6,5-bicyclic 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. 24-2207-WON-S1 / SetA6,5-BICYCLIC COMPOUNDSCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This International Application claims the benefit of U.S. Provisional Application no.63 / 738,133, filed December 23, 2024 and U.S. Provisional Application no. 63 / 844,225, filed July 15, 2025, each of which are incorporated herein by reference 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) or (II):Docket no. 24-2207-WON-S1 / SetAand pharmaceutically acceptable salts thereof, whereinX and Y are each independently nitrogen, C-H, or C-R6, wherein at least one of X and Y is nitrogen;R1is 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) -NO2R15is H, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy(Ci-Ce alkyl), or C3- 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-C2 alkyl), C3-C12 cycloalkyl(Co-C2 alkyl), aryl(Co-Ce alkyl), 6- to 12-membered spirocyclyl(Co-C2 alkyl) or 5- or 6-membered heteroaryl (Co-Ce alkyl), each of which is optionally substituted on the cyclic portion 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-C8cycloalkyl), (vii) -NHSO2(Ci-Ce alkyl), (viii) -NHSO2(C3-Cs cycloalkyl), (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 groups;R57is H, Ci-C6alkyl, or-(CH2CH2O)i-2(Ci-C6 alkyl), Ci-C6haloalkyl, C3-C8 cycloalkyl(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. 24-2207-WON-S1 / SetAR60is H or Ci-Ce alkyl; andR61is -SO2(Ci-C6alkyl) or Ci-Ce haloalkyl;R62is Ci-Ce alkyl optionally substituted with one Ci-Ce alkoxy; and R6is H, halogen, Ci-Ce alkyl, C3-C6 cycloalkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy,or -NR8R9where R8and R9independently represent H or Ci-Ce alkyl; and R7is H, -OH, Ci-Ce alkyl, Ci-Ce haloalkyl or Ci-Ce alkoxy.

[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.Docket no. 24-2207-WON-S1 / SetADETAILED 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, of 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.Docket no. 24-2207-WON-S1 / SetA

[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, Cs, C7, Cs, C9, C10, Cn, and C12 groups. 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, C11, 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-Cs alkyl)-O(Ci-Cs alkyl).

[0027] An “aryl” group is a Cs-C aromatic moiety comprising one to three aromatic rings. As such, “aryl” includes Cs, C10, C13, and C14 cyclic hydrocarbon groups. A representative aryl group is a Cs-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.Docket no. 24-2207-WON-S1 / SetA

[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, and naphthylmethyl. 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.Docket no. 24-2207-WON-S1 / SetA

[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 ring systems 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 2-thiaspiro[3.3]heptan-6-yl, 2-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,Docket no. 24-2207-WON-S1 / SetAisoindazolyl, 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, pyridazinyl, 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 theDocket no. 24-2207-WON-S1 / SetAsubstitution 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 on the 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) and the compounds within Formulae (II) to (Ila), 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. 24-2207-WON-S1 / SetAand pharmaceutically acceptable salts thereof, whereinX and Y are each independently nitrogen, C-H, or C-R6, wherein at least one of X and Y is nitrogen;R1is 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) -NO2R15is H, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy(Ci-Ce alkyl), or C3- 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-C2 alkyl), C3-C12 cycloalkyl(Co-C2 alkyl), aryl(Co-Ce alkyl), 6- to 12-membered spirocyclyl(Co-C2 alkyl) or 5- or 6-membered heteroaryl (Co-Ce alkyl), each of which is optionally substituted on the cyclic portion 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-C8cycloalkyl), (vii) -NHSO2(Ci-Ce alkyl), (viii) -NHSO2(C3-Cs cycloalkyl), (ix) -CO2(Ci-C6alkyl), (x) oxo, (xi) -OR57, (xii) -CN, (xiii) -C(O)R58, (xiv) -(C0-C4al kyl) 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 groups;R57is H , Ci-C6alkyl, -(CH2CH2O)I-2(CI-C6 alkyl), Ci-C6haloalkyl, C3- Cs cycloalkyl(Co-C2 alkyl), or 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 -NR60R61whereinR60is H or Ci-Ce alkyl; andDocket no. 24-2207-WON-S1 / SetAR61is -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, Ci-Ce alkoxy,or -NR8R9where R8and R9independently represent H or Ci-Ce alkyl; and R7is H, -OH, Ci-Ce alkyl, Ci-Ce haloalkyl or Ci-Ce alkoxy.

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

[0051] In certain embodiments of Formula (I) or (la), X and Y are each independently nitrogen, C-H, or C-R6, wherein at least one of X and Y is nitrogen. In certain embodiments, X is nitrogen and Y is C-H or C-R6. In certain embodiments, X is C-H or C-R6and Y is nitrogen. In certain embodiments, X and Y are each nitrogen.

[0052] In certain embodiments of Formula (I) or (la), X is nitrogen, C-H, or C-R6; and Y is nitrogen or C-H, wherein at least one of X and Y is nitrogen. In certain embodiments, X is nitrogen and Y is C-H. In certain embodiments, X is C-H and Y is nitrogen. In certain embodiments, X is C-R6and Y is nitrogen. In certain embodiments, X and Y are each nitrogen.

[0053] For example, in certain embodiments of Formula (la), the disclosure provides compounds of Formulae (lb) to (If):Docket no. 24-2207-WON-S1 / SetA

[0054] In certain embodiments of Formula (la), the disclosure provides compounds of Formulae (lb) or (Id)

[0055] In certain embodiments of Formula (I), (II), (la), or (Ila) 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), or C3-C8 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.

[0056] In certain embodiments of Formula (I), (II), (la), or (Ila) as disclosed herein, R1is an unsubstituted 5- to 10-membered heteroaryl group (i.e., having no R2substituents). For example, in certain embodiments, R1is an unsubstituted 5- or 6-membered heteroaryl group. In certain embodiments, R1is an unsubstituted 5-membered heteroaryl group. In certain embodiments, R1is an unsubstituted 5- or 6-membered heteroaryl group containing at least one nitrogen member. In certain embodiments, R1is an unsubstituted 5-membered heteroaryl group containing at least one nitrogen member. In certain embodiments, R1is an unsubstituted 5-membered heteroaryl containing at least one nitrogen member and at least one sulfur or oxygen member.

[0057] In certain embodiments of Formula (I), (II), (la), or (Ila) as disclosed herein, each R2is independently C1-C3 alkyl, cyclopropyl or cyclopropylmethyl. In certain embodiments of Formula (I), (II), (la), or (Ila) as disclosed herein, each R2is independently methyl, ethyl, propyl, isopropyl, fluorine, chlorine, methoxy, ethoxy, or cyano. In certain embodiments of Formula (I), (II), (la), or (Ila) as disclosed herein, each R2is independently methyl, ethyl, fluorine, methoxy, or cyano.

[0058] In certain embodiments of Formula (I), (II), (la), or (Ila) as disclosed herein, R1is pyrrolyl, thiazolyl, imiadozlyl, pyrazolyl, oxazolyl, or isoxazolyl, each of which is optionallyDocket no. 24-2207-WON-S1 / SetAsubstituted 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 unsubstituted 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-Ce alkyl (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. In certain embodiments, R1is unsubstituted imidazolyl (e.g., 1H-imidazol-1-yl). In certain embodiments, R1is pyrazolyl (e.g., pyrazol-4-yl) optionally substituted with one R2group, wherein the R2group is Ci-Ce alkyl (e.g., methyl). In certain embodiments, R1is 3-methyl-1H-pyrazol-4-yl. For example, in certain embodiments, R1is:

[0059] In certain embodiments of Formula (I), (II), (la), or (Ila) as disclosed herein, R4is H or Ci-Ce alkyl. In certain embodiments, R4is H. In certain embodiments R4is Ci-Ce alkyl.

[0060] In certain embodiments of Formula (I), (II), (la), or (Ila) as disclosed herein, R5is 4-to 13-membered heterocyclyl(Co-C2 alkyl), C3-C12 cycloalkyl(Co-C2 alkyl), aryl(Co-Ce alkyl), or 5- or 6-membered heteroaryl(Co-Ce alkyl), each of which is optionally substituted on the cyclic portion 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) -NHSC>2(CI-C6 alkyl), (viii) -NHSO2(C3-Cs cycloalkyl), (ix) -CO2(Ci-Ce alkyl), (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 groups. In certain embodiments of Formula (I), (II), (la), or (Ila) as disclosed herein, R57is H, Ci-Ce alkyl, -(CH2CH2O)I-2(CI-C6 alkyl), Ci-Ce haloalkyl, C3-C8 cycloalkyl(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 . In certain embodiments, R58and R59are each independently -NR60R61, wherein R60is H or Ci-Ce alkyl; and R61is -SO2(Ci-Ce alkyl) or Ci-Ce haloalkyl. In certain embodiments, R62is Ci-Ce alkyl optionally substituted with one Ci-Ce alkoxy.Docket no. 24-2207-WON-S1 / SetA

[0061] In certain embodiments of Formula (I), (II), (la), or (Ila) 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 (Illa):wherein n is 0 or 1.

[0062] In certain embodiments wherein R5is a group of formula (Illa), n is 0, and R3is C1-Ce alkyl (e.g., methyl). For example, in certain embodiments, R5is:

[0063] In certain embodiments, R5is a group of formula (II lb):wherein n is 0 or 1.

[0064] In certain embodiments, R5is a group of formula (II Ic) or (Hid):Docket no. 24-2207-WON-S1 / SetA

[0065] In certain embodiments wherein R5is a group of formula (111 b) , (I I Ic), or (Hid), n is 0. In certain embodiments wherein R5is a group of formula (II lb), (I lie), or (Hid), R3is -SO2(C C6alkyl), -SO2(C3-C8cycloalkyl), -NHSO2(CI-C6alkyl), -NHSO2(C3-C8cycloalkyl), -OR57, or -(C0-C4 alkyl)R59. In certain embodiments, R5is a group of formula (lllb) or (Hid), wherein n is 0 and R3is -SO2(Ci-C8alkyl) (e.g., -SO2Me). In certain embodiments, wherein R5is a group of formula (lllb) or (Hid), n is 0 and R3is -NHSO2(CI-C8alkyl) (e.g., -NHSO2Me). In certain embodiments wherein R5is a group of formula (lib), (He), or (I Id), n is 0 and R3is -OR57. In certain embodiments, R57is H, Ci-C8alkyl (e.g., methyl), or -(CH2CH2O)I-2(CI-C6 alkyl) (e.g., -(CH2CH2O)(CI alkyl)). In certain embodiments, R57is Ci-C8haloalkyl (e.g., trifluoromethyl, or 2,2-difluoroethyl). In certain embodiments, R57is C3-C8cycloalkyl(Co-C2alkyl) (e.g., cyclopropylmethyl). In certain embodiments, R57is 4- to 8-membered heterocyclyl(Co-C2alkyl) (e.g., oxetan-3-ylmethyl). In certain embodiments, R3is -(C0-C4 alkyl)R59wherein R59is -NR60R61, R60is H or Ci-C8alkyl, and R61is -SO2(Ci-C8alkyl) 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:

[0066] In certain embodiments wherein R5is a group of formula (lllb), (I I Ic), or (Hid), 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-C8alkyl 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 :Docket no. 24-2207-WON-S1 / SetA

[0067] In certain embodiments wherein R5is a group of formula (lllb), (lllc), or (Hid), n is 1. In certain embodiments wherein R5is a group of formula (lllb), (lllc), or (Hid), n is 1 and at least one R3is halogen, (e.g., fluorine). For example, in certain embodiments, R5is:

[0068] In certain embodiments of Formula (I), (II), (la), or (Ha) 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 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.

[0069] 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:

[0070] In certain embodiments of Formula (I), (II), (la), or (Ha) 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 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 (IVa):Docket no. 24-2207-WON-S1 / SetAwhereinR3ais H, halogen, or -OH;n is 0, 1, or 2; andp is 1 or 2.

[0071] In certain embodiments wherein R5is a group of formula (IVa), p is 1. In certain embodiments wherein R5is a group of formula (IVa), p is 1 and n is 0. In certain embodiments wherein R5is a group of formula (IVa), p is 1 , n is 0, and R3ais -OH or halogen (e.g., fluorine). In certain embodiments wherein R5is a group of formula (IVa), p is 1 and n is 2. In certain embodiments wherein R5is a group of formula (IVa), p is 1, n is 2, and each R3is independently -OH or halogen (e.g., fluorine). In certain embodiments wherein R5is a group of formula (IVa), p is 1, R3ais H, n is 2, and each R3is independently halogen (e.g., fluorine). In certain embodiments, R3ais H, n is 1, and R3is -OR57wherein R57is Ci-Ce alkyl (e.g., methyl) or -(CH2CH2O)I-2(CI-C6 alkyl). For example, in certain embodiments, R5is:<

[0072] In certain embodiments of Formula (I), (II), (la), or (Ila) as disclosed herein, R5is aryl(Co-Ce alkyl), the cyclic portion of which is optionally substituted with one or more independently selected R3groups. In certain embodiments of Formula (I), (II), (la), or (Ila) 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.

[0073] In certain embodiments of Formula (I), (II), (la), or (Ila) 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 (Va):Docket no. 24-2207-WON-S1 / SetAwhereinX, 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.

[0074] In certain embodiments wherein R5is a group of formula (Va), Z is C-R3. In certain embodiments wherein R5is a group of formula (Va), Y is nitrogen. In certain embodiments wherein R5is a group of formula (Va), Z is C-R3and Y is nitrogen. For example, in certain embodiments, R5is a group of formula (Vb) or (Vc):(Vb) (Vc) wherein n is 0 or 1.

[0075] In certain embodiments of Formula (I), (II), (la), or (Ila) as disclosed herein, R5is pyrazinyl substituted with one or more R3. In certain embodiments of Formula (I), (II), (la), or (Ila) as disclosed herein, R5is pyrazin-5-yl substituted with one or more R3. In certain embodiments of Formula (I), (II), (la), or (Ila) as disclosed herein, R5is pyridinyl substituted with one or more R3. In certain embodiments of Formula (I), (II), (la), or (Ila) as disclosed herein, R5is pyrdin-3-yl or pyridin-5-yl substituted with one or more R3. For example, in certain embodiments, R5is a group of formula (Vd) or (Ve):(Vd) (Ve)Docket no. 24-2207-WON-S1 / SetAwherein n is 0 or 1.

[0076] In certain embodiments wherein R5is a group of formula (Vd) or (Ve), n is 0. In certain embodiments wherein R5is a group of formula (Vd), n is 0 and R3is -OR57and R57is -(CH2CH20)O-2(CI-C6 alkyl). For example, in certain embodiments, R5is:

[0077] In certain embodiments of Formula (I), (II), (la), or (Ila) as disclosed herein, R5is bicyclic Cs-Ci2cycloalkyl(Co-C2alkyl), 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 2 atoms. In certain embodiments of Formula (I), (II), (la), or (Ila) as disclosed herein, R5is a group of the formula (Via):whereinR3ais H, halogen, or -OH;n is 0 or 1; andm is 0, 1, or 2.

[0078] In certain embodiments wherein R5is a group of formula (Via), n is 0 and m is 0. For example, in certain embodiments, R5is:

[0079] In certain embodiments of Formula (I), (II), (la), or (Ila) as disclosed herein, R5is 4-to 13-membered heterocyclyl(Co-C2alkyl), the cyclic portion of which is optionally substituted with one or more independently selected R3groups. In certain embodiments of Formula (I), (II), (la), or (Ila) as disclosed herein, R5is 4- to 13-membered heterocyclyl. In certain embodiments of Formula (I), (II), (la), or (Ila) as disclosed herein, R5is a group of formula (Vila):Docket no. 24-2207-WON-S1 / SetAm2(rX(r3)- (Vila)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-C8alkyl or halogen groups.

[0080] In certain embodiments wherein R5is a group of formula (Vila), m1and m2are each 1, and p is 0. In certain embodiments wherein R5is a group of formula (Vila), m1and m2are each 1, p is 0, n is 0, and Z is N-R31. In certain embodiments wherein R5is a group of formula (Vila), R31is Ci-C8haloalkyl (e.g., trifluoroethyl). In certain embodiments wherein R5is a group of formula (Vila), R31is 4- to 8-membered heterocyclyl optionally substituted with one or more independently selected Ci-C8alkyl or halogen groups. In certain embodiments wherein R5is a group of formula (Vila), R31is 4- to 8-membered heterocyclyl optionally substituted with 1, 2, or 3 independently selected Ci-C8alkyl or halogen groups. In certain embodiments wherein R5is a group of formula (Vila), R31is 4- to 8-membered heterocyclyl (e.g., oxetan-3-yl) substituted with one Ci-C8alkyl group (e.g., methyl). In certain embodiments wherein R5is a group of formula (Vila), m1and m2are each 1, p is 0, n is 2, Z is sulfur, and R3is oxo. In certain embodiments wherein R5is a group of formula (Vila), m1and m2are each 1, p is 0, n is 1, Z is oxygen, and R3is Ci-C8alkyl (e.g., methyl). For example, in certain embodiments, R5is:

[0081] In certain embodiments of Formula (I), (II), (la), or (Ila) as disclosed herein, R5is a 6- to 12-membered spirocyclyl(Co-C2alkyl), 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 leastDocket no. 24-2207-WON-S1 / SetAtwo of the ring systems share 1 ring member (i.e. , atom). In certain embodiments of Formula (I), (II), (la), or (Ila) as disclosed herein, R5is a group of formula (Villa):<(VI 11 a)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;p is 0, 1, or 2; ando1and o2are each independently 0 or 1.

[0082] In certain embodiments wherein R5is a group of formula (Villa), 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 o1and o2are each 0, and R3is -SO2(Ci-Ce alkyl) (e.g., -SChMe) or -SO2(C3-Cs cycloalkyl). 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, and o1and o2are each 0, and R3is oxo. 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, o1and o2are each 1, and R3is Ci-Ce haloalkyl (e.g., 1,1 -difluoroethyl or trifluoroethyl), -SO2(Ci-Ce alkyl) (e.g., -SChMe), -SO2(C3-C8cycloalkyl), or -C(O)R62, wherein R62is Ci-C8alkyl optionally substituted with one Ci-C8alkoxy. In certain embodiments, R3is -C(O)R62, wherein R62is Ci-Ce alkyl (e.g., methyl) optionally substituted with one Ci-C8alkoxy (e.g., methoxy). In certain embodiments, Ring A has 4 ring members, one ring member of which is nitrogen, n is 0, m is 0, p is 0, and o1and o2are each 1. 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 , o1and o2are each 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, p is 1, and o1and o2are each 1. For example, in certain embodiments, R5is:Docket no. 24-2207-WON-S1 / SetA

[0083] In certain embodiments of Formula (I), (II), (la), or (Ila) as disclosed herein, R3is independently halogen, -OR57, -NHSO2(Ci-Ce alkyl), -NHSO2(C3-Cs cycloalkyl), Ci-Ce haloalkyl, -SO2(Ci-Ce alkyl), Ci-Ce alkyl, -C(O)R62, -(Co-C4)R59, or 4- to 8-membered heterocyclyl optionally substituted with one or more independently selected Ci-Ce alkyl or halogen groups.

[0084] In certain embodiments of Formula (I), (II), (la), or (Ila) as disclosed herein, R6is H, halogen, Ci-Ce alkyl, C3-C6 cycloalkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy, or -NR8R9where R8and R9independently represent H or Ci-Ce alkyl. In certain embodiments of Formula (I), (II), (la), or (Ila) as disclosed herein, R6is H. In certain embodiments of Formula (I), (II), (la), or (Ila) as disclosed herein, R6is Ci-Ce alkyl (e.g., methyl). In certain embodiments of Formula (I), (II), (la), or (Ila) as disclosed herein, R6is Ci-Ce alkoxy (e.g., methoxy).

[0085] In certain embodiments of Formula (I), (II), (la), or (Ila) as disclosed herein, R7is H, -OH, Ci-Ce alkyl, Ci-Ce haloalkyl, or Ci-Ce alkoxy. In certain embodiments, R7is H. In certain embodiments, R7is -OH. In certain embodiments, R7is Ci-Ce alkyl (e.g., methyl, ethyl, propyl, or isopropyl). In certain embodiments, R7is Ci-Ce haloalkyl (e.g., trifluoromethyl). In certain embodiments, R7is Ci-Ce alkoxy (e.g., methoxy or ethoxy). In certain embodiments, R7is -OH, methyl, ethyl, isopropyl, methoxy, ethoxy, or trifluoromethyl. In certain embodiments, R7is -OH or methyl.

[0086] As disclosed above, the disclosure provides compounds having the structural Formula (la) 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 (IXa) to (IXd):Docket no. 24-2207-WON-S1 / SetA(IXc) (IXd) whereinn is 0 or 1; andX, Y, R2, R4, R5, and R7are each as described hereinabove.

[0087] In certain embodiments of Formula (IXa), (IXb), (IXc), or (IXd), n is 0.

[0088] In certain aspects, the disclosure provides compounds having the structural formula (IXb) wherein X is nitrogen, C-H, or C-R6; and Y is nitrogen or C-H, wherein at least one of X and Y is nitrogen. In certain embodiments, X is nitrogen and Y is C-H. In certain embodiments, X is C-H and Y is nitrogen. In certain embodiments, X is C-R6and Y is nitrogen. In certain embodiments, X and Y are each nitrogen. For example, in certain aspects, the disclosure provides compounds having the structural Formulae (IXe) to (IXh):Docket no. 24-2207-WON-S1 / SetA(IXg) (IXh) whereinn is 0 or 1; andR2, R4, R5, R6, and R7are each as described hereinabove.

[0089] In certain embodiments of Formula (IXe), (IXf), (IXg), or (IXh), n is 0.

[0090] As disclosed above, the disclosure provides compounds having the structural Formula (la) 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 (Xa) to (Xd):whereinn is 0 or 1; andR2, R4, R5, R6, and R7are each as described hereinabove.

[0091] In certain embodiments of Formula (Xa), (Xb), (Xc), or (Xd), n is 0.

[0092] Enumerated EmbodimentsEmbodiment 1. A compound of formula (I) or (II):Docket no. 24-2207-WON-S1 / SetAor a pharmaceutically acceptable salt thereof, whereinX and Y are each independently nitrogen, or C-R6, wherein at least one of X and Y is nitrogen;R1is a 5- to 10-membered heteroaryl group optionally substituted with one or more independently selected R2, where each R2is (i) Ci-C6alkyl, (ii) C3-C8cycloalkyl, (iii) C3-C6 cycloalkyl(Ci-C2 alkyl), (iv) Ci-C8haloalkyl, (v) Ci-C8alkoxy(Co-Ce alkyl), (vi) halogen, (vii) -OR15, (viii) -NR16R17, (ix) -CN, or (x) -NO2R15is H, Ci-Ce alkyl, Ci-C8haloalkyl, Ci-C8alkoxy(Ci-C8alkyl), 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), 6- to 12-membered spirocyclyl(Co-C2 alkyl) or 5- or 6- membered heteroaryl(Co-C6alkyl), each of which is optionally substituted on the cyclic portion 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) C3-C8cycloalkyl 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 (Co- 02 alkyl) , or 5- or 6-membered heteroaryl optionally substitutedDocket no. 24-2207-WON-S1 / SetAwith one or more independently selected Ci-C6alkyl, halogen, or C1-C6 alkoxy groups;R58and R59are each independently -NR60R61whereinR60is H or Ci-C6alkyl; andR61is - SO2(Ci-Ce alkyl) 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, Ci-Ce alkoxy, or -NR8R9where R8and R9independently represent H or Ci-Ce alkyl; and R7is H, -OH, Ci-Ce alkyl, Ci-Ce haloalkyl or Ci-Ce alkoxy.Embodiment 2. A compound according to embodiment 1, which has formula (la) orand R1is a 5- or 6-membered heteroaryl optionally substituted with one or more independently selected R2.Embodiment 3. A compound according to embodiment 1, which has formula (lb) or formula (Id):and R1is a 5- or 6-membered heteroaryl optionally substituted with one or more independently selected R2.Docket no. 24-2207-WON-S1 / SetAEmbodiment 4. A compound according to any one of embodiments 1-3, wherein R1is an 5-membered heteroaryl group containing at least one nitrogen and the heteroaryl is optionally substituted with 1 or 2 R2.Embodiment 5. A compound according to any one of embodiments 1-3, wherein R1is an 5-membered heteroaryl group containing one nitrogen and one sulfur or oxygen, and the heteroaryl is optionally substituted with 1 or 2 R2.Embodiment 6. A compound according to any one of embodiments 1-3, wherein R1is pyrrolyl, thiazolyl, imidazolyl, pyrazolyl, oxazolyl or isoxazolyl, each of which is optionally substituted with 1 or 2 R2.Embodiment 7. A compound according to any of embodiments 1-6, wherein R5is C3-C12 cycloalkyl(Co-C2 alkyl), and R5is optionally substituted with 1-3 of R3.Embodiment 8. A compound according to embodiment 7, wherein R5is cycloalkyl optionally substituted with 1, 2 or 3 of R3.Embodiment 9. A compound according to embodiment 8, wherein R5is a group of the formula (Illa):(R3)n((Illa)wherein n is 0 or 1.Embodiment 10. A compound according to embodiment 8, wherein R5is a group of the formula (I I lb):wherein n is 0 or 1.Docket no. 24-2207-WON-S1 / SetAEmbodiment 11. A compound according to embodiment 8, wherein R5is a group of the formula (I He) or (Hid):(lllc) (Hid) wherein n is 0 or 1.Embodiment 12. A compound according to embodiment 8, wherein R5is a group of the formula (Hie)wherein n is 0 or 1.Embodiment 13. A compound according to embodiment 7, wherein R5is a group of the formula (IVa):whereinR3ais H, halogen, -OH;n is 0, 1 or 2; andp is 1 or 2.Embodiment 14. A compound according to any of embodiments 1-6, wherein R5is aryl(Co-Ce alkyl), and R5is optionally substituted with 1-3 of R3.Docket no. 24-2207-WON-S1 / SetAEmbodiment 15. A compound according to any of embodiments 1-6, wherein R5is 5- or 6-membered heteroaryl(Co-Ce alkyl), and R5is optionally substituted with 1-3 of R3.Embodiment 16. A compound according to embodiment 14, wherein R5is a group of the formula (Va):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 17. A compound according to embodiment 16, wherein n is 1 and Y is N.Embodiment 18. A compound according to embodiment 16, wherein R5is a group of the formulawherein n is 0 or 1.Embodiment 19. A compound according to embodiment 16, wherein R5is a group of the formulawherein n is 0 or 1.Docket no. 24-2207-WON-S1 / SetAEmbodiment 20. A compound according to any of embodiments 1-6, wherein R5is a bicyclic C8-C12 cycloalkyl (C0-C2 alkyl) where the rings share 2 atoms, and R5is optionally substituted with 1-3 of R3.Embodiment 21. A compound according to embodiment 20, wherein the bicyclic cycloalkyl is a group of the formula (Via):whereinR3ais H, halogen, or -OH;n is 0 or 1; andm is 0, 1 or 2.Embodiment 22. A compound according to any of embodiments 1-6, wherein R5is a 6-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 R5has the formula (Villa):(Villa)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.Embodiment 24. A compound according to any of embodiments 1-6, wherein R5is a 4-to 13-membered heterocyclyl(Co-C2 alkyl), and R5is optionally substituted with 1-3 of R3.Docket no. 24-2207-WON-S1 / SetAEmbodiment 25. A compound according to embodiment 24, wherein the heterocyclyl is a group of the Formula (Vila):wherein m1and m2are each 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-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 groups.Embodiment 26. A compound according to any 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 R6is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or -NR8R9where R8and R9independently represent H or C1-C3 alkyl.Embodiment 28. A compound according to any one of embodiments 1-26, wherein R6is hydrogen, C1-C3 alkyl, or C3-C6 cycloalkyl.Embodiment 29. A compound according to any one of embodiments 1-28, wherein R2is Ci-Ce alkyl.Embodiment 30. A compound according to any one of embodiments 1-28, wherein R2is methyl, ethyl, propyl or isopropyl, fluorine, chlorine, methoxy, ethoxy, or cyano.Docket no. 24-2207-WON-S1 / SetAEmbodiment 31. A compound according to any one of embodiments 1-28, wherein R1is unsubstituted or substituted with one R2where R2is methyl.Embodiment 32. A compound according to any one of embodiments 1-31, wherein R1is thiazolyl which is optionally substituted with one or more independently selected R2.Embodiment 33. A compound according to any one of embodiments 1-31, wherein R1is unsubstituted imidazolyl or R1is imidazolyl which is substituted with one or more independently selected R2.Embodiment 34. A compound according to any one of embodiments 1-31, wherein R1is pyrrolyl, each of which is optionally substituted with one or more independently selected R2.Embodiment 35. A compound according to any one of embodiments 1-31, wherein R1is pyrazolyl, each of which is optionally substituted with one or more independently selected R2.Embodiment 36. A compound according to any one of embodiments 1-31, wherein R1is oxazolyl, each of which is optionally substituted with one or more independently selected R2.Embodiment 37. A compound according to any one of embodiments 1-31, wherein R1is isoxazolyl, each of which is optionally substituted with one or more independently selected R2.Embodiment 38. A compound according to any one of embodiments 1-31, wherein R1is thiazol-5-yl, imidazol-5-yl or imidazol-1-yl, each of which is optionally substituted with one or more independently selected R2.Embodiment 39. A compound according to embodiment any one of embodiments 1-38, wherein R1is substituted with two R2.Embodiment 40. A compound according to embodiment any one of embodiments 1-38, wherein R1is substituted with one R2.Embodiment 41. A compound according to embodiment 39 or embodiment 40, wherein each R2is independently Ci-Ce alkyl, C3-C6 cycloalkyl or C3-C6 cycloalkyl(Ci-C2)alkyl.Docket no. 24-2207-WON-S1 / SetAEmbodiment 42. A compound according to any one of embodiments 1-41, wherein R4is H, methyl or ethyl.Embodiment 43. A compound according any one of embodiments 1-41, wherein R4is H or methyl.Embodiment 44. A compound according to any one of embodiments 1-41, wherein R4is H.Embodiment 45. A compound according to any one of embodiments 1-44, wherein R7is H.Embodiment 46. A compound according to any one of embodiments 1-44, wherein R7-OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, or trifluoromethyl.Embodiment 47. A compound according to any one of embodiments 1-46, wherein R6is Ci-Ce alkyl, Ci-Ce cycloalkyl, or Ci-Ce haloalkyl.Embodiment 48. A compound according to any one of embodiments 1-46, wherein R6is hydrogen, methyl, trifluoromethyl or cyclopropyl.Embodiment 49. A compound of formula (la) or (Ila):or a pharmaceutically acceptable salt thereof, whereinone of X and Y is N and the other is CH or CR6, or both X and Y are nitrogen; R1is a 5- to 10-membered heteroaryl group optionally substituted with one or more independently selected R2, where each R2is Ci-Ce alkyl, C3-C6 cycloalkyl, C3-C6 cycloal kyl(Ci-C2 alkyl), Ci-Ce haloalkyl, Ci-Ce alkoxy(Co-Ce alkyl), halogen, -OR15, -NR16R17, -CN, -NO2 orCs-Cs cycloalkyl;R15is H, Ci-C6alkyl, Ci-C6haloalkyl, Ci-C6alkoxy(Ci-C6alkyl), or C3-C8 cycloalkyl;Docket no. 24-2207-WON-S1 / SetAR16is H or Ci-C6alkyl; andR17is H, Ci-C6alkyl;R4is H or Ci-Ce alkyl;R5is C3-C12 cycloalkyl(Co-C2alkyl) or 6- to 12-membered spirocyclyl(Co-C2), 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-Cs cycloalkyl), (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-C8cycloalkyl optionally substituted with one or more independently selected Ci-Ce alkyl or halogen groups;R57is H, Ci-C6alkyl, -(CH2CH2O)I-2(CI-C6alkyl), Ci-C6haloalkyl, C3-C8cycloalkyl(C0-C2alkyl), 4- to 8-membered heterocyclyl (Co-C2alkyl), or 5- or 6-membered heteroaryl optionally substituted with one or more independently selected Ci-C6alkyl, halogen, or Ci-C6alkoxy groups;R58and R59are each independently -NR60R61whereinR60is H or Ci-Ce alkyl; andR61is -SO2(Ci-C6alkyl) or Ci-C6haloalkyl;R62is Ci-Ce alkyl optionally substituted with one Ci-Ce alkoxy;R6is H, halogen, Ci-Ce alkyl, C3-C6 cycloalkyl, halo Ci-Ce alkyl, Ci-Ce alkoxy, or -NR8R9where R8and R9independently represent H or Ci-C6alkyl; and R7is H, -OH, Ci-Ce alkyl, Ci-Ce haloalkyl or Ci-Ce alkoxy.Embodiment 50. A compound according to embodiment 1, which has formula (lb) or (Id):Docket no. 24-2207-WON-S1 / SetAand R1is a 5- or 6-membered heteroaryl optionally substituted with one or more independently selected R2.Embodiment 51. A compound according to embodiment 49 or 50, wherein R5is a 6- to 12-membered spirocyclyl(Co-C2 alkyl) which is optionally substituted with 1-3 of R3.Embodiment 52. A compound according to embodiment 49 or 50, wherein R5has the formula (Villa):<<(Villa)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.Embodiment 53. A compound according to embodiment 52, wherein n is 0 and m is 1.Embodiment 54. A compound according to embodiment 49 or embodiment 50, wherein each R3is independently -SO2(Ci-Ce alkyl), Ci-Ce haloalkyl, oxo, or -C(O)R62.Embodiment 55. A compound according to embodiment 49 or embodiment 50, wherein R5is:Docket no. 24-2207-WON-S1 / SetAEmbodiment 56. A compound according to embodiment 49 or 50, wherein R5is a group of the formula (Illa):wherein n is 0 or 1.Embodiment 57. A compound according to embodiment 56, wherein R5is:Embodiment 58. A compound according to embodiment 49 or 50, wherein R5is a group of the formula (I I lb):wherein n is 0 or 1.Docket no. 24-2207-WON-S1 / SetAEmbodiment 59. A compound according to embodiment 49 or 50, wherein R5is a group of the formula (I He) or (Hid):wherein n is 0 or 1.Embodiment 60. A compound according to embodiment 58 or embodiment 59, wherein n is 0 and R3is -SO2(Ci-Ce alkyl).Embodiment 61. A compound according to embodiment 58 or embodiment 59, wherein n is 0 and R3is -OR57, wherein R57is H, Ci-Ce alkyl, -(CH2CH2O)I-2(CI-C6 alkyl), Ci-Ce haloalkyl, C3-C8 cycloalkyl(Co-C2 alkyl), or 4- to 8-membered heterocyclyl (C0-C2 alkyl).Embodiment 62. A compound according to embodiment 58 or embodiment 59, wherein n is 0 and R3is -(C0-C4 alkyl)R59.Embodiment 63. A compound according to embodiment 58 or embodiment 59, whereinEmbodiment 64. A compound according to embodiment 58 or embodiment 59, wherein n is 0 and R3is 4- to 8-membered heterocyclyl optionally substituted with one or more independently selected halogen groups.Docket no. 24-2207-WON-S1 / SetAEmbodiment 65. A compound according to embodiment 58 or embodiment 59, wherein R5is:Embodiment 66. A compound according to embodiment 58 or embodiment 59, wherein n is 1 and at least one R3is halogen.Embodiment 67. A compound according to embodiment 58 or embodiment 59, wherein R5is:Embodiment 68. A compound according to embodiment 49 or 50, wherein R5is a group of the formula (Hie):wherein n is 0 or 1.Embodiment 69. A compound according to embodiment 68, wherein R5is:Embodiment 70. A compound according to embodiment 49 or 50, wherein R5is a group of the formula (IVa)Docket no. 24-2207-WON-S1 / SetAwhereinR3ais H, halogen or -OH;n is 0, 1 or 2; andp is 1 or 2.Embodiment 71. A compound according to embodiment 70, whereinR3ais H or -OH; andR3is -OR57wherein R57is Ci-C6alkyl or-(CH2CH2O)i-2(Ci-C6 alkyl).Embodiment 72. A compound according to embodiment 70, wherein R5is:Embodiment 73. A compound according to any one of embodiments 49-72, wherein R1is thiazol-5-yl which is optionally substituted with one or two independently selected R2.Embodiment 74. A compound according to any one of embodiments 49-72, wherein R1is imidazol-5-yl which is optionally substituted with one R2.Embodiment 75. A compound according to any one of embodiments 49-72, wherein R1is unsubstituted imidazolyl or R1is imidazol-1-yl which is substituted with one R2.Embodiment 76. A compound according to any one of embodiments 73-75, wherein each R2is independently Ci-Ce alkyl, C3-C6 cycloalkyl or C3-C6 cycloalkyl(Ci-C2alkyl).Embodiment 77. A compound according to any one of embodiments 73-75, wherein each R2is independently C1-C3 alkyl, cyclopropyl or cyclopropylmethyl.Docket no. 24-2207-WON-S1 / SetAEmbodiment 78. A compound according to any one of embodiments 73-75, wherein each R2is independently methyl, ethyl, propyl or isopropyl.Embodiment 79. A compound according to any one of embodiments 49-78, wherein R4is H, methyl or ethyl.Embodiment 80. A compound according to any one of embodiments 49-78, wherein R4is H or methyl.Embodiment 81. A compound according to any one of embodiments 49-78, wherein R4is H.Embodiment 82. A compound according to any one of embodiments 49-81 , wherein R6is Ci-Ce alkyl.Embodiment 83. A compound according to any one of embodiments 49-81 , wherein R6is hydrogen or methyl.Embodiment 84. A compound according to any one of embodiments 49-83, wherein R7is H.Embodiment 85. A compound according to any one of embodiments 49-83, wherein R7is methyl or -OH.

