2,8-Diazaspiro[4.5]decane compounds

Abstract

Disclosed are 2,8-diazaspiro[4.5]decane compounds, including (pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane compounds, (2,6-naphthyridin-1-yl)-2,8-diazaspiro[4.5]decane compounds, and (1,7-naphthyridin-4-yl)-2,8-diazaspiro[4.5]decane compounds, that are inhibitors of LATS1 / 2, compositions containing these compounds, and methods of inhibiting LATS1 / 2 activity.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to International Patent Application No. PCT / CN2021 / 098358, filed June 4, 2021, the contents of which are incorporated herein by reference in their entirety. [Background technology]

[0002] Large tumor suppressor kinase 1 (LATS1) and large tumor suppressor kinase 2 (LATS2) are regulatory serine / threonine kinases in the Hippo pathway that constitutively phosphorylate the effector transcription factors Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), thereby inactivating them. When the Hippo pathway is active, a series of upstream factors phosphorylate the Hippo kinases MST1 / 2, which in turn phosphorylate LATS1 / 2. LATS1 / 2 phosphorylates YAP and TAZ, causing them to be sequestrated in the cytoplasm and degraded. When the Hippo pathway is inactive and LATS1 / 2 is eliminated, reduced, and / or not phosphorylated, YAP and TAZ are not phosphorylated and instead translocate to the nucleus. In the nucleus, YAP and TAZ form complexes with transcription factors, such as the TEAD family of transcription factors, that regulate a series of downstream genes associated with functions including cancer resistance, cell proliferation, apoptosis, and other cellular properties. Literature reports also indicate that YAP / TAZ activation after injury promotes tissue regeneration and repair in multiple cell types, including lung injury models. See, e.g., LaCanna, R. et al. J Clin Invest. 2019;129(5):2107-2122; and JCI Insight. 2019;4(14):e128674.

[0003] Consequently, inactivation of the LATS1 and LATS2 pathways may be an option for pharmacological intervention in human diseases or conditions such as idiopathic pulmonary fibrosis (IPF) and acute respiratory distress syndrome (ARDS). Summary of the Invention

[0004] Disclosed are 2,8-diazaspiro[4.5]decane compounds, including (pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane compounds, (2,6-naphthyridin-1-yl)-2,8-diazaspiro[4.5]decane compounds, and (1,7-naphthyridin-4-yl)-2,8-diazaspiro[4.5]decane compounds, that are inhibitors of LATS1 / 2; compositions containing these compounds; and methods for inhibiting LATS1 / 2 in cells or subjects, promoting tissue regeneration after injury, and treating diseases, disorders, or conditions that can benefit from LATS1 / 2 inhibition.

[0005] In one aspect, there is provided a compound of formula (I), or any variation thereof, such as formula (IA), (IB), or (IC), or an N-oxide thereof, or a salt thereof (e.g., a pharmaceutically acceptable salt thereof), as detailed herein. Also provided is a pharmaceutical composition comprising a compound of formula (I), or any variation thereof detailed herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

[0006] In another aspect, there is provided a method of promoting tissue regeneration after injury or treating a disease or condition that can benefit from LATS1 / 2 inhibition (e.g., ARDS), comprising administering to a subject in need thereof an effective amount of a compound of Formula (I), or any variant thereof, such as Formula (IA), (IB), or (IC) as detailed herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the subject is a human.

[0007] Also provided is a compound of formula (I), or any variation thereof, such as formula (IA), (IB) or (IC) as detailed herein, or a pharmaceutically acceptable salt thereof, for use in a method of promoting tissue regeneration after injury or in a method of treating a disease or condition that may benefit from LATS1 / 2 inhibition (e.g., ARDS).

[0008] Also provided is the use of a compound of formula (I), or any variant thereof, such as formula (IA), (IB) or (IC) as detailed herein, or a pharmaceutically acceptable salt thereof, in the methods detailed herein (e.g., promoting tissue regeneration after injury or treating ARDS).

[0009] Also provided is the use of a compound of formula (I), or any variation thereof as detailed herein, such as formula (IA), (IB) or (IC), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use in the methods detailed herein (e.g., promoting tissue regeneration after injury or treatment of ARDS).

[0010] Also provided are kits for promoting tissue regeneration after injury or for treating a disease or condition that can benefit from LATS1 / 2 inhibition (e.g., ARDS), comprising a pharmaceutical composition comprising a compound of formula (I), or any variant thereof, such as formula (IA), (IB) or (IC) as detailed herein, or a pharmaceutically acceptable salt thereof; and instructions for use.

[0011] In another aspect, there is provided a method of making a compound of formula (I) or any variation thereof, such as formula (IA), (IB), or (IC). Also provided are compound intermediates useful in the synthesis of a compound of formula (I) or any variation thereof, such as formula (IA), (IB), or (IC). DETAILED DESCRIPTION OF THE INVENTION

[0012] Disclosed herein are compounds of formula (I) or variants thereof, such as formulas (IA), (IB), (IC), (II-A), (II-B), (II-C), (III)-(IX), e.g., compound numbers 101-201 in Table 1, and pharmaceutical compositions thereof, that are inhibitors of LATS1 / 2. Accordingly, the compounds and compositions are useful for treating diseases, disorders, or conditions that can benefit from LATS1 / 2 inhibition.

[0013] The presently disclosed subject matter is now described more fully below. However, many modifications and other embodiments of the presently disclosed subject matter described herein will occur to one skilled in the art to which the presently disclosed subject matter pertains having the benefit of the teachings presented in the foregoing description. Therefore, the presently disclosed subject matter should not be limited to the particular embodiments disclosed, but rather it should be considered that modifications and other embodiments are intended to be included within the scope of the appended claims. In other words, the subject matter described herein embraces all alternatives, modifications, and equivalents. In the event that one or more of the incorporated literature, patents, and similar materials differs from or conflicts with this application, including, but not limited to, defined terms, term usage, described techniques, etc., this application controls. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety.

[0014] definition As used herein, "alkyl" refers to an alkyl group having a specified number of carbon atoms (i.e., C 1~10 "C" refers to a saturated, linear (i.e., unbranched) or branched monovalent hydrocarbon chain, or combinations thereof. Particular alkyl groups are those having 1 to 20 carbon atoms ("C 1~20 alkyl"), those having 1 to 8 carbon atoms ("C 1~8 alkyl"), those having 1 to 6 carbon atoms ("C 1~6 alkyl"), those with 2 to 6 carbon atoms ("C 2~6 alkyl"), or those having 1 to 4 carbon atoms ("C 1~4 Examples of alkyl groups include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl; homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, etc.

[0015] As used herein, "alkenyl" refers to an alkyl group having at least one site of olefinic unsaturation (i.e., having at least one moiety of the formula C=C) and having the specified number of carbon atoms (i.e., C 2~10 "C" means 2 to 10 carbon atoms). Alkenyl groups can be in the "cis" or "trans" configuration, or the "E" or "Z" configuration. Particular alkenyl groups are those having 2 to 20 carbon atoms ("C" means 2 to 10 carbon atoms). 2~20 alkenyl"), those having 2 to 8 carbon atoms ("C 2~8 alkenyl"), those having 2 to 6 carbon atoms ("C 2~6 alkenyl) or those having 2 to 4 carbon atoms ("C 2~4 Examples of alkenyl groups include, but are not limited to, groups such as ethenyl (or vinyl), prop-1-enyl, prop-2-enyl (or allyl), 2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, buta-1,3-dienyl, 2-methylbuta-1,3-dienyl, homologs and isomers thereof.

[0016] As used herein, "alkynyl" refers to an alkyl group having the specified number of carbon atoms (i.e., C 2~10 "C" refers to an unsaturated, linear (i.e., unbranched) or branched monovalent hydrocarbon chain having at least one site of acetylenic unsaturation (i.e., having at least one moiety of the formula C≡C), or combinations thereof. Particular alkynyl groups are those having 2 to 20 carbon atoms ("C 2~20 alkynyl"), those having 2 to 8 carbon atoms ("C 2~8 alkynyl) with 2 to 6 carbon atoms ("C 2~6 alkynyl) with 2 to 4 carbon atoms ("C 2~4Examples of alkynyl groups include, but are not limited to, groups such as ethynyl (or acetylenyl), prop-1-ynyl, prop-2-ynyl (or propargyl), but-1-ynyl, but-2-ynyl, but-3-ynyl, homologs and isomers thereof.

[0017] As used herein, "alkylene" refers to a residue the same as alkyl, but which has divalent character. Particular alkylene groups are those containing 1 to 6 carbon atoms ("C 1~6 alkylene), 1 to 5 carbon atoms ("C 1~5 alkylene) and those having 1 to 4 carbon atoms ("C 1~4 alkylene"), or 1 to 3 carbon atoms ("C 1~3 Examples of alkylene include, but are not limited to, groups such as methylene (-CH-), ethylene (-CH-CH-), 1,3-propylene (-CH-CH-CH-), 1,2-propylene (-CH(CH)-CH-), 1,4-butylene (-CH-CH-CH-CH-), and the like.

[0018] As used herein, "alkylidene" refers to the same residues as alkyl, but having divalency at the point of attachment and connected to the parent structure through a double bond. Particular alkylidene groups are those containing 1 to 6 carbon atoms ("C 1~6 alkylidene"), 1 to 5 carbon atoms ("C 1~5 alkylidene) having 1 to 4 carbon atoms ("C 1~4 alkylidene") or 1 to 3 carbon atoms ("C 1~3 Examples of alkylidene include, but are not limited to, groups such as methylidene (=CH), ethylidene (=CH-CH), 1-propylidene (=CH-CH-CH), 2-propylidene (=C(CH)), 1-butylidene (=CH-CH-CH-CH-CH), and the like.

[0019] As used herein, "cycloalkyl" refers to a group having a specified number of carbon atoms (i.e., C3~10 "C" refers to a non-aromatic, saturated or unsaturated, cyclic monovalent hydrocarbon structure of 3 to 10 carbon atoms. Cycloalkyl can consist of one ring, such as cyclohexyl, or multiple rings, such as adamantyl, but excludes aryl groups. Cycloalkyls containing more than one ring can be fused, spiro, or bridged, or combinations thereof. Particular cycloalkyl groups are those having 3 to 12 ring carbon atoms. Preferred cycloalkyls are those having 3 to 8 ring carbon atoms ("C"). 3~8 cycloalkyl"), or 3 to 6 carbon atoms ("C 3~6 Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, norbornyl, and the like.

[0020] As used herein, "aryl" refers to an unsaturated aromatic carbocyclic group having one ring (e.g., phenyl) or multiple fused rings (e.g., naphthyl or anthryl), which may or may not be aromatic. Particular aryl groups have from 6 to 14 annular (i.e., ring) carbon atoms ("C 6~14 Aryl groups are groups having two or more rings, wherein at least one ring is non-aromatic. Aryl groups having two or more rings, wherein at least one ring is non-aromatic, can be attached to the parent structure at either an aromatic ring position or a non-aromatic ring position. In one variation, an aryl group having two or more rings, wherein at least one ring is non-aromatic, is attached to the parent structure at an aromatic ring position.

[0021] As used herein, "heteroaryl" refers to an unsaturated aromatic cyclic group having 1 to 14 annular (i.e., ring) carbon atoms and at least one annular heteroatom, including, but not limited to, a heteroatom such as nitrogen, phosphorus, oxygen, and sulfur. Heteroaryl groups can have a single ring (e.g., pyridyl, furyl) or multiple fused rings (e.g., indolizinyl, benzothienyl), which fused rings may or may not be aromatic. Particular heteroaryl groups are 5- to 14-membered rings having 1 to 12 annular (i.e., ring) carbon atoms and 1 to 6 annular (i.e., ring) heteroatoms independently selected from nitrogen, phosphorus, oxygen, and sulfur; 5- to 10-membered rings having 1 to 8 annular carbon atoms and 1 to 4 annular heteroatoms independently selected from nitrogen, phosphorus, oxygen, and sulfur; and 5-, 6-, or 7-membered rings having 1 to 5 annular carbon atoms and 1 to 4 annular heteroatoms independently selected from nitrogen, phosphorus, oxygen, and sulfur. In one variation, heteroaryl includes a monocyclic aromatic 5-, 6-, or 7-membered ring having 1 to 6 ring carbon atoms and 1 to 4 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. In another variation, heteroaryl includes a polycyclic aromatic ring having 1 to 12 ring carbon atoms and 1 to 6 ring heteroatoms independently selected from nitrogen, phosphorus, oxygen, and sulfur. Heteroaryl groups having two or more rings, in which at least one ring is non-aromatic, can be attached to the parent structure at either an aromatic ring position or a non-aromatic ring position. In one variation, heteroaryl groups having two or more rings, in which at least one ring is non-aromatic, are attached to the parent structure at an aromatic ring position.

[0022] As used herein, "heterocycle," "heterocyclic," or "heterocyclyl" refers to a saturated or unsaturated non-aromatic cyclic group having one ring or multiple fused rings and having 1 to 14 annular (i.e., ring) carbon atoms and 1 to 6 annular (i.e., ring) heteroatoms, such as nitrogen, phosphorus, sulfur, or oxygen. Heterocycles containing two or more rings can be fused, spiro, or bridged, or any combination thereof. In fused ring systems, one or more of the fused rings can be cycloalkyl. Specific heterocyclyl groups are 3- to 14-membered rings having 1 to 13 ring carbon atoms and 1 to 6 ring heteroatoms independently selected from nitrogen, phosphorus, oxygen, and sulfur; 3- to 12-membered rings having 1 to 11 ring carbon atoms and 1 to 6 ring heteroatoms independently selected from nitrogen, phosphorus, oxygen, and sulfur; 3- to 10-membered rings having 1 to 9 ring carbon atoms and 1 to 4 ring heteroatoms independently selected from nitrogen, phosphorus, oxygen, and sulfur; 3- to 8-membered rings having 1 to 7 ring carbon atoms and 1 to 4 ring heteroatoms independently selected from nitrogen, phosphorus, oxygen, and sulfur; and 3- to 6-membered rings having 1 to 5 ring carbon atoms and 1 to 4 ring heteroatoms independently selected from nitrogen, phosphorus, oxygen, and sulfur. In one variation, heterocyclyl includes a monocyclic 3-, 4-, 5-, 6-, or 7-membered ring having 1 to 2, 1 to 3, 1 to 4, 1 to 5, or 1 to 6 ring carbon atoms and 1 to 2, 1 to 3, or 1 to 4 ring heteroatoms independently selected from nitrogen, phosphorus, oxygen, and sulfur. In another variation, heterocyclyl includes a polycyclic non-aromatic ring having 1 to 12 ring carbon atoms and 1 to 6 ring heteroatoms independently selected from nitrogen, phosphorus, oxygen, and sulfur.

[0023] "Halo" or "halogen" refers to fluoro, chloro, bromo, and / or iodo. When a residue is substituted with more than one halogen, the compound can be referred to using a prefix corresponding to the number of halogen moieties attached. For example, dihaloaryl, dihaloalkyl, trihaloaryl, etc. refer to an aryl and alkyl substituted with two ("di") or three ("tri") halo groups, which may be, but are not necessarily, the same halo. Thus, 4-chloro-3-fluorophenyl is within the scope of dihaloaryl. An alkyl group in which one or more hydrogens have been replaced with a halo group is referred to as "haloalkyl," e.g., "C 1~6 An alkyl group in which each hydrogen is replaced with a halo group is called a "perhaloalkyl." A preferred perhaloalkyl group is trifluoroalkyl (-CF3). Similarly, a "perhaloalkoxy" refers to an alkoxy group in which a halogen atom replaces each H in the hydrocarbon group making up the alkyl portion of the alkoxy group. An example of a perhaloalkoxy group is trifluoromethoxy (-OCF3).

[0024] "Carbonyl" refers to the group C=O.

[0025] "Oxo" refers to the moiety =O.

[0026] "Geminal" refers to the relationship of two moieties attached to the same atom, e.g., the residue -CH2-CR x R y -In R x and R y is geminal and R x is R y can be referred to as a geminal R group relative to

[0027] Unless otherwise specified, "optionally substituted" means that a group may be unsubstituted or may be substituted with one or more (e.g., 1, 2, 3, 4, or 5) substituents listed for that group, which may be the same or different. In one embodiment, an optionally substituted group has one substituent. In another embodiment, an optionally substituted group has two substituents. In another embodiment, an optionally substituted group has three substituents. In another embodiment, an optionally substituted group has four substituents. In some embodiments, an optionally substituted group has 1 to 2, 1 to 3, 1 to 4, or 1 to 5 substituents.

[0028] The term "inhibitor" as used herein refers to a molecule that inhibits the activity of a molecular target (e.g., LATS1 / 2). As used herein, "inhibiting" refers to reducing the activity of a target enzyme compared to the activity of that enzyme in the absence of the inhibitor. In some embodiments, the term "inhibiting" refers to a reduction in target enzyme activity by at least about 5%, at least about 10%, at least about 20%, at least about 25%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or at least about 95%. In other embodiments, "inhibiting" refers to a reduction in target enzyme activity by about 5% to about 25%, about 25% to about 50%, about 50% to about 75%, or about 75% to 100%. In some embodiments, "inhibiting" refers to a reduction in target enzyme activity by about 95% to 100%, e.g., a reduction in activity of 95%, 96%, 97%, 98%, 99%, or 100%. Such a decrease can be measured using a variety of techniques that will be recognized by those skilled in the art, including in vitro kinase assays.

[0029] As used herein, "treatment" or "treating" with respect to a disease or condition refers to obtaining a desired pharmacological and / or physiological effect. The effect may be a partial or complete cure of the disease or condition and / or therapeutic with respect to adverse effects resulting from the disease or condition. As used herein, "treatment" includes, but is not limited to, one or more of the following: reducing one or more symptoms resulting from the disease or condition, reducing the severity of the disease or condition, stabilizing the disease or condition (e.g., preventing or slowing the progression of the disease or condition), slowing or delaying the progression of the disease or condition, ameliorating the pathology, reducing the dose of one or more drugs required to treat the disease or condition, enhancing the effect of another drug, improving quality of life, interfering with one or more points in a biological pathway leading to or involved in the disease or condition, and / or prolonging survival. "Treatment" also includes reducing the pathological consequences of tissue damage and promoting the recovery of damaged tissue. The methods of the present invention contemplate any one or more of these aspects of treatment.

[0030] As used herein, the term "effective amount" refers to that amount of a compound of the present invention that should be effective in a given therapeutic regimen, in combination with efficacy and toxicity parameters. As understood in the art, an effective amount can be one or more doses, i.e., a single dose or multiple doses may be required to achieve a desired therapeutic endpoint. An effective amount can be considered in the context of administration of one or more therapeutic agents and a compound, or a pharmaceutically acceptable salt thereof, and can be considered to be given in an effective amount if, together with one or more other agents, a desired or beneficial result can be achieved or is achieved. The appropriate dose of any co-administered compound can be optionally lowered due to the combined effect (e.g., additive or synergistic effect) of the compounds.

[0031] A "therapeutically effective amount" refers to an amount of a compound or salt thereof sufficient to produce a desired therapeutic outcome (e.g., a decrease / reduction in the severity or duration of a disease or condition being treated by LATS1 / 2 (e.g., ARDS), a stabilization of the severity of cancer, or elimination of one or more symptoms of cancer). With respect to therapeutic use, beneficial or desired results include, for example, a reduction in one or more symptoms (biochemical, histological, and / or behavioral) caused by the disease, including complications and intermediate pathological phenotypes that appear during the progression of the disease, an increase in the quality of life of a subject suffering from the disease, a reduction in the dosage of other drugs required to treat the disease, an enhancement effect of another drug, a delay in the progression of the disease, and / or an increase in patient survival.

[0032] As used herein, "pharmaceutically acceptable" or "pharmacologically acceptable" means a material that is not biologically or otherwise undesirable; for example, the material can be incorporated into a pharmaceutical composition administered to a patient without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained. A pharmaceutically acceptable carrier or excipient should meet required standards for toxicity and manufacturing testing and / or be included in the Inactive Ingredients Guide prepared by the U.S. Food and Drug Administration.

[0033] In some embodiments, the salts of the compounds of the present invention are pharmaceutically acceptable salts. A "pharmaceutically acceptable salt" is a salt that retains at least the biological activity of the free (non-salt) compound and can be administered to a subject as a drug or pharmaceutical. Such salts include, for example, (1) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or organic acids such as acetic acid, oxalic acid, propionic acid, succinic acid, maleic acid, tartaric acid, etc.; and (2) salts formed when an acidic proton present in the parent compound is either replaced by a metal ion, such as an alkali metal, alkaline earth ion, or aluminum ion, or coordinated with an organic base. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, etc. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, etc. Pharmaceutically acceptable salts may be prepared in situ during a manufacturing process or by separately reacting a purified compound of the invention in its free acid or base form with a suitable organic or inorganic base or acid, respectively, and isolating the salt thus formed during subsequent purification.

[0034] As used herein, the term "excipient" refers to an inactive or non-active substance that may be used in the manufacture of a drug or pharmaceutical product, such as a tablet, that contains a compound of the invention as an active ingredient. A variety of substances can be encompassed by the term excipient, including, but not limited to, any substance used as a binder, disintegrant, coating, tableting / encapsulating aid, cream or lotion, lubricant, parenteral solution, chewable tablet material, sweetener or flavoring agent, suspending / gelling agent, or wet granulation agent. Binders include, for example, carbomer, povidone, xanthan gum, etc.; coating materials include, for example, cellulose acetate phthalate, ethyl cellulose, gellan gum, maltodextrin, enteric coatings, etc.; compression / encapsulation materials include, for example, calcium carbonate, glucose, fructose dc (dc—“directly compressible”), honey dc, lactose (anhydrous or monohydrate; optionally combined with aspartame, cellulose, or microcrystalline cellulose), starch dc, sucrose, etc.; disintegrants include, for example, croscarmellose sodium, gellan gum, sodium starch glycolate, etc.; creams or lotions include, for example, lubricants include, for example, magnesium stearate, stearic acid, sodium stearyl fumarate, etc.; chewable tablet materials include, for example, dextrose, fructose dc, lactose (monohydrate, optionally combined with aspartame or cellulose), etc.; suspending / gelling agents include, for example, carrageenan, sodium starch glycolate, xanthan gum, etc.; sweeteners include, for example, dextrose, fructose dc, sorbitol, sucrose dc, etc.; and wet granulating agents include, for example, calcium carbonate, maltodextrin, microcrystalline cellulose, etc. In some cases, the terms "additive" and "carrier" are used interchangeably.

[0035] The term "subject" or "patient" means an animal such as a mammal, including, but not limited to, a primate (e.g., a human), cow, sheep, goat, horse, dog, cat, rabbit, rat, mouse, etc. In certain embodiments, the subject is a human or a human patient.

[0036] compound The compounds disclosed herein are compounds of Formula (I), or salts (e.g., pharmaceutically acceptable salts), solvates (e.g., hydrates), prodrugs, metabolites, or derivatives thereof. These compounds bind to and inhibit the activity of LATS1 / 2 with greater potency and selectivity than other kinases (e.g., AKT1, ROCK1, and PKA), and are therefore useful as selective inhibitors of LATS1 / 2 for the treatment of diseases and conditions that can benefit from LATS1 / 2 inhibition.

[0037] In one embodiment, the compound of formula (I): TIFF2024521929000001.tif68170 or an N-oxide or salt (e.g., a pharmaceutically acceptable salt), solvate (e.g., hydrate), prodrug, metabolite, or derivative thereof is provided, R 1 is R 10 is a 5- to 14-membered heteroaryl optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from R 2 is hydrogen, halogen, C 1~6 Alkyl, -O(C 1~6 alkyl), -NH(C 1~6 alkyl) or -N(C 1~6 alkyl)2, where each C 1~6 Alkyl is R 10 and optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R 3 is hydrogen, C 1~6 Alkyl, halogen, cyano, hydroxyl, -O(C 1~6 alkyl), C 2~6 Alkenyl or C 2~6 alkynyl, where C 1~6Alkyl, C 2~6 Alkenyl and C 2~6 Each alkynyl is R 10 and optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R 4 is hydrogen, halogen, cyano, -NR 43a R 43b , -OR 44 , C 1~6 Alkyl or C 3~6 cycloalkyl, where C 1~6 Alkyl and C 3~6 Each cycloalkyl is R 10 and optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from G 1 is N or CR 41 and G 2 is N or CR 42 where G 1 and G 2 is N, R 41 and R 42 are independently hydrogen, halogen, cyano, -NR 43a R 43b , -OR 44 , C 1~6 Alkyl or C 3~6 cycloalkyl, where C 1~6 Alkyl and C 3~6 Each cycloalkyl is R 10 and optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Each R 43a and R 43b are independently hydrogen or C 1~6 is alkyl, R 44 is hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~8 cycloalkyl, 3- to 14-membered heterocyclyl, where R 44 C 1~6 Alkyl, C 2~6Alkenyl, C 2~6 Alkynyl, C 3~8 Cycloalkyl and 3- to 14-membered heterocyclyl are each R 10 and optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 5 is hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~8 Cycloalkyl, C 6~14 Aryl, 5- to 14-membered heteroaryl, 3- to 14-membered heterocyclyl, -C(O)R 14 , -C(O)OR 15 or -C(O)NR 16a R 16b where R 5 C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~8 Cycloalkyl, C 6~14 Aryl, 5- to 14-membered heteroaryl, and 3- to 14-membered heterocyclyl are each R 10 or R 6a or R 6b and together with the atoms to which they are attached, R 10 and forming a 3- to 14-membered heterocyclyl optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from Each R 6a and R 6b are independently hydrogen, C 1~6 Alkyl, C 3~8 Cycloalkyl, C 6~10 Aryl, 5-14 membered heteroaryl, 3-12 membered heterocyclyl, -C(O)R 14 , -C(O)OR 15 or -C(O)NR 16a R 16b where R 6a and R 6b C 1~6 Alkyl, C 3~8 Cycloalkyl, C 6~10Aryl, 5- to 14-membered heteroaryl, and 3- to 12-membered heterocyclyl are each R 10 or R 5 and together with the atoms to which they are attached, R 10 or R 6a and R 6b combine with the carbon to which they are attached to form a carbonyl, Each R 7a and R 7b are independently hydrogen or R 10 C optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from 1~6 alkyl, or R 7a and R 7b combine with the carbon to which they are attached to form a carbonyl, Each R 8a and R 8b are independently hydrogen, halogen, hydroxyl, -O(C 1~6 alkyl) or C 1~6 alkyl, where each C 1~6 Alkyl is R 10 and optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from n is 0 to 8, Each R 9 is independently C 1~6 alkyl, or, if present, two geminal R 9 groups, taken together with the carbon to which they are attached, form a carbonyl, Each R 14 are independently hydrogen or C 1~6 is alkyl, Each R 15 is independently C 1~6 is alkyl, Each R 16a and R 16b are independently hydrogen or C 1~6 alkyl, or R 16a and R16b together with the nitrogen atom to which they are attached, form R 10 and forming a 4- to 12-membered heterocyclyl optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from Each R 10 are independently oxo, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~8 Cycloalkyl, C 6~14 Aryl, 5- to 14-membered heteroaryl, 3- to 14-membered heterocyclyl, halogen, cyano, -C(O)R a , -C(O)OR b , -C(O)NR c R d , -OR b , -OC(O)R a , -OC(O)NR c R d , -SR b , -S(O)R e , -S(O)2R e , -S(O)(=NH)R e , -S(O)NR c R d , -NR c R d , -N(R f )C(O)R a , -N(R f )C(O)OR b , -N(R f )C(O)NR c R d , -N(R f )S(O)2R e , -N(R f )S(O)NR c R d Or-P(O)R g R h where R 10 C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~8 Cycloalkyl, C 6~14 Aryl, 5- to 14-membered heteroaryl, and 3- to 14-membered heterocyclyl are each R 11and optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R a are independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~8 Cycloalkyl, C 6~10 aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, where R a C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~8 Cycloalkyl, C 6~10 Aryl, 5- to 10-membered heteroaryl, and 3- to 12-membered heterocyclyl are each R 11 and optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R b are independently hydrogen, C 1~6 Alkyl, C 3~8 Cycloalkyl, C 6~10 aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, where R b C 1~6 Alkyl, C 3~8 Cycloalkyl, C 6~10 Aryl, 5- to 10-membered heteroaryl, and 3- to 12-membered heterocyclyl are each R 11 and optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R c and R d are independently hydrogen, C 1~6 Alkyl, C 3~8 Cycloalkyl, C 6~10 aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, where R c and R d C 1~6 Alkyl, C 3~8 Cycloalkyl, C 6~10 Aryl, 5- to 10-membered heteroaryl, and 3- to 12-membered heterocyclyl are each R 11and optionally substituted with 1, 2, 3, or 4 substituents independently selected from Or R c and R d together with the nitrogen atom to which they are attached, form R 11 and forming a 4- to 12-membered heterocyclyl optionally substituted by 1, 2, 3, or 4 substituents independently selected from Each R e independently, C 1~6 Alkyl, C 3~8 Cycloalkyl, C 6~10 aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, where R e C 1~6 Alkyl, C 3~8 Cycloalkyl, C 6~10 Aryl, 5- to 10-membered heteroaryl, and 3- to 12-membered heterocyclyl are each R 11 and optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R f are independently hydrogen or C 1~6 is alkyl, Each R g and R h independently, C 1~6 Alkyl, C 3~8 Cycloalkyl, C 6~10 Aryl, 5- to 10-membered heteroaryl, 3- to 12-membered heterocyclyl, or -OC 1~6 alkyl, where R g and R h C 1~6 Alkyl, C 3~8 Cycloalkyl, C 6~10 Aryl, 5- to 10-membered heteroaryl, and 3- to 12-membered heterocyclyl are each R 11 and optionally substituted with 1, 2, 3, or 4 substituents independently selected from Or R g and R h together with the phosphorus atom to which they are attached, form R 11 and forming a 4- to 12-membered heterocyclyl optionally substituted by 1, 2, 3, or 4 substituents independently selected from Each R 11 are independently oxo, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 6~10 Aryl, 5-10 membered heteroaryl, 3-8 membered heterocyclyl, halogen, cyano, -C(O)R a1 , -C(O)OR b1 , -C(O)NR c1 R d1 , -OR b1 , -OC(O)R a1 , -OC(O)NR c1 R d1 , -SR b1 , -S(O)R e1 , -S(O)2R e1 , -S(O)NR c1 R d1 , -NR c1 R d1 , -N(R f1 )C(O)R a1 , -N(R f1 )C(O)OR b1 , -N(R f1 )C(O)NR c1 R d1 , -N(R f1 )S(O)2R e1 , -N(R f1 )S(O)NR c1 R d1 Or-P(O)R g1 R h1 where R 11 C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 6~10 Aryl, 5- to 10-membered heteroaryl, and 3- to 8-membered heterocyclyl are each R 12 and optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R a1 are independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C3~6 Cycloalkyl, C 6~10 aryl, 5- to 10-membered heteroaryl, or 3- to 8-membered heterocyclyl, where R a1 C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 6~10 Aryl, 5- to 10-membered heteroaryl, and 3- to 8-membered heterocyclyl are each R 12 and optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R b1 are independently hydrogen, C 1~6 Alkyl, C 3~6 Cycloalkyl, C 6~10 aryl, 5- to 10-membered heteroaryl, or 3- to 8-membered heterocyclyl, where R b1 C 1~6 Alkyl, C 3~6 Cycloalkyl, C 6~10 Aryl, 5- to 10-membered heteroaryl, and 3- to 8-membered heterocyclyl are each R 12 and optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R c1 and R d1 are independently hydrogen, C 1~6 Alkyl, C 3~6 Cycloalkyl, C 6~10 aryl, 5- to 10-membered heteroaryl, or 3- to 8-membered heterocyclyl, where R c1 and R d1 C 1~6 Alkyl, C 3~6 Cycloalkyl, C 6~10 Aryl, 5- to 10-membered heteroaryl, and 3- to 8-membered heterocyclyl are each R 12 and optionally substituted with 1, 2, 3, or 4 substituents independently selected from Or R c1 and R d1 together with the nitrogen atom to which they are attached, form R 12and forming a 4- to 8-membered heterocyclyl optionally substituted by 1, 2, 3, or 4 substituents independently selected from Each R e1 independently, C 1~6 Alkyl, C 3~6 Cycloalkyl, C 6~10 aryl, 5- to 10-membered heteroaryl, or 3- to 8-membered heterocyclyl, where R e1 C 1~6 Alkyl, C 3~6 Cycloalkyl, C 6~10 Aryl, 5- to 10-membered heteroaryl, and 3- to 8-membered heterocyclyl are each R 12 and optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R f1 are independently hydrogen or C 1~6 is alkyl, Each R g1 and R h1 independently, C 1~6 Alkyl, C 3~6 Cycloalkyl, C 6~10 Aryl, 5- to 10-membered heteroaryl, 3- to 8-membered heterocyclyl, or -OC 1~6 alkyl, where R g1 and R h1 C 1~6 Alkyl, C 3~6 Cycloalkyl, C 6~10 Aryl, 5- to 10-membered heteroaryl, and 3- to 8-membered heterocyclyl are each R 12 and optionally substituted with 1, 2, 3, or 4 substituents independently selected from Or R g1 and R h1 together with the phosphorus atom to which they are attached, form R 12 and forming a 4- to 8-membered heterocyclyl optionally substituted by 1, 2, 3, or 4 substituents independently selected from Each R 12 are independently oxo, C 1~6 Alkyl, C 3~6 Cycloalkyl, C6 aryl, 5-6 membered heteroaryl, 3-6 membered heterocyclyl, halogen, cyano, -C(O)Ra2 , -C(O)OR b2 , -C(O)NR c2 R d2 , -OR b2 , -OC(O)R a2 , -OC(O)NR c2 R d2 , -S(O)2R e2 , -S(O)NR c2 R d2 , -NR c2 R d2 , -N(R f2 )C(O)R a2 , -N(R f2 )C(O)OR b2 , -N(R f2 )C(O)NR c2 R d2 , -N(R f2 )S(O)2R e2 , -N(R f2 )S(O)NR c2 R d2 Or-P(O)R g2 R h2 where R 12 C 1~6 Alkyl, C 3~6 Cycloalkyl, C6 aryl, 5- to 6-membered heteroaryl and 3- to 6-membered heterocyclyl are each R 13 and optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R a2 are independently hydrogen, C 1~6 Alkyl, C 3~6 cycloalkyl, C6 aryl, 5- to 6-membered heteroaryl, or 3- to 6-membered heterocyclyl, where R a2 C 1~6 Alkyl, C 3~6 Cycloalkyl, C6 aryl, 5- to 6-membered heteroaryl and 3- to 6-membered heterocyclyl are each R 13 and optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R b2 are independently hydrogen, C 1~6 Alkyl, C 3~6 cycloalkyl or 3- to 6-membered heterocyclyl, where Rb2 C 1~6 Alkyl, C 3~6 Cycloalkyl and 3- to 6-membered heterocyclyl are each R 13 and optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R c2 and R d2 are independently hydrogen, C 1~6 Alkyl, C 3~6 cycloalkyl or 3- to 8-membered heterocyclyl, where R c2 and R d2 C 1~6 Alkyl, C 3~6 Cycloalkyl and 3- to 8-membered heterocyclyl are each R 13 and optionally substituted with 1, 2, 3, or 4 substituents independently selected from Or R c2 and R d2 together with the nitrogen atom to which they are attached, form R 13 and forming a 4- to 6-membered heterocyclyl optionally substituted by 1, 2, 3, or 4 substituents independently selected from Each R e2 independently, C 1~6 Alkyl, C 3~6 cycloalkyl, C6 aryl, 5- to 6-membered heteroaryl, or 3- to 6-membered heterocyclyl, where R e2 C 1~6 Alkyl, C 3~6 Cycloalkyl, C6 aryl, 5- to 6-membered heteroaryl and 3- to 6-membered heterocyclyl are each R 13 and optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R f2 are independently hydrogen or C 1~6 is alkyl, Each R g2 and R h2 independently, C 1~6 Alkyl, C 3~6 Cycloalkyl, 3- to 8-membered heterocyclyl or -OC 1~6 alkyl, where R g2 and R h2 C1~6 Alkyl, C 3~6 Cycloalkyl and 3- to 8-membered heterocyclyl are each R 13 and optionally substituted with 1, 2, 3, or 4 substituents independently selected from Or R g2 and R h2 together with the phosphorus atom to which they are attached, form R 13 and forming a 4- to 6-membered heterocyclyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R 13 are independently oxo, halogen, hydroxyl, -O(C 1~6 alkyl), cyano, C 1~6 Alkyl or C 1~6 It is haloalkyl.

[0038] In one embodiment, the compound of formula (I): TIFF2024521929000002.tif68170 or a salt (e.g., a pharmaceutically acceptable salt), solvate (e.g., hydrate), prodrug, metabolite, or derivative thereof is provided, R 1 is R 10 is a 5- to 14-membered heteroaryl optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from R 2 is hydrogen, C 1~6 Alkyl, or -O(C 1~6 alkyl), where each C 1~6 Alkyl is R 10 and optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R 3 is hydrogen, C 1~6 Alkyl, or -O(C 1~6 alkyl), where each C 1~6 Each alkyl is R 10 and optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R 4 is hydrogen, halogen, cyano, -O(C 1~6 alkyl), C1~6 Alkyl or C 3~6 cycloalkyl, where C 1~6 Alkyl and C 3~6 Each cycloalkyl is R 10 and optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from G 1 is N or CR 41 and G 2 is N or CR 42 where G 1 and G 2 is N, R 41 and R 42 are independently hydrogen, halogen, cyano, -O(C 1~6 alkyl), C 1~6 Alkyl or C 3~6 cycloalkyl, where C 1~6 Alkyl and C 3~6 Each cycloalkyl is R 10 and optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R 5 is hydrogen, C 1~6 Alkyl, C 3~8 Cycloalkyl, C 6~14 Aryl, 5- to 14-membered heteroaryl, 3- to 14-membered heterocyclyl, -C(O)R 14 , -C(O)OR 15 or -C(O)NR 16a R 16b where R 5 C 1~6 Alkyl, C 3~8 Cycloalkyl, C 6~14 Aryl, 5- to 14-membered heteroaryl, and 3- to 14-membered heterocyclyl are each R 10 and optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Each R 6a and R 6b are independently hydrogen, C 1~6 Alkyl, C 3~8 Cycloalkyl, C 6~10Aryl, 5-14 membered heteroaryl, 3-12 membered heterocyclyl, -C(O)R 14 , -C(O)OR 15 or -C(O)NR 16a R 16b where R 6a and R 6b C 1~6 Alkyl, C 3~8 Cycloalkyl, C 6~10 Aryl, 5- to 14-membered heteroaryl, and 3- to 12-membered heterocyclyl are each R 10 or R 6a and R 6b combine with the carbon to which they are attached to form a carbonyl, Each R 7a and R 7b are independently hydrogen or R 10 C optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from 1~6 alkyl, or R 7a and R 7b combine with the carbon to which they are attached to form a carbonyl, Each R 8a and R 8b are independently hydrogen, halogen, hydroxyl, -O(C 1~6 alkyl) or C 1~6 alkyl, where each C 1~6 Alkyl is R 10 and optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from n is 0 to 8, Each R 9 is independently C 1~6 alkyl, or, if present, two geminal R 9 groups, taken together with the carbon to which they are attached, form a carbonyl, Each R 14 are independently hydrogen or C 1~6 is alkyl, Each R 15 is independently C 1~6 is alkyl, Each R 16a and R 16b are independently hydrogen or C 1~6 alkyl, or R 16a and R 16b together with the nitrogen atom to which they are attached, form R 10 and forming a 4- to 12-membered heterocyclyl optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from Each R 10 is as defined herein.

[0039] In some embodiments, the compounds are other than the compounds of Table 1X and salts thereof. In some embodiments, the compounds herein, such as compounds of Formula (I), are other than compounds selected from one or more of Compound Nos. 1x-3x in Table 1X. In some embodiments, the compounds of the present disclosure and methods of using the compounds detailed herein encompass any of the compounds of Formula (I), including those listed in Table 1X and salts thereof. TIFF2024521929000003.tif38170

[0040] In some embodiments, the compound is of Formula (I), or a salt (e.g., a pharmaceutically acceptable salt), solvate (e.g., hydrate), prodrug, metabolite, or derivative thereof, and (i) G 1 and G 2 Both are N, or (ii) G 1 is N and G 2 is CR 42 or (iii) G 1 is CR 41 and G 2 is N.

[0041] In some embodiments, G 1 is CR 41 and R 41 is hydrogen, and G 2 is N and R 1 is 2-substituted-4-pyridinyl, and each R 2 , R 3 and R 4is hydrogen, and each R 7a and R 7b are independently hydrogen, or R 10 C optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from 1~6 When it is alkyl, the compound is of formula (I), or a salt (eg, a pharmaceutically acceptable salt), solvate (eg, hydrate), prodrug, metabolite, or derivative thereof.

[0042] In one embodiment, a compound of formula (IA): TIFF2024521929000004.tif68170, or a salt (e.g., a pharmaceutically acceptable salt), solvate (e.g., hydrate), prodrug, metabolite, or derivative thereof, is provided, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6a , R 6b , R 7a , R 7b , R 8a , R 8b , R 9 and n are as defined for formula (I) or variations detailed herein.

[0043] In one embodiment, a compound of formula (IB): TIFF2024521929000005.tif68170, or a salt (e.g., a pharmaceutically acceptable salt), solvate (e.g., hydrate), prodrug, metabolite, or derivative thereof, wherein R 1 , R 2 , R 3 , R 4 , R 42 , R 5 , R 6a , R 6b , R 7a , R 7b , R 8a , R 8b , R 9 and n are as defined for formula (I) or variations detailed herein.

[0044] In some embodiments, the compound is R 42 is hydrogen; or a pharmaceutically acceptable salt thereof.

[0045] In one embodiment, a compound of formula (IC): TIFF2024521929000006.tif68170, or a salt (e.g., a pharmaceutically acceptable salt), solvate (e.g., hydrate), prodrug, metabolite, or derivative thereof, wherein R 1 , R 2 , R 3 , R 4 , R 41 , R 5 , R 6a , R 6b , R 7a , R 7b , R 8a , R 8b , R 9 and n are as defined for formula (I) or variations detailed herein.

[0046] In some embodiments, the compound is a compound of Formula (I) or (IC) or a pharmaceutically acceptable salt thereof, other than a compound selected from one or more of Compound Nos. 1x-3x of Table 1X and salts thereof. ... 41 is hydrogen. In some embodiments, R 7a and R 7b do not combine with the carbon to which they are attached to form a carbonyl. In some embodiments, R 1 is other than 2-substituted-4-pyridinyl. In some embodiments, R 1 When R is 2-substituted-4-pyridinyl, each R 7a and R 7b are independently hydrogen or R 10 C optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from 1~6 It is alkyl.

[0047] In some embodiments, the compound is of formula (I), or a variant thereof, such as formulas (IA), (IB), and (IC), if applicable, or a salt thereof (e.g., a pharmaceutically acceptable salt), wherein R 1 is R 10 In some of these embodiments, R is a 5- to 14-membered heteroaryl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from: 1 is a 5-14 membered heteroaryl having 1 to 12 cyclic (or ring) carbon atoms and 1 to 6 cyclic (or ring) heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some of these embodiments, R 1 is a 5-10 membered heteroaryl having 1 to 8 ring carbon atoms and 1 to 4 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some of these embodiments, R 1 is a 5-, 6-, or 7-membered heteroaryl having 1 to 5 ring carbon atoms and 1 to 4 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some of these embodiments, R 1 is a monocyclic 5-, 6-, or 7-membered heteroaryl having 1 to 6 ring carbon atoms and 1 to 4 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some of these embodiments, R 1 is a polycyclic heteroaryl having 1 to 12 ring carbon atoms and 1 to 6 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur.

[0048] In some embodiments, R 1 has 1, 2 or 3 ring heteroatoms selected from nitrogen, oxygen and sulfur, and R 10 In some embodiments, R is a monocyclic 5-membered heteroaryl optionally substituted with 1, 2, 3, or 4 substituents independently selected from 1 is R 10 In some embodiments, R is a monocyclic 5-membered heteroaryl having 1 or 2 ring nitrogen atoms, optionally substituted with 1, 2, 3, or 4 substituents independently selected from1 is R 10 In some embodiments, R is a monocyclic 6-membered heteroaryl having 1 or 2 ring nitrogen atoms, optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from 1 is a fused bicyclic heteroaryl having 1 to 4 ring heteroatoms selected from nitrogen, oxygen, and sulfur, each of which is 10 In some embodiments, R 1 is R 10 In some embodiments, R is a 5,6-fused bicyclic heteroaryl having 1, 2, 3, or 4 ring nitrogen atoms, optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from 1 is R 10 is a 5,6-fused bicyclic heteroaryl having 1 or 2 ring nitrogen atoms optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from:

[0049] In some embodiments, R 1 is pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, or 1,2,4-triazolyl, each of which is represented by R 10 It may be substituted with 1 to 3 substituents independently selected from:

[0050] In some embodiments, R 1 is R 10 In one variation, R is pyrazolyl optionally substituted with 1 to 3 substituents independently selected from 1 is R 10 In some embodiments, R is a pyrazol-3-yl, pyrazol-4-yl, or pyrazol-5-yl group optionally substituted with 1 to 3 substituents independently selected from 1 is R 10 In some embodiments, R 1 is R 10In one variation, R is isothiazolyl optionally substituted with 1 to 3 substituents independently selected from 1 is R 10 In some embodiments, R is an isothiazol-3-yl, an isothiazol-4-yl, or an isothiazol-5-yl group, each of which may be substituted with 1 to 3 substituents independently selected from 1 is R 10 In some of these embodiments, R is isothiazol-5-yl, optionally substituted with 1 to 3 substituents independently selected from 10 is optionally substituted with halogen (e.g., chloro), cyano, and halogen; 1~6 In some embodiments, R is selected from alkyl (e.g., methyl or trifluoromethyl). 1 is halogen (e.g., chloro), cyano, unsubstituted C 1~6 Alkyl (e.g., methyl) and C 1~6 In some particular embodiments, R is pyrazol-4-yl, optionally substituted with 1 to 3 substituents independently selected from the group consisting of haloalkyl (e.g., trifluoromethyl). 1 is 3-methylpyrazol-4-yl or 5-methylpyrazol-4-yl. In some particular embodiments, R 1 is 4-methylisothiazol-5-yl.

