1,2,4]triazolo[1,5-a]pyridine-6-yl)thiophene-2-carboxamide [ka]

[0388] Scheme 8 is R, such as the specific compounds shown in Table 1E (e.g., compounds 389-391). E C(O)NHCR 1 R 2 R 3 The following describes a method for preparing the compound of formula (Z), where X is carbon, Y is nitrogen, and Z is hydrogen.

[0389] Preparation of scheme 8-substituted 6-(5-carbamoylthiophen-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-8-carboxamide [ka]

[0390] Scheme 9 is R, such as the specific compounds shown in Table 1F (e.g., compounds 395-396). EHowever, (C6~C 10 The present invention provides a method for preparing a compound of formula (Z) that is )-aryl or heteroaryl, where X is carbon and Y is nitrogen.

[0391] Scheme 9 - Heteroaryl substitution 4-(2-amino-[1,2,4]triazolo[1,5-a]pyridine-6-yl)thiophene-2-carboxamide [ka] A typical procedure for intermediate 27 related to scheme 9 is shown below. Using this procedure, as well as the procedures shown elsewhere in this specification, compounds of formula (Z) shown in Table 1F (e.g., compounds 395-396) were prepared by appropriately changing specific desired substituents as understood by those skilled in the art.

[0392] Intermediate 27 6-Bromo-8-[1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-yl][1,2,4]triazolo[1,5-a]pyridine-2-amine [ka] Using 0.06 equivalents of catalyst, 6-bromo-8-iodo[1,2,4]triazolo[1,5-a]pyridine-2-amine (3.50 g, 10.3 mmol) was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole [CAS-RN1883816-46-3] (3.42 g, 12.4 mmol) at 90°C for 2 hours according to general procedure B. The reaction mixture was diluted with ethyl acetate (400 ml) and water (50 ml). The precipitate was collected by suction filtration and washed with water and acetonitrile to obtain 440 mg (100% purity, 12% yield) of the title compound. The organic layer of the filtrate was separated, washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure to a volume of 15 ml, the precipitate was collected by suction filtration, and washed with acetonitrile to obtain a second batch of 2.70 g (100% purity, 72% yield) of the title compound. The mother liquor was concentrated and purified by column chromatography (Biotage® SNAP Ultra 50 g cartridge, eluent: cyclohexane / ethyl acetate gradient = 90:10 to 10:90) to obtain a third batch of 230 mg (92% purity, 6% yield) of the title compound. The overall yield was 90%.

[0393] LC-MS (Method 2): R t = 0.78 min;MS (ESIpos): m / z = 361 [M+H] + 1 H-NMR (500 MHz, DMSO-d6) δ [ppm]: 5.28 (q,2H), 6.21 (s, 2H), 8.02 (d, 1H), 8.46 (s, 1H), 8.74 (s, 1H), 8.81 (d, 1H).

[0394] Scheme 10 is a scheme for R, such as the specific compounds shown in Table 1F (e.g., compound 402). E However, (C6~C 10 The present invention provides a method for preparing a compound of formula (Z) that is )-aryl or heteroaryl, where Y is carbon and X is nitrogen.

[0395] Scheme 10-Substitution 4-(2-amino-5-(1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-7-yl)thiophene-2-carboxamide [ka] A typical procedure for intermediate 28 related to scheme 10 is shown below. Using this procedure, as well as the procedures shown elsewhere in this specification, compounds of formula (Z) shown in Table 1F (e.g., compound 402) were prepared by appropriately changing specific desired substituents as understood by those skilled in the art.

[0396] Intermediate 28 7-Chloro-5-[1-(2,2,2-trifluoroethyl)-1H-pyrazole-4-yl][1,2,4]triazolo[1,5-a]pyridine-2-amine [ka] Using 0.1 equivalents of catalyst, 5,7-dichloro[1,2,4]triazolo[1,5-a]pyridine-2-amine [CAS-RN1233526-60-7] (300 mg, 90% purity, 1.33 mmol) was reacted with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole [CAS-RN1049730-42-8] (511 mg, 97% purity, 1.80 mmol) at 90°C for 1.5 hours according to general procedure C. The reaction mixture was directly purified by column chromatography (Biotage® SNAP Ultra 50g cartridge, eluent: dichloromethane / methanol gradient = 100:0~85:15). The isolated substance was polished with THF (3.0 ml), recovered by suction filtration, and washed with THF (1.0 ml) to obtain 260 mg (97% purity, 60% yield) of the title compound. The mother liquor was purified by column chromatography (Biotage® SNAP KP-NH 28 g cartridge, eluent: cyclohexane / ethyl acetate gradient = 100:0 to 10:90) to obtain a second batch of 40.0 mg (100% purity, 9% yield). The overall yield was 69%.

[0397] LC-MS (Method 2): R t = 0.77 min;MS (ESIpos): m / z = 317 [M+H] + 1 H-NMR (500 MHz, DMSO-d6) δ [ppm]: 5.34 (q,2H), 6.23 (s, 2H), 7.41 (d, 1H), 7.55 (d, 1H), 8.62 (s, 1H), 9.01 (s, 1H).

[0398] Scheme 11 is R, such as the specific compounds shown in Table 1F (e.g., compounds 392-394 and 397-401). E However, (C6~C 10 The present invention provides a method for preparing a compound of formula (Z) that is )-aryl or heteroaryl, where X is carbon and Y is nitrogen.

[0399] Scheme 11-Substitution 4-(2-amino-8-(1,3,4-thiadiazole-2-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-yl)thiophene-2-carboxamide [ka] Representative procedures for intermediates 29-36 related to Scheme 10 are shown below. Using these procedures, as well as those shown elsewhere in this specification, compounds of formula (Z) shown in Table 1F (e.g., compounds 392-394 and 397-401) were prepared by appropriately changing specific desired substituents as understood by those skilled in the art.

[0400] Intermediate 29 2-amino-5-bromo-N'-propanoylpyridine-3-carbohydrazide [ka] 2-amino-5-bromopyridine-3-carboxylic acid (8.21 g, 37.8 mmol), propanehydrazide (4.00 g, 45.4 mmol), and triethylamine (21 ml, 150 mmol) were added to DMF (28 ml) and a solution of T3P (66 ml, 50% in DMF, 113 mmol) was added dropwise at room temperature. The reaction mixture was then stirred at room temperature for 5 hours. After that, the mixture was diluted with water and ethyl acetate, the aqueous layer was separated and extracted twice with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue was smeared with ethyl acetate / tert-butyl methyl ether, and the precipitate was collected by suction filtration to obtain 3.90 g (purity 75%, yield 27%) of the title compound.

[0401] LC-MS (Method 2): R t = 0.40 min;MS (ESIpos): m / z = 287, 289 [M+H] + 1H-NMR (500 MHz, DMSO-d6) δ [ppm]: 1.06 (t,3H), 2.19 (q, 2H), 7.21 (s, 2H), 8.11 (d, 1H), 8.20 (d, 1H), 9.83 (s, 1H), 10.29(s, 1H).

[0402] Intermediate 30 5-Bromo-3-(5-ethyl-1,3,4-thiadiazol-2-yl)pyridine-2-amine [ka] 1.50 g of 2-amino-5-bromo-N'-propanoylpyridine-3-carbohydrazide (75% purity, 3.92 mmol) was dissolved in 30 ml of THF, and Lawson's reagent (1.90 g, 4.70 mmol) was added. The mixture was heated under reflux for 3 hours. The solid was then filtered off, and the filter was rinsed with ethyl acetate. Water was added to the filtrate, the aqueous layer was separated, and extracted twice with ethyl acetate. The combined organic layers were filtered through a hydrophobic phase separation filter, and the solvent was removed under reduced pressure. The residue was purified by column chromatography (Biotage® SNAP KP-NH 110 g cartridge, eluent: cyclohexane / ethyl acetate gradient = 90:10~15:85) to obtain 829 mg of the title compound (100% purity, 74% yield).

[0403] LC-MS (Method 1): R t = 1.65 min; MS (ESIpos): m / z = 285,287 [M+H] + 1 H-NMR (500 MHz, DMSO-d6) δ [ppm]: 1.36 (t,3H), 3.15 (q, 2H), 7.73 (br s, 2H), 8.06 (d, 1H), 8.21 (d, 1H).

[0404] Intermediate 31 Ethyl {[5-bromo-3-(5-ethyl-1,3,4-thiadiazole-2-yl)pyridine-2-yl]carbamate}carbamate [ka] 5-bromo-3-(5-ethyl-1,3,4-thiadiazole-2-yl)pyridine-2-amine (850 mg, 2.98 mmol) was dissolved in 1,4-dioxane (15 ml), and ethyl carboisothiocyanate (390 μl, 3.3 mmol) was added dropwise. The mixture was heated at 50°C overnight. After this, the mixture was concentrated under reduced pressure, and the residue was macerated with cyclohexane / tert-butyl methyl ether. The precipitate was collected by suction filtration to obtain 972 mg (purity 93%, yield 73%) of the title compound.

[0405] LC-MS (Method 1): R t = 1.81 min; MS (ESIpos): m / z = 416, 418 [M+H] + 1 H-NMR (500 MHz, DMSO-d6) δ [ppm]: 1.28 (t,3H), 1.34 (t, 3H), 3.17 (q, 2H), 4.25 (q, 2H), 8.73 (d, 1H), 8.80 (d, 1H), 11.60- 11.74 (m, 2H).