[0093] In certain embodiments, the compound is2-(1H-imidazol-1-yl)-N-(((1r,4r)-4-methoxycyclohexyl)methyl)imidazo[1,5- b]pyridazin-7-amine;N-(((1r,4r)-4-methoxycyclohexyl)methyl)-2-(1-methyl-1H-imidazol-5- yl)imidazo[1,5-b]pyridazin-7-amine;N-(((1r,4r)-4-methoxycyclohexyl)methyl)-2-(thiazol-5-yl)imidazo[1,5- b]pyridazin-7-amine;6-(1H-imidazol-1-yl)-N-(((1r,4r)-4-methoxycyclohexyl)methyl)imidazo[1,2- b]pyridazin-3-amine;2-(1H-imidazol-1-yl)-N-((1r,4r)-4-methoxycyclohexyl)imidazo[1,5-b]pyridazin- 7-amine;Docket no. 24-2207-WON-S1 / SetA2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)imidazo[1,5- b]pyridazin-7-amine;N-((2-oxaspiro[3.5]nonan-7-yl)methyl)-6-(1H-imidazol-1-yl)imidazo[1,2- b]pyridazin-3-amine;4-((6-(1H-imidazol-1-yl)imidazo[1,2-b]pyridazin-3-yl)amino)tetrahydro-2H- thiopyran 1,1 -dioxide;6-(1H-imidazol-1-yl)-N-(((1r,4r)-4-methoxycyclohexyl)methyl)- [1,2,4]triazolo[4,3-b]pyridazin-3-amine;2-(1H-imidazol-1-yl)-N-(2-(methylsulfonyl)-2-azaspiro[3.5]nonan-7- yl)imidazo[1,5-b]pyridazin-7-amine;N-((1r,4r)-4-((2-(1H-imidazol-1-yl)imidazo[1,5-b]pyridazin-7- yl)amino)cyclohexyl)methanesulfonamide;N-((2-oxaspiro[3.5]nonan-7-yl)methyl)-2-(1-methyl-1H-imidazol-5- yl)imidazo[1,5-b]pyridazin-7-amine;6-((6-(1H-imidazol-1-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)amino)-2- thiaspiro[3.3]heptane 2,2-dioxide;7-(((6-(1H-imidazol-1-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)amino)methyl)-2- thiaspiro[3.5]nonane 2,2-dioxide;6-(1H-imidazol-1-yl)-N-(2-(methylsulfonyl)-2-azaspiro[3.3]heptan-6- yl)imidazo[1,2-b]pyridazin-3-amine;2-(1H-imidazol-1-yl)-N-(((1r,4r)-4-methoxycyclohexyl)methyl)pyrrolo[2,1- f][1 ,2,4]triazin-7-amine;2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)pyrrolo[2,1- f][1 ,2,4]triazin-7-amine;7-(((2-(1-methyl-1H-imidazol-5-yl)imidazo[1,5-b]pyridazin-7-yl)amino)methyl)- 2-thiaspiro[3.5]nonane 2,2-dioxide;N-(((1r,4r)-4-methoxycyclohexyl)methyl)-6-(1-methyl-1H-imidazol-5-yl)- [1,2,4]triazolo[4,3-b]pyridazin-3-amine;N-(((1r,4r)-4-methoxycyclohexyl)methyl)-6-(1-methyl-1H-imidazol-5- yl)imidazo[1,2-b]pyridazin-3-amine;N-((4,4-difluorocyclohexyl)methyl)-6-(1-methyl-1H-imidazol-5-yl)imidazo[1,2- b]pyridazin-3-amine;6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)imidazo[1,2- b]pyridazin-3-amine;6-(1H-imidazol-1-yl)-N-((1r,4r)-4-methoxycyclohexyl)imidazo[1,2-b]pyridazin- 3-amine;Docket no. 24-2207-WON-S1 / SetA6-(1H-imidazol-1-yl)-N-(2-oxaspiro[3.5]nonan-7-yl)imidazo[1,2-b]pyridazin-3- amine;2-(1H-imidazol-1-yl)-N-(2-oxaspiro[3.5]nonan-7-yl)imidazo[1,5-b]pyridazin-7- amine;2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(oxetan-3-ylmethoxy)cyclohexyl)imidazo[1,5- b]pyridazin-7-amine;N-((1r,4r)-4-(2,2-difluoroethoxy)cyclohexyl)-2-(1H-imidazol-1-yl)imidazo[1,5- b]pyridazin-7-amine;2-(1H-imidazol-1-yl)-N-(1-(3-methyloxetan-3-yl)piperidin-4-yl)imidazo[1,5- b]pyridazin-7-amine;N-((1r,4r)-4-(cyclopropylmethoxy)cyclohexyl)-2-(1H-imidazol-1- yl)imidazo[1,5-b]pyridazin-7-amine;2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-5- methylimidazo[1,5-b]pyridazin-7-amine;2-(1H-imidazol-1-yl)-N-((1r,4r)-4-methoxycyclohexyl)pyrrolo[2,1- f][1 ,2,4]triazin-7-amine;2-(1H-imidazol-1-yl)-N-(2-(methylsulfonyl)-2-azaspiro[3.5]nonan-7- yl)pyrrolo[2, 1 -f] [ 1 ,2,4]triazin-7-amine;2-(1H-imidazol-1-yl)-N-(2-oxaspiro[3.5]nonan-7-yl)pyrrolo[2,1-f][1,2,4]triazin- 7-amine;N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-2-(5-methyl-1H-imidazol-1- yl)imidazo[1,5-b]pyridazin-7-amine;2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-4- methylimidazo[1,5-b]pyridazin-7-amine;2-(1 H-imidazol-1-yl)-N-((1 R,3R)-3-(2-methoxyethoxy)cyclopentyl)imidazo[1 ,5- b]pyridazin-7-amine;(1r,4r)-N1-(2-(1H-imidazol-1-yl)imidazo[1,5-b]pyridazin-7-yl)-N4-(2,2,2- trifluoroethyl)cyclohexane-1,4-diamine;N-((1r,4r)-4-(3,3-difluoropyrrolidin-1-yl)cyclohexyl)-2-(1H-imidazol-1- yl)imidazo[1,5-b]pyridazin-7-amine;6-(1H-imidazol-1-yl)-N-((3R,4S)-3-methyltetrahydro-2H-pyran-4- yl)imidazo[1,2-b]pyridazin-3-amine;N-(4,4-difluorocyclohexyl)-6-(1H-imidazol-1-yl)imidazo[1,2-b]pyridazin-3- amine;N-(4,4-difluorocyclohexyl)-2-(1H-imidazol-1-yl)imidazo[1,5-b]pyridazin-7- amine;Docket no. 24-2207-WON-S1 / SetAN-((1r,4r)-4-(3,3-difluoropyrrolidin-1-yl)cyclohexyl)-6-(1H-imidazol-1- yl)imidazo[1,2-b]pyridazin-3-amine;5-cyclopropyl-2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2- methoxyethoxy)cyclohexyl)imidazo[1,5-b]pyridazin-7-amine;2-(1H-imidazol-1-yl)-N-((1r,4r)-4-methoxycyclohexyl)-5-methylimidazo[1,5- b]pyridazin-7-amine;N-((1r,4r)-4-(3,3-difluoroazetidin-1-yl)cyclohexyl)-6-(1H-imidazol-1- yl)imidazo[1,2-b]pyridazin-3-amine;N-((1r,4r)-4-(cyclopropylmethoxy)cyclohexyl)-6-(1H-imidazol-1- yl)imidazo[1,2-b]pyridazin-3-amine;(1r,4r)-N1-(6-(1H-imidazol-1-yl)imidazo[1,2-b]pyridazin-3-yl)-N4-(2,2,2- trifluoroethyl)cyclohexane-1,4-diamine;6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-2- methylimidazo[1,2-b]pyridazin-3-amine;N-((1r,4r)-4-(3,3-difluoropyrrolidin-1-yl)cyclohexyl)-6-(1H-imidazol-1-yl)-2- methylimidazo[1,2-b]pyridazin-3-amine;N-((1r,4r)-4-(3,3-difluoropyrrolidin-1-yl)cyclohexyl)-2-(1H-imidazol-1-yl)-4- methylimidazo[1,5-b]pyridazin-7-amine;2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(trifluoromethoxy)cyclohexyl)imidazo[1,5- b]pyridazin-7-amine;2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-5- (trifluoromethyl)imidazo[1,5-b]pyridazin-7-amine;2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-4,5- dimethylimidazo[1,5-b]pyridazin-7-amine;1-(7-((6-(1H-imidazol-1-yl)imidazo[1,2-b]pyridazin-3-yl)amino)-2- azaspiro[3.5]nonan-2-yl)-2-methoxyethan-1-one;N-(2-(2,2-difluoroethyl)-2-azaspiro[3.5]nonan-7-yl)-6-(1H-imidazol-1- yl)imidazo[1 ,2-b]pyridazin-3-amine; ;6-(1H-imidazol-1-yl)-8-methoxy-N-((1r,4r)-4-(2- methoxyethoxy)cyclohexyl)imidazo[1,2-b]pyridazin-3-amine;6-(1 H-imidazol-1-yl)-3-(((1 r,4r)-4-(2- methoxyethoxy)cyclohexyl)amino)imidazo[1,2-b]pyridazin-8-ol;6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(trifluoromethoxy)cyclohexyl)imidazo[1,2- b]pyridazin-3-amine;N-((1r,4r)-4-(2,2-difluoroethoxy)cyclohexyl)-6-(1H-imidazol-1-yl)imidazo[1,2- b]pyridazin-3-amine;Docket no. 24-2207-WON-S1 / SetAN-((1r,4r)-4-(2,2-difluoroethoxy)cyclohexyl)-2-(1H-imidazol-1-yl)-5- methylimidazo[1,5-b]pyridazin-7-amine;or a pharmaceutically acceptable salt thereof.

[0094] Pharmaceutical Compositions

[0095] 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.

[0096] 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).

[0097] 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.

[0098] 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.Docket no. 24-2207-WON-S1 / SetA

[0099] 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 from about 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.

[0100] 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).

[0101] 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.

[0102] 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.

[0103] Methods of TreatmentDocket no. 24-2207-WON-S1 / SetA

[0104] 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 described herein, a pharmaceutically acceptable salt thereof, or one or more of the pharmaceutical compositions as described herein to a subject in need thereof.

[0105] 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 pulomonary fibrosis, systemic scleroderma, osteoarthritis, sarcopenia, and rheumatoid arthritis.EXAMPLES

[0106] 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.

[0107] AbbreviationsDocket no. 24-2207-WON-S1 / SetADocket no. 24-2207-WON-S1 / SetADocket no. 24-2207-WON-S1 / SetA

[0108] General conditions:

[0109] Commercial anhydrous solvents are used in reactions where specified. HPLC grade solvents are used for all other reactions, work-up and chromatography.

[0110] Reported yields are corrected for LC / MS purity (determined by LIV (215 nm) or ELS detection) unless otherwise stated.

[0111] Microwave experiments are carried out using a Biotage Initiator.

[0112] 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.

[0113] Example 1: Synthesis of 2-(1H-imidazol-1-yl)-N-(((1r,4r)-4-methoxycyclohexyl)methyl)imidazo[1,5-b]pyridazin-7-aminePreparation of 1-4"Preparation of Compound 1Docket no. 24-2207-WON-S1 / SetA1-7 Compound 1

[0114] Synthesis of (1r,4r)-4-((dibenzylamino)methyl)cyclohexan-1-ol

[0115] To a stirred solution of (1r,4r)-4-(aminomethyl)cyclohexan-1-ol (4.5 g, 34.8 mmol, 1 eq) in ACN (100 mL) is added K2CO3 (14.4 g, 104.4 mmol, 3 eq) and BnBr (17.8 g, 104.4 mmol, 3 eq) at room temperature. The resulting mixture is stirred at 70°C for overnight. The resulting mixture is filtered, the filter cake is washed with MeCN. The filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography, eluted with PE I EA (1:1) to afford (1r,4r)-4-[(dibenzylamino) methyl]cyclohexan-1-ol (8 g, 74% yield) as an off-white solid. LC / MS: mass calcd. For C2iH2?NO: 309.2, found: 310.2 [M+H]+.

[0116] Synthesis of dibenzyl({[(1 r,4r)-4-methoxycyclohexyl]methyl})amine

[0117] To a solution of (1r,4r)-4-[(dibenzylamino)methyl]cyclohexan-1-ol (1 g, 3.2 mmol, 1 eq) in 1,3-dimethyl-1,3-diazinan-2-one (15 mL) is added NaH (1.3 g, 32.3 mmol, 10 eq, 60% in oil) at 0 °C under N2 atmosphere. The reaction is stirred at 0°C for 1 hour and then Mel (676 mg, 4.8 mmol, 1.5 eq) is added. The reaction is stirred at room temperature for 2 h. The reaction is cooled to 0°C and quenched with sat. NH4CI solution (50 mL). The resulting mixture is extracted with EtOAc (3x50 mL). The combined organic layers are washed with brine (1x50 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford dibenzyl({[(1r,4r)-4-methoxycyclohexyl]methyl})amine (800 mg, 76% yield) as a colorless oil. LC / MS: mass calcd. For C22H29NO: 323.2, found:324.2 [M+H]+.

[0118] Synthesis of ((1r,4r)-4-methoxycyclohexyl)methanamine hydrochloride

[0119] A mixture of dibenzyl({[(1r,4r)-4-methoxycyclohexyl]methyl})amine (800 mg, 2.5 mmol, 1 eq) and palladium hydroxide (200 mg, 25% w / w) in EtOH (10 mL) is stirred at room temperature for 4 hours under hydrogen atmosphere. 4 N HCI (0.7 mL) in MeOH is added toDocket no. 24-2207-WON-S1 / SetAthe reaction. The resulting mixture is filtered, the filter cake is washed with EtOH (2x10 mL). The filtrate is concentrated under reduced pressure to afford ((1 r,4r)-4-methoxycyclohexyl)methanamine hydrochloride (400 mg, crude) as an off-white solid.LC / MS: mass calcd. C8HI7NO: 143.1, found: 144.2 [M+H]+.

[0120] Synthesis of 1-(6-chloropyridazin-3-yl)methanamine

[0121] To a solution of 3-chloro-6-(chloromethyl)pyridazine (1.5 g, 9.2 mmol, 1 eq) in methanol (38 mL) is added NHsin MeOH (150 mL) at 0°C. The reaction is stirred at room temperature for 48h. The reaction is concentrated. The residue is purified by silica gel column chromatography, eluted with ChhCh / MeOH (5:1) to afford 1-(6-chloropyridazin-3-yl)methanamine (1 g, 75% yield) as a light brown solid. LC / MS: mass calcd. For CsHeCINs: 143.0, found: 144.0 [M+H]+.

[0122] Synthesis of 1-[(6-chloropyridazin-3-yl)methyl]-3-{[(1r,4r)-4-methoxycyclohexyl]methyl}thiourea

[0123] A solution of 1-[(1r,4r)-4-methoxycyclohexyl]methanamine (330 mg, 2.3 mmol, 1 eq) in CHCI3 (10 mL) is treated with Et3N (940 uL, 6.9 mmol, 3 eq) at 0°C, then thiophosgene (265 mg, 2.3 mmol, 1 eq) in CHCh(5 mL) is added dropwise to the above solution at 0°C. The reaction is stirred at room temperature for 1h. 1-(6-chloropyridazin-3-yl)methanamine (330 mg, 2.3 mmol, 1 eq) is added in batches and then the reaction is stirred at room temperature for 17 h. The reaction is quenched by NaHCO3(aq) (20 mL) at 0°C. The resulting mixture is extracted with CH2CI2 (3x20 mL). The combined organic layers are washed with brine (1x20 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography, eluted with CFLCh / MeOH (20:1) to afford 1-[(6-chloropyridazin-3-yl)methyl]-3-{[(1r,4r)-4-methoxycyclohexyl]methyl}thiourea (168 mg, 22% yield) as a red solid. LC / MS: mass calcd. For C14H21CIN4OS: 328.1, found:329.1 [M+H]+.

[0124] Synthesis of 2-chloro-N-{[(1 r,4r)-4-methoxycyclohexyl]methyl}imidazo[1 ,5-b]pyridazin-7-amine

[0125] A mixture of 1-[(6-chloropyridazin-3-yl)methyl]-3-{[(1r,4r)-4-methoxycyclohexyl]methyl}thiourea (150 mg, 0.4 mmol, 1 eq) and DCC (247 mg, 1.2 mmol, 3 eq) in toluene (5 mL) is stirred for 6h at 110°C under nitrogen atmosphere. The reaction is quenched by NaHCCh (aq.) (10 mL) at 0 °C. The resulting mixture is extracted with EtOAc (3x20 mL). The combined organic layers are washed with brine (1x20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography, eluted with CFhCh / MeOH (15:1) toDocket no. 24-2207-WON-S1 / SetAafford 2-chloro-N-{[(1r,4r)-4-methoxycyclohexyl]methyl}imidazo[1,5-b]pyridazin-7-amine (100 mg, 74% yield) as a red solid. LC / MS: mass calcd. For C14H19CIN4O: 294.1, found:295.0[M+H]+.

[0126] Synthesis of 2-(1H-imidazol-1-yl)-N-(((1r,4r)-4-methoxycyclohexyl)methyl)imidazo[1,5-b]pyridazin-7-amine

[0127] Into a 30 mL tube is added 2-chloro-N-{[(1r,4r)-4-methoxycyclohexyl]methyl}imidazo[1,5-b]pyridazin-7-amine (100 mg, 0.3 mmol, 1 eq), imidazole (41 mg, 0.6 mmol, 2 eq), CS2CO3 (325 mg, 1 mmol, 3 eq) and DMF (5 mL), the reaction is stirred at 100°C for 2 h in a microwave reactor. The mixture is filtered and purified by Prep-HPLC (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%): 9%B to 39%B in 7min, Wave Length: UV 254 nm) to afford 2-(1H-imidazol-1-yl)-N-(((1r,4r)-4-methoxycyclohexyl)methyl)imidazo[1,5-b]pyridazin-7-amine (28.5 mg, 25% yield) as a red solid. LC / MS: mass calcd. For CI7H22N6O: 326.2, found: 327.2 [M+H]+.1H NMR (400 MHz, DMSO-cfe) 58.62 (s, 1H), 8.07 (s, 1H), 8.01 (d, J= 4.8 Hz, 1H), 7.10 - 7.20 (m, 2H), 6.86 (d, J= 6.0 Hz, 1H), 6.49 (t, J= 6.0 Hz, 1H), 3.22 - 3.32 (m, 5H), 3.01 - 3.13 (m, 1H), 1.95 - 2.05 (m, 2H), 1.76 - 1.91 (m, 2H), 1.56 - 1.71 (m, 1H), 0.90 - 1.15 (m, 4H).

[0128] Example 2: Synthesis of N-(((1r,4r)-4-methoxycyclohexyl)methyl)-2-(1-methyl-1 H-imidazol-5-yl)imidazo[1 ,5-b]pyridazin-7-amine

[0129] To a stirred solution of 2-chloro-N-{[(1r,4r)-4-methoxycyclohexyl]methyl}imidazo[1,5-b]pyridazin-7-amine (110 mg, 0.4 mmol, 1 eq) and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazole (166 mg, 0.8 mmol, 2 eq) in dioxane (4 mL) and H2O (0.8 mL) are added Na2CO3 (148 mg, 1.4 mmol, 3.5 eq), Pd(dppf)Cl2.DCM (65 mg, 0.08 mmol, 0.2 eq) at room temperature under nitrogen atmosphere. The resulting mixture is stirred at 100°C for 2h under nitrogen atmosphere. The resulting mixture is filtrated and concentrated. The residue is diluted with water (10 mL), extracted with CH2CI2 (3x10 mL). The combined organic layers are washed with brine (1x20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate is concentrated under reduced pressure. The residue is purified by Prep-HPLC ( Column: YMC Triart C18 ExRs Column, 30*150 mm, 5 urn; Mobile Phase A: waterDocket no. 24-2207-WON-S1 / SetA(10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 10%B to 40%B in 11min; Wave Length: 254 / 220 nm ) to afford N-(((1r,4r)-4-methoxycyclohexyl)methyl)-2-(1-methyl-1H-imidazol-5-yl)imidazo[1,5-b]pyridazin-7-amine (25.1 mg, 20% yield) as an orange solid. LC / MS: mass calcd. For Ci8H24N6O: 340.2, found: 341.1 [M+H]+.1H NMR (300 MHz, DMSO-cfe) 67.81 (s, 1H), 7.77 (d, J= 9.0 Hz, 1H), 7.65 (s, 1 H), 6.99 (s, 1 H), 6.66 (d, J = 9.0 Hz, 1 H), 6.08 (t, J = 6.0 Hz, 1 H), 4.01 (s, 3H), 3.23 (t, J = 6.0 Hz, 2H), 3.20 (s, 3H), 2.96 - 3.10 (m, 1H), 1.92 - 2.04 (m, 2H), 1.73 - 1.83 (m, 2H), 1.55 -1.68 (m, 1H), 0.85 - 1.12 (m, 4H).

[0130] Example 3: Synthesis of N-(((1r,4r)-4-methoxycyclohexyl)methyl)-2-(thiazol-5-yl)imidazo[1,5-b]pyridazin-7-amine

[0131] To a stirred solution of 2-chloro-N-{[(1r,4r)-4-methoxycyclohexyl]methyl}imidazo[1,5-b]pyridazin-7-amine (80 mg, 0.3 mmol, 1 eq) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-thiazole (126 mg, 0.6 mmol, 2 eq) in dioxane (2.4 mL) and H2O (0.6 mL) are added Na2CO3 (111 mg, 1.1 mmol, 3.5 eq) and Pd(dppf)CI2.CH2CI2(49 mg, 0.06 mmol, 0.2 eq) in portions at room temperature under nitrogen atmosphere. The resulting mixture is stirred at 100°C for 2h under nitrogen atmosphere. The resulting mixture is filtrated and concentrated. The residue is extracted with CH2CI2(3x10 mL) and water (3x10 mL). The combined organic layers are washed with brine (20 mL), and dried over anhydrous Na2SC>4. After filtration, the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography, eluted with CH2CI21 MeOH (20:1). The fractions are combined and concentrated under reduced pressure. The crude product is purified by Prep-HPLC (Column: XBridge BEH Shield RP18 Column, 30*150 mm, 5 pm; Mobile Phase A: water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient (B%): 6% B to 25% B in 7 min; Wave Length: 254nm / 220 nm) to afford N-(((1r,4r)-4-methoxycyclohexyl)methyl)-2-(thiazol-5-yl)imidazo[1,5-b]pyridazin-7-amine (18.8 mg, 18% yield) as a reddish brown solid. LC / MS: mass calcd. For CI7H2IN5OS: 343.1, found: 344.1 [M+H]+.1H NMR (300 MHz, DMSO-cfe) 69.24 (s, 1H), 8.66 (s, 1H), 7.88 (d, J= 9.6 Hz, 1H), 7.07 (s, 1H), 6.92 (d, J= 9.3 Hz, 1H), 6.28 (t, J = 6.0 Hz, 1H), 3.25 (t, J = 6.3 Hz, 2H), 3.22 (s, 3H), 2.99 - 3.13 (m, 1H), 1.94 - 2.05 (m, 2H), 1.75 - 1.85 (m, 2H), 1.57 - 1.73 (m, 1H), 0.87 - 1.14 (m, 4H).Docket no. 24-2207-WON-S1 / SetA

[0132] Example 4: Synthesis of 6-(1H-imidazol-1-yl)-N-(((1r,4r)-4-methoxycyclohexyl)methyl)imidazo[1,2-b]pyridazin-3-amine

[0133] Synthesis of 3-bromo-6-(1H-imidazol-1-yl)imidazo[1,2-b]pyridazine

[0134] To a stirred solution of 3-bromo-6-chloroimidazo[1,2-b]pyridazine (500 mg, 2.1 mmol, 1 eq) in DMF (10 mL) is added K2CO3 (896 mg, 6.3 mmol, 3 eq) and 1H-imidazole (286 mg, 4.2 mmol, 2 eq). The resulting mixture is stirred for 17h at 100°C. The reaction is poured into 30 mL ice / water. The solid is filtered and washed by water, dried under vacuum.3-bromo-6-(1H-imidazol-1-yl)imidazo[1,2-b]pyridazine (400 mg, 70% yield) is obtained as an off-white solid. LC / MS: mass calcd. for CgHeBrNs: 262.9, found: 263.9 [M+H]+.

[0135] Synthesis of 6-(1H-imidazol-1-yl)-N-(((1r,4r)-4-methoxycyclohexyl)methyl)imidazo[1,2-b]pyridazin-3-amine

[0136] To a stirred solution of 3-bromo-6-(1H-imidazol-1-yl)imidazo[1,2-b]pyridazine (80 mg, 0.3 mmol, 1 eq) in dioxane (7 mL) is added 1-[(1r,4r)-4-methoxycyclohexyl]methanamine (107 mg, 0.6 mmol, 2 eq), CS2CO3 (292 mg, 0.9 mmol, 3 eq) and Pd-PEPPSI-IPentCI-o-picoline (25.2 mg, 30 umol, 0.1 eq) under a nitrogen atmosphere. The resulting mixture is stirred for 3h at 100°C. The resulting mixture is filtered, the filter cake is washed with MeOH (3x15mL). The filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography, eluted with DCM / MeOH (15:1) to afford the crude product. 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%): 17% B to 32% B in 10 min; Wave Length: 254nm / 220nm nm to afford 6-(1H-imidazol-1-yl)-N-(((1r,4r)-4-methoxycyclohexyl)methyl)imidazo[1,2-b]pyridazin-3-amine (36.1 mg, 29%yield) is obtained as a orange solid. LC / MS: mass calcd. for C17H22N6O: 326.1, found: 327.1 [M+H]+.1H NMR (300 MHz, DMSO-cfe) 68.65 (s, 1H), 8.03 - 8.13 (m, 2H), 7.38 (d, J= 9.9 Hz, 1H), 7.11 - 7.20 (m, 2H), 5.91 (t, J = 6.3 Hz, 1 H), 3.21 (s, 3H), 3.07 (t, J = 6.3 Hz, 3H), 1.95 - 2.05 (m, 2H), 1.80 - 1.90 (m, 2H), 1.52 - 1.69 (m, 1H), 0.89 - 1.16 (m, 4H).Docket no. 24-2207-WON-S1 / SetA

[0137] Example 5: Synthesis of 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-methoxycyclohexyl)imidazo[1,5-b]pyridazin-7-amine5-3 Compound 5

[0138] Synthesis of 1-((6-chloropyridazin-3-yl)methyl)-3-((1r,4r)-4-methoxycyclohexyl)thiourea

[0139] A solution of (1r,4r)-4-methoxycyclohexan-1 -amine (270 mg, 2.1 mmol, 1 eq) in THF (8 mL) is treated with Et3N (875 uL, 6.3 mmol, 3 eq) and 1-[(1H-imidazol-1-yl)carbothioyl]-1H-imidazole (374 mg, 2.1 mmol, 1 eq) at 0°C, The reaction is stirred at room temperature for 1 h. 1-(6-chloropyridazin-3-yl)methanamine (300 mg, 2.1 mmol, 1 eq) is added and then the reaction is stirred at room temperature for 17 h. The reaction is quenched by NaHCO3(aq) (30 mL) at 0°C. The resulting mixture is extracted with EA (3x30 mL). The combined organic layers are washed with brine (1x30 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography, eluted with CH2CI2 / EA (2:1) to afford 3-[(6-chloropyridazin-3-yl)methyl]-1-[(1r,4r)-4-methoxycyclohexyl]thiourea (300 mg, 46% yield) as a yellow solid. LC / MS: mass calcd. for C13H19CIN4OS: 314.1, found: 315.2 [M+H]+.

[0140] Synthesis of 2-chloro-N-((1r,4r)-4-methoxycyclohexyl)imidazo[1 ,5-b]pyridazin-7-amine

[0141] To a stirred solution of 3-[(6-chloropyridazin-3-yl)methyl]-1-[(1r,4r)-4-methoxycyclohexyl]thiourea (290 mg, 0.9 mmol, 1 eq) in toluene (7 mL) is added DCC (560 mg, 2.7 mmol, 3 eq) under a nitrogen atmosphere. The resulting mixture is stirred for6h at 110°C. The reaction is quenched by NaHCO3(aq) (20 mL) at 0°C. The resulting mixture is extracted with EA (3x20 mL). The combined organic layers are washed with brine (1x20 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 CH2CI2 / EA (2:1) to afford 2-chloro-N-[(1r,4r)-4-methoxycyclohexyl]imidazo[1,5-b]pyridazin-7-amine (160Docket no. 24-2207-WON-S1 / SetAmg, 61.8%) as a yellow solid. LC / MS: mass calcd. for C13H17CIN4O: 280.1, found: 281.1 [M+H]+.

[0142] Synthesis of 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-methoxycyclohexyl)imidazo[1,5-b]pyridazin-7-amine

[0143] To a stirred solution of 2-chloro-N-[(1r,4r)-4-methoxycyclohexyl]imidazo[1,5-b]pyridazin-7-amine (90 mg, 0.3 mmol, 1 eq) in DMF (3 mL) is added CS2CO3 (325 mg, 1 mmol, 3 eq) and imidazole (40 mg, 0.6 mmol, 2 eq). The final reaction mixture is irradiated with microwave radiation at 100°C for 2h. The reaction mixture is filtered and the filtration in DMF 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%): 28% B to 43% B in 15 min; Wave Length: 254 nm / 220 nm ) to afford 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-methoxycyclohexyl)imidazo[1,5-b]pyridazin-7-amine (45.7 mg, 45% yield) is obtained as a red solid. LC / MS: mass calcd. for CieFLoNeO: 312.17, found: 313.05 [M+H]+.1H NMR (300 MHz, DMSO-cfe) 68.61 (s, 1H), 7.96 - 8.10 (m, 2H), 7.11 - 7.19 (m, 2H), 6.85 (d, J= 9.6 Hz, 1H), 6.14 (d, J= 8.0 Hz, 1H), 3.59 - 3.74 (m, 1H), 3.24 (s, 3H), 3.07 - 3.20 (m, 1H), 1.98 - 2.10 (m, 4H), 1.32 - 1.50 (m, 2H), 1.23 - 1.30 (m, 2H).

[0144] Example 6: Synthesis of 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)imidazo[1,5-b]pyridazin-7-amineompoun

[0145] Synthesis of 1-[(6-chloropyridazin-3-yl)methyl]-3-[(1r,4r)-4-(2-methoxyethoxy)cyclohexyl]thioureaDocket no. 24-2207-WON-S1 / SetA

[0146] To a stirred solution of (1r,4r)-4-(2-methoxyethoxy)cyclohexan-1 -amine (301 mg, 1.7 mmol, 1 eq) in THF (15 mL) are added TEA (725 uL, 5.2 mmol, 3 eq) and TCDI (310 mg, 1.7 mmol, 1 eq) at 0°C. The resulting mixture is stirred at room temperature for 1 h. To the above mixture is added 1-(6-chloropyridazin-3-yl)methanamine (250 mg, 1.7 mmol, 1 eq) at room temperature. The resulting mixture is stirred at room temperature overnight. The reaction is quenched with sat. NaHCCh (aq.) at 0°C. The resulting mixture is extracted with EtOAc (3 x 30 mL). The combined organic layers are washed with brine (3x10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography and eluted with PE / EA (1:1) to afford 1-[(6-chloropyridazin-3-yl)methyl]-3-[(1r,4r)-4-(2-methoxyethoxy)cyclohexyl]thiourea (310 mg, 49.6% yield) as a dark red solid. LC / MS: mass calcd. for C15H23CIN4O2S: 358.1, found: 359.1 [M+H]+.

[0147] Synthesis of 2-chloro-N-[4-(2-methoxyethoxy)cyclohexyl]imidazo[1,5-b]pyridazin-7-amine

[0148] A solution of 1-[(6-chloropyridazin-3-yl)methyl]-3-[(1r,4r)-4-(2-methoxyethoxy)cyclohexyl]thiourea (300 mg, 0.8 mmol, 1 eq) and DCC (517 mg, 2.5 mmol, 3 eq) in toluene (15 mL) is stirred at 110°C overnight under nitrogen atmosphere. The reaction is quenched by the addition of sat. NaHCOs (aq.) (20 mL) at 0°C. The resulting mixture is extracted with EtOAc (3x20 mL). The combined organic layers are washed with brine (1x10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate is concentrated under reduced pressure. The residue is purified by Prep-TLC (100% EA) to afford 2-chloro-N-[4-(2-methoxyethoxy)cyclohexyl]imidazo[1,5-b]pyridazin-7-amine (140 mg, 51% yield) as a red solid. LC / MS: mass calcd. for C15H21CIN4O2: 324.1, found: 325.1 [M+H]+.

[0149] Synthesis of 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)imidazo[1,5-b]pyridazin-7-amine

[0150] A solution of 2-chloro-N-[4-(2-methoxyethoxy)cyclohexyl]imidazo[1 ,5-b]pyridazin-7-amine (70 mg, 0.2 mmol, 1 eq), imidazole (29 mg, 0.4 mmol, 2 eq) and CS2CO3 (195 mg, 0.6 mmol, 3 eq) in DMF (5 mL) is irradiated with microwave radiation at 100°C for 2h. 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 mL / min; Gradient (B%): 13% B to 28% B in 10 min; Wave Length: 254 nm / 220 nm) to afford 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)imidazo[1,5-b]pyridazin-7-amine (44.9 mg, 58% yield) as a red semi-solid. LC / MS: mass calcd. for C18H24N6O2: 356.2, found: 357.2 [M+H]+.1H NMR (300 MHz, DMSO-d6) 58.61 (s, 1H), 8.07 (s, 1H), 8.01 (d, J= 9.6 Hz, 1H), 7.13 - 7.16 (m, 2H), 6.85 (d, J= 9.6 Hz, 1H), 6.14 (d, J= 8.1Docket no. 24-2207-WON-S1 / SetAHz, 1 H), 3.59 - 3.73 (m, 1 H), 3.50 - 3.56 (m, 2H), 3.24 - 3.29 (m, 2H), 3.23 (s, 3H), 1.96 -2.08 (m, 4H), 1.32 - 1.49 (m, 2H), 1.15 - 1.32 (m, 2H).