[0051] In some embodiments, R 1 is R 10 In one variation, R is pyridyl optionally substituted with 1 to 5 substituents independently selected from 1 is R 10 In some particular embodiments, R 1 is 4-pyridyl (also known as pyridin-4-yl).

[0052] In some embodiments, R 1 is R 10In one variation, R is pyrimidyl optionally substituted with 1 to 5 substituents independently selected from 1 is R 10 In some particular embodiments, R 1 is pyrimidin-4-yl.

[0053] In some embodiments, R 1 is R 10 and a 5,6-fused heteroaryl having 1 to 4 ring nitrogen atoms (e.g., pyrrolo-pyridinyl, indazolyl, imidazo-pyridinyl, pyrrolo-pyrimidinyl, or pyrazolo-pyrimidinyl) optionally substituted with 1 to 5 substituents independently selected from:

[0054] In some embodiments, R 1 is R 10 In one variation, R is pyrrolo-pyridinyl optionally substituted with 1 to 5 substituents independently selected from 1 is R 10 In some particular embodiments, pyrrolo[2,3-b]pyridinyl (e.g., pyrrolo[2,3-b]pyridin-4-yl) optionally substituted with 1 to 5 substituents independently selected from

[0055] In some embodiments, R 1 is pyrazolyl (e.g., pyrazol-3-yl, pyrazol-4-yl, or pyrazol-5-yl), pyridinyl (e.g., 4-pyridyl), or pyrrolo-pyridinyl (e.g., pyrrolo[2,3-b]pyridin-4-yl), each of which can be represented by R 10 In some embodiments, R 1 is pyrazol-4-yl, 4-pyridyl, or pyrrolo[2,3-b]pyridin-4-yl, each of which is substituted with halogen (e.g., chloro), cyano, unsubstituted C 1~6 Alkyl (e.g., methyl) and C 1~6It may be optionally substituted with 1 to 3 substituents independently selected from the group consisting of haloalkyl (eg, trifluoromethyl).

[0056] In some embodiments, R 1 teeth, TIFF2024521929000007.tif75170, where the wavy line in each group indicates the point of attachment to the parent structure. 1 teeth, TIFF2024521929000008.tif43170, and the wavy lines in each group indicate the point of attachment to the parent structure.

[0057] In some embodiments, the compound is of Formula (I), or a variant thereof, such as Formulas (IA), (IB), and (IC), or a salt thereof (e.g., a pharmaceutically acceptable salt), wherein R 2 is hydrogen, halogen, C 1~6 Alkyl, -O(C 1~6 alkyl), -NH(C 1~6 alkyl) or -N(C 1~6 alkyl)2, and each C 1~6 Alkyl is R 10 In some embodiments, R 2 is hydrogen, C 1~6 Alkyl or -O(C 1~6 alkyl), and each C 1~6 Alkyl is R 10 In some embodiments, R 2 is hydrogen, -NH(C 1~6 alkyl), or R 10 C optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from 1~6 In some embodiments, R 2 is hydrogen or R 10 C optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from 1~6In some embodiments, R 2 is hydrogen. In some embodiments, R 2 is hydrogen or C 1~6 In some embodiments, R 2 is R 10 C optionally substituted with 1 to 5 substituents independently selected from 1~6 In some embodiments, R 2 is C optionally substituted with one or more halogens (e.g., fluoro) 1~6 In some embodiments, R 2 is R 11 C optionally substituted with 1, 2, 3 or 4 substituents independently selected from 6~10 C optionally substituted with aryl (e.g., phenyl) 1~6 In some embodiments, R 2 is R 11 C optionally substituted with a 5- to 10-membered heteroaryl (e.g., pyrazolyl) optionally substituted with 1, 2, 3, or 4 substituents independently selected from 1~6 In some embodiments, R 2 is -N(R f )C(O)R a C optionally substituted with 1~6 In some of these embodiments, R f is hydrogen and R a is C 1~6 In some embodiments, R 2 is -NH(C 1~6 alkyl), where C 1~6 Alkyl is R 10 In some embodiments, R 2 is -NH(C 1~6 alkyl) (e.g., NHMe).

[0058] In some embodiments, R 2 is hydrogen, C1~6 C substituted with alkyl (e.g., methyl), or halogen, acylamino, phenyl, or pyrazolyl, which may be further substituted with halogen. 1~6 alkyl (e.g., 2,2,2-trifluoroethyl, —CHNHC(O)CHCH, benzyl, and 4-chloropyrazol-1-yl). 2 is hydrogen, -NH(C 1~6 alkyl) (e.g., NHMe), C 1~6 C substituted with alkyl (e.g., methyl), or halogen, acylamino, phenyl, or pyrazolyl, which may be further substituted with halogen. 1~6 alkyl (for example, 2,2,2-trifluoroethyl, —CH 2 NHC(O)CH 2 CH 3 , benzyl, and 4-chloropyrazol-1-yl).

[0059] In some embodiments, R 2 is hydrogen, methyl, TIFF2024521929000009.tif18170, where the wavy line in each group indicates the point of attachment to the parent structure. 2 NHMe, CF3, TIFF2024521929000010.tif14170, and the wavy line in each group indicates the point of attachment to the parent structure.

[0060] In some embodiments, the compound is of Formula (I), or a variant thereof, such as Formulas (IA), (IB), and (IC), or a salt thereof (e.g., a pharmaceutically acceptable salt), wherein R 3 is hydrogen, C 1~6 Alkyl, halogen, cyano, hydroxyl, -O(C 1~6 alkyl), C 2~6 Alkenyl or C 2~6 Alkynyl, C 1~6 Alkyl, C 2~6 Alkenyl and C 2~6 Each alkynyl is R 10In some embodiments, R 3 is hydrogen, halogen, cyano, hydroxyl, -O(C 1~6 alkyl), C 1~6 Alkyl or C 2~6 Alkynyl, C 1~6 Alkyl and C 2~6 Each alkynyl is R 10 In some embodiments, R 3 is hydrogen, halogen, C 1~6 Alkyl or -O(C 1~6 alkyl), and each C 1~6 Alkyl is R 10 In some embodiments, R 3 is hydrogen, C 1~6 Alkyl or -O(C 1~6 alkyl), and each C 1~6 Alkyl is R 10 In some embodiments, R 3 is hydrogen or R 10 C optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from 1~6 In some embodiments, R 3 is hydrogen, C 1~6 Alkyl or C 1~6 In some embodiments, R 3 is hydrogen or C 1~6 In some embodiments, R 3 is hydrogen. In some embodiments, R 3 is hydrogen, halogen (e.g., chloro), cyano, hydroxyl or -O(C 1~6 In some embodiments, R 3 is C 1~6 In some embodiments, R 3is optionally substituted with alkoxy (e.g., CH2OCH3), 1~6 In some embodiments, R 3 is C 1~6 haloalkyl (e.g., 2,2,2-trifluoroethyl). In some embodiments, R 3 -O(C 1~6 alkyl), where C 1~6 Alkyl is R 10 In some embodiments, R 3 -O(C 1~6 alkyl) (e.g., methoxy). In some embodiments, R 3 is R 10 C optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from 2~6 In some embodiments, R is alkynyl. 3 C optionally substituted with one or more hydroxyl 2~6 alkynyl (e.g., 3-hydroxyprop-1-yn-1-yl or 3-hydroxy-3-methylbut-1-yn-1-yl). In some embodiments, R 3 is selected from the group consisting of hydrogen, methyl, and 2,2,2-trifluoroethyl. 3 is selected from the group consisting of chloro, cyano, hydroxyl, methoxy, 3-hydroxyprop-1-yn-1-yl, 3-hydroxy-3-methylbut-1-yn-1-yl, and methoxymethyl.

[0061] In some embodiments, the compound is of Formula (I), or a variant thereof, such as Formulas (IA), (IB), and (IC), or a salt thereof (e.g., a pharmaceutically acceptable salt), wherein R 4 is hydrogen, halogen, cyano, -NR 43a R 43b , -OR 44 , C 1~6 Alkyl or C 3~6 is cycloalkyl, C 1~6 Alkyl and C 3~6Each cycloalkyl is R 10 and each R 43a and R 43b are independently hydrogen or C 1~6 alkyl, and R 44 is hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~8 cycloalkyl, 3- to 14-membered heterocyclyl, where R 44 C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~8 Cycloalkyl and 3- to 14-membered heterocyclyl are each R 10 In some embodiments, R 4 is hydrogen, halogen, -NR 43a R 43b , -OR 44 , C 1~6 Alkyl or C 3~6 is cycloalkyl, C 1~6 Alkyl and C 3~6 Each cycloalkyl is R 10 In some embodiments, R 4 is hydrogen, halogen, C 1~6 Alkyl or -O(C 1~6 alkyl), and each C 1~6 Alkyl is R 10 In some embodiments, R 4 is hydrogen, halogen, cyano, -O(C 1~6 alkyl), C 1~6 Alkyl or C 3~6 is cycloalkyl, C 1~6 Alkyl and C 3~6 Each cycloalkyl is R 10In some embodiments, R 4 is hydrogen, halogen, or R 10 C optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from 1~6 In some embodiments, R 4 is R 10 C optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from 1~6 In some embodiments, R 4 is R 10 -O(C 1~6 In some embodiments, R 4 is hydrogen, halogen, C 1~6 Alkyl or C 3~6 In some embodiments, R 4 is hydrogen, halogen or C 1~6 In some embodiments, R 4 is hydrogen. In some embodiments, R 4 is halogen (e.g., fluoro, chloro, or bromo). In some embodiments, R 4 is C 1~6 alkyl (e.g., methyl, ethyl, 1-propyl, or 2-propyl). In some embodiments, R 4 is selected from the group consisting of hydrogen, fluoro, chloro, methyl and cyclopropyl.

[0062] In some embodiments, R 4 HA-OR 44 where R 44 is hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~8 cycloalkyl, 3- to 14-membered heterocyclyl, and R 44 C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6Alkynyl, C 3~8 Cycloalkyl and 3- to 14-membered heterocyclyl are each R 10 In some of these embodiments, R 44 is hydrogen. In some of these embodiments, R 44 is R 10 C optionally substituted with 1, 2, 3 or 4 substituents independently selected from 1~6 In some of these embodiments, R 44 is halogen (e.g., fluoro), hydroxyl, alkoxy (e.g., methoxy), 3- to 14-membered heterocyclyl (e.g., oxetanyl), C 2~6 Alkenyl (e.g., vinyl) and C 2~6 C optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of alkynyl (e.g., ethynyl), 1~6 In some of these embodiments, R 44 is C 2~6 In some of these embodiments, R is an alkenyl (e.g., allyl). 44 C may be substituted with hydroxyl 2~6 alkynyl (e.g., 3-hydroxy-3-methylbut-3-yn-1-yl). In some of these embodiments, R 44 is R 10 C optionally substituted with 1, 2, 3 or 4 substituents independently selected from 3~8 In some of these embodiments, R is cycloalkyl. 44 may be substituted with cyano; 3~8 In some of these embodiments, R is cycloalkyl (e.g., 3-cyanocyclobutyl). 44 is R 10 In some of these embodiments, R is a 3- to 14-membered heterocyclyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from 44is 3- to 14-membered heterocyclyl (e.g., oxetan-3-yl). In some of these embodiments, R 44 is a 3- to 14-membered heterocyclyl optionally substituted with acyl (e.g., 1-acetylazetidin-3-yl). 4 is -NR 43a R 43b where each R 43a and R 43b are independently hydrogen or C 1~6 In some embodiments, R 4 is -NR 43a R 43b where each R 43a and R 43b independently, C 1~6 In some embodiments, R 4 is hydrogen, fluoro, chloro, bromo, methyl, TIFF2024521929000011.tif49170, and the wavy line in each group indicates the point of attachment to the parent structure.

[0063] R as described for formula (I), (IA), (IB) or (IC) 1 , R 2 , R 3 and R 4 It is intended and understood that each and every variation of may be combined as if each and every combination were specifically and individually set forth. For example, in some embodiments, R 1 is pyrazolyl (e.g., pyrazol-3-yl, pyrazol-4-yl, or pyrazol-5-yl), pyridinyl (e.g., 4-pyridyl), or pyrrolo-pyridinyl (e.g., pyrrolo[2,3-b]pyridin-4-yl), each of which can be represented by R 10 and R 2 is hydrogen or R 10 C optionally substituted with 1 to 5 substituents independently selected from 1~6 alkyl (e.g., methyl), and R3 is hydrogen or C 1~6 alkyl (e.g., methyl), and R 4 is hydrogen, halogen or C 1~6 In some embodiments, R 1 is pyrazol-4-yl, 4-pyridyl, or pyrrolo[2,3-b]pyridin-4-yl, each of which is substituted with halogen (e.g., chloro), cyano, unsubstituted C 1~6 Alkyl (e.g., methyl) and C 1~6 haloalkyl (e.g., trifluoromethyl), and each R 2 and R 3 are independently hydrogen or C 1~6 alkyl, and R 4 is hydrogen, halogen (e.g., chloro) or C 1~6 In some embodiments, R 1 is pyrazolyl (e.g., pyrazol-3-yl, pyrazol-4-yl, or pyrazol-5-yl), isothiazolyl (e.g., 4-methylisothiazol-5-yl), pyridinyl (e.g., 4-pyridyl), or pyrrolo-pyridinyl (e.g., pyrrolo[2,3-b]pyridin-4-yl), each of which can be represented by R 10 and R 2 is hydrogen or R 10 C optionally substituted with 1 to 5 substituents independently selected from 1~6 alkyl (e.g., methyl), and R 3 is hydrogen, halogen (e.g., chloro) or C 1~6 alkyl (e.g., methyl), and R 4 is hydrogen, halogen, C 1~6 Alkyl or -O(C 1~6 alkyl), where each C 1~6 Alkyl is R 10 In some embodiments, R 1is pyrazol-4-yl or 4-pyridyl, which are each substituted with halogen (e.g., chloro), cyano, unsubstituted C 1~6 Alkyl (e.g., methyl) and C 1~6 haloalkyl (e.g., trifluoromethyl), and R 2 is hydrogen or C 1~6 alkyl, and R 3 is hydrogen, halogen (e.g., chloro) or C 1~6 alkyl (e.g., methyl), and R 4 is hydrogen, halogen (e.g., chloro), C 1~6 Alkyl (e.g., methyl) or -O(C 1~6 alkyl) (e.g., methoxy).

[0064] In some embodiments, the compound is of formula (I), or a variant thereof, such as formulas (IA), (IB), and (IC), or a salt thereof (e.g., a pharmaceutically acceptable salt), wherein R 5 is hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~8 Cycloalkyl, C 6~14 Aryl, 5- to 14-membered heteroaryl, 3- to 14-membered heterocyclyl, -C(O)R 14 , -C(O)OR 15 or -C(O)NR 16a R 16b where R 5 C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~8 Cycloalkyl, C 6~14 Aryl, 5- to 14-membered heteroaryl, and 3- to 14-membered heterocyclyl are each R 10 or R 6a or R 6b and together with the atoms to which they are attached, R 10In some embodiments, R 5 is hydrogen, C 1~6 Alkyl, C 3~8 Cycloalkyl, C 6~14 Aryl, 5- to 14-membered heteroaryl, 3- to 14-membered heterocyclyl, -C(O)R 14 , -C(O)OR 15 or -C(O)NR 16a R 16b where R 5 C 1~6 Alkyl, C 3~8 Cycloalkyl, C 6~14 Aryl, 5- to 14-membered heteroaryl, and 3- to 14-membered heterocyclyl are each R 10 In some embodiments, R 5 is hydrogen, C 1~6 Alkyl, C 3~8 Cycloalkyl, C 6~14 Aryl, 5- to 14-membered heteroaryl, 3- to 14-membered heterocyclyl, or —C(O)R 14 where R 5 C 1~6 Alkyl, C 3~8 Cycloalkyl, C 6~14 Aryl, 5- to 14-membered heteroaryl, and 3- to 14-membered heterocyclyl are each R 10 In some embodiments, R 5 is hydrogen or R 10 C optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from 1~6 In some embodiments, R 5 is R 6a or R 6b and together with the atoms to which they are attached, R 10 and forming a 3- to 14-membered heterocyclyl optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from:

[0065] In some embodiments, R 5 is hydrogen or -C(O)R 14 In some embodiments, R 14 is hydrogen or C 1~6 In some embodiments, R 14 is C 1~6 In some embodiments, R 5 is hydrogen or acetyl. In some embodiments, R 5 is hydrogen.

[0066] In some embodiments, R 5 is R 10 C optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from 1~6 In some embodiments, R 5 is R 10 C optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from 1~6 alkyl, where R 10 is halogen (e.g., fluoro), cyano, -OR b , -N(R f )C(O)R a , -N(R f )S(O)2R e , -S(O)NR c R d , -C(O)NR c R d , R 11 C optionally substituted with 1, 2, 3 or 4 substituents independently selected from 6~10 Aryl, R 11 and 3- to 12-membered heterocyclyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from: a is C 1~6 alkyl, and R b is hydrogen or C 1~6 alkyl, and R e is C 1~6 alkyl, and each R c , Rd and R f is hydrogen. In some embodiments, R 5 is halogen (e.g., fluoro), cyano, hydroxyl, -O(C 1~6 alkyl), -NHC(O)(C 1~6 alkyl), -NHS(O)2(C 1~6 C(O) optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of alkyl, -S(O)NH, -C(O)NH, phenyl, and 3- to 12-membered heterocyclyl (e.g., oxetan-3-yl). 1~6 It is alkyl.

[0067] In some embodiments, R 5 is C 1~6 alkyl (e.g., methyl, ethyl, 1-propyl, 2-propyl, 2-methyl-1-propyl, and 2-methyl-2-propyl). In some embodiments, R 5 teeth, Substitution C selected from the group consisting of TIFF2024521929000012.tif84170 1~6 alkyl, and the wavy line in each group indicates the point of attachment to the parent structure. 5 teeth, Substitution C selected from the group consisting of TIFF2024521929000013.tif45170 1~6 alkyl, and the wavy line in each group indicates the point of attachment to the parent structure.

[0068] In some embodiments, R 5 is R 10 C optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from 3~8 In some embodiments, R 5 is R 10 C optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from 4~8 In some embodiments, R 5 is R 10C optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from 3~6 In some embodiments, R 5 is R 10 C optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from 4~6 In some embodiments, R 5 is R 10 C optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from 4~8 cycloalkyl, where R 10 is selected from the group consisting of halogen (e.g., fluoro), cyano, and hydroxyl. In some embodiments, R 5 is C 3~6 In some embodiments, R 5 is C substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen (e.g., fluoro), cyano, and hydroxyl; 3~6 It is cycloalkyl.

[0069] In some embodiments, R 5 teeth, TIFF2024521929000014.tif89170, where the wavy line in each group indicates the point of attachment to the parent structure.

[0070] In some embodiments, R 5 is R 10 3- to 14-membered heterocyclyl optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from 10 C optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from 6~14 Aryl, or R 10 and 5 to 14-membered heteroaryl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from:

[0071] In some embodiments, R 5 is R 10In some embodiments, R is a 3- to 14-membered heterocyclyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from 5 is R 10 In some embodiments, R is a 3- to 10-membered heterocyclyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from 5 has 1 to 9 cyclic carbon atoms and 1 to 4 cyclic heteroatoms independently selected from nitrogen, oxygen, and sulfur; R 10 In some embodiments, R is a 3- to 10-membered heterocyclyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from 5 has 1 to 2, 1 to 3, 1 to 4, 1 to 5, or 1 to 6 cyclic carbon atoms and 1 to 2, 1 to 3, or 1 to 4 cyclic heteroatoms independently selected from nitrogen, oxygen, and sulfur; R 10 In some embodiments, R is a monocyclic 3-, 4-, 5-, 6-, or 7-membered heterocyclyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from 5 has 1 to 2, 1 to 3, 1 to 4, or 1 to 5 cyclic carbon atoms and one cyclic heteroatom selected from nitrogen, oxygen, and sulfur; R 10 In some embodiments, R is a monocyclic 3-, 4-, 5-, or 6-membered heterocyclyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from 5 is R 10 and R is a monocyclic 3- to 6-membered heterocyclyl having one ring heteroatom which is oxygen, optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from:

[0072] In some embodiments, R 5 is C 6~14 aryl or 5- to 14-membered heteroaryl, each of which is R 10 In some embodiments, R 5 is R 10 C optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from 6~14In some embodiments, R 5 is R 10 In some embodiments, R is phenyl, optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from 5 is R 10 In some embodiments, R is a 5-14 membered heteroaryl having 1 to 12 ring carbon atoms and 1 to 6 ring heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from 5 has 1 to 8 cyclic carbon atoms and 1 to 4 cyclic heteroatoms independently selected from nitrogen, oxygen, and sulfur; R 10 In some embodiments, R is a 5- to 10-membered heteroaryl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from 5 has 1 to 3 cyclic heteroatoms independently selected from nitrogen, oxygen, and sulfur; R 10 In some embodiments, R is a 5- or 6-membered heteroaryl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from 5 is R 10 and pyrazolyl (for example, 3-pyrazolyl, 4-pyrazolyl or 5-pyrazolyl) optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from:

[0073] In some embodiments, R 5 are R 10 and optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from TIFF2024521929000015.tif47170, where the wavy line in each group indicates the point of attachment to the parent structure.

[0074] In some embodiments, R 5 is hydrogen, C 1~6 Alkyl, C 3~8 Cycloalkyl, C 6~14Aryl, 5- to 14-membered heteroaryl, 3- to 14-membered heterocyclyl, or —C(O)R 14 where R 5 C 1~6 Alkyl, C 3~8 Cycloalkyl, C 6~14 Aryl, 5- to 14-membered heteroaryl, and 3- to 14-membered heterocyclyl are each R 10 In some embodiments, R 5 is halogen (e.g., fluoro), cyano, hydroxyl, -O(C 1~6 alkyl), -NHC(O)(C 1~6 alkyl), -NHS(O)2(C 1~6 C(O) optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of alkyl, -S(O)NH, -C(O)NH, phenyl, and 3- to 12-membered heterocyclyl (e.g., oxetan-3-yl). 1~6 C substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of alkyl, halogen (e.g., fluoro), cyano, and hydroxyl 3~6 In some of these embodiments, R is a monocyclic 3- to 6-membered heterocyclyl having one ring heteroatom that is cycloalkyl, oxygen, phenyl, or pyrazolyl (e.g., 3-pyrazolyl, 4-pyrazolyl, or 5-pyrazolyl). 14 is C 1~6 It is alkyl (eg, methyl).

[0075] In some embodiments, R 5 is hydrogen, acetyl, methyl, ethyl, 1-propyl, 2-propyl, 2-methyl-1-propyl, 2-methyl-2-propyl, TIFF2024521929000016.tif234170, each of which is selected from the group consisting of R 10 The wavy line in each group indicates the point of attachment to the parent structure.

[0076] In some embodiments, the compound has Formula (I) or a variant thereof, such as Formulas (IA), (IB), and (IC), or a salt thereof (e.g., a pharmaceutically acceptable salt), wherein each R 6a and R 6b are independently hydrogen, C 1~6 Alkyl, C 3~8 Cycloalkyl, C 6~10 Aryl, 5-14 membered heteroaryl, 3-12 membered heterocyclyl, -C(O)R 14 , -C(O)OR 15 or -C(O)NR 16a R 16b where R 6a and R 6b C 1~6 Alkyl, C 3~8 Cycloalkyl, C 6~10 Aryl, 5- to 14-membered heteroaryl, and 3- to 12-membered heterocyclyl are each R 10 or R 5 and together with the atoms to which they are attached, R 10 or R 6a and R 6b together with the carbon to which they are attached to form a carbonyl. In some embodiments, each R 6a and R 6b are independently hydrogen, C 1~6 Alkyl, C 3~8 Cycloalkyl, C 6~10 Aryl, 5-14 membered heteroaryl, 3-12 membered heterocyclyl, -C(O)R 14 , -C(O)OR 15 or -C(O)NR 16a R 16b where R 6a and R 6b C 1~6 Alkyl, C 3~8 Cycloalkyl, C 6~10 Aryl, 5- to 14-membered heteroaryl, and 3- to 12-membered heterocyclyl are each R 10or R 6a and R 6b combine with the carbon to which they are attached to form a carbonyl.

[0077] In some embodiments, each R 6a and R 6b are independently hydrogen or C 1~6 In some embodiments, R 6a and R 6b together with the carbon to which they are attached to form a carbonyl. In some embodiments, each R 6a and R 6b are independently hydrogen or C 1~6 alkyl, or R 6a and R 6b combine with the carbon to which they are attached to form a carbonyl.

[0078] In some embodiments, each R 6a and R 6b are independently hydrogen, -C(O)OR 15 , -C(O)NR 16a R 16b , or R 10 C optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from 1~6 In some embodiments, each R 6a and R 6b are independently hydrogen or C 1~6 In some embodiments, each R 6a and R 6b is hydrogen. In some embodiments, R 6a and R 6b is hydrogen and R 6a and R 6b The other is C 1~6 In some embodiments, R 6a and R 6b is hydrogen and R 6a and R 6b The other is R 10C optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from 1~6 In some of these embodiments, R 10 is a halogen (e.g., fluoro), each R b are independently hydrogen or C 1~6 alkyl (e.g., methyl), -OR b , or R e independently C 1~6 alkyl (e.g., methyl), and R f are independently hydrogen or C 1~6 alkyl, -N(R f )S(O)2R e is selected from the group consisting of:

[0079] In some embodiments, R 6a and R 6b is hydrogen and R 6a and R 6b The other is hydrogen, -C(O)OR 15 , -C(O)NR 16a R 16b , or R 10 C optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from 1~6 In some embodiments, R 6a and R 6b is hydrogen and R 6a and R 6b The other is -C(O)OR 15 or -C(O)NR 16a R 16b In some embodiments, R 15 is C 1~6 In some embodiments, R 6a and R 6b One of them is -C(O)O(C 1~6 alkyl).

[0080] In some embodiments, R 6a and R 6b is hydrogen and R 6a and R 6b The other is -C(O)NR16a R 16b In some embodiments, each R 16a and R 16b are independently hydrogen or C 1~6 alkyl or R 16a and R 16b together with the nitrogen atom to which they are attached, form R 10 In some embodiments, R 6a and R 6b One of them is -C(O)NR 16a R 16b where each R 16a and R 16b are independently hydrogen or C 1~6 In some embodiments, R 6a and R 6b One of the groups is -C(O)NR 16a R 16b where R 16a and R 16b together with the nitrogen atom to which they are attached, form R 10 In some of these embodiments, R 16a and R 16b have, together with the nitrogen atom to which they are attached, 1 to 3 cyclic heteroatoms selected from nitrogen, oxygen, and sulfur; R 10 In some of these embodiments, R 16a and R 16b have, together with the nitrogen atom to which they are attached, one to two cyclic heteroatoms selected from nitrogen, oxygen, and sulfur; R 10 In some of these embodiments, R 16a and R 16btogether with the nitrogen atom to which they are attached form pyrrolidin-1-yl or morpholin-4-yl, which are respectively represented by R 10 and optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from:

[0081] In some embodiments, each R 6a and R 6b are independently hydrogen, C 1~6 Alkyl (e.g., methyl), -C(O)O(C 1~6 alkyl) or -C(O)NR 16a R 16b or R 6a and R 6b together with the carbon to which they are attached to form a carbonyl. In some embodiments, R 6a and R 6b is hydrogen and R 6a and R 6b The other is hydrogen, C 1~6 Alkyl (e.g., methyl), -C(O)O(C 1~6 alkyl) or -C(O)NR 16a R 16b or R 6a and R 6b together with the carbon to which they are attached to form a carbonyl. In some of these embodiments, each R 16a and R 16b are independently hydrogen or C 1~6 alkyl (e.g., methyl) or R 16a and R 16b together with the nitrogen atom to which they are attached form pyrrolidin-1-yl or morpholin-4-yl.

[0082] In some embodiments, R 6a and R 6b One of them is hydrogen, methyl, TIFF2024521929000017.tif36170, where the wavy line in each group indicates the point of attachment to the parent structure. 6a and R 6b On the other hand, TIFF2024521929000018.tif17170, and the wavy line in each group indicates the point of attachment to the parent structure.

[0083] In some embodiments, R 6a and R 6b One of them is R 5 and together with the atoms to which they are attached, R 10 and R 6a and R 6b The other is hydrogen, C 1~6 Alkyl, C 3~8 Cycloalkyl, C 6~10 Aryl, 5-14 membered heteroaryl, 3-12 membered heterocyclyl, -C(O)R 14 , -C(O)OR 15 or -C(O)NR 16a R 16b and C 1~6 Alkyl, C 3~8 Cycloalkyl, C 6~10 Aryl, 5- to 14-membered heteroaryl, and 3- to 12-membered heterocyclyl are each R 10 In some embodiments, R 6a and R 6b One of them is R 5 and together with the atoms to which they are attached, R 10 and R 6a and R 6b The other is hydrogen or C 1~6 In some embodiments, R 6a and R 6b One of them is R 5 and together with the atoms to which they are attached, R 10 and R 6a and R 6band the other is hydrogen. In some embodiments, R 6a and R 6b One of them is R 5 and together with the atom to which they are attached form a 5- or 6-membered heterocyclyl (e.g., morpholine), R 6a and R 6b The other is hydrogen.

[0084] In some embodiments, the compound is of Formula (I), or a variant thereof, such as Formulas (IA), (IB), and (IC), or a salt thereof (e.g., a pharmaceutically acceptable salt), wherein each R 7a and R 7b are independently hydrogen or R 10 C optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from 1~6 alkyl, or R 7a and R 7b together with the carbon to which they are attached to form a carbonyl. In some embodiments, each R 7a and R 7b are independently hydrogen or R 10 C optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from 1~6 It is alkyl.

[0085] In some embodiments, each R 7a and R 7b are independently hydrogen or C 1~6 alkyl, or R 7a and R 7b together with the carbon to which they are attached to form a carbonyl. In some embodiments, R 7a and R 7b combine with the carbon to which they are attached to form a carbonyl.

[0086] In some embodiments, each R 7a and R 7b are independently hydrogen or C 1~6 In some embodiments, each R 7a and R 7bis hydrogen. In some embodiments, R 7a and R 7b is hydrogen and R 7a and R 7b The other is C 1~6 It is alkyl (eg, methyl).

[0087] In some embodiments, R 7a and R 7b is hydrogen and R 7a and R 7b The other is hydrogen or C 1~6 alkyl (e.g., methyl) or R 7a and R 7b combine with the carbon to which they are attached to form a carbonyl.

[0088] In some embodiments, the compound is of Formula (I), or a variant thereof, such as Formulas (IA), (IB), and (IC), or a salt thereof (e.g., a pharmaceutically acceptable salt), wherein each R 8a and R 8b are independently hydrogen, halogen, hydroxyl, -O(C 1~6 alkyl) or C 1~6 alkyl, and each C 1~6 Alkyl is R 10 In some of these embodiments, R 8a and R 8b is hydrogen and R 8a and R 8b The other is hydrogen, halogen, hydroxyl, C 1~6 Alkyl or -O(C 1~6 In some of these embodiments, R 8a and R 8b is hydrogen and R 8a and R 8b The other of R is hydrogen, halogen (e.g., fluoro), or hydroxyl. In some of these embodiments, R 8a and R 8b is hydrogen and R 8a and R 8band the other is hydrogen, fluoro, or hydroxyl. In some embodiments, each R 8a and R 8b is hydrogen. In some embodiments, each R 8a and R 8b is fluoro.

[0089] R as described for formula (I), (IA), (IB) or (IC) 1 , R 2 , R 3 and R 4 Each and every variation of R described for formula (I), (IA), (IB) or (IC) 5 , R 6a , R 6b , R 7a , R 7b , R 8a and R 8b It is intended and understood that R may be combined with each and every variation of R as if each and every combination were specifically and individually listed. 1 is pyrazolyl (e.g., pyrazol-3-yl, pyrazol-4-yl, or pyrazol-5-yl), pyridinyl (e.g., 4-pyridyl), or pyrrolo-pyridinyl (e.g., pyrrolo[2,3-b]pyridin-4-yl), each of which can be represented by R 10 and R 2 is hydrogen or R 10 C optionally substituted with 1 to 5 substituents independently selected from 1~6 alkyl (e.g., methyl), and R 3 is hydrogen or C 1~6 alkyl (e.g., methyl), and R 4 is hydrogen, halogen or C 1~6 alkyl, and R 5 is hydrogen, C 1~6 Alkyl, C 3~8 Cycloalkyl, C 6~14 Aryl, 5- to 14-membered heteroaryl, 3- to 14-membered heterocyclyl, or —C(O)R 14 where R 5 C1~6 Alkyl, C 3~8 Cycloalkyl, C 6~14 Aryl, 5- to 14-membered heteroaryl, and 3- to 14-membered heterocyclyl are each R 10 and each R 6a and R 6b are independently hydrogen or -C(O)OR 15 , -C(O)NR 16a R 16b or R 10 C optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from 1~6 alkyl or R 6a and R 6b combine with the carbon to which they are attached to form a carbonyl, and each R 7a and R 7b are independently hydrogen or C 1~6 alkyl or R 7a and R 7b combine with the carbon to which they are attached to form a carbonyl, and R 8a and R 8b one of which is hydrogen and R 8a and R 8b The other is hydrogen, halogen, hydroxyl, C 1~6 Alkyl or -O(C 1~6 In some of these embodiments, R 1 is pyrazolyl (e.g., pyrazol-3-yl, pyrazol-4-yl, or pyrazol-5-yl), isothiazolyl (e.g., isothiazol-5-yl), pyridinyl (e.g., 4-pyridyl), or pyrrolo-pyridinyl (e.g., pyrrolo[2,3-b]pyridin-4-yl), each of which can be represented by R 10 and R 2 is hydrogen or R 10 C optionally substituted with 1 to 5 substituents independently selected from 1~6 alkyl (e.g., methyl), and R 3 is hydrogen, halogen (e.g., chloro), or C1~6 alkyl (e.g., methyl), and R 4 is hydrogen, halogen, -O(C 1~6 alkyl) or C 1~6 alkyl, and R 5 is hydrogen, C 1~6 Alkyl, C 3~8 Cycloalkyl, C 6~14 Aryl, 5- to 14-membered heteroaryl, 3- to 14-membered heterocyclyl, or —C(O)R 14 where R 5 C 1~6 Alkyl, C 3~8 Cycloalkyl, C 6~14 Aryl, 5- to 14-membered heteroaryl, and 3- to 14-membered heterocyclyl are each R 10 and each R 6a and R 6b are independently hydrogen or -C(O)OR 15 , -C(O)NR 16a R 16b or R 10 C optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from 1~6 alkyl or R 6a and R 6b combine with the carbon to which they are attached to form a carbonyl, and each R 7a and R 7b are independently hydrogen or C 1~6 alkyl or R 7a and R 7b combine with the carbon to which they are attached to form a carbonyl, and R 8a and R 8b one of which is hydrogen and R 8a and R 8b The other is hydrogen, halogen, hydroxyl, C 1~6 Alkyl or -O(C 1~6 In some embodiments, R 14 is C 1~6 In some embodiments, R 15 is C 1~6In some embodiments, each R 16a and R 16b are independently hydrogen or C 1~6 alkyl (e.g., methyl) or R 16a and R 16b have, together with the nitrogen atom to which they are attached, one to two cyclic heteroatoms selected from nitrogen, oxygen, and sulfur; R 10 Forms a 5- or 6-membered heterocyclyl optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from:

[0090] In some embodiments, R 1 is pyrazol-4-yl, isothiazol-5-yl, 4-pyridyl or pyrrolo[2,3-b]pyridin-4-yl, each of which is substituted with halogen (e.g., chloro), cyano, unsubstituted C 1~6 Alkyl (e.g., methyl) and C 1~6 haloalkyl (e.g., trifluoromethyl), and each R 2 and R 3 are independently hydrogen or C 1~6 alkyl (e.g., methyl), and R 4 is hydrogen, halogen (e.g., chloro), -O(C 1~6 alkyl) (e.g., methoxy) or C 1~6 alkyl (e.g., methyl), and R 5 is (i) halogen (e.g., fluoro), cyano, hydroxyl, -O(C 1~6 alkyl), -NHC(O)(C 1~6 alkyl), -NHS(O)2(C 1~6 C(O) optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of alkyl, -S(O)NH, -C(O)NH, phenyl, and 3- to 12-membered heterocyclyl (e.g., oxetan-3-yl). 1~6 (ii) C substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen (e.g., fluoro), cyano, and hydroxyl. 3~6(iii) a monocyclic 3- to 6-membered heterocyclyl having one ring heteroatom which is oxygen; (iv) phenyl; or (v) pyrazolyl (e.g., 3-pyrazolyl, 4-pyrazolyl, or 5-pyrazolyl), and R 6a and R 6b is hydrogen and R 6a and R 6b The other is hydrogen, C 1~6 Alkyl (e.g., methyl), -C(O)O(C 1~6 alkyl) or -C(O)NR 16a R 16b or R 6a and R 6b combine with the carbon to which they are attached to form a carbonyl, and R 7a and R 7b is hydrogen and R 7a and R 7b The other is hydrogen or C 1~6 alkyl (e.g., methyl) or R 7a and R 7b combine with the carbon to which they are attached to form a carbonyl, and R 8a and R 8b is hydrogen. In some embodiments, R 1 is pyrazol-4-yl, 4-pyridyl, or pyrrolo[2,3-b]pyridin-4-yl, each of which is substituted with halogen (e.g., chloro), cyano, unsubstituted C 1~6 Alkyl (e.g., methyl) and C 1~6 haloalkyl (e.g., trifluoromethyl), and each R 2 and R 3 are independently hydrogen or C 1~6 alkyl (e.g., methyl), and R 4 is hydrogen, halogen (e.g., chloro), or C 1~6 alkyl (e.g., methyl), and R 5 is (i) halogen (e.g., fluoro), cyano, hydroxyl, -O(C 1~6 alkyl), -NHC(O)(C 1~6 alkyl), -NHS(O)2(C1~6 C(O) optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of alkyl, -S(O)NH, -C(O)NH, phenyl, and 3- to 12-membered heterocyclyl (e.g., oxetan-3-yl). 1~6 (ii) C substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen (e.g., fluoro), cyano, and hydroxyl. 3~6 (iii) a monocyclic 3- to 6-membered heterocyclyl having one ring heteroatom which is oxygen; (iv) phenyl; or (v) pyrazolyl (e.g., 3-pyrazolyl, 4-pyrazolyl, or 5-pyrazolyl), and R 6a and R 6b is hydrogen and R 6a and R 6b The other is hydrogen, C 1~6 Alkyl (e.g., methyl), -C(O)O(C 1~6 alkyl) or -C(O)NR 16a R 16b or R 6a and R 6b combine with the carbon to which they are attached to form a carbonyl, and R 7a and R 7b is hydrogen and R 7a and R 7b The other is hydrogen or C 1~6 alkyl (e.g., methyl) or R 7a and R 7b combine with the carbon to which they are attached to form a carbonyl, and R 8a and R 8b is hydrogen. In some embodiments, each R 16a and R 16b are independently hydrogen or C 1~6 alkyl (e.g., methyl) or R 16a and R 16b together with the nitrogen atom to which they are attached form pyrrolidin-1-yl or morpholin-4-yl.

[0091] In some embodiments, the compound is of Formula (I), or a variant thereof, such as Formulas (IA), (IB), and (IC), or a salt thereof (e.g., a pharmaceutically acceptable salt) where n is 0 to 8. The piperidine portion of the spiro ring is unsubstituted (n is 0) or substituted with 1 to 8 R 9 In some embodiments, each R 9 If present, independently C 1~6 alkyl or, if present, two geminal R 9 The groups together with the carbon to which they are attached form a carbonyl.

[0092] R as described for formula (I), (IA), (IB) or (IC) 1 , R 2 , R 3 , R 4 , R 5 , R 6a , R 6b , R 7a , R 7b , R 8a and R 8b Each and every variation of R is described for formula (I), (IA), (IB) or (IC). 9 and n, and it is intended and understood that each and every combination is the same as if specifically and individually set forth. For example, in some embodiments, R 1 , R 2 , R 3 , R 4 , R 5 , R 6a , R 6b , R 7a , R 7b , R 8a and R 8b is as detailed herein or any combination thereof detailed herein, and n is 0 (i.e., R 9 does not exist).

[0093] In some embodiments, the compound of formula (I) has formula (II): TIFF2024521929000019.tif68170 or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4 , G 1 , G 2 , R 5 , R 6a , R 6b , R 7a , R 7b , R 8a and R 8b is as detailed herein for formula (I), or includes variations detailed herein.

[0094] In some embodiments, the compound of Formula (I) or (II) has the formula (II-A): TIFF2024521929000020.tif68170 or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6a , R 6b , R 7a , R 7b , R 8a and R 8b is as detailed herein for formula (I) or (II), or provides variations as detailed herein.

[0095] In some embodiments, the compound of Formula (I) or (II) has the formula (II-B): TIFF2024521929000021.tif68170 or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4 , R 42 , R 5 , R 6a , R 6b , R 7a , R 7b , R 8a and R 8bis as detailed herein for formula (I) or (II), or provides variations as detailed herein.

[0096] In some embodiments, the compound of Formula (I) or (II) has the formula (II-C): TIFF2024521929000022.tif68170 or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4 , R 41 , R 5 , R 6a , R 6b , R 7a , R 7b , R 8a and R 8b is as detailed herein for formula (I) or (II), or provides variations as detailed herein.