[0406] Intermediate 32 6-Bromo-8-(5-ethyl-1,3,4-thiadiazole-2-yl)[1,2,4]triazolo[1,5-a]pyridine-2-amine [ka] A methanol / ethanol (1:1, 15 ml) solution of hydroxylamine hydrochloride (771 mg, 11.1 mmol) and N,N-diisopropylethylamine (1.8 ml, 10 mmol) was heated to 60°C, and ethyl {[5-bromo-3-(5-ethyl-1,3,4-thiadiazole-2-yl)pyridine-2-yl]carbamate (920 mg, purity 93%, 2.06 mmol) was added. The mixture was stirred at 60°C for 1 hour and then cooled to room temperature. The pH was adjusted to 6-7 by adding saturated sodium bicarbonate solution, and the mixture was poured into water (100 mL). This was stirred for 10 minutes, the precipitate was collected by suction filtration, washed with water (5 ml), and dried under reduced pressure to obtain 658 mg (purity 90%, yield 89%) of the title compound.

[0407] LC-MS (Method 1): R t = 1.28 min;MS (ESIpos): m / z = 325, 327 [M+H] + 1 H-NMR (500 MHz, DMSO-d6) δ [ppm]: 1.40 (t,3H), 3.20 (q, 2H), 6.56 (s, 2H), 8.36 (s, 1H), 9.16 (s, 1H).

[0408] Intermediate 33 2-amino-5-bromo-N'-(2-methylpropanoyl)pyridine-3-carbohydrazide [ka] A mixture of 2-amino-5-bromopyridine-3-carboxylic acid (8.85 g, 40.8 mmol), 2-methylpropanehydrazide (5.00 g, 49.0 mmol), and triethylamine (23 ml, 160 mmol) was added to DMF (30 ml). To this mixture, a solution of T3P (71 ml, 50% purity, 120 mmol) was added dropwise at room temperature. The reaction mixture was then stirred at room temperature for 5 hours. After that, the mixture was diluted with water and ethyl acetate, the aqueous layer was separated, and extracted twice with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was smeared with ethyl acetate / tert-butyl methyl ether, and the precipitate was collected by suction filtration to obtain 7.87 g (99% purity, 63% yield) of the title compound.

[0409] LC-MS (Method 1): R t = 0.85 min; MS (ESIpos): m / z = 301, 303 [M+H] + 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.07 (d,6H), 7.21 (s, 2H), 8.12 (d, 1H), 8.20 (d, 1H), 9.84 (s, 1H), 10.29 (br s, 1H).

[0410] Intermediate 34 5-Bromo-3-[5-(propan-2-yl)-1,3,4-thiadiazol-2-yl)pyridine-2-amine [ka] 2-amino-5-bromo-N'-(2-methylpropanoyl)pyridine-3-carbohydrazide (3.00 g, 9.96 mmol) was dissolved in THF (60 ml), and Lawson's reagent (4.84 g, 12.0 mmol) was added. The mixture was heated under reflux for 3 hours. The reaction mixture was added to the experimental mixture using 500 mg of the starting material. The solid material was then filtered off, and the filter was rinsed with ethyl acetate. The solvent was removed under reduced pressure. The residue was purified by column chromatography (Biotage® SNAP Ultra C18 60 g cartridge, eluent: acetonitrile / water gradient = 25:75~77:23, then to 95:5). The product fraction was concentrated under reduced pressure, and the remaining aqueous solution was extracted three times with ethyl acetate. The combined organic layers were washed with brine, filtered through a hydrophobic phase separation filter, and the solvent was removed under reduced pressure to obtain 1.86 g (80% purity, 43% yield) of the title compound, which was used without further purification.

[0411] LC-MS (Method 1): R t = 1.84 min; MS (ESIpos): m / z = 299, 301 [M+H] + 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.41 (d,6H), 3.49 (spt, 1H), 7.73 (br s, 2H), 8.07 (d, 1H), 8.21 (d, 1H).

[0412] Intermediate 35 Ethyl ({5-bromo-3-[5-(propan-2-yl)-1,3,4-thiadiazol-2-yl]pyridine-2-yl}carbamotioil)carbamate [ka] 5-bromo-3-[5-(propan-2-yl)-1,3,4-thiadiazole-2-yl)pyridine-2-amine (1.80 g, 80% purity, 4.81 mmol) was dissolved in 1,4-dioxane (20 ml), and ethyl carboisothiocyanate (620 μl, 5.3 mmol) was added dropwise. The mixture was stirred overnight at room temperature, and then heated at 60°C for 6 hours. After this, the mixture was concentrated under reduced pressure, and the residue was polished with tert-butyl methyl ether. The precipitate was recovered by suction filtration, and the residue was purified by column chromatography (Biotage® SNAP Ultra 25 g cartridge, eluent: cyclohexane / ethyl acetate gradient = 90:10~46:54) to obtain 1.15 g (80% purity, 44% yield) of the title compound.

[0413] LC-MS (Method 1): R t = 1.98 min; MS (ESIpos): m / z = 430, 432 [M+H] + 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.28 (t,3H), 1.39 (d, 6H), 3.53 (spt, 1H), 4.25 (q, 2H), 8.72 (d, 1H), 8.80 (d, 1H), 11.66(s, 1H), 11.73 (s, 1H).

[0414] Intermediate 36 6-Bromo-8-[5-(propan-2-yl)-1,3,4-thiadiazole-2-yl)[1,2,4]triazolo[1,5-a]pyridine-2-amine [ka] A methanol / ethanol (1:1, 25 ml) solution of hydroxylamine hydrochloride (698 mg, 10.0 mmol) and N,N-diisopropylethylamine (1.6 ml, 9.3 mmol) was heated to 60°C, and ethyl ({5-bromo-3-[5-(propan-2-yl)-1,3,4-thiadiazole-2-yl)pyridine-2-yl}carbamotioyl)carbamate (1.00 g, 80% purity, 1.86 mmol) was added. The mixture was stirred at 60°C for 1 hour and then cooled to room temperature. The pH was adjusted to 6-7 by adding saturated sodium bicarbonate solution, and the mixture was poured into water (100 mL). This was stirred for 10 minutes, the precipitate was collected by suction filtration, washed with water (5 ml), and dried under reduced pressure to obtain 630 mg (98% purity, 97% yield) of the title compound.

[0415] LC-MS (Method 2): R t = 0.78 min; MS (ESIpos): m / z = 338, 340 [M+H] + 1 H-NMR (400 MHz, DMSO-d6) δ [ppm]: 1.43 (d,6H), 3.55 (spt, 1H), 6.57 (s, 2H), 8.38 (d, 1H), 9.17 (d, 1H).

[0416] Part II: Biological Data The pharmacological activity of the compounds of formulas (Z), (Y), (X), (A), (I), (IA), (IB), (IC), and (ID) can be demonstrated by in vitro and in vivo tests, as is well known to those skilled in the art. The following examples describe the biological effects of the compounds of formulas (Z), (Y), (X), (A), (I), (IA), (IB), (IC), and (ID), but this disclosure is not limited to these examples.

[0417] Materials and methods: DLK Biochemical Assay The DLK assay is a biochemical assay format designed to screen for DLK inhibitors. DLK enzymatic activity was measured by monitoring the phosphorylation of the physiological substrate MKK7 (MAP2K7, bispecific mitogen-activated protein kinase kinase 7). Phosphorylation was detected by a TR-FRET system, which labels His-tagged MKK7 with an XL665-labeled anti-His antibody (FRET acceptor, emission 665 nm). DLK phosphorylates T275 / S277 of MKK7, which was detected by an Eu-labeled anti-phospho-MKK7 (T275 / S277) antibody (FRET donor, excitation 340 nm). Phosphorylation of MKK7 resulted in an increase in the TR-FRET signal (XL665 channel / Eu channel ratio), while inhibition of DLK enzymatic activity decreased the TR-FRET signal.

[0418] Assay protocol in 1536MTP format: Each test compound was pre-dispensed (60 nl) into a test plate. + 3 μl DLK solution (10 nM DLK, catalytic domain, Carna Biosiences, 0.6 mM DTT, in assay buffer); + 2 μl substrate solution (15 nM MKK7, LDB; 60 μM ATP; 0.4 mM DTT, in assay buffer); incubated at RT for 90 minutes; + 2 μl detection mix (5 nM XL665-labeled anti-His antibody, Cisbio; 0.1 nM Eu-labeled anti-phospho MKK7 (T275 / S277), Cisbio / Millipore, in detection buffer); incubated at 37°C for 16 hours; endpoint measurement by BMG (HTRF).

[0419] Assay protocol in 384 low-volume MTP format: 1 μl of each test compound was pipetteed into the test plate. + 5 μl DLK solution (10 nM DLK, catalytic domain, Carna Biosiences, in assay buffer); + 5 μl substrate solution (15 nM MKK7, LDB; 60 μM ATP, in assay buffer); incubated at RT for 90 minutes; + 9 μl detection mix (20 nM XL665-labeled anti-His antibody, Cisbio; 0.4 nM Eu-labeled anti-phospho MKK7 (T275 / S277), Cisbio / Millipore, in detection buffer); incubated at 4°C for 16 hours; endpoint measurement by BMG (HTRF).

[0420] All concentrations shown are final concentrations.

[0421] Assay buffer (1536 format): 50 mM Hepes pH 7.5, 10 mM MgCl2, 1 mM EGTA, 0.01% Triton® X-100, 0.01% BSA, 1:500 Smart Block.

[0422] Assay buffer (384 format): 50 mM Hepes pH 7.5, 10 mM MgCl2, 1 mM EGTA, 1 mM DTT, 0.01% Triton® X-100, 0.01% BSA, 1:500 Smart Block.

[0423] Detection buffer: 25mM Tris / HCl pH 7.5, 100mM EDTA, 100mM NaCl, 200mM KF, 0.01% Tween® 20, 1:500 smart block.

