Pyridopyrimidine compounds useful as CD38 inhibitors

Abstract

The present invention relates to compounds that have activity as cluster of differentiation 38 (CD38) inhibitors, compositions of such compounds, and methods using such compounds for preventing or treating diseases and disorders such as, for example, diseases and disorders of metabolism.

Description

Docket no. 24-2208-WON-S1 / Set BPYRIMIDINE COMPOUNDS CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This International Application claims the benefit of U.S. Provisional Application no.63 / 738,151, filed December 23, 2024 and U.S. Provisional Application no. 63 / 844,229, filed July 15, 2025, each of which are incorporated by reference herein in their entirety.FIELD OF INVENTION

[0002] This application relates to compounds that have activity as cluster of differentiation 38 (CD38) inhibitors, compositions of such compounds, and methods using such compounds for preventing or treating diseases and disorders such as, for example, diseases and disorders of metabolism.BACKGROUND

[0003] Nicotinamide adenine dinucleotide (NAD) is a biochemical that is found in all cells and is a key participant in monitoring the metabolic status of the cell. While cellular NAD levels at any given time are subject to circadian rhythms, decreased cellular NAD levels have been linked to aging, as well as metabolic disorders such as obesity. Increasing NAD levels in such disease states can likely have medical benefits. Increasing cellular NAD levels can be achieved by upregulating the production of NAD, or downregulating the consumption of NAD. Cyclic ADP ribose cyclase, otherwise known as CD38, is one such consumer of NAD.

[0004] CD38 (i.e., cluster of differentiation 38) is a glycoprotein that catalyzes the conversion of nicotinamide adenine dinucleotide (NAD) into adenosine diphosphate ribose (ADPR) or cyclic adenosine diphosphate ribose (cADPR). Accordingly, it is plausible that disease states resulting from decreased cellular NAD levels can result from increased expression of CD38. Inhibition of CD38, which would downregulate the consumption of NAD, thus represents a way to increase cellular NAD levels in such disease states.

[0005] Accordingly, there exists an ongoing need for small molecule CD38 inhibitors for treating diseases and disorders such as, for example, diseases and disorders of metabolism.SUMMARY

[0006] One aspect of the disclosure provides compounds having the structural formula (I):Docket no. 24-2208-WON-S1 / Set Band pharmaceutically acceptable salts thereof, whereinR1is a 5- to 10-membered heteroaryl group optionally substituted with one or more independently selected R2, where each R2is (i) Ci-Ce alkyl, (ii) C3-C8 cycloalkyl, (iii) C3-C6 cycloalkyl(Ci-C2 alkyl), (iv) Ci-Ce haloalkyl, (v) Ci-Ce alkoxy(Co-Ce alkyl), (vi) halogen, (vii) -OR15, (viii) -NR16R17, (ix) -CN, or (x) -NO2;R15is H, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy(Ci-Ce alkyl), or C3-C8 cycloalkyl;R16is H or Ci-Ce alkyl; andR17is H, Ci-C6alkyl;R4is H or Ci-Ce alkyl;R5is 4- to 13-membered heterocyclyl(Co-C2 alkyl), C3-C12 cycloalkyl(Co-C2 alkyl), aryl(Co-Ce alkyl), 8- to 12-membered spirocyclyl(Co-C2 alkyl), or 5- or 6- membered heteroaryl(Co-Ce alkyl), each of which is optionally substituted on a cyclic portion thereof with one or more independently selected R3, where each R3is (i) Ci-Ce alkyl, (ii) Ci-Ce haloalkyl, (iii) Ci-Ce alkoxy, (iv) halogen, (v) -SO2(Ci-Ce alkyl), (vi) -SO2(C3-Cs cycloalkyl), (vii) -NHSO2(Ci-Ce alkyl), (viii) -NHSO2(C3-C8cycloalkyl), (ix) -CO2(Ci-C6alkyl), (x) oxo, (xi) -OR57, (xii) -CN, (xiii) -C(O)R58, or (xiv) -(C0-C4alkyl)R59;R57is H, Ci-C6alkyl, or-(CH2CH2O)0-2(Ci-C6 alkyl);R58and R59are each independently -NR60R61whereinR60is H or Ci-Ce alkyl; andR61is -SO2(Ci-Ce alkyl) or Ci-Ce haloalkyl;R6is H, halogen, Ci-Ce alkyl, C3-C6 cycloalkyl, Ci-Ce haloalkyl, or Ci-Ce alkoxy;andDocket no. 24-2208-WON-S1 / Set BR7is H, Ci-Ce alkyl, C3-C6 cycloalkyl, or -NR8R9where R8and R9are each independently H or Ci-Ce alkyl; andR10is H, halogen, C1-C3 haloalkyl or C1-C3 alkyl.

[0007] Another aspect of the disclosure provides a pharmaceutical composition, comprising a compound of Formula (I) as described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.

[0008] Yet another aspect of the disclosure provides methods of treating a disease, disorder, or condition mediated by CD38 activity in a subject in need thereof. Such methods include administering a compound of formula (I) as described herein, ora pharmaceutically acceptable salt thereof, ora pharmaceutical composition as described herein.

[0009] In certain embodiments of the methods of the disclosure, the disease, disorder, or condition mediated by CD38 activity is cancer, a hyperproliferative disease or condition, an inflammatory disease or condition, a metabolic disorder, a cardiac disease or condition, chemotherapy induced tissue damage, a renal disease, a metabolic disease, a neurological disease or injury, a neurodegenerative disorder or disease, diseases caused by impaired stem cell function, diseases caused by DNA damage, primary mitochondrial disorders, a muscle disease, and a muscle wasting disorder. In certain embodiments of the methods of the disclosure, the disease, disorder, or condition mediated by CD38 activity is selected from the group consisting of obesity, atherosclerosis, insulin resistance, type 2 diabetes, cardiovascular disease, Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, depression, Down syndrome, neonatal nerve injury, aging, axonal degeneration, carpal tunnel syndrome, Guillain-Barre syndrome, nerve damage, polio (poliomyelitis), spinal cord injury, nonalcoholic steatohepatitis, chronic obstructive pulmonary disease, and rheumatoid arthritis.

[0010] Another aspect of the disclosure provides a method of inhibiting CD38 activity in a cell. Such method includes exposing the cell to a compound of Formula (I) as described herein, or a pharmaceutically acceptable salt thereof.

[0011] These and other features and advantages of the claimed invention will be more fully understood from the following detailed description taken together with the accompanying claims. It is noted that the scope of the claims is defined by the recitations therein and not by the specific discussion of features and advantages set forth in the description.DETAILED DESCRIPTION

[0012] Before the disclosed processes and materials are described, it is to be understood that the aspects described herein are not limited to specific embodiments, and as such can,Docket no. 24-2208-WON-S1 / Set Bof course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and, unless specifically defined herein, is not intended to be limiting.

[0013] Definitions

[0014] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs. All patents, patent applications, and publications referred to herein are incorporated by reference to the extent they are consistent with this disclosure. Terms and ranges have their generally defined definition unless expressly defined otherwise.

[0015] For simplicity, chemical moieties are defined and referred to throughout primarily as univalent chemical moieties (e.g., alkyl, aryl, etc.). Nevertheless, such terms may also be used to convey corresponding multivalent moieties under the appropriate structural circumstances clear to those skilled in the art. For example, while an “alkyl” moiety generally refers to a monovalent radical (e.g. CH3-CH2-), in certain circumstances a bivalent linking moiety can be “alkyl,” in which case those skilled in the art will understand the alkyl to be a divalent radical (e.g., -CH2-CH2-), which is equivalent to the term “alkylene.” Similarly, in circumstances in which a divalent moiety is required and is stated as being “aryl,” those skilled in the art will understand that the term “aryl” refers to the corresponding divalent moiety, arylene. All atoms are understood to have their normal number of valences for bond formation (i.e. , 4 for carbon, 3 for N, 2 for O, and 2, 4, or 6 for S, depending on the oxidation state of the S).

[0016] The term “acetyl” refers to -C(O)CH3.

[0017] As herein employed, the term “acyl” refers to an alkylcarbonyl or arylcarbonyl substituent wherein the alkyl and aryl portions are as defined herein.

[0018] The term “alkyl” as employed herein refers to saturated straight and branched chain aliphatic groups having from 1 to 12 carbon atoms. As such, “alkyl” encompasses Ci , C2, C3, C4, C5, Ce, C7, Cs, C9, C10, C11, and C12 groups. Alkyl groups may be branched or unbranched. Examples of alkyl groups include, without limitation, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl.

[0019] The term “amino” refers to -NH2.

[0020] The term “alkenyl" as used herein means an unsaturated straight or branched chain aliphatic group with one or more carbon-carbon double bonds, having from 2 to 12 carbon atoms. As such, “alkenyl” encompasses C2, C3, C4, C5, Ce, C7, Cs, C9, C10, C11, and C12Docket no. 24-2208-WON-S1 / Set Bgroups. Examples of alkenyl groups include, without limitation, ethenyl, propenyl, butenyl, pentenyl, and hexenyl.

[0021] The term “alkynyl" as used herein means an unsaturated straight or branched chain aliphatic group with one or more carbon-carbon triple bonds, having from 2 to 12 carbon atoms. As such, “alkynyl” encompasses C2, C3, C4, C5, Ce, C7, Cs, C9, C10, Cn, and C12 groups. Examples of alkynyl groups include, without limitation, ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

[0022] An “alkylene,” “alkenylene,” or “alkynylene” group is an alkyl, alkenyl, or alkynyl group, as defined hereinabove, that is positioned between and serves to connect two other chemical groups. Examples of alkylene groups include, without limitation, methylene, ethylene, propylene, and butylene. Examples of alkenylene groups include, without limitation, ethenylene, propenylene, and butenylene. Examples of alkynylene groups include, without limitation, ethynylene, propynylene, and butynylene.

[0023] The term “alkoxy” refers to -O-alkyl.

[0024] The term “cycloalkyl” as employed herein is a saturated and partially unsaturated cyclic hydrocarbon group having 3 to 14 carbons. As such, “cycloalkyl” includes C3, C4, C5, Ce, C7, Cs, C9, C10, C11, C12, C13, and C14 cyclic hydrocarbon groups. Examples of cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. A “cycloalkyl” group also includes fused multicyclic (e.g., bicyclic) ring systems such as decahydronaphthyl and octahydro-1 H-indenyl, provided that at least one of the fused rings is non-aromatic.

[0025] The term “C3-C6 cycloalkyloxy” refers to groups of the formula -O(C3-Ce cycloalkyl).

[0026] The term Ci-Ce alkoxyalkyl refers to groups of the formula -(Ci-Ce alkyl)-O(Ci-Ce alkyl).

[0027] An “aryl” group is a Ce-C aromatic moiety comprising one to three aromatic rings. As such, “aryl” includes Ce, C10, C13, and C14 cyclic hydrocarbon groups. A representative aryl group is a Ce-C aryl group. Particular aryl groups include, without limitation, phenyl, naphthyl, anthracenyl, and fluorenyl. An “aryl” group also includes fused multicyclic (e.g., bicyclic) ring systems in which one or more of the fused rings is non-aromatic, provided that at least one ring is aromatic, such as indenyl.

[0028] An “aralkyl” or “arylalkyl” group comprises an aryl group covalently linked to an alkyl group wherein the moiety is linked to another group via the alkyl moiety. An representative aralkyl group is -(Ci-C6)alkyl(C6-Cio)aryl, including, without limitation, benzyl, phenethyl, andDocket no. 24-2208-WON-S1 / Set Bnaphthylmethyl. For example, an arCi-Csalkyl is an aryl group covalently linked to a C1-C3 alkyl.

[0029] As used herein, the term “fused” when used to define rings, e.g., bicyclic fused ring systems, refers to bicyclic, tricyclic, etc. ring systems sharing 2 or more atoms, including bridged systems. Examples of such fused ring systems are (1S,4R)-2-azabicyclo[2.2.1]heptane; 2-azabicyclo[2.2.2]octane; 2,5-diazabicyclo[2.2.2]octane; 2-oxa-5-azabicyclo[2.2.2]octane; isoindoline; 1,2,3,4-tetrahydro-2,6-naphthyridine; 1, 2,3,4-tetrahydroisoquinoline; 1 ,2,3,4-tetrahydro-1 ,4-(epiminomethano)naphthalene; 3-azabicyclo[3.1.0]hexane; bicyclo[1.1.1]pentan-1-yl; and 2-oxabicyclo[2.1.1]hexan-1-yl.

[0030] A “heterocyclyl” or “heterocyclic” or “heterocycloalkyl” group is a mono- or bicyclic (e.g., fused) ring structure having from 3 to 13 ring atoms or members, (3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 atoms), for example 4 to 8 atoms, wherein one or more ring atoms are independently N, O, or S, and the remainder of the ring atoms are quaternary or carbonyl carbons. Examples of heterocyclic groups include, without limitation, epoxy, oxiranyl, oxetanyl, azetidinyl, aziridinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, thiazolidinyl, thiatanyl, dithianyl, trithianyl, azathianyl, oxathianyl, dioxolanyl, oxazolidinyl, oxazolidinonyl, decahydroquinolinyl, piperidonyl, 4-piperidonyl, thiomorpholinyl, dimethyl-morpholinyl, and morpholinyl.Specifically excluded from the scope of this term are compounds having adjacent ring O and / or S atoms. The heterocyclic groups can be attached to a parent group (i.e. , the point of attachment) via any ring atom, including one of the heteroatoms or one of the carbon atoms, in the heterocyclic ring group. As chemically required, the heterocyclic ring may be attached to one or more other groups, for instance if operating as a bridging group. The term “heterocyclyl” also includes fused multicyclic (e.g., bicyclic) ring systems in which one or more of the fused rings is aromatic or non-aromatic, provided that at least one ring is nonaromatic contains an N, O, or S ring atom. Examples of such fused multicyclic ring systems are indolinyl; indolin-2-yl; 2,3-dihydrobenzofuran-2-yl; 2,3,4,5-tetrahydrobenzo[d]oxazol-2-yl; and (3aR,7aS)-octahydro-1H-pyrrolo[3,2-c]pyridin-1-yl. Each of these examples is a 9-membered heterocyclyl. Additional examples of such fused multicyclic ring systems include 4,6-dihydropyrrolo[3,4-c]pyrazol-5(1H)-yl; 4,6-dihydro-5H-pyrrolo[3,4-d]thiazol-5-yl;(3aR,6aS)-tetrahydro-1 H-furo[3,4-c]pyrrol-5(3H)-yl; and (3aR,6aR)-tetrahydro-1 H-furo[3,4-c]pyrrol-5(3H)-yl, each of which are 8-membered heterocyclyl substituents.

[0031] The term “spirocyclyl” refers to multicyclic ring systems in which at least two ring systems of the ring system share one common atom (i.e., a spirocenter), such as a carbon atom. The term “spirocyclyl” includes multicyclic ring systems having a spirocenter where each of the members of the ring systems is carbon. Examples of such spiro multicyclic ringDocket no. 24-2208-WON-S1 / Set Bsystems are spiro[2.5]octan-6-yl, spiro[3.3]heptan-1-yl, spiro[3.3]heptan-2-yl, spiro[3.5]nonan-1-yl, spiro[3.5]nonan-2-yl, spiro[3.5]nonan-6-yl, spiro[3.5]nonan-7-yl, or spiro[4.5]decan-8-yl. The term “spirocyclyl” also includes mutlicyclic ring systems having a spirocenter where at least one of the members of at least on of the ring systems is a heteroatom (e.g., nitrogen, oxygen, or sulfur). Examples of such spiro multicyclic ring systems are thiaspiro[3.5]nonan-7-yl, 4',5'-dihydro-1'H-spiro[cyclopropane-1,6'-pyrrolo[3,4-c]pyrazol-yl], 2-azaspiro[3.3]heptan-6-yl, 2-oxaspiro[3.3]heptan-6-yl, 7-oxaspiro[3.5]nonan-1-yl, 2-oxaspiro[3.5]nonan-7-yl, 2-azaspiro[3.5]nonan-7-yl, 2-oxa-6-azaspiro[3.4]octan-6-yl, 1-oxa-6-azaspiro[3.4]octan-6-yl, 7-oxa-2-azaspiro[3.5]nonan-2-yl, 1-oxa-7-azaspiro[4.4]nonan-7-yl, 2-oxa-7-azaspiro[4.4]nonan-7-yl, 2-oxa-6-azaspiro[3.3]heptan-6-yl, 1-oxa-6-azaspiro[3.3]heptan-6-yl, 6-oxa-2-azaspiro[3.4]octan-2-yl, 5-oxa-2-azaspiro[3.4]octan-2-yl, and 2,6-diazaspiro[3.4]octan-6-yl. As used herein, the number of ring atoms or members of a spirocyclyl group, i.e., a spiro multicyclic ring system, is the total number of members in the ring systems. For example, 4',5'-dihydro-1'H-spiro[cyclopropane-1,6'-pyrrolo[3,4-c]pyrazol-yl] is a 10-membered ring system.

[0032] As used herein, the term “heteroaryl” refers to a group having 5 to 14 ring atoms, preferably 5, 6, 10, 13, or 14 ring atoms; having 6, 10, or 14 TT electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to three heteroatoms that are each independently N, O, or S. “Heteroaryl” also includes fused multicyclic (e.g., bicyclic) ring systems in which one or more of the fused rings is non-aromatic, provided that at least one ring is aromatic and at least one ring contains an N, O, or S ring atom. The heteroaryl groups can be attached to a parent group (i.e., the point of attachment) via any ring atom, including one of the heteroatoms or one of the carbon atoms, in the heteroaryl ring group. As chemically required, the heteroaryl may be attached to one or more other groups, for instance if operating as a bridging group.

[0033] Examples of heteroaryl groups include acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzo[d]oxazol-2(3H)-one, 2H-benzo[b][1 ,4]oxazin-3(4H)-one, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, furanyl, furazanyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl,Docket no. 24-2208-WON-S1 / Set Bpyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1 ,2,5-thiadiazinyl, 1 ,2,3-thiadiazolyl, 1 ,2,4-thiadiazolyl, 1 ,2,5-thiadiazolyl, 1 ,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1 ,2,4-triazolyl, 1 ,2,5-triazolyl, 1 ,3,4-triazolyl, and xanthenyl.

[0034] An “arylene,” “heteroarylene,” or “heterocyclylene” group is a bivalent aryl, heteroaryl, or heterocyclyl group, respectively, as defined hereinabove, that is positioned between and serves to connect two other chemical groups.

[0035] As employed herein, when a moiety (e.g., cycloalkyl, aryl, heteroaryl, heterocyclyl, urea, etc.) is described as “optionally substituted” without expressly stating the substituents, it is meant that the group optionally has multiple non-hydrogen substituents, for example, from one to five, or from one to four, or from one to three, or one, or two non-hydrogen substituents.

[0036] The term “halogen” or “halo” as employed herein refers to chlorine, bromine, fluorine, or iodine.

[0037] The term “haloalkyl” refers to an alkyl chain in which one or more hydrogens have been replaced by a halogen. Representative haloalkyls are trifluoromethyl, difluoromethyl, fluorochloromethyl, chloromethyl, and fluoromethyl.

[0038] The term “haloalkoxy” refers to —O— alkyl , wherein the alkyl chain in which one or more hydrogens have been replaced by a halogen. Representative haloalkoxy are trifluoromethoxy, difluoromethoxy, and trifluoroethoxy.

[0039] The term “hydroxyl” refers to -OH. The term “hydroxyalkyl” refers to -alkylene-OH.

[0040] The term “oxo” refers to =0. As used herein, a compound bearing an oxo substituent is understood to refer to a tautomer or resonance structure that results in a stable or chemically feasible compound. As used herein, can be represented by (O).Representative examples include acyl (i.e. , -C(O)R) and sulfonyl (i.e. , -S(O)2R) substituents.

[0041] The term "substituted", as used herein, means that a hydrogen radical of the designated moiety is replaced with the radical of a specified substituent, provided that the substitution results in a stable or chemically feasible compound. The term "substitutable", when used in reference to a designated atom, means that attached to the atom is a hydrogen radical, which can be replaced with the radical of a suitable substituent.

[0042] The phrase "one or more” substituents, as used herein, refers to a number of substituents that equals from one to the maximum number of substituents possible based onDocket no. 24-2208-WON-S1 / Set Bthe number of available bonding sites, provided that the above conditions of stability and chemical feasibility are met. Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group, and the substituents may be either the same or different. As used herein, the term "independently selected" means that the same or different values may be selected for multiple instances of a given variable in a single compound.

[0043] It is to be understood that each individual atom present in Formulae (I) to (If) may be present in the form of any of its naturally occurring isotopes, with the most abundant isotope(s) being preferred. Thus, by way of example, each individual hydrogen atom present in Formula (I), or in the formulae depicted hereinafter, may be present as a1H,2H (deuterium; D), or3H (tritium; T) atom, preferably1H. Similarly, by way of example, each individual carbon atom present in formula (I), or in the formulae depicted hereinafter, may be present as a12C,13C, or14C atom, preferably12C.

[0044] As used herein, “an effective amount” of a compound, with reference to CD38, is an amount that is sufficient to negatively modulate or inhibit the activity of CD38.

[0045] As used herein, a “therapeutically effective amount” of a compound, with reference to CD38, is an amount that is sufficient to ameliorate or in some manner reduce a symptom or stop or reverse progression of a condition, or negatively modulate or inhibit the activity of CD38.

[0046] As used herein, “treatment” means any manner in which the symptoms or pathology of a condition, disorder or disease in a patient are ameliorated or otherwise beneficially altered.

[0047] The methods described herein can be configured by the person of ordinary skill in the art to meet the desired need. This disclosure provides improvements in treating diseases and disorders associated with CD38 activity. Specifically, the inventors found that the compounds of the disclosure are potent inhibitors of CD38.

[0048] Compounds

[0049] In a broad aspect, the disclosure provides compounds having the structural Formula (I):Docket no. 24-2208-WON-S1 / Set Band pharmaceutically acceptable salts thereof, whereinR1is a 5- to 10-membered heteroaryl group optionally substituted with one or more independently selected R2, where each R2is (i) Ci-Ce alkyl, (ii) C3-C8 cycloalkyl, (iii) C3-C6 cycloalkyl(Ci-C2 alkyl), (iv) Ci-Ce haloalkyl, (v) Ci-Ce alkoxy(Co-Ce alkyl), (vi) halogen, (vii) -OR15, (viii) -NR16R17, (ix) -CN, or (x) -NO2;R15is H, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy(Ci-Ce alkyl), or C3-C8 cycloalkyl;R16is H or Ci-Ce alkyl; andR17is H, Ci-C6alkyl;R4is H or Ci-Ce alkyl;R5is 4- to 13-membered heterocyclyl(Co-C2 alkyl), C3-C12 cycloalkyl(Co-C2 alkyl), aryl(Co-Ce alkyl), 8- to 12-membered spirocyclyl(Co-C2 alkyl), or 5- or 6- membered heteroaryl(Co-Ce alkyl), each of which is optionally substituted on a cyclic portion thereof with one or more independently selected R3, where each R3is (i) Ci-Ce alkyl, (ii) Ci-Ce haloalkyl, (iii) Ci-Ce alkoxy, (iv) halogen, (v) -SO2(Ci-Ce alkyl), (vi) -SO2(C3-Cs cycloalkyl), (vii) -NHSO2(Ci-Ce alkyl), (viii) -NHSO2(C3-C8cycloalkyl), (ix) -CO2(Ci-C6alkyl), (x) oxo, (xi) -OR57, (xii) -CN, (xiii) -C(O)R58, (xiv) -(C0-C4alkyl)R59, (xv) -C(O)R62, (xvi) 4- to 8- membered heterocyclyl optionally substituted with one or more independently selected Ci-Ce alkyl or halogen groups, or (xvii) (C3-C8 cycloalkyl) optionally substituted with one or more independently selected Ci-Ce alkyl or halogen group;R57is H, Ci-C6alkyl, -(CH2CH2O)I-2(CI-C6 alkyl), Ci-C6haloalkyl, C3-C8cycloalkyl(Co-C2 alkyl), 4- to 8-membered heterocyclyl(Co-C2 alkyl), or 5- or 6-membered heteroaryl optionally substituted with one or more independently selected Ci-Ce alkyl, halogen, or Ci-Ce alkoxy groups; R58and R59are each independently -NR60R61whereinDocket no. 24-2208-WON-S1 / Set BR60is H or Ci-Ce alkyl; andR61is -SO2(Ci-C6alkyl) or Ci-Ce haloalkyl;R62is Ci-Ce alkyl optionally substituted with one Ci-Ce alkoxy;R6is H, halogen, Ci-Ce alkyl, C3-C6 cycloalkyl, Ci-Ce haloalkyl, or Ci-Ce alkoxy; R7is H, Ci-Ce alkyl, C3-C6 cycloalkyl, or -NR8R9where R8and R9are each independently H or Ci-Ce alkyl; andR10is H, halogen, C1-C3 haloalkyl or C1-C3 alkyl.

[0050] In certain aspects, the disclosure provides compounds having the structural Formula (la):

[0051] In certain embodiments of Formula (I) or (la) as disclosed herein, R1is a 5- to 10-membered heteroaryl group optionally substituted with one or more independently selected R2, each R2is (i) Ci-Ce alkyl, (ii) C3-C6 cycloalkyl, (iii) C3-C6 cycloalkyl(Ci-C2)alkyl, (iv) Ci-Ce haloalkyl, (v) Ci-Ce alkoxy(Co-Ce alkyl), (vi) halogen, (vii) -OR15, (viii) -NR16R17, (ix) -CN, or (x) -NO2; wherein R15is H, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy(Ci-Ce alkyl), orCs-Cs cycloalkyl; R16is H or Ci-Ce alkyl; and R17is H, Ci-Ce alkyl. In certain embodiments, R1is a 5- to 10-membered heteroaryl group optionally substituted with 1, 2, or 3 R2groups. In certain embodiments, R1is a 5- or 6-membered heteroaryl group optionally substituted with 1 or 2 R2groups. In certain embodiments, R1is a 5- or 6-membered heteroaryl group containing at least one nitrogen member, optionally substituted with 1 or 2 R2groups. In certain embodiments, R1is 5-membered heteroaryl, optionally substituted with 1 R2group. In certain embodiments, R1is 5-membered heteroaryl containing at least one nitrogen member, optionally substituted with 1 R2group. In certain embodiments, R1is 5-membered heteroaryl containing at least one nitrogen member and at least one sulfur or oxygen member, optionally substituted with one R2group.

[0052] In certain embodiments of Formula (I) or (la) as disclosed herein, each R2is independently C1-C3 alkyl, cyclopropyl or cyclopropylmethyl. In certain embodiments of Formula (I) or (la) as disclosed herein, each R2is independently methyl, ethyl, propyl,Docket no. 24-2208-WON-S1 / Set Bisopropyl, fluoro, chloro, methoxy, ethoxy, or cyano. In certain embodiments of Formula (I) or (la) as disclosed herein, each R2is independently methyl, ethyl, fluoro, methoxy, or cyano.

[0053] In certain embodiments of Formula (I) or (la) as disclosed herein, R1is pyrrolyl, thiazolyl, imiadozlyl, pyrazolyl, oxazolyl, or isoxazolyl, each of which is optionally substituted with one or two R2groups. In certain embodiments, R1is thiazolyl, imidazolyl, or pyrazolyl, each of each of which is optionally substituted with one or two R2groups. In certain embodiments, R1is thiazolyl, imidazolyl, or pyrazolyl, each of each of which is optionally substituted with one R2group. In certain embodiments, R1is thiazolyl (e.g., thiazol-5-yl). In certain embodiments, R1is imidazolyl (e.g., imidazol-5-yl) optionally substituted with one R2group, wherein the R2group is Ci-C8alkyl (e.g., methyl), C3-C6 cycloalkyl (e.g., cyclopropyl), or C3-C6 cyclaolkyl(Ci-C2 alkyl) (e.g., cyclopropylmethyl). In certain embodiments, R1is 1 -methyl-1H-imidazol-5-yl or 1H-imidazol-1-yl. In certain embodiments, R1is pyrazolyl (e.g., pyrazol-4-yl) optionally substituted with one R2group, wherein the R2group is Ci-C8alkyl (e.g., methyl). In certain embodiments, R1is 3-methyl-1H-pyrazol-4-yl. For example, in certain embodiments, R1is:

[0054] In certain embodiments of Formula (I) or (la) as disclosed herein, R4is H or Ci-C8alkyl. In certain embodiments, R4is H. In certain embodiments R4is Ci-C8alkyl. In certain embodiments, R4is H, methyl or ethyl. In certain embodiments, R4is H or methyl.

[0055] In certain embodiments of Formula (I) or (la) as disclosed herein, R5is 4- to 13-membered heterocyclyl(Co-C2 alkyl), C3-C12 cycloalkyl(Co-C2 alkyl), aryl(Co-C8alkyl), 8- to 12-membered spirocyclyl(Co-C2 alkyl), or 5- or 6-membered heteroaryl(Co-C8alkyl), each of which is optionally substituted on the cyclic portion with one or more independently selected R3, where each R3is (i) Ci-C8alkyl, (ii) Ci-C8haloalkyl, (iii) Ci-C8alkoxy, (iv) halogen, (v) -SO2(Ci-C6alkyl), (vi) -SO2(C3-C8cycloalkyl), (vii) -NHSO2(CI-C6alkyl), (viii) -NHSO2(C3-C8cycloalkyl), (ix) -CO2(Ci-C8alkyl), (x) oxo, (xi) -OR57, (xii) -CN, (xiii) -C(O)R58, (xiv) -(C0-C4 alkyl) R59, (xv) -C(O)R62, (xvi) 4- to 8-membered heterocyclyl optionally substituted with one or more independently selected Ci-C8alkyl or halogen groups, or (xvii) (C8-C8cycloalkyl) optionally substituted with one or more independently selected Ci-C8alkyl or halogen groups. In certain embodiments of Formula (I) or (la) as disclosed herein, R57is H, Ci-C8alkyl, -(CH2CH2O)I-2(CI-C6 alkyl), Ci-C8haloalkyl, C8-C8cycloalkyl(Co-C2 alkyl), 4- to 8-membered heterocyclyl (C0-C2 alkyl), or 5- or 6-membered heteroaryl optionally substituted with one or more independently selected Ci-C8alkyl, halogen, or Ci-C8alkoxy groups. In certain embodiments, R58and R59are each independently -NR60R61, wherein R60is H or Ci-C8alkyl;Docket no. 24-2208-WON-S1 / Set Band R61is -S02(Ci-Ce alkyl) or Ci-Ce haloalkyl. In certain embodiments, R62is Ci-Ce alkyl optionally substituted with one Ci-Ce alkoxy.

[0056] In certain embodiments of Formula (I) or (la) as disclosed herein, R5is C3-C12 cycloalkyl(Co-C2 alkyl), the cyclic portion of which is optionally substituted with 1, 2, or 3 independently selected R3. In certain embodiments, R5is C3-C12 cycloalkyl (e.g., Ce cycloalkyl) optionally substituted with 1, 2, or 3 independently selected R3. For example, in certain embodiments, R5is a group of formula (Ila):wherein n is 0 or 1.

[0057] In certain embodiments wherein R5is a group of formula (Ila), n is 0, and R3is Ci- Ce alkyl (e.g., methyl). For example, in certain embodiments, R5is:

[0058] In certain embodiments, R5is a group of formula (lib):wherein n is 0 or 1.

[0059] In certain embodiments, R5is a group of formula (lie) or (lid):Docket no. 24-2208-WON-S1 / Set B

[0060] In certain embodiments wherein R5is a group of formula (lib), (He), or (lid), n is 0. In certain embodiments wherein R5is a group of formula (lib), (lie), or (lid), R3is -SO2(Ci-C8alkyl), -SO2(C3-C8cycloalkyl), -NHSO2(CI-C6alkyl), -NHSO2(C3-C8cycloalkyl), -OR57, or -(COC4)R59. In certain embodiments, R5is a group of formula (lib) or (lid), wherein n is 0 and R3is -SO2(Ci-C8alkyl) (e.g., -SO2Me). In certain embodiments, wherein R5is a group of formula (lib) or (lid), n is 0 and R3is -NHSO2(CI-C8alkyl) (e.g., -NHSO2Me). In certain embodiments wherein R5is a group of formula (lib), (He), or (lid), n is 0 and R3is -OR57. In certain embodiments, R57is H, Ci-C8alkyl (e.g., methyl or isopropyl), or-(CH2CH2O)i-2(Ci-C6 alkyl) (e.g., -(CH2CH2OMe)). In certain embodiments, R57is Ci-C8haloalkyl (e.g., trifluoromethyl, 2,2-difluoroethyl, or trifluoroethyl). In certain embodiments, R57is C3-C8cycloalkyl(Co-C2alkyl) (e.g., cyclopropyl methyl). In certain embodiments, R57is (4- to 8- membered heterocyclyl)(Co-C2alkyl) (e.g., oxetan-3-ylmethyl). In certain embodiments, R57is 5- or 6-membered heteroaryl optionally substituted with 1 , 2, or 3 independently selected Ci-C8alkyl (e.g., methyl), halogen, or Ci-C8alkoxy groups. In certain embodiments, the 5- or 6- membered heteroaryl of R57is pyrazol-4-yl or pyrazin-2-yl. In certain embodiments, R3is -(Co-C4alkyl)R59wherein R59is -NR60R61, R60is H or Ci-C6alkyl, and R61is -SO2(Ci-C6alkyl) or Ci-C8haloalkyl. In certain embodiments, R3is -NR60R61(i.e. , wherein R3is -(Co alkyl)R59), R60is H, and R61is C2haloalkyl (e.g., trifluoroethyl). For example, in certain embodiments R5is:

[0061] In certain embodiments wherein R5is a group of formula (lib), (He), or (I Id), n is 0 and R3is 4- to 8-membered heterocyclyl optionally substituted with one or more independently selected Ci-C8alkyl or halogen groups. In certain embodiments, R3is 4- to 8- membered heterocyclyl optionally substituted with 1, 2, or 3 independently selected Ci-C8Docket no. 24-2208-WON-S1 / Set Balkyl or halogen groups. In certain embodiments, the 4- to 8-membered heterocyclyl of R3is azetidinyl or pyrrolidinyl. In certain embodiments, R3is 4- to 8-membered heterocyclyl substituted with 23 independently selected halogen groups (e.g., fluorine). For example, in certain embodiments, R5is :

[0062] In certain embodiments wherein R5is a group of formula (lib), (He), or (lid), n is 1. In certain embodiments wherein R5is a group of formula (lib), (lie), or (lid), n is 1 and at least one R3is halogen, (e.g., fluorine). For example, in certain embodiments, R5is:

[0063] In certain embodiments of Formula (I) or (la) as disclosed herein, R5is C3-C12 cycloalkyl(Ci-C2 alkyl), the cyclic portion of which is optionally substituted with 1, 2, or 3 independently selected R3. In certain embodiments, R5is C4-C12 cycloalkyl optionally substituted with 1, 2, or 3 independently selected R3. For example, in certain embodiments, R5is a group of formula (Hie):wherein n is 0 or 1.