[0097] In some embodiments, the compound is a compound of Formula (II), (II-A), (II-B), or (II-C), or a salt thereof (e.g., a pharmaceutically acceptable salt), and R 1 is pyrazolyl (e.g., pyrazol-3-yl, pyrazol-4-yl, or pyrazol-5-yl), pyridinyl (e.g., 4-pyridyl), or pyrrolo-pyridinyl (e.g., pyrrolo[2,3-b]pyridin-4-yl), each of which can be represented by R 10 and R 2 is hydrogen or R 10 C optionally substituted with 1 to 5 substituents independently selected from 1~6 alkyl (e.g., methyl), and R 3 is hydrogen or C 1~6 alkyl (e.g., methyl), and R 4 is hydrogen, halogen or C 1~6 alkyl, and R 5 is hydrogen, C 1~6 Alkyl, C 3~8 Cycloalkyl, C 6~14Aryl, 5- to 14-membered heteroaryl, 3- to 14-membered heterocyclyl, or —C(O)R 14 where R 5 C 1~6 Alkyl, C 3~8 Cycloalkyl, C 6~14 Aryl, 5- to 14-membered heteroaryl, and 3- to 14-membered heterocyclyl are each R 10 and each R 6a and R 6b are independently hydrogen or -C(O)OR 15 , -C(O)NR 16a R 16b or R 10 C optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from 1~6 alkyl or R 6a and R 6b combine with the carbon to which they are attached to form a carbonyl, and each R 7a and R 7b are independently hydrogen or C 1~6 alkyl or R 7a and R 7b combine with the carbon to which they are attached to form a carbonyl, and R 8a and R 8b one of which is hydrogen and R 8a and R 8b The other is hydrogen, halogen, hydroxyl, C 1~6 Alkyl or -O(C 1~6 In some embodiments, R 14 is C 1~6 In some embodiments, R 15 is C 1~6 In some embodiments, each R 16a and R 16b are independently hydrogen or C 1~6 alkyl (e.g., methyl) or R 16a and R 16bhave, together with the nitrogen atom to which they are attached, one to two cyclic heteroatoms selected from nitrogen, oxygen, and sulfur; R 10 Forms a 5- or 6-membered heterocyclyl optionally substituted by 1, 2, 3, 4 or 5 substituents independently selected from:

[0098] In some embodiments, the compound is of formula (II), (II-A), (II-B), or (II-C), or a salt thereof (e.g., a pharmaceutically acceptable salt), wherein R 1 is pyrazol-4-yl, isothiazol-5-yl, 4-pyridyl or pyrrolo[2,3-b]pyridin-4-yl, each of which is substituted with halogen (e.g., chloro), cyano, unsubstituted C 1~6 Alkyl (e.g., methyl) and C 1~6 haloalkyl (e.g., trifluoromethyl), and R 2 are independently hydrogen or C 1~6 alkyl (e.g., methyl), and R 3 are independently hydrogen, halogen (e.g., chloro) or C 1~6 alkyl (e.g., methyl), and R 4 is hydrogen, halogen (e.g., chloro), -O(C 1~6 alkyl) (e.g., methoxyl) or C 1~6 alkyl (e.g., methyl), and R 5 is (i) halogen (e.g., fluoro), cyano, hydroxyl, -O(C 1~6 alkyl), -NHC(O)(C 1~6 alkyl), -NHS(O)2(C 1~6 C(O) optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of alkyl, -S(O)NH, -C(O)NH, phenyl, and 3- to 12-membered heterocyclyl (e.g., oxetan-3-yl). 1~6 (ii) C substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen (e.g., fluoro), cyano, and hydroxyl. 3~6(iii) monocyclic 3- to 6-membered heterocyclyl having one ring heteroatom which is oxygen; (iv) phenyl; or (v) pyrazolyl (e.g., 3-pyrazolyl, 4-pyrazolyl, or 5-pyrazolyl), and R 6a and R 6b is hydrogen and R 6a and R 6b The other is hydrogen, C 1~6 Alkyl (e.g., methyl), -C(O)O(C 1~6 alkyl) or -C(O)NR 16a R 16b or R 6a and R 6b combine with the carbon to which they are attached to form a carbonyl, and R 7a and R 7b is hydrogen and R 7a and R 7b The other is hydrogen or C 1~6 alkyl (e.g., methyl) or R 7a and R 7b combine with the carbon to which they are attached to form a carbonyl, and R 8a and R 8b is hydrogen. In some embodiments, R 1 is pyrazol-4-yl, 4-pyridyl, or pyrrolo[2,3-b]pyridin-4-yl, each of which is substituted with halogen (e.g., chloro), cyano, unsubstituted C 1~6 Alkyl (e.g., methyl) and C 1~6 haloalkyl (e.g., trifluoromethyl), and each R 2 and R 3 are independently hydrogen or C 1~6 alkyl (e.g., methyl), and R 4 is hydrogen, halogen (e.g., chloro), or C 1~6 alkyl (e.g., methyl), and R 5 is (i) halogen (e.g., fluoro), cyano, hydroxyl, -O(C 1~6 alkyl), -NHC(O)(C 1~6 alkyl), -NHS(O)2(C1~6 C(O) optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of alkyl, -S(O)NH, -C(O)NH, phenyl, and 3- to 12-membered heterocyclyl (e.g., oxetan-3-yl). 1~6 (ii) C substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen (e.g., fluoro), cyano, and hydroxyl. 3~6 (iii) a monocyclic 3- to 6-membered heterocyclyl having one ring heteroatom which is oxygen; (iv) phenyl; or (v) pyrazolyl (e.g., 3-pyrazolyl, 4-pyrazolyl, or 5-pyrazolyl), and R 6a and R 6b is hydrogen and R 6a and R 6b The other is hydrogen, C 1~6 Alkyl (e.g., methyl), -C(O)O(C 1~6 alkyl) or -C(O)NR 16a R 16b or R 6a and R 6b combine with the carbon to which they are attached to form a carbonyl, and R 7a and R 7b is hydrogen and R 7a and R 7b The other is hydrogen or C 1~6 alkyl (e.g., methyl) or R 7a and R 7b combine with the carbon to which they are attached to form a carbonyl, and R 8a and R 8b is hydrogen. In some embodiments, each R 16a and R 16b are independently hydrogen or C 1~6 alkyl (e.g., methyl) or R 16a and R 16b together with the nitrogen atom to which they are attached form pyrrolidin-1-yl or morpholin-4-yl.

[0099] In some embodiments, the compound of Formula (I), (IA), (II) or (II-A) has Formula (III): TIFF2024521929000023.tif69170 or a pharmaceutically acceptable salt thereof, wherein R 2 , R 3 , R 4 , R 5 , R 6a , R 6b , R 7a , R 7b , R 8a and R 8b is as detailed herein for formula (I), (IA), (II) or (II-A) or applicable variations thereof, p is 0, 1, 2, 3 or 4, and each R Z are independent, R 10 hydrogen, halogen, cyano or C optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from 1~6 In some embodiments, p is 0 (R Z In some embodiments, p is 1 and R Z is fluoro (e.g., 3-fluoro) or cyano (e.g., 3-cyano). In some of these embodiments, each R 2 , R 3 and R 4 is hydrogen.

[0100] In some embodiments, the compound of Formula (I), (IA), (II) or (II-A) has Formula (IV): TIFF2024521929000024.tif69170 or a pharmaceutically acceptable salt thereof, wherein R 2 , R 3 , R 4 , R 5 , R 6a , R 6b , R 7a , R 7b , R 8a and R 8b is as detailed herein for formula (I), (IA), (II) or (II-A) or applicable variations thereof, q is 0, 1, 2 or 3, and each RY are independently hydrogen, halogen, cyano, -O(C 1~6 alkyl) or C 1~6 alkyl, and R Y C 1~6 Alkyl is R 10 In some embodiments, each R Y are independently 10 hydrogen, halogen, cyano or C optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from 1~6 In some embodiments, q is 1. In some embodiments, q is 1 and R Y is methyl, fluoro, chloro, cyano, or trifluoromethyl. In some embodiments, R Y is attached to the pyrazol-4-yl at the 3- or 5-position. Y is 5-methyl or 3-methyl. In some of these embodiments, each R 2 , R 3 and R 4 is hydrogen.

[0101] In some embodiments, the compound of Formula (I), (IA), (II), (II-A) or (III) has Formula (V): TIFF2024521929000025.tif69170 or a pharmaceutically acceptable salt thereof, wherein R 2 , R 3 , R 4 , R 5 , R 6a , R 6b , R 7a , R 7b , R 8a and R 8b is as detailed herein for formula (I), (IA), (II), (II-A), or (III) or applicable variations thereof. In some of these embodiments, each R 2 , R 3 and R 4 is hydrogen and R 5 , R 6a, R 6b , R 7a , R 7b , R 8a and R 8b is as detailed herein for formula (I), (IA), (II), (II-A) or (III) or applicable variations thereof.

[0102] In some embodiments, the compound of formula (I), (IA), (II), (II-A) or (IV) has formula (VI): TIFF2024521929000026.tif69170 or a pharmaceutically acceptable salt thereof, wherein R 2 , R 3 , R 4 , R 5 , R 6a , R 6b , R 7a , R 7b , R 8a and R 8b is as detailed herein for formula (I), (IA), (II), (II-A), or (IV) or applicable variations thereof. In some of these embodiments, each R 2 , R 3 and R 4 is hydrogen and R 5 , R 6a , R 6b , R 7a , R 7b , R 8a and R 8b is as detailed herein for formula (I), (IA), (II), (II-A) or (IV) or applicable variations thereof.

[0103] In some embodiments, the compound of Formula (I), (IB), (II) or (II-B) has Formula (VII) or (VIII): TIFF2024521929000027.tif69170(VII) (VIII) or a pharmaceutically acceptable salt thereof, wherein R 2 , R 3 , R 4 , R 5 , R 6a, R 6b , R 7a , R 7b , R 8a and R 8b is as detailed herein for formula (I), (IB), (II), or (II-B), or applicable variations thereof. In some of these embodiments, each R 2 , R 3 and R 4 is hydrogen and R 5 , R 6a , R 6b , R 7a , R 7b , R 8a and R 8b is as detailed herein for formula (I), (IB), (II), or (II-B) or applicable variations thereof.

[0104] In some embodiments, the compound of Formula (I), (IC), (II), or (II-C) has Formula (IX): TIFF2024521929000028.tif69170 or a pharmaceutically acceptable salt thereof, wherein R 2 , R 3 , R 4 , R 5 , R 6a , R 6b , R 7a , R 7b , R 8a and R 8b is as detailed herein for formula (I), (IC), (II), or (II-C) or applicable variations thereof. In some of these embodiments, each R 2 , R 3 and R 4 is hydrogen and R 5 , R 6a , R 6b , R 7a , R 7b , R 8a and R 8b is as detailed herein for formula (I), (IC), (II), or (II-C) or applicable variations thereof. In some of these embodiments, each R 7a and R7b are independently hydrogen or R 10 C optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from 1~6 It is alkyl.

[0105] In some embodiments of a compound of Formula (I) or a variant thereof, such as Formula (II) or a salt thereof (e.g., a pharmaceutically acceptable salt), each R 10 are independently oxo, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~8 Cycloalkyl, C 6~14 Aryl, 5- to 14-membered heteroaryl, 3- to 14-membered heterocyclyl, halogen, cyano, -C(O)R a , -C(O)OR b , -C(O)NR c R d , -OR b , -OC(O)R a , -OC(O)NR c R d , -SR b , -S(O)R e , -S(O)2R e , -S(O)(=NH)R e , -S(O)NR c R d , -NR c R d , -N(R f )C(O)R a , -N(R f )C(O)OR b , -N(R f )C(O)NR c R d , -N(R f )S(O)2R e , or -N(R f )S(O)NR c R d where R 10 C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~8 Cycloalkyl, C 6~14Aryl, 5- to 14-membered heteroaryl, and 3- to 14-membered heterocyclyl are each R 11 and optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

[0106] In one variation, R 10 are independently oxo, C 1~6 Alkyl, C 3~8 Cycloalkyl, C 6~10 Aryl, 5-10 membered heteroaryl, 3-12 membered heterocyclyl, halogen, cyano, -C(O)R a , -C(O)OR b , -C(O)NR c R d , -OR b , -OC(O)R a , -OC(O)NR c R d , -S(O)2R e , -S(O)NR c R d , -NR c R d , -N(R f )C(O)R a , -N(R f )C(O)OR b , -N(R f )C(O)NR c R d , -N(R f )S(O)2R e , or -N(R f )S(O)NR c R d where R 10 C 1~6 Alkyl, C 3~8 Cycloalkyl, C 6~10 Aryl, 5- to 10-membered heteroaryl, and 3- to 12-membered heterocyclyl are each R 11 and optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

[0107] In one variation, R 10 are independently halogen (e.g., chloro or fluoro), cyano, -OR b , -N(R f)C(O)R a , -N(R f )S(O)2R e , -S(O)NR c R d , -C(O)NR c R d , R 11 C optionally substituted with 1, 2, 3 or 4 substituents independently selected from 1~6 Alkyl, R 11 C optionally substituted with 1, 2, 3 or 4 substituents independently selected from 3~8 Cycloalkyl, R 11 C optionally substituted with 1, 2, 3 or 4 substituents independently selected from 6~10 Aryl, R 11 or R 11 and 3- to 12-membered heterocyclyl optionally substituted by 1, 2, 3, or 4 substituents independently selected from:

[0108] In one variation, R 10 is independently halogen (e.g., chloro or fluoro), cyano, or hydroxyl.

[0109] In one variation, R 10 are independently selected from halogen (e.g., fluoro or chloro), cyano, and C optionally substituted with halogen. 1~6 alkyl (eg, methyl or trifluoromethyl).

[0110] In one variation, R 10 are hydroxyl, cyano, fluoro, chloro, -CH2F, -CHF2, -CF3, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 alkyl)2, -O(C 1~6 alkyl), -SO2(C 1~6 alkyl), -S(O)NR c R d , -C(O)NR c Rd , or -N(R f )C(O)R a is.

[0111] In one variation, R 10 is C 2~6 alkenyl (e.g., ethenyl) or C 2~6 alkynyl (e.g., ethynyl), and each R 11 and optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

[0112] In one variation, R 10 are independently halogen (e.g., fluoro or chloro), cyano, —OR b , -N(R f )C(O)R a , -N(R f )S(O)2R e , -S(O)NR c R d , -C(O)NR c R d , R 11 C optionally substituted with 1, 2, 3 or 4 substituents independently selected from 6~10 Aryl, or R 11 In some of these embodiments, R is a 3- to 12-membered heterocyclyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from: a is C 1~6 alkyl, and R b is hydrogen or C 1~6 alkyl, and R e is C 1~6 alkyl, and R f is hydrogen, and each R c and R d are independently hydrogen or C 1~6 alkyl or R c and R d together with the nitrogen atom to which they are attached, form R 11 Forms a 4- to 7-membered heterocyclyl having 1 to 3 ring heteroatoms selected from nitrogen, oxygen and sulfur, optionally substituted by 1, 2, 3 or 4 substituents independently selected from:

[0113] In some embodiments, a group (e.g., R 1 ) is R 10 and R 10 is halogen (e.g., fluoro or chloro), cyano, oxo, C 1~6 Alkyl, C 1~6 Haloalkyl and -OR b wherein R b is hydrogen or C 1~6 It is alkyl.

[0114] In some embodiments, a group (e.g., R 2 , R 3 , R 4 , R 44 , R 5 , R 6a , R 6b , R 7a , R 7b , R 8a , R 8b or R 9 ) but R 10 C optionally substituted with 1 to 5 (e.g., 1, 2, 3, 4, or 5; 1, 2, 3, or 4; or 1, 2, 3; or 1 or 2) substituents independently selected from 1~6 When alkyl is contained, each R 10 independently, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~8 Cycloalkyl, C 6~14 Aryl, 5-14 membered heteroaryl, 3-14 membered heterocyclyl, halogen, cyano, -C(O)OR b , -C(O)NR c R d , -OR b , -S(O)NR c R d , -NR c R d , -N(R f )C(O)R a or -N(Rf )S(O)2R e and R 10 C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~8 Cycloalkyl, C 6~14 Aryl, 5- to 14-membered heteroaryl, and 3- to 14-membered heterocyclyl are each R 11 In some of these embodiments, R 11 is halogen (e.g., fluoro or chloro), cyano, C 1~6 Alkyl, C 1~6 Haloalkyl and -OR b wherein R b is hydrogen or C 1~6 In some of these embodiments, R 11 is selected from the group consisting of halogen (e.g., fluoro or chloro), cyano, and hydroxyl. 2 Substitution of C 1~6 For alkyl, R 10 is a halogen (e.g., fluoro or chloro), halogen or C 1~6 C optionally substituted with alkyl 6~14 aryl (e.g., phenyl), halogen or C 1~6 5-14 membered heteroaryl optionally substituted with alkyl (e.g., pyridyl or pyrazolyl), -OR b (where R b is hydrogen or C 1~6 alkyl) and -N(R f )C(O)R a (R a is C 1~6 alkyl, and R f is hydrogen). 3 Substitution of C 1~6 For alkyl, R 10 is a halogen (e.g., fluoro or chloro) and -OR b wherein R b is hydrogen or C1~6 alkyl. In one variation (e.g., R 4 or R 44 Substitution of C 1~6 For alkyl, R 10 is halogen (e.g., fluoro or chloro), C 2~6 Alkenyl, C 2~6 Alkynyl, -OR b and -C(O)NR c R d wherein R b is hydrogen or C 1~6 alkyl, and R c and R d are independently hydrogen or C 1~6 alkyl. In one variation (e.g., R 5 Substitution of C 1~6 For alkyl, R 10 is halogen (e.g., fluoro or chloro), C 2~6 alkenyl (e.g., ethenyl), C 2~6 C optionally substituted with alkynyl (e.g., ethynyl), halogen, cyano, or hydroxyl 3-5 cycloalkyl, optionally substituted with halogen 6~14 aryl (e.g., phenyl), 4- or 5-membered heterocyclyl (e.g., oxetanyl or azetidinyl) optionally substituted with halogen, hydroxyl, or acetyl, C(O)NR c R d (R c and R d are independently hydrogen or C 1~6 alkyl), -OR b (R b are independently hydrogen or C 1~6 alkyl), S(O)NR c R d (R c and R d are independently hydrogen or C 1~6 alkyl) and -N(R f )C(O)R a (R a is C 1~6 alkyl, and R fis hydrogen). 6a , R 6b , R 7a , R 7b , R 8a , R 8b or R 9 Substitution of C 1~6 For alkyl, R 10 is a halogen (e.g., fluoro or chloro) and -OR b wherein R b is hydrogen or C 1~6 It is alkyl.

[0115] In some embodiments, a group (e.g., R 5 ) but R 10 C optionally substituted with 1 to 5 (e.g., 1, 2, 3, 4, or 5; 1, 2, 3, or 4; or 1, 2, 3; or 1 or 2) substituents independently selected from 3~8 When it contains cycloalkyl, R 10 is halogen (e.g., fluoro or chloro), cyano, and -OR b wherein R b is hydrogen or C 1~6 It is alkyl.

[0116] In some embodiments, each R a are independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~8 Cycloalkyl, C 6~10 aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein R a C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~8 Cycloalkyl, C 6~10 Aryl, 5- to 10-membered heteroaryl, and 3- to 12-membered heterocyclyl are each R 11 In one variation, R aare independently hydrogen or C 1~6 It is alkyl.

[0117] In some embodiments, each R b are independently hydrogen, C 1~6 Alkyl, C 3~8 Cycloalkyl, C 6~10 aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein R b C 1~6 Alkyl, C 3~8 Cycloalkyl, C 6~10 Aryl, 5- to 10-membered heteroaryl, and 3- to 12-membered heterocyclyl are each R 11 In one variation, R b are independently hydrogen or C 1~6 It is alkyl.

[0118] In some embodiments, each R c and R d are independently hydrogen, C 1~6 Alkyl, C 3~8 Cycloalkyl, C 6~10 aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, where R c and R d C 1~6 Alkyl, C 3~8 Cycloalkyl, C 6~10 Aryl, 5- to 10-membered heteroaryl, and 3- to 12-membered heterocyclyl are each R 11 or R c and R d together with the nitrogen atom to which they are attached, form R 11 In one variation, each R c and R d are independently hydrogen or C 1~6 It is alkyl.

[0119] In some embodiments, each R e independently, C 1~6 Alkyl, C 3~8 Cycloalkyl, C 6~10 aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, wherein R e C 1~6 Alkyl, C 3~8 Cycloalkyl, C 6~10 Aryl, 5- to 10-membered heteroaryl, and 3- to 12-membered heterocyclyl are each R 11 In one variation, R e is independently C 1~6 It is alkyl.

[0120] In some embodiments, each R f are independently hydrogen or C 1~6 In one variation, R f is hydrogen.

[0121] In some embodiments, each R 11 are independently oxo, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 6~10 Aryl, 5-10 membered heteroaryl, 3-8 membered heterocyclyl, halogen, cyano, -C(O)R a1 , -C(O)OR b1 , -C(O)NR c1 R d1 , -OR b1 , -OC(O)R a1 , -OC(O)NR c1 R d1 , -SR b1 , -S(O)R e1 , -S(O)2R e1 , -S(O)NR c1 R d1 , -NR c1 R d1 , -N(R f1 )C(O)R a1 , -N(R f1)C(O)OR b1 , -N(R f1 )C(O)NR c1 R d1 , -N(R f1 )S(O)2R e1 , or -N(R f1 )S(O)NR c1 R d1 where R 11 C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 6~10 Aryl, 5- to 10-membered heteroaryl, and 3- to 8-membered heterocyclyl are each R 12 and optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

[0122] In one variation, each R 11 are independently oxo, C 1~6 Alkyl, C 3~6 Cycloalkyl, 3- to 8-membered heterocyclyl, halogen, cyano or -OR b1 where R 11 C 1~6 Alkyl, C 3~6 Cycloalkyl and 3- to 8-membered heterocyclyl are each R 12 and optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

[0123] In one variation, R 11 is R 12 C optionally substituted with 1, 2, 3 or 4 substituents independently selected from 1~6 In one variation, R 11 is R 12 and a 3- to 8-membered heterocyclyl optionally substituted by 1, 2, 3, or 4 substituents independently selected from:

[0124] In one variation, R 11 is halogen, cyano, -NR c1 R d1 , -C(O)NR c1 Rd1 , -OR b1 , -S(O)2R e1 , C 1~6 Haloalkyl, -(C 1~6 alkylene)-OH or -(C 1~6 alkylene)-NH2.

[0125] In one variation, R 11 are hydroxyl, cyano, halogen, -CHF2, -CF3, -NH2, -NH(C 1~6 alkyl), -N(C 1~6 alkyl)2, -O(C 1~6 alkyl), -SO2(C 1~6 alkyl), -S(O)NR c1 R d1 , -C(O)NR c1 R d1 , or -N(R f1 )C(O)R a1 is.

[0126] In one variation, R 11 is halogen, cyano, -O(C 1~6 alkyl), -O(C 1~6 alkylene)-NH2 or -(C 1~6 alkylene)-OH.

[0127] In some embodiments, each R a1 are independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 6~10 aryl, 5- to 10-membered heteroaryl, or 3- to 8-membered heterocyclyl, wherein R a1 C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 6~10 Aryl, 5- to 10-membered heteroaryl, and 3- to 8-membered heterocyclyl are each R 12 and optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

[0128] In some embodiments, each R b1 are independently hydrogen, C 1~6 Alkyl, C 3~6 Cycloalkyl, C 6~10 aryl, 5- to 10-membered heteroaryl, or 3- to 8-membered heterocyclyl, wherein R b1 C 1~6 Alkyl, C 3~6 Cycloalkyl, C 6~10 Aryl, 5- to 10-membered heteroaryl, and 3- to 8-membered heterocyclyl are each R 12 In one variation, R b1 are independently hydrogen or C 1~6 It is alkyl.

[0129] In some embodiments, each R c1 and R d1 are independently hydrogen, C 1~6 Alkyl, C 3~6 Cycloalkyl, C 6~10 aryl, 5- to 10-membered heteroaryl, or 3- to 8-membered heterocyclyl, where R c1 and R d1 C 1~6 Alkyl, C 3~6 Cycloalkyl, C 6~10 Aryl, 5- to 10-membered heteroaryl, and 3- to 8-membered heterocyclyl are each R 12 or R c1 and R d1 together with the nitrogen atom to which they are attached, form R 12 In one variation, each R c1 and R d1 are independently hydrogen or C 1~6 It is alkyl.

[0130] In some embodiments, each R e1 independently, C1~6 Alkyl, C 3~6 Cycloalkyl, C 6~10 aryl, 5- to 10-membered heteroaryl, or 3- to 8-membered heterocyclyl, wherein R e1 C 1~6 Alkyl, C 3~6 Cycloalkyl, C 6~10 Aryl, 5- to 10-membered heteroaryl, and 3- to 8-membered heterocyclyl are each R 12 In one variation, R e1 is independently C 1~6 It is alkyl.

[0131] In some embodiments, each R f1 are independently hydrogen or C 1~6 In one variation, R f1 is hydrogen.

[0132] In some embodiments, each R 12 are independently oxo, C 1~6 Alkyl, C 3~6 Cycloalkyl, C6 aryl, 5-6 membered heteroaryl, 3-6 membered heterocyclyl, halogen, cyano, -C(O)R a2 , -C(O)OR b2 , -C(O)NR c2 R d2 , -OR b2 , -OC(O)R a2 , -OC(O)NR c2 R d2 , -S(O)2R e2 , -S(O)NR c2 R d2 , -NR c2 R d2 , -N(R f2 )C(O)R a2 , -N(R f2 )C(O)OR b2 , -N(R f2 )C(O)NR c2 R d2 , -N(R f2 )S(O)2R e2 , or -N(R f2)S(O)NR c2 R d2 where R 12 C 1~6 Alkyl, C 3~6 Cycloalkyl, C6 aryl, 5- to 6-membered heteroaryl and 3- to 6-membered heterocyclyl are each R 13 and optionally substituted with 1, 2, 3, or 4 substituents independently selected from:

[0133] In one variation, each R 12 are independently oxo, halogen, cyano, -OR b2 , or R 13 C optionally substituted with 1, 2, 3 or 4 substituents independently selected from 1~6 In one variation, each R 12 is independently oxo, halogen, cyano, or hydroxyl.

[0134] In one variation, R 12 is R 13 C optionally substituted with 1, 2, 3 or 4 substituents independently selected from 1~6 It is alkyl.

[0135] In one variation, R 12 is oxo, hydroxyl, C 1~6 Alkyl or -O(C 1~6 alkyl).

[0136] In some embodiments, each R a2 are independently hydrogen, C 1~6 Alkyl, C 3~6 cycloalkyl, C6 aryl, 5- to 6-membered heteroaryl, or 3- to 6-membered heterocyclyl, where R a2 C 1~6 Alkyl, C 3~6 Cycloalkyl, C6 aryl, 5- to 6-membered heteroaryl and 3- to 6-membered heterocyclyl are each R 13 In one variation, R a2 are independently hydrogen or C1~6 It is alkyl.

[0137] In some embodiments, each R b2 are independently hydrogen, C 1~6 Alkyl, C 3~6 cycloalkyl or 3- to 6-membered heterocyclyl, wherein R b2 C 1~6 Alkyl, C 3~6 Cycloalkyl and 3- to 6-membered heterocyclyl are each R 13 In one variation, R b2 is hydrogen.

[0138] In some embodiments, each R c2 and R d2 are independently hydrogen, C 1~6 Alkyl, C 3~6 cycloalkyl or 3- to 8-membered heterocyclyl, where R c2 and R d2 C 1~6 Alkyl, C 3~6 Cycloalkyl and 3- to 8-membered heterocyclyl are each R 13 or R c2 and R d2 together with the nitrogen atom to which they are attached, form R 13 In one variation, each R c2 and R d2 are independently hydrogen or C 1~6 It is alkyl.

[0139] In some embodiments, each R e2 independently, C 1~6 Alkyl, C 3~6 cycloalkyl, C6 aryl, 5- to 6-membered heteroaryl, or 3- to 6-membered heterocyclyl, wherein R e2 C 1~6 Alkyl, C 3~6Cycloalkyl, C6 aryl, 5- to 6-membered heteroaryl and 3- to 6-membered heterocyclyl are each R 13 In one variation, R e2 is independently C 1~6 It is alkyl.

[0140] In some embodiments, each R f2 are independently hydrogen or C 1~6 In one variation, R f2 is hydrogen.

[0141] In some embodiments, each R 13 are independently oxo, halogen, hydroxyl, -O(C 1~6 alkyl), cyano, C 1~6 Alkyl or C 1~6 It is haloalkyl.

[0142] In one variation, each R 13 are independently halogen, hydroxyl, -O(C 1~6 alkyl), cyano or C 1~6 It is alkyl.

[0143] In one variation, R 13 is oxo, hydroxyl, C 1~6 Alkyl or -O(C 1~6 alkyl).

[0144] Representative compounds are shown in Table 1. In some instances, enantiomers or diastereomers are identified by their respective properties, e.g., their relative retention times in chiral HPLC / SFC or their biological activity, and the absolute configuration of the chiral centers is arbitrarily assigned. TIFF2024521929000029.tif214170TIFF2024521929000030.tif236170TIFF2024521929000031.tif181170TIFF2024521929000032.tif172170TIFF2024521929000033.tif228170TIFF2024521929000034.tif224170TIFF2024521929000035.tif216170TIFF2024521929000036.tif215170TIFF2024521929000037.tif229170TIFF2024521929000038.tif214170TIFF2024521929000039.tif227170TIFF2024521929000040.tif210170TIFF2024521929000041.tif228170TIFF2024521929000042.tif250170TIFF2024521929000043.tif243170TIFF2024521929000044.tif248170TIFF2024521929000045.tif155170TIFF2024521929000046.tif229170TIFF2024521929000047.tif174170TIFF2024521929000048.tif226170TIFF2024521929000049.tif208170TIFF2024521929000050.tif215170TIFF2024521929000051.tif205170TIFF2024521929000052.tif255170TIFF2024521929000053.tif218170TIFF2024521929000054.tif205170TIFF2024521929000055.tif213170TIFF2024521929000056.tif248170TIFF2024521929000057.tif255170TIFF2024521929000058.tif253170TIFF2024521929000059.tif255170TIFF2024521929000060.tif207170TIFF2024521929000061.tif236170TIFF2024521929000062.tif238170TIFF2024521929000063.tif222170TIFF2024521929000064.ti f242170TIFF2024521929000065.tif248170TIFF2024521929000066.tif242170TIFF2024521929000067.tif2 43170TIFF2024521929000068.tif253170TIFF2024521929000069.tif249170TIFF2024521929000070.tif255 170TIFF2024521929000071.tif255170TIFF2024521929000072.tif213170TIFF2024521929000073.tif66170.

[0145] In some embodiments, a compound selected from compound numbers 101-292 in Table 1, or a salt thereof (e.g., a pharmaceutically acceptable salt) is provided. In some embodiments, the compound is selected from compound numbers 101-201 in Table 1, or a salt thereof (e.g., a pharmaceutically acceptable salt). In some embodiments, the compound is selected from compound numbers 101-198 in Table 1, or a salt thereof (e.g., a pharmaceutically acceptable salt). In some embodiments, the compound is selected from compound numbers 202-292 in Table 1, or a salt thereof (e.g., a pharmaceutically acceptable salt).

[0146] The compounds of formula (I) or salts thereof described herein can exist in stereoisomeric forms (e.g., contain one or more asymmetric carbon atoms). Each stereoisomer (enantiomer and diastereomer) and mixtures thereof are included within the scope of the subject matter disclosed herein. It should be understood that the subject matter disclosed herein includes combinations and subsets of the specific groups described herein. The scope of the subject matter disclosed herein includes mixtures of stereoisomers as well as purified enantiomers or enantiomerically / diastereomerically enriched mixtures. It should be understood that the subject matter disclosed herein includes combinations and subsets of the specific groups defined herein.

[0147] Likewise, it is understood that compounds or salts of formula (I) may exist in tautomeric forms other than that shown in the formula and these are also within the scope of the presently disclosed subject matter. For example, a pyrazolyl group may exist as either or both of the tautomeric forms shown below: TIFF2024521929000074.tif17170 When one specific tautomer is shown in a structural diagram, both tautomers are intended, regardless of whether the one shown is the major or minor tautomer present.

[0148] The subject matter disclosed herein also includes isotopically labeled forms of the compounds described herein except for the fact that one or more atoms have been replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Examples of isotopes that can be incorporated into the compounds described herein and their pharmaceutically acceptable salts include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, e.g., 2 H, 3 H, 11 C. 13 C. 14 C. 15 N, 17 O. 18 O. 31 P,32 P, 35 S, 18 F, 36 Cl, 123 I and 125 I can be mentioned.

[0149] The presently disclosed subject matter includes prodrugs, metabolites, derivatives, and pharmaceutically acceptable salts of compounds of Formula (I). Metabolites of compounds of Formula (I) include compounds produced by a process comprising contacting a compound of Formula (I) with a mammal for a period of time sufficient to yield a metabolic product thereof.

[0150] When the compound of formula (I) is a base, the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, by treating the free base with an inorganic acid (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, methanesulfonic acid, phosphoric acid, etc.), or an organic acid (e.g., acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidylic acid (e.g., glucuronic acid or galacturonic acid), an alpha hydroxy acid (e.g., citric acid or tartaric acid), an amino acid (e.g., aspartic acid or glutamic acid), an aromatic acid (e.g., benzoic acid or cinnamic acid), a sulfonic acid (e.g., p-toluenesulfonic acid or ethanesulfonic acid), etc.).

[0151] If the compound of formula (I) is an acid, the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, by treating the free acid with an inorganic or organic base, such as an amine (primary, secondary, or tertiary), an alkali metal hydroxide, or an alkaline earth metal hydroxide. Illustrative examples of suitable salts include, but are not limited to, organic salts derived from amino acids (such as glycine and arginine), ammonia, primary, secondary, and tertiary amines, and cyclic amines (such as piperidine, morpholine, and piperazine), and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.

[0152] The compounds of formula (I) can be in the form of "prodrugs," which include compounds having moieties that can be metabolized in vivo. Generally, prodrugs are metabolized in vivo by esterases or other mechanisms to active drugs. Examples of prodrugs and their uses are well known in the art (see, for example, Berge et al. (1977) "Pharmaceutical Salts," J. Pharm. Sci. 66:1-19). Prodrugs can be prepared during the final isolation and purification of a compound, or in situ by separately reacting its free acid form or a hydroxyl purified compound with a suitable esterifying agent. Hydroxyl groups can be converted to esters via treatment with a carboxylic acid. Examples of prodrug moieties include substituted and unsubstituted, branched or unbranched lower alkyl ester moieties (e.g., propionate ester), lower alkenyl ester, di-lower alkylamino lower alkyl ester (e.g., dimethylaminoethyl ester), acylamino lower alkyl ester (e.g., acetyloxymethyl ester), acyloxy lower alkyl ester (e.g., pivaloyloxymethyl ester), aryl ester (phenyl ester), aryl lower alkyl ester (e.g., benzyl ester), substituted aryl and aryl lower alkyl ester (e.g., with methyl, halo, or methoxy substituents), amide, lower alkyl amide, di-lower alkyl amide, and hydroxyamide. Prodrugs that are converted to active forms by other in vivo mechanisms are also included. In several embodiments, the compounds of the present invention are prodrugs of any of the formulas herein.

[0153] General synthesis method The compounds of the present disclosure can be made by a variety of methods illustrated in the exemplary synthetic reaction schemes shown and described below, where the R groups are as described for formula (I). The starting materials and reagents used in the preparation of these compounds are generally available from commercial suppliers such as Sigma-Aldrich Chemical Co., or may be obtained from other sources, such as Fieser and Fieser's Reagents for Organic Synthesis; Wiley & Sons: New York, vol. 1-21; R.C. LaRock, Comprehensive Organic Transformations, 2nd edition Wiley-VCH, New York 1999; Comprehensive Organic Synthesis, B. Trost and I. Fleming (Eds.) vol. 1-9 Pergamon, Oxford, 1991; Comprehensive Heterocyclic Chemistry, A.R. Katrittzky and C.W. Rees (Eds.) Pergamon, Oxford 1984, vol. 1-9; Comprehensive Heterocyclic Chemistry II, A.R. Katrittzky and C.W. Rees (Eds) Pergamon, Oxford 1996, vol. 1-11; and Organic Reactions, Wiley & Sons: New and subsequent editions thereof. The following synthetic reactions are merely illustrative of some of the ways in which the compounds of the present disclosure may be synthesized, and various modifications to these synthetic reaction schemes may be made and will be suggested to those skilled in the art having reference to the disclosure contained herein.

[0154] For illustrative purposes, the following reaction schemes provide routes for the synthesis of compounds of the present invention and key intermediates. For a more detailed description of the individual reaction steps, see the Examples section below. Those skilled in the art will understand that other synthetic routes may be used. While some specific starting materials and reagents are depicted in the schemes and discussed below, other starting materials and reagents may be substituted to provide a variety of derivatives or reaction conditions. In addition, many of the compounds prepared by the methods described below can be further modified in light of this disclosure using conventional chemistry well known to those skilled in the art.

[0155] The starting materials and the intermediates of the synthetic reaction schemes can be isolated and purified if necessary using conventional techniques, including, but not limited to, filtration, distillation, crystallization, chromatography, etc. Such materials can be characterized using conventional means, including physical constants and spectral data.

[0156] Unless otherwise specified, the reactions described herein are preferably carried out under an inert atmosphere at atmospheric pressure, at reaction temperatures in the range of about −78° C. to about 150° C., more preferably about 0° C. to about 125° C., and most preferably and conveniently about room temperature (or ambient temperature), i.e., about 20° C.

[0157] In the following schemes, some compounds are depicted with generalized substituents. However, one skilled in the art will readily appreciate that the nature of the substituents can be varied to obtain a variety of compounds contemplated by the present invention. Furthermore, the reaction conditions are exemplary, and alternative conditions are well known. The reaction sequences in the following examples are not intended to limit the scope of the invention as set forth in the claims. Scheme 1 TIFF2024521929000075.tif119170

[0158] Scheme 1 shows a general synthetic scheme for preparing compounds of formula (I), where R 1 , R 2 , R3 , R 4 , G 1 , G 2 , R 5 , R 6a , R 6b , R 7a , R 7b , R 8a , R 8b , R 9 and n are as detailed herein via the SnAr reaction of a heteroaromatic compound of formula (I-4) with a 2-N-protected 2,8-diazaspiro[4.5]decane compound of formula (I-3), X is selected from the group consisting of Cl, Br, I, F, OM, and OT, P can be any suitable protecting group known to those skilled in the art, including but not limited to Boc, Fmoc, Cbz, etc., and X' is a leaving group, including but not limited to Cl, Br, I, OT, and OM. In step 1, a compound of formula (I-4) is reacted with a compound of formula (I-3) in the presence of any suitable organic or inorganic base to form a compound of formula (I-2). In step 2, the protecting group P is removed from the compound of formula (I-2) to form a compound of formula (I-1). Suitable deprotection techniques are known in the art and vary depending on the protecting group used. In one embodiment, the protecting group P is Boc and the compound of formula (I-2) is deprotected by contacting the compound of formula (I-2) with a strong or weak acid such as TFA, TsOH, HCl, etc. In step 3, the compound of formula (I-1) is deprotected by contacting the compound of formula (I-2) with a strong or weak acid such as TFA, TsOH, HCl, etc. In step 4, the compound of formula (I-1) is deprotected by contacting the compound of formula (I-2) with a strong or weak acid such as TFA, TsOH, HCl, etc. In step 5, the compound of formula (I-1) is deprotected by contacting the compound of formula (I-2) with a strong or weak acid such as TFA, TsOH, HCl, etc. In step 6, the compound of formula (I-1) is deprotected by contacting the compound of formula (I-2) with a strong or weak acid such as TFA, TsOH, HCl, 5 -X', where X' is a leaving group, or in the presence of a reducing agent, 5 -CHO with an aldehyde compound to form a compound of formula (I). Suitable reducing agents include, but are not limited to, NaBH, NaBHCN, NaBH(OAc), and the like.

[0159] Compounds of formula (I-4) can be prepared from appropriate starting materials and reagents by methods detailed herein (including the illustrative examples) and known in the art. 1 , R 2 , R 3 , R 4 , G1 and G 2 may vary depending on the nature of the Scheme 2 TIFF2024521929000076.tif109170

[0160] Scheme 2 shows a general synthetic scheme for preparing compounds of formula (IA), where R 1 , R 2 , R 3 , R 4 , R 5 , R 6a , R 6b , R 7a , R 7b , R 8a , R 8b , R 9and n are as detailed herein via the SnAr reaction of a pyrido[3,4-d]pyrimidine compound of Formula 4 with a 2-N-protected 2,8-diazaspiro[4.5]decane compound of Formula 5, X is selected from the group consisting of Cl, Br, I, F, OM, and OT, P can be any suitable protecting group known to those skilled in the art, including but not limited to, Boc, Fmoc, Cbz, etc., and X' is a leaving group, including but not limited to, Cl, Br, I, OM, and OT. In step 1, a compound of Formula 1 and a compound of Formula 2 are mixed in the presence of any suitable organic or inorganic base to form a compound of Formula 3. In step 2, the compound of Formula 3 is contacted with an activating agent to form a compound of Formula 4. Suitable activating agents include, but are not limited to, POCl, POBr, MsCl, TsCl, etc. In step 3, the compound of formula 4 is reacted with a compound of formula 5 in the presence of any suitable organic or inorganic base to form a compound of formula 6. In step 4, the protecting group P is removed from the compound of formula 6 to form a compound of formula 7. Suitable deprotection techniques are known in the art and vary depending on the protecting group used. In one embodiment, the protecting group P is Boc, and the compound of formula 6 is deprotected by contacting the compound of formula 6 with a strong or weak acid, such as TFA, TsOH, or HCl. In step 5, the compound of formula 7 is contacted with a compound of formula 8 in the presence of a suitable inorganic or organic base, or with a compound of formula 9 in the presence of a reducing agent to form a compound of formula (I). Suitable reducing agents include, but are not limited to, NaBH, NaBHCN, NaBH(OAc), and the like.

[0161] Alternatively, compounds of formula 3 can be prepared by reacting an imidamide of formula 1a with 3-fluoronicotinic acid of formula 2a in the presence of a base, or by reacting an aldehyde of formula 1b with 3-aminonicotinamide of formula 2b in the presence of an oxidizing agent (e.g., copper oxide). TIFF2024521929000077.tif27170 Scheme 3 TIFF2024521929000078.tif109170

[0162] Scheme 3 shows a general synthetic scheme for preparing compounds of formula (IA), where R 1 , R 2 , R 3 , R 4 , R 5 , R 6a , R 6b , R 7a , R 7b , R 8a , R 8b , R 9 and n are as described herein, and are obtained from the cross-coupling of a heteroaryl boronate of formula 12 with an N-protected (pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane compound of formula 11, which can be prepared by the SnAr reaction of a pyrido[3,4-d]pyrimidine compound of formula 10 with an N-protected 2,8-diazaspiro[4.5]decane compound of formula 5, wherein X is selected from the group consisting of Cl, Br, I, F, OM, and OT; P is any suitable protecting group known to those skilled in the art, including, but not limited to, Boc, Fmoc, Cbz; and X′ is a leaving group, including, but not limited to, Cl, Br, I, OM, and OT. In step 1, a compound of formula 5 is coupled to a compound of formula 10 in the presence of any suitable inorganic or organic base to form a compound of formula 11. In step 2, a compound of formula 11 is contacted with a compound of formula 12 in the presence of a Pd catalyst and any suitable organic or inorganic base to form a compound of formula 6. Any suitable Pd catalyst can be used, including, but not limited to, Pd(PPh3)4. In step 3, the protecting group P is removed from the compound of formula 6 to form a compound of formula 7. Suitable deprotection techniques are known in the art and vary depending on the protecting group used. In one embodiment, the protecting group P is Boc, and the compound of formula 6 is deprotected by contacting the compound of formula 6 with a strong or weak acid, such as TFA, TsOH, or HCl. In step 4, the compound of formula 7 is contacted with a compound of formula 8 in the presence of a suitable inorganic or organic base, or with a compound of formula 9 in the presence of a reducing agent to form a compound of formula (IA). Suitable reducing agents include, but are not limited to, NaBH4, NaBH3CN, NaBH(OAc)3, and the like. In step 2, the appropriate R 1-Zn or R 1 -Sn compounds can be used as an alternative to the boronates of formula 12, along with a preparable Pd catalyst and base.

[0163] In the methods for preparing compounds of formula (I) or (IA) illustrated in the reaction sequences of Schemes 1-3, compounds of formula (I) or (IA) can be prepared using starting materials having substituents that differ from the corresponding substituents in the intermediates and final products. The substituents in the starting materials can be precursors that are converted to the desired substituents in the next intermediate or final product. For example, R is fluoro. 4 The starting material having an R group can be subsequently converted to an alkoxy group. 4 In another example, R is ethyl (-CH2CH3). 4 The final product has a vinyl (-CH=CH) group, R 4 R is made from a starting material having a hydroxymethyl (-CHOH) group or 4 The final product has a vinyl (-CH=CH) group, R 4 R is a formyl (-CH=O) group prepared from a starting material 4 Similarly, an alkynyl R 3 The final product with a group (e.g., -C≡CC(Me)OH) will have R that is chloro. 3 Compounds of formula (I) or (IA) may also be prepared from other compounds of formula (I) or (IA) by modifying one or more of the substituents. For example, R may be 1-hydroxybenzyl or 1-pyridyl-1-hydroxymethyl. 2 Compounds of formula (IA) having a group R 2 It can be prepared from a compound of formula (IA) having a group.

[0164] Thus, in one embodiment, a compound of formula (I): Methods for making TIFF2024521929000079.tif68170 or a salt (e.g., a pharmaceutically acceptable salt), solvate (e.g., hydrate), prodrug, metabolite, or derivative thereof are provided, wherein R 1 , R 2 , R 3 , R 4 , G 1 , G 2 , R 5 , R 6a , R 6b , R 7a , R 7b , R 8a , R 8b , R 9 and n is as defined herein, and the method comprises: a) a compound of formula (I-4): TIFF2024521929000080.tif28170 to prepare a compound of formula (I-3): TIFF2024521929000081.tif33170 in the presence of a base to give a compound of formula (I-2): TIFF2024521929000082.tif52170, wherein X is selected from the group consisting of Cl, Br, I, F, OM, and OT, and P is a protecting group; b) removing the protecting group P from the compound of formula (I-2) to obtain a compound of formula (I-1): To produce TIFF2024521929000083.tif52170, c) converting a compound of formula (I-1) to a compound of formula (I); Includes.

[0165] In one embodiment, the compound of formula (I-1) can be prepared by reacting the compound of formula (I-1) with a compound of formula R 5 -X' in the presence of a base to form a compound of formula (I). In some embodiments, X' is selected from the group consisting of Cl, Br, I, OM, and OT.

[0166] In another embodiment, the compound of formula (I-1) can be converted to a compound of formula R 5 The compound of formula (I-1) is converted to a compound of formula (I) by contacting it with an aldehyde compound of -CHO. In one embodiment, the reducing agent is selected from the group consisting of NaBH, NaBHCN, and NaBH(OAc).