[0424] LZK Biochemical Assay The LZK assay is a biochemical assay format designed to screen for LZK inhibitors. LZK enzymatic activity was measured by monitoring the phosphorylation of the physiological substrate MKK7 (MAP2K7, bispecific mitogen-activated protein kinase kinase 7). Phosphorylation was detected by a TR-FRET system, which labels His-tagged MKK7 with an XL665-labeled anti-His antibody (FRET acceptor, emission 665 nm). LZK phosphorylates T275 / S277 of MKK7, which was detected by an Eu-labeled anti-phospho-MKK7 (T275 / S277) antibody (FRET donor, excitation 340 nm). Phosphorylation of MKK7 resulted in an increase in the TR-FRET signal (XL665 channel / Eu channel ratio), while inhibition of LZK enzymatic activity decreased the TR-FRET signal.

[0425] Assay protocol in 384 low-volume MTP format: 1 μl of test compound was pipetteed into the test plate. + 5 μl LZK solution (10 nM LZK, catalytic domain, Carna Biosiences, in assay buffer); + 5 μl substrate solution (15 nM MKK7, LDB; 15 μM ATP, in assay buffer); incubated at RT for 90 minutes; + 5 μl detection mix (20 nM XL665-labeled anti-His antibody, Cisbio; 0.4 nM Eu-labeled anti-phospho MKK7 (T275 / S277), Cisbio / Millipore, in detection buffer); incubated at 32°C for 16 hours; endpoint measurement by BMG (HTRF).

[0426] All concentrations shown are final concentrations.

[0427] Assay buffer (384 format): 50 mM Hepes pH 7.5, 10 mM MgCl2, 1 mM EGTA, 1 mM DTT, 0.01% Triton® X-100, 0.01% BSA, 1:500 Smart Block.

[0428] Detection buffer: 25mm Tris / HCl pH 7.5, 100mm EDTA, 100mm NaCl, 200mm KF, 0.01% Tween® 20, 1:500 Smart Block.

[0429] metabolic stability Each compound is subjected to low concentrations (e.g., less than 1 μM) and low cell numbers (e.g., 1 x 10⁻¹⁶) to achieve linear kinetics. 6 Metabolic stability of rat hepatocytes was measured by incubation with (cells / ml). Seven time points were extracted from the incubation mixture for analysis to define the half-lives of the compounds. From these half-lives, the endogenous clearance within hepatocytes was calculated, and this was further used to determine the blood clearance of each compound (using a well-mixed model) and the corresponding F2. max The values ​​(maximum expected bioavailability after first pass-through of the liver) were extrapolated. CL and F max The values ​​reflect the phase I and phase II metabolism of hepatocytes. To minimize the influence of organic solvents in the incubation mixture, their content was limited to a maximum of 1% for ACN and a maximum of 0.2% for DMSO. The values ​​shown in the fifth column of the table in Figure 1 are for rat hepatocyte CL. 血液 [L / h / kg] and rat hepatocytes F max It is [%].

[0430] Retinal ganglion cell (RGC) survival assay In the RGC assay, the viability of primary mouse retinal ganglion cells was detected by Cell Titer Glo (Promega), using the previously described assay (Proc. Natl. Acad. Sci. USA. 2013, 110(10), 4045-50.), which is incorporated herein by reference in its entirety.

[0431] RGCs were newly isolated from approximately P2 mouse retinas by immunopanning using plates coated with mouse anti-CD90. Cells were seeded on plates coated with poly-D-lysine or laminin in Neurobasal medium supplemented with 1% Pen / Strep (Gibco 15140-122), 0.01 mg / ml insulin, 1 mM sodium pyruvate, 1% 100xSato (400 mg transferrin, 400 mg BSA, 0.25 mg progesterone, 64 mg putrescine, 160 μg sodium selenite (in 40 mL of Neurobasal medium), 0.04 μg / ml triiodothyronine, 2 mM L-glutamine, 0.05 mg / ml N-acetylcysteine, 10 μM forskolin, and 2% 50xB27 (Gibco 17504-044).

[0432] The assay used 500–2000 cells per well in 40 μl volumes (384 MTP format). After 72 hours, 20 μl of Cell Titer Glo reagent was added, and viability was measured by quantifying ATP luminescence. The amount of ATP was directly proportional to the number of cells present in the culture.

[0433] solubility The solubility of each compound at pH 6.5 was investigated by precipitation. Dilutions of each compound were prepared from DMSO stock solution or powder. The equilibrium time was 24 hours. The concentration of the compounds in the supernatant after ultracentrifugation or in the filtrate after filtration was determined by LC-MSMS or HPLC analysis. The solubility data are shown in mg / L in Figure 2.

[0434] transparency To determine permeability values ​​as an in vitro model for screening each compound for intestinal absorption in mammals, selected compounds were tested using the Caco-2 drug permeability assay. Caco-2 cells were cultured in 24-well plates for 14 days. Each test compound was dissolved in DMSO and diluted to a final concentration of 2 μM. The residual organic solvent was less than 1%. Flux in both directions was examined by adding the solution to the apical or basal compartment. Cover plates were incubated at 37°C for 2 hours. Samples were measured by LC-MS / MS, and the data were analyzed using the Caco-2 permeability assay. app AB[nm / s], Caco-2 transmission P app The BA [nm / s] and quotient Caco-2 permeation-outflow ratio were recorded. Ratios greater than 2 suggest active transport.

[0435] Unbound ratio For several selected compounds, the unbound percentage was measured and recorded as a percentage (%) for mice, rats, and / or humans. The distribution of compounds between plasma water, plasma proteins, and solid-supported egg lecithin membranes (Transil) was measured. Test substances were added to a Transil-plasma (water) suspension. After incubation, Transil was separated from the aqueous phase by centrifugation at 1800 g. Drug concentrations were measured before centrifugation and in the aqueous phase. The free fraction was calculated as the ratio of membrane affinity in plasma (MA plasma) to membrane affinity in plasma water (MA buffer).

[0436] CYP inhibition rate The inhibition of CYP enzymes mediated by each compound has been reported for CYP1A2, CYP2C8, CYP2C9, CYP2D6, and CYP3A4, using pooled human liver microsomes as the enzyme source. Furthermore, inhibition of CYP3A4 was determined after a 30-minute pre-incubation with the compound. The inhibitory effects were determined at six concentrations of the test compound (0.625, 1.25, 2.5, 5, 10, and 20 μM) and compared with the degree of metabolite production in the absence of the potential inhibitor (phenacetin, amodiaquine, diclofenac, dextromethorphan, midazolam) to determine IC50.50 The values ​​were calculated. The values ​​are shown in the table below, with the last row corresponding to the CYP3A4 inhibition rate after pre-incubation.

[0437] CYP induction CYP induction was measured by the following method. Human hepatocyte cultures were treated with media containing eight different concentrations of test compounds (typical concentration range: 5–10,000 ng / mL), the prototype inducer omeprazole (CYP1A2), and rifampicin (CYP3A4), as well as the solvent alone. The media were prepared and changed daily for a typical 5-day treatment period. After the treatment period, specific enzyme activity was measured by incubating the probe substrate in situ with intact hepatocyte cultures (CYP1A2 activity: phenacetin O-deethylation activity, CYP3A4 activity: testosterone 6β-hydroxylation activity). CYP activity was quantified by LC-MS / MS analysis. NOEL was recorded in μM.

[0438] SPR assay Surface plasmon resonance (SPR)-based biosensor technology has been widely used to characterize protein / protein and protein / small molecule interactions in the absence of labeling. Here, we characterized the interaction between DLK protein immobilized on the surface of a biosensor chip and small molecules to measure the equilibrium dissociation constant (KD[M]) and kinetic binding and dissociation rate constants (kon[1 / Ms] and koff[1 / s], respectively). Measurements were performed using a Biacore® T200 instrument (GE Healthcare, Uppsala, Sweden). Biotinylated DLK (catalytic domain, amino acids 1-520, Carna-Biosciences09-411-20N) was diluted to a concentration of 10 μg / ml in immobilization buffer (10 mM HEPES, 150 mM NaCl, 3 mM EDTA, and 0.05% v / v surfactant P20, 5 mM MgCl2, 0.5 mM TCEP, pH 7.4) and immobilized on SA-Chip (GE-Healthcare, #29104992) at 18°C. Each compound was obtained at a concentration of 10 mM in 100% dimethyl sulfoxide (DMSO) and diluted in running buffer (10 mM HEPES, 150 mM NaCl, 3 mM EDTA, and 0.05% v / v surfactant P20, 5 mM MgCl2, 0.5 mM TCEP, 1% DMSO). For SPR measurements, sequential dilutions of the compound (typically 8 dilution steps ranging from 0.5 nM to 1 μM) were injected onto the immobilized protein. Binding affinity and kinetics were measured at 18°C ​​and a flow rate of 100 μl / min. After injecting each compound for 70 seconds, a dissociation time of up to 350 seconds was allowed. A dual reference sensorgram was fitted to a simple reversible Langmuir 1:1 reaction mechanism performed with Biacore® T200 (T200 evaluation software version 2.0).

[0439] In vivo pharmacokinetics In vivo pharmacokinetic parameters were investigated in rats after IV administration. The following parameters were recorded: the applied dose, expressed in [mg / kg] body weight; and AUC (0-24). norm= Area under the time curve of plasma concentration divided by dose from 0 to 24 hours, expressed as [kg*h / L]; C max,norm : The maximum drug concentration in plasma, expressed in [kg / L], divided by the dose; CL マトリックス =[L / h / kg], representing the systemic clearance of a drug from plasma; CL 血液 Systemic drug clearance from the blood, expressed as [L / h / kg] = (CL マトリックス *C p / C b ), however C p / C b = Distribution of blood to plasma; V ss The apparent volume of the distribution in a steady state, expressed as [L / kg]; MRT iv =[h] represents the mean residence time; t1 / 2=[h] represents the terminal half-life.

