OA20638A - Aza-heterobicyclic inhibitors Of MAT2A and methods of use for treating cancer. - Google Patents

Abstract

The present disclosure provides for compounds according to Formula I and their pharmaceutically acceptable salts, tautomers, and/or isotopologues as described in the disclosure. The compounds are inhibitors of methionine adenosyltransferase isoform 2A (MAT2A). Also provided are pharmaceutical compositions and methods of using the compounds for treating cancers, including some cancers in which the gene encoding methyltliioadenosine phosphorylase (MTAP) is deleted.

Description

AZA-HETEROBICYCLIC INHIBITORS OF MAT2A AND METHODS OF USE FOR TREATING CANCER

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Patent Application No. 62/785,519, filed December 27, 2018, the disclosure of which is incorporated by reference herein in its entirety.

BACKGROUND

Méthionine adenosyltransferase (MAT), which is also known as S-adenosylmethionine synthetase, is a cellular enzyme that catalyzes the synthesis of S-adenosyl méthionine (SAM or AdoMet) from méthionine and ATP; the catalysis is considered to be rate-limiting step of the méthionine cycle. SAM is the propylamino donor in polyamine biosynthesis, the principal methyl donor for DNA méthylation, and is involved in gene transcription and cellular prolifération as well as the production of secondary métabolites.

Two genes designated as ΜΑΤΙΑ and MAT2A encode two distinct catalytic MAT isoforms, respectively. A third gene, MAT2B, encodes a MAT2A regulatory subunit. ΜΑΤΙΑ is specifically expressed in the adult liver, whereas MAT2A is widely distributed. Because MAT isoforms differ in catalytic kinetics and regulatory properties, ΜΑΤΙ A-expressing cells hâve considerably higher SAM levels than do MAT2A-expressing cells. It has been found that hypomethylation of the MAT2A promoter and histone acétylation causes upregulation of MAT2A expression. See, e.g. M. Vâzquez-Chantada et al., Gastroenterology 138 (2010) i

1943-53; M. Frau et al., J. Hepatol. 59 (2013) 830-41 ; M. Frau et al., Hepatology 56 (2012)|

165-75; and R. M. Pascale et al., Transi. Gastroenterol. Hepatol. 3 (2018) 36.J

In hepatocellular carcinoma (HCC), the downregulation of ΜΑΤΙΑ and the up-regulation of}

MAT2A occur, which is known as the ΜΑΤΙ A:MAT2A switch. The switch, accompanied with up-regulation of MAT2B, results in lower SAM contents, which provide a growth advantage to hepatoma cells. Because MAT2A plays a crucial rôle in facilitating the growth of hepatoma cells, it is a target for antineoplastic therapy. Recent studies hâve shown that silencing by using small interfering RNA substantially suppresses growth and induces apoptosis in hepatoma cells. See, e.g., T. Li et al., J. Cancer 7(10) (2016) 1317-1327.

Some cancer cell fines that are MTAP déficient are particularly sensitive to inhibition of

MAT2A. Marjon et al. (Cell Reports 15(3) (2016) 574—587). MTAP (methylthioadenosineI phosphorylase) is an enzyme widely expressed in normal tissues that catalyzes the| i

-1i i

conversion of methylthioadenosine (MTA) into adenine and 5-methylthioribose-l-phosphate. The adenine is salvaged to generate adenosine monophosphate, and the 5-methylthioribose1-phosphate is converted to méthionine and formate. Because of this salvage pathway, MTA can serve as an alternative purine source when de novo purine synthesis is blocked, e.g., with 5 antimetabolites, such as L-alanosine.

MAT2A is dysregulated in additional cancers that lack MTAP-deletion, including hepatocellular carcinoma and leukemia. J. Cai et al., Cancer Res. 58 (1998) 1444-1450; T.

S. Jani et al., Cell. Res. 19 (2009) 358-369. Silencing of MAT2A expression via RNAinterference results in anti-proliferative effects in several cancer models. H. Chen et al., 10 Gastroenterology 133 (2007) 207-218; Q. Liu et al. Hepatol. Res. 37 (2007) 376-388.

Many human and murine malignant cells lack MTAP activity. MT AP deficiency is found not only in tissue culture cells but the deficiency is also présent in primary leukemias, gliomas, melanomas, pancreatic cancers, non-small cell lung cancers (NSCLC), bladder cancers, astrocytomas, osteosarcomas, head and neck cancers, myxoid chondrosarcomas, 15 ovarian cancers, endométrial cancers, breast cancers, soft tissue sarcomas, non-Hodgkin lymphoma, and mesotheliomas. The gene encoding for human MT AP maps to région 9p21 on human chromosome 9p. This région also contains the tumor suppressor genes pl6INK4A (also known as CDKN2A) and p!5INK4B. These genes code for pl6 and pl5, which are inhibitors of the cyclin D-dependent kinases cdk4 and cdk6, respectively.

The pl6INK4A transcript can altematively be alternative reading frame (ARF) spliced into a transcript encoding pl4ARF. pl4ARF binds to MDM2 and prevents dégradation of p53 (Pomerantz et al. (1998) Cell 92:713-723). The 9p21 chromosomal région is of interest because it is frequently homozygously deleted in a variety of cancers, including leukemias, NSLC, pancreatic cancers, gliomas, melanomas, and mesothelioma. The délétions often inactivate more than one gene. For example, Caims et al. ((1995) Nat. Gen. 11:210-212) reported that after studying more than 500 primary tumors, almost ail the délétions identified in such tumors involved a 170 kb région containing MTAP, p!4ARF and P16INK4A. Carson et al. (WO 99/67634) reported that a corrélation exists between the stage of tumor development and loss of homozygosity of the gene encoding MTAP and the gene encoding 30 pl6. For example, délétion of the MTAP gene, but not pl6INK4A was reported to be indicative of a cancer at an early stage of development, whereas délétion of the genes encoding for pl6 and MTAP was reported to be indicative of a cancer at a more advanced stage of tumor development. In some osteosarcoma patients, the MTAP gene was présent at

-220638 diagnosis but was deleted at a later time point (Garcia-Castellano et al.. Clin. Cancer Res. 8(3) 2002 782-787).

SUMMARY

The présent disclosure provides compounds that inhibit MAT2A. The compounds and their pharmaceutical compositions are useful in methods for treating varions cancers, including those that are refractory to standard treatments, such as surgery, radiation therapy, chemotherapy, and hormonal therapy.

Thus, in accordance with some embodiments, the présent disclosure provides a compound according to formula I or a pharmaceutically acceptable sait, tautomer, and/or isotopologue thereof:

In Formula I, L is O, S, NR, or a bond. R is H or Ci-C₆-alkyl.

R¹ is selected from the group consisting of Ci-C₆-alkyl, C₂-C₆-alkenyl, C₃-C₆-carbocyclyl, (Ci-Cg-alkylXCs-Ce-carbocyclyl), and -(Ci-C6-alkyl)(C3-C6-cycloalkenyl) wherein any alkyl in R¹ is straight or branched. In an embodiment, R¹ is optionally substituted by 1-6 halo or 1-6 deuterium.

Altematively, in an embodiment, when L is NR, then R and R¹ in combination with L represent a 3- to 6-membered heterocycloalkyl (wherein 1-4 ring members are independently selected from N, O, and S) optionally substituted by one or more R^A.

R² and R³ are independently selected from the group consisting of C2-C6-alkynyl, C6-Cioaryl, C3-C6-carbocyclyl, 5- to 10-membered heteroaryl (wherein 1-4 heteroaryl members are independently selected from N, O, and S), and 3- to 14-membered heterocycloalkyl (wherein 1-4 heterocycloalkyl members are independently selected from N, O, and S). R² and R³ are independently and optionally substituted by one or more substituents that are selected from the group consisting of R^A, OR^A, halo, -N=N-R^A, -NR^AR^B, -(Ci-C6-alkyl)NR^AR^B, -C(O)OR^A, -C(O)NR^AR^B, -OC(O)R^a, -Si(Ci-C₆-alkyl)₃ and -CN.

R⁴ is selected from the group consisting of H, Ci-C₆-alkyl (optionally substituted by one or more halo, hydroxy or 3- to 14-membered heterocycloalkoxy (wherein 1-4 heterocycloalkoxy members are independently selected from N, O, and S)), -O(Ci-C₆-alkyl)

-320638 (optionally substituted by one or more halo), -OH, halo, -CN, -(Ci-C₆-alkyl)NR^AR^B, and NR^aR^b.

R⁵ is selected from the group consisting of H, Ci-Cô-alkyl, Ci-C₆-alkoxy, C₂-Ce-alkenyl, C₂Ce-alkynyl, halo, -CN, and -NR^CR^D.

R^a and R^Bare independently selected from the group consisting of H, -CN, -hydroxy, oxo, Ci-C₆-alkyl, Ci-C₆-alkoxy, C₂-C₆-alkenyl, C₂-C₆-alkynyl, -NH₂, -S(O)₀.₂-(Ci-C₆-alkyl), S(0)o.₂-(C₆-Cio-aryl), -C(O)(Ci-C₆-alkyl), -C(O)(C₃-Cj4-carbocyclyl), -C₃-Ci4-carbocyclyl, (Ci-C6-alkyl)(C3-Ci4-carbocyclyl), Ce-Cio-aryl, 3- to 14-membered heterocycloalkyl and (Ci-Ce-alkyl)-(3- to 14-membered heterocycloalkyl) (wherein 1-4 heterocycloalkyl members are independently selected from N, O, and S), and 5- to 10-membered heteroaryl (wherein 14 heteroaryl members are independently selected from N, O, and S).

Each alkyl, alkoxy, alkenyl, alkynyl, aryl, carbocyclyl, heterocycloalkyl, and heteroaryl moiety of R^A and R^B is optionally substituted with one or more substituents selected from the group consisting of deuterium, hydroxy, halo, -NR’2 (wherein each R’ is independently selected from the group consisting of Ci-C6-alkyl, C2-Ce-alkenyl, C2-Ce-alkynyl, Ce-C10-aryl, 3- to 14-membered heterocycloalkyl and -(Ci-Cg-alkyl)-(3- to 14-membered heterocycloalkyl) (wherein 1-4 ring members are independently selected from N, O, and S), and 5- to 10-membered heteroaryl (wherein 1-4 heteroaryl members are independently selected from N, O, and S)), -NHC(O)(OCi-C6-alkyl), -NO2, -CN, oxo, -C(O)OH, C(O)O(Ci-C6-alkyl), -Ci-C6-alkyl(CrC6-alkoxy), -C(O)NH2, Ci-C6-alkyl, -CiOjCrCe-alkyl, -OCi-C6-alkyl, -Si(Ci-C6-alkyl)3, -S(O)0.2-(Ci-C6-alkyl), C6-Ci0-aryl, -(Ci-C6-alkyl)(Ce-C10aryl), 3- to 14-membered heterocycloalkyl, and -(Ci-Ce-alkyl)-(3- to 14-membered heterocycle) (wherein 1-4 heterocycle members are independently selected from N, O, and S), and -O(C(1-C14-aryl). Each alkyl, alkenyl, aryl, and heterocycloalkyl substituent in R^A and R^b is optionally substituted with one or more substituents selected from the group consisting of deuterium, hydroxy, -OCi-C6-alkyl, halo, -NH₂, -(Ci-C₆-alkyl)NH₂, -C(O)OH, CN, and oxo.

C' Π

R and R are each independently selected from H and Ci-Ce-alkyl.

The disclosure provides in another embodiment a pharmaceutical composition comprising a therapeutically effective amount of a compound or a pharmaceutically acceptable sait, tautomer, and/or isotopologue thereof as described herein, and a pharmaceutically acceptable carrier.

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In another embodiment, the discio sure pro vides a method for treating a cancer in a subject suffering therefrom, comprising administering to the subject an effective amount of a MAT2A inhibitor compound as described herein.

Yet another embodiment of the disclosure is a method for inhibiting the synthesis of Sadenosyl méthionine (SAM) in a cell, comprising introducing into the cell an effective amount of a compound, or a pharmaceutically acceptable sait, tautomer, and/or isotopologue thereof, as described herein.

The disclosure, in another embodiment, relates to a method for inhibiting the synthesis of Sadenosyl méthionine (SAM) in a subject, comprising administering to the subject an effective amount of at least one compound or a sait, tautomer, and/or isotopologue thereof as described herein.

In an embodiment, the disclosure provides a method for treating a cancer in a subject suffering therefrom, wherein the cancer is characterized by a réduction or absence of methylthioadenosine phosphorylase (MTAP) gene expression, the absence of the MT AP gene, or reduced fonction of MTAP protein, as compared to cancers where the MT AP gene or protein is présent and/or folly fonctioning, the method comprising administering to the subject a therapeutically effective amount of a compound, or a pharmaceutically acceptable sait, tautomer, and/or isotopologue thereof, as described herein.

The disclosure also provides in another embodiment a compound or a pharmaceutically acceptable sait, tautomer, and/or isotopologue thereof, as described herein, for inhibiting the synthesis of S-adenosyl méthionine (SAM).

In still a further embodiment, the disclosure provides a compound or a pharmaceutically acceptable sait, tautomer, and/or isotopologue thereof, as described herein, for use in treating a cancer in a subject suffering therefrom.

The disclosure also provides the use of a compound as described herein, or a pharmaceutically acceptable sait thereof, for the manufacture of a médicament for treating cancer.

DETAILED DESCRIPTION

The compounds described herein are inhibitors of MAT2A. The présent disclosure thus relates not only to such compounds in conformity with Formula I, but also to their pharmaceutical compositions, tautomers, and isotopologues. The compounds and compositions are usefol in treating cancers. Some cancers include various MTAP-deleted

-5- 'j i i cancers, i.e., those cancers characterized by the absence or délétion of the MT AP gene/protein or reduced fonction of the MTAP protein.

Définitions

Alkyl refers to straight, branched chain hydrocarbyl groups, from 1 to about 20 carbon atoms. For instance, an alkyl can hâve from 1 to 10 carbon atoms or 1 to 6 carbon atoms. Exemplary alkyl includes straight chain alkyl groups such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, and the like, and also includes branched chain isomers of straight chain alkyl groups, for example without limitation, CH(CH₃)₂, -CH(CH₃)(CH₂CH₃), -CH(CH₂CH₃)₂, -C(CH₃)₃, -C(CH₂CH₃)₃, -CH₂CH(CH₃)_2î CH₂CH(CH₃)(CH₂CH₃), -CH₂CH(CH₂CH₃)₂, -CH₂C(CH₃)₃, -CH₂C(CH₂CH₃)₃, CH(CH₃)CH(CH₃)(CH₂CH₃), -CH₂CH₂CH(CH₃)₂, -CH₂CH₂CH(CH₃)(CH₂CH₃), CH₂CH₂CH(CH₂CH₃)₂, -CH₂CH₂C(CH₃)₃, -CH₂CH₂C(CH₂CH₃)₃, -CH(CH₃)CH₂CH(CH₃)₂, -CH(CH₃)CH(CH₃)CH(CH₃)₂, and the like. Thus, alkyl groups include primary alkyl groups, secondary alkyl groups, and tertiary alkyl groups. An alkyl group can be unsubstituted or optionally substituted with one or more substituents as described herein below.

The phrase “substituted alkyl” refers to alkyl substituted at one or more positions, for example, 1, 2, 3, 4, 5, or even 6 positions, which substituents are attached at any available atom to produce a stable compound, with substitution as described herein. “Optionally substituted alkyl” refers to alkyl or substituted alkyl.

Each of the ternis “halogen,” “halide,” and “halo” refers to -F, -Cl, -Br, or -I.

The term “alkenyl” refers to straight or branched chain hydrocarbyl groups including from 2 to about 20 carbon atoms having 1-3, 1-2, or at least one carbon to carbon double bond. An alkenyl group can be unsubstituted or optionally substituted with one or more substituents as described herein below.

“Substituted alkenyl” refers to alkenyl substituted at 1 or more, e.g., 1, 2, 3, 4, 5, or even 6 positions, which substituents are attached at any available atom to produce a stable compound, with substitution as described herein. “Optionally substituted alkenyl” refers to alkenyl or substituted alkenyl.

“Alkyne or “alkynyl” refers to a straight or branched chain unsaturated hydrocarbon having the indicated number of carbon atoms and at least one triple bond. Examples of an alkynyl group include, but are not limited to, acetylene, propyne, 1-butyne, 2-butyne, 1-pentyne, 2pentyne, 1-hexyne, 2-hexyne, 3-hexyne, 1-heptyne, 2-heptyne, 3-heptyne, 1-octyne, 2

-620638 octyne, 3-octyne and 4-octyne. An alkynyl group canbe unsubstituted or optionally substituted with one or more substituents as described herein below.

“Substituted alkynyl” refers to an alkynyl substituted at 1 or more, e.g., 1, 2, 3, 4, 5, or even 6 positions, which substituents are attached at any available atom to produce a stable compound, with substitution as described herein. “Optionally substituted alkynyl” refers to alkynyl or substituted alkynyl.

The term “alkoxy” refers to an -O-alkyl group having the indicated number of carbon atoms. For example, a (Ci-Cô)alkoxy group includes -O-methyl, -O-ethyl, -O-propyl, -O-isopropyl, O-butyl, -O-sec-butyl, -O-iert-butyl, -O-pentyl, -O-isopentyl, -O-neopentyl, -O-hexyl, -Oisohexyl, and -O-neohexyl.

The term “carbocyclyl” refers to a monocyclic, bicyclic, tricyclic, or polycyclic, 3- to 14membered ring System, which is either saturated, such as “cycloalkyl,” or unsaturated, such as “cycloalkenyl.” The term “cycloalkenyl” refers specifically to cyclic alkenyl, such as C3Ce-cycloalkenyl. The carbocyclyl may be attached via any atom. Carbocyclyl, for instance, also contemplâtes fused rings wherein, for instance, a carbocyclyl is fused to an aryl or heteroaryl ring as defined herein. Représentative examples of carbocyclyl include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, phenyl, naphthyl, anthracyl, benzofuranyl, and benzothiophenyl. A carbocyclyl group can be unsubstituted or optionally substituted with one or more substituents as described herein below.

“Substituted carbocyclyl” refers to carbocyclyl substituted at 1 or more, e.g., 1, 2, 3, 4, 5, or even 6 positions, which substituents are attached at any available atom to produce a stable compound, with substitution as described herein. “Optionally substituted carbocyclyl” refers to carbocyclyl or substituted carbocyclyl.

“Aryl” when used alone or as part of another term means a carbocyclic aromatic group whether or not fused having the number of carbon atoms designated or if no number is designated, up to 14 carbon atoms, such as a Q-Cn-aryl. Particular aryl groups are phenyl, naphthyl, biphenyl, phenanthrenyl, naphthacenyl, and the like (see e.g. Lang’s Handbookof Chemistry (Dean, J. A., ed) 13^th ed. Table 7-2 [1985]). A particular aryl is phenyl. “Aryl” also includes aromatic ring Systems that are optionally fused with a carbocyclyl ring, as herein defined. An aryl group can be unsubstituted or optionally substituted with one or more substituents as described herein below.

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A substituted aryl” is an aryl that is independently substituted with one or more substituents attached at any available atom to produce a stable compound, wherein the substituents are as described herein. “Optionally substituted aryl” refers to aryl or substituted aryl.

The term “heteroatom” refers to N, O, and S. Compounds that contain N or S atoms can be optionally oxidized to the corresponding N-oxide, sulfoxide, or sulfone compounds.

“Heteroaryl,” alone or in combination with any other moiety described herein, refers to a monocyclic aromatic ring structure containing 5 to 10, such as 5 or 6 ring atoms, or a bicyclic aromatic group having 8 to 10 atoms, containing one or more, such as 1-4, 1-3, or 1-2, heteroatoms independently selected from the group consisting of O, S, and N. Heteroaryl is also intended to include oxidized S or N, such as sulfmyl, sulfonyl and N-oxide of a tertiary ring nitrogen. A carbon or heteroatom is the point of attachment of the heteroaryl ring structure such that a stable compound is produced. Examples of heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, pyrazinyl, quinoxalyl, indolizinyl, benzo[b]thienyl, quinazolinyl, purinyl, indolyl, quinolinyl, pyrimidinyl, pyrrolyl, pyrazolyl, oxazolyl, thiazolyl, thienyl, isoxazolyl, oxathiadiazolyl, isothiazolyl, tetrazolyl, imidazolyl, triazolyl, furanyl, benzofuryl, and indolyl. A heteroaryl group can be unsubstituted or optionally substituted with one or more substituents as described herein below.

A substituted heteroaryl” is a heteroaryl that is independently substituted, unless indicated otherwise, with one or more, e.g., 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents, also 1 substituent, attached at any available atom to produce a stable compound, wherein the substituents are as described herein. “Optionally substituted heteroaryl” refers to heteroaryl or substituted heteroaryl.

“Heterocycloalkyl” means a saturated or unsaturated non-aromatic monocyclic, bicyclic, tricyclic or polycyclic ring System that has from 3 to 14, such as 3 to 6, atoms in which from 1 to 4 carbon atoms in the ring are replaced by heteroatoms of O, S or N. A heterocycloalkyl is optionally fused with aryl or heteroaryl of 5-6 ring members, and includes oxidized S or N, such as sulfmyl, sulfonyl and N-oxide of a tertiary ring nitrogen. The point of attachment of the heterocycloalkyl ring is at a carbon or heteroatom such that a stable ring is retained. Examples of heterocycloalkyl groups include without limitation morpholino, tetrahydrofuranyl, dihydropyridinyl, piperidinyl, pyrrolidinyl, piperazinyl, dihydrobenzofuryl, and dihydroindolyl. A heterocycloalkyl group can be unsubstituted or optionally substituted with one or more substituents as described herein below.

-820638 “Optionally substituted heterocycloalkyl” dénotés a heterocycloalkyl that is substituted with 1 to 3 substituents, e.g., 1, 2 or 3 substituents, attached at any available atom to produce a stable compound, wherein the substituents are as described herein.

“Heterocycloalkoxy” refers to an -O-heterocycloalkyl group having the indicated number of 5 member atoms in a monocyclic, bicyclic, tricyclic or polycyclic ring System and where 1 to 4 carbon atoms in the ring are replaced by heteroatoms of O, S or N.

“Optionally substituted heterocycloalkoxy” refers to a heterocycloalkoxy group that is substituted with 1 to 3 substituents, e.g., 1, 2 or 3 substituents, attached at any available atom to produce a stable compound, wherein the substituents are as described herein.

The term “nitrile” or “cyano” can be used interchangeably and refer to a -CN group which is bound to a carbon atom of a heteroaryl ring, aryl ring and a heterocycloalkyl ring.

The term “oxo” refers to a =0 atom attached to a saturated or unsaturated moiety. The =0 atom can be attached to a carbon, sulfiir, or nitrogen atom that is part of a cyclic or acyclic moiety.

A “hydroxyl” or “hydroxy” refers to an -OH group.

The substituent -CO₂H may be replaced with bioisosteric replacements such as:

-920638 and the like, wherein R has the same définition as R^A as defined herein. See, e.g., The Practice OF Médicinal Chemistry (Academie Press: New York, 1996), at page 203.

Compounds described herein can exist in varions isomeric forms, including configurational, géométrie, and conformational isomers, including, for example, cis- or trans- conformations. The compounds may also exist in one or more tautomeric forms, including both single tautomers and mixtures of tautomers. The term “isomer” is intended to encompass ail isomeric forms of a compound of this disclosure, including tautomeric forms of the compound. The compounds of the présent disclosure may also exist in open-chain or cyclized forms. In some cases, one or more of the cyclized forms may resuit from the loss of water, The spécifie composition of the open-chain and cyclized forms may be dépendent on how the compound is isolated, stored or administered. For example, the compound may exist primarily in an open-chained form under acidic conditions but cyclize under neutral conditions. Ail forms are included in the disclosure.

Some compounds described herein can hâve asymmetric centers and therefore exist in different enantiomeric and diastereomeric forms. A compound of the disclosure can be in the form of an optical isomer or a diastereomer. Accordingly, the disclosure encompasses compounds and their uses as described herein in the form of their optical isomers, diastereoisomers and mixtures thereof, including a racemic mixture. Optical isomers of the compounds of the disclosure can be obtained by known techniques such as asymmetric synthesis, chiral chromatography, simulated moving bed technology or via Chemical séparation of stereoisomers through the employment of optically active resolving agents.

Unless otherwise indicated, the term “stereoisomer” means one stereoisomer of a compound that is substantially free of other stereoisomers of that compound. Thus, a stereomerically pure compound having one chiral center will be substantially free of the opposite enantiomer of the compound. A stereomerically pure compound having two chiral centers will be substantially free of other diastereomers of the compound. A typical stereomerically pure compound comprises greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, for example greater than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of the other stereoisomers of the compound, or greater than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of the other stereoisomers of the compound, or greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of the other stereoisomers of the compound, or greater than about 99% by weight of one stereoisomer of the compound and less than

-1020638 about 1% by weight of the other stereoisomers of the compound. The stereoisomer as described above can be viewed as composition comprising two stereoisomers that are présent in their respective weight percentages described herein.

As used herein, the term “isotopologue” is an isotopically enriched compound. As used herein, and unless otherwise indicated, the term “isotopically enriched” refers to an atom having an isotopic composition other than the naturally abundant isotopic composition of that atom. “Isotopically enriched” may also refer to a compound containing at least one atom having an isotopic composition other than the natural isotopic composition of that atom. In an isotopologue, “isotopic enrichment” refers to the percentage of incorporation of an amount of a spécifie isotope of a given atom in a molécule in the place of that atom's natural isotopic composition. For example, deuterium enrichment of 1% at a given position means that 1% of the molécules in a given sample contain deuterium at the specified position. Because the naturally occurring distribution of deuterium is about 0.0156%, deuterium enrichment at any position in a compound synthesized using non-enriched starting materials is about 0.0156%.

Thus, as used herein, and unless otherwise indicated, the term “isotopic enrichment factor” refers to the ratio between the isotopic composition and the natural isotopic composition of a specified isotope.

With regard to the compounds provided herein, when a particular atom’s position is designated as having deuterium or “D” or “H²”, it is understood that the abundance of deuterium at that position is substantially greater than the natural abundance of deuterium, which is about 0.015%. A position designated as having deuterium typically has a minimum isotopic enrichment factor of, in particular embodiments, at least 1000 (15% deuterium incorporation), at least 2000 (30% deuterium incorporation), at least 3000 (45% deuterium incorporation), at least 3500 (52.5% deuterium incorporation), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation) at each designated deuterium atom. The isotopic enrichment and isotopic enrichment factor of the compounds provided herein can be determined using conventional analytical methods known to one of ordinary skill in the art, including mass spectrometry and nuclear magnetic résonance spectroscopy.

-1120638

If there is a discrepancy between a depicted structure and a name given to that structure, then the depicted structure Controls. Additionally, if the stereochemistry of a structure or a portion of a structure is not indicated with, for example, bold or dashed lines, the structure or portion of the structure is to be interpreted as encompassing ail stereoisomers of it. In some cases, however, where more than one chiral center exists, the structures and names may be represented as single enantiomers to help describe the relative stereochemistry. Those skilled in the art of organic synthesis will know if the compounds are prepared as single enantiomers from the methods used to préparé them.

As used herein, and unless otherwise specified to the contrary, the term “compound” is inclusive in that it encompasses a compound or a pharmaceutically acceptable sait, stereoisomer, isotopologue, and/or tautomer thereof. Thus, for instance, a compound of Formula I or II includes a pharmaceutically acceptable sait of an isotopologue of the compound.

In this description, a “pharmaceutically acceptable sait” is a pharmaceutically acceptable, organic or inorganic acid or base sait of a compound of the disclosure. Représentative pharmaceutically acceptable salts include, e.g., alkali métal salts, alkali earth salts, ammonium salts, water-soluble and water-insoluble salts, such as the acetate, amsonate (4,4diaminostilbene-2,2-disulfonate), benzenesulfonate, benzonate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate, carbonate, chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycolylarsanilate, hexafluorophosphate, hexylresorcinate, hydrab amine, hydrobromide, hydro chloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium sait, 3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate (l,l-methene-bis-2-hydroxy-3naphthoate, einbonate), pantothenate, phosphate/diphosphate, picrate, polygalacturonate, propionate, p-toluenesulfonate, salicylate, stéarate, sub acetate, succinate, sulfate, sulfosalicylate, suramate, tannate, tartrate, teoclate, tosylate, triethiodide, and valerate salts. A pharmaceutically acceptable sait can hâve more than one charged atom in its structure. In this instance the pharmaceutically acceptable sait can hâve multiple counterions. Thus, a pharmaceutically acceptable sait can hâve one or more charged atoms and/or one or more ;

counterions.;

The ternis “treat”, “treating” and “treatment” refer to the amelioration or éradication of aî disease or symptoms associated with a dîsease. In certain embodiments, such tenus refer toi

-1220638 minimizing the spread or worsening of the disease resulting from the administration of one or more prophylactic or therapeutic agents to a patient with such a disease.

The ternis “prevent,” “preventing,” and “prévention” refer to the prévention of the onset, récurrence, or spread of the disease in a patient resulting from the administration of a prophylactic or therapeutic agent.

The terni “effective amount” refers to an amount of a compound of the disclosure or other active ingrédient sufficient to provide a therapeutic or prophylactic benefit in the treatment or prévention of a disease or to delay or minimize symptoms associated with a disease. Further, a therapeutically effective amount with respect to a compound of the disclosure means that amount of therapeutic agent alone, or in combination with other thérapies, that provides a therapeutic benefit in the treatment or prévention of a disease. Used in connection with a compound of the disclosure, the term can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of disease, or enhances the therapeutic efficacy of or synergizes with another therapeutic agent.

A “patient” or subjecf ’ includes an animal, such as a human, cow, horse, sheep, lamb, pig, chicken, turkey, quail, cat, dog, mouse, rat, rabbit or guinea pig. In accordance with some embodiments, the animal is a mammal such as a non-primate and a primate (e.g., monkey and human). In one embodiment, a patient is a human, such as a human infant, child, adolescent or adult.

“Inhibitor” means a compound which prevents or reduces the amount of synthesis of SAM. In an embodiment, an inhibitor binds to MAT2A. In one embodiment, the inhibitor inhibits the function of MAT2A.

Compounds

As described generally above, the présent disclosure provides compounds and pharmaceutically acceptable salts, tautomers, and/or isotopologues thereof, wherein the compounds conform to formula I:

R⁴

R²

In Formula I, L is O, S, NR, or a bond. R is H or Ci-C₆-alkyl.

-1320638

R¹ is selected from the group consisting of Ci-Cg-alkyl, C₂-C₆-alkenyl, C₃-C6-carbocyclyl, (C[-C6-alkyl)(C3-C6-carbocyclyl), and -(Ci-C6-alkyl)(CrQ,-cycloalkenyl) wherein any alkyl in R¹ is straight or branched. In an embodiment, R¹ is optionally substituted by 1 - 6 halo or 1-6 deuterium.

Altematively, in an embodiment, when L is NR, then R and R¹ in combination with L represent a 3- to 6-membered heterocycloalkyl (wherein 1-4 ringmembers are independently selected from N, O, and S) optionally substituted by one or more R^A.

R and R are independently selected from the group consisting of C₂-C6-alkynyl, Ce-Choaryl, Ch-Cg-carbocyclyl, 5- to 10-membered heteroaryl (wherein 1-4 heteroaryl members are independently selected from N, O, and S), and 3- to 14-membered heterocycloalkyl (wherein 1-4 heterocycloalkyl members are independently selected from N, O, and S). R² and R³ are independently and optionally substituted by one or more substituents that are selected from the group consisting of R^A, OR^A, halo, -N=N-R^A, -NR^AR^B, -(Ci-C6-alkyl)NR^AR^B, -C(O)OR^A, -C(O)NR^aR^b, -OC(O)R^a, -Si(Ci-C6-alkyl)₃ and -CN.

R⁴ is selected from the group consisting of H, Cj-Ce-alkyl (optionally substituted by one or more halo, hydroxy or 3- to 14-membered heterocycloalkoxy (wherein 1-4 heterocycloalkoxy members are independently selected from N, O, and S)), -O(Ci-C₆-alkyl) (optionally substituted by one or more halo), -OH, halo, -CN, -(Ci-C₆-alkyl)NR^AR^B, and nr^ar^b

R⁵ is selected from the group consisting of H, C[-C₆-alkyl, Ci-C₆-alkoxy, C₂-C₆-alkenyl, C₂C₆-alkynyl, halo, CN, and -NR^CR^D.

R^a and R^b are independently selected from the group consisting of H, -CN, -hydroxy, oxo, Ci-Ce-alkyl, Ci-C_fi-alkoxy, C₂-C₆-alkenyl, C₂-C₆-alkynyl, -NH₂, -S(O)₀-₂-(Ci-C₆-alkyl), S(0)o.₂-(C6-Cio-aryl), -C(O)(Ci-C6-alkyl), -C(O)(C3-Ci4-carbocyclyl), -C3-Ci4-carbocyclyl, (C]-C6-alkyl)(C3-Ci4-carbocyclyl), Cg-Cio-aryl, 3- to 14-membered heterocycloalkyl and (C|-C(,-aIkyl)-(3- to 14-membered heterocycloalkyl) (wherein 1-4 heterocycloalkyl members are independently selected from N, O, and S), and 5- to 10-membered heteroaryl (wherein 14 heteroaryl members are independently selected from N, O, and S).