[0064] In certain embodiments wherein R5is a group of formula (Hie), n is 0, R3is -OR57, and R57is -(CH2CH2O)I-2(CI-C6 alkyl) (e.g., -(CH2CH2OXC1 alkyl)). For example, in certain embodiments, R5is:

[0065] In certain embodiments of Formula (I) or (la) as disclosed herein, R5is C3-C12 cycloalkyl(Ci-C2 alkyl), the cyclic portion of which is optionally substituted with 1, 2, or 3Docket no. 24-2208-WON-S1 / Set Bindependently selected R3. In certain embodiments, R5is C3-C12 cycloalkyl(Ci-C2 alkyl), the cyclic portion of which is optionally substituted with 1, 2, or 3 independently selected R3. For example, in certain embodiments, R5is a group of formula (Illa):>whereinR3ais H, halogen, or -OH;n is 0, 1, or 2; andp is 1 or 2.

[0066] In certain embodiments wherein R5is a group of formula (Illa), p is 1. In certain embodiments wherein R5is a group of formula (Illa), p is 1 and n is 0. In certain embodiments wherein R5is a group of formula (Illa), p is 1 , n is 0, and R3ais -OH or halogen (e.g., fluorine). In certain embodiments wherein R5is a group of formula (Illa), p is 1 and n is 2. In certain embodiments wherein R5is a group of formula (Illa), p is 1 , n is 2, and each R3is independently -OH or halogen (e.g., fluorine). For example, in certain embodiments, R5is:

[0067] In certain embodiments of Formula (I) or (la) as disclosed herein, R5is aryl(Co-C6 alkyl), the cyclic portion of which is optionally substituted with one or more independently selected R3groups. In certain embodiments of Formula (I) or (la) as disclosed herein, R5is aryl(Co-Ce alkyl), the cyclic portion of which is optionally substituted with 1, 2, 3, or 4 independently selected R3groups.

[0068] In certain embodiments of Formula (I) or (la) as disclosed herein, R5is 5- or 6-membered heteroaryl(Co-Ce alkyl), the cyclic portion of which is optionally substituted with one or more independently selected R3groups. In certain embodiments, R5is 5- or 6-membered heteroaryl optionally substituted with one or more independently selected R3groups. In certain embodiments, R5is 5- or 6-membered heteroaryl optionally substituted with 1, 2, 3, or 4 independently selected R3groups. In certain embodiments, R5is a group of formula (IVa):Docket no. 24-2208-WON-S1 / Set BwhereinX, Y, and Z independently represent nitrogen, C-H, or C-R3, provided no more than one of X, Y and Z is nitrogen;n is 0 or 1.

[0069] In certain embodiments wherein R5is a group of formula (IVa), Z is C-R3. In certain embodiments wherein R5is a group of formula (IVa), Y is nitrogen. In certain embodiments wherein R5is a group of formula (IVa), Z is C-R3and Y is nitrogen. For example, in certain embodiments, R5is a group of formula (IVb) or (IVc):(IVb) (IVc) wherein n is 0 or 1.

[0070] In certain embodiments of Formula (I) or (la) as disclosed herein, R5is pyrazinyl substituted with one or more R3. In certain embodiments of Formula (I) or (la) as disclosed herein, R5is pyrazin-5-yl substituted with one or more R3. In certain embodiments of Formula (I) or (la) as disclosed herein, R5is pyridinyl substituted with one or more R3. In certain embodiments of Formula (I) or (la) as disclosed herein, R5is pyridin-3-yl or pyridin-5-yl substituted with one or more R3. For example, in certain embodiments, R5is a group of formula (IVd) or (IVe):(IVd) (IVe) wherein n is 0 or 1.Docket no. 24-2208-WON-S1 / Set B

[0071] In certain embodiments wherein R5is a group of formula (IVd) or (IVe), n is 0. In certain embodiments wherein R5is a group of formula (IVd), n is 0 and R3is -OR57and R57is -(CH2CH2O C1-C6 alkyl). For example, in certain embodiments, R5is:

[0072] In certain embodiments of Formula (I) or (la) as disclosed herein, R5is bicyclic C8-C12 cycloalkyl(Co-C2 alkyl), the cyclic portions of which are optionally substituted with 1, 2, or 3 independently selected R3groups. As discussed above, as used herein, bicyclic refers to a cycloalkyl having two ring systems wherein the ring systems share at least 2 atoms. In certain embodiments of Formula (I) or (la) as disclosed herein, R5is a fused bicyclic group of the formula (Va):>whereinR3ais H, halogen, or -OH;n is 0 or 1; andm is 0, 1, or 2.

[0073] In certain embodiments wherein R5is a group of formula (Va), n is 0 and m is 0. For example, in certain embodiments, R5is:

[0074] In certain embodiments of Formula (I) or (la) as disclosed herein, R5is a bridged bicyclic group of the formula (Vb):whereinDocket no. 24-2208-WON-S1 / Set Bp is 1 or 2; andeach of m1, m2, and m3are independently 0 or 1.

[0075] In certain embodiments wherein R5is a group of formula (Va), p is 1 , and each of m1, m2, and m3are 0. In certain embodiments wherein R5is a group of formula (Va), R3is halogen (e.g., fluorine. For example, in certain embodiments, R5is:

[0076] In certain embodiments of Formula (I) or (la) as disclosed herein, R5is 4- to 13-membered heterocyclyl(Co-C2 alkyl), the cyclic portion of which is optionally substituted with one or more independently selected R3groups. In certain embodiments of Formula (I) or (la) as disclosed herein, R5is 4- to 13-membered heterocyclyl. In certain embodiments of Formula (I) or (la) as disclosed herein, R5is a group of formula (Via):wherein m1and m2are each independently 0, 1, or 2;p is 0, 1, or 2;n is 0, 1, or 2;Z is N-H, N-R31, sulfur, or oxygen ; andR31is H, Ci-Ce alkyl, Ci-Ce haloalkyl, -SO2(Ci-Ce alkyl), -SO2(C3-Cs cycloalkyl), or 4- to 8-membered heterocyclyl optionally substituted with one or more independently selected Ci-Ce alkyl or halogen groups.

[0077] In certain embodiments wherein R5is a group of formula (Via), m1and m2are each 1 and p is 0. In certain embodiments wherein R5is a group of formula (Via), m1and m2are each 1, p is 0, n is 0, and Z is N-R31. In certain embodiments wherein R5is a group of formula (Via), R31is Ci-Ce haloalkyl (e.g., trifluoroethyl). In certain embodiments wherein R5is a group of formula (Via), R31is 4- to 8-membered heterocyclyl optionally substituted with one or more independently selected Ci-Ce alkyl or halogen groups. In certain embodiments wherein R5is a group of formula (Via), R31is 4- to 8-membered heterocyclyl optionally substituted with one, two, or 3 independently selected Ci-Ce alkyl or halogen groups. In certain embodiments wherein R5is a group of formula (Via), R31is 4- to 8-Docket no. 24-2208-WON-S1 / Set Bmembered heterocyclyl (e.g., oxetan-3-yl) substituted with one Ci-Ce alkyl group (e.g., methyl). In certain embodiments wherein R5is a group of formula (Via), m1and m2are each 1, p is 0, n is 2, Z is sulfur, and each R3is oxo. In certain embodiments of formula (Via), m1and m2are each 0, p is 1, n is 1, Z is oxygen, and R3is Ci-Ce alkyl (e.g., methyl). For example, in certain embodiments, R5is:

[0078] In certain embodiments of Formula (I) or (la) as disclosed herein, R5is a 8- to 12-membered spirocyclyl(Co-C2 alkyl), the cyclic portions of which are optionally substituted with 1, 2, or 3 independently selected R3groups. As discussed above, as used herein, the term spirocyclyl refers to a group having at least two ring systems wherein at least two of the ring systems share 1 ring member (i.e. , atom). In certain embodiments of Formula (I) or (la) as disclosed herein, R5is a group of formula (Vila):whereinRing A has from 3-5 ring members, one ring member of which is optionally a heteroatom selected from sulfur, oxygen, or nitrogen;n is 0 or 1;m is 0, 1 or 2; andp is 0, 1, or 2.

[0079] In certain embodiments wherein R5is a group of formula (Vila), Ring A has 3, 4, or 5 ring members, n is 0, and p is 0 or 1. In certain embodiments, Ring A has 4 ring members. In certain embodiments, Ring A has 4 ring members, wherein one ring member is a heteroatom selected from sulfur, oxygen, or nitrogen. In certain embodiments, Ring A has 4 ring members, one ring member of which is nitrogen, n is 0, m is 1, p is 0, and R3is Ci-Ce haloalkyl (e.g., trifluoroethyl), -SO2(Ci-Ce alkyl) (e.g., -SChMe), -SO2(C3-Cs cycloalkyl), or -C(O)R62, wherein R62is Ci-Ce alkyl optionally substituted with one Ci-Ce alkoxy. In certain embodiments, R3is -C(O)R62, wherein R62is Ci-Ce alkyl (e.g., methyl) optionally substituted with one Ci-Ce alkoxy (e.g., methoxy). In certain embodiments, Ring A has 4 ring members,Docket no. 24-2208-WON-S1 / Set Bone ring member of which is nitrogen, n is 0, m is 0, and p is 0. In certain embodiments, Ring A has 4 ring members, one ring member of which is sulfur, n is 0, m is 2, p is 0 or 1, and R3is oxo. In certain embodiments, Ring A has 4 ring members, one ring member of which is oxygen, n is 0, m is 0, and p is 0 or 1. For example, in certain embodiments, R5is:

[0080] In certain embodiments of Formula (I) or (la) as disclosed herein, R3is independently halogen, -OR57, -NHSO2(Ci-Ce alkyl), -NHSO2(C3-Cs cycloalkyl), Ci-Ce haloalkyl, -SO2(Ci-Ce alkyl), or Ci-Ce alkyl.

[0081] In certain embodiments of Formula (I) or (la) as disclosed herein, R6is H, halogen, Ci-Ce alkyl, C3-C6 cycloalkyl, Ci-Ce haloalkyl, or Ci-Ce alkoxy. In certain embodiments of Formula (I) or (la) as disclosed herein, R6is H. In certain embodiments of Formula (I) or (la) as disclosed herein, R6is Ci-Ce alkyl (e.g., methyl). In certain embodiments of Formula (I) or (la) as disclosed herein, R6is Ci-Ce alkoxy (e.g., methoxy). In certain embodiments of Formula (I) or (la) as disclosed herein, R6is Ci-Ce haloalkyl (e.g., trifluoromethyl). In certain embodiments of Formula (I) or (la) as disclosed herein, R6is H, methoxy, or trifluoromethyl. In certain embodiments, R6is methoxy. In certain embodiments, R6is trifluoromethyl.

[0082] In certain embodiments of Formula (I) or (la) as disclosed herein, R7is H, Ci-Ce alkyl, C3-C6 cycloalkyl, or -NR8R9where R8and R9are each independently H or Ci-Ce alkyl. In certain embodiments of Formula (I) or (la) as disclosed herein, R7is H, Ci-Ce alkyl, or C3-Ce cycloalkyl. In certain embodiments of Formula (I) or (la) as disclosed herein, R7is H. In certain embodiments of Formula (I) or (la) as disclosed herein, R7is Ci-Ce alkyl (e.g., methyl). In certain embodiments of Formula (I) or (la) as disclosed herein, R7is C3-C6 alkyl (e.g., cyclopropyl). In certain embodiments of Formula (I) or (la) as disclosed herein, R7is methyl, ethyl, n-propyl, isopropyl, or cyclopropyl.

[0083] In certain embodiments of Formula (I) or (la) as disclosed herein, R10is H, halogen, C1-C3 haloalkyl, or C1-C3 alkyl. In certain embodiments, R10is H. In certain embodiments, R10is halogen (e.g., fluorine). In certain embodiments, R10is trifluoromethyl or methyl.Docket no. 24-2208-WON-S1 / Set B

[0084] As disclosed above, the disclosure provides compounds having the structural Formula (lb) wherein R1is 5-membered heteroaryl (e.g., thiazolyl, pyrazolyl, or imidazolyl) optionally substituted with one or more independently selected R2groups. In certain aspects, the disclosure provides compounds having the structural Formulae (Ic) to (If):whereinn is 0 or 1; andR2, R4, R5, R6, R7, and R10are each as described hereinabove.

[0085] Enumerated EmbodimentsEmbodiment 1. A compound of formula (I)or a pharmaceutically acceptable salt thereof, whereinR1is a 5- to 10-membered heteroaryl group optionally substituted with one or more independently selected R2, where each R2is (i) Ci-Ce alkyl, (ii) Cs-Cs cycloalkyl, (iii) C3-C6 cycloalkyl(Ci-C2 alkyl), (iv) Ci-Ce haloalkyl, (v) Ci-CeDocket no. 24-2208-WON-S1 / Set Balkoxy(Co-Ce alkyl), (vi) halogen, (vii) -OR15, (viii) -NR16R17, (ix) -CN, or (x) -NO2;R15is H, Ci-Ce alkyl, Ci-C8haloalkyl, Ci-C8alkoxy(Ci-C8alkyl), or C3-C8 cycloalkyl;R16is H or Ci-C6alkyl; andR17is H, Ci-C6alkyl;R4is H or Ci-Ce alkyl;R5is 4- to 13-membered heterocyclyl(Co-C2 alkyl), C3-C12 cycloalkyl(Co-C2 alkyl), aryl(Co-Ce alkyl), 8- to 12-membered spirocyclyl(Co-C2 alkyl), or 5- or 6- membered heteroaryl(Co-C6 alkyl), each of which is optionally substituted on a cyclic portion thereof with one or more independently selected R3, where each R3is (i) Ci-Ce alkyl, (ii) Ci-C8haloalkyl, (iii) Ci-C8alkoxy, (iv) halogen, (v) -SO2(Ci-C6alkyl), (vi) -SO2(C3-C8cycloalkyl), (vii) -NHSO2(CI-C6alkyl), (viii) -NHSO2(C3-C8cycloalkyl), (ix) -CO2(Ci-C6alkyl), (x) oxo, (xi) -OR57, (xii) -CN, (xiii) -C(O)R58, (xiv) -(C0-C4 alkyl) R59, (xv) -C(O)R62, (xvi) 4- to 8- membered heterocyclyl optionally substituted with one or more independently selected Ci-C8alkyl or halogen groups, or (xvii) (Cs-Cs cycloalkyl) optionally substituted with one or more independently selected Ci-C8alkyl or halogen groups;R57is H, Ci-C6alkyl, -(CH2CH2O)I-2(CI-C6 alkyl), Ci-C6haloalkyl, C3-C8cycloalkyl(Co-C2 alkyl), 4- to 8-membered heterocyclyl (C0-C2 alkyl), or 5- or 6-membered heteroaryl optionally substituted with one or more independently selected Ci-C8alkyl, halogen, or Ci-C8alkoxy groups;R58and R59are each independently -NR60R61whereinR60is H or Ci-C8alkyl; andR61is -SO2(Ci-C8alkyl) or Ci-C8haloalkyl;R62is Ci-C8alkyl optionally substituted with one Ci-C8alkoxy; R6is H, halogen, Ci-C8alkyl, C8-C8cycloalkyl, Ci-C8haloalkyl, orCi-C8alkoxy; R7is H, Ci-C8alkyl, C8-C8cycloalkyl, or -NR8R9where R8and R9are each independently H or Ci-C6alkyl; andR10is H, halogen, C1-C3 haloalkyl or C1-C3 alkyl.Embodiment 2. A compound according to embodiment 1, which has the formula (la)Docket no. 24-2208-WON-S1 / Set BEmbodiment 3. A compound according to any one of embodiments 1-2, wherein R1is a 5-membered heteroaryl group containing at least one nitrogen and the heteroaryl is optionally substituted with 1 or 2 R2.Embodiment 4. A compound according to embodiment 1 or embodiment 2, wherein R1is a 5-membered heteroaryl group containing one nitrogen and one sulfur or oxygen, and the heteroaryl is optionally substituted with 1 or 2 R2.Embodiment 5. A compound according to embodiment 1 or embodiment 2, wherein R1is pyrrolyl, thiazolyl, imidazolyl, pyrazolyl, oxazoly or isoxazolyl, each of which is optionally substituted with 1 or 2 R2.Embodiment 6. A compound according to any one of embodiments 1-5, wherein R5is C3-C12 cycloalkyl(Co-C2 alkyl), and R5is optionally substituted with 1-3 of R3.Embodiment 7. A compound according to embodiment 6, wherein R5is cycloalkyl optionally substituted with 1, 2 or 3 of R3.Embodiment 8. A compound according to embodiment 7, wherein R5is a group of the formula (Ila):wherein n is 0 or 1.Embodiment 9. A compound according to embodiment 7, wherein R5is a group of the formula (lib):Docket no. 24-2208-WON-S1 / Set Bwherein n is 0 or 1.Embodiment 10. A compound according to embodiment 7, wherein R5is a group of the formula (He) or (lid):wherein n is 0 or 1.Embodiment 11. A compound according to embodiment 7, wherein R5is a group of the formula (He):wherein n is 0 or 1.Embodiment 12. A compound according to embodiment 7, wherein R5is a group of the formula (Illa):whereinDocket no. 24-2208-WON-S1 / Set BR3ais H, halogen, or -OH;n is 0, 1 or 2; andp is 1 or 2.Embodiment 13. A compound according to any one of embodiments 1-5, wherein R5is aryl(Co-Ce alkyl), and R5is optionally substituted with 1-3 of R3.Embodiment 14. A compound according to any one of embodiments 1-5, wherein R5is 5- or 6-membered heteroaryl(Co-Ce alkyl), and R5is optionally substituted with 1-3 of R3.Embodiment 15. A compound according to embodiment 14, wherein R5is a group of the formula (IVa):whereinX, Y and Z independently represent nitrogen, C-H or C-R3, provided that no more than one of X, Y and Z is nitrogen; andn is 0 or 1.Embodiment 16. A compound according to embodiment 15, wherein n is 1 and Y is N.Embodiment 17. A compound according to embodiment 15, wherein R5is a group of the formula (IVb) or (IVc):(IVb) (IVc) wherein n is 0 or 1.Docket no. 24-2208-WON-S1 / Set BEmbodiment 18. A compound according to embodiment 15, wherein R5is a group of the formula (IVd) or (IVe):(IVd) (IVe) wherein n is 0 or 1.Embodiment 19. A compound according to any one of embodiments 1-5, wherein R5is a bicyclic C8-C12 cycloal kyl(Co-C2 alkyl) where the rings share at least 2 atoms, and R5is optionally substituted with 1-3 of R3.Embodiment 20. A compound according to embodiment 19, wherein R5is a group of the formula (Va):R3ais H, halogen, or -OH;n is 0 or 1; andm is 0, 1 or 2.Embodiment 21. A compound according to embodiment 19, wherein R5is a group of the formula (Vb):whereinp is 1 or 2; andeach of m1, m2, and m3are independently 0 or 1.Docket no. 24-2208-WON-S1 / Set BEmbodiment 22. A compound according to any one of embodiments 1-5, wherein R5is a 8- to 12-membered spirocyclyl(Co-C2 alkyl) which is optionally substituted with 1-3 of R3.Embodiment 23. A compound according to embodiment 22, wherein R5is a group of the formula (Vila):whereinRing A has from 3-5 ring members, one ring member of which is optionally a heteroatom selected from sulfur, oxygen, and nitrogen;n is 0 or 1;m is 0, 1 or 2; andp is 0, 1, or 2.Embodiment 24. A compound according to any one of embodiments 1-5, wherein R5is a 4- to 13-membered heterocyclyl(Co-C2 alkyl), and R5is optionally substituted with 1-3 of R3.Embodiment 25. A compound according to embodiment 24, wherein R5is a group of the Formula (Via):wherein m1and m2are each independently an integer of 0, 1 , or 2;p is an integer of 0, 1 , or 2;n is an integer of 0, 1 , or 2;Z is N-H, N-R31, sulfur, or oxygen ; andR31is H, Ci-C6alkyl, Ci-C6haloalkyl, -SO2(Ci-C6alkyl), -SO2(C3-C8cycloalkyl), or 4- to 8-membered heterocyclyl optionally substituted with one or more independently selected Ci-C6alkyl or halogen groups.Docket no. 24-2208-WON-S1 / Set BEmbodiment 26. A compound according to any one of embodiments 1-25, wherein each R3is independently halogen, -OR57, -NHSO2(Ci-Ce alkyl), -NHSO2(C3-Cs cycloalkyl), Ci-Ce haloalkyl, -SO2(Ci-C6alkyl), Ci-C6alkyl, oxo, -C(O)R58, -(C0-C4alkyl)R59, -C(O)R62, 4- to 8-membered heterocyclyl optionally substituted with one or more independently selected Ci-Ce alkyl or halogen groups, or (Cs-Cs cycloalkyl) optionally substituted with one or more independently selected Ci-Ce alkyl or halogen group.Embodiment 27. A compound according to any one of embodiments 1-26, wherein R1is substituted with one R2.Embodiment 28. A compound according to any one of embodiments 1-26, wherein R1is substituted with two R2.Embodiment 29. A compound according to any one of embodiments 1-28, wherein R2is methyl, ethyl, propyl, isopropyl, fluoro, chloro, methoxy, ethoxy, or cyano.Embodiment 30. A compound according to any one of embodiments 1-28, wherein R2methyl, ethyl, fluoro, methoxy or cyano.Embodiment 31. A compound according to any one of embodiments 1-30, wherein R6is Ci-Ce alkoxy.Embodiment 32. A compound according to any one of embodiments 1-30, wherein R6is Ci-Ce haloalkyl.Embodiment 33. A compound according to any one of embodiments 1-30, wherein R6is hydrogen, methoxy, or trifluoromethyl.Embodiment 34. A compound according to any one of embodiments 1-33, wherein R7is Ci-Ce alkyl.Embodiment 35. A compound according to any one of embodiments 1-33, wherein R7is methyl, ethyl, propyl or isopropyl.Embodiment 36. A compound according to any one of embodiments 1-32, wherein R7is C3-C6 cycloalkyl.Docket no. 24-2208-WON-S1 / Set BEmbodiment 37. A compound according to any one of embodiments 1-32, wherein R7is cyclopropyl.Embodiment 38. A compound according to any one of embodiments 1-33, wherein R7is hydrogen, methyl, cyclopropyl.Embodiment 39. A compound according to any one of embodiments 1-38, wherein R10is H.Embodiment 40. A compound according to any one of embodiments 1-38, wherein R10is halogen.Embodiment 41. A compound according to any one of embodiments 1-38, wherein R10is fluorine.Embodiment 42. A compound according to any one of embodiments 1-38, wherein R10is C1-C3 alkyl or C1-C3 haloalkyl.Embodiment 43. A compound according to any one of embodiments 1-38, wherein R10is methyl or trifluoromethyl.Embodiment 44. A compound according to any one of embodiments 1-43, wherein R1is thiazolyl.Embodiment 45. A compound according to any one of embodiments 1-43, wherein R1is imidazolyl.Embodiment 46. A compound according to any one of embodiments 1-43, wherein R1is pyrrolyl.Embodiment 47. A compound according to any one of embodiments 1-43, wherein R1is pyrazolyl.Embodiment 48. A compound according to any one of embodiments 1-43, wherein R1is oxazolyl.Docket no. 24-2208-WON-S1 / Set BEmbodiment 49. A compound according to any one of embodiments 1-43, wherein R1is isoxazolyl.Embodiment 50. A compound according to any one of embodiments 1-43, wherein R1is thiazol-5-yl, imidazol-5-yl or imidazol-1-yl, each of which is optionally substituted.Embodiment 51. A compound according to any one of embodiments 1-43, wherein R1is imidazol-5-yl substituted with one or two R2.Embodiment 52. A compound according to embodiment 51 , wherein the imidazol-5-yl is substituted with one R2, and R2is methyl, ethyl, propyl, isopropyl, fluoro, chloro, methoxy, ethoxy, or cyano.Embodiment 53. A compound according to embodiment 51 or embodiment 52, wherein R2is methyl, ethyl, fluoro, methoxy or cyano.Embodiment 54. A compound according to embodiment 51 or embodiment 52, wherein R2is methyl.Embodiment 55. A compound according to any one of embodiments 1-43, wherein R1is 1-methyl-1 H-imidazol-5-yl.Embodiment 56. A compound according to any one of embodiments 1-55, wherein R4is H, methyl or ethyl.Embodiment 57. A compound according to any one of embodiments 1-55, wherein R4is H or methyl.Embodiment 58. A compound according to any one of embodiments 1-55, wherein R4is H.Embodiment 59. A compound of formula (la)Docket no. 24-2208-WON-S1 / Set B(la)or a pharmaceutically acceptable salt thereof, whereinR1is a 5- to 10-membered heteroaryl group optionally substituted with one or more independently selected R2, where each R2is where each R2is (i) Ci-C8alkyl, (ii) C3-C8cycloalkyl, (iii) C3-C6cycloalkyl(Ci-C2alkyl), (iv) Ci-C6haloalkyl, (v) Ci-C8alkoxy(Co-C8alkyl), (vi) halogen, (vii) -OR15, (viii) -NR16R17, (ix) -CN, or (x) -NO2;R15is H, Ci-Ce alkyl, Ci-C8haloalkyl, Ci-C8alkoxy(Ci-C8alkyl), or C3-Cs cycloalkyl;R16is H or Ci-Ce alkyl; andR17is H, Ci-C6alkyl;R4is H or Ci-Ce alkyl;R5is an 8- to 12-membered spirocyclyl(C0-C2alkyl) or a C3-Ci2cycloalkyl(C0-C2alkyl), each of which is optionally substituted on a cyclic portion thereof with one or more independently selected R3, where each R3is (i) Ci-C8alkyl, (ii) Ci-C6haloalkyl, (iii) Ci-C6alkoxy, (iv) halogen, (v) -SO2(Ci-C6alkyl), (vi) -SO2(C3-C8cycloalkyl), (vii) -NHSO2(CI-C6alkyl), (viii) -NHSO2(C3-C8cycloalkyl), (ix) -CO2(Ci-C8alkyl), (x) oxo, (xi) -OR57, (xii) -CN, (xiii) -C(O)R58, (xiv) -(C0-C4 alkyl)R59, (xv) -C(O)R62, (xvi) 4- to 8-membered heterocyclyl optionally substituted with one or more independently selected Ci-C8alkyl or halogen groups, or (xvii) (C3-C8cycloalkyl) optionally substituted with one or more independently selected Ci-C6alkyl or halogen groups;R57is H, Ci-C6alkyl, or-(CH2CH2O)i-2(Ci-C6alkyl) , Ci-C6haloalkyl, C3-C8cycloalkyl(Co-C2alkyl), 4-to 8-membered heterocyclyl (C0-C2alkyl), or 5- or 6-membered heteroaryl optionally substituted with one or more independently selected Ci-C8alkyl, halogen, or Ci-C8alkoxy groups;R58and R59are each independently -NR60R61whereinR60is H or Ci-C8alkyl; andR61is -SO2(Ci-C8alkyl) or Ci-C8haloalkyl;R62is Ci-C6alkyl optionally substituted with one Ci-C6alkoxy; R6is H, Ci-C8alkyl, Ci-C8haloalkyl, or Ci-C8alkoxy; andR7is H, Ci-C8alkyl, orC3-C8cycloalkyl; andR10is H, halogen, Ci-C3haloalkyl or Ci-C3alkyl.Docket no. 24-2208-WON-S1 / Set BEmbodiment 60. A compound according to embodiment 59, wherein R1is imidazol-5-yl or imidazol-1-yl, each of which is optionally substituted with one or more independently selected R2.Embodiment 61. A compound according to embodiment 60, wherein R1is substituted with one R2and R2is Ci-Ce alkyl, C3-C6 cycloalkyl or C3-C6 cycloalkyl(Ci-C2)alkyl.Embodiment 62. A compound according to embodiment 60 or embodiment 61 , wherein R2is C1-C3 alkyl, cyclopropyl or cyclopropylmethyl.Embodiment 63. A compound according to embodiment 60 or embodiment 61 , wherein R2is methyl, ethyl, propyl or isopropyl.Embodiment 64. A compound according to embodiment 60 or embodiment 61 , wherein R1is 1-methyl-1H-imidazol-5-yl.Embodiment 65. A compound according to any one of embodiments 59-64, wherein R5is a 8- to 12-membered spirocyclyl(Co-C2 alkyl) which is optionally substituted with 1-3 of R3.Embodiment 66. A compound according to embodiment 65, wherein R5has the formula (Vila):whereinRing A has from 3-5 ring members, one ring member of which is optionally a heteroatom selected from sulfur, oxygen, or nitrogen;n is 0 or 1;m is 0, 1 or 2; ando1and o2are each independently 0 or 1 ; andp is 0, 1, or 2.Embodiment 67. A compound according to embodiment 66, wherein R3is Ci-Ce haloalkyl, -SO2(Ci-Ce alkyl) (e.g., -SChMe), -SO2(C3-Cs cycloalkyl), or -C(O)R62.Docket no. 24-2208-WON-S1 / Set BEmbodiment 68. A compound according to embodiment 66 or embodiment 67, whereinEmbodiment 69. A compound according to any of embodiments 66-68, wherein R5is:Embodiment 70. A compound according to any one of embodiments 59-64, wherein R5is a group of the formula (Ila):wherein n is 0 or 1.Embodiment 71. A compound according to embodiment 70, wherein R5is:Embodiment 72. A compound according to any one of embodiments 59-64, wherein R5is a group of the formula (lib):Docket no. 24-2208-WON-S1 / Set Bwherein n is 0 or 1.Embodiment 73. A compound according to any one of embodiments 59-64, wherein R5is a group of the formula (lie) or (lid):wherein n is 0 or 1.Embodiment 74. A compound according to embodiment 72 or embodiment 73, wherein n is 0 and R3is -SO2(Ci-Ce alkyl).Embodiment 75. A compound according to embodiment 72 or embodiment 73, wherein n is 0 and R3is -OR57and R57is H, Ci-C6alkyl, -(CH2CH2O)I-2(CI-C6 alkyl), Ci-C6haloalkyl, Cs-Cs cycloalkyl(Co-C2alkyl), or 5- or 6-membered heteroaryl optionally substituted with 1, 2, or 3 independently selected Ci-Ce alkyl.Embodiment 76. A compound according to embodiment 72 or embodiment 73, wherein n is 0 and R3is -(CoC4)R59.Embodiment 77. A compound according to embodiment 72 or embodiment 73, wherein R5is:Docket no. 24-2208-WON-S1 / Set BEmbodiment 78. A compound according to embodiment 72 or embodiment 73, wherein n is 0 and R3is 4- to 8-membered heterocyclyl optionally substituted with 1, 2, or 3 independently selected halogen groups.Embodiment 79. A compound according to embodiment 72 or embodiment 73, wherein R5is:Embodiment 80. A compound according to embodiment 72 or embodiment 73, wherein n is 1 and at least one R3is halogen.Embodiment 81. A compound according to embodiment 72 or embodiment 73, wherein R5is:Embodiment 82. A compound according to any one of embodiments 59-64, wherein R5is a group of the formula (lie):Docket no. 24-2208-WON-S1 / Set Bwherein n is 0 or 1.Embodiment 83. A compound according to embodiment 82, wherein R5is:Embodiment 84. A compound according any one of embodiments 59-64, wherein R5is a group of the formula (Illa):whereinR3ais H, halogen or -OH;n is 0, 1 or 2; andp is 1 or 2.Embodiment 85. A compound according to embodiment 84, whereinR3ais fluoro; andn is 0.Embodiment 86. A compound according to embodiment 84, wherein R5is:Embodiment 87. A compound according to any one of embodiments 59-64, wherein R5is a group of the formula (Vb):Docket no. 24-2208-WON-S1 / Set B(Vb)whereinp is 1 or 2; andeach of m1, m2, and m3are independently 0 or 1.Embodiment 88. A compound according to embodiment 87, wherein R5is:Embodiment 89. A compound according to embodiment 59-64, wherein R5is a group of the Formula (Via):wherein m1and m2are each independently 0, 1, or 2;p is 0, 1, or 2;n is 0, 1, or 2;Z is N-H, N-R31, sulfur, or oxygen ; andR31is H, Ci-C6alkyl, Ci-C6haloalkyl, -SO2(Ci-C6alkyl), -SO2(C3-C8cycloalkyl), or 4- to 8-membered heterocyclyl optionally substituted with one or more independently selected Ci-Ce alkyl or halogen groups.Embodiment 90. A compound according to embodiment 89, wherein R5is:Embodiment 91. A compound according to any one of embodiments 59-90, wherein R4is H, methyl or ethyl.Docket no. 24-2208-WON-S1 / Set BEmbodiment 92. A compound according to any one of embodiments 59-90, wherein R4is H or methyl.Embodiment 93. A compound according to any one of embodiments 59-90, wherein R4is H.Embodiment 94. A compound according to any one of embodiments 59-93, wherein R6is H, Ci-Ce haloalkyl, or Ci-Ce alkoxy.Embodiment 95. A compound according to any one of embodiments 59-93, wherein R6is H, trifluoromethyl, or methoxyEmbodiment 96. A compound according to any one of embodiments 59-95, wherein R7is H, Ci-Ce alkyl, or C3-C6 cycloalkyl.Embodiment 97. A compound according to any one of embodiments 59-95, wherein R7is H, methyl, or cyclopropyl.Embodiment 98. A compound according to any one of embodiments 59-97, wherein R10is H or halogen.Embodiment 99. A compound according to any one of embodiments 59-97, wherein R10is H or fluorine.Embodiment 100. A compound according to any one of embodiments 59-97, wherein R10is H.