[0151] Example 7: Synthesis of N-((2-oxaspiro[3.5]nonan-7-yl)methyl)-6-(1H-imidazol-1-yl)imidazo[1,2-b]pyridazin-3-amine4-2 Dioxane, 100°C, 3 h Compound 7

[0152] To a stirred solution of 1-{3-bromoimidazo[1,2-b]pyridazin-6-yl}imidazole (80 mg, 0.3 mmol, 1 eq) in dioxane (7 mL) is added 1-{2-oxaspiro[3.5]nonan-7-yl}methanamine (47 mg, 0.3 mmol, 1 eq), CS2CO3 (325 mg, 1 mmol, 3 eq) and Pd-PEPPSI-IPentCI-o-picoline (25 mg, 0.03 mmol, 0.1 eq) under a nitrogen atmosphere. The resulting mixture is stirred for 3h at 100°C. The resulting mixture is filtered and the filter cake is washed with MeOH (3x15mL). The filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography and eluted with DCM / MeOH (15 / 1) to afford the crude product. 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 NH4HCC>3+0.1% NH3.H2O), Mobile Phase B: ACN; Flow rate: 25 mL / min; Gradient (B%): 19%B to 40%B in 12min; Wave Length: 254 / 220 nm) to afford N-((2-oxaspiro[3.5]nonan-7-yl)methyl)-6-(1H-imidazol-1-yl)imidazo[1,2-b]pyridazin-3-amine (34.4 mg, 33% yield) as as an orange solid. LC / MS: mass calcd. for CI8H22N6O: 338.18, found: 339.20 [M+H]+.1H NMR (300 MHz, DMSO-d6) 58.65 (s, 1H), 8.04 - 8.11 (m, 2H), 7.38 (d, J= 9.6 Hz, 1H), 7.11 - 7.20 (m, 2H), 5.90 (t, J = 6.3 Hz, 1H), 4.28 (s, 2H), 4.18 (s, 2H), 3.05 (t, J = 6.6 Hz, 2H), 1.98 - 2.09 (m, 2H), 1.67 - 2.78 (m, 2H), 1.49 - 1.66 (m, 1 H), 1.29 - 1.45 (m, 2H), 0.85 - 1.03 (m, 2H).

[0153] Example 8: Synthesis of 4-((6-(1H-imidazol-1-yl)imidazo[1,2-b]pyridazin-3-yl)amino)tetrahydro-2H-thiopyran 1,1 -dioxide, ,

[0154] To a stirred solution of 1-{3-bromoimidazo[1,2-b]pyridazin-6-yl}imidazole (80 mg, 0.3 mmol, 1 eq) in dioxane (3 mL) is added 4-amino-1A6-thiane-1, 1-dione (75 mg, 0.5 mmol, 1.5 eq), CS2CO3 (325 mg, 1 mmol, 3 eq) and Pd-PEPPSI-IPentCI-o-picoline (25 mg, 0.03Docket no. 24-2207-WON-S1 / SetAmmol, 0.1 eq) in portions at room temperature. The final reaction mixture is stirred for 3 h at 100°C under N2atmosphere. The reaction mixture is purified by Prep-HPLC (Column:XBridge Prep OBD C18 Column, 30*150 mm, 5pm; Mobile Phase A: water(10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient (B%): 13% B to 25% B in 10 min; Wave Length: 254nm / 220nm to afford 4-((6-(1H-imidazol-1-yl)imidazo[1,2-b]pyridazin-3-yl)amino)tetrahydro-2H-thiopyran 1,1 -dioxide (46.4 mg, 40% yield) as a white solid. LC / MS: mass calcd. for Ci4Hi6N6O2S: 332.1, found: 333.1 [M+H]+.1H NMR (300 MHz, DMSO-cfe) 68.66 (s, 1H), 8.06 - 8.16 (m, 2H), 7.45 (d, J= 9.6 Hz, 1H), 7.15 - 7.27 (m, 2H), 5.92 (d, J= 8.7 Hz, 1H), 3.66 - 3.82 (m, 1H), 3.22 - 3.31 (m, 2H), 3.10 - 3.22 (m, 2H), 2.19 -2.31 (m, 2H), 2.00 - 2.19 (m, 2H).

[0155] Example 9: Synthesis of 6-(1H-imidazol-1-yl)-N-(((1r,4r)-4-methoxycyclohexyl)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-amine

[0156] Synthesis of 1-{3-chloro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl}imidazole

[0157] To a stirred solution of 3,6-dichloro-[1,2,4]triazolo[4,3-b]pyridazine (1 g, 5.3 mmol, 1 eq) and imidazole (0.4 g, 5.4 mmol, 1 eq) in DMF (15 mL) is added K2COs (2.2 g, 15.9 mmol, 3 eq) at room temperature. The resulting mixture is stirred at 100°C overnight. The mixture is allowed to cool down to room temperature. The reaction is diluted with water (20 mL). The resulting mixture is extracted with EtOAc (3x30 mL). The combined organic layers are combined and washed with brine, dried over anhydrous Na2SC>4. After filtration, the filtrate is concentrated under reduced pressure. This resulted in 1-{3-chloro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl}imidazole (600 mg, crude) as an off-white solid. The crude product is used in the next step directly without further purification. LC / MS: mass calcd. for CsHsCINe: 220.0, found: 221.0 [M+H]+.

[0158] Synthesis of 6-(1H-imidazol-1-yl)-N-(((1r,4r)-4-methoxycyclohexyl)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-amine

[0159] To a stirred solution of 1-{3-chloro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl}imidazole (70 mg, 0.3 mmol, 1 eq) and 1-[(1r,4r)-4-methoxycyclohexyl]methanamine (91 mg, 0.6 mmol, 2 eq) in dioxane (5 mL) is added Cs2CC>3 (310 mg, 0.9 mmol, 3 eq) and Pd-PEPPSI-IPentCI-o-picoline (26.7 mg, 0.03 mmol, 0.1 eq) at room temperature under nitrogen atmosphere. TheDocket no. 24-2207-WON-S1 / SetAresulting mixture is stirred at 90°C for 32h. The mixture is allowed to cool down to room temperature. The resulting mixture is filtered and the filter cake is washed with CH2CI2 (3x5 mL). The filtrate is concentrated under reduced pressure. The residue is purified by reversephase flash chromatography (column C18; mobile phase, MeCN in water (0.1% TFA), 10% to 20% gradient in 10 min; detector, LIV 254 nm). The fractions are combined and concentrated. 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%): 8% B to 23% B in 10 min; Wave Length: 254 nm / 220 nm) to afford 6-(1H-imidazol-1-yl)-N-(((1r,4r)-4-methoxycyclohexyl)methyl)- [1,2,4]triazolo[4,3-b]pyridazin-3-amine (9.5 mg, 9% yield) as a light yellow solid. LC / MS: mass calcd. for CI6H2IN7O: 327.2, found: 328.1 [M+H]+.1H NMR (300 MHz, DMSO-d6) 5 8.64 (s, 1H), 8.26 (d, J= 9.9 Hz, 1H), 8.06 (s 1H), 7.63 (d, J= 9.9 Hz, 1H), 7.20 (s, 1H), 6.86 (t, J = 6.0 Hz, 1H), 3.26 (t, J = Q.Q Hz, 2H), 3.21 (s, 3H), 2.99 - 3.13 (m, 1H), 1.95 - 2.06 (m, 2H), 1.76 - 1.87 (m, 2H), 1.59 - 1.73 (m, 1H), 0.89 - 1.15 (m, 4H).

[0160] Example 10: Synthesis of 2-( 1 H-imidazol-1 -yl)-N-(2-(methylsulfonyl)-2- azaspiro[3.5]nonan-7-yl)imidazo[1,5-b]pyridazin-7-amine

[0161] Synthesis of tert-butyl 7-({[(6-chloropyridazin-3-yl)methyl]carbamothioyl}amino)-2- azaspiro[3.5] nonane-2-carboxylate

[0162] To a stirred solution of tert-butyl 7-amino-2-azaspiro[3.5]nonane-2-carboxylate (300 mg, 1.2 mmol, 1 eq) in THF (15 mL) is added TEA (0.5 mL, 3.6 mmol, 3 eq) and 1-[(1H- imidazol-1-yl)carbothioyl]-1H-imidazole (222 mg, 1.2 mmol, 1 eq) at O°C. The mixture is stirred for 1.0 h at room temperature, then 1-(6-chloropyridazin-3-yl)methanamine (179 mg, 1.2 mmol, 1 eq) in THF (5 mL) is added at 0°C. The mixture is stirred for 17h at room temperature. The reaction is quenched with sat. NaHCCh (aq.), 30 mL at 0°C. The resulting mixture is extracted with EtOAc (3x30 mL). The combined organic layers are washed withDocket no. 24-2207-WON-S1 / SetAbrine (2x30 mL) and dried over anhydrous Na2SC>4. The residue is purified by silica gel column chromatography and eluted with CF^Ch / MeOH (9:1) to afford tert-butyl 7-({[(6-chloropyridazin-3-yl)methyl]carbamothioyl} amino)-2-azaspiro[3.5]nonane-2-carboxylate (250 mg, 47% yield) as a yellow solid. LC / MS: mass calcd. for C19H28CIN5O2S: 425.2, found: 426.1 [M+H]+.

[0163] Synthesis of tert-butyl 7-({2-chloroimidazo[1 ,5-b]pyridazin-7-yl}amino)-2-azaspiro[3.5]nonane-2-carboxylate

[0164] To a stirred solution of tert-butyl 7-({[(6-chloropyridazin-3-yl)methyl]carbamothioyl}amino)-2-azaspiro[3.5] nonane-2-carboxylate (230 mg, 0.5 mmol, 1 eq) in toluene (10 mL) is added DCC (334 mg, 1.5 mmol, 3 eq) at room temperature. The resulting mixture is stirred for 6h at 110°C. The reaction is quenched by the addition of sat. NaHCOs (aq.) (20 mL) at 0°C. The resulting mixture is extracted with EtOAc (3x20 mL). The combined organic layers are washed with brine (2x50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate is concentrated under reduced pressure. The residue is purified by Prep-TLC and eluted with DCM / MeOH (20:1) to afford tert-butyl 7-({2-chloroimidazo[1,5-b]pyridazin-7-yl}amino)-2-azaspiro[3.5]nonane-2-carboxylate (100 mg, 47% yield) as a yellow solid. LC / MS: mass calcd. for C19H26CIN5O2: 391.2, found: 392.3 [M+H]+.

[0165] Synthesis of tert-butyl 7-{[2-(imidazol-1-yl)imidazo[1,5-b]pyridazin-7-yl]amino}-2-azaspiro[3.5] nonane-2-carboxylate

[0166] To a stirred solution of tert-butyl 7-({2-chloroimidazo[1,5-b]pyridazin-7-yl}amino)-2-azaspiro[3.5]nonane-2-carboxylate (90 mg, 0.2 mmol, 1 eq) in DMF (3 mL) is added CS2CO3 (224 mg, 0.6 mmol, 3 eq) and imidazole (41 mg, 0.6 mmol, 3 eq) at room temperature. The final reaction mixture is irradiated with microwave radiation at 100°C for 2h. The reaction mixture is filtered and the filtrate is concentrated. The residue is purified by reverse flash chromatography with the following conditions (C18 column; mobile phase, ACN in water (0.05% NH4HCO3), 5% to 36% gradient in 30 min; detector, UV 254 nm) to afford tert-butyl 7-{[2-(imidazol-1-yl)imidazo[1,5-b]pyridazin-7-yl]amino}-2-azaspiro[3.5]nonane-2-carboxylate (65 mg, 67 % yield) as a reddish brown solid. LC / MS: mass calcd. for C22H29N7O2: 423.2, found: 424.2 [M+H]+.

[0167] Synthesis of tert-butyl 7-{[2-(imidazol-1-yl)imidazo[1,5-b]pyridazin-7-yl]amino}-2-azaspiro[3.5] nonane-2-carboxylate

[0168] To a stirred solution of N-[2-(imidazol-1-yl)imidazo[1,5-b]pyridazin-7-yl]-2-azaspiro[3.5]nonan-7-amine (65 mg, 0.2 umol, 1 eq) in DCM (10 mL) is added HCI in 1,4-dioxane (4 M) (2.5 mL) dropwise at room temperature. The resulting mixture is stirred forDocket no. 24-2207-WON-S1 / SetA4. Oh at room temperature. The resulting mixture is concentrated under vacuum. Tert-butyl 7-{[2-(imidazol-1-yl)imidazo[1,5-b]pyridazin-7-yl]amino}-2-azaspiro[3.5]nonane-2-carboxylate (50 mg, crude) is obtained as an off-white solid. LC / MS: mass calcd. forCi7H2iN7: 323.2, found: 324.1 [M+H]+.

[0169] Synthesis of 2-(1H-imidazol-1-yl)-N-(2-(methylsulfonyl)-2-azaspiro[3.5]nonan-7-yl)imidazo[1,5-b]pyridazin-7-amine

[0170] To a stirred solution of N-[2-(imidazol-1-yl)imidazo[1,5-b]pyridazin-7-yl]-2-azaspiro[3.5]nonan-7-amine (40 mg, 0.1 mmol, 1 eq) in DMF (3 mL) is added TEA (206 uL, 1.2 mmol, 12 eq) and MsCI (31 uL, 0.5 mmol, 5 eq) at 0°C. The resulting mixture is stirred for 1 h at room temperature. The mixture 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%): 18% B to 35% B in 7 min; Wave Length: 254 / 220 nm) to afford 2-(1H-imidazol-1-yl)-N-(2-(methylsulfonyl)-2-azaspiro[3.5]nonan-7-yl)imidazo[1,5-b]pyridazin-7-amine (18.3 mg, 36% yield) as an orange solid. LC / MS: mass calcd. for C18H23N7O2S: 401.2, found: 402.2 [M+H]+.1H NMR (300 MHz, DMSO-cfe) 68.61 (s, 1H), 8.06 (s, 1H), 8.00 (d, J= 9.6 Hz, 1H), 7.15 (s, 1H), 7.14 (s, 1H), 6.85 (d, J= 9.6 Hz, 1H), 6.14 (d, J= 8.1 Hz, 1H), 3.66 - 3.73 (m, 1H), 3.64 (s, 2H), 3.55 (s, 2H), 3.00 (s, 3H), 1.82 - 2.02 (m, 4H), 1.48 - 1.63 (m, 2H), 1.28 - 1.48 (m, 2H).

[0171] Example 11: Synthesis of N-((1r,4r)-4-((2-(1H-imidazol-1-yl)imidazo[1,5-b]pyridazin-7-yl)amino)cyclohexyl)methanesulfonamide

[0172] Synthesis of 3-[(6-chloropyridazin-3-yl)methyl]-1-[(1r,4r)-4-methanesulfonamidocyclohexyl]thioureaDocket no. 24-2207-WON-S1 / SetA

[0173] To a stirred solution of N-[(1r,4r)-4-aminocyclohexyl]methanesulfonamide (321.4 mg, 1.7 mmol, 1.2 eq) in THF (10 mL) are added TEA (423 mg, 4.2 mmol, 3 eq) and 1-(imidazole-l-carbothioyl)imidazole (298 mg, 1.7 mmol, 1.2 eq) at O°C. The resulting mixture is stirred at room temperature for 1h. To the above mixture is added 1-(6-chloropyridazin-3-yl)methanamine (200 mg, 1.4 mmol, 1 eq) at 0°C. The resulting mixture is stirred at room temperature overnight. The reaction is quenched with sat. NaHCCh (aq.) (30 mL) at 0°C. The resulting mixture is extracted with EtOAc (3x30 mL). The combined organic layers are washed with brine (1x30 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 CH2CI21 MeOH (20:1) to afford 3-[(6-chloropyridazin-3-yl)methyl]-1-[(1r,4r)-4-methanesulfonamidocyclohexyl] thiourea (180 mg, 34 % yield) as a red solid. LC / MS: mass calcd. for C13H20CIN5O2S2: 377.1, found: 378.2 [M+H]+.

[0174] Synthesis of N-[(1 r,4r)-4-({2-chloroimidazo[1 ,5-b]pyridazin-7 yl}amino)cyclohexyl] methanesulfonamide

[0175] A solution of 3-[(6-chloropyridazin-3-yl)methyl]-1-[(1r,4r)-4-methanesulfonamidocyclohexyl]thiourea (160 mg, 0.4 mmol, 1 eq) and DCC (262 mg, 1.2 mmol, 3 eq) in toluene (10 mL) is stirred at 130°C for24h under nitrogen atmosphere. The reaction is poured into sat. NaHCOs (aq.) at 0°C. The precipitated solids are collected by filtration and washed with ethyl acetate (3x10 mL) (the solid is the starting material). The resulting mixture is extracted with EtOAc (3x10 mL). The combined organic layers are washed with brine (1x20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate is concentrated under reduced pressure. The residue is purified by TLC-plate (CFhCh / MeOH 20:1) to afford N-[(1r,4r)-4-({2-chloroimidazo[1,5-b]pyridazin-7-yl}amino)cyclohexyl]methanesulfonamide (40 mg, 27 % yield) as a red solid. LC / MS: mass calcd. for C13H18CIN5O2S: 343.1, found: 344.1 [M+H]+.

[0176] Synthesis of N-((1r,4r)-4-((2-(1H-imidazol-1-yl)imidazo[1,5-b]pyridazin-7-yl)amino)cyclohexyl)methanesulfonamide

[0177] To a stirred solution of N-[(1r,4r)-4-({2-chloroimidazo[1,5-b]pyridazin-7-yl}amino)cyclohexyl] methanesulfonamide (35 mg, 0.1 mmol, 1 eq) in DMF (2 mL) is added CS2CO3 (100 mg, 0.3 mmol, 3 eq) and imidazole (14 mg, 0.2 mmol, 2 eq) at room temperature. The final reaction mixture is irradiated with microwave radiation at 100°C for 2h. After filtration, the filtrate is purified by Prep-HPLC (Column: Xselect CSH Phenyl Hexy Column, 19*250 mm, 5 pm; Mobile Phase A: Water (10 mmol / L NH4HCC>3+0.1% NH3.H2O), Mobile Phase B: ACN; Flow rate: 25 mL / min; Gradient (B%): 11 %B to 33%B in 12min; Wave Length: 254 / 220 nm) to afford N-((1r,4r)-4-((2-(1H-imidazol-1-yl)imidazo[1,5-b]pyridazin-7-Docket no. 24-2207-WON-S1 / SetAyl)amino)cyclohexyl)methanesulfonamide (14.9 mg, 39% yield) as a yellow solid. LC / MS: mass calcd. for C16H21N7O2S: 375.1, found: 376.1 [M+H]+.1H NMR (300 MHz, DMSO-d6) 5 8.62 (s, 1H), 8.08 (s, 1H), 8.02 (d, J= 9.6 Hz, 1H), 7.13 - 7.20 (m, 2H), 7.05 (d, J= 7.1 Hz, 1H), 6.87 (d, J= 9.6 Hz, 1H), 6.19 (d, J= 8.0 Hz, 1H), 3.55 - 3.71 (m, 1H), 3.06 - 3.22 (m, 1H), 2.93 (s, 3H), 1.89 - 2.11 (m, 4H), 1.27 - 1.57 (m, 4H).

[0178] Example 12: Synthesis of N-((2-oxaspiro[3.5]nonan-7-yl)methyl)-2-(1-methyl-1 H-imidazol-5-yl)imidazo[1 ,5-b]pyridazin-7-amine

[0179] Synthesis of 1-[(6-chloropyridazin-3-yl)methyl]-3-{2-oxaspiro[3.5]nonan-7-ylmethyljthiourea

[0180] A solution of 1-{2-oxaspiro[3.5]nonan-7-yl}methanamine (216 mg, 1.4 mmol, 1 eq) in THF (9 mL) is treated with Et3N (581 uL, 4.2 mmol, 3 eq) and 1-[(1H-imidazol-1-yl)carbothioyl]-1H-imidazole (248 mg, 1.4 mmol, 1 eq) at 0°C. The reaction is stirred at room temperature for 1h. Then 1-(6-chloropyridazin-3-yl) methanamine (200 mg, 1.4 mmol, 1 eq) is added to the above solution and the reaction is stirred at room temperature for 17 hours. The reaction is quenched by NaHCOs(aq) (20 mL) at 0°C. The resulting mixture is extracted with EA (3x20 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 CH2CI2 / EA (2:1) to afford 1-[(6-chloropyridazin-3-yl)methyl]-3-{2-oxaspiro[3.5]nonan-7-ylmethyl}thiourea (300 mg, 63% yield) as a yellow solid. LC / MS: mass calcd. for C15H21CIN4OS: 340.1, found: 341.2 [M+H]+.

[0181] Synthesis of 2-chloro-N-{2-oxaspiro[3.5]nonan-7-ylmethyl}imidazo[1,5-b]pyridazin-7-amine

[0182] To a stirred solution of 1-[(6-chloropyridazin-3-yl)methyl]-3-{2-oxaspiro[3.5]nonan-7-ylmethyljthiourea (280 mg, 0.8 mmol, 1 eq) in toluene (10 mL) is added DCC (495 mg, 2.4 mmol, 3 eq) under a nitrogen atmosphere. The resulting mixture is stirred for 6 h at 110°C. The reaction is quenched by NaHCOs(aq) (30 mL) at 0°C. The resulting mixture is extractedDocket no. 24-2207-WON-S1 / SetAwith EA (3x20 mL). The combined organic layers are washed with brine (1x100 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography, eluted with CH2CI2 / EA (2:1) to afford 2-chloro-N-{2-oxaspiro[3.5]nonan-7-ylmethyl}imidazo[1,5-b]pyridazin-7-amine (100 mg, 39% yield) as a yellow solid. LC / MS: mass calcd. for C15H19CIN4O: 306.1, found: 307.1 [M+H]+.

[0183] Synthesis of N-((2-oxaspiro[3.5]nonan-7-yl)methyl)-2-(1-methyl-1H-imidazol-5-yl)imidazo[1,5-b]pyridazin-7-amine

[0184] To a stirred solution of 2-chloro-N-{2-oxaspiro[3.5]nonan-7-ylmethyl}imidazo[1,5-b]pyridazin-7-amine (65 mg, 0.2 mmol, 1 eq) in dioxane (4 mL) / water (1 mL) is added 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazole (66 mg, 0.3 mmol, 1.5 eq), Na2CO3 (67 mg, 0.6 mmol, 3 eq) and Pd(dppf)Cl2.CH2Cl2 (17.3 mg, 0.02 mmol, 0.1 eq) under a nitrogen atmosphere. The resulting mixture is stirred for 17h at 100°C. The resulting mixture is filtered and the filter cake is washed with MeOH (3x15mL). The filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography and eluted with DCM / MeOH (15 / 1) to afford the 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%): 35% B to 52% B in 7 min; Wave Length: 254 / 220 nm) to afford N-((2-oxaspiro[3.5]nonan-7-yl)methyl)-2-(1-methyl-1H-imidazol-5-yl)imidazo[1,5-b]pyridazin-7-amine (3.2 mg, 4% yield) as an orange solid. LC / MS: mass calcd. for C19H24N6O: 352.44, found: 353.15 [M+H]+.1H NMR (300 MHz, DMSO-d6) 57.83 (s, 1H), 7.78 (d, J= 9.5 Hz, 1H), 7.67 (s, 1H), 7.01 (s, 1H), 6.68 (d, J= 9.5 Hz, 1H), 6.08 (t, J = Q.2 Hz, 1H), 4.29 (s, 2H), 4.19 (s, 2H), 4.02 (s, 3H), 3.23 (t, J = 6.4 Hz, 2H), 1.98 - 2.09 (m, 2H), 1.54 - 1.73 (m, 3H), 1.28 -1.44 (m, 2H), 0.82 - 1.02 (m, 3H).

[0185] Example 13: Synthesis of 6-((6-(1H-imidazol-1-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)amino)-2-thiaspiro[3.3]heptane 2,2-dioxide

[0186] To a stirred solution of 1-{3-chloro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl}imidazole (60 mg, 0.3 mmol, 1 eq) and 6-amino-2-thiaspiro[3.3]heptane 2,2-dioxide (88 mg, 0.5 mmol, 2Docket no. 24-2207-WON-S1 / SetAeq) in dioxane (3 mL) is added CS2CO3 (292 mg, 0.9 mmol, 3 eq) and GPhos Pd G6 TES (25.7 mg, 0.03 mmol, 0.1 eq) at room temperature under nitrogen atmosphere. The resulting mixture is stirred at 90°C for 6 h under nitrogen atmosphere. The mixture is allowed to cool to room temperature. The residue is purified by reverse-phase flash chromatography with the following conditions (C18 column; mobile phase, MeCN in water (0.05% TFA), 2% to 20% gradient in 15 min; detector, LIV 254 nm). The fractions are combined and concentrated under reduced pressure. The residue is basified with 10 mM aq. NH4HCO3. The precipitated solids are collected by filtration and washed with water and dried by lyophilization. This resulted in 6-((6-(1 H-imidazol-1-yl)-[1 ,2,4]triazolo[4,3-b]pyridazin-3-yl)amino)-2-thiaspiro[3.3]heptane 2,2-dioxide (24.5 mg, 26% yield) as a yellow solid. LC / MS: mass calcd. For C14H15N7O2S: 345.1, found: 346.1 [M+H]+.1H N MR (300 MHz, DMSO-cfe) 68.65 (s, 1H), 8.30 (d, J= 9.9 Hz, 1H), 8.06 (s, 1H), 7.67 (d, J= 10.0 Hz, 1H), 7.23 (s, 1H), 7.15 (d, J= 7.4 Hz, 1H), 4.29 - 4.40 (m, 3H), 4.26 (s, 2H), 2.67 - 2.81 (m, 2H), 2.51 - 2.60 (m, 2H).

[0187] Example 14: Synthesis of 7-(((6-(1H-imidazol-1-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)amino)methyl)-2-thiaspiro[3.5]nonane 2,2-dioxide

[0188] Synthesis of 2-thiaspiro[3.5]nonane-7-carbonitrile

[0189] To a stirred solution of 2-thiaspiro[3.5]nonan-7-one (1.9 g, 12.1 mmol, 1 eq) and 1-(isocyanomethane)sulfonyl-4-methylbenzene (3.1 g, 15.8 mmol, 1.3 eq) in DME (57 mL) and EtOH (1.9 mL) is added t-BuOK (3.3 g, 29 mmol, 2.4 eq) in portions at -10°C. The resulting mixture is stirred at 0°C for 2h. The reaction is quenched by the addition of sat. NH4CI (aq.) (50 mL) at -10°C. The resulting mixture is extracted with EtOAc (3 x 20 mL). The combined organic layers are washed with brine 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 (0-15%) to afford 2-thiaspiro[3.5]nonane-7-carbonitrile (1.3 g, 63% yield) as an off-white solid. GC / MS: mass calcd. for C9H13NS: 167.0, found: 167.0 [M+H]+.1H NMR (300 MHz, DMSO) 52.90 (s, 2H), 2.85 (s, 2H), 2.73 - 2.82 (m, 1H), 1.68 - 1.90 (m, 4H), 1.50 - 1.68 (m, 4H).Docket no. 24-2207-WON-S1 / SetA

[0190] Synthesis of 2,2-dioxo-2A6-thiaspiro[3.5]nonane-7-carbonitrile

[0191] Into a 40 mL vial are added Oxone (2.4 g, 7.1 mmol, 2 eq) and H2O (18 mL) at 0°C. To the above mixture is added a solution of 2-thiaspiro[3.5]nonane-7-carbonitrile (600 mg, 3.6 mmol, 1 eq) in MeOH (5 mL) dropwise at 0°C. The resulting mixture is stirred at 20°C for 4h. The resulting mixture is filtered and the filter cake is washed with MeOH (3x10 mL). The filtrate is concentrated to evaporate methanol under reduced pressure. 20 mL H2O is added and the mixture is extracted with EtOAc (3 x 20 mL). The combined organic layers are washed with brine (1x20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate is concentrated under reduced pressure. This resulted in 2,2-dioxo-2A6-thiaspiro[3.5]nonane-7-carbonitrile (550 mg, crude) as an off-white solid. The crude product is used in the next step directly without further purification.1H NMR (300 MHz, DMSO) 53.96 (s, 2H), 3.91 (s, 2H), 2.78 - 2.90 (m, 1 H), 1.73 - 1.88 (m, 4H), 1.53 - 1.73 (m, 4H).

[0192] Synthesis of 7-(aminomethyl)-2A6-thiaspiro[3.5]nonane-2, 2-dione

[0193] To a solution of 2,2-dioxo-2A6-thiaspiro[3.5]nonane-7-carbonitrile (500 mg, 2.5 mmol, 1 eq) in 30 mL MeOH is added Raney-Ni (150 mg, 30% w / w). To the above mixture is added ammonia methanol solution (4 mL, 7M). The mixture is hydrogenated at room temperature overnight under hydrogen atmosphere using a hydrogen balloon. The resulting mixture is filtered and the filter cake is washed with MeOH (30 mL). The filtrate is concentrated under reduced pressure and dried under vacuum. This resulted in 7-(aminomethyl)-2A6-thiaspiro[3.5]nonane-2, 2-dione (450 mg, crude) as a colorless oil. The crude product is used in the next step directly without further purification. LC / MS: mass calcd. for C9HI7NO2S: 203.1, found: 204.1 [M+H]+.

[0194] Synthesis of 7-(((6-(1H-imidazol-1-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)amino)methyl)-2-thiaspiro[3.5]nonane 2,2-dioxide

[0195] To a stirred solution of 1-{3-chloro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl}imidazole (60 mg, 0.3 mmol, 1 eq) and 7-(aminomethyl)-2A6-thiaspiro[3.5]nonane-2, 2-dione (83 mg, 0.4 mmol, 1.5 eq) in dioxane (1.5 mL) is added Cs2CC>3 (265.8 mg, 0.8 mmol, 3 eq) and Pd-PEPPSI-IPentcl-o-picoline (22.9 mg, 0.03 mmol, 0.1 eq) at room temperature under nitrogen atmosphere. The resulting mixture is stirred at 90°C for 6h under nitrogen atmosphere. The residue is purified by reversed-phase flash chromatography with the following conditions (C18 column; mobile phase, MeCN in water (0.05% TFA), 2% to 50% gradient in 10 min; detector, UV 254 nm). The fractions are combined and concentrated under reduced pressure. 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%): 8% B to 23% B in 10 min; Wave Length:Docket no. 24-2207-WON-S1 / SetA254nm / 220nm) to afford 7-(((6-(1 H-imidazol-1 -yl)-[1, 2, 4]triazolo[4,3-b]pyridazin-3-yl)amino)methyl)-2-thiaspiro[3.5]nonane 2,2-dioxide (34.8 mg, 33% yield) as a yellow solid. LC / MS: mass calcd. For C17H21N7O2S: 387.1, found: 388.1 [M+H]+.1H NMR (400 MHz, DMSO-cfe) 68.66 (s, 1H), 8.27 (d, J= 9.9 Hz, 1H), 8.07 (s, 1H), 7.64 (d, J= 9.9 Hz, 1H), 7.21 (s, 1 H), 6.90 (t, J = 6.0 Hz, 1 H), 3.93 (s, 2H), 3.87 (s, 2H), 3.28 (t, J = 6 Hz, 2H), 1.89 - 1.96 (m, 2H), 1.67 - 1.80 (m, 3H), 1.48 - 1.59 (m, 2H), 0.95 - 1.09 (m, 2H).

[0196] Example 15: Synthesis of 6-( 1 H-imidazol-1 -yl)-N-(2-(methylsulfonyl)-2-azaspiro[3.3]heptan-6-yl)imidazo[1 ,2-b]pyridazin-3-amine

[0197] To a stirred solution of 1-{3-bromoimidazo[1,2-b]pyridazin-6-yl}imidazole (100 mg, 0.4 mmol, 1 eq) and 2-methanesulfonyl-2-azaspiro[3.3]heptan-6-amine (288 mg, 1.5 mmol, 4 eq) in N,N-dimethylacetamide (3 mL) is added Ni(‘Bustb)3 (35.5 mg, 0.04 mmol, 0.1 eq), Zn (5 mg, 0.08 mmol, 0.2 eq) and 1,4-diazabicyclo[2.2.2]octane (76.5 mg, 0.7 mmol, 1.8 eq) at room temperature under nitrogen atmosphere. The resulting mixture is stirred at 90°C for 16h under nitrogen atmosphere. The mixture is allowed to cool down to room temperature. The residue is purified by reverse-phase flash chromatography with the following conditions (C18 column; mobile phase, MeCN in water (10 mmol / L NH4HCO3), 2% to 50% gradient in 15 min; detector, LIV 254 nm). The fractions are combined and concentrated under reduced pressure. 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%): 2% B to 16% B in 10 min; Wave Length: 254 / 220 nm) to afford 6-(1 H-imidazol-1 -yl)-N-(2-(methylsulfonyl)-2-azaspiro[3.3]heptan-6-yl)imidazo[1,2-b]pyridazin-3-amine (10.1 mg, 7% yield) as an orange solid. LC / MS: mass calcd. For C16H19N7O2S: 373.1, found: 374.1 [M+H]+.1H NMR (300 MHz, DMSO-cfe) 68.98 (s, 1H), 8.19 - 8.28 (m, 2H), 7.59 (d, J = 9.6 Hz, 1 H), 7.40 (s, 1 H), 7.23 (s, 1 H), 6.29 (br, 1 H), 3.97 (s, 2H), 3.88 -3.95 (m, 1H), 3.86 (s, 2H), 2.98 (s, 3H), 2.64 - 2.77 (m, 2H), 2.20 - 2.34 (m, 2H).

[0198] Example 16: Synthesis of 2-( 1 H-imidazol-1 -y l)-N -((( 1 r,4r)-4-methoxycyclohexyl)methyl)pyrrolo[2,1-f][1,2,4]triazin-7-amineDocket no. 24-2207-WON-S1 / SetA

[0199] Synthesis of 1-{7-bromopyrrolo[2,1-f][1,2,4]triazin-2-yl}imidazole

[0200] To a stirred solution of 7-bromo-2-chloropyrrolo[2,1-f][1,2,4]triazine (300 mg, 1.3 mmol, 1 eq) in DMF (10 mL) is added imidazole (131.8 mg, 1.9 mmol, 1.5 eq) and K2CO3 (535 mg, 3.9 mmol, 3 eq). The resulting mixture is stirred for 3h at 100°C. The resulting mixture is poured into ice water (50 mL). The precipitated solids are collected by filtration and washed with water (50 mL), then dried under vacuum. 1-{7-bromopyrrolo[2,1-f][1,2,4]triazin-2-yl}imidazole (220 mg, 64% yield) as a yellow solid is obtained. The crude product is used in the next step directly without further purification. LC / MS: mass calcd. for CgHeBrNs: 262.9, found: 263.9 [M+H]+.

[0201] Synthesis of 2-(1H-imidazol-1-yl)-N-(((1r,4r)-4-methoxycyclohexyl)methyl)pyrrolo[2,1-f][1,2,4]triazin-7-amine

[0202] To a stirred solution of 1-{7-bromopyrrolo[2,1-f][1,2,4]triazin-2-yl}imidazole (60 mg, 0.2 mmol, 1 eq) in dioxane (6 mL) is added ((1r,4r)-4-methoxycyclohexyl)methanamine hydrochloride (54 mg, 0.3 mmol, 1.5 eq), CS2CO3 (222 mg, 0.7 mmol, 3 eq) and Pd-PEPPSI-IPentcl-o-picoline (19.1 mg, 0.02 mmol, 0.1 eq) under a nitrogen atmosphere. The resulting mixture is stirred for 3h at 100°C. The resulting mixture is filtered and the filter cake is washed with MeOH (3x15mL). The filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography and eluted with DCM / MeOH (15 / 1) to afford the crude product. The crude product is purified by Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5pm; Mobile Phase A: Water(10 mmol / L NH4HCO3), Mobile Phase B: CAN; Flow rate: 60 mL / min mL / min; Gradient (B%): 30% B to 50% B in 10 min; Wave Length: 254nm / 220nm) to afford 2-(1H-imidazol-1-yl)-N-(((1r,4r)-4-methoxycyclohexyl)methyl)pyrrolo[2,1-f][1,2,4]triazin-7-amine (21.2 mg, 28% yield) as an orange solid. LC / MS: mass calcd. for CI7H22N6O: 326.2, found: 327.2 [M+H]+.1H NMR (300 MHz, DMSO cfe) 58.61 (s, 1H), 8.54 (s, 1H), 7.98 (s, 1H), 7.13 (s, 1H), 7.04 (d, J = 4.9 Hz, 1H), 6.45 - 6.58 (m, 4H), 3.212s, 3H), 3.19 (t, J = 6.9 Hz, 2H), 2.99 - 3.13 (m, 1H), 1.96 - 2.07 (m, 2H), 1.76 - 1.89 (m, 2H), 1.50 - 1.65 (m, 1H), 1.91 - 1.17 (m, 4H).