Each alkyl, alkoxy, alkenyl, alkynyl, aryl, carbocyclyl, heterocycloalkyl, and heteroaryl moiety of R^A and R^B is optionally substituted with one or more substituents selected from the group consisting of deuterium, hydroxy, halo, -NR’₂ (wherein each R’ is independently selected from the group consisting of Ci-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₆-Ci₀-aryl, 3- to 14-membered heterocycloalkyl and -(Ci-C₆-alkyl)-(3- to 14-membered

-1420638 heterocycloalkyl) (wherein 1-4 ring members are independently selected from N, O, and S), and 5- to 10-membered heteroaryl (wherein 1-4 heteroaryl members are independently selected from N, O, and S), -NHC(O)(OCi-C₆-alkyl), -NO₂, -CN, oxo, -C(O)OH, C(O)O(Ci-C₆-alkyl), -Ci-C₆-alkyl(Ci-C₆-alkoxy), -C(O)NH₂, Ci-C₆-alkyl, -C(O)Ci-C₆-alkyl, -OCi-C₆-alkyl, -Si(Ci-C₆-alkyl)₃, -S(O)₀.₂-(Ci-C₆-alkyl), C₆-Ci₀-aryl, -(C_rC₆-alkyl)(C₆-Ci₀aryl), 3- to 14-membered heterocycloalkyl, and -(Ci-C₆-alkyl)-(3- to 14-membered heterocycle) (wherein 1-4 heterocycle members are independently selected from N, O, and S), and -O(C6-Ci4-aryl). Each alkyl, alkenyl, aryl, and heterocycloalkyl substituent in R^A and R is optionally substituted with one or more substituents selected from the group consisting of hydroxy, -OCi-C₆-alkyl, halo, -NH₂, -(Ci-C₆-alkyl)NH2, -C(O)OH, CN, and oxo.

C D

R and R are each independently selected from H and Ci-Ce-alkyl.

In some embodiments, R⁴ is selected from the group consisting of H, Ci-Cg-alkyl (optionally substituted by one or more halo, hydroxy or 3- to 14-membered heterocycloalkoxy (wherein 1-4 heterocycloalkoxy members are independently selected from N, O, and S)), -O(Ci-C6alkyl), -(Ci-C6-alkyl)NR^AR^B, and -NR^AR^B (wherein R^A and R^B are independently selected from H and Ci-Cô-alkyl); and R⁵ is selected from the group consisting of H, Ci-C6-alkyl, CiCe-alkoxy, and -NR^CR^D.

In other embodiments, at least one of R⁴ and R⁵ is H. For instance, R⁴ is H or R⁵ is H. Altematively, each of R⁴ and R⁵ is H.

Optionally in combination with any other embodiment herein described, various embodiments provide for a Formula I compound wherein R² is optionally substituted C6-Cioaryl or optionally substituted 5- to 10-membered heteroaryl. In one embodiment, R² is optionally substituted C6-Cio-aryl, such as optionally substituted phenyl. In another embodiment, R² is optionally substituted 5- to 10-membered heteroaryl, and wherein 1 ring member is N. For instance, R² is an optionally substituted 5- or 6-membered heteroaryl, or an optionally substituted 6-membered heteroaryl, an example of which is optionally substituted pyridyl.

In some embodiments, optionally in combination with any other described herein, R³ is optionally substituted 3- to 14-membered heterocycloalkyl or optionally substituted 5- to 10membered heteroaryl. Non-limiting examples of R³ are selected from the group consisting of benzothiazolyl, benzoisothiazolyl, benzoxazolyl, pyridinyl, pyridinonyl, pyridazinyl, benzimidazolyl, benzotriazolyl, indazolyl, quinoxalinyl, quinolinyl, quinazolinyl, imidazopyridinyl, pyrazolopyridinyl, triazolopyridinyl, cinnolinyl, isoxazolyl, pyrazolyl,

-1520638 benzofuranyl, dihydrobenzofuranyl, dihydrobenzodioxinyl, and tetrahydrobenzodioxinyl, each of which may be optionally substituted.

In other embodiments, R³ is optionally substituted Cg-Cjo-aryl. An example is optionally substituted phenyl.

The disclosure provides some Formula I compounds wherein R² is optionally substituted phenyl and R³ is optionally substituted 3- to 14-membered heterocycloalkyl or optionally substituted 5- to 10-membered heteroaryl.

In various embodiments, the disclosure provides a Formula I compound wherein L is O or NR. Further, in accordance with additional embodiments, R¹ is optionally substituted Ci-Cealkyl or optionally substituted Cs-Câ-carbocyclyl. An example of R^f is Cj-Cî-alkyl that is optionally substituted by 1-3 F.

A subset of Formula I compounds, according to an embodiment, are those in which L is O or NR and R is H; R¹ is Ci-Ch-alkyl that is optionally substituted by 1 - 3 F; R² is optionally substituted 3- to 14-membered heterocycloalkyl or optionally substituted 5- to 10-membered heteroaryl (wherein 1 heterocycloalkyl or heteroaryl member is N) or optionally substituted Cô-Cio-aryl; R³ is optionally substituted 3- to 14-membered heterocycloalkyl or optionally substituted 5- to 10-membered heteroaryl wherein 1 to 3 heterocycloalkyl or heteroaryl members are independently selected from N, O, and S; and each of R⁴ and R⁵ is H. In some embodiments, L is NR.

In various embodiments, the disclosure provides spécifie examples of Formula I compounds, and their pharmaceutically acceptable salts, tautomers, and/or isotopologues as set forth in Table 1 below:

Table 1

-1620638

102	cf3 N^O^C η f2 0 ochf2	160	LL? Ο ζχ \ / LL \—1 ,—, r 'ζ 1
103	λ—λ Αζ α~\ 7—<χ ζ - \__/ y // ζ /) \\ // ΖΖ J	161	An. .* ν d3 0 ochf2
104	Ν' A 0 ocf3	162	Am ,Λ 0 f N N 1 H ochf2
105	» LU X Ο < ο <Wz cm \ , Ll \___/ .___. X ο y ζ V—ά β— Ο ζ—Ζ Ρ ° Ο φ S	163	—N | 1 A/1 ochf2
106	CM υ_ I Ο < ο f^z \___/ , , φ Άλ ΑΛ Ζ 7--(\ 0— Ο A ζ	164	0 ochf2
107	CM LL Τ Ο < ο 'Η/^Χ/Ι ίΓ 'ζ	165	LL LL V w \___( ,___, X + A /^\ o ° 0” 'z 1

108	CM LL T O < O \__/ ____ O H' 'z 1	166	—N ] ] 0Z^Zxn<^0^CHF2 ochf2
109	0 ocf3	167	0 ochf2
110	—N ] | U^'n'B:A qZxZ'· 0 ocd3	168	J Λ—Λ /--T _ \_/ A // Z 0 O )
111	N¾^ÏZ ’°Χη 0 ochf2	169	ω^ζ G /~z O—/ x)—G z o \_/ Z // 1 — /—\ 171 O > O
112	s CD .U A=/y^ yj O )	170	νθ o \__/ A // i '— )—( J1 Z h O > O “Π M
113	λΑ C/AZG r Z 1	171	1 Ta o fr—0 z O—A A-G Z o \_/ A 0 I --- )---< -/ \ ΓΌ ^ // // O > O ΞΓ K>

-1820638

-1920638

120	—N ] | O^ y'' hTO^ ochf2	178	ιψό^'ύ' F F Q ochf2
121	O—F V—(\ 2 O / V, // T] ---f )----( ω / \ C)	179	o \ / A // I --- ) \ Π -/ \ O Tl— T|
122	MeO.,^. o,.. ο^'γ n^o^ fil ochf2	180	N'^î^xN'N%/% 1 xÿkxi>L Jx x^\xF n ο γ F M ochf2
123	cO LL. O O <\~^z /y-yy! » Z 1	181	C^y^N^Q^Y'F F ochf2
124	-Aaq Ο^γ ’ N^O^CH F2 Cl	182	zyyys ϋ ' 2 ,z Z 1
125	—N | | cry^ n^o^chf2 ochf2	183	✓ N./¾. OCÇn^q F M ochf2

-2020638

126	LL? X Ο < ο \ / u- ίΓ 'ζ 1	184	fi °——4 Λ ο \__/ XX_ χ — /—X -π _/ \ Μ
127	ζ Ζ—Λ ν—ζ ο—/—\\ 2 τ \=/ ο )	185	fi 0^4^—4 Λ ο \__/ χχ__// a: — )—\ -Π -fi \ u yfi ο 4 “Π
128	J o—fi~\—4 Λ ° ζ=/ y f ο > ο τ J1	186	ω^ζ Ο fi=J f,—λ y—2 ° —A fi ο \_J XX // τ — )—X Π V \ ο ΤΙ--
129	□? ο < ο <4 - \ , ΟΧ___/ ,___, I ω % 44^° ίΓ 'ζ 1	187	LL --LL Ο /Ο « X / ll ^\χ /^χ ΰ fi^ Ο\
130	J φ 2 /\ yj ο > ο X Π Νί	188	^ν'νΠ il F ochf2
131	Ϋ 0^'V^'N 'σ 0 ochf2	189	0 H U- -N^ N ' y /L F ochf2

-2120638

132	-CQ,n 0<AAnA0x^cf3 ochf2	190	LL r O /“4 c. \ / zyy^y§ P” ° O
133	(N LL X O O (jC QO r 'z 1	191	'a-Yï N^'O^y F Q ochf2
134	CM LL X O O fS ---<Λ Z r 'z 1	192	ÇO^ry^ N^o^yF A. F Q ochf2
135	g CD O v0 λ—λ y—z o-(p—A Λ o \__/ w_// X ) \ Tl ' \ “ yj cf	193	H N^, - 1Ύ1 n'o^y F Il F ochf2
136	A-v, Ο ΐίγ^ n ' ^o'^ Γη ocf3	194	J O \__/ A // “Π -/ \ Ο -Π O X M
137	N^'O^'y 0 ochf2	195	N\>X^ÿ>L F - N yy O<i'''y'N>''O''''· 0 ochf2

-2220638

138	Ο^^γ'N ' 0 ochf2	196	qAAAA nAx n 1 H 0 OCHF2
139	J O—Z 8 z=/>Y ω -A \ O > O I M	197	J °—Λ O \__/ \_// I -- Z--\ “Π -y \ Vf 12 “Π > O GJ '
140	CM U. I O O Q r Z 1	198	—N ] ] NÎ^O'X^ ô Br
141	N=s/% OCHF2	199	C \ AvJ^œ H ’Z. 1
142	THPO. ’^Ά 0^'^' n^0^CHF2 OCHFZ	200	ol T Q < O €az r 'z 1
143	(Α·η ., F o'^r n 0 y F 0 Ci	201	ΓΜ LL. X 0 O c$ Q

-2320638

-2420638

150	b ο U Z 1	208	LL? T Q < O \ “ LX. X___/ ,____ x O %. O \ Jib a ° HL z \ 1 '
151	V T b D—/=\ /Z z n \\ // O b Π	209	H0\ —n || | 0^%^ N^O^CHFï ochf2
152	1 Z J /--V V-Z ° T) O b	210	CM U. X O < O CM / ll ,----( x TV z ll? X____( ,____, x FA /^\ ΰ r Z 1
153	b O r 'z 1	211	1 yP ο—V v—4 z \ O \-/ \_// \ 1 '—X /Z— /T— O > O X M
154	n^cf, 1 H 3 Cl	212	J o—bb—b z O \_/ A_y T — )—K hd^ Z /)--Z V // x /----/ O > O X ro
155	^ZI bz tbCX0 r 'z 1	213	CM LL· X O < p A X___/ co F\\ _ s Z V— ΞΞΖ --1β” z 1

-2520638

156	IX I O < ZI tHo^3 r Z 1	214	L C d 1
U 1	N U Unr2
157	—N 7 ] ô ocd3	215	-CQ - N 1 HN-	1
158	0 ochf2	216	CM LU T O O /Y - \ / ll )—( /—, =E 0 ° O
		217	0AA 0 ochf2

In other varions embodiments, the disclosure provides additional spécifie examples of Formula I compounds, and their pharmaceutically acceptable salts, tautomers, and/or isotopologues as set forth in Table 2 below.

Table 2

-2620638

-2720638

-2820638

Pharmaceutical Composition

-2920638

The disclosure also provides a pharmaceutical composition comprising a therapeutically effective amount of one or more compounds according to Formula I or a pharmaceutically acceptable sait, stereoisomer, tautomer, and/or isotopologue, in admixture with a pharmaceutically acceptable carrier. In some embodiments, the composition further contains, in accordance with accepted practices of pharmaceutical compounding, one or more additional therapeutic agents, pharmaceutically acceptable excipients, diluents, adjuvants, stabilizers, emulsifiers, preservatives, colorants, buffers, flavor imparting agents.

In one embodiment, the pharmaceutical composition comprises a compound selected from those illustrated in Table 1 or a pharmaceutically acceptable sait, stereoisomer, tautomer, and/or isotopologue thereof, and a pharmaceutically acceptable carrier.

The pharmaceutical composition of the présent disclosure is formulated, dosed, and administered in a fashion consistent with good medical practice. Factors for considération in this context include the particular disorder being treated, the particular subject being treated, the clinical condition of the subject, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners.

The “therapeutically effective amount” of a compound (or a pharmaceutically acceptable sait, stereoisomer, tautomer, and/or isotopologue thereof that is administered is govemed by such considérations, and is the minimum amount necessary to exert a cytotoxic effect on a cancer, or to inhibit MAT2A activity, or both. Such amount may be below the amount that is toxic to normal cells, or the subject as a whole. Generally, the initial therapeutically effective amount of a compound (or a pharmaceutically acceptable sait, stereoisomer, or tautomer thereof) of the présent disclosure that is administered is in the range of about 0.01 to about 200 mg/kg or about 0.1 to about 20 mg/kg of patient body weight per day, with the typical initial range being about 0.3 to about 15 mg/kg/day. Oral unit dosage forms, such as tablets and capsules, may contain from about 1 mg to about 1000 mg of a compound (or a pharmaceutically acceptable sait, stereoisomer, or tautomer thereof) of the présent disclosure. In another embodiment, such dosage forms contain from about 50 mg to about 500 mg of a compound (or a pharmaceutically acceptable sait, stereoisomer, or tautomer thereof) of the présent disclosure. In yet another embodiment, such dosage forms contain from about 25 mg to about 200 mg of a compound (or a pharmaceutically acceptable sait, stereoisomer, or tautomer thereof) of the présent disclosure. In still another embodiment, such dosage forms contain from about 10 mg to about 100 mg of a compound (or a pharmaceutically acceptable sait, stereoisomer, or tautomer thereof) of the présent disclosure. In a further embodiment

-3020638 such dosage forms contain from about 5 mg to about 50 mg of a compound (or a pharmaceutically acceptable sait, stereoisomer, or tautomer thereof) of the présent disclosure.

The compositions can be administered orally, topically, parenterally, by inhalation or spray or rectally in dosage unit formulations. The term parentéral as used herein includes subcutaneous injections, intravenous, intramuscular, intrastemal injection or infusion techniques.

Suitable oral compositions in accordance with the disclosure include without limitation tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, émulsion, hard or soft capsules, syrups or élixirs.

Encompassed within the scope of the disclosure are pharmaceutical compositions suitable for single unit dosages that comprise a compound of the disclosure or its pharmaceutically acceptable stereoisomer, sait, or tautomer and a pharmaceutically acceptable carrier.

Compositions suitable for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions. For instance, liquid formulations of the compounds contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically palatable préparations of the MAT2A inhibitor.

For tablet compositions, a compound of the présent disclosure in admixture with non-toxic pharmaceutically acceptable excipients is used for the manufacture of tablets. Examples of such excipients include without limitation inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnésium stéarate, stearic acid or talc. The tablets may be uncoated or they may be coated by known coating techniques to delay disintegration and absorption in the gastrointestinal tract and thereby to provide a sustained therapeutic action over a desired time period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.

Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingrédient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingrédient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.

For aqueous suspensions, a compound of the présent disclosure is admixed with excipients suitable for maintaining a stable suspension. Examples of such excipients include without

-3120638 limitation are sodium carboxymethylcellulose, methylcellulose, hydropropylmethyl cellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia.

Oral suspensions can also contain dispersing or wetting agents, such as naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stéarate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example, heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived ffom fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

Oily suspensions may be formulated by suspending a compound of the présent disclosure in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a minerai oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol.

Sweetening agents such as those set forth above, and flavoring agents may be added to provide palatable oral préparations. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for préparation of an aqueous suspension by the addition of water provide a compound of the présent disclosure in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be présent.

Pharmaceutical compositions of the présent disclosure may also be in the form of oil-inwater émulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a minerai oil, for example liquid paraffin or mixtures of these, Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The émulsions may also contain sweetening and flavoring agents.

-3220638

Syrups and élixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, and flavoring and coloring agents. The pharmaceutical compositions may be in the form of a stérile injectable, an aqueous suspension or an oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which hâve been mentioned above. The stérile injectable préparation may also be stérile injectable solution or suspension in a non-toxic parentally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer’s solution and isotonie sodium chloride solution. In addition, stérile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use in the préparation of injectables.

The compounds of general Formula I may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary températures but liquid at the rectal température and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.

Compositions for parentéral administrations are administered in a stérile medium. Depending on the vehicle used and concentration the concentration of the drug in the formulation, the parentéral formulation can either be a suspension or a solution containing dissolved drug. Adjuvants such as local anesthetics, preservatives and buffering agents can also be added to parentéral compositions.

Methods of Use

The MAT2A enzyme catalyzes the synthesis of S-adenosyl méthionine (SAM) from méthionine and ATP in cells. Accordingly, in another embodiment of the présent disclosure there is provided a method of inhibiting in a cell the synthesis of SAM comprising introducing into the cell an effective amount of a compound of Formula I or a pharmaceutically acceptable sait, stereoisomer, tautomer, and/or isotopologue thereof. In an embodiment, the cell is in a subject. In some embodiments, a Formula I compound is used to identify other compounds that are inhibitors of MAT2A, for example, in a compétition assay for binding to MAT2A or for the inhibition of SAM production. Binding to MAT2A or the

-3320638 inhibition of SAM production by a test compound having a détectable label can be measured with and without the presence of an unlabeled compound of the présent disclosure.

The présent disclosure also provides a method for treating a cancer in a subject suffering therefrom, comprising administering to the subject an effective amount of a MAT2A inhibitor compound as described herein. In some embodiments, the MAT2A inhibitor is a compound of Formula I or a pharmaceutically acceptable sait thereof. In an embodiment, optionally in combination with any other embodiment, the subject is a mammal, such as a human.

In an embodiment, the cancer is an MTAP-deleted cancer. In some embodiments, the cancer as one selected from the group consisting of mesothelioma, neuroblastoma, intestine carcinoma such as rectum carcinoma, colon carcinoma, familiary adenomatous polyposis carcinoma and hereditary non-polyposis colorectal cancer, esophageal carcinoma, labial carcinoma, larynx carcinoma, hypopharynx carcinoma, tongue carcinoma, salivary gland carcinoma, gastric carcinoma, adeno carcinoma, medullary thyroidea carcinoma, papillary thyroidea carcinoma, rénal carcinoma, kidney parenchym carcinoma, ovarian carcinoma, cervix carcinoma, uterine corpus carcinoma, endometrium carcinoma, chorion carcinoma, pancreatic carcinoma, prostate carcinoma, bladder carcinoma, testis carcinoma, breast carcinoma, urinary carcinoma, melanoma, brain tumors, head and neck cancer, lymphoma, acute lymphatic leukemia (ALL), chronic lymphatic leukemia (CLL), acute myeloîd leukemia (AML), chronic myeloid leukemia (CML), hepatocellular carcinoma, gall bladder carcinoma, bronchial carcinoma, small cell lung carcinoma (SCLC), non-small cell lung carcinoma (NSCLC), multiple myeloma (MM), basalioma, teratoma, retinoblastoma, choroidea melanoma, seminoma, rhabdomyo sarcoma, osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma, Ewing sarcoma, and plasmocytoma.

In other embodiments, the cancer is selected from lung cancer, non-small cell lung cancer, bronchioloalviolar cell lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal région, stomach cancer, gastric cancer, colon cancer, breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine System, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the pénis, prostate cancer, cancer of the bladder, cancer of the kidney or ureter, rénal cell carcinoma, carcinoma of the rénal pelvis,

-3420638 mesothelioma, hepato cellular cancer, biliary cancer, chronic or acute leukemia, lymphocytic lymphoma, neoplasms of the central nervous System (CNS), spinal axis tumors, brain stem glioma, glioblastoma multiforme, astrocytomas, schwannomas, ependymomas, medulloblastomas, meningiomas, squamous cell carcinomas, pituitary adenomas, including résistant and/or refractory versions of any of the above cancers, and a combination of one or more of the above cancers.

In some embodiments, the cancer is selected from the group consisting of B-cell acute lymphocytic leukemia (B-ALL), mesothelioma, lymphoma, pancreatic carcinoma, lung cancer, gastric cancer, esophageal cancer, bladder carcinoma, brain cancer, head and neck cancer, melanoma and breast cancer.

In other embodiments the lung cancer is non-small cell lung cancer, small cell lung cancer, adenocarcinoma of the lung, and squamous cell carcinoma of the lung.

In other embodiments the breast cancer is triple négative breast cancer (TNBC).

In other embodiments, the brain cancer is a brain tumor selected from the group consisting of glioma, glioblastoma, astrocytoma, meningioma, medulloblastoma, peripheral neuroectodermal tumors, and craniopharyngioma.

In still other embodiments, the cancer is a lymphoma selected from the group consisting of mantle cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, Burkitt lymphoma, diffuse large B-cell lymphoma (DLBCL), and adult T-cell leukemia/lymphoma (ATLL). As used herein, the expression adult T-cell leukemia/lymphoma refers to a rare and often aggressive T-cell lymphoma that can be found in the blood (leukemia), lymph no des (lymphoma), skin, or multiple areas of the body.

As described generally above, methylthioadenosine phosphorylase (MTAP) is an enzyme found in ail normal tissues that catalyzes the conversion of methylthioadenosine (MTA) into adenine and 5-methylthioribose-l-phosphate. The adenine is salvaged to generate adenosine monophosphate, and the 5-methylthioribose-l-phosphate is converted to méthionine and formate. Because of this salvage pathway, MTA can serve as an alternative purine source when de novo purine synthesis is blocked, e.g., with antimetabolites, such as L-alanosine. Many human and murine malignant cells lack MTAP activity. MT AP deficiency is not only found in tissue culture cells but the deficiency is also présent in primary leukemias, gliomas, melanomas, pancreatic cancers, non-small cell lung cancers (NSCLC), bladder cancers, astrocytomas, osteosarcomas, head and neck cancers, myxoid chondrosarcomas, ovarian cancers, endométrial cancers, breast cancers, soft tissue sarcomas, non-Hodgkin lymphomas,

-3520638 and mesotheliomas. For example, prolifération of cancer cells that are MTAP null, i.e., MTAP-deleted, is inhibited by knocking down MAT2A expression with shRNA which was confirmed using small molécule inhibitors of MAT2A. K. Marjon et al., Cell Reports 15 (2016) 574-587, incorporated herein by référencé. An MTAP null or MTAP-deleted cancer is a cancer in which the MTAP gene has been deleted or lost or otherwise deactivated or a cancer in which the MTAP protein has a reduced or impaired function, or a reduced presence. j

Accordingly, in an embodiment of the présent disclosure there is provided a method for treating a cancer in a subject wherein the cancer is characterized by a réduction or absence of MTAP expression or absence of the MTAP gene or reduced function of MTAP protein as compared to cancers where the MTAP gene and/or protein is présent and fully functioning, or as compared to cancers with the wild type MTAP gene. The method comprises administering to the subject a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable sait, tautomer, and/or isotopologue thereof.

In another embodiment, there is provided a method of treating an MTAP deleted cancer in a subject comprising administering to the subject an effective amount of a compound of Formula I or a pharmaceutically acceptable sait thereof. In an embodiment, the MTAP deleted cancer is selected from leukemia, glioma, melanoma, pancreatic cancer, non-small cell lung cancer (NSCLC), bladder cancer, astrocytoma, osteosarcoma, head and neck cancer, myxoid chondrosarcoma, ovarian cancer, endométrial cancer, breast cancer, soft tissue sarcoma, lymphoma, and mesothelioma.

In an embodiment, the MTAP deleted cancer is pancreatic cancer. In another embodiment, the MTAP deleted cancer is selected from bladder cancer, melanoma, brain cancer, lung cancer, pancreatic cancer, breast cancer, liver cancer, esophageal cancer, gastric cancer, colon cancer, head and neck cancer, kidney cancer, colon cancer, diffuse large B cell lymphoma (DLBCL), acute lymphoblastic leukemia (ALL), mantle cell lymphoma (MCL), glioblastoma multiforme (GBM), and non-small cell lung cancer (NSCLC).

Genomic analysis of MTAP null cell lines revealed that cell Unes incorporating a KRAS mutation or a p53 mutation were sensitive to MAT2A inhibition. Accordingly, an embodiment of the présent disclosure provides a method for treating a cancer in a subject wherein the cancer is characterized by réduction or absence of MTAP expression or absence of the MTAP gene or reduced function of MTAP protein, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula I, wherein said cancer is further characterized by the presence of mutant KRAS or mutant p53.

i

-3620638

In an embodiment, there is provided a method of treating an MT AP null cancer having a mutant KRAS or mutant p53 in a subject, comprising administering to the subject an effective amount of a compound of Formula I or a pharmaceutically acceptable sait, tautomer, and/or isotopologue thereof. For example, the cancer is MT AP null and KRAS mutant, MTAP null and p53 mutant, or each of MTAP null, KRAS mutant and p53 mutant.

The term “mutant KRAS” or “KRAS mutation” refers to a KRAS protein incorporating an activating mutation that alters its normal fonction and the gene encoding such a protein. For example, a mutant KRAS protein may încorporate a single amino acid substitution at position 12 or 13. In a particular embodiment, the KRAS mutant incorporâtes a G12X or G13X substitution, wherein X represents any amino acid change at the indicated position. In a particular embodiment, the substitution is G12V, G12R, G12C or G13D. In another embodiment, the substitution is G13D. By “mutant p53” or “p53 mutation” is meant p53 protein (or gene encoding said protein) incorporating a mutation that inhibits or éliminâtes its tumor suppressor function. In an embodiment, said p53 mutation is, Y126_splice, K132Q, M133K, R174fs, R175H, R196*, C238S, C242Y, G245S, R248W, R248Q, I255T, D259V, S261_splice, R267P, R273C, R282W, A159V or R280K. In an embodiment, the foregoing cancer is non-small cell lung cancer (NSCLC), pancreatic cancer, head and neck cancer, gastric cancer, breast cancer, colon cancer or ovarian cancer.

In another embodiment, the compounds disclosed herein are usefol as ligands for dégradation of disease-associated proteins. An example of this approach is PROTACs (PROteolysis TArgeting Chimeras). PROTACs are bifonctional molécules that comprise both a ligand moiety selected from one of the compounds disclosed herein, which is capable of binding the target protein, and a ligase targeting moiety, such as a peptide portion (referred to as the degron) that is recognized and polyubiquitinated by E3 ligase. Thus, the PROTAC noncovalently binds to a target protein, and recruits E3 ligase via the degron, which results in polyubiquination and dégradation of the bound target. A number of publications describe the pre-clinical use of PROTACs in a variety of therapeutic areas including oncology. See, e.g., Lu et al. Chemistry <è Biology 22 (2015) 755-763.

ASPECTS

Aspect 1. A compound according to Formula I:

-3720638 wherein

L is O, S, NR, or a bond;

R is H or Ci-C₆-alkyl;

R¹ is selected from the group consisting of C]-C₆-alkyl, C₂-C₆-alkenyl, C₃-C₆-carbocyclyl, (Ci-C₆-alkyl)(C₃-C6-carbocyclyl), and -(Ci-C6-alkyl)(C₃-C6-cycloalkenyl) wherein any alkyl in R¹ is straight or branched, and

R¹ is optionally substituted by 1 - 6 halo;

or when L is NR, then R and R¹ in combination with L represent a 3- to 6-membered heterocycloalkyl (wherein 1-4 ring members are independently selected from N, O, and S) optionally substituted by one or more R^A;

R² and R³ are independently selected from the group consisting of C₆-Cio-aryl, C₃-C₆carbocyclyl, 5- to 10-membered heteroaryl (wherein 1-4 heteroaryl members are independently selected from N, O, and S), and 3- to 14-membered heterocycloalkyl (wherein 1-4 heterocycloalkyl members are independently selected from N, O, and S), wherein R and R are independently and optionally substituted by one or more substituents that are selected from the group consisting of R^A, OR^A, halo, -N=N- R^A, NR^AR^B, -(Ci-C₆alkyl)NR^AR^B, -C(O)OR^A, -C(O)NR^AR^B, -OC(O)R^A, and -CN;

R⁴ is selected from the group consisting of H, Ci-C₆-alkyl (optionally substituted by one or more halo), -O(Ci-C6-alkyl) (optionally substituted by one or more halo), -OH, halo, CN, -(Ci-C₆-alkyl)NR^AR^B, and -NR^AR^B;

R⁵ is selected from the group consisting of H, Ci-C₆-alkyl, Ci-C₆-alkoxy, C₂-C₆-alkenyl, C₂C₆-alkynyl, halo, -CN, and -NR^CR^D;

R^a and R^b are independently selected from the group consisting of H, -CN, -hydroxy, oxo, Ci-C₆-alkyl, C_rC₆-alkoxy, C₂-C₆-alkenyl, C₂-C₆-alkynyl, -NH₂, -S(O)₀.₂-(Ci-C6-alkyl), S(0)o-₂-(C₆-Cio-aryl), -C(O)(Ci-C₆-alkyl), -C(O)(C₃-Ci₄-carbocyclyl), -C₃-Ci₄carbocyclyl, -(Ci-C6-alkyl)(C₃-Ci₄-carbocyclyl), Ce-Cio-aryl, 3- to 14-membered heterocycloalkyl and -(C]-C6-alkyl)-(3- to 14-membered heterocycloalkyl) (wherein 1-4 heterocycloalkyl members are independently selected from N, O, and S), and 5- to 10membered heteroaryl (wherein 1-4 heteroaryl members are independently selected from N, O, and S);

wherein each alkyl, alkoxy, alkenyl, alkynyl, aryl, carbocyclyl, heterocycloalkyl, and heteroaryl moiety of R^A and R^B is optionally substituted with one or more substituents

-3820638 selected from the group consisting of hydroxy, halo, -NR’₂ (wherein each R’ is independently selected from the group consisting of Ci-Cô-alkyl, CS-Cg-alkenyl, C₂-C6alkynyl, C₆-Ci₀-aryl, 3- to 14-membered heterocycloalkyl and -(Ci-C₆-alkyl)-(3- to 14membered heterocycloalkyl) (wherein 1-4 ring members are independently selected from N, O, and S), and 5- to 10-membered heteroaryl (wherein 1-4 heteroaryl members are independently selected from N, O, and S), -NHC(O)(OCi-C6-alkyl), -NO₂, -CN, oxo, -C(O)OH, -C(O)O(Ci-C₆-alkyl), -Ci-C₆-alkyl(Ci-C₆-alkoxy), -C(0)NH₂, Ci-C₆alkyl, -QOjCj-Ce-alkyl, -OCi-C₆-alkyl, -Si(Ci-C₆-alkyl)₃, -S(0)o-2-(Ci-C₆-alkyl), C₆-Ci₀aryl, -(Ci-C6-alkyl)(Câ-Cjo-aryl), 3- to 14-membered heterocycloalkyl, and -(Ci-Céalkyl)-(3- to 14-membered heterocycle) (wherein 1-4 heterocycle members are independently selected from N, O, and S), and -O(C6-Ci₄-aryl), wherein each alkyl, alkenyl, aryl, and heterocycloalkyl in R^A and R^B is optionally substituted with one or more substituents selected from the group consisting of hydroxy, -OC]-C₆-alkyl, halo, NH₂, -(Ci-C₆-alkyl)NH₂, -C(O)OH, CN, and oxo,

R and R are each independently selected from H and Ci-C₍₁-alkyl;

or a pharmaceutically acceptable sait thereof.

Aspect 2. The compound according to Aspect 1, wherein

R⁴ is selected from the group consisting of H, Ci-C₆-alkyl optionally substituted by one or more halo, -O(Ci-C₆-alkyl), -(Ci-C₆-alkyl)NR^AR^B, and -NR^AR^B (wherein R^A and R^B are independently selected from H and Ci-Cô-alkyl); and

R⁵ is selected from the group consisting of H, Ci-C₆-alkyl, Ci-C₆-alkoxy, and -NR^CR^D.

Aspect 3. The compound according to Aspect 1 or 2, wherein at least one of R⁴ and R⁵ is H.

Aspect 4. The compound according to any one of Aspects 1-3, wherein R⁴ is H.

Aspect 5. The compound according to any one of Aspects 1 - 4, wherein R⁵ is H.

Aspect 6. The compound according to any one of Aspects 1-5, wherein each of R⁴ and R⁵ is

H.

Aspect 7. The compound according to any one of Aspects 1 to 6, wherein R² is Cô-Cio-aryl or 5- to 10-membered heteroaryl.

Aspect 8. The compound according to Aspect 7, wherein R² is Ce-CiQ-aryl.

Aspect 9. The compound according to Aspect 8, wherein R² is phenyl.

-3920638

Aspect 10. The compound according to Aspect 7, wherein R² is 5- to 10-membered heteroaryl, and wherein 1 ring member is N.

Aspect 11. The compound according to Aspect 10, wherein R² is a 5- or 6-membered heteroaryl.