[0086] In certain embodiments, the compound isN-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-(1-methyl-1H-imidazol-5- yl)pyrido[3,4-d]pyrimidin-4-amine;N-((1r,4r)-4-((6-(1-methyl-1H-imidazol-5-yl)pyrido[3,4-d]pyrimidin-4- yl)amino)cyclohexyl)methanesulfonamide;N-((1r,4r)-4-methoxycyclohexyl)-6-(1-methyl-1H-imidazol-5-yl)pyrido[3,4- d]pyrimidin-4-amine;6-(1-methyl-1H-imidazol-5-yl)-N-(2-azaspiro[3.5]nonan-7-yl)pyrido[3,4- d]pyrimidin-4-amine;Docket no. 24-2208-WON-S1 / Set B6-(1 -methyl-1 H-imidazol-5-yl)-N-(2-(methylsulfonyl)-2-azaspiro[3.5]nonan-7- yl)pyrido[3,4-d]pyrimidin-4-amine;6-(1H-imidazol-1-yl)-N-((1r,4r)-4-methoxycyclohexyl)pyrido[3,4-d]pyrimidin-4- amine;6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)pyrido[3,4- d]pyrimidin-4-amine;N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-(thiazol-5-yl)pyrido[3,4- d]pyrimidin-4-amine;N-((1r,4r)-4-methoxycyclohexyl)-6-(thiazol-5-yl)pyrido[3,4-d]pyrimidin-4- amine;N-((1r,4r)-4-methoxycyclohexyl)-2-methyl-6-(1 -methyl-1 H-imidazol-5- yl)pyrido[3,4-d]pyrimidin-4-amine;N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-2-methyl-6-(1 -methyl-1 H-imidazol- 5-yl)pyrido[3,4-d]pyrimidin-4-amine;8-methoxy-N-((1r,4r)-4-methoxycyclohexyl)-6-(1 -methyl-1 H-imidazol-5- yl)pyrido[3,4-d]pyrimidin-4-amine;8-methoxy-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-(1-methyl-1H- imidazol-5-yl)pyrido[3,4-d]pyrimidin-4-amine;6-(1 -methyl-1 H-imidazol-5-yl)-N-((1S,2R)-2-methylcyclohexyl)pyrido[3, 4- d]pyrimidin-4-amine;N-((1-fluorocyclohexyl)methyl)-6-(1-methyl-1H-imidazol-5-yl)pyrido[3,4- d]pyrimidin-4-amine;6-(1 -methyl-1 H-imidazol-5-yl)-N-(2-(2, 2, 2-trifluoroethyl)-2- azaspiro[3.5]nonan-7-yl)pyrido[3,4-d]pyrimidin-4-amine;6-(1 -methyl-1 H-imidazol-5-yl)-N-((1r,4r)-4- (methylsulfonyl)cyclohexyl)pyrido[3,4-d]pyrimidin-4-amine;4-((6-(1 -methyl-1 H-imidazol-5-yl)pyrido[3,4-d]pyrimidin-4- yl)amino)tetrahydro-2H-thiopyran 1 , 1 -dioxide;7-((6-(1 -methyl-1 H-imidazol-5-yl)pyrido[3,4-d]pyrimidin-4-yl)amino)-2- thiaspiro[3.5]nonane 2,2-dioxide;2-methyl-6-(1 -methyl-1 H-imidazol-5-yl)-N-((3-methyloxetan-3- yl)methyl)pyrido[3,4-d]pyrimidin-4-amine;Docket no. 24-2208-WON-S1 / Set B4-((2-methyl-6-(1 -methyl-1 H-imidazol-5-yl)pyrido[3,4-d]pyrimidin-4- yl)amino)tetrahydro-2H-thiopyran 1 , 1 -dioxide;N-(4,4-difluorocyclohexyl)-2-methyl-6-(1 -methyl-1 H-imidazol-5- yl)pyrido[3,4-d]pyrimidin-4-amine;N-((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)-2-methyl-6-(1-methyl-1 H- imidazol-5-yl)pyrido[3,4-d]pyrimidin-4-amine;N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-(1 -methyl-1 H-imidazol-5-yl)- 8-(trifluoromethyl)pyrido[3,4-d]pyrimidin-4-amine;6-(1 H-imidazol-1 -y I )-N -( 1 -(3-methyloxetan-3-yl)piperidin-4-yl)pyrido[3,4- d]pyrimidin-4-amine;2-methyl-6-(1 -methyl-1 H-imidazol-5-yl)-N-((1 r,4r)-4-(oxetan-3- ylmethoxy)cyclohexyl)pyrido[3,4-d]pyrimidin-4-amine;N-((1 r,4r)-4-(2,2-difluoroethoxy)cyclohexyl)-2-methyl-6-(1 -methyl-1 H- imidazol-5-yl)pyrido[3,4-d]pyrimidin-4-amine;2-methyl-6-(1 -methyl-1 H-imidazol-5-yl)-N-(1 -(3-methyloxetan-3- yl)piperidin-4-yl)pyrido[3,4-d]pyrimidin-4-amine;N-((1 r,4r)-4-(cyclopropylmethoxy)cyclohexyl)-2-methyl-6-(1 -methyl-1 H- imidazol-5-yl)pyrido[3,4-d]pyrimidin-4-amine;2-methyl-6-(1 -methyl-1 H-imidazol-5-yl)-N-(2-oxaspiro[3.5]nonan-7- yl)pyrido[3,4-d]pyrimidin-4-amine;2-methyl-6-(1 -methyl-1 H-imidazol-5-yl)-N-((1 r,4r)-4-((1 -methyl-1 H- pyrazol-4-yl)oxy)cyclohexyl)pyrido[3,4-d]pyrimidin-4-amine;N-((1 R,3R)-3-(2-methoxyethoxy)cyclopentyl)-2-methyl-6-(1 -methyl-1 H- imidazol-5-yl)pyrido[3,4-d]pyrimidin-4-amine;(1 r,4r)-N 1 -(2-methyl-6-(1 -methyl-1 H-imidazol-5-yl)pyrido[3,4-d]pyrimidin- 4-yl)-N4-(2,2,2-trifluoroethyl)cyclohexane-1,4-diamine;N-((1 r, 4r)-4-(3, 3-difluoropy rrolidin-1 -yl)cyclohexyl)-2-methyl-6-(1 -methyl- 1H-imidazol-5-yl)pyrido[3,4-d]pyrimidin-4-amine;N-((1 s,4s)-4-methoxycyclohexyl)-2-methyl-6-(1 -methyl-1 H-imidazol-5- yl)pyrido[3,4-d]pyrimidin-4-amine;N-(2-(3,3-difluorocyclobutyl)-2-azaspiro[3.5]nonan-7-yl)-2-methyl-6-(1- methyl-1H-imidazol-5-yl)pyrido[3,4-d]pyrimidin-4-amine;N-((1r,4r)-4-(3,3-difluoroazetidin-1-yl)cyclohexyl)-2-methyl-6-(1-methyl- 1H-imidazol-5-yl)pyrido[3,4-d]pyrimidin-4-amine;Docket no. 24-2208-WON-S1 / Set B2-methyl-6-(1 -methyl-1 H-imidazol-5-yl)-N-(1 -(2 , 2 , 2-trifl uoroethy I ) pi peri d i n- 4-yl)pyrido[3,4-d]pyrimidin-4-amine;2-methyl-6-(1 -methyl-1 H-imidazol-5-yl)-N-((1 r,4r)-4- (trifluoromethoxy)cyclohexyl)pyrido[3,4-d]pyrimidin-4-amine; N-((1 r,4r)-4-isopropoxycyclohexyl)-2-methyl-6-(1 -methyl-1 H-imidazol-5- yl)pyrido[3,4-d]pyrimidin-4-amine;2-methyl-6-(1 -methyl-1 H-imidazol-5-yl)-N-((1 r,4r)-4-(pyrazin-2- yloxy)cyclohexyl)pyrido[3,4-d]pyrimidin-4-amine;2-cyclopropyl-N-((1 r,4r)-4-methoxycyclohexyl)-6-(1 -methyl-1 H-imidazol-5- yl)pyrido[3,4-d]pyrimidin-4-amine;2-cyclopropyl-N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-(1 -methyl-1 H- imidazol-5-yl)pyrido[3,4-d]pyrimidin-4-amine;2-cyclopropyl-N-((1 r,4r)-4-(3,3-difluoroazetidin-1 -yl)cyclohexyl)-6-(1 - methyl-1 H-imidazol-5-yl)pyrido[3,4-d]pyrimidin-4-amine;N-((1 r,4r)-4-methoxycyclohexyl)-2-methyl-6-(1 -methyl-1 H-imidazol-5-yl)-8- (trifluoromethyl)pyrido[3,4-d]pyrimidin-4-amine;N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-2-methyl-6-(1 -methyl-1 H- imidazol-5-yl)-8-(trifluoromethyl)pyrido[3,4-d]pyrimidin-4-amine;5-fluoro-N-((1 r,4r)-4-methoxycyclohexyl)-6-(1 -methyl-1 H-imidazol-5- yl)pyrido[3,4-d]pyrimidin-4-amine;N-((1 r,4r)-4-methoxycyclohexyl)-6-(1 -methyl-1 H-imidazol-5-yl)-8- (trifluoromethyl)pyrido[3,4-d]pyrimidin-4-amine;N-((1 r,4r)-4-(2,2-difluoroethoxy)cyclohexyl)-6-(1 -methyl-1 H-imidazol-5-yl)- 8-(trifluoromethyl)pyrido[3,4-d]pyrimidin-4-amine;2-methoxy-1 -(7-((2-methyl-6-(1 -methyl-1 H-imidazol-5-yl)pyrido[3,4- d]pyrimidin-4-yl)amino)-2-azaspiro[3.5]nonan-2-yl)ethan-1-one;2-methyl-6-(1 -methyl-1 H-imidazol-5-yl)-N-((1 r,4r)-4-(2,2,2- trifluoroethoxy)cyclohexyl)pyrido[3,4-d]pyrimidin-4-amine;6-(1 -methyl-1 H-imidazol-5-yl)-N-((1 r,4r)-4- (trifluoromethoxy)cyclohexyl)pyrido[3,4-d]pyrimidin-4-amine; N-((1 r,4r)-4-(2,2-difluoroethoxy)cyclohexyl)-6-(1 -methyl-1 H-imidazol-5- yl)pyrido[3,4-d]pyrimidin-4-amine; ora pharmaceutically acceptable salt thereof.

[0087] Pharmaceutical CompositionsDocket no. 24-2208-WON-S1 / Set B

[0088] Also provided herein are pharmaceutical compositions comprising compounds or a pharmaceutically acceptable salt thereof as described herein and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0089] Pharmaceutically acceptable excipient, carrier, adjuvant, stabilizer, diluent, etc. to be included are determined by the composition being administered and by the method of administering the composition. There are a wide variety of suitable formulations of pharmaceutical composition including optional pharmaceutically acceptable carriers, excipients, stabilizers, etc. Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical art, and are described, for example, in Remington's Pharmaceutical Sciences, 18th Ed., Mack Publishing Co., Easton, Pa. (1990).

[0090] Pharmaceutical compositions suitable for parenteral administration, such as, for example, by intraarticular (in the joints), intravenous, intramuscular, intradermal, intraperitoneal, and subcutaneous routes, include aqueous and non-aqueous, isotonic sterile injection solutions, which can contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives. Compositions can be administered, for example, by intravenous infusion, orally, topically, intraperitoneally, intravesically or intrathecally.

[0091] As used herein, the term “pharmaceutically acceptable salts” refers to salts that retain the desired biological activity of the above-identified compounds and exhibit minimal or no undesired toxicological effects. Examples of such salts include, but are not limited to acid addition salts formed with inorganic acids (for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like), and salts formed with organic acids such as acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, and polygalacturonic acid. Non-toxic pharmaceutical base addition salts include salts of bases such as sodium, potassium, calcium, ammonium, and the like. In certain embodiments, the pharmaceutically acceptable salt is a sodium salt. In certain embodiments, the pharmaceutically acceptable salt is a potassium salt. Those skilled in the art will recognize a wide variety of non-toxic pharmaceutically acceptable addition salts.

[0092] The active compound (e.g., the compounds of formula (I)) is included in the pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver to a patient a therapeutically effective amount without causing serious toxic effects in the patient treated. A dose of the active compound for all of the above-mentioned conditions is in the range fromDocket no. 24-2208-WON-S1 / Set Babout 0.01 to 300 mg / kg, preferably 0.1 to 100 mg / kg per day, more generally 0.5 to about 25 mg per kilogram body weight of the recipient per day. A typical topical dosage will range from 0.01-3% wt / wt in a suitable carrier. The effective dosage range of the pharmaceutically acceptable derivatives can be calculated based on the weight of the parent compound to be delivered. If the derivative exhibits activity in itself, the effective dosage can be estimated as above using the weight of the derivative, or by other means known to those skilled in the art.

[0093] In certain embodiments, the dose of the active compound as described herein is administered based on the mg per kilogram body weight of the recipient. In certain embodiments, the dose of the active compound as described herein is administered once per every 7 days (e.g., once per week).

[0094] In certain embodiments, the dose of the active compound for all of the above-mentioned conditions may be in the range of about 0.1 to 20 mg / kg, or about 0.1 to 15 mg / kg, or about 0.1 to 10 mg / kg, or about 0.1 to 5 mg / kg, or about 0.5 to 20 mg / kg, or about 0.5 to 15 mg / kg, or about 0.5 to 10 mg / kg, or about 0.5 to 5 mg / kg, or about 1 to 20 mg / kg, or about 1 to 15 mg / kg, or about 1 to 10 mg / kg, or about 1 to 5 mg / kg, or about 2 to 20 mg / kg, or about 2 to 15 mg / kg, or about 2 to 10 mg / kg, or about 2 to 5 mg / kg. In certain embodiments as described herein, the dose of active compound is from about 0.254 to about 0.45 mg / kg, about 0.6 to about 0.75 mg / kgm about 1.3 to about 1.6 mg / kg, about 3.4 to about 3.8 mg / kg, about 8 to about 10 mg / kg, or about 15 to about 20 mg / kg. In certain embodiments, doses of the active compound of formula (I) are about 0.36 mg / kg, abot 0.72 mg / kg, about 1.44 mg / kg, about, about 9 mg / kg or about 18 mg / kg. In certain embodiments as described herein, the dose of active compound is at least 0.36 mg / kg per every 7 days, or at least 0.72 mg / kg per every 7 days, or at least 1.44 mg / kg per every 7 days, or at least 3.6 mg / kg per every 7 days, or at least 9 mg / kg per every 7 days, or at least 18 mg / kg per every 7 days.

[0095] The pharmaceutical compositions disclosed herein may be manufactured by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tableting processes. The pharmaceutical compositions can be prepared as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to use, or as emulsions.

[0096] Methods of Treatment

[0097] In certain aspects, the disclosure also provides methods of using the disclosed compounds for therapeutic purposes. For example, the disclosure provides methods of treating or ameliorating a disease, disorder, or condition mediated by CD38 activity that can include administering an effective amount of one or more of the compounds as describedDocket no. 24-2208-WON-S1 / Set Bherein, a pharmaceutically acceptable salt thereof, or one or more of the pharmaceutical compositions as described herein to a subject in need thereof.

[0098] In certain embodiments of the methods of the disclosure, the disease, disorder, or condition mediated by CD38 activity is cancer, a hyperproliferative disease or condition, an inflammatory disease or condition, an autoimmune disease, a metabolic disorder, a cardiac disease or condition, chemotherapy induced tissue damage, a renal disease, a metabolic disease, a vascular disease, a fibrotic disease, a neurological disease or injury, a neurodegenerative disorder or disease, diseases caused by impaired stem cell function, diseases caused by DNA damage, diseases caused by hypoxia or ischemia / reperfusion injuty, primary mitochondrial disorders, a muscle disease, a muscle wasting disorder, and diseases of aging where restoration of NAD restores cellular homeostasis and metabolism, including preseravation of fertility. In certain embodiments of the methods of the disclosure, the disease, disorder, or condition mediated by CD38 activity is selected from the group consisting of obesity, atherosclerosis, insulin resistance, type 2 diabetes, cardiovascular disease, Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, muscular dystrophies, mitochondrial myopathies, depression, Down syndrome, neonatal nerve injury, aging, axonal degeneration, carpal tunnel syndrome, Guillain-Barre syndrome, nerve damage, polio (poliomyelitis), spinal cord injury, nonalcoholic steatohepatitis, transplantation, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, systemic scleroderma, osteoarthritis, sarcopenia, and rheumatoid arthritis.EXAMPLES

[0099] Having now described the present invention in detail, the same will be more clearly understood by reference to the following examples, which are included herewith for purposes of illustration only and are not intended to be limiting of the invention.

[0100] AbbreviationsDocket no. 24-2208-WON-S1 / Set BDocket no. 24-2208-WON-S1 / Set BDocket no. 24-2208-WON-S1 / Set B

[0101] General conditions:

[0102] Commercial anhydrous solvents are used in reactions where specified. HPLC grade solvents are used for all other reactions, work-up and chromatography.

[0103] Reported yields are corrected for LC / MS purity (determined by LIV (215 nm) or ELS detection) unless otherwise stated.

[0104] Microwave experiments are carried out using a Biotage Initiator*.

[0105] Flash column chromatography is carried out on either Biotage Isolera 4, Biotage Selekt or Teledyne ISCO CombiFlash Rf+ machines. Biotage Star KP-Sil Silica D Duo, Interchim Silica or Biotage Star KP-Amino D Duo (KP-NH) columns are used for normal phase chromatography and Biotage Star C18 Duo or BGB Analytik Aquarius columns are used for reverse phase chromatography

[0106] Example 1 : Synthesis of N -(( 1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-(1 -methyl-1H-imidazol-5-yl)pyrido[3,4-d]pyrimidin-4-amine

[0107] Synthesis of 6-bromopyrido[3,4-d] pyrimidin-4-ol

[0108] A solution of 5-amino-2-bromopyridine-4-carboxylic acid (5.0 g, 23 mmol, 1 eq) in formamide (50 mL) is stirred at 170°C for 5h. The mixture is allowed to cool down to room temperature. The precipitated solids are collected by filtration and washed with water (3x20 mL) to afford 6-bromopyrido[3,4-d] pyrimidin-4-ol (3 g, crude) as a black solid. LC / MS: mass calcd. for C7H4BrN3O: 225.0, found: 226.1 [M+H]+.

[0109] Synthesis of 6-(3-methylimidazol-4-yl) pyrido[3,4-d] pyrimidin-4-ol

[0110] To a stirred solution of 6-bromopyrido[3,4-d] pyrimidin-4-ol (600 mg, 2.7 mmol, 1 eq) in dioxane (10 mL) and H2O (2 mL) is added 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-Docket no. 24-2208-WON-S1 / Set Bdioxaborolan-2-yl) imidazole (1.1 g, 5.3 mmol, 2 eq), Na2COs (562 mg, 5.3 mmol, 2 eq) and Pd(dppf)Cl2.CH2Cl2 (220 mg, 270 umol, 0.1 eq) in portions at room temperature. The final reaction mixture is irradiated with microwave radiation at 140°C for 5h under N2 atmosphere. The reaction mixture is filtered and the filtrate is concentrated. The residue is extracted with CH2CI2 (3x50 mL). The combined organic layers are washed with brine (1x50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography, eluted with DCM / MeOH (20:1) to afford 6-(3-methylimidazol-4-yl) pyrido[3,4-d] pyrimidin-4-ol (200 mg, 33% yield) as a black solid. LC / MS: mass calcd. for CnH9N5O: 227.1, found: 228.1 [M+H]+.

[0111] Synthesis of 6-(3-methylimidazol-4-yl)-N-[(1r,4r)-4-(2-methoxyethoxy) cyclohexyl] pyrido[3,4-d] pyrimidin-4-amine

[0112] To a stirred solution of 6-(3-methylimidazol-4-yl) pyrido[3,4-d] pyrimidin-4-ol (90 mg, 0.4 mmol, 1 eq) in DMF (5 mL) is added PyBOP (312 mg, 0.6 mmol, 1.5 eq), DBll (121.6 mg, 0.8 mmol, 2 eq), DIEA (64.5 mg, 0.5 mmol, 1.2 eq) and (1r,4r)-4-(2-methoxyethoxy) cyclohexan-1 -amine (275 mg, 1.6 mmol, 4 eq) at room temperature. The resulting mixture is stirred for 17h at 80°C under N2 atmosphere. The reaction mixture is purified by reverse phase column (C18 column, mobile phase, ACN in water (0.05% NH4HCO3), 5% to 27% gradient in 30 min; Wavelength: LIV 254 nm) to afford N-((1r,4r)-4-(2-methoxyethoxy) cyclohexyl)-6-(1-methyl-1H-imidazol-5-yl) pyrido[3,4-d] pyrimidin-4-amine (60 mg, 39% yield) as a white solid. LC / MS: mass calcd. for C20H26N6O2: 382.2, found: 383.1 [M+H]+.1H NMR (300 MHz, DMSO-cfe) 69.05 (s, 1H), 8.54 (s, 1H), 8.49 (s, 1H), 8.23 (d, J= 7.5 Hz, 1H), 7.76 (s, 1H), 7.47 (s, 1H), 4.09 - 4.24 (m, 1H), 3.93 (s, 3H), 3.51 -3.58 (m, 2H), 3.39 - 3.46 (m, 2H), 3.25 - 3.31 (m, 1H), 3.24 (s, 3H), 1.96 - 2.11 (m, 4H), 1.37 - 1.55 (m, 2H), 1.18 - 1.36 (m, 2H).

[0113] Example 2: Synthesis of N-((1r,4r)-4-((6-(1-methyl-1H-imidazol-5-yl)pyrido[3,4-d]pyrimidin-4-yl)amino)cyclohexyl)methanesulfonamide

[0114] To a stirred solution of 6-(3-methylimidazol-4-yl) pyrido[3,4-d] pyrimidin-4-ol (90 mg, 0.4 mmol, 1 eq) and N-[(1r,4r)-4-aminocyclohexyl] methanesulfonamide (308 mg, 1.6 mmol, 4 eq) in DMF (4 mL) is added DIEA (85 uL, 0.5 mmol, 1.2 eq), DBU (120 uL, 0.8 mmol, 2 eq) and PyBOP (310 mg, 0.6 mmol, 1.5 eq) at room temperature under nitrogen atmosphere.Docket no. 24-2208-WON-S1 / Set BThe resulting mixture is stirred at 80°C for 17h under nitrogen atmosphere. The reaction is poured into ice / water (10 mL). The precipitated solids are collected by filtration and washed with water (2x3 mL). The crude product is purified by Prep-HPLC (Column: XBridge BEH Shield RP18 Column, 30*150 mm, 5 pm; Mobile Phase A: water (10 mmoL / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient (B%): 18% B to 36% B in 7 min; Wavelength: 254nm / 220nm) to afford N-((1r,4r)-4-((6-(1-methyl-1H-imidazol-5-yl)pyrido[3,4-d]pyrimidin-4-yl)amino)cyclohexyl)methanesulfonamide (16.7 mg, 10% yield) as a white solid. LC / MS: mass calcd. For C18H23N7O2S: 401.2, found: 402.2 [M+H]+.1H NMR (300 MHz, DMSO-cfe) 59.07 (s, 1H), 8.55 (s, 1H), 8.52 (s, 1H), 8.29 (d, J= 7.2 Hz, 1H), 7.78 (s, 1H), 7.49 (s, 1H), 7.09 (s, 1 H), 4.04 - 4.22 (m, 1H), 3.95 (s, 3H), 3.11 - 3.26 (m, 1H), 2.95 (s, 3H), 1.93 - 2.14 (s, 4H), 1.31 - 1.62 (m, 4H).

[0115] Example 3: Synthesis of N-((1r,4r)-4-methoxycyclohexyl)-6-(1-methyl-1H-imidazol-5-yl)pyrido[3,4-d]pyrimidin-4-amine

[0116] To a stirred solution of 6-(3-methylimidazol-4-yl)pyrido[3,4-d] pyrimidin-4-ol (170 mg, 0.8 mmol, 1 eq) and (1r,4r)-4-methoxycyclohexan-1 -amine (310 mg, 2.4 mmol, 3 eq) in DMF (9 mL) is added DIEA (170 uL, 0.9 mmol, 1.2 eq), DBU (240 uL, 1.6 mmol, 2 eq) and PyBOP (624 mg, 1.2 mmol, 1.5 eq) dropwise at room temperature under nitrogen atmosphere. The resulting mixture is stirred at 80°C overnight under nitrogen atmosphere. The reaction mixture is purified by reversed-phase column (C18 column, mobile phase, MeCN in water (0.05% TFA), 20% to 30% gradient in 10 min; Wavelength: UV 254 nm to afford crude product. The crude product is purified by Prep-HPLC (UV 254 / 220 XBridge Prep OBD C18 Column, 30*150 mm, 5 pm water (10 mmol / L NH4HCO3) 9%B to 39%B in7min, RT1(min):6.32) to afford N-((1r,4r)-4-methoxycyclohexyl)-6-(1-methyl-1H-imidazol-5-yl)pyrido[3,4-d]pyrimidin-4-amine (55.1 mg, 21% yield) as a light yellow solid. LC / MS: mass calcd. For CI8H22N6O: 338.2, found: 339.1 [M+H] +.1H NMR (400 MHz, DMSO-d6) 59.06 (s, 1H), 8.55 (s, 1H), 8.50 (s, 1H), 8.25 (d, J = 7.2 Hz, 1H), 7.78 (s, 1H), 7.49 (s, 1H), 4.11 - 4.22 (m, 1H), 3.95 (s, 3H), 3.27 (s, 3H), 3.14 - 3.22 (m, 1H), 2.01 - 2.11 (m, 4H), 1.41 - 1.51 (m, 2H), 1.21 - 1.31 (m, 2H).Docket no. 24-2208-WON-S1 / Set B

[0117] Example 4: Synthesis of 6-(1-methyl-1H-imidazol-5-yl)-N-(2-azaspiro[3.5]nonan-7-yl)pyrido[3,4-d]pyrimidin-4-amine

[0118] Synthesis of tert-butyl 7-{[6-(3-methylimidazol-4-yl) pyrido [3,4-d] pyrimidin-4-yl] amino}-2-azaspiro [3.5] nonane-2-carboxylate

[0119] To a stirred solution of 6-(3-methylimidazol-4-yl) pyrido[3,4-d] pyrimidin-4-ol (140 mg, 0.6 mmol, 1 eq) in DMF (5 mL) is added PyBOP (481 mg, 0.9 mmol, 1.5 eq), DBll (184 uL, 1.2 mmol, 2 eq), DIEA (125 uL, 0.7 mmol, 1.2 eq) and tert-butyl 7-amino-2-azaspiro [3.5] nonane-2-carboxylate (432 mg, 1.8 mmol, 3 eq) at room temperature. The resulting mixture is stirred for 17 h at 80°C under N2 atmosphere. The reaction mixture is purified by reverse phase column (C18 column, mobile phase, ACN in water (0.05% NH4HCO3), 5% to 46% gradient in 50 min; Wavelength: LIV 254 nm) to afford tert-butyl 7-{[6-(3-methylimidazol-4-yl) pyrido [3,4-d] pyrimidin-4-yl] amino}-2-azaspiro [3.5] nonane-2-carboxylate (180 mg, 64% yield) as a yellow solid. LC / MS: mass calcd. for C24H31N7O2: 449.3, found: 450.1 [M+H]+.

[0120] Synthesis of 6-(1-methyl-1H-imidazol-5-yl)-N-(2-azaspiro[3.5]nonan-7-yl)pyrido[3,4-d]pyrimidin-4-amine

[0121] To a stirred solution of tert-butyl 7-{[6-(3-methylimidazol-4-yl) pyrido[3,4-d] pyrimidin-4-yl] amino}-2-azaspiro [3.5] nonane-2-carboxylate (80 mg, 0.2 mmol, 1 eq) in DCM (10 mL) is added HCI (4M in dioxane, 2.5 mL) dropwise at room temperature. The resulting mixture is stirred for 1h at room temperature. The resulting mixture is concentrated under vacuum to afford N-[6-(3-methylimidazol-4-yl) pyrido[3,4-d] pyrimidin-4-yl]-2-azaspiro [3.5] nonan-7-amine (80 mg, crude) as an off-white solid. 20 mg of the crude product is purified by Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 pm; Mobile Phase A: water (10 mmoL / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient (B%): 2% B to 20% B in 15 min; Wavelength: 254nm / 220nm) to afford 6-(1-methyl-1H-imidazol-5-yl)-N-(2-azaspiro[3.5]nonan-7-yl)pyrido[3,4-d]pyrimidin-4-amine (5.2 mg, 33% yield) as a white solid. LC / MS: mass calcd. for C19H23N7: 349.2, found: 350.2 [M+H]+.1H NMR (300 MHz, DMSO-d6) 59.03 (s, 1H), 8.50 (s, 1H), 8.48 (s, 1H), 8.24 (d, J = 6.9 Hz, 1H), 7.75 (s, 1H), 7.47 (s, 1H), 4.06 - 4.26 (m, 1H), 3.92 (s, 3H), 3.56 (s, 2H), 3.48 (s, 2H), 3.16 - 3.28 (m, 1H), 1.80 - 1.99 (m, 4H), 1.31 - 1.64 (m, 4H).Docket no. 24-2208-WON-S1 / Set B

[0122] Example 5: Synthesis of 6-( 1 -methyl-1 H-imidazol-5-yl)-N-(2-(methylsulfonyl)-2-azaspiro[3.5]nonan-7-yl)pyrido[3,4-d]pyrimidin-4-amine

[0123] To a stirred solution of 6-(1-methyl-1H-imidazol-5-yl)-N-(2-azaspiro[3.5]nonan-7-yl)pyrido[3,4-d]pyrimidin-4-amine (60 mg, 0.2 mmol, 1 eq) in DMF (3 mL) is added TEA (501 uL, 3.6 mmol, 18 eq) and methanesulfonyl chloride (260 uL, 3 mmol, 15 eq) at 0°C. The resulting mixture is stirred for 17h at rt. The reaction mixture is filtered and the filtration is purified by Prep-HPLC (Column:Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 pm; Mobile Phase A: water (10 mmoL / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient (B%): 23% B to 36% B in 15 min; Wavelength: 254nm / 220nm) to afford 6-(1-methyl-1H-imidazol-5-yl)-N-(2-(methylsulfonyl)-2-azaspiro[3.5]nonan-7-yl)pyrido[3,4-d]pyrimidin-4-amine (18.1 mg, 24% yield) as a light yellow solid. LC / MS: mass calcd. for C20H25N7O2S: 427.2, found: 428.2 [M+H]+.1H NMR (300 MHz, DMSO-cfe) 69.07 (s, 1H), 8.55 (s, 1H), 8.50 (s, 1H), 8.26 (d, J= 7.5 Hz, 1H), 7.78 (s, 1H), 7.49 (d, J= 0.9 Hz, 1H), 4.09 - 4.29 (m, 1H), 3.95 (s, 3H), 3.71 (s, 2H), 3.58 (s, 2H), 3.04 (s, 3H), 1.88 - 2.05 (m, 4H), 1.54 - 1.68 (m, 2H), 1.34 - 1.52 (m, 2H).

[0124] Example 6: Synthesis of 6-(1H-imidazol-1-yl)-N-((1r,4r)-4-methoxycyclohexyl)pyrido[3,4-d]pyrimidin-4-amine

[0125] Synthesis of 6-bromo-N-[(1r,4r)-4-methoxycyclohexyl] pyrido[3,4-d] pyrimidin-4-amineDocket no. 24-2208-WON-S1 / Set B

[0126] To a stirred solution of 6-bromopyrido[3,4-d] pyrimidin-4-ol (300 mg, 1.3 mmol, 1 eq) in DMF (5 mL) is added PyBOP (1 g, 2 mmol, 1.5 eq), DBll (390 uL, 2.6 mmol, 2 eq) and DIEA (280 uL, 1.6 mmol, 1.2 eq) in portions at room temperature. The resulting mixture is stirred for 17h at 80°C under N2 atmosphere. The reaction mixture is purified by reverse phase column (C18 column, mobile phase, ACN in water (0.05% TFA), 5% to 23% gradient in 10 min; Wavelength: LIV 254 nm) to afford 6-bromo-N-[(1r,4r)-4-methoxycyclohexyl] pyrido[3,4-d] pyrimidin-4-amine (200 mg, 48% yield) as a yellow solid. LC / MS: mass calcd. for Ci4Hi7BrN4O: 336.1 , found: 337.0 [M+H]+.