[0167] In one embodiment, the compound of formula (IA): Methods for making TIFF2024521929000084.tif68170 or a salt (e.g., a pharmaceutically acceptable salt), solvate (e.g., hydrate), prodrug, metabolite, or derivative thereof are provided, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6a , R 6b , R 7a , R 7b , R 8a , R 8b , R 9 and n is as defined herein, and the method comprises: a) a compound of formula 4: TIFF2024521929000085.tif25170 to the compound of formula 5: TIFF2024521929000086.tif32170 in the presence of a base to produce a compound of formula 6: TIFF2024521929000087.tif54170 (wherein X is selected from the group consisting of Cl, Br, I, F, OM and OT, and P is a protecting group). and b) removing the protecting group P from a compound of formula 6 to give a compound of formula 7: To produce TIFF2024521929000088.tif54170, c) converting a compound of formula 7 to a compound of formula (IA); Includes.

[0168] In one embodiment, the compound of formula 7 is prepared by converting the compound of formula 7 in the presence of a base to a compound of formula 8: TIFF2024521929000089.tif15170, where X' is a leaving group. In some embodiments, X' is selected from the group consisting of Cl, Br, I, OM, and OT. In some embodiments, the compound of formula 8 is an epoxide, where X' is a leaving group ... 5 It is an oxide that becomes a hydroxyl group that is part of the group.

[0169] In another embodiment, a compound of formula 7 can be converted in the presence of a reducing agent to a compound of formula 9: TIFF2024521929000090.tif11170, the compound of formula 7 is converted to a compound of formula (IA).

[0170] In one embodiment, the reducing agent is selected from the group consisting of NaBH4, NaBH3CN, and NaBH(OAc)3.

[0171] In another embodiment, the method further comprises preparing a compound of formula 4. In particular, the method comprises: d) a compound of formula 1: TIFF2024521929000091.tif16170 Compound of Formula 2: TIFF2024521929000092.tif32170 in the presence of a base to form a compound of formula 3: forming TIFF2024521929000093.tif31170; e) contacting the compound of formula 3 with an activating agent to form a compound of formula 4; It may further include:

[0172] In some embodiments, the method further comprises producing a compound of formula 4: d) a compound of formula 1a: TIFF2024521929000094.tif18170 to a compound of formula 2a: TIFF2024521929000095.tif27170 in the presence of a base to form a compound of formula 3.

[0173] In some embodiments, the method further comprises producing a compound of formula 4: d) a compound of formula 1b: TIFF2024521929000096.tif18170 to compound of formula 2b: TIFF2024521929000097.tif27170 in the presence of an oxidizing agent (e.g., CuO) to form a compound of Formula 3.

[0174] In one embodiment, the activating agent is selected from the group consisting of POCl3, POBr3, MsCl, and TsCl.

[0175] In another embodiment, the compound of formula (IA): Methods for making TIFF2024521929000098.tif68170 or a salt (e.g., a pharmaceutically acceptable salt), solvate (e.g., hydrate), prodrug, metabolite, or derivative thereof are provided, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6a , R 6b , R 7a , R 7b , R 8a , R 8b , R 9 and n is as defined herein, and the method comprises: a) a compound of formula 12: TIFF2024521929000099.tif23170 to the compound of formula 11: TIFF2024521929000100.tif53170 in the presence of a palladium catalyst and a base to produce a compound of formula 6: TIFF2024521929000101.tif49170 (wherein X is selected from the group consisting of Cl, Br, I, F, OM, and OT, and P is a protecting group). and forming b) removing the protecting group P from a compound of formula 6 to give a compound of formula 7: and TIFF2024521929000102.tif54170c) converting a compound of formula 7 to a compound of formula (IA) Includes.

[0176] In one embodiment, the compound of formula 7 is prepared by converting the compound of formula 7 in the presence of a base to a compound of formula 8: TIFF2024521929000103.tif15170, where X' is a leaving group. In some embodiments, X' is selected from the group consisting of Cl, Br, I, OM, and OT.

[0177] In another embodiment, a compound of formula 7 can be converted in the presence of a reducing agent to a compound of formula 9: TIFF2024521929000104.tif11170, the compound of formula 7 is converted to a compound of formula (IA).

[0178] In one embodiment, the reducing agent is selected from the group consisting of NaBH4, NaBH3CN, and NaBH(OAc)3.

[0179] In another embodiment, the method further comprises preparing a compound of formula 11. In particular, the method comprises: d) A compound of formula 5: TIFF2024521929000105.tif36170 to compound of formula 10: TIFF2024521929000106.tif32170 in the presence of a base to form a compound of formula 11, wherein X and P are as defined herein.

[0180] Also provided are products manufactured according to any one or more of the methods or processes described herein.

[0181] Pharmaceutical Compositions and Formulations The compounds disclosed herein can be formulated into pharmaceutical compositions together with pharmaceutically acceptable carriers or excipients.

[0182] The compound of formula (I) or its variants can be formulated as a pharmaceutical composition according to standard pharmaceutical practice. According to this embodiment, there is provided a pharmaceutical composition comprising a compound of formula (I) or its variants, such as formulas (IA), (IB), and (IC), in association with a pharmaceutically acceptable excipient, diluent, or carrier. Preferred compositions depend on the mode of administration, and typically contain one or more conventional pharmaceutically acceptable carriers, adjuvants, and / or vehicles (also referred to as "excipients"). Such compositions can be formulated for various routes of systemic or local delivery, for example, by oral, topical, transmucosal, rectal, or vaginal administration, or by subcutaneous, intrathecal, intravenous, intramuscular, intraperitoneal, intranasal, intraocular, or intracerebroventricular injection.

[0183] Oral solid dosage forms include capsules, tablets, pills, powders, and granules. In such compositions, the compound or salt is usually combined with one or more additives. For oral administration, the compound or salt can be mixed with, for example, lactose, sucrose, starch powder, cellulose esters of alkanoic acid, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric acid and sulfate, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone, and / or polyvinyl alcohol, and then tableted or encapsulated for convenient administration. Such capsules or tablets can contain controlled-release formulations, such as those provided in a dispersion of the compound or salt in hydroxypropylmethylcellulose. In the case of capsules, tablets, and pills, the dosage form can also include a pH modifier such as sodium citrate; magnesium or calcium carbonate or bicarbonate; tartaric acid, fumaric acid, citric acid, succinic acid, malic acid, and phosphoric acid, and combinations thereof. Tablets and pills can additionally be prepared with enteric coatings.

[0184] Liquid dosage forms for oral administration include, for example, pharmaceutically acceptable emulsions (including both oil-in-water emulsions and water-in-oil emulsions), solutions (including both aqueous and non-aqueous solutions), suspensions (including both aqueous and non-aqueous suspensions), syrups, and elixirs containing inert diluents commonly used in the art (e.g., water). Such compositions may also contain, for example, wetting agents, emulsifying agents, suspending agents, perspiring agents, and flavoring agents.

[0185] Parenteral administration includes subcutaneous injection, intravenous injection, intramuscular injection, intrasternal injection, and infusion. Injectable preparations (e.g., sterile injectable aqueous or oily suspensions) can be formulated according to known techniques using appropriate dispersants, wetting agents, and / or suspending agents. Acceptable vehicles and solvents include, for example, water, 1,3-butanediol, Ringer's solution, isotonic sodium chloride solution, bland fixed oils (e.g., synthetic mono- or diglycerides), fatty acids (e.g., oleic acid), dimethylacetamide, surfactants (e.g., ionic detergents and non-ionic detergents), and / or polyethylene glycol.

[0186] The formulation for parenteral administration can be prepared from sterile powder or granules, for example, with one or more of the additives mentioned for use in the formulation for oral administration.The compound or salt of the present invention can be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and / or various pH modifiers.If necessary, pH can be adjusted with suitable acid, base, or pH modifier.

[0187] Suppositories for rectal administration can be prepared, for example, by mixing the compound or salt of the present invention with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore melts in the rectum to release the drug. Suitable excipients include, for example, cocoa butter; synthetic mono-, di-, or triglycerides, fatty acids, and / or polyethylene glycols.

[0188] The compounds of the present disclosure may be formulated for topical administration to the skin or mucosa, i.e., dermally or transdermally, such administration may involve, for example, the use of a transdermal patch or iontophoresis device.

[0189] In addition to the representative dosage forms described above, pharmaceutically acceptable additives and carriers are generally known to those skilled in the art and are therefore included in the present invention. Drug formulations are generally discussed in, for example, Hoover, J., Remington's Pharmaceutical Sciences (Mack Publishing Co., 1975) and Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems (Lippincott Williams & Wilkins, 2005), and subsequent editions.

[0190] Pharmaceutical compositions (or formulations) for application may be packaged in a variety of ways depending on the method used to administer the drug. Generally, an article for distribution includes a container having disposed therein the pharmaceutical formulation in an appropriate form. Suitable containers are well known to those skilled in the art and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, etc. The container may also include a tamper-evident assembly to prevent unintentional access to the contents of the package. In addition, the container has disposed thereon a label that describes the contents of the container. The label may also include appropriate warnings.

[0191] Pharmaceutical compositions comprising a compound of Formula (I) or a variant thereof, such as Formulas (IA), (IB), and (IC), can be formulated, dosed, and administered in a manner, i.e., amount, concentration, schedule, course, vehicle, and route of administration, consistent with good medical practice. Factors to consider in this regard include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of drug delivery, the method of administration, the administration schedule, and other factors known to medical practitioners. The "therapeutically effective amount" of the compound to be administered will be governed by such considerations and is the minimum amount necessary to prevent, alleviate, or treat a coagulation factor-mediated disorder. In some embodiments, the amount is below an amount that is toxic to the host or that renders the host more susceptible to bleeding.

[0192] How to use The compounds of the present disclosure are used to inhibit the activity of LATS1 / 2.

[0193] In one embodiment, the presently disclosed subject matter relates to a method of inhibiting LATS1 / 2 in a cell, comprising contacting the cell with an effective amount of a compound of formula (I), or a variant thereof, such as formulas (IA), (IB), and (IC), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.

[0194] In another embodiment, the presently disclosed subject matter relates to a method of treating a disease or condition, comprising administering to a subject in need thereof an effective amount of a compound of Formula (I), or a variant thereof, such as Formulas (IA), (IB), and (IC), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein. In certain aspects of this embodiment, the disease or condition is mediated by LATS1 / 2. In some aspects, the disease or condition is acute respiratory distress syndrome (ARDS). In other aspects, the disease or condition is idiopathic pulmonary fibrosis (IPF).

[0195] In another aspect, there is provided a method for promoting tissue regeneration after injury or treating a disease or condition that can benefit from LATS1 / 2 inhibition, the method comprising administering to a subject in need thereof an effective amount of a compound of formula (I), or a variant thereof, such as formulas (IA), (IB) and (IC), or a pharmaceutically acceptable salt thereof. In one embodiment, the disease or condition is ARDS. In another aspect, the disease or condition is IPF.

[0196] Also provided herein are compounds of formula (I) or variants thereof, such as formulas (IA), (IB) and (IC), or pharmaceutically acceptable salts thereof, for use in a method of inhibiting LATS1 / 2 in a cell.

[0197] Also provided herein is a compound of formula (I) or its variants, such as formulas (IA), (IB) and (IC), or a pharmaceutically acceptable salt thereof, for use in a method for promoting tissue regeneration after injury or in a method for treating a disease or condition that can benefit from LATS1 / 2 inhibition. In one embodiment, the disease or condition is ARDS. In another aspect, the disease or condition is IPF.

[0198] In another aspect, there is provided the use of a compound of formula (I) or a variant thereof, such as formulas (IA), (IB) and (IC), or a pharmaceutically acceptable salt thereof, in the methods detailed herein (e.g., promoting tissue regeneration after injury or treating ARDS or IPF).

[0199] Also provided is the use of a compound of formula (I) or any variant thereof, such as formulas (IA), (IB) and (IC), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for use in the methods detailed herein (e.g., promoting tissue regeneration after injury or treatment of ARDS or IPF).

[0200] In any of the embodiments described herein, the subject may be a human.

[0201] Further provided are kits for practicing the methods detailed herein, comprising one or more compounds described herein or pharmaceutical compositions comprising the compounds described herein. The kits can employ any of the compounds disclosed herein. In one variation, the kits employ a compound described herein, or a pharmaceutically acceptable salt thereof. The kits can be used for any one or more of the uses described herein and thus can contain instructions for use, for example, in promoting tissue regeneration after injury and / or in treating a disease or condition that can benefit from LATS1 / 2 inhibition. In some embodiments, the kits include instructions for use in treating ARDS. In some embodiments, the kits include instructions for use in treating IPF.

[0202] The kit generally includes suitable packaging. The kit may include one or more containers containing any of the compounds or compositions described herein. Each component (if more than one component is present) may be packaged in a separate container, or, if cross-reactivity and shelf life permit, several components may be combined in one container. One or more components of the kit may be sterile and / or contained in sterile packaging.

[0203] The kits can be in unit dosage form, bulk packages (e.g., multi-dose packages), or sub-unit doses. For example, kits can be provided that contain a sufficient dose (e.g., a therapeutically effective amount) of a compound disclosed herein and / or a second pharmaceutically active compound useful for LATS1 / 2-dependent disorders (e.g., ARDS) to provide effective treatment for an individual over an extended period of time, such as 1 week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 7 months, 8 months, 9 months, or more. The kits can also include multiple unit doses of the compound and instructions for use, and can be packaged in sufficient quantities for storage and use in pharmacies (e.g., hospital pharmacies and compounding pharmacies).

[0204] The kit may optionally include a set of instructions, typically written instructions, although electronic storage media (e.g., magnetic or optical disks) containing instructions are also acceptable, depending on the use of the components in the methods of the invention. Instructions included with the kit generally include information regarding the components and their administration to a subject.

[0205] The following examples are offered by way of illustration and not by way of limitation. Additional Embodiments Embodiment 1. A compound of formula (I): TIFF2024521929000107.tif58170 or a pharmaceutically acceptable salt thereof, R 1 is R 10 is a 5- to 14-membered heteroaryl optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from R 2 is hydrogen, C 1~6 Alkyl or -O(C 1~6 alkyl), where each C 1~6 Alkyl is R 10 and optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R 3 is hydrogen, C 1~6 Alkyl, or -O(C 1~6 alkyl), where each C 1~6 Alkyl is R 10 and optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R 4 is hydrogen, halogen, cyano, -O(C 1~6 alkyl), C 1~6 Alkyl or C 3~6 cycloalkyl, where C 1~6 Alkyl and C 3~6 Each cycloalkyl is R 10 and optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from G 1 is N or CR 41and G 2 is N or CR 42 where G 1 and G 2 is N, R 41 and R 42 are independently hydrogen, halogen, cyano, -O(C 1~6 alkyl), C 1~6 Alkyl or C 3~6 cycloalkyl, where C 1~6 Alkyl and C 3~6 Each cycloalkyl is R 10 and optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from R 5 is hydrogen, C 1~6 Alkyl, C 3~8 Cycloalkyl, C 6~14 Aryl, 5- to 14-membered heteroaryl, 3- to 14-membered heterocyclyl, -C(O)R 14 , -C(O)OR 15 or -C(O)NR 16a R 16b where R 5 C 1~6 Alkyl, C 3~8 Cycloalkyl, C 6~14 Aryl, 5- to 14-membered heteroaryl, and 3- to 14-membered heterocyclyl are each R 10 and optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Each R 6a and R 6b are independently hydrogen, C 1~6 Alkyl, C 3~8 Cycloalkyl, C 6~10 Aryl, 5-14 membered heteroaryl, 3-12 membered heterocyclyl, -C(O)R 14 , -C(O)OR 15 or -C(O)NR 16a R 16b where R 6a and R 6b C 1~6 Alkyl, C 3~8 Cycloalkyl, C 6~10Aryl, 5- to 14-membered heteroaryl, and 3- to 12-membered heterocyclyl are each R 10 and R 6a and R 6b combine with the carbon to which they are attached to form a carbonyl, Each R 7a and R 7b are independently hydrogen or R 10 C optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from 1~6 alkyl, or R 7a and R 7b combine with the carbon to which they are attached to form a carbonyl, Each R 8a and R 8b are independently hydrogen, halogen, hydroxyl, -O(C 1~6 alkyl) or C 1~6 alkyl, where each C 1~6 Alkyl is R 10 and optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from n is 0 to 8, Each R 9 is independently C 1~6 alkyl, or, if present, two geminal R 9 groups, taken together with the carbon to which they are attached, form a carbonyl, Each R 14 are independently hydrogen or C 1~6 is alkyl, Each R 15 is independently C 1~6 is alkyl, Each R 16a and R 16b are independently hydrogen or C 1~6 alkyl, or R 16a and R 16b together with the nitrogen atom to which they are attached, form R 10 and forming a 4- to 12-membered heterocyclyl optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from Each R 10 are independently oxo, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~8 Cycloalkyl, C 6~14 Aryl, 5- to 14-membered heteroaryl, 3- to 14-membered heterocyclyl, halogen, cyano, -C(O)R a , -C(O)OR b , -C(O)NR c R d , -OR b , -OC(O)R a , -OC(O)NR c R d , -SR b , -S(O)R e , -S(O)2R e , -S(O)(=NH)R e , -S(O)NR c R d , -NR c R d , -N(R f )C(O)R a , -N(R f )C(O)OR b , -N(R f )C(O)NR c R d , -N(R f )S(O)2R e , -N(R f )S(O)NR c R d Or-P(O)R g R h where R 10 C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~8 Cycloalkyl, C 6~14 Aryl, 5- to 14-membered heteroaryl, and 3- to 14-membered heterocyclyl are each R 11 and optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R a are independently hydrogen, C 1~6 Alkyl, C 2~6Alkenyl, C 2~6 Alkynyl, C 3~8 Cycloalkyl, C 6~10 aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, where R a C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~8 Cycloalkyl, C 6~10 Aryl, 5- to 10-membered heteroaryl, and 3- to 12-membered heterocyclyl are each R 11 and optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R b are independently hydrogen, C 1~6 Alkyl, C 3~8 Cycloalkyl, C 6~10 aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, where R b C 1~6 Alkyl, C 3~8 Cycloalkyl, C 6~10 Aryl, 5- to 10-membered heteroaryl, and 3- to 12-membered heterocyclyl are each R 11 and optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R c and R d are independently hydrogen, C 1~6 Alkyl, C 3~8 Cycloalkyl, C 6~10 aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, where R c and R d C 1~6 Alkyl, C 3~8 Cycloalkyl, C 6~10 Aryl, 5- to 10-membered heteroaryl, and 3- to 12-membered heterocyclyl are each R 11 and optionally substituted with 1, 2, 3, or 4 substituents independently selected from Or R c and R d together with the nitrogen atom to which they are attached, form R 11and forming a 4- to 12-membered heterocyclyl optionally substituted by 1, 2, 3, or 4 substituents independently selected from Each R e independently, C 1~6 Alkyl, C 3~8 Cycloalkyl, C 6~10 aryl, 5- to 10-membered heteroaryl, or 3- to 12-membered heterocyclyl, where R e C 1~6 Alkyl, C 3~8 Cycloalkyl, C 6~10 Aryl, 5- to 10-membered heteroaryl, and 3- to 12-membered heterocyclyl are each R 11 and optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R f are independently hydrogen or C 1~6 is alkyl, Each R g and R h independently, C 1~6 Alkyl, C 3~8 Cycloalkyl, C 6~10 Aryl, 5- to 10-membered heteroaryl, 3- to 12-membered heterocyclyl, or -OC 1~6 alkyl, where R g and R h C 1~6 Alkyl, C 3~8 Cycloalkyl, C 6~10 Aryl, 5- to 10-membered heteroaryl, and 3- to 12-membered heterocyclyl are each R 11 and optionally substituted with 1, 2, 3, or 4 substituents independently selected from Or, R g and R h together with the phosphorus atom to which they are attached, form R 11 and forming a 4- to 12-membered heterocyclyl optionally substituted by 1, 2, 3, or 4 substituents independently selected from Each R 11 are independently oxo, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C6~10 Aryl, 5-10 membered heteroaryl, 3-8 membered heterocyclyl, halogen, cyano, -C(O)R a1 , -C(O)OR b1 , -C(O)NR c1 R d1 , -OR b1 , -OC(O)R a1 , -OC(O)NR c1 R d1 , -SR b1 , -S(O)R e1 , -S(O)2R e1 , -S(O)NR c1 R d1 , -NR c1 R d1 , -N(R f1 )C(O)R a1 , -N(R f1 )C(O)OR b1 , -N(R f1 )C(O)NR c1 R d1 , -N(R f1 )S(O)2R e1 , -N(R f1 )S(O)NR c1 R d1 Or-P(O)R g1 R h1 where R 11 C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 6~10 Aryl, 5- to 10-membered heteroaryl, and 3- to 8-membered heterocyclyl are each R 12 and optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R a1 are independently hydrogen, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 6~10 aryl, 5- to 10-membered heteroaryl, or 3- to 8-membered heterocyclyl, where R a1 C 1~6 Alkyl, C 2~6Alkenyl, C 2~6 Alkynyl, C 3~6 Cycloalkyl, C 6~10 Aryl, 5- to 10-membered heteroaryl, and 3- to 8-membered heterocyclyl are each R 12 and optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R b1 are independently hydrogen, C 1~6 Alkyl, C 3~6 Cycloalkyl, C 6~10 aryl, 5- to 10-membered heteroaryl, or 3- to 8-membered heterocyclyl, where R b1 C 1~6 Alkyl, C 3~6 Cycloalkyl, C 6~10 Aryl, 5- to 10-membered heteroaryl, and 3- to 8-membered heterocyclyl are each R 12 and optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R c1 and R d1 are independently hydrogen, C 1~6 Alkyl, C 3~6 Cycloalkyl, C 6~10 aryl, 5- to 10-membered heteroaryl, or 3- to 8-membered heterocyclyl, where R c1 and R d1 C 1~6 Alkyl, C 3~6 Cycloalkyl, C 6~10 Aryl, 5- to 10-membered heteroaryl, and 3- to 8-membered heterocyclyl are each R 12 and optionally substituted with 1, 2, 3, or 4 substituents independently selected from Or, R c1 and R d1 together with the nitrogen atom to which they are attached, form R 12 and forming a 4- to 8-membered heterocyclyl optionally substituted by 1, 2, 3, or 4 substituents independently selected from Each R e1 independently, C 1~6 Alkyl, C 3~6 Cycloalkyl, C 6~10aryl, 5- to 10-membered heteroaryl, or 3- to 8-membered heterocyclyl, where R e1 C 1~6 Alkyl, C 3~6 Cycloalkyl, C 6~10 Aryl, 5- to 10-membered heteroaryl, and 3- to 8-membered heterocyclyl are each R 12 and optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R f1 are independently hydrogen or C 1~6 is alkyl, Each R g1 and R h1 independently, C 1~6 Alkyl, C 3~6 Cycloalkyl, C 6~10 Aryl, 5- to 10-membered heteroaryl, 3- to 8-membered heterocyclyl, or -OC 1~6 alkyl, where R g1 and R h1 C 1~6 Alkyl, C 3~6 Cycloalkyl, C 6~10 Aryl, 5- to 10-membered heteroaryl, and 3- to 8-membered heterocyclyl are each R 12 and optionally substituted with 1, 2, 3, or 4 substituents independently selected from Or, R g1 and R h1 together with the phosphorus atom to which they are attached, form R 12 and forming a 4- to 8-membered heterocyclyl optionally substituted by 1, 2, 3, or 4 substituents independently selected from Each R 12 are independently oxo, C 1~6 Alkyl, C 3~6 Cycloalkyl, C6 aryl, 5-6 membered heteroaryl, 3-6 membered heterocyclyl, halogen, cyano, -C(O)R a2 , -C(O)OR b2 , -C(O)NR c2 R d2 , -OR b2 , -OC(O)R a2 , -OC(O)NR c2 R d2, -S(O)2R e2 , -S(O)NR c2 R d2 , -NR c2 R d2 , -N(R f2 )C(O)R a2 , -N(R f2 )C(O)OR b2 , -N(R f2 )C(O)NR c2 R d2 , -N(R f2 )S(O)2R e2 , -N(R f2 )S(O)NR c2 R d2 Or-P(O)R g2 R h2 where R 12 C 1~6 Alkyl, C 3~6 Cycloalkyl, C6 aryl, 5- to 6-membered heteroaryl and 3- to 6-membered heterocyclyl are each R 13 and optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R a2 are independently hydrogen, C 1~6 Alkyl, C 3~6 cycloalkyl, C6 aryl, 5- to 6-membered heteroaryl, or 3- to 6-membered heterocyclyl, where R a2 C 1~6 Alkyl, C 3~6 Cycloalkyl, C6 aryl, 5- to 6-membered heteroaryl and 3- to 6-membered heterocyclyl are each R 13 and optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R b2 are independently hydrogen, C 1~6 Alkyl, C 3~6 cycloalkyl or 3- to 6-membered heterocyclyl, where R b2 C 1~6 Alkyl, C 3~6 Cycloalkyl and 3- to 6-membered heterocyclyl are each R 13 and optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each Rc2 and R d2 are independently hydrogen, C 1~6 Alkyl, C 3~6 cycloalkyl or 3- to 8-membered heterocyclyl, where R c2 and R d2 C 1~6 Alkyl, C 3~6 Cycloalkyl and 3- to 8-membered heterocyclyl are each R 13 and optionally substituted with 1, 2, 3, or 4 substituents independently selected from Or, R c2 and R d2 together with the nitrogen atom to which they are attached, form R 13 and forming a 4- to 6-membered heterocyclyl optionally substituted by 1, 2, 3, or 4 substituents independently selected from Each R e2 independently, C 1~6 Alkyl, C 3~6 cycloalkyl, C6 aryl, 5- to 6-membered heteroaryl, or 3- to 6-membered heterocyclyl, where R e2 C 1~6 Alkyl, C 3~6 Cycloalkyl, C6 aryl, 5- to 6-membered heteroaryl and 3- to 6-membered heterocyclyl are each R 13 and optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R f2 are independently hydrogen or C 1~6 is alkyl, Each R g2 and R h2 independently, C 1~6 Alkyl, C 3~6 Cycloalkyl, 3- to 8-membered heterocyclyl or -OC 1~6 alkyl, where R g2 and R h2 C 1~6 Alkyl, C 3~6 Cycloalkyl and 3- to 8-membered heterocyclyl are each R 13 and optionally substituted with 1, 2, 3, or 4 substituents independently selected from Or, R g2and R h2 together with the phosphorus atom to which they are attached, form R 13 and forming a 4- to 6-membered heterocyclyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from Each R 13 are independently oxo, halogen, hydroxyl, -O(C 1~6 alkyl), cyano, C 1~6 Alkyl or C 1~6 is haloalkyl, However, the compound is other than the compounds in Table 1X and salts thereof. A compound of formula (I) or a pharmaceutically acceptable salt thereof. Embodiment 2.G 1 and G 2 and N. The compound of embodiment 1, wherein both are N, and the compound is of formula (IA): TIFF2024521929000108.tif57170 (in the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 6a , R 6b , R 7a , R 7b , R 8a , R 8b , R 9 and n is as defined in embodiment 1), or a pharmaceutically acceptable salt thereof. Embodiment 3.G 1 is N and G 2 is CR 42 2. The compound of embodiment 1, wherein the compound is a compound of formula (IB): TIFF2024521929000109.tif54170 (in the formula, R 1 , R 2 , R 3 , R 4 , R 42 , R 5 , R 6a , R 6b , R 7a , R 7b , R 8a , R 8b , R 9and n is as defined in embodiment 1), or a pharmaceutically acceptable salt thereof. Embodiment 4.G 1 is CR 41 and G 2 The compound of embodiment 1, wherein is N, wherein the compound is of formula (IC): TIFF2024521929000110.tif55170 (in the formula, R 1 , R 2 , R 3 , R 4 , R 41 , R 5 , R 6a , R 6b , R 7a , R 7b , R 8a , R 8b , R 9 and n is as defined in embodiment 1), or a pharmaceutically acceptable salt thereof. Embodiment 5.R 1 But R 10 The compound of any one of embodiments 1 to 4, wherein the compound is a 6-membered heteroaryl having 1 or 2 ring nitrogen atoms, optionally substituted with 1, 2, 3, or 4 substituents independently selected from: Embodiment 6.R 1 But R 10 The compound of embodiment 5, which is 4-pyridyl optionally substituted with 1 to 5 substituents independently selected from: Embodiment 7.R 1 But R 10 The compound of any one of embodiments 1 to 4, wherein the compound is a 5-membered heteroaryl having 1 or 2 ring nitrogen atoms, optionally substituted with 1, 2, 3, or 4 substituents independently selected from: Embodiment 8.R 1 But R 10 The compound of embodiment 7, wherein the compound is pyrazol-4-yl optionally substituted with 1 to 3 substituents independently selected from: Embodiment 9.R 1 But R 10The compound of any one of embodiments 1 to 4, wherein the compound is a 5,6-fused heteroaryl having 1 or 2 ring nitrogen atoms, optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from: Embodiment 10.R 1 but, TIFF2024521929000111.tif75170, wherein the wavy line in each group indicates the point of attachment to the parent structure. Embodiment 11.R 2 is hydrogen or R 10 C optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from 1~6 The compound of any one of embodiments 1 to 10, wherein is alkyl. Embodiment 12:R 2 are hydrogen, methyl, TIFF2024521929000112.tif18170, wherein the wavy line in each group indicates the point of attachment to the parent structure. Embodiment 13:R 3 is hydrogen, C 1~6 Alkyl or C 1~6 The compound of any one of embodiments 1 to 12, wherein the compound is haloalkyl. Embodiment 14.R 3 is selected from the group consisting of hydrogen, methyl, and 2,2,2-trifluoroethyl. Embodiment 15.R 4 But hydrogen, halogens, C 1~6 Alkyl or C 3~6 The compound of any one of embodiments 1 to 14, which is cycloalkyl. Embodiment 16.R 4 is selected from the group consisting of hydrogen, fluoro, chloro, methyl, and cyclopropyl. Embodiment 17.R 5 But hydrogen, C 1~6 Alkyl, C 3~8 Cycloalkyl, C 6~14Aryl, 5- to 14-membered heteroaryl, 3- to 14-membered heterocyclyl, or —C(O)R 14 and R 5 C 1~6 Alkyl, C 3~8 Cycloalkyl, C 6~14 Aryl, 5- to 14-membered heteroaryl, and 3- to 14-membered heterocyclyl are each R 10 17. The compound of any one of embodiments 1 to 16, optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from: Embodiment 18.R 5 is hydrogen or -C(O)R 14 18. The compound of embodiment 17, wherein Embodiment 19.R 5 The compound of embodiment 18, wherein is hydrogen or acetyl. Embodiment 20.R 5 But R 10 C optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from 1~6 The compound of embodiment 17, wherein the aryl is alkyl. Embodiment 21.R 5 methyl, ethyl, 1-propyl, 2-propyl, 2-methyl-1-propyl and 2-methyl-2-propyl, TIFF2024521929000113.tif84170, wherein the wavy line in each group indicates the point of attachment to the parent structure. Embodiment 22.R 5 But R 10 C optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from 4~8 The compound of embodiment 17, wherein the compound is cycloalkyl. Embodiment 23.R 5 but TIFF2024521929000114.tif90170, wherein the wavy line in each group indicates the point of attachment to the parent structure. Embodiment 24.R 5 But R 103- to 14-membered heterocyclyl optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from 10 C optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from 6~14 Aryl, or R 10 The compound of embodiment 17, wherein the heteroaryl is a 5-14 membered heteroaryl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from: Embodiment 25.R 5 but, TIFF2024521929000115.tif42170, each of which is selected from the group consisting of R 10 wherein the wavy line at each group indicates the point of attachment to the parent structure. Embodiment 26. Each R 6a and R 6b are independently hydrogen or C 1~6 alkyl, or R 6a and R 6b The compound of any one of embodiments 1 to 25, wherein: together with the carbon to which they are attached form a carbonyl. Embodiment 27.R 6a and R 6b is hydrogen and R 6a and R 6b The other is hydrogen, -C(O)OR 15 , -C(O)NR 16a R 16b , or R 10 C optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from 1~6 The compound of any one of embodiments 1 to 25, wherein is alkyl. Embodiment 28.R 6a and R 6b is hydrogen and R 6a and R 6b The other is -C(O)OR 15 or -C(O)NR 16a R 16b where each R 16a and R16b are independently hydrogen or C 1~6 The compound of embodiment 27, wherein the aryl is alkyl. Embodiment 29.R 6a and R 6b is hydrogen and R 6a and R 6b The other is -C(O)NR 16a R 16b where R 16a and R 16b together with the nitrogen atom to which they are attached, form R 10 The compound of embodiment 27, wherein the compound forms a 4- to 12-membered heterocyclyl optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from: Embodiment 30.R 6a and R 6b is hydrogen and R 6a and R 6b The other is hydrogen, methyl, TIFF2024521929000116.tif36170, wherein the wavy line in each group indicates the point of attachment to the parent structure. Embodiment 31. Each R 7a and R 7b are independently hydrogen or C 1~6 alkyl, or R 7a and R 7b The compound of any one of embodiments 1 to 30, wherein: together with the carbon to which they are attached form a carbonyl. Embodiment 32.R 8a and R 8b is hydrogen and R 8a and R 8b The other is hydrogen, halogen, hydroxyl, C 1~6 Alkyl or -O(C 1~6 32. The compound of any one of embodiments 1 to 31, wherein R is 1 or 2; Embodiment 33. Each R 8a and R 8b The compound of embodiment 32, wherein is hydrogen. Embodiment 34. A compound according to any one of embodiments 1 to 33, wherein n is 0. Embodiment 35. A compound of formula (II): TIFF2024521929000117.tif58170 (in the formula, R 1 , R 2 , R 3 , R 4 , G 1 , G 2 , R 5 , R 6a , R 6b , R 7a , R 7b , R 8a and R 8b or a pharmaceutically acceptable salt thereof. Embodiment 36.G 1 and G 2 and N are both N. The compound of formula (II-A): TIFF2024521929000118.tif58170 (in the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 6a , R 6b , R 7a , R 7b , R 8a , and R 8b is as defined in embodiment 35), or a pharmaceutically acceptable salt thereof. Embodiment 37.G 1 is N and G 2 is CR 42 36. The compound of embodiment 35, wherein the compound is a compound of formula (II-B): TIFF2024521929000119.tif58170 (in the formula, R 1 , R 2 , R 3 , R 4 , R 42 , R 5 , R 6a , R 6b , R 7a , R 7b , R 8a , and R8b is as defined in embodiment 35), or a pharmaceutically acceptable salt thereof. Embodiment 38.R 42 The compound of embodiment 37, wherein is hydrogen. Embodiment 39.G 1 is CR 41 and G 2 is N, and the compound is of formula (II-C): TIFF2024521929000120.tif58170 (in the formula, R 1 , R 2 , R 3 , R 4 , R 41 , R 5 , R 6a , R 6b , R 7a , R 7b , R 8a , and R 8b is as defined in embodiment 35), or a pharmaceutically acceptable salt thereof. Embodiment 40.R 41 The compound of embodiment 39, wherein is hydrogen. Embodiment 41.R 1 is pyrazolyl, pyridinyl, or pyrrolo-pyridinyl, each of which is R 10 and optionally substituted with 1 to 3 substituents independently selected from R 2 is hydrogen or R 10 C optionally substituted with 1 to 5 substituents independently selected from 1~6 is alkyl, R 3 is hydrogen or C 1~6 is alkyl, R 4 is hydrogen, halogen, or C 1~6 is alkyl, R 5 is hydrogen, C 1~6 Alkyl, C 3~8 Cycloalkyl, C 6~14 Aryl, 5- to 14-membered heteroaryl, 3- to 14-membered heterocyclyl, or —C(O)R14 where R 5 C 1~6 Alkyl, C 3~8 Cycloalkyl, C 6~14 Aryl, 5- to 14-membered heteroaryl, and 3- to 14-membered heterocyclyl are each R 10 and optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from Each R 6a and R 6b are independently hydrogen or -C(O)OR 15 , -C(O)NR 16a R 16b or R 10 C optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from 1~6 alkyl or R 6a and R 6b combine with the carbon to which they are attached to form a carbonyl, Each R 7a and R 7b are independently hydrogen or C 1~6 alkyl or R 7a and R 7b combine with the carbon to which they are attached to form a carbonyl, R 8a and R 8b is hydrogen and R 8a and R 8b The other is hydrogen, halogen, hydroxyl, C 1~6 Alkyl or -O(C 1~6 alkyl), R 14 is C 1~6 is alkyl, R 15 is C 1~6 is alkyl, and Each R 16a and R 16b are independently hydrogen or C 1~6 alkyl or R 16a and R 16btogether with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclyl having 1 to 2 ring heteroatoms selected from nitrogen, oxygen, and sulfur; R 10 and optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from The compound of any one of embodiments 35 to 40. Embodiment 42.R 1 is pyrazol-4-yl, 4-pyridyl, or pyrrolo[2,3-b]pyridin-4-yl, each of which is selected from the group consisting of halogen, cyano, unsubstituted C 1~6 Alkyl and C 1~6 and optionally substituted with 1 to 3 substituents independently selected from the group consisting of haloalkyl; Each R 2 and R 3 are independently hydrogen or C 1~6 is alkyl, R 4 is hydrogen, halogen, or C 1~6 is alkyl, R 5 are (i) halogen, cyano, hydroxyl, -O(C 1~6 alkyl), -NHC(O)(C 1~6 alkyl), -NHS(O)2(C 1~6 C(O) optionally substituted by 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of alkyl, -S(O)NH, -C(O)NH, phenyl, and 3- to 12-membered heterocyclyl 1~6 Alkyl, (ii) C substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogen, cyano, and hydroxyl. 3~6 cycloalkyl, (iii) a monocyclic 3- to 6-membered heterocyclyl having one ring heteroatom which is oxygen; (iv) phenyl, or (v) pyrazolyl and R 6a and R 6b is hydrogen and R 6a and R 6b The other is hydrogen, C1~6 Alkyl, -C(O)O(C 1~6 alkyl) or -C(O)NR 16a R 16b or R 6a and R 6b combine with the carbon to which they are attached to form a carbonyl, R 7a and R 7b is hydrogen and R 7a and R 7b The other is hydrogen or C 1~6 alkyl or R 7a and R 7b combine with the carbon to which they are attached to form a carbonyl, R 8a and R 8b is hydrogen, and Each R 16a and R 16b are independently hydrogen or C 1~6 alkyl or R 16a and R 16b together with the nitrogen atom to which they are attached form pyrrolidin-1-yl or morpholin-4-yl, The compound of any one of embodiments 35 to 40. Embodiment 43. Formula (III): TIFF2024521929000121.tif59170 (in the formula, R 2 , R 3 , R 4 , R 5 , R 6a , R 6b , R 7a , R 7b , R 8a and R 8b is as defined in any one of embodiments 1 to 30, where applicable; p is 0, 1, 2, 3 or 4, and Each R Z are independently hydrogen, halogen, cyano or R 10 C optionally substituted with 1, 2, 3, 4 or 5 substituents independently selected from 1~6or a pharmaceutically acceptable salt thereof. Embodiment 44. A compound according to embodiment 43, wherein p is 0, having formula (V): TIFF2024521929000122.tif59170 or a pharmaceutically acceptable salt thereof. Embodiment 45. Formula (IV): TIFF2024521929000123.tif58170 (in the formula, R 2 , R 3 , R 4 , R 5 , R 6a , R 6b , R 7a , R 7b , R 8a and R 8b is as defined in any one of embodiments 1 to 30, where applicable; q is 0, 1, 2 or 3, and Each R Y are independently hydrogen, halogen, cyano, -O(C 1~6 alkyl) or C 1~6 alkyl, and R Y C 1~6 Alkyl is R 10 or a pharmaceutically acceptable salt thereof. Embodiment 46.q is 1 and R Y The compound of embodiment 45, wherein is methyl, fluoro, chloro, cyano, or trifluoromethyl. Embodiment 47. Formula (VII) or (VIII): TIFF2024521929000124.tif59170(VII) (VIII) (In the formula, R 2 , R 3 , R 4 , R 5 , R 6a , R 6b , R 7a , R7b , R 8a and R 8b is as defined in any one of embodiments 1 to 34, as applicable), a compound of any one of embodiments 1 to 34, or a pharmaceutically acceptable salt thereof. Embodiment 48. Formula (IX): TIFF2024521929000125.tif59170 (in the formula, R 2 , R 3 , R 4 , R 5 , R 6a , R 6b , R 7a , R 7b , R 8a and R 8b and R is as defined in any one of embodiments 1 to 34, as applicable), or a pharmaceutically acceptable salt thereof. Embodiment 49. Each R 2 , R 3 and R 4 The compound of any one of embodiments 1 to 48, wherein is hydrogen. Embodiment 50. The compound of embodiment 1, wherein the compound is selected from the group consisting of compound numbers 101 to 201 in Table 1 or a pharmaceutically acceptable salt thereof. Embodiment 51. A pharmaceutical composition comprising a compound according to any one of embodiments 1 to 50 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. Embodiment 52. A compound of formula (I): TIFF2024521929000126.tif52170 (in the formula, R 1 , R 2 , R 3 , R 4 , G 1 , G 2 , R 5 , R 6a , R 6b , R 7a , R 7b , R 8a , R 8b , R 9and n is as defined in embodiment 1), or a pharmaceutically acceptable salt thereof, comprising: a) a compound of formula (I-4): TIFF2024521929000127.tif28170, wherein X is selected from the group consisting of Cl, Br, I, F, OM, and OT, to form a compound of formula (I-3): TIFF2024521929000128.tif33170, wherein P is a protecting group, in the presence of a base to give a compound of formula (I-2): To produce TIFF2024521929000129.tif52170, b) removing the protecting group P from the compound of formula (I-2) to obtain a compound of formula (I-1): TIFF2024521929000130.tif48170(I-1) and c) converting a compound of formula (I-1) to a compound of formula (I); A method comprising: Embodiment 53. (i) In the presence of a base, a compound of formula (I-1) is reacted with a compound of formula R 5 -X', where X' is a leaving group, or (ii) by contacting a compound of formula (I-1) with a compound of formula R 5 53. The method of embodiment 52, wherein the compound of formula (I-1) is converted to the compound of formula (I) by contacting with an aldehyde of -CHO. Embodiment 54.G 1 and G 2 53. The method of embodiment 52, wherein both of d) a compound of formula 1: TIFF2024521929000131.tif16170 Compound of Formula 2: TIFF2024521929000132.tif32170 in the presence of a base to form a compound of formula 3: forming TIFF2024521929000133.tif31170; e) contacting the compound of formula 3 with an activating agent to form G 1 and G 2and forming a compound of formula (I-4) wherein both are N. The method further comprises: Embodiment 55. A compound of formula (IA): TIFF2024521929000134.tif49170 (in the formula, R 1 , R 2 , R 3 , R 4 , R 5 , R 6a , R 6b , R 7a , R 7b , R 8a , R 8b , R 9 and n is as defined in embodiment 1), or a pharmaceutically acceptable salt thereof, comprising: a) a compound of formula 12: TIFF2024521929000135.tif23170 to the compound of formula 11: TIFF2024521929000136.tif53170 in the presence of a palladium catalyst and a base to produce a compound of formula 6: TIFF2024521929000137.tif49170, wherein X is selected from the group consisting of Cl, Br, I, F, OM, and OT, and P is a protecting group; b) removing the protecting group P from a compound of formula 6 to give a compound of formula 7: To produce TIFF2024521929000138.tif54170, c) converting a compound of formula 7 to a compound of formula (IA); A method comprising: Embodiment 56.d) In the presence of a base, a compound of formula 5: TIFF2024521929000139.tif36170 to compound of formula 10: TIFF2024521929000140.tif31170, where X is selected from the group consisting of Cl, Br, I, F, OM, and OT, to form a compound of formula 11. Embodiment 57. (i) In the presence of a base, a compound of Formula 7 is reacted with a compound of Formula 8: TIFF2024521929000141.tif15170, wherein X′ is a leaving group; or (ii) reacting a compound of formula 7 with a compound of formula 9: By contacting with TIFF2024521929000142.tif9170, The method of embodiment 55 or 56, wherein the compound of formula 7 is converted to a compound of formula (IA). Embodiment 58. A method for inhibiting LATS1 / 2 in a cell, comprising contacting the cell with a compound of any one of embodiments 1 to 50 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of embodiment 51. Embodiment 59. A method for treating a disease or condition, comprising administering to a subject in need thereof an effective amount of a compound described in any one of embodiments 1 to 50 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described in embodiment 51. Embodiment 60. The method of embodiment 54, wherein the disease or condition is acute respiratory distress syndrome (ARDS). [Example]

[0206] Abbreviation AcOH acetic acid

[0207] Boc tert-butyloxycarbonyl

[0208] Cbz Carboxybenzyl

[0209] DBU 1,8-diazabicyclo[5.4.0]undec-7-ene

[0210] DCM dichloromethane

[0211] DIEA or DIPEA N,N-Diisopropylethylamine

[0212] DMA Dimethylacetamide

[0213] DMF Dimethylformamide

[0214] DMSO dimethyl sulfoxide

[0215] DTT Dithiothreitol

[0216] EtOAc ethyl acetate

[0217] EtOH ethanol

[0218] Fmoc Fluorenylmethyloxycarbonyl

[0219] HATU 1-[bis(dimethylamino)methylene]1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate

[0220] HEPES 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid

[0221] LiHMDS Lithium bis(trimethylsilyl)amide

[0222] MeCN acetonitrile

[0223] MeOH Methanol

[0224] Ms. Mesir

[0225] NaBH(OAc)3 Sodium triacetoxyborohydride

[0226] NBS N-Bromosuccinimide

[0227] NMO N-methylmorpholine-N-oxide

[0228] Pd(PPh3)4 tetrakis(triphenylphosphine)palladium(0)

[0229] SEM(2-(trimethylsilyl)ethoxy)methyl

[0230] SFC Supercritical Fluid Chromatography

[0231] TBS tert-butyldimethylsilyl

[0232] TBSCl tert-butyldimethylsilyl chloride

[0233] TFA trifluoroacetic acid

[0234] THF tetrahydrofuran

[0235] Ts Tosil

[0236] Synthesis Example Example 101 2-(Pyridin-4-yl)-4-(2,8-diazaspiro[4.5]decan-8-yl)pyrido[3,4-d]pyrimidine (Compound 101) TIFF2024521929000143.tif68170Step 1: 2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-ol TIFF2024521929000144.tif27170 To a solution of potassium 2-methyl-2-butoxide (12.45 g, 98.59 mmol) in THF (80 mL) was added dropwise (approximately 4 mL / min) a solution of ethyl methyl 3-aminoisonicotinate (6.0 g, 39.43 mmol) and 4-cyanopyridine (4.93 g, 47.32 mmol) in THF (80 mL) at 0 °C. The reaction was allowed to warm to room temperature and stirred for 16 h. Water (50 mL) and acetic acid (15 mL) were added. The mixture was stirred at room temperature for 20 min, and the resulting yellow precipitate was filtered. The solid was washed with water (30 mL × 2) to afford the title compound (5 g, 49%) as a yellow solid. 1H NMR(400 MHz,DMSO-d6)δ 13.08(s,1H),9.15(s,1H),8.81(d,J=6.0 Hz,2H),8.70(d,J=5.2 Hz,1H),8.11(d,J=6.0 Hz,2H),8.00(d,J=5.2 Hz,1H).LCMS(ESI)m / z:225.2 [M+H] + .