Aspect 12. The compound according to Aspect 10 or 11, wherein R² is a 6-membered heteroaryl.

Aspect 13. The compound according to any one of Aspects 10-12, wherein R² is pyridyl. Aspect 14. The compound according to any one of Aspects 1 to 12, wherein R³ is 3- to 14membered heterocycloalkyl or 5- to 10-membered heteroaryl.

Aspect 15. The compound according to Aspect 14, wherein R³ is selected from the group consisting of benzothiazolyl, benzoisothiazolyl, benzoxazolyl, pyridinyl, pyridinonyl, pyradazinyl, benzimidazolyl, benzotriazolyl, indazolyl, quinoxalinyl, quinolinyl, quinazolinyl, imidazopyridinyl, pyrazolopyridinyl, triazolopyridinyl, cinnolinyl, isoxazolyl, pyrazolyl, benzofuranyl, dihydrobenzofuranyl, dihydrobenzodioxinyl, and tetrahydrobenzodioxinyl.

Aspect 16. The compound according to any one of Aspects 1 to 12, wherein R is Cg-Cioaryl.

Aspect 17. The compound according to Aspect 16, wherein R³ is phenyl.

Aspect 18. The compound according to any one of Aspects 1 to 6, wherein R² is phenyl and R³ is 3- to 14-membered heterocycloalkyl or 5- to 10-membered heteroaryl.

Aspect 19. The compound according to any one of Aspects 1 to 18, wherein L is O or NR.

Aspect 20. The compound according to Aspect 19, wherein R¹ is Ci-Cô-alkyl or C₃-C6carbocyclyl.

Aspect 21. The compound according to Aspect 19 or 20, wherein R¹ is Ci-C₃-alkyl that is optionally substituted by 1 - 3 F.

Aspect 22. The compound according to Aspect 1, wherein

L is O or NR and R is H;

R¹ is Ci-C₃-alkyl that is optionally substituted by 1 - 3 F;

R² is 3- to 14-membered heterocycloalkyl or 5- to 10-membered heteroaryl (wherein 1 heterocycloalkyl or heteroaryl member is N) or Cg-Cio-aryl;

-4020638

R³ is 3- to 14-membered heterocycloalkyl or 5- to 10-membered heteroaryl wherein 1 to 3 heterocycloalkyl or heteroaryl members are independently selected from N, O, and S; and each of R⁴ and R⁵ is H.

Aspect 23. The compound according to Aspect 22, wherein L is NR.

Aspect 24. The compound according to Aspect 1, wherein the compound is selected from the folio wing table:

-4120638

-4220638

-4320638

118	η LL Ο < ο ΑΑ ΑΑ ϋ Ρ ° Ο φ
119	; ο )
120	—Ν ] 1 , 0A A (A^cA'''' (il ochf2
121	Ν^·'ΌΧ\ ρΐΐ Α,Ν ocf3
122	( ο ΑΑ v Ζ ™ \ 7 LL. 0 ° Ο φ
123	<ο LL Ο Ο Æ Ν \ / U- \___/ ,___„ X ΑΑ ΑΑ ° ζ 0—\ 0— ο A ζ 1

176	0 À oyyy > X ' )—\ -π _Λ \ Μ yj Ο 4
177	ÇXX-ny%. 0ΑγΑ Ν·ίΑοηχ^ F 4% f V ochf2
178	Ο'Α+ <44^ 4 ^f N 0 γ ιΊ F ochf2
179	Y o \.__/ y // x — )—\ J1 z \ O A “Π
180	' ΐ4ίί4 4 O^Y N 0 y f Q ochf2
181	4Χ·γγ N^O^Y F ιΊ f ochf2

-4420638

124	n^O^CHFz Cl
125	J ,—\ y—z O—Z X /—\ ΊΊ ™ \ M yj O > O I hd^
126	0^''γχΝ^ A ochf2
127	j cY 7—Γ z Z Λ w // O )
128	N^^ïs (τγ n^o^c h f2 A 'γ N ocf3
129	^J X O < O /A \ / u- \___/ ,___, X Xp-T Y Z 1

182	zK » /=\ Y^ O Y ύ-ά Z O y. Y Y_Λ X '--- )--\ π V \ M yj a 4
183	N^O'^y F .À F Q ochf2
184	NVN^ ,Ν^ζκ N y y erY^ Ν^ο^γ F F V ochf2
185	H ^Ν'ΎΊί Ο'^γ^ Ν^Ο^γ F F M ochf2
186	Z X s n γη Ο^^γ^ Ν^Ο'^γ F F 0 ochf2
187	'o λ—λ y^-^· ° \^/—X Λ o \_/ w_ T ) \ ΠΊ -/ \ “ Y? o 4 ΊΊ

-4520638

-4620638

-4720638

-4820638

-4920638

Aspect 25. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of Aspects 1 to 24 or a pharmaceutically acceptable sait thereof, and a pharmaceutically acceptable carrier.

-5020638

Aspect 26. A method for treating a cancer in a subject suffering therefrom, comprising administering to the subject an effective amount of a MAT2A inhibitor compound according to any one of Aspects 1 - 24.

Aspect 27. The method according to Aspect 26, wherein the cancer is an MTAP-deleted cancer.

Aspect 28. A method for inhibiting the synthesis of S-adenosyl méthionine (SAM) in a cell, comprising introducing into the cell an effective amount of a compound, or a pharmaceutically acceptable sait thereof, according to any one of Aspects 1 to 24.

Aspect 29. The method according to Aspect 28, wherein the cell is in a subject.

Aspect 30. A method for inhibiting the synthesis of S-adenosyl méthionine (SAM) in a subject, comprising administering to the subject an effective amount of at least one compound or a sait thereof according to any one of Aspects 1 to 24.

Aspect 31. A method for treating a cancer in a subject suffering therefrom, comprising administering to the subject an effective amount of a compound according to any one of Aspects 1 to 24.

Aspect 32. The method according to Aspect 31, wherein the cancer is an MTAP-deleted cancer.

Aspect 33. The method according to any one of Aspects 26, 27, 31, and 32, wherein the cancer is selected from the group consisting of mesothelioma, neuroblastoma, rectum carcinoma, colon carcinoma, familiary adenomatous polyposis carcinoma and hereditary non-polyposis colorectal cancer, esophageal carcinoma, labial carcinoma, larynx carcinoma, hypopharynx carcinoma, tongue carcinoma, salivary gland carcinoma, gastric carcinoma, adenocarcinoma, medullary thyroidea carcinoma, papillary thyroidea carcinoma, rénal carcinoma, kidney parenchym carcinoma, ovarian carcinoma, cervix carcinoma, uterine corpus carcinoma, endometrium carcinoma, chorion carcinoma, pancreatic carcinoma, prostate carcinoma, bladder carcinoma, testis carcinoma, breast carcinoma, urinary carcinoma, melanoma, brain tumors, lymphoma, head and neck cancer, acute lymphatic leukemia (ALL), chronic lymphatic leukemia (CLL), acute myeloid leukemia (AML), chronîc myeloid leukemia (CML), hepatocellular carcinoma, gall bladder carcinoma, bronchial carcinoma, small cell lung carcinoma, non-small cell lung carcinoma, multiple myeloma, basalioma, teratoma, retinoblastoma, choroidea melanoma, seminoma, rhabdomyo sarcoma, osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma, Ewing sarcoma, and plasmocytoma.

-5120638

Aspect 34. The method according to Aspect 31 or 32, wherein the cancer is selected from the group consisting of B-cell acute lymphocytic leukemia (B-ALL), mesothelioma, lymphoma, pancreatic carcinoma, lung cancer, gastric cancer, esophageal cancer, bladder carcinoma, brain cancer, head and neck cancer, melanoma, and breast cancer.

Aspect 35. The method according to Aspect 34, wherein the cancer is a lung cancer selected from the group consisting of non-small cell lung cancer, small cell lung cancer, adenocarcinoma of the lung, and squamous cell carcinoma of the lung.

Aspect 36. The method according to Aspect 34, wherein cancer is a brain tumor selected from the group consisting of glioma, glioblastoma, astrocytoma, meningioma, medulloblastoma, peripheral neuroectodermal tumors, and craniopharyngioma.

Aspect 37. The method according to Aspect 34, wherein the cancer is triple négative breast cancer (TNBC).

Aspect 38. The method according to Aspect 34, wherein the cancer is a lymphoma selected from the group consisting of mantle cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, Burkitt lymphoma, diffuse large B-cell lymphoma, and adult T-cell leukemia/lymphoma.

Aspect 39. A method for treating a cancer in a subject suffering therefrom, wherein the cancer is characterized by a réduction or absence of methylthioadenosine phosphorylase (MTAP) gene expression, the absence of the MTAP gene, or reduced function of MTAP protein, as compared to cancers where the MTAP gene or protein is présent and/or fully functioning, the method comprising administering to the subject a therapeutically effective amount of a compound, or a pharmaceutically acceptable sait thereof, according to any one of Aspects 1 to 24.

Aspect 40. A compound according to any one of Aspects 1 to 24, or a pharmaceutically acceptable sait thereof, for inhibiting the synthesis of S-adenosyl méthionine (SAM).

Aspect 41. A compound according to any one of Aspects 1 to 24, or a pharmaceutically acceptable sait thereof, for treating a cancer in a subject suffering therefrom.

Aspect 42. The compound according to Aspect 41, wherein the cancer is an MTAP-deleted cancer.

Aspect 43. The compound according to Aspect 41 or 42, wherein the cancer is selected from the group consisting of mesothelioma, neuroblastoma, rectum carcinoma, colon carcinoma, familiary adenomatous polyposis carcinoma and hereditary non-polyposis colorectal cancer,

-5220638 esophageal carcinoma, labial carcinoma, larynx carcinoma, hypopharynx carcinoma, tongue carcinoma, salivary gland carcinoma, gastric carcinoma, adenocarcinoma, medullary thyroidea carcinoma, papillary thyroidea carcinoma, rénal carcinoma, kidney parenchym carcinoma, ovarian carcinoma, cervix carcinoma, uterine corpus carcinoma, endometrium carcinoma, chorion carcinoma, pancreatic carcinoma, prostate carcinoma, bladder carcinoma, testis carcinoma, breast carcinoma, urinary carcinoma, melanoma, brain tumors, lymphoma, head and neck cancer, acute lymphatic leukemia (ALL), chronic lymphatic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), hepatocellular carcinoma, gall bladder carcinoma, bronchial carcinoma, small cell lung carcinoma, nonsmall cell lung carcinoma, multiple myeloma, basalioma, teratoma, retinoblastoma, choroidea melanoma, seminoma, rhabdomyo sarcoma, osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma, Ewing sarcoma, and plasmocytoma.

Aspect 44. The compound according to Aspect 41 or 42, wherein the cancer is selected from the group consisting of B-cell acute lymphocytic leukemia (B-ALL), mesothelioma, lymphoma, pancreatic carcinoma, lung cancer, gastric cancer, esophageal cancer, bladder carcinoma, brain cancer, head and neck cancer, melanoma, and breast cancer.

Aspect 45. The compound according to Aspect 44, wherein the cancer is a lung cancer selected from the group consisting of non-small cell lung cancer, small cell lung cancer, adenocarcinoma of the lung, and squamous cell carcinoma of the lung.

Aspect 46. The compound according to Aspect 44, wherein the cancer is triple négative breast cancer (TNBC).

Aspect 47. The compound according to Aspect 44, wherein the cancer is a brain tumor selected from the group consisting of glioma, glioblastoma, astrocytoma, meningioma, medulloblastoma, peripheral neuroectodermal tumors, and craniopharyngioma.

Aspect 48. The compound according to any one of Aspects 41 to 43, wherein the cancer is a lymphoma selected from the group consisting of mantle cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, Burkitt lymphoma, diffuse large B-cell lymphoma (DLBCL), and adult T-cell leukemia/lymphoma.

EXAMPLES

The présent disclosure will be more fully understood by reference to the following examples. The examples should not, however, be construed as limiting the scope of the présent disclosure.

-5320638

Units and ternis list:
anhy.	anhydrous
aq.	aqueous
min	minute(s)
mL	milliliter
mmol	millimole(s)
mol	mole(s)
MS	mass spectrometry
NMR	nuclear magnetic résonance
TLC	thin layer chromatography
HPLC	high-performance liquid chromatography
RT(r.t.)	room température
NMR Spectra

Hz	hertz
δ	Chemical shift
J	coupling constant
s	singlet
d	doublet
t	triplet
q	quartet
m	multiplet
br	broad
qd	quartet of doublets
dquin	doublet of quintets
dd	doublet of doublets
dt	doublet of triplets

Solvents and Reagents:

-5420638

CHC13	chloroform
DCM	dichloromethane
DMF	dimethylformamide
Et2O	diethyl ether
EtOH	ethyl alcohol
EtOAc	ethyl acetate
EA	ethyl acetate
MeOH	methyl alcohol
MeCN	acetonitrile
PE	Petroleum ether
THF	tetrahydrofuran
AcOH	acetic acid
HCl	hydrochloric acid
H2SO4	sulfuric acid
NH4C1	ammonium chloride
KOH	potassium hydroxide
NaOH	sodium hydroxide
K2co3	potassium carbonate
Na2CO3	sodium carbonate
TFA	trifluoroacetic acid
Na2SO4	sodium sulfate
NaBH4	sodium borohydride
NaHCO3	sodium bicarbonate
LiHMDS	lithium hexamethyldisilylamide
NaHMDS	sodium hexamethyldisilylamide
LAH	lithium aluminum hydride
NaBH4	sodium borohydride

-5520638

LDA	lithium diisopropylamide
Et3N	triethylamine
DMAP	4-(dimethyl amino)pyridine
DIPEA	ACV-diisopropylethylaminc
NH4OH	ammonium hydroxide
EDCI	1 -ethyl- 3 -(3 -dimethylaminopropyl) carbodiimide
HOBt	1 -hydroxybenzotriazole
HATU	O-(7-azabcnzotriazol-l-yl)-A0VA'(AZctra-methyluroniurn
Xphos	2-Dicyclohexylphosphino-2 ',4', 6 '-triisopropylbiphenyl
BINAP	2,2 ’ -bis(diphenylphosphanyl)-1,1’ -binaphthyl

General Experimental

In the following examples, the reagents and solvents were purchased from commercial sources (such as Alfa, Acros, Sigma Aldrich, TCI and Shanghai Chemical Reagent

Company), and used without further purification unless otherwise specified. Flash chromatography was performed on an Ez Purifier III using column with silica gel particles of 200-300 mesh. Analytical and préparative thin layer chromatography (TLC) plates were HSGF 254 (0.15-0.2 mm thickness, Shanghai Anbang Company, China). Nuclear magnetic résonance (NMR) spectra were obtained on a Brucker AMX-400 NMR (Brucker,

Switzerland). Chemical shifts were reported in parts per million (ppm, δ) downfield from tetramethylsilane. Mass spectra were given with electrospray ionization (ESI) from a Waters LCT TOF Mass Spectrometer (Waters, USA). HPLC chromatographs were record on an Agilent 1200 Liquid Chromatography (Agilent, USA, column: Ultimate 4.6mmx50mm, 5pm, mobile phase A: 0.1% formic acid in water; mobile phase B: acetonitrile). Microwave reactions were run on an Initiator 2.5 Microwave Synthesizer (Biotage, Sweden).

General Procedure I:

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Method A:

Br₂, Base

Bpin CO₂Et

1.4

[Pd]/L, Base

Method B:

__^Rs

Bu₃Sn CO₂Et

1.5

[Pd]/L, [Cu], Base

1.12

Compounds of structure 1.9,1.11 and 1.12 were obtained through the scheme depicted as General Procedure I. Beginning with pyridazinone 1.1, electrophilic bromination was used to generate heterocyclic bromide 1.2. The desired R₃ group was installed using a Chan-Lam 5 coupling to generate compound 1.3. At this stage, the desired R4 and R₅ groups were installed by using either a Suzuki cross-coupling with reagent 1.4 (Method A), or a Stille . cross-coupling with reagent 1.5 (Method B). The resulting intermediate 1.6 was then cyclized to the desired bicyclic core 1.7 under basic conditions. The desired R₂ group was installed using a Suzuki cross-coupling to generate compound 1.8. Compound 1.8 was then 10 alkylated to install the desired R[ group and provide final compounds of structure 1.9.

Altematively, compound 1.8 was chlorinated to give aryl-chloride 1.10, and the desired Ri was installed via nucleophilic aromatic substitution to yield final compounds of structure 1.11 (Method C). Altematively, compound 1.8 was activai ed using B OP, and the desired N-5720638 linked Ri was installed via nucleophilic aromatic substitution to yield final compounds of structure 1.12 (Method D).

Préparation of Example 101 via General Procedure I (Method A):

Step A

Method A:

Step B

DMF

Pd(dppf)CI₂, K₂CO₃

K₂CO₃

EtOH

Step C

Step D

Step A: 5-amino-6-bromo-4-chloropyridazin-3(2H)-one

To a suspension of 5-amino-4-chloropyridazin-3(2H)-one (1.2 g, 8.2 mmol, 1.0 eq.) and NaOAc (0.74 g, 9.1 mmol, 1.1 eq.) in MeCN (40 mL) was added Br2 (1.45 g, 9.1 mmol, 1.1 eq.) at 80 °C over 5 min via a syringe. The resulting mixture was stirred at 80 °C for additional 1 hr. After cooling to room température, the volatiles were removed under reduced pressure, diluted with ice-cooled H2O (20 mL), the resulting white precipitate was filtered, and the filter cake was collected and dried under reduced pressure to give 5-amino-6-bromo4-chloropyridazin-3(2H)-one (1.48 g, 80% yield) as a white solid. LC-MS (ESI): m/z 224, 226 [M+H]⁺.

Step B: 5-amino-6-bromo-4-chloro-2-(2-methyl-2H-indazol-5-yl)pyridazin-3(2H)-one

To a suspension of 5-amino-6-bromo-4-chloropyridazin-3(2H)-one (590 mg, 2.63 mmol, 1.0 eq.) in DMF (15 mL) was added (2-methyl-2H-indazol-5-yl)boronic acid (555 mg, 3.15 mmol, 1.2 eq.), Cu(OAc)₂ (478 mg, 2.63 mmol, 1.0 eq.) and pyridine (422 pL, 5.26 mmol, 2.0 eq.). The resulting mixture was stirred at 50 °C (air atmosphère) for 8h, and the reaction

-5820638 was monitored by TLC. After completion, the reaction mixture was diluted with H₂O (30 mL), the resulting suspension was stirred additional 30 min, the precipitate was collected and washed over ice-cooled H₂O (30 mL x 3) and dried under reduced pressure to afford 5amino-6-bromo-4-chloro-2-(2-methyl-2H-indazol-5-yl)pyridazin-3(2H)-one (770 mg, 82% yield) as a gray-white solid. LC-MS (ESI): m/z 354, 356 [M+H]⁺.

Step C: ethyl (E)-3-(4-amino-5-chloro-l-(2-methyl-2H-indazol-5-yl)-6-oxo-l,6dihydropyridazin-3 -yl)acrylate

To a solution of 5-amino-6-bromo-4-chloro-2-(2-methyl-2H-indazol-5-yl)pyridazin-3(2H)one (500 mg, 1.41 mmol, 1.0 eq.) in DMF (10 mL) was added ethyl (E)-3-(4,4,5,5tetramethyl-l,3,2-dioxaborolan-2-yl)acrylate (350 mg, 1.55 mmol, 1.1 eq.), Pd(dppf)Cl₂ (103 mg, 0.14 mmol, 0.1 eq.) and K₂CO₃ (389 mg, 2.82 mmol, 2.0 eq.). The reaction mixture was stirred at 80 °C for 16 hrs under N₂ atmosphère. The reaction mixture was poured into ice water (30 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were dried over Na₂SO4, concentrated under reduced pressure, the crude residue was purified by flash column chromatography on silica gel to give ethyl (E)-3-(4-amino-5-chloro-l-(2methyl-2H-indazol-5-yl)-6-oxo-l,6-dihydropyridazin-3-yl)acrylate (316 mg, 60% yield) as a yellow solid. LC-MS (ESI): m/z 374 [M+H]⁺.

Step D: 4-chloro-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyridazine-3,6(2H,5H)-dione

To a solution of ethyl (E)-3-(4-amino-5-chloro-l-(2-methyl-2H-indazol-5-yl)-6-oxo-l,6dihydropyridazin-3-yl)acryIate (400 mg, 1.07 mmol, 1.0 eq.) in EtOH (10 mL) was added K₂CO₃ (295 mg, 2.14 mmol, 2.0 eq.) at room température. The reaction mixture was stirred at 80°C for 3 hrs. Then ice water (30 mL) was added and the mixture was extracted with EtOAc (30 mL x 3). The combined organic layers were dried over Na₂SO4, concentrated under reduced pressure, the crude residue was purified by flash column chromatography on silica gel to give 4-chloro-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyridazine-3,6(2H,5H)dione (319 mg, 85% yield) as a yellow solid. LC-MS (ESI): m/z 328 [M+H]⁺.

Step E: 4-(4-chlorophenyl)-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyridazine3,6(2H,5H)-dione

A solution of 4-chloro-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyridazine-3,6(2H,5H)dione (1 g, 3.05 mmol, 1.0 eq.), (4-chlorophenyl)boronic acid (954 mg, 6.1 mmol, 2.0 eq.), Pd(OAc)₂ (68 mg, 0.3 mmol, 0.1 eq.), S-Phos (251 mg, 0.61 mmol, 0.2 eq.) and K₂CO₃ (1.26 g, 9.15 mmol, 3.0 eq.) in dioxane/H₂O (110 mL, 10/1, v/v) was stirred at 110°C under N₂ atmosphère for 2 hrs. Ice water (30 mL) was added and the mixture was extracted with

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EtOAc (30 mL x 3), the combined organic layers were dried over Na₂SO₄, concentrated under reduced pressure, the crude residue was purified by flash column chromatography on silica gel to give 4-(4-chlorophenyl)-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c|pyridazine3,6(2H,5H)-dione (700 mg, 57% yield) as a yellow solid. LC-MS: m/z 404 [M+H]⁺.

Step F: 4-(4-chlorophenyl)-6-(cyclopropylmethoxy)-2-(2-methyl-2H-indazol-5yl)pyrido [3,2-c]pyridazin-3 (2H)-one

A solution of 4-(4-chlorophenyl)-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyridazine3,6(2H,5H)-dione (200 mg, 0.495 mmol, 1.0 eq.), (bromomethyl)cyclopropane (0.2 mL, 2.0 mmol, 4.0 eq.), Cs₂CO₃ (484 mg, 1.5 mmol, 3.0 eq.) in DMF (3 mL) was stirred at room 10 température for 16 hrs. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by prep-HPLC to give 4-(4-chlorophenyl)-6(cyclopropylmethoxy)-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyridazin-3(2H)-one (Example 101).

^lH NMR (400 MHz, DMSO-d₆) δ: 8.55 (s, 1H), 8.07 (d, J = 2.0 Hz, 1H), 8.04 (d, J = 9.6 Hz, 15 1H), 7.86 (d, J = 8.8 Hz, 2H), 7.76 (d, J = 9.2 Hz, 1H), 7.56 (d, J = 8.4 Hz, 2H), 7.51 (dd, J -

9.2 Hz, 1.6 Hz, 1H), 7.04 (d, J = 9.2 Hz, 1H), 4.28 (s, 3H), 4.21 (d, J = 7.2 Hz, 2H), 1.361.19 (m, 1H), 0.64-0.57 (m, 2H), 0.37-0.33 (m, 2H).

LC-MS (ESI): m/z 458 [M+H]⁺

Préparation of Example 102 via General Procedure I (Method B):

Method B:

Step C: 4-chloro-6-hydroxy-2-(2-methyl-2H-indazol-5-yl)-8-(trifluoromethyl)pyrido[3,2c]pyridazin-3 (2H)-one

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A solution of 5-amino-6-bromo-4-chloro-2-(2-methyl-2H-indazol-5-yl)pyridazin-3(2H)-one (1 g, 2.8 mmol, 1.0 eq.), ethyl (Z)-4,4,4-trifluoro-3-(tributylstannyl)but-2-enoate (Ref: Synlett, 2012, 23, 755-759) (2.6 g, 5.6 mmol, 2.0 eq.), Pd(PPh3)4 (655 mg, 0.567 mmol, 0.2 eq.) and Cul (216 mg, 1.13 mmol, 0.4 eq.) in DMF (10 mL) under N₂ atmosphère was stirred at 100 °C for 16 hrs. The reaction mixture was quenched with CsF (sat. aq.) (30 mL) and stirred for additional 30 min, the resulting suspension was filtered, the precipitate was collected and triturated with EtOAc (20 mL) to afford 4-chloro-6-hydroxy-2-(2-methyl-2Hindazol-5-yl)-8-(trifluoromethyl)pyrido[3,2-c]pyridazin-3(2H)-one (800 mg, 71% yield) as a yellow solid. LC-MS (ESI): m/z 396 [M+H]⁺.

6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)-2-(2-methyl-2H-indazol-5-yl)-8(trifluoromethyl)pyrido[3,2-c]pyridazin-3(2H)-one (Example 102) was synthesized from 2-(4-(difluoromethoxy)phenyl)-4,4,5,5-tetramethyl-l ,3,2-dioxaborolane and 2,2difluoroethyl trifluoromethanesulfonate via general procedure I (Step E, F).

^XH NMR (400 MHz, DMSO-d₆) δ: 8.56 (s, 1H), 8.07 (s, 1H), 7.87 (d, J = 8.8 Hz, 2H), 7.76 (d, J = 9.2 Hz, 1H), 7.61 (s, 1H), 7.50 (dd, J = 9.2 Hz, 1.6 Hz, 1H), 7.38 (t, J_HF = 73.6 Hz, 1H), 7.29 (d, J = 8.4 Hz, 2H), 6.43 (tt, J_HF = 54.0 Hz, J = 2.8 Hz, 1H), 4.63 (td, J_HF= 14.8 Hz, J = 2.8 Hz, 2H), 4.25 (s, 3H).

LC-MS (ESI): m/z 568 [M+H]⁺.

Préparation of Example 103 via General Procedure I (Method C):

Method C:

Step G: 6-chloro-4-(4-chlorophenyl)-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyridazin3(2H)-one

A solution of 4-(4-chlorophenyl)-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyridazine3,6(2H,5H)-dione (100 mg, 0.284 mmol 1.0 eq.) in POCI3 (5 mL) was stirred at 80 °C for 2 hrs. Excess POC1₃ was removed under reduced pressure and the residue was poured into ice cooled NaHCO₃ (sat. aq.) (10 mL) carefully, the resulting mixture was extracted with DCM (10 mL x 3), the combined organic layers were washed with brine (10 mL) and dried over Na₂SO₄, concentrated under reduced pressure, the crude residue was purified by flash

-6120638 column chromatography on silica gel to give 6-chloro-4-(4-chlorophenyl)-2-(2-methyl-2Hindazol-5-yl)pyrido[3,2-c]pyridazin-3(2H)-one (60 mg, 57% yield) as ared solid. LC-MS (ESI): m/z 422 [M+H]⁺.

Step H: 4-(4-chlorophenyl)-6-(ethylamino)-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2c]pyridazin-3 (2H)-one

A solution of 6-chloro-4-(4-chlorophenyl)-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2c]pyridazin-3(2H)-one (60 mg, 0.142 mmol, 1.0 eq.), ethylamine hydrochloride (58 mg, 0.71 mmol, 5.0 eq.), CsF (108 mg, 0.71 mmol 5.0 eq.), and DIPEA (92 mg, 0.71 mmol, 5.0 eq.) in THF (3 mL) was stirred at room température for 16 hrs. The reaction mixture was concentrated under reduced pressure, the crude residue was purified by prep-HPLC to give 4(4-chlorophenyl)-6-(ethylamino)-2-(2-methyI-2H-indazol-5-yl)pyrido[3,2-c]pyridazin-3(2H)one (Example 103).

^XH NMR (400 MHz, DMSO-d₆) δ: 8.46 (s, 1H), 8.34 (t, J = 5.2 Hz, 1H), 7.94 (d, J = 1.2 Hz, 1H), 7.82 (d, J = 8.4 Hz, 2H), 7.67 (d, J = 9.2 Hz, 1H), 7.61 (d, J = 9.2 Hz, 1H), 7.45-7.40 (m, 3H), 6.79 (d, J = 9.2 Hz, 1H), 4.22 (s, 3H), 3.37-3.30 (m, 2H), 1.15 (t, J = 7.2 Hz, 3H).

LC-MS (ESI): m/z 431 [M+H]⁺.

Préparation of Example 301 via General Procedure I (Method D):

Method D:

Step I: 2-(2-methyl-2H-indazol-5-yl)-4-(6-methylpyridin-3-yl)-6-((2,2,2trifluoroethyl)amino)pyrido[3,2-c]pyridazin-3(2H)-one (Example 301)

To a solution of 6-hydroxy-2-(2-methyl-2H-indazol-5-yl)-4-(6-methylpyridin-3yl)pyrido[3,2-c]pyridazin-3(2H)-one (100 mg, 0.26 mmol, 1.0 eq.), BOP (173 mg, 0.39 mmol, 1.5 eq.), in DMF(5 mL) was added DIEA (0.13 mL, 0.78 mmol, 3.0 eq.). The resulting mixture was stirred at room température for 30 min, then 2,2,2-trifluoroethan-lamine (0.06 mL, 0.78 mmol, 3.0 eq.) was added and stirred for additional 2 hrs. at room température. After the completion, the reaction was quenched b y adding ice water (10 mL) and extracted with EtOAc (10 ml x 3), dried over Na₂SÛ4 and concentrated under reduced

-6220638 pressure, the residue was purified by flash column chromatography on silica gel to give 2-(2methyl-2H-indazol-5-yl)-4-(6-methylpyridin-3-yl)-6-((2,2,2-trifluoroethyl)amino)pyrido[3,2c]pyridazin-3(2H)-one (Example 301).

^XH NMR (400 MHz, DMSO-rid) δ: 8.86 (s, 1H), 8.80 (s, 1H), 8.47 (s, 1H), 8.02 (d, J = 7.5

Hz, 1H), 7.96 (s, 1H), 7.77 (d, J = 9.5 Hz, 1H), 7.68 (d, J = 8.8 Hz, 1H), 7.42 (d, J - 9.7 Hz, 1H), 7.28 (d, J = 8.1 Hz, 1H), 6.92 (d, J = 9.6 Hz, 1H), 4.30-4.22 (m, 2H), 4.21 (s, 3H), 2.51 (s, 3H).

LC-MS (ESI): m/z 466 [M+H]⁺.

The procedure set forth above for General Procedure I (Method A) was used to synthesize the foliowing compounds by using appropriate starting materials:

Cpd No.	Structure	Characterization
Example 104	—N | ] 0 ocf3 6-ethoxy-2-(2-methyl-2H-indazol- 5-yl)-4-(4- (trifluoromethoxy)phenyl)pyrido [3, 2-c] pyridazin-3 (2H)-one	LC-MS (ESI): m/z 482.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ: 8.50 (s, 1H), 8.02 (d, J = 1.6 Hz, 1H), 7.99 (d, J = 9.6 Hz, 1H), 7.92 (d, J = 8.8 Hz, 2H), 7.71 (d, J = 9.2 Hz, 1H), 7.47 (d, J = 2.0 Hz, 1H), 7.44 (d, J = 8.0 Hz, 2H), 6.96 (d, J = 9.6 Hz, 1H), 4.34 (q, J = 6.8 Hz, 2H), 4.23 (s, 3H), 1.31 (t, J = 7.2 Hz, 3H).
Example 105	Uy n^o^CHF2 0 ochf2 6-(2,2-difluoroethoxy)-4-(4(difluoromethoxy)phenyl)-2-(4methoxyphenyl)pyrido[3,2c]pyridazin-3(2H)-one	LC-MS (ESI): m/z 476.1 [M+H]+, 1H NMR (400 MHz, DMSO-d6) δ: 7.99 (d, J = 9.6 Hz, 1H), 7.82 (d, J = 8.8 Hz, 2H), 7.57 (d, J = 8.8 Hz, 2H), 7.30 (t, Jhf = 73.6 Hz, 1H), 7.23 (d, J = 8.4 Hz, 2H), 7.07 (d, J = 8.8 Hz, 2H), 7.01 (d, J = 9.2 Hz, 1H), 6.36 (t, JHF = 54.4 Hz, 1H), 4.55 (td, Jhf = 15.2 Hz, J = 2.8 Hz, 2H), 3.82 (s, 3H).