[0127] Synthesis of 6-(1H-imidazol-1-yl)-N-((1r,4r)-4-methoxycyclohexyl)pyrido[3,4-d]pyrimidin-4-amine

[0128] To a stirred solution of 6-bromo-N-[(1r,4r)-4-methoxycyclohexyl] pyrido[3,4-d] pyrimidin-4-amine (160 mg, 0.5 mmol, 1 eq) in DMF (1 mL) is added N, N-dimethylglycine (10 mg, 0.1 mmol, 0.2 eq), t-BuONa (96 mg, 1 mmol, 2 eq), imidazole (40 mg, 0.6 mmol, 1.2 eq) and Cui (19 mg, 0.1 mmol, 0.2 eq) at room temperature. The resulting mixture is stirred for 17 h at 120°C under N2atmosphere. The reaction mixture is purified by reverse phase column (C18 column, mobile phase, ACN in water (0.05% NI-LHCO3), 2% to 28% gradient in 30 min; Wavelength: LIV 254 nm) to afford 6-(1H-imidazol-1-yl)-N-((1r,4r)-4-methoxycyclohexyl)pyrido[3,4-d]pyrimidin-4-amine (68.7 mg, 44% yield) as a white solid. LC / MS: mass calcd. for Ci7H2oN60: 324.2, found: 325.2 [M+H]+.1H NMR (300 MHz, DMSO-cfe) 69.00 (s, 1H), 8.56 (s, 1H), 8.49 (s, 1H), 8.47 (s, 1H), 8.16 (d, J= 7.5 Hz, 1H), 7.89 (t, J = 1.5 Hz, 1H), 7.19 (s, 1H), 4.07 - 4.24 (m, 1H), 3.26 (s, 3H), 3.13 - 3.24 (m, 1H), 2.00 - 2.14 (m, 4H), 1.36 - 1.55 (m, 2H), 1.17 - 1.36 (m, 2H).

[0129] Example 7: Synthesis of 6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)pyrido[3,4-d]pyrimidin-4-amineCompound 7Docket no. 24-2208-WON-S1 / Set B

[0130] Synthesis of 6-bromo-N-[(1r,4r)-4-(2-methoxyethoxy) cyclohexyl] pyrido[3,4-d] pyrimidin-4-amine

[0131] A solution of 6-bromopyrido [3,4-d] pyrimidin-4-ol (400 mg, 1.7 mmol, 1 eq), benzotriazole-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (1.2 g, 2.3 mmol, 1.3 eq) and DBll (404 mg, 2.6 mmol, 1.5 eq) in DMF (9 mL) is stirred at room temperature for 30min under nitrogen atmosphere. To the above mixture is added (1r,4r)-4-(2-methoxyethoxy) cyclohexan-1-amine (613 mg, 3.5 mmol, 2 eq) at room temperature. The resulting mixture is stirred at 80°C overnight. The reaction mixture is purified by reversephase flash (C18 column, mobile phase, MeCN in water (10 mmol / L NH4HCO3), 5% to 34% gradient in 20 min; detector, LIV 254 nm) to afford 6-bromo-N-[(1r,4r)-4-(2-methoxyethoxy)cyclohexyl]pyrido[3,4-d]pyrimidin-4-amine (350 mg, 51 %yield) as an off-white solid. LCMS: mass calcd. For Ci6H2iBrN4O2: 380.0, found: 381.0 [M+H]+.

[0132] Synthesis of 6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)pyrido[3,4-d]pyrimidin-4-amine

[0133] A solution of 6-bromo-N-[(1r,4r)-4-(2-methoxyethoxy) cyclohexyl] pyrido[3,4-d] pyrimidin-4-amine (200 mg, 0.5 mmol, 1 eq), imidazole (42.8 mg, 0.6 mmol, 1.2 eq), Cui (9.9 mg, 0.1 mmol, 0.1 eq), N, N-dimethylglycine (10.8 mg, 0.1 mmol, 0.2 eq) and K2CO3 (145 mg, 1.0 mmol, 2 eq) in DMF (4 mL) is stirred at 100°C for2h under nitrogen atmosphere. The resulting mixture is filtered; the filtrate is purified by Prep-HPLC (Column: YMC Triart C18 ExRs Column, 30*150 mm, 5 umL; Mobile Phase A: water (10 mmoL / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 18% B to 33%B in 10 min;Wavelength: 254 / 220 nm) to afford 6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)pyrido[3,4-d]pyrimidin-4-amine (33.1 mg, 17% yield) as a white solid. LCMS: mass calcd. For C19H24N6O2: 368.1, found: 369.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) 59.02 (s, 1H), 8.58 (s, 1H), 8.47 - 8.52 (m, 2H), 8.10 - 8.21 (m, 1H), 7.91 (s, 1H), 7.21 (s, 1H), 4.08 - 4.21 (m, 1H), 3.54 - 3.59 (m, 2H), 3.41 - 3.46 (m, 2H), 3.29 - 3.32 (m, 1H), 3.24 - 3.27 (m, 3H), 2.02 - 2.15 (m, 4H), 1.39 - 1.54 (m, 2H), 1.21 - 1.37 (m, 2H).

[0134] Example 8: Synthesis of N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-(thiazol-5-yl)pyrido[3,4-d]pyrimidin-4-amineDocket no. 24-2208-WON-S1 / Set B

[0135] A solution of 6-bromo-N-[(1 r,4r)-4-(2-methoxyethoxy)cyclohexyl]pyrido[3,4-d]pyrimidin-4-amine (200 mg, 0.5 mmol, 1.5 eq), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-thiazole (74 mg, 0.4 mmol, 1 eq), K2CO3 (145 mg, 1.0 mmol, 3 eq) and Pd(dppf)Cl2CH2Cl2 (57.1 mg, 0.1 mmol, 0.2 eq) in dioxane (3.5 mL) and H2O (0.7 mL) is stirred at 80°C for 1h under nitrogen atmosphere. The resulting mixture is diluted with water (10 mL). The resulting mixture is extracted with EtOAc (3x10 mL). The combined organic layers are dried over anhydrous Na2SO4. After filtration, the filtrate is concentrated under reduced pressure. The crude product (200 mg) is purified by Prep-HPLC (Column: XSelect CSH Fluoro Pheny, 19*250 mm, 5pm; Mobile Phase A: Water (10mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 25 mL / min; Gradient (B%): 25% B to 50% B inlOmin; Wavelength: 254nm) to afford N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-(thiazol-5-yl)pyrido[3,4-d]pyrimidin-4-amine (48.1 mg, 35% yield) as a white solid. LC / MS: mass calcd. For C19H23N5O2S: 385.0, found: 386.0 [M+H]+.1H NMR (300 MHz, DMSO-d6) 59.19 (s, 1H), 9.06 (s, 1H), 8.77 (s, 1H), 8.59 (s, 1H), 8.52 (s, 1H), 8.22 - 8.30 (m, 1H), 4.14 - 4.23 (m, 1H), 3.53 - 3.62 (m, 2H), 3.40 - 3.49 (m, 2H), 3.30 - 3.38 (m, 1H), 3.27 (s, 3H), 2.02 - 2.11 (m, 4H), 1.40 - 1.57 (m, 2H), 1.22 - 1.38 (m, 2H).

[0136] Example 9: Synthesis of N-((1r,4r)-4-methoxycyclohexyl)-6-(thiazol-5-yl)pyrido[3,4-d]pyrimidin-4-amine

[0137] A solution of 6-bromo-N-[(1r,4r)-4-methoxycyclohexyl] pyrido[3,4-d] pyrimidineamine (400 mg, 1.2 mmol, 1.5 eq), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-thiazole (167 mg, 0.7 mmol, 1 eq), K2CO3 (328 mg, 2.4 mmol, 3 eq) and Pd(dppf)Cl2.CH2Cl2 (130 mg, 0.1 mmol, 0.2 eq) in dioxane (8 mL) and H2O (1.6 mL) is stirred at 80°C for 1h under nitrogen atmosphere. The resulting mixture is diluted with ethyl acetate (20 mL) and water (20 mL). The resulting mixture is extracted with EtOAc (3x20 mL). The combined organic layers are washed with water (2x10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford crude product (120 mg). The crude product (120 mg) is purified by Prep-HPLC (Column: Xselect CSH Prep Fluoro Phenyl Column, 19*250 mm, 5 pm; Mobile Phase A: Water (10 mmoL / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 25 mL / min; Gradient (B%): 28%B to 48%B in 10 min; Wavelength: 254 / 220 nm) to afford N-((1r,4r)-4-methoxycyclohexyl)-6-(thiazol-5-yl)pyrido[3,4-d]pyrimidin-4-amineDocket no. 24-2208-WON-S1 / Set B(40.3 mg, 14% yield) as a white solid. LC / MS: mass calcd. For C17H19N5OS: 341.0, found: 342.0 [M+H]+.1H NMR (300 MHz, DMSO-d6) 69.18 (s, 1H), 9.05 (s, 1H), 8.76 (s, 1H), 8.58 (s, 1H), 8.52 (s, 1H), 8.21 - 8.31 (m, 1H), 4.08 - 4.29 (m, 1H), 3.28 (s, 3H), 3.15 - 3.22 (m, 1H), 1.97 - 2.21 (m, 4H), 1.38 - 1.60 (m, 2H), 1.17 - 1.37 (m, 2H).

[0138] Example 10: Synthesis of N-((1r,4r)-4-methoxycyclohexyl)-2-methyl-6-(1-methyl-1H-imidazol-5-yl)pyrido[3,4-d]pyrimidin-4-amine

[0139] Synthesis of 6-bromo-2-methylpyrido[3,4-d] pyrimidin-4-ol

[0140] To a stirred solution of 5-amino-2-bromopyridine-4-carboxylic acid (2 g, 9.2 mmol, 1 eq) and Acetamidine hydrochloride (3 g, 23 mmol, 2.5 eq) in 1-methoxypropan-2-ol (20 mL) is added sodium acetate (1.9 g, 23 mmol, 2.5 eq) in portions at room temperature. The resulting mixture is stirred at 145°C for 2 days. The resulting mixture is diluted with water (20 mL) and stirred at room temperature for 1h. The precipitated solids are collected by filtration and washed with water (3x10 mL) then dried under vacuum. This resulted in 6-bromo-2-methylpyrido[3,4-d] pyrimidin-4-ol (1.5 g, 67% yield) as a light brown solid. LC / MS: mass calcd. for C8H6BrN3O: 239.0, found: 240.0 [M+H]+.

[0141] Synthesis of 2-methyl-6-(3-methylimidazol-4-yl) pyrido[3,4-d] pyrimidin-4-ol

[0142] To a stirred solution of 6-bromo-2-methylpyrido[3,4-d]pyrimidin-4-ol (800 mg, 3.3 mmol, 1 eq) in dioxane (20 mL) and H2O (2 mL) is added 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazole (1.4 g, 6.6 mmol, 2 eq), Na2CO3(706 mg, 6.6 mmol, 2 eq) and Pd(dppf)CI2.CH2CI2(487 mg, 0.6 mmol, 0.2 eq) at room temperature under N2atmosphere. The final reaction mixture is irradiated with microwave radiation for 5h at 140°C. The resulting mixture is filtered and the filter cake is washed with DCM (3x20 mL). The reaction mixture is extracted by DCM (3x20 mL). The organic phases are combined and washed with brine (1x200 mL) and then dried over anhydrous Na2SC>4. After filtration, theDocket no. 24-2208-WON-S1 / Set Bfiltrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography, eluted with DCM / MeOH (20:1) to afford 2-methyl-6-(3-methylimidazol-4-yl)pyrido[3,4-d]pyrimidin-4-ol (350 mg, 43%yield) as a brown solid. LC / MS: mass calcd. for C12H11N5O: 241.1, found: 242.1 [M+H]+.

[0143] Synthesis of N-((1r,4r)-4-methoxycyclohexyl)-2-methyl-6-(1-methyl-1 H-imidazol-5-yl)pyrido[3,4-d]pyrimidin-4-amine

[0144] To a stirred solution of 2-methyl-6-(3-methylimidazol-4-yl)pyrido[3,4-d]pyrimidin-4-ol (90 mg, 0.4 mmol, 1 eq) in DMF (3 mL) is added (1r,4r)-4-methoxycyclohexan-1 -amine (144 mg, 1.2 mmol, 3 eq), DBll (112 uL, 0.8 mmol, 2 eq), DIEA (78 pL, 0.5 mmol, 1.2 eq) and PyBOP (291 mg, 0.6 mmol, 1.5 eq) at 0°C. The resulting mixture is stirred for 17h at 80°C under N2 atmosphere. The reaction mixture is poured into ice / water (20 mL) and extracted by EA (3x20 mL), the organic phases are combined and washed with brine (1x50 mL) and then dried over anhydrous Na2SC>4. After filtration, the filtrate is concentrated under reduced pressure. The crude product is purified by Prep-HPLC (Column: Xselect CSH Phenyl Hexy Column, 19*250 mm, 5 pm; Mobile Phase A: water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 25 mL / min; Gradient (B%): 19%B to 40%B in 11min; Wavelength: 254 / 220 nm) to afford N-((1r,4r)-4-methoxycyclohexyl)-2-methyl-6-(1-methyl-1H-imidazol-5-yl)pyrido[3,4-d]pyrimidin-4-amine (52.6 mg, 40% yield) as a white solid. LC / MS: mass calcd. for C19H24N6O: 352.1, found: 353.1 [M+H]+.1H NMR (300 MHz, DMSO-cfe) 68.96 (s, 1H), 8.44 (s, 1 H), 8.08 (d, J = 7.7 Hz, 1 H), 7.74 (s, 1 H), 7.44 (s, 1 H), 4.06 - 4.22 (m, 1 H), 3.98 (s, 3H), 3.25 (s, 3H), 3.11 - 3.23 (m, 1H), 2.47 (s, 3H), 1.94 - 2.14 (m, 4H), 1.36 - 1.55 (m, 2H), 1.15 - 1.33 (m, 2H).

[0145] Example 11 : Synthesis of N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-2-methyl-6-(1-methyl-1H-imidazol-5-yl)pyrido[3,4-d]pyrimidin-4-amine

[0146] To a stirred solution of 2-methyl-6-(3-methylimidazol-4-yl)pyrido[3,4-d]pyrimidin-4-ol (90 mg, 0.4 mmol, 1 eq) in DMF (3 mL) is added (1r,4r)-4-(2-methoxyethoxy)cyclohexan-1-amine (194 mg, 1.2 mmol, 3 eq), DBU (115 pL, 0.8 mmol, 2 eq), DIEA (78 pL, 0.5 mmol, 1.2 eq) and PyBOP (291 mg, 0.6 mmol, 1.5 eq) in portions at 0°C. The resulting mixture is stirred for 17h at 80°C under N2atmosphere. The reaction mixture is poured into ice / water (20 mL) and extracted by EA (3x20 mL). The organic phases are combined and washed by brineDocket no. 24-2208-WON-S1 / Set B(1x50 mL), and then dried over anhydrous Na2SC>4. After filtration, the filtrate is concentrated under reduced pressure. The crude product is purified by Prep-HPLC (Column: YMC Triart C18 ExRs Column, 20*250 mm, 5 pm; Mobile Phase A: water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 13%B to 35%B in 11 min; Wavelength: 254 / 220 nm) to afford N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-2-methyl-6-(1-methyl-1H-imidazol-5-yl)pyrido[3,4-d]pyrimidin-4-amine (36.0 mg, 24 % yield) as a white solid. LC / MS: mass calcd. for C21H28N6O2: 396.1, found: 397.1 [M+H]+.1H NMR (300 MHz, DMSO-cfe) 6 8.96 (s, 1 H), 8.44 (s, 1 H), 8.07 (d, J = 7.5 Hz, 1 H), 7.74 (s, 1 H), 7.44 (s, 1 H), 4.05 - 4.21 (m, 1H), 3.90 (s, 3H), 3.49 - 3.56 (m, 2H), 3.37 - 3.43 (m, 2H), 3.25 - 3.33 (m, 1H), 3.24 (s, 3H), 2.47 (s, 3H), 1.91 - 2.11 (m, 4H), 1.33 - 1.52 (m, 2H), 1.16 - 1.32 (m, 2H).

[0147] Example 12: Synthesis of 8-methoxy-N-((1r,4r)-4-methoxycyclohexyl)-6-(1-methyl-1H-imidazol-5-yl)pyrido[3,4-d]pyrimidin-4-amine

[0148] Synthesis of 3-amino-6-bromo-2-methoxypyridine-4-carboxylic acid

[0149] To a stirred solution of 3-amino-2-methoxypyridine-4-carboxylic acid (2 g, 11.9 mmol, 1 eq) in DMF (30 mL) is added NBS (2.2 g, 12.5 mmol, 1.1 eq) at room temperature. The resulting mixture is stirred at room temperature for 1h. The reaction is poured into ice / water. The precipitated solids are collected by filtration and washed with water and dried under vacuum. This resulted in 3-amino-6-bromo-2-methoxypyridine-4-carboxylic acid (2.5 g) as an orange solid. The crude product is used in the next step directly without further purification. LC / MS: mass calcd. for CyHyBrN2C>3: 246.0, found: 247.0 [M+H]+.

[0150] Synthesis of 6-bromo-8-methoxypyrido[3,4-d] pyrimidin-4-ol

[0151] To a stirred solution of 3-amino-6-bromo-2-methoxypyridine-4-carboxylic acid (1 g, 4.1 mmol, 1 eq) in 2-methoxyethanol (15 mL) is added formamidine acetate (0.8 g, 8.1 mmol, 2 eq) at room temperature. The resulting mixture is stirred at 170°C for 2h under microwave conditions. The reaction is poured into ice / water (20 mL). The precipitated solids areDocket no. 24-2208-WON-S1 / Set Bcollected by filtration and washed with water and dried under vacuum. This resulted in 6-bromo-8-methoxypyrido[3,4-d]pyrimidin-4-ol (660 mg) as a brown solid. The crude product is used in the next step directly without further purification. LC / MS: mass calcd. for CsHeBrNaCh: 255.0, found: 256.0 [M+H]+.

[0152] Synthesis of 8-methoxy-6-(3-methylimidazol-4-yl)pyrido[3,4-d]pyrimidin-4-ol

[0153] To a stirred solution of 6-bromo-8-methoxypyrido[3,4-d]pyrimidin-4-ol (400 mg, 1.6 mmol, 1 eq) and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazole (975 mg, 4.7 mmol, 3 eq) in dioxane (6 mL) is added H2O (40 uL, 1.5 eq), Na2COs (331 mg, 3 mmol, 2 eq) and Pd(dppf)Cl2.CH2Cl2 (255 mg, 0.3 mmol, 0.2 eq) at room temperature under nitrogen atmosphere. The resulting mixture is stirred at 90°C for 16h under nitrogen atmosphere. The resulting mixture is filtered and the filter cake is washed with MeOH. The filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography, eluted with CH2CI2 / MeOH (10:1) to afford 8-methoxy-6-(3-methylimidazol-4-yl)pyrido[3,4-d]pyrimidin-4-ol (129 mg, 32% yield) as a brown yellow solid. LC / MS: mass calcd. for C12H11N5O2: 257.1, found: 258.1 [M+H]+.

[0154] Synthesis of 8-methoxy-N-((1r,4r)-4-methoxycyclohexyl)-6-(1-methyl-1H-imidazol-5-yl)pyrido[3,4-d]pyrimidin-4-amine

[0155] To a stirred solution of 8-methoxy-6-(3-methylimidazol-4-yl)pyrido[3,4-d]pyrimidin-4-ol (50 mg, 0.2 mmol, 1 eq) and (1r,4r)-4-methoxycyclohexan-1 -amine (100 mg, 0.8 mmol, 4 eq) in DMF (1.5 mL) is added DIEA (40 uL, 0.2 mmol, 1.2 eq), DBU (59 mg, 0.4 mmol, 2 eq) and PyBOP (152 mg, 0.3 mmol, 1.5 eq) at room temperature under nitrogen atmosphere. The resulting mixture is stirred at 80°C for 16h under nitrogen atmosphere. The reaction is poured into ice / water (8 mL). The precipitated solids are collected by filtration and washed with water. The crude product is purified by Prep-HPLC (Column: Xselect CSH OBD Column, 30*150mm, 5um; Mobile Phase A: water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 17% B to 34% B in 7 min; Wavelength: 254 / 220 nm) to afford 8-methoxy-N-((1r,4r)-4-methoxycyclohexyl)-6-(1-methyl-1H-imidazol-5-yl)pyrido[3,4-d]pyrimidin-4-amine (20.6 mg, 28% yield) as a white solid. LC / MS: mass calcd. for C19H24N6O2: 368.1, found: 369.1 [M+H]+.1H NMR (300 MHz, DMSO-cfe) 68.49 (s, 1H), 8.06 (s, 1 H), 7.99 (d, J = 7.6 Hz, 1 H), 7.75 (s, 1 H), 7.50 (s, 1 H), 4.09 - 4.23 (m, 1 H), 4.01 (s, 3H), 4.05 (s, 3H), 3.27 (s, 3H), 3.12 - 3.24 (m, 1H), 1.96 - 2.14 (m, 4H), 1.37 - 1.55 (m, 2H), 1.16 -1.34 (m, 2H).

[0156] Example 13: Synthesis of 8-methoxy-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-(1-methyl-1H-imidazol-5-yl)pyrido[3,4-d]pyrimidin-4-amineDocket no. 24-2208-WON-S1 / Set B"<><>12-4 Compound 13

[0157] To a stirred solution of 8-methoxy-6-(3-methylimidazol-4-yl)pyrido[3,4-d]pyrimidin-4-ol (50 mg, 0.2 mmol, 1 eq) and (1r,4r)-4-(2-methoxyethoxy)cyclohexan-1 -amine (67.3 mg, 0.4 mmol, 2 eq) in DMF (1.5 mL) is added DIEA (40 uL, 0.2 mmol, 1.2 eq), DBU (60 uL, 0.4 mmol, 2 eq) and PyBOP (152 mg, 0.3 mmol, 1.5 eq) at room temperature under nitrogen atmosphere. The resulting mixture is stirred at 80°C for 17h under nitrogen atmosphere. The residue is purified by reverse-phase flash (C18 column, mobile phase, MeCN in water (0.05% TFA), 2% to 50% gradient in 10 min; detector, UV 254 nm) to afford a crude product. The crude product is purified by Prep-HPLC (Column: XBridge BEH Shield RP18 Column, 30*150 mm, 5 pm; Mobile Phase A: water (10 mmoL / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 42% B to 58% B in 7 min; Wavelength: 254 / 220 nm) to afford 8-methoxy-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-(1-methyl-1H-imidazol-5-yl)pyrido[3,4-d]pyrimidin-4-amine (19.1 mg, 23% yield) as a white solid. LC / MS: mass calcd. For C2IH28N6O3: 412.1, found: 413.1 [M+H]+.1H NMR (300 MHz, DMSO-cfe) 68.49 (s, 1H), 8.06 (s, 1 H), 7.99 (d, J = 7.6 Hz, 1 H), 7.75 (s, 1 H), 7.49 (s, 1 H), 4.09 - 4.23 (m, 1 H), 4.01 (s, 3H), 4.05 (s, 3H), 3.52 - 3.61 (m, 2H), 3.39 - 3.49 (m, 2H), 3.29 - 3.33 (m, 1H), 3.26 (s, 3H), 1.96 - 2.12 (m, 4H), 1.37 - 1.55 (m, 2H), 1.19 - 1.37 (m, 2H).

[0158] Example 14: Synthesis of 6-(1-methyl-1H-imidazol-5-yl)-N-((1S,2R)-2-methylcyclohexyl)pyrido[3,4-d]pyrimidin-4-amine

[0159] To a stirred solution of 6-(3-methylimidazol-4-yl)pyrido[3,4-d]pyrimidin-4-ol (65 mg, 0.3 mmol, 1 eq), (1S,2R)-2-methylcyclohexan-1 -amine (40.7 mg, 0.4 mmol, 1.2 eq) and PyBOP (210.7 mg, 0.4 mmol, 1.3 eq) in DMF (3 mL) are added DIEA (46 mg, 0.4 mmol, 1.2 eq) and DBU (114 mg, 0.7 mmol, 2.5 eq) at room temperature under nitrogen atmosphere. The resulting mixture is stirred at 80°C overnight under nitrogen atmosphere. The reaction is poured into 10 mL of ice / water. The precipitated solids are collected by filtration and washed with H2O (3X5 mL). The crude product is purified by Prep-HPLC (Column: XBridge Prep OBDDocket no. 24-2208-WON-S1 / Set BC18 Column, 30*150 mm, 5pm; Mobile Phase A: water (10 mmol / L NH3HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 28% B to 48% B in 10 min; Wavelength: 254nm / 220nm) to afford 6-(1-methyl-1H-imidazol-5-yl)-N-((1S,2R)-2-methylcyclohexyl)pyrido[3,4-d]pyrimidin-4-amine (27.3 mg, 28% yield) as a white solid. LC / MS: mass calcd. For Ci8H22N6: 322.1, found:323.1 [M+H]+.1H NMR (300 MHz, DMSO-cfe) 69.08 (s, 1H), 8.65 (s, 1H), 8.55 (s, 1H), 7.97 (d, J= 7.8 Hz, 1H), 7.81 (s, 1H), 7.54 (s, 1 H), 4.41 - 4.49 (m, 1H), 3.95 (s, 3H), 2.20 - 2.31 (m, 1H), 1.72 -1.89 (m, 2H), 1.51 -1.65 (m, 4H), 1.37 - 1.45 (m, 2H), 0.92 (d, J = 7.2 Hz, 3H).

[0160] Example 15: Synthesis of N-((1-fluorocyclohexyl)methyl)-6-(1-methyl-1H-imidazol-5-yl)pyrido[3,4-d]pyrimidin-4-amine

[0161] To a stirred solution of 6-(3-methylimidazol-4-yl)pyrido[3,4-d]pyrimidin-4-ol (45 mg, 0.2 mmol, 1 eq) in DMF (2 mL) is added PyBOP (155 mg, 0.3 mmol, 1.5 eq), DBU (60 mg, 0.4 mmol, 2 eq), DIEA (31 mg, 0.2 mmol, 1.2 eq) and 1-(1-fluorocyclohexyl)methanamine (31 mg, 0.2 mmol, 1.2 eq) at room temperature. The resulting mixture is stirred for 17h at 80°C under N2atmosphere. The reaction mixture is poured into water (30 mL). The reaction mixture is extracted by EA (3x30 mL), the organic phases are combined and washed by brine (1x30 mL) and dried over anhydrous Na2SO4. After filtration the filtrate is concentrated under reduced pressure. The residue is purified by Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 pm; Mobile Phase A: water (10 mmoL / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 28% B to 43% B; Wavelength:254nm / 220nm) to afford N-((1-fluorocyclohexyl)methyl)-6-(1-methyl-1H-imidazol-5-yl)pyrido[3,4-d]pyrimidin-4-amine (18.8 mg, 27% yield) as a white solid. LC / MS: mass calcd. For CI8H2IFN6: 340.2, found: 341.2 [M+H]+.1H NMR (300 MHz, DMSO-cfe) 69.08 (s, 1H), 8.70 (t, J = 6.0 Hz, 1 H), 8.61 (s, 1 H), 8.54 (s, 1 H), 7.76 (s, 1 H), 7.50 (s, 1 H), 3.95 (s, 3H), 3.91 (d, J = 5.7 Hz, 1 H), 3.84 (d, J = 5.4 Hz, 1 H), 1.69 - 1.84 (m, 2H), 1.40 - 1.67 (m, 7H), 1.18 - 1.34 (m, 1H).

[0162] Example 16: Synthesis of 6-(1-methyl-1H-imidazol-5-yl)-N-(2-(2,2,2-trifluoroethyl)-2-azaspiro[3.5]nonan-7-yl)pyrido[3,4-d]pyrimidin-4-amineDocket no. 24-2208-WON-S1 / Set B

[0163] To a stirred solution of N-[6-(3-methylimidazol-4-yl)pyrido[3,4-d]pyrimidin-4-yl]-2-azaspiro[3.5]nonan-7-amine (50 mg, 0.1 mmol, 1 eq) in DMF (2 mL) was added K2CO3 (59 mg, 0.4 mmol, 3 eq) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (40 mg, 0.2 mmol, 1.2 eq) in portions at room temperature. The resulting mixture was stirred for 4h at 50°C. The reaction was poured into ice water (10 mL) at 0°C. The precipitated solids were collected by filtration and washed with water (3 x 5 mL). The residue was dissolved in DMF (2 mL) and purified by Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 pm; Mobile Phase A: water (10 mmoL / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min;Gradient (B%): 24% B to 39% B; Wavelength: 254nm / 220nm) to afford 6-(1-methyl-1H-imidazol-5-yl)-N-(2-(2,2,2-trifluoroethyl)-2-azaspiro[3.5]nonan-7-yl)pyrido[3,4-d]pyrimidin-4-amine (9.4 mg, 15% yield) as a white solid. LC / MS: mass calcd. for C21H24F3N7: 431.1, found: 432.1 [M+H]+.1H NMR (300 MHz, DMSO-cfe) 69.07 (s, 1H), 8.54 (s, 1H), 8.49 (s, 1H), 8.20 (d, J = 7.5 Hz, 1 H), 7.78 (s, 1 H), 7.48 (s, 1 H), 4.08 - 4.22 (m, 1 H), 3.94 (s, 3H), 3.14 - 3.29 (m, 4H), 3.10 (s, 2H), 1.84 - 2.03 (m, 4H), 1.32 - 1.61 (m, 4H).

[0164] Example 17: Synthesis 6-(1-methyl-1H-imidazol-5-yl)-N-((1r,4r)-4-(methylsulfonyl)cyclohexyl)pyrido[3,4-d]pyrimidin-4-amine

[0165] To a stirred solution of 6-(3-methylimidazol-4-yl)pyrido[3,4-d]pyrimidin-4-ol (75 mg, 0.3 mmol, 1 eq) and (1r,4r)-4-methanesulfonylcyclohexan-1-amine (117 mg, 0.6 mmol, 2 eq) in DMF (3 mL) was added DIEA (69 uL, 0.4 mmol, 1.2 eq), DBU (99 uL, 0.6 mmol, 2 eq) and PyBOP (257.2 mg, 0.5 mmol, 1.5 eq) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80°C for 17h under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The reaction mixture was purified by reversephase flash (C18 column; mobile phase, MeCN in water (0.05% TFA), 2% to 30% gradient in 10 min; detector, UV 254 nm). The fractions were combined and concentrated under reducedDocket no. 24-2208-WON-S1 / Set Bpressure. The crude product was purified by Prep-HPLC (Column: XSelect Prep CSH Phenyl-Hexyl OBD Column, 19*250 mm, 5 pm; Mobile Phase A: water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 25 mL / min; Gradient (B%): isocratic 14% to 38% B in 8 min; Wavelength: 254 / 220 nm) to afford 6-(1 -methyl-1 H-imidazol-5-yl)-N-((1r,4r)-4-(methylsulfonyl)cyclohexyl)pyrido[3,4-d]pyrimidin-4-amine (33.7 mg, 26% yield) as a white solid. LC / MS: mass calcd. For C18H22N6O2S: 386.1, found: 387.1 [M+H]+.1H NMR (300 MHz, DMSO-cfe) 69.07 (s, 1H), 8.55 (s, 1H), 8.50 (s, 1H), 8.32 (d, J= 7.5 Hz, 1H), 7.77 (s, 1H), 7.47 (s, 1H), 4.11 - 4.27 (s, 1H), 3.93 (s, 3H), 3.07 - 3.20 (m, 1H), 2.95 (s, 3H), 2.10 - 2.26 (m, 4H), 1.41 - 1.69 (m, 4H).

[0166] Example 18: Synthesis of 4-((6-( 1 -methyl-1 H-imidazol-5-yl)pyrido[3,4-d]pyrimidin-4-yl)amino)tetrahydro-2H-thiopyran 1,1 -dioxideTo a stirred solution of 6-(3-methylimidazol-4-yl)pyrido[3,4-d]pyrimidin-4-ol (70 mg, 0.3 mmol, 1 eq) in DMF (2.5 mL) was added PyBOP (192 mg, 0.4 mmol, 1.2 eq), DBU (92 uL, 0.6 mmol, 2 eq), DIEA (64 uL, 0.4 mmol, 1.2 eq) and 4-aminotetrahydro-2H-thiopyran 1,1-dioxide (92 mg, 0.6 mmol, 2 eq) at 0°C. The resulting mixture was stirred for 17h at 80°C under N2 atmosphere. The reaction mixture was poured into water (30 mL), The reaction mixture was extracted with EA (3 x 50 mL), the organic phases were combined and washed with H2O (1 x 50 mL), NaCI soln. (1 x 50 mL), and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Column: XBridge BEH Shield RP18 Column, 30*150 mm, 5 pm; Mobile Phase A: water(10 mmoL / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 8% B to 22% B; Wavelength: 254 / 220 nm) to afford 4-((6-(1 -methyl-1 H-imidazol-5-yl)pyrido[3, 4-d]pyrimidin-4-yl)amino)tetrahydro-2H-thiopyran 1,1-dioxide (36.8 mg, 33% yield) as a white solid. LC / MS: mass calcd. for Ci6Hi8N6O2S: 358.1, found: 359.1 [M+H]+.1HNMR (300 MHz, DMSO-cfe) 69.09 (s, 1H), 8.58 (s, 1H), 8.47 (s, 1H), 8.36 (d, J= 7.5 Hz, 1H), 7.16 - 8.13 (m, 2H), 4.53 - 4.70 (m, 1H), 3.93 (s, 3H), 3.26 - 3.49 (m, 2H), 3.08 - 3.24 (m, 2H), 2.04 - 2.35 (m, 4H).

[0167] Example 19: Synthesis of 7-((6-( 1 -methyl-1 H-imidazol-5-yl)pyrido[3,4-d]pyrimidin-4-yl)amino)-2-thiaspiro[3.5]nonane 2,2-dioxideDocket no. 24-2208-WON-S1 / Set B1.3 Compound 19To a stirred solution of 6-(3-methylimidazol-4-yl)pyrido[3,4-d]pyrimidin-4-ol (60 mg, 0.3 mmol, 1 eq), 7-amino-2lambda6-thiaspiro [3.5] nonane-2, 2-dione (85 mg, 0.4 mmol, 1.7 eq) and PyBOP (185 mg, 0.4 mmol, 1.3 eq) in DMF (2 mL) were added DBU (100 mg, 0.7 mmol, 2.5 eq) and DIEA (41 mg, 0.3 mmol, 1.2 eq) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80°C overnight under nitrogen atmosphere. The reaction mixture was purified by Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 pm; Mobile Phase A: water (10 mmoL / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 12% B to 25% B in 7 min; Wavelength: 254 nm / 220 nm) to afford 7-((6-(1-methyl-1H-imidazol-5-yl)pyrido[3,4-d]pyrimidin-4-yl)amino)-2-thiaspiro[3.5]nonane 2,2-dioxide (28.7 mg, 27% yield) as a white solid. LC / MS: mass calcd. For C19H22N6O2S: 398.1, found: 399.1 [M+H]+.1HNMR (300 MHz, DMSO-cfe) 69.05 (s, 1H), 8.53 (s, 1H), 8.48 (s, 1H), 8.25 (d, J = 7.5 Hz, 1H), 7.76 (s, 1H), 7.46 (s, 1H), 4.12 - 4.26 (m, 1H), 4.05 (s, 2H), 3.94 (s, 2H), 3.93 (s, 3H), 1.90 - 2.06 (m, 4H), 1.65 - 1.80 (m, 2H), 1.35 - 1.52 (m, 2H).