[0440] ischemia / reperfusion The animals were anesthetized (Rompane (xylazine, xylazine hydrochloride) 2%, Bayer, PZN-1320422; Ketabet (ketamine hydrochloride) 100 mg / mL, Pfizer, PZN-3151811), and the pupil of the right eye was dilated (Neosynephrine-POS 5%). Augentropfen, URSAPHARM, PZN0828584).

[0441] Upon anesthesia, a local anesthetic eye drop (Alkaine, local anesthetic augentropfen, Alcon, 37516058) was applied to the right eye. The rat was placed on its left side. After a short exposure time, a 30G cannula was inserted laterally into the anterior chamber. To do this, the eyeball was held in place with a cotton swab so that it protruded from the orbit. Once the cannula was in place, the eye was carefully released. The 30G cannula was connected to an isotonic infusion bag via an infusion set. The infusion bag was suspended from a pressure cuff. The pressure was adjusted using the pressure cuff and manometer. In this model, the intraocular pressure was raised to 120 mmHg. The duration was set to 20 minutes. When the cannula was properly fitted, the eye would turn white as blood circulation was cut off. During the procedure, the rat lay on a warm mat (level 2). The anesthetic state of the animals needed to be observed. If necessary, the animals were sprayed as soon as they began to move their whiskers (usually after about 15 minutes). I applied moisturizing gel to my eyes.

[0442] Treatment began two days before the ischemic event and continued until two days after the ischemic event. Eye movement tracking (OKT) measurements were performed within 2-3 days of the last day of treatment.

[0443] After a period of time had elapsed, the cannula was removed, and antibiotic eye drops and bepanten ophthalmic ointment were applied to the treated eye. The animal was then returned to its cage.

[0444] In optometry readings, only spatial resolution (spatial frequency) is measured. Both eyes were measured. The cycle / degree [c / d] values ​​were graphically displayed comparing the left and right eyes.

[0445] Device settings: Psychophysics: Simple Staircases Stimulation: 100% contrast Spatial frequency Optic nerve compression Male C57BL / 6 mice, approximately 3 months old, were anesthetized with 100 / 10 mg / kg ketamine / xylazine, followed by local administration of propalacaine. Under binocular endoscopic guidance, the optic nerve was surgically exposed and crushed with Dumont N7 self-closing forceps 1-2 mm behind the eyeball. A small incision was made in the conjunctiva located in the lateral orbit of the eyeball using spring scissors. Minimal incisions were continued until the optic nerve was exposed to avoid bleeding from the vascular system. After clean exposure, the optic nerve was grasped for 3-7 seconds using fine microforceps approximately 1-2 mm from the eyeball. After carefully removing the microforceps, the eyeball was repositioned and tobramycin was administered. Ten days after nerve compression, the eyeball was extracted and fixed, and the surviving RGCs were immunostained for SNCG, RBPMS, and βIII-tubulin. Next, the retina was imaged using a Nikon EclipseTE2000-5 fluorescence microscope and a Plan-fluor 40 angstrom / 0.6 objective lens. Images were obtained from four quadrants: 1 mm above, below, temporal, and nasal, from the optic disc. RGCs were manually counted from each image. In a separate cohort of animals, the optic nerve and retina were transected and stained for phospho-JUN (an indicator of DLK pathway activation) 24 hours after optic nerve compression. Intravitreal injection, optic nerve compression, immunofluorescence, and RGC counting were performed using a masked method.

[0446] light damage After acclimatizing to dim light (less than 10-30 lux) for two weeks (14 days), female BALBc / J mice (10-12 weeks old) were subjected to 24-hour dark acclimation. All compound injections were performed in the dark using dark red light as needed. After topical application of a stimulant (tropicamide or phenylephrine), all mice were placed in a light-up chamber. Next, the light was left on at approximately 3000 lux for four hours, followed by dark recovery under the same conditions with dark acclimation until the experimental procedure was ready or until placed under dim light conditions (less than 10-30 lux). The mice were then followed up for 3-7 days with OCT, ERG, functional tests, and / or immunohistochemical analysis.

[0447] result The DLK, LZK, retinal ganglion cell viability assay data, permeability data, metabolic data, and clearance data for compounds 4, 19, 94, and 112 are shown in the table in Figure 1. Compound 112 showed the highest activity in the DLK, LZK, and RGC assays. In silico absorption, distribution, metabolism, excretion, and toxicological properties (ADMET), molecular properties, in vitro physicochemical properties, safety data, and in vitro PK properties for compound 112 are obtained and shown in Figure 2. The in vitro physicochemical and PK properties characterized this compound as chemically stable but metabolically unstable. In vivo PK data for compound 112 in male Wistar rats are shown in Figure 6. To demonstrate in vivo target involvement, mouse optic nerve crush experiments were performed (see Figure 3), and p-JUN immunoreactivity was measured in the retinal ganglion cell (RGC) layer after injury. The decrease in p-cJun intensity in RGCs treated with compound 112 indicated inhibited activation of the DLK pathway compared to RGCs treated with the solvent. Compound 112 also showed neuroprotective effects in an ischemia / reperfusion (I / R) rat model. Under prophylactic conditions after a 20-minute ischemic event, animals treated with compound 112 maintained approximately 80% of their visual acuity, compared to approximately 5% in untreated animals (solvent) (see Figure 4). Compound 112 was also tested using continuous optical coherence tomography (OCT) and continuous electroretinography (ERG) (see Figure 5). In continuous OCT, compound 112 showed a higher outer retinal layer (ORL) thickness than the solvent, demonstrating a dose-dependent effect. In continuous ERG, compound 112 showed higher a-wave amplitude in photoreceptors and higher b-wave amplitude in intraretinal cells compared to the solvent, demonstrating a dose-dependent effect. These results demonstrate that compound 112 exhibited neuroprotective effects in a mouse photodamage model, showing conservation of both the morphology (by serial OCT) and function (by serial ERG) of the photoreceptor.

[0448] The DLK and LZK values ​​of the compound of formula Z are disclosed in Table A below. [Table 8-1] [Table 8-2] [Table 8-3] [Table 8-4] [Table 8-5] [Table 8-6] [Table 8-7] [Table 8-8] [Table 8-9] [Table 8-10] [Table 8-11] [Table 8-12]