[0203] Example 17: Synthesis of 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)pyrrolo[2,1-f][1,2,4]triazin-7-amineDocket no. 24-2207-WON-S1 / SetA

[0204] To a stirred solution of 1-{7-bromopyrrolo[2,1-f][1,2,4]triazin-2-yl}imidazole (80 mg, 0.3 mmol, 1 eq) in dioxane (8 mL) is added (1r,4r)-4-(2-methoxyethoxy)cyclohexan-1 -amine (78.7 mg, 0.5 mmol, 1.5 eq), CS2CO3 (296 mg, 0.9 mmol, 3 eq) and Pd-PEPPSI-IPentcl-o-picoline (25.4 mg, 0.03 mmol, 0.1 eq) under a nitrogen atmosphere. The resulting mixture is stirred for 3h at 100°C. The resulting mixture is filtered and the filter cake is washed with MeOH (3x15 mL). The filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography and eluted with DCM / MeOH (15 / 1) to afford the crude product. 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%): 16% B to 31% B in 7 min; Wave Length: 254 / 220 nm) to afford 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)pyrrolo[2,1-f][1,2,4]triazin-7-amine (23.1 mg, 21% yield) as an orange solid. LC / MS: mass calcd. for C18H24N6O2: 356.2, found: 357.2 [M+H]+.1H NMR (300 MHz, DMSO) 58.61 (s, 1H), 8.55 (s, 1H), 7.99 (s, 1H), 7.12 (s, 1H), 7.05 (d, J= 4.9 Hz, 1H), 6.59 (d, J = 4.9 Hz, 1 H), 6.15 (d, J = 8.8 Hz, 1H), 3.52 - 3.58 (m, 2H), 3.46 - 3.52(m, 1H), 3.40 - 3.46 (m, 2H), 3.28 - 3.31(m, 1H), 3.25 (s, 3H), 1.94 - 2.11 (m, 4H), 1.22 - 1.54 (m, 4H).

[0205] Example 18: Synthesis of 7-(((2-(1-methyl-1H-imidazol-5-yl)imidazo[1,5-b]pyridazin-7-yl)amino)methyl)-2-thiaspiro[3.5]nonane 2,2-dioxide

[0206] Synthesis of 1-[(6-chloropyridazin-3-yl)methyl]-3-({2,2-dioxo-2A6-thiaspiro[3.5]nonan-7-yl}methyl)thioureaDocket no. 24-2207-WON-S1 / SetA

[0207] A solution of 7-(aminomethyl)-2A6-thiaspiro[3.5]nonane-2, 2-dione (221 mg, 1.1 mmol, 1.2 eq) in THF (10 mL) is treated with Et3N (377.6 uL, 2.7 mmol, 3 eq) and 1-[(1H-imidazol-1-yl)carbothioyl]-1H-imidazole (161.4 mg, 0.9 mmol, 1 eq) atO °C, The reaction is stirred at room temperature for 1h. 1-(6-chloropyridazin-3-yl)methanamine (130 mg, 0.9 mmol, 1 eq) is added in batches and then the reaction is stirred at room temperature for 17h. The reaction is quenched with sat. NaHCO3(aq) (20 mL) at 0°C. The resulting mixture is extracted with EA (3x20 mL). The combined organic layers are washed with brine (1x50 mL) and dried over anhydrous Na3SO4. After filtration, the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography and eluted with CH2CI2 / EA (2:1) to afford 1-[(6-chloropyridazin-3-yl)methyl]-3-({2,2-dioxo-2A6-thiaspiro[3.5]nonan-7-yl}methyl)thiourea (140 mg, 39% yield) as a yellow solid. LC / MS: mass calcd. for C15H21CIN4O2S2: 388.1, found: 389.15 [M+H]+.

[0208] Synthesis of 7-[({2-chloroimidazo[1 ,5-b]pyridazin-7-yl}amino)methyl]-2A6-thiaspiro[3.5]nonane-2, 2-dione

[0209] To a stirred solution of 1-[(6-chloropyridazin-3-yl)methyl]-3-({2,2-dioxo-2A6-thiaspiro[3.5]nonan-7-yl}methyl)thiourea (115 mg, 0.3 mmol, 1 eq) in toluene (10 mL) is added DCC (183 mg, 0.9 mmol, 3 eq) under a nitrogen atmosphere. The resulting mixture is stirred for 24h at 120°C. The reaction is quenched with sat. NaHCO3(aq) (30 mL) at 0°C. The resulting mixture is extracted with EA (3x20 mL). The combined organic layers are washed with brine (1x100 mL) and dried over anhydrous Na2SC>4. After filtration, the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography and eluted with CH2CI2 / EA (2:1) to afford 7-[({2-chloroimidazo[1,5-b]pyridazin-7-yl}amino)methyl]-2A6-thiaspiro[3.5]nonane-2, 2-dione (50 mg, 47% yield) as a yellow solid. LC / MS: mass calcd. for C15H19CIN4O2S: 354.1, found: 355.1 [M+H]+.

[0210] Synthesis of 7-({[2-(3-methylimidazol-4-yl)imidazo[1,5-b]pyridazin-7-yl]amino}methyl)-2A6-thiaspiro[3.5]nonane-2, 2-dione

[0211] To a stirred solution of 7-[({2-chloroimidazo[1,5-b]pyridazin-7-yl}amino)methyl]-2A6-thiaspiro[3.5] nonane-2, 2-dione (45 mg, 0.1 mmol, 1 eq) in dioxane (4 mL) / H2O (0.8 mL) is added 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazole (52.7 mg, 0.2 mmol, 2 eq), K2CO3(52.6 mg, 0.4 mmol, 3 eq) and CataCXium A Pd G4 (14.1 mg, 0.02 mmol, 0.1 eq) under a nitrogen atmosphere. The resulting mixture is stirred for 17h at 100°C. The resulting mixture is filtered and the filter cake is washed with MeOH (3x15mL). The filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography and eluted with DCM / MeOH (15 / 1) to afford the crude product. The resulting mixture is purified by Prep-HPLC (Column: XBridge Prep C18 OBD Column, 19*250 mm, 5Docket no. 24-2207-WON-S1 / SetApm; Mobile Phase A: Water (0.01 M NH4HCO3 + 0.05% NH3.H2O), Mobile Phase B: ACN; Flow rate: 25 mL / min; Gradient (B%): isocratic 22% to 40% B in 10 min; Wave Length:254 / 220 nm) to afford 7-({[2-(3-methylimidazol-4-yl)imidazo[1,5-b]pyridazin-7-yl]amino}methyl)-2A6-thiaspiro[3.5]nonane-2, 2-dione (12.1 mg, 24% yield) as an orange solid. LC / MS: mass calcd. for C19H24N6O2S: 400.1, found: 401.1 [M+H]+.1H NMR (300 MHz, DMSO) 57.81 (s, 1 H), 7.77 (d, J = 9.3 Hz, 1 H), 7.65 (s, 1 H), 6.99 (s, 1 H), 6.66 (d, J = 9.5 Hz, 1H), 6.10 (t, J= 6.1 Hz, 1H), 4.01 (s, 3H), 3.89 (s, 2H), 3.85 (s, 2H), 3.24 (t, J= 6.4 Hz, 2H), 1.85 - 1.95 (m, 2H), 1.59 - 1.75 (m, 3H), 1.43 - 1.58 (m, 2H), 1.89 - 1.07 (m, 2H).

[0212] Example 19: Synthesis of N-(((1r,4r)-4-methoxycyclohexyl)methyl)-6-(1-methyl-1H-imidazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-amine

[0213] Synthesis of 5-{3-chloro-[1, 2, 4]triazolo[4,3-b]pyridazin-6-yl}-1 -methylimidazole

[0214] To a stirred solution of 3,6-dichloro-[1 ,2,4]triazolo[4,3-b]pyridazine (200 mg, 1 mmol, 1 eq) in dioxane (16 mL) I H2O (3 mL) is added 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazole (440 mg, 2.0 mmol, 2 eq), K2CO3 (438 mg, 3 mmol, 3 eq) and CataCXium A Pd G4 (111 mg, 0.15 mmol, 0.15 eq) under a nitrogen atmosphere. The resulting mixture is stirred for 3h at 100°C. The resulting mixture is filtered and the filter cake is washed with MeOH (3x15mL). The filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography; eluted with DCM / MeOH (15 / 1) to afford 5-{3-chloro-[1, 2, 4]triazolo[4,3-b]pyridazin-6-yl}-1 -methylimidazole (75 mg, 30% yield) as a yellow solid. LC / MS: mass calcd. for C9H7CIN6: 234.0, found: 235.0 [M+H]+.

[0215] Synthesis of N-(((1r,4r)-4-methoxycyclohexyl)methyl)-6-(1-methyl-1H-imidazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-amine

[0216] To a stirred solution of 5-{3-chloro-[1 ,2,4]triazolo[4,3-b]pyridazin-6-yl}-1-methylimidazole (70 mg, 0.3 mmol, 1 eq) in dioxane (3 mL) is added ((1 r,4r)-4-methoxycyclohexyl)methanamine hydrochloride (72 mg, 0.4 mmol, 1.5 eq), CS2CO3 (291.6 mg, 0.9 mmol, 3 eq) and GPhos Pd G6 (28.2 mg, 0.03 mmol, 0.1 eq) under a nitrogen atmosphere. The resulting mixture is stirred for 16h at 100°C. The resulting mixture is filtered and the filter cake is washed with MeOH (3x15mL). The filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography and elutedDocket no. 24-2207-WON-S1 / SetAwith DCM / MeOH (15 / 1) to afford the crude product. The resulting mixture is purified by Prep-HPLC (Column: Xselect CSH Phenyl Hexy Column, 30*150 mm, 5 pm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient (B%): 2% B to 20% B in 10 min; Wave Length: 254nm / 220nm) to afford 6-(3-methylimidazol-4-yl)-N-{[(1r,4r)-4-methoxycyclohexyl]methyl}-[1,2,4]triazolo[4,3-b]pyridazin-3-amine (6.3 mg, 6% yield) as a yellow solid. LC / MS: mass calcd. for C17H23N7O: 341.2, found: 342.2 [M+H]+.1H NMR (300 MHz, DMSO) 58.00 (d, J = 9.8 Hz, 1 H), 7.87 (s, 1 H), 7.81 (s, 1 H), 7.43 (d, J = 9.8 Hz, 1H), 6.59 (t, J = 6.1 Hz, 1H), 4.02 (s, 3H), 3.26 (t, J = 6.4 Hz, 2H), 3.21 (s, 3H), 3.00 -3.13 (m, 1H), 1.95 - 2.04 (m, 2H), 1.75 - 1.85 (m, 2H), 1.62 - 1.75 (m, 1H), 0.77 - 1.15 (m, 4H).

[0217] Example 20: Synthesis of 2-(1H-imidazol-1-yl)-N-{2-oxaspiro[3.5]nonan-7-yl}imidazo[1,5-b]pyridazin-7-amine

[0218] Synthesis of 1-[(6-chloropyridazin-3-yl)methyl]-3-{2-oxaspiro[3.5]nonan-7-yljthiourea

[0219] To a stirred solution of 2-oxaspiro[3.5]nonan-7-amine (295 mg, 2.1 mmol, 1 eq) in THF (8 mL) were added TEA (634 mg, 6.3 mmol, 3 eq) and TCDI (372 mg, 2.1 mmol, 1 eq) at 0°C. The resulting mixture was stirred at room temperature for 1h. To the above mixture was added 1-(6-chloropyridazin-3-yl)methanamine (300 mg, 2.1 mmol, 1 eq) at room temperature. The resulting mixture was stirred at room temperature overnight. The reaction was quenched by the addition of sat. NaHCCh (aq.) (50 mL) at 0°C. The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (3x50 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 CH2CI21 EA (10:1) to afford 1-[(6-chloropyridazin-3-yl)methyl]-3-{2-oxaspiro[3.5]nonan-7-yl}thiourea (480 mg, 70% yield) as a yellow solid. LC / MS: mass calcd. For C14H19CIN4OS: 326.1, found:327.1[M+H]+.Docket no. 24-2207-WON-S1 / SetA

[0220] Synthesis of 2-chloro-N-{2-oxaspiro[3.5]nonan-7-yl}imidazo[1 ,5-b]pyridazin-7-amine

[0221] To a stirred solution of 1-[(6-chloropyridazin-3-yl)methyl]-3-{2-oxaspiro[3.5]nonan-7-yljthiourea (470 mg, 1.4 mmol, 1 eq) in toluene (10 mL) were added DCC (1.2 g, 5.7 mmol, 4 eq) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 110 °C for overnight under nitrogen atmosphere. The reaction was quenched by the addition of sat. NaHCOs (aq.) (50 mL) at 0 °C. The resulting mixture was extracted with EtOAc (3x50 mL). The combined organic layers were washed with brine (3x50 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2CI21 MeOH (20:1) to afford 2-chloro-N-{2-oxaspiro[3.5]nonan-7-yl}imidazo[1,5-b]pyridazin-7-amine (150 mg, 36% yield) as a red solid. LC / MS: mass calcd. For C14H17CIN4O: 292.1, found: 293.2 [M+H]+.

[0222] Synthesis of 2-(1H-imidazol-1-yl)-N-(2-oxaspiro[3.5]nonan-7-yl)imidazo[1,5-b]pyridazin-7-amine

[0223] To a stirred solution of 2-chloro-N-{2-oxaspiro[3.5]nonan-7-yl}imidazo[1,5-b]pyridazin-7-amine (80 mg, 0.3 mmol, 1 eq) and imidazole (19 mg, 0.3 mmol, 1 eq) in DMF (1 mL) was added CS2CO3 (267 mg, 0.8 mmol, 3 eq) at room temperature. The resulting mixture was stirred at 100°C for 2h. The resulting mixture was filtered and the filter cake was washed with DMF (2x1 mL). The filtrate was purified by reverse-phase flash chromatography (column, C18 column; mobile phase, MeCN in water (10 mmol / L NH4HCO3), 30% to 50% gradient in 20 min; detector, UV 254 nm), to afford a crude product. The crude product was purified by prep-HPLC (Column: Xselect CSH Phenyl Hexy 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%): 13% B to 28% B in 10 min; Wavelength: 254nm / 220nm) to afford 2-(imidazol-1-yl)-N-{2-oxaspiro[3.5]nonan-7-yl}imidazo[1,5-b]pyridazin-7-amine (30.1 mg, 11% yield) as an orange solid. LC / MS: mass calcd. For C17H20N6O: 324.1, found:325.1 [M+H]+.1H NMR (300 MHz, DMSO-cfe) 68.61 (s, 1H), 7.93 - 8.12 (m, 2H), 7.08 - 7.19 (m, 2H), 6.84 (d, J = 9.6 Hz, 1H), 6.09 (d, J= 8.1 Hz, 1H), 4.34 (s, 2H), 4.23 (s, 2H), 3.54 - 3.74 (m, 1H), 1.98 -2.18 (m, 2H), 1.83 - 1.99 (m, 2H), 1.43 - 1.61 (m, 2H), 1.25 - 1.43 (m, 2H).

[0224] Example 21 : Synthesis of 2-( 1 H-imidazol-1 -y l)-N -(( 1 r,4r)-4-(oxetan-3-ylmethoxy)cyclohexyl)imidazo[1,5-b]pyridazin-7-amineDocket no. 24-2207-WON-S1 / SetA

[0225] Synthesis of oxetan-3-yl methyl 4-methylbenzenesulfonate

[0226] To a stirred solution of oxetan-3-yl methanol (5 g, 57 mmol, 1 eq) in DCM (100 mL) was added TEA (17.2 g, 170 mmol, 3 eq), DMAP (1.4 g, 11 mmol, 0.2 eq) and TsCI (11 g, 57 mmol, 1 eq) in portions at 0°C. The resulting mixture was stirred for 17h at room temperature. Then the mixture was diluted with water (100 mL). The resulting mixture was extracted with DCM (3 x 100 mL). The combined organic layers were washed with brine (300 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EA (5 / 1) to afford oxetan-3-yl methyl 4-methylbenzenesulfonate (11.5 g, 84% yield) as a yellow oil. LC / MS: mass calcd. for C11H14O4S: 242.0, found: 243.1 [M+H]+.

[0227] Synthesis of (1r,4r)-N,N-dibenzyl-4-(oxetan-3-ylmethoxy)cyclohexan-1 -amine

[0228] To a solution of (1r,4r)-4-(dibenzylamino)cyclohexan-1-ol (6.1 g, 21 mmol, 1 eq) in DMF (50 mL) was added NaH (1.5 g, 41 mmol, 2 eq, 60% wt) at 0°C under N2atmosphere. The reaction was stirred at 0°C for 1 hour and then oxetan-3-ylmethyl 4- methylbenzenesulfonate (5 g, 21 mmol, 1 eq) was added. The reaction was stirred at room temperature for 17 hours. Then the mixture was diluted with water (250 mL) at 0°C. The resulting mixture was extracted with EA (3 x 100 mL). The combined organic layers were washed with brine (300 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 (10 / 1) to afford (1r,4r)-N,N-dibenzyl-4-(oxetan-3-ylmethoxy)cyclohexan-1 -amine (1.6 g, 21% yield) as a yellow oil. LC / MS: mass calcd. for C24H3INO2: 365.2, found: 365.2 [M+H]+.

[0229] Synthesis of (1r,4r)-4-(oxetan-3-ylmethoxy)cyclohexan-1-amineDocket no. 24-2207-WON-S1 / SetA

[0230] To a solution of (1r,4r)-N,N-dibenzyl-4-(oxetan-3-ylmethoxy)cyclohexan-1-amine (700 mg, 1.9 mmol, 1 eq) in EtOH (18 mL) was added Pd(OH)2 / C (140 mg, 20% w / w) under nitrogen atmosphere. The mixture was hydrogenated at 50°C for 17 h under hydrogen atmosphere using a hydrogen balloon, then filtered through a Celite pad and concentrated under reduced pressure to afford (1r,4r)-4-(oxetan-3-ylmethoxy)cyclohexan-1 -amine (250 mg, 70% yield) as a yellow oil. LC / MS: mass calcd. for C10H19NO2: 185.1, found: 186.0 [M+H]+.

[0231] Synthesis of 3-[(6-chloropyridazin-3-yl)methyl]-1-[(1r,4r)-4-(oxetan-3-ylmethoxy)cyclohexyl]thiourea

[0232] A solution of (1r,4r)-4-(oxetan-3-ylmethoxy)cyclohexan-1 -amine (230 mg, 1.2 mmol, 1.3 eq) in THF (10 mL) was treated with Et3N (0.4 mL, 2.9 mmol, 3 eq) and 1-[(1H-imidazol-1-yl)carbothioyl]-1H-imidazole (170 mg, 0.9 mmol, 1 eq) at 0°C. The reaction was stirred at room temperature for 1 hour. 1-(6-chloropyridazin-3-yl)methanamine (105 mg, 0.7 mmol, 0.8 eq) was added in batches and then the reaction was stirred at room temperature for 17 hours. The reaction was quenched by NaHCO3(aq) (30 mL) at 0°C. The resulting mixture was extracted with EA (3x30 mL). The combined organic layers were washed with brine (1x50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with CH2CI2 / EA (2:1) to afford 3-[(6-chloropyridazin-3-yl)methyl]-1-[(1r,4r)-4-(oxetan-3-ylmethoxy)cyclohexyl]thiourea (250 mg, 70% yield) as a yellow solid. LC / MS: mass calcd. for Ci6H23CIN4O2S: 370.1, found: 371.0 [M+H]+.

[0233] Synthesis of 2-chloro-N-[(1 r,4r)-4-(oxetan-3-ylmethoxy)cyclohexyl]imidazo[1 ,5-b]pyridazin-7-amine

[0234] To a stirred solution of 3-[(6-chloropyridazin-3-yl)methyl]-1-[(1r,4r)-4-(oxetan-3-ylmethoxy)cyclohexyl] thiourea (240 mg, 0.6 mmol, 1 eq) in toluene (10 mL) was added DCC (400 mg, 1.8 mmol, 3 eq) under a nitrogen atmosphere. The resulting mixture was stirred for 6h at 110°C. The reaction was quenched by NaHCO3(aq) (20 mL) at 0°C. The resulting mixture was extracted with EA (3x20 mL). The combined organic layers were washed with brine (1x100 mL) and dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with CH2CI2 / EA (2:1) to afford 2-chloro-N-[(1r,4r)-4-(oxetan-3-ylmethoxy)cyclohexyl]imidazo[1,5-b]pyridazin-7-amine (150 mg, 69% yield) as a yellow solid. LC / MS: mass calcd. for Ci6H2iCIN4O2: 336.1, found: 337.0 [M+H]+.

[0235] Synthesis of 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(oxetan-3-ylmethoxy)cyclohexyl) imidazo[1 ,5-b]pyridazin-7-amineDocket no. 24-2207-WON-S1 / SetA

[0236] To a stirred solution of 2-chloro-N-[(1r,4r)-4-(oxetan-3-ylmethoxy)cyclohexyl]imidazo[1,5-b]pyridazin-7-amine (70 mg, 0.2 mmol, 1 eq) in DMF (2 mL) was added CS2CO3 (203 mg, 0.6 mmol, 3 eq) and imidazole (14 mg, 0.2 mmol, 1 eq). The final reaction mixture was irradiated with microwave radiation at 100°C for 2h. The resulting mixture was filtered and the filter cake was washed with DMF (2x0.5mL). The filtrate 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 mL / min; Gradient (B%): 10% B to 30% B inlOmin; Wavelength: 254nm nm) to afford 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(oxetan-3-ylmethoxy)cyclohexyl)imidazo[1,5-b]pyridazin-7-amine (29.7 mg, 39% yield) as a red solid. LC / MS: mass calcd. for C19H24N6O2: 368.19, found:369.15 [M+H]+.1H NMR (300 MHz, DMSO-c / 6) 58.61 (s, 1H), 8.06 (s, 1H), 8.00 (d, J= 9.6 Hz, 1H), 7.11 - 7.18 (m, 2H), 6.85 (d, J= 9.6 Hz, 1H), 6.14 (d, J = 8.0 Hz, 1H), 4.55 - 4.66 (m, 2H), 4.27 (t, J= 5.9 Hz, 2H), 3.53 - 3.75(m, 2H), 3.21 - 3.31 (m, 1H), 3.00 - 3.20 (m, 1H), 1.96 - 2.11 (m, 4H), 1.33 - 1.51 (m, 2H), 1.16 - 1.33 (m, 2H).

[0237] Example 22: Synthesis of N-((1r,4r)-4-(2,2-difluoroethoxy)cyclohexyl)-2-(1H-imidazol-1-yl)imidazo[1 ,5-b]pyridazin-7-amine

[0238] Synthesis of (1r,4r)-N,N-dibenzyl-4-(2,2-difluoroethoxy)cyclohexan-1-amine

[0239] To a stirred solution of (1r,4r)-4-(dibenzylamino)cyclohexan-1-ol (5 g, 17 mmol, 1 eq) in DMF (85 mL) was added NaH (1 g, 25 mmol, 1.5 eq, 60%) in portions at 0°C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 h under nitrogen atmosphere. To the above mixture was added 2,2-difluoroethyl 4-methylbenzenesulfonate (4.4 g, 19 mmol, 1.1 eq) in DMF (20 mL) dropwise over 20 min atDocket no. 24-2207-WON-S1 / SetA0°C. The resulting mixture was stirred at 60°C for 1h. The reaction was quenched by the addition of sat. NH4CI (aq.) (100 mL) at 0°C. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (1x100 mL) and dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with CH2CI21 PE (10:1) to afford 1.5 g of crude product. The crude product was purified by reverse phase flash (C18 column; mobile phase, MeCN in Water (10 mmol / L NH4HCO3), 30% to 80% gradient in 50 min; detector, UV 254 nm) to afford (1r,4r)-N,N-dibenzyl-4-(2,2-difluoroethoxy)cyclohexan-1-amine (1 g, 16% yield) as a white solid. LC / MS: mass calcd. for C22H27F2NO: 359.2, found: 360.2 [M+H]+.

[0240] Synthesis of (1r,4r)-4-(2,2-difluoroethoxy)cyclohexan-1 -amine

[0241] To a solution of (1r,4r)-N,N-dibenzyl-4-(2,2-difluoroethoxy)cyclohexan-1-amine (500 mg, 1.4 mmol, 1 eq) in EtOH (18 mL) was added Pd(OH)2 / C (100 mg, 20% w / w) under nitrogen atmosphere. The mixture was hydrogenated at 50°C for 17 h under hydrogen atmosphere using a hydrogen balloon, then filtered through a Celite pad and concentrated under reduced pressure to afford (1r,4r)-4-(2,2-difluoroethoxy)cyclohexan-1 -amine (220 mg, 88% yield) as a yellow oil. LC / MS: mass calcd. for C8H15F2NO: 179.1, found: 180.1 [M+H]+.

[0242] Synthesis of 3-[(6-chloropyridazin-3-yl)methyl]-1-[(1r,4r)-4-(2,2-difluoroethoxy)cyclohexyl]thiourea

[0243] A solution of (1r,4r)-4-(2,2-difluoroethoxy)cyclohexan-1-amine (190 mg, 1 mmol, 1.2 eq) in THF (12 mL) was treated with Et3N (0.4 mL, 2.7 mmol, 3 eq) and 1-[(1H-imidazol-1-yl)carbothioyl]-1H-imidazole (157 mg, 0.9 mmol, 1 eq) at 0°C. The reaction was stirred at room temperature for 1h. 1-(6-chloropyridazin-3-yl)methanamine (127 mg, 0.9 mmol, 1 eq) was added in batches and then the reaction was stirred at room temperature for 17h. The reaction was quenched by NaHCO3(aq) (30 mL) at 0°C. The resulting mixture was extracted with EA (3x30 mL). The combined organic layers were washed with brine (1x50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with CH2CI2 / EA (2:1) to afford 3-[(6-chloropyridazin-3-yl)methyl]-1-[(1r,4r)-4-(2,2-difluoroethoxy)cyclohexyl]thiourea (160 mg, 49% yield) as a yellow solid. LC / MS: mass calcd. for C14H19CIF2N4OS: 364.0, found: 365.0 [M+H]+.

[0244] Synthesis of 2-chloro-N-[(1 r,4r)-4-(2,2-difluoroethoxy)cyclohexyl]imidazo[1 ,5-b]pyridazin-7-amineDocket no. 24-2207-WON-S1 / SetA

[0245] To a stirred solution of 3-[(6-chloropyridazin-3-yl)methyl]-1-[(1r,4r)-4-(2,2-difluoroethoxy)cyclohexyl] thiourea (160 mg, 0.4 mmol, 1 eq) in toluene (8 mL) was added DCC (271 mg, 1.3 mmol, 3 eq) under a nitrogen atmosphere. The reaction was stirred at 110°C for 17h. The reaction was quenched with NaHCOa(aq) (20 mL) at 0°C. The resulting mixture was extracted with EA (3x20 mL). The combined organic layers were washed with brine (1x100 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 CH2CI2 / EA (2:1) to afford 2-chloro-N-[(1r,4r)-4-(2,2-difluoroethoxy)cyclohexyl]imidazo[1,5-b]pyridazin-7-amine (110 mg, 76% yield) as a yellow solid. LC / MS: mass calcd. for C14H17CIF2N4O: 330.1, found: 331.0 [M+H]+.

[0246] Synthesis of N-((1r,4r)-4-(2,2-difluoroethoxy)cyclohexyl)-2-(1H-imidazol-1-yl)imidazo[1,5-b]pyridazin-7-amineTo a stirred solution of 2-chloro-N-[(1r,4r)-4-(2,2-difluoroethoxy)cyclohexyl]imidazo[1,5-b]pyridazin-7-amine (70 mg, 0.2 mmol, 1 eq) in DMF (1.5 mL) was added CS2CO3 (207 mg, 0.6 mmol, 3 eq) and imidazole (17 mg, 0.25 mmol, 1.2 eq). The resulting mixture was stirred for 2h at 100°C. The resulting mixture was filtered, the filtrate (3 mL) was purified by Perp-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 mL / min; Gradient (B%): 17% B to 42% B in10 min; Wavelength: 254nm nm) to afford N-((1r,4r)-4-(2,2-difluoroethoxy)cyclohexyl)-2-(1 H-imidazol-1-yl)imidazo[1 ,5-b]pyridazin-7-amine (16.3 mg, 21% yield) as an orange solid. LC / MS: mass calcd. for C17H20F2N6O: 362.16, found: 363.15 [M+H]+.1H NMR (300 MHz, DMSO) 58.62 (s, 1H), 7.96 - 8.10 (m, 2H), 7.11 - 7.18 (m, 2H), 6.85 (d, J = 9.6 Hz, 1 H), 5.90 - 6.40 (m, 2H), 3.62 - 3.82 (m, 3H), 3.32 - 3.45 (m, 1 H), 1.99 -2.09 (m, 4H), 1.28 - 1.51 (m, 4H).19F NMR (282 MHz, DMSO-cfe) 6 -125.91.

[0247] Example 23: 2-(1H-imidazol-1-yl)-N-(1-(3-methyloxetan-3-yl)piperidin-4-yl)imidazo[1,5-b]pyridazin-7-amineCompound 23Docket no. 24-2207-WON-S1 / SetA

[0248] Synthesis of 3-[(6-chloropyridazin-3-yl)methyl]-1-[1-(3-methyloxetan-3-yl)piperidin-4-yl]thiourea

[0249] A solution of 1-(3-methyloxetan-3-yl)piperidin-4-amine (356 mg, 2 mmol, 2.5 eq) in THF (6 mL) was treated with Et3N (700 uL, 5 mmol, 6 eq) and TCDI (150 mg, 0.8 mmol, 1 eq) at 0°C for 2h, followed by the addition of 1-(6-chloropyridazin-3-yl)methanamine (120 mg, 0.8 mmol, 1 eq) at 0°C.The resulting mixture was stirred at room temperature for 17h. The reaction was quenched with sat. NaHCO3(aq.) (20 mL) at 0°C. The resulting mixture was extracted with EtOAc (3x20 mL). The combined organic layers were washed with brine 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 CH2CI21 MeOH (10:1) to afford 3-[(6-chloropyridazin-3-yl)methyl]-1-[1-(3-methyloxetan-3-yl)piperidin-4-yl]thiourea (180 mg, 60% yield) as a yellow solid. LC / MS: mass calcd. For C15H22CIN5OS: 355.1, found: 356.2 [M+H]+.

[0250] Synthesis of N-{2-chloroimidazo[1,5-b]pyridazin-7-yl}-1-(3-methyloxetan-3-yl)piperidin-4-amine

[0251] To a stirred solution of 3-[(6-chloropyridazin-3-yl)methyl]-1-[1-(3-methyloxetan-3-yl)piperidin-4-yl]thiourea (160 mg, 0.45 mmol, 1 eq) in toluene (7 mL) was added DCC (278 mg, 1.35 mmol, 3 eq) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 110°C for 17h under nitrogen atmosphere. The mixture was allowed to cool to room temperature. The reaction was quenched with sat. NaHCO3(aq.) (10 mL) at 0°C. The resulting mixture was extracted with EtOAc (3x 20 mL). The combined organic layers were washed with brine 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 CH2CI21 MeOH (10:1) to afford N-{2-chloroimidazo[1,5-b]pyridazin-7-yl}-1-(3-methyloxetan-3-yl)piperidin-4-amine (80 mg, 55% yield) as a red semisolid. LC / MS: mass calcd. For C15H20CIN5O: 321.1, found: 322.1 [M+H]+.

[0252] Synthesis of 2-(1H-imidazol-1-yl)-N-(1-(3-methyloxetan-3-yl)piperidin-4-yl)imidazo[1,5-b]pyridazin-7-amine

[0253] To a stirred solution of N-{2-chloroimidazo[1 ,5-b]pyridazin-7-yl}-1-(3-methyloxetan-3-yl)piperidin-4-amine (70 mg, 0.2 mmol, 1 eq) and imidazole (30 mg, 0.4 mmol, 2 eq) in DMF (5 mL) was added Cs2CO3(213 mg, 0.6 mmol, 3 eq) at room temperature. The resulting mixture was stirred at 100°C for 2 h. The mixture was allowed to cool down to room temperature. The reaction was poured into ice / water (25 mL). The resulting mixture was filtered and the filter cake was washed with water. The filtrate was extracted with EtOAc (3x30 mL). The combined organic layers were washed with brine and dried over anhydrousDocket no. 24-2207-WON-S1 / SetANa2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC (Column: XBridge Prep OBD C18 Column, 19*250 mm, 5 pm; Mobile Phase A: water (10 mmol / L NH4HCC>3+0.1% NH3.H2O), Mobile Phase B: ACN; Flow rate: 25 mL / min; Gradient (B%): 13%B to 29%B in 13min; Wavelength: 254 / 220 nm) to afford N-[2-(imidazol-1-yl)imidazo[1,5-b]pyridazin-7-yl]-1-(3-methyloxetan-3-yl)piperidin-4-amine (26 mg, 33% yield) as an orange solid. LC / MS: mass calcd. For C18H23N7O: 353.2, found: 354.1 [M+H]+.1H NMR (300 MHz, DMSO-cfe) 68.62 (s, 1H), 8.07 (s, 1H), 8.00 (d, J = 9.6 Hz, 1H), 7.11 - 7.19 (m, 2H), 6.85 (d, J= 9.6 Hz, 1H), 6.20 (d, J= 8.1 Hz, 1H), 4.37 (d, J = 5.5 Hz, 2H), 4.09 (d, J= 5.5 Hz, 2H), 3.56 - 3.72 (m, 1H), 2.51 - 2.55 (m, 2H), 2.10 (t, J = 11.2 Hz, 2H), 1.92 - 2.01 (m, 2H), 1.55 - 1.80 (m, 2H), 1.26 (s, 3H).

[0254] Example 24: Synthesis of N-((1r,4r)-4-(cyclopropylmethoxy)cyclohexyl)-2-(1H-imidazol-1-yl)imidazo[1 ,5-b]pyridazin-7-amine

[0255] Synthesis of 3-[(6-chloropyridazin-3-yl)methyl]-1-[(1r,4r)-4-(cyclopropylmethoxy)cyclohexyl]thiourea

[0256] A solution of (1r,4r)-4-(cyclopropylmethoxy)cyclohexan-1-amine (153 mg, 0.9 mmol, 1 eq) in THF (10 mL) was treated with Et3N (377 uL, 2.7 mmol, 3 eq) and 1-[(1H-imidazol-1-yl)carbothioyl]-1H-imidazole (161 mg, 0.9 mmol, 1 eq) at 0°C. The reaction was stirred at room temperature for 1h. 1-(6-chloropyridazin-3-yl)methanamine (130 mg, 0.9 mmol, 1 eq) was added in batches and then the reaction was stirred at room temperature for 17h. The reaction was quenched by NaHCO3(aq) (20 mL) at 0°C. The resulting mixture was extracted with EA (3x20 mL). The combined organic layers were washed with brine (1x50 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 CH2CI2 / EA (2:1) to afford 3-[(6-chloropyridazin-3-yl)methyl]-1-[(1r,4r)-4-Docket no. 24-2207-WON-S1 / SetA(cyclopropylmethoxy)cyclohexyl]thiourea (200 mg, 63% yield) as a yellow solid. LC / MS: mass calcd. for C16H23CIN4OS: 354.1, found: 355.2 [M+H]+.