Example 106	0' T' '' OMe 6-(2,2-difluoroethoxy)-4-(4methoxyphenyl) -2-(2-methyl-2Hindazol-5-yl)pyrido[3,2- c]pyridazin-3 (2H) -one	LC-MS (ESI): m/z 464.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ: 8.50 (s, 1H), 8.03 (d, J - 9.2 Hz, 1H), 8.01 (s, 1H), 7.80 (d, J = 8.8 Hz, 2H), 7.71 (d, J = 9.2 Hz, 1H), 7.50-7.41 (m, 1H), 7.05 (d, J = 9.6 Hz, 1H), 7.01 (d, J = 8.8 Hz, 2H), 6.41 (t, Jhf = 54.4 Hz, 1H), 4.60 (td, Jhf ~ 14.8 Hz, J = 2.8 Hz, 2H), 4.23 (s, 3H), 3.83 (s, 3H).
Example 107	n^O^CHF2 A Y .N 4-(6-cyclopropylpyridin-3-yl)-6(2,2-difluoroethoxy)-2-(2-methyl2H-indazol-5-yl)pyrido [3,2 c]pyridazin-3 (2H)-one	LC-MS (ESI): m/z 475.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ: 8.81 (d, J = 2.0 Hz, 1H), 8.52 (s, 1H), 8.09 (s, 1H), 8.07 (d, J = 1.2 Hz, 1H), 8.04 (s, 1H), 7.73 (d, J = 9.2 Hz, 1H), 7.48 (dd, J = 8.8 Hz, 1.6 Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.09 (d, J = 9.2 Hz, 1H), 6.42 (tt, Jhf ~ 54.5 Hz, J = 3.2 Hz, 1H), 4.62 (td, Jhf = 15.2, J = 3.2 Hz, 2H), 4.24 (s, 3H), 2.23-2.13 (m, 1H), 1.04-0.98 (m, 4H).
Example 108	0 ocd3 6-(2,2-difluoroethoxy)-4-(4(methoxy-d3)phenyl)-2-(2-methyl2H-indazol- 5 -yl)pyrido [3,2c]pyridazin-3 (2H)-one	LC-MS (ESI): m/z 467.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ: 8.49 (s, 1H), 8.03 (d, J = 9.6 Hz, 1H), 8.01 (d, J= 1.6 Hz, 1H), 7.80 (d, J = 8.8 Hz, 2H), 7.71 (d, J = 9.2 Hz, 1H), 7.45 (dd, J = 9.2 Hz, 2.0 Hz, 1H), 7.04 (d, J = 9.6 Hz, 1H), 7.01 (d, J = 8.8 Hz, 2H), 6.41 (tt, Jhf = 54.4 Hz, J = 3.2 Hz,

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		1H), 4.60 (td, JHF = 15.2 Hz, 3.2 Hz, 2H), 4.22 (s, 3H).
Example 109	N^XA —N ] | 0 ocf3 6-(2,2-difluoroethoxy)-2-(2methyl-2H-indazol-5-yl)-4-(4(trifluoromethoxy)phenyl)pyrido [3, 2-c]pyridazin-3(2H)-one	LC-MS (ESI): m/z 518.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ: 8.51 (s, 1H), 8.08 (d, J = 9.2 Hz, 1H), 8.04 (d, J = 1.6 Hz, 1H), 7.92 (d, J = 8.8 Hz, 2H), 7.72 (d, J = 9.2 Hz, 1H), 7.48 (dd, J = 9.2 Hz, 2.0 Hz, 1H), 7.45 (d, J = 8.4 Hz, 2H), 7.08 (d, J = 9.2 Hz, 1H), 6-39 (tt, Jhf = 54.4 Hz, J = 3.6 Hz, 1H), 4.58 (td, Jhf = 15.2 Hz, J = 3.2 Hz, 2H), 4.23 (s, 3H).
Example 110	—N | 1 0 ocd3 6-ethoxy-4-(4-(methoxyd3)phenyl)-2-(2-methyl-2Hindazol-5-yl)pyrido[3,2c]pyridazin-3(2H)-one	LC-MS (ESI): m/z 431.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ: 8.49 (s, 1H), 7.99 (s, 1H), 7.94 (d, J = 9.2 Hz, 1H), 7.79 (d, J = 8.4 Hz, 2H), 7.70 (d, J = 8.8 Hz, 1H), 7.44 (d, J = 8.4 Hz, 1H), 7.00 (d, J = 8.0 Hz, 2H), 6.93 (d, J = 9.2 Hz, 1H), 4.35 (d, J = 6.8 Hz, 2H), 4,22 (s, 3H), 1.33 (t, J = 6.8 Hz, 3H).
Example 111	NisXA, Άχ 0 ochf2 4-(4-(difluoromethoxy)phenyl)-2(2-methyl-2H-indazol-5-yl)-6propoxypyrido [3,2- c]pyridazin3(2H)-one	LC-MS (ESI): m/z 478.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ: 8.50 (s, 1H), 8.01 (d, J = 1.6 Hz, 1H), 7.97 (d, J = 9.2 Hz, 1H), 7.85 (d, J = 8.8 Hz, 2H), 7.71 (d, J = 9.2 Hz, 1H), 7.46 (dd, J - 9.2 Hz, 2.0 Hz, 1H), 7.34 (t, Jhf = 74.0 Hz, 1H), 7.25 (d, J = 8.8 Hz, 2H), 6.96 (d, J = 9.2 Hz, 1H), 4.25

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		(t, J = 6.8 Hz, 2H), 4.23 (s, 3H), 1.72 (q, J = 7.2 Hz, 2H), 0.92 (t, J = 7.6 Hz, 3H).
Example 112	fil 6-ethoxy-2-(4-methoxyphenyl) -4(6-methylpyridin-3 -yl)pyrido [3,2c]pyridazin-3 (2H)-one	LC-MS (ESI): m/z 389.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ: 8.82 (d, J = 2.0 Hz, 1H), 8.06 (dd, J = 8.0 Hz, 2.0 Hz, 1H), 7.97 (d, J = 9.2 Hz, 1H), 7.59 (dd, J = 7.2 Hz, 2.0 Hz, 2H), 7.34 (d, J = 8.0 Hz, 1H), 7.08 (dd, J = 6.8 Hz, 2.0 Hz, 2H), 6.95 (d, J = 9.6 Hz, 1H), 4.32 (q, J = 6.8 Hz, 2H), 3.83 (s, 3H), 2.51 (s, 3H), 1.31 (t, J = 7.2 Hz, 3H).
Example 113	-cCl.n^ XXX a N O 0 Cl 4-(4-chlorophenyl)-6cyclopropoxy-2-(2-methyl-2Hindazol-5 -yl)pyrido [3,2c]pyridazin- 3 (2H)-one	LC-MS (ESI): m/z 444.1 [M+H]+. 1H NMR (400 MHz, DMSO- d6) δ: 8.51 (s, 1H), 8.02 (d, J = 1.6 Hz, 1H), 7.99 (d, J = 9.6 Hz, 1H), 7.93 (dd, J = 6.8 Hz, 1.6 Hz, 2H), 7.71 (d, J = 9.3 Hz, 1H), 7.53 (dd, J = 6.8 Hz, 2.0 Hz, 2H), 7.47 (dd, J = 8.8 Hz, 1.6Hz, 1H), 6.93 (d, J = 9.2 Hz, 1H), 4.28-4.24 (m, 1H), 4.29 (s, 3H), 0.91-0.83 (m, 4H).
Example 114	0 4-(4-cyclopropylphenyl)-6-(2,2difluoroethoxy)-2-(2-methyl-2Hindazol-5-yl)pyrido[3,2-	LC-MS (ESI): m/z 474.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ: 8.50 (s, 1H), 8.03 (d, J = 9.6 Hz, 1H), 8.01 (d, J = 2.0 Hz, 1H), 7.72-7.68 (m, 3H), 7.45 (dd, J = 9.2 Hz, 2.0 Hz, 1H), 7.14 (d, J = 8.8 Hz, 2H), 7.04 (d, J = 9.6 Hz, 1H), 6.40 (tt, Jhf = 54.4 Hz, J =

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	c]pyridazin-3 (2H)-one	3.6 Hz, 1H), 4.58 (td, Jhf = 15.2 Hz, J = 3.2 Hz, 2H), 4.22 (s, 3H), 2.01-1.95 (m, 1H), 1.04-0.97 (m, 2H), 0.77-0.70 (m, 2H).
Example 115	0 OMe 6-ethoxy-4-(4-methoxyphenyl)-2(2-methyl-2H-indazol-5yl)pyrido[3,2-c]pyridazin-3(2H)one	LC-MS (ESI): m/z 428.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ: 8.49 (s, 1H), 7.99 (d, J = 1.6 Hz, 1H), 7.94 (d, J = 9.6 Hz, 1H), 7.80 (d, J = 8.8 Hz, 2H), 7.70 (d, J = 9.2 Hz,, 1H), 7.45 (dd, J - 9.2 Hz, 2.0 Hz, 1H), 7.00 (d, J = 8.8 Hz, 2H), 6.93 (d, J = 9.2 Hz, 1H), 4.35 (q, J = 7.2 Hz, 2H), 4.22 (s, 3H), 3.82 (s, 3H), 1.33 (t, J = 7.2 Hz, 3H).
Example 116	N^x^, N^O^CFs 0 Cl 4-(4-chlorophenyl)-2-(2-methyl2H-indazol-5-yl)-6-(2,2,2trifluoroethoxy)pyrido [3,2c]pyridazin-3(2H)-one	LC-MS (ESI): m/z 486.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ: 8.50 (s, 1H), 8.11 (d, J = 9.4 Hz, 1H), 8.03 (s, 1H), 7.84 (d, J = 8.4 Hz, 2H), 7.71 (d, J = 9.2 Hz, 1H), 7.52 (d, J = 8.4 Hz, 2H), 7.47 (d, J = 9.7 Hz, 1H), 7.12 (d, J = 9.4 Hz, 1H), 4.99 (q, Jhf = 8.9 Hz, 2H), 4.22 (s, 3H).
Example 117	ΜθΟ-,χχ θ·Ύϊ 0 Cl 4-(4-chlorophenyl)-6-ethoxy-2-(4methoxyphenyl)pyrido [3,2-	LC-MS (ESI): m/z 408.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ: 7.95 (d, J = 9.3 Hz, 1H), 7.79 (d, J = 8.2 Hz, 2H), 7.59 (d, J = 8.6 Hz, 2H), 7.50 (d, J = 8.2 Hz, 2H), 7.08 (d, J = 8.6 Hz, 2H), 6.93 (d, J = 9.4 Hz, 1H), 4.32 (q, J = 6.8 Hz, 2H), 3.84 (s, 3H), 1.31 (t,

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	c]pyridazm-3 (2H) -one	J = 6.9 Hz, 3H).
Example 118	XAyj N<'O'''''CF3 0 Cl 4-(4-chlorophenyl)-2-(4methoxyphenyl)-6-(2,2,2 trifluoroethoxy)pyrido[3,2c]pyridazin-3 (2H)-one	LC-MS (ESI): m/z 462.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ: 8.09 (d, J = 9.4 Hz, 1H), 7.82 (d, J = 8.5 Hz, 2H), 7.61 (d, J = 8.9 Hz, 2H), 7.52 (d, J = 8.5 Hz, 2H), 7.14-7.07 (m, 3H), 4.98 (q, Jhf = 8.9Hz, 2H), 3.84 (s, 3H).
Example 119	0 Cl 4- (4- chlorophenyl)-6 -ethoxy-2-(2 methyl-2H-indazol-5-yl)pyrido[3,2- c]pyridazin-3(2H)-one	LC-MS (ESI): m/z 432.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ: 8.50 (s, 1H), 8.01 (d, J = 1.6 Hz, 1H), 7.98 (d, J = 9.4 Hz, 1H), 7.81 (d, J = 9.7 Hz, 2H), 7.71 (d, J = 9.1 Hz, 1H), 7.51 (d, J = 8.5 Hz, 2H), 7.46 (dd, J = 9.1 Hz, 1.8 Hz, 1H), 6.95 (d, J = 9.4 Hz, 1H), 4.34 (q, 2H), 4.23 (s, 3H), 1.32 (t, J = 7.0 Hz, 3H).
Example 120	ochf2 4-(6-(difluoromethoxy)pyridin-3 yl)-6 -ethoxy-2 - (2-methyl-2Hindazol-5 -yl)pyrido [3,2c]pyridazin-3 (2H) -one	LC-MS (ESI): m/z 465.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) Ô: 8.70 (d, J = 2.1 Hz, 1H), 8.52 (s, 1H), 8.36 (dd, J = 8.5 Hz, 2.2 Hz, 1H), 8.02 (d, J = 9.7 Hz, 2H), 7.82 (t, Jhf = 72.0 Hz, 1H), 7.74 (d, J = 9.1 Hz, 1H), 7.49 (dd, J = 9.0 Hz, 1.9 Hz, 1H), 7.22 (d, J = 8.5 Hz, 1H), 7.00 (d, J = 9.4 Hz, 1H), 4.38 (q, J = 7.0 Hz, 2H), 4.24 (s, 3H), 1.35 (t, J = 7.0 Hz, 3H).

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Example 121	—N ] ] (Il ocf3 6-ethoxy-2-(2-methyl-2H-indazol5-yl)-4-(6- (trifluoromethoxy)pyridin-3 yl)pyrido [3,2-c]pyridazin-3 (2H)one	LC-MS (ESI): m/z 483.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ: 8.78 (d, J = 2.0 Hz, 1H), 8.52 (s, 1H), 8.49-8.42 (m, 1H), 8.04 (d, J = 9.3 Hz, 2H), 7.74 (d, J = 9.0 Hz, 1H), 7.49 (d, J = 9.1 Hz, 1H), 7.43 (d, J = 8.5 Hz, 1H), 7.01 (d, J = 9.5 Hz, 1H), 4.37 (q, J = 7.0 Hz, 2H), 4.24 (s, 3H), 1.34 (t, J = 7.0 Hz, 3H).
Example 122	ochf2 4-(6-(difluoromethoxy)pyridin-3yl)-6-ethoxy-2-(4methoxyphenyl)pyrido [ 3,2c]pyridazin-3 (2H) -one	LC-MS (ESI): m/z 441.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ: 8.66 (d, J = 1.9 Hz, 1H), 8.32 (dd, J = 8.6 Hz, 2.4 Hz, 1H), 7.98 (d, J = 9.4 Hz, 1H), 7.80 (t, JHF = 72 Hz, 1H), 7.67-7.57 (m, 2H), 7.24-7.15 (m, 1H), 7.15-7.05 (m, 2H), 6.97 (d, J = 9.4 Hz, 1H), 4.35 (q, J = 7.1 Hz, 2H), 3.84 (s, 3H), 1.32 (t, J = 7.1 Hz, 3H).
Example 123	—n j । N^O^CFa ochf2 4- (4-(difluoromethoxy)phenyl)-2(2-methyl-2H-indazol-5-yl)-6(2,2,2-trifluoroethoxy)pyrido[3,2- c] pyridazin-3 (2H)-one	LC-MS (ESI): m/z 518.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ: 8.50 (s, 1H), 8.10 (d, J = 9.4 Hz, 1H), 8.03 (d, J = 1.4 Hz, 1H), 7.88 (d, J = 8.0 Hz, 2H), 7.71 (d, J = 9.2 Hz, 1H), 7.47 (dd, J = 9.1 Hz, 2.0 Hz, 1H), 7.35 (t, JHF = 72.0 Hz, 1H), 7.25 (d, Jhf - 8.8 Hz, 2H), 7.11 (d, J = 9.4 Hz, 1H), 5.00 (q, J = 9.0 Hz, 2H), 4.22 (s, 3H).

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Example 124	XBy 0 Cl 4-(4-chlorophenyl)- 6 -(2,2difluoroethoxy)-2-(2-methyl-2Hindazol-5-yl)pyrido [3,2 c]pyridazin~ 3 (2H) -one	LC-MS (ESI): m/z 468.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ: 8.50 (s, 1H), 8.07 (d, J = 9.2 Hz, 1H), 8.02 (d, J = 1.6 Hz, 1H), 7.83 (d, J = 8.4 Hz, 2H), 7.71 (d, J = 9.2 Hz, 1H), 7.52 (d, J = 8.4 Hz, 2H), 7.47 (dd, J = 9.2 Hz, 2.0 Hz, 1H), 7.07 (d, J = 9.6 Hz, 1H), 6.38 (tt, JHF = 54.4 Hz, J = 3.2 Hz, 1H), 4.59 (td, Jhf = 15.2 Hz, J = 3.2 Hz, 2H), 4.23 (s, 3H).
Example 125	X,y O0y'N A'O/xcHF2 0 ochf2 6-(2,2-difluoroethoxy)-4-(4(difiuoromethoxy)phenyl)-2-(2methyl-2H-indazol-5-yl)pyrido[3,2c]pyridazin-3 (2H)-one	LC-MS (ESI): m/z 500.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ: 8.50 (s, 1H), 8.06 (d, J = 9.6 Hz, 1H), 8.02 (d, J = 1.2 Hz, 1H), 7.87 (d, J = 8.8 Hz, 2H), 7.71 (d, J = 9.2 Hz, 1H), 7.46 (dd, J = 9.2 Hz, 2.0 Hz, 1H), 7.34 (t, Jhf = 74.0 Hz, 1H), 7.25 (d, J = 8.8 Hz, 2H), 7.06 (d, J = 9.6 Hz, 1H), 6.40 (tt, Jhf = 54.4 Hz, J = 3.2 Hz, 1H), 4.59 (td, Jhf = 15.2 Hz, J = 3.2 Hz, 2H), 4.22 (s, 3H).
Example 126	N^O^C HF2 Xi VN ochf2 6-(2,2 -difluoroethoxy)-4- (6- (difluoromethoxy)pyridin-3-yl)-2- (2-methyl-2H-indazol-5- yl)pyrido [3,2- c] pyridazin-3 (2H)-	LC-MS (ESI): m/z 501.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ: 8.68 (d, J = 2.4 Hz, 1H), 8.51 (s, 1H), 8.34 (dd, J = 8.4 Hz, 2.4 Hz, 1H), 8.09 (d, J = 9.2 Hz, 1H), 8.03 (d, J = 1.6 Hz, 1H), 7.80 (t, Jhf = 74.0 Hz, 1H), 7.72 (d, J = 9.2 Hz, 1H), 7.47 (dd, J = 9.2 Hz, 1.6 Hz, 1H), 7.20 (d, 1H)„7.O9 (d,

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	one	J = 8.8 Hz, 1H), 6.41 (tt, JHF = 54.4 Hz, J = 3.2 Hz, 1H), 4.61 (td, Jhf = 15.2 Hz, J = 3.2 Hz, 2H), 4.22 (s, 3H).
Example 127	—N ] | nÇj) cf3 6-ethoxy-2-(2-methyl-2H-indazol5-yl)-4-(6-(trifluoromethyl)pyridin3 -yl)pyrido[3,2-c]pyridazin-3 (2H)one	LC-MS (ESI): m/z 467.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ: 9.15 (s, 1H), 8.52 (s, 1H), 8.49 (d, J = 6.8 Hz, 1H), 8.06-8.02 (m, 3H), 7.73 (d, J = 8.8 Hz, 1H), 7.49 (dd, J = 8.8 Hz, 1.6 Hz, 1H), 7.01 (d, J = 9.6 Hz, 1H), 4.35 (q, J = 7.2 Hz, 2H), 4.23 (s, 3H), 1.32 (t, J = 7.2 Hz, 3H).
Example 128	fil ocf3 6 -(2,2-difluoro ethoxy)-2-(2 methyl-2H-indazol-5-yl)-4-(6(trifluoromethoxy)pyridin-3 yl)pyrido[3,2-c]pyridazin-3 (2H)one	LC-MS (ESI): m/z 519.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ: 8.77 (s, 1H), 8.51 (s, 1H), 8.43 (dd, J = 8.8 Hz, 2.0 Hz, 1H), 8.10 (d, J = 9.6 Hz, 1H), 8.04 (s, 1H), 7.72 (d, J = 9.2 Hz, 1H), 7.47 (dd, J = 8.8 Hz, 1.6 Hz, 1H), 7.40 (d, J = 8.8 Hz, 1H), 7.10 (d, J = 9.6 Hz, 1H), 6.40 (tt, Jhf = 54.4 Hz, J = 3.2 Hz, 1H), 4.60 (td, Jhf = 15.2 Hz, J = 3.2 Hz, 2H), 4.22 (s, 3H).
Example 129	fLO^C h2f 0 ochf2 4-(4-(difluoromethoxy)phenyl)-6(2-fluoroethoxy)-2-(2-methyl-2Hindazol-5-yl)pyrido[3,2-	LC-MS (ESI): m/z 482.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ: 8.50 (s, 1H), 8.03-8.01 (m, 2H), 7.86 (dd, J = 6.8 Hz, 2.0 Hz, 2H), 7.70 (d, J = 8.8 Hz, 1H), 7.45 (dd, J = 9.2 Hz, 2.0 Hz, 1H), 7.34 (t, Jhf = 74.0 Hz, 1H), 7.25 (d, J =

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	c]pyridazin-3 (2H)-one	8.8 Hz, 2H), 7.02 (d, J = 9.6 Hz, 1H), 4.82-4.80 (m, 1H), 4.70-4.69 (m, 1H), 4.58-4.56 (m, 1H), 4.514.49 (m, 1H), 4.22 (s, 3H).
Example 130	N^O^C H F2 (Il OMe 6-(2,2-difluoroethoxy)-4-(6methoxypyridin-3-yl)-2-(2-methyl2H-indazol-5-yl)pyrido[3,2c]pyridazitL-3(2H)-one	LC-MS (ESI): m/z 465.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ: 8.64 (d, J = 1.2 Hz, 1H), 8.51 (s, 1H), 8.16 (dd, J = 8.4 Hz, 2.0 Hz, 1H), 8.06 (d, J = 9.6 Hz, 1H), 8.03 (s, 1H), 7.72 (d, J = 8.8 Hz, 1H), 7.47 (dd, J = 9.2 Hz, 1.2 Hz, 1H), 7.08 (d, J = 9.6 Hz, 1H), 6.92 (d, J = 8.4 Hz, 1H), 6.42 (t, JHF = 54.4 Hz, 1H), 4.62 (td, JHf = 14.8 Hz, J= 2.8 Hz, 2H), 4.23 (s, 3H), 3.93 (s, 3H).
Example 131	0 ochf2 6-(cyclobutylmethoxy)-4-(4(difluoromethoxy)phenyl)-2-(2methyl-2H-indazol-5-yl)pyrido[3,2c]pyridazin-3(2H)-one	LC-MS (ESI): m/z 504.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ: 8.50 (s, 1H), 8.01 (d, J = 1.6 Hz, 1H), 7.97 (d, J = 13.6 Hz, 1H), 7.86 (d, J = 8.8 Hz, 2H), 7.71 (d, J = 8.8 Hz, 1H), 7.46 (dd, J = 9.2 Hz, 2.0 Hz, 1H), 7.35 (t, JHF = 74.0 Hz, 1H), 7.25 (d, J = 8.8 Hz, 2H), 6.96 (d, J = 9.2 Hz, 1H), 4.30 (d, J = 6.8 Hz, 2H), 4.23 (s, 3H), 2.8-2.63 (m, 1H), 2.11-1.97 (m, 2H), 1.92-1.70 (m, 4H).

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Example 132	0ΑΛ n^o^^CF3 ochf2 4-(4-(difluoromethoxy)phenyl)-2(2-methyl-2H-indazol-5-yl)-6(3,3,3 -trifluoropropoxy)pyrido [3,2c] pyridazin-3 (2H) -one-one	LC-MS (ESI): m/z 532.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ: 8.51 (s, 1H), 8.03 (d, J = 9.6 Hz, 1H), 8.02 (d, J = 1.6 Hz, 1H), 7.86 (d, J = 8.8 Hz, 2H), 7.71 (d, J = 9.2 Hz, 1H), 7.46 (dd, J = 9.2 Hz, 2.0 Hz, 1H), 7.34 (t, Jhf = 72.0 Hz, 1H), 7.25 (d, J = 8.8 Hz, 2H), 6.97 (d, J = 9.6 Hz, 1H), 4.53 (t, J = 6.0 Hz, 2H), 4.23 (s, 3H), 2.87-2.75 (m, 2H).
Example 133	—N ] ] N^O^CHF2 0 6-(2,2-difluoroethoxy)-2-(2methyl-2H-indazol-5-yl)-4phenylpyrido[3,2-c]pyridazin3(2H)-one	LC-MS (ESI): m/z 434.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) Ô: 8.50 (s, 1H), 8.06 (d, J = 9.2 Hz, 1H), 8.02 (d, J = 2.0 Hz, 1H), 7.76 (d, J = 8.0 Hz, 2H), 7.71 (d, J = 8.8 Hz, 1H), 7.48-7.39 (m, 4H), 7.06 (d, J = 9.6 Hz, 1H), 6.39 (tt, Jhf = 54.4 Hz, J = 3.2 Hz, 1H), 4.56 (td, Jhf = 15.2 Hz, J = 3.6 Hz, 2H), 4.22 (s, 3H).
Example 134	—N | ] D^X^N^O^CHFz O 6-(2,2-difluoroethoxy)-2-(2methyl-2H-indazol-5-yl)-4(pyridin-4-yl)pyrido [3,2c] pyridazin-3 (2H)- one	LC-MS (ESI): m/z 435.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ: 8.67 (d, J = 5.6 Hz, 2H), 8.51 (s, 1H), 8.10 (d, J = 9.6 Hz, 1H), 8.04 (d, J = 1.2 Hz, 1H), 7.75 (d, J = 6.0 Hz, 1H), 7.72 (d, J = 9.2 Hz, 1H), 7.72 (d, J = 9.2 Hz, 1H), 7.47 (dd, J = 8.8 Hz, 2.0 Hz, 1H), 7.09 (d, J = 9.2 Hz, 1H), 6.40 (tt, JHF = 54.0 Hz, J = 3.2 Hz, 1H), 4.59 (td, Jhf = 15.2 Hz, J = 3.2 Hz, 2H),

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		4.22 (s, 3H).
Example 135	0 ochf2 4-(4-(difluoromethoxy)phenyl)-6ethoxy-2-(4methoxyphenyl)pyrido[3,2c]pyridazin-3(2H)-one	LC-MS (ESI): m/z 440.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) 8: 8.01 (d, J = 9.6 Hz, 1H), 7.90 (d, J = 8.8 Hz, 2H), 7.65 (d, J = 8.8 Hz, 2H), 7.41 (t, Jhf = 74.0 Hz, 1H), 7.30 (d, J = 8.8 Hz, 2H), 7.15 (d, J = 9.2 Hz, 2H), 7.00 (d, J = 9.2 Hz, 1H), 4.39 (q, J = 7.2 Hz, 2H), 3.90 (s, 3H), 1.37 (t, J = 7.2 Hz, 3H).
Example 136	Γη ocf3 6 -ethoxy-2 -(4-methoxyphenyl) -4(6-(trifluoromethoxy)pyridin- 3 yl)pyrido[3,2-c]pyridazin-3(2H)one	LC-MS (ESI): m/z 459.1 [M+H]+, 1H NMR (400 MHz, DMSO-d6) δ: 8.74 (d, J = 2.4 Hz, 1H), 8.40 (dd, J = 8.8 Hz, 2.0 Hz, 1H), 8.00 (d, J = 9.2 Hz, 1H), 7.60 (d, J = 9.2 Hz, 2H), 7.40 (d, J = 8.4 Hz, 1H), 7.09 (d, J = 8.8 Hz, 2H), 6.98 (d, J = 9.2 Hz, 1H), 4.34 (q, J = 7.2 Hz, 2H), 3.84 (s, 3H), 1.31 (t, J = 7.2 Hz, 3H).
Example 137	ô ochf2 6-(cyclopropylmethoxy)-4-(4(difluoromethoxy)phenyl)-2-(2methyl-2H-indazol-5-yl)pyrido[3,2c]pyridazin-3 (2H) -one	LC-MS (ESI): m/z 490.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ: 8.49 (s, 1H), 8.00 (dd, J = 2.0 Hz, 0.8 Hz, 1H), 7.97 (d, J = 9.2 Hz, 1H), 7.84 (d, J = 8.8 Hz, 2H), 7.70 (d, J = 8.8 Hz, 1H), 7.45 (dd, J = 9.2 Hz, 2.0 Hz, 1H), 7.34 (t, Jhf = 74.0 Hz, 1H), 7.24 (d, J = 8.8 Hz, 2H), 6.98 (d, J = 9.2 Hz, 1H), 4.22 (s, 3H), 4.15 (d, J = 7.2 Hz, 2H), 1.28-1.08 (m, 1H), 0.62-

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		0.42 (m, 2H), 0.32-0.13 (m, 2H).
Example 138	—N ] ] 0 ochf2 4-(4-(difluoromethoxy)phenyl)-6isopropoxy-2-(2-methyl-2Hmdazol-5-yl)pyrido[3,2- c] pyridazin-3 (2H)-one	LC-MS (ESI): m/z 478.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ: 8.49 (s, 1H), 8.00 (dd, J = 2.0 Hz, 0.8 Hz, 1H), 7.96 (d, J = 9.2 Hz, 1H), 7.82 (d, J = 8.8 Hz, 2H), 7.70 (d, J = 8.8 Hz, 1H), 7.45 (dd, J = 9.2 Hz, 2.0 Hz, 1H), 7.34 (t, Jhf = 74.0 Hz, 1H), 7.24 (d, J = 8.8 Hz, 2H), 6.90 (d, J = 9.2 Hz, 1H), 5.23-5.08 (m, 1H), 4.22 (s, 3H), 1.30 (d, J = 6.0 Hz, 6H).
Example 139	Γιΐ γΝ ocd3 6-(2,2-difluoroethoxy)-4-(6(methoxy-d3)pyridin-3 -yl)-2-(2methyl-2H-indazol-5-yl)pyrido[3,2c]pyridazin-3 (2H)-one	LC-MS (ESI): m/z 468.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ: 8.64 (d, J = 1.2 Hz, 1H), 8.51 (s, 1H), 8.16 (dd, J = 8.4 Hz, 2.0 Hz, 1H), 8.07 (d, J = 9.6 Hz, 1H), 8.03 (s, 1H), 7.72 (d, J = 9.2 Hz, 1H), 7.47 (dd, J = 9.2 Hz, 2.0 Hz, 1H), 7.08 (d, J = 9.6 Hz, 1H), 6.92 (d, J = 8.8 Hz, 1H), 6.43 (tt, JHF = 54.4 Hz, J = 3.2 Hz, 1H), 4.62 (td, Jhf = 15.2 Hz, J = 3.2 Hz, 2H), 4.23 (s, 3H).
Example 140	’^Ν'ΝΪ1 N^O^CHFs A 4-(3 -chlorophenyl)-6-(2,2difluoroethoxy)-2-(2-methyl-2Hindazol-5-yl)pyrido[3,2- c]pyridazin-3(2H)-one	LC-MS (ESI): m/z 468.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.50 (s, 1H), 8.07 (d, J = 9.2 Hz, 1H), 8.03 (s, 1H), 7.84 (s, 1H), 7.75-7.74 (m, 1H), 7.71 (d, J = 9.2 Hz, 1H), 7.48-7.46 (m, 3H), 7.07 (d, J = 9.2 Hz, 1H), 6.40 (t, JHF = 54.4 Hz, 1H), 4.58 (t, Jhf = 14.0

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		Hz, 2H), 4.22 (s, 3H).
Example 141	0 ochf2 4-(4-(difluoromethoxy)phenyl)-6isobutoxy-2-(2-methyl-2H-indazol5-yl)pyrido [3,2-c]pyridazin-3 (2H)one	LC-MS (ESI): m/z 492.5 [M+H]+. 1H NMR (400 MHz, DMSO-d6) Ô: 8.49 (s, 1H), 8.00 (d, J = 2.4 Hz, 1H), 7.97 (d, J = 9.2 Hz, 1H), 7.85 (d, J = 9.6 Hz, 2H), 7.70 (d, J = 9.2 Hz, 1H), 7.45 (dd, J = 9.2 Hz, 2.0 Hz, 1H), 7.33 (t, JHf = 74.0 Hz, 1H), 7.22 (d, J = 8.8 Hz, 2H), 6.96 (d, J = 9.2 Hz, 1H), 4.22 (s, 3H), 4.09 (d, J = 6.8 Hz, 2H), 2.10-1.98 (m, 1H), 0.92 (d, J = 6.7 Hz, 6H).
Example 142	Ν·γ^ THPCX	LC-MS (ESI): m/z 614.0
(Synthesized		[M+H]+.
using (E)-	oAAn^O^CHFj	1H NMR (400 MHz, DMSO-d6)
methyl 4-		8: 8.51 (s, 1H), 8.03 (d, J = 1.6
(tetrahydro-		Hz, 1H), 7.85 (d, J = 8.8 Hz, 2H),
2H-pyran-2-	ochf2	7.71 (d, J = 9.2 Hz, 1H), 7.48 (dd,
yloxy)-3-	6-(2,2-difluoroethoxy)-4-(4-	J = 9.2 Hz, 2.0 Hz, 1H), 7.34 (t,
(4,4,5,5-	(difluoromethoxy)phenyl)-2-(2-	Jhf = 74.0 Hz, 1H), 7.25 (d, J =
tetramethyl-	methyl-2H-indazol-5-yl)-8-	8.8 Hz, 2H), 6.95 (s, 1H), 6.40 (tt,
1,3,2-	(((tetrahydro-2H-pyran-2-	Jhf = 54.4 Hz, J = 3.2 Hz, 1H),
dioxaborolan-	yl)oxy)methyl)pyrido [3,2-	4.98 (d, J = 16.4 Hz, 1H), 4.83 (d,
2-yl)but-2enoate (Ref: Tetrahedron 2012, 68, 3444.3449)	c]pyridazin- 3 (2H)-one	J = 16.4 Hz, 2H), 4.59 (td, JHF = 15.2 Hz, J = 3.2 Hz, 2H), 4.23 (s, 3H), 3.79-3.74 (m, 1H), 3.49-3.40 (m, 1H), 1.83-1.45 (m, 6H).