[0449] The present invention has been described above with a detailed description thereof, but the above description is intended to illustrate, and not to limit, the scope of the present invention as defined by the appended claims. Other embodiments, advantages, and modifications are included in the following claims. The present invention provides, for example, the following items: (Item 1) Compound of formula (Z): [ka] [In the formula, Is X nitrogen and Y carbon? or X is carbon, and Y is nitrogen. R E This is hydrogen, -C(O)-NR A R B , C(O)OR 6 , -S(O) 2 NH(C 1 ~C 6 )-alkyl, (C 1 ~C 6 )-alkyl, halo, (C 6 ~C 10 )-aryl or heteroaryl, provided that the (C 1 ~C 6 )-alkyl, (C 6 ~C 10 )-aryl and heteroaryl are one or more independently selected (C 1 ~C 4 )-alkyl, (C 3 ~C 7 )-cycloalkyl, (C 3 ~C 7 )-cycloalkyl-(C 1 ~C 3 )-alkyl, 4-7 member heterocyclyl, (C 1 ~C 4 )-alkoxy, (C 3 ~C 7 )-cycloalkoxy, -SO 2 R 4 , -NR 4 R 5 , may be substituted with cyano, hydroxyl, or halo, provided that the above (C 1 ~C 4 )-alkyl, (C 3 ~C 7 )-cycloalkyl, (C 1 ~C 4 )-alkoxy, (C 3 ~C 7 )-cycloalkyl-(C 1 ~C 3 )-alkyl, and (C 3 ~C 7 The )-cycloalkoxy may be substituted with one or more independently selected hydroxyl, cyano, or halo groups. R A is hydrogen or -CR 1 R 2 R 3 And, R B is hydrogen or (C 1 ~C 6 )-alkyl, R 1 and R 2 Each is independently of hydrogen or (C 1 ~C 3 )-alkyl, provided that the above (C 1 ~C 3 )-alkyl may be substituted with one or more independently selected halos. R 3 is hydrogen, (C 1 ~C 6 )-alkyl, (C 3 ~C 7 )-cycloalkyl, or (C 3 ~C 7 )-cycloalkyl-(C 1 ~C 3 )-alkyl, provided that the above (C 1 ~C 6 )-alkyl, (C 3 ~C 7 )-cycloalkyl, or (C 3 ~C 7 )-cycloalkyl-(C 1 ~C 3 )-alkyl is one or more independently selected hydroxyls, (C 1 ~C 4 )- may be substituted with alkoxy, oxo, cyano, or halo, provided that the above (C 1 ~C 4 The )-alkoxy group may be substituted with one or more independently selected halos. or R 1 is hydrogen, R 2 and R 3 These atoms bond to each other to form a 3- to 7-membered ring containing up to two heteroatoms selected from the group consisting of O or N, wherein the ring contains one or more independently selected hydroxyls, (C 1 ~C 4 )-alkoxy, (C 1 ~C 4 (C) may be substituted with alkyl, oxo, cyano, or halo, provided that the above (C) 1 ~C 4 )-alkoxy and (C 1 ~C 4 )-alkyl may be substituted with one or more independently selected hydroxyl or halo groups. R C is hydrogen, (C 6 ~C 10 )-aryl, or CR 4 R 5 R 7 And, however, the above (C 6 ~C 10 )-Aaryl may, depending on the case, be one or more independently selected (C 1 ~C 4 )-alkyl, (C 1 ~C 4 )-alkoxy or halo substituted, and the (C 1 ~C 4 )-alkyl and (C 1 ~C4 The )-alkoxy may be substituted with one or more independently selected hydroxyls or halos. R 4 is hydrogen, (C 1 ~C 6 )-alkyl, (C 3 ~C 7 )-cycloalkyl or 4-7 member heterocycline, provided that the (C 1 ~C 6 )-alkyl, (C 3 ~C 7 )-Cycloalkyl, or 4- to 7-membered heterocyclyl, one or more independently selected (C 1 ~C 4 )-alkyl, (C 1 ~C 4 )- may be substituted with alkoxy, hydroxyl, oxo, cyano, or halo, provided that the above (C 1 ~C 4 )-alkoxy and (C 1 ~C 4 )-alkyl may be substituted with one or more independently selected halos, and any nitrogen of the 4-7 member heterocycline may be C(O)OR 6 or C(O)R 6 It can be replaced with, R 5 is, (C 1 ~C 6 )-alkyl, (C 3 ~C 7 )-Cycloalkyl, cyanomethyl, (C 6 ~C 10 )-aryl, (C 6 ~C 10 )-Aryl-(C 1 ~C 4 )-alkyl, heteroaryl, or 4- to 7-membered heterocyclyl, however, (i) Said (C 1 ~C 6 )-alkyl, (C 3 ~C 7 )-cycloalkyl, (C 6 ~C 10 )-aryl, (C 6 ~C 10 )-Aryl-(C 1 ~C 4 )-alkyl, heteroaryl, or 4- to 7-membered heterocyclyl is one or more independently selected (C 1 ~C 4 )-alkyl, (C 1 ~C 4 )-alkoxy, C(O)OR 6 、(C 3 ~C 7 (C) may be substituted with a cycloalkoxy, cyano, 4- to 7-membered heterocyclyl, or halo, provided that the (C) 1 ~C 4 )-alkyl and (C 1 ~C 4 )-alkoxy is oxo, (C 1 ~C 4 )-alkyl, (C 1 ~C 4 It may be substituted with one or more independently selected 4- to 7-membered heterocyclines optionally substituted with )-alkoxy, -NR'R'', or halo. (ii) The above (C 3~C 7 )-cycloalkyl, (C 6 ~C 10 )-aryl, (C 6 ~C 10 )-Aryl-(C 1 ~C 4 )-alkyl, heteroaryl, or 4-7 membered heterocyclyl is a 4-7 membered heterocyclyl or (C 3 ~C 7 )-It may also be condensed with a cycloalkyl group, or R 4 and R 5 These atoms bond to each other to form a 3- to 8-membered monocyclic or bridged bicyclic ring containing up to two heteroatoms selected from the group consisting of O or N, however, (i) The ring is one or more independently selected (C 6 ~C 10 )-Aryl-(C 1 ~C 4 )-alkyl, (C 6 ~C 10 )-aryl, 4-7 member heterocyclyl, (C 1 ~C 4 )-alkyl, (C 1 ~C 4 )- may be substituted with alkoxy, oxo, cyano, or halo, provided that the above (C 1 ~C 4 )-alkyl and (C 6 ~C 10 )-aryl is one or more independently selected 4-7 member heterocyclines, (C 1 ~C 4 )-alkoxy or halo may be substituted, and each nitrogen of the 4- to 7-membered heterocyclyl is C(O)OR 6 or C(O)R 6 It is either independently replaced or (ii) Each of the rings is one or more independently selected (C 1 ~C 4 (C) optionally substituted with alkoxy or halo 6 ~C 10 )-aryl, heteroaryl, or 4- to 7-membered heterocyclyl may be condensed with, R 6 is hydrogen or (C 1 ~C 4 )-alkyl, R 7 is hydrogen, (C 1 ~C 6 )-alkyl, (C 3 ~C 7 )-cycloalkyl, (C 6 ~C 10 )-aryl, or a 4- to 7-membered heterocycline, provided that the (C 1 ~C 6 )-alkyl, (C 3 ~C 7 )-cycloalkyl, (C 6 ~C10 )-aryl, or 4- to 7-membered heterocyclyl, one or more independently selected (C 1 ~C 4 )-alkyl, (C 1 ~C 4 )- may be substituted with alkoxy, oxo, cyano, or halo, provided that the above (C 1 ~C 4 )-alkoxy and (C 1 ~C 4 )-alkyl may be substituted with one or more independently selected halos, and the nitrogen of the 4-7 member heterocycline may be C(O)OR 6 or C(O)R 6 It can be replaced with, R D is hydrogen or (C 1 ~C 6 )-alkyl, or R C and R D These atoms bond to each other to form a 4- to 10-membered monocyclic or bicyclic ring containing up to 3 heteroatoms selected from the group consisting of O or N, wherein the 4- to 10-membered monocyclic or bicyclic ring consists of one or more independently selected (C 1 ~C 6 )-alkyl or (C 1 ~C 4 )-substituted in some cases with alkoxy, Z is -NHR F or H, R F is hydrogen or (C 1 ~C 6 )-alkyl, provided that the above (C 1 ~C 6 )-alkyl is optionally substituted with one or more independently selected -NR'R'', The presence of R' and R'' respectively is due to hydrogen and (C 1 ~C 4 )-Selected from alkyl groups, or R' and R'' bond to each other to form a 3-6 member heterocycline with the nitrogen atom to which they are bonded. R G is hydrogen or halo, R H is hydrogen, halo, or (C 1 ~C 4 )-alkyl] and their salts, solvates, and solvates of salts. (Item 2) The compounds listed in item 1, where Z is H. (Item 3) Z, -NHR F The compound described in item 1. (Item 4) R E However, C(O)OR 6A compound described in any one of items 1 to 3. (Item 5) R E However, -S(O) 2 NH(C 1 ~C 6 A compound that is )-alkyl, as described in any one of items 1 to 3. (Item 6) R E However, (C 1 ~C 6 )-alkyl, provided that the above (C 1 ~C 6 )-alkyl is one or more independently selected (C 1 ~C 4 )-alkyl, (C 3 ~C 7 )-cycloalkyl, (C 3 ~C 7 )-cycloalkyl-(C 1 ~C 3 )-alkyl, 4-7 member heterocyclyl, (C 1 ~C 4 )-alkoxy, (C 3 ~C 7 )-cycloalkoxy, -SO 2 R 4 , -NR 4 R 5 , may be substituted with cyano, hydroxyl, or halo, provided that the above (C 1 ~C 4 )-alkyl, (C 3 ~C 7 )-cycloalkyl, (C 1 ~C 4 )-alkoxy, (C 3 ~C 7 )-cycloalkyl-(C 1 ~C 3 )-alkyl, and (C 3 ~C 7 )-Cycloalkoxy may be substituted with one or more independently selected cyano, hydroxyl, or halo compounds as described in any one of items 1 to 3. (Item 7) R E However, it is a halo, and is one of the compounds listed in any one of items 1 to 3. (Item 8) R E However, (C 6 ~C 10 )-aryl, provided that the above (C 6 ~C 10 )-Aaryl is one or more independently selected (C 1 ~C 4 )-alkyl, (C 3 ~C 7 )-cycloalkyl, (C 3 ~C 7 )-cycloalkyl-(C 1 ~C 3 )-alkyl, 4-7 member heterocyclyl, (C 1 ~C 4 )-alkoxy, (C 3 ~C 7 )-cycloalkoxy, -SO 2 R 4 , -NR 4 R 5 , may be substituted with cyano, hydroxyl, or halo, provided that the above (C 1 ~C 4 )-alkyl, (C 3 ~C 7 )-cycloalkyl, (C 1 ~C 4 )-alkoxy, (C 3 ~C 7 )-cycloalkyl-(C 1 ~C 3 )-alkyl, and (C 3 ~C 7 )-Cycloalkoxy may be substituted with one or more independently selected cyano, hydroxyl, or halo compounds as described in any one of items 1 to 3. (Item 9) R E However, the heteroaryl is a heteroaryl, wherein the heteroaryl is one or more independently selected (C 1 ~C 4 )-alkyl, (C 3 ~C 7 )-cycloalkyl, (C 3 ~C 7 )-cycloalkyl-(C 1 ~C 3 )-alkyl, 4-7 member heterocyclyl, (C 1 ~C 4 )-alkoxy, (C 3 ~C 7 )-cycloalkoxy, -SO 2 R 4 , -NR 4 R 5 , may be substituted with cyano, hydroxyl, or halo, provided that the above (C 1 ~C 4 )-alkyl, (C 3 ~C 7 )-cycloalkyl, (C 1 ~C 4 )-alkoxy, (C 3 ~C 7 )-cycloalkyl-(C 1 ~C 3 )-alkyl, and (C 3 ~C 7 )-Cycloalkoxy may be substituted with one or more independently selected cyano, hydroxyl, or halo compounds as described in any one of items 1 to 3. (Item 10) The compound according to item 9, wherein the heteroaryl is thiadiazolyl. (Item 11) The compound according to item 9, wherein the heteroaryl is oxadiazolyl. (Item 12) Compounds of formula (Y) listed in item 1:

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Claims

1. Compound of formula (Z): 【Chemistry 74】 [In the formula, Is X nitrogen and Y carbon? or X is carbon, and Y is nitrogen. R Ｅ is hydrogen, -C(O)-NR Ａ R Ｂ , C(O)OR ６ , -S(O) ２ NH(C １ ~C ６ )-alkyl, (C １ ~C ６ )-alkyl, halo, (C ６ ~C １０ )-aryl, or heteroaryl, provided that the said (C １ ~C ６ )-alkyl, (C ６ ~C １０ )-aryl, and heteroaryl are optionally substituted with one or more independently selected (C １ ~C ４ )-alkyl, (C ３ ~C ７ )-cycloalkyl, (C ３ ~C ７ )-cycloalkyl-(C １ ~C ３ )-alkyl, 4-7 membered heterocyclyl, (C １ ~C ４ )-alkoxy, (C ３ ~C ７ )-cycloalkoxy, -SO ２ R ４ , -NR ４ R ５ , cyano, hydroxyl, or halo, provided that the said (C １ ~C ４ )-alkyl, (C ３ ~C ７ )-cycloalkyl, (C １ ~C ４ )-alkoxy, (C ３ ~C ７ )-cycloalkyl-(C １ ~C ３ )-alkyl, and (C ３ ~C ７ )-cycloalkoxy may be optionally substituted with one or more independently selected hydroxyl, cyano, or halo, R Ａ is hydrogen or -CR １ R ２ R ３ And, R Ｂ is hydrogen or (C １ ~C ６ ) - Alkyl, R １ and R ２ Each is independently hydrogen or (C １ ~C ３ ) - alkyl, provided that the above (C １ ~C ３ )-alkyl may be substituted with one or more independently selected halos, R ３ is hydrogen, (C １ ~C ６ )-alkyl, (C ３ ~C ７ )-cycloalkyl, or (C ３ ~C ７ )-cycloalkyl-(C １ ~C ３ ) - alkyl, provided that the above (C １ ~C ６ )-alkyl, (C ３ ~C ７ )-cycloalkyl, or (C ３ ~C ７ )-cycloalkyl-(C １ ~C ３ )-alkyl is one or more independently selected hydroxyls, (C １ ~C ４ ) - May be substituted with alkoxy, oxo, cyano, or halo, provided that the above (C １ ~C ４ The )-alkoxy group may be substituted with one or more independently selected halos. or R １ is hydrogen, R ２ and R ３ These atoms bond to each other to form a 3- to 7-membered ring containing up to two heteroatoms selected from the group consisting of O and N, wherein the ring contains one or more independently selected hydroxyls, (C １ ~C ４ )-alkoxy, (C １ ~C ４ ) - May be substituted with alkyl, oxo, cyano, or halo, provided that the above (C １ ~C ４ )-alkoxy and (C １ ~C ４ )-alkyl may be substituted with one or more independently selected hydroxyl or halo groups. R Ｃ is hydrogen, (C ６ ~C １０ )-aryl, or CR ４ R ５ R ７ wherein the (C ６ ~C １０ )-aryl is unsubstituted or substituted with one or more independently selected (C １ ~C ４ )-alkyl, (C １ ~C ４ )-alkoxy, or halo, and the (C １ ~C ４ )-alkyl and (C １ ~C ４ )-alkoxy may be substituted with one or more independently selected hydroxyl or halo. R ４ is hydrogen, (C １ ~C ６ )-alkyl, (C ３ ~C ７ )-cycloalkyl or 4- to 7-membered heterocycline, provided that the above (C １ ~C ６ )-alkyl, (C ３ ~C ７ )-Cycloalkyl or 4- to 7-membered heterocyclyl, one or more independently selected (C １ ~C ４ )-alkyl, (C １ ~C ４ ) - May be substituted with alkoxy, hydroxyl, oxo, cyano, or halo, provided that the above (C １ ~C ４ )-alkoxy and (C １ ~C ４ )-alkyl may be substituted with one or more independently selected halos, and any nitrogen of the 4- to 7-membered heterocycline may be C(O)OR ６ or C(O)R ６ It can be replaced with, R ５ is, (C １ ~C ６ )-alkyl, (C ３ ~C ７ )-Cycloalkyl, cyanomethyl, (C ６ ~C １０ ) - Aryl, (C ６ ~C １０ ) - Aryl - (C １ ~C ４ ) - Alkyl, heteroaryl, or 4- to 7-membered heterocyclyl, however, (i) Said (C １ ~C ６ )-alkyl, (C ３ ~C ７ )-cycloalkyl, (C ６ ~C １０ ) - Aryl, (C ６ ~C １０ ) - Aryl - (C １ ~C ４ )-alkyl, heteroaryl, or 4- to 7-membered heterocyclyl is one or more independently selected (C １ ~C ４ )-alkyl, (C １～ C ４ )-alkoxy, C(O)OR ６ , (C ３ ~C ７ ) - May be substituted with a cycloalkoxy, cyano, 4- to 7-membered heterocyclyl, or halo, provided that the above (C １ ~C ４ )-alkyl and (C １ ~C ４ )-alkoxy is unsubstituted or oxo, (C １ ~C ４ )-alkyl, (C １ ~C ４ ) may be substituted with one or more independently selected 4- to 7-membered heterocyclines substituted with -alkoxy, -NR'R'', or halo. (ii) The above (C ３ ~C ７ )-cycloalkyl, (C ６ ~C １０ ) - Aryl, (C ６ ~C １０ ) - Aryl - (C １ ~C ４ )-alkyl, heteroaryl, or 4- to 7-membered heterocyclyl is a 4- to 7-membered heterocyclyl or (C ３ ~C ７ ) - May be condensed with a cycloalkyl group, or R ４ and R ５ These atoms bond to each other, forming a 3- to 8-membered monocyclic or bridged bicyclic ring containing up to two heteroatoms selected from the group consisting of O and N, however, (i) The ring is one or more independently selected (C ６ ~C １０ ) - Aryl - (C １ ~C ４ )-alkyl, (C ６ ~C １０ )-aryl, 4-7 member heterocyclyl, (C １ ~C ４ )-alkyl, (C １ ~C ４ ) - May be substituted with alkoxy, oxo, cyano, or halo, provided that the above (C １ ~C ４ )-alkyl and (C ６ ~C １０ )-aryl is one or more independently selected 4- to 7-membered heterocyclines, (C １ ~C ４ ) may be substituted with an alkoxy or halo, and each nitrogen of the 4- to 7-membered heterocyclyl is C(O)OR ６ or C(O)R ６ It is either independently replaced or (ii) Each of the rings is either unsubstituted or one or more independently selected (C １ ~C ４ )-substituted with alkoxy or halo, (C ６ ~C １０ ) May condense with an aryl, heteroaryl, or a 4- to 7-membered heterocyclyl, or R ６ is hydrogen or (C １ ~C ４ ) - Alkyl, R ７ is hydrogen, (C １ ~C ６ )-alkyl, (C ３ ~C ７ )-cycloalkyl, (C ６ ~C １０ )-aryl, or a 4- to 7-membered heterocycline, provided that the above (C １ ~C ６ )-alkyl, (C ３ ~C ７ )-cycloalkyl, (C ６ ~C １０ )-aryl, or 4- to 7-membered heterocyclyl, one or more independently selected (C １ ~C ４ )-alkyl, (C １ ~C ４ ) - May be substituted with alkoxy, oxo, cyano, or halo, provided that the above (C １ ~C ４ )-alkoxy and (C １ ~C ４ )-alkyl may be substituted with one or more independently selected halos, and the nitrogen of the 4- to 7-membered heterocycline is C(O)OR ６ or C(O)R ６ It can be replaced with, R Ｄ is hydrogen or (C １ ~C ６ ) - Alkyl or R Ｃ and R Ｄ These atoms bond to each other to form a 4- to 10-membered monocyclic or bicyclic ring containing up to three heteroatoms selected from the group consisting of O and N, wherein the 4- to 10-membered monocyclic or bicyclic ring is unsubstituted or composed of one or more independently selected (C) atoms. １ ~C ６ )-alkyl or (C １ ~C ４ )-substituted with alkoxy, Z is -NHR Ｆ or H, R Ｆ is hydrogen or (C １ ~C ６ ) - alkyl, provided that the above (C １ ~C ６ ) -alkyl is unsubstituted or substituted with one or more independently selected -NR'R'', The presence of R' and R'' respectively is due to hydrogen and (C １ ~C ４ ) - Selected from alkyl groups, or R' and R'' bond to each other to form a 3- to 6-membered heterocycline with the nitrogen atom to which they are bonded. R Ｇ is hydrogen or halo, R Ｈ is hydrogen, halo, or (C １ ~C ４ ) - Alkyl] or their salts, solvates, or solvates of salts.

2. Z is NH ２ And, R Ｅ is a heteroaryl, wherein the heteroaryl is one or more independently selected (C １ ~C ４ )-alkyl, (C ３ ~C ７ )-cycloalkyl, (C ３ ~C ７ )-cycloalkyl-(C １ ~C ３ )-alkyl, 4-7 member heterocyclyl, (C １ ~C ４ )-alkoxy, (C ３ ~C ７ ) -cycloalkoxy, -SO ２ R ４ , -NR ４ R ５ , may be substituted with cyano, hydroxyl, or halo, provided that the above (C １ ~C ４ )-alkyl, (C ３ ~C ７ )-cycloalkyl, (C １ ~C ４ )-alkoxy, (C ３ ~C ７ )-cycloalkyl-(C １ ~C ３ )-alkyl, and (C ３ ~C ７ The cycloalkoxy may be substituted with one or more independently selected hydroxyl, cyano, or halo groups. R Ｃ CR ４ R ５ R ７ And, R Ｄ It is hydrogen, X is carbon, and Y is nitrogen. R ４ is hydrogen, (C １ ~C ６ )-cycloalkyl, (C ３ ~C ７ )-cycloalkyl or 4- to 7-membered heterocyclyl, each of which is one or more independently selected (C １ ~C ４ )-alkyl, (C １ ~C ４ ) - May be substituted with alkoxy, oxo, cyano, or halo, provided that the above (C １ ~C ４ )-alkoxy and (C １ ~C ４ )-alkyl may be substituted with one or more fluorocarbons, and any nitrogen of the 4- to 7-membered heterocycline is C(O)OR ６ or C(O)R ６ It can be replaced with, R ５ is, (C ３ ~C ７ ) - Cycloalkyl, phenyl, or heteroaryl, provided that the (C ３ ~C ７ ) - Cycloalkyl, phenyl, or heteroaryl is one or more independently selected (C １ ~C ４ )-alkyl, (C １ ~C ４ ) - May be substituted with an alkoxy, cyano, 4- to 7-membered heterocyclyl, or halo, provided that the above (C １ ~C ４ )-alkyl and (C １ ~C ４ )-alkoxy may be substituted with one or more fluoropolymers. R ６ is, (C １ ~C ４ The compound according to claim 1, wherein it is an alkyl group.