[0257] Synthesis of 2-chloro-N-[(1 r,4r)-4-(cyclopropylmethoxy)cyclohexyl]imidazo[1 ,5-b]pyridazin-7-amine

[0258] To a stirred solution of 3-[(6-chloropyridazin-3-yl)methyl]-1-[(1r,4r)-4-(cyclopropylmethoxy)cyclohexyl] thiourea (180 mg, 0.5 mmol, 1 eq) in toluene (15 mL) was added DCC (732 mg, 3.5 mmol, 7 eq) under a nitrogen atmosphere. The resulting mixture was stirred for 17h at 110°C. The reaction was quenched by NaHCOs(aq) (30 mL) at 0°C. The resulting mixture was extracted with EA (3x20 mL). The combined organic layers were washed with brine (1x100 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 CH2CI2 / EA (2:1) to afford 2-chloro-N-[(1r,4r)-4-(cyclopropylmethoxy)cyclohexyl]imidazo[1,5-b]pyridazin-7-amine (80 mg, 49% yield) as a yellow solid. LC / MS: mass calcd. for C16H21CIN4O: 320.14, found: 321.25 [M+H]+.

[0259] Synthesis of N-((1r,4r)-4-(cyclopropylmethoxy)cyclohexyl)-2-(1H-imidazol-1-yl)imidazo[1,5-b]pyridazin-7-amine

[0260] To a stirred solution of 2-chloro-N-[(1r,4r)-4-(cyclopropylmethoxy)cyclohexyl]imidazo[1,5-b]pyridazin-7-amine (70 mg, 0.2 mmol, 1 eq) in DMF (2 mL) was added CS2CO3 (213 mg, 0.6 mmol, 3 eq) and imidazole (22 mg, 0.3 mmol, 1.5 eq). The reaction mixture was irradiated with microwave radiation at 100 °C for 2 h. The resulting mixture was filtered and the filter cake was washed with DMF (2x0.5ml). The filtrate was purified by Prep-HPLC (Column: Xselect CSH Phenyl Hexy 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%): 24% B to 37% B in 10 min; Wavelength: 254nm / 220nm) to afford N-((1r,4r)-4-(cyclopropylmethoxy)cyclohexyl)-2-(1H-imidazol-1-yl)imidazo[1,5-b]pyridazin-7-amine (24.3 mg, 31% yield) as an orange solid. LC / MS: mass calcd. for C19H24N6O: 352.2, found: 353.2 [M+H]+.1H NMR (300 MHz, DMSO-cfe) 68.61 (s, 1H), 8.06 (s, 1H), 8.00 (d, J = 9.6 Hz, 1H), 7.11 - 7.18 (m, 2H), 6.85 (d, J= 9.6 Hz, 1H), 6.13 (d, J= 8.1 Hz, 1H), 3.58 - 3.74 (m, 1H), 3.17 - 3.29 (m, 3H), 1.93 - 2.09 (m, 4H), 1.33 - 1.49 (m, 2H), 1.15 - 1.32 (m, 2H), 0.86 - 1.03 (m, 1H), 0.38 - 0.49 (m, 2H), 0.08 - 0.19 (m, 2H).

[0261] Example 25: Synthesis of 2-(1H-imidazol-1-yl)-N-((1R,3R)-3-(2-methoxyethoxy)cyclopentyl)imidazo[1,5-b]pyridazin-7-amineDocket no. 24-2207-WON-S1 / SetA

[0262] Synthesis of 1-[(6-chloropyridazin-3-yl)methyl]-3-[(1R,3R)-3-(2-methoxyethoxy)cyclopentyl]thiourea

[0263] A solution of (1 R,3R)-3-(2-methoxyethoxy)cyclopentan-1 -amine hydrochloride (320 mg, 1.6 mmol, 1 eq) in THF (10 mL) was treated with TEA (3.6 mL, 26 mmol, 16 eq) and TCDI (291 mg, 1.6 mmol, 1 eq) at 0°C, and then the mixture was stirred for 2h at room temperature, followed by the addition of 1-(6-chloropyridazin-3-yl)methanamine (94 mg, 0.6 mmol, 0.4 eq) dropwise at 0°C. The resulting mixture was stirred at room temperature for 17 h. The reaction was quenched with sat. NaHCCh (aq.) (20 mL) at 0°C. The resulting mixture was extracted with EtOAc (3x 30 mL). The combined organic layers were washed with brine and dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:3) to afford 1-[(6-chloropyridazin-3-yl)methyl]-3-[(1R,3R)-3-(2-methoxyethoxy)cyclopentyl]thiourea (170 mg, 30% yield) as a yellow solid. LC / MS: mass calcd. C14H21CIN4O2S: 344.1, found: 345.1 [M+H]+.

[0264] Synthesis of 2-chloro-N-[(1S,3S)-3-(2-methoxyethoxy)cyclopentyl]imidazo[1,5-b]pyridazin-7-amine

[0265] To a stirred solution of 1-[(6-chloropyridazin-3-yl)methyl]-3-[(1 R,3R)-3-(2-methoxyethoxy)cyclopentyl] thiourea (160 mg, 0.5 mmol, 1 eq) in toluene (8 mL) was added DCC (479 mg, 2.3 mmol, 5 eq) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 110°C for 17h under nitrogen atmosphere. The reaction was quenched with sat. NaHCCh (aq.) (20 mL) at 0°C. The resulting mixture was extracted with EtOAc (3x30 mL). The combined organic layers were washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. TheDocket no. 24-2207-WON-S1 / SetAresidue was purified by silica gel column chromatography, eluted with PE I EA (1 :3) to afford 2-chloro-N-[(1S,3S)-3-(2-methoxyethoxy)cyclopentyl]imidazo[1,5-b]84yridazine-7-amine (60 mg, 41 % yield) as a red solid. LC / MS: mass calcd. For C14H19CIN4O2: 310.1 , found: 311.0 [M+H]+.

[0266] Synthesis of 2-(1H-imidazol-1-yl)-N-((1R,3R)-3-(2-methoxyethoxy)cyclopentyl)imidazo[1,5-b]pyridazin-7-amine

[0267] To a stirred solution of 2-chloro-N-[(1S,3S)-3-(2-methoxyethoxy)cyclopentyl]imidazo[1,5-b]pyridazin-7-amine (50 mg, 0.16 mmol, 1 eq) and imidazole (22 mg, 0.3 mmol, 1.8 eq) in DMF (3 mL) was added Cs2CC>3(157 mg, 0.5 mmol, 3 eq) at room temperature. The resulting mixture was stirred at 100°C for 2h. The mixture was allowed to cool to room temperature. The solid was filtered out and filtrate 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 mL / min; Gradient (B%): 12% B to 37% B inlOmin; Wavelength: 254nm). The fractions were combined and lyophilized directly. This resulted in 2-(1H-imidazol-1-yl)-N-((1R,3R)-3-(2-methoxyethoxy)cyclopentyl)imidazo[1,5-b]pyridazin-7-amine (30.3 mg, 55% yield) as a red semi-solid. LC / MS: mass calcd. For C17H22N6O2: 342.2, found: 343.2 [M+H]+.1H NMR (300 MHz, DMSO-cfe) 68.61 (s, 1H), 8.06 (s, 1H), 8.01 (d, J= 9.6 Hz, 1H), 7.15 (s, 2H), 6.86 (d, J = 9.6 Hz, 1 H), 6.26 (d, J = 7.4 Hz, 1 H), 4.22 - 4.38 (m, 1 H), 3.97 - 4.05 (m, 1 H), 3.37 - 3.51 (m, 4H), 3.24 (s, 3H), 1.92 - 2.13 (m, 3H), 1.80 - 1.90 (m, 1H), 1.60 - 1.75 (m, 2H).

[0268] Example 26: Synthesis of (1r,4r)-N1-(2-(1H-imidazol-1-yl)imidazo[1,5-b]pyridazin-7-yl)-N4-(2,2,2-trifluoroethyl)cyclohexane-1,4-diamineCompound 26

[0269] Synthesis of 3-[(6-chloropyridazin-3-yl)methyl]-1-[(1r,4r)-4-[(2,2,2-trifluoroethyl)amino]cyclohexyl]thiourea

[0270] A solution of (1r,4r)-N1-(2,2,2-trifluoroethyl)cyclohexane-1,4-diamine (300 mg, 1.5 mmol, 1.1 eq) in THF (10 mL) was treated with Et3N (580 uL, 4.2 mmol, 3 eq) and 1-[(1H-Docket no. 24-2207-WON-S1 / SetAimidazol-1-yl)carbothioyl]-1H-imidazole (248 mg, 1.4 mmol, 1 eq) at 0°C. The reaction was stirred at room temperature for 1 h. 1-(6-chloropyridazin-3-yl)methanamine (200 mg, 1.4 mmol, 1 eq) was added in batches and then the reaction was stirred at room temperature for 17h. The reaction was quenched by NaHCOa(aq) (20 mL) at 0°C. The resulting mixture was extracted with EA (3x20 mL). The combined organic layers were washed with brine (1x50 mL) anf dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2CI2 / EA (2:1) to afford 3-[(6-chloropyridazin-3-yl)methyl]-1-[(1r,4r)-4-[(2,2,2-trifluoroethyl)amino]cyclohexyl]thiourea (310 mg, 54% yield) as a yellow solid. LC / MS: mass calcd. for C14H19CIF3N5S: 381.10, found: 382.00 [M+H]+.

[0271] Synthesis of (1r,4r)-N1-{2-chloroimidazo[1,5-b]pyridazin-7-yl}-N4-(2,2,2-trifluoroethyl)cyclohexane-1,4-diamine

[0272] To a stirred solution of 3-[(6-chloropyridazin-3-yl)methyl]-1-[(1r,4r)-4-[(2,2,2-trifluoroethyl)amino] cyclohexyl]thiourea (280 mg, 0.7 mmol, 1 eq) in toluene (15 mL) was added DCC (756 mg, 3.7 mmol, 5 eq) under a nitrogen atmosphere. The resulting mixture was stirred for 17 h at 110°C. The reaction was quenched by NaHCOs(aq) (30 mL) at 0°C. The resulting mixture was extracted with EA (3x20 mL). The combined organic layers were washed with brine (1x100 mL) and dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2CI2 / EA (2:1) to afford (1r,4r)-N1-{2-chloroimidazo[1,5-b]pyridazin-7-yl}-N4-(2,2,2-trifluoroethyl)cyclohexane-1,4-diamine (200 mg, 78% yield) as a yellow solid. LC / MS: mass calcd. for C14H17CIF3N5: 347.11, found: 348.15 [M+H]+.

[0273] Synthesis of (1r,4r)-N1-(2-(1H-imidazol-1-yl)imidazo[1,5-b]pyridazin-7-yl)-N4-(2,2,2-trifluoroethyl)cyclohexane-1,4-diamine

[0274] To a stirred solution of (1r,4r)-N1-{2-chloroimidazo[1,5-b]pyridazin-7-yl}-N4-(2,2,2-trifluoroethyl) cyclohexane- 1,4-diamine (80 mg, 0.2 mmol, 1 eq) in DMF (2 mL) were added CS2CO3 (224 mg, 0.7 mmol, 3 eq) and imidazole (23 mg, 0.3 mmol, 1.5 eq). The final reaction mixture was irradiated with microwave radiation at 100°C for 2 h. The resulting mixture was filtered and the filter cake was washed with DMF (2x0.5ml). The filtrate 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%): 20% B to 45% B inlOmin; Wavelength: 254nm) to afford (1r,4r)-N1-(2-(1H-imidazol-1-yl)imidazo[1 ,5-b]pyridazin-7-yl)-N4-(2,2,2-trifluoroethyl)cyclohexane-1 ,4-diamine (43.5 mg, 49% yield) as a red solid. LC / MS: mass calcd. for C17H20F3N7: 379.39, found: 380.20 [M+H]+.1H NMR (300 MHz, DMSO-cfe) 68.61 (s, 1H), 8.06 (s, 1H), 8.00 (d, J= 9.6 Hz, 1H), 7.15 -Docket no. 24-2207-WON-S1 / SetA7.18 (m, 1H), 7.13 (s, 1H), 6.84 (d, J= 9.6 Hz, 1H), 6.13 (d, J= 8.2 Hz, 1H), 3.56 - 3.72 (m, 1H), 3.15 - 3.30 (m, 2H), 2.41 - 2.52 (m, 1H), 2.18 - 2.32 (m, 1H), 1.90- 2.11 (m, 4H), 1.29 -1.47 (m, 2H), 1.02 - 1.25 (m, 2H).19F NMR (282 MHz, DMSO-cfe) 6 -70.66.

[0275] Example 27: Synthesis of N-((1r,4r)-4-(3,3-difluoropyrrolidin-1-yl)cyclohexyl)-2-( 1 H-imidazol-1 -yl)imidazo[1 ,5-b]pyridazin-7-amine

[0276] Synthesis of (1r,4r)-N,N-dibenzyl-4-(3,3-difluoropyrrolidin-1-yl)cyclohexan-1-amine

[0277] To a stirred solution of 4-(dibenzylamino)cyclohexan-1-one (2 g, 6.8 mmol, 1 eq) and 3,3-difluoropyrrolidine hydrochloride (1.2 g, 8.1 mmol, 1.2 eq) in CHCh (20 mL) was added AcOH (409 mg, 6.8 mmol, 1 eq) at room temperature. The resulting mixture was stirred at room temperature for 1 h. To the above mixture was added STAB (2.2 g, 10.2 mmol, 1.5 eq) at 0°C. The resulting mixture was stirred at room temperature for an additional 5h. The reaction was quenched by NaHCOs(aq) (40 mL) at 0°C, extracted with DCM (3x30 mL). The combined organic layers were washed with brine (1x50 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 (5:1) to afford (1r,4r)-N,N-dibenzyl-4-(3,3-difluoropyrrolidin-1-yl)cyclohexan-1-amine (1 g, 38% yield) as a yellow solid. LC / MS: mass calcd. for C24H30F2N2: 384.23, found: 385.15 [M+H]+.1H NMR (300 MHz, DMSO-cfe) 67.25 - 7.38 (m, 8H), 57.15 - 7.25 (m, 2H), 3.58 (s, 4H), 2.87 (t, J = 13.8 Hz, 2H), 2.68 (t, J = 6.9 Hz, 2H), 2.32 - 2.46 (m, 1H), 1.99 - 2.28 (m, 3H), 1.77 - 1.97 (m, 4H), 1.30 - 1.49 (m, 2H), 0.83 - 1.08 (m, 2H).

[0278] Synthesis of (1r,4r)-4-(3,3-difluoropyrrolidin-1-yl)cyclohexan-1-amineDocket no. 24-2207-WON-S1 / SetA

[0279] To a solution of (1r,4r)-N,N-dibenzyl-4-(3,3-difluoropyrrolidin-1-yl)cyclohexan-1-amine (1 g, 2.6 mmol, 1 eq) in EtOH (20 mL) was added Pd(OH)2 / C (200 mg, 20% w / w) under nitrogen atmosphere. The mixture was hydrogenated at 50°C for 17h under hydrogen atmosphere using a hydrogen balloon, then filtered through a Celite pad and concentrated under reduced pressure. (1r,4r)-4-(3,3-difluoropyrrolidin-1-yl)cyclohexan-1-amine (350 mg, 65% yield) was obtained as a yellow oil. LC / MS: mass calcd. for C10H18F2N2: 204.14, found: 205.15 [M+H]+.

[0280] Synthesis of 3-[(6-chloropyridazin-3-yl)methyl]-1-[(1r,4r)-4-(3,3-difluoropyrrolidin-1-yl)cyclohexyl] thiourea

[0281] To a stirred solution of (1r,4r)-4-(3,3-difluoropyrrolidin-1-yl)cyclohexan-1-amine (200 mg, 1.2 mmol, 1.2 eq) in THF (5 mL) were added TEA (296 mg, 2.9 mmol, 3 eq) and TCDI (174 mg, 1 mmol, 1 eq) at 0°C. The resulting mixture was stirred at room temperature for 1h. To the above mixture was added 1-(6-chloropyridazin-3-yl)methanamine (140 mg, 1 mmol, 1 eq) at 0°C. The resulting mixture was stirred at room temperature overnight. The reaction was poured into 30 mL sat. NaHCCh (aq.) at 0°C. The aqueous layer was extracted with CH2CI2 (3x 30 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2CI21 MeOH (12:1) to afford 3-[(6-chloropyridazin-3-yl)methyl]-1-[(1r,4r)-4-(3,3-difluoropyrrolidin-1-yl)cyclohexyl]thiourea (240 mg, 63% yield) as a yellow solid. LC / MS: mass calcd. For C16H22CIF2N5S: 389.1, found: 390.0 [M+H]+

[0282] Synthesis of 2-chloro-N-[(1 r,4r)-4-(3,3-difluoropyrrolidin-1-yl)cyclohexyl]imidazo[1 ,5-b]pyridazin-7-amine

[0283] To a stirred solution of 3-[(6-chloropyridazin-3-yl)methyl]-1-[(1r,4r)-4-(3,3-difluoropyrrolidin-1-yl)cyclohexyl]thiourea (220 mg, 0.5 mmol, 1 eq) in toluene (5 mL) were added DCC (583 mg, 2.8 mmol, 5 eq) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 110°C overnight under nitrogen atmosphere. The reaction was poured into 30 mL sat. NaHCCh (aq.) at 0°C. The resulting mixture was extracted with CH2CI2 (3 x 30 mL). The combined organic layers were washed with brine (1x 30 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 CH2CI2 / MeOH (12:1) to afford 2-chloro-N-[(1r,4r)-4-(3,3-difluoropyrrolidin-1-yl)cyclohexyl]imidazo[1,5-b]pyridazin-7-amine (130 mg, 65% yield) as a red solid. LC / MS: mass calcd. For C16H20CIF2N5: 355.1, found: 356.0 [M+H]+.

[0284] Synthesis of N-((1r,4r)-4-(3,3-difluoropyrrolidin-1-yl)cyclohexyl)-2-(1H-imidazol-1-yl)imidazo[1,5-b]pyridazin-7-amineDocket no. 24-2207-WON-S1 / SetA

[0285] To a stirred solution of 2-chloro-N-[(1r,4r)-4-(3,3-difluoropyrrolidin-1-yl)cyclohexyl]imidazo[1,5-b]pyridazin-7-amine (65 mg, 0.2 mmol, 1 eq) and imidazole (12 mg, 0.2 mmol, 1 eq) in DMF (4 mL) was added CS2CO3 (178 mg, 0.5 mmol, 3 eq) at room temperature. The resulting mixture was stirred at 100°C for 2h. The resulting mixture was filtered and the filter cake was washed with CH2CI2 (3x3 mL). The filtrate was concentrated under reduced pressure. The reaction was poured into 5 mL water. The resulting mixture was extracted with EtOAc (3 x 5 mL). The combined organic layers were washed with brine (1x5 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. 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%): 20% B to 45% B inlOmin; Wavelength: 254nm) to afford N-((1r,4r)-4-(3,3-difluoropyrrolidin-1-yl)cyclohexyl)-2-(1H-imidazol-1-yl)imidazo[1,5-b]pyridazin-7-amine (27.7 mg, 39 % yield) as an orange solid. LC / MS: mass calcd. For C19H23F2N7: 387.2, found: 388.3 [M+H]+.1H NMR (300 MHz, DMSO-cfe) 68.61 (s, 1H), 8.06 (s, 1H), 8.00 (d, J= 9.6 Hz, 1H), 7.10 - 7.18 (m, 2H), 6.84 (d, J= 9.6 Hz, 1H), 6.15 (d, J= 8.1 Hz, 1H), 3.52 - 3.79 (m, 1H), 2.92 (t, J= 13.8 Hz, 2H), 2.73 (t, J= 6.9 Hz, 2H), 2.08 - 2.30 (m, 3H), 1.99 - 2.09 (m, 2H), 1.86 - 1.99 (m, 2H), 1.31 - 1.50 (m, 2H), 1.12 - 1.31 (m, 2H).19F NMR (282 MHz, DMSO-cfe) 6 -90.67.

[0286] Example 28: Synthesis of N-(4,4-difluorocyclohexyl)-2-(1H-imidazol-1-yl)imidazo[1,5-b]pyridazin-7-amine

[0287] Synthesis of 1-[(6-chloropyridazin-3-yl)methyl]-3-(4,4-difluorocyclohexyl)thiourea

[0288] To a stirred solution of 4,4-difluorocyclohexan-1-amine (250 mg, 1.8 mmol, 1.1 eq) in THF (5 mL) were added TEA (402 mg, 4 mmol, 3 eq) and TCDI (236 mg, 1.3 mmol, 1 eq) at 0°C. The resulting mixture was stirred at room temperature for 1h. To the above mixture was added 1-(6-chloropyridazin-3-yl)methanamine (190 mg, 1.3 mmol, 1 eq) at roomDocket no. 24-2207-WON-S1 / SetAtemperature. The resulting mixture was stirred at room temperature overnight. The reaction was poured into 20 mL sat. NaHCOs (aq.) at 0°C. The aqueous layer was extracted with CH2CI2 (3x20 mL). The residue was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2CI21 MeOH (12:1) to afford 1-[(6-chloropyridazin-3-yl)methyl]-3-(4,4-difluorocyclohexyl)thiourea (300 mg, 64% yield) as a yellow solid. LC / MS: mass calcd. For C12H15CIF2N4S: 320.0, found: 320.9 [M+H]+.

[0289] Synthesis of 2-chloro-N-(4,4-difluorocyclohexyl)imidazo[1 ,5-b]pyridazin-7-amine

[0290] To a stirred solution of 1-[(6-chloropyridazin-3-yl)methyl]-3-(4,4-difluorocyclohexyl)thiourea (280 mg, 0.9 mmol, 1 eq) in toluene (5 mL) were added DCC (900 mg, 4.4 mmol, 5 eq) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 110°C overnight under nitrogen atmosphere. The reaction was poured into 20 mL sat. NaHCCh (aq.) at 0°C and extracted with CH2CI2 (3 x 20 mL). The combined organic layers were washed with brine (1x5 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 CH2CI21 MeOH (12:1) to afford 2-chloro-N-(4,4-difluorocyclohexyl)imidazo[1,5-b]pyridazin-7-amine (200 mg, 79 % yield) as a red solid. LC / MS: mass calcd. For C12H13CIF2N4: 286.0, found: 287.0 [M+H]+.

[0291] Synthesis of N-(4,4-difluorocyclohexyl)-2-(1H-imidazol-1-yl)imidazo[1,5-b]pyridazin-7-amine

[0292] To a stirred solution of 2-chloro-N-(4,4-difluorocyclohexyl)imidazo[1,5-b]pyridazin-7-amine (100 mg, 0.3 mmol, 1 eq) and imidazole (24 mg, 0.3 mmol, 1 eq) in DMF (5 mL) were added CS2CO3 (341 mg, 1 mmol, 3 eq) at room temperature. The resulting mixture was stirred at 100°C for 2 h. The resulting mixture was filtered and the filter cake was washed with CH2CI2 (3x10 mL). The filtrate was concentrated under reduced pressure. 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 in 10min; Wavelength: 254 nm) to afford N-(4,4-difluorocyclohexyl)-2-(1H-imidazol-1-yl)imidazo[1,5-b]pyridazin-7-amine (51.0 mg, 46% yield) as an orange solid. LC / MS: mass calcd. For C15H16F2N6: 318.1, found: 319.2 [M+H]+.1H NMR (300 MHz, DMSO-cfe) 68.64 (s, 1H), 8.00 - 8.12 (m, 2H), 7.18 (a, 2H), 6.87 (d, J= 9.6 Hz, 1H), 6.30 (d, J= 8.0 Hz, 1H), 3.80 - 4.00 (m, 1H), 2.01 - 2.20 (m, 5H), 1.82 - 2.01 (m, 1H), 1.62 - 1.82 (m, 2H).19F NMR (282 MHz, DMSO-cfe) 6 -91.93, -92.76, -98.34, -99.17.

[0293] Example 29: Synthesis of 2-( 1 H-imidazol-1 -y l)-N -(( 1 r,4r)-4-(trifluoromethoxy)cyclohexyl)imidazo[1,5-b]pyridazin-7-amineDocket no. 24-2207-WON-S1 / SetA

[0294] Synthesis of 3-[(6-chloropyridazin-3-yl)methyl]-1-[(1r,4r)-4-(trifluoromethoxy)cyclohexyl]thiourea

[0295] To a stirred solution of (1r,4r)-4-(trifluoromethoxy)cyclohexan-1 -amine hydrochloride (214 mg, 0.98 mmol, 1 eq) in THF (10 mL) was added TEA (4 mL, 2.9 mmol, 3 eq) and TCDI (174 mg, 1 mmol, 1 eq) at 0°C. The mixture was stirred for 1h at room temperature, then 1-(6-chloropyridazin-3-yl)methanamine (140 mg, 1 mmol, 1 eq) was added at 0°C. The mixture was stirred for 17h at room temperature. The reaction was quenched by the addition of sat. NaHCOs (aq.) (50mL) at 0°C.The resulting mixture was extracted with EtOAc (3 x 50mL). The combined organic layers were washed with brine (2x50 mL) and dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2CI21 MeOH (20:1) to afford 3-[(6-chloropyridazin-3-yl)methyl]-1-[(1r,4r)-4-(trifluoromethoxy)cyclohexyl]thiourea (280 mg, 78% yield) as a yellow solid. LC / MS: mass calcd. for C13H16CIF3N4OS: 368.1, found: 369.1 [M+H]+.

[0296] Synthesis of 2-chloro-N-[(1 r,4r)-4-(trifluoromethoxy)cyclohexyl]imidazo[1 ,5-b]pyridazin-7-amine

[0297] To a stirred solution of 3-[(6-chloropyridazin-3-yl)methyl]-1-[(1r,4r)-4-(trifluoromethoxy)cyclohexyl] thiourea (260 mg, 0.7 mmol, 1 eq) in toluene (20 mL) was added DCC (436 mg, 2 mmol, 3 eq) at room temperature under N2 atmosphere. The final reaction mixture was stirred for 17h at 120°C. The reaction was quenched with sat. NaHCCh (aq.) at 0°C.The mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (2x100 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 (10:1) to afford 2-chloro-N-[(1r,4r)-4-(trifluoromethoxy)cyclohexyl]imidazo[1,5-b]pyridazin-7-amine (100 mg, 42% yield) as an orange solid. LC / MS: mass calcd. for C13H14CIF3N4O: 334.1, found: 335.1 [M+H]+.Docket no. 24-2207-WON-S1 / SetA

[0298] Synthesis of 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(trifluoromethoxy)cyclohexyl)imidazo[1,5-b]pyridazin-7-amine

[0299] To a solution of 2-chloro-N-[(1r,4r)-4-(trifluoromethoxy)cyclohexyl]imidazo[1 ,5-b]pyridazin-7-amine (100 mg, 0.3 mmol, 1 eq) in DMF (2 mL) was added imidazole (31 mg, 0.5 mmol, 1.5 eq) and CS2CO3 (292 mg, 0.9 mmol, 3 eq) at room temperature. Then the reaction was stirred for 2h at 100°C. The reaction mixture was filtered and the filtrate was purified by Prep-HPLC (Column: YMC-Triart C18 EXRS 19*250mm, 5um; Mobile Phase A: water / 10mM NH4HCO3, Mobile Phase B: ACN; Flow rate: 60ml / min; Gradient (B%): 41% B to 61% B in 10 min; Wavelength: 254nm / 220nm) to afford 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(trifluoromethoxy)cyclohexyl)imidazo[1,5-b]pyridazin-7-amine (30.4 mg, 27% yield) as an orange solid. LC / MS: mass calcd. for C16H17F3N6O: 366.1, found: 367.1 [M+H]+.1H NMR (300 MHz, DMSO-cfe) 68.63 (s, 1H), 7.97 - 8.11 (m, 2H), 7.17 (s, 2H), 6.86 (d, J= 9.6 Hz, 1H), 6.21 (d, J= 7.5 Hz, 1 H), 4.30 - 4.47 (m, 1H), 3.64 - 3.81 (m, 1H), 1.97 - 2.20 (m, 4H), 1.43 - 1.75 (m, 4H)..19F NMR (282 MHz, DMSO-cfe) 655.93.

[0300] Example 30: Synthesis of 2-( 1 H-imidazol-1 -y l)-N -(( 1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-5-methylimidazo[1,5-b]pyridazin-7-amine

[0301] Synthesis of 5-bromo-2-chloro-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)imidazo[1,5-b]pyridazin-7-amine

[0302] A solution of 2-chloro-N-[(1 r,4r)-4-(2-methoxyethoxy)cyclohexyl]imidazo[1 ,5-b]pyridazin-7-amine (400 mg, 1.2 mmol, 1 eq) and NBS (218 mg, 1.2 mmol, 1 eq) in DCM (40 mL) was stirred at room temperature for 10 min 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 (72:28) to afford 5-bromo-2-chloro-N-[(1r,4r)-4-(2-methoxyethoxy)cyclohexyl]imidazo[1,5-b]pyridazin-7-amine (240 mg, 56% yield) as a red oil. For Ci5H2oBrCIN402: 402.2, found: 403.0 [M+H]+.Docket no. 24-2207-WON-S1 / SetA

[0303] Synthesis of 5-bromo-2-(imidazol-1-yl)-N-[(1r,4r)-4-(2-methoxyethoxy)cyclohexyl]imidazo[1,5-b]pyridazin-7-amine

[0304] A solution of 5-bromo-2-chloro-N-[(1r,4r)-4-(2-methoxyethoxy)cyclohexyl]imidazo[1,5-b]pyridazin-7-amine (230 mg, 0.5 mmol, 1 eq), imidazole (194 mg, 2.8 mmol, 5 eq) and CS2CO3 (557 mg, 1.7 mmol, 3 eq) in DMF (4 mL) was stirred at 100°C for 1h under nitrogen atmosphere. The reaction mixture was filtered and the filtrate was purified by reverse-phase flash (C18 column, mobile phase, MeCN in water (10 mmol / L NH4HCO3), 5% to 33% gradient in 25 min; detector, LIV 254 nm) to afford 5-bromo-2-(imidazol-1-yl)-N-[(1 r,4r)-4-(2-methoxyethoxy) cyclohexyl]imidazo[1 ,5-b]pyridazin-7-amine (200 mg, 80 %yield) as a red solid. For Cis^sBrNeCh: 434.1, found: 435.1 [M+H]+.

[0305] Synthesis of 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-5-methylimidazo[1,5-b]pyridazin-7-amine

[0306] A solution of 5-bromo-2-(imidazol-1-yl)-N-[(1 r,4r)-4-(2-methoxyethoxy)cyclohexyl]imidazo[1,5-b] pyridazin-7-amine (100 mg, 0.2 mmol, 1 eq), trimethylboroxine (87 mg, 0.6 mmol, 3 eq), Pd(dppf)Cl2CH2Cl2 (19 mg, 0.02 mmol, 0.1 eq) and K2CO3 (95 mg, 0.6 mmol, 3 eq) in 1,4-dioxane (3 mL) and H2O (0.6 mL) was stirred at 100°C for 3h under nitrogen atmosphere. The reaction mixture was concentrated and the residue was purified by silica gel column chromatography, eluted with PE I EA (2:1) to afford crude product (60 mg). The crude product (60 mg) 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%): 18%B to 40%B in 8 min; Wavelength: 254 / 220 nm) to afford 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-5-methylimidazo[1,5-b]pyridazin-7-amine (12.5 mg, 14% yield) as a red solid. For C19H26N6O2: 370.2, found: 371.1 [M+H]+.1H NMR (300 MHz, MeOD) 5 8.56 (s, 1H), 7.95 (s, 1H), 7.85 - 7.90 (m, 1H), 7.18 (s, 1H), 6.60 (d, J= 9.6 Hz, 1H), 3.76 (s, 1H), 3.62 - 3.71 (m, 2H), 3.51 - 3.61 (m, 2H), 3.36 - 3.40 (m, 4H), 2.41 (s, 3H), 2.10 - 2.20 (m, 4H), 1.39 - 1.51 (m, 4H).

[0307] Example 31: Synthesis of 5-cyclopropyl-2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)imidazo[1,5-b]pyridazin-7-amineDocket no. 24-2207-WON-S1 / SetA

[0308] A solution of 5-bromo-2-(imidazol-1-yl)-N-[(1 r,4r)-4-(2-methoxyethoxy)cyclohexyl]imidazo[1,5-b] pyridazin-7-amine (50 mg, 0.1 mmol, 1 eq), cyclopropylboronic acid (99 mg, 1.1 mmol, 10 eq), Pd(dppf)Cl2CH2Cl2 (9.3 mg, 0.01 mmol, 0.1 eq) and K2CO3 (48 mg, 0.3 mmol, 3 eq) in 1,4-dioxane (2.5 mL) was stirred at80°C for2h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2CI21 MeOH (6:1) to afford crude product. The crude product was purified by Prep- HPLC (Column:Xbridge Prep Shield RP185pm OBD 30*150mm; Mobile Phase A: water (10 mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 22% B to 47% B in 9 min; Wavelength: 254nm / 220nm) to afford 5-cyclopropyl-2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)imidazo[1,5-b]pyridazin-7-amine (19.1 mg, 41% yield) as a red solid. ForC2iH28N6O2: 396.2, found: 397.2 [M+H]+.1H NMR (300 MHz, CD3OD) 58.55 (s, 1H), 7.88 - 7.98 (m, 2H), 7.18 (s, 1H), 6.56 (d, J = 9.7, 1H), 3.76 (s, 1H), 3.62 - 3.71 (m, 2H), 3.50 - 3.59 (m, 2H), 3.35 - 3.41 (m, 4H), 2.01 - 2.18 (m, 5H), 1.28 - 1.55 (m, 4H), 0.85 - 1.04 (m, 4H).

[0309] Example 32: Synthesis of 2-( 1 H-imidazol-1 -y l)-N -(( 1 r,4r)-4-methoxycyclohexyl)-5-methylimidazo[1,5-b]pyridazin-7-amine

[0310] Synthesis of 5-bromo-2-chloro-N-[(1r,4r)-4-methoxycyclohexyl]imidazo[1,5-b]pyridazin-7-amine

[0311] To a stirred solution of 2-chloro-N-[(1r,4r)-4-methoxycyclohexyl]imidazo[1,5-b]pyridazin-7-amine (300 mg, 1 mmol, 1 eq) in DCM (15 mL) was added NBS (133 mg, 0.7 mmol, 0.7 eq). The resulting mixture was stirred for 1h at room temperature. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / EA (5 / 1) to afford 5-bromo-2-chloro-N-[(1r,4r)-4-methoxycyclohexyl]imidazo[1,5-b]pyridazin-7-amine (220 mg, 57 % yield) as a yellow solid. LC / MS: mass calcd. for CisHieBrCIIXLO: 358.02, found: 359.95 [M+H]+.Docket no. 24-2207-WON-S1 / SetA

[0312] Synthesis of 5-bromo-2-(imidazol-1-yl)-N-[(1r,4r)-4-methoxycyclohexyl]imidazo[1,5-b]pyridazin-7-amine

[0313] To a stirred solution of 5-bromo-2-chloro-N-[(1r,4r)-4-methoxycyclohexyl]imidazo[1,5-b]pyridazin-7-amine (200 mg, 0.6 mmol, 1 eq) in DMF (5 mL) was added CS2CO3 (543 mg, 1.7 mmol, 3 eq) and imidazole (38 mg, 0.6 mmol, 1 eq). The final reaction mixture was irradiated with microwave radiation at 100°C for 2h. The mixture was purified by reversed-phase flash chromatography (C18 column; mobile phase, MeCN in water (0.1% NH4HCO3), 10% to 50% gradient in 40 min; detector, LIV 254 nm to afford 5-bromo-2-(imidazol-1-yl)-N-[(1r,4r)-4-methoxycyclohexyl]imidazo[1,5-b]pyridazin-7-amine (150 mg, 69 % yield) as a yellow solid. LC / MS: mass calcd. for CieHigBrNeO: 390.0, found: 391.0 [M+H]+.1H N MR (300 MHz, DMSO-cfe) 58.63 (s, 1H), 8.07 (s, 1H), 7.85 (d, J = 9.7 Hz, 1H), 7.16 (s, 1H), 6.93 (d, J= 9.7 Hz, 1H), 6.49 (d, J= 8.1 Hz, 1H), 3.54 - 3.72 (m, 1H), 3.24 (s, 3H), 3.05 - 3.20 (m, 1H), 1.95 - 2.09 (m, 4H), 1.13 - 1.31 (m, 2H), 1.31 - 1.51 (m, 4H).