[0237] Step 2: 4-chloro-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidine TIFF2024521929000145.tif27170 A solution of 2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-ol (2.5 g, 11.15 mmol) in phosphorus oxychloride (17 mL, 182.38 mmol) was heated to 110° C. for 16 h. After cooling to room temperature, the mixture was concentrated in vacuo. The crude residue was dissolved in DCM (200 mL) and basified with saturated aqueous NaHCO (100 mL) to pH 8 at 0° C. The organic layer was dried over anhydrous NaSO, filtered, and concentrated in vacuo to give the title compound (2.4 g, crude) as a brown solid. 1 H NMR(400 MHz,DMSO-d6)δ 9.64(s,1H),8.95(d,J=5.6 Hz,1H),8.88-8.85(m,2H),8.39-8.34(m,2H),8.18(m,J=5.2 Hz,1H).LCMS(ESI)m / z:242.9 [M+H] + .

[0238] Step 3: 2-(pyridin-4-yl)-4-(2,8-diazaspiro[4.5]decan-8-yl)pyrido[3,4-d]pyrimidine To a 2-dram vial was added 4-chloro-2-(4-pyridyl)pyrido[3,4-d]pyrimidine (300 mg, 1.236 mmol, 1 equiv.), potassium fluoride (215 mg, 3.71 mmol, 3 equiv.), followed by 1-methyl-2-pyrrolidinone (4.10 mL, 0.3 M), triethylamine (0.862 mL, 6.18 mmol, 5 equiv.), and tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate (310 mg, 1.24 mmol, 1 equiv.). The reaction was stirred at room temperature for 2 hours. The reaction was then quenched by the addition of water (3 mL) and diluted with EtOAc (5 mL). The layers were separated; the organics were washed with water (3 × 3 mL) followed by brine (2 × 3 mL). The organic layer was dried over NaSO, filtered, and concentrated in vacuo. The crude residue was further concentrated on a Genevac for 16 hours to remove residual DMSO. 1 mL of DCM was then added to the crude residue, followed by 0.5 mL of TFA. The mixture was stirred at room temperature for 4 hours, after which it was concentrated in vacuo and then further concentrated 2x from DCM (5 mL) to remove as much residual TFA as possible. The crude residue was then purified by HPLC to give 4-(2,8-diazaspiro[4.5]decan-8-yl)-2-(4-pyridyl)pyrido[3,4-d]pyrimidine (348 mg, 1.00 mmol, 81% yield). 1 H NMR (400 MHz, DMSO) δ 9.26 (s, 1H), 8.79-8.74 (m, 2H), 8.59 (d, J = 5.6 Hz, 1H), 8.35-8.29 (m, 2H), 7.90 (d, J = 5.7 Hz, 1H), 4.02-3.88 (m, 4H), 2.85 (t, J = 7.0 Hz, 2H), 2.67 (s, 2H), 1.72 (t, J = 5.7 Hz, 4H), 1.61 (t, J = 7.1 Hz, 2H). No exchangeable amine NH protons were observed. LCMS (ESI) m / z: 347.2 [M+H] + .

[0239] Example 102 4-(2-methyl-2,8-diazaspiro[4.5]decan-8-yl)-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidine (Compound 102) To a solution of 4-(2,8-diazaspiro[4.5]decan-8-yl)-2-(4-pyridyl)pyrido[3,4-d]pyrimidine hydrochloride (100 mg, 0.26 mmol) in 1,2-dichloroethane (3 mL) was added formaldehyde (106 mg, 1.31 mmol, 37% in water) and acetic acid (0.03 mL, 0.52 mmol). The mixture was stirred at room temperature for 10 minutes, and then sodium triacetoxyborohydride (277 mg, 1.31 mmol) was added. The mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo. The crude residue was dissolved in EtOAc (20 mL) and washed with saturated aqueous NaHCO3 (10 mL) and brine (10 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by reverse-phase chromatography (35-65% acetonitrile / 0.05% NH3·H2O+10 mM aqueous NH4HCO3) to afford the title compound (10 mg, 10%) as a white solid. 1 H NMR(400 MHz,DMSO-d6)δ 9.25(s,1H),8.79-8.74(m,2H),8.58(d,J=5.6 Hz,1H),8.35-8.29(m,2H),7.88(d,J=6.0 Hz,1H),4.03-3.93(m,2H),3.93-3.82(m,2H),2.53-2.48(m,2H),2.39(s,2H),2.23(s,3H),1.78-1.66(m,6H).LCMS(ESI)m / z:361.2 [M+H] + .

[0240] Examples 103 and 104 (R)-2-(8-(2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decan-2-yl)propan-1-ol and (S)-2-(8-(2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decan-2-yl)propan-1-ol (Compounds 103 and 104) TIFF2024521929000148.tif52170 Step 1: 2-(8-(2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decan-2-yl)propan-1-ol To a solution of 4-(2,8-diazaspiro[4.5]decan-8-yl)-2-(4-pyridyl)pyrido[3,4-d]pyrimidine hydrochloride (110 mg, 0.29 mmol) in MeOH (4 mL) was added N,N-diisopropylethylamine (0.11 mL, 0.58 mmol). The reaction mixture was stirred at room temperature for 5 minutes, and acetic acid (0.03 mL, 0.52 mmol) and hydroxyacetone (0.06 mL, 0.81 mmol) were added to the mixture. After stirring the mixture at room temperature for 20 minutes, sodium cyanoborohydride (60 mg, 0.95 mmol) was added. The mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo. The crude residue was purified by reverse phase chromatography (10-40% acetonitrile / 0.225% formic acid in water) to afford the title compound (50 mg, 43%) as a yellow solid. LCMS (ESI) m / z: 405.3 [M+H] + .

[0241] Step 2: (R)-2-(8-(2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decan-2-yl)propan-1-ol and (S)-2-(8-(2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decan-2-yl)propan-1-ol TIFF2024521929000150.tif52170 2-(8-(2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decan-2-yl)propan-1-ol (50 mg, 0.12 mmol) was separated by using chiral SFC (Chiralpak AD (250 mm * 30 mm, 10 um), supercritical CO2 / EtOH+0.1%NH4OH=45 / 55; 60 mL / min) to give the title compounds both as white solids. The absolute configuration was arbitrarily assigned to each enantiomer. Example 103 (3.9 mg, second peak): 1 H NMR(400 MHz,CD3OD)δ 9.24(s,1H),8.70(d,J=5.6 Hz,2H),8.54(d,J=5.6 Hz,1H),8.45(d,J=6.0 Hz,2H),7.92(d,J=5.2 Hz,1H),4.15-4.06(m,2H),4.02-3.92(m,2H),3.71-3.59(m,2H),3.12-3.02(m,2H),2.99-2.88(m,2 H),2.80-2.70(m,1H),1.97-1.93(m,2H),1.92-1.86(m,4H),1.28-1.23(m,3H).LCMS(ESI)m / z:405.1 [M+H] + Example 104 (3.9 mg, first peak): 1 H NMR(400 MHz,CD3OD)δ 9.23(s,1H),8.70(d,J=6.4 Hz,2H),8.54(d,J=5.6 Hz,1H),8.44(d,J=6.0 Hz,2H),7.91(d,J=5.6 Hz,1H),4.15-4.05(m,2H),4.01-3.90(m,2H),3.71-3.59(m,2H),3.12-3.02(m,2H),2.98-2.88(m,2 H),2.80-2.70(m,1H),1.97-1.92(m,2H),1.91-1.87(m,4H),1.28-1.22(m,3H).LCMS(ESI)m / z:405.1 [M+H] + .

[0242] Example 105 2-(Pyridin-4-yl)-4-(2-(2,2,2-trifluoroethyl)-2,8-diazaspiro[4.5]decan-8-yl)pyrido[3,4-d]pyrimidine (Compound 105) To a solution of 4-(2,8-diazaspiro[4.5]decan-8-yl)-2-(4-pyridyl)pyrido[3,4-d]pyrimidine hydrochloride (30 mg, 0.09 mmol) in DMF (1 mL) was added N,N-diisopropylethylamine (0.05 mL, 0.26 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (24 mg, 0.1 mmol). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo, and the resulting residue was purified by reverse-phase chromatography (7-37% acetonitrile / 0.225% formic acid in water) to afford the title compound (11 mg, 28%) as a yellow solid. 1 H NMR(400 MHz,DMSO-d6)δ 9.25(s,1H),8.76(d,J=6.0 Hz,2H),8.58(d,J=6.0 Hz,1H),8.33-8.31(m,2H),7.89(d,J=6.0 Hz,1H),4.03-3.96(m,2H),3.92-3.84(m,2H),3.33-3.28(m,2H),2.80(t,J=6.8 Hz,2H),2.67(s,2H),1.82-1.71(m,6H).LCMS(ESI)m / z:429.1 [M+H] + .

[0243] Example 106 4-(2-Cyclopentyl-2,8-diazaspiro[4.5]decan-8-yl)-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidine formate (Compound 106) To a solution of 4-(2,8-diazaspiro[4.5]decan-8-yl)-2-(4-pyridyl)pyrido[3,4-d]pyrimidine hydrochloride (54 mg, 0.14 mmol) in acetonitrile (2 mL) was added triethylamine (0.06 mL, 0.43 mmol) and cyclopentyl bromide (0.03 mL, 0.29 mmol). The mixture was heated to 50° C. under a nitrogen atmosphere for 6 hours. After cooling to room temperature, the mixture was diluted with EtOAc (30 mL) and washed with water (20 mL) and brine (20 mL). The organic layer was dried over anhydrous NaSO, filtered, and concentrated in vacuo. The crude residue was purified by reverse-phase chromatography (1-30% acetonitrile / 0.225% formic acid in water) to afford the title compound (8.3 mg, 12%) as a white solid. 1 H NMR(400 MHz,DMSO-d6)δ 9.27(s,1H),8.78(d,J=6.0 Hz,2H),8.60(d,J=5.6 Hz,1H),8.33(d,J=6.0 Hz,2H),8.23(s,1H),7.89(d,J=6.0 Hz,1H),4.03-3.99(m,2H),3.91-3.85(m,2H),2.73(t,J=6.8 Hz,2H),2.63-2.60(m,3H),1.82-1.72(m,8H),1.67-1.61(m,2H),1.53-1.43(m,4H).LCMS(ESI)m / z:415.2 [M+H] + .

[0244] Example 107 2-Methyl-2-(8-(2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decan-2-yl)propan-1-ol (Compound 107) formate TIFF2024521929000153.tif52170 Step 1: Methyl 2-methyl-2-(8-(2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decan-2-yl)propanoate To a solution of 4-(2,8-diazaspiro[4.5]decan-8-yl)-2-(4-pyridyl)pyrido[3,4-d]pyrimidine hydrochloride (150 mg, 0.39 mmol) in MeOH (3.9 mL) was added N,N-diisopropylethylamine (0.34 mL, 1.96 mmol) and methyl 2-bromo-2-methylpropanoate (0.2 mL, 1.57 mmol). The mixture was heated to 60 °C under a nitrogen atmosphere for 16 h. After cooling to room temperature, the mixture was concentrated in vacuo. The crude residue was purified by reverse-phase chromatography (8-38% acetonitrile / 0.225% formic acid in water) to afford the title compound (104 mg, 60%) as a brown solid. 1 H NMR(400 MHz,DMSO-d6)δ 9.26(s,1H),8.81-8.73(m,2H),8.59(d,J=5.6 Hz,1H),8.37-8.27(m,2H),7.89(d,J=5.6 Hz,1H),3.97-3.92(m,4H),3.63(s,3H),2.82(t,J=6.8 Hz,2H),2.71-2.66(m,2H),1.79-1.65(m,6H),1.29(s,6H).LCMS(ESI)m / z:447.1 [M+H] + .

[0245] Step 2: 2-methyl-2-(8-(2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decan-2-yl)propan-1-ol formate To a solution of methyl 2-methyl-2-(8-(2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decan-2-yl)propanoate (80 mg, 0.18 mmol) in THF (3 mL) was added lithium aluminum hydride (20 mg, 0.54 mmol) slowly at 0 °C. The reaction mixture was stirred at 0 °C for 1 h. The reaction was quenched with water (0.02 mL) and 15% aqueous NaOH, diluted with EtOAc (20 mL), dried over anhydrous MgSO, filtered, and concentrated in vacuo. The crude residue was purified by reverse-phase chromatography (5–35% acetonitrile / 0.225% aqueous formic acid) to afford the title compound (22 mg, 29%) as a yellow solid. 1 H NMR(400 MHz,DMSO-d6)δ 9.25(s,1H),8.76(d,J=5.2 Hz,2H),8.58(d,J=5.6 Hz,1H),8.33-8.29(m,3H),7.87(d,J=5.6 Hz,1H),4.07-3.83(m,4H),3.36(s,2H),3.01(t,J=6.4 Hz,2H),2.87(s,2H),1.85-1.65(m,6H),1.08(s,6H).LCMS(ESI)m / z:419.1 [M+H] + .

[0246] Example 108 3-(8-(2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decan-2-yl)cyclobutanol (compound 108) formate To a solution of 4-(2,8-diazaspiro[4.5]decan-8-yl)-2-(4-pyridyl)pyrido[3,4-d]pyrimidine hydrochloride (100 mg, 0.26 mmol) in 1,2-dichloroethane (1 mL) and MeOH (1 mL) was added N,N-diisopropylethylamine (0.14 mL, 0.78 mmol). The reaction mixture was stirred at room temperature for 5 minutes, and then acetic acid (0.07 mL, 1.31 mmol), 3-hydroxycyclobutanone (67 mg, 0.78 mmol), and sodium triacetoxyborohydride (166 mg, 0.78 mmol) were added. The reaction mixture was heated to 60 °C for 16 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated in vacuo. The crude residue was purified by reverse phase chromatography (1-31% acetonitrile / 0.225% formic acid in water) to afford the title compound (15 mg, 14%) as a yellow solid and a mixture of diastereomers. 1 H NMR(400 MHz,DMSO-d6)δ 9.26(s,1H),8.80-8.73(m,2H),8.59(d,J=5.6 Hz,1H),8.35-8.30(m,2H),8.18(s,1H),7.89(d,J=5.6 Hz,1H),4.96(s,1H),4.28-4.17(m,1H),4.05-3.96(m,2H),3.94-3.86(m,2H),3.83-3.73(m,1H),2.92- 2.84(m,1H),2.55-2.51(m,1H),2.41(s,2H),2.32-2.11(m,2H),1.93-1.65(m,8H).LCMS(ESI)m / z:417.3 [M+H] + .

[0247] Example 109 2-(8-(2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decan-2-yl)ethanesulfonamide (Compound 109) To a solution of 4-(2,8-diazaspiro[4.5]decan-8-yl)-2-(4-pyridyl)pyrido[3,4-d]pyrimidine hydrochloride (50 mg, 0.13 mmol) in MeOH (1 mL) was added N,N-diisopropylethylamine (0.11 mL, 0.65 mmol). The reaction mixture was stirred at room temperature for 5 minutes, and ethenesulfonamide (21 mg, 0.20 mmol) was added. The reaction mixture was heated to 60 °C for 16 hours. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated in vacuo. The crude residue was purified by reverse-phase chromatography (25-55% acetonitrile / 0.05% NH₃·H₂O + 10 mM aqueous NH₄HCO₃) to afford the title compound (10 mg, 17%) as a yellow solid. 1 H NMR(400 MHz,DMSO-d6)δ 9.26(s,1H),8.80-8.74(m,2H),8.59(d,J=6.0 Hz,1H),8.35-8.30(m,2H),7.89(d,J=5.6 Hz,1H),6.79(s,2H),4.05-3.85(m,4H),3.32-3.27(m,2H),3.20-3.12(m,2H),2.85-2.74(m,2H),2.61(t,J=7.2 Hz,2H),1.81-1.67(m,6H).LCMS(ESI)m / z:454.1 [M+H] + .

[0248] Example 110 2-Methyl-1-(8-(2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decan-2-yl)propan-2-ol (Compound 110) To a solution of 4-(2,8-diazaspiro[4.5]decan-8-yl)-2-(4-pyridyl)pyrido[3,4-d]pyrimidine hydrochloride (50 mg, 0.13 mmol) in EtOH (1 mL) was added isobutylene oxide (94 mg, 1.31 mmol) and K2CO3 (90 mg, 0.65 mmol). The reaction vessel was sealed and stirred at 110 °C for 30 min in a microwave oven. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated in vacuo. The crude residue was purified by reverse-phase chromatography (37–67% acetonitrile / 0.05% NH3·H2O + 10 mM aqueous NH4HCO3) to afford the title compound (6.5 mg, 12%) as a yellow solid. 1 H NMR(400 MHz,DMSO-d6)δ 9.24(s,1H),8.76(d,J=4.8 Hz,2H),8.57(d,J=5.2 Hz,1H),8.34-8.27(m,2H),7.90-7.86(m,1H),4.07-4.03(m,1H),4.02-3.95(m,2H),3.91-3.81(m,2H),2.69(t,J=6.4 Hz,2H),2.57-2.55(m,2H),2.36-2.31(m,2H),1.83-1.68(m,4H),1.65(t,J=6.4 Hz,2H),1.10(s,6H).LCMS(ESI)m / z:419.2 [M+H] + .

[0249] Example 111 2-(Pyridin-4-yl)-4-(2-(tetrahydrofuran-3-yl)-2,8-diazaspiro[4.5]decan-8-yl)pyrido[3,4-d]pyrimidine (Compound 111) Following the procedure described in TIFF2024521929000159.tif56170 Example 103, making minor modifications as necessary to replace hydroxyacetone with 3-oxotetrahydrofuran, the title compound was obtained as a white solid and a mixture of enantiomers. 1H NMR(400 MHz,CD3OD)δ 9.25(s,1H),8.70(d,J=5.2 Hz,2H),8.55(d,J=5.6 Hz,1H),8.45(d,J=5.6 Hz,2H),7.92(d,J=6.0 Hz,1H),4.14-4.08(m,2H),4.03-3.93(m,4H),3.86-3.83(m,2H),3.79-3.74(m,1H),3.47-3.39(m,1 H),3.14-3.03(m,2H),2.29-2.21(m,1H),2.05-1.96(m,4H),1.92-1.88(m,4H).LCMS(ESI)m / z:417.1 [M+H] + .

[0250] Examples 112 and 113 (R)-2-(pyridin-4-yl)-4-(2-(tetrahydrofuran-3-yl)-2,8-diazaspiro[4.5]decan-8-yl)pyrido[3,4-d]pyrimidine and (S)-2-(pyridin-4-yl)-4-(2-(tetrahydrofuran-3-yl)-2,8-diazaspiro[4.5]decan-8-yl)pyrido[3,4-d]pyrimidine (Compounds 112 and 113) TIFF2024521929000160.tif55170 2-(pyridin-4-yl)-4-(2-(tetrahydrofuran-3-yl)-2,8-diazaspiro[4.5]decan-8-yl)pyrido[3,4-d]pyrimidine (80 mg, 0.19 mmol) was separated by using chiral SFC (Chiralpak IG (250 mm * 30 mm, 10 um), supercritical CO / EtOH + 0.1% NH OH = 40 / 60; 80 mL / min) to give the title compound as both white solids. The absolute configuration was arbitrarily assigned to each enantiomer. Example 112 (5 mg, second peak): 1H NMR(400 MHz,DMSO-d6)δ 9.26(s,1H),8.77(d,J=6.0 Hz,2H),8.59(d,J=6.0 Hz,1H),8.32(d,J=6.0 Hz,2H),7.89(d,J=5.6 Hz,1H),4.04-3.96(m,2H),3.91-3.84(m,2H),3.79-3.70(m,2H),3.69-3.61(m,1H),3.53-3.46(m,1 H),2.88-2.74(m,1H),2.63-2.54(m,2H),2.02-1.87(m,2H),1.83-1.60(m,8H).LCMS(ESI)m / z:417.1 [M+H] + Example 113 (10 mg, first peak): 1 H NMR(400 MHz,DMSO-d6)δ 9.25(s,1H),8.77(d,J=5.2 Hz,2H),8.58(d,J=5.6 Hz,1H),8.32(d,J=5.2 Hz,2H),7.88(d,J=5.2 Hz,1H),4.04-3.95(m,2H),3.91-3.83(m,2H),3.79-3.70(m,2H),3.68-3.62(m,1H),3.55-3.46(m,1 H),2.93-2.76(m,1H),2.65-2.56(m,2H),2.02-1.86(m,2H),1.84-1.64(m,8H).LCMS(ESI)m / z:417.1 [M+H] + .

[0251] Example 114 2-(8-(2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decan-2-yl)ethanol (Compound 114) formate Following the procedure described in TIFF2024521929000161.tif47170 Example 107, making minor modifications as necessary to replace methyl 2-bromo-2-methylpropanoate with 2-bromoethanol, the title compound was obtained as a yellow solid. 1H NMR(400 MHz,DMSO-d6)δ 9.27-9.25(m,1H),8.81-8.74(m,2H),8.63-8.56(m,1H),8.36-8.28(m,3H),7.92-7.86(m,1H),4.02-3.93(m,4H),3 .91-3.85(m,2H),3.52-3.48(m,2H),3.36-3.17(m,1H),3.06(s,1H),2.65-2.63(m,1H),2.53(s,2H),1.89(t,J=6.8 Hz,1H),1.84-1.68(m,5H).LCMS(ESI)m / z:391.1 [M+H] + .

[0252] Examples 115 and 116 (S)-1-(8-(2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decan-2-yl)propan-2-ol and (R)-1-(8-(2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decan-2-yl)propan-2-ol (Compounds 115 and 116) TIFF2024521929000162.tif50170 Step 1: 1-(8-(2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decan-2-yl)propan-2-ol TIFF2024521929000163.tif55170 To a solution of 4-(2,8-diazaspiro[4.5]decan-8-yl)-2-(4-pyridyl)pyrido[3,4-d]pyrimidine hydrochloride (110 mg, 0.29 mmol) in EtOH (4 mL) was added 2-methyloxirane (80 mg, 1.38 mmol) and triethylamine (0.16 mL, 1.18 mmol). The mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuo. The crude residue was purified by reverse-phase chromatography (33-63% acetonitrile / 0.05% NH₃·H₂O + 10 mM aqueous NH₄HCO₃) to afford the title compound (40 mg, 34%) as a yellow solid. LCMS (ESI) m / z: 405.2 [M+H] + .

[0253] Step 2: (S)-1-(8-(2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decan-2-yl)propan-2-ol and (R)-1-(8-(2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decan-2-yl)propan-2-ol TIFF2024521929000164.tif50170 1-(8-(2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decan-2-yl)propan-2-ol (38 mg, 0.09 mmol) was separated by using chiral SFC (ChiralpakOJ (250 mm * 30 mm, 10 um), supercritical CO2 / EtOH+0.1%NH4OH=60 / 40; 80 mL / min) to give the title compound as both yellow solids. The absolute configuration was arbitrarily assigned to each enantiomer. Example 115 (12 mg, second peak): 1 H NMR(400 MHz,DMSO-d6)δ 9.24(s,1H),8.76(d,J=4.4 Hz,2H),8.58(d,J=5.6 Hz,1H),8.31(d,J=4.4 Hz,2H),7.87(d,J=5.2 Hz,1H),4.03-3.93(m,2H),3.92-3.80(m,2H),3.79-3.62(m,2H),2.71-2.61(m,2H),2. 54-2.47(m,2H),2.42-2.32(m,2H),1.82-1.72(m,4H),1.71-1.64(m,2H),1.06(d,J=5.6 Hz,2H).LCMS(ESI)m / z:405.1 [M+H] + Example 116 (12 mg, first peak): 1H NMR(400 MHz,DMSO-d6):δ 9.24(s,1H),8.76(d,J=4.4 Hz,2H),8.57(d,J=5.6 Hz,1H),8.31(d,J=4.4 Hz,2H),7.86(d,J=5.6 Hz,1H),4.05-3.91(m,2H),3.90-3.82(m,2H),3.76-3.65(m,2H),2.65-2.55(m,2H),2. 51-2.43(m,2H),2.36-2.24(m,2H),1.81-1.69(m,4H),1.68-1.62(m,2H),1.05(d,J=5.6 Hz,2H).LCMS(ESI)m / z:405.1 [M+H] + .

[0254] Example 117 4-(2-Isopropyl-2,8-diazaspiro[4.5]decan-8-yl)-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidine (Compound 117) Following the procedure described in TIFF2024521929000165.tif51170 Example 105, making minor modifications as necessary to replace 2,2,2-trifluoroethyl trifluoromethanesulfonate with 2-iodopropane, the title compound was obtained as a yellow solid. 1 H NMR(400 MHz,DMSO-d6)δ 9.25(s,1H),8.79-8.73(m,2H),8.58(d,J=5.6 Hz,1H),8.35-8.28(m,2H),7.88(d,J=5.6 Hz,1H),4.04-3.95(m,2H),3.90-3.82(m,2H),2.59(t,J=6.8 Hz,2H),2.47(s,2H),2.35-2.25(m,1H),1.77-1.65(m,6H),1.02(d,J=6.4 Hz,6H).LCMS(ESI)m / z:389.2 [M+H] + .

[0255] Example 118 3-(8-(2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decan-2-yl)cyclobutanecarbonitrile (Compound 118) Following the procedure described in TIFF2024521929000166.tif32170 Example 103, with minor modifications as necessary to replace hydroxyacetone with 3-oxocyclobutanecarbonitrile, the title compound was obtained as a mixture of diastereomers as a yellow solid. 1 H NMR(400 MHz,DMSO-d6)δ 9.25(s,1H),8.79-8.74(m,2H),8.58(d,J=5.6 Hz,1H),8.33-8.29(m,2H),7.87(d,J=5.6 Hz,1H),3.98-3.85(m,4H),3.11-2.99(m,2H),2.60-5.55(m,2H),2.48-2.38(m,4H),2.24-2.15(m,2H),1.81-1.67(m,6H).LCMS(ESI)m / z:448.1 [M+Na] + .

[0256] Example 119 4-(2-Cyclohexyl-2,8-diazaspiro[4.5]decan-8-yl)-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidine (Compound 119) formate Following the procedure described in TIFF2024521929000167.tif55170 Example 103, making minor modifications as necessary to replace hydroxyacetone with cyclohexanone, the title compound was obtained as a white solid. 1H NMR(400 MHz,DMSO-d6)δ 9.26(s,1H),8.77(d,J=4.8 Hz,2H),8.59(d,J=5.6 Hz,1H),8.33(d,J=4.4 Hz,2H),8.22(s,1H),7.89(d,J=5.6 Hz,1H),4.04-3.89(m,4H),2.94-2.82(m,2H),2.77-2.65(m,2H),2.39-3.29(m,1H),1.96- 1.88(m,2H),1.71-1.81(m,7H),1.58-1.52(m,1H),1.32-1.05(m,6H).LCMS(ESI)m / z:429.1 [M+H] + .

[0257] Example 120 3-(8-(2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decan-2-yl)propan-1-ol (Compound 120) Following the procedure described in TIFF2024521929000168.tif47170 Example 107, making minor modifications as necessary to replace methyl 2-bromo-2-methylpropanoate with 3-bromo-1-propanol, the title compound was obtained as a white solid. 1 H NMR(400 MHz,DMSO-d6)δ 9.27(s,1H),8.80-8.74(m,2H),8.60(d,J=5.6 Hz,1H),8.35-8.31(m,2H),7.89(d,J=5.6 Hz,1H),4.04-3.97(m,2H),3.93-3.85(m,2H),3.46(t,J=6.0 Hz,2H),2.78-2.50(m,6H),1.81-1.71(m,6H),1.67-1.59(m,2H).LCMS(ESI)m / z:405.1 [M+H] + .

[0258] Example 121 4-(2-(2-Methoxyethyl)-2,8-diazaspiro[4.5]decan-8-yl)-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidine (Compound 121) Following the procedure described in TIFF2024521929000169.tif47170 Example 107, making minor modifications as necessary to replace methyl 2-bromo-2-methylpropanoate with 2-bromoethyl methyl ether, the title compound was obtained as a yellow solid. 1 H NMR(400 MHz,DMSO-d6)δ 9.25(s,1H),8.76(d,J=5.2 Hz,2H),8.59(d,J=5.6 Hz,1H),8.32(d,J=5.2 Hz,2H),7.88(d,J=5.6 Hz,1H),4.04-3.95(m,2H),3.91-3.84(m,2H),3.55-3.44(m,2H),3.35(s,3H),3.03-2.53(m,6H),1.95-1.65(m,6H).LCMS(ESI)m / z:405.1 [M+H] + .

[0259] Example 122 2-(Pyridin-4-yl)-4-(2-(tetrahydro-2H-pyran-4-yl)-2,8-diazaspiro[4.5]decan-8-yl)pyrido[3,4-d]pyrimidine (Compound 122) formate Following the procedure described in TIFF2024521929000170.tif56170 Example 103, with minor modifications as necessary to replace hydroxyacetone with dihydro-2H-pyran-4(3H)-one, the title compound was obtained as a white solid. 1 H NMR(400 MHz,DMSO-d6)δ 9.26(s,1H),8.77(d,J=6.0 Hz,2H),8.59(d,J=5.6 Hz,1H),8.33(d,J=6.0 Hz,2H),8.18(s,1H),7.89(d,J=5.6 Hz,1H),4.05-3.97(m,2H),3.92-3.83(m,4H),3.42-3.25(m,2H),2.73-2.66(m,2H),2.5 8(s,2H),2.34-2.26(m,1H),1.82-1.68(m,8H),1.46-1.35(m,2H).LCMS(ESI)m / z:431.1 [M+H] + .

[0260] Example 123 N-(2-(8-(2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decan-2-yl)ethyl)acetamide (Compound 123) TIFF2024521929000171.tif48170 Step 1: tert-Butyl (2-(8-(2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decan-2-yl)ethyl)carbamate Following the procedure described in TIFF2024521929000172.tif32170 Example 107, with minor modifications as necessary to replace methyl 2-bromo-2-methylpropanoate with tert-butyl (2-bromoethyl)carbamate, the title compound was obtained as a yellow solid. 1 H NMR(400 MHz,DMSO-d6)δ 9.24(s,1H),8.76(d,J=5.6 Hz,2H),8.58(d,J=5.6 Hz,1H),8.31(d,J=5.6 Hz,2H),8.19(s,1H),7.86(d,J=5.6 Hz,1H),6.76(t,J=5.6 Hz,1H),3.97-3.80(m,4H),3.12-2.98(m,2H),2.65(t,J=6.8 Hz,2H),2.54(s,2H),2.49-2.42(m,2H),1.78-1.66(m,6H),1.38(s,9H).LCMS(ESI)m / z:490.1 [M+H] + .

[0261] Step 2: 2-(8-(2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decan-2-yl)ethanamine hydrochloride TIFF2024521929000173.tif32170 To a solution of tert-butyl (2-(8-(2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decan-2-yl)ethyl)carbamate (50 mg, 0.1 mmol) in EtOAc (0.6 mL) was added 4 M HCl in EtOAc (0.6 mL, 2.2 mmol). The mixture was stirred at room temperature for 2 hours. The mixture was concentrated in vacuo to give the title compound (42 mg, crude) as a yellow solid which required no further purification. LCMS (ESI) m / z: 390.1 [M+H] + .

[0262] Step 3: N-(2-(8-(2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decan-2-yl)ethyl)acetamide To a solution of 2-(8-(2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decan-2-yl)ethanamine hydrochloride (15 mg, 0.04 mmol) and triethylamine (17 µL, 0.12 mmol) in DCM (0.5 mL) was added acetyl chloride (4 µL, 0.06 mmol) at 0 °C. The reaction was then warmed to room temperature and stirred for 2 h. The reaction was quenched with saturated aqueous NaHCO3 (5 mL) and extracted with DCM (10 mL × 2). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by reverse-phase chromatography (13-43% acetonitrile / 0.05% NH3·H2O+10 mM aqueous NH4HCO3) to afford the title compound (7.6 mg, 49%) as a yellow solid. 1H NMR(400 MHz,CD3OD)δ 9.26(s,1H),8.75-8.67(m,2H),8.55(d,J=5.6 Hz,1H),8.50-8.43(m,2H),7.95(d,J=5.6 Hz,1H),4.13-4.05(m,2H),4.04-3.95(m,2H),3.37-3.35(m,2H),2.75(t,J=6.8 Hz,2H),2.67-2.58(m,4H),1.95(s,3H),1.91-1.79(m,6H).LCMS(ESI)m / z:432.1 [M+H] + .

[0263] Example 124 4-(2-(oxetan-3-ylmethyl)-2,8-diazaspiro[4.5]decan-8-yl)-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidine (compound 124) Following the procedure described in TIFF2024521929000175.tif51170 Example 103, making minor modifications as necessary to replace hydroxyacetone with oxetane-3-carbaldehyde, the title compound was obtained as a yellow solid. 1 H NMR(400 MHz,DMSO-d6)δ 9.25(s,1H),8.76(d,J=5.6 Hz,2H),8.58(d,J=5.6 Hz,1H),8.32(d,J=5.6 Hz,2H),7.88(d,J=6.0 Hz,1H),4.63-4.58(m,2H),3.53-3.28(m,7H),2.54-2.47(m,4H),1.88-1.84(m,2H),2.42(s,2H),1.40-1.31(m,6H).LCMS(ESI)m / z:417.1 [M+H] + .

[0264] Example 125 1-(8-(2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decan-2-yl)ethan-1-one (Compound 125) Following the procedure described in TIFF2024521929000176.tif32170 Example 101, Step 3, making minor modifications as necessary to replace tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate with 1-(2,8-diazaspiro[4.5]decan-2-yl)ethan-1-one, the title compound was obtained. LCMS (ESI) m / z: 389.2 [M+H] + . 1 H NMR(400 MHz,DMSO-d6)δ 9.28(d,J=2.5,1H),8.83-8.73(m,2H),8.64-8.58(m,1H),8.37-8.28(m,2H),7.91(d,J=5.8,1H),4.12-3.86(m,4H),3.67-3.58(m,1H) ,3.57-3.51(m,1H),3.42-3.36(m,1H),3.19-3.09(m,1H),1.99-1.93(m,3H),1.94-1.90(m,1H),1.86-1.81(m,1H),1.80-1.72(m,4H).

[0265] Example 126 N-(2-(8-(2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decan-2-yl)ethyl)methanesulfonamide (Compound 126) To a solution of 2-(8-(2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decan-2-yl)ethanamine hydrochloride (42 mg, 0.1 mmol), 4-dimethylaminopyridine (2.4 mg, 0.02 mmol), and triethylamine (43 μL, 0.3 mmol) in DCM (1 mL) was added methanesulfonyl chloride (10 μL, 0.11 mmol) at 0° C. The reaction was then warmed to room temperature and stirred for 4 hours. The reaction was added saturated aqueous NaHCO (10 mL) and extracted with DCM (20 mL × 2). The combined organic layers were dried over anhydrous NaSO, filtered, and concentrated in vacuo. The mixture was concentrated in vacuo. The crude residue was purified by reverse-phase chromatography (25-55% acetonitrile / 0.05% NH3·H2O+10 mM aqueous NH4HCO3) to afford the title compound (7.6 mg, 16%) as a yellow solid. 1 H NMR(400 MHz,DMSO-d6)δ 9.25(s,1H),8.83-8.70(m,2H),8.58(d,J=5.6 Hz,1H),8.36-8.24(m,2H),7.88(d,J=5.6 Hz,1H),6.93(s,1H),4.02-3.84(m,4H),3.05(t,J=6.8 Hz,2H),2.93(s,3H),2.59(t,J=6.8 Hz,2H),2.54-2.50(m,2H),2.48(s,2H),1.81-1.65(m,6H).LCMS(ESI)m / z:468.1 [M+H] + .

[0266] Example 127 4-(2-(2,2-difluoroethyl)-2,8-diazaspiro[4.5]decan-8-yl)-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidine (Compound 127) To a solution of 4-(2,8-diazaspiro[4.5]decan-8-yl)-2-(4-pyridyl)pyrido[3,4-d]pyrimidine hydrochloride (30 mg, 0.09 mmol) in acetonitrile (1.5 mL) was added triethylamine (0.04 mL, 0.26 mmol) and 2,2-difluoroethyl trifluoromethanesulfonate (28 mg, 0.13 mmol). The mixture was heated to 50 °C under a nitrogen atmosphere for 16 h. After cooling to room temperature, the mixture was concentrated in vacuo, and the resulting residue was purified by reverse-phase chromatography (2-32% acetonitrile / 0.225% formic acid in water) to afford the title compound (12 mg, 32%) as a yellow solid. 1 H NMR(400 MHz,DMSO-d6)δ 9.27(s,1H),8.82(d,J=6.0 Hz,2H),8.78(d,J=6.0 Hz,1H),8.33(d,J=6.0 Hz,2H),7.89(d,J=6.0 Hz,1H),6.47-6.09(m,1H),4.05-3.97(m,2H),3.92-3.83(m,2H),3.30-2.65(m,6H),1.90-1.73(m,6H).LCMS(ESI)m / z:411.3 [M+H] + .

[0267] Examples 128 and 129 (1R,2R)-2-(8-(2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decan-2-yl)cyclopentanol and (1S,2S)-2-(8-(2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decan-2-yl)cyclopentanol (Compounds 128 and 129) TIFF2024521929000179.tif54170 Step 1: trans-2-(8-(2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decan-2-yl)cyclopentanol To a solution of 4-(2,8-diazaspiro[4.5]decan-8-yl)-2-(4-pyridyl)pyrido[3,4-d]pyrimidine hydrochloride (200 mg, 0.52 mmol) in EtOH (5 mL) was added 1,2-epoxycyclopentane (0.46 mL, 5.22 mmol) and K2CO3 (361 mg, 2.61 mmol). The reaction mixture was heated to 80 °C for 16 h. After cooling to room temperature, the reaction mixture was diluted with DCM (100 mL) and washed with water (30 mL) and brine (30 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by reverse-phase chromatography (25–55% acetonitrile / 0.05% NH H O + 10 mM aqueous NH HCO) to give the title compound (83 mg, 37%) as a yellow solid. LCMS (ESI) m / z: 431.2 [M+H].

[0268] Step 2: (1R,2R)-2-(8-(2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decan-2-yl)cyclopentanol and (1S,2S)-2-(8-(2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decan-2-yl)cyclopentanol TIFF2024521929000181.tif32170 trans-2-(8-(2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decan-2-yl)cyclopentanol (30 mg, 0.07 mmol) was separated by using chiral SFC (Phenomenex-Chiralpak-IG (250 mm * 30 mm, 10 um), supercritical CO2 / i-PrOH + 0.1% NH4OH = 60 / 40; 80 mL / min) to give the title compounds, both as white solids. The absolute configuration was arbitrarily assigned to each enantiomer. Example 128 (8.1 mg, first peak): 1H NMR(400 MHz,DMSO-d6)δ 9.25(s,1H),8.76(d,J=5.6 Hz,2H),8.58(d,J=5.6 Hz,1H),8.31(d,J=5.6 Hz,2H),7.88(d,J=5.6 Hz,1H),4.56-4.42(s,1H),4.04-3.95(m,2H),3.93-3.80(m,3H),2.64-2.57( m,2H),2.47-2.44(m,1H),2.35-2.25(m,1H),1.82-1.67(m,6H),1.64(t,J=6.8 Hz,2H),1.59-1.50(m,2H),1.48-1.36(m,2H).LCMS(ESI)m / z:431.2 [M+H] + Example 129 (12.6 mg, second peak): 1 H NMR(400 MHz,DMSO-d6)δ 9.25(s,1H),8.76(d,J=5.6 Hz,2H),8.58(d,J=5.6 Hz,1H),8.31(d,J=5.6 Hz,2H),7.88(d,J=5.6 Hz,1H),4.56-4.42(s,1H),4.04-3.95(m,2H),3.93-3.80(m,3H),2.64-2.57( m,2H),2.47-2.44(m,1H),2.35-2.25(m,1H),1.82-1.67(m,6H),1.64(t,J=6.8 Hz,2H),1.59-1.50(m,2H),1.48-1.36(m,2H).LCMS(ESI)m / z:431.2 [M+H] + .

[0269] Example 130 2-(8-(2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decan-2-yl)acetamide (Compound 130) formate Following the procedure described in TIFF2024521929000182.tif51170 Example 106, with minor modifications as necessary to replace methylcyclopentyl bromide with 2-bromoacetamide, the title compound was obtained as a white solid. 1H NMR(400 MHz,CD3OD)δ 9.24(s,1H),8.70(d,J=5.6 Hz,2H),8.54(d,J=5.6 Hz,1H),8.44(d,J=4.8 Hz,2H),8.36(s,1H),7.91(d,J=5.6 Hz,1H),4.12-4.05(m,2H),4.02-3.95(m,2H),3.64(s,2H),3.20(t,J=7.2 Hz,2H),3.06(s,2H),2.02(t,J=7.2 Hz,2H),1.97-1.90(m,4H).LCMS(ESI)m / z:404.1 [M+H] + .

[0270] Example 131 4-(2-cyclobutyl-2,8-diazaspiro[4.5]decan-8-yl)-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidine (Compound 131) Following the procedure described in TIFF2024521929000183.tif32170 Example 103, making minor modifications as necessary to replace hydroxyacetone with cyclobutanone, the title compound was obtained as a yellow solid. 1 H NMR(400 MHz,DMSO-d6)δ 9.26(s,1H),8.79-8.75(m,2H),8.59(d,J=5.6 Hz,1H),8.35-8.31(m,2H),7.89(d,J=6.0 Hz,1H),4.02-3.95(m,2H),3.93-3.86(m,2H),2.89(m,1H),2.49-2.45(m,2 H),2.37(s,2H),1.97-1.83(m,4H),1.82-1.60(m,8H).LCMS(ESI)m / z:401.2 [M+H] + .

[0271] Example 132 3-(8-(2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decan-2-yl)propanamide (Compound 132) Following the procedure described in TIFF2024521929000184.tif47170 Example 109, and making minor modifications as necessary to replace ethenesulfonamide with acrylamide, the title compound was obtained as a white solid. 1 H NMR(400 MHz,DMSO-d6)δ 9.22(s,1H),8.76-8.73(m,2H),8.56(d,J=5.6 Hz,1H),8.32-8.26(m,2H),7.84(s,1H),7.40(s,1H),6.78(s,1H),3.99-3. 90(m,2H),3.89-3.80(m,2H),2.60-2.53(m,4H),2.43(s,2H),2.22(t,J=7.2 Hz,2H),1.78-1.62(m,6H).LCMS(ESI)m / z:418.1 [M+H] + .

[0272] Example 133 4-(2-benzyl-2,8-diazaspiro[4.5]decan-8-yl)-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidine (Compound 133) Following the procedure described in TIFF2024521929000185.tif51170 Example 103, making minor modifications as necessary to replace hydroxyacetone with benzaldehyde, the title compound was obtained as a yellow solid. 1 H NMR(400 MHz,DMSO-d6)δ 9.25(s,1H),8.79-8.74(m,2H),8.58(d,J=6.0 Hz,1H),8.33-8.29(m,2H),7.87(d,J=6.0 Hz,1H),7.40-7.25(m,5H),4.03-3.94(m,2H),3.90-3.81(m,2H),3.68(s,2 H),3.34-3.26(m,2H),2.67(s,2H),1.86-1.70(m,6H).LCMS(ESI)m / z:437.1 [M+H] + .