Example 143

Cl

2-(benzo[d]thiazol-6-yl)-4-(4chlorophenyl)-6-(2,2difluoroethoxy)pyrido[3,2

c]pyridazin-3 (2H)-one

Example 144

2-(benzo[d]thiazol-6-yl)-6-(2,2difluoroethoxy)-4-(4 methoxyphenyl)pyrido [3,2 LC-MS (ESI): m/z 471 [M+H]+. 1H NMR (400 MHz, DMSO-d₆) δ 9.55 (s, 1H), 8.55 (d, J = 2.1 Hz, 1H), 8.26 (d, J = 8.7 Hz, 1H), 8.08 (d, J = 9.4 Hz, 1H), 7.92 - 7.79 (m, 3H), 7.60-7.47 (m, 2H), 7.11 (d, J = 9.4 Hz, 1H), 6.42 (tt, J = 54.3, 3.3 Hz, 1H), 4.61 (td, J = 15.2,3.3 Hz, 2H).

LC-MS (ESI): m/z 467 [M+H]+. 1H NMR (400 MHz, DMSO-d₆) δ 9.54 (s, 1H), 8.53 (s, 1H), 8.24 (d, J = 8.7 Hz, 1H), 8.03 (d, J = 9.4 Hz, 1H), 7.94-7.70 (m, 3H), 7.126.96 (m, 3H), 6.42 (t, J = 54.3 Hz, 1H), 4.61 (td, J = 15.2, 3.3 Hz, 2H), 3.83 (s, 3H).

c]pyridazin-3 (2H)-one

Example 145

2-(benzo[d]thiazol-6-yl)-4-(4(difluoromethoxy)phenyl)-6ethoxypyrido[3,2-c]pyridazm3(2H)-one

LC-MS (ESI): m/z 467 [M+H]+. 1H NMR (400 MHz, DMSO-d₆) δ 9.53 (s, 1H), 8.53 (d, J = 2.1 Hz, 1H), 8.24 (d, J = 8.7 Hz, 1H), 7.97 (d, J = 9.4 Hz, 1H), 7.91-7.80 (m, 3H), 7.35 (t, J = 74.0 Hz, 1H), 7.25 (d, J = 8.8 Hz, 2H), 6.97 (d, J = 9.4 Hz, 1H), 4.34 (q, J = 7.1 Hz, 2H), 1.32 (t, J = 7.1 Hz, 3H).

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Example 146	χ.·Ν η , 0AA- /'A 0 ochf2 2-(benzo[d]thiazol-6-yl)-4-(4(difluoromeÎhoxy)phcnyl)-6isopropoxypyrido [3,2- c] pyridazin3(2H)-one	LC-MS (ESI): m/z 481 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 9.53 (s, 1H), 8.52 (d, J = 2.1 Hz, 1H), 8.24 (d, J = 8.7 Hz, 1H), 7.96 (d, J = 9.4 Hz, 1H), 7.83 (m, 3H), 7.35 (t, J = 74.0 Hz, 1H), 7.25 (d, J = 8.8 Hz, 2H), 6.92 (d, J = 9.4 Hz, 1H), 5.16 (hept, J = 6.6 Hz, 1H), 1.31 (d, J = 6.2 Hz, 6H).
Example 147	NXY A, xL A x ο^γ n o y XX F I 11 An 2-(benzo[d]thiazol-6-yl)-4-(6cyclopropylpyridin-3-yl)-6-(2,2difluoroethoxy)pyrido[3,2c]pyridazin-3(2H)-one	LC-MS (ESI): m/z 478 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 9.59 (s, 1H), 8.86 (d, J = 2.1 Hz, 1H), 8.59 (d, J = 2.1 Hz, 1H), 8.31 (d, J = 8.7 Hz, 1H), 8.18 - 8.02 (m, 2H), 7.90 (dd, J = 8.7, 2.1 Hz, 1H), 7.45 (d, J = 8.1 Hz, 1H), 7.15 (d, J = 9.4 Hz, 1H), 6.46 (tt, J = 54.3, 3.4 Hz, 1H), 4.66 (td, J = 15.1, 3.4 Hz, 2H), 2.23 (tt, J = 7.7, 5.0 Hz, 1H), 1.10-0.98 (m, 4H).
Example 148	N-X% ÇAN-yy 0^A' F F Γ 11 ochf2 2-(benzo[d]thiazol-6-yl)-6-(2,2difluoroethoxy)-4-(6(difluoromethoxy)pyridin-3 yl)pyrido [3,2-c]pyridazin-3 (2H)- one	LC-MS (ESI): m/z 504 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 9.54 (s, 1H), 8.69 (d, J = 2.4 Hz, 1H), 8.54 (d, J = 2.2 Hz, 1H), 8.35 (dd, J = 8.6, 2.4 Hz, 1H), 8.25 (d, J = 8.8 Hz, 1H), 8.09 (d, J = 9.4 Hz, 1H), 7.86 (dd, J = 8.7, 2.2 Hz, 1H), 7.80 (t, J = 72.8 Hz, 1H), 7.21 (d, J = 8.6 Hz, 1H), 7.11 (d, J = 9.4 Hz, 1H), 6.41 (tt, J = 54.2, 3.3 Hz, 1H), 4.62 (td, J = 15.1, 3.4 Hz, 3H).

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Example 149	Ο^γ^ N^O^'Y F Jx F OH 6-(2,2-difluoroethoxy)-4-(4hydroxycyclohex-1 -en-1 -yl)-2-(2methyl-2H-indazol-5-yl)pyrido[3,2c]pyridazin-3 (2H)-one	LC-MS: m/z 454.2 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ: 8.47 (s, 1H), 7.99-7.94 (m, 2H), 7.68 (d, J = 9.2 Hz, 1H), 7.39 (dd, J = 9.2 Hz, 2.0 Hz, 1H), 7.00 (d, J = 9.6 Hz, 1H), 6.46 (tt, JHF = 54.4 Hz, 3.6 Hz, 1H), 5.86-5.80 (m, 1H), 4.74 (d, J = 4.0 Hz, 1H), 4.71 (td, J = 14.8 Hz, 3.6 Hz, 2H), 4.19 (s, 3H), 3.92-3.79 (m, 1H), 2.512.41 (m, 3H), 2.15-2.02 (m, 1H), 1.95-1.85 (m, 1H), 1.65-1.53 (m, 1H).
Example 150	AxAx A ^-x .F Ο^γ N 0 Y Αχ F γί H N A 6-(2,2-difluoroethoxy)-4-(lHindol-5-yl)-2-(2-methyl-2Hindazol- 5 -yl)pyrido [3,2c]pyridazin-3 (2H)-one	LC-MS: m/z 473.1 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ: 11.18 (br s, 1H), 8.49 (s, 1H), 8.06-8.01 (m, 3H), 7.71 (d, J = 9.2 Hz, 1H), 7.56 (dd, J = 8.4 Hz, 1.6 Hz, 1H), 7.47 (dd, J = 9.2 Hz, 2.0 Hz, 1H), 7.42 (d, J — 8.8 Hz, 1H), 7.36 (t, J = 2.8 Hz, 1H), 7.03 (d, J = 9.2 Hz, 1H), 6.49-6.46 (m, 1H), 6.40 (tt, Jhf = 54.8 Hz, 3.6 Hz, 1H), 4.56 (td, J = 14.8 Hz, 3.6 Hz, 2H), 4.22 (s, 3H).
Example 151	νΟ,γ. O^Y N^O^Y f JL F Q d^° 4 2-(benzo[d]thiazol-6-yl)-6-(2,2difluoro ethoxy)-4-(4-methoxy-d3 phenyl)pyrido [3,2-c] pyridazin-	LC-MS : m/z 470.1 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ: 9.52 (s, 1H), 8.52 (s, 1H), 8.24 (d, J = 8.8 Hz, 1H), 8.03 (d, J = 9.2 Hz, 1H), 7.87-7.76 (m, 3H), 7.06 (d, J = 9.6 Hz, 1H), 7.01 (d, J = 8.8 Hz, 2H), 6.41 (tt, JHF = 54.4 Hz, 3.2 Hz, 1H), 4.60 (td, J = 14.8 Hz, 3.2 Hz, 2H).

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	3(2H)-one
Example 152		LC-MS: m/z 468.2 (M+H)+.
		1H NMR (400 MHz, DMSO-d6)
		δ: 8.47 (s, 1H), 7.99-7.93 (m, 2H),
	F	7.68 (d, J = 9.2 Hz, 1H), 7.39 (dd, J = 9.2 Hz, 2.0 Hz, 1H), 7.01 (d, J
		= 9.6 Hz, 1H), 6.46 (tt, Jhf = 56.4
	6-(2,2-diflu.oroethoxy) -4-(4-	Hz, 3.6 Hz, 1H), 5.88-5.82 (m,
	methoxycyclohex-1 -en-1 -yl) -2-(2-	1H), 4.71 (td, Jhf = 15.2 Hz, 3.6
	methyl-2H -indazol-5 -yl)pyrido[3,2-	Hz, 2H), 4.21 (s, 3H), 3.60-3.51
	c]pyridazin-3 (2H)-one	(m, 1H), 3.31 (s, 3H), 2.61-2.41 (m, 3H) 2.21-2.09 (m, 1H), 2.041.94 (m, 1H), 1.72-1.58 (m, 1H).
Example 153		LC-MS: m/z 424.1 (M+H)+.
	\ΧλΝ.Ν^	1H NMR (400 MHz, DMSO-d6)
	o y n o y	δ: 13.31 (br s, 1H), 8.52 (s, 1H),
	À F U nh	8.13 (d, J = 9.2 Hz, 1H), 8.02 (d, J
	6-(2,2-difluoroethoxy)-2-(2methyl-2H-indazol-5-yl)-4-(lHpyrazol- 5 -yl)pyrido [3,2c]pyridazin-3(2H)-one (synthesized from 4-chloro-2-(2-methyl-2Hindazol-5-yl)pyrido[3,2- c]pyridazine-3,6(2H,5H)-dione & tert-butyl 5-(4,4,5,5-tetramethyl1,3,2-dioxaborolan-2-yl)-1Hpyrazole-l-carboxylate, then deBoc with TFA-DCM)	= 1.2 Hz, 1H), 7.76-7.69 (m, 2H), 7.56-7.50 (m, 1H), 7.47 (dd, J = 9.2 Hz, 1.6 Hz, 1H), 6.78 (d, J = 9.2 Hz, 1H), 6.55 (tt, Jhf = 54.0 Hz, 3.2 Hz, 1H), 4.92 (td, J = 14.8 Hz, 3.2 Hz, 2H), 4.23 (s, 3H).
Example 302		LC-MS: m/z 439 (M+H)+.
	-N. X^. '~ N V H	1H NMR (400 MHz, DMSO-d6)
		δ: 8.82 (d, J = 1.8 Hz, 1H), 8.49
	μ ||	(s, 1H), 8.07 (dd, J = 8.0 Hz, 2.2
		Hz, 1H), 8.01 (dd, J = 2.0 Hz, 0.7 Hz, 1H), 7.99 (d, J = 9.4 Hz, 1H),

	6 -(cyclopropylmethoxy) -2-(2methyl-2H-indazol-5-yl)-4-(6methylpyridin-3-yl)pyrido[3,2c] pyridazin-3 (2H)-one	7.70 (d, J = 9.1 Hz, 1H), 7.45 (dd, J = 9.1 Hz, 2.0 Hz, 1H), 7.34 (d, J = 8.1 Hz, 1H), 6.99 (d, J = 9.4 Hz, 1H), 4.22 (s, 3H), 4.16 (d, J = 7.3 Hz, 2H), 2.53 (s, 3H), 1.27-1.17 (m, 1H), 0.58-0.50 (m, 2H), 0.330.25 (m, 2H).
Example 303	[H YN 6-(cyclopropylmethoxy)-4-(6cyclopropylpyridin-3 -yl)-2-(2methyl-2H-indazol-5-yl)pyrido[3,2c] pyridazin- 3 (2H) -one	LC-MS: m/z 465 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ: 8.77 (d, J = 1.8 Hz, 1H), 8.49 (s, 1H), 8.03 (dd, J = 8.1 Hz, 2.2 Hz, 1H), 8.00 (d, J = 1.3 Hz, 1H), 7.98 (d, J = 9.4 Hz, 1H), 7.70 (d, J = 9.2 Hz, 1H), 7.45 (dd, J = 9.2 Hz, 2.0 Hz, 1H), 7.37 (d, J = 7.6 Hz, 1H), 6.99 (d, J = 9.4 Hz, 1H), 4.22 (s, 3H), 4.16 (d, J = 7.3 Hz, 2H), 2,21-2,11 (m, 1H), 1.25-1.21 (m, 1H), 1.05-0.93 (m, 4H), 0.590.47 (m, 2H), 0.33-0.22 (m, 2H).
Example 304	ü N 'y Y. F 2- (benzo [ d] thiazol-6-yl)-4- (4cyclopropylphenyl)-6-(2,2difluoroethoxy)pyrido [3,2c]pyridazin-3(2H)-one	LC-MS: m/z 477 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ: 9.53 (s, 1H), 8.52 (d, J = 2.1 Hz, 1H), 8.23 (d, J = 8.7 Hz, 1H), 8.03 (d, J = 9.4 Hz, 1H), 7.83 (dd, J = 8.7 Hz, 2.1 Hz, 1H), 7.70 (d, J = 8.3 Hz, 2H), 7,15 (d, J = 8.4 Hz, 2H), 7.07 (d, J = 9.4 Hz, 1H), 6.40 (tt, Jhf = 54.4 Hz, J = 3.3 Hz, 1H), 4.59 (td, Jhf = 15.1 Hz, J = 3.3 Hz, 2H), 2.07-1.90 (m, 1H), 1.080.95 (m, 2H), 0.84-0.64 (m, 2H).

The procedure set forth above for General Procedure I (Method C) was used to synthesize the folio wing compounds by using appropriate starting materials:

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Cpd No.	Structure	Characterization
Example 154	0^''Y N ^CFo 1 H 3 0 Cl 4-(4-chlorophenyl)-2-(2-methyl-2Hindazol-5-yl)-6-((2,2,2trifluoroethyl)amino)pyrido [3,2c]pyridazin-3 (2H)-one	LC-MS (ESI): m/z 485.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) Ô: 8.83 (t, J = 6.0 Hz, 1H), 8.47 (s, 1H), 7.96 (d, J = 1.2 Hz, 1H), 7.78-7.76 (m, 3H), 7.68 (d, J = 9.2 Hz, 1H), 7.45-7.41 (m, 3H), 6.92 (d, J = 9.2 Hz, 1H), 4.274.17 (m, 2H), 4.21 (s, 3H).
Example 155	1 H 0 Cl 4-(4-chlorophenyl)-6- (cyclopropylamino)-2-(2-methyl-2HindazoI-5-yl)pyrido [3,2-c]pyridazin3(2H)-one	LC-MS (ESI): m/z 443.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ: 8.46 (s, 1H), 8.45 (s, 1H), 7.977.95 (m, 3H), 7.67 (d, J = 9.2 Hz, 1H), 7.61 (d, J = 9.2 Hz, 1H), 7.45-7.41 (m, 3H), 6.73 (d, J = 8.4 Hz, 1H), 4.22 (s, 3H), 2.882.86 (m, 1H), 0.76-0.74 (m, 2H), 0.59-0.54 (m, 2H).
Example 156	N N ^CH f2 1 H 0 Cl 4-(4-chlorophenyl)-6-((2,2difluoroethyl) amino) -2-(2-methyl2H-indazol-5-yl)pyrido[3,2- c] pyridazin-3 (2H)-one	LC-MS (ESI): m/z 467.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ: 8.67 (t, J = 6.0 Hz, 1H), 8.47 (s, 1H), 7.96 (d, J = 2.0 Hz, 1H), 7.79 (d, J = 8.8 Hz, 2H), 7.73 (d, J = 9.2 Hz, 1H), 7.68 (d, J = 9.2 Hz, 1H), 7.45-7.41 (m, 3H), 6.90 (d, J = 9.2 Hz, 1H), 6.17 (tt, JHf = 56.0 Hz, J = 3.6 Hz, 1H), 4.22 (s, 3H), 3.79-3.69 (m, 2H).

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Example 157	n F 0 ocd3 6-(2-fluoroethoxy)-4-(4-(methoxyd3)phenyl)-2-(2-methyl-2H-indazol5-yl)pyrido[3,2-c]pyridazin-3(2H)one	LC-MS (ESI): m/z 449.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ: 8.49 (s, 1H), 8.00-7.98 (m, 2H), 7.79 (d, J = 8.8 Hz, 2H), 7.71 (d, J = 9.2 Hz, 1H), 7.45 (dd, J = 9.2 Hz, 2.0 Hz, 1H), 7.01-6.99 (m, 3H), 4.83 (t, J = 4.0 Hz, 1H), 4.71 (t, J = 4.0 Hz, 1H), 4.59 (t, J = 4.0 Hz, 1H), 4.51 (t, J = 4.0 Hz, 1 H), 4.23 (s, 3H).
Example 158	ochf2 4-(4-(difluoromethoxy)phenyl)-6 (ethylthio)-2 -(2 -methyl-2H-indazol5-yl)pyrido [3,2-c]pyridazin-3 (2H)- one	LC-MS (ESI): m/z 480.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ: 8.50 (s, 1H), 8.03 (d, J = 1.6 Hz, 1H), 7.86-7.83 (m, 3H), 7.71 (d, J = 9.2 Hz, 1H), 7.47 (dd, J = 8.8 Hz, 1.6 Hz, 1H), 7.34 (t, JHF = 74.0 Hz, 1H), 7.26 (d, J = 8.8 Hz, 2H), 7.21 (d, J = 9.2 Hz, 1H), 4.23 (s, 3H), 3.08 (q, J = 7.2 Hz, 2H), 1.22 (t, J = 7.2 Hz, 3H).
Example 159	-CUL .N^, n γη À H 0 ochf2 4-(4-(difluoromethoxy)phenyl)-6(ethylamino)-2-(2-methyl-2Hindazol-5-yl)pyrido[3,2-c]pyridazin3(2H)-one	LC-MS (ESI): m/z 463.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ: 8.46 (s, 1H), 8.32 (t, J = 5.2 Hz, 1H), 7.94 (d, J = 1.2 Hz, 1H), 7.86 (d, J = 8.8 Hz, 2H), 7.67 (d, J = 9.2 Hz, 1H), 7.61 (d, J = 9.6 Hz, 1H), 7.41 (dd, J = 9.2 Hz, 2.0 Hz, 1H), 7.31 (t, Jhf = 74.0 Hz, 1H), 7.18 (d, J = 8.8 Hz, 2H), 6.79 (d, J = 9.6 Hz, 1H), 4.22 (s, 3H), 3.45-3.21 (m, 2H), 1.15 (t, J = 7.2 Hz, 3H).

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Example 160	-gCl '- N VX O^X bX N X3 JL H 0 ochf2 4-(4-(difluoromethoxy)phenyl)-2-(2methyl-2H-indazol-5-yl)-6-((2,2,2trifluoroethyl)amino)pyrido[3,2c]pyridazin-3 (2H)-one	LC-MS (ESI): m/z 517.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ: 8.80 (i, J = 6.4 Hz, 1H), 8.47 (s, 1H), 7.96 (d, J = 2.0 Hz, 1H), 7.81 (d, J = 8.8 Hz, 2H), 7.77 (d, J = 9.6 Hz, 1H), 7.68 (d, J = 9.2 Hz, 1H), 7.42 (dd, J = 9.2 Hz, 2.0 Hz, 1H), 7.32 (t, Jhf = 74.0 Hz, 1H), 7.18 (d, J = 8.8 Hz, 2H), 6.91 (d, J = 9.6 Hz, 1H), 4.274.18 (m, 2H), 4.21 (s, 3H).
Example 161	O^X^ kXcXcD3 0 ochf2 4-(4-(difluoromethoxy)phenyl)-6(ethoxy-d5)-2-(2-methyl-2H-indazol5-yl)pyrido[3,2-c]pyridazin-3(2H)one	LC-MS (ESI): m/z 469.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ: 8.43 (s, 1H), 7.94 (d, J = 1.6 Hz, 1H), 7.91 (d, J = 9.2 Hz, 1H), 7.80 (d, J = 8.8 Hz, 2H), 7.64 (d, J = 9.2 Hz, 1H), 7.39 (dd, J = 8.8 Hz, 2.0 Hz, 1H), 7.28 (t, JHF = 74.0 Hz, 1H), 7.18 (d, J = 8.8 Hz, 2H), 6.88 (d, J = 9.6 Hz, 1H), 4.16 (s, 3H).
Example 162	Χχι 1 H 0 ochf2 6-(cyclopropylamino)-4-(4(difluoromethoxy)phenyl) -2-(2methyl-2H-indazol-5-yl)pyrido[3,2c]pyridazin-3 (2H)-one	LC-MS (ESI): m/z 475.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ: 8.47 (s, 1H), 8.42 (d, J = 4.4 Hz, 1H), 8.00 (d, J = 9.2 Hz, 2H), 7.95 (d, J = 1.2 Hz, 1H), 7.68 (d, J = 9.2 Hz, 1H), 7.61 (d, J = 9.6 Hz, 1H), 7.42 (dd, J = 9.2 Hz, 2.0 Hz, 1H), 7.30 (t, Jhf = 74.0 Hz, 1H), 7.18 (d, J = 8.8 Hz, 2H), 6.73 (d, J = 9.6 Hz, 1H), 4.22 (s, 3H), 2.89-2.86 (m, 1H) 0.77-0.73

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		(m, 2H), 0.58-0.54 (m, 2H).
Example 163	°J NO 0 ochf2 4-(4-(difluoromethoxy)phenyl)-2-(2methyl-2H-indazol-5-yl)-6(pyrrolidin-1 -yl)pyrido [ 3,2c] pyridazin- 3 (2H)-one	1H NMR (400 MHz, DMSO-d6) δ 8.46 (s, 1H), 7.95 (d, J = 2.0 Hz, 1H), 7.92 (d, J = 8.8 Hz, 2H), 7.73 (d, J = 9.7 Hz, 1H), 7.67 (d, J = 9.2 Hz, 1H), 7.43 (dd, J = 9.1, 2.0 Hz, 1H), 7.31 (t, J = 74.3 Hz, 1H), 7.20-7.15 (m, 2H), 7.06 (d, J = 9.7 Hz, 1H), 4.21 (s, 3H), 3.64 (t, J = 6.8 Hz, 2H), 3.55 (t, J = 6.8 Hz, 2H), 1.99 (p, J = 6.2 Hz, 2H), 1.89 (p, J = 6.4 Hz, 2H).
Example 164	0 ochf2 6-(azetidin-l -yl)-4-(4(difluoromethoxy)phenyl)-2-(2methyl-2H-indazol-5-yl)pyrido[3,2c]pyridazin-3 (2H)-one	1H NMR (400 MHz, DMSO-d6) δ 8.46 (s, 1H), 7.94 (dd, J = 2.0, 0.8 Hz, 1H), 7.92-7.84 (m, 2H), 7.70 (d, J = 9.5 Hz, 1H), 7.70 7.63 (m, 1H), 7.42 (dd, J = 9.2, 2.0 Hz, 1H), 7.30 (t, J = 74.2 Hz, 1H), 7.16 (d, J = 8.9 Hz, 2H), 6.80 (d, J = 9.5 Hz, 1H), 4.364.26 (m, 2H), 4.21 (s, 3H), 4.144.04 (m, 2H), 2.34 (h, J = 7.3 Hz, 2H).
Example 165	0 F ochf2 4-(4-(difluoromethoxy)phenyl)-2-(2 methyl-2H-indazol-5-yl)-6-((2,2,2trifluoroethyl)thio)pyrido[3,2c]pyridazin-3(2H)-one	LC-MS: m/z 534.1 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ: 8.51 (s, 1H), 8.04 (d, J = 1.2 Hz, 1H), 7.99 (d, J = 9.2 Hz, 2H), 7.80 (d, J = 8.8 Hz, 2H), 7.71 (d, J = 9.2 Hz, 1H), 7.48 (dd, J = 9.2 Hz, 2.0 Hz, 1H), 7.38 (d, J = 9.2 Hz, 1H), 7.33 (t, Jhf = 74.0 Hz, 1H), 7.24 (d, J = 8.8 Hz, 2H), 4.22 (s, 3H), 4.19 (q, J = 10.4 Hz, 2H).

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Example 305	—N ] | , 1 H pii 6-(ethylamino)-2-(2-methyl-2Hindazol-5-yl)-4-(6-methylpyridin-3- yl)pyrido [3,2-c]pyridazin- 3 (2H) -one	LC-MS: m/z 412 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ: 8.84 (d, J = 2.0 Hz, 1H), 8.46 (s, 1H), 8.36 (t, J = 5.3 Hz, 1H), 8.07 (dd, J = 8.0 Hz, 2.2 Hz, 1H), 7.93 (d, J = 1.4 Hz, 1H), 7.66 (d, J = 9.2 Hz, 1H), 7.62 (d, J = 9.2 Hz, 1H), 7.41 (dd, J = 9.2 Hz, 2.0 Hz, 1H), 7.27 (d, J = 8.1 Hz, 1H), 6.80 (d, J = 9.5 Hz, 1H), 4.21 (s, 3H), 3.21 (br, 2H), 2.5 (s, 3H), 1.13 (t, J = 7.2 Hz, 3H).
Example 306	λ N N 1 H fil 6-(cyclopropylamino)-2-(2-methyl2H-indazol-5-yl)-4-(6methylpyridin-3-yl)pyrido[3,2- c]pyridazin-3 (2H)-one	LC-MS: m/z 424 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ: 8.95 (s, 1H), 8.52 (d, J = 4.1 Hz, 1H), 8.46 (s, 1H), 8.19 (dd, J = 8.1 Hz, 2.1 Hz, 1H), 7.94 (s, 1H), 7.67 (d, J = 9.2 Hz, 1H), 7.61 (d, J = 9.4 Hz, 1H), 7.41 (dd, J = 9.2 Hz, 2.0 Hz, 1H), 7.27 (d, J = 8.2 Hz, 1H), 6.75 (d, J = 9.5 Hz, 1H), 4.21 (s, 3H), 2.89-2.82 (m, 1H), 2.51 (s, 3H), 0.76-0.72 (m, 2H), 0.59-0.54 (m, 2H).
Example 307	N 1 H Γη 0^ 6-(ethylamino)-4-(6methoxypyridin-3 -yl)-2-(2-methyl2H-indazol- 5 -yl)pyrido [3,2 c] pyridazin-3 (2H)-one	LC-MS: m/z 428 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ: 8.61 (d, J = 2.3 Hz, 1H), 8.45 (s, 1H), 8.36 (d, J = 5.8 Hz, 1H), 8.13 (dd, J = 8.6 Hz, 2.3 Hz, 1H), 7.93 (d, J = 1.3 Hz, 1H), 7.66 (d, J = 9.1 Hz, 1H), 7.60 (d, J = 9.5 Hz, 1H), 7.40 (dd, J = 9.1 Hz, 2.0 Hz, 1H), 6.85 (d, J = 8.9 Hz, 1H), 6.82 (d, J = 8.9 Hz, 1H), 4.21 (s, 3H), 3.89 (s, 3H), 3.45 (s, 2H),

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		1.14 (t, J = 7.2 Hz, 3H).
Example 308	X -λ o r N N ! H (il °\ 6-(cyclopropylamino)-4-(6methoxypyridin- 3 -yl)-2-(2 -methyl2H-indazol- 5 -yl)pyrido [3,2c]pyridazin-3 (2H)-one	LC-MS: m/z 440 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ: 8.72 (s, 1H), 8.60 (s, 1H), 8.46 (s, 1H), 8.27 (d, J = 8.4 Hz, 1H), 7.94 (s, 1H), 7.67 (d, J = 9.1 Hz, 1H), 7.60 (d, J = 9.4 Hz, 1H), 7.41 (dd, J = 9.2 Hz, 1.9 Hz, 1H), 6.83 (s, 1H), 6.78 (s, 1H), 4.21 (s, 3H), 3.88 (s, 3H), 2.89-2.82 (m, 1H), 0.76-0.72 (m, 2H), 0.59-0.54 (m, 2H).
Example 309	O^r' N 1 H fil VN 4-(6-cyclopropylpyridin-3-yl)-6- (ethylamino) -2- (2 -methyl-2H- indazol-5 -yl)pyrido [3,2 -c] pyridazin- 3(2H)-one	LC-MS: m/z 438 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ: 8.77 (d, J = 2.0 Hz, 1H), 8.45 (s, 1H), 8.33 (d, J = 5.5 Hz, 1H), 8.03 (dd, J = 8.1 Hz, 2.2 Hz, 1H), 7.93 (d, J = 1.4 Hz, 1H), 7.66 (d, J - 9.1 Hz, 1H), 7.60 (d, J = 9.5 Hz, 1H), 7.40 (dd, J = 9.2 Hz, 2.0 Hz, 1H), 7.30 (d, J = 8.2 Hz, 1H), 6.78 (d, J = 9.6 Hz, 1H), 4.20 (s, 3H), 3.24 (br, 2H), 2.14-2.11 (m, 1H), 1.14 (t, J = 7.2 Hz, 3H), 0.97-0.94 (m, 4H).
Example 310	N 1 H F^F 4-(6-(difluoromethyl)pyridin-3-yl)-6(ethylamino)-2-(2-methyl-2Hindazol-5-yl)pyrido[3,2-c]pyridazin-	LC-MS: m/z 448 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ: 9.06 (s, 1H), 8.52-8.43 (m, 2H), 8.38 (dd, J = 8.1 Hz, 1.9 Hz, 1H), 7.96 (d, J = 1.4 Hz, 1H), 7.73 (d, J = 8.2 Hz, 1H), 7.67 (d, J = 9.2 Hz, 1H), 7.65 (d, J = 9.6 Hz, 1H), 7.42 (dd, J = 9.1 Hz, 2.0 Hz, 1H), 6.99 (t, Jhf = 55.1 Hz, 1H), 6.82 (d, J = 9.6 Hz, 1H),

-8720638

	3(2H)-one	4.21 (s, 3H), 3.34 (br, 2H), 1.14 (t, J = 7.2 Hz, 3H).
Example 311	O - N 1 H 0 2-(benzo[d]thiazol-6-yl)-4-(4cyclopropylphenyl)- 6 - (ethylamino)pyrido [ 3,2-c] pyridazin3(2H)-one	LC-MS: m/z 440 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ: 9.49 (s, 1H), 8.46 (d, J = 2.0 Hz, 1H), 8.29 (t, J = 5.7 Hz, 1H), 8.19 (d, J = 8.6 Hz, 1H), 7.77 (dd, J = 8.8 Hz, 2.1Hz, 1H), 7.69 (d, J = 8.3 Hz, 2H), 7.59 (d, J = 9.5 Hz, 1H), 7.07 (d, J = 8.3 Hz, 2H), 6.79 (d, J = 9.6 Hz, 1H), 3.41 (br, 2H), 1.98-1.92 (m, 1H), 1.14 (t, J = 7.2 Hz, 3H), 1.02-0.91 (m, 2H), 0.76-0.62 (m, 2H).
Example 312	1 H 4-(4-cyclopropylphenyl)- 6(ethylamino)-2-(2-methyl-2Hindazol-5-yl)pyrido[3,2-c]pyridazin- 3(2H)-one	LC-MS: m/z 437 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ: 8.45 (s, 1H), 8.22 (t, J = 5.6 Hz, 1H), 7.91 (s, 1H), 7.67 (t, J = 9.3 Hz, 3H), 7.58 (d, J = 9.5 Hz, 1H), 7.39 (dd, J = 9.1 Hz, 2.0 Hz, 1H), 7.06 (d, J = 8.4 Hz, 2H), 6.76 (d, J = 9.5 Hz, 1H), 4.21 (s, 3H), 3.30 (br, 2H), 2.02-1.87 (m, 1H), 1.14 (t, J = 7.2 Hz, 3H), 1.02-0.90 (m, 2H), 0.77-0.64 (m, 2H).
Example 313	1 H pii O^F F 4-(6-(difluoromethoxy)pyridin-3-yl)- 6-(ethylamino)-2-(2-methyl-2H-	LC-MS: m/z 464 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ: 8.63 (d, J = 2.3 Hz, 1H), 8.43 (s, 1H), 8.30 (dd, J = 8.6 Hz, 2.3 Hz, 1H), 7.92 (s, 1H), 1.12 (t, Jhf = 73.2 Hz, 1H), 7.66 (d, J = 9.1 Hz, 1H), 7.61 (d, J = 9.5 Hz, 1H), 7.40 (dd, J = 9.1 Hz, 2.0 Hz, 1H), 7.11 (d, J = 8.6 Hz, 1H), 6.79 (d,

-8820638

	indazol-5-yl)pyrido[3,2-c]pyridazin3(2H)-one	J = 9.5 Hz, 1H), 4.18 (s, 3H), 3.34 (q, J = 7.2 Hz, 2H), 1.12 (t, J = 7.2 Hz, 3H).
Example 314	aa <0 Af OZV N 0 Vf y n 4-(6-cyclopropylpyridin-3-yl)-6((2,2-difluorocyclopropyl)methoxy)2-(2-methyl-2H-indazol-5- yl)pyrido [3,2-c]pyridazin-3 (2H)-one	LC-MS: m/z 501 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ: 8.77 (d, J = 1.9 Hz, 1H), 8.50 (s, 1H), 8.07-7.98 (m, 3H), 7.70 (d, J = 9.1 Hz, 1H), 7.45 (dd, J = 9.2 Hz, 2.0 Hz, 1H), 7.38 (d, J = 7.8 Hz, 1H), 7.02 (d, J = 9.4 Hz, 1H), 4.57-4.46 (m, 1H), 4.35-4.14 (m, 4H), 2.26-2.11 (m, 2H), 1.711.98 (m, 1H), 1.50-1.45 (m, 1H), 1.02-0.83 (m,4H).