[0314] Synthesis of 2-(imidazol-1-yl)-5-methyl-N-[(1r,4r)-4-methoxycyclohexyl]imidazo[1,5-b]pyridazin-7-amine

[0315] To a stirred solution of 5-bromo-2-(imidazol-1-yl)-N-[(1r,4r)-4-methoxycyclohexyl]imidazo[1,5-b]pyridazin-7-amine (100 mg, 0.3 mmol, 1 eq) in dioxane (7 mL) was added Pd(dppf)Cl2CH2Cl2 (21 mg, 0.02 mmol, 0.1 eq), dimethylzinc(1.2 M in toluene) (0.3 mL, 0.4 mmol, 1.5 eq) under a nitrogen atmosphere. The resulting mixture was stirred for 17h at 80°C. The resulting mixture was poured into NH4CI (aq, 20 mL). The resulting mixture was extracted with EA (3 x 20mL). The combined organic layers were washed with brine (20 mL) and dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The crude product 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 16% B in 10 min; Wavelength: 254 / 220 nm) to afford 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-methoxycyclohexyl)-5-methylimidazo[1,5-b]pyridazin-7-amine (27.9 mg, 33% yield) as a red solid. LC / MS: mass calcd. for C17H22N6O: 326.1, found: 327.1 [M+H]+.1H NMR (300 MHz, DMSO-cfe) 58.60 (s, 1H), 7.93 - 8.06 (m, 2H), 7.13 (s, 1H), 6.65 (d, J= 9.6 Hz, 1H), 6.03 (d, J= 8.2 Hz, 1H), 3.57 - 3.73 (m, 1H), 3.23 (s, 3H), 3.05 - 3.18 (m, 1H), 2.31 (s, 3H), 1.95 - 2.18 (m, 4H), 1.30 - 1.47 (m, 2H), 1.12 - 1.30 (m, 2H).

[0316] Example 33: Synthesis of 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-5-(trifluoromethyl)imidazo[1,5-b]pyridazin-7-amineDocket no. 24-2207-WON-S1 / SetA

[0317] Synthesis of 2-chloro-N-[(1 r,4r)-4-(2-methoxyethoxy)cyclohexyl]-5-(trifluoromethyl)imidazo[1,5-b]pyridazin-7-amine

[0318] To a stirred solution of 2-chloro-N-[(1r,4r)-4-(2-methoxyethoxy)cyclohexyl]imidazo[1,5-b]pyridazin-7-amine (150 mg, 0.4 mmol, 1 eq) in ACN (7 mL) was added Ru(bpy)3Ch(17 mg, 0.02 mmol, 0.05 eq) and TMEDA (107 mg, 0.9 mmol, 2 eq) in portions at room temperature under nitrogen atmosphere. To the above mixture was added trifluoromethyl iodide (25% in DMF) (717 uL, 1.9 mmol, 4 eq, 25% wt.) dropwise at room temperature. The resulting mixture was stirred at room temperature overnight under 455 nm blue LED. The resulting mixture was filtered and the filter cake was washed with ACN (3x5 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography (C18 column; mobile phase, MeCN in Water (0.1% TFA), 20% to 50% gradient in 30 min; detector, UV 254 nm) to afford 2-chloro-N-[(1r,4r)-4-(2-methoxyethoxy)cyclohexyl]-5-(trifluoromethyl)imidazo[1,5-b]pyridazin-7-amine (70 mg, 38 %yield) as a red solid. LC / MS: mass calcd. for C16H20CIF3N4O2: 392.1, found: 393.1 [M+H]+.

[0319] Synthesis of 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-5-(trifluoromethyl)imidazo[1,5-b]pyridazin-7-amine

[0320] To a stirred solution of 2-chloro-N-[(1r,4r)-4-(2-methoxyethoxy)cyclohexyl]-5-(trifluoromethyl)imidazo [1,5-b]pyridazin-7-amine (60 mg, 0.2 mmol, 1 eq) in DMF (2 mL) was added CS2CO3 (100 mg, 0.3 mmol, 2 eq) and imidazole (15.6 mg, 0.2 mmol, 1.5 eq) in portions at room temperature. The resulting mixture was stirred at 100°C for 2h. The resulting mixture was filtered and the filtrate 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%): 28%B to 48%B in 10min;Wavelength: 254 / 220 nm) to afford 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-5-(trifluoromethyl)imidazo[1,5-b]pyridazin-7-amine (21.2 mg, 32% yield) as a yellow solid. LC / MS: mass calcd. for C19H23F3N6O2: 424.18, found: 425.10 [M+H]+.1H NMR (300 MHz, DMSO-cfe) 68.70 (s, 1H), 8.06 - 8.19 (m, 2H), 7.30 (d, J= 9.9 Hz, 1H), 7.18 (s, 1H), 6.62 (d, J= 8.1 Hz, 1H), 3.60 - 3.80 (m, 1H), 3.54 (t, J = 4.2 Hz, 2H), 3.44 (t, J = 3.3 Hz, 2H), 3.29 - 3.42 (m, 1H), 3.24 (s, 3H), 2.00 - 2.15 (m, 4H), 1.35 - 1.60 (m, 2H), 1.18 -1.35 (m, 2H).19F NMR (282 MHz, DMSO-cfe) 6 -58.39.Docket no. 24-2207-WON-S1 / SetA

[0321] Example 34: Synthesis of N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-2-(5-methyl-1 H-imidazol-1 -yl)imidazo[1 ,5-b]pyridazin-7-amineTo a stirred solution of 2-chloro-N-[(1r,4r)-4-(2-methoxyethoxy)cyclohexyl]imidazo[1,5-b]pyridazin-7-amine (70 mg, 0.2 mmol, 1 eq) and 4-methylimidazole (18 mg, 0.2 mmol, 1 eq) in DMF (3 mL) was added CS2CO3 (211 mg, 0.6 mmol, 3 eq) at room temperature. The resulting mixture was stirred at 100°C for 2h. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (30 mL) and extracted with EtOAc (3x30 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The crude product 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%): 3% B to 19% B in 10 min; Wavelength: 254 / 220 nm) to afford N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-2-(5-methyl-1H-imidazol-1-yl)imidazo[1,5-b]pyridazin-7-amine (10.9 mg, 13% yield) as a red viscous oil. LC / MS: mass calcd. For C19H26N6O2: 370.2, found: 371.1 [M+H]+.1H NMR (300 MHz, DMSO-cfe) 69.01 (s, 1H), 8.15 (d, J= 9.6 Hz, 1H), 7.44 (d, J= 2.0 Hz, 1H), 7.35 (s, 1H), 7.11 (br, 1H), 6.84 (d, J= 9.6 Hz, 1H), 3.61 - 3.73 (m, 1H), 3.48 - 3.55 (m, 2H), 3.37 - 3.43 (m, 2H), 3.15 - 3.30 (m, 4H), 2.44 (s, 3H), 1.90 - 2.07 (m, 4H), 1.36 - 1.53 (m, 2H), 1.14 - 1.31 (m, 2H).

[0322] Example 35: Synthesis of 2-( 1 H-imidazol-1 -y l)-N -(( 1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-4-methylimidazo[1,5-b]pyridazin-7-amineDocket no. 24-2207-WON-S1 / SetA

[0323] Synthesis of tert-butyl N-[(6-chloro-4-methylpyridazin-3-yl)methyl]carbamate

[0324] To a stirred solution of 3-bromo-6-chloro-4-methylpyridazine (1 g, 4.8 mmol, 1 eq) and potassium tert-butyl N-[(trifluoroboranuidyl)methyl]carbamate (1.1 g, 4.8 mmol, 1 eq) in dioxane (75 mL) and H2O (15 mL) was added CS2CO3 (4.7 g, 14.5 mmol, 3 eq) and Pd(OAc)2(110 mg, 0.5 mmol, 0.1 eq) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80°C for 5h under nitrogen atmosphere. The mixture was allowed to cool to room temperature. The resulting mixture was filtered and the filter cake was washed with EtOAc (3x 20 mL). The filtrate was concentrated under reduced pressure. The residue was dissolved in water. The resulting mixture was extracted with EtOAc (3x100 mL). The combined organic layers were 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 tert-butyl N-[(6-chloro-4-methylpyridazin-3-yl)methyl]carbamate (690 mg, 55% yield) as a yellow solid. LC / MS: mass calcd. For CIIHI6CIN3O2: 257.1, found: 258.1 [M+H]+.

[0325] Synthesis of 1-(6-chloro-4-methylpyridazin-3-yl)methanamine

[0326] To a stirred solution of tert-butyl N-[(6-chloro-4-methylpyridazin-3-yl)methyl]carbamate (640 mg, 2.5 mmol, 1 eq) in DCM (3.5 mL) was added HCI in 1,4-dioxane (4.0 M) (3.5 mL) at 0°C. The resulting mixture was stirred at room temperature for 1h. The resulting mixture was concentrated under reduced pressure. This resulted in 1-(6-chloro-4-methylpyridazin-3-yl)methanamine (310 mg) as a white solid. The crude product was used in the next step directly without further purification. LC / MS: mass calcd. For C6H8CIN3: 157.0, found: 158.0 [M+H]+.

[0327] Synthesis of 1-(6-chloro-4-methylpyridazin-3-yl)methanamine

[0328] To a stirred solution of (1r,4r)-4-(2-methoxyethoxy)cyclohexan-1 -amine (329 mg, 1.9 mmol, 1 eq) in THF (15 mL) was added TEA (794 uL, 5.7 mmol, 3 eq) and TCDI (339Docket no. 24-2207-WON-S1 / SetAmg, 1.9 mmol, 1 eq) at 0°C. The resulting mixture was stirred at room temperature for 2h. To the above mixture was added 1-(6-chloro-4-methylpyridazin-3-yl)methanamine (300 mg, 1.9 mmol, 1 eq) at 0°C. The resulting mixture was stirred at room temperature for an additional 17h. The reaction was poured into ice water (50 mL) at 0°C. The resulting mixture was extracted with EtOAc (3x 100 mL). The combined organic layers were dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE I EA (1:4) to afford 1-[(6-chloro-4-methylpyridazin-3-yl)methyl]-3-[(1r,4r)-4-(2-methoxyethoxy)cyclohexyl]thiourea (315 mg, 44% yield) as a yellow viscous oil. LC / MS: mass calcd. For CI6H25CIN4O2S: 372.1, found: 373.1 [M+H]+.

[0329] Synthesis of 2-chloro-4-methyl-N-[(1r,4r)-4-(2-methoxyethoxy)cyclohexyl]imidazo[1,5-b]pyridazin-7-amine

[0330] To a stirred solution of 1-[(6-chloro-4-methylpyridazin-3-yl)methyl]-3-[(1r,4r)-4-(2-methoxyethoxy) cyclohexyl]thiourea (300 mg, 0.8 mmol, 1 eq) in toluene (9 mL) was added DCC (498 mg, 2.4 mmol, 3 eq) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 110°C for 17h under nitrogen atmosphere. The mixture was allowed to cool to room temperature. The reaction was poured into ice water (30 mL). The resulting mixture was extracted with EtOAc (3x 100 mL). The combined organic layers were 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 (1:3) to afford 2-chloro-4-methyl-N-[(1r,4r)-4-(2-methoxyethoxy)cyclohexyl]imidazo[1,5-b]pyridazin-7-amine (80 mg, 29% yield) as a red solid. LC / MS: mass calcd. For C16H23CIN4O2: 338.2, found: 339.2 [M+H]+.

[0331] Synthesis of 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-4-methylimidazo[1,5-b]pyridazin-7-amine

[0332] To a stirred solution of 2-chloro-4-methyl-N-[(1r,4r)-4-(2-methoxyethoxy)cyclohexyl]imidazo[1,5-b]pyridazin-7-amine (70 mg, 0.2 mmol, 1 eq) and imidazole (21 mg, 0.3 mmol, 1.5 eq) in DMF (3 mL) was added CS2CO3 (201 mg, 0.6 mmol, 3 eq) at room temperature. The resulting mixture was stirred at 100°C for 2h. The resulting mixture was diluted with water (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product 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%): 3% B to 16% B in 10 min; Wavelength: 254 / 220 nm) to afford 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-Docket no. 24-2207-WON-S1 / SetAmethoxyethoxy)cyclohexyl)-4-methylimidazo[1,5-b]pyridazin-7-amine (36.2 mg, 47% yield) as an orange solid. LC / MS: mass calcd. For C19H26N6O2: 370.2, found: 371.2 [M+H]+.1H NMR (300 MHz, DMSO-cfe) 68.58 (s, 1H), 8.04 (s, 1H), 7.19 (s, 1H), 7.14 (s, 1H), 6.80 (s, 1H), 6.07 (d, J= 8.1 Hz, 1H), 3.58 - 3.73 (m, 1H), 3.50 - 3.56 (m, 2H), 3.38 - 3.44 (m, 2H), 3.19 -3.29 (m, 4H), 2.38 (s, 3H), 1.95 - 2.09 (m, 4H), 1.32 - 1.49 (m, 2H), 1.15 - 1.32 (m, 2H).

[0333] Example 36: Synthesis of 2-( 1 H-imidazol-1 -y l)-N -(( 1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-4,5-dimethylimidazo[1,5-b]pyridazin-7-amine

[0334] Synthesis of 5-bromo-2-chloro-4-methyl-N-[(1 r,4r)-4-(2-methoxyethoxy)cyclohexyl]imidazo[1,5-b]pyridazin-7-amine

[0335] To a stirred solution of 2-chloro-4-methyl-N-[(1r,4r)-4-(2-methoxyethoxy)cyclohexyl]imidazo[1,5-b]pyridazin-7-amine (140 mg, 0.4 mmol, 1 eq) in DCM (5 mL) was added NBS (73.5 mg, 0.4 mmol, 1 eq) at 0°C. The resulting mixture was stirred at room temperature for 1h. The reaction was poured into ice water (30 mL) at room temperature. The resulting mixture was extracted with CH2CI2 (3x 30 mL). The combined organic layers were 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 (1:1) to afford 5-bromo-2-chloro-4-methyl-N-[(1r,4r)-4-(2-methoxyethoxy)cyclohexyl]imidazo[1,5-b]pyridazin-7-amine (120 mg, 69% yield) as a red solid. LC / MS: mass calcd. For Ci6H22BrCIN4O2: 416.1, found: 419.1 [M+H]+.1H NMR (300 MHz, DMSO-cfe) 66.50 (d, J = 8.2 Hz, 1 H), 6.30 (s, 1 H), 3.53 - 3.64 (m, 1 H) 3.48 - 3.55 (m, 2H), 3.37 - 3.44 (m, 2H), 3.24 (s, 3H), 3.14 - 3.22 (m, 1H), 2.47 (s, 3H), 1.87 - 2.04 (m, 4H), 1.12 - 1.31 (m, 2H), 1.31 - 1.49 (m, 2H).

[0336] Synthesis of 5-bromo-2-(imidazol-1-yl)-4-methyl-N-[(1r,4r)-4-(2-methoxyethoxy)cyclohexyl]imidazo[1,5-b]pyridazin-7-amine

[0337] To a stirred solution of 5-bromo-2-chloro-4-methyl-N-[(1r,4r)-4-(2-methoxyethoxy)cyclohexyl]imidazo [1,5-b]pyridazin-7-amine (95 mg, 0.2 mmol, 1 eq) and imidazole (23 mg, 0.3 mmol, 1.5 eq) in MeCN (3 mL) was added CS2CO3 (74 mg, 0.2 mmol, 1 eq) at room temperature. The resulting mixture was stirred at 80°C for 60h. The resulting mixture was filtered and the filter cake was washed with MeCN (3x 10 mL). The filtrate wasDocket no. 24-2207-WON-S1 / SetAconcentrated under reduced pressure. The residue was dissolved in water (10 mL). The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2CI21 MeOH 20:1) to afford 5-bromo-2-(imidazol-1-yl)-4-methyl-N-[(1r,4r)-4-(2-methoxyethoxy)cyclohexyl] imidazo[1,5-b]pyridazin-7-amine (70 mg, 68% yield) as a red solid. LC / MS: mass calcd. For Cig^sBrNeCh: 448.1, found: 451.1 [M+H]+.

[0338] Synthesis of 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-4,5-dimethylimidazo[1,5-b]pyridazin-7-amine

[0339] To a stirred solution of 5-bromo-2-(imidazol-1-yl)-4-methyl-N-[(1r,4r)-4-(2-methoxyethoxy)cyclohexyl] imidazo[1,5-b]pyridazin-7-amine (65 mg, 0.2 mmol, 1 eq) in dioxane (1 mL) was added Pd(dppf)Ch (11 mg, 0.01 mmol, 0.1 eq) and dimethylzinc (1.0 M in toluene) (150 uL, 0.22 mmol, 1.5 eq) at 0°C. The resulting mixture was stirred at 80°C for an additional 17h. The mixture was allowed to cool down to room temperature. The reaction was poured into sat. NH4CI (aq.) (10 mL) at 0°C. The resulting mixture was extracted with EtOAc (3x 10 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography: C18 column; mobile phase, MeCN in water (0.1% TFA), 10% to 50% gradient in 10 min; detector, UV 254 nm to afford a crude product. The crude product 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%): 19%B to 39%B in 10min; Wavelength: 254 / 220 nm) to afford 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-4,5-dimethylimidazo[1,5-b]pyridazin-7-amine (17.4 mg, 31% yield) as an orange solid. LC / MS: mass calcd. For C20H28N6O2: 384.2, found: 385.2 [M+H]+.1H NMR (300 MHz, DMSO-cfe) 68.57 (s, 1H), 8.03 (s, 1H), 7.14 (s, 1H), 6.58 (s, 1H), 5.94 (d, J = 8.3 Hz, 1H), 3.58- 3.73 (m, 1H), 3.50 - 3.55 (m, 2H), 3.40 - 3.46 (m, 2H), 3.18 - 3.32 (m, 4H), 2.42 - 2.50 (m, 6H), 1.94 - 2.09 (m, 4H), 1.15 -1.33 (m, 2H), 1.49 (m, 2H).

[0340] Example 37: Synthesis of N-((1r,4r)-4-(3,3-difluoropyrrolidin-1-yl)cyclohexyl)-2-(1H-imidazol-1-yl)-4-methylimidazo[1,5-b]pyridazin-7-amineDocket no. 24-2207-WON-S1 / SetA

[0341] Synthesis of 3-[(6-chloro-4-methylpyridazin-3-yl)methyl]-1-[(1r,4r)-4-(3,3-difluoropyrrolidin-1-yl)cyclohexyl]thiourea

[0342] To a stirred solution of (1r,4r)-4-(3,3-difluoropyrrolidin-1-yl)cyclohexan-1-amine (117 mg, 0.6 mmol, 1 eq) in THF (6 mL) was added TEA (182 mg, 1.8 mmol, 3 eq) and TCDI (102 mg, 0.6 mmol, 1 eq) at 0°C. The mixture was stirred for 1h at room temperature, then 1-(6-chloro-4-methylpyridazin-3-yl)methanamine (90 mg, 0.6 mmol, 1 eq) was added at 0°C. The mixture was stirred for 17h at room temperature. The reaction was quenched by the addition of sat. NaHCOs (aq.) (50mL) at 0°C. The mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (2x50 mL) and dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2CI21 MeOH 20:1) to afford 3-[(6-chloro-4-methylpyridazin-3-yl)methyl]-1-[(1r,4r)-4-(3,3-difluoropyrrolidin-1-yl)cyclohexyl]thiourea (180 mg, 78% yield) as a yellow solid. LC / MS: mass calcd. for C17H24CIF2N5S: 403.1, found: 404.2 [M+H]+.

[0343] Synthesis of 2-chloro-4-methyl-N-[(1r,4r)-4-(3,3-difluoropyrrolidin-1-yl)cyclohexyl]imidazo[1,5-b]pyridazin-7-amine

[0344] To a stirred solution of 3-[(6-chloro-4-methylpyridazin-3-yl)methyl]-1-[(1r,4r)-4-(3,3-difluoropyrrolidin-1-yl)cyclohexyl]thiourea (160 mg, 0.4 mmol, 1 eq) in toluene (1 mL) was added DCC (409 mg, 2 mmol, 5 eq) at room temperature under N2 atmosphere. The reaction mixture was stirred for 36h at 120°C under N2 atmosphere. The reaction was poured into sat. NaHCOs (aq.) (10 mL) at 0°C.The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (2x100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE I EA 1:3) to afford 2-chloro-4-methyl-N-[(1r,4r)-4-(3,3-difluoropyrrolidin-1-yl)cyclohexyl]imidazo[1,5-b]pyridazin-7-amine (80 mg, 55% yield) as a yellow solid. LC / MS: mass calcd. for C17H22CIF2N5: 369.2, found: 370.1 [M+H]+.Docket no. 24-2207-WON-S1 / SetA

[0345] Synthesis of N-((1r,4r)-4-(3,3-difluoropyrrolidin-1-yl)cyclohexyl)-2-(1H-imidazol-1-yl)-4-methylimidazo[1,5-b]pyridazin-7-amine

[0346] To a solution of 2-chloro-4-methyl-N-[(1r,4r)-4-(3,3-difluoropyrrolidin-1-yl)cyclohexyl]imidazo[1,5-b]pyridazin-7-amine (80 mg, 0.2 mmol, 1 eq) in DMF (1.5 mL) was added CS2CO3 (211 mg, 0.7 mmol, 3 eq) and imidazole (22 mg, 0.3 mmol, 1.5 eq) at room temperature. Then the reaction was stirred for 2h at 100°C. The reaction mixture was filtered and the filtrate was purified by Perp-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%): 24%B to 44%B in 10min; Wavelength: 254 / 220 nm) to afford N-((1r,4r)-4-(3,3-difluoropyrrolidin-1-yl)cyclohexyl)-2-(1H-imidazol-1-yl)-4-methylimidazo[1,5-b]pyridazin-7-amine (17.6 mg, 20% yield) as an orange solid. LC / MS: mass calcd. for C20H25F2N7: 401.2, found: 402.2 [M+H]+.1H NMR (400 MHz, DMSO-cfe) 68.61 (s, 1H), 8.06 (s, 1H), 7.12 - 7.22 (m, 2H), 6.82 (s, 1H), 6.11 (d, J = 8.4 Hz, 1H), 3.56 - 3.74 (m, 1H), 2.86 -3.03 (m, 2H), 2.65 - 2.81 (m, 2H), 2.40 (s, 3H), 2.00 - 2.29 (m, 5H), 1.86 - 2.00 (m, 2H), 1.32 - 1.49 (m, 2H), 1.14 - 1.31 (m, 2H).19F NMR (377 MHz, DMSO-cfe) 6 -90.65.

[0347] Example 38: Synthesis of N-(((1r,4r)-4-methoxycyclohexyl)methyl)-6-(1-methyl-1 H-imidazol-5-yl)imidazo[1 ,2-b]pyridazin-3-amineCompound 38

[0348] Synthesis of 6-(3-methylimidazol-4-yl)imidazo[1 ,2-b]pyridazin-3-amine

[0349] To a stirred solution of 6-chloroimidazo[1,2-b]pyridazin-3-amine (500 mg, 3 mmol, 1.00 eq) in dioxane (20 mL) and H2O (2 mL) was added 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazole (1.2 g, 5.9 mmol, 2 eq), K2CO3 (1.2 g, 8.9 mmol, 3 eq) and Pd(dppf)Ch (217 mg, 0.3 mmol, 0.1 eq) at room temperature under N2 atmosphere. The final reaction mixture was stirred for 17h at 100°C. The reaction mixture was poured into water (50 mL), The reaction mixture was extracted by EA (3 x 100 mL), the organic phases wereDocket no. 24-2207-WON-S1 / SetAcombined and washed by brine (1 x 100 mL), then dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase column ( C18 column; mobile phase, ACN in water (0.05% NH4HCO3), 5% to 16% gradient in 10 min; detector, LIV 254 nm) to afford 6-(3-methylimidazol-4-yl)imidazo[1,2-b]pyridazin-3-amine (400 mg, 63% yield) was obtained as a yellow solid. LC / MS: mass calcd. forCioHi0N6: 214.1, found: 215.1 [M+H]+.

[0350] Synthesis of 5-{3-iodoimidazo[1,2-b]pyridazin-6-yl}-1 -methylimidazole

[0351] To a stirred solution of 6-(3-methylimidazol-4-yl)imidazo[1 ,2-b]pyridazin-3-amine (400 mg, 1.9 mmol, 1 eq) in 2M HCI (5 mL) was added NaNO2(193 mg, 2.8 mmol, 1.5 eq) in portions at 0°C. The mixture was stirred for 0.5 h at 0°C. Then KI (775 mg, 4.7 mmol, 2.5 eq) was added at 0°C. The resulting mixture was stirred for 17h at room temperature. The reaction mixture was purified by reverse phase column directly (C18 column; mobile phase, ACN in water (0.05% NH4HCO3), 5% to 12% gradient in 20 min; detector, LIV 254 nm) to afford 5-{3-iodoimidazo[1,2-b]pyridazin-6-yl}-1-methylimidazole (120 mg, 20% yield) as a yellow solid. LC / MS: mass calcd. for C HsINs: 325.0, found: 326.0 [M+H]+.

[0352] Synthesis of N-(((1r,4r)-4-methoxycyclohexyl)methyl)-6-(1-methyl-1 H-imidazol-5-yl)imidazo[1,2-b]pyridazin-3-amine

[0353] To a stirred solution of 5-{3-bromoimidazo[1,2-b]pyridazin-6-yl}-1 -methylimidazole (100 mg, 0.4 mmol, 1 eq) in dioxane (3 mL) was added 1-[(1r,4r)-4-methoxycyclohexyl]methanamine (88 mg, 0.6 mmol, 2 eq), CS2CO3 (301 mg, 0.9 mmol, 3 eq), Ephos (5 mg, 0.06 mmol, 0.2 eq) and EPhos Pd G4 (28 mg, 0.03 mmol, 0.1 eq) at room temperature. The reaction mixture was stirred for 17h at 100°C under N2atmosphere. The reaction mixture was poured into water (50 mL), The reaction mixture was extracted by EA (3 x 50 mL), the organic phases were combined and washed with brine (1 x 50 mL), then dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was taken up in DMF (1 mL) and purified by Perp-HPLC (Column: XBridge Prep C18 OBD Column, 30*150 mm, 5 pm; Mobile Phase A: water (0.01 M NH4HCO3 + 0.05% NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): isocratic 16% to 31% B in 10 min; Wavelength: 254 / 220 nm) to afford N-(((1r,4r)-4-methoxycyclohexyl)methyl)-6-(1-methyl-1H-imidazol-5-yl)imidazo[1,2-b]pyridazin-3-amine (27.5 mg, 26% yield) as an orange solid. LC / MS: mass calcd. for CisH^NeO: 340.2, found: 341.2 [M+H]+.1H NMR (300 MHz, DMSO-cfe) 67.82-7.88 (m, 2H), 7.67 (s, 1H), 7.24 (d, J = 9.3 Hz, 1H), 7.04 (s, 1H), 5.51 (t, J= 6.3 Hz, 1H), 4.03 (s, 3H), 3.20 (s, 3H), 2.97 - 3.10 (m, 3H), 1.94 - 2.05 (m, 2H), 1.76 - 1.88 (m, 2H), 1.52 - 1.70 (m, 1H), 0.88 - 1.13 (m, 4H).Docket no. 24-2207-WON-S1 / SetA

[0354] Example 39: Synthesis of N-((4,4-difluorocyclohexyl)methyl)-6-(1-methyl-1H-imidazol-5-yl)imidazo[1 ,2-b]pyridazin-3-amine

[0355] To a stirred solution of 6-(3-methylimidazol-4-yl)imidazo[1 ,2-b]pyridazin-3-amine (70 mg, 0.3 mmol, 1 eq) and 4,4-difluorocyclohexane-1-carbaldehyde (72.6 mg, 0.5 mmol, 1.5 eq) in DCM (3 mL) was added TFA (25 uL, 0.6 mmol, 2 eq) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2h under nitrogen atmosphere. To the above mixture was added STAB (138.5 mg, 0.6 mmol, 2 eq) at 0°C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for an additional 17h. The reaction was quenched with sat. NH4CI (aq.)( 20 mL) at 0°C. The resulting mixture was extracted with CH2CI2 (3 x 30 mL). The combined organic layers were washed with brine (1 x 20 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (C18 column; mobile phase, MeCN in Water (0.1% TFA), 10% to 30% gradient in 20 min; detector, UV 254 nm) to afford the crude product. 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 NI-LHCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient (B%): 24% B to 39% B in 10 min; Wavelength: 254nm / 220nm) to afford N-((4,4-difluorocyclohexyl)methyl)-6-(1-methyl-1H-imidazol-5-yl)imidazo[1,2-b]pyridazin-3-amine (34.5 mg, 30% yield) as a yellow solid. LC / MS: mass calcd. for C17H20F2N6: 346.1, found: 347.1 [M+H]+.1H NMR (300 MHz, DMSO-cfe) 67.81 - 7.93 (m, 2H), 7.69 (s, 1H), 7.27 (d, J= 9.5 Hz, 1H), 7.10 (s, 1H), 5.63 (t, J = 6.4 Hz, 1H), 4.05 (s, 3H), 3.15 (t, J = 6.6 Hz, 2H), 1.94 - 2.11 (m, 2H), 1.63 - 1.94 (m, 5H), 1.15 - 1.37 (m 2H).

[0356] Example 40: Synthesis of 6-( 1 H-imidazol-1 -y l)-N -(( 1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)imidazo[1,2-b]pyridazin-3-amineDocket no. 24-2207-WON-S1 / SetA

[0357] To a stirred solution of 1-{3-bromoimidazo[1,2-b]pyridazin-6-yl}imidazole (150 mg, 0.6 mmol, 1 eq) in dioxane (10 mL) was added (1r,4r)-4-(2-methoxyethoxy)cyclohexan-1-amine (197 mg, 1.1 mmol, 2 eq), CS2CO3 (370 mg, 1.1 mmol, 2 eq), Ephos Pd G4 (55 mg, 0.06 mmol, 0.1 eq) and Ephos (61 mg, 0.1 mmol, 0.2 eq) under a nitrogen atmosphere. The resulting mixture was stirred for 17h at 100°C. The resulting mixture was filtered, and the filter cake was washed with MeOH (3x15mL). The filtrate was concentrated under reduced pressure. The mixture was purified by Prep-HPLC (Column: Xselect CSH OBD Column, 30*150 mm, 5 urn; Mobile Phase A: Water(0.1% FA, Mobile Phase B: ACN; Gradient (B%): 10% B to 26% B in 7 min; Flow rate: 60 mL / min; Wavelength: 254 / 220 nm). The fractions were combined and lyophilized. 6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)imidazo[1,2-b]pyridazin-3-amine (29.4 mg, 14% yield) was obtained as a red solid. LC / MS: mass calcd. for C18H24N6O2: 356.19, found: 357.20 [M+H]+.1H NMR (300 MHz, DMSO-cfe) 68.67 (s, 1H), 8.05 - 8.15 (m, 2H), 7.41 (d, J= 9.5 Hz, 1H), 7.16 - 7.26 (m, 2H), 5.59 (d, J = 8.3 Hz, 1 H), 3.50 - 3.59 (m, 2H), 3.39 - 3.48 (m, 2H), 3.27 -3.36 (m, 2H), 3.26 (s, 3H), 1.96 - 2.13 (m, 4H), 1.21 - 1.50 (m, 4H).

[0358] Example 41 : Synthesis of 6-( 1 H-imidazol-1 -y l)-N -(( 1 r,4r)-4-methoxycyclohexyl)imidazo[1,2-b]pyridazin-3-amineE Cs2CO3, dioxane, 100 CCompound 41

[0359] To a stirred solution of 1-{3-bromoimidazo[1,2-b]pyridazin-6-yl}imidazole (150 mg, 0.6 mmol, 1 eq) in dioxane (10 mL) was added (1r,4r)-4-methoxycyclohexan-1 -amine (147 mg, 1.1 mmol, 2 eq), CS2CO3 (370 mg, 1.1 mmol, 2 eq), Ephos Pd G4 (55 mg, 0.06 mmol, 0.1 eq), Ephos (61 mg, 0.1 mmol, 0.2 eq) under a nitrogen atmosphere. The resulting mixture was stirred for 17h at 100°C. The resulting mixture was filtered, the filter cake was washed with MeOH (3 x 15 mL). The filtrate was concentrated under reduced pressure. 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 / minDocket no. 24-2207-WON-S1 / SetAmL / min; Gradient (B%): 12% B to 27% B in 10 min; Wavelength: 254nm / 220nm) to afford 6-(1 H-imidazol-1 -yl)-N-((1 r,4r)-4-methoxycyclohexyl)imidazo[1 ,2-b]pyridazin-3-amine (55.4 mg, 31% yield) as an orange solid. LC / MS: mass calcd. for C16H20N6O: 312.1, found: 313.1 [M+H]+.1H NMR (300 MHz, DMSO-cfe) 68.68 (s, 1H), 8.10 - 8.15 (m, 1H), 8.08 (s, 1H), 7.41 (d, J= 9.5 Hz, 1H), 7.22 (s, 1H), 7.18 - 7.20 (m, 1H), 5.60 (d, J = 8.4 Hz, 1H), 3.27 - 3.41 (m, 1 H), 3.26 (s, 3H), 3.10 - 3.23 (m, 1H), 1.98 - 2.12 (m, 4H), 1.19 - 1.50 (m, 4H).

[0360] Example 42: Synthesis of 6-(1 H-imidazol-1 -yl)-N-(2-oxaspiro[3.5]nonan-7-yl)imidazo[1,2-b]pyridazin-3-amine

[0361] To a stirred solution of 1-{3-bromoimidazo[1,2-b]pyridazin-6-yl}imidazole (100 mg, 0.4 mmol, 1 eq) in dioxane (10 mL) was added 2-oxaspiro[3.5]nonan-7-amine (107 mg, 0.7 mmol, 2 eq), CS2CO3 (247 mg, 0.7 mmol, 2 eq), Ephos (41 mg, 0.07 mmol, 0.2 eq) and EPhos Pd G4 (35 mg, 0.03 mmol, 0.1 eq) under a nitrogen atmosphere. The resulting mixture was stirred for 17h at 100°C. The resulting mixture was filtered, and the filter cake was washed with MeOH (3 x 15 mL). The filtrate was concentrated under reduced pressure. The 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 mL / min; Gradient (B%): 11% B to 24% B in 10 min; Wavelength: 254nm / 220nm nm). The fractions were combined and lyophilized. 6-(1H-imidazol-1-yl)-N-(2-oxaspiro[3.5]nonan-7-yl)imidazo[1,2-b]pyridazin-3-amine (37.4 mg, 30% yield) was obtained as an orange solid. LC / MS: mass calcd. for C17H20N6O: 324.17, found: 325.05 [M+H]+.1H NMR (300 MHz, DMSO-cfe) 68.67 (s, 1H), 8.05 - 8.15 (m, 2H), 7.41 (d, J= 9.5 Hz, 1H), 7.21 (s, 1H), 7.16 - 7.20 (m, 1H), 5.55 (d, J= 8.4 Hz, 1H), 4.36 (s, 2H), 4.26 (s, 2H), 3.21 - 3.32 (m, 1H), 2.05 - 2.15 (m, 2H), 1.88 - 2.00 (m, 2H), 1.49 - 1.64 (m, 2H), 1.20 - 1.43 (m, 2H).

[0362] Example 43: Synthesis of 6-(1 H-imidazol-1 -yl)-N-((3R, 4S)-3-methyltetrahydro-2H-pyran-4-yl)imidazo[1,2-b]pyridazin-3-aminep Docket no. 24-2207-WON-S1 / SetA

[0363] To a stirred solution of 1-{3-bromoimidazo[1,2-b]pyridazin-6-yl}imidazole (100 mg, 0.4 mmol, 1 eq) and (3R,4S)-3-methyloxan-4-amine hydrochloride (115 mg, 0.8 mmol, 2 eq) in dioxane (5 mL) were added Ephos Pd G4 (35 mg, 0.04 mmol, 0.1 eq), Ephos (20 mg, 0.04 mmol, 0.1 eq) and CS2CO3 (308 mg, 0.9 mmol, 2.5 eq) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100°C overnight under nitrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with DCM (5x3 mL). The filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions (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%): 11% B to 24% B in 10 min; Wavelength: 254nm / 220nm) to afford 6-(1H-imidazol-1-yl)-N-((3R,4S)-3-methyltetrahydro-2H-pyran-4-yl)imidazo[1,2-b]pyridazin-3-amine (15.1 mg, 13% yield) as a yellow solid. LC / MS: mass calcd. for CI5HI8N6O: 298.1, found: 299.1 [M+H]+.1H NMR (300 MHz, DMSO-cfe) 68.67 (s, 1H), 8.12 (s, 1H), 8.07 (d, J= 5.4 Hz, 1H), 7.39 (d, J= 9.5 Hz, 1H), 7.22 (s, 1H), 7.17 (s, 1H), 5.69 (d, J = 9.4 Hz, 1 H), 3.77 - 3.95 (m, 2H), 3.41 (t, J = 11.8 Hz, 1 H), 3.09 - 3.23 (m, 1 H), 3.04 (t, J = 10.8 Hz, 1H), 1.87 - 1.97 (m, 1H), 1.74 - 1.87 (m, 1H), 1.44 - 1.64 (m, 1H), 0.87 (d, J = Q.Q Hz, 3H).