[0168] Example 20: Synthesis of 2-methyl-6-(1-methyl-1H-imidazol-5-yl)-N-((3-methyloxetan-3-yl)methyl)pyrido[3,4-d]pyrimidin-4-amine

[0169] To a stirred solution of 2-methyl-6-(3-methylimidazol-4-yl)pyrido[3,4-d]pyrimidin-4-ol (55 mg, 0.2 mmol, 1 eq) in DMF (2 mL) was added PyBOP (142 mg, 0.3 mmol, 1.2 eq), DBU (68 uL, 0.4 mmol, 2 eq), DIEA (48 uL, 0.3 mmol, 1.2 eq) and 1-(3-methyloxetan-3-yl)methanamine (28 mg, 0.3 mmol, 1.2 eq) at room temperature. The resulting mixture was stirred for 17h at 80°C under N2 atmosphere. The reaction mixture was filtered and the filtrate was purified by Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 pm; Mobile Phase A: water (10 mmoL / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 10% B to 25% B; Wavelength: 254 nm / 220 nm) to afford 2-methyl-6-(1-methyl-1H-imidazol-5-yl)-N-((3-methyloxetan-3-yl)methyl)pyrido[3,4-d]pyrimidin-4-amineDocket no. 24-2208-WON-S1 / Set B(25.0 mg, 33% yield) as a white solid. LC / MS: mass calcd. for C H^NeO: 324.2, found: 325.2 [M+H]+.1HNMR (300 MHz, DMSO-cfe) 68.99 (s, 1H), 8.51 (t, J= 6.0 Hz, 1H), 8.44 (s, 1H), 7.75 (s, 1H), 7.43 (s, 1H), 4.58 (d, J= 5.7 Hz, 2H), 4.22 (d, J= 5.7 Hz, 2H), 3.92 (s, 3H), 3.80 (d, J= 5.7 Hz, 2H), 2.47 (s, 3H), 1.30 (s, 3H).

[0170] Example 21: Synthesis of 4-((2-methyl-6-(1-methyl-1H-imidazol-5-yl)pyrido[3,4-d]pyrimidin-4-yl)amino)tetrahydro-2H-thiopyran 1,1-dioxide

[0171] To a stirred solution of 2-methyl-6-(3-methylimidazol-4-yl)pyrido[3,4-d]pyrimidin-4-ol (60 mg, 0.25 mmol, 1 eq), 4-amino-1lambda6-thiane-1,1 -dione (44 mg, 0.3 mmol, 1.2 eq) and PyBOP (174 mg, 0.3 mmol, 1.3 eq) in DMF (2 mL) were added DBll (95 mg, 0.6 mmol, 2.5 eq) and DIEA (39 mg, 0.3 mmol, 1.2 eq) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80°C overnight under nitrogen atmosphere. The reaction solution was purified by Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 pm; Mobile Phase A: water (10 mmoL / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 22% B to 54% B in 15 min; Wavelength: 254 nm / 220 nm) to afford 4-((2-methyl-6-(1-methyl-1H-imidazol-5-yl)pyrido[3,4-d]pyrimidin-4-yl)amino)tetrahydro-2H-thiopyran 1,1-dioxide (17.4 mg, 18% yield) as a white solid. LC / MS: mass calcd. For Ci7H2oN602S: 372.1, found: 373.1[M+H]+.1HNMR (300 MHz, DMSO-cfe) 6 9.02 (s, 1 H), 8.45 (s, 1 H), 8.22 (d, J = 7.8 Hz, 1 H), 7.77 (s, 1 H), 7.46 (s, 1 H), 4.54 - 4.70 (m, 1H), 3.94 (s, 3H), 3.35 - 3.50 (m, 2H), 3.10 - 3.24 (m, 2H), 2.52 (s, 3H), 2.13 - 2.35 (m, 4H).

[0172] Example 22: Synthesis of N-(4,4-difluorocyclohexyl)-2-methyl-6-(1-methyl-1H-imidazol-5-yl)pyrido[3,4-d]pyrimidin-4-amine

[0173] To a stirred solution of 2-methyl-6-(3-methylimidazol-4-yl)pyrido[3,4-d]pyrimidin-4-ol (65 mg, 0.3 mmol, 1 eq) and 4,4-difluorocyclohexan-1-amine (55 mg, 0.4 mmol, 1.5 eq) inDocket no. 24-2208-WON-S1 / Set BDMF (1 mL) was added DIEA (58 uL, 0.3 mmol, 1.2 eq), DBU (85 uL, 0.6 mmol, 2 eq) and PyBOP (210 mg, 0.4 mmol, 1.5 eq) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80°C for 17h under nitrogen atmosphere. The mixture was allowed to cool to room temperature, then it was purified by Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 pm; Mobile Phase A: water (10 mmoL / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 24% B to 39% B in 10 min; Wavelength: 254 nm / 220 nm) to afford N-(4,4-difluorocyclohexyl)-2-methyl-6-(1-methyl-1H-imidazol-5-yl)pyrido[3,4-d]pyrimidin-4-amine (22.1 mg, 22% yield) as a white solid. LC / MS: mass calcd. For C18H20F2N6: 358.2, found: 359.2 [M+H]+.1HNMR (300 MHz, DMSO-cfe) 6 8.98 (s, 1H), 8.43 (s, 1 H), 8.12 (d, J = 7.7 Hz, 1H), 7.75 (s, 1H), 7.44 (s, 1H), 4.30 - 4.51 (m, 1H), 3.92 (s, 3H), 2.00 - 2,16 (m, 4H), 1.99 (m, 2H), 1.63 - 1.81 (m, 2H).19FNMR (282 MHz, DMSO-cfe) 6 -91.53, -92.35, -99.34, -100.16.

[0174] Example 23: Synthesis of N-((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)-2-methyl-6-(1-methyl-1H-imidazol-5-yl)pyrido[3,4-d]pyrimidin-4-amine10-3 Compound 23

[0175] To a stirred solution of 2-methyl-6-(3-methylimidazol-4-yl)pyrido[3,4-d] pyrimidin-4-ol (70 mg, 0.3 mmol, 1 eq) and 1-{3-fluorobicyclo [1.1.1] pentan-1-yl}methanamine (67 mg, 0.6 mmol, 2 eq) in DMF (3 mL) was added DIEA (61 uL, 0.4 mmol, 1.2 eq), DBU (87 uL, 0.6 mmol, 2 eq) and PyBOP (226 mg, 0.4 mmol, 1.5 eq) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80°C for 17h under nitrogen atmosphere. The mixture was allowed to cool to room temperature, then it was purified by Prep-HPLC (Column: XBridge BEH Shield RP18 Column, 30*150 mm, 5 pm; Mobile Phase A: water (10 mmol / L NH4HCO3+0.1% NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%) 24% B to 47% B in 7 min; Wavelength: 254 nm / 220 nm) to afford N-((3-fluorobicyclo[1.1.1]pentan-1-yl)methyl)-2-methyl-6-(1-methyl-1H-imidazol-5-yl)pyrido[3,4-d]pyrimidin-4-amine (36.9 mg, 37% yield) as a white solid. LC / MS: mass calcd. For C18H19FN6: 338.2, found: 339.2 [M+H]+.1HNMR (300 MHz, DMSO-cfe) 58.98 (s, 1H), 8.60 (t, J= 6.0 Hz, 1H), 8.38 (s, 1H), 7.75 (s, 1H), 7.42 (s, 1H), 3.93 (s, 3H), 3.90 (d, J= 6.0 Hz, 2H), 2.46 (s, 3H), 1.98 (d, J = 2.7 Hz, 6H).19FNMR (282 MHz, DMSO-c / 6) 5 -142.89.Docket no. 24-2208-WON-S1 / Set B

[0176] Example 24: Synthesis of N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-(1-methyl-1H-imidazol-5-yl)-8-(trifluoromethyl)pyrido[3,4-d]pyrimidin-4-amine

[0177] Synthesis of 3-amino-2-(trifluoromethyl) pyridine-4-carboxylic acid

[0178] To a stirred solution of 3-fluoro-2-(trifluoromethyl)pyridine-4-carboxylic acid (3 g, 14 mmol, 1 eq) was added NH3 in MeOH (100 mL) at room temperature in an autoclave. The resulting mixture was stirred at 110 °C for 4 days. The resulting mixture was concentrated under reduced pressure. The residue was purified by trituration with ethyl ether (10 mL). The precipitated solids were collected by filtration and washed with ethyl ether (3 x 10 mL), then dried under vacuum. This resulted in 3-amino-2-(trifluoromethyl)pyridine-4-carboxylic acid (2.3 g, 76% yield) as a grey solid. LC / MS: mass calcd. For C7H5F3N2O2: 206.0, found: 207.1 [M+H]+.

[0179] Synthesis of 3-amino-6-bromo-2-(trifluoromethyl)pyridine-4-carboxylic acid

[0180] To a stirred solution of 3-amino-2-(trifluoromethyl)pyridine-4-carboxylic acid (2 g, 9.7 mmol, 1 eq) in ACN (20 mL) was added NBS (2.6 g, 14.5 mmol, 1.5 eq) at room temperature. The resulting mixture was stirred at room temperature overnight. The resulting mixture was filtered, and the filter cake was washed with ACN (3 x 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2CI21 MeOH (10:1) to afford 3-amino-6-bromo-2-(trifluoromethyl) pyridine-4-carboxylic acid (2 g, 72% yield) as a light yellow solid. LC / MS: mass calcd. For C?H4BrF3N2O2: 283.9, found: 285.0[M+H]+.

[0181] Synthesis of 6-bromo-8-(trifluoromethyl)pyrido[3,4-d]pyrimidin-4-ol)

[0182] To a stirred solution of 3-amino-6-bromo-2-(trifluoromethyl)pyridine-4-carboxylic acid (1.9 g, 6.8 mmol, 1 eq) in 2-methoxyethanol (25 mL) was added formamidine acetate (1.4 g, 13.7 mmol, 2 eq) at room temperature. The resulting mixture was stirred at 170°CDocket no. 24-2208-WON-S1 / Set Bunder microwave irradiation for 2h. The reaction was poured into ice water. The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (1 x 15 mL), then dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase column: C18 column, mobile phase, MeCN in water (0.05% TFA), 30% to 50% gradient in 20 min; detector, LIV 254 nm to afford 6-bromo-8-(trifluoromethyl) pyrido[3,4-d] pyrimidin-4-ol) (1.2 g, 60% yield) as an off-white solid. LC / MS: mass calcd. For CsHsBrFsNsO: 292.9, found: 293.8 [M+H]+.

[0183] Synthesis of 6-(3-methylimidazol-4-yl)-8-(trifluoromethyl)pyrido[3,4-d] pyrimidin-4-ol

[0184] To a stirred solution of 6-bromo-8-(trifluoromethyl)pyrido[3,4-d]pyrimidin-4-ol (500 mg, 1.7 mmol, 1 eq) and 1-methyl-1H-imidazole-5-boronic acid pinacol ester (707 mg, 3.4 mmol, 2 eq) in dioxane (24 mL) and H2O (5 mL) were added Pd(dppf)Cl2CH2Cl2 (277 mg, 0.3 mmol, 0.2 eq), Na2CC>3 (360 mg, 3.4 mmol, 2 eq) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 140°C under microwave irradiation for an additional 5h. The resulting mixture was filtered, and the filter cake was washed with ethyl acetate. The resulting mixture was extracted with EtOAc (3 x 5 mL). The combined organic layers were washed with brine (1 x 5 mL), then dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversephase flash chromatography: C18 column, mobile phase, MeCN in water (0.05% TFA), 10% to 50% gradient in 10 min; detector, UV 254 nm to afford 6-(3-methylimidazol-4-yl)-8-(trifluoromethyl)pyrido[3,4-d]pyrimidin-4-ol (250 mg, 49% yield) as a white solid. LC / MS: mass calcd. For C12H8F3N5O: 295.1, found: 296.1 [M+H]+.

[0185] Synthesis of N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-(1-methyl-1H-imidazol-5-yl)-8-(trifluoromethyl)pyrido[3,4-d]pyrimidin-4-amine

[0186] To a stirred solution of 6-(3-methylimidazol-4-yl)-8-(trifluoromethyl)pyrido[3,4-d]pyrimidin-4-ol (80 mg, 0.3 mmol, 1 eq), (1r,4r)-4-(2-methoxyethoxy)cyclohexan-1-amine (56 mg, 0.3 mmol, 1.2 eq) and PyBOP (190 mg, 0.4 mmol, 1.3 eq) in DMF (4 mL) were added DIEA (42 mg, 0.3 mmol, 1.2 eq) and DBU (103 mg, 0.7 mmol, 2.5 eq) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80°C overnight under nitrogen atmosphere. The residue was purified by Prep-HPLC (Column: XBridge BEH C18, 19*250 mm, 5pm; Mobile Phase A: Water(10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 25 mL / min; Gradient (B%): 30%B to 46%B in 10min; Wavelength: 254 / 220 nm) to afford N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-(1-methyl-1H-imidazol-5-yl)-8-(trifluoromethyl)pyrido[3,4-d]pyrimidin-4-amine (22.1 mg, 18% yield) as an off-white solid. LC / MS: mass calcd. For C21H25F3N6O2: 450.2, found: 451.2 [M+H]+.1HNMR (300 MHz,Docket no. 24-2208-WON-S1 / Set BDMSO-cfe) 68.82 (s, 1 H), 8.61 (s, 1 H), 8.52 (d, J= 7.5 Hz, 1H), 7.83 (s, 1H), 7.61 (s, 1H), 4.11 - 4.35 (m, 1H), 3.97 (s, 3H), 3.53 - 3.60 (m, 2H), 3.40 - 3.48 (m, 2H), 3.27 - 3.34 (m, 1H), 3.26 (s, 3H), 1.97 - 2.17 (m, 4H), 1.39 - 1.60 (m, 2H), 1.18 - 1.39 (m, 2H).19FNMR (282 MHz, DMSO-cfe) 6 -62.99.

[0187] Example 25: Synthesis of 6-( 1 H-imidazol-1 -y l)-N -( 1 -(3-methyloxetan-3-yl)piperidin-4-yl)pyrido[3,4-d]pyrimidin-4-amine

[0188] Synthesis of 6-(1H-imidazol-1-yl) pyrido[3,4-d] pyrimidin-4-ol

[0189] A solution of 6-bromopyrido[3,4-d] pyrimidin-4-ol (200 mg, 0.8 mmol, 1 eq), imidazole (602 mg, 8.8 mmol, 10 eq), Cui (34 mg, 0.1 mmol, 0.2 eq), N, N-dimethylglycine (18 mg, 0.1 mmol, 0.2 eq) and K2CO3 (367 mg, 2.6 mmol, 3 eq) in DMF (5 mL) was stirred at 100°C for 3h under nitrogen atmosphere. The reaction was filtered and the filtrate was purified by reverse-phase column (C18 column, mobile phase, MeCN in water (0.1% FA), 5% to 11% gradient in 10 min; detector, LIV 254 nm) to afford 6-(1H-imidazol-1-yl) pyrido[3,4-Docket no. 24-2208-WON-S1 / Set Bd]pyrimidin-4-ol (160 mg, 84% yield) as an off-white solid. For C10H7N5O: 213.2, found: 214.1 [M+H]+.

[0190] Synthesis of tert-butyl (1-(3-((phenylsulfonyl)methyl)oxetan-3-yl)piperidin-4-yl)carbamate

[0191] A solution of 3-[(benzenesulfonyl)methylidene]oxetane (1.5 g, 7.1 mmol, 1 eq) and tert-butyl N-(piperidin-4-yl)carbamate (1.8 g, 9.2 mmol, 1.3 eq) in methanol (36 mL) was stirred at 50°C overnight under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE I EA (2:1) to afford tert-butyl (1-(3-((phenylsulfonyl)methyl)oxetan-3-yl)piperidin-4-yl)carbamate (2.5 g, 85% yield) as a white solid. For C20H30N2O5S: 410.1, found: 411.1 [M+H]+.

[0192] Synthesis of tert-butyl (1-(3-methyloxetan-3-yl)piperidin-4-yl)carbamate

[0193] A solution of tert-butyl N-(1-{3-[(benzenesulfonyl)methyl]oxetan-3-yl}piperidin-4-yl)carbamate (2.5 g, 6 mmol, 1 eq) and magnesium (2.9 g, 122 mmol, 20 eq) in methanol (45 mL) was stirred at 0°C for 30 min under nitrogen atmosphere. The resulting mixture was stirred at room temperature overnight under nitrogen atmosphere, then was filtered and the filter cake was washed with EtOAc (3 x 20 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2CI21 MeOH (85:15) to afford tert-butyl (1-(3-methyloxetan-3-yl)piperidin-4-yl)carbamate (700 mg, 42% yield) as a white solid. For C14H26N2O3: 270.1, found: 271.0 [M+H]+.

[0194] Synthesis of 1-(3-methyloxetan-3-yl)piperidin-4-amine

[0195] A solution of tert-butyl N-[1-(3-methyloxetan-3-yl)piperidin-4-yl]carbamate (500 mg, 1.8 mmol, 1 eq) and TFA (2 mL) in DCM (10 mL) was stirred at room temperature for 3h. The resulting mixture was concentrated under reduced pressure. The resulting mixture was washed with Et20 ( 3x 10 mL) and dried under vacuum. This resulted in 1-(3-methyloxetan-3-yl)piperidin-4-amine (720 mg, crude) as an off-white solid. ForCgHisIXLO: 170.1, found: 171.0 [M+H]+.

[0196] Synthesis of 6-(1H-imidazol-1-yl)-N-(1-(3-methyloxetan-3-yl)piperidin-4-yl)pyrido[3,4-d]pyrimidin-4-amine

[0197] A solution of 6-(imidazol-1-yl)pyrido[3,4-d] pyrimidin-4-ol (100 mg, 0.4 mmol, 1 eq), 1-(3-methyloxetan-3-yl)piperidin-4-amine (80 mg, 0.4 mmol, 1 eq), PyBOP (244 mg, 0.4 mmol, 1 eq), DBU (107 mg, 0.7 mmol, 1.5 eq) and DIEA (182 mg, 1.4 mmol, 3 eq) in DMF (3 mL) was stirred at room temperature for 20 min under nitrogen atmosphere. The resulting mixture was stirred at 80°C for 5h under nitrogen atmosphere. The mixture was purified byDocket no. 24-2208-WON-S1 / Set BPrep-HPLC (Column: XBridge BEH Shield RP18 Column, 30*150 mm, 5 pm; Mobile Phase A: water (10 mmoL / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 4%B to 34%B in 10 min; Wavelength: 254 / 220 nm) to afford 6-(1H-imidazol-1-yl)-N-(1-(3-methyloxetan-3-yl)piperidin-4-yl)pyrido[3,4-d]pyrimidin-4-amine (11.5 mg, 6% yield) as a yellow solid. For C19H23N7O: 365.1, found: 366.1 [M+H]+.1HNMR (300 MHz, DMSO) 59.04 (s, 1 H), 8.61 - 8.47 (m, 3H), 8.26 (d, J = 7.4 Hz, 1 H), 7.92 (s, 1 H), 7.22 (s, 1 H), 4.39 - 4.45 (m, 2H), 4.09 - 4.20 (m, 3H), 2.57 - 2.64 (m, 2H), 2.15 - 2.23 (m, 2H), 2.00 - 2.08 (m, 2H), 1.59 -1.70 (m, 2H), 1.28 - 1.34 (m, 3H).

[0198] Example 26: Synthesis of 2-methyl-6-(1-methyl-1H-imidazol-5-yl)-N-((1r,4r)-4-(oxetan-3-ylmethoxy)cyclohexyl)pyrido[3,4-d]pyrimidin-4-amine

[0199] A solution of 2-methyl-6-(3-methylimidazol-4-yl)pyrido[3,4-d]pyrimidin-4-ol (50 mg, 0.2 mmol, 1 eq) (1r,4r)-4-(oxetan-3-ylmethoxy)cyclohexan-1 -amine (77 mg, 0.4 mmol, 2 eq), PyBOP (140 mg, 0.3 mmol, 1.3 eq) and DBll (47 mg, 0.3 mmol, 1.5 eq) in DMF (2 mL) was stirred at 80°C for 16h under nitrogen atmosphere. The resulting mixture was purified by Prep-HPLC (Column: XBridge BEH Shield RP18 Column, 30*150 mm, 5 pm; Mobile Phase A: Water (10 mmoL / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 10%B to 40%B in10 min; Wavelength: 254 / 220 nm) to afford 2-methyl-6-(1-methyl-1H-imidazol-5-yl)-N-((1r,4r)-4-(oxetan-3-ylmethoxy)cyclohexyl)pyrido[3,4-d]pyrimidin-4-amine (27.2 mg, 32% yield) as a white solid. LC / MS: mass calcd. For C22H28N6O2: 408.1, found: 409.1 [M+H]+.1HNMR (300 MHz, DMSO-d6) 59.19 (s, 1H), 9.06 (s, 1H), 8.77 (s, 1H), 8.59 (s, 1H), 8.52 (s, 1H), 8.22 - 8.30 (m, 1H), 4.14 - 4.23 (m, 1H), 3.53 - 3.62 (m, 2H), 3.40 - 3.49 (m, 2H), 3.30 - 3.38 (m, 1H), 3.27 (s, 3H), 2.02 - 2.11 (m, 4H), 1.40 - 1.57 (m, 2H), 1.22 -1.38 (m, 2H).

[0200] Example 27: Synthesis of N-((1r,4r)-4-(2,2-difluoroethoxy)cyclohexyl)-2-methyl-6-(1-methyl-1H-imidazol-5-yl)pyrido[3,4-d]pyrimidin-4-amineDocket no. 24-2208-WON-S1 / Set B

[0201] A solution of 2-methyl-6-(3-methylimidazol-4-yl)pyrido[3,4-d] pyrimidin-4-ol (50 mg, 0.2 mmol, 1 eq) (1r,4r)-4-(2,2-difluoroethoxy)cyclohexan-1 -amine (37.1 mg, 0.2 mmol, 1 eq), PyBOP (140 mg, 0.3 mmol, 1.3 eq) and DBll (47 mg, 0.3 mmol, 1.5 eq) in DMF (2 mL) was stirred at 80°C for 16h under nitrogen atmosphere. The resulting mixture was purified by Prep-HPLC (Column: XBridge BEH Shield RP18 Column, 30*150 mm, 5 pm; Mobile Phase A: Water (10 mmoL / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 20%B to 50%B inlOmin; Wavelength: 254 / 220 nm; RT1(min): 8.5) to afford N-((1r,4r)-4-(2,2-difluoroethoxy)cyclohexyl)-2-methyl-6-(1-methyl-1H-imidazol-5-yl)pyrido[3,4-d]pyrimidin-4-amine (10.3 mg, 12% yield) as a white solid. LC / MS: mass calcd. For C20H24F2N6O: 402.1, found: 403.1 [M+H]+.1HNMR (300 MHz, DMSO-d6) 58.99 (s, 1H), 8.46 (s, 1H), 8.05 - 8.13 (m, 1H), 7.76 (s, 1H), 7.42 - 7.48 (m, 1H), 5.83 - 6.39 (m, 1H), 4.08 - 4.37 (m, 1H), 3.94 (s, 3H), 3.64 - 3.82 (m, 2H), 3.36 - 3.50 (m, 4H), 1.96 - 2.14 (m, 4H), 1.41 -1.57 (m, 2H), 1.24 - 1.40 (m, 2H).

[0202] Example 28: Synthesis of 2-methyl-6-(1-methyl-1H-imidazol-5-yl)-N-(1-(3-methyloxetan-3-yl)piperidin-4-yl)pyrido[3,4-d]pyrimidin-4-amine

[0203] To a stirred solution of 2-methyl-6-(3-methylimidazol-4-yl)pyrido[3,4-d]pyrimidin-4-ol (50 mg, 0.2 mmol, 1 eq) and 1-(3-methyloxetan-3-yl)piperidin-4-amine (106 mg, 0.6 mmol, 3 eq) in DMF (3 mL) was added DIEA (285 uL, 1.6 mmol, 8 eq), DBll (62 uL, 0.4 mmol, 2 eq) and PyBOP (161 mg, 0.3 mmol, 1.5 eq) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80°C for 17h under nitrogen atmosphere. The mixture was allowed to cool to room temperature. Then it was purified by Prep-HPLC (Column: YMC-Triart C18 ExRs 30*150mm, 5 urn; Mobile Phase A: water (10 mmol / L NH4HCO3), MobileDocket no. 24-2208-WON-S1 / Set BPhase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 10% B to 30% B in 10 min;Wavelength: 254 nm / 220 nm) to afford 2-methyl-6-(1-methyl-1H-imidazol-5-yl)-N-(1-(3-methyloxetan-3-yl)piperidin-4-yl)pyrido[3,4-d]pyrimidin-4-amine (26.6 mg, 32% yield) as a white solid. LC / MS: mass calcd. For C21H27N7O: 393.2, found: 394.2 [M+H]+.1HNMR (300 MHz, DMSO-cfe) 69.00 (s, 1H), 8.49 (s, 1H), 8.18 (d, J= 7.5 Hz, 1H), 7.77 (s, 1H), 7.48 (s, 1H), 4.42 (d, J= 5.5 Hz, 2H), 4.14 - 4.29 (m, 1H), 4.14 (d, J= 5.5 Hz, 2H), 3.95 (s, 3H), 2.50 - 2.62 (m, 2H), 2.49 (s, 3H), 2.18 (t, J= 11.2 Hz, 2H), 1.91 - 2.05 (m, 2H), 1.59 - 1.76 (m, 2H), 1.32 (s, 3H).

[0204] Example 29: Synthesis of N-((1r,4r)-4-(cyclopropylmethoxy)cyclohexyl)-2-methyl-6-(1-methyl-1H-imidazol-5-yl)pyrido[3,4-d]pyrimidin-4-amine

[0205] To a stirred solution of 2-methyl-6-(3-methylimidazol-4-yl)pyrido[3,4-d] pyrimidin-4-ol (50 mg, 0.2 mmol, 1 eq) in DMF (2 mL) was added DIEA (43 uL, 0.2 mmol, 1.2 eq), DBll (62 uL, 0.4 mmol, 2 eq), (1r,4r)-4-(cyclopropylmethoxy)cyclohexan-1 -amine (53 mg, 0.3 mmol, 1.5 eq) and PyBOP (129 mg, 0.2 mmol, 1.2 eq) in portions at 0°C. The resulting mixture was stirred for 17h at 80°C. The resulting mixture was poured into ice water (20 mL). The precipitated solids were collected by filtration and washed with water (10 mL), then dried under vacuum. The crude product was purified by Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 pm; Mobile Phase A: water (10 mmoL / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 26% B to 41% B in 10 min;Wavelength: 254nm / 220nm) to afford N-((1r,4r)-4-(cyclopropylmethoxy)cyclohexyl)-2-methyl-6-(1-methyl-1H-imidazol-5-yl)pyrido[3,4-d]pyrimidin-4-amine (30.7 mg, 37% yield) as a white solid. LC / MS: mass calcd. for C22H28N6O: 392.2, found: 393.2 [M+H]+.1HNMR (300 MHz, DMSO-cfe) 68.96 (s, 1H), 8.44 (s, 1H), 8.07 (d, J= 7.6 Hz, 1H), 7.74 (s, 1H), 7.43 (s, 1H), 4.08 - 4.25 (m, 1 H), 3.92 (s, 3H), 3.20 - 3.30 (m, 3H), 2.47 (s, 3H), 1.94 - 2.09 (m, 4H), 1.35 -1.53 (m, 2H), 1.17 - 1.35 (m, 2H), 0.88 - 1.04 (m, 1H), 0.36 - 0.50 (m, 2H), 0.08 - 0.19 (m, 2H).

[0206] Example 30: Synthesis of 2-methyl-6-(1-methyl-1H-imidazol-5-yl)-N-(2-oxaspiro[3.5]nonan-7-yl)pyrido[3,4-d]pyrimidin-4-amineDocket no. 24-2208-WON-S1 / Set B

[0207] A mixture of 2-methyl-6-(3-methylimidazol-4-yl)pyrido[3,4-d]pyrimidin-4-ol (50 mg, 0.2 mmol, 1 eq), 2-oxaspiro [3.5]nonan-7-amine (29 mg, 0.2 mmol, 1 eq), PyBOP (1404 mg, 0.3 mmol, 1.3 eq) and DBll (47 mg, 0.3 mmol, 1.5 eq) in DMF (0.5 mL) was stirred at 80°C for 6h under nitrogen atmosphere. The mixture was purified by Prep-HPLC (Column: XSelect CSH C18 Column, 19*250 mm, 5pm; Mobile Phase A: water (0.1% FA), Mobile Phase B: ACN; Flow rate: 25 mL / min; Gradient (B%): 5% B to 25% B in10 min; Wavelength: 254nm) to afford 2-methyl-6-(1-methyl-1H-imidazol-5-yl)-N-(2-oxaspiro[3.5]nonan-7-yl)pyrido[3,4-d]pyrimidin-4-amine (15.6 mg, 20.6% yield) as a yellow solid. LC / MS: mass calcd. For C2oH24N60: 364.2, found: 365.1 [M+H]+.1HNMR (300 MHz, DMSO) 58.99 (s, 1H), 8.43 (s, 1H), 8.06 (d, J= 7.8 Hz, 1H), 7.76 (s, 1H), 7.45 (s, 1H), 4.41 (s, 2H), 4.27 (s, 2H), 4.13 - 4.23 (m, 1H), 3.94 (s, 3H), 2.49 (s, 3H), 2.15 (d, J= 12.8 Hz, 2H), 1.85 - 1.96 (m, 2H), 1.50 - 1.66 (m, 2H), 1.30 - 1.48 (m, 2H).

[0208] Example 31: Synthesis of 2-methyl-6-(1-methyl-1H-imidazol-5-yl)-N-((1r,4r)-4-((1-methyl-1H-pyrazol-4-yl)oxy)cyclohexyl)pyrido[3,4-d]pyrimidin-4-amine

[0209] Synthesis of tert-butyl N-[(1r,4r)-4-[(1-methylpyrazol-4-yl) oxy] cyclohexyl]carbamateDocket no. 24-2208-WON-S1 / Set B

[0210] To a stirred solution of tert-butyl N-[(1s,4s)-4-hydroxycyclohexyl]carbamate (3.3 g, 15 mmol, 3 eq) and 1-methylpyrazol-4-ol (500 mg, 5 mmol, 1.00 eq) in THF (30 mL) was added PPhs (4 g, 15 mmol, 3 eq) and N-[(ethoxycarbonyl)imino]ethoxyformamide (2.7 g, 15 mmol, 3 eq) at 0°C under nitrogen atmosphere. The resulting mixture was stirred at room temperature overnight under nitrogen atmosphere. The reaction was poured into ice water (100 mL) at 0°C. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (1 x 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford the crude product (300 mg). The crude product was purified by reverse phase flash with the following conditions (C18 column; mobile phase, MeCN in Water (0.1% NH3.H2O), 10% to 60% gradient in 30 min; detector, UV 254 nm) to afford tert-butyl N-[(1r,4r)-4-[(1-methylpyrazol-4-yl)oxy]cyclohexyl]carbamate (200 mg, 13% yield) as an off-white solid. LC / MS: mass calcd. for C15H25N3O3: 295.1, found: 296.1 [M+H]+.

[0211] Synthesis of (1 r,4r)-4-[(1-methylpyrazol-4-yl) oxy]cyclohexan-1-amine

[0212] To a stirred solution of tert-butyl N-[(1r,4r)-4-[(1-methylpyrazol-4-yl)oxy]cyclohexyl]carbamate (190 mg, 0.6 mmol, 1 eq) in DCM (2 mL) was added TFA (0.5 mL) dropwise at 0°C. The resulting mixture was stirred at room temperature for 1h. The resulting mixture was concentrated under vacuum. The residue was purified by trituration with diethyl ether (2 mL). The precipitated solids were collected by filtration and washed with diethyl ether and dried under vacuum. This resulted in (1r,4r)-4-[(1-methylpyrazol-4-yl)oxy] cyclohexan-1 -amine (100 mg, crude product) as an off-white solid. The crude product was used in the next step directly without further purification. LC / MS: mass calcd. for C10H17N3O: 195.1, found: 196.2 [M+H]+.