3. Z is NH ２ And, R Ｅ is thiadiazolyl or oxadiazolyl, each of which is one or more independently selected (C １ ~C ４ ) - may be substituted with alkyl, provided that (C １ ~C ４ )-alkyl may be substituted with one or more independently selected hydroxyl, cyano, or halo. R Ｃ CR ４ R ５ R ７ And, R Ｄ It is hydrogen, X is carbon, and Y is nitrogen. R ４ is, (C １ ~C ６ ) - alkyl, provided that the above (C １ ~C ６ )-alkyl may be substituted with one or more fluoropolymers. R ５ is a phenyl or heteroaryl compound, wherein the phenyl or heteroaryl compound is one or more independently selected (C １ ~C ４ )-alkyl, (C １ ~C ４ ) - May be substituted with alkoxy, cyano, or fluoro, provided that the above (C １ ~C ４ )-alkyl and (C １ ~C ４ The compound according to any one of claims 1 to 2, wherein the alkoxy may be substituted with one or more fluoropolymers.

4. The compound according to claim 1, which is a compound of formula (I): 【Transformation 78】 [In the formula, Is X nitrogen and Y carbon? or X is carbon, and Y is nitrogen. R １ and R ２ Each is independently of hydrogen, or unsubstituted or substituted with one or more fluorocarbons (C １ ~C ３ ) - Alkyl, R ３ is, (C １ ~C ６ )-alkyl, (C ３ ~C ７ )-cycloalkyl, or (C ３ ~C ７ )-cycloalkyl-(C １ ~C ３ ) - alkyl, provided that the above (C １ ~C ６ )-alkyl, (C ３ ~C ７ )-cycloalkyl, or (C ３ ~C ７ )-cycloalkyl-(C １ ~C ３ )-alkyl is one or more independently selected hydroxyls, (C １ ~C ４ ) - May be substituted with alkoxy, oxo, cyano, or halo, provided that the above (C １ ~C ４ The )-alkoxy group may be substituted with one or more independently selected halos. or R １ is hydrogen, R ２ and R ３ These atoms bond to each other to form a 4- to 7-membered ring containing up to two heteroatoms selected from the group consisting of O and N, wherein the ring contains one or more independently selected hydroxyls, (C １ ~C ４ )-alkoxy, (C １ ~C ４ ) - May be substituted with alkyl, oxo, cyano, or halo, provided that the above (C １ ~C ４ )-alkoxy and (C １ ~C ４ )-alkyl may be substituted with one or more independently selected halos, R ４ is hydrogen, (C １ ~C ６ )-alkyl, (C ３ ~C ７ )-cycloalkyl or 4- to 7-membered heterocycline, provided that the above (C １ ~C ６ )-alkyl, (C ３ ~C ７ )-Cycloalkyl or 4- to 7-membered heterocyclyl, one or more independently selected (C １ ~C ４ )-alkyl, (C １ ~C ４ ) - May be substituted with alkoxy, oxo, cyano, or halo, provided that the above (C １ ~C ４ )-alkoxy and (C １ ~C ４ )-alkyl may be substituted with one or more independently selected halos, and any nitrogen of the 4- to 7-membered heterocycline may be C(O)OR ６ or C(O)R ６ It can be replaced with, R ５ is, (C ３ ~C ７ )-cycloalkyl, (C ６ ~C １０ ) -aryl or heteroaryl, provided that the above (C ３ ~C ７ )-cycloalkyl, (C ６ ~C １０ )-aryl or heteroaryl is one or more independently selected (C １ ~C ４ )-alkyl, (C １ ~C ４ ) - May be substituted with an alkoxy, cyano, 4- to 7-membered heterocyclyl, or halo, provided that the above (C １ ~C ４ )-alkyl and (C １ ~C ４ )-alkoxy may be substituted with one or more fluoropolymers. or R ４ and R ５ These atoms bond to each other, forming a 4- to 7-membered ring containing up to two heteroatoms selected from the group consisting of O and N, however, (i) The ring is one or more independently selected (C ６ ~C １０ ) - Aryl - (C １ ~C ４ )-alkyl, 4-7 member heterocyclyl, (C １ ~C ４ )-alkyl, (C １ ~C ４ ) - May be substituted with alkoxy, oxo, cyano, or halo, provided that the above (C １ ~C ４ )-alkyl may be unsubstituted or substituted with one or more independently selected 4- to 7-membered heterocyclines or fluoropolymers, wherein each nitrogen atom of the 4- to 7-membered heterocycline is C(O)OR ６ or C(O)R ６ It can be independently replaced by, (ii) The ring is (C ６ ~C １０ ) May condense with -aryl or heteroaryl, R ６ is, (C １ ~C ４ ) - Alkyl].

5. A compound of formula (I-C) according to any one of claims 1 and 4: 【Chemistry 80】 [In the formula, R １ It is hydrogen, R ２ This is an unsubstituted or substituted methyl group with one or more fluoropolymers. R ３ Each is one or more independently selected hydroxyls, (C １ ~C ４ ) - Methyl or ethyl which may be substituted with alkoxy, chloro, or fluoro, provided that the above (C １ ~C ４ )-alkoxy may be substituted with one or more fluoropolymers. or R ２ and R ３ These combine with each other to form pyrrolidinone, cyclobutyl, or tetrahydrofuranyl with the carbon atoms to which they are bonded. R ４ is hydrogen, (C １ ~C ６ )-alkyl, cyclopropyl, cyclobutyl, cyclopentyl, or 4- to 7-membered heterocyclyl, provided that the above (C １ ~C ６ )-alkyl, cyclopropyl, cyclobutyl, cyclopentyl, or 4- to 7-membered heterocyclyl is one or more independently selected (C １ ~C ４ ) - May be substituted with an alkoxy or halo, and any nitrogen of the 4- to 7-membered heterocyclyl is C(O)OR ６ or C(O)R ６ It can be replaced with, R ５ is phenyl or benzoxazolyl, each of which is one or more independently selected (C １ ~C ４ )-alkyl, (C １ ~C ４ ) - May be substituted with an alkoxy, cyano, or halo, provided that the above (C １ ~C ４ )-alkyl and (C １ ~C ４ )-alkoxy may be substituted with one or more fluoropolymers. R ４ and R ５ These atoms bond to each other, forming a 5-6 membered ring containing up to one oxygen atom together with the carbon atoms to which they are bonded, wherein the ring may be condensed with phenyl. R ６ is, (C １ ~C ４ ) - Alkyl].

6. The compound according to any one of claims 1 and 4, wherein X is nitrogen and Y is carbon.

7. The compound according to any one of claims 1 and 4, wherein X is carbon and Y is nitrogen.

8. R １ The compound according to any one of claims 1, 4, and 6 to 7, wherein is hydrogen.

9. R ２ However, unsubstituted or substituted with one or more fluoro(C) １ ~C ３ The compound according to any one of claims 1 and 4, wherein it is an alkyl group.

10. R ２ The compound according to any one of claims 1 and 4 to 7, wherein is methyl.

11. R ３ is, (C １ ~C ６ ) - alkyl, provided that the above (C １ ~C ６ )-alkyl is one or more independently selected hydroxyls, (C １ ~C ４ ) - May be substituted with alkoxy, oxo, cyano, or halo, provided that the above (C １ ~C ４ The compound according to any one of claims 1, 4, and 6-10, wherein the alkoxy may be substituted with one or more independently selected halos.

12. R ３ The compound according to any one of claims 1 and 4 to 11, wherein is an ethyl which may be substituted with one or more fluoropolymers.

13. R ４ is, (C １ ~C ６ ) - alkyl, provided that the above (C １ ~C ６ )-alkyl is one or more independently selected (C １ ~C ４ )-alkyl, (C １ ~C ４ ) - May be substituted with alkoxy, oxo, cyano, or halo, provided that the above (C １ ~C ４ )-alkoxy and (C １ ~C ４ The compound according to any one of claims 1 to 4 and 6 to 12, wherein the alkyl group may be substituted with one or more independently selected halos.

14. R ４ The compound according to any one of claims 1 to 2 and 4 to 12, wherein is hydrogen, methyl, ethyl, or methoxymethyl.

15. R ５ is, (C ６ ~C １０ ) - aryl, provided that the above (C ６ ~C １０ ) - Aryl is one or more independently selected (C １ ~C ４ )-alkyl, (C １ ~C ４ ) - May be substituted with an alkoxy, cyano, 4- to 7-membered heterocyclyl, or halo, provided that the above (C １ ~C ４ )-alkyl and (C １ ~C ４ The compound according to any one of claims 1, 4, and 6-7, wherein the alkoxy may be substituted with one or more fluoropolymers.

16. R ５ is phenyl, and the phenyl is one or more independently selected (C １ ~C ４ )-alkyl, (C １ ~C ４ ) - May be substituted with an alkoxy, cyano, or halo, provided that the above (C １ ~C ４ )-alkyl and (C １ ~C ４ The compound according to any one of claims 1 to 15, wherein the )-alkoxy may be substituted with one or more fluoropolymers.

17. R ５ is phenyl, and the phenyl is one or more independently selected (C １ -C ４ The compound according to any one of claims 1 to 16, which may be substituted with an alkoxy or halo.