[0364] Example 44: Synthesis of N-(4,4-difluorocyclohexyl)-6-(1H-imidazol-1-yl)imidazo[1,2-b]pyridazin-3-amine

[0365] To a stirred solution of 1-{3-bromoimidazo[1,2-b]pyridazin-6-yl}imidazole (100 mg, 0.4 mmol, 1 eq) and 4,4-difluorocyclohexan-1-amine (82 mg, 0.6 mmol, 1.6 eq) in toluene (4.5 mL) were added Ephos (41 mg, 0.07 mmol, 0.2 eq), Ephos Pd G4 (35 mg, 0.04 mmol, 0.1 eq) and CS2CO3 (248 mg, 0.7 mmol, 2 eq) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100°C overnight under nitrogen atmosphere. The resulting mixture was filtered and the filter cake was washed with DCM (3 x 5 mL). The filtrate was concentrated under reduced pressure. 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 mL / min; Gradient (B%): 20% B to 35% B in 10 min; Wavelength: 254nm / 220nm) to afford N N-(4,4-difluorocyclohexyl)-6-(1H-imidazol-1-yl)imidazo[1,2-b]pyridazin-3-amine (34.1 mg, 28% yield) as an orange solid. LC / MS: mass calcd. For C15H16F2N6: 318.1, found: 319.1 [M+H]+.Docket no. 24-2207-WON-S1 / SetA1H NMR (300 MHz, DMSO-cfe) 68.68 (s, 1H), 8.07 - 8.16 (m, 2H), 7.44 (d, J= 9.6 Hz, 1H), 7.27 (s, 1 H), 7.20 (s, 1 H), 5.76 (d, J = 8.4 Hz, 1 H), 3.46 - 3.68 (m, 1 H), 1.83 - 2.23 (m, 6H), 1.58 - 1.78 (m, 2H).19F NMR (300 MHz, DMSO-cfe) 6 -98.69, -97.84, -92.99, -92.17.

[0366] Example 45: Synthesis of 6 N-((1r,4r)-4-(3,3-difluoropyrrolidin-1-yl)cyclohexyl)-6-(1H-imidazol-1-yl)imidazo[1,2-b]pyridazin-3-amine

[0367] A mixture of 1-{3-bromoimidazo[1,2-b]pyridazin-6-yl}imidazole (70 mg, 0.3 mmol, 1 eq), (1r,4r)-4-(3,3-difluoropyrrolidin-1-yl)cyclohexan-1-amine (54 mg, 0.3 mmol, 1 eq), EPhos Pd G4 (49 mg, 0.05 mmol, 0.2 eq), Ephos (28 mg, 0.05 mmol, 0.2 eq) and CS2CO3 (259 mg, 0.8 mmol, 3 eq) in dioxane (2 mL) was stirred at 100°C for 2h under nitrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with EtOAc (3x 10 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Mobile Phase A: Water(10mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 25 mL / min; Gradient (B%): 22% B to 47% B in10 min; Wavelength: 254 nm) to afford N-((1r,4r)-4-(3,3-difluoropyrrolidin-1-yl)cyclohexyl)-6-(1H-imidazol-1-yl)imidazo[1,2-b]pyridazin-3-amine (34.0 mg, 33% yield) as an orange solid. LC / MS: mass calcd. For C19H23F2N7: 387.2, found: 388.1 [M+H]+.1H NMR (400 MHz, DMSO) 58.67 (s, 1H), 8.05 - 8.14 (m, 2H), 7.40 (d, J= 9.6 Hz, 1H), 7.16 - 7.25 (m, 2H), 5.61 (d, J= 8.4 Hz, 1H), 3.20 - 3.31 (m, 1H), 2.95 (t, J = 13.7 Hz, 2H), 2.75 (t, J= 6.9 Hz, 2H), 2.02 - 2.30 (m, 5H), 1.92 - 2.00 (m, 2H), 1.21 - 1.46 (m, 4H).19F NMR (376 MHz, DMSO) 5 -90.72.

[0368] Example 46: Synthesis of N-((1r,4r)-4-(3,3-difluoroazetidin-1-yl)cyclohexyl)-6-(1 H-imidazol-1-yl)imidazo[1,2-b]pyridazin-3-amineDocket no. 24-2207-WON-S1 / SetA

[0369] To a stirred solution of 1-{3-bromoimidazo[1,2-b]pyridazin-6-yl}imidazole (100 mg, 0.4 mmol, 1 eq) in dioxane (5 mL) was added (1r,4r)-4-(3,3-difluoroazetidin-1-yl)cyclohexan-1-amine (79 mg, 0.4 mmol, 1.1 eq), CS2CO3 (370 mg, 1.1 mmol, 3 eq), Ephos (41 mg, 0.08 mmol, 0.2 eq) and Ephos Pd G4 (35 mg, 0.04 mmol, 0.1 eq) in portions at room temperature under N2 atmosphere. The final reaction mixture was stirred for 17h at 100°C. The reaction mixture was filtered, and the filtrate was concentrated. The residue was purified by Prep-HPLC (Column: YMC-Actus Triart C18 ExRS30*150mm, 5pm; Mobile Phase A: water(10mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 10% B to 35% B inlOmin; Wavelength: 254 nm) to afford N-((1r,4r)-4-(3,3-difluoroazetidin-1-yl)cyclohexyl)-6-(1H-imidazol-1-yl)imidazo[1,2-b]pyridazin-3-amine (32.5 mg, 22% yield) as an orange solid. LC / MS: mass calcd. for C17H20N6O: 324.2, found: 325.2 [M+H]+.1H NMR (300 MHz, DMSO-cfe) 58.67 (s, 1 H), 8.04 - 8.13 (m, 2H), 7.41 (d, J= 9.6 Hz, 1H), 7.14 - 7.22 (m, 2H), 5.63 (d, J= 8.7 Hz, 1H), 3.55 (t, J= 12.3 Hz, 4H), 3.19 - 3.30 (m, 1H), 2.08 - 2.20 (m, 1H), 1.95 - 2.08 (m, 2H), 1.72 - 1.83 (m, 2H), 1.26 - 1.44 (m, 2H), 1.02 - 1.23 (m, 2H).19F NMR (282 MHz, DMSO-cfe) 6 -98.13.

[0370] Example 47: Synthesis of N-((1r,4r)-4-(cyclopropylmethoxy)cyclohexyl)-6-(1H-imidazol-1-yl)imidazo[1 ,2-b]pyridazin-3-amineCompound 47

[0371] To a stirred solution of 1-{3-bromoimidazo[1,2-b]pyridazin-6-yl}imidazole (150 mg, 0.5 mmol, 1 eq) and (1r,4r)-4-(cyclopropylmethoxy)cyclohexan-1-amine (115 mg, 0.7 mmol, 1.2 eq) in dioxane (8 mL) was added Ephos Pd G4 (52 mg, 0.05 mmol, 0.1 eq), Ephos (60 mg, 0.1 mmol, 0.2 eq) and CS2CO3 (370 mg, 1.1 mmol, 2 eq) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 90°C for 17h under nitrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with DCM (3 x 10 mL). The filtrate was concentrated under reduced pressure. 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%): 18% B to 43% B inlOmin; Wavelength: 254nm) to afford N-((1r,4r)-4-(cyclopropylmethoxy)cyclohexyl)-6-(1 H-imidazol-1-yl)imidazo[1 ,2-b]pyridazin-3-amine (32.0 mg, 15% yield) as an orange solid. LC / MS: mass calcd. for C19H24N6O: 352.2, found: 353.1 [M+H]+.1H NMR (300 MHz, DMSO-cfe) 68.65 (s, 1H), 8.03 - 8.13 (m, 2H), 7.39 (d, J= 9.5 Hz, 1H), 7.13 - 7.23 (m, 2H), 5.57 (d, J= 8.4 Hz, 1H), 3.31 (s, 1H), 3.24 (d, J= 6.7 Hz, 3H),Docket no. 24-2207-WON-S1 / SetA1.92 - 2.12 (m, 4H), 1.18 - 1.47 (m, 4H), 0.86 - 1.05 (m, 1 H), 0.35 - 0.51 (m, 2H), 0.08 - 0.19 (m, 2H).

[0372] Example 48: Synthesis of (1r,4r)-N1-(6-(1H-imidazol-1-yl)imidazo[1,2-b]pyridazin-3-yl)-N4-(2,2,2-trifluoroethyl)cyclohexane-1,4-diamine,Compound 48

[0373] To a stirred solution of 1-{3-bromoimidazo[1,2-b]pyridazin-6-yl}imidazole (100 mg, 0.4 mmol, 1 eq) in dioxane (5 mL) was added (1r,4r)-N1-(2,2,2-trifluoroethyl)cyclohexane-1,4-diamine (88 mg, 0.4 mmol, 1.1 eq), CS2CO3 (247 mg, 0.8 mmol, 2 eq), Ephos (41 mg, 0.08 mmol, 0.2 eq) and Ephos Pd G4 (35 mg, 0.04 mmol, 0.1 eq) in portions at room temperature under N2 atmosphere. The final reaction mixture was stirred for 17 h at 90°C. The reaction mixture was filtered, and the filtrate was concentrated. 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%): 13% B to 38% B in 10min; Wavelength: 254nm nm ) to give (1r,4r)-N1-(6-(1H-imidazol-1-yl)imidazo[1 ,2-b]pyridazin-3-yl)-N4-(2,2,2-trifluoroethyl)cyclohexane-1 ,4-diamine (23.0 mg, 16% yield) as an orange solid. LC / MS: mass calcd. for C17H20N6O: 324.2, found: 325.2 [M+H]+.1H NMR (300 MHz, DMSO-cfe) 68.67 (s, 1H), 8.03 - 8.14 (m, 2H), 7.41 (d, J= 9.6 Hz, 1H), 7.13 - 7.24 (m, 2H), 5.59 (d, J= 8.4 Hz, 1H), 3.14 - 3.30 (m, 3H), 2.36 - 2.46 (m, 1H), 2.15 - 2.29 (m, 1H), 1.98 - 2.11 (m, 2H), 1.85 - 1.98 (m, 2H), 1.26 - 1.47 (m, 2H), 1.05 -1.25 (m, 2H).19F NMR (300 MHz, DMSO-cfe) 6 -70.67, -70.75.

[0374] Example 49: Synthesis of 1-(7-((6-(1H-imidazol-1-yl)imidazo[1,2-b]pyridazin-3-yl)amino)-2-azaspiro[3.5]nonan-2-yl)-2-methoxyethan-1-oneDocket no. 24-2207-WON-S1 / SetA

[0375] Synthesis of tert-butyl 7-{[6-(111yridazin-1-yl)imidazo[1,2-b]111yridazine-3-yl]amino}-2-azaspiro[3.5]nonane-2-carboxylate

[0376] To a stirred solution of 1-{3-bromoimidazo[1,2-b]pyridazin-6-yl}imidazole (300 mg, 1.1 mmol, 1 eq) and tert-butyl 7-amino-2-azaspiro[3.5]nonane-2-carboxylate (300 mg, 1.2 mmol, 1.1 eq) in dioxane (15 mL) were added Ephos Pd G4 (104 mg, 0.1 mmol, 0.1 eq), Ephos (4 mg, 0.01 mmol, 0.2 eq) and CS2CO3 (740 mg, 2.3 mmol, 2 eq) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 90°C for 17h under nitrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with CH2CI2 (3 x 5 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2CI21 MeOH (12:1) to afford tert-butyl 7-{[6-(imidazol-1-yl)imidazo[1,2-b]pyridazin-3-yl]amino}-2-azaspiro[3.5]nonane-2-carboxylate (300 mg, 62% yield) as an orange solid. LC / MS: mass calcd. For C22H29N7O2: 423.2, found: 424.2 [M+H]+.

[0377] Synthesis of N-[6-(imidazol-1-yl)imidazo[1,2-b]pyridazin-3-yl]-2-azaspiro[3.5]nonan-7-amine)

[0378] To a stirred solution of tert-butyl 7-{[6-(imidazol-1-yl)imidazo[1 ,2-b]pyridazin-3-yl]amino}-2-azaspiro[3.5]nonane-2-carboxylate (300 mg, 0.7 mmol, 1 eq) in DCM (3.5 mL) were added HCI in 1,4-dioxane (4.0 M) (3.5 mL) at 0°C. The resulting mixture was stirred at room temperature for 2h. The resulting mixture was concentrated under reduced pressure. This resulted in N-[6-(imidazol-1-yl)imidazo[1,2-b]pyridazin-3-yl]-2-azaspiro[3.5]nonan-7-amine) (250 mg crude) as a yellow oil. LC / MS: mass calcd. For C17H21 N7: 323.1 , found: 324.1 [M+H]+.

[0379] Synthesis of 11-(7-((6-(1H-imidazol-1-yl)imidazo[1,2-b]pyridazin-3-yl)amino)-2-azaspiro[3.5]nonan-2-yl)-2-methoxyethan-1-one

[0380] To a stirred solution of methoxyacetic acid (28 mg, 0.3 mmol, 1 eq) in DMF (2 mL) were added N-[6-(imidazol-1-yl)imidazo[1 ,2-b]pyridazin-3-yl]-2-azaspiro[3.5]nonan-7-amine (100 mg, 0.3 mmol, 1 eq), DIEA (479 mg, 3.7 mmol, 12 eq) and PyBOP (192.9 mg, 0.4 mmol, 1.2 eq) at 0°C. The resulting mixture was stirred at room temperature for 1h. 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 mL / min; Gradient (B%): 10% B to 30% B in 10 min; Wavelength: 254nm) to afford 1-(7-((6-(1H-imidazol-1-yl)imidazo[1,2-b]pyridazin-3-yl)amino)-2-azaspiro[3.5]nonan-2-yl)-2-methoxyethan-1-one (18.1 mg, 14% yield) as an orange solid. LC / MS: mass calcd. For C20H25N7O2: 395.2, found: 396.2 [M+H]+.1H NMR (300 MHz, DMSO-cfe) 68.67 (s, 1H), 8.04 -8.15 (m, 2H), 7.40 (d, J = 9.6 Hz, 1 H), 7.15 - 7.25 (m, 2H), 5.57 (t, J = 8.0 Hz, 1 H), 3.76 -Docket no. 24-2207-WON-S1 / SetA3.92 (m, 4H), 3.58 (d, J = 21.3 Hz, 2H), 3.21 - 3.31 (m, 4H), 1.85 - 2.05 (m, 4H), 1.50 - 1.64 (m, 2H), 1.28 - 1.48 (m, 2H).

[0381] Example 50: Synthesis of N-(2-(2,2-difluoroethyl)-2-azaspiro[3.5]nonan-7-yl)-6-(1 H-imidazol-1 -yl)imidazo[1,2-b]pyridazin-3-amine

[0382] To a stirred solution of BEHT triflate (435 mg, 0.7 mmol, 3 eq) in DCM (6 mL) was added 2,2-difluoroethanol (41 mg, 0.5 mmol, 2 eq), N-[6-(imidazol-1-yl)imidazo[1,2-b]pyridazin-3-yl]-2-azaspiro[3.5]nonan-7-amine (80 mg, 0.3 mmol, 1 eq) and DIEA (90 uL, 0.5 mmol, 2 eq) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 17h under nitrogen atmosphere, then was diluted with water ( 30 mL) and extracted with CH2CI2 (3x 50 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product 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%): 0% B to 4% B in 7 min; Wavelength: 254 / 220 nm) to afford N-(2-(2,2-difluoroethyl)-2-azaspiro[3.5]nonan-7-yl)-6-(1 H-imidazol-1 -yl)imidazo[1,2-b]pyridazin-3-amine (38.0 mg, 39% yield) as a red semi-solid. LC / MS: mass calcd. For C19H23F2N7: 387.2, found: 388.2 [M+H]+.1H NMR (300 MHz, DMSO-cfe) 68.66 (s, 1H), 8.03 - 8.16 (m, 2H), 7.39 (d, J = 9.5 Hz, 1H), 7.18 (d, J= 3.9 Hz, 2H), 5.74 - 6.19 (m, 1H), 5.54 (d, J= 8.4 Hz, 1H), 3.22 - 3.35 (m, 1H), 3.15 (s, 2H), 3.05 (s, 2H), 2.86 (t, J= 16.0, 4.2 Hz, 2H), 1.76 - 1.90 (m, 4H), 1.25 -1.45 (m, 2H), 1.45 - 1.59 (m, 2H).

[0383] Example 51 : Synthesis of 2-( 1 H-imidazol-1 -y l)-N -(( 1 r,4r)-4-methoxycyclohexyl)pyrrolo[2,1-f][1,2,4]triazin-7-amineouene.,

[0384] Synthesis of 1-{7-bromopyrrolo[2,1-f][1,2,4]triazin-2-yl}imidazoleTo a stirred solution of 7-bromo-2-chloropyrrolo[2,1-f][1,2,4]triazine (1 g, 4.3 mmol, 1 eq) and imidazole (0.4 g, 6.5 mmol, 1.5 eq) in DMF (15 mL) was added K2CO3 (1.8 g, 12.9 mmol, 3 eq) at room temperature. The resulting mixture was stirred at 100°C for 3h. The mixture wasDocket no. 24-2207-WON-S1 / SetAallowed to cool to room temperature. The reaction was poured into ice / water (100 mL). The precipitated solids were collected by filtration and washed with water. The fractions were combined and dried under reduced pressure. This resulted in 1-{7-bromopyrrolo[2,1-f][1 ,2,4]triazin-2-yl}imidazole (890 mg, crude) as a yellow solid. The crude product was used in the next step directly without further purification. LC / MS: mass calcd. For CgHeBrNs: 263.0, found: 266.0 [M+H]+.

[0385] Synthesis of 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-methoxycyclohexyl)pyrrolo[2,1-f][1 ,2,4]triazin-7-amine

[0386] To a stirred solution of 1-{7-bromopyrrolo[2,1-f][1,2,4]triazin-2-yl}imidazole (90 mg, 0.3 mmol, 1 eq) and (1r,4r)-4-methoxycyclohexan-1 -amine (88 mg, 0.6 mmol, 2 eq) in toluene (5 mL) were added CS2CO3 (222 mg, 0.6 mmol, 2 eq), Ephos (37 mg, 0.06 mmol, 0.2 eq) and Ephos Pd G4 (31 mg, 0.03 mmol, 0.1 eq) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 70°C for 17h under nitrogen atmosphere. The resulting mixture was filtered, and the filter cake was washed with MeCN (3x 20 mL). The filtrate was concentrated under reduced pressure. 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 mL / min; Gradient (B%): 31% B to 54% B in 7 min; Wavelength: 254nm / 220nm). The fractions were combined and lyophilized directly. This resulted in 2-(1H-imidazol-1-yl)-N-((1r,4r)-4-methoxycyclohexyl)pyrrolo[2,1-f][1,2,4]triazin-7-amine (39.3 mg, 36% yield) as an orange solid. LC / MS: mass calcd. For Ci6H2oN60: 312.2, found: 313.2 [M+H]+.1H NMR (300 MHz, DMSO-cfe) 68.50 - 8.65 (m, 2H), 7.98 (s, 1H), 7.10 (s, 1H), 7.03 (d, J = 4.9 Hz, 1H), 6.57 (d, J= 4.9 Hz, 1H), 6.14 (d, J= 8.8 Hz, 1H), 3.41 - 3.58 (m, 1H), 3.24 (s, 3H), 3.06 - 3.20 (m, 1H), 1.91 - 2.11 (m, 4H), 1.35 - 1.55 (m, 2H), 1.18 - 1.35 (m, 2H).

[0387] Example 52: Synthesis of 2-(1H-imidazol-1-yl)-N-(2-(methylsulfonyl)-2-azaspiro[3.5]nonan-7-yl)pyrrolo[2,1-f][1,2,4]triazin-7-amineDocket no. 24-2207-WON-S1 / SetA

[0388] Synthesis of tert-butyl 7-{[2-(imidazol-1-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]amino}-2-azaspiro[3.5]nonane-2-carboxylate

[0389] To a stirred solution of 1-{7-bromopyrrolo[2,1-f][1,2,4]triazin-2-yl}imidazole (150 mg, 0.5 mmol, 1 eq) and tert-butyl 7-amino-2-azaspiro[3.5]nonane-2-carboxylate (273 mg, 1 mmol, 2 eq) in toluene (8 mL) was added CS2CO3 (370 mg, 1 mmol, 2 eq), Ephos (61 mg, 0.1 mmol, 0.2 eq) and Ephos Pd G4 (52 mg, 0.05 mmol, 0.1 eq) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100°C for 3h under nitrogen atmosphere. The mixture was allowed to cool to room temperature. The resulting mixture was filtered, and the filter cake was washed with MeCN (3 x 20 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography (C18 column; mobile phase, MeCN in water (0.05% TFA), 15% to 40% gradient in 20 min; detector, LIV 254 nm). The fractions were combined and concentrated under reduced pressure. This resulted in tert-butyl 7-{[2-(imidazol-1-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]amino}-2-azaspiro[3.5]nonane-2-carboxylate (96 mg, 39% yield) as a red oil. LC / MS: mass calcd. For C22H29N7O2: 423.2, found: 424.2 [M+H]+.

[0390] Synthesis of N-[2-(imidazol-1-yl)pyrrolo[2,1-f][1 ,2,4]triazin-7-yl]-2-azaspiro[3.5]nonan-7-amine

[0391] To a stirred solution of tert-butyl 7-{[2-(imidazol-1-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]amino}-2-azaspiro[3.5]nonane-2-carboxylate (86 mg, 0.2 mmol, 1 eq) in DCM (1 mL) was added 4M HCI in dioxane (1 mL) at room temperature. The resulting mixture was stirred at room temperature for 2h. The resulting mixture was concentrated under reduced pressure. This resulted in N-[2-(imidazol-1-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-azaspiro[3.5]nonan-7-amine (65 mg) as a white solid. The crude product was used in the next step directly without further purification. LC / MS: mass calcd. For CiyFLiN?: 323.2, found: 324.2 [M+H]+.

[0392] Synthesis of 2-(1H-imidazol-1-yl)-N-(2-(methylsulfonyl)-2-azaspiro[3.5]nonan-7-yl)pyrrolo[2, 1 -f] [ 1 ,2,4]triazin-7-amine

[0393] To a stirred solution of N-[2-(imidazol-1-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-2-azaspiro[3.5]nonan-7-amine (45 mg, 0.1 mmol, 1 eq) in THF (1 mL) was added TEA (58 uL, 0.3 mmol, 3 eq) and MS2O (73 mg, 0.4 mmol, 3 eq) at 0°C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2h under nitrogen atmosphere. The resulting mixture was quenched with water (10 mL) and extracted with CH2CI2 (3 x 30 mL). The combined organic layers were dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. 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 mL / min; Gradient (B%): 31% B toDocket no. 24-2207-WON-S1 / SetA46% B in 7 min; Wavelength: 254nm / 220nm) to afford 2-(1H-imidazol-1-yl)-N-(2-(methylsulfonyl)-2-azaspiro[3.5]nonan-7-yl)pyrrolo[2,1-f][1,2,4]triazin-7-amine (13.9 mg, 24% yield) as an orange solid. LC / MS: mass calcd. For C18H23N7O2S: 401.2, found: 402.1 [M+H]+.1H NMR (300 MHz, DMSO) 68.60 (s, 1H), 8.53 (s, 1H), 7.97 (s, 1H), 7.11 (s, 1H), 7.03 (d, J = 4.9 Hz, 1H), 6.56 (d, J= 5.0 Hz, 1H), 6.14 (d, J= 8.7 Hz, 1H), 3.65 (s, 2H), 3.56 (s, 2H), 3.44 (d, J= 9.5 Hz, 1H), 3.00 (s, 3H), 1.92 (t, J= 16.7 Hz, 4H), 1.58 (t, J= 12.0 Hz, 2H), 1.34 - 1.46 (m, 2H).

[0394] Example 53: Synthesis of 2-(1H-imidazol-1-yl)-N-(2-oxaspiro[3.5]nonan-7-yl)pyrrolo[2,1-f][1,2,4]triazin-7-amine

[0395] A mixture of 1-{7-bromopyrrolo[2,1-f][1,2,4]triazin-2-yl}imidazole (50 mg, 0.2 mmol, 1 eq), 2-oxaspiro[3.5]nonan-7-amine (27 mg, 0.2 mmol, 1 eq), EPhos Pd G4 (17 mg, 0.02 mmol, 0.1 eq), Ephos (20 mg, 0.04 mmol, 0.2 eq) and CS2CO3 (185 mg, 0.6 mmol, 3 eq) in dioxane (1.5 mL) was stirred at 90°C for 12h under nitrogen atmosphere. The resulting mixture was filtered, and then the filter cake was washed with EtOAc (3 x10 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (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 mL / min; Gradient (B%): 29% B to 53% B inlOmin; Wavelength: 254nm nm) to afford 2-(1H-imidazol-1-yl)-N-(2-oxaspiro[3.5]nonan-7-yl)pyrrolo[2,1-f][1,2,4]triazin-7-amine (30.3 mg, 49% yield) as orange solid. LC / MS: mass calcd. For C17H20N6O: 324.2, found: 325.2 [M+H]+.1H NMR (300 MHz, DMSO-cfe) 68.62 (s, 1H), 8.55 (s, 1H), 7.99 (s, 1H), 7.15 (s, 1H), 7.04 (d, J= 4.8 Hz, 1H), 6.58 (d, J = 4.9 Hz, 1H), 6.11 (d, J= 8.9 Hz, 1H), 4.37 (s, 2H), 4.26 (s, 2H), 3.42-3.45 (m, 1H), 2.05 - 2.17 (m, 2H), 1.87 - 1.93 (m, 2H), 1.52 - 1.60 (m, 2H), 1.28 - 1.47 (m, 2H).

[0396] Example 54: Synthesis of 6-( 1 H-imidazol-1 -y l)-N -(( 1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-2-methylimidazo[1,2-b]pyridazin-3-amineDocket no. 24-2207-WON-S1 / SetA

[0397] Synthesis of 1-{3-bromo-2-methylimidazo[1,2-b]pyridazin-6-yl}imidazole

[0398] To a stirred solution of 3-bromo-6-chloro-2-methylimidazo[1,2-b]pyridazine (1 g, 4.0 mmol, 1 eq) and imidazole (0.4 g, 6 mmol, 1.5 eq) in DMF (30 mL) was added K2CO3 (1.7 g, 12 mmol, 3 eq) at room temperature. The resulting mixture was stirred at 100°C for 5h. The mixture was allowed to cool down to room temperature. The reaction mixture was poured into ice water (300 mL) at 0°C. The precipitated solids were collected by filtration and washed with water, dried under vacuum. This resulted in 1-{3-bromo-2-methylimidazo[1,2-b]pyridazin-6-yl}imidazole (900 mg) as a yellow solid. The crude product was used in the next step directly without further purification. LC / MS: mass calcd. For CioH8BrN5:277.0, found: 278.0 [M+H]+.

[0399] Synthesis of 6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-2-methylimidazo[1,2-b]pyridazin-3-amine

[0400] To a stirred solution of 1-{3-bromo-2-methylimidazo[1,2-b]pyridazin-6-yl}imidazole (100 mg, 0.4 mmol, 1 eq) and (1r,4r)-4-(2-methoxyethoxy)cyclohexan-1 -amine (93 mg, 0.5 mmol, 1.5 eq) in THF (5 mL) was added TMSONa (42 mg, 0.4 mmol, 1 eq) and GPhos Pd G6 TES (34 mg, 0.04 mmol, 0.1 eq) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 50°C for 3h 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), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 33% B to 48% B in 10 min; Wavelength: 254 / 220 nm) to afford 6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)-2-methylimidazo[1,2-b]pyridazin-3-amine (41.5 mg, 31% yield) as a yellow solid. LC / MS: mass calcd. For Ci9H26N6O:370.2, found: 371.2 [M+H]+.1H NMR (300 MHz, DMSO-cfe) 68.58 (s, 1 H), 8.02 (d, J = 9.6 Hz, 1 H), 7.99 (s, 1 H), 7.45 (d, J = 9.4 Hz, 1H), 7.18 (s, 1H), 4.79 (d, J= 8.4 Hz, 1H), 3.45 - 3.52 (m, 2H), 3.34 - 3.43 (m, 2H), 3.18 -3.31 (m, 5H), 2.36 (s, 3H), 1.89 - 1.99 (m, 2H), 1.78 - 1.99 (m, 2H), 1.25 - 1.42 (m, 2H), 1.09 - 1.25 (m, 2H).

[0401] Example 55: Synthesis of 6-(1H-imidazol-1-yl)-8-methoxy-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)imidazo[1,2-b]pyridazin-3-amineDocket no. 24-2207-WON-S1 / SetACompound 55

[0402] Synthesis of 6-chloro-3-iodo-8-methoxyimidazo[1 ,2-b]pyridazine

[0403] To a stirred solution of 8-bromo-6-chloro-3-iodoimidazo[1 ,2-b]pyridazine (950 mg, 2.7 mmol, 1 eq) in MeOH (10 mL) was added sodium methoxide (5-5.4M in methanol) (214 mg, 4 mmol, 1.5 eq) dropwise at 0°C. The resulting mixture was stirred at room temperature for 4h. The resulting mixture was concentrated under reduced pressure. The residue was diluted with water (10 mL). The resulting mixture was extracted with CH2CI2 (3 x 10 mL). The combined organic layers were washed with brine (3 x 10 mL), dried over anhydrous Na2SC>4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2CI21 EA (20:1) to afford 6-chloro-3-iodo-8-methoxyimidazo[1,2-b]pyridazine (648 mg, 78% yield) as a white solid.LC / MS: mass calcd. For C7H5CIIN3O: 308.9, found: 309.9 [M+H]+.

[0404] Synthesis of 1-{3-iodo-8-methoxyimidazo[1,2-b]pyridazin-6-yl}imidazole

[0405] To a stirred solution of 6-chloro-3-iodo-8-methoxyimidazo[1,2-b]pyridazine (700 mg, 2.3 mmol, 1 eq) and imidazole (231 mg, 3.4 mmol, 1.5 eq) in DMF (20 mL) was added CS2CO3 (2.2 g, 6.9 mmol, 3 eq) at room temperature. The resulting mixture was stirred at 100°C for 2 h. The mixture was allowed to cool down to room temperature. Then it was purified by reversed-phase flash chromatography (C18 column; mobile phase, MeCN in water (10 mmol / L NH4HCO3), 10% to 30% gradient in 30 min; detector, UV 254 nm) to afford 1-{3-iodo-8-methoxyimidazo[1,2-b]pyridazin-6-yl}imidazole (200 mg, 25% yield) as a yellow solid. LC / MS: mass calcd. For C HsINsO: 341.0, found: 342.0 [M+H]+.

[0406] Synthesis of 6-(1H-imidazol-1-yl)-8-methoxy-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)imidazo[1,2-b]pyridazin-3-amineDocket no. 24-2207-WON-S1 / SetA

[0407] To a stirred solution of 1-{3-iodo-8-methoxyimidazo[1,2-b]pyridazin-6-yl}imidazole (150 mg, 0.4 mmol, 1 eq) and (1r,4r)-4-(2-methoxyethoxy)cyclohexan-1 -amine (114 mg, 0.7 mmol, 1.5 eq) in N,N-dimethylacetamide (5 mL) was added NiBr2(glyme) (6.8 mg, 0.02 mmol, 0.05 eq) and 4CzlPN (3.5 mg, 0.004 mmol, 0.01 eq) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 5 min under nitrogen atmosphere. To the above mixture was added tert-Butylamine (230 uL, 2.2 mmol, 5 eq) at room temperature. The resulting mixture was stirred for 16h at room temperature under nitrogen atmosphere with the irradiation by 455 nm blue light. The reaction mixture was purified Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 pm; Mobile Phase A: water / 0.05%NH3.H20+5mM NH4HCO3, Mobile Phase B: ACN; Flow rate: 60ml / min; Gradient (B%): 16% B to 34% B in 10 min; Wavelength: 254nm / 220nm) to afford 6-(1H-imidazol-1-yl)-8-methoxy-N-((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)imidazo[1,2-b]pyridazin-3-amine (5.1 mg, 3% yield) as a yellow solid. LC / MS: mass calcd. For C19H26N6O3: 386.2, found: 387.1 [M+H]+.1H NMR (300 MHz, DMSO-cfe) 58.68 (s, 1H), 8.12 (s, 1H), 7.17 (s, 1H), 6.96 (d, J= 9.8 Hz, 2H), 5.39 (d, J= 8.3 Hz, 1H), 4.14 (s, 3H), 3.52 - 3.55 (m, 2H), 3.40 -3.45 (m, 2H), 3.18 - 3.36 (m, 5H), 1.91 - 2.12 (m, 4H), 1.19 - 1.48 (m, 4H).

[0408] Example 56: Synthesis N-((1r,4r)-4-(3,3-difluoropyrrolidin-1-yl)cyclohexyl)-6-(1H-imidazol-1-yl)-2-methylimidazo[1,2-b]pyridazin-3-amine

[0409] To a stirred solution of 1-{3-bromo-2-methylimidazo[1,2-b]pyridazin-6-yl}imidazole (150 mg, 0.54 mmol, 1 eq) and (1r,4r)-4-(3,3-difluoropyrrolidin-1-yl)cyclohexan-1-amine (165 mg, 0.8 mmol, 1.5 eq) in THF (6 mL) was added TMSONa (64 mg, 0.57 mmol, 1.05 equiv) and GPhos Pd G6 TES (51 mg, 0.05 mmol, 0.1 eq) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 50°C for 5h under nitrogen atmosphere. The mixture was allowed to cool to room temperature. The resulting mixture was filtered, and then the filter cake was washed with MeCN (3 x 5 mL). The filtrate was concentrated under reduced pressure. 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%): 10% B to 35% B inlOmin; Wavelength: 254nm) to afford N-((1r,4r)-4-(3,3-difluoropyrrolidin-1-yl)cyclohexyl)-6-(1H-imidazol-1-yl)-2-Docket no. 24-2207-WON-S1 / SetAmethylimidazo[1,2-b]pyridazin-3-amine (22.1 mg, 10% yield) as a yellow solid. LC / MS: mass calcd. For C20H25F2N7: 401.2, found: 402.2 [M+H]+.1H NMR (300 MHz, DMSO-cfe) 68.58 (s, 1H), 7.95 - 8.07 (m, 2H), 7.45 (d, J= 9.5 Hz, 1H), 7.18 (s, 1H), 4.81 (d, J= 8.5 Hz, 1H), 3.15 - 3.30 (m, 1H), 2.88 (t, J = 13.8 Hz, 2H), 2.69 (t, J = 6.9 Hz, 2H), 2.36 (s, 3H), 2.01 - 2.27 (m, 3H), 1.78 - 1.95 (m, 4H), 1.23 - 1.40 (m, 2H), 1.05 - 1.23 (m, 2H).19F NMR (282 MHz, DMSO-cfe) 6 -90.72.