[0213] Synthesis of 2-methyl-6-(3-methylimidazol-4-yl)-N-[(1r,4r)-4-[(1-methylpyrazol-4-yl) oxy] cyclohexyl] pyrido[3,4-d] pyrimidin-4-amine

[0214] To a stirred solution of 2-methyl-6-(3-methylimidazol-4-yl)pyrido[3,4-d]pyrimidin-4-ol (40 mg, 0.2 mmol, 1 eq) and (1r,4r)-4-[(1-methylpyrazol-4-yl)oxy]cyclohexan-1 -amine (36 mg, 0.2 mmol, 1.1 eq) in DMF (3 mL) was added PyBOP (103 mg, 0.2 mmol, 1.2 eq) and DBU (37 uL, 0.3 mmol, 1.5 eq) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80°C overnight under nitrogen atmosphere. The resulting mixture was poured into 10 mL ice / water. The precipitated solids were collected by filtration and washed with water (3 x 1 mL). The residue was purified by reverse-phase flash chromatography with the following conditions: C18 column, mobile phase, MeCN in water (10 mmol / L NH4HCO3), 10% to 30% gradient in 20 min; detector, UV 254 nm to afford 2-methyl-Docket no. 24-2208-WON-S1 / Set B6-(1-methyl-1 H-imidazol-5-yl)-N-((1 r,4r)-4-((1 -methyl- 1 H-pyrazol-4-yl)oxy)cyclohexyl)pyrido[3,4-d]pyrimidin-4-amine (19.7 mg, 28% yield) as a white solid.LC / MS: mass calcd. for C22H26N8O: 418.2, found: 419.3 [M+H]+.1HNMR (300 MHz, DMSO-cfe) 68.99 (s, 1H), 8.48 (s, 1H), 8.12 (d, J= 7.6 Hz, 1H), 7.76 (s, 1H), 7.47 (d, J= 8.5 Hz, 2H), 7.20 (s, 1H), 4.15 - 4.32 (m, 1H), 3.94 (s, 3H), 3.82 - 3.92 (m, 1H), 3.74 (s, 3H), 2.50 (s, 3H), 2.12 - 2.22 (m, 2H), 2.02 - 2.12 (m, 2H), 1.37 - 1.64 (m, 4H).

[0215] Example 32: Synthesis of N-((1R,3R)-3-(2-methoxyethoxy)cyclopentyl)-2-methyl-6-(1-methyl-1H-imidazol-5-yl)pyrido[3,4-d]pyrimidin-4-amine

[0216] To a stirred solution of 2-methyl-6-(3-methylimidazol-4-yl)pyrido[3,4-d]pyrimidin-4-ol (70 mg, 0.3 mmol, 1 eq) and (1R*,3R*)-3-(2-methoxyethoxy)cyclopentan-1-amine (69 mg, 0.4 mmol, 1.5 eq) in DMF (5 mL) was added DIEA (65 uL, 0.4 mmol, 1.3 eq), DBll (88 uL, 0.6 mmol, 2 eq) and PyBOP (226 mg, 0.4 mmol, 1.5 eq) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80°C for 17h under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. Then it was purified by Prep-HPLC (Column: Xselect CSH OBD Column, 30*150 mm, 5 pm; Mobile Phase A: water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 2% B to 17% B in 7 min; Wavelength: 254 / 220 nm) to afford N-((1R,3R)-3-(2-methoxyethoxy)cyclopentyl)-2-methyl-6-(1-methyl-1H-imidazol-5-yl)pyrido[3,4-d]pyrimidin-4-amine 0.6 formic acid (mixture of trans isomers) (35.2 mg, 24% yield) as a light yellow solid. LC / MS: mass calcd. For C2oH26Ne02: 382.2, found: 383.2 [M+H]+.1HNMR (300 MHz, DMSO-cfe) 69.07 (s, 1H), 8.82 (s, 1H), 8.73 (s, 1H), 8.63 (s, 1H), 7.89 (s, 1H), 4.71 - 4.85 (m, 1H), 4.05 - 4.10 (m, 1H), 4.04 (s, 3H), 3.46 - 3.53 (m, 2H), 3.38 - 3.46 (m, 2H), 3.25 (s, 3H), 2.55 (s, 3H), 2.07 - 2.21 (m, 2H), 1.95 - 2.07 (m, 1H), 1.75 - 1.91 (m, 1H), 1.53 - 1.74 (m, 2H).

[0217] Example 33: Synthesis of (1r,4r)-N1-(2-methyl-6-(1-methyl-1H-imidazol-5-yl)pyrido[3,4-d]pyrimidin-4-yl)-N4-(2,2,2-trifluoroethyl)cyclohexane-1,4-diamineDocket no. 24-2208-WON-S1 / Set BCompound 33

[0218] To a stirred solution of 2-methyl-6-(3-methylimidazol-4-yl)pyrido[3,4-d]pyrimidin-4-ol (50 mg, 0.2 mmol, 1 eq) in DMF (2 mL) was added DIEA (43 uL, 0.24 mmol, 1.2 eq), (1 r,4r)-N1-(2,2,2-trifluoroethyl) cyclohexane-1,4-diamine (61 mg, 0.3 mmol, 1.5 eq), DBll (62 uL, 0.4 mmol, 2 eq) and PyBOP (129 mg, 0.24 mmol, 1.2 eq) in portions at 0°C. The resulting mixture was stirred for 17h at 80°C. The resulting mixture was poured into ice water (10 mL). The precipitated solids were collected by filtration, washed with water (5 mL) and dried under vacuum. The crude product was purified by Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 pm; Mobile Phase A: water (10 mmoL / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 22% B to 37% B in 10 min; Wavelength: 254 nm / 220 nm) to afford (1r,4r)-N1-(2-methyl-6-(1-methyl-1H-imidazol-5-yl)pyrido[3,4-d]pyrimidin-4-yl)-N4-(2,2,2-trifluoroethyl)cyclohexane-1,4-diamine (24.4 mg, 28% yield) as a white solid. LC / MS: mass calcd. for C20H24F3N7: 419.2, found: 420.2 [M+H]+.1HNMR (300 MHz, DMSO-cfe) 68.96 (s, 1 H), 8.44 (s, 1 H), 8.09 (d, J = 7.7 Hz, 1 H), 7.74 (s, 1 H), 7.44 (s, 1H), 4.08 - 4.25 (m, 1H), 3.92 (s, 3H), 3.16 - 3.33 (m, 2H), 2.47 - 2.50 (m, 4H), 2.16 - 2.29 (m, 1 H), 1.90 - 2.05 (m, 4H), 1.33 - 1.52 (m, 2H), 1.06 - 1.24 (m, 2H).19FNMR (282 MHz, DMSO-cfe) 6 -70.69.

[0219] Example 34: Synthesis of N-((1r,4r)-4-(3,3-difluoropyrrolidin-1-yl)cyclohexyl)-2-methyl-6-(1-methyl-1H-imidazol-5-yl)pyrido[3,4-d]pyrimidin-4-amine

[0220] A mixture of 2-methyl-6-(3-methylimidazol-4-yl)pyrido[3,4-d]pyrimidin-4-ol (70 mg, 0.3 mmol, 1 eq), (1r,4r)-4-(3,3-difluoropyrrolidin-1-yl)cyclohexan-1 -amine (59 mg, 0.3 mmol, 1 eq), PyBOP (196 mg, 0.4 mmol, 1.3 eq) and DBU (66 mg, 0.4 mmol, 1.5 eq) in DMF (2 mL) was stirred at 80°C for 2h under nitrogen atmosphere. The mixture was purified by Prep-HPLC (Column: XSelect CSH Fluoro Pheny, 19*250 mm, 5pm; Mobile Phase A: water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 25 mL / min; Gradient (B%): 33% B toDocket no. 24-2208-WON-S1 / Set B58% B in10 min; Wavelength: 254 nm) to afford N-((1 r,4r)-4-(3,3-difluoropyrrolidin-1 -yl)cyclohexyl)-2-methyl-6-(1-methyl-1H-imidazol-5-yl)pyrido[3,4-d]pyrimidin-4-amine (53.4 mg, 43% yield) as a white solid. LC / MS: mass calcd. For C22H27F2N7: 427.2, found: 428.1 [M+H]+.1HNMR (300 MHz, CD3OD) 59.02 (s, 1H), 8.40 (s, 1H), 7.77 (s, 1H), 7.52 (s, 1H), 4.30 - 4.37 (m, 1 H), 4.05 (s, 3H), 3.06 (t, J = 13.5 Hz, 2H), 2.90 (t, J = 7.0 Hz, 2H), 2.59 (s, 3H), 2.13 - 2.41 (m, 3H), 2.07 - 2.26 (m, 4H), 1.35 - 1.64 (m, 4H).19FNMR (376 MHz, DMSO) 5 -90.48, -90.69, -91.13.

[0221] Example 35: Synthesis of N-((1s,4s)-4-methoxycyclohexyl)-2-methyl-6-(1-methyl-1H-imidazol-5-yl)pyrido[3,4-d]pyrimidin-4-amine

[0222] To a stirred solution of 2-methyl-6-(3-methylimidazol-4-yl)pyrido[3,4-d]pyrimidin-4-ol (50 mg, 0.2 mmol, 1 eq) in DMF (2 mL) was added DIEA (43 uL, 0.24 mmol, 1.2 eq), (1s, 4s)-4-methoxycyclohexan-1-amine hydrochloride (52 mg, 0.3 mmol, 1.5 eq), DBll (62 uL, 0.4 mmol, 2 eq) and PyBOP (129 mg, 0.24 mmol, 1.2 eq) at 0°C. The resulting mixture was stirred for 17h at 80°C. The resulting mixture was poured into ice water (10 mL). The precipitated solids were collected by filtration and washed with water (5 mL), then dried under vacuum. The crude product was purified by Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 pm; Mobile Phase A: water (10 mmoL / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 19% B to 34% B in 10 min;Wavelength: 254 nm / 220 nm) to afford N-((1s,4s)-4-methoxycyclohexyl)-2-methyl-6-(1-methyl-1H-imidazol-5-yl)pyrido[3,4-d]pyrimidin-4-amine (13.6 mg, 19% yield) as a white solid. LC / MS: mass calcd. for Ci9H24N6O: 352.20, found: 353.25 [M+H]+.1HNMR (300 MHz, DMSO-cfe) 68.95 (s, 1H), 8.48 (s, 1H), 8.12 (d, J= 8.0 Hz, 1H), 7.74 (s, 1H), 7.45 (s, 1H), 4.20 - 4.36 (m, 1 H), 3.93 (s, 3H), 3.38 - 3.46 (m, 1 H), 3.24 (s, 3H), 2.46 (s, 3H), 1.88 - 1.99 (m, 2H), 1.64 - 1.77 (m, 4H), 1.41 - 1.58 (m, 2H).

[0223] Example 36: Synthesis of N-(2-(3,3-difluorocyclobutyl)-2-azaspiro[3.5]nonan-7-yl)-2-methyl-6-(1-methyl-1H-imidazol-5-yl)pyrido[3,4-d]pyrimidin-4-amineDocket no. 24-2208-WON-S1 / Set B

[0224] Synthesis of tert-butyl 7-{[2-methyl-6-(3-methylimidazol-4-yl)pyrido[3,4-d]pyrimidin-4-yl]amino}-2-azaspiro[3.5]nonane-2-carboxylate.

[0225] To a stirred solution of 2-methyl-6-(3-methylimidazol-4-yl)pyrido[3,4-d]pyrimidin-4-ol (100 mg, 0.4 mmol, 1 eq) in DMF (5 mL) was added DIEA (87 uL, 0.5 mmol, 1.2 eq), tertbutyl 7-amino-2-azaspiro[3.5]nonane-2-carboxylate (149 mg, 0.6 mmol, 1.5 eq), DBll (124 uL, 0.8 mmol, 2 eq) and PyBOP (258 mg, 0.5 mmol, 1.2 eq) atO°C. The resulting mixture was stirred for 17h at 80°C. The resulting mixture was poured into ice water (20 mL). The precipitated solids were collected by filtration and washed with water (10 mL), then dried under vacuum. Tert-butyl 7-{[2-methyl-6-(3-methylimidazol-4-yl)pyrido[3,4-d]pyrimidin-4-yl]amino}-2-azaspiro[3.5]nonane-2-carboxylate (130 mg, 67% yield) was obtained as a white solid. LC / MS: mass calcd. for C25H33N7O2: 463.2, found: 464.2 [M+H]+.

[0226] Synthesis of N-[2-methyl-6-(3-methylimidazol-4-yl)pyrido[3,4-d]pyrimidin-4-yl]-2-azaspiro[3.5] nonan-7-amine

[0227] To a stirred solution of tert-butyl 7-{[2-methyl-6-(3-methylimidazol-4-yl)pyrido[3,4-d]pyrimidin-4-yl]amino}-2-azaspiro[3.5]nonane-2-carboxylate (120 mg, 0.3 mmol, 1 eq) in DCM (2 mL) was added HCI in 1,4-dioxane (4.0 M) (0.5 mL) in portions at 0°C. The resulting mixture was stirred for 3h at 25°C. The resulting mixture was concentrated under reduced pressure. The residue was washed with Et20 (10 mL) and dried under vacuum to afford N-[2-methyl-6-(3-methylimidazol-4-yl)pyrido[3,4-d]pyrimidin-4-yl]-2-azaspiro[3.5]nonan-7-amine (100 mg, crude) as a yellow solid. LC / MS: mass calcd. for C20H25N7: 363.2, found: 364.2 [M+H]+.

[0228] Synthesis of N-(2-(3,3-difluorocyclobutyl)-2-azaspiro[3.5]nonan-7-yl)-2-methyl-6-(1-methyl-1H-imidazol-5-yl)pyrido[3,4-d]pyrimidin-4-amineDocket no. 24-2208-WON-S1 / Set B

[0229] A solution of N-[2-methyl-6-(3-methylimidazol-4-yl)pyrido[3,4-d]pyrimidin-4-yl]-2-azaspiro[3.5]nonan-7-amine (76 mg, 0.2 mmol, 1 eq) in methanol (5 mL) was treated with 3,3-difluorocyclobutan-1-one (44 mg, 0.4 mmol, 2 eq) and HOAc (250 uL) at 0°C. The reaction was stirred at room temperature for 1 hour. Sodium cyanoborohydride (26 mg, 0.4 mmol, 2 eq) was added at 0°C and then the reaction was stirred at room temperature for 17 hours. The resulting mixture was poured into ice water (10 mL). The resulting mixture was concentrated under reduced pressure. The mixture was purified Prep-HPLC (Column:XBridge Prep C18 OBD Column, 30*150 mm, 5pm; Mobile Phase A: water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 28% B to 52% B inlOmin; Wavelength: 254nm) to afford N-(2-(3,3-difluorocyclobutyl)-2-azaspiro[3.5]nonan-7-yl)-2-methyl-6-(1-methyl-1H-imidazol-5-yl)pyrido[3,4-d]pyrimidin-4-amine (6.1 mg, 6% yield) as a white solid. LC / MS: mass calcd. for C24H29F2N7: 453.2, found: 454.2 [M+H]+.1HNMR (300 MHz, DMSO-cfe) 68.98 (s, 1H), 8.45 (s, 1H), 8.07 (d, J = 7.7 Hz, 1H), 7.76 (s, 1H), 7.46 (s, 1H), 4.11 - 4.27 (m, 1H), 3.94 (s, 3H), 2.98 - 3.11 (m, 1H), 2.98 (s, 2H), 2.88 (s, 2H), 2.52 - 2.74 (m, 2H), 2.49 (s, 3H), 2.22 - 2.47 (m, 2H), 1.82 - 2.01 (m, 4H), 1.31 - 1.67 (m, 4H).19FNMR (282 MHz, DMSO-cfe) 6 -81.34, -82.02, -90.98, -91.66.

[0230] Example 37: Synthesis of N-((1r,4r)-4-(3,3-difluoroazetidin-1-yl)cyclohexyl)-2-methyl-6-(1-methyl-1H-imidazol-5-yl)pyrido[3,4-d]pyrimidin-4-amine

[0231] To a stirred solution of 2-methyl-6-(3-methylimidazol-4-yl)pyrido[3,4-d]pyrimidin-4-ol (70 mg, 0.3 mmol, 1 eq) in DMF (3 mL) was added PyBOP (181 mg, 0.4 mmol, 1.2 eq), DBU (88 mg, 0.6 mmol, 2 eq), DIEA (45 mg, 0.4 mmol, 1.2 eq) and (1r,4r)-4-(3,3-difluoroazetidin-1-yl)cyclohexan-1 -amine (66 mg, 0.4 mmol, 1.2 eq) at 0°C. The resulting mixture was stirred for 17h at 80°C under N2atmosphere. The reaction was poured into water / ice (30 mL). The precipitated solids were collected by filtration and washed with H2O (3 x 2 mL), then dried under vacuum. The residue was filtered and the filtration in DMF (1 mL) was purified by Prep-HPLC: (Column: XBridge Prep C18 OBD Column, 30*150 mm, 5pm; Mobile Phase A: water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 18% B to 42% B in 10 min; Wavelength: 254 nm) to afford N-((1r,4r)-4-(3,3-difluoroazetidin-1-yl)cyclohexyl)-2-methyl-6-(1-methyl-1H-imidazol-5-yl)pyrido[3,4-d]pyrimidin-4-amine (28.2 mg, 23.5% yield) as a white solid. LC / MS: mass calcd. for C2IH25F2N?: 413.2, found: 414.2Docket no. 24-2208-WON-S1 / Set B[M+H]+.1HNMR (300 MHz, DMSO-cfe) 58.98 (s, 1H), 8.46 (s, 1H), 8.11 (d, J= 7.5 Hz, 1H), 7.78 (s, 1 H), 7.46 (s, 1 H), 4.07 - 4.24 (m, 1 H), 3.93 (s, 3H), 3.58 (t, J = 12.3 Hz, 4H), 2.09 -2.28 (m, 1H), 1.91 - 2.07 (m, 2H), 1.74 - 1.90 (m, 2H), 1.33 - 1.52 (m, 2H), 1.19 - 1.29 (m, 1H), 1.02 - 1.18 (m, 2H).19FNMR (377 MHz, DMSO-cfe) 5 -98.12.

[0232] Example 38: Synthesis of 2-methyl-6-(1-methyl-1H-imidazol-5-yl)-N-(1 -(2,2,2-trifluoroethyl)piperidin-4-yl)pyrido[3,4-d]pyrimidin-4-amine

[0233] To a stirred solution of 2-methyl-6-(3-methylimidazol-4-yl)pyrido[3,4-d]pyrimidin-4-ol (60 mg, 0.2 mmol, 1 eq) and 1-(2,2,2-trifluoroethyl)piperidin-4-amine (54 mg, 0.3 mmol, 1.2 eq) in DMF (3 mL) was added DIEA (55 uL, 0.3 mmol, 1.2 eq), DBU (75 uL, 0.5 mmol, 2 eq) and PyBOP (194 mg, 0.3 mmol, 1.5 eq) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80°C for 17h under nitrogen atmosphere. The mixture was allowed to cool to room temperature. The residue was purified by Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 pm; Mobile Phase A: water (10 mmoL / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 25% B to 40% B in 10 min; Wavelength: 254 nm / 220 nm) to afford 2-methyl-6-(1-methyl-1H-imidazol-5-yl)-N-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)pyrido[3,4-d]pyrimidin-4-amine (29.6 mg, 29% yield) as a white solid. LC / MS: mass calcd. For C19H22F3N7: 405.2, found: 406.2 [M+H]+.1HNMR (300 MHz, DMSO-cfe) 58.98 (s, 1H), 8.45 (s, 1H), 8.13 (d, J= 7.6 Hz, 1H), 7.76 (s, 1H), 7.46 (s, 1H), 4.12 - 4.30 (m, 1H), 3.94 (s, 3H), 3.14 - 3.30 (m, 2H), 2.94 - 3.06 (m, 2H), 2.51 - 2.56 (m, 2H), 2.49 (s, 3H), 1.88- 2.01 (m, 2H), 1.59 - 1.76 (m, 2H).19FNMR (282 MHz, DMSO-cfe) 5 -68.17.

[0234] Example 39: Synthesis of 2-methyl-6-(1-methyl-1H-imidazol-5-yl)-N-((1r,4r)-4-(trifluoromethoxy)cyclohexyl)pyrido[3,4-d]pyrimidin-4-amine

[0235] To a stirred solution of 2-methyl-6-(3-methylimidazol-4-yl)pyrido[3,4-d]pyrimidin-4-ol (60 mg, 0.2 mmol, 1 eq), (1r,4r)-4-(trifluoromethoxy)cyclohexan-1-amine hydrochloride (71Docket no. 24-2208-WON-S1 / Set Bmg, 0.3 mmol, 1.3 eq) and PyBOP (174 mg, 0.3 mmol, 1.3 eq) in DMF (3 mL) were added DIEA (39 mg, 0.3 mmol, 1.2 eq) and DBll (95 mg, 0.6 mmol, 2.5 eq) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80°C overnight under nitrogen atmosphere. The reaction was poured into 10 mL of ice water. The precipitated solids were collected by filtration and washed with water (3 x 5 mL). The crude product was purified by Prep-HPLC (Column: XBridge Prep C18 OBD Column, 30*150 mm, 5pm; Mobile Phase A: water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min;Gradient (B%): 34% B to 55% B in 10 min; Wavelength: 254 nm) to afford 2-methyl-6-(1-methyl-1H-imidazol-5-yl)-N-((1r,4r)-4-(trifluoromethoxy)cyclohexyl)pyrido[3,4-d]pyrimidin-4-amine (23.0 mg, 22.7% yield) as a white solid. LC / MS: mass calcd. For C19H21F3N6O: 406.1, found: 407.0 [M+H]+.1HNMR (400 MHz, DMSO-cfe) 68.99 (s, 1H), 8.47 (s, 1H), 8.13 (d, J = 7.3 Hz, 1H), 7.76 (s, 1H), 7.45 (s, 1H), 4.40 - 4.52 (m, 1H), 4.11 - 4.33 (m, 1H), 3.93 (s, 3H), 2.50 (s, 3H), 2.02 - 2.20 (m, 4H), 1.55 - 1.72 (m, 4H).19FNMR (377 MHz, DMSO-cfe) 6 -55.92.

[0236] Example 40: Synthesis of N-((1r,4r)-4-isopropoxycyclohexyl)-2-methyl-6-(1-methyl-1H-imidazol-5-yl)pyrido[3,4-d]pyrimidin-4-amine

[0237] To a stirred solution of 2-methyl-6-(3-methylimidazol-4-yl)pyrido[3,4-d]pyrimidin-4-ol (65 mg, 0.3 mmol, 1 eq) in DMF (3 mL) was added (1r,4r)-4-isopropoxycyclohexan-1 -amine hydrochloride (57 mg, 0.3 mmol, 1 eq), DBU (82 mg, 0.6 mmol, 2 eq), DIEA (42 mg, 0.32 mmol, 1.2 eq) and PyBOP (154 mg, 0.3 mmol, 1 eq) at 0°C. The resulting mixture was stirred for 17h at 80°C under N2atmosphere. The reaction mixture was purified by Prep-HPLC (Column: Xselect CSH Phenyl Hexy Column, 19*250 mm, 5 pm; Mobile Phase A: water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 25 mL / min; Gradient (B%): 19%B to 40%B in 11 min; Wavelength: 254 / 220 nm) to afford N-((1r,4r)-4-isopropoxycyclohexyl)-2-methyl-6-(1-methyl-1H-imidazol-5-yl)pyrido[3,4-d]pyrimidin-4-amine (40.6 mg, 40% yield) an off-white solid. LC / MS: mass calcd. For C2IH28N6O: 380.2, found: 381.2 [M+H]+.1HNMR (300 MHz, DMSO-cfe) 68.98 (s, 1 H), 8.46 (s, 1 H), 8.09 (d, J = 7.5 Hz, 1 H), 7.76 (s, 1 H), 7.45 (s, 1H), 4.07 - 4.24 (m, 1H), 3.93 (s, 3H), 3.62 - 3.78 (m, 1H), 3.22-3.29 (m, 1H), 2.49 (s, 3H), 1.87 - 2.09 (m, 4H), 1.36 - 1.57 (m, 5H), 1.17 - 1.35 (m, 5H), 1.07 (d, J= 6.0 Hz, 6H).

[0238] Example 41: Synthesis of 2-methyl-6-(1-methyl-1H-imidazol-5-yl)-N-((1r,4r)-4-(pyrazin-2-yloxy)cyclohexyl)pyrido[3,4-d]pyrimidin-4-amineDocket no. 24-2208-WON-S1 / Set B

[0239] Synthesis of tert-butyl N-[(1r,4r)-4-(pyrazin-2-yloxy)cyclohexyl]carbamate

[0240] To a stirred solution of tert-butyl N-[(1r,4r)-4-hydroxycyclohexyl]carbamate (2.3 g, 11 mmol, 1.2 eq) in DMF (50 mL) was added NaH (0.5 g, 13 mmol, 1.4 eq, 60%) at 0°C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 30 min under nitrogen atmosphere. To the above mixture was added 2-chloropyrazine (1 g, 8.7 mmol, 1 eq) in DMF (5 mL) at 0°C. The resulting mixture was stirred at room temperature for an additional 2h. The reaction was quenched with ice water (500 mL) at 0°C. The resulting mixture was extracted with EtOAc (3x 500 mL). The combined organic layers were washed with brine, then dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE I EA (10:1) to afford tert-butyl N-[(1r,4r)-4-(pyrazin-2-yloxy)cyclohexyl]carbamate (630 mg, 25% yield) as a white solid. LC / MS: mass calcd. For C15H23N3O3: 293.2, found: 294.2 [M+H]+.

[0241] Synthesis of (1r,4r)-4-(pyrazin-2-yloxy) cyclohexan-1 -amine

[0242] To a stirred solution of tert-butyl N-[(1r,4r)-4-(pyrazin-2-yloxy)cyclohexyl]carbamate (150 mg, 0.5 mmol, 1 eq) in DCM (1.5 mL) was added HCI in dioxane (1.5 mL, 4M) at 0°C. The resulting mixture was stirred at room temperature for 1h. The resulting mixture was concentrated under reduced pressure. This resulted in (1r,4r)-4-(pyrazin-2-yloxy)cyclohexan-1-amine (98 mg) as a white solid. The crude product was used in the next step directly without further purification. LC / MS: mass calcd. For C10H15N30: 193.1, found: 194.2 [M+H]+.

[0243] Synthesis of 2-methyl-6-(1-methyl-1 H-imidazol-5-yl)-N-((1 r,4r)-4-(pyrazin-2-yloxy)cyclohexyl)pyrido[3,4-d]pyrimidin-4-amine

[0244] To a stirred solution of 2-methyl-6-(3-methylimidazol-4-yl)pyrido[3,4-d]pyrimidin-4-ol (70 mg, 0.3 mmol, 1 eq) and (1r,4r)-4-(pyrazin-2-yloxy)cyclohexan-1 -amine (84 mg, 0.4Docket no. 24-2208-WON-S1 / Set Bmmol, 1.5 eq) in DMF (5 mL) was added DIEA (61 uL, 0.4 mmol, 1.2 eq), DBll (87 uL, 0.6 mmol, 2 eq) and PyBOP (226 mg, 0.4 mmol, 1.5 eq) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80°C for 17h under nitrogen atmosphere. The mixture was allowed to cool to room temperature. The residue was purified by Prep-HPLC (Column: XBridge BEH Shield RP18 Column, 30*150 mm, 5 pm; Mobile Phase A: water (10 mmoL / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 22% B to 38% B in 7 min; Wavelength: 254 / 220 nm) to afford 2-methyl-6-(1-methyl-1H-imidazol-5-yl)-N-((1 r,4r)-4-(pyrazin-2-yloxy)cyclohexyl)pyrido[3,4-d]pyrimidin-4-amine (18.0 mg, 15% yield) as an off-white solid. LC / MS: mass calcd. For C22H24N8O: 416.2, found: 417.2 [M+H]+.1HNMR (400 MHz, DMSO-cfe) 69.00 (s, 1H), 8.48 (s, 1H), 8.29 (s, 1H), 8.22 - 8.24 (m, 1H), 8.20 (d, J= 2.7 Hz, 1H), 8.16 (d, J= 7.6 Hz, 1H), 7.77 (s, 1H), 7.47 (s, 1H), 4.95 -5.08 (m, 1H), 4.24 - 4.38 (m, 1H), 3.94 (s, 3H), 2.49 (s, 3H), 2.19 - 2.27 (m, 2H), 2.07 - 2.16 (m, 2H), 1.55 - 1.71 (m, 4H).

[0245] Example 42: Synthesis of 2-cyclopropyl-N-((1r,4r)-4-methoxycyclohexyl)-6-(1-methyl-1H-imidazol-5-yl)pyrido[3,4-d]pyrimidin-4-amine

[0246] Synthesis of 6-bromo-2-cyclopropylpyrido[3,4-d] pyrimidin-4-ol

[0247] To a stirred solution of 5-amino-2-bromopyridine-4-carboxylic acid (3 g, 14 mmol, 1 eq) in 1-methoxypropan-2-ol (30 mL) was added AcONa (2.8 g, 35 mmol, 2.5 eq) and cyclopropanecarboximidamide hydrochloride (2.5 g, 21 mmol, 1.5 eq) at room temperature. The reaction mixture was stirred for 3 days at 150°C. The mixture was allowed to cool down to 0 C. The precipitated solids were collected by filtration and washed with water (3 x 5 mL), dried under vacuum. 6-bromo-2-cyclopropylpyrido[3,4-d]pyrimidin-4-ol (1.2 g, crude) was obtained as a black solid. LC / MS: mass calcd. for C HsBrNaO: 267.0, found: 268.0 [M+H]+.

[0248] Synthesis of 2-cyclopropyl-6-(3-methylimidazol-4-yl) pyrido[3,4-d] pyrimidin-4-olDocket no. 24-2208-WON-S1 / Set B

[0249] To a stirred solution of 6-bromo-2-cyclopropylpyrido[3,4-d]pyrimidin-4-ol (1.1 g, 4.3 mmol, 1 eq) in dioxane (20 mL) and H2O (4 mL) was added 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) imidazole (1.3 g, 6.5 mmol, 1.5 eq), Na2COs (1.4 g, 13 mmol, 3 eq) and Pd(dtbpf)Ch (282 mg, 0.4 mmol, 0.1 eq) at room temperature under N2 atmosphere. The reaction mixture was stirred for 17h at 100°C. The resulting mixture was filtered, and the filter cake was washed with DCM / MeOH (1: 1) (3 x 100 mL). The filtrate was concentrated under reduced pressure. The residue was purified by washing with DCM / MeOH (20 : 1) (50 mL) to afford 2-cyclopropyl-6-(3-methylimidazol-4-yl)pyrido[3,4-d]pyrimidin-4-ol (500 mg, 43% yield) as a white solid. LC / MS: mass calcd. for C14H13N5O: 267.1, found: 268.1 [M+H]+.

[0250] Synthesis of 2-cyclopropyl-N-((1r,4r)-4-methoxycyclohexyl)-6-(1-methyl-1H-imidazol-5-yl)pyrido[3,4-d]pyrimidin-4-amine

[0251] To a stirred solution of 2-cyclopropyl-6-(3-methylimidazol-4-yl)pyrido[3,4-d]pyrimidin-4-ol (100 mg, 0.4 mmol, 1 eq) in DMF (3 mL) was added PyBOP (233 mg, 0.5 mmol, 1.2 eq), DBU (112 uL, 0.8 mmol, 2 eq), DIEA (78 uL, 0.5 mmol, 1.2 eq) and (1 r,4r)-4-methoxycyclohexan-1-amine (53 mg, 0.44 mmol, 1.1 eq) at 0°C. The resulting mixture was stirred for 17h at 80°C under N2 atmosphere. The reaction was poured into water / ice (15 mL). The precipitated solids were collected by filtration and washed with H2O (3 x2 mL), then dried under vacuum. The crude product was purified by Prep-HPLC (Column: XBridge Prep C18 OBD Column, 30*150 mm, 5pm; Mobile Phase A: water (10mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 22% B to 47% B in 10min;Wavelength: 254 nm) to afford 2-cyclopropyl-N-((1r,4r)-4-methoxycyclohexyl)-6-(1-methyl-1H-imidazol-5-yl)pyrido[3,4-d]pyrimidin-4-amine (30.3 mg, 21% yield) as a white solid.LC / MS: mass calcd. ForC2iH26N6O: 378.1, found: 379.1 [M+H]+.1HNMR (300 MHz, DMSO-de) 68.95 (s, 1H), 8.44 (s, 1H), 8.12 (d, J = 7.3 Hz, 1H), 7.75 (s, 1H), 7.44 (s, 1H), 3.98 - 4.16 (m, 1 H), 3.93 (s, 3H), 3.27 (s, 3H), 3.06 - 3.22 (m, 1 H), 1.89 - 2.21 (m, 5H), 1.32 - 1.57 (m, 2H), 1.13 - 1.33 (m, 2H), 0.99 - 1.11 (m, 2H), 0.85 - 0.99 (m, 2H).

[0252] Example 43: Synthesis of 2-cyclopropyl-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-(1-methyl-1H-imidazol-5-yl)pyrido[3,4-d]pyrimidin-4-amineDocket no. 24-2208-WON-S1 / Set B

[0253] To a stirred solution of 2-cyclopropyl-6-(3-methylimidazol-4-yl)pyrido[3,4-d]pyrimidin-4-ol (90 mg, 0.3 mmol, 1 eq), (1r,4r)-4-(2-methoxyethoxy) cyclohexan-1 -amine (70 mg, 0.4 mmol, 1.2 eq) and PyBOP (236 mg, 0.4 mmol, 1.3 eq) in DMF (9 mL) were added DIEA (52 mg, 0.4 mmol, 1.2 eq) and DBll (128 mg, 0.8 mmol, 2.5 eq) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80°C overnight under nitrogen atmosphere. The residue was purified by Prep-HPLC (Column: XBridge Prep C18 OBD Column, 30*150 mm, 5pm; Mobile Phase A: water (10mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 22% B to 47% B inlOmin; Wavelength: 254 nm) to afford 2-cyclopropyl-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-(1-methyl-1H-imidazol-5-yl)pyrido[3,4-d]pyrimidin-4-amine (49.2 mg, 34% yield) as a white solid. LC / MS: mass calcd. For C23H30N6O2: 422.2, found: 423.1 [M+H]+.1HNMR (300 MHz, DMSO-cfe) 6 8.93 (s, 1H), 8.42 (s, 1H), 8.09 (d, J= 7.2 Hz, 1H), 7.74 (s, 1H), 7.43 (s, 1H), 4.01 - 4.19 (m, 1H), 3.92 (s, 3H), 3.53 - 3.58 (m, 2H), 3.40 - 3.46 (m, 2H), 3.28 - 3.41 (m, 1H), 3.26 (s, 3H), 1.97 - 2.13 (m, 5H), 1.36 - 1.54 (m, 2H), 1.20 - 1.37 (m, 2H), 1.00 - 1.09 (m, 2H), 0.91 - 1.00 (m, 2H).