The procedure set forth above for General Procedure I (Method D) was used to synthesize the folio wing compounds by using appropriate starting materials:

Cpd No.	Structure	Characterization
Example 315	0ΑγΑ N 1 H V On 6-((cyclopropylmethyl)amino)-4(6-cyclopropylpyridin-3-yl)-2-(2methyl -2H-indazol- 5 -yl)pyrido [3,2c] pyridazin- 3 (2H)-one	LC-MS: m/z 464 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ: 8.75 (d, J = 2.2 Hz, 1H), 8.48 (t, J = 5.7 Hz, 1H), 8.45 (s, 1H), 8.00 (dd, J = 8.1 Hz, 2.1 Hz, 1H), 7.93 (d, J = 1.3 Hz, 1H), 7.66 (d, J = 9.0 Hz, 1H), 7.61 (d, J = 9.5 Hz, 1H), 7.40 (dd, J = 9.2 Hz, 1.9 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 6.85 (d, J = 9.5 Hz, 1H), 4.20 (s, 3H), 3.20 (t, J = 6.2 Hz, 2H), 2.15-2.09 (m, 1H), 1.12-0.86 (m, 5H), 0.50-0.36 (m, 2H), 0.22-0.09 (m, 2H).

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Example 316	N N i H An Φ 6-(ethylamino)-2-(2-methyl-2Hindazol-5-yl)-4-(6(trifluoromethyl)pyridin-3 yl)pyrido [3,2- c]pyridazin-3 (2H)one	LC-MS: m/z 466 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ: 9.15 (s, 1H), 8.53 (t, J = 5.2 Hz, 1H), 8.48 (d, J = 7.2 Hz, 2H), 8.017.88 (m, 2H), 7.66 (t, J = 8.4 Hz, 2H), 7.43 (dd, J = 9.2 Hz, 1.9 Hz, 1H), 6.83 (d, J = 9.6 Hz, 1H), 4.21 (s, 3H), 3.31 (br, 2H), 1.14 (t, J = 7.2 Hz, 3H).
Example 317	—N ] 1 F FPF A H On F F 4-(6-(difluoromethyl)pyridin-3-yl)2 -(2-methyl-2H-indazol-5 -yl)-6((2,2,2trifluoroethyl)amîno)pyrido [ 3,2c]pyridazin- 3 (2H) -one	LC-MS: m/z 502 (M+H)+. 1H NMR (400 MHz, DMSO-dÊ) δ: 9.06 (s, 1H), 9.01 (s, 1H), 8.48 (s, 1H), 8.33 (d, J = 9.7 Hz, 1H), 7.98 (d, J =1.7 Hz, 1H), 7.81 (d, J = 9.3 Hz, 1H), 7.73 (d, J = 7.9 Hz, 1H), 7.69 (d, J = 9.2 Hz, 1H), 7.44 (dd, J = 9.1 Hz, 1.9 Hz, 1H), 7.00 (d, J = 3.6 Hz, 1H), 6.92 (t, Jhf = 55.2 Hz, 1H), 4.21 (s, 5H).
Example 318	—N | ] FyF 1 H On 6-((2,2-difluoroethyl)amino)-2-(2methyl-2H-indazol-5-yl)-4-(6methylpyridin-3 -yl)pyrido[3,2c] pyridazin-3 (2H)-one	LC-MS: m/z 448 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ: 8.79 (d, J = 1.8 Hz, 1H), 8.73 (t, J = 5.2 Hz, 1H), 8.46 (s, 1H), 8.04 (dd, J = 8.0 Hz, 2.2 Hz, 1H), 7.95 (d, J = 1.4 Hz, 1H), 7.71 (d, J - 9.2 Hz, 1H), 7.68 (dd, J = 9.2 Hz, 1H), 7.41 (dd, J = 9.2 Hz, 2.0 Hz, 1H), 7.27 (d, J = 8.2 Hz, 1H), 6.92 (d, J = 9.6 Hz, 1H), 6.15 (tt, JHf = 56.0 Hz, J = 3.8 Hz, 1H), 4.21 (s, 3H), 3.75 (t, Jhf = 15.8 Hz, 2H), 2.51 (s,

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		3H).
Example 319	1 H On F^F 6-(ethylamino)-2-(2-methyl-2Hindazol-5-yl)-4-(6-(methyld3)pyridin-3 -yl)pyrido [3,2c]pyridazin-3(2H)-one	LC-MS: m/z 484 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ: 9.02 (s, 1H), 8.81 (t, J = 5.2 Hz, 1H), 8.48 (s, 1H), 8.36 (d, J = 9.7 Hz, 1H), 7.98 (d, J = 1.3 Hz, 1H), 7.76 (d, J = 9.5 Hz, 1H), 7.73 (d, J = 8.2 Hz, 1H), 7.69 (d, J = 9.1 Hz,
1H), 7.43 (dd, J = 9.1 Hz, 1.9 Hz,
1H), 7.00 (t, Jhf = 55.0 Hz, 1H),
6.94 (d, J = 9.5 Hz, 1H), 6.16 (tt,
Jhf = 56.4 Hz, J = 3.8 Hz, 1H),
4.21 (s, 3H), 3.75 (t, Jhf = 15.8 Hz,
2H).
Example 320	Z 5	LC-MS: m/z 415 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ
		(ppm): 8.85 (d, J = 1.5 Hz, 1H),
	JL H	8.46 (s, 1H), 8.38 (s, 1H), 8.07 (dd,
	II	J = 8.1 Hz, 2.2 Hz, 1H), 7.94 (d, J
	2h02h	= 1.4 Hz, 1H), 7.66 (d, J = 9.2 Hz,
		1H), 7.61 (d, J = 9.6 Hz, 1H), 7.41
	6-(ethylamino)-2-(2-methyl-2H-	(dd, J = 9.1 Hz, 2.0 Hz, 1H), 7.27
	indazol-5-yl)-4-(6-(methyl-	(d, J = 8.1 Hz, 1H), 6.80 (d, J = 9.5
	d3)pyridin- 3 -yl)pyrido [3,2 -	Hz, 1H), 4.21 (s, 3H), 3.33 (q, J
	c]pyridazin-3 (2H)-one	= 7.2 Hz, 2H, overlapped with H2O peak), 1.14 (t, J = 7.2 Hz,
	Prepared using Intermediate (6(methyl-d3)pyridin-3 -yl)boronic acid as described.	3H).

Synthesis of Intermediate (6-(methyl-d₃)pyridin-3-yl)boronic acid:

-9120638 ο

/U CD₃MgBr, Fe(acac)₃ ίγΝ THF, NMP

Br

Step A

B₂Pin₂, AcOK, Pd(dppf)CI₂ dioxane

Step D

Step A: 5-methoxy-2-i

O /Y L-selectride toluene

CD₃

Step B

B(OH)₂ φ

cd₃ iethyl-d₃ )pyridine

OH OTf

A γΝ DCM AyN cd₃ cd₃

4

Step C

To a solution of 2-bromo-5-methoxypyridine (7 g, 37.2 mmol, 1.0 eq.) and Fe(acac)₃ (1.31 g, 3.71 mmol, 0.1 eq.) in anhydrous THF (70 mL) was added CD₃MgI (1 M in THF) (93 mL, 93 mmol, 2.5 eq.) dropwise at 0°C under N₂ atmosphère, the resulting mixture was stirred for 3 hrs at 0 °C. After the completion, the reaction was quenched by adding NH4CI (sat. aq.) (200 mL), then extracted with EtOAc (70 mL x 3), the combined organic layers were washed with brine (100 mL), dried over Na2SO4 and concentrated under reduced pressure, the residue was purified by flash column chromatography on silica gel to give 5-methoxy-2(methyl-d₃)pyridine (4 g, 85%) as a colorless oil. LC-MS (ESI) :wz 127 [M+H]⁺.

Step B: 6-(methyl-d₃)pyridin-3-ol

To a solution of 5-methoxy-2-(methyl-d₃)pyridine (1.6 g, 12.6 mmol, 1.0 eq.) in dry toluene (20 mL) was added L-Selectride (1 M in THF) (37.8 mL, 37.8 mmol, 3.0 eq.) via dropping ftmnel at 0 °C dropwise, after the addition, the reaction mixture was allowed to warm to room température, then moved to pre-heated oil bath (110 °C) stirred for additional 3 hrs. After the completion, the reaction was cooled down to 0 °C again, quenched by adding MeOH (10 mL) carefully, the resulting mixture was concentrated under reduced pressure, the residue was purified by flash column chromatography on silica gel to give 6-(methyld₃)pyridin-3-ol (1.2 g, 84.3%) as a pale-yellow solid. LC-MS (ESI):m/z 113 [M+H]⁺.

Step C: 6-(methyl-d₃)pyridin-3-yl trifluoromethanesulfonate

To a solution of 6-(methyl-d₃)pyridin-3-ol (500 mg, 4.46 mmol, 1.0 eq.) and pyridine (0.54 mL, 6.69 mmol, 1.5 eq.) in dry DCM (10 mL), was added triflic anhydride (1.13 mL, 6.69 mmol, 1.5 eq.) via the syringe at 0 °C dropwise. The resulting mixture was allowed to warm

-9220638 to room température and stirred for additional 2 hrs. After completion, the reaction was quenched by adding H₂O (20 mL), then extracted with EtOAc (20 mL x 3), the combined organic layers were washed with dilute HCl (0.5 N, aq.) (20 mL), brine (20 mL), dried over Na₂SO4 and concentrated under reduced pressure, the residue was purified by flash column chromatography on silica gel to give 6-(methyl-d3)pyridin-3-yl trifluoromethanesulfonate (1.0 g, 91%) as a colorless oil. LC-MS (ESI): m/z 245 [M+H]⁺.

Step D: (6-(methyl-d3)pyridin-3-yl)boronic acid

To a solution of 6-(methyl-d3)pyridin-3-yl trifluoromethanesulfonate (1.0 g, 4.09 mmol, 1.0 eq.) in dry 1,4-dioxane (10 ml), was added bis(pinacolato)diboron (2.08 g, 8.2 mmol, 2.0 eq.), KOAc (1.6 g, 16.4 mmol, 4.0 eq.) and Pd(dppf)Cl₂ (300 mg, 0.41 mmol, 0.1 eq.). The resulting mixture was stirred at 100 °C under N₂ atmosphère for 16 hrs. After the completion, the crude mixture was fîltered through a short pad of Celite®, the filtrate was concentrated under reduced pressure, the residue was purified by RP-prep-HPLC to give (6-(methyld3)pyridin-3-yl)boronic acid (460 mg, 80%). LC-MS (ESI): m/z 141 [M+H]⁺.

General Procedure II:

Compounds of structure 2.8 and 2.11 were obtained through the scheme depicted as General Procedure IL Beginning with pyridazinone 2.1, the heterocycle was benzylated to generated compound 2.2. The desired R4 and R5 groups were introduced using a Suzuki cross-coupling to afford compounds of structure 2.3. Compound 2.3 was then cyclized under basic conditions to generate bicyclic compound 2.4. The desired R₂ group was introduced using a Suzuki coupling to generate compound 2.5. Compound 2.5 was then chlorinated to generate aryl-chloride 2.6. The desired Ri group was introduced via nucleophilic aromatic

-9320638 substitution, winch concurrently debenzylated the heterocyclic core to generate compound 2.7. Lastly, the desired R₃ group was introduced using an Ullmann coupling (Method A) or a Chan-Lam coupling (Method B) to afford compounds of structure 2.8. Altematively, Compound 2.5 could be activated with BOP and reacted with the desired Ri-amine to afford heterocycle 2.9 (Method C). The benzyl group was removed using t-BuOK to afford heterocycle 2.10 and the desired R₃ group was introduced using an Ullmann coupling to afford compounds of structure 2.11.

General Procedure lia (Method C):

2.14

RîB(OH)2 or R₂BPin

[Pd]/L, Base

Method C

2.1 D

R₃-Br

[Cu]/L, Base

2.11

General Procedure lia (Method C) was later developed using PMB as an alternative protecting group to the Bn protecting group shown in General Procedure II (Method C). Deprotection of heterocycle 2.16 under acidic conditions led to a convergent synthesis of compound structures 2.11.

Préparation of Example 166 via General Procedure II (Method A):

-94I

I

BnBr, K₂CO₃

DMF

PinB^⁰⁰*'

Pd(dppf)CI₂, K₂CO₃

DMF

Step A ^steP B ^steP ^c

ochf₂ ochf₂

Step D step E

Method A:

Step F Step G

Step A: 5-amino-2-benzyl-6-bromo-4-chloropyridazin-3(2H)-one

To a solution of 5-amino-6-bromo-4-chloropyridazin-3(2H)-one (3 g, 13.4 mmol, 1.0 eq.), K2CO3 (3.7 g, 26.8 mmol, 2.0 eq.) in DMF (50 mL) was added BnBr (2.5 g, 14,7 mmol, 1.1 eq.), the reaction mixture stirred at 80 °C ovemight. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL x 3), the combined organic layers were washed with brine (50 mL), dried over Na₂SO4 and concentrated under reduced pressure, the residue was purified by flash column chromatography on silica gel to afford 5-amino-2benzyl-6-bromo-4-chloropyridazin-3(2H)-one as a white solid (2.46 g, 59% yield). LC-MS (ESI) m/z 314, 316 [M+H]⁺.

Step B: ethyl (E)-3-(4-amino-l-benzyl-5-chloro-6-oxo-l,6-dihydropyridazin-3-yl)acrylate

To a solution of 5-amino-2-benzyl-6-bromo-4-chloropyridazin-3(2H)-one (2.46 g, 7.8 mmol, 1.0 eq.), K2CO3 (2.2 g, 15.6 mmol, 2.0 eq.), ethyl (E)-3-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)acrylate (1.94 g, 8.6 mmol, 1.1 eq.) in DMF (40 mL) was added

Pd(dppf)C12 (0.57 g, 0.8 mmol, 0.1 eq.) under N₂ atmosphère, the reaction mixture stirred at 100°C for 3 hrs. The reaction mixture was diluted with H₂O (50 mL) and extracted with EtOAc (50 mL x 3), the combined organic layers were washed with brine (50 mL), dried over Na₂SO₄ and concentrated under reduced pressure, the residue was purified by column chromatography to afford on silica gel to give ethyl (E)-3-(4-amino-l-benzyl-5-chloro-6

-9520638 oxo-l,6-dihydropyridazin-3-yl)acrylate as abrown solid (1.89 g, 71% yield). LC-MS (ESI): m/z 334 [M+H]⁺.

Step C: 2-benzyl-4-chloropyrido[3,2-c]pyridazine-3,6(2H,5H)-dione

To a stirred solution of ethyl (E)-3-(4-amino-l-benzyl-5-chloro-6-oxo-l,6-dihydropyridazin3-yl)acrylate (1.89 g, 5.66 mmol, 1.0 eq.) in EtOH (20 mL) was added K₂CO₃ (2.34 g, 16.98 mmol, 3.0 eq.), the reaction mixture stirred at 80 °C ovemight. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL x 3), the combined organic layers were dried over Na₂SO4 and concentrated under reduced pressure to give crude 2benzyl-4-chloropyrido[3,2-c]pyridazine-3,6(2H,5H)-dione as abrown solid (1.5 g), which used in next step without further purification. LC-MS (ESI): m/z 288 [M+H]⁺.

Step D: 2-benzyl-4-(4-(difluoromethoxy)phenyl)pyrido[3,2-c]pyridazine-3,6(2H,5H)-dione

To a stirred solution of 2-benzyl-4-chloropyrido[3,2-c]pyridazine-3,6(2H,5H)-dione (1.5 g, 5.2 mmol, 1.0 eq.), 2-(4-(difluoromethoxy)phenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (2 g, 7.2 mmol, 1.4 eq.), K₂CO₃ (1.54 g, 11.1 mmol, 2.1 eq.), X-Phos (0.52 g, 1.1 mmol, 0.2 eq.) in dioxane/H₂O mixture (88 mL, 10/1, v/v) was added Pd(OAc)₂ (0.12 g, 0.55 mmol, 0.1 eq.) under N₂ atmosphère. The reaction mixture stirred at 110°C ovemight. The reaction mixture was concentrated under reduced pressure, purified by column chromatography on silica gel to afford 2-benzyl-4-(4-(difluoromethoxy)phenyl)pyrido[3,2-c]pyridazine3,6(2H,5H)-dione (1.4 g, 68% yield) as a white solid. LC-MS (ESI): m/z 396 [M+H]⁺.

Step E: 2-benzyl-6-chloro-4-(4-(difluoromethoxy)phenyl)pyrido[3,2-c]pyridazin-3(2H)-one 2-benzyl-4-(4-(difluoromethoxy)phenyl)pyrido[3,2-c]pyridazine-3,6(2H,5H)-dione (400 mg, 1.01 mmol, 1.0 eq) was dissolved in POC1₃ (4 mL), the resulting mixture stirred at 80°C for 4 hrs. Excess POC1₃ was removed under reduced pressure and the residue was pour onto icecooled NaHCO₃ (sat. aq.) (20 mL) and extracted with DCM (30 mL x 3), the combined organic layers were dried over Na₂SO4 and concentrated under reduced pressure to give crude 2-benzyl-6-chloro-4-(4-(difluoromethoxy)phenyl)pyrido[3,2-c]pyridazin-3(2H)-one, as a yellow solid (400 mg, 95% yield). LC-MS (ESI): m/z 414 [M+H]⁺.

Step F : 6 -(2,2-difluoroethoxy)-4- (4 -(difluoromethoxy)phenyl)pyrido [ 3,2- c] pyridazin- 3 (2H)one

To a solution of 2-benzyl-6-chloro-4-(4-(difluoromethoxy)phenyl)pyrido[3,2-c]pyridazin3(2H)-one (400 mg, 0.97 mmol, 1.0 eq.), 2,2-difluoroethan-l-ol (396 mg, 4.8 mmol, 5.0 eq.) in anhy. THF (8 mL) was added t-BuOK (541 mg, 4.8 mmol, 5.0 eq.) in several portions at 0°C, after addition, the reaction mixture stirred at room température ovemight. The reaction

-9620638 mixture was diluted with H₂O (10 mL) and extracted with EtOAc (30 mL x 3), the combined organic layers were dried over Na₂SO₄ and concentrated under reduced pressure, the residue was purified by flash column chromatography on silica gel to give 6-(2,2-difluoroethoxy)-4(4-(difluoromethoxy)phenyl)pyrido[3,2-c]pyridazin-3(2H)-one as a yellow solid (150 mg, 42% yield). LC-MS (ESI): m/z 370 [M+H]⁺.

Step G: 6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)-2-(2,3-dimethyl-2H-indazol5-yl)pyrido[3,2-c]pyridazin-3(2H)-one (Method A)

To a stirred suspension of 6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)pyrido[3,2c]pyridazin-3(2H)-one (70 mg, 0.19 mmol, 1.0 eq.) in MeCN (3 mL) was added 5-bromo2,3-dimethyl-2H-indazole (64.0 mg, 0.28 mmol, 1.5 eq.), Cul (36.2 mg, 0.19 mmol, 1.0 eq.), A⁷,A²-dimethylcyclohexane-l,2-diamine (26.9 mg, 0.19 mmol, 1.0 eq.) and CsF (57.6 mg, 0.38 mmol, 2.0 eq.). The reaction was stirred in a seal tube at 85°C ovemight under N₂ atmosphère and concentrated under reduced pressure. The residue was purified by prepHPLC to afford 6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)-2-(2,3-dimethyl-2Hindazol-5-yl)pyrido[3,2-c]pyridazin-3(2H)-one (Example 166).

NMR (400 MHz, DMSO-d₆) δ: 8.07 (d, J = 9.4 Hz, 1H), 7.98 (d, J = 1.4 Hz, 1H), 7.87 (d, J = 8.0 Hz, 2H), 7.62 (d, J = 8.0 Hz, 1H), 7.42 (dd, J = 9.1 Hz, 2.0 Hz, 1H), 7.35 (t, Jhf = 72.0 Hz, 1H), 7.26 (d, J = 8.8 Hz, 2H), 7.06 (d, J = 9.4 Hz, 1H), 6.41 (tt, Jhf = 54.4 Hz, J = 3.3 Hz, 1H), 4.59 (td, J_Hf = 15.1 Hz, J = 3.3 Hz, 2H), 4.10 (s, 3H), 2.64 (s, 3H).

LC-MS (ESI): m/z 514 [M+H]⁺.

Préparation of Example 167 via General Procedure II (Method B):

Method B:

Step G: 6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)-2-(l-methyl-lHbenzo[d]imidazol-6-yl)pyrido[3,2-c]pyridazin-3(2H)-one (Method B)

To a suspension of 6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)pyrido[3,2c]pyridazin-3(2H)-one (70 mg, 0.19 mmol, 1.0 eq.) inDMF (5 mL) was added 1-methyl-lHbenzo[d]imidazol-6-ylboronic acid (33.4 mg, 0.23 mmol, 1.2 eq.), Cu(OAc)₂ (34.5 mg, 0.19

-9720638 mmol, 1.0 eq.) and pyridine (30.0 mg, 0.38 mmol, 2.0 eq.). After the mixture was stirred at 50 °C ovemight under air atmosphère, the reaction mixture was quenched by adding H₂O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layer was dried over anhydrous Na₂SO₄ and concentrated under reduced pressure, the residue was purified by prep-HPLC to afford 6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)-2-(l-methyl-lHbenzo[d]imidazol-6-yl)pyrido[3,2-c]pyridazin-3(2H)-one (Example 167).

^XH NMR (400 MHz, DMSO-d₆) δ: 8.34 (s, 1H), 8.06 (d, J = 9.4 Hz, 1H), 7.92 (d, J = 1.8 Hz, 1H), 7.88 (d, J = 8.0 Hz, 2H), 7.79 (d, J = 8.6 Hz, 1H), 7.47 (dd, J = 8.6 Hz, 2.0 Hz, 1H), 7.35 (t, Jhf = 72.0 Hz, 1H), 7.26 (d, J = 8.8 Hz, 2H), 7.07 (d, J = 9.4 Hz, 1H), 6.41 (tt, Jhf = 54.4 Hz, 3.3 Hz, 1H), 4.60 (td, Jhf = 15.1 Hz, 3.3 Hz, 2H), 3.88 (s, 3H).

LC-MS (ESI): m/z 500 [M+H]⁺.

Préparation of Example 321 via General Procedure II (Method C):

Step H Step I

Step J ^CHF*

Step H: 2-benzyl-4-(6-(difluoromethyl)pyridin-3-yl)-6“((ethyl-d5)amino)pyrido[3,2c]pyridazin-3 (2H)-one

To a solution of 2-benzyl-4-(6-(difluoromethyl)pyridin-3-yl)pyrido[3,2-c]pyridazine3,6(2H,5H)-dione (250 mg, 0.66 mmol, 1.0 eq.) in DMF (2 mL) was added BOP (436 mg, 0.99 mmol, 1.5 eq.) and DIEA (584 pL, 3.29 mmol, 5.0 eq.), the reaction mixture was stirred at room température for 1 hour, then added ethylamine-ds hydrochloride (86 mg, 0.99 mmol, 1.5 eq.), the resulting mixture was stirred at room température for additional 0.5 hour. After the completion, the reaction was quenched by adding ice water (10 mL) and extracted with EtOAc (10 ml x 3), dried over Na₂SO₄ and concentrated under reduced pressure, the residue was purified by flash column chromatography on silica gel to give 4-(6-9820638 (difluoromethyl)pyridin-3-yl)-6-((ethyl-d5)amino)pyridopyridazin-3(2H)-one (234 mg, 86%) as a yellow solid. LC-MS (ESI): m/z 413 [M+H]⁺.

Step I: 4-(6-(difluoromethyl)pyridin-3-yl)-6-((ethyl-d5)amino)pyrido[3,2-c]pyridazin-3(2H)one

To a solution of 2-benzyl-4-(6-(difluoromethyl)pyridin-3-yl)-6-((ethyld5)amino)pyridopyridazin-3(2H)-one (185 mg, 0.45 mmol, 1.0 eq.) in THF/DMF (2 mL, l/l)was added t-BuOK (251 mg, 2.25 mmol, 5.0 eq.), the reaction mixture was stirred at 70 °C for 8 hrs. After the completion, the pH was adjusted to ~7 by adding 1 N HCl (aq.), then the mixture was extracted with DCM (10 mL x 3). The combined organic layers were washed with brine (20mL) and dried over Na₂SÛ4, concentrated under reduced pressure, the residue was purified by flash chromatography to give 4-(6-(difluoromethyl)pyridin-3-yl)-6((ethyl-d₅)amino)pyridopyridazin-3(2H)-one (50 mg) as a yellow solid. LC-MS (ESI): m/z 323 [M+H]⁺.

Step J: 4-(6-(difluoromethyl)pyridin-3-yl)-6-((ethyl-d5)amino)-2-(2-(methyl-d3)-2H-indazol5 -yl)pyrido [3,2- c]pyridazin- 3 (2H)-one

To a solution of 4-(6-(difluoromethyl)pyridin-3-yl)-6-((ethyl-d5)amino)pyridopyridazin3(2H)-one (50 mg, 0.16 mmol, 1.0 eq.) and 5-bromo-2-(methyl-d3)-2H-indazole (50 mg, 0.23 mmol, 1.5 eq.) in ACN (1 mL) was added Cul (30 mg, 0.16 mmol, 1.0 eq.), CsF (47 mg, 0.31 mmol, 2.0 eq.), Nl,N2-dimethylcyclohexane-l,2-diamine (22 mg, 0.16 mmol, 1.0 eq.), the resulting mixture was stirred at 85°C for 14 hrs. After the completion, the reaction mixture was diluted with H₂O (5 mL), extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (20 mL) and dried over Na₂SO4, concentrated under reduced pressure, the residue was purified by RP-prep-HPLC to give 4-(6-(difluoromethyl)pyridin-3yl)-6-((ethyl-d₅)amino)-2-(2-(methyl-d3)-2H-indazol-5-yl)pyridopyridazin-3(2H)-one (Example 321).

^XH NMR (400 MHz, DMSO-Y) δ (ppm): 9.06 (s, 1H), 8.46 (d, J= 2.6 Hz, 2H), 8.39 (d, J= 8.0 Hz, 1H), 7.95 (s, 1H), 7.73 (d, J= 8.2 Hz, 1H), 7.66 (dd, J= 11.5, 9.4 Hz, 2H), 7.42 (dd, J =9.2, 1.9 Hz, 1H), 6.99 (t, J= 55.1 Hz, 1H), 6.82 (d,J=9.6Hz, 1H).

LC-MS (ESI): m/z 456 [M+H]⁺.

Préparation of Example 322 via General Procedure lia (Method C):

-9920638

Step A: 5-amino-6-bromo-4-chloro-2-(4-methoxybenzyl)pyridazin-3(2H)-one

To a solution of 5-amino-6-bromo-4-chloropyridazin-3(2H)-one (2.0 g, 8.91 mmol, 1.0 eq.) and K2CO3 (2.5 g, 17.8 mmol, 2.0 eq.) in DMF (20 mL) was added PMBC1 (1.3 mL, 9.8 mmol, 1.1 eq.), the reaction mixture stirred at 80 °C for 14hrs. After completion, the reaction mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL x 3), the combined organic layers were washed with brine (50 mL), dried over Na₂SO₄ and concentrated under reduced pressure, the residue was purified by flash column chromatography on silica gel to give 5-amino-6-bromo-4-chloro-2-(4methoxybenzyl)pyridazin-3(2H)-one (2.0 g, 45%) as a white solid. LC-MS (ESI): m/z 344 [M+H]⁺.

Step B: ethyl (E)-3-(4-amino-5-chloro-l-(4-methoxÿbenzyl)-6-oxo-l,6-dihydropyridazin-3yl)acrylate

To a solution of 5-amino-6-bromo-4-chloro-2-(4-methoxybenzyl)pyridazin-3(2H)-one (2.0 g, 5.8 mmol, 1.0 eq.), K₂CO₃ (2.0 g, 14.5 mmol, 2.5 eq.) and ethyl (E)-3-(4,4,5,5-tetramethyll,3,2-dioxaborolan-2-yl)acrylate (1.44 g, 6.4 mmol, 1.1 eq.) in DMF (20 mL) was added Pd(dppf)Cl₂ (0.43 g, 0.6 mmol, 0.1 eq.), the reaction mixture stirred at 100°C under N₂ atmosphère for 5 hrs. The reaction mixture was diluted with H₂O (30 mL) and extracted with EtOAc (50 mL x 3), the combined organic layers were washed with brine (40 mL), dried over Na₂SO₄ and concentrated under reduced pressure, the residue was purified by column chromatography to afford on silica gel to give ethyl (E)-3-(4-amino-5-chloro-l-(4methoxybenzyl)-6-oxo-l,6-dihydropyridazin-3-yl)acrylate as a brown solid (1.4 g, 53%). LC-MS (ESI): m/z 364 [M+H]⁺.

Step C: 4-chloro-2-(4-methoxybenzyl)pyrido[3,2-c]pyridazine-3,6(2H,5H)-dione

To a stirred solution of ethyl (E)-3-(4-amino-5-chloro-l-(4-methoxybenzyl)-6-oxo-l,6dihydropyridazin-3-yl)acrylate (1.4 g, 3.85 mmol, 1.0 eq.) in EtOH (20 mL) was added K₂CO₃ (1.6 g, 11.54 mmol, 3.0 eq.), the reaction mixture stirred at 80 °C for 14 hrs. The

-10020638 réaction mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL x 3), the combined organic layers were dried over Na₂SO4 and concentrated under reduced pressure to give crude 4-chloro-2-(4-methoxybenzyl)pyrido[3,2-c]pyridazine-3,6(2H,5H)-dione (0.6 g, crude) as a brown solid, which used in next step without further purification. LC-MS (ESI): m/z 318 [M+H]⁺.

Step D: 4-(6-(difluoromethyl)pyridin-3-yl)-2-(4-methoxybenzyl)pyrido[3,2-c]pyridazine3,6(2H,5H)-dione

To a solution of 4-chloro-2-(4-methoxybenzyl)pyrido[3,2-c]pyridazine-3,6(2H,5H)-dione (0.2 g, 0.63 mmol, 1.0 eq.), 2-(4-(difluoromethoxy)phenyl)-4,4,5,5-tetramethyl-l,3,2dioxaborolane (152 mg, 0.88 mmol, 1.4 eq.), K2CO3 (217 mg, 1.57 mmol, 2.5 eq.) and XPhos (33 mg, 0.06 mmol, 0.1 eq.) in l,4-dioxane/H2O mixture (8 mL, 10/1, v/v) was added Pd(OAc)₂ (15 mg, 0.06 mmol, 0.1 eq.), the reaction mixture stirred at 110°C under N₂ atmosphère ovemight. After completion, the reaction mixture was concentrated under reduced pressure, the residue was purified by column chromatography on silica gel to give 4(6-(difluoromethyl)pyridin-3-yl)-2-(4-methoxybenzyl)pyrido[3,2-c]pyridazine-3,6(2H,5H)dîone (120mg, 46%) as a white solid. LC-MS (ESI): m/z 411 [M+H]⁺.

Step E: 4-(6-(difluoromethyl)pyridin-3-yl)-2-(4-methoxybenzyl)-6-((2,2,2trifluoroethyl)amino)pyrido[3,2-c]pyridazin-3(2H)-one

To a solution of 4-(6-(difluoromethyl)pyridin-3-yl)-2-(4-methoxybenzyl)pyrido[3,2c]pyridazine-3,6(2H,5H)-dione (100 mg, 0.24 mmol, 1.0 eq.) in DMF (2 mL) was added BOP (180 mg, 0.36 mmol, 1.5 eq.) and DIEA (157 mg, 1.22 mmol, 5.0 eq.), the reaction mixture was stirred at room température for 1 hr, then 2,2,2-trifluoroethan-l-amine (36 mg, 0.36 mmol, 1.5 eq.) was added, the resulting mixture was stirred at room température for additional 0.5 hr. After the completion, the reaction was quenched by adding ice water (10 mL) and extracted with EtOAc (10 ml x 3), dried over Na₂SO4 and concentrated under reduced pressure, the residue was purified by flash column chromatography on silica gel to give 4-(6-(difluoromethyl)pyridin-3-yl)-2-(4-methoxybenzyl)-6-((2,2,2trifluoroethyl)amino)pyrido[3,2-c]pyridazin-3(2H)-one (80 mg, 67%) as a yellow solid. LCMS (ESI): m/z 492 [M+H]⁺.

Step F: 4-(6-(difluoromethyl)pyridin-3-yl)-6-((2,2,2-trifluoroethyl)amino)pyrido[3,2c]pyridazin-3 (2H)-one

To a solution of 4-(6-(difluoromethyl)pyridin-3-yl)-2-(4-methoxybenzyl)-6-((2,2,2trifluoroethyl)amino)pyrido[3,2-c]pyridazin-3(2H)-one (80 mg, 0.16 mmol, 1.0 eq.) in TFA (2 mL) was added TfüH (142 pL, 1.6 mmol, 10.0 eq.) and EtjSiH (128 pL, 0.8 mmol, 5.0 eq.), the reaction mixture was stirred at room température for 2 hrs. After the completion, the reaction was quenched with 10 mL ofNaHCOa (sat. aq.), extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (20mL) and dried over Na₂SO4, concentrated under reduced pressure, the residue was purified by flash chromatography on silica gel to give 4-(6-(difluoromethyl)pyridin-3-yl)-6-((2,2,2trifluoroethyl)amino)pyrido[3,2-c]pyridazin-3(2H)-one (40 mg, 66 %) as a yellow solid. LCMS (ESI): m/z 372 [M+H]⁺.