[0410] Example 57: Synthesis of 6-(1H-imidazol-1-yl)-3-(((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)amino)imidazo[1,2-b]pyridazin-8-ol" " >>p

[0411] To a stirred solution of 6-(imidazol-1-yl)-8-methoxy-N-[(1r,4r)-4-(2-methoxyethoxy)cyclohexyl] imidazo[1,2-b]pyridazin-3-amine (70 mg, 0.2 mmol, 1 eq) in DMF (1.5 mL) was added LiCI (23 mg, 0.6 mmol, 3 eq) and TsOH (94 mg, 0.6 mmol, 3 eq) at room temperature. The resulting mixture was stirred at 80°C for 17h. The mixture was allowed to cool to room temperature. After filtration, the filtrate 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%): 3% B to 16% B in 7 min; Wavelength: 254 / 220 nm) to afford 6-(1H-imidazol-1-yl)-3-(((1r,4r)-4-(2-methoxyethoxy)cyclohexyl)amino)imidazo[1,2-b]pyridazin-8-ol (14.6 mg, 21 %yield) as a light yellow solid. LC / MS: mass calcd. For C18H24N6O3: 372.2, found: 373.2 [M+H]+.1H NMR (300 MHz, DMSO-cfe) 59.43 (s, 1H), 8.33 (s, 1H), 7.64 (s, 1H), 7.15 (s, 1H), 6.53 (s, 1H), 5.70 (br, 1H), 3.52 - 3.58 (m, 2H), 3.40 - 3.46 (m, 2H), 3.11 - 3.33 (m, 5H), 1.97 - 2.10 (m, 4H), 1.20 -1.20 (m, 4H).

[0412] Example 58: Synthesis of 6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(trifluoromethoxy)cyclohexyl)imidazo[1,2-b]pyridazin-3-amine

[0413] To a stirred solution of 1-{3-bromoimidazo[1,2-b]pyridazin-6-yl}imidazole (70 mg, 0.2 mmol, 1 eq) in dioxane (10 mL) was added trans-4-(trifluoromethoxy)cyclohexan-1-amineDocket no. 24-2207-WON-S1 / SetA(49 mg, 0.2 mmol, 1 eq), EPhos Pd G4 (24 mg, 0.02 mmol, 0.1 eq), Ephos (28 mg, 0.04 mmol, 0.2 eq) and CS2CO3 (259 mg, 0.8 mmol, 3 eq) under a nitrogen atmosphere. The resulting mixture was stirred for 17h at 90°C. After filtration, the filtrate 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%): 27%B to 47%B in 10min; Wavelength: 254 / 220 nm) to afford 6-(1H-imidazol-1-yl)-N-((1r,4r)-4-(trifluoromethoxy)cyclohexyl)imidazo[1,2-b]pyridazin-3-amine (25.3 mg, 26%yield) was obtainedas an orange solid. LC / MS: mass calcd. for C16H17F3N6O: 366.14, found: 367.15 [M+H]+.1H NMR (400 MHz, DMSO-cfe) 68.67 (s, 1H), 8.07 - 8.14 (m, 2H), 7.43 (d, J = 9.5 Hz, 1H), 7.26 (s, 1H), 7.19 (s, 1H), 5.67 (d, J= 8.0 Hz, 1H), 4.38 - 4.47 (m, 1H), 3.33 - 3.43 (m, 1H), 2.05 - 2.13 (m, 4H), 1.61 - 1.75 (m, 2H), 1.47 - 1.60 (m, 2H).19F NMR (377 MHz, DMSO-cfe) 6 -55.89.

[0414] Example 59: Synthesis of N-((1r,4r)-4-(2,2-difluoroethoxy)cyclohexyl)-6-(1H-imidazol-1-yl)imidazo[1 ,2-b]pyridazin-3-amine

[0415] To a stirred solution of 1-{3-bromoimidazo[1,2-b]pyridazin-6-yl}imidazole (100 mg, 0.4 mmol, 1.0 eq) and trans-4-(2,2-difluoroethoxy)cyclohexan-1-amine (102 mg, 0.6 mmol, 1.5 eq) in THF (5 mL) was added TMSONa (45 mg, 0.4 mmol, 1.0 eq) and GPhos Pd G6 TES (36 mg, 0.04 mmol, 0.1 eq) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 50°C for 17h under nitrogen atmosphere. The mixture was allowed to cool to room temperature. After filtration, the filtrate 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%): 17%B to37 %B in 10min; Wavelength: 254 / 220 nm) to afford N-((1r,4r)-4-(2,2-difluoroethoxy)cyclohexyl)-6-(1H-imidazol-1-yl)imidazo[1,2-b]pyridazin-3-amine (40.5 mg, 30%yield) as a dark yellow solid. LC / MS: mass calcd. For Ci7H2oF2N60: 362.2, found: 363.0 [M+H]+.1H NMR (300 MHz, DMSO-cfe) 58.67 (s, 1H), 8.05 - 8.15 (m, 2H), 7.41 (d, J= 9.5 Hz, 1H), 7.15 - 7.26 (m, 2H), 5.89- 6.32 (m, 1 H), 5.61 (d, J = 8.4 Hz, 1 H), 3.60 - 3.80 (m, 2H), 3.39 - 3.51 (m, 1 H), 3.25 -3.39 (m, 1H), 1.99 - 2.15 (m, 4H), 1.25 - 1.50 (m, 4H).19F NMR (282 MHz, DMSO-d6) 5 -125.08.Docket no. 24-2207-WON-S1 / SetA

[0416] Example 60: Synthesis of N-((1r,4r)-4-(2,2-difluoroethoxy)cyclohexyl)-2-(1H-imidazol-1-yl)-5-methylimidazo[1,5-b]pyridazin-7-amine

[0417] Synthesis of 5-bromo-2-chloro-N-[(1 r,4r)-4-(2,2-difluoroethoxy)cyclohexyl]imidazo[1,5-b]pyridazin-7-amine

[0418] To a stirred solution of 2-chloro-N-[(1r,4r)-4-(2,2-difluoroethoxy)cyclohexyl]imidazo[1,5-b]pyridazin-7-amine (70 mg, 0.2 mmol, 1 eq) in DCM (7 mL) was added NBS (26 mg, 0.14 mmol, 0.7 eq) at 0°C. The resulting mixture was stirred at room temperature for 1h. The reaction was poured into water (30 mL). The residue was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (1x30 mL), then dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2CI21 MeOH = 20:1) to afford 5-bromo-2-chloro-N-[(1r,4r)-4-(2,2-difluoroethoxy)cyclohexyl]imidazo[1,5-b]pyridazin-7-amine (45 mg, 52% yield) as an orange solid. LC / MS: mass calcd. For Ci4HieBrCIF2N4O: 408.0, found: 409.0 [M+H]+.

[0419] Synthesis of 5-bromo-2-(imidazol-1-yl)-N-[(1r,4r)-4-(2,2-difluoroethoxy)cyclohexyl]imidazo[1,5-b]pyridazin-7-amine

[0420] To a stirred solution of 5-bromo-2-chloro-N-[(1r,4r)-4-(2,2-difluoroethoxy)cyclohexyl]imidazo[1,5-b]pyridazin-7-amine (45 mg, 0.1 mmol, 1 eq) and imidazole (11 mg, 0.2 mmol, 1.5 eq) in DMF (2 mL) was added CS2CO3 (72 mg, 0.2 mmol, 2 eq) at room temperature. The resulting mixture was stirred at 100°C for 2. The reaction was poured into 20 mL water. The residue was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (1x20 mL) then dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH2CI2 / MeOH = 10:1) to afford 5-bromo-2-(imidazol-1-yl)-N-[(1r,4r)-4-(2,2-Docket no. 24-2207-WON-S1 / SetAdifluoroethoxy)cyclohexyl]imidazo[1,5-b]pyridazin-7-amine (40 mg, 83% yield) as an orange solid. LC / MS: mass calcd. For Ci7Hi9BrF2N6O: 440.0, found: 441.0 [M+H]+.

[0421] Synthesis of N-((1r,4r)-4-(2,2-difluoroethoxy)cyclohexyl)-2-(1H-imidazol-1-yl)-5-methylimidazo[1,5-b]pyridazin-7-amine

[0422] To a stirred solution of 5-bromo-2-(imidazol-1-yl)-N-[(1r,4r)-4-(2,2-difluoroethoxy)cyclohexyl]imidazo [1,5-b]pyridazin-7-amine (40 mg, 0.1 mmol, 1 eq) and K2CO3 (38 mg, 0.3 mmol, 3 eq) in 1,4-dioxane (5 mL) and H2O (1 mL) was added Pd(dppf)Ch (7 mg, 0.01 mmol, 0.1 eq) and trimethylboroxine (50 % in THF) (114 mg, 0.9 mmol, 10 eq) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100°C overnight under nitrogen atmosphere. The resulting mixture was filtered, the the filter cake was washed with CH2CI2 (3x10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Column: XBridge BEH Shield RP18 2.1*50mm, 2.5um; Mobile Phase A: water(10 mmoL / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient (B%): 29% B to 44% B in 10 min; Wavelength:254 / 220 nm) to afford N-((1r,4r)-4-(2,2-difluoroethoxy)cyclohexyl)-2-(1H-imidazol-1-yl)-5-methylimidazo[1,5-b]pyridazin-7-amine (9.4 mg, 28% yield) as an orange solid. LC / MS: mass calcd. For Ci8H22F2N6O: 376.1, found: 377.1 [M+H]+.1H NMR (300 MHz, DMSO-cfe) 68.60 (s, 1H), 7.95 - 8.10 (m, 2H), 7.15 (s, 1H), 6.68 (d, J= 9.6 Hz, 1H), 5.90 - 6.35 (m, 2H), 3.60 -3.83 (m, 3H), 3.33 - 3.48 (m, 1H), 2.33 (s, 3H), 1.98 - 2.12 (m, 4H), 1.20 - 1.50 (m, 4H).19F NMR (282 MHz, DMSO-cfe) 6 -125.06.

[0423] Example 61 : Human CD38 Colorimetric Assay

[0424] 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 eachDocket no. 24-2207-WON-S1 / SetAcompound 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.,

[0425] Table tA: IC50 < 20 nM; B: IC50 - 20 nM and < 125 nM; C: IC50 > 125 nM and < 1250 nM; D: IC50 > 1250 nM.

[0426] The references cited herein are incorporated by reference. Aspects of the disclosure can be modified, if necessary, to employ the systems, functions, and concepts ofDocket no. 24-2207-WON-S1 / SetAthe 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.

[0427] 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.

[0428] 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.

[0429] 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. 24-2207-WON-S1 / SetAWhat is claimed is:

1. A compound of formula (I) or (II):or a pharmaceutically acceptable salt thereof, whereinX and Y are each independently nitrogen, or C-R6, wherein at least one of X and Y is nitrogen;R1is a 5- to 10-membered heteroaryl group optionally substituted with one or more independently selected R2, where each R2is (i) Ci-C6alkyl, (ii) C3-C8cycloalkyl, (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) -NO2R15is H, Ci-Ce alkyl, Ci-Ce haloalkyl, Ci-Ce alkoxy(Ci-Ce alkyl), 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-C2alkyl), C3-C12 cycloalkyl(Co-C2alkyl), aryl(Co-Ce alkyl), 6- to 12-membered spirocyclyl(Co-C2 alkyl) or 5- or 6- membered heteroaryl(Co-C6 alkyl), each of which is optionally substituted on the cyclic portion 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-C4 alkyl) 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 groups;Docket no. 24-2207-WON-S1 / SetAR57is H, Ci-C6alkyl ,-(CH2CH2O)I-2(CI-C6 alkyl), Ci-C6haloalkyl, Cs-Cs cycloalkyl(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-C6alkyl, halogen, or C1-C6 alkoxy groups;R58and R59are each independently -NR60R61whereinR60is H or C1-C6 alkyl; andR61is - SO2(Ci-Ce alkyl) 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, Ci-Ce alkoxy, or -NR8R9where R8and R9independently represent H or Ci-Ce alkyl; and R7is H, -OH, Ci-C6alkyl, Ci-C6haloalkyl or Ci-C6alkoxy.

2. A compound according to claim 1 , which has formula (la) or (Ila):and R1is a 5- or 6-membered heteroaryl optionally substituted with one or more independently selected R2.

3. A compound according to claim 1 , which has formula (lb) or formula (Id):and R1is a 5- or 6-membered heteroaryl optionally substituted with one or more independently selected R2.Docket no. 24-2207-WON-S1 / SetA4. A compound according to any one of claims 1-3, wherein R1is an 5-membered heteroaryl group containing at least one nitrogen and the heteroaryl is optionally substituted with 1 or 2 R2.

5. A compound according to any one of claims 1-3, wherein R1is an 5-membered heteroaryl group containing one nitrogen and one sulfur or oxygen, and the heteroaryl is optionally substituted with 1 or 2 R2.

6. A compound according to any one of claims 1-3, wherein R1is pyrrolyl, thiazolyl, imidazolyl, pyrazolyl, oxazolyl or isoxazolyl, each of which is optionally substituted with 1 or 2 R2.

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

8. A compound according to claim 7, wherein R5is cycloalkyl optionally substituted with 1, 2 or 3 of R3.

9. A compound according to claim 8, wherein R5is a group of the formula (Illa):wherein n is 0 or 1.

10. A compound according to claim 8, wherein R5is a group of the formula (111 b):wherein n is 0 or 1.

11. A compound according to claim 8, wherein R5is a group of the formula (I He) or (Hid):Docket no. 24-2207-WON-S1 / SetAwherein n is 0 or 1.

12. A compound according to claim 8, wherein R5is a group of the formula (Hie)wherein n is 0 or 1.

13. A compound according to claim 7, wherein R5is a group of the formula (IVa):whereinR3ais H, halogen, -OH;n is 0, 1 or 2; andp is 1 or 2.

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

15. A compound according to any of claims 1-6, wherein R5is 5- or 6-membered heteroaryl(Co-Ce alkyl), and R5is optionally substituted with 1-3 of R3.Docket no. 24-2207-WON-S1 / SetA16. A compound according to claim 14, wherein R5is a group of the formula (Va):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.

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

18. A compound according to claim 16, wherein R5is a group of the formulawherein n is 0 or 1.

19. A compound according to claim 16, wherein R5is a group of the formulawherein n is 0 or 1.

20. A compound according to any of claims 1-6, wherein R5is a bicyclic C8-C12 cycloalkyl (C0-C2 alkyl) where the rings share 2 atoms, and R5is optionally substituted with 1-3 of R3.

21. A compound according to claim 20, wherein the bicyclic cycloalkyl is a group of the formula (Via):Docket no. 24-2207-WON-S1 / SetAwhereinR3ais H, halogen, or -OH;n is 0 or 1; andm is 0, 1 or 2.

22. A compound according to any of claims 1-6, wherein R5is a 6- to 12-membered spirocyclyl(Co-C2 alkyl) which is optionally substituted with 1-3 of R3.

23. A compound according to claim 22, wherein R5has the formula (Villa):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.

24. A compound according to any of claims 1-6, 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 the heterocyclyl is a group of the Formula (Vila):wherein m1and m2are each an integer of 0, 1 , or 2;Docket no. 24-2207-WON-S1 / SetAp 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-Ce alkyl groups.

26. A compound according to any of claims 1-25, wherein each R3is independently halogen, -OR57, -NHSO2(Ci-Ce alkyl), -NHSO2(C3-Cs cycloalkyl), Ci-Ce haloalkyl, -SO2(C C6alkyl), C 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 (C3-C8 cycloalkyl) optionally substituted with one or more independently selected Ci-Ce alkyl or halogen group.

27. A compound according to any one of claims 1-26, wherein R6is hydrogen, C1-C3 alkyl, C3-C6 cycloalkyl, or -NR8R9where R8and R9independently represent H or C1-C3 alkyl.

28. A compound according to any one of claims 1-26, wherein R6is hydrogen, C1-C3 alkyl, or C3-C6 cycloalkyl.

29. A compound according to any one of claims 1-28, wherein R2is Ci-Ce alkyl.

30. A compound according to any one of claims 1-28, wherein R2is methyl, ethyl, propyl or isopropyl, fluorine, chlorine, methoxy, ethoxy, or cyano.

31. A compound according to any one of claims 1-28, wherein R1is unsubstituted or substituted with one R2where R2is methyl.

32. A compound according to any one of claims 1-31, wherein R1is thiazolyl which is optionally substituted with one or more independently selected R2.

33. A compound according to any one of claims 1-31, wherein R1is unsubstituted imidazolyl or R1is imidazolyl which is substituted with one or more independently selected R2.Docket no. 24-2207-WON-S1 / SetA34. A compound according to any one of claims 1-31, wherein R1is pyrrolyl, each of which is optionally substituted with one or more independently selected R2.

35. A compound according to any one of claims 1-31, wherein R1is pyrazolyl, each of which is optionally substituted with one or more independently selected R2.

36. A compound according to any one of claims 1-31, wherein R1is oxazolyl, each of which is optionally substituted with one or more independently selected R2.

37. A compound according to any one of claims 1-31, wherein R1is isoxazolyl, each of which is optionally substituted with one or more independently selected R2.

38. A compound according to any one of claims 1-31, wherein R1is thiazol-5-yl, imidazol-5-yl or imidazol-1-yl, each of which is optionally substituted with one or more independently selected R2.

39. A compound according to claim any one of claims 1-38, wherein R1is substituted with two R2.

40. A compound according to claim any one of claims 1-38, wherein R1is substituted with one R2.

41. A compound according to claim 39 or claim 40, wherein each R2is independently Ci-Ce alkyl, C3-C6 cycloalkyl or C3-C6 cycloalkyl(Ci-C2)alkyl.

42. A compound according to any one of claims 1-41, wherein R4is H, methyl or ethyl.

43. A compound according any one of claims 1-41, wherein R4is H or methyl.

44. A compound according to any one of claims 1-41, wherein R4is H.

45. A compound according to any one of claims 1-44, wherein R7is H.

46. A compound according to any one of claims 1-44, wherein R7-OH, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, or trifluoromethyl.Docket no. 24-2207-WON-S1 / SetA47. A compound according to any one of claims 1-46, wherein R6is Ci-C8alkyl, Ci-C8cycloalkyl, or Ci-C8haloalkyl.

48. A compound according to any one of claims 1-46, wherein R6is hydrogen, methyl, trifluoromethyl or cyclopropyl.

49. A compound of formula (la) or (Ila):or a pharmaceutically acceptable salt thereof, whereinone of X and Y is N and the other is CH or CR6, or both X and Y are nitrogen; R1is a 5- to 10-membered heteroaryl group optionally substituted with one or more independently selected R2, where each R2is Ci-C8alkyl, C3-C6 cycloalkyl, C3-C6 cycloal kyl(Ci-C2 alkyl), Ci-C8haloalkyl, Ci-C8alkoxy(Co-C8alkyl), halogen, -OR15, -NR16R17, -CN, -NO2orC3-C8cycloalkyl;R15is H, Ci-Ce alkyl, Ci-C8haloalkyl, Ci-C8alkoxy(Ci-C8alkyl), or C3-C8 cycloalkyl;R16is H or Ci-Ce alkyl; andR17is H, Ci-C6alkyl;R4is H or Ci-Ce alkyl;R5is C3-C12 cycloalkyl(Co-C2 alkyl) or 6- to 12-membered spirocyclyl(Co-C2), each of which is optionally substituted on a cyclic portion thereof with one or more independently selected R3, where each R3is (i) Ci-C6alkyl, (ii) Ci-C6haloalkyl, (iii) Ci-C8alkoxy, (iv) halogen, (v) -SO2(Ci-C8alkyl), (vi) -SO2(C3-Cs cycloalkyl), (vii) -NHSO2(CI-C8alkyl), (viii) -NHSO2(C3-Cs cycloalkyl), (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-C8alkyl or halogen groups, or (xvii) C3-C8cycloalkyl optionally substituted with one or more independently selected Ci-C8alkyl or halogen groups;Docket no. 24-2207-WON-S1 / SetAR57is H, Ci-C6alkyl, -(CH2CH2O)I-2(CI-C6 alkyl), Ci-C6haloalkyl, Cs-Cs cycloalkyl(Co-C2alkyl), 4- to 8-membered heterocyclyl(Co-C2alkyl), or 5- or 6-membered heteroaryl optionally substituted with one or more independently selected C1-C6 alkyl, halogen, or Ci-Ce alkoxy groups;R58and R59are each independently -NR60R61whereinR60is H or Ci-Ce alkyl; andR61is - SO2(Ci-Ce alkyl) or Ci-Ce haloalkyl;R62is Ci-Ce alkyl optionally substituted with one Ci-Ce alkoxy; R6is H, halogen, Ci-Ce alkyl, C3-C6 cycloalkyl, halo Ci-Ce alkyl, Ci-Ce alkoxy, or -NR8R9where R8and R9independently represent H or Ci-Ce alkyl; and R7is H, -OH, Ci-C6alkyl, Ci-C6haloalkyl or Ci-C6alkoxy.

50. A compound according to claim 1 , which has formula (lb) or (Id):and R1is a 5- or 6-membered heteroaryl optionally substituted with one or more independently selected R2.

51. A compound according to claim 49 or 50, wherein R5is a 6- to 12-membered spirocyclyl(Co-C2alkyl) which is optionally substituted with 1-3 of R3.

52. A compound according to claim 49 or 50, wherein R5has the formula (Villa):whereinDocket no. 24-2207-WON-S1 / SetARing 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.

53. A compound according to claim 52, wherein n is 0 and m is 1.

54. A compound according to claim 49 or claim 50, wherein each R3is independently -SO2(Ci-C6alkyl), Ci-C6haloalkyl, oxo, or -C(O)R62.

55. A compound according to claim 49 or claim 50, wherein R5is:

56. A compound according to claim 49 or 50, wherein R5is a group of the formula (Illa):wherein n is 0 or 1.

57. A compound according to claim 56, wherein R5is:Docket no. 24-2207-WON-S1 / SetA58. A compound according to claim 49 or 50, wherein R5is a group of the formula (111 b) :wherein n is 0 or 1.

59. A compound according to claim 49 or 50, wherein R5is a group of the formula (I I Ic) or (Hid):wherein n is 0 or 1.

60. A compound according to claim 58 or claim 59, wherein n is 0 and R3is -SO2(Ci-Ce alkyl).

61. A compound according to claim 58 or claim 59, wherein n is 0 and R3is -OR57, wherein R57is H, Ci-Ce alkyl, -(CH2CH2O)I-2(CI-C6 alkyl), Ci-Ce haloalkyl, Cs-Cs cycloalkyl(Co-C2 alkyl), or 4- to 8-membered heterocyclyl(Co-C2 alkyl).

62. A compound according to claim 58 or claim 59, wherein n is 0 and R3is -(C0-C4 alkyl)R59.

63. A compound according to claim 58 or claim 59, wherein R5is:Docket no. 24-2207-WON-S1 / SetA64. A compound according to claim 58 or claim 59, wherein n is 0 and R3is 4- to 8- membered heterocyclyl optionally substituted with one or more independently selected halogen groups.

65. A compound according to claim 58 or claim 59, wherein R5is:

66. A compound according to claim 58 or claim 59, wherein n is 1 and at least one R3is halogen.

67. A compound according to claim 58 or claim 59, wherein R5is:

68. A compound according to claim 49 or 50, wherein R5is a group of the formula (Hie):Docket no. 24-2207-WON-S1 / SetAwherein n is 0 or 1.

69. A compound according to claim 68, wherein R5is:

70. A compound according to claim 49 or 50, wherein R5is a group of the formula (IVa)whereinR3ais H, halogen or -OH;n is 0, 1 or 2; andp is 1 or 2.

71. A compound according to claim 70, whereinR3ais H or -OH; andR3is -OR57wherein R57is Ci-C6alkyl or-(CH2CH2O)i-2(Ci-C6 alkyl).

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

73. A compound according to any one of claims 49-72, wherein R1is thiazol-5-yl which is optionally substituted with one or two independently selected R2.

74. A compound according to any one of claims 49-72, wherein R1is imidazol-5-yl which is optionally substituted with one R2.Docket no. 24-2207-WON-S1 / SetA75. A compound according to any one of claims 49-72, wherein R1is unsubstituted imidazolyl or R1is imidazol-1-yl which is substituted with one R2.

76. A compound according to any one of claims 73-75, wherein each R2is independently Ci-Ce alkyl, C3-C6 cycloalkyl or C3-C6 cycloalkyl(Ci-C2 alkyl).

77. A compound according to any one of claims 73-75, wherein each R2is independently C1-C3 alkyl, cyclopropyl or cyclopropylmethyl.

78. A compound according to any one of claims 73-75, wherein each R2is independently methyl, ethyl, propyl or isopropyl.

79. A compound according to any one of claims 49-78, wherein R4is H, methyl or ethyl.

80. A compound according to any one of claims 49-78, wherein R4is H or methyl.

81. A compound according to any one of claims 49-78, wherein R4is H.

82. A compound according to any one of claims 49-81 , wherein R6is Ci-Ce alkyl.

83. A compound according to any one of claims 49-81, wherein R6is hydrogen or methyl.

84. A compound according to any one of claims 49-83, wherein R7is H.

85. A compound according to any one of claims 49-83, wherein R7is methyl or -OH.

86. A compound according to claim 1 , which is:2-(1 H-imidazol-1 -y I )-N -((( 1 r,4r)-4-methoxycyclohexyl)methyl)imidazo[1 ,5- b]pyridazin-7-amine;N-(((1 r,4r)-4-methoxycyclohexyl)methyl)-2-(1 -methyl-1 H-imidazol-5- yl)imidazo[1,5-b]pyridazin-7-amine;N-(((1r,4r)-4-methoxycyclohexyl)methyl)-2-(thiazol-5-yl)imidazo[1,5- b]pyridazin-7-amine;6-(1 H-imidazol-1 -y I )-N -((( 1 r,4r)-4-methoxycyclohexyl)methyl)imidazo[1 ,2- b]pyridazin-3-amine;Docket no. 24-2207-WON-S1 / SetA2-(1 H-imidazol-1 -y I )-N -(( 1 r,4r)-4-methoxycyclohexyl)imidazo[1 ,5- b]pyridazin-7-amine;2-(1 H-imidazol-1 -y l)-N-(( 1 r,4r)-4-(2- methoxyethoxy)cyclohexyl)imidazo[1,5-b]pyridazin-7-amine;N-((2-oxaspiro[3.5]nonan-7-yl)methyl)-6-(1 H-imidazol-1 -yl)imidazo[1 ,2- b]pyridazin-3-amine;4-((6-(1 H-imidazol-1 -yl)imidazo[1 ,2-b]pyridazin-3-yl)amino)tetrahydro-2H- thiopyran 1,1 -dioxide;6-(1 H-imidazol-1 -y I )-N -((( 1 r,4r)-4-methoxycyclohexyl)methyl)- [1,2,4]triazolo[4,3-b]pyridazin-3-amine;2-(1 H-imidazol-1 -yl)-N-(2-(methylsulfonyl)-2-azaspiro[3.5]nonan-7- yl)imidazo[1,5-b]pyridazin-7-amine;N-((1 r,4r)-4-((2-( 1 H-imidazol-1 -yl)imidazo[1 ,5-b]pyridazin-7- yl)amino)cyclohexyl)methanesulfonamide;N-((2-oxaspiro[3.5]nonan-7-yl)methyl)-2-(1 -methyl-1 H-imidazol-5- yl)imidazo[1,5-b]pyridazin-7-amine;6-((6-(1 H-imidazol-1 -y l)-[ 1 ,2,4]triazolo[4,3-b]pyridazin-3-yl)amino)-2- thiaspiro[3.3]heptane 2,2-dioxide;7-(((6-(1 H-imidazol-1 -y l)-[ 1 , 2, 4]triazolo[4, 3-b]py ridazi n-3- yl)amino)methyl)-2-thiaspiro[3.5]nonane 2,2-dioxide;6-(1 H-imidazol-1 -yl)-N-(2-(methylsulfonyl)-2-azaspiro[3.3]heptan-6- yl)imidazo[1,2-b]pyridazin-3-amine;2-(1 H-imidazol-1 -y I )-N -((( 1 r,4r)-4-methoxycyclohexyl)methyl)pyrrolo[2, 1 - f][1 ,2,4]triazin-7-amine;2-(1 H-imidazol-1 -y I )-N -(( 1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)pyrrolo[2, 1 - f][1 ,2,4]triazin-7-amine;7-(((2-(1 -methyl-1 H-imidazol-5-yl)imidazo[1 ,5-b]pyridazin-7- yl)amino)methyl)-2-thiaspiro[3.5]nonane 2,2-dioxide;N-(((1 r,4r)-4-methoxycyclohexyl)methyl)-6-(1 -methyl-1 H-imidazol-5-yl)- [1,2,4]triazolo[4,3-b]pyridazin-3-amine;N-(((1 r,4r)-4-methoxycyclohexyl)methyl)-6-(1 -methyl-1 H-imidazol-5-yl)imidazo[1,2-b]pyridazin-3-amine;N-((4,4-difluorocyclohexyl)methyl)-6-(1 -methyl-1 H-imidazol-5-yl)imidazo[1,2-b]pyridazin-3-amine;Docket no. 24-2207-WON-S1 / SetA6-(1 H-imidazol-1 -y l)-N-(( 1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)imidazo[1,2-b]pyridazin-3-amine;6-(1 H-imidazol-1 -y I )-N -(( 1 r,4r)-4-methoxycyclohexyl)imidazo[1 ,2-b]pyridazin-3-amine;6-(1 H-imidazol-1 -yl)-N-(2-oxaspiro[3.5]nonan-7-yl)imidazo[1 ,2-b]pyridazin-3-amine;2-(1 H-imidazol-1 -yl)-N-(2-oxaspiro[3.5]nonan-7-yl)imidazo[1 ,5-b]pyridazin-7-amine;2-(1 H-imidazol-1 -y l)-N-(( 1 r,4r)-4-(oxetan-3-ylmethoxy)cyclohexyl)imidazo[1,5-b]pyridazin-7-amine;N-((1 r,4r)-4-(2,2-difluoroethoxy)cyclohexyl)-2-(1 H-imidazol-1 -yl)imidazo[1,5-b]pyridazin-7-amine;2-(1 H-imidazol-1 -y I )-N -( 1 -(3-methyloxetan-3-yl)piperidin-4-yl)imidazo[1 ,5-b]pyridazin-7-amine;N-((1 r,4r)-4-(cyclopropylmethoxy)cyclohexyl)-2-(1 H-imidazol-1 -yl)imidazo[1,5-b]pyridazin-7-amine;2-(1 H-imidazol-1 -y I )-N -(( 1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-5-methylimidazo[1,5-b]pyridazin-7-amine;2-(1 H-imidazol-1 -y I )-N -(( 1 r,4r)-4-methoxycyclohexyl)pyrrolo[2, 1 -f][1 ,2,4]triazin-7-amine;2-(1 H-imidazol-1 -yl)-N-(2-(methylsulfonyl)-2-azaspiro[3.5]nonan-7-y I ) py rrolo[2 , 1 -f] [ 1 ,2,4]triazin-7-amine;2-(1 H-imidazol-1 -yl)-N-(2-oxaspiro[3.5]nonan-7-yl)pyrrolo[2, 1 -f][1 ,2,4]triazin-7-amine;N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-2-(5-methyl-1 H-imidazol-1 -yl)imidazo[1,5-b]pyridazin-7-amine;2-(1 H-imidazol-1 -y I )-N -(( 1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-4-methylimidazo[1,5-b]pyridazin-7-amine;2-(1 H-imidazol-1 -y l)-N-(( 1 R,3R)-3-(2-methoxyethoxy)cyclopentyl)imidazo[1,5-b]pyridazin-7-amine;(1 r,4r)-N 1 -(2-(1 H-imidazol-1 -yl)imidazo[1 , 5-b]py ridazin-7-y l)-N4-(2 ,2 ,2-trifluoroethyl)cyclohexane-1,4-diamine;N-((1 r, 4r)-4-(3, 3-difluoropy rrolidin-1 -yl)cyclohexyl)-2-(1 H-imidazol-1 -yl)imidazo[1,5-b]pyridazin-7-amine;Docket no. 24-2207-WON-S1 / SetA6-(1 H-imidazol-1 -yl)-N-((3R,4S)-3-methyltetrahydro-2H-pyran-4-yl)imidazo[1,2-b]pyridazin-3-amine;N-(4,4-difluorocyclohexyl)-6-(1 H-imidazol-1 -yl)imidazo[1 ,2-b]pyridazin-3-amine;N-(4,4-difluorocyclohexyl)-2-(1 H-imidazol-1 -yl)imidazo[1 ,5-b]pyridazin-7-amine;N-((1 r, 4r)-4-(3, 3-difluoropy rrolidin-1 -yl)cyclohexyl)-6-(1 H-imidazol-1 -yl)imidazo[1,2-b]pyridazin-3-amine;5-cyclopropyl-2-(1 H-imidazol-1 -yl)-N-((1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)imidazo[1,5-b]pyridazin-7-amine;2-(1 H-imidazol-1 -y I )-N -(( 1 r,4r)-4-methoxycyclohexyl)-5-methylimidazo[1,5-b]pyridazin-7-amine;N-((1r,4r)-4-(3,3-difluoroazetidin-1-yl)cyclohexyl)-6-(1 H-imidazol-1 -yl)imidazo[1,2-b]pyridazin-3-amine;N-((1 r,4r)-4-(cyclopropylmethoxy)cyclohexyl)-6-(1 H-imidazol-1 -yl)imidazo[1,2-b]pyridazin-3-amine;(1 r,4r)-N 1 -(6-(1 H-imidazol-1 -yl)imidazo[1 , 2-b]py ridazin-3-y l)-N4-(2 ,2 ,2-trifluoroethyl)cyclohexane-1,4-diamine;6-(1 H-imidazol-1 -y I )-N -(( 1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-2-methylimidazo[1,2-b]pyridazin-3-amine;N-((1 r, 4r)-4-(3, 3-difluoropy rrolidin-1 -yl)cyclohexyl)-6-(1 H-imidazol-1 -yl)-2-methylimidazo[1,2-b]pyridazin-3-amine;N-((1 r, 4r)-4-(3, 3-difluoropy rrolidin-1 -yl)cyclohexyl)-2-(1 H-imidazol-1 -yl)-4-methylimidazo[1,5-b]pyridazin-7-amine;2-(1 H-imidazol-1 -y I )-N -(( 1 r,4r)-4-(trifluoromethoxy)cyclohexyl)imidazo[1 ,5-b]pyridazin-7-amine;2-(1 H-imidazol-1 -y I )-N -(( 1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-5- (trifluoromethyl)imidazo[1,5-b]pyridazin-7-amine;2-(1 H-imidazol-1 -y I )-N -(( 1 r,4r)-4-(2-methoxyethoxy)cyclohexyl)-4,5-dimethylimidazo[1,5-b]pyridazin-7-amine;1 -(7-((6-(1 H-imidazol-1 -yl)imidazo[1 ,2-b]pyridazin-3-yl)amino)-2-azaspiro[3.5]nonan-2-yl)-2-methoxyethan-1-one;N-(2-(2,2-difluoroethyl)-2-azaspiro[3.5]nonan-7-yl)-6-(1 H-imidazol-1 -yl)imidazo[1 ,2-b]pyridazin-3-amine; ;Docket no. 24-2207-WON-S1 / SetA6-(1 H-imidazol-1 -yl)-8-methoxy-N-((1 r,4r)-4-(2- methoxyethoxy)cyclohexyl)imidazo[1,2-b]pyridazin-3-amine;6-(1 H-imidazol-1 -y l)-3-((( 1 r,4r)-4-(2- methoxyethoxy)cyclohexyl)amino)imidazo[1,2-b]pyridazin-8-ol;6-(1 H-imidazol-1 -y I )-N -(( 1 r,4r)-4-(trifluoromethoxy)cyclohexyl)imidazo[1 ,2- b]pyridazin-3-amine;N-((1 r,4r)-4-(2,2-difluoroethoxy)cyclohexyl)-6-(1 H-imidazol-1 - yl)imidazo[1,2-b]pyridazin-3-amine;N-((1 r,4r)-4-(2,2-difluoroethoxy)cyclohexyl)-2-(1 H-imidazol-1 -yl)-5- methylimidazo[1,5-b]pyridazin-7-amine;or a pharmaceutically acceptable salt thereof.

87. A pharmaceutical composition, comprising a therapeutically effective amount of a compound as described in any of claims 1-86 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.

88. 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 1-86, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 87.

89. The method of claim 88, 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.

90. The method of claim 88, 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,Docket no. 24-2207-WON-S1 / SetAneonatal 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.

91. A method of inhibiting CD38 activity in a cell comprising exposing the cell to a compound as described in any of claims 1-86.

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