[0254] Example 44: Synthesis of 2-cyclopropyl-N-((1r,4r)-4-(3,3-difluoroazetidin-1-yl)cyclohexyl)-6-(1-methyl-1H-imidazol-5-yl)pyrido[3,4-d]pyrimidin-4-amine

[0255] To a stirred solution of 2-cyclopropyl-6-(3-methylimidazol-4-yl) pyrido[3,4-d] pyrimidin-4-ol (100 mg, 0.4 mmol, 1 eq) and (1r,4r)-4-(3,3-difluoroazetidin-1-yl) cyclohexan-1-amine (85 mg, 0.5 mmol, 1.2 eq) in DMF (5 mL) were added DIEA (80 uL, 0.5 mmol, 1.2 eq), DBll (115 uL, 0.8 mmol, 2 eq) and PyBOP (291 mg, 0.6 mmol, 1.5 eq) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80°C for 17h under nitrogen atmosphere. The mixture was allowed to cool to room temperature, then it was purified by Prep-HPLC (Column: XBridge Prep C18 OBD Column, 30*150 mm, 5pm; Mobile Phase A: water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 24% B to 49% B in 10 min; Wavelength: 254 nm) to afford 2-cyclopropyl-N-((1r,4r)-4-(3,3-difluoroazetidin-1-yl)cyclohexyl)-6-(1-methyl-1H-imidazol-5-yl)pyrido[3,4-d]pyrimidin-4-amine (20.7 mg, 12% yield) as a white solid. LC / MS: mass calcd. For C23H27F2N7: 439.2, found: 440.3 [M+H]+.1HNMR (300 MHz, DMS-cfe) 68.93 (s, 1H), 8.41 (s, 1H), 8.10 (d, J= 7.3 Hz,Docket no. 24-2208-WON-S1 / Set B1H), 7.73 (s, 1H), 7.42 (s, 1H), 3.96 - 4.13 (m, 1H), 3.91 (s, 3H), 3.56 (t, J= 12.4 Hz, 4H), 2.11 - 2.29 (m, 1H), 1.92 - 2.11 (m, 3H), 1.76 - 1.88 (m, 2H), 1.30 - 1.49 (m, 2H), 1.05 - 1.25 (m, 2H), 0.98 - 1.05 (m, 2H), 0.89 - 0.98 (m, 2H).19FNMR (282 MHz, DMSO-cfe) 6 -98.13.

[0256] Example 45: Synthesis of 2 N-((1r,4r)-4-methoxycyclohexyl)-2-methyl-6-(1-methyl-1H-imidazol-5-yl)-8-(trifluoromethyl)pyrido[3,4-d]pyrimidin-4-amineCompound 45

[0257] Synthesis of methyl 3-amino-6-bromo-2-(trifluoromethyl) pyridine-4-carboxylate

[0258] To a stirred solution of 3-amino-6-bromo-2-(trifluoromethyl)pyridine-4-carboxylic acid (1.6 g, 5.6 mmol, 1 eq) in methanol (16 mL) was added H2SO4 (1.6 mL). The resulting mixture was stirred at 100°C for 48h. The resulting mixture was concentrated under reduced pressure. The resulting mixture was poured into ice water (100 mL). The precipitated solids were collected by filtration and washed with water (50 mL), dried under vacuum to afford methyl 3-amino-6-bromo-2-(trifluoromethyl)pyridine-4-carboxylate (1.2 g, 71% yield) as a yellow solid. LC / MS: mass calcd. for C8H6BrF3N2O2: 297.9, found: 299.0 [M+H]+.

[0259] Synthesis of 6-bromo-2-methyl-8-(trifluoromethyl)pyrido[3,4-d]pyrimidin-4-ol

[0260] To a stirred solution of methyl 3-amino-6-bromo-2-(trifluoromethyl)pyridine-4-carboxylate (1.2 g, 4 mmol, 1 eq) in MeCN (14 mL) was added MsOH (2.5 mL). The resulting mixture was stirred for 24h at 130°C. The resulting mixture was poured into ice water (50 mL). The precipitated solids were collected by filtration and washed with water (30 mL), then dried under vacuum to give 6-bromo-2-methyl-8-(trifluoromethyl)pyrido[3,4-d]pyrimidin-4-ol (900 mg, 72.8% yield) as a yellow solid. LC / MS: mass calcd. for CgHsBrFaNaO: 306.9, found: 307.9 [M+H]+.

[0261] Synthesis of 2-methyl-6-(3-methylimidazol-4-yl)-8-(trifluoromethyl)pyrido[3,4-d]pyrimidin-4-olDocket no. 24-2208-WON-S1 / Set B

[0262] To a stirred solution of 6-bromo-2-methyl-8-(trifluoromethyl)pyrido[3,4-d]pyrimidin-4-ol (850 mg, 2.7 mmol, 1 eq) in dioxane (20 mL) / H2O (4 mL) was added 1 -methyl-5-(4, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazole (861 mg, 4 mmol, 1.5 eq), Pd(dtbpf)Ch (180 mg, 0.3 mmol, 0.1 eq) and Na2COs (877 mg, 8 mmol, 3 eq) under a nitrogen atmosphere. The resulting mixture was stirred for 17h at 100°C. After cooling and addition of water (50 mL), the resulting mixture was extracted with EA (3 x 50mL). The combined organic layers were washed with brine (3 x 50 mL), then dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / EA (5 / 1) to afford 2-methyl-6-(3-methylimidazol-4-yl)-8-(trifluoromethyl)pyrido[3,4-d]pyrimidin-4-ol (550 mg, 73% yield) as a yellow solid.LC / MS: mass calcd. for C13H10F3N5O: 309.08, found: 310.05 [M+H]+.

[0263] Synthesis of N-((1r,4r)-4-methoxycyclohexyl)-2-methyl-6-(1-methyl-1 H-imidazol-5-yl)-8-(trifluoromethyl)pyrido[3,4-d]pyrimidin-4-amine

[0264] To a stirred solution of 2-methyl-6-(3-methylimidazol-4-yl)-8-(trifluoromethyl)pyrido[3,4-d]pyrimidin-4-ol (70 mg, 0.2 mmol, 1 eq) in DMF (2 mL) was added DIEA (47.3 uL, 0.3 mmol, 1.2 eq), (1r,4r)-4-methoxycyclohexan-1 -amine (44 mg, 0.3 mmol, 1.5 eq), DBU (68 uL, 0.4 mmol, 2 eq) and PyBOP (141 mg, 0.3 mmol, 1.2 eq) at 0°C. The resulting mixture was stirred for 17h at 80°C. The resulting mixture was poured into ice water (20 mL). The precipitated solids were collected by filtration and washed with water (10 mL), then dried under vacuum. The crude product was purified by Prep-HPLC (Column: XBridge Prep OBD C18 Column 30*150 mm, 5pm; Mobile Phase A: water / 10mM NH4HCO3, Mobile Phase B: ACN; Flow rate: 60mL / min; Gradient (B%): 43% B to 60% B in 10 min;Wavelength: 220 nm) to afford N-((1r,4r)-4-methoxycyclohexyl)-2-methyl-6-(1-methyl-1H-imidazol-5-yl)-8-(trifluoromethyl)pyrido[3,4-d]pyrimidin-4-amine (30.0 mg, 32% yield) as an off-white solid. LC / MS: mass calcd. for C20H23F3N6O: 420.1, found: 421.1 [M+H]+.1HNMR (300 MHz, DMSO-cfe) 68.76 (s, 1H), 8.34 (d, J= 7.6 Hz, 1H), 7.79 (s, 1H), 7.57 (s, 1H), 4.10 - 4.28 (m, 1H), 3.96 (s, 3H), 3.32 (s, 3H), 3.11 - 3.22 (m, 1H), 2.05 (s, 3H), 1.96 - 2.14 (m, 4H), 1.36 - 1.55 (m, 2H), 1.16 - 1.34 (m, 2H).19FNMR (282 MHz, DMSO-cfe) 6 -62.88.

[0265] Example 46: Synthesis of N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-2-methyl-6-(1-methyl-1H-imidazol-5-yl)-8-(trifluoromethyl)pyrido[3,4-d]pyrimidin-4-amineDocket no. 24-2208-WON-S1 / Set B45-4 Compound 45

[0266] To a stirred solution of 2-methyl-6-(3-methylimidazol-4-yl)-8-(trifluoromethyl)pyrido[3,4-d]pyrimidin-4-ol (70 mg, 0.2 mmol, 1 eq) in DMF (2 mL) was added DIEA (47 uL, 0.2 mmol, 1.2 eq), (1r,4r)-4-(2-methoxyethoxy) cyclohexan-1-amine (59 mg, 0.3 mmol, 1.5 eq), DBU (68 uL, 0.4 mmol, 2 eq) and PyBOP (141 mg, 0.2 mmol, 1.2 eq) at 0°C. The resulting mixture was stirred for 17h at 80°C. The resulting mixture was poured into ice water (20 mL). The precipitated solids were collected by filtration and washed with water (10 mL), then dried under vacuum. The crude product was purified by Prep-HPLC (Column: XBridge Prep OBD C18 Column 30*150 mm, 5pm; Mobile Phase A: water / 10mM NH4HCO3, Mobile Phase B: ACN; Flow rate: 60mL / min; Gradient (B%): 41% B to 60% B in 10 min; Wavelength: 220 nm) to afford 2-methyl-6-(3-methylimidazol-4-yl)-N-[(1r,4r)-4-(2-methoxyethoxy)cyclohexyl]-8-(trifluoromethyl)pyrido[3, 4-d]pyrimidin-4-amine (34.7 mg, 33% yield) as a white solid. LC / MS: mass calcd. for C22H27F3N6O2: 464.21, found: 465.15 [M+H]+.1HNMR (300 MHz, DMSO-cfe) 68.76 (s, 1H), 8.33 (d, J= 7.4 Hz, 1H), 7.79 (s, 1H), 7.56 (s, 1H), 4.09 - 4.29 (m, 1H), 3.94 (s, 3H), 3.55 (t, J = 4.8 Hz, 2H), 3.42 (t, J= 4.8 Hz, 2H), 3.19 -3.29 (m, 4H), 2.49 (s, 3H), 1.94 - 2.14 (m, 4H), 1.37 - 1.55 (m, 2H), 1.17 - 1.37 (m, 2H).19F NMR (282 MHz, DMSO-cfe) 6 -62.89.

[0267] Example 47: Synthesis of 5-fluoro-N-((1r,4r)-4-methoxycyclohexyl)-6-(1-methyl-1H-imidazol-5-yl)pyrido[3,4-d]pyrimidin-4-amineDocket no. 24-2208-WON-S1 / Set B

[0268] Synthesis of 3-bromo-5-fluoropyridine-4-carboxylate

[0269] To a solution of 3-bromo-5-fluoropyridine-4-carboxylic acid (10 g, 46 mmol, 1 eq) in DMF (250 mL) was added K2CO3 (19 g, 136 mmol, 3 eq) and CH3I (13 g, 91 mmol, 2 eq) at 0°C. Then the reaction was stirred for 3h at room temperature. The reaction mixture was filtered, and the filtrate was poured into water (1 L). The reaction mixture was extracted by EA (3 x 1 L), the organic phases were combined and washed by brine (2 x 1L), then dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (20:1) to afford methyl 3-bromo-5-fluoropyridine-4-carboxylate (7.5 g, 71% yield) as a colorless solid. LC / MS: mass calcd. For CyHsBrFNCh: 232.9, found: 233.9 [M+H]+.

[0270] Synthesis of methyl 3-[(tert-butoxycarbonyl)amino]-5-fluoropyridine-4-carboxylate

[0271] To a stirred solution of methyl 3-bromo-5-fluoropyridine-4-carboxylate (3.2 g, 14 mmol, 1 eq) in dioxane (320 mL) was added NH2Boc (2.4 g, 21 mmol, 1.5 eq), CS2CO3 (13.4 g, 41 mmol, 3 eq) and (SP-4-1)-[1,3-Bis[2,6-bis(1-ethylpropyl)phenyl]-4,5-dichloro-1,3-dihydro-2H-imidazol-2-ylidene]dichloro(2-methylpyridine)palladium (1.2 g, 1.4 mmol, 0.1 eq) at room temperature in glove box. The final reaction mixture was stirred for 17h at 90°C. The resulting mixture was filtered, and the filter cake was washed with MeOH (3 x 5 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography with the following conditions: C18 column, mobile phase, MeCN in water (0.1% TFA), 2% to 48% gradient in 50 min; detector, UV 254 nm to afford methyl 3-[(tert-butoxycarbonyl)amino]-5-fluoropyridine-4-carboxylate (1.9 g, 51 %yield) as a white solid. LC / MS: mass calcd. For C12H15FN2O4: 270.1, found: 271.1 [M+H]+.

[0272] Synthesis of 3-[(tert-butoxycarbonyl)amino]-5-fluoropyridine-4-carboxylic acidDocket no. 24-2208-WON-S1 / Set B

[0273] To a stirred solution of methyl 3-[(tert-butoxycarbonyl) amino]-5-fluoropyridine-4-carboxylate (1.9 g, 7 mmol, 1 eq) in THF (35 mL) was added LiOH solution (2 M in H2O, 14 mL, 28 mmol, 4 eq) at room temperature. The resulting mixture was stirred for 2h at 45 °C. The reaction mixture was acidified to pH 3~5 with 2M HCI. The mixture was diluted with water (50 mL). The reaction mixture was extracted by EA (3 x 50 mL), the organic phases were combined and washed by H2O (1 x 100 mL) and sat. NaCI soln. (1 x 100 mL), then dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. 3-[(tert-butoxycarbonyl)amino]-5-fluoropyridine-4-carboxylic acid (1.5 g, crude) was obtained as a white solid. LC / MS: mass calcd. For C11H13FN2O4: 256.1, found: 257.0 [M+H]+.

[0274] Synthesis of 2-bromo-5-[(tert-butoxycarbonyl) amino]-3-fluoropyridine-4-carboxylic acid

[0275] To a stirred solution of 3-[(tert-butoxycarbonyl)amino]-5-fluoropyridine-4-carboxylic acid (800 mg, 3 mmol, 1 eq) in DMF (16 mL) was added NBS (1.6 g, 9 mmol, 3 eq) at 0°C. The resulting mixture was stirred for 17h at room temperature. The reaction mixture was purified by reverse-phase flash: C18 column, mobile phase, MeCN in water (0.1% TFA), 5% to 38% gradient in 10 min; detector, UV 254 nm to afford 2-bromo-5-[(tert-butoxycarbonyl)amino]-3-fluoropyridine-4-carboxylic acid (250 mg, 24%yield) as a white solid. LC / MS: mass calcd. For CnH^BrFIXLC 334.0, found: 335.0 [M+H]+.1HNMR (300 MHz, DMSO-cfe) 69.73 (s, 1H), 8.48 (s, 1H), 1.46 (s, 9H).

[0276] Synthesis of tert-butyl N-(6-bromo-4-carbamoyl-5-fluoropyridin-3-yl) carbamate

[0277] To a stirred solution of 2-bromo-5-[(tert-butoxycarbonyl)amino]-3-fluoropyridine-4-carboxylic acid (120 mg, 0.3 mmol, 1 eq) in DMF (5 mL) was added HATU (204 mg, 0.5 mmol, 1.5 eq), DIEA (374 uL, 2.1 mmol, 6 eq) and NH4CI (48 mg, 0.9 mmol, 2.5 eq) at room temperature under N2 atmosphere. The resulting mixture was stirred for 1h at room temperature under N2 atmosphere. The reaction mixture was filtered, and the filtrate was purified by reverse phase (C18 column, mobile phase, ACN in water (0.05% FA), 5% to 32% gradient in 30 min; detector, UV 254 nm) to afford tert-butyl N-(6-bromo-4-carbamoyl-5-fluoropyridin-3-yl) carbamate (110 mg, 92% yield) as a light yellow solid. LC / MS: mass calcd. For CiiHi3BrFN3O3: 333.0, found: 336.0 [M+H]+.

[0278] Synthesis of 5-amino-2-bromo-3-fluoropyridine-4-carboxamide

[0279] To a stirred solution of tert-butyl N-(6-bromo-4-carbamoyl-5-fluoropyridin-3-yl)carbamate (400 mg, 1.2 mmol, 1 eq) in DCM (5 mL) was added TFA (2 mL) at 0°C. The resulting mixture was stirred at room temperature for 2h. The resulting mixture was concentrated under reduced pressure to give 5-amino-2-bromo-3-fluoropyridine-4-carboxamide (260 mg) as a yellow solid. The crude product was used for the next stepDocket no. 24-2208-WON-S1 / Set Bdirectly without further purification. LC / MS: mass calcd. For CeHsBrFNsO: 233.0, found: 236.0 [M+H]+.

[0280] Synthesis of 6-bromo-5-fluoropyrido[3,4-d] pyrimidin-4-ol

[0281] A solution of 5-amino-2-bromo-3-fluoropyridine-4-carboxamide (260 mg, 1 mmol, 1 eq) in trimethoxymethane (30 mL) was stirred at 110°C for 17h. The mixture was allowed to cool to room temperature. The residue was purified by reverse-phase flash chromatography: C18 column; mobile phase, MeCN in water (0.1% FA), 10% to 30% gradient in 30 min; detector, LIV 254 nm to afford 6-bromo-5-fluoropyrido[3,4-d]pyrimidin-4-ol (120 mg, 44% yield) as a yellow solid. LC / MS: mass calcd. For CyHsBrFNsO: 242.9, found: 243.9 [M+H]+.

[0282] Synthesis of 5-fluoro-6-(3-methylimidazol-4-yl) pyrido[3,4-d] pyrimidin-4-ol

[0283] To a stirred solution of 6-bromo-5-fluoropyrido[3,4-d]pyrimidin-4-ol (120 mg, 0.5 mmol, 1 eq) and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazole (205 mg, 1.0 mmol, 2 eq) in dioxane (7.5 mL) and H2O (1.5 mL) was added Na2CC>3 (156 mg, 1.5 mmol, 3 eq) and Pd(dtbpf)CI2(32 mg, 0.05 mmol, 0.1 eq) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100°C for 17h under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The residue was purified by reverse-phase flash chromatography: C18 column; mobile phase, MeCN in water (0.1% TFA), 10% to 50% gradient in 30 min; detector, UV 254 nm to afford 5-fluoro-6-(3-methylimidazol-4-yl) pyrido[3,4-d]pyrimidin-4-ol (54 mg, 44% yield) as a light yellow solid. LC / MS: mass calcd. For CIIH8FN5O: 245.1, found: 246.1 [M+H]+.

[0284] Synthesis of 5-fluoro-N-((1r,4r)-4-methoxycyclohexyl)-6-(1-methyl-1H-imidazol-5-yl)pyrido[3,4-d]pyrimidin-4-amine

[0285] To a stirred solution of 5-fluoro-6-(3-methylimidazol-4-yl)pyrido[3,4-d]pyrimidin-4-ol (50 mg, 0.2 mmol, 1 eq) and (1r,4r)-4-methoxycyclohexan-1 -amine (40 mg, 0.3 mmol, 1.5 eq) in DMF (3 mL) was added DIEA (110 uL, 0.6 mmol, 3 eq), DBU (100 uL, 0.67 mmol, 3.3 eq) and PyBOP (160 mg, 0.3 mmol, 1.5 eq) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80°C for 17h under nitrogen atmosphere. The mixture was allowed to cool to room temperature. Then it was purified by Prep-HPLC (Column: YMC Triart C18 ExRS, 30*150 mm, 5pm; Mobile Phase A: water (10 mmoL / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 17%B to 30%B in 13min; Wavelength: 254 / 220 nm) to afford 5-fluoro-N-((1r,4r)-4-methoxycyclohexyl)-6-(1-methyl-1H-imidazol-5-yl)pyrido[3,4-d]pyrimidin-4-amine (15.2 mg, 20% yield) as a white solid. LC / MS: mass calcd. For CI8H2IFN6O:356.2, found: 357.2 [M+H]+.1HNMR (300 MHz, DMSO-cfe) 58.96 (s, 1H), 8.59 (s, 1H), 7.84 (s, 1H), 7.43 - 7.50 (m, 2H), 4.16 - 4.35 (m, 1H), 3.87 (s, 3H), 3.24 (s, 3H),Docket no. 24-2208-WON-S1 / Set B3.09 - 3.18 (m, 1H), 1.91 - 2.11 (m, 4H), 1.57 - 1.62 (m, 2H), 1.23 - 1.27 (m, 2H).19FNMR (282 MHz, DMSO-cfe) 6 -121.71.

[0286] Example 48: Synthesis of N-((1r,4r)-4-methoxycyclohexyl)-6-(1-methyl-1H-imidazol-5-yl)-8-(trifluoromethyl)pyrido[3,4-d]pyrimidin-4-amine

[0287] To a stirred solution of 6-(3-methylimidazol-4-yl)-8-(trifluoromethyl)pyrido[3,4-d]pyrimidin-4-ol (90 mg, 0.3 mmol, 1 eq), (1r,4r)-4-methoxycyclohexan-1-amine (236 mg, 1.8 mmol, 6 eq) and PyBOP (214 mg, 0.4 mmol, 1.3 eq) in DMF (2.5 mL) were added DIEA (47 mg, 0.3 mmol, 1.2 eq) and DBU (116 mg, 0.7 mmol, 2.5 eq) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80°C overnight under nitrogen atmosphere. The reaction mixture was purified by reverse-phase column: C18 column, mobile phase: MeCN in water (10mmol / L NH4HCO3), 10% to 30% gradient in 20 min; detector, UV 254 nm to afford N-((1r,4r)-4-methoxycyclohexyl)-6-(1-methyl-1H-imidazol-5-yl)-8-(trifluoromethyl)pyrido[3,4-d]pyrimidin-4-amine (9.6 mg, 8% yield) as a yellow solid. LC / MS: mass calcd. For C19H21F3N6O: 406.1, found: 407.2 [M+H]+.1HNMR (300 MHz, DMSO-cfe) 6 8.80 (s, 1 H), 8.59 (s, 1 H), 8.50 (d, J = 6.6 Hz, 1 H), 7.81 (s, 1 H), 7.59 (s, 1 H), 4.09 - 4.29 (m, 1H), 3.95 (s, 3H), 3.25 (s, 3H), 2.92 - 3.23(m, 1H), 1.97 - 2.17 (m, 4H), 1.35 - 1.55 (m, 2H), 1.15 - 1.35 (m, 2H).19FNMR (300 MHz, DMSO-cfe) 6 -62.99.

[0288] Example 49: Synthesis of N-((1r,4r)-4-(2,2-difluoroethoxy)cyclohexyl)-6-(1-methyl-1H-imidazol-5-yl)-8-(trifluoromethyl)pyrido[3,4-d]pyrimidin-4-amine

[0289] To a stirred solution of 6-(3-methylimidazol-4-yl)-8-(trifluoromethyl)pyrido[3,4-d]pyrimidin-4-ol (120 mg, 0.4 mmol, 1 eq) and (1r,4r)-4-(2,2-difluoroethoxy)cyclohexan-1-amine (87 mg, 0.5 mmol, 1.2 eq) in DMF (5 mL) was added DIEA (120 uL, 0.7 mmol, 1.7 eq),Docket no. 24-2208-WON-S1 / Set BDBU (120 uL, 0.8 mmol, 2 eq) and PyBOP (317 mg, 0.6 mmol, 1.5 eq) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80°C for 17h under nitrogen atmosphere. The mixture was allowed to cool to room temperature. The resulting mixture was diluted with water (50 mL) and extracted with EtOAc (3x 50 mL). The combined organic layers were washed with brine, then dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Column: XBridge C18 OBD Prep Column, 30*150 mm, 5 pm; Mobile Phase A: Water(10 mmoL / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 34%B to 54%B in 10min; Wavelength: 254 / 220 nm) to afford N-((1r,4r)-4-(2,2-difluoroethoxy)cyclohexyl)-6-(1-methyl-1H-imidazol-5-yl)-8-(trifluoromethyl)pyrido[3,4-d]pyrimidin-4-amine (40.6 mg, 21% yield) as a white solid. LC / MS: mass calcd. For C2oH2iF5N60: 456.2, found: 457.2 [M+H]+.1HNMR (300 MHz, DMSO-cfe) 58.81 (s, 1H), 8.60 (s, 1H), 8.51 (d, J = 7.4 Hz, 1H), 7.82 (s, 1H), 7.60 (s, 1H), 6.11 (t, J= 55.5 Hz, 1H), 4.09 -4.28 (m, 1H), 3.95 (s, 3H), 3.72 (t, J= 15.3 Hz, 2H), 3.38 - 3.61 (m, 1H), 1.95 - 2.18 (m, 4H), 1.40 - 1.57 (m, 2H), 1.21 - 1.40 (m, 2H).19FNMR (282 MHz, DMSO-d6) 5 -62.99, -125.11.

[0290] Example 50: Synthesis of 2-methoxy-1 -(7-((2-methyl-6-(1 -methyl-1 H-imidazol-5-yl)pyrido[3,4-d]pyrimidin-4-yl)amino)-2-azaspiro[3.5]nonan-2-yl)ethan-1-one

[0291] To a stirred solution of N-[2-methyl-6-(3-methylimidazol-4-yl)pyrido[3,4-d]pyrimidin-4-yl]-2-azaspiro [3.5] nonan-7-amine (60 mg, 0.1 mmol, 1eq) and methoxyacetic acid (22 mg, 0.2 mmol, 1.5eq) in DMF (2 mL) was added PyBOP (103 mg, 0.2 mmol, 1.2eq) and DIEA (52 mg, 0.4 mmol, 3eq) dropwise at 0°C. The resulting mixture was stirred at room temperature for 1h. The residue was purified by reverse-phase flash chromatography: C18 column; mobile phase, MeCN in Water (10 mmol / L NH4HCO3), 10% to 30% gradient in 20 min; detector, LIV 254 nm to afford 2-methoxy-1 -(7-((2-methyl-6-(1 -methyl-1 H-imidazol-5-yl)pyrido[3,4-d]pyrimidin-4-yl)amino)-2-azaspiro[3.5]nonan-2-yl)ethan-1-one (12.4 mg, 17% yield) as a white solid. LC / MS: mass calcd. for C23H29N7O2: 435.2, found: 436.2 [M+H]+.1HNMR (300 MHz, DMSO-cfe) 68.97 (s, 1H), 8.43 (d, J= 7.5 Hz, 1H), 8.00 - 8.14 (m, 1H), 7.77 (s, 1 H), 7.45 (s, 1 H), 4.09 - 4.27(m, 1 H), 3.86 - 3.96 (m, 6H), 3.81 (s, 1 H), 3.66 (s, 1 H), 3.55 (s, 1 H), 3.27 (d, J = 3.8 Hz, 3H), 2.47 (s, 2H), 1.85 - 1.99 (m, 4H), 1.52 - 1.66 (m, 2H), 1.35 - 1.48 (m, 2H).Docket no. 24-2208-WON-S1 / Set B

[0292] Example 51: Synthesis of 2-methyl-6-(1-methyl-1H-imidazol-5-yl)-N-((1r,4r)-4- (2,2,2-trifluoroethoxy)cyclohexyl)pyrido[3,4-d]pyrimidin-4-amine

[0293] To a stirred solution of 2-methyl-6-(3-methylimidazol-4-yl)pyrido[3,4-d]pyrimidin-4-ol (65 mg, 0.3 mmol, 1 eq) in DMF (3 mL) was added PyBOP (168 mg, 0.3 mmol, 1 eq), DBll (81 uL, 0.5 mmol, 2 eq), DIEA (56 uL, 0.3 mmol, 1 eq) and (1 r,4r)-4-(2,2,2-trifluoroethoxy)cyclohexan-1 -amine hydrochloride (69 mg, 0.3 mmol, 1 eq) at 0°C. The resulting mixture was stirred for 17h at 80°C under N2 atmosphere. The reaction was poured into water / ice (15 mL). The precipitated solids were collected by filtration and washed with H2O (3 x2 mL), then dried under vacuum. The residue was purified by Prep-HPLC: Column: XBridge BEH C18, 2.1*30mm, 2.5um; Mobile Phase A: water / 10mM NH4HCO3, Mobile Phase B: ACN; Flow rate: 60mL / min; Gradient (B%): 35% B to 55 % B in 10 min;Wavelength: 254 nm / 220 nm to afford 2-methyl-6-(1-methyl-1H-imidazol-5-yl)-N-((1r,4r)-4-(2,2,2-trifluoroethoxy)cyclohexyl)pyrido[3,4-d]pyrimidin-4-amine (19.0 mg, 17% yield) as a white solid. LC / MS: mass calcd. for C20H23F3N6O: 420.2, found: 421.2 [M+H]+.1HNMR (300 MHz, DMSO-cfe) 68.98 (s, 1 H), 8.45 (s, 1 H), 8.09 (d, J = 7.5 Hz, 1 H), 7.76 (s, 1 H), 7.45 (s, 1 H), 4.04 - 4.29 (m, 3H), 3.93 (s, 3H), 3.44 - 3.60 (m, 1H), 2.51 (s, 3H), 1.93 - 2.20 (m, 4H), 1.15 - 1.60 (m, 4H).19FNMR (282 MHz, DMSO-cfe) 6 -73.16.

[0294] Example 52: Synthesis of 6-(1-methyl-1H-imidazol-5-yl)-N-((1r,4r)-4-(trifluoromethoxy)cyclohexyl)pyrido[3,4-d]pyrimidin-4-amine

[0295] To a stirred solution of 6-(3-methylimidazol-4-yl)pyrido[3,4-d]pyrimidin-4-ol (100 mg, 0.4 mmol, 1 eq) in DMF (3 mL) was added PyBOP (274 mg, 0.5 mmol, 1.2 eq), DBU (134 mg, 0.9 mmol, 2 eq), DIEA (68 mg, 0.5 mmol, 1.2 eq) and (1 r,4r)-4-(trifluoromethoxy)cyclohexan-l-amine hydrochloride (106 mg, 0.5 mmol, 1.1 eq) at O°C. The resulting mixture was stirred for 17h at 80°C under N2 atmosphere. The reaction was pouredDocket no. 24-2208-WON-S1 / Set Binto water / ice (15 mL). The precipitated solids were collected by filtration and washed with H2O (3 x2 mL), dried under vacuum. The residue was purified by Prep-HPLC (Column: XBridge Prep C18 OBD Column, 30*150 mm, 5pm; Mobile Phase A: water (10mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 27% B to 52% B in 10min; Wavelength: 254 nm) to afford 6-(1-methyl-1H-imidazol-5-yl)-N-((1r,4r)-4-(trifluoromethoxy)cyclohexyl)pyrido[3,4-d]pyrimidin-4-amine (33.7 mg, 20% yield) as a white solid. LC / MS: mass calcd. for C20H23F3N6O: 420.2, found: 421.2 [M+H]+.1HNMR (300 MHz, DMSO-cfe) 69.08 (s, 1 H), 8.50 - 8.60 (m, 2H), 8.28 (d, J = 7.5 Hz, 1 H), 7.78 (s, 1 H), 7.49 (s, 1H), 4.39 - 4.55 (m, 1H), 4.11 - 4.29 (m, 1H), 3.95 (s, 3H), 1.99 - 2.21 (m, 4H), 1.47 - 1.79 (m, 4H).19FNMR (282 MHz, DMSO-cfe) 655.88.

[0296] Example 53: Synthesis of N-((1r,4r)-4-(2,2-difluoroethoxy)cyclohexyl)-6-(1-methyl-1H-imidazol-5-yl)pyrido[3,4-d]pyrimidin-4-amine

[0297] To a stirred solution of 6-(3-methylimidazol-4-yl)pyrido[3,4-d]pyrimidin-4-ol (70 mg, 0.3 mmol, 1 eq) in DMF (2 mL) was added DIEA (64 uL, 0.4 mmol, 1.2 eq), (1 r,4r)-4-(2,2-difluoroethoxy)cyclohexan-1-amine (83 mg, 0.5 mmol, 1.5 eq), DBU (92 uL, 0.6 mmol, 2 eq) and PyBOP (192 mg, 0.4 mmol, 1.2 eq) at 0°C. The resulting mixture was stirred for 17h at 80°C. The resulting mixture was poured into ice water (10 mL). The precipitated solids were collected by filtration and washed with water (5 mL), dried under vacuum. The crude product was purified by Prep-HPLC (Column: XBridge BEH Shield RP18 Column, 30*150 mm, 5 pm; Mobile Phase A: water (10 mmoL / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 24% B to 37% B in 10 min; Wavelength: 254 / 220 nm) to afford N-((1r,4r)-4-(2,2-difluoroethoxy)cyclohexyl)-6-(1-methyl-1H-imidazol-5-yl)pyrido[3,4-d]pyrimidin-4-amine (24.2 mg, 20% yield) as a white solid. LC / MS: mass calcd. for C19H22F2N6O: 388.18, found: 389.15 [M+H]+.1HNMR (300 MHz, DMSO-cfe) 59.06 (s, 1H), 8.54 (s, 1H), 8.49 (s, 1H), 8.23 (d, J = 7.6 Hz, 1 H), 7.76 (s, 1 H), 7.47 (s, 1 H), 5.90 - 6.33 (m, 1 H), 4.08 - 4.25 (m, 1 H), 3.93 (s, 3H), 3.61 - 3.80 (m, 2H), 3.36 - 3.49 (m, 1H), 1.97 - 2.13 (m, 4H), 1.18 - 1.55 (m, 4H).19FNMR (282 MHz, DMSO-cfe) 5 -125.09.Docket no. 24-2208-WON-S1 / Set B

[0298] Example 54: Human CD38 Colorimetric Assay

[0299] A base exchange based colorimetric assay is used to assess the compounds for CD38 transglycosidation inhibiting activity. The assay is performed in 384-well plates (Greiner UV-Star, Flat bottom, clear plates) in a total volume of 30 pL. The compounds to be tested are dispensed using ECHO Acoustic liquid handler (10-point dose response with top concentration at 10 pM, 0.5% DMSO final concentration). The test compounds are incubated with CD38 enzyme (BPS Biosciences) in a buffer comprising 50 mM HEPES, pH 7.4, 1 mM CHAPS, and 1 mM EDTA for a duration of 15 minutes. The reaction is initiated by addition of 15 pL of Nicotinamide Adenosine dinucleotide (NAD, Sigma) and GW323434. The enzyme and substrate are prepared at 2X concentration and the final concentrations in the assay are 2 nM CD38, 100uM NAD and 50 pM GW323434. The CD38 enzyme catalyses the exchange of the nicotinamidyl moiety of NAD+ with an alternative base (GW323434) resulting in the formation of a novel chromophore that absorbs at 405nm. The absorbance is monitored at 405 nm every 135 s for 1 hour on a BMG Pherastar FSX. Genedata Screener is used for data analysis. Plotting the initial velocity of the reaction (5-50 minutes of reaction) at each compound concentration led to the generation of a dose response which is fitted to a four-parameter logistic equation to generate IC50 values. Similarly, the assay can be run in a 96-well plate format using identical conditions except that the total reaction volume is scaled up from 30 pL to 300 pL. The results of this assay are summarized below in Table 1.