Step G: 4-(6-(difluoromethyl)pyridin-3-yl)-2-(4-(methoxy-d3)phenyl)-6-((2,2,2trifluoroethyl)amino)pyrido[3,2-c]pyridazin-3(2H)-one (Example 322)

4-(6-(difluoromethyl)pyridin-3-yl)-2-(4-(methoxy-d3)phenyl)-6-((2,2,2trifluoroethyl)amino)pyrido[3,2-c]pyridazin-3(2H)-one (Ëxample 322) was synthesized from 4-(6-(difluoromethyl)pyridin-3-yl)-6“((2,2,2-trifluoroethyl)amino)pyrido[3,2-c]pyridazin3(2H)-one & l-bromo-4-(methoxy-d3)benzene via General Procedure II (Method C, Step J).

^!H NMR (400 MHz, DMSO-î/₆) δ (ppm): 8.98 (s, 1H), 8.93 (t, J= 5.9 Hz, 1H), 8.30 (dd, J~ 8.0 Hz, 1.6 Hz, 1H), 7.79 (d, J= 9.5 Hz, 1H), 7.73 (d, J= 8.2 Hz, 1H), 7.59-7.53 (m, 2H), 7.09-7.04 (m, 2H), 7.00 (t, Jhf = 56.0 Hz, 1H), 6.93 (d, J= 9.5 Hz, 1H), 4.23-4.15 (m, 2H).

LC-MS (ESI): m/z 481 [M+H]⁺.

The procedure set forth above for General Procedure II (Method A) was used to synthesize the foliowing compounds by using appropriate starting materials:

Cpd No.	Structure	Characterization
Example 168	Cl 4-(4-chlorophenyl)-6-ethoxy-2(quinolin-6-yl)pyrido[3,2c]pyridazin-3 (2H)-one	LC-MS (ESI): m/z 429.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ: 9.00 (dd, J = 4.4 Hz, 1.6 Hz, 1H), 8.51 (d, J = 7.2 Hz, 1H), 8.37 (d, J - 2.4 Hz, 1H), 8.17 (d, J = 9.2 Hz, 1H), 8.07 (dd, J = 8.8 Hz, J = 2.4 Hz, 1H), 8.01 (d, J = 9.2 Hz, 1H), 7.83 (d, J = 8.8 Hz, 2H), 7.64 (dd, J = 8.4 Hz, 4.4 Hz, 1H), 7.52 (d, J = 8.8 Hz, 2H), 7.0 (d, J = 9.2 Hz, 1H), 4.34 (q, J - 6.8 Hz, 2H), 1.32 (t, J =

		7.2 Hz, 3H).
Example 169	N œV^N^o^CHF2 0 ochf2 2-(benzo[d]thiazol-6-yl)-6-(2,2di fluoroethoxy)-4- (4(difluoromethoxy)phenyl)pyrido [ 3,2-c] pyridazin- 3 (2H)-one	LC-MS (ESI): m/z 503.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) Ô: 9.53 (s, 1H), 8.54 (d, J = 2.0 Hz, 1H), 8.24 (d, J = 8.4 Hz, 1H), 8.06 (d, J = 9.2 Hz, 1H), 7.88 (d, J = 8.8 Hz, 2H), 7.85 (dd, J = 8.8 Hz, 2.4 Hz, 1H), 7.35 (t, Jhf = 74.0 Hz, 1H), 7.26 (d, J = 8.8 Hz, 2H), 7.09 (d, J = 9.6 Hz, 1H), 6.41 (tt, Jhf = 54.4 Hz, J = 3.2 Hz, 1H), 4.60 (td, Jhf = 15.2 Hz, J = 3.2 Hz, 2H).
Example 170	CO,..Q J ’ N^O^CH F2 ochf2 6-(2,2-difluoroethoxy)-4-(4(difluoromethoxy)phenyl)-2(imidazo[ 1,2-a]pyridin-6yl)pyrido [3,2-c]pyridazin-3 (2H)one	LC-MS (ESI): m/z 486.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ: 9.13 (s, 1H), 8.11 (s, 1H), 8.06 (d, J = 9.6 Hz, 1H), 7.87 (d, J = 8.8 Hz, 2H), 7.73 (d, J = 9.6 Hz, 1H), 7.70 (s, 1H), 7.58 (dd, J = 9.6 Hz, 1.6 Hz, 1H), 7.35 (t, Jhf = 74.0 Hz, 1H), 7.26 (d, J = 8.8 Hz, 2H), 7.10 (d, J = 9.2 Hz, 1H), 6.37 (tt, JHF = 54.4 Hz, J = 3.2 Hz, 1H), 4.60 (td, JHF = 15.2 Hz, J = 3.2 Hz, 2H).
Example 171 (synthesized using 5- bromo-3methoxy-2methyl-2Hindazole (Ref: Organic Letters, 2011, 13, 3138- 3141)	Meo J .1 À λ Ο γ N O CHF2 0 ochf2 6-(2,2-difluoroethoxy)-4-(4(difluoromethoxy)phenyl)-2-(3methoxy-2-methyl-2H-indazol-5yl)pyrido[3,2-c]pyridazin-3 (2H)one	LC-MS (ESI): m/z 530.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ: 8.12 (d, J = 1.6 Hz, 1H), 8.07 (d, J = 9.6 Hz, 1H), 7.86 (d, J = 8.8 Hz, 2H), 7.49 (d, J = 9.2 Hz, 1H), 7.37 (dd, J = 9.2 Hz, 2.0 Hz, 1H), 7.34 (t, Jhf = 74.0 Hz, 1H), 7.25 (d, J = 8.8 Hz, 2H), 7.06 (d, J = 9.2 Hz, 1H), 6.40 (tt, Jhf = 54.4 Hz, J = 3.2 Hz, 1H), 4.59 (td, JHF = 15.2 Hz, J = 3.2 Hz, 2H), 4.29 (s, 3H), 3.91 (s, 3H).

Example 172 (synthesized using 6- bromo-2methoxy-1methyl-lHbenzo[d]imida zole (Ref: Heterocycles, 2008, 75, 1907-1911)	Μθ°Υ ] J „ N-YV'XY 0<yY'N^O^'CHF2 ochf2 6-(2,2-difluoroethoxy)-4-(4(difluoromethoxy)phenyl)-2-(2methoxy-1 -methyl -1 Hbenzo [d] imidazol-6-yl)pyrido[3,2c]pyridazin-3 (2H)-one	LC-MS (ESI): m/z 530.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ: 8.05 (d, J = 9.2 Hz, 1H), 7.86 (d, J = 8.4 Hz, 2H), 7.68 (d, J = 2.0 Hz, 1H), 7.52 (d, J = 8.4 Hz, 1H), 7.34 (dd, J = 8.4 Hz, 2.0 Hz, 1H), 7.34 (t, Jhf = 74.0 Hz, 1H), 7.24 (d, J = 8.4 Hz, 2H), 7.06 (d, J = 9.2 Hz, 1H), 6.36 (tt, Jhf = 54.4 Hz, J = 3.2 Hz, 1H), 4.60 (td, Jhf = 15.2 Hz, J = 3.2 Hz, 2H), 4.15 (s, 3H), 3.57 (s, 3H).
Example 173	bfO^CHF2 0 Cl 4-(4-chlorophenyl)-6-(2,2difluoroethoxy)-2-(2,3-dimethyl2H-indazol-5-yl)pyrido[3,2c]pyridazin-3 (2H)-one	LC-MS (ESI): m/z 482.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ: 8.07 (d, J = 9.2 Hz, 1H), 7.98 (d, J = 2.0 Hz, 1H), 7.82 (d, J = 8.4 Hz, 2H), 7.61 (d, J = 9.2 Hz, 1H), 7.51 (d, J = 8.8 Hz, 2H), 7.41 (dd, J = 9.2 Hz, 2.0 Hz, 1H), 7.07 (d, J = 9.2 Hz, 1H), 6.41 (tt, Jhf = 54.2 Hz, J = 3.2 Hz, 1H), 4.59 (td, JHF = 15.2 Hz, J = 3.2 Hz, 2H), 4.10 (s, 3H), 2.64 (s, 3H).
Example 174 (synthesized using 5- bromo-3methoxy-2methyl-2Hindazole (Ref: Organic Letters, 2011, 13, 3138- 3141)	MeO \ λ A . N O CHF2 0 Cl 4-(4-chlorophenyl)-6-(2,2difluoroethoxy)-2-(3-methoxy-2methyl-2H-indazol-5yl)pyrido [3,2-c]pyridazin-3 (2H)one	LC-MS (ESI): m/z 498.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ: 8.12 (d, J = 2.0 Hz, 1H), 8.08 (d, J = 9.2 Hz, 1H), 7.82 (d, J = 8.4 Hz, 2H), 7.51 (d, J = 8.4 Hz, 2H), 7.48 (s, 1H), 7.36 (dd, J = 9.2 Hz, 2.0 Hz, 1H), 7.07 (d, J = 9.2 Hz, 1H), 6.40 (tt, Jhf = 54.4 Hz, J = 3.2 Hz, 1H), 4.58 (td, Jhf = 15.2 Hz, J = 3.2 Hz, 2H), 4.29 (s, 3H), 3.91 (s, 3H).

Example 175 (synthesized using 5- bromo-3(methoxy-di)2-methyl-2Hindazole (Ref: Organic Letters, 2011, 13, 3138- 3141)	d3co J JL A N 0 CHF2 0 ochf2 6-(2,2-difluoroethoxy)-4-(4(difluoromethoxy)phenyl)-2-(3 (methoxy-d3)-2-methyl-2Hindazol- 5 -yl)pyrido [ 3,2c]pyridazin- 3 (2H)-one	LC-MS (ESI): m/z 533.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ: 8.12 (d, J = 1.2 Hz, 1H), 8.07 (d, J = 9.6 Hz, 1H), 7.87 (d, J = 8.8 Hz, 2H), 7.50 (d, J = 9.2 Hz, 1H), 7.37 (dd, J = 9.2 Hz, 1.6 Hz, 1H), 7.34 (t, Jhf = 74.0 Hz, 1H), 7.25 (d, J = 8.8 Hz, 2H), 7.07 (d, J = 9.2 Hz, 1H), 6.40 (tt, Jhf = 54.2 Hz, J = 3.2 Hz, 1H), 4.59 (td, Jhf = 15.2 Hz, J = 3.2 Hz, 2H), 3.91 (s, 3H).
Example 176	T Π ν^'ό^Ύ f F ochf2 2-(cinnolin-6-yl)-6-(2,2difluoroethoxy)-4-(4(difluoromethoxy)phenyl)pyrido[ 3,2-c]pyridazin-3 (2H)-one	LC-MS (ESI): m/z 498 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 9.48 (d, J = 5.9 Hz, 1H), 8.63 (d, J = 9.2 Hz, 1H), 8.51 (d, J = 2.2 Hz, 1H), 8.38 (d, J = 5.8 Hz, 1H), 8.30 (dd, J = 9.1, 2.3 Hz, 1H), 8.08 (d, J = 9.4 Hz, 1H), 7.94-7.86 (m, 2H), 7.36 (t, J = 73.9 Hz, 1H), 7.32-7.22 (m, 2H), 7.12 (d, J = 9.4 Hz, 1H), 6.41 (tt, J = 54.3, 3.3 Hz, 1H), 4.61 (td, J = 15.1,3.3 Hz, 2H).
Example 177	ΤΌ^'γ'F F ochf2 6-(2,2-difluoro ethoxy)-4-(4- (difluoromethoxy)phenyl)-2-(2,3 dihydrobenzo [b] [ 1,4] dioxin-6yl)pyrido [3,2-c]pyridazin-3 (2H)one	LC-MS (ESI): m/z 504 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.02 (d, J = 9.4 Hz, 1H), 7.84 (d, J = 8.8 Hz, 2H), 7.34 (t, J = 74.0 Hz, 1H), 7.24 (d, J = 8.7 Hz, 2H), 7.20 (d, J = 2.5 Hz, 1H), 7.12 (dd, J = 8.7, 2.5 Hz, 1H), 7.05 (d, J = 9.4 Hz, 1H), 7.00 (d, J = 8.7 Hz, 1H), 6.39 (tt, J = 54.1, 3.3 Hz, 1H), 4.57 (td, J = 15.1, 3.4 Hz, 2H), 4.31 (s, 4H).

-10520638

Example 178	F ochf2 6-(2,2-difluoroethoxy)-4-(4- (difluoromethoxy)phenyl)-2-(2,3 - dihydrobenzofuran-5 - yl)pyrido [3,2- c]pyridazin-3 (2H)- one	LC-MS (ESI): m/z 488 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.03 (d, J = 9.4 Hz, 1H), 7.84 (d, J = 8.8 Hz, 2H), 7.51 (d, J = 2.2 Hz, 1H), 7.39-7.35 (m, 1H), 7.35 (t, J = 74.2 Hz, 1H), 7.24 (d, J = 8.8 Hz, 2H), 7.05 (d, J = 9.4 Hz, 1H), 6.89 (d, J = 8.5 Hz, 1H), 6.39 (tt, J = 54.4, 3.3 Hz, 1H), 4.67-4.51 (m, 4H), 3.26 (t, J = 8.8 Hz, 2H).
Example 179	cr γ n o γ À. F O ochf2 6-(2,2-difluoroethoxy)-4-(4- (difluoromethoxy)phenyl)-2(quinazolin-6-yl)pyrido [3,2c]pyridazin-3(2H)-one	LC-MS (ESI): m/z 498 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 9.76 (s, 1H), 9.41 (s, 1H), 8.58 (d, J = 2.4 Hz, 1H), 8.38 (dd, J = 9.0, 2.4 Hz, 1H), 8.20 (d, J = 9.0 Hz, 1H), 8.09 (d, J = 9.4 Hz, 1H), 7.90 (d, J = 8.7 Hz, 2H), 7.35 (t, J = 73.8 Hz, 1H), 7.27 (d, J = 8.8 Hz, 2H), 7.12 (d, J = 9.4 Hz, 1H), 6.41 (t, J = 54.4 Hz, 1H), 4.61 (td, J = 15.1, 3.3 Hz, 2H).
Example 180	,0.,..,¾¾ N 0 y F Q] ochf2 6-(2,2-difluoroethoxy)-4-(4- (difluoromethoxy)phenyl)-2-(4methyl-3,4-dihydro-2Hb enzo [b] [ 1,4] oxazin-6 - yl)pyrido [3,2-c] pyridazin-3 (2H) one	LC-MS (ESI): m/z 517 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.01 (d, J = 9.4 Hz, 1H), 7.87-7.79 (m, 2H), 7.32 (t, J = 74.0 Hz, 1H), 7.24 (d, J = 8.8 Hz, 2H), 7.03 (d, J = 9.4 Hz, 1H), 6.92 (s, 1H), 6.79 (br s, 2H), 6.38 (tt, J = 54.4, 3.4 Hz, 1H), 4.57 (td, J = 15.1, 3.4 Hz, 2H), 4.29 (dd, J = 5.3, 3.5 Hz, 2H), 3.29 (t, J = 4.4 Hz, 2H), 2.83 (s, 3H).

Example 181	ν^'ό^Ύ f zYx F O ochf2 4-(6-(2,2-difluoro ethoxy) -4-(4(difluoromethoxy)phenyl)-3 oxopyrido[3,2-c]pyridazin-2(3H)yl)benzonitrile	LC-MS (ESI): m/z 471 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.10-8.01 (m, 3H), 7.95 (d, J - 8.3 Hz, 2H), 7.85 (d, J = 8.8 Hz, 2H), 7.35 (t, J = 74.0 Hz, 1H), 7.25 (d, J = 8.5 Hz, 2H), 7.10 (d, J = 9.4 Hz, 1H), 6.40 (tt, J = 54.3, 3.4 Hz, 1H), 4.59 (td, J = 15.1,3.4 Hz, 2H).
Example 182	Ν^γγ n ο γ Q ochf2 6-(2,2-difluoroethoxy)-4-(4(difluoromethoxy)phenyl)-2-(2methyl-2H-benzo[d] [ 1,2,3]triazol5 -yl)pyrido [3,2 -c]pyridazin3(2H)-one	LC-MS: m/z 501.1 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ: 8.27 (d, J = 1.2 Hz, 1H), 8.07 (d, J = 9.2 Hz, 1H), 7.87 (d, J = 8.8 Hz, 2H), 7.70 (dd, J = 9.2 Hz, 2.0 Hz, 1H), 7.34 (t, Jhf = 74.0 Hz, 1H), 7.25 (d, J = 8.8 Hz, 2H), 7.08 (d, J = 9.6 Hz, 1H), 6.40 (tt, JHf = 54.4 Hz, 3.2 Hz, 1H), 4.58 (td, J = 14.8 Hz, 3.6 Hz, 2H), 4.56 (s, 3H).
Example 183	^Αγ3 ' Ν^'Ό^'Ύ f A. f O ochf2 6-(2,2-difluoroethoxy)-4-(4(difluoromethoxy)phenyl)-2(quinolm-6-yl)pyrido[3,2c]pyridazin-3(2H)-one	LC-MS: m/z 497.1 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ: 9.01 (s, 1H), 8.51 (d, J = 8.4 Hz, 1H), 8.37 (s, 1H), 8.12-8.02 (m, 1H), 7.89 (d, J = 8.0 Hz, 2H), 7.687.59 (m, 1H), 7.35 (t, Jhf = 74.0 Hz, 1H), 7.26 (d, J = 8.0 Hz, 2H), 7.10 (d, J = 9.6 Hz, 1H), 6.41 (tt, Jhf = 54.4 Hz, 3.6 Hz, 1H), 4.60 (td, J= 14.8 Hz, 3.6 Hz, 2H).

Example 184	N 1 | ΥχΑ,Λ/χ.. N y η	LC-MS: m/z 487.1 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ:
	N^O^Y f Jx. F Q ochf2 2- ( [ 1,2,4] triazolo[4,3 -a]pyridin-6yl)-6-(2,2-difluoroethoxy)-4-(4(difluoromethoxy)phenyl)pyrido [ 3,2-c]pyridazin-3 (2H)-one	9.41 (s, 1H), 9.18 (s, 1H), 8.06 (d, J = 9.2 Hz, 1H), 7.94 (d, J = 9.6 Hz, 1H), 7.87 (d, J = 8.4 Hz, 2H), 7.75 (dd, J = 9.2 Hz, 2.0 Hz, 1H), 7.35 (t, Jhf = 74.0 Hz, 1H), 7.26 (d, J = 8.4 Hz, 2H), 7.12 (d, J = 9.2 Hz, 1H), 6.40 (tt, Jhf = 54.4 Hz, 3.6 Hz, 1H), 4.60 (td, J = 14.8 Hz, 3.6 Hz, 2H).
Example 185	H θ^ηγ A'cYY F Jx F 0 ochf2 6-(2,2-difluoroethoxy)-4-(4(difluoromethoxy)phenyl)-2 -(4(methylamino)phenyl)pyrido [3,2c] pyridazin-3 (2H)-one	LC-MS: m/z 475.1 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ: 8.02 (d, J = 9.2 Hz, 1H), 7.83 (d, J = 8.8 Hz, 2H), 7.40 (d, J = 8.8 Hz, 2H), 7.33 (t, Jhf = 74.0 Hz, 1H), 7.23 (d, J = 8.8 Hz, 2H), 7.03 (d, J = 9.2 Hz, 1H), 6.62 (d, J = 8.8 Hz, 2H), 6.39 (tt, Jhf = 54.4 Hz, 3.2 Hz, 1H), 6.06 (q, J = 4.8 Hz, 1H), 4.56 (td, Jhf = 14.8 Hz, 3.2 Hz, 2H), 2.73 (d, J = 4.8 Hz, 3H).
Example 186	N^O^Y F X F ochf2 6-(2,2-difluoroethoxy)-4-(4(difluoromethoxy)phenyl)-2(thiazol-5-yl)pyrido[3,2c]pyridazin-3 (2H) -one	LC-MS: m/z 466.1 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ: 9.05 (s, 1H), 8.66 (s, 1H), 8.12 (d, J = 9.2 Hz, 1H), 7.85 (d, J = 8.8 Hz, 2H), 7.37 (t, Jhf = 74.0 Hz, 1H), 7.28 (d, J = 8.8 Hz, 2H), 7.17 (d, J = 9.2 Hz, 1H), 6.40 (tt, Jhf = 54.4 Hz, 3.2 Hz, 1H), 4.58 (td, JHF = 15.2 Hz, 3.2 Hz, 2H).

Example 187		LC-MS: m/z 480.1 (M+H)+.
(synthesized		1H NMR (400 MHz, DMSO-d6) δ:
using 4-	a. a a o y n o y	8.03 (d, J = 9.2 Hz, 1H), 7.81 (d, J
methoxycyclo	y. f	= 8.4 Hz, 2H), 7.33 (t, JHf = 74.0
hex-l-en-l-yl	M	Hz, 1H), 7.32 (d, J = 8.8 Hz, 2H),
trifluorometha	ochf2	7.02 (d, J = 9.6 Hz, 1H), 6.37 (tt,
nesulfonate	6-(2,2-difluoroethoxy)-4-(4-	Jhf = 54.4 Hz, 3.2 Hz, 1H), 5.94-
(Ref: Journal	(difluoromethoxy)phenyl)-2-(4-	5.89 (m, 1H), 4.55 (td, Jhf = 14.8
of the	methoxycyclohex-1 -en-1 -	Hz, 3.2 Hz, 2H), 3.63-3.52 (m, 1H),
American	yl)pyrido [ 3,2-c] pyridazin-3 (2H)-	3.31 (s, 3H), 2.61-2.41 (m, 3H).
Chemical Society, 2018, 140, 2446- 2449)	one	2.24-2.15 (m, 1H), 2.03-1.92 (m, 1H), 1.85-1.71 (m, 1H).

The procedure set forth above for General Procedure II (Method B) was used to synthesize the following compounds by using appropriate starting materials:

Cpd No.	Structure	Characterization
Example 188	o^y^ F Ax F M| ochf2 6-(2,2-difluoroethoxy)-4-(4(difluoromethoxy)phenyl)-2(pyridin-4-yl)pyrido[3,2c] pyridazin-3 (2H)-one	LC-MS (ESI): m/z 447 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.82-8.76 (m, 2H), 8.05 (d, J = 9.5 Hz, 1H), 7.89-7.78 (m, 4H), 7.35 (t, J = 74.0 Hz, 1H), 7.26 (d, J = 8.8 Hz, 2H), 7.10 (d, J = 9.4 Hz, 1H), 6.40 (tt, J = 54.3, 3.3 Hz, 1H), 4.59 (td, J = 15.1, 3.3 Hz, 2H).
Example 189	O xk F O ochf2	LC-MS: m/z 503.1 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ: 8.59 (q, J = 4.4 Hz, 1H), 8.05 (d, J = 9.6 Hz, 1H), 7.99 (d, J = 8.8 Hz, 2H), 7.85 (d, J = 8.8 Hz, 2H), 7.81 (d, J = 8.4 Hz, 2H), 7.34 (t, JHF =

	4-(6-(2,2 -difluoroeth.oxy)-4-(4(difluoromethoxy)phenyl)-3 oxopyrido[3,2-c]pyridazin-2(3H)yl)-N -methylbenzamide	74.0 Hz, 1H), 7.25 (d, J = 8.8 Hz, 2H), 7.08 (d, J = 9.6 Hz, 1H), 6.39 (tt, Jhf = 54.4 Hz, 3.6 Hz, 1H), 4.58 (td, J = 14.8 Hz, 3.2 Hz, 2H), 2.82 (d, J = 4.8 Hz, 3H).
Example 190	0 ' Y F F Q ochf2 2-(4-chlorophenyl)-6-(2,2difluoroethoxy)-4-(4(difluoromethoxy)phenyl)pyrido [ 3,2-c]pyridazin-3(2H)-one	LC-MS: m/z 480.1 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ: 8.04 (d, J = 9.6 Hz, 1H), 7.84 (d, J = 8.8 Hz, 2H), 7.73 (d, J = 8.8 Hz, 2H), 7.63 (d, J = 8.8 Hz, 2H), 7.34 (t, Jhf = 74.0 Hz, 1H), 7.24 (d, J = 8.8 Hz, 2H), 7.07 (d, J = 9.6 Hz, 1H), 6.39 (tt, Jhf = 54.0 Hz, 3.2 Hz, 1H), 4.58 (td, J = 15.2 Hz, 3.2 Hz, 2H).
Example 191	ΊΧγ. ογ^' F /L F Q ochf2 6-(2,2-difluoroethoxy)-4-(4(difluoromethoxy)phenyl)-2-(4fluorophenyl)pyrido[ 3,2c]pyridazin-3(2H)-one	LC-MS: m/z 464.1 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ: 8.04 (d, J = 9.6 Hz, 1H), 7.85 (d, J = 8.8 Hz, 2H), 7.76-7.71 (m, 2H), 7.40 (t, J = 8.8 Hz, 2H), 7.35 (t, Jhf = 74.0 Hz, 1H), 7.25 (d, J = 8.4 Hz, 2H), 7.07 (d, J = 9.2 Hz, 1H), 6.40 (tt, Jhf = 54.0 Hz, 3.6 Hz, 1H), 4.58 (td, J = 15.2 Hz, 3.6 Hz, 2H).
Example 192	NAo γ F xY F Q ochf2 6-(2,2-difluoroethoxy)-4-(4(difhioromethoxy)phenyl)-2- (quinoxalin-6-yl)pyrido [3,2c] pyridazin-3 (2H) -one	LC-MS: m/z 498.1 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ: 9.06-9.04 (m, 2H), 8.48 (d, J = 2.0 Hz, 1H), 8.27 (d, J = 9.2 Hz, 1H), 8.12 (dd, J = 9.2 Hz, 2.0 Hz, 1H), 8.09 (d, J = 9.6 Hz, 1H), 7.89 (d, J = 8.8 Hz, 2H), 7.35 (t, JHf = 74.0 Hz, 1H), 7.27 (d, J = 8.8 Hz, 2H), 7.11 (d, J = 9.2Hz, 1H), 6.41 (tt, JHf = 54.4 Hz, 3.2 Hz, 1H), 4.61 (td, J

		= 14.8 Hz, 3.6 Hz, 2H).
Example 193	H	LC-MS: m/z 436.1 (M+H)+.
	NA-x%	1H NMR (400 MHz, DMSO-d6) δ:
	n y y A. A- A x	13.23 (br s, 1H), 8.60-8.51 (m, 1H),
	0 γ N 0 γ XX F Q	8.22-8.13 (m, 1H), 8.07 (d, J = 9.2 Hz, 1H), 7.84 (d, J = 8.8 Hz, 2H),
	ochf2 6-(2,2-difluoroethoxy)-4-(4(difluoromethoxy)phenyl)-2-(l Hpyrazol-4-yl)pyrido[3,2c]pyridazin-3(2H)-one	7.34 (t, Jhf = 74.0 Hz, 1H), 7.26 (d, J = 8.4 Hz, 2H), 7.08 (d, J = 9.2 Hz, 1H), 6.38 (tt, Jhf = 54.4 Hz, 3.2 Hz, 1H), 4.56 (td, J = 14.8 Hz, 3.2 Hz, 2H).

The procedure set forth above for General Procedure II (Method C) was used to synthesize the following compounds by using appropriate starting materials:

Cpd No.	Structure	Ch ar acterization
Example 323	n^xx A A A AH °γ sa2h XX 2h2h Γ il Xn 6- ((ethyl-d5)amino)-2 -(2 -methyl2H-indazol-5-yl)-4-(6methylpyridin-3 -yl)pyrido [3,2 c]pyridazin-3 (2H)-one	LC-MS: m/z 417 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ: 8.84 (d, J = 1.9 Hz, 1H), 8.46 (s, 1H), 8.34 (s, 1H), 8.06 (dd, J = 8.2 Hz, 2.1 Hz, 1H), 7.94 (d, J = 1.4 Hz, 1H), 7.67 (d, J = 9.2 Hz, 1H), 7.61 (d, J = 9.5 Hz, 1H), 7.41 (dd, J = 9.1 Hz, 2.0 Hz, 1H), 7.27 (d, J = 8.0 Hz, 1H), 6.79 (d, J = 9.6 Hz, 1H), 4.21 (s, 3H), 2.51 (s, 3H).
Example 324	ΛγΧ. °Yn n* χΚ 2h2h f il fxf 4- (6-(difluoromethyl)pyridin-3 - yl)-6-((ethyl-d5)amino)-2-(2-	LC-MS: m/z 453 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ: 9.06 (s, 1H), 8.47 (s, 2H), 8.38 (dd, J = 8.1 Hz, 1.8 Hz, 1H), 7.96 (d, J = 1.4 Hz, 1H), 7.73 (d, J = 8.2 Hz, 1H), 7.66 (t, J = 9.6 Hz, 2H), 7.42 (dd, J = 9.2 Hz, 2.0 Hz, 1H), 6.99 (t, JHF = 55.1 Hz, 1H), 6.82 (d, J =

	methyl-2H-indazol-5- yl)pyrido[3,2-c]pyridazin-3(2H)one	9.6 Hz, 1H), 4.21 (s, 3H).
Example 325	2h 2h-)—n' J ] 2H > Π A ZH2H [ H γ,Ν 6-((ethyl-d5)amino)-2-(2-(methyl“ d3)-2H-indazol-5-yl)-4-(6methylpyridin-3-yl)pyrido[3,2c]pyridazin-3(2H)-one	LC-MS: m/z 420 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ: 8.84 (d, J = 1.5 Hz, 1H), 8.46 (s, 1H), 8.32 (s, 1H), 8.07 (dd, J = 8.1 Hz, 2.1 Hz, 1H), 7.94 (d, J = 1.1 Hz, 1H), 7.67 (d, J = 9.2 Hz, 1H), 7.61 (d, J = 9.5 Hz, 1H), 7.41 (dd, J = 9.1 Hz, 2.0 Hz, 1H), 7.27 (d, J = 8.1 Hz, 1H), 6.79 (d, J = 9.5 Hz, 1 H), 2.51 (s, 3H).
Example 326	0^γ· N [ H On F^F 4-(6-(diflu.oromethyl)pyridin-3yl)-6-(ethylamino)-2-(l-methyl-6oxo-1,6-dihydropyridin- 3 yl)pyrido [ 3,2 - c] pyridazin-3 (2H) one	LC-MS: m/z 425 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ: 9.03 (s, 1H), 8.54 (t, J = 5.3 Hz, 1H), 8.35 (d, J = 9.7 Hz, 1H), 8.21 (d, J = 2.8 Hz, 1H), 7.77-7.69 (m, 2H), 7.63 (d, J = 9.5 Hz, 1H), 7.06 (t, Jhf = 55.2 Hz, 1H), 6.83 (d, J = 9.6 Hz, 1H), 6.47 (d, J = 9.7 Hz, 1H), 3.49 (s, 3H), 3.31 (q, J = 7.2 Hz, 2H), 1.13 (t, J = 7.2 Hz, 3H).
Example 327	0 1 H Γιΐ AxN F A 4-(6-(difluoromethyl)pyridin-3 yl )-2-( 1,2-dimethyl-1Hbenzo[d]imîdazol-6-yl)-6(ethylamino)pyrido [3,2-	LC-MS: m/z 462 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ: 9.06 (s, 1H), 8.50 (t, J = 5.7 Hz, 1H), 8.38 (d, J = 9.8 Hz, 1H), 7.76 (d, J = 1.6 Hz, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.65 (d, J = 9.6 Hz, 1H), 7.60 (d, J = 8.2 Hz, 1H), 7.33 (dd, J = 8.5 Hz, 2.0 Hz, 1H), 6.99 (t, JHF = 55.1 Hz, 1H), 6.83 (d, J = 9.6 Hz, 1H), 3.75 (s, 3H), 3.32 (q, J = 7.2

	c]pyridazin-3 (2H)-one	Hz, 2H), 2.56 (s, 3H), 1.14 (t, J = 7.2 Hz, 3H).
Example 328	- N Y y n O^'yF À. F CxN F^F 6-(2,2-difluoroethoxy)-4-(6(difluoromethyl)pyridin- 3 -yl)-2(1 -methyl-6-oxo-1,6- dihydropyridin- 3 -yl)pyrido [ 3,2c]pyridazin-3 (2H)-one	LC-MS: m/z 462 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ; 9.03 (s, 1H), 8.38 (d, J = 7.3 Hz, 1H), 8.30 (d, J = 2.6 Hz, 1H), 8.09 (d, J = 9.4 Hz, 1H), 7.82-7.77 (m, 2H), 7.12 (d, J = 9.6 Hz, 1H), 7.04 (t, Jhf = 54.8 Hz, 1H), 6.52 (d, J = 9.7 Hz, 1H), 6.39 (t, JHf = 54.4 Hz, 1H), 4.59 (td, Jhf = 15.2 Hz, J = 2.8 Hz, 2H), 3.51 (s, 3H).
Example 329	fVf 1 H On F^F 4-(6-(difluoromethyl)pyridin-3 yl)-2-( 1 -methyl-6-oxo-l,6dihydropyridin-3 -yl)-6- ((2,2,2trifluoro ethyl)amino)pyri do [ 3,2c]pyridazin-3 (2H)- one	LC-MS: m/z 479 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ: 9.20 (t, J = 6.4 Hz, 1H), 8.97 (s, 1H), 8.29 (d, J = 8.8 Hz, 1H), 8.23 (d, J = 2.9 Hz, 1H), 7.79 (d, J = 9.4 Hz, 1H), 7.73 (d, J = 9.0 Hz, 2H), 7.01 (d, J = 9.6 Hz, 1H), 7.01 (t, JHf = 55.0 Hz, 1H), 6.48 (d, J = 9.8 Hz, 1H), 4.25-4.18 (m, 2H), 3.50 (s, 3H).
Example 330	2H 2h+n J J w 2H N ' N JL H LUn 6-(ethylamino)-2-(2-(methyl-d3)2H-indazol-5-yl)-4-(6methylpyridin-3 -yl)pyrido [3,2c]pyridazin-3 (2H)-one	LC-MS: m/z 415 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ: 8.85 (d, J = 1.8 Hz, 1H), 8.46 (s, 1H), 8.35 (t, J = 5.2 Hz, 1H), 8.07 (dd, J = 8.0 Hz, 2.2 Hz, 1H), 7.94 (d, J = 1.4 Hz, 1H), 7.67 (d, J = 9.1 Hz, 1H), 7.61 (d, J = 9.5 Hz, 1H), 7.41 (dd, J = 9.1 Hz, 1.9 Hz, 1H), 7.27 (d, J = 8.1 Hz, 1H), 6.79 (d, J = 9.5 Hz, 1H), 3.36 (q, J = 7.2 Hz,

2H), 2.50 (s, 3H), 1.14 (t, J = 7.2 Hz, 3H).