[0273] Example 134 4-(2-(2-fluoroethyl)-2,8-diazaspiro[4.5]decan-8-yl)-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidine (compound 134) formate Following the procedure described in TIFF2024521929000186.tif47170 Example 106, making minor modifications as necessary to replace methylcyclopentyl bromide with 1-bromo-2-fluoroethane, the title compound was obtained as a yellow solid. 1 H NMR(400 MHz,DMSO-d6)δ 9.25(s,1H),8.78-8.75(m,2H),8.58(d,J=5.6 Hz,1H),8.35-8.29(m,2H),8.18(s,1H),7.88(d,J=5.6 Hz,1H),4.60-4.45(m,2H),4.03-3.96(m,2H),3.91-3.84(m,2H),2.77-2.66(m,2H),2.64(t,J=6.8 Hz,2H),2.52(s,2H),1.81-1.72(m,4H),1.72-1.68(m,2H).LCMS(ESI)m / z:393.1 [M+H] + .

[0274] Example 135 4-(2-(3-fluoropropyl)-2,8-diazaspiro[4.5]decan-8-yl)-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidine (compound 135) formate Following the procedure described in TIFF2024521929000187.tif47170 Example 107, making minor modifications as necessary to replace methyl 2-bromo-2-methylpropanoate with 1-bromo-3-fluoropropane, the title compound was obtained as a light yellow solid. 1H NMR(400 MHz,DMSO-d6)δ 9.24(s,1H),8.76(d,J=5.6 Hz,2H),8.58(d,J=5.6 Hz,1H),8.31(d,J=6.0 Hz,2H),8.20(s,1H),7.87(d,J=5.6 Hz,1H),4.57-4.41(m,2H),4.01-3.94(m,2H),3.91-3.85(m,2H),2.66(t,J=6.8 Hz,2H),2.58-2.53(m,4H),1.91-1.76(m,4H),1.73-1.69(m,4H).LCMS(ESI)m / z:407.1 [M+H] + .

[0275] Example 136 3-(8-(2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decan-2-yl)propanenitrile (Compound 136) Following the procedure described in TIFF2024521929000188.tif47170 Example 107, making minor modifications as necessary to replace methyl 2-bromo-2-methylpropanoate with 3-bromopropanenitrile, the title compound was obtained as a yellow solid. 1 H NMR(400 MHz,DMSO-d6)δ 9.26(s,1H),8.77(d,J=6.0 Hz,2H),8.59(d,J=5.6 Hz,1H),8.33(d,J=6.0 Hz,2H),7.89(d,J=5.6 Hz,1H),4.03-3.95(m,2H),3.92-3.84(m,2H),2.71-2.58(m,6H),2.52-2.51(m,2H),1.80-1.67(m,6H).LCMS(ESI)m / z:400.1 [M+H] + .

[0276] Example 137 4-(2-(oxetan-3-yl)-2,8-diazaspiro[4.5]decan-8-yl)-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidine (compound 137) formate Following the procedure described in TIFF2024521929000189.tif54170 Example 103, with minor modifications as necessary to replace hydroxyacetone with oxetan-3-one, the title compound was obtained as a yellow solid. 1 H NMR(400 MHz,DMSO-d6)δ 9.26(s,1H),8.77(d,J=5.6 Hz,2H),8.59(d,J=5.6 Hz,1H),8.33(d,J=6.0 Hz,2H),8.15(s,1H),7.89(d,J=6.0 Hz,1H),4.59-4.54(m,2H),4.49-4.44(m,2H),4.03-3.86(m,4H),3.62-3.54(m ,1H),2.58-2.55(m,2H),2.39(s,2H),1.83-1.68(m,6H).LCMS(ESI)m / z:403.1 [M+H] + .

[0277] Example 138 4-(2-ethyl-2,8-diazaspiro[4.5]decan-8-yl)-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidine (Compound 138) To a solution of 4-(2,8-diazaspiro[4.5]decan-8-yl)-2-(4-pyridyl)pyrido[3,4-d]pyrimidine hydrochloride (50 mg, 0.13 mmol) in acetonitrile (2 mL) was added K2CO3 (22 mg, 0.16 mmol) and iodoethane (0.01 mL, 0.12 mmol). The mixture was stirred at room temperature for 16 h. The mixture was filtered, and the filtrate was concentrated in vacuo. The crude residue was purified by reverse-phase chromatography (35–65% acetonitrile / 0.05% NH3·H2O + 10 mM aqueous NH4HCO3) to afford the title compound (8.3 mg, 12%) as a white solid. 1H NMR(400 MHz,DMSO-d6)δ 9.27(s,1H),8.82-8.73(m,2H),8.60(d,J=6.0 Hz,1H),8.36-8.30(m,2H),7.90(d,J=6.0 Hz,1H),4.06-3.96(m,2H),3.95-3.85(m,2H),3.31-3.24(m,2H),3.10-2.70(m,4H),1.89-1.73(m,6H),1.21-1.06(m,3H).LCMS(ESI)m / z:375.1 [M+H] + .

[0278] Example 139 4-(2-(1H-pyrazol-3-yl)-2,8-diazaspiro[4.5]decan-8-yl)-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidine (Compound 139) TIFF2024521929000191.tif32170 Step 1: 2-(pyridin-4-yl)-4-(2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-2,8-diazaspiro[4.5]decan-8-yl)pyrido[3,4-d]pyrimidine TIFF2024521929000192.tif331704-(2,8-diazaspiro[4.5]decan-8-yl)-2-(4-pyridyl)pyrido[3,4-d]pyrimidine hydrochloride (200 mg, 0.52 mmol), 3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (217 mg, 0.78 mmol) (International Publication No. 201934890 pamphlet) To a solution of allylpalladium(II) chloride dimer (19 mg, 0.05 mmol) and 2-(di-tert-butylphosphino)-2',4',6'-triisopropyl-3,6-dimethoxy-1,1'-biphenyl (51 mg, 0.1 mmol) in 2-methyl-2-butanol (5 mL) was added allylpalladium(II) chloride dimer (19 mg, 0.05 mmol) and 2-(di-tert-butylphosphino)-2',4',6'-triisopropyl-3,6-dimethoxy-1,1'-biphenyl (51 mg, 0.1 mmol). The reaction mixture was heated to 90 °C under a nitrogen atmosphere for 16 h. After cooling to room temperature, the solvent was removed in vacuo, and the residue was purified by silica gel chromatography (solvent gradient: 0-5% MeOH in DCM) to give the title compound (100 mg, 35%) as a yellow oil. LCMS (ESI) m / z: 543.3 [M+H] + .

[0279] Step 2: 4-(2-(1H-pyrazol-3-yl)-2,8-diazaspiro[4.5]decan-8-yl)-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidine To a solution of 2-(pyridin-4-yl)-4-(2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-3-yl)-2,8-diazaspiro[4.5]decan-8-yl)pyrido[3,4-d]pyrimidine (100 mg, 0.18 mmol) in DCM (2 mL) was added trifluoroacetic acid (0.53 mL, 7.13 mmol). The mixture was stirred at room temperature for 2 hours. The mixture was concentrated in vacuo, and the residue was diluted with MeOH (2 mL), and the pH was adjusted to 8 by the addition of ammonium hydroxide (30% in water). The crude mixture was purified by reverse-phase chromatography (25-55% acetonitrile / 0.05% NH3·H2O+10 mM aqueous NH4HCO3) to give the title compound (6 mg, 8%) as a white solid. 1 H NMR(400 MHz,DMSO-d6)δ 11.63(s,1H),9.27(s,1H),8.80-8.74(m,2H),8.60(d,J=5.6 Hz,1H),8.36-8.30(m,2H),7.92(d,J=6.0 Hz,1H),7.44(s,1H),5.53(s,1H),4.09-4.01(m,2H),4.01-3.93(m,2H),3.30-3.28(m,2H),3.19(s,2H),1.91(t,J=6.4 Hz,2H),1.84-1.77(m,4H).LCMS(ESI)m / z:413.1 [M+H] + .

[0280] Example 140 4-(2-phenyl-2,8-diazaspiro[4.5]decan-8-yl)-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidine (Compound 140) To a solution of 4-(2,8-diazaspiro[4.5]decan-8-yl)-2-(4-pyridyl)pyrido[3,4-d]pyrimidine hydrochloride (100 mg, 0.26 mmol), iodobenzene (0.04 mL, 0.35 mmol), and CsCO (280 mg, 0.87 mmol) in 1,4-dioxane (2 mL) was added palladium(II) acetate (13 mg, 0.06 mmol) and (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (36 mg, 0.06 mmol). The reaction mixture was heated to 110°C under a nitrogen atmosphere for 16 h. After cooling to room temperature, the mixture was filtered, and the filtrate was concentrated in vacuo. The crude residue was purified by reverse-phase chromatography (20-50% acetonitrile / 0.05% NH3·H2O+10 mM aqueous NH4HCO3) to afford the title compound (9 mg, 7%) as a white solid. 1 H NMR(400 MHz,DMSO-d6)δ 9.27(s,1H),8.75(d,J=4.0 Hz,2H),8.58(d,J=5.2 Hz,1H),8.34(d,J=4.0 Hz,2H),7.92(d,J=5.2 Hz,1H),7.19-7.12(m,2H),6.62-6.31(m,3H),4.12-3.91(m,4H),3.34-3.30(m ,2H),3.24(s,2H),2.12-1.89(m,2H),1.88-1.72(m,4H).LCMS(ESI)m / z:423.2 [M+H] + .

[0281] Example 141 4-(2-(1H-pyrazol-4-yl)-2,8-diazaspiro[4.5]decan-8-yl)-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidine (compound 141) trifluoroacetate Following the procedure described in TIFF2024521929000195.tif55170 Example 139, with minor modifications as necessary to replace 3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole with 4-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole, the title compound was obtained as a yellow solid. 1 H NMR(400 MHz,DMSO-d6)δ 9.26(s,1H),8.77(d,J=5.2 Hz,2H),8.59(d,J=5.6 Hz,1H),8.33(d,J=5.6 Hz,2H),8.23(s,1H),7.90(d,J=5.6 Hz,1H),7.09(s,2H),4.06-3.92(m,4H),3.10(t,J=6.8 Hz,2H),2.99(s,2H),1.90-1.86(m,2H),1.85-1.72(m,4H).LCMS(ESI)m / z:413.3 [M+H] + .

[0282] Example 142 2-(3-methyl-1H-pyrazol-4-yl)-4-(2,8-diazaspiro[4.5]decan-8-yl)pyrido[3,4-d]pyrimidine (Compound 142) TIFF2024521929000196.tif43170Step 1: 3-Methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carbaldehyde To a stirred solution of 3-methyl-1H-pyrazole-4-carbaldehyde (5 g, 45.41 mmol) in THF (100 mL) was added NaH (2.0 g, 50 mmol, 60%) under a nitrogen atmosphere at 0 °C. After 30 min, (2-(chloromethoxy)ethyl)trimethylsilane (10.26 g, 40.54 mmol) was added. The reaction was allowed to warm to room temperature and stirred for 16 h. The reaction was poured into saturated aqueous NH4Cl (50 mL) and extracted with EtOAc (150 mL × 2). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (solvent gradient: 0-20% EtOAc in petroleum ether) to afford the title compound (10.0 g, 92%) as a colorless oil. 1 H NMR(400 MHz,CDCl3)δ 9.96-9.94(m,1H),8.05-7.88(m,1H),5.53-5.36(m,2H),3.65-3.56(m,2H),2.69-2.50(m,3H),0.98-0.90(m,2H),0.05-0.01(m,9H).

[0283] Step 2: 2-(3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4-ol To a solution of 3-aminopyridine-4-carboxamide (5 g, 36.46 mmol) in DMA (50 mL) was added 3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-4-carbaldehyde (10.5 g, 43.75 mmol) and CuO (5.8 g, 72.92 mmol). The mixture was heated to 135° C. under an oxygen atmosphere for 40 hours. After cooling to room temperature, the reaction was poured into water (500 mL), the suspension was filtered, and the filter cake was dried in vacuo to give the title compound (9.1 g, 70%) as a yellow solid. 1H NMR(400 MHz,CDCl3)δ 12.51(s,1H),9.02(s,1H),8.69(s,0.5H),8.59(s,1H),8.31(s,0.5H),7.92(s,1H),5.52-5.34(m,2H) ),3.56-3.54(m,2H),2.79-2.55(m,3H),0.89-0.82(m,2H),-0.03--0.05(m,9H).LCMS(ESI)m / z:358.3 [M+H] + .

[0284] Step 3: 2-(3-methyl-1H-pyrazol-4-yl)-4-(2,8-diazaspiro[4.5]decan-8-yl)pyrido[3,4-d]pyrimidine To a solution of 2-(3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4-ol (200 mg, 0.56 mmol) in DMF (5 mL) was added DIEA (0.22 mL, 1.12 mmol) and 2,4,6-triisopropylbenzenesulfonyl chloride (200 mg, 0.67 mmol). The reaction mixture was stirred at room temperature for 1 hour. Then, tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate (135 mg, 0.56 mmol) was added to the reaction mixture. The reaction mixture was stirred at room temperature for 16 hours. The mixture was diluted with EtOAc (50 mL) and washed with water (30 mL × 3) and brine (30 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0-5% MeOH in DCM) to afford tert-butyl 8-(2-(3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2-carboxylate (200 mg, 62%) as a yellow solid. This residue was treated with 1 mL of DCM and 1 mL of TFA and stirred at room temperature for 2 hours. The reaction mixture was then concentrated in vacuo and then further concentrated 2-fold from DCM (5 mL) to remove residual TFA. The crude residue was then purified by HPLC to afford the title compound. 1 H NMR(400 MHz,DMSO)δ 12.78(br s,1H),9.08(d,J=2.1 Hz,1H),8.47-8.41(m,1H),8.14(s,1H),7.80-7.73(m,1H),3.97-3.74(m,4H),3.42-3.35(m,4H),2.85(t,J=7.1 Hz,1H),2.69-2.60(m,5H),1.87-1.79(m,1H),1.76-1.65(m,2H),1.60(t,J=7.1 Hz,1H).LCMS(ESI)m / z:350.2 [M+H] + .

[0285] Example 143 2-(3-methyl-1H-pyrazol-4-yl)-4-(2-methyl-2,8-diazaspiro[4.5]decan-8-yl)pyrido[3,4-d]pyrimidine (Compound 143) Following the procedure described in TIFF2024521929000200.tif32170 Example 102, with minor modifications as necessary to replace 4-(2,8-diazaspiro[4.5]decan-8-yl)-2-(4-pyridyl)pyrido[3,4-d]pyrimidine hydrochloride with 2-(3-methyl-1H-pyrazol-4-yl)-4-(2,8-diazaspiro[4.5]decan-8-yl)pyrido[3,4-d]pyrimidine hydrochloride, the title compound was obtained as a yellow solid. 1 H NMR(400 MHz,DMSO-d6)δ 9.06(s,1H),8.42(d,J=5.6 Hz,2H),8.13(s,1H),7.72(d,J=5.6 Hz,1H),3.86-3.66(m,4H),2.64(s,3H),2.51-2.46(m,2H),2.36(s,2H),2.22(s,3H),1.74-1.62(m,6H).LCMS(ESI)m / z:364.2 [M+H] + .

[0286] Examples 144 and 145 (S)-1-(8-(2-(3-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decan-2-yl)propan-2-ol and (R)-1-(8-(2-(3-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decan-2-yl)propan-2-ol (Compounds 144 and 145) TIFF2024521929000201.tif51170 Step 1: 1-(8-(2-(3-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decan-2-yl)propan-2-ol Following the procedure described in TIFF2024521929000202.tif38170 Example 113, with minor modifications as necessary to replace 4-(2,8-diazaspiro[4.5]decan-8-yl)-2-(4-pyridyl)pyrido[3,4-d]pyrimidine hydrochloride with 2-(3-methyl-1H-pyrazol-4-yl)-4-(2,8-diazaspiro[4.5]decan-8-yl)pyrido[3,4-d]pyrimidine hydrochloride, the title compound was obtained as a yellow solid. LCMS (ESI) m / z: 408.1 [M+H] + .

[0287] Step 2: (S)-1-(8-(2-(3-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decan-2-yl)propan-2-ol and (R)-1-(8-(2-(3-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decan-2-yl)propan-2-ol TIFF2024521929000203.tif51170 1-(8-(2-(3-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decan-2-yl)propan-2-ol (110 mg, 0.27 mmol) was separated using chiral SFC (Phenomenex-Cellulose-2 (250 mm * 30 mm, 10 um), supercritical CO2 / EtOH+0.1% NH4OH=50 / 50; 80 mL / min) to give the title compounds, both as white solids. The absolute configurations were arbitrarily assigned to each enantiomer. Example 144 (18 mg, second peak): 1H NMR(400 MHz, DMSO-d6)δ 12.87(s,1H),9.07(s,1H),8.44(d,J=6.0 Hz,1H),8.06(s,1H),7.75(d,J=5.6 Hz,1H),4.32(s,1H),3.89-3.80(m,2H),3.79-3.65(m,3H),2.67(s,2H),2.60-2.57(m,2 H),2.47(s,3H),2.36-2.27(m,2H),1.79-1.68(m,4H),1.68-1.62(m,2H),1.05(d,J=6.4 Hz,3H).LCMS(ESI)m / z:408.2 [M+H] + .Example 145 (15 mg, first のピーク): 1 H NMR(400 MHz, DMSO-d6)δ 12.86(s,1H),9.07(s,1H),8.44(d,J=5.6 Hz,1H),8.07(s,1H),7.76(d,J=6.0 Hz,1H),4.30(d,J=4.0 Hz,1H),3.89-3.81(m,2H),3.80-3.68(m,3H),2.67(s,2H),2.61-2.57(m,2H),2. 45(s,3H),2.34-2.30(m,2H),1.76-1.68(m,4H),1.67-1.62(m,2H),1.05(d,J=6.0 Hz,3H).LCMS(ESI)m / z:408.2 [M+H] + .

[0288] Example 146 2-(8-(2-(3-メチル-1H-ピラゾール-4-イル)ピリド[3,4-d]ピリミジン-4 -イル)-2,8-ジアザスピロ[4.5]デカン-2-イル)エタン-1-オール (Compound 146) Following the procedure described in TIFF2024521929000204.tif32170 Example 107, making minor variations as necessary to replace 4-(2,8-diazaspiro[4.5]decan-8-yl)-2-(4-pyridyl)pyrido[3,4-d]pyrimidine hydrochloride and methyl 2-bromo-2-methylpropanoate with 2-(3-methyl-1H-pyrazol-4-yl)-4-(2,8-diazaspiro[4.5]decan-8-yl)pyrido[3,4-d]pyrimidine hydrochloride and 2-bromoethanol, the title compound was obtained as a yellow solid. 1 H NMR(400 MHz,DMSO-d6)δ 12.86(s,1H),9.07(s,1H),8.44(d,J=5.6 Hz,1H),8.13(s,1H),7.75(d,J=5.6 Hz,1H),4.41(s,1H),3.87-3.73(m,4H),3.47(t,J=6.4 Hz,,2H),2.65(s,3H),2.57(t,J=6.4 Hz,2H),2.48-2.43(m,4H),1.76-1.63(m,6H).LCMS(ESI)m / z:394.1 [M+H] + .

[0289] Example 147 4-(2-Cyclopentyl-2,8-diazaspiro[4.5]decan-8-yl)-2-(3-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidine (Compound 147) Following the procedure described in TIFF2024521929000205.tif32170 Example 106, making minor modifications as necessary to replace 4-(2,8-diazaspiro[4.5]decan-8-yl)-2-(4-pyridyl)pyrido[3,4-d]pyrimidine hydrochloride with 2-(3-methyl-1H-pyrazol-4-yl)-4-(2,8-diazaspiro[4.5]decan-8-yl)pyrido[3,4-d]pyrimidine hydrochloride, the title compound was obtained as a yellow solid. 1H NMR(400 MHz,DMSO-d6)δ 12.87(s,1H),9.07(s,1H),8.43(d,J=6.0 Hz,1H),8.09(s,1H),7.75(d,J=6.0 Hz,1H),4.07-4.05(m,1H),3.88-3.82(m,2H),3.78-3.71(m,2H),2.67-2 .62(m,4H),1.83-1.55(m,10H),1.54-1.29(m,4H).LCMS(ESI)m / z:418.2 [M+H] + .

[0290] Example 148 2-(3-methyl-1H-pyrazol-4-yl)-4-(2-(tetrahydrofuran-3-yl)-2,8-diazaspiro[4.5]decan-8-yl)pyrido[3,4-d]pyrimidine (Compound 148) Following the procedure described in TIFF2024521929000206.tif32170 Example 103, with minor modifications as necessary to replace 4-(2,8-diazaspiro[4.5]decan-8-yl)-2-(4-pyridyl)pyrido[3,4-d]pyrimidine hydrochloride and hydroxyacetone with 2-(3-methyl-1H-pyrazol-4-yl)-4-(2,8-diazaspiro[4.5]decan-8-yl)pyrido[3,4-d]pyrimidine hydrochloride and 3-oxotetrahydrofuran, the title compound was obtained as a yellow solid. 1 H NMR(400 MHz,DMSO-d6)δ 12.86(s,1H),9.07(s,1H),8.44(d,J=5.6 Hz,1H),8.09(s,1H),7.75(d,J=5.6 Hz,1H),3.89-3.80(m,2H),3.79-3.74(m,2H),3.74-3.68(m,2H),3.68-3.62(m,1H),3.49(m,1H),2.85-2.75(m,1H),2.69-2.62(m,1 H),2.65(s,2H),2.60-2.54(m,2H),2.47-2.40(m,2H),1.97-1.89(m,1H),1.82-1.75(m,1H),1.74-1.64(m,6H).LCMS(ESI)m / z:420.1 [M+H] + .

[0291] Example 149 3-(8-(2-(3-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decan-2-yl)propan-1-ol (Compound 149) Following the procedure described in TIFF2024521929000207.tif32170 Example 107, making minor variations as necessary to replace 4-(2,8-diazaspiro[4.5]decan-8-yl)-2-(4-pyridyl)pyrido[3,4-d]pyrimidine hydrochloride and methyl 2-bromo-2-methylpropanoate with 2-(3-methyl-1H-pyrazol-4-yl)-4-(2,8-diazaspiro[4.5]decan-8-yl)pyrido[3,4-d]pyrimidine hydrochloride and 3-bromo-1-propanol, the title compound was obtained as a white solid. 1 H NMR(400 MHz,DMSO-d6)δ 9.06(s,1H),8.43(d,J=5.6 Hz,1H),8.14(s,1H),7.73(d,J=5.6 Hz,1H),3.86-3.80(m,2H),3.77-3.71(m,2H),3.45(t,J=6.4 Hz,2H),2.65(s,3H),2.55-2.51(m,2H),2.44-2.37(m,4H),1.76-1.63(m,6H),1.61-1.54(m,2H).LCMS(ESI)m / z:408.2 [M+H] + .

[0292] Example 150 2-Methyl-1-(8-(2-(3-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decan-2-yl)propan-2-ol (Compound 150) Following the procedure described in TIFF2024521929000208.tif32170 Example 110, making minor modifications as necessary to replace 4-(2,8-diazaspiro[4.5]decan-8-yl)-2-(4-pyridyl)pyrido[3,4-d]pyrimidine hydrochloride with 2-(3-methyl-1H-pyrazol-4-yl)-4-(2,8-diazaspiro[4.5]decan-8-yl)pyrido[3,4-d]pyrimidine hydrochloride, the title compound was obtained as a yellow solid. 1 H NMR(400 MHz,DMSO-d6)δ 12.86(s,1H),9.06(s,1H),8.42(d,J=5.6 Hz,1H),8.07(s,1H),7.74(d,J=5.6 Hz,1H),4.05(s,1H),3.91-3.79(m,2H),3.79-3.69(m,2H),2.71-2.61(m,4H),2.55(s,2 H),2.32(s,3H),1.82-1.66(m,4H),1.66-1.59(m,2H),1.08(s,6H).LCMS(ESI)m / z:422.1 [M+H] + .

[0293] Example 151 4-(2-ethyl-2,8-diazaspiro[4.5]decan-8-yl)-2-(5-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidine (Compound 151) Following the procedure described in TIFF2024521929000209.tif47170 Example 138, making minor modifications as necessary to replace 4-(2,8-diazaspiro[4.5]decan-8-yl)-2-(4-pyridyl)pyrido[3,4-d]pyrimidine hydrochloride with 2-(3-methyl-1H-pyrazol-4-yl)-4-(2,8-diazaspiro[4.5]decan-8-yl)pyrido[3,4-d]pyrimidine hydrochloride, the title compound was obtained as a yellow solid. 1H NMR(400 MHz,DMSO-d6)δ 12.84(s,1H),9.07(s,1H),8.43(d,J=5.6 Hz,1H),8.11(s,1H),7.75(d,J=5.6 Hz,1H),3.88-3.72(m,4H),2.65(s,3H),2.55-2.51(m,2H),2.41(s,2H),2.39-2.36(m,2H),1.74-1.64(m,6H),1.02(t,J=7.2 Hz,3H).LCMS(ESI)m / z:378.1 [M+H] + .

[0294] Example 152 2-(3-Methyl-1H-pyrazol-4-yl)-4-(2-(oxetan-3-ylmethyl)-2,8-diazaspiro[4.5]decan-8-yl)pyrido[3,4-d]pyrimidine (Compound 152) Following the procedure described in TIFF2024521929000210.tif49170 Example 103, with minor modifications as necessary to replace 4-(2,8-diazaspiro[4.5]decan-8-yl)-2-(4-pyridyl)pyrido[3,4-d]pyrimidine hydrochloride and hydroxyacetone with 2-(3-methyl-1H-pyrazol-4-yl)-4-(2,8-diazaspiro[4.5]decan-8-yl)pyrido[3,4-d]pyrimidine hydrochloride and oxetane-3-carbaldehyde, the title compound was obtained as a yellow solid. 1 H NMR(400 MHz,DMSO-d6)δ 12.86(s,1H),9.07(s,1H),8.44(d,J=6.0 Hz,1H),8.06(s,1H),7.75(d,J=5.6 Hz,1H),4.66-4.62(m,2H),4.28-4.25(m,2H),3.89-3.81(m,2H),3.78-3.72(m,2H),3.20- 3.02(m,1H),2.74-2.65(m,4H),2.43-2.27(m,2H),1.73-1.62(m,6H).LCMS(ESI)m / z:420.2 [M+H] + .

[0295] Example 153 2-(5-chloro-1H-pyrazol-4-yl)-4-(2,8-diazaspiro[4.5]decan-8-yl)pyrido[3,4-d]pyrimidine (Compound 153) TIFF2024521929000211.tif48170 Step 1: tert-Butyl 8-(2-chloropyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2-carboxylate TIFF2024521929000212.tif37170 2,4-Dichloropyrido[3,4-d]pyrimidine (800 mg, 4 mmol, 1 equiv.), potassium fluoride (700 mg, 10 mmol, 3 equiv.), and tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate (1000 mg, 4 mmol, 1 equiv.) were added to a 40 mL vial. Dimethyl sulfoxide (10 mL, 0.3 M) was added, followed by triethylamine (3 mL, 20 mmol, 5 equiv.), and the reaction was stirred at room temperature for 1 h. The reaction was monitored by LCMS and was complete at this point. The mixture was transferred to a separatory funnel and diluted with EtOAc (15 mL), saturated aqueous NH4Cl (10 mL), and water (10 mL). The layers were separated and the aqueous layer was extracted with additional EtOAc (3 x 20 mL). The combined organic extracts were dried over NaSO, filtered, and concentrated in vacuo. The crude organic residue was flushed through a 24 g Isco cartridge eluting with 0 to 15% MeOH in DCM to give tert-butyl 8-(2-chloropyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2-carboxylate (1200 mg, 74% yield). LCMS (ESI) m / z: 426.05 [M+Na] + .

[0296] Step 2: 2-(5-chloro-1H-pyrazol-4-yl)-4-(2,8-diazaspiro[4.5]decan-8-yl)pyrido[3,4-d]pyrimidine TIFF2024521929000213.tif44170 tert-Butyl 8-(2-chloropyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2-carboxylate (190 mg, 0.470 mmol, 1 equiv.), tetrakis(triphenylphosphine)palladium(0) (54 mg, 0.047 mmol, 0.1 equiv.), sodium carbonate (150 mg, 1.40 mmol, 3 equiv.), and 3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (166 mg, 0.706 mmol, 1.5 equiv.) were added to a 2-dram vial. The vial was purged with N2, then 1,4-dioxane (2.35 mL) was added, followed by water (0.24 mL), and the reaction mixture was sparged with N2 for 5 minutes. The vial was then sealed and heated to 90 °C for 16 hours. The reaction was then cooled to room temperature, transferred to a 20 mL vial, and diluted with water (5 mL) and EtOAc (5 mL). The layers were separated, and the aqueous layer was extracted with additional EtOAc (4 x 5 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was dissolved in DCM (1 mL) and TFA (1 mL) and stirred at room temperature for 1 hour. The reaction mixture was then concentrated in vacuo and then further concentrated 2x from DCM (5 mL) to remove residual TFA. The crude residue was then purified by HPLC to give 2-(5-chloro-1H-pyrazol-4-yl)-4-(2,8-diazaspiro[4.5]decan-8-yl)pyrido[3,4-d]pyrimidine (47 mg, 0.127 mmol, 27% yield). LCMS (ESI) m / z: 370.1 [M+H] + . 1 H NMR(400 MHz,DMSO-d6)δ 9.09(s,1H),8.54-8.44(m,3H),7.81(d,J=5.7 Hz,1H),4.02-3.82(m,4H),2.89(t,J=7.1 Hz,2H),2.71(s,2H),1.82(t,J=7.1 Hz,1H),1.74-1.67(m,4H),1.63(t,J=7.1 Hz,2H).

[0297] Example 154 4-(2,8-diazaspiro[4.5]decan-8-yl)-2-(5-(trifluoromethyl)-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidine (Compound 154) Following the procedure described in TIFF2024521929000214.tif43170 Example 153, Step 2, making minor modifications as necessary to replace 3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)-1H-pyrazole, the title compound was obtained (44 mg, 24% yield). LCMS (ESI) m / z: 404.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d) δ 10.1 (br s, 1H), 9.09 (s, 1H), 8.63 (s, 1H), 8.50 (d, J = 5.6 Hz, 1H), 7.82 (d, J = 6.0 Hz, 1H), 4.01-3.81 (m, 4H), 2.91 (t, J = 7.1 Hz, 2H), 2.71 (s, 2H), 1.66 (dt, J = 18.4, 6.5 Hz, 6H). No exchangeable amine NH protons were observed.

[0298] Example 155 4-(4-(2,8-diazaspiro[4.5]decan-8-yl)pyrido[3,4-d]pyrimidin-2-yl)-1H-pyrazole-5-carbonitrile (Compound 155) Following the procedure described in TIFF2024521929000215.tif43170 Example 153, Step 2, making minor modifications as necessary to replace 3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole-5-carbonitrile, the title compound was obtained as a yellow solid (5 mg, 15%). 1H NMR(400 MHz,DMSO-d6)δ 9.08(s,1H),8.56(s,1H),8.48(d,J=5.6 Hz,1H),7.82(d,J=5.6 Hz,1H),4.00-3.91(m,4H),2.99-2.94(m,2H),2.77(s,2H),1.72-1.61(m,6H).LCMS(ESI)m / z:361.1 [M+H] + .

[0299] Example 156 2-(1H-pyrrolo[2,3-b]pyridin-4-yl)-4-(2,8-diazaspiro[4.5]decan-8-yl)pyrido[3,4-d]pyrimidine (Compound 156) Following the procedure described in TIFF2024521929000216.tif43170 Example 153, Step 2, making minor modifications as necessary to replace 3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine, the title compound was obtained. 1 H NMR(400 MHz,DMSO-d6)11.83(s,1H),9.33(d,J=0.7 Hz,1H),8.59(d,J=5.6 Hz,1H),8.38(d,J=5.0 Hz,1H),8.13(d,J=5.0 Hz,1H),7.94-7.84(m,1H),7.68-7.61(m,1H),7.48(d,J=3.4 Hz,1H),4.11-3.84(m,4H),3.44-3.29(m,3H),2.98(t,J=7.1 Hz,1H),1.85(t,J=7.1 Hz,1H),1.81-1.75(m,4H),1.71(t,J=7.2 Hz, 1H). No exchangeable amine NH protons were observed. LCMS (ESI) m / z: 386.1 [M+H] + .

[0300] Example 157 6-benzyl-2-(pyridin-4-yl)-4-(2,8-diazaspiro[4.5]decan-8-yl)pyrido[3,4-d]pyrimidine (Compound 157) TIFF2024521929000217.tif44170Step 1: 6-Chloro-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-ol To a solution of potassium 2-methyl-2-butoxide (22.02 g, 174.46 mmol) in THF (100 mL), a solution of ethyl 5-amino-2-chloro-pyridine-4-carboxylate (14 g, 69.78 mmol) (prepared according to the procedure in US2016176871) and 4-cyanopyridine (8.72 g, 83.74 mmol) in THF (300 mL) was added dropwise (approximately 4 mL / min) at 0 °C. The reaction was allowed to warm to room temperature and stirred for 16 h. Water (40 mL) and acetic acid (10 mL) were added. The mixture was stirred at room temperature for 20 min, and the resulting yellow precipitate was filtered. The solid was washed with water (30 mL × 2) to afford the title compound (11 g, 55%) as a yellow solid. 1 H NMR(400 MHz,DMSO-d6)δ 8.96(s,1H),8.81-8.77(m,2H),8.11-8.07(m,2H),7.99(s,1H).LCMS(ESI)m / z:259.1 [M+H] + .

[0301] Step 2: 6-chloro-2-(pyridin-4-yl)-4-((2-(trimethylsilyl)ethoxy)methoxy)pyrido[3,4-d]pyrimidine To a solution of 6-chloro-2-(4-pyridyl)pyrido[3,4-d]pyrimidin-4-ol (10 g, 38.66 mmol) and triethylamine (27 mL, 193 mmol) in DCM (100 mL) was added 2-(trimethylsilyl)ethoxymethyl chloride (27 mL, 155 mmol) in DCM (100 mL) dropwise at 0 °C. The mixture was heated to 45 °C under a nitrogen atmosphere for 16 h. After cooling to room temperature, the mixture was diluted with DCM (200 mL), saturated aqueous NaHCO (150 mL), and brine (150 mL). The organic layer was dried over anhydrous NaSO, filtered, and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0-5% EtOAc in petroleum ether) to afford the title compound (15 g, 99%) as a yellow oil. 1 H NMR(400 MHz,CDCl3)δ 8.96(s,1H),8.85-8.80(m,2H),8.14(s,1H),7.72-7.68(m,2H),5.27(s,2H) ),3.88-3.65(m,2H),1.05-0.88(m,2H),0.02(s,9H).LCMS(ESI)m / z:389.2 [M+H]+.

[0302] Step 3: 6-benzyl-2-(pyridin-4-yl)-4-((2-(trimethylsilyl)ethoxy)methoxy)pyrido[3,4-d]pyrimidine To a solution of 6-chloro-2-(pyridin-4-yl)-4-((2-(trimethylsilyl)ethoxy)methoxy)pyrido[3,4-d]pyrimidine (3 g, 7.71 mmol) and (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (330 mg, 0.39 mmol) in 15 mL of THF, benzylzinc(II) chloride (19.5 mL, 9.75 mmol) (0.5 M in THF) (prepared according to the procedure in WO 2019123011) was added dropwise under a nitrogen atmosphere. The mixture was stirred at room temperature for 5 hours. The reaction was quenched with water (50 mL) and extracted with EtOAc (100 mL × 2). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0 to 70% EtOAc in petroleum ether) to afford the title compound (1.85 g, 54%) as a yellow oil. 1 H NMR(400 MHz,CDCl3)δ 9.14(s,1H),8.96(d,J=5.6 Hz,2H),8.03-7.94(m,3H),7.38-7.29(m,4H),7.27-7.22(m,1H),5.27(s,2H),4.3 5(s,2H),3.84-3.74(m,2H),1.02-0.94(m,2H),0.03(s,9H).LCMS(ESI)m / z:445.1 [M+H]+.

[0303] Step 4: 6-benzyl-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-ol To a solution of 6-benzyl-2-(pyridin-4-yl)-4-((2-(trimethylsilyl)ethoxy)methoxy)pyrido[3,4-d]pyrimidine (1 g, 1.8 mmol) in DCM (20 mL) was added trifluoroacetic acid (5 mL, 6.73 mmol). The mixture was stirred at room temperature for 16 hours. The mixture was concentrated in vacuo to give the title compound (700 mg, crude) as a brown solid which required no further purification. LCMS (ESI) m / z: 314.9 [M+H] + .

[0304] Step 5: 6-benzyl-4-chloro-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidine TIFF2024521929000222.tif26170 A solution of 6-benzyl-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-ol (700 mg, 2.23 mmol) in phosphorus oxychloride (5 mL) was heated to 110 °C for 16 h. After cooling to room temperature, the mixture was concentrated in vacuo, and the crude residue was dissolved in DCM (100 mL) and basified with saturated aqueous NaHCO (50 mL) to pH 8 at 0 °C. The organic layer was dried over anhydrous NaSO, filtered, and concentrated in vacuo to give the title compound (6.7 g, crude) as a black solid. LCMS (ESI) m / z: 333.1 [M+H] + .

[0305] Step 6: tert-butyl 8-(6-benzyl-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2-carboxylate To a solution of 6-benzyl-4-chloro-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidine (50 mg, 0.15 mmol) in 1-methyl-2-pyrrolidinone (2 mL) was added tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate (40 mg, 0.17 mmol), triethylamine (8.6 mL, 61.81 mmol), and potassium fluoride (46 mg, 0.45 mmol). The mixture was heated to 80 °C under a nitrogen atmosphere for 16 h. After cooling to room temperature, the reaction was diluted with water (20 mL) and extracted with EtOAc (50 mL). The organic layer was washed with brine (20 mL x 3), dried over anhydrous NaSO, filtered and concentrated in vacuo to give the title compound (74 mg, crude) as a yellow solid. LCMS (ESI) m / z: 537.4 [M+H] + .

[0306] Step 7: 6-benzyl-2-(pyridin-4-yl)-4-(2,8-diazaspiro[4.5]decan-8-yl)pyrido[3,4-d]pyrimidine To a solution of tert-butyl 8-(6-benzyl-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2-carboxylate (74 mg, 0.14 mmol) in DCM (1.5 mL) was added trifluoroacetic acid (0.5 mL, 6.54 mmol). The mixture was stirred at room temperature for 2 h. The mixture was concentrated in vacuo, and the residue was purified by reverse-phase chromatography (10-40% acetonitrile / 0.225% formic acid in water) to afford the title compound (17 mg, 27%) as a yellow solid. 1H NMR(400 MHz,DMSO-d6)δ 9.21(s,1H),8.75(d,J=6.0 Hz,2H),8.39(s,1H),8.33-8.26(m,2H),7.67(s,1H),7.35-7.29(m,4H),7.25-7.19(m,1H),4.29(s,2H),3. 95-3.81(m,4H),3.23-3.14(m,2H),2.99(s,2H),1.86-1.80(m,2H),1.77-1.68(m,4H).LCMS(ESI)m / z:437.3 [M+H] + .

[0307] Example 158 6-Methyl-2-(pyridin-4-yl)-4-(2,8-diazaspiro[4.5]decan-8-yl)pyrido[3,4-d]pyrimidine (compound 158) trifluoroacetate TIFF2024521929000225.tif43170Step 1: 6-Methyl-2-(pyridin-4-yl)-4-((2-(trimethylsilyl)ethoxy)methoxy)pyrido[3,4-d]pyrimidine To a stirred solution of 6-chloro-2-(pyridin-4-yl)-4-((2-(trimethylsilyl)ethoxy)methoxy)pyrido[3,4-d]pyrimidine (600 mg, 1.54 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was added methylboronic acid (462 mg, 7.71 mmol), CsCO (1.5 g, 4.63 mmol), and 1,1′-bis(diphenylphosphino)ferrocenepalladium dichloride (115 mg, 0.15 mmol). The mixture was heated to 110° C. under a nitrogen atmosphere for 16 h. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0-5% MeOH in DCM) to afford the title compound (320 mg, 56%) as a yellow solid. LCMS (ESI) m / z: 369.2 [M+H] + .

[0308] Step 2: 6-methyl-2-(pyridin-4-yl)-4-(2,8-diazaspiro[4.5]decan-8-yl)pyrido[3,4-d]pyrimidine trifluoroacetate Following the procedure described in TIFF2024521929000227.tif43170 Example 157, with minor modifications as necessary to replace 6-benzyl-2-(pyridin-4-yl)-4-((2-(trimethylsilyl)ethoxy)methoxy)pyrido[3,4-d]pyrimidine with 6-methyl-2-(pyridin-4-yl)-4-((2-(trimethylsilyl)ethoxy)methoxy)pyrido[3,4-d]pyrimidine, the title compound was obtained as a yellow solid. 1 H NMR(400 MHz,DMSO-d6)δ 9.20(s,1H),8.79-8.74(m,2H),8.34-8.30(m,2H),8.21(s,1H),7.71(s,1H),4.00-3.86(m,4H),3.3 6-3.27(m,2H),3.11(s,2H),2.67(s,3H),1.93-1.88(m,2H),1.85-1.72(m,4H).LCMS(ESI)m / z:361.4 [M+H] + .

[0309] Example 159 N-((2-(pyridin-4-yl)-4-(2,8-diazaspiro[4.5]decan-8-yl)pyrido[3,4-d]pyrimidin-6-yl)methyl)propionamide (Compound 159) TIFF2024521929000228.tif44170Step 1: Ethyl 5-amino-2-bromoisonicotinate To a solution of ethyl 3-aminoisonicotinate (250.0 g, 1.50 mol) in DMF (4000 mL) was added NBS (281 g, 1.58 mol). The mixture was heated to 50° C. and stirred for 5 hours. After the reaction was complete, it was cooled to room temperature, water (12.5 L) was added, and the reaction mixture was extracted with EtOAc (5000 mL × 3). The combined organic layer was washed with brine (10 L × 3). The mixture was dried over anhydrous NaSO and then concentrated under reduced pressure to give a crude product, which was purified by silica gel chromatography (petroleum ether / EtOAc = 10:1) to give ethyl 5-amino-2-bromoisonicotinate (254.4 g, 69.2%) as a yellow solid. LCMS(ESI)m / z:245.0,247.0(Brpattern)[M+H] + . 1 H NMR(400 MHz,DMSO-d6):δ 8.06(d,J=0.4 Hz,1H),7.61(s,1H),6.81(brs,2H),4.33(q,J=7.2 Hz,2H),1.32(t,J=7.2 Hz,3H).

[0310] Step 2: 6-Bromo-2-(4-pyridyl)pyrido[3,4-d]pyrimidin-4-ol TIFF2024521929000230.tif25170 Potassium 2-methyl-2-butoxide (158 g, 1.25 mol) was added to THF (930 mL). Then, a solution of ethyl 5-amino-2-bromoisonicotinate (122.5 g, 499.8 mmol, 1.0 equiv.) and isonicotinonitrile (62.5 g, 599.8 mmol, 1.2 equiv.) in THF (2450 mL) was added dropwise at 0°C under N2. The mixture was stirred at room temperature for 2 hours. After completion of the reaction, water (6.2 L) and AcOH (93 mL) were added. The mixture was stirred at room temperature for 20 minutes. The solid was then collected by filtration and washed with water (500 mL x 3). The solid was dried to give 6-bromo-2-(4-pyridyl)pyrido[3,4-d]pyrimidin-4-ol (145.0 g, 47.9% yield in two batches) as a yellow solid. LCMS (ESI) m / z: 300.9, 302.9 (Br pattern) [M−H] + . 1 H NMR (400 MHz, DMSO-d6): δ 13.21(s,1H),8.99(s,1H),8.82(q,J=3.2 Hz,2H),8.16-8.09(m,3H).

[0311] Step 3: tert-butyl 8-(6-bromo-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2-carboxylate To a solution of 6-bromo-2-(4-pyridyl)pyrido[3,4-d]pyrimidin-4-ol (200 mg, 0.66 mmol) in DMA (5 mL) was added 4-dimethylaminopyridine (8 mg, 0.07 mmol) and N,N-diisopropylethylamine (0.34 mL, 2.0 mmol). 2,4,6-Triisopropylbenzenesulfonyl chloride (240 mg, 0.79 mmol) was added last, and the reaction mixture was stirred at room temperature for 30 minutes. tert-Butyl 2,8-diazaspiro[4.5]decane-2-carboxylate (190 mg, 0.79 mmol) was added, and the reaction mixture was stirred at room temperature for 3 hours. A saturated solution of NaHCO3 (25 mL) and ethyl acetate (40 mL) were added. The phases were separated, and the organic layer was washed with water (30 mL), brine (30 mL), dried over Na2SO4, filtered, and concentrated to give a brown oil. The crude oil was purified by silica gel column chromatography (MeOH / DCM) to give the title compound tert-butyl 8-[6-bromo-2-(4-pyridyl)pyrido[3,4-d]pyrimidin-4-yl]-2,8-diazaspiro[4.5]decane-2-carboxylate (197 mg, 57% yield) as a brown gum. LCMS (ESI) m / z: 525-527 (Br pattern) [M+H] + .