[0300] Table tA: IC50 < 20 nM; B: IC50 - 20 nM and < 125 nM; C: IC50 > 125 nM and < 1250 nM; D: IC50 > 1250 nM.Docket no. 24-2208-WON-S1 / Set B53 AAll of the references cited herein are incorporated by reference. Aspects of the disclosure can be modified, if necessary, to employ the systems, functions, and concepts of the above references and application to provide yet further embodiments of the disclosure. These and other changes can be made to the disclosure in light of the detailed description.

[0301] Specific elements of any foregoing embodiments can be combined or substituted for elements in other embodiments. Moreover, the inclusion of specific elements in at least some of these embodiments may be optional, wherein further embodiments may include one or more embodiments that specifically exclude one or more of these specific elements.

[0302] Furthermore, while advantages associated with certain embodiments of the disclosure have been described in the context of these embodiments, other embodiments may also exhibit such advantages, and not all embodiments need necessarily exhibit such advantages to fall within the scope of the disclosure.

[0303] It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be incorporated within the spirit and purview of this application and scope of the appended claims.

Claims

Docket no. 24-2208-WON-S1 / Set BWhat is claimed is:

1. A compound of formula (I)or a pharmaceutically acceptable salt thereof, whereinR1is a 5- to 10-membered heteroaryl group optionally substituted with one or more independently selected R2, where each R2is (i) Ci-Ce alkyl, (ii) C3-Cs cycloalkyl, (iii) C3-C6cycloalkyl(Ci-C2alkyl), (iv) Ci-C6haloalkyl, (v) Ci-C6alkoxy(Co-Ce alkyl), (vi) halogen, (vii) -OR15, (viii) -NR16R17, (ix) -CN, or (x) -NO2;R15is H, Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6alkoxy(Ci-C6alkyl), or Cs-Cs cycloalkyl;R16is H or Ci-Ce alkyl; andR17is H, Ci-C6alkyl;R4is H or Ci-Ce alkyl;R5is 4- to 13-membered heterocyclyl(Co-C2alkyl), C3-Ci2cycloalkyl(Co-C2alkyl), aryl(C0-C6alkyl), 8- to 12-membered spirocyclyl(C0-C2alkyl), or 5- or 6- membered heteroaryl(Co-C6 alkyl), each of which is optionally substituted on a cyclic portion thereof with one or more independently selected R3, where each R3is (i) Ci-Ce alkyl, (ii) Ci-Ce haloalkyl, (iii) Ci-Ce alkoxy, (iv) halogen, (v) -SO2(Ci-Ce alkyl), (vi) -SO2(C3-Cs cycloalkyl), (vii) -NHSO2(CI-CS alkyl), (viii) -NHSO2(C3-C8cycloalkyl), (ix) -CO2(Ci-C6alkyl), (x) oxo, (xi) -OR57, (xii) -CN, (xiii) -C(O)R58, (xiv) -(C0-C4 alkyl) R59, (xv) -C(O)R62, (xvi) 4- to 8- membered heterocyclyl optionally substituted with one or more independently selected Ci-C6alkyl or halogen groups, or (xvii) (Cs-Cs cycloalkyl) optionally substituted with one or more independently selected Ci-C6alkyl or halogen groups;R57is H, Ci-C6alkyl, -(CH2CH2O)I-2(CI-C6alkyl), Ci-C6haloalkyl, Cs-Cs cycloalkyl(C0-C2alkyl), 4- to 8-membered heterocyclyl (Co-C2alkyl), or 5- or 6-membered heteroarylDocket no. 24-2208-WON-S1 / Set Boptionally substituted with one or more independently selected Ci-C6alkyl, halogen, or Ci-C6alkoxy groups;R58and R59are each independently -NR60R61whereinR60is H or C1-C6 alkyl; andR61is -SO2(Ci-C6alkyl) or Ci-C6haloalkyl;R62is C1-C6 alkyl optionally substituted with one Ci-Ce alkoxy; R6is H, halogen, Ci-Ce alkyl, C3-C6 cycloalkyl, Ci-Ce haloalkyl, orCi-Ce alkoxy; R7is H, Ci-Ce alkyl, C3-C6 cycloalkyl, or -NR8R9where R8and R9are each independently H or Ci-Ce alkyl; andR10is H, halogen, C1-C3 haloalkyl or C1-C3 alkyl.

2. A compound according to claim 1, which has the formula (la)3. A compound according to any one of claims 1-2, wherein R1is a 5-membered heteroaryl group containing at least one nitrogen and the heteroaryl is optionally substituted with 1 or 2 R2.

4. A compound according to claim 1 or claim 2, wherein R1is a 5-membered heteroaryl group containing one nitrogen and one sulfur or oxygen, and the heteroaryl is optionally substituted with 1 or 2 R2.

5. A compound according to claim 1 or claim 2, wherein R1is pyrrolyl, thiazolyl, imidazolyl, pyrazolyl, oxazoly or isoxazolyl, each of which is optionally substituted with 1 or 2 R2.

6. A compound according to any one of claims 1-5, wherein R5is C3-C12 cycloalkyl(Co-C2 alkyl), and R5is optionally substituted with 1-3 of R3.

7. A compound according to claim 6, wherein R5is cycloalkyl optionally substituted with 1, 2 or 3 of R3.Docket no. 24-2208-WON-S1 / Set B8. A compound according to claim 7, wherein R5is a group of the formula (Ila):wherein n is 0 or 1.

9. A compound according to claim 7, wherein R5is a group of the formula (lib):wherein n is 0 or 1.

10. A compound according to claim 7, wherein R5is a group of the formula (He) or (lid):wherein n is 0 or 1.

11. A compound according to claim 7, wherein R5is a group of the formula (He):wherein n is 0 or 1.Docket no. 24-2208-WON-S1 / Set B12. A compound according to claim 7, wherein R5is a group of the formula (Illa):whereinR3ais H, halogen, or -OH;n is 0, 1 or 2; andp is 1 or 2.

13. A compound according to any one of claims 1-5, wherein R5is aryl(Co-Ce alkyl), and R5is optionally substituted with 1-3 of R3.

14. A compound according to any one of claims 1-5, wherein R5is 5- or 6-membered heteroaryl(Co-Ce alkyl), and R5is optionally substituted with 1-3 of R3.

15. A compound according to claim 14, wherein R5is a group of the formula (IVa):whereinX, Y and Z independently represent nitrogen, C-H or C-R3, provided that no more than one of X, Y and Z is nitrogen; andn is 0 or 1.

16. A compound according to claim 15, wherein n is 1 and Y is N.

17. A compound according to claim 15, wherein R5is a group of the formula (IVb) or (IVc):Docket no. 24-2208-WON-S1 / Set Bwherein n is 0 or 1.

18. A compound according to claim 15, wherein R5is a group of the formula (IVd) or (IVe):(IVd) (IVe) wherein n is 0 or 1.

19. A compound according to any one of claims 1-5, wherein R5is a bicyclic C8-C12 cycloalkyl(Co-C2 alkyl) where the rings share at least 2 atoms, and R5is optionally substituted with 1-3 of R3.

20. A compound according to claim 19, wherein R5is a group of the formula (Va):whereinR3ais H, halogen, or -OH;n is 0 or 1; andm is 0, 1 or 2.

21. A compound according to claim 19, wherein R5is a group of the formula (Vb):Docket no. 24-2208-WON-S1 / Set Bwhereinp is 1 or 2; andeach of m1, m2, and m3are independently 0 or 1.

22. A compound according to any one of claims 1-5, wherein R5is a 8- to 12-membered spirocyclyl(Co-C2 alkyl) which is optionally substituted with 1-3 of R3.

23. A compound according to claim 22, wherein R5is a group of the formula (Vila):whereinRing A has from 3-5 ring members, one ring member of which is optionally a heteroatom selected from sulfur, oxygen, and nitrogen;n is 0 or 1;m is 0, 1 or 2; andp is 0, 1, or 2.

24. A compound according to any one of claims 1-5, wherein R5is a 4- to 13-membered heterocyclyl(Co-C2 alkyl), and R5is optionally substituted with 1-3 of R3.

25. A compound according to claim 24, wherein R5is a group of the Formula (Via):wherein m1and m2are each independently an integer of 0, 1 , or 2;p is an integer of 0, 1 , or 2;Docket no. 24-2208-WON-S1 / Set Bn is an integer of 0, 1 , or 2;Z is N-H, N-R31, sulfur, or oxygen ; andR31is H, Ci-C6alkyl, Ci-C6haloalkyl, -SO2(Ci-C6alkyl), -SO2(C3-C8cycloalkyl), or 4- to 8-membered heterocyclyl optionally substituted with one or more independently selected Ci-C6alkyl or halogen groups.

26. A compound according to any one of claims 1-25, wherein each R3is independently halogen, -OR57, -NHSO2(CI-C6alkyl), -NHSO2(C3-C8cycloalkyl), Ci-C6haloalkyl, -SO2(C C6alkyl), Ci-C6alkyl, oxo, -C(O)R58, -(C0-C4alkyl)R59, -C(O)R62, 4- to 8-membered heterocyclyl optionally substituted with one or more independently selected Ci-C8alkyl or halogen groups, or (C3-C8cycloalkyl) optionally substituted with one or more independently selected Ci-C8alkyl or halogen group.

27. A compound according to any one of claims 1-26, wherein R1is substituted with one R2.

28. A compound according to any one of claims 1-26, wherein R1is substituted with two R2.

29. A compound according to any one of claims 1-28, wherein R2is methyl, ethyl, propyl, isopropyl, fluoro, chloro, methoxy, ethoxy, or cyano.

30. A compound according to any one of claims 1-28, wherein R2methyl, ethyl, fluoro, methoxy or cyano.

31. A compound according to any one of claims 1 -30, wherein R6is Ci-C8alkoxy.

32. A compound according to any one of claims 1-30, wherein R6is Ci-C8haloalkyl.

33. A compound according to any one of claims 1-30, wherein R6is hydrogen, methoxy, or trifluoromethyl.

34. A compound according to any one of claims 1-33, wherein R7is Ci-C8alkyl.

35. A compound according to any one of claims 1-33, wherein R7is methyl, ethyl, propyl or isopropyl.Docket no. 24-2208-WON-S1 / Set B36. A compound according to any one of claims 1-32, wherein R7is C3-C6 cycloalkyl.

37. A compound according to any one of claims 1-32, wherein R7is cyclopropyl.

38. A compound according to any one of claims 1-33, wherein R7is hydrogen, methyl, cyclopropyl.

39. A compound according to any one of claims 1-38, wherein R10is H.

40. A compound according to any one of claims 1-38, wherein R10is halogen.

41. A compound according to any one of claims 1 -38, wherein R10is fluorine.

42. A compound according to any one of claims 1-38, wherein R10is C1-C3 alkyl or C1-C3 haloalkyl.

43. A compound according to any one of claims 1-38, wherein R10is methyl or trifluoromethyl.

44. A compound according to any one of claims 1-43, wherein R1is thiazolyl.

45. A compound according to any one of claims 1-43, wherein R1is imidazolyl.

46. A compound according to any one of claims 1-43, wherein R1is pyrrolyl.

47. A compound according to any one of claims 1-43, wherein R1is pyrazolyl.

48. A compound according to any one of claims 1-43, wherein R1is oxazolyl.

49. A compound according to any one of claims 1-43, wherein R1is isoxazolyl.

50. A compound according to any one of claims 1-43, wherein R1is thiazol-5-yl, imidazol- 5-yl or imidazol-1-yl, each of which is optionally substituted.

51. A compound according to any one of claims 1-43, wherein R1is imidazol-5-yl substituted with one or two R2.Docket no. 24-2208-WON-S1 / Set B52. A compound according to claim 51 , wherein the imidazol-5-yl is substituted with one R2, and R2is methyl, ethyl, propyl, isopropyl, fluoro, chloro, methoxy, ethoxy, or cyano.

53. A compound according to claim 51 or claim 52, wherein R2is methyl, ethyl, fluoro, methoxy or cyano.

54. A compound according to claim 51 or claim 52, wherein R2is methyl.

55. A compound according to any one of claims 1-43, wherein R1is 1-methyl-1 H-imidazol-5-yl.

56. A compound according to any one of claims 1-55, wherein R4is H, methyl or ethyl.

57. A compound according to any one of claims 1-55, wherein R4is H or methyl.

58. A compound according to any one of claims 1-55, wherein R4is H.

59. A compound of formula (la)or a pharmaceutically acceptable salt thereof, whereinR1is a 5- to 10-membered heteroaryl group optionally substituted with one or more independently selected R2, where each R2is where each R2is (i) Ci-Ce alkyl, (ii) C3-C8 cycloalkyl, (iii) C3-C6 cycloalkyl(Ci-C2 alkyl), (iv) Ci-Ce haloalkyl, (v) Ci-Ce alkoxy(Co-Ce alkyl), (vi) halogen, (vii) -OR15, (viii) -NR16R17, (ix) -CN, or (x) -NO2;R15is H, C1-C6 alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy(Ci-Ce alkyl), or C3-C8cycloalkyl;R16is H or Ci-Ce alkyl; andR17is H, Ci-C6alkyl;R4is H or Ci-C6alkyl;Docket no. 24-2208-WON-S1 / Set BR5is an 8- to 12-membered spirocyclyl(Co-C2 alkyl) or a C3-C12 cycloalkyl(Co-C2 alkyl), each of which is optionally substituted on a cyclic portion thereof with one or more independently selected R3, where each R3is (i) Ci-C8alkyl, (ii) C1-C6 haloalkyl, (iii) Ci-C8alkoxy, (iv) halogen, (v) -SO2(Ci-C8alkyl), (vi) -SO2(C3-C8cycloalkyl), (vii) -NHSO2(CI-C6alkyl), (viii) -NHSO2(C3-C8cycloalkyl), (ix) -CO2(Ci-C8alkyl), (x) oxo, (xi) -OR57, (xii) -CN, (xiii) -C(O)R58, (xiv) -(C0-C4 alkyl)R59, (xv) -C(O)R62, (xvi) 4- to 8-membered heterocyclyl optionally substituted with one or more independently selected Ci-C8alkyl or halogen groups, or (xvii) (C3-C8cycloalkyl) optionally substituted with one or more independently selected Ci-C8alkyl or halogen groups;R57is H, Ci-C6alkyl, or-(CH2CH2O)i-2(Ci-C6 alkyl) , Ci-C6haloalkyl, C3-C8cycloalkyl(Co-C2 alkyl), 4-to 8-membered heterocyclyl (C0-C2 alkyl), or 5- or 6-membered heteroaryl optionally substituted with one or more independently selected Ci-C8alkyl, halogen, or Ci-C8alkoxy groups;R58and R59are each independently -NR60R61whereinR60is H or Ci-C8alkyl; andR61is - SO2(Ci-C8alkyl) or Ci-C8haloalkyl;R62is Ci-C6alkyl optionally substituted with one Ci-C6alkoxy; R6is H, Ci-C8alkyl, Ci-C8haloalkyl, or Ci-C8alkoxy; andR7is H, Ci-C8alkyl, orC3-C8cycloalkyl; andR10is H, halogen, Ci-C3haloalkyl or Ci-C3alkyl.

60. A compound according to claim 59, wherein R1is imidazol-5-yl or imidazol-1-yl, each of which is optionally substituted with one or more independently selected R2.

61. A compound according to claim 60, wherein R1is substituted with one R2and R2is Ci-C8alkyl, C3-C6 cycloalkyl or C3-C6 cycloalkyl(Ci-C2)alkyl.

62. A compound according to claim 60 or claim 61, wherein R2is C1-C3 alkyl, cyclopropyl or cyclopropylmethyl.

63. A compound according to claim 60 or claim 61, wherein R2is methyl, ethyl, propyl or isopropyl.Docket no. 24-2208-WON-S1 / Set B64. A compound according to claim 60 or claim 61 , wherein R1is 1-methyl-1 H-imidazol-5- yi.

65. A compound according to any one of claims 59-64, wherein R5is a 8- to 12- membered spirocyclyl(Co-C2 alkyl) which is optionally substituted with 1-3 of R3.

66. A compound according to claim 65, wherein R5has the formula (Vila):whereinRing A has from 3-5 ring members, one ring member of which is optionally a heteroatom selected from sulfur, oxygen, or nitrogen;n is 0 or 1;m is 0, 1 or 2; ando1and o2are each independently 0 or 1 ; andp is 0, 1, or 2.

67. A compound according to claim 66, wherein R3is Ci-Ce haloalkyl, -SO2(Ci-Ce alkyl) (e.g., -SO2Me), -SO2(C3-C8cycloalkyl), or-C(O)R62.

68. A compound according to claim 66 or claim 67, wherein n is 0.

69. A compound according to any of claims 66-68, wherein R5is:Docket no. 24-2208-WON-S1 / Set B70. A compound according to any one of claims 59-64, wherein R5is a group of the formula (Ila):wherein n is 0 or 1.

71. A compound according to claim 70, wherein R5is:

72. A compound according to any one of claims 59-64, wherein R5is a group of the formula (lib):wherein n is 0 or 1.

73. A compound according to any one of claims 59-64, wherein R5is a group of the formula (He) or (lid):wherein n is 0 or 1.

74. A compound according to claim 72 or claim 73, wherein n is 0 and R3is -SO2(Ci-Ce alkyl).Docket no. 24-2208-WON-S1 / Set B75. A compound according to claim 72 or claim 73, wherein n is 0 and R3is -OR57and R57is H, Ci-Ce alkyl, -(CH2CH2O)I-2(CI-C6 alkyl), Ci-Ce haloalkyl, Cs-Cs cycloalkyl(Co-C2 alkyl), or 5- or 6-membered heteroaryl optionally substituted with 1 , 2, or 3 independently selected Ci-Ce alkyl.

76. A compound according to claim 72 or claim 73, wherein n is 0 and R3is -(CoC4)59.

77. A compound according to claim 72 or claim 73, wherein R5is:

78. A compound according to claim 72 or claim 73, wherein n is 0 and R3is 4- to 8- membered heterocyclyl optionally substituted with 1, 2, or 3 independently selected halogen groups.

79. A compound according to claim 72 or claim 73, wherein R5is:

80. A compound according to claim 72 or claim 73, wherein n is 1 and at least one R3is halogen.

81. A compound according to claim 72 or claim 73, wherein R5is:-HI-Docket no. 24-2208-WON-S1 / Set B82. A compound according to any one of claims 59-64, wherein R5is a group of the formula (He):wherein n is 0 or 1.

83. A compound according to claim 82, wherein R5is:

84. A compound according any one of claims 59-64, wherein R5is a group of the formula (Illa):whereinR3ais H, halogen or -OH;n is 0, 1 or 2; andp is 1 or 2.

85. A compound according to claim 84, whereinR3ais fluoro; andn is 0.Docket no. 24-2208-WON-S1 / Set B86. A compound according to claim 84, wherein R5is:

87. A compound according to any one of claims 59-64, wherein R5is a group of the formula (Vb):whereinp is 1 or 2; andeach of m1, m2, and m3are independently 0 or 1.

88. A compound according to claim 87, wherein R5is:

89. A compound according to claim 59-64, wherein R5is a group of the Formula (Via):wherein m1and m2are each independently 0, 1, or 2;p is 0, 1, or 2;n is 0, 1, or 2;Z is N-H, N-R31, sulfur, or oxygen ; andR31is H, Ci-C6alkyl, Ci-C6haloalkyl, -SO2(Ci-C6alkyl), -SO2(C3-C8cycloalkyl), or 4- to 8-membered heterocyclyl optionally substituted with one or more independently selected Ci-Ce alkyl or halogen groups.Docket no. 24-2208-WON-S1 / Set B90. A compound according to claim 89, wherein R5is:

91. A compound according to any one of claims 59-90, wherein R4is H, methyl or ethyl.

92. A compound according to any one of claims 59-90, wherein R4is H or methyl.

93. A compound according to any one of claims 59-90, wherein R4is H.

94. A compound according to any one of claims 59-93, wherein R6is H, Ci-Ce haloalkyl, or Ci-Ce alkoxy.

95. A compound according to any one of claims 59-93, wherein R6is H, trifluoromethyl, or methoxy96. A compound according to any one of claims 59-95, wherein R7is H, Ci-Ce alkyl, or C3-C6 cycloalkyl.

97. A compound according to any one of claims 59-95, wherein R7is H, methyl, or cyclopropyl.

98. A compound according to any one of claims 59-97, wherein R10is H or halogen.

99. A compound according to any one of claims 59-97, wherein R10is H or fluorine.

100. A compound according to any one of claims 59-97, wherein R10is H.

101. A compound according to claim 1, which is:N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-(1 -methyl-1 H-imidazol-5- yl)pyrido[3,4-d]pyrimidin-4-amine;N-((1 r,4r)-4-((6-( 1 -methyl-1 H-imidazol-5-yl)pyrido[3,4-d]pyrimidin-4- yl)amino)cyclohexyl)methanesulfonamide;Docket no. 24-2208-WON-S1 / Set BN-((1 r,4r)-4-methoxycyclohexyl)-6-(1 -methyl-1 H-imidazol-5-yl)pyrido[3,4- d]pyrimidin-4-amine;6-(1 -methyl-1 H-imidazol-5-yl)-N-(2-azaspiro[3.5]nonan-7-yl)pyrido[3, 4- d]pyrimidin-4-amine;6-(1 -methyl-1 H-imidazol-5-yl)-N-(2-(methylsulfonyl)-2-azaspiro[3.5]nonan- 7-yl)pyrido[3,4-d]pyrimidin-4-amine;6-(1 H-imidazol-1 -y I )-N -(( 1 r,4r)-4-methoxycyclohexyl)pyrido[3,4- d]pyrimidin-4-amine;6-(1 H-imidazol-1 -y I )-N -(( 1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)pyrido[3,4- d]pyrimidin-4-amine;N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-(thiazol-5-yl)pyrido[3,4- d]pyrimidin-4-amine;N-((1r,4r)-4-methoxycyclohexyl)-6-(thiazol-5-yl)pyrido[3,4-d]pyrimidin-4- amine;N-((1 r,4r)-4-methoxycyclohexyl)-2-methyl-6-(1 -methyl-1 H-imidazol-5- yl)pyrido[3,4-d]pyrimidin-4-amine;N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-2-methyl-6-(1 -methyl-1 H- imidazol-5-yl)pyrido[3,4-d]pyrimidin-4-amine;8-methoxy-N-((1 r,4r)-4-methoxycyclohexyl)-6-(1 -methyl-1 H-imidazol-5- yl)pyrido[3,4-d]pyrimidin-4-amine;8-methoxy-N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-(1 -methyl-1 H- imidazol-5-yl)pyrido[3,4-d]pyrimidin-4-amine;6-(1 -methyl-1 H-imidazol-5-yl)-N-((1 S,2R)-2-methylcyclohexyl)pyrido[3,4- d]pyrimidin-4-amine;N-((1 -fluorocyclohexyl)methyl)-6-(1 -methyl-1 H-imidazol-5-yl)pyrido[3,4- d]pyrimidin-4-amine;6-(1 -methyl-1 H-imidazol-5-yl)-N-(2-(2,2,2-trifluoroethyl)-2- azaspiro[3.5]nonan-7-yl)pyrido[3,4-d]pyrimidin-4-amine;6-(1 -methyl-1 H-imidazol-5-yl)-N-((1 r,4r)-4- (methylsulfonyl)cyclohexyl)pyrido[3,4-d]pyrimidin-4-amine;4-((6-(1 -methyl-1 H-imidazol-5-yl)pyrido[3,4-d]pyrimidin-4- yl)amino)tetrahydro-2H-thiopyran 1 , 1 -dioxide;7-((6-(1 -methyl-1 H-imidazol-5-yl)pyrido[3,4-d]pyrimidin-4-yl)amino)-2- thiaspiro[3.5]nonane 2,2-dioxide;Docket no. 24-2208-WON-S1 / Set B2-methyl-6-(1 -methyl-1 H-imidazol-5-yl)-N-((3-methyloxetan-3- yl)methyl)pyrido[3,4-d]pyrimidin-4-amine;4-((2-methyl-6-(1 -methyl-1 H-imidazol-5-yl)pyrido[3,4-d]pyrimidin-4- yl)amino)tetrahydro-2H-thiopyran 1 , 1 -dioxide;N-(4,4-difluorocyclohexyl)-2-methyl-6-(1 -methyl-1 H-imidazol-5- yl)pyrido[3,4-d]pyrimidin-4-amine;N-((3-fluorobicyclo[1.1 ,1]pentan-1-yl)methyl)-2-methyl-6-(1 -methyl-1 H- imidazol-5-yl)pyrido[3,4-d]pyrimidin-4-amine;N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-(1 -methyl-1 H-imidazol-5-yl)- 8-(trifluoromethyl)pyrido[3,4-d]pyrimidin-4-amine;6-(1 H-imidazol-1 -y I )-N -( 1 -(3-methyloxetan-3-yl)piperidin-4-yl)pyrido[3,4- d]pyrimidin-4-amine;2-methyl-6-(1 -methyl-1 H-imidazol-5-yl)-N-((1 r,4r)-4-(oxetan-3- ylmethoxy)cyclohexyl)pyrido[3,4-d]pyrimidin-4-amine;N-((1 r,4r)-4-(2,2-difluoroethoxy)cyclohexyl)-2-methyl-6-(1 -methyl-1 H- imidazol-5-yl)pyrido[3,4-d]pyrimidin-4-amine;2-methyl-6-(1 -methyl-1 H-imidazol-5-yl)-N-(1 -(3-methyloxetan-3- yl)piperidin-4-yl)pyrido[3,4-d]pyrimidin-4-amine;N-((1 r,4r)-4-(cyclopropylmethoxy)cyclohexyl)-2-methyl-6-(1 -methyl-1 H- imidazol-5-yl)pyrido[3,4-d]pyrimidin-4-amine;2-methyl-6-(1 -methyl-1 H-imidazol-5-yl)-N-(2-oxaspiro[3.5]nonan-7- yl)pyrido[3,4-d]pyrimidin-4-amine;2-methyl-6-(1 -methyl-1 H-imidazol-5-yl)-N-((1 r,4r)-4-((1 -methyl-1 H- pyrazol-4-yl)oxy)cyclohexyl)pyrido[3,4-d]pyrimidin-4-amine;N-((1 R,3R)-3-(2-methoxyethoxy)cyclopentyl)-2-methyl-6-(1 -methyl-1 H- imidazol-5-yl)pyrido[3,4-d]pyrimidin-4-amine;(1 r,4r)-N 1 -(2-methyl-6-(1 -methyl-1 H-imidazol-5-yl)pyrido[3,4-d]pyrimidin- 4-yl)-N4-(2,2,2-trifluoroethyl)cyclohexane-1,4-diamine;N-((1 r, 4r)-4-(3, 3-difluoropy rrolidin-1 -yl)cyclohexyl)-2-methyl-6-(1 -methyl- 1H-imidazol-5-yl)pyrido[3,4-d]pyrimidin-4-amine;N-((1 s,4s)-4-methoxycyclohexyl)-2-methyl-6-(1 -methyl-1 H-imidazol-5- yl)pyrido[3,4-d]pyrimidin-4-amine;N-(2-(3,3-difluorocyclobutyl)-2-azaspiro[3.5]nonan-7-yl)-2-methyl-6-(1- methyl-1H-imidazol-5-yl)pyrido[3,4-d]pyrimidin-4-amine;Docket no. 24-2208-WON-S1 / Set BN-((1r,4r)-4-(3,3-difluoroazetidin-1-yl)cyclohexyl)-2-methyl-6-(1-methyl- 1H-imidazol-5-yl)pyrido[3,4-d]pyrimidin-4-amine;2-methyl-6-(1 -methyl-1 H-imidazol-5-yl)-N-(1 -(2 , 2 , 2-trifl uoroethy I ) pi peri d i n- 4-yl)pyrido[3,4-d]pyrimidin-4-amine;2-methyl-6-(1 -methyl-1 H-imidazol-5-yl)-N-((1 r,4r)-4- (trifluoromethoxy)cyclohexyl)pyrido[3,4-d]pyrimidin-4-amine; N-((1 r,4r)-4-isopropoxycyclohexyl)-2-methyl-6-(1 -methyl-1 H-imidazol-5- yl)pyrido[3,4-d]pyrimidin-4-amine;2-methyl-6-(1 -methyl-1 H-imidazol-5-yl)-N-((1 r,4r)-4-(pyrazin-2- yloxy)cyclohexyl)pyrido[3,4-d]pyrimidin-4-amine;2-cyclopropyl-N-((1 r,4r)-4-methoxycyclohexyl)-6-(1 -methyl-1 H-imidazol-5- yl)pyrido[3,4-d]pyrimidin-4-amine;2-cyclopropyl-N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-6-(1 -methyl-1 H- imidazol-5-yl)pyrido[3,4-d]pyrimidin-4-amine;2-cyclopropyl-N-((1 r,4r)-4-(3,3-difluoroazetidin-1 -yl)cyclohexyl)-6-(1 - methyl-1 H-imidazol-5-yl)pyrido[3,4-d]pyrimidin-4-amine;N-((1 r,4r)-4-methoxycyclohexyl)-2-methyl-6-(1 -methyl-1 H-imidazol-5-yl)-8- (trifluoromethyl)pyrido[3,4-d]pyrimidin-4-amine;N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-2-methyl-6-(1 -methyl-1 H- imidazol-5-yl)-8-(trifluoromethyl)pyrido[3,4-d]pyrimidin-4-amine;5-fluoro-N-((1 r,4r)-4-methoxycyclohexyl)-6-(1 -methyl-1 H-imidazol-5- yl)pyrido[3,4-d]pyrimidin-4-amine;N-((1 r,4r)-4-methoxycyclohexyl)-6-(1 -methyl-1 H-imidazol-5-yl)-8- (trifluoromethyl)pyrido[3,4-d]pyrimidin-4-amine;N-((1 r,4r)-4-(2,2-difluoroethoxy)cyclohexyl)-6-(1 -methyl-1 H-imidazol-5-yl)- 8-(trifluoromethyl)pyrido[3,4-d]pyrimidin-4-amine;2-methoxy-1 -(7-((2-methyl-6-(1 -methyl-1 H-imidazol-5-yl)pyrido[3,4- d]pyrimidin-4-yl)amino)-2-azaspiro[3.5]nonan-2-yl)ethan-1-one;2-methyl-6-(1 -methyl-1 H-imidazol-5-yl)-N-((1 r,4r)-4-(2,2,2- trifluoroethoxy)cyclohexyl)pyrido[3,4-d]pyrimidin-4-amine;6-(1 -methyl-1 H-imidazol-5-yl)-N-((1 r,4r)-4- (trifluoromethoxy)cyclohexyl)pyrido[3,4-d]pyrimidin-4-amine; N-((1 r,4r)-4-(2,2-difluoroethoxy)cyclohexyl)-6-(1 -methyl-1 H-imidazol-5- yl)pyrido[3,4-d]pyrimidin-4-amine; ora pharmaceutically acceptable salt thereof.Docket no. 24-2208-WON-S1 / Set B102. A pharmaceutical composition, comprising a therapeutically effective amount of a compound as described in any one of claims 1-101 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.

103. A method of treating a disease, disorder, or condition mediated by CD38 activity in a subject in need thereof, comprising administering to the subject an effective amount of a compound of any one of claims 1-101, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 102.

104. The method of claim 103, wherein the disease, disorder, or condition is selected from the group consisting of cancer, a hyperproliferative disease or condition, an inflammatory disease or condition, an autoimmune disease, a metabolic disorder, a cardiac disease or condition, chemotherapy induced tissue damage, a renal disease, a metabolic disease, a vascular disease, a fibrotic disease, a neurological disease or injury, a neurodegenerative disorder or disease, diseases caused by impaired stem cell function, diseases caused by DNA damage, diseases caused by hypoxia or ischemia / reperfusion injury, primary mitochondrial disorders, a muscle disease, a muscle wasting disorder, and diseases of aging where restoration of NAD restores cellular homeostasis and metabolism, including preservation of fertility.

105. The method of claim 103, wherein the disease, disorder, or condition is group consisting of obesity, atherosclerosis, insulin resistance, type 2 diabetes, cardiovascular disease, Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, muscular dystrophies, mitochondrial myopathies, depression, Down’s syndrome, neonatal nerve injury, aging, axonal degeneration, carpal tunnel syndrome, Guillain-Barre syndrome, nerve damage, polio (poliomyelitis), spinal cord injury, nonalcoholic steatohepatitis, transplantation, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, systemic scleroderma, osteoarthritis, sarcopenia, and rheumatoid arthritis.

106. A method of inhibiting CD38 activity in a cell comprising exposing the cell to a compound as described in any one of claims 1-101.

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