General Procedure III:

Compounds of structure 3.6 were obtained through the scheme depicted as General

Procedure III. Beginning with substituted pyridazinone 3.1 (synthesized via General Procedure I (Steps A-B)), the desired R4 group was introduced using a Suzuki cross-coupling to generate vinyl compound 3.2. The double bond in 3.2 was then oxidized to afford carbonyl 3.3. The desired R₂ group was introduced using a Suzuki cross-coupling to generate compound 3.4. The desired R5 group was introduced using a Homer-Wadsworth10 Emmons olefination, which led to the génération of bicyclic heterocycle 3.5 following a tandem, intramolecular cyclization. Lastly, the desired R, group was introduced through an alkylation reaction to afford compounds of structure 3.6.

Préparation of Example 194 via General Procedure III:

ΡίηΒ'Ά

Pd(dppf)CI₂,K₂CO₃ dioxane-EtOH

1) K₂OsO₄.2H₂O

2) NalO₄, THF-H₂O

Step B

Step A

Step A: 5-amino-4-chloro-2-(2-methyl-2H-indazol-5-yl)-6-vinylpyridazin-3(2H)-one

A solution of 5-amino-6-bromo-4-chloro-2-(2-methyl-2H-indazol-5-yl)pyridazin-3(2H)-one (2 g, 5.67 mmol, 1.0 eq., General Procedure I, (Steps A-B)), 4,4,5,5-tetramethyl-2-vinyl-

1,3,2- dioxaborolane (1.738 g, 11.34 mmol, 2.0 eq.), Pd(dppf)Cl₂ (0.826 g,1.13 mmol, 0.2 eq.), K₂CO₃ (2.336 g, 16.99 mmol, 3.0 eq.) in dioxane/EtOH (48 mL, 3/1, v/v) under N₂ atmosphère was stirred at 80 °C for 16 hrs. The reaction mixture was filtered and concentrated under reduced pressure, the residue was purified by flash column chromatography on silica gel to give 5-amino-4-chloro-2-(2-methyl-2H-indazol-5-yl)-6vinylpyridazin-3(2H)-one (1.02 g, 60% yield) as a yellow solid. LC-MS (ESI): m/z 302 [M+H]⁺.

Step B: 4-amino-5-chloro-l -(2-methyl-2H-indazol-5-yl)-6-oxo-l ,6-dihydropyridazine-3carb aldéhyde

A solution of 5-amino-4-chloro-2-(2-methyl-2H-indazol-5-yl)-6-vinylpyridazin-3(2H)-one (1.6 g, 5.3 mmol, 1.0 eq.), NaIO4 (3.4 g, 15.9 mmol, 3.0 eq.) and K₂OsO4-2H₂O (98 mg, 0.26 mmol, 0.05 eq.) in THF/H₂O (20 mL, 3:1) was stirred at room température for 3 hrs, and the resulting mixture was filtered and extracted with DCM (50 mL x 3). The fïltrate was washed with brine (30 mL) and the combined organic layers were dried over Na₂SÛ4 and

concentrated under reduced pressure. The crude residue was purified by flash column chromatography on silica gel to afford 4-amino-5-chloro-l-(2-methyl-2H-indazol-5-yl)-6oxo-l,6-dihydropyridazine-3-carbaldehyde as a white solid (1 g, 62% yield). LC-MS (ESI): m/z 304 [M+H]⁺.

Step C: 4-amino-5-(4-(difluoromethoxy)phenyl)-1 -(2-methyl-2H-indazol-5-yl)-6-oxo-1,6dihydropyridazine-3 -carbaldehyde

A solution of 4-amino-5-chloro-l-(2-methyl-2H-indazol-5-yl)-6-oxo-l,6-dihydropyridazine3-carbaldehyde (650 mg, 2.15 mmol, 1.0 eq.), 2-(4-(difluoromethoxy)phenyl)-4,4,5,5tetramethyl-l,3,2-dioxaborolane (934 mg, 3.46 mmol, 1.6 eq.), Pd(OAc)₂ (52 mg, 0.215 mmol, 0.1 eq.), X-Phos (205 mg, 0.43 mmol, 0.2 eq.), K₂CO₃ (594 mg, 4.3 mmol, 2.0 eq.) in dioxane/H₂O (11 mL, 10/1, v/v) was stirred at 110 °C under N₂ atmosphère for 3 hrs. H₂O was added and the resulting mixture was extracted with EtOAc (30 mL x 3), the combined organic layers were dried over Na₂SO₄, concentrated under reduced pressure, the residue was purified by flash column chromatography on silica gel to give 4-amino-5-(4(difluoromethoxy)phenyl)-l-(2-methyl-2H-indazol-5-yl)-6-oxo-l,6-dihydropyridazine-3carbaldehyde (650 mg, 69% yield) as a yellow solid. LC-MS (ESI): m/z 412 [M+H]⁺.

Step D : 4- (4- (difluoromethoxy)phenyl)-7-fluoro-2-(2 -methyl-2H-indazol-5-yl)pyrido [3,2c]pyridazine-3,6(2H,5H)-dione

To a suspension of 4-amino-5-(4-(difluoromethoxy)phenyl)-l-(2-methyl-2H-indazol-5-yl)-6oxo-l,6-dihydropyridazine-3-carbaldehyde (150 mg, 0.36 mmol, 1.0 eq.) and ethyl 2(diethoxyphosphoryl)-2-fluoroacetate (132 mg, 0.55 mmol, 1.5 eq.) in MeCN (5 mL) was added NaH (30% suspend in minerai oil, 175 mg, 2.19 mmol, 6.0 eq.) in several portions at 0°C under N₂ atmosphère. After stimng at room température ovemight, the resulting mixture was poured into ice-cooled NH₄C1 (sat. aq.) (10 mL), then extracted with EtOAc (10 mL x 3), the combined organic layers were washed with brine (20 mL) and dried over Na₂SO₄, concentrated under reduced pressure, the residue was purified by flash column chromatography on silica gel to give 4-(4-(difluoromethoxy)phenyl)-7-fluoro-2-(2-methyl2H-indazol-5-yl)pyrido[3,2-c]pyridazine-3,6(2H,5H)-dione (120 mg, 73% yield) as a yellow solid. LC-MS (ESI): m/z 454 [M+H]⁺.

6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)-7-fluoro-2-(2-methyl-2H-indazol-5yl)pyrido[3,2-c]pyridazin-3(2H)-one (Example 194) was synthesized from 4-(4(difluoromethoxy)phenyl)-7-fluoro-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyridazine3,6(2H,5H)-dione and 2,2-difluoroethyl trifluoromethanesulfonate via similar procedure described in General Procedure I (Step F).

^XH NMR (400 MHz, DMSO-d₆) δ: 8.56 (s, 1H), 8.10 (d, J = 10.0 Hz, 1H), 8.07 (d, J = 1.2 Hz, 1H), 7.91 (d, J = 9.2 Hz, 2H), 7.77 (d, J = 9.2 Hz, 1H), 7.51 (dd, J = 9.2 Hz, 2.0 Hz, 1H), 7.41 (t, Jhf = 74.0 Hz, 1H), 7.32 (d, J = 9.2 Hz, 2H), 6.50 (tt, J_HF = 54.0 Hz, 3.2 Hz, 1H), 4.71 (td, Jhf = 15.2 Hz, J = 3.2 Hz, 2H), 4.28 (s, 3H).

LC-MS (ESI): m/z 518 [M+H]⁺.

The procedure set forth above for General Procedure III was used to synthesize the foliowing compounds by using appropriaie starting materials:

Cpd No.	Structure	Characterization
Example 195	J ' N^''O A ochf2 4-(4-(difluoromethoxy)phenyl)-6~ ethoxy-7-fluoro-2-(2-methyl-2Hindazol- 5 -yl)pyrido [3,2- c]pyridazin-3(2H)-one	LC-MS (ESI): m/z 482.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ: 8.50 (s, 1H), 8.00 (d, J = 1.2 Hz, 1H), 7.94 (d, J = 10.4 Hz, 1H), 7.88-7.83 (m, 2H), 7.71 (d, J = 9.2 Hz, 1H), 7.45 (dd, J = 9.2 Hz, 2.0 Hz, 1H), 7.35 (t, Jhf = 74.0 Hz, 1H), 7.28-7.23 (m, 2H), 4.42 (q, J = 7.2 Hz, 2H), 4.23 (s, 3H), 1.36 (t, J = 7.2 Hz, 3H).
Example 196	N ' ' N 1 H ochf2 4-(4- (difluoromethoxy)phenyl) -6 (ethylamino)-7-fluoro-2-(2- methyl-2H-indazol- 5 yl)pyrido[3,2-c]pyridazin-3(2H)- one	LC-MS (ESI): m/z 481.2 [M+H]+, 1H NMR (400 MHz, DMSO-d6) δ: 8.58 (t, J = 5.6 Hz, 1H), 8.47 (s, 1H), 7.96-7.91 (m, 1H), 7.90-7.79 (J = 8.4 Hz, 2H), 7.68 (d, J = 9.2 Hz, 1H), 7.58 (d, J = 11.2 Hz, 1H), 7.41 (dd, J = 9.2 Hz, 2.0 Hz, 1H), 7.31 (t, Jhf = 74.4 Hz, 1H), 7.20 (d, J = 8.4 Hz, 2H), 4.22 (s, 3H), 3.553.33 (m, 2H), 1.15 (t, J = 7.2 Hz, 3H).

Example 197

ochf₂

4-(4-(difluoromethoxy)phenyl)-7fluoro -2- (2-methyl-2H-indazol-5 yl)-6-((2,2,2trifluoroethyl)amino)pyrido[3,2c]pyridazin-3 (2H)-one

LC-MS (ESI): m/z 535.1 [M+H]+.

1H NMR (400 MHz, DMSO-d₆) δ: 9.05 (s, 1H), 8.48 (s, 1H), 7.97 (d, J = 1.2 Hz, 1H), 7.80 (d, J = 8.8 Hz, 2H), 7.77 (d, J = 10.8 Hz, 1H), 7.69 (d, J = 8.8 Hz, 1H), 7.43 (dd, J = 9.2 Hz, 2.0 Hz, 1H), 7.33 (t, Jhf = 74.4 Hz, 1H), 7.19 (d, J = 8.8 Hz, 2H), 4.22 (s, 3H), 4.22-4.14 (m, 2H).

Synthesis of 4-(4-bromophenyl)-6-ethoxy-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2c]pyridazin-3(2H)-one (Ëxample 198)

Step A: 4-(4-aminophenyl)-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyridazine3,6(2H,5H)-dione

A solution of tert-butyl (4-(2-(2-methyl-2H-indazol-5-yl)-3,6-dioxo-2,3,5,6tetrahydropyrido[3,2-c]pyridazin-4-yl)phenyl)carbamate (synthesized from 4-chloro-2-(2methyl-2H-indazol-5-yl)pyrido[3,2-c]pyridazine-3,6(2H,5H)-dione & (4-((tert10 butoxycarbonyl)amino)phenyl)boronic acid via General Procedure I (Method A, Step E)) (180 mg, 0.372 mmol) in TFA/DCM (1 mL/5 mL) was stirred at room température for 1 hr. The reaction mixture was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na₂SO4 and concentrated under reduced

pressure, the residue was purified by flash column chromatography on silica gel to give 4-(4aminophenyl)-2-(2-methyl-2H-indazol- 5 -yl)pyrido [ 3,2-c]pyridazine-3, 6(2H, 5H)-dione (116 mg, 79% yield) as a yellow solid. LC-MS (ESI): m/z 385 [M+H]⁺.

Step B: 4-(4-bromophenyl)-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyridazine3,6(2H,5H)-dione

To a solution of 4-(4-aminophenyl)-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyridazine3,6(2H,5H)-dione (200 mg, 0.52 mmol, 1.0 eq.) and CuBr (299 mg, 2.08 mmol, 4.0 eq.) in ACN (10 mL) was added teit-butyl nitrite (215 mg, 2.08 mmol, 4.0 eq.) at 0 °C drop-wise over 10 min. The reaction mixture was stirred at room température for 4 hrs. The resulting mixture was quenched with Na2SO₃ (sat. aq.) (20 mL), extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SÛ4 and concentrated under reduced pressure, the residue was purified by flash column chromatography on silica gel to afford 4-(4-bromophenyl)-2-(2-methyl-2H-indazol-5yl)pyrido[3,2-c]pyridazine-3,6(2H,5H)-dione as a yellow solid (70 mg, 30% yield). LC-MS (ESI): m/z 448 [M+H]⁺.

Step C:

4-(4-Bromophenyl)-6-ethoxy-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyridazin-3(2H)one (Example 198) was synthesized from 4-(4-bromophenyl)-2-(2-methyl-2H-indazol-5yl)pyrido[3,2-c]pyridazine-3,6(2H,5H)-dione & iodoethane via General Procedure I (Method A, Step F).

'11 NMR (400 MHz, DMSO-d₆) δ (ppm): 8.49 (s, 1H), 8.00 (d, J = 1.6 Hz, 1H), 7.97 (d, J= 9.6 Hz, 1H), 7.75 (d, J= 8.4 Hz, 2H), 7.70 (d, J= 9.2 Hz, 1H), 7.64 (d, J= 8.4 Hz, 2H), 7.45 (dd, J= 8.8 Hz, 1.6 Hz, 1H), 6.95 (d, J= 9.2 Hz, 1H), 4.33 (q, J= 7.2 Hz, 2H), 4.22 (s, 3H), 1.32 (t, J= 7.2 Hz, 3H).

LC-MS (ESI): m/z 476, 478 [M+H]⁺.

Synthesis of 4-(4-bromophenyl)-6-isopropoxy-2-(2-methyl-2H-i]idazoI-5-yl)pyrido [3,2c]pyridazin-3(2H)-one (Example 199)

4-(4-Bromophenyl)-6-isopropoxy-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyridazin3(2H)-one (Example 199) was synthesized from 4-(4-bromophenyl)-2-(2-methyl-2Hindazol-5-yl)pyrido[3,2-c]pyridazine-3,6(2H,5H)-dione & 2-iodopropane via General Procedure I (Method A, Step F).

^XH NMR (400 MHz, DMSO-d₆) δ (ppm): 8.49 (s, 1H), 8.00 (dd, J= 2.0 Hz, 0.8 Hz, 1H), 7.96 (d, J= 9.4 Hz, 1H), 7.74-7.68 (m, 3H), 7.64 (d, 8.6 Hz, 2H), 7.45 (dd, J= 9.1 Hz, .0 Hz, 1H), 6.90 (d, J= 9.4 Hz, 1H), 5.15 (hept, J= 6.2 Hz, 1H), 4.22 (s, 3H), 1.30 (d, J= 6.2 Hz, 6H).

LC-MS (ESI): m/z 490, 492 [M+H]⁺.

Synthesis of 4-(4-bromopheny 1)-6-(2,2-difluoroethoxy)-2-(2-methyl-2H-indazol-5yl)pyrido[3,2-c]pyridazin-3(2H)-one (Example 200)

4-(4-bromophenyl)-6-(2,2-difluoroethoxy)-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2c]pyridazin-3(2H)-one (Example 200) was synthesized from 4-(4-bromophenyl)-2-(2methyl-2H-indazol-5-yl)pyrido[3,2-c]pyridazine-3,6(2H,5H)-dione & 2,2-difluoroethyl trifluoromethanesulfonate via General Procedure I (Method A, Step F).

^lH NMR (400 MHz, DMSO-d₆) δ (ppm): 8.51 (s, 1H), 8.07 (d, 9.2 Hz, 1H), 8.03 (d, J= .6 Hz, 1H), 7.76 (d, J= 8.8 Hz, 2H), 7.72 (d, J= 9.2 Hz, 1H), 7.66 (d, J= 8.4 Hz, 2H), 7.47 (dd, 9.2 Hz, 2.0 Hz, 1H), 7.08 (d, J= 9.2 Hz, 1H), 6.41 (tt, J_HF= 54.4 Hz, 3.2 Hz, 1H), 4.59 (td, J_HP = 15.2 Hz, J= 3.2 Hz, 2H), 4.23 (s, 3H).

LC-MS (ESI): m/z 512, 514 [M+H]⁺.

Synthesis of 2-(benzo[d]thiazol-6-yl)-4-(4-bromophenyl)-6-(2,2difluoroethoxy)pyrido[3,2-c]pyridazin-3(2H)-one (Example 201)

Procedures similar to those described for Example 198 were followed. 2-(Benzo[d]thiazol-6yl)-4-(4-bromophenyl)-6-(2,2-difluoroethoxy)pyrido[3,2-c]pyridazin-3(2H)-one (Example 201) was synthesized from tert-butyl (4-(2-(benzo[d]thiazol-6-yl)-3,6-dioxo-2,3,5,6-

Îetrahydropyrido[3,2-c]pyridazin-4-yl)phenyl)carbamate via Step A-B (Example 198) and 2,2-difluoroethyl trifluoromethanesulfonate via General Procedure I (Method A, Step F). *Η NMR (400 MHz, DMSO-d₆) δ (ppm): 9.53 (s, 1H), 8.54 (d, J= 2.1 Hz, 1H), 8.25 (d, J= 8.7 Hz, 1H), 8.07 (d, J = 9.4 Hz, 1H), 7.85 (dd, J =8.7 Hz, 2.1 Hz, 1H), 7.76 (d,J=8.6Hz, 2H), 7.66 (d, J= 8.6 Hz, 2H), 7.09 (d, J= 9.4 Hz, 1H), 6.41 (tt, J_HF = 54.4, 3.4 Hz, 1H), 4.60 10 (td, J= 15.2, 3.4 Hz, 2H).

LC-MS (ESI): m/z 515, 517 [M+H]⁺.

Synthesis of 2-(benzo[d]thiazol-6-yl)-4-(4-bromophenyl)-6-isopropoxypyrido[3,2c]pyridazin-3(2H)-one (Example 202)

Br

2-(Benzo[d]thiazol-6-yl)-4-(4-bromophenyl)-6-isopropoxypyrido[3,2-c]pyridazin-3(2H)-one (Example 202) was synthesized from 2-(benzo[d]thiazol-6-yl)-4-(4-bromophenyl)pyrido[3,2c]pyridazine-3,6(2H,5H)-dione and 2-iodopropane via General Procedure I (Method A, Step F).

’Π NMR (400 MHz, DMSO-d₆) δ 9.53 (s, 1H), 8.52 (d, J= 2.1 Hz, 1H), 8.24 (d, J= 8.7 Hz, 1H), 7.96 (d, J= 9.4 Hz, 1H), 7.83 (dd, J= 8.7, 2.1 Hz, 1H), 7.72 (d, J= 8.6 Hz, 2H), 7.65 (d, J= 8.6 Hz, 2H), 6.93 (d, J= 9.4 Hz, 1H), 5.16 (hept, J= 6.4 Hz, 1H), 1.31 (d, J= 6.4 Hz, 6H).

LC-MS (ESI): m/z 493, 495 [M+H]⁺.

Synthesis of 6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)-2-(3(dimethylamino)-2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyridazm-3(2H)-one (Example 203)&4-(4- (difluoromethoxy)phenyl)-6-(dimethyIamino)-2- (3-(dimethylamino)-2methyl-2H-mdazol-5-yl)pyrido[3,2-c]pyridazin-3(2H)-one (Example 204)

Step A: 2-(3-bromo-2-methyl-2H-indazol-5-yl)-6-(2,2-difluoroethoxy)-4-(4(difiuoromethoxy)phenyl)pyrido [3,2-c] pyridazin- 3 (2H)-one

To a suspension, of 6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)-2-(2-methyl-2Hindazol-5-yl)pyrido[3,2-c]pyridazin-3(2H)-one (Example 125) (200 mg, 0.4 mmol, 1.0 eq.) in ACN (4 mL) was added NBS (75 mg, 0.42 mmol, 1.05 eq.). Then the reaction was stirring at 80°C for 3 hrs. The reaction was concentrated under reduced pressure and the residue was purified directly by flash column chromatography on silica gel to afford 2-(3-bromo-2methyl-2H-indazol-5-yl)“6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)pyrido[3,2c]pyridazin-3(2H)-one (160 mg, 69% yield) as a yellow solid. LC-MS (ESI): m/z 578; 580 [M+H]⁺.

Step B: 6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)-2-(3-(dimethylamino)-2methyl-2H-indazol-5-yl)pyrido[3,2-c]pyridazin-3(2H)-one & 4-(4(difluoromethoxy)phenyl)-6-(dimethylamino)-2-(3-(dimethylamino)-2-methyl-2H-indazol-5yl)pyrido[3,2-c]pyridazin-3(2H)-one

To a suspension of 2-(3-bromo-2-methyl-2H-indazol-5-yl)-6-(2,2-difluoroethoxy)-4-(4(difluoromethoxy)phenyl)pyrido[3,2-c]pyridazin-3(2H)-one (160 mg, 0.28 mmol, 1.0 eq.) in toluene (3 mL) was added Cs₂CO₃ (90 mg, 0.28 mmol, 1.0 eq.), Pd₂(dba)₃ (25 mg, 0.028 mmol, 0.10 eq.), Ru-Phos (26 mg, 0.055 mmol, 0.2 eq.) and dimethylamine (2 M in THF) (1.4 mL, 2.8 mmol, 10.0 eq.). Then the reaction was sealed in a pressure-resistant tube and stirring at 100°C for 5 hrs under N₂ atmosphère. The reaction was cooled to room

température and concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel and RP-prep-HPLC to afford 6-(2,2-difluoroethoxy)-4(4-(difhiorometlioxy)phenyl)-2-(3-(dimethylamino)-2-methyl-2H-indazol-5-yl)pyrido[3,2c]pyridazin-3(2H)-one (Example 203) and 4-(4-(difluoromethoxy)phenyl)-6(dimethylamino)-2-(3-(dimethylamino)-2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyridazin3(2H)-one (Example 204).

Example 203:

^]H NMR (400 MHz, DMSO-d₆) δ (ppm): 8.11 (s, 1H), 8.08 (d, J= 9.4 Hz, 1H), 7.87 (d, J= 8.4 Hz, 2H), 7.55 (d, 9.2 Hz, 1H), 7.36 (d, J= 10.6 Hz, 1H), 7.35 (t, J_HF = 74.0 Hz, 1H),

7.26 (d, J= 8.2 Hz, 2H), 7.06 (d, J= 9.3 Hz, 1H), 6.41 (tt, J_HF = 54.4 Hz, J= 3.3 Hz, 1H), 4.59 (td, Jhf~ 15.1 Hz, 3.3 Hz, 2H), 3.99 (s, 3H), 2.97 (s, 6H).

LC-MS (ESI): m/z 543 [M+H]⁺.

Example 204:

^XH NMR (400 MHz, DMSO-d₆) δ (ppm): 8.04 (dd, J= 2.0, 0.8 Hz, 1H), 7.93-7.84 (m, 2H), 7.76 (d, 0=9.8 Hz, 1H),7.52 (dd, J= 9.1, 0.8 Hz, 1H), 7.33 (dd, 0=9.2,2.0 Hz, 1H), 7.31 (t, Jhf = 74.2, 1H), 7.27 (d, 0= 9.8 Hz, 1H), 7.22-7.16 (m, 2H), 3.99 (s, 3H), 3.23 (s, 3H), 3.17 (s, 3H), 2.96 (s, 6H).

LC-MS (ESI): m/z 506 [M+H]⁺.

Synthesis of 4-(4-(difluoromethoxy)phenyl)-2-(2-methyl-2H-indazol-5-yl)-6propyIpyrido[3,2-c]pyridazin-3(2H)-one (Example 205)

To a mixture of 6-chloro-4-(4-(difluoromethoxy)phenyl)-2-(2-methyl-2H-indazol-5yl)pyrido[3,2-c]pyridazin-3(2H)-one (synthesized from 4-chloro-2-(2-methyl-2H-indazol-5yl)pyrido[3,2-c]pyridazine-3,6(2H,5H)-dione & 2-(4-(difluoromethoxy)phenyl)-4,4,5,5tetramethyLl,3,2-dioxaborolane via General Procedure I (Method C, Step E, G) (120 mg, 0.26 mmol, 1.0 eq.) and Fe(acac)₃ (93 mg, 0.26 mmol, 1.0 eq.) in THF (5 mL) and NMP (1 mL) was added n-propylmagnesium bromide (1 M in diethyl ether) (4.0 mL, 4.0 mmol, 15.4 eq.) drop-wisely at 0°C under N₂ atmosphère. The reaction mixture was stirred at room

température ovemight and quenched carefully with ice water (10 mL). The crude mixture was extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na₂SO₄ and concentrated under reduced pressure. The crude residue was purified by RP-prep-HPLC to give 4-(4-(difluoromethoxy)phenyl)-2-(2-methyl2H-indazol-5-yl)-6-propylpyrido[3,2-c]pyridazin-3(2H)-one (Example 205).

*^H NMR (400 MHz, DMSO-ri_â) δ (ppm): 8.51 (s, 1H), 8.04 (s, 1H), 7.99 (d, J= 9.1 Hz, 1H), 7.83 (d, J= 8.6 Hz, 2H), 7.72 (d, J= 9.2 Hz, 1H), 7.49 (d, J= 9.1 Hz, 1H), 7.35 (t, J_HF = 72.0 Hz, 1H), 7.29 (d, J= 9.3 Hz, 1H), 7.26 (d, J= 8.6 Hz, 2H), 4.23 (s, 3H), 2.78 (t, J= 7.4 Hz, 2H), 1.82-1.61 (m, 2H), 0.94 (t, J= 7.4 Hz, 3H).

LC-MS (ESI): m/z 462 [M+H]⁺.

Synthesis of4-cyclohexyl-6-(2,2-difluoroethoxy)-2-(2-methyl-2H-indazol-5yl)pyrido[3,2-c]pyridazin-3(2H)-one (Example 206)

Step A: 4-chloro-6-(2,2-difluoroethoxy)-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2c]pyridazin-3(2H)-one

A mixture of 4,6-dichloro-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyridazin-3(2H)-one (300 mg, 0.87 mmol, 1.0 eq., Synthesized via General Procedure I (Method A, Steps A-D). 2,2-difluoroethyl trifluoromethanesulfonate (278 mg, 1.3 mmol, 1.49 eq.) and Cs₂CO₃ (565 mg, 1.7 mmol, 1.95 eq.) in DMF (8 mL) was stirred at room température for 3 hrs and quenched with ice water (10 mL). The crude mixture was extracted with EtOAc (10 mL x 3) The combined organic layers were washed with brine (20 mL), dried over Na₂SO₄ and concentrated under reduced pressure. The crude residue was purified by flash column chromatography on silica gel to afford 4-chloro-6-(2,2-difluoroethoxy)-2-(2-methyl-2Hindazol-5-yl)pyrido[3,2-c]pyridazin-3(2H)-one (250 mg, 74% yield) as a yellow solid. LCMS (ESI): m/z 392 [M+H]⁺.

Step B: 4-cyclohexyl-6-(2,2-difluoroethoxy)-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2c]pyridazin-3(2H)-one

A mixture of 4-chloro-6-(2,2-difluoroethoxy)-2-(2-methyI-2H-indazol-5-yl)-2H,3Hpyrido[3,2-c]pyridazin-3-one (100 mg, 0.26 mmol, 1.0 eq.), Fe(acac)₃ (90 mg, 0.26 mmol, 1.0 eq.) and NMP/ THF mixture (0.5mL/5 mL) was stirred at 0°C under N₂ atmosphère.

cyclohexylmagnesium bromide (1 M in diethyl ether) (2.6 mL, 2.6 mmol, 10.0 eq.) was added drop-wisely at 0°C. Then the mixture was allowed to warm to room température and stirred ovemight, the reaction was monitored by TLC, after the completion, the reaction was quenched with ice water (10 mL), the crude mixture was extracted with EtOAc (10 mL x 3), the combined organic layers were washed with brine (30 mL), dried over Na₂SO₄ and concentrated under reduced pressure, the crude residue was purified by RP-prep-HPLC to give 4-cyclohexyl-6-(2,2-difluoroethoxy)-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2c]pyridazin-3(2H)-one (Example 206).

Ή NMR (400 MHz, DMSOY) δ (ppm) 8.48 (s, 1H), 7.99-7.92 (m, 2H), 7.69 (d, J= 9.1 Hz, 1H), 7.39 (dd, J= 9.1, 2.0 Hz, 1H), 7.02 (d, J =9.4 Hz, 1H), 6.50 (t, J_Hp— 54.2 Hz, 1H), 4.79 (td,J^= 15.1, 3.2 Hz, 2H), 4.22 (s, 3H), 2.36-2.32 (m, 1H), 1.88-1.69 (m, 4H), 1.63-1.55 (m,2H), 1.43-1.19 (m, 4H).

LC-MS (ESI): m/z 439 [M+H]⁺.

Synthesis of 6-(2,2-difluoroethoxy)-4-(4-hydroxyphenyl)-2-(2-methyl-2H-indazol-5yl)pyrido[3,2-c]pyridazin-3(2H)-one (Example 207)

OH

A mixture of 4-chloro-6-(2,2-difluoroethoxy)-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2c]pyridazin-3(2H)-one (100 mg, 0.25 mmol, 1.0 eq.), Pd(OAc)₂ (12 mg, 0.05 mmol, 0.2 eq.), K₂CO₃ (105 mg, 0.75 mmol, 3.0 eq.) and (4-hydroxyphenyl)boronic acid (53 mg, 0.38 mmol) in dioxane/water mixture (5 mL, 10/1, v/v) was stirred at 100 °C under N₂ atmosphère. Then the reaction mixture was poured into ice water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na₂SO₄ and concentrated under reduced pressure. The crude residue was purified by RP-prep-HPLC to give 6-(2,2-difluoroethoxy)-4-(4-hydroxyphenyl)-2-(2-methyl-2Hindazol-5-yl)pyrido[3,2-c]pyridazin-3(2H)-one (Example 207).

NMR (400 MHz, DMSOY) δ (ppm): 8.49 (s, 1H), 8.04-7.97 (m, 2H), 7.77-7.62 (m, 3H), 7.44 (dd, J= 9.1, 1.9 Hz, 1H), 7.03 (d, J= 9.4 Hz, 1H), 6.83 (d, J= 8.4 Hz, 2H), 6.42 (tt, Jhf= 54.5, 3.5 Hz, 1H), 4.61 (td, J= 15.0, 3.5 Hz, 2H), 4.22 (s, 3H).

LC-MS (ESI): m/z 450 [M+H]⁺.

Synthesis of 6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)-2-(3-ethyl-2-methyl2H-mdazol-5-yl)pyrido[3,2-c] pyridazin-3 (2H)-one (Example 208)

O Λ n-BuLi, THF

Step A

Step A: l-(5-bromo-2-methyl-2H-indazol-3-yl)ethanol

To a solution of 5-bromo-2-methyl-2H-indazole (500 mg, 2.37 mmol, 1 eq.) in THF (10 mL) was added n-BuLi (2.5 M in hexane) (4.7 mL, 11.85 mmol, 5 eq.) drop-wisely at -65°C under N₂ atmosphère. After 3 hrs, acetaldehyde (5 M in THF) (0.6 mL, 3.0 mmol, 1.27 eq.) was added. Then the reaction was warmed to room température slowly and stirred for 16 hrs. The reaction mixture was poured into sat. NH₄C1 aq. (10 mL) and was extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (20 mL), dried over

Na₂SO₄ and concentrated under reduced pressure. The crude residue was purified by flash column chromatography on silica gel to give l-(5-bromo-2-methyl-2H-indazol-3-yl)ethanol (500 mg, 83% yield) as a yellow solid. LC-MS (ESI): m/z 255, 257 [M+H]⁺.

Step B: 5-bromo-3-ethyl-2-methyl-2H-indazole

A mixture of l-(5-bromo-2-methyl-2H-indazol-3-yl)ethanol (200 mg, 0.78 mmol, 1 eq.), triethylsilane (453 mg, 3.9 mmol, 5 eq.), TFA (889 mg, 7.8 mmol, 10 eq.) in DCM (5 mL) was stirred at 40°C for 16 hrs. Then the mixture was poured into sat. NaHCO₃ aq. (10 mL) at 0 °C, and was extracted with DCM (10 mL x 3). The combined organic layers were dried over Na₂SO4, concentrated under reduced pressure. The crude residue was purified by flash column chromatography on silica gel to give 5-bromo-3-ethyl-2-methyl-2H-indazole (80 mg, 43% yield) as a yellow solid. LC-MS (ESI): m/z 239, 241 [M+H]⁺.

6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)-2-(3-ethyl-2-methyl-2H-indazoI-5yl)pyrido[3,2-c]pyridazin-3