[0312] Step 4: tert-butyl 8-(2-(pyridin-4-yl)-6-vinylpyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2-carboxylate TIFF2024521929000232.tif48170 tert-Butyl 8-[6-bromo-2-(4-pyridyl)pyrido[3,4-d]pyrimidin-4-yl]-2,8-diazaspiro[4.5]decane-2-carboxylate (197 mg, 0.38 mmol) and potassium vinyltrifluoroborate (56 mg, 0.42 mmol) were dissolved in 1,4-dioxane (3 mL), and the solution was degassed with a stream of nitrogen for 10 minutes. Triethylamine (0.11 mL, 0.76 mmol) was added while the solution was degassed for an additional 5 minutes. [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (28 mg, 0.04 mmol) was then added to the reaction mixture, which was capped under nitrogen and heated to 85 °C for 4 hours. The reaction mixture was cooled to room temperature and filtered through Celite. The filtrate was diluted with a saturated solution of sodium bicarbonate (15 mL) and extracted three times with ethyl acetate (20 mL). The organics were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The crude residue was purified by column chromatography on silica gel (MeOH / DCM) to afford the title compound tert-butyl 8-[2-(4-pyridyl)-6-vinyl-pyrido[3,4-d]pyrimidin-4-yl]-2,8-diazaspiro[4.5]decane-2-carboxylate (106 mg, 59% yield) as a brown solid. LCMS (ESI) m / z: 473.1 [M+H] + .

[0313] Step 5: tert-butyl 8-(6-formyl-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2-carboxylate TIFF2024521929000233.tif48170 Under a nitrogen atmosphere, a solution of tert-butyl 8-[2-(4-pyridyl)-6-vinyl-pyrido[3,4-d]pyrimidin-4-yl]-2,8-diazaspiro[4.5]decane-2-carboxylate (106 mg, 0.22 mmol) and NMO (53 mg, 0.45 mmol) in DCM (4 mL) was added with 4% wt aqueous osmium tetroxide (71 μL, 0.01 mmol). The reaction mixture was stirred at room temperature for 16 h. After complete conversion of the olefin to the diol, sodium periodate (72 mg, 0.34 mmol) in water (2 mL) was added, and the mixture was stirred at room temperature for an additional 16 h. The reaction mixture was diluted with dichloromethane, washed with water (100 mL), brine (100 mL), dried over anhydrous sodium sulfate, and evaporated. The crude residue was purified by silica gel column chromatography (MeOH / DCM) to give the title compound tert-butyl 8-[6-formyl-2-(4-pyridyl)pyrido[3,4-d]pyrimidin-4-yl]-2,8-diazaspiro[4.5]decane-2-carboxylate (106 mg, >99% yield) as a yellow solid. LCMS (ESI) m / z: 475.1 [M+H] + .

[0314] Step 6: tert-butyl 8-(6-(((2,4-dimethoxybenzyl)amino)methyl)-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2-carboxylate To a solution of tert-butyl 8-[6-formyl-2-(4-pyridyl)pyrido[3,4-d]pyrimidin-4-yl]-2,8-diazaspiro[4.5]decane-2-carboxylate (80 mg, 0.17 mmol) in dichloromethane (4 mL) was added 2,4-dimethoxybenzylamine (30 μL, 0.2 mmol) and one drop of acetic acid. Sodium triacetoxyborohydride (106 mg, 0.51 mmol) was added, and the reaction mixture was stirred at room temperature for 1 h. After complete conversion to the amine, a saturated solution of sodium bicarbonate (15 mL) was added to the reaction mixture, which was extracted three times with ethyl acetate (3 × 20 mL). The organics were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The compound was used directly in the next step.

[0315] Step 7: tert-butyl 8-(6-((N-(2,4-dimethoxybenzyl)propionamido)methyl)-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2-carboxylate The crude residue from step 4 was re-diluted in dichloromethane (4 mL) containing triethylamine (70 μL, 0.51 mmol), and propionyl chloride (20 μL, 0.19 mmol) was added to the mixture. The reaction mixture was stirred at room temperature for 30 minutes, concentrated to dryness, and loaded directly onto a silica gel chromatography column. Elution with 1 to 12% MeOH in DCM afforded the title compound tert-butyl 8-[6-[[(2,4-dimethoxyphenyl)methyl-propanoylamino]methyl]-2-(4-pyridyl)pyrido[3,4-d]pyrimidin-4-yl]-2,8-diazaspiro[4.5]decane-2-carboxylate (62 mg, 54% yield) as a beige solid. LCMS (ESI) m / z: 682.6 [M+H] + .

[0316] Step 8: N-((2-(pyridin-4-yl)-4-(2,8-diazaspiro[4.5]decan-8-yl)pyrido[3,4-d]pyrimidin-6-yl)methyl)propionamide; Formate To a solution of tert-butyl 8-[6-[[(2,4-dimethoxyphenyl)methyl-propanoylamino]methyl]-2-(4-pyridyl)pyrido[3,4-d]pyrimidin-4-yl]-2,8-diazaspiro[4.5]decane-2-carboxylate (39 mg, 0.06 mmol) in dichloromethane (4 mL) was added HBr in acetic acid (0.3 mL, 1.45 mmol), and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was then concentrated under reduced pressure. The residual solid was loaded directly onto a C18 column in water and purified by reverse-phase column chromatography (MeCN / aqueous 10 mM ammonium formate buffered at pH 3.8). The pure fractions were directly lyophilized to give the title compound N-[[4-(2,8-diazaspiro[4.5]decan-8-yl)-2-(4-pyridyl)pyrido[3,4-d]pyrimidin-6-yl]methyl]propanamide; formate salt (16 mg, 54% yield) as an off-white solid. LCMS (ESI) m / z: 432.3 [M+H] + . 1 H NMR(400 MHz,DMSO-d6)δ 9.21(s,1H),8.74(dd,J=4.6,1.4 Hz,2H),8.55(t,J=5.7 Hz,1H),8.37(s,2H),8.30(dd,J=4.5,1.4 Hz,2H),7.65(s,1H),4.50(d,J=5.8 Hz,2H),3.96-3.80(m,4H),3.19(t,J=7.3 Hz,2H),3.02(s,2H),2.26-2.17(m,2H),1.84(t,J=7.3 Hz,2H),1.81-1.65(m,4H),1.05(t,J=7.6 Hz,3H).

[0317] Example 160 6-Methyl-2-(3-methyl-1H-pyrazol-4-yl)-4-(2,8-diazaspiro[4.5]decan-8-yl)pyrido[3,4-d]pyrimidine (compound 160) formate TIFF2024521929000237.tif43170 Step 1: 6-chloro-2-(3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4-ol Following the procedure described in TIFF2024521929000238.tif30170 Example 142, Step 2, making minor modifications as necessary to replace 3-aminopyridine-4-carboxamide with 5-amino-2-chloroisonicotinamide (prepared according to the procedure in U.S. Patent Application Publication No. 2019270742), the title compound was obtained as an off-white solid. 1 H NMR(400 MHz,DMSO-d6)δ 12.59(s,1H),8.84-8.78(m,1H),8.69-8.28(m,1H),7.91(s,1H),5.54-5.35(m,2H),3.61-3 .51(m,2H),2.78-2.52(m,3H),0.91-0.79(m,2H),0.01--0.09(m,9H).LCMS(ESI)m / z:392.0 [M+H] + .

[0318] Step 2: 4,6-Dichloro-2-(3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidine TIFF2024521929000239.tif30170 To a solution of 6-chloro-2-(3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4-ol (2 g, 5.10 mmol) in phosphorus oxychloride (14 mL) was added N,N-diisopropylethylamine (0.89 mL, 5.1 mmol). The reaction mixture was stirred at room temperature for 16 h and concentrated in vacuo. The crude residue was dissolved in DCM (150 mL) and basified with saturated aqueous NaHCO3 (50 mL) to pH 8 at 0 °C. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0–30% EtOAc in petroleum ether) to afford the title compound (620 mg, 30%) as a yellow solid. LCMS(ESI)m / z:410.4 [M+H] + .

[0319] Step 3: tert-butyl 8-(6-chloro-2-(3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2-carboxylate Following the procedure described in TIFF2024521929000240.tif53170 Example 101, with minor modifications as necessary to replace 4-chloro-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidine with 4,6-dichloro-2-(3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidine, the title compound was obtained as a yellow solid. LCMS (ESI) m / z: 614.2 [M+H] + .

[0320] Step 4: tert-butyl 8-(6-methyl-2-(3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2-carboxylate Following the procedure described in TIFF2024521929000241.tif53170 Example 158, with minor modifications as necessary to replace 6-chloro-2-(pyridin-4-yl)-4-((2-(trimethylsilyl)ethoxy)methoxy)pyrido[3,4-d]pyrimidine with tert-butyl 8-(6-chloro-2-(3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2-carboxylate, the title compound was obtained as a yellow solid. LCMS (ESI) m / z: 594.2 [M+H] + .

[0321] Step 5: 6-methyl-2-(3-methyl-1H-pyrazol-4-yl)-4-(2,8-diazaspiro[4.5]decan-8-yl)pyrido[3,4-d]pyrimidine formate To a solution of tert-butyl 8-(6-methyl-2-(3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2-carboxylate (60 mg, 0.1 mmol) in EtOAc (1 mL) was added 4 M HCl in EtOAc (1 mL, 4.0 mmol). The mixture was stirred at room temperature for 5 h and concentrated in vacuo. The resulting residue was purified by reverse-phase chromatography (1-30% acetonitrile / 0.225% formic acid in water) to afford the title compound (6 mg, 16%) as a white solid. 1 H NMR(400 MHz,DMSO-d6)δ 9.00(s,1H),8.40(s,1H),8.13(s,1H),7.58(s,1H),3.83-3.72(m,4H),3.23-3.17(m ,2H),3.02(s,2H),2.65(s,3H),2.61(s,3H),1.98-1.62(m,6H).LCMS(ESI)m / z:364.1 [M+H] + .

[0322] Example 161 5-chloro-2-(pyridin-4-yl)-4-(2,8-diazaspiro[4.5]decan-8-yl)pyrido[3,4-d]pyrimidine (Compound 161) TIFF2024521929000243.tif43170Step 1: 3,5-Dichloro-N-(imino(pyridin-4-yl)methyl)isonicotinamide TIFF2024521929000244.tif21170 2,6-Dichloroisonicotinic acid (1309 mg, 6.82 mmol) and HATU (2852 mg, 7.5 mmol) were dissolved in DMF (10 mL). DIEA (3.56 mL, 20.5 mmol) was added to this solution and stirred at room temperature for 10 minutes. Pyridine-4-carboxamidine hydrochloride (1289 mg, 8.18 mmol) was then added to the reaction mixture. After 3 hours, a saturated aqueous solution of NaHCO3 (20 mL) was added to the reaction mixture. This was then extracted with EtOAc (2 x 100 mL) and 10% MeOH / DCM (100 mL). The combined organic layers were dried over NaSO, filtered, and concentrated to dryness to give the title compound 3,5-dichloro-N-(imino(pyridin-4-yl)methyl)isonicotinamide (765 mg, 38% yield) as a yellow solid. LCMS (ESI) m / z: 295.1, [M+H] + .

[0323] Step 2: 5-chloro-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-ol TIFF2024521929000245.tif251703,5-Dichloro-N-(pyridine-4-carboximidoyl)pyridine-4-carboxamide (740 mg, 2.51 mmol) was suspended in DMA (6 mL) in a microwave vial. To this was then added KCO (347 mg, 2.51 mmol), DIEA (0.44 mL, 2.51 mmol), and DBU (0.37 mL, 2.51 mmol). The vial was sealed and irradiated in a microwave reactor at 150 °C for 45 min. The reaction mixture was concentrated under airflow, then redissolved in DMF, and purified by C18 reverse-phase chromatography (MeCN / aqueous 10 mM ammonium formate buffered at pH = 3.8). The product containing fractions were combined and lyophilized to give the title compound 5-chloro-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-ol as a yellow solid. LCMS (ESI) m / z: 259.2, [M+H] + .

[0324] Step 3: tert-butyl 8-(5-chloro-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2-carboxylate Following the procedure described in TIFF2024521929000246.tif43170 Example 159, Step 3, with minor modifications as necessary to replace 6-bromo-2-(4-pyridyl)pyrido[3,4-d]pyrimidin-4-ol with 5-chloro-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-ol, the title compound was obtained as a yellow waxy solid (5 mg, 22% yield). LCMS (ESI) m / z: 481.1, [M+H] + .

[0325] Step 4: 5-chloro-2-(pyridin-4-yl)-4-(2,8-diazaspiro[4.5]decan-8-yl)pyrido[3,4-d]pyrimidine TIFF2024521929000247.tif43170 tert-Butyl 8-[5-chloro-2-(4-pyridyl)pyrido[3,4-d]pyrimidin-4-yl]-2,8-diazaspiro[4.5]decane-2-carboxylate (5.0 mg, 0.0100 mmol) was dissolved in 2 mL of EtOAc and treated with 4 N HCl in dioxane (0.5 mL) and stirred at room temperature. After 1 h, the mixture was concentrated to dryness to give a solid residue. The residue was triturated with 3 mL of MeCN and concentrated to dryness again (repeated twice). The resulting residue was dissolved in a mixture of water and MeCN and lyophilized to give the title compound 5-chloro-2-(pyridin-4-yl)-4-(2,8-diazaspiro[4.5]decan-8-yl)pyrido[3,4-d]pyrimidine hydrochloride (4.5 mg, quantitative yield) as a yellow solid. LCMS (ESI) m / z: 381.1, [M+H] + . 1 H NMR(400 MHz,DMSO-d6)δ 9.21(s,1H),9.03(br,1H),8.90-8.83(m,2H),8.67(s,1H),8.49-8.39(m,2H) ,3.86-3.76(m,4H),3.29-3.21(m,2H),3.17-2.95(m,2H),1.89-1.60(m,6H).

[0326] Example 162 5-Methyl-2-(pyridin-4-yl)-4-(2,8-diazaspiro[4.5]decan-8-yl)pyrido[3,4-d]pyrimidine (Compound 162) TIFF2024521929000248.tif43170 Step 1: 3-Bromo-5-fluoro-N-(imino(pyridin-4-yl)methyl)isonicotinamide TIFF2024521929000249.tif22170 Pyridine-4-carboxamidine hydrochloride (1.38 g, 8.75 mmol) and 3-bromo-5-fluoro-pyridine-4-carboxylic acid (2.0 g, 9.1 mmol) were dissolved in DMF (45 mL) with diisopropylethylamine (4.75 mL, 27 mmol). Finally, HATU (3.63 g, 9.55 mmol) was added, and the reaction mixture was stirred at room temperature for 16 h. A saturated solution of sodium bicarbonate (80 mL) was added to the reaction mixture, which was then extracted three times with a 2:8 mixture of iPrOH-CHCl3 (3 × 50 mL). The organic layers were combined, washed thoroughly with water, brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The crude residue was purified by trituration in MeOH. The off-white precipitate was filtered, rinsed with MeOH, and dried to give the title compound 3-bromo-5-fluoro-N-(imino(pyridin-4-yl)methyl)isonicotinamide (1.93 g, 66% yield) as a beige solid. LCMS (ESI) m / z: 323.0 / 325.0 (Br pattern) [M+H] + .

[0327] Step 2: 5-Bromo-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one TIFF2024521929000250.tif25170 3-Bromo-5-fluoro-N-(imino(pyridin-4-yl)methyl)isonicotinamide (1.93 g, 5.96 mmol) was dissolved in DMF (15 mL) and cesium carbonate (3.9 g, 11.9 mmol) was added. The reaction mixture was stirred at 100 °C for 2 h. Upon complete conversion, the reaction mixture was cooled to room temperature and added dropwise to a stirred solution of NH4Cl (sat.) diluted 1:1 with water (150 mL total). An off-white precipitate formed, which was filtered and rinsed with water and acetonitrile. The solid was dried to afford the title compound, 5-bromo-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (1.72 g, 95% yield) as an off-white solid. LCMS(ESI)m / z:302.9 / 304.9(Brpattern)[M+H] + .

[0328] Step 3: 5-methyl-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one A microwave vial was charged with 5-bromo-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (400 mg, 1.32 mmol), methylboronic acid (180 mg, 3.0 mmol), Pd(PPh) (154 mg, 0.13 mmol), and KCO (548 mg, 3.96 mmol). The vial was capped, DMA (6 mL) was added, and the mixture was flushed with N for 5 min and then irradiated in a microwave reactor at 150 °C for 1 h. The volatiles were removed under a stream of air. The crude residue was suspended in MeOH (30 mL) and EtOAc (30 mL), 5 g of silica gel was added, and the mixture was concentrated in vacuo to dry load the material. Purification by column chromatography (MeOH / EtOAc / heptane) afforded the title compound 5-methyl-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one (26 mg, 7% yield) as a yellow solid. LCMS (ESI) m / z: 239.2 [M+H] + .

[0329] Step 4: tert-butyl 8-(5-methyl-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2-carboxylate Following the procedure described in TIFF2024521929000252.tif43170 Example 159, Step 3, with minor modifications as necessary to replace 6-bromo-2-(4-pyridyl)pyrido[3,4-d]pyrimidin-4-ol with 5-methyl-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4(3H)-one, the title compound was obtained as a yellow solid (16 mg, 26% yield). LCMS (ESI) m / z: 461.1 [M+H] + .

[0330] Step 5: 5-Methyl-2-(pyridin-4-yl)-4-(2,8-diazaspiro[4.5]decan-8-yl)pyrido[3,4-d]pyrimidine; formate salt TIFF2024521929000253.tif45170 Step 6: Following the procedure described for Example 159, starting from 16 mg, 0.04 mmol of tert-butyl 8-(5-methyl-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2-carboxylate, 5-methyl-2-(pyridin-4-yl)-4-(2,8-diazaspiro[4.5]decan-8-yl)pyrido[3,4-d]pyrimidine formate (6 mg, 59% yield) was obtained as a beige solid. 1 H NMR(400 MHz,CD3OD)δ 9.10(s,1H),8.72(d,J=5.9 Hz,2H),8.54(bs,1H),8.47(dd,J=4.6,1.6 Hz,2H),8.43(s,1H),3.91-3.68(m,4H),3.41(t,J=7.4 Hz,2H),3.21-3.05(m,2H),2.77(s,3H),2.20-1.94(m,2H),1.92-1.74(m,4H).LCMS(ESI)m / z:361.1 [M+H] + .

[0331] Example 163 8-Methyl-2-(3-methyl-1H-pyrazol-4-yl)-4-(2,8-diazaspiro[4.5]decan-8-yl)pyrido[3,4-d]pyrimidine (Compound 163) Following the procedure described in TIFF2024521929000254.tif43170 Example 142, making minor modifications as necessary to replace 3-aminopyridine-4-carboxamide with 3-amino-2-methylisonicotinamide (prepared according to the procedure in Synthesis, 2016, 48, 1226), the title compound was obtained as a yellow solid. 1H NMR(400 MHz,DMSO-d6)δ 8.34(s,1H),8.30(d,J=5.6 Hz,1H),8.17(s,1H),7.58(d,J=5.6 Hz,1H),3.84-3.76(m,4H),3.13(t,J=7.2 Hz,2H),2.94(s,2H),2.85(s,3H),2.68(s,3H),1.80(t,J=7.6 Hz,2H),1.76-1.71(m,4H).LCMS(ESI)m / z:364.1 [M+H] + .

[0332] Example 164 8-(2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decan-3-one (Compound 164) Following the procedure described in TIFF2024521929000255.tif48170 Example 101, Step 3, making minor modifications as necessary to replace tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate with 2,8-diazaspiro[4.5]decan-3-one, the title compound was obtained. 1 H NMR(400 MHz,DMSO-d6)δ 9.27(d,J=0.8 Hz,1H),8.80-8.75(m,2H),8.60(d,J=5.7 Hz,1H),8.36-8.31(m,2H),7.90(dd,J=5.8,0.9 Hz,1H),7.60(s,1H),4.12-4.01(m,2H),3.94-3.84(m,2H),3.17(s,2H),2.21(s,2H),1.87-1.75(m,4H).LCMS(ESI)m / z:361.1 [M+H] + .

[0333] Example 165 8-(2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decan-1-one (Compound 165) Following the procedure described in TIFF2024521929000256.tif43170 Example 101, Step 3, making minor modifications as necessary to replace tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate with 2,8-diazaspiro[4.5]decan-1-one hydrochloride, the title compound was obtained as a solid. 1 H NMR(400 MHz,DMSO-d6)δ 9.28(d,J=0.8 Hz,1H),8.80-8.75(m,2H),8.60(d,J=5.7 Hz,1H),8.36-8.31(m,2H),7.93(dd,J=5.7,0.9 Hz,1H),7.67(s,1H),4.52-4.42(m,2H),3.67-3.57(m,2H),3.28-3.21(m,2H), 2.14-2.07(m,2H),1.99-1.88(m,2H),1.67-1.57(m,2H).LCMS(ESI)m / z:361.01 [M+H] + .

[0334] Example 166 4-(1-methyl-2,8-diazaspiro[4.5]decan-8-yl)-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidine (Compound 166) TIFF2024521929000257.tif43170Step 1: Benzyl 1-methyl-2,8-diazaspiro[4.5]decane-2-carboxylate trifluoroacetate To a solution of 2-benzyl 8-tert-butyl 1-methyl-2,8-diazaspiro[4.5]decane-2,8-dicarboxylate (200 mg, 0.51 mmol) (prepared according to J. Org. Chem., 2016, 81, 3509) in DCM (4 mL) was added trifluoroacetic acid (2 mL, 2.69 mmol). The mixture was stirred at room temperature for 1 hour. The mixture was concentrated in vacuo to give the title compound (200 mg, crude) as a yellow oil that required no further purification. LCMS (ESI) m / z: 289.3 [M+H] + .

[0335] Step 2: Benzyl 1-methyl-8-(2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2-carboxylate Following the procedure described in TIFF2024521929000259.tif48170 Example 102, making minor modifications as necessary to replace tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate with benzyl 1-methyl-2,8-diazaspiro[4.5]decane-2-carboxylate trifluoroacetate, the title compound was obtained as a yellow solid. LCMS (ESI) m / z: 495.6 [M+H] + .

[0336] Step 3: 4-(1-methyl-2,8-diazaspiro[4.5]decan-8-yl)-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidine To a solution of benzyl 1-methyl-8-(2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2-carboxylate (60 mg, 0.12 mmol) in AcOH (1 mL) was added HBr (1 mL, 33% in AcOH). The mixture was stirred at room temperature for 16 h. The mixture was concentrated in vacuo. The residue was purified by reverse-phase chromatography (6-36% acetonitrile / 0.225% formic acid in water) to afford the title compound (18 mg, 41%) as a white solid. 1 H NMR(400 MHz,DMSO-d6)δ 9.27(s,1H),8.77(d,J=4.8 Hz,2H),8.60(d,J=5.2 Hz,1H),8.35-8.32(m,3H),7.92(d,J=5.2 Hz,1H),4.53-4.45(m,2H),3.54-3.42(m,3H),3.23-3.16(m,2H),2.25-2.19(m,1H),1.92- 1.72(m,2H),1.70-1.68(m,1H),1.66-1.54(m,2H),1.21-1.13(m,3H).LCMS(ESI)m / z:361.1 [M+H] + .

[0337] Example 167 4-(3-methyl-2,8-diazaspiro[4.5]decan-8-yl)-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidine (Compound 167) Following the procedure described in TIFF2024521929000261.tif47170 Example 166, making minor modifications as necessary to replace 2-benzyl 8-tert-butyl 1-methyl-2,8-diazaspiro[4.5]decane-2,8-dicarboxylate with 2-benzyl 8-tert-butyl 3-methyl-2,8-diazaspiro[4.5]decane-2,8-dicarboxylate (prepared according to the procedure in J. Org. Chem. 2016, 81, 3509), the title compound was obtained as a yellow solid. 1 H NMR(400 MHz,DMSO-d6)δ 9.27(s,1H),8.79-8.75(m,2H),8.60(d,J=5.6 Hz,1H),8.36(s,1H),8.34-8.32(m,2H),7.90(d,J=5.6 Hz,1H),4.01-3.90(m,4H),3.59-3.54(m,1H),3.10-2.96(m,2H),2.17-2.10(m,1H),1.84-1.76(m,4H),1.44-1.35(m,1H),1.27(d,J=6.4 Hz,3H).LCMS(ESI)m / z:361.4 [M+H] + .

[0338] Example 168 4-(2,3-dimethyl-2,8-diazaspiro[4.5]decan-8-yl)-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidine (Compound 168) Following the procedure described in TIFF2024521929000262.tif48170 Example 102, with minor modifications as necessary to replace 4-(2,8-diazaspiro[4.5]decan-8-yl)-2-(4-pyridyl)pyrido[3,4-d]pyrimidine hydrochloride with 4-(3-methyl-2,8-diazaspiro[4.5]decan-8-yl)-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidine, the title compound was obtained as a yellow solid. 1 H NMR(400 MHz,DMSO-d6)δ 9.25(s,1H),8.76(d,J=5.2 Hz,2H),8.58(d,J=5.6 Hz,1H),8.31(d,J=5.6 Hz,2H),7.87(d,J=5.6 Hz,1H),4.06-3.78(m,5H),3.47-3.43(m,1H),3.12-3.08(m,1H),2.29(s,3 H),1.99-1.93(m,1H),1.81-1.66(m,4H),1.38-1.32(m,1H),1.11(d,J=5.6 Hz,3H).LCMS(ESI)m / z:375.1 [M+H] + .

[0339] Examples 169 and 170 (1S,3R)-3-(8-(2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decan-2-yl)cyclopentanol and (1R,3S)-3-(8-(2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decan-2-yl)cyclopentanol (compounds 169 and 170) formate TIFF2024521929000263.tif54170 Step 1: trans-3-((tert-butyldimethylsilyl)oxy)cyclopentanol A solution of 1,3-cyclopentanediol (2.3 mL, 24.5 mmol, trans:cis = 2:1) and imidazole (2.5 g, 37.0 mmol) in DCM (30 mL) was stirred for 10 min. TBSCl (3.7 g, 24.5 mmol) was then added to the reaction mixture, which was stirred at room temperature for 16 h. The mixture was diluted with DCM (50 mL) and washed with water (30 mL) and brine (30 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0–10% EtOAc in petroleum ether) to afford the title compound (2.7 g, 51%) as a yellow oil. 1 H NMR(400 MHz,CDCl3)δ 4.49-4.35(m,2H),2.13-1.97(m,2H),1.84-1.77(m,2H),1.61-1.45(m,2H),0.87(s,9H),0.04(s,6H).

[0340] Step 2: trans-3-((tert-butyldimethylsilyl)oxy)cyclopentyl methanesulfonate To a solution of trans-3-((tert-butyldimethylsilyl)oxy)cyclopentanol (1.0 g, 4.62 mmol) and triethylamine (1.6 mL, 11.6 mmol) in DCM (10 mL) was added methanesulfonyl chloride (0.43 mL, 5.55 mmol). The solution was stirred at room temperature for 2 h. The mixture was diluted with DCM (50 mL) and washed with water (30 mL) and brine (30 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give the title compound (1.1 g, crude) as a yellow oil that required no further purification.

[0341] Step 3: cis-4-(2-(3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-2,8-diazaspiro[4.5]decan-8-yl)-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidine To a solution of 4-(2,8-diazaspiro[4.5]decan-8-yl)-2-(4-pyridyl)pyrido[3,4-d]pyrimidine hydrochloride (500 mg, 1.31 mmol), trans-3-((tert-butyldimethylsilyl)oxy)cyclopentyl methanesulfonate (800 mg, 2.7 mmol) in DMF (10 mL) and acetonitrile (2 mL) was added K2CO3 (541 mg, 3.92 mmol). The mixture was heated to 90 °C and stirred for 16 h. After cooling to room temperature, the mixture was diluted with EtOAc (100 mL) and washed with water (50 mL × 3) and brine (50 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0-5% MeOH in DCM) to afford the title compound (220 mg, 31%) as a yellow solid. LCMS (ESI) m / z: 545.1 [M+H] + .

[0342] Step 4: cis-3-(8-(2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decan-2-yl)cyclopentanol To a solution of cis-4-(2-(3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-2,8-diazaspiro[4.5]decan-8-yl)-2-(pyridin-4-yl)pyrido[3,4-d]pyrimidine (220 mg, 0.4 mmol) in THF (10 mL) was added TBAF (2.4 mL, 2.4 mmol, 1 M). The solution was stirred at room temperature for 16 h. The mixture was concentrated in vacuo. The crude residue was purified by reverse-phase chromatography (5-35% acetonitrile / 0.225% formic acid in water) to afford the title compound (80 mg, 46%) as a yellow solid. LCMS (ESI) m / z: 431.2 [M+H] + .

[0343] Step 5: (1S,3R)-3-(8-(2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decan-2-yl)cyclopentanol and (1R,3S)-3-(8-(2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decan-2-yl)cyclopentanol formate TIFF2024521929000268.tif54170 cis-3-(8-(2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decan-2-yl)cyclopentanol (80 mg, 0.19 mmol) was separated by using chiral SFC (Chiralpak-AD (250 mm * 30 mm, 10 um), supercritical CO2 / EtOH + 0.1% NH3·H2O = 50 / 50; 80 mL / min) to give the title compound as a white solid. The absolute configuration was arbitrarily assigned to each enantiomer. Example 169 (40 mg, first peak): 1 H NMR(400 MHz,DMSO-d6)δ 9.25(s,1H),8.76(d,J=6.0 Hz,2H),8.58(d,J=5.6 Hz,1H),8.31(d,J=6.0 Hz,2H),7.87(d,J=6.0 Hz,1H),4.05-3.95(m,3H),3.89-3.83(m,2H),2.68-2.65(m,2H),2.58-2.52(m,3 H),2.11-2.00(m,1H),1.81-1.65(m,9H),1.55-1.36(m,2H).LCMS(ESI)m / z:431.2 [M+H] + Example 170 (33 mg, second peak): 1H NMR(400 MHz,DMSO-d6)δ 9.24(s,1H),8.76(d,J=5.6 Hz,2H),8.58(d,J=5.6 Hz,1H),8.31(d,J=5.6 Hz,2H),8.27(s,1H),7.86(d,J=6.0 Hz,1H),4.07-4.03(m,1H),4.00-3.95(m,2H),3.92-3.83(m,2H),2.83-2.72(m,2H),2.75-2.69(m ,1H),2.66(s,2H),2.12-2.00(m,1H),1.80-1.65(m,9H),1.56-1.41(m,2H).LCMS(ESI)m / z:431.2 [M+H] + .

[0344] Example 171 Methyl 8-(2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate (Compound 171) TIFF2024521929000269.tif51170 Step 1: 2-(tert-butyl)3-methyl 8-(2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate TIFF2024521929000270.tif51170 4-Chloro-2-(4-pyridyl)pyrido[3,4-d]pyrimidine (770 mg, 3.2 mmol) and potassium fluoride (550 mg, 9.5 mmol, 3 equiv.) were added to a 20 mL vial. 2-tert-Butyl 3-methyl 2,8-diazaspiro[4.5]decane-2,3-dicarboxylate hydrochloride (1100 mg, 3.2 mmol, 1 equiv.) was added to a 20 mL vial, followed by the addition of dimethyl sulfoxide (11 mL, 0.3 M) and triethylamine (2.2 mL, 16 mmol, 5 equiv.). The reaction was stirred at room temperature for 45 minutes. The reaction mixture was transferred to a separatory funnel and diluted with water (10 mL), saturated aqueous NH4Cl (10 mL), and EtOAc (20 mL), and the layers were separated. The aqueous layer was extracted with additional EtOAc (3 x 15 mL), and the combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was further concentrated under reduced pressure in a Genevac for 16 hours to remove residual DMSO. The crude residue was then flushed through a 24 g Isco cartridge eluting with 0 to 15% MeOH in DCM to give 2-(tert-butyl)3-methyl 8-(2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (1.12 g, 70% yield). LCMS (ESI) m / z: 527.2 [M+Na] + .

[0345] Step 2: Methyl 8-(2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate TIFF2024521929000271.tif51170 2-(tert-Butyl)3-methyl 8-(2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate was dissolved in 1 mL of DCM and 1 mL of TFA. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was then concentrated in vacuo and then further concentrated 2-fold from DCM (5 mL) to remove residual TFA. The crude residue was then purified by HPLC to give methyl 8-(2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate. 1 H NMR (400 MHz, DMSO-d6) δ 1 H NMR(400 MHz,DMSO)δ 9.27(d,J=3.3 Hz,1H),8.79-8.74(m,2H),8.59(dd,J=5.7,2.6 Hz,1H),8.35-8.30(m,2H),7.90(d,J=5.7 Hz,1H),4.05-3.86(m,4H),3.85-3.74(m,1H),3.65(s,3H),3.23-2.97(m,1H),2.85-2.78(m,1H), 2.25-2.14(m,1H),2.12-2.02(m,1H),2.02-1.89(m,1H),1.84-1.67(m,4H).LCMS(ESI)m / z:405.2 [M+H] + .

[0346] Example 172 N-methyl-8-(2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxamide (Compound 172) TIFF2024521929000272.tif51170 Step 1: 2-(tert-butoxycarbonyl)-8-(2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid TIFF2024521929000273.tif51170 2-(tert-butyl)3-methyl 8-(2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (1100 mg, 2.2 mmol) was added to a 20 mL vial, followed by tetrahydrofuran (9700 mg, 11 mL, 130 mmol, 0.2 M), water (11000 mg, 11 mL, 610 mmol, 0.2 M), and lithium hydroxide (100 mg, 0.046 mL, 4.4 mmol, 2 equiv.). After stirring at room temperature for 1 h, the mixture was diluted with DCM (10 mL), and the reaction was carefully quenched with 1 N HCl. The aqueous layer was tested with pH paper to confirm neutral / acidic. The layers were separated and the aqueous layer was extracted with 1×15 mL of DCM and 8×15 mL of 80% CHCl3 / 20% IPA solution. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was concentrated in vacuo 1× from PhMe (10 mL) to solidify the product and give the title compound (700 mg, 1.43 mmol, 700 mg, 65% yield). LCMS (ESI) m / z: 547.3 [M+H] + .

[0347] Step 2: N-methyl-8-(2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxamide To a 20 mL vial was added 2-(tert-butoxycarbonyl)-8-(2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (50 mg, 0.102 mmol, 1 equiv.), HATU (48 mg, 0.12 mmol, 1.2 equiv.), followed by DMF (1.1 mL), N,N-diisopropylethylamine (66 mg, 5 equiv.), and methylamine (2 M in THF solution, 0.11 mL, 2 equiv.). The reaction was stirred at room temperature for 2 h and then concentrated on a Genevac for 16 h. The crude residue was then dissolved in DCM (5 mL) and water (5 mL). The layers were separated; the aqueous layer was extracted with DCM (4 × 5 mL). The combined organic extracts were dried over NaSO, filtered, and concentrated in vacuo. To this crude residue, 0.5 mL of DCM and 0.5 mL of TFA were added and stirred at room temperature for 1 hour. The reaction mixture was then concentrated in vacuo and then further concentrated 2-fold from DCM (5 mL) to remove as much residual TFA as possible. The crude residue was then purified by HPLC to give N-methyl-8-[2-(4-pyridyl)pyrido[3,4-d]pyrimidin-4-yl]-2,8-diazaspiro[4.5]decane-3-carboxamide (4.1 mg, 10% yield). 1 H NMR(400 MHz,DMSO-d6)δ 9.26(s,1H),8.80-8.73(m,2H),8.59(d,J=5.7 Hz,1H),8.36-8.30(m,2H),7.97-7.91(m,1H),7.90(d,J=5.7 Hz,1H),3.98(t,J=5.6 Hz,2H),3.95-3.89(m,2H),3.65(t,J=8.1 Hz,1H),2.88(d,J=10.8 Hz,1H),2.70(d,J=10.8 Hz,1H),2.62(d,J=4.8 Hz,3H),2.08(dd,J=12.9,8.7 Hz, 1H), 1.75-1.68 (m, 4H), 1.58 (dd, J = 12.9, 7.5 Hz, 1H). No exchangeable NH amine protons were observed. LCMS (ESI) m / z: 404.2 [M+H] + .

[0348] Example 173 N,N-Dimethyl-8-(2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxamide (Compound 173) TIFF2024521929000275.tif51170 Following the procedure described in Example 172, Step 2, and minor modifications where necessary to replace methylamine with dimethylamine, the title compound was obtained (4.11 mg, 10% yield). 1 H NMR (400 MHz, DMSO-d6) δ 1 H NMR (400 MHz, DMSO) δ 9.26 (s, 1H), 8.80-8.72 (m, 2H), 8.59 (d, J = 5.8 Hz, 1H), 8.35-8.31 (m, 2H), 7.89 (d, J = 5.7 Hz, 1H), 4.05-3.84 (m, 5H), 3.00 (s, 3H), 2.97 (d, J = 11.0 Hz, 1H), 2.86 (s, 3H), 2.64 (d, J = 11.1 Hz, 1H), 2.07 (dd, J = 12.8, 8.9 Hz, 1H), 1.83-1.63 (m, 4H), 1.59 (dd, J = 12.8, 6.9 Hz, 1H). No exchangeable NH amine protons were observed. LCMS(ESI)m / z:418.2 [M+H] + .

[0349] Example 174 (8-(2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decan-3-yl)(pyrrolidin-1-yl)methanone (compound 174) TIFF2024521929000276.tif51170 After performing the procedure described in Example 172, Step 2 and minor modifications required to replace methylamine with pyrrolidine, the title compound was obtained (8.6 mg, 19% yield). 1H NMR(400 MHz,DMSO-d6)δ 9.26(s,1H),8.81-8.73(m,2H),8.59(d,J=5.6 Hz,1H),8.36-8.30(m,2H),7.90(d,J=5.7 Hz,1H),4.03-3.82(m,5H),3.54(dt,J=10.1,6.6 Hz,1H),3.41-3.34(m,2H),2.96(d,J=11.0 Hz,1H),2.64(d,J=11.0 Hz,1H),2.06(dd,J=12.7,8.7 Hz, 1H), 1.92-1.84 (m, 2H), 1.83-1.66 (m, 7H), 1.62 (dd, J = 12.7, 6.9 Hz, 1H). No exchangeable NH protons were observed. LCMS (ESI) m / z: 444.2 [M+H] + .

[0350] Example 175 Morpholino(8-(2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decan-3-yl)methanone (Compound 175) TIFF2024521929000277.tif51170 After performing the procedure described in Example 172, Step 2 and minor modifications required to replace methylamine with morpholine, the title compound was obtained (4.3 mg, 7.5% yield). 1 H NMR(400 MHz,DMSO-d6)δ 9.26(s,1H),8.79-8.73(m,2H),8.59(d,J=5.6 Hz,1H),8.36-8.31(m,2H),7.90(d,J=5.7 Hz,1H),4.04-3.82(m,5H),3.57(q,J=5.8 Hz,5H),3.53-3.44(m,4H),2.96(d,J=11.0 Hz,1H),2.65(d,J=11.1 Hz,1H),2.04(dd,J=12.9,9.0 Hz, 1H), 1.81-1.73 (m, 2H), 1.73-1.67 (m, 1H), 1.64 (dd, J = 12.8, 6.8 Hz, 1H). No exchangeable NH amine protons were observed. LCMS (ESI) m / z: 460.2 [M+H] + .

[0351] Examples 176 and 177 (3R,4S)-4-(8-(2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decan-2-yl)tetrahydrofuran-3-ol and (3S,4R)-4-(8-(2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decan-2-yl)tetrahydrofuran-3-ol (Compounds 176 and 177) Following the procedure described in TIFF2024521929000278.tif51170 Example 128, with minor modifications necessary to replace 1,2-epoxycyclopentane with 3,6-dioxabicyclo[3.1.0]hexane, trans-4-(8-(2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decan-2-yl)tetrahydrofuran-3-ol was obtained as a mixture of enantiomers. Separation by chiral SFC afforded the title compound. The absolute stereochemistry of the product was arbitrarily assigned. Example 176: 1 H NMR(400 MHz,DMSO-d6)δ 9.25(s,1H),8.80-8.72(m,2H),8.58(d,J=5.6 Hz,1H),8.36-8.28(m,2H),7.88(d,J=5.6 Hz,1H),5.00(d,J=4.4 Hz,1H),4.20-4.10(m,1H),4.05-3.94(m,2H),3.93-3.85(m,2H),3.85-3.81(m,1H),3.80-3.74(m,1H),3.61-3.54(m,1 H),3.51-3.45(m,1H),2.65-2.58(m,3H),2.56-2.52(m,1H),2.48-2.43(m,1H),1.80-1.63(m,6H).LCMS(ESI)m / z:433.1 [M+H] + Example 177: 1H NMR(400 MHz,DMSO-d6)δ 9.26(s,1H),8.83-8.72(m,2H),8.59(d,J=5.6 Hz,1H),8.37-8.28(m,2H),7.89(d,J=5.6 Hz,1H),5.00(d,J=4.4 Hz,1H),4.19-4.12(m,1H),4.07-3.94(m,2H),3.93-3.85(m,2H),3.85-3.81(m,1H),3.80-3.75(m,1H),3.60-3.54(m,1 H),3.51-3.43(m,1H),2.66-2.58(m,3H),2.56-2.52(m,1H),2.48-2.43(m,1H),1.80-1.64(m,6H).LCMS(ESI)m / z:433.1 [M+H] + .

[0352] Examples 178 and 179 (1R,2R)-2-(8-(2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decan-2-yl)cyclobutan-1-ol and (1S,2S)-2-(8-(2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decan-2-yl)cyclobutan-1-ol (Compounds 178 and 179) TIFF2024521929000279.tif48170Step 1: 2-(8-(2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decan-2-yl)cyclobutanone To a solution of 4-(2,8-diazaspiro[4.5]decan-8-yl)-2-(4-pyridyl)pyrido[3,4-d]pyrimidine hydrochloride (400 mg, 1 mmol) in MeOH (5 mL) was added N,N-diisopropylethylamine (0.2 mL, 0.12 mmol). The reaction mixture was stirred at room temperature for 5 minutes, and then 1,2-bis((trimethylsilyl)oxy)cyclobut-1-ene (0.3 mL, 1.1 mmol) was added. The mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated in vacuo. The crude residue was purified by silica gel chromatography (solvent gradient: 0-5% MeOH in DCM) to afford the title compound (300 mg, 69%) as a yellow solid. LCMS (ESI) m / z: 415.0 [M+H] + .

[0353] Step 2: trans-2-(8-(2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decan-2-yl)cyclobutanol and cis-2-(8-(2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decan-2-yl)cyclobutanol To a solution of 2-(8-(2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decan-2-yl)cyclobutanone (300 mg, 0.72 mmol) in MeOH (7 mL) was added sodium borohydride (80 mg, 2.2 mmol). The mixture was stirred at room temperature for 2 h. The reaction was poured into saturated aqueous NH4Cl (20 mL) and extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by reverse-phase chromatography (28-58% acetonitrile / 0.225% formic acid in water) to give both the racemic trans isomer (35 mg, 12%) and cis isomer (36 mg, 12%) as yellow solids. LCMS (ESI) m / z: 417.3 [M+H] + .

[0354] Step 3: (1R,2R)-2-(8-(2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decan-2-yl)cyclobutan-1-ol and (1S,2S)-2-(8-(2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decan-2-yl)cyclobutan-1-ol TIFF2024521929000282.tif48170 trans-2-(8-(2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decan-2-yl)cyclobutan-1-ol (35 mg, 0.08 mmol) was separated using chiral SFC (Chiralpak IG (250 mm * 30 mm, 10 um), supercritical CO2 / IPA + 0.1% NH4OH = 40 / 60; 80 mL / min) to give the title compound as a white solid. The absolute configuration was arbitrarily assigned to each enantiomer. Example 178 (10 mg, first peak): 1 H NMR(400 MHz,DMSO-d6)δ 9.26(s,1H),8.77(d,J=5.6 Hz,2H),8.59(d,J=6.0 Hz,1H),8.32(d,J=5.6 Hz,2H),7.89(d,J=5.6 Hz,1H),5.17(s,1H),4.03-3.81(m,5H),2.61-2.53(m,3H),2.47(s,2H),2.43-2.36(m,1H),1. 99-1.90(m,1H),1.81-1.66(m,6H),1.50-1.36(m,1H),1.26-1.21(m,1H).LCMS(ESI)m / z:417.1 [M+H] + Example 179 (5 mg, second peak): 1H NMR(400 MHz,DMSO-d6)δ 9.26(s,1H),8.77(d,J=5.6 Hz,2H),8.59(d,J=5.6 Hz,1H),8.32(d,J=5.6 Hz,2H),7.89(d,J=6.0 Hz,1H),5.08(d,J=7.2 Hz,1H),4.03-3.94(m,2H),3.92-3.84(m,2H),3.82-3.72(m,1H),2.61-2.53(m,3H),2.47(s,2H),2.43-2.36(m,1H), 1.99-1.90(m,1H),1.76-1.71(m,3H),1.69-1.61(m,3H),1.45-1.34(m,1H),1.26-1.21(m,1H).LCMS(ESI)m / z:417.1 [M+H] + .

[0355] Examples 180 and 181 (1S,2R)-2-(8-(2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decan-2-yl)cyclobutan-1-ol and (1R,2S)-2-(8-(2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decan-2-yl)cyclobutan-1-ol (Compounds 180 and 181) TIFF2024521929000283.tif48170 cis-2-(8-(2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decan-2-yl)cyclobutan-1-ol (35 mg, 0.08 mmol) was separated by using chiral SFC (Chiralpak IG (250 mm * 30 mm, 10 um), supercritical CO2 / IPA + 0.1% NH4OH = 40 / 60, 80 mL / min) to give the title compounds both as white solids. The absolute configuration was arbitrarily assigned to each enantiomer. Example 180 (13 mg, first peak): 1H NMR(400 MHz,DMSO-d6)δ 9.25(s,1H),8.76(d,J=5.6 Hz,2H),8.58(d,J=5.6 Hz,1H),8.32(d,J=5.6 Hz,2H),7.88(d,J=6.0 Hz,1H),4.79(s,1H),4.08(d,J=4.4 Hz,1H),4.01-3.84(m,4H),2.89-2.86(m,1H),2.78-2.69(m,1H),2.66-2.56(m,2 H),2.09-1.97(m,1H),1.87-1.66(m,9H),1.26-1.21(m,1H).LCMS(ESI)m / z:417.1 [M+H] + Example 181 (12 mg, second peak): 1 H NMR(400 MHz,DMSO-d6)δ 9.25(s,1H),8.76(d,J=5.6 Hz,2H),8.58(d,J=5.6 Hz,1H),8.32(d,J=5.6 Hz,2H),7.89(d,J=5.6 Hz,1H),4.67(s,1H),4.09-4.02(m,1H),4.01-3.85(m,4H),2.85-2.77(m,1H),2.72-2.63(m,1H),2.60-2.5 7(m,1H),2.44-2.39(m,1H),2.08-1.94(m,1H),1.83-1.65(m,9H),1.26-1.21(m,1H).LCMS(ESI)m / z:417.1 [M+H] + .

[0356] Example 182 2-(3-fluoropyridin-4-yl)-4-(2,8-diazaspiro[4.5]decan-8-yl)pyrido[3,4-d]pyrimidine (Compound 182) Following the procedure described in TIFF2024521929000284.tif40170 Example 153, Step 2, making minor modifications as necessary to replace 3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole with (3-fluoropyridin-4-yl)boronic acid, the title compound was obtained. 1H NMR(400 MHz,CD3OD)δ 9.20(s,1H),8.60(d,J=3.2 Hz,1H),8.56(d,J=6.0 Hz,1H),8.52(d,J=4.8 Hz,1H),8.17-8.12(m,1H),7.93(d,J=5.6 Hz,1H),4.14-4.06(m,2H),4.00-3.94(m,2H),3.14(t,J=7.2 Hz,2H),2.94(s,2H),1.88(t,J=7.2 Hz,2H),1.84-1.78(m,4H).LCMS(ESI)m / z:365.3 [M+H] + .

[0357] Example 183 4-(4-(2,8-diazaspiro[4.5]decan-8-yl)pyrido[3,4-d]pyrimidin-2-yl)nicotinonitrile (Compound 183) Following the procedure described in TIFF2024521929000285.tif44170 Example 153, Step 2, with minor modifications required to replace 3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile, the title compound was obtained. 1 H NMR(400 MHz,CD3OD)δ 9.30(s,1H),9.07(s,1H),8.94(d,J=5.2 Hz,1H),8.63-8.57(m,2H),8.50(s,1H),7.98(d,J=6.0 Hz,1H),4.30-4.20(m,2H),4.15-4.05(m,2H),3.45(t,J=7.2 Hz,2H),3.24(s,2H),2.10(t,J=7.2 Hz,2H),1.96-1.86(m,4H).LCMS(ESI)m / z:372.3 [M+H] + .

[0358] Examples 184 and 185 (1R,2R)-2-(8-(2-(5-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decan-2-yl)cyclopentan-1-ol and (1S,2S)-2-(8-(2-(5-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decan-2-yl)cyclopentan-1-ol (Compounds 184 and 185) Following the procedure described in TIFF2024521929000286.tif50170 Example 128, minor modifications were made as necessary to replace 4-(2,8-diazaspiro[4.5]decan-8-yl)-2-(4-pyridyl)pyrido[3,4-d]pyrimidine with 2-(5-methyl-1H-pyrazol-4-yl)-4-(2,8-diazaspiro[4.5]decan-8-yl)pyrido[3,4-d]pyrimidine, to obtain trans-2-(8-(2-(5-methyl-1H-pyrazol-4-yl)pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decan-2-yl)cyclopentan-1-ol as a mixture of enantiomers. Separation by chiral SFC afforded the title compound. The absolute stereochemistry of the product was arbitrarily assigned. Example 184: 1 H NMR(400 MHz,DMSO-d6)δ 12.86(s,1H),9.07(s,1H),8.43(d,J=5.6 Hz,1H),8.09(s,1H),7.75(d,J=5.6 Hz,1H),4.49(d,J=4.8 Hz,1H),3.98-3.80(m,3H),3.79-3.69(m,2H),2.71-2.63(m,2H),2.63-2.57(m,2H),2.55-2.52(m,1H),2.49-2.42(m,3 H),2.34-2.24(m,1H),1.83-1.74(m,2H),1.73-1.66(m,3H),1.65-1.61(m,2H),1.60-1.32(m,4H).LCMS(ESI)m / z:434.2 [M+H] + Example 185: 1H NMR(400 MHz,DMSO-d6)δ 12.85(s,1H),9.07(s,1H),8.43(d,J=5.6 Hz,1H),8.08(s,1H),7.75(d,J=5.6 Hz,1H),4.48(d,J=4.8 Hz,1H),3.96-3.79(m,3H),3.78-3.68(m,2H),2.71-2.63(m,2H),2.62-2.57(m,2H),2.55-2.52(m,1H),2.48-2.40(m,3 H),2.35-2.24(m,1H),1.83-1.74(m,2H),1.73-1.67(m,3H),1.65-1.62(m,2H),1.61-1.28(m,4H).LCMS(ESI)m / z:434.2 [M+H] + .

[0359] Example 186 5-Fluoro-2-(5-methyl-1H-pyrazol-4-yl)-4-(2,8-diazaspiro[4.5]decan-8-yl)pyrido[3,4-d]pyrimidine (Compound 186) Following the procedure described in TIFF2024521929000287.tif40170 Example 142, Step 2, with minor modifications as necessary to replace 3-aminopyridine-4-carboxamide with 3-amino-5-fluoroisonicotinamide, the title compound was obtained as an off-white solid. 1 H NMR(400 MHz,DMSO-d6)δ 8.92(s,1H),8.43-8.38(m,2H),8.16(s,1H),3.68-3.64(m,4H),3.17-3.12(m,2H),2 .96(s,2H),2.65(s,3H),1.83-1.76(m,2H),1.74-1.65(m,4H).LCMS(ESI)m / z:368.0 [M+H] + .

[0360] Example 187 8-(2-(pyridin-4-yl)pyrido[3,4-d]pyrimidin-4-yl)-2,8-diazaspiro[4.5]decan-4-ol (Compound 187) TIFF2024521929000288.tif40170Step 1: Benzyl 4-hydroxy-1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate To a solution of 1-benzyl 4-methylpiperidine-1,4-dicarboxylate (5.0 g, 18.0 mmol) in THF (50 mL) at −78° C. was added LiHMDS (39.7 mL, 39.7 mmol, 1 M). The reaction mixture was warmed to room temperature and stirred for 1 hour, then cooled to −78° C., and tert-butyl (2-oxoethyl)carbamate (3.4 g, 21.6 mmol) in THF (25 mL) was added to the reaction mixture at −78° C. The reaction was then warmed to room temperature and stirred for 16 hours. The reaction was quenched with saturated aqueous NH4Cl (30 mL) and extracted with EtOAc (80 mL × 2). The combined organic layers were dried over anhydrous Na2SO4, filtered, and conc...

Claims

1. Compound of formula (I): or its N-oxide or a pharmaceutically acceptable salt thereof, R １ is a 6-membered heteroaryl having one or two ring nitrogen atoms, which may be substituted with one, two, three or four substituents independently selected from R 10; a 5-membered heteroaryl having one or two ring nitrogen atoms, which may be substituted with one, two, three or four substituents independently selected from R 10; or a 5,6-condensed heteroaryl having one or two ring nitrogen atoms, which may be substituted with one, two, three, four or five substituents independently selected from R 10. R ２ is hydrogen, halogen, C １～６ alkyl, -O(C １～６ alkyl), -NH(C １～６ alkyl) or -N(C １～６ alkyl), ２ where each C １～６ alkyl may be substituted with 1, 2, 3, 4 or 5 substituents independently selected from R １０ and may be substituted, R ３ is hydrogen, C １～６ Alkyl, halogen, cyano, hydroxyl, -O(C) １～６ Alkyl), C ２～６ Alkenyl or C ２～６ It is an alkinyl, and here, C １～６ Alkyl, C ２～６ Alkenyl and C ２～６ Alkinyl is R １０ It may be substituted with one, two, three, four, or five substituents independently selected from the above, R ４ Hydrogen, halogen, cyano, -NR ４３ａ R ４３ｂ , -OR ４４ , C １～６ Alkyl or C ３～６ It is a cycloalkyl, where C １～６ Alkyl and C ３～６ Each cycloalkyl is R １０ It may be substituted with one, two, three, four, or five substituents independently selected from the above, G １ is N or CR ４１ G ２ is N or CR ４２ And, however, G １ and G ２ Provided that one or both of the following are N, R ４１ and R ４２ It is hydrogen, Each R ４３ａ and R ４３ｂ These are, independently, hydrogen or C １～６ It is alkyl, R ４４ is hydrogen, C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C ３～８ It is a cycloalkyl, 3-14 member heterocyclyl, where R ４４ C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C ３～８ Cycloalkyls and 3-14 membered heterocyclines are, respectively, R １０ They may be substituted with one, two, three, or four substituents independently selected from the above, R ５ is hydrogen, C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C ３～８ Cycloalkyl, C ６～１４ Aryl, 5-14 member heteroaryl, 3-14 member heterocyclyl, -C(O)R １４ , -C(O)OR １５ or -C(O)NR １６ａ R １６ｂ And here, R ５ C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C ３～８ Cycloalkyl, C ６～１４ Aryl, 5-14 member heteroaryl, and 3-14 member heterocyclyl are, respectively, R １０ It may be substituted with one, two, three, four, or five substituents independently selected from R ６ａ Or R ６ｂ And together with the atoms to which they are bonded, R １０ They form a 3- to 14-membered heterocycline which may be substituted with 1, 2, 3, 4, or 5 substituents independently selected from the above, Each R ６ａ and R ６ｂ These are, independently, hydrogen, C １～６ Alkyl, C ３～８ Cycloalkyl, C ６～１０ Aryl, 5-14 member heteroaryl, 3-12 member heterocyclyl, -C(O)R １４ , -C(O)OR １５ or -C(O)NR １６ａ R １６ｂ And here, R ６ａ and R ６ｂ C １～６ Alkyl, C ３～８ Cycloalkyl, C ６～１０ Aryl, 5-14 member heteroaryl, and 3-12 member heterocyclyl are, respectively, R １０ It may be substituted with 1, 2, 3, 4, or 5 substituents independently selected from or R ５ And together with the atoms to which they are bonded, R １０ It forms a 3- to 14-membered heterocycline which may be substituted with 1, 2, 3, 4, or 5 substituents independently selected from, or R ６ａ and R ６ｂ These, together with the carbon atoms to which they are bonded, form a carbonyl group. Each R ７ａ and R ７ｂ is independently hydrogen or C １０ alkyl which may be substituted with 1, 2, 3, 4 or 5 substituents independently selected from R １～６ or R ７ａ and R ７ｂ together with the carbon to which they are attached form a carbonyl, Each R ８ａ and R ８ｂ is independently hydrogen, halogen, hydroxyl, -O(C １～６ alkyl) or C １～６ alkyl, where each C １～６ alkyl may be substituted with 1, 2, 3, 4 or 5 substituents independently selected from R １０ and may be substituted, n is 0, Each R ９ C is independent １～６ If alkyl, or if present, two geminal R ９ The groups, together with the carbon atoms to which they are bonded, form a carbonyl group. Each R １４ These are independently hydrogen or C １～６ It is alkyl, Each R １５ C is independent １～６ It is alkyl, Each R １６ａ and R １６ｂ These are, independently, hydrogen or C １～６ It is alkyl, or R １６ａ and R １６ｂ Together with the nitrogen atom to which they are bonded, R １０ Forming a 4- to 12-membered heterocycline which may be substituted with 1, 2, 3, 4, or 5 substituents independently selected from, Each R １０ They are independent of oxo and C. １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C ３～８ Cycloalkyl, C ６～１４ Aryl, 5-14 member heteroaryl, 3-14 member heterocyclyl, halogen, cyano, -C(O)R ａ , -C(O)OR ｂ , -C(O)NR ｃ R ｄ , -OR ｂ , -OC(O)R ａ , -OC(O)NR ｃ R ｄ ,-SR ｂ , -S(O)R ｅ , -S(O) ２ R ｅ , -S(O)(=NH)R ｅ , -S(O) ２ NR ｃ R ｄ , -NR ｃ R ｄ , -N(R ｆ ) C(O)R ａ , -N(R ｆ ) C(O)OR ｂ , -N(R ｆ ) C(O)NR ｃ R ｄ , -N(R ｆ ) S(O) ２ R ｅ , -N(R ｆ ) S(O) ２ NR ｃ R ｄ or -P(O)R ｇ R ｈ And here, R １０ C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C ３～８ Cycloalkyl, C ６～１４ Aryl, 5-14 member heteroaryl, and 3-14 member heterocyclyl are, respectively, R １１ They may be substituted with one, two, three, or four substituents independently selected from the above, Each R ａ These are independently hydrogen and C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C ３～８ Cycloalkyl, C ６～１０ The aryl, 5-10 membered heteroaryl, or 3-12 membered heterocyclyl, where R ａ C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C ３～８ Cycloalkyl, C ６～１０ Aryl, 5-10 membered heteroaryl, and 3-12 membered heterocyclyl are, respectively, R １１ They may be substituted with one, two, three, or four substituents independently selected from the above, Each R ｂ These are independently hydrogen and C １～６ Alkyl, C ３～８ Cycloalkyl, C ６～１０ The aryl, 5-10 membered heteroaryl, or 3-12 membered heterocyclyl, where R ｂ C １～６ Alkyl, C ３～８ Cycloalkyl, C ６～１０ Aryl, 5-10 membered heteroaryl, and 3-12 membered heterocyclyl are, respectively, R １１ They may be substituted with one, two, three, or four substituents independently selected from the above, Each R ｃ and R ｄ These are independently hydrogen and C １～６ Alkyl, C ３～８ Cycloalkyl, C ６～１０ The aryl, 5-10 membered heteroaryl, or 3-12 membered heterocyclyl, where R ｃ and R ｄ C １～６ Alkyl, C ３～８ Cycloalkyl, C ６～１０ Aryl, 5-10 membered heteroaryl, and 3-12 membered heterocyclyl are, respectively, R １１ They may be substituted with one, two, three, or four substituents independently selected from the above, Or, R ｃ and R ｄ Together with the nitrogen atom to which they are bonded, R １１ They form a 4- to 12-membered heterocycline which may be substituted with 1, 2, 3, or 4 substituents independently selected from the above, Each R ｅ C is independent １～６ Alkyl, C ３～８ Cycloalkyl, C ６～１０ The aryl, 5-10 membered heteroaryl, or 3-12 membered heterocyclyl, where R ｅ C １～６ Alkyl, C ３～８ Cycloalkyl, C ６～１０ Aryl, 5-10 membered heteroaryl, and 3-12 membered heterocyclyl are, respectively, R １１ They may be substituted with one, two, three, or four substituents independently selected from the above, Each R ｆ These are independently hydrogen or C １～６ It is alkyl, Each R ｇ and R ｈ Independently, C １～６ Alkyl, C ３～８ Cycloalkyl, C ６～１０ Aryl, 5-10 membered heteroaryl, 3-12 membered heterocyclyl, or -O-C １～６ It is alkyl, and here, R ｇ and R ｈ C １～６ Alkyl, C ３～８ Cycloalkyl, C ６～１０ Aryl, 5-10 membered heteroaryl, and 3-12 membered heterocyclyl are, respectively, R １１ They may be substituted with one, two, three, or four substituents independently selected from the above, Or, R ｇ and R ｈ Together with the phosphorus atom to which they are bonded, R １１ They form a 4- to 12-membered heterocycline which may be substituted with 1, 2, 3, or 4 substituents independently selected from the above, Each R １１ They are independent of oxo and C. １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C ３～６ Cycloalkyl, C ６～１０ Aryl, 5-10 membered heteroaryl, 3-8 membered heterocyclyl, halogen, cyano, -C(O)R ａ１ , -C(O)OR ｂ１ , -C(O)NR ｃ１ R ｄ１ , -OR ｂ１ , -OC(O)R ａ１ , -OC(O)NR ｃ１ R ｄ１ ,-SR ｂ１ , -S(O)R ｅ１ , -S(O) ２ R ｅ１ , -S(O) ２ NR ｃ１ R ｄ１ , -NR ｃ１ R ｄ１ , -N(R ｆ１ ) C(O)R ａ１ , -N(R ｆ１ ) C(O)OR ｂ１ , -N(R ｆ１ ) C(O)NR ｃ１ R ｄ１ , -N(R ｆ１ ) S(O) ２ R ｅ１ , -N(R ｆ１ ) S(O) ２ NR ｃ１ R ｄ１ or -P(O)R ｇ１ R ｈ１ And here, R １１ C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C ３～６ Cycloalkyl, C ６～１０ Aryl, 5-10 membered heteroaryl, and 3-8 membered heterocyclyl are, respectively, R １２ They may be substituted with one, two, three, or four substituents independently selected from the above, Each R ａ１ These are independently hydrogen and C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C ３～６ Cycloalkyl, C ６～１０ The aryl, 5-10 membered heteroaryl, or 3-8 membered heterocyclyl, where R ａ１ C １～６ Alkyl, C ２～６ Alkenil, C ２～６ Alkinyl, C ３～６ Cycloalkyl, C ６～１０ Aryl, 5-10 membered heteroaryl, and 3-8 membered heterocyclyl are, respectively, R １２ They may be substituted with one, two, three, or four substituents independently selected from the above, Each R ｂ１ These are independently hydrogen and C １～６ Alkyl, C ３～６ Cycloalkyl, C ６～１０ The aryl, 5-10 membered heteroaryl, or 3-8 membered heterocyclyl, where R ｂ１ C １～６ Alkyl, C ３～６ Cycloalkyl, C ６～１０ Aryl, 5-10 membered heteroaryl, and 3-8 membered heterocyclyl are, respectively, R １２ They may be substituted with one, two, three, or four substituents independently selected from the above, Each R ｃ１ and R ｄ１ These are independently hydrogen and C １～６ Alkyl, C ３～６ Cycloalkyl, C ６～１０ The aryl, 5-10 membered heteroaryl, or 3-8 membered heterocyclyl, where R ｃ１ and R ｄ１ C １～６ Alkyl, C ３～６ Cycloalkyl, C ６～１０ Aryl, 5-10 membered heteroaryl, and 3-8 membered heterocyclyl are, respectively, R １２ They may be substituted with one, two, three, or four substituents independently selected from the above, Or, R ｃ１ and R ｄ１ Together with the nitrogen atom to which they are bonded, R １２ They form a 4- to 8-membered heterocycline which may be substituted with 1, 2, 3, or 4 substituents independently selected from the above, Each R ｅ１ Independently, C １～６ Alkyl, C ３～６ Cycloalkyl, C ６～１０ The aryl, 5-10 membered heteroaryl, or 3-8 membered heterocyclyl, where R ｅ１ C １～６ Alkyl, C ３～６ Cycloalkyl, C ６～１０ Aryl, 5-10 membered heteroaryl, and 3-8 membered heterocyclyl are, respectively, R １２ They may be substituted with one, two, three, or four substituents independently selected from the above, Each R ｆ１ These are, independently, hydrogen or C １～６ It is alkyl, Each R ｇ１ and R ｈ１ Independently, C １～６ Alkyl, C ３～６ Cycloalkyl, C ６～１０ Aryl, 5-10 membered heteroaryl, 3-8 membered heterocyclyl, or -O-C １～６ It is alkyl, and here, R ｇ１ and R ｈ１ C １～６ Alkyl, C ３～６ Cycloalkyl, C ６～１０ Aryl, 5-10 membered heteroaryl, and 3-8 membered heterocyclyl are, respectively, R １２ They may be substituted with one, two, three, or four substituents independently selected from the above, Or, R ｇ１ and R ｈ１ Together with the phosphorus atom to which they are bonded, R １２ They form a 4- to 8-membered heterocycline which may be substituted with 1, 2, 3, or 4 substituents independently selected from the above, Each R １２ These are independently oxo and C. １～６ Alkyl, C ３～６ Cycloalkyl, C ６ Aryl, 5-6 member heteroaryl, 3-6 member heterocyclyl, halogen, cyano, -C(O)R ａ２ , -C(O)OR ｂ２ , -C(O)NR ｃ２ R ｄ２ , -OR ｂ２ , -OC(O)R ａ２ , -OC(O)NR ｃ２ R ｄ２ , -S(O) ２ R ｅ２ , -S(O) ２ NR ｃ２ R ｄ２ , -NR ｃ２ R ｄ２ , -N(R ｆ２ ) C(O)R ａ２ , -N(R ｆ２ ) C(O)OR ｂ２ , -N(R ｆ２ ) C(O)NR ｃ２ R ｄ２ , -N(R ｆ２ ) S(O) ２ R ｅ２ , -N(R ｆ２ ) S(O) ２ NR ｃ２ R ｄ２ or -P(O)R ｇ２ R ｈ２ And here, R １２ C １～６ Alkyl, C ３～６ Cycloalkyl, C ６ Aryl, 5-6 membered heteroaryl, and 3-6 membered heterocyclyl are, respectively, R １３ They may be substituted with one, two, three, or four substituents independently selected from the above, Each R ａ２ These are, independently, hydrogen, C １～６ Alkyl, C ３～６ Cycloalkyl, C ６ The aryl, 5-6 membered heteroaryl, or 3-6 membered heterocyclyl, where R ａ２ C １～６ Alkyl, C ３～６ Cycloalkyl, C ６ Aryl, 5-6 membered heteroaryl, and 3-6 membered heterocyclyl are, respectively, R １３ They may be substituted with one, two, three, or four substituents independently selected from the above, Each R ｂ２ These are, independently, hydrogen, C １～６ Alkyl, C ３～６ It is a cycloalkyl or a 3-6 membered heterocycline, where R ｂ２ C １～６ Alkyl, C ３～６ Cycloalkyls and 3-6 membered heterocyclines are, respectively, R １３ They may be substituted with one, two, three, or four substituents independently selected from the above, Each R ｃ２ and R ｄ２ These are, independently, hydrogen, C １～６ Alkyl, C ３～６ It is a cycloalkyl or a 3- to 8-membered heterocycline, where R ｃ２ and R ｄ２ C １～６ Alkyl, C ３～６ Cycloalkyls and 3- to 8-membered heterocyclines are, respectively, R １３ They may be substituted with one, two, three, or four substituents independently selected from the above, Or, R ｃ２ and R ｄ２ Together with the nitrogen atom to which they are bonded, R １３ They form a 4-6 member heterocycline which may be substituted with 1, 2, 3, or 4 substituents independently selected from the above, Each R ｅ２ Independently, C １～６ Alkyl, C ３～６ Cycloalkyl, C ６ The aryl, 5-6 membered heteroaryl, or 3-6 membered heterocyclyl, where R ｅ２ C １～６ Alkyl, C ３～６ Cycloalkyl, C ６ Aryl, 5-6 membered heteroaryl, and 3-6 membered heterocyclyl are, respectively, R １３ They may be substituted with one, two, three, or four substituents independently selected from the above, Each R ｆ２ These are, independently, hydrogen or C １～６ It is alkyl, Each R ｇ２ and R ｈ２ Independently, C １～６ Alkyl, C ３～６ Cycloalkyl, 3-8 membered heterocyclyl, or -O-C １～６ It is alkyl, and here, R ｇ２ and R ｈ２ C １～６ Alkyl, C ３～６ Cycloalkyls and 3- to 8-membered heterocyclines are, respectively, R １３ They may be substituted with one, two, three, or four substituents independently selected from the above, Or, R ｇ２ and R ｈ２ Together with the phosphorus atom to which they are bonded, R １３ It forms a 4-6 member heterocycline which may be substituted with 1, 2, 3 or 4 substituents independently selected from and Each R １３ These are independently oxo, halogen, hydroxyl, and -O(C) １～６ Alkyl), cyano, C １～６ Alkyl or C １～６ It is a haloalkyl, However, the compounds are shown in Table 1X. Other than the compounds and salts thereof, A compound of formula (I), its N-oxide, or a pharmaceutically acceptable salt thereof.

2. G １ and G ２ A compound according to claim 1, wherein both are N, and the compound of formula (IA): (In the formula, R １ , R ２ , R ３ , R ４ , R ５ , R ６ａ , R ６ｂ , R ７ａ , R ７ｂ , R ８ａ , R ８ｂ , R ９ (and n is as defined in claim 1) A compound or a pharmaceutically acceptable salt thereof.

3. G １ N is G ２ CR ４２ The compound according to claim 1, wherein the compound is of formula (IB): (In the formula, R １ , R ２ , R ３ , R ４ , R ４２ , R ５ , R ６ａ , R ６ｂ , R ７ａ , R ７ｂ , R ８ａ , R ８ｂ , R ９ (and n is as defined in claim 1) A compound or a pharmaceutically acceptable salt thereof.

4. G １ CR ４１ G ２ A compound according to claim 1, wherein is N, and is a compound of formula (IC): (In the formula, R １ , R ２ , R ３ , R ４ , R ４１ , R ５ , R ６ａ , R ６ｂ , R ７ａ , R ７ｂ , R ８ａ , R ８ｂ , R ９ A compound or a pharmaceutically acceptable salt thereof (where n is as defined in claim 1).

5. R １ However, R １０ The compound according to claim 1, which is a six-membered heteroaryl having one or two cyclic nitrogen atoms, which may be substituted with one, two, three or four substituents independently selected from the above.

6. R １ However, R １０ The compound according to claim 5, which is 4-pyridyl that may be substituted with 1 to 5 substituents independently selected from the above.

7. R １ However, R １０ The compound according to claim 1, which is a five-membered heteroaryl having one or two cyclic nitrogen atoms, which may be substituted with one, two, three or four substituents independently selected from the above.

8. R １ However, R １０ The compound according to claim 7, which is isothiazole-5-yl or pyrazole-4-yl, which may be substituted with one to three substituents independently selected from the above.

9. R １ However, R １０ The compound according to claim 1, which is a 5,6-condensed heteroaryl having one or two cyclic nitrogen atoms, which may be substituted with one, two, three, four or five substituents independently selected from the above.

10. R １ but, The compound according to claim 1, selected from the group consisting of the following, wherein the wavy line of each group indicates a bond point to the parent structure.

11. R ２ However, hydrogen, -NH(C １～６ Alkyl), or R １０ C may be substituted with 1, 2, 3, 4, or 5 substituents independently selected from the above. １～６ The compound according to claim 1, wherein it is alkyl.

12. R ２ However, hydrogen, NHMe, methyl, CF ３ , The compound according to claim 11, selected from the group consisting of the following, wherein the wavy line of each group indicates a bond point to the parent structure.

13. R ３ is hydrogen, halogen, cyano, hydroxyl, -O(C) １～６ Alkyl), C １～６ Alkyl or C ２～６ It is alkinyl, C １～６ Alkyl and C ２～６ Alkinyl is R １０ The compound according to claim 1, which may be substituted with one, two, three, four, or five substituents independently selected from the above.

14. R ３ The compound according to claim 13, wherein the compound is selected from the group consisting of hydrogen, chloro, cyano, hydroxyl, methoxy, 3-hydroxypropane-1-in-1-yl, 3-hydroxy-3-methylbuta-1-in-1-yl, methyl, methoxymethyl, and 2,2,2-trifluoroethyl.

15. R ４ Hydrogen, halogen, -NR ４３ａ R ４３ｂ , -OR ４４ , C １～６ Alkyl or C ３～６ It is a cycloalkyl, C １～６ Alkyl and C ３～６ Each of the cycloalkyl groups is R １０ The compound according to claim 1, which may be substituted with one, two, three, four, or five substituents independently selected from the above.

16. R ４ However, hydrogen, halogen, C １～６ Alkyl or -O(C) １～６ Alkyl) and each C １～６ Alkyl, R １０ The compound according to claim 15, which may be substituted with one, two, three, four, or five substituents independently selected from the above.

17. R ４ However, hydrogen, fluoro, chloro, bromo, methyl, A compound according to claim 15, selected from the group consisting of the following.

18. R ５ However, hydrogen, C １～６ Alkyl, C ３～８ Cycloalkyl, C ６～１４ Aryl, 5-14 member heteroaryl, 3-14 member heterocyclyl, or -C(O)R １４ And R ５ C １～６ Alkyl, C ３～８ Cycloalkyl, C ６～１４ Aryl, 5-14 member heteroaryl, and 3-14 member heterocyclyl are respectively R １０ The compound according to claim 1, which may be substituted with one, two, three, four, or five substituents independently selected from the above.

19. R ５ is hydrogen or -C(O)R １４ The compound according to claim 18.

20. R ５ However, hydrogen, or R １０ C may be substituted with 1, 2, 3, 4, or 5 substituents independently selected from the above. １～６ The compound according to claim 18, wherein it is alkyl.

21. R ５ However, methyl, ethyl, 1-propyl, 2-propyl, 2-methyl-1-propyl and 2-methyl-2-propyl, The compound according to claim 20, selected from the group consisting of the following, wherein the wavy line of each group indicates a bond point to the parent structure.

22. R ５ However, R １０ C may be substituted with 1, 2, 3, 4, or 5 substituents independently selected from the above. ４～８ The compound according to claim 18, wherein it is a cycloalkyl compound.

23. R ５ but, The compound according to claim 22, selected from the group consisting of the above, wherein the wavy line of each group indicates a bond point to the parent structure.

24. R ５ However, R １０ A 3- to 14-membered heterocycline, R, which may be substituted with one, two, three, four, or five substituents independently selected from the above. １０ C may be substituted with 1, 2, 3, 4, or 5 substituents independently selected from the above. ６～１４ Aryl, or R １０ The compound according to claim 17, which is a 5- to 14-membered heteroaryl that may be substituted with one, two, three, four, or five substituents independently selected from the above.

25. R ５ but, A group consisting of R is selected, and each of these is R １０ The compound according to claim 24, which may be substituted with one, two, three, four, or five substituents independently selected from the group, and the wavy line of each group indicates a bond point to the parent structure.

26. Each R ６ａ and R ６ｂ Independently, hydrogen or C １～６ It is alkyl, or R ６ａ and R ６ｂ The compound according to claim 1, wherein the carbon atoms to which they are bonded form a carbonyl group.

27. R ６ａ and R ６ｂ One of them is hydrogen, R ６ａ and R ６ｂ The other is hydrogen, -C(O)OR １５ , -C(O)NR １６ａ R １６ｂ , or R １０ C may be substituted with 1, 2, 3, 4, or 5 substituents independently selected from the above. １～６ The compound according to claim 1, wherein it is alkyl.

28. R ６ａ and R ６ｂ One of them is hydrogen, R ６ａ and R ６ｂ The other is -C(O)OR １５ or -C(O)NR １６ａ R １６ｂ And in the formula, each R １６ａ and R １６ｂ These are, independently, hydrogen or C １～６ The compound according to claim 27, wherein it is alkyl.

29. R ６ａ and R ６ｂ One of them is hydrogen, R ６ａ and R ６ｂ The other is -C(O)NR １６ａ R １６ｂ And in the formula, R １６ａ and R １６ｂ Together with the nitrogen atom to which they are bonded, R １０ The compound according to claim 27, which forms a 4- to 12-membered heterocycline that may be substituted with 1, 2, 3, 4, or 5 substituents independently selected from the above.

30. R ６ａ and R ６ｂ One of them is hydrogen, R ６ａ and R ６ｂ The other is hydrogen, methyl, The compound according to claim 27, selected from the group consisting of the following, wherein the wavy lines of each group indicate a bond point to the parent structure.

31. R ５ However, R ６ａ and R ６ｂ Together with one of them and the atom to which they are bonded, R １０ Forms a 3- to 14-membered heterocycline which may be substituted with 1, 2, 3, 4, or 5 substituents independently selected from R ６ａ and R ６ｂ The other side is hydrogen, C １～６ Alkyl, C ３～８ Cycloalkyl, C ６～１０ Aryl, 5-14 member heteroaryl, 3-12 member heterocyclyl, -C(O)R １４ , -C(O)OR １５ or -C(O)NR １６ａ R １６ｂ C １～６ Alkyl, C ３～８ Cycloalkyl, C ６～１０ Aryl, 5-14 member heteroaryl, and 3-12 member heterocyclyl are, respectively, R １０ The compound according to claim 1, which may be substituted with one, two, three, four, or five substituents independently selected from the above.

32. R ５ However, R ６ａ and R ６ｂ Together with one of them and the atom to which they are bonded, R １０ Forms a 4- to 8-membered heterocycline which may be substituted with 1, 2, 3, 4, or 5 substituents independently selected from R ６ａ and R ６ｂ The compound according to claim 31, wherein the other is hydrogen.

33. Each R ７ａ and R ７ｂ Independently, hydrogen or C １～６ It is alkyl, or R ７ａ and R ７ｂ The compound according to claim 1, wherein the carbon atoms to which they are bonded form a carbonyl group.

34. R ８ａ and R ８ｂ One of them is hydrogen, R ８ａ and R ８ｂ The other is hydrogen, halogen, hydroxyl, C １～６ Alkyl or -O(C) １～６ The compound according to claim 1, wherein it is alkyl.

35. Each R ８ａ and R ８ｂ Is it hydrogen, or R ８ａ and R ８ｂ One of them is hydrogen R ８ａ and R ８ｂ The other is hydrogen, fluoro, or hydroxyl, or each R ８ａ and R ８ｂ The compound according to claim 32, wherein is fluoro.

36. Compound of formula (II): (In the formula, R １ , R ２ , R ３ , R ４ G １ G ２ , R ５ , R ６ａ , R ６ｂ , R ７ａ , R ７ｂ , R ８ａ and R ８ｂ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein (is as defined in claim 1).

37. G １ and G ２ The compound according to claim 36, wherein both are N, and the compound of formula (II-A): (In the formula, R １ , R ２ , R ３ , R ４ , R ５ , R ６ａ , R ６ｂ , R ７ａ , R ７ｂ , R ８ａ , and R ８ｂ A compound or a pharmaceutically acceptable salt thereof (as defined in claim 36).

38. G １ N is G ２ CR ４２ The compound according to claim 36, wherein the compound is of formula (II-B): (In the formula, R １ , R ２ , R ３ , R ４ , R ４２ , R ５ , R ６ａ , R ６ｂ , R ７ａ , R ７ｂ , R ８ａ , and R ８ｂ A compound or a pharmaceutically acceptable salt thereof (as defined in claim 36).

39. G １ CR ４１ G ２ A compound according to claim 36, wherein is N, and is a compound of formula (II-C): (In the formula, R １ , R ２ , R ３ , R ４ , R ４１ , R ５ , R ６ａ , R ６ｂ , R ７ａ , R ７ｂ , R ８ａ , and R ８ｂ A compound or a pharmaceutically acceptable salt thereof (as defined in claim 36).

40. R １ These are pyrazolyl, pyridinyl, isothiazolyl, or pyrrolopyridinyl, which are each R １０ It may be substituted with 1 to 3 substituents independently selected from the above, R ２ is hydrogen or R １０ C may be substituted with 1 to 5 substituents independently selected from the above. １～６ It is alkyl, R ３ is hydrogen, halogen or C １～６ It is alkyl, R ４ is hydrogen, halogen, -O(C) １～６ Alkyl) or C １～６ It is alkyl, R ５ is hydrogen, C １～６ Alkyl, C ３～８ Cycloalkyl, C ６～１４ Aryl, 5-14 member heteroaryl, 3-14 member heterocyclyl, or -C(O)R １４ And here, R ５ C １～６ Alkyl, C ３～８ Cycloalkyl, C ６～１４ Aryl, 5-14 member heteroaryl, and 3-14 member heterocyclyl are, respectively, R １０ It may be substituted with one, two, three, four, or five substituents independently selected from the above, Each R ６ａ and R ６ｂ It is independently hydrogen or -C(O)OR １５ , -C(O)NR １６ａ R １６ｂ Or R １０ C may be substituted with 1, 2, 3, 4, or 5 substituents independently selected from the above. １～６ Alkyl or R ６ａ and R ６ｂ These, together with the carbon atoms to which they are bonded, form a carbonyl group. Each R ７ａ and R ７ｂ These are, independently, hydrogen or C １～６ Is it alkyl, or R ７ａ and R ７ｂ These, together with the carbon atoms to which they are bonded, form a carbonyl group. R ８ａ and R ８ｂ One of them is hydrogen, R ８ａ and R ８ｂ The other is hydrogen, halogen, hydroxyl, C １～６ Alkyl or -O(C) １～６ It is alkyl, R １４ is C １～６ It is alkyl, R １５ is C １～６ It is alkyl, and Each R １６ａ and R １６ｂ These are, independently, hydrogen or C １～６ Alkyl or R １６ａ and R １６ｂ Together with the nitrogen atom to which they are bonded, they form a 5 or 6-membered heterocycline having one or two cyclic heteroatoms selected from nitrogen, oxygen, and sulfur, R １０ It may be substituted with 1, 2, 3, 4, or 5 substituents independently selected from the above. The compound according to claim 36.

41. R １ These are pyrazole-4-yl, 4-pyridyl, isothiazole-5-yl, or pyrrolo[2,3-b]pyridin-4-yl, each of which is a halogen, cyano, or unsubstituted C. １～６ Alkyl and C １～６ It may be substituted with 1 to 3 substituents independently selected from the group consisting of haloalkyl groups. Each R ２ and R ３ These are, independently, hydrogen or C １～６ It is alkyl, R ４ is hydrogen, halogen, -O(C) １～６ Alkyl) or C １～６ It is alkyl, R ５ (i) halogen, cyano, hydroxyl, -O(C) １～６ Alkyl), -NHC(O)(C １～６ Alkyl), -NHS(O) ２ (C １～６ Alkyl), -S(O) ２ NH ２ , -C(O)NH ２ C may be substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of phenyl and 3- to 12-membered heterocyclines. １～６ Alkyl, (ii) C substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of halogens, cyanos, and hydroxyls. ３～６ Cycloalkyl, (iii) Monocyclic 3-6 membered heterocycline having one cyclic heteroatom which is oxygen, (iv) Phenyl, or (v) Pyrazolyl And, R ６ａ and R ６ｂ One of them is hydrogen, R ６ａ and R ６ｂ The other is hydrogen, C １～６ Alkyl, -C(O)O(C １～６ Alkyl) or -C(O)NR １６ａ R １６ｂ is or R ６ａ and R ６ｂ These, together with the carbon atoms to which they are bonded, form a carbonyl group. R ７ａ and R ７ｂ One of them is hydrogen, R ７ａ and R ７ｂ The other is hydrogen or C １～６ Alkyl or R ７ａ and R ７ｂ These, together with the carbon atoms to which they are bonded, form a carbonyl group. R ８ａ and R ８ｂ It is hydrogen, and Each R １６ａ and R １６ｂ These are, independently, hydrogen or C １～６ Is it alkyl, or R １６ａ and R １６ｂ These, together with the nitrogen atom to which they are bonded, form pyrrolidine-1-yl or morpholine-4-yl. The compound according to claim 36.

42. Compound of formula (III): (In the formula, R ２ , R ３ , R ４ , R ５ , R ６ａ , R ６ｂ , R ７ａ , R ７ｂ , R ８ａ and R ８ｂ If applicable, this is as defined in claim 1, p is 0, 1, 2, 3 or 4, and Each R Ｚ These are independently hydrogen, halogen, cyano or R １０ C may be substituted with 1, 2, 3, 4, or 5 substituents independently selected from the above. １～６ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is alkyl.

43. A compound according to claim 42, wherein p is 0, and the compound of formula (V): A compound or a pharmaceutically acceptable salt thereof.

44. Compound of formula (IV): (In the formula, R ２ , R ３ , R ４ , R ５ , R ６ａ , R ６ｂ , R ７ａ , R ７ｂ , R ８ａ and R ８ｂ If applicable, this is as defined in claim 1, q is 0, 1, 2 or 3, and Each R Ｙ These are independently hydrogen, halogen, cyano, -O(C) １～６ Alkyl) or C １～６ It is alkyl, R Ｙ C １～６ Alkyl is R １０ The compound according to claim 1 or a pharmaceutically acceptable salt thereof (which may be substituted with one, two, three, four, or five substituents independently selected from the above).

45. q is 1, R Ｙ The compound according to claim 44, wherein is methyl, fluoro, chloro, cyano, or trifluoromethyl.

46. Compounds of formula (VII) or (VIII): (VII) (VIII) (In the formula, R ２ , R ３ , R ４ , R ５ , R ６ａ , R ６ｂ , R ７ａ , R ７ｂ , R ８ａ and R ８ｂ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is as defined in claim 1, where applicable.

47. Compounds of formula (IX): (In the formula, R ２ , R ３ , R ４ , R ５ , R ６ａ , R ６ｂ , R ７ａ , R ７ｂ , R ８ａ and R ８ｂ The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is as defined in claim 1, where applicable.

48. Each R ２ , R ３ and R ４ The compound according to claim 1, wherein the compound is hydrogen.

49. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of compound numbers 101 to 292 in Table 1.

50. A pharmaceutical composition comprising a compound according to any one of claims 1 to 49 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable additive.

51. Compound of formula (I): (In the formula, R １ , R ２ , R ３ , R ４ G １ G ２ , R ５ , R ６ａ , R ６ｂ , R ７ａ , R ７ｂ , R ８ａ , R ８ｂ , R ９ A method for producing a pharmaceutically acceptable salt thereof (where n is as defined in claim 1), a) Compound of formula (I-4): [In the formula, X is selected from the group consisting of Cl, Br, I, F, OMs and OTs], the compound of formula (I-3): [In the formula, P is a protecting group] is reacted in the presence of a base to form the compound of formula (I-2): To produce, b) Remove the protecting group P from the compound of formula (I-2) to obtain the compound of formula (I-1): To produce, c) Converting the compound of formula (I-1) to the compound of formula (I), Methods that include...

52. (i) In the presence of a base, the compound of formula (I-1) is converted to formula R ５ By contacting a compound of -X' (wherein X' is a leaving group), or by (ii) in the presence of a reducing agent, the compound of formula R ５ The method according to claim 51, wherein the compound of formula (I-1) is converted to the compound of formula (I) by contact with the aldehyde of CHO.

53. G １ and G ２ The method according to claim 51, wherein both are N, d) Compound of formula 1: Compound of formula 2: When mixed in the presence of a base, the compound of formula 3 is formed: To form, e) Contact the compound of formula 3 with the activator, G １ and G ２ The compound of formula (I-4) is formed in which both are N, Methods that further include the above.

54. Compound of formula (IA): (In the formula, R １ , R ２ , R ３ , R ４ , R ５ , R ６ａ , R ６ｂ , R ７ａ , R ７ｂ , R ８ａ , R ８ｂ , R ９ A method for producing a pharmaceutically acceptable salt thereof (where n is as defined in claim 1), a) Compound of formula 12: The compound of formula 11: When brought into contact with a palladium catalyst and a base, the compound of formula 6 is obtained: [In the formula, X is selected from the group consisting of Cl, Br, I, F, OMs and OTs, and P is a protecting group] and, b) Remove the protecting group P from the compound of formula 6 to obtain the compound of formula 7: To produce, c) Converting the compound of formula 7 to the compound of formula (IA) Methods that include...

55. d) Compound of formula 5 in the presence of a base: The compound of formula 10: The method according to claim 54, further comprising coupling with (wherein X is selected from the group consisting of Cl, Br, I, F, OMs and OTs) to form a compound of formula 11.

56. (i) In the presence of a base, the compound of formula 7 is converted to the compound of formula 8: By contacting [wherein X' is a leaving group], or (ii) In the presence of a reducing agent, the compound of formula 7 is converted to the compound of formula 9: By bringing it into contact with, The method according to claim 54 or 55, wherein the compound of formula 7 is converted to the compound of formula (IA).

57. (i) A compound according to any one of claims 1 to 49 or a pharmaceutically acceptable salt thereof, (ii) A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 49, and a pharmaceutically acceptable additive. A pharmaceutical product for treating a disease or condition, including, A pharmaceutical product in which an effective dose of (i) or (ii) above is administered to a subject requiring treatment.

58. The pharmaceutical product according to claim 57, wherein the disease or condition is acute respiratory distress syndrome (ARDS).

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