18. Compounds with compound numbers 1 to 403 disclosed in Tables 1A, 1B, 1C, 1D, 1E, and 1F Table 1-1 Table 1-2 Table 1-3 Table 1-4 Table 1-5 Table 1-6 Table 1-7 Table 1-8 Table 1-9 Table 1-10 Table 1-11 Table 1-12 Table 1-13 Table 1-14 Table 1-15 Table 1-16 Table 1-17 Table 1-18 Table 1-19 Table 1-20 Table 1-21 Table 1-22 Table 1-23 Table 1-24 Table 1-25 Table 1-26 Table 1-27 Table 1-28 Table 1-29 Table 1-30 Table 1-31 Table 1-32 Table 1-33 Table 1-34 Table 1-35 Table 1-36 Table 1-37 Table 1-38 Table 1-39 Table 2-1 Table 2-2 Table 2-3 Table 2-4 Table 2-5 Table 3-1 Table 3-2 Table 3-3 Table 3-4 Table 3-5 Table 3-6 Table 3-7 Table 3-8 Table 3-9 Table 3-10 Table 3-11 Table 3-12 Table 3-13 Table 3-14 Table 3-15 Table 3-16 Table 3-17 Table 3-18 Table 3-19 Table 3-20 Table 3-21 Table 3-22 Table 3-23 Table 3-24 Table 3-25 Table 3-26 Table 3-27 Table 3-28 Table 3-29 Table 3-30 Table 3-31 Table 3-32 Table 3-33 Table 3-34 Table 3-35 Table 3-36 Table 3-37 Table 3-38 Table 3-39 Table 3-40 Table 3-41 Table 3-42 Table 3-43 Table 3-44 Table 3-45 Table 3-46 Table 3-47 Table 3-48 Table 3-49 Table 3-50 Table 1D Table 4-1 Table 4-2 Table 5-1 Table 5-2 Table 5-3 Table 5-4 Table 5-5 Table 5-6 Table 5-7 Table 5-8 Table 6-1 Table 6-2 Table 6-3 Table 6-4 A compound or a pharmaceutically acceptable salt thereof, selected from the above.

19. A pharmaceutical composition comprising a compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

20. Use of the compound according to any one of claims 1 to 18 in the manufacture of a drug for the treatment of neurodegenerative diseases.

21. Use of the compound according to any one of claims 1 to 18 in the manufacture of a drug for the treatment of optic neuropathy.

22. A composition for use in inhibiting DLK and / or LZK activity in mammalian cells, comprising a compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof.

23. A composition for use in the treatment of neurodegenerative diseases, comprising a compound according to any one of claims 1 to 18.

24. A composition for use in the treatment of optic neuropathy, comprising the compound described in any one of claims 1 to 18.

25. The pharmaceutical composition according to claim 19, wherein the pharmaceutical composition is for ocular administration.

26. The pharmaceutical composition according to any one of claims 19 and 25, wherein the pharmaceutical composition is for intravitreal administration.

27. The aforementioned neurodegenerative diseases include amyotrophic lateral sclerosis (ALS), Alzheimer's disease, Parkinson's disease, Parkinson's Plus disease, Huntington's disease, peripheral neuropathy, ischemia, stroke, intracranial hemorrhage, cerebral hemorrhage, nerve damage caused by exposure to toxic compounds, nerve system damage, trigeminal neuralgia, glossopharyngeal neuralgia, Bell's palsy, myasthenia gravis, muscular dystrophy, progressive muscular atrophy, primary lateral sclerosis (PLS), spinal muscular atrophy, hereditary muscular atrophy, intervertebral disc syndrome, cervical spondylosis, nerve plexus disorders, thoracic outlet destruction syndrome, and porphyria. The use according to claim 20, selected from pseudobulbar palsy, progressive bulbar palsy, multiple system atrophy, progressive supranuclear palsy, corticobasal degeneration, Lewy body dementia, frontotemporal dementia, demyelinating diseases, Guillain-Barré syndrome, multiple sclerosis, Charcot-Marietooth disease, prion diseases, Creutzfeldt-Jakob disease, Gerstmann-Straussler-Scheinker syndrome (GSS), fatal familial insomnia (FFI), bovine spongiform encephalopathy, Pick's disease, epilepsy, sensorineural hearing loss, traumatic brain injury, and AIDS dementia complex.

28. The use according to claim 20, wherein the neurodegenerative disease is a neurodegenerative ophthalmic disease.

29. The aforementioned neurodegenerative ophthalmic diseases include age-related macular degeneration (AMD), choroidal neovascularization (CNV), choroidal neovascular membrane (CNVM), cystoid macular edema (CME), epiretinal membrane (ERM) and macular perforation, myopia-related choroidal neovascularization, vascular and striate vascularis, retinal detachment, diabetic retinopathy, diabetic macular edema (DME), atrophic and hypertrophic lesions of the retinal pigment epithelium, retinal vein occlusion, choroidal retinal vein occlusion, macular edema, macular edema associated with renal vein occlusion, retinitis pigmentosa and other hereditary retinal degenerations, retinopathy of prematurity, glaucoma, toxic optic neuropathy, and non-arteritic ischemic disease. Use according to claim 28, selected from optic neuropathy, arteritis-induced ischemic optic neuropathy / giant cell arteritis, traumatic optic neuropathy, idiopathic intracranial hypertension / pseudomyelitis, inflammatory optic neuropathy, compressive optic neuropathy, infiltrative optic neuropathy, autoimmune optic neuropathy, lipid storage, nutritional optic neuropathy, Leber's hereditary optic neuropathy, dominant optic atrophy, Friedrich's ataxia, radiation-induced optic neuropathy, other optic neuropathy including iatrogenic optic neuropathy, space flight-related neuroophthalmopathy syndrome (SANS), inflammatory diseases of the eye, refractive myopia, neurotrophic keratopathy, corneal denervation, and diabetic keratopathy.

30. The use according to claim 29, wherein the inflammatory optic neuropathy is optic neuritis.

31. The use according to claim 28, wherein the neurodegenerative ophthalmic disease is selected from glaucoma, age-related macular degeneration (AMD), choroidal neovascularization (CNV), myopia-related choroidal neovascularization, diabetic retinopathy, macular edema, and retinal vein occlusion.

32. The use according to claim 21, wherein the optic neuropathy is selected from glaucoma, hereditary retinal degeneration, non-exudative AMD / geographic atrophy, ischemic retinal vascular disease, retinal detachment, and edema-causing disease.

33. The composition for use according to claim 22, wherein the cells are nerve cells.

34. The aforementioned neurodegenerative diseases include amyotrophic lateral sclerosis (ALS), Alzheimer's disease, Parkinson's disease, Parkinson's Plus disease, Huntington's disease, peripheral neuropathy, ischemia, stroke, intracranial hemorrhage, cerebral hemorrhage, nerve damage caused by exposure to toxic compounds, nerve system damage, trigeminal neuralgia, glossopharyngeal neuralgia, Bell's palsy, myasthenia gravis, muscular dystrophy, progressive muscular atrophy, primary lateral sclerosis (PLS), spinal muscular atrophy, hereditary muscular atrophy, intervertebral disc syndrome, cervical spondylosis, nerve plexus disorders, thoracic outlet destruction syndrome, porphyria, and pseudoglobulin disease. A composition for use according to claim 23, selected from paralysis, progressive bulbar palsy, multiple system atrophy, progressive supranuclear palsy, corticobasal degeneration, Lewy body dementia, frontotemporal dementia, demyelinating diseases, Guillain-Barré syndrome, multiple sclerosis, Charcot-Marietooth disease, prion diseases, Creutzfeldt-Jakob disease, Gerstmann-Straussler-Scheinker syndrome (GSS), fatal familial insomnia (FFI), bovine spongiform encephalopathy, Pick's disease, epilepsy, sensorineural hearing loss, traumatic brain injury, and AIDS dementia complex.

35. The composition for use according to claim 23, wherein the neurodegenerative disease is a neurodegenerative ophthalmic disease.

36. The aforementioned neurodegenerative ophthalmic diseases include age-related macular degeneration (AMD), choroidal neovascularization (CNV), choroidal neovascular membrane (CNVM), cystoid macular edema (CME), epiretinal membrane (ERM) and macular perforation, myopia-related choroidal neovascularization, vascular and striate vascularization, retinal detachment, diabetic retinopathy, diabetic macular edema (DME), atrophic and hypertrophic lesions of the retinal pigment epithelium, retinal vein occlusion, choroidal retinal vein occlusion, macular edema, macular edema associated with renal vein occlusion, retinitis pigmentosa and other hereditary retinal degenerations, retinopathy of prematurity, glaucoma, toxic optic neuropathy, and non-arteritic ischemic optic neuropathy. A composition for use according to claim 35, selected from arteritis-induced ischemic optic neuropathy / giant cell arteritis, traumatic optic neuropathy, idiopathic intracranial hypertension / pseudomyelitis, inflammatory optic neuropathy, compressive optic neuropathy, infiltrative optic neuropathy, autoimmune optic neuropathy, lipid storage disease, nutritional optic neuropathy, Leber's hereditary optic neuropathy, dominant optic atrophy, Friedrich's ataxia, radiation-induced optic neuropathy, other optic neuropathy including iatrogenic optic neuropathy, space flight-related neuroophthalmopathy syndrome (SANS), inflammatory diseases of the eye, refractive myopia, neurotrophic keratopathy, corneal denervation, and diabetic keratopathy.

37. The composition for use according to claim 36, wherein the inflammatory optic neuropathy is optic neuritis.

38. The composition for use according to claim 36, wherein the neurodegenerative ophthalmic disease is selected from glaucoma, age-related macular degeneration (AMD), choroidal neovascularization (CNV), myopia-related choroidal neovascularization, diabetic retinopathy, macular edema, and retinal vein occlusion.

39. The composition for use according to claim 24, wherein the optic neuropathy is selected from glaucoma, hereditary retinal degeneration, non-exudative AMD / geographic atrophy, ischemic retinal vascular disease, retinal detachment, and edema-causing disease.

40. An eye drop, eye ointment, eye gel, eye coil, contact lens, or ophthalmic insert comprising the pharmaceutical composition according to any one of claims 19 and 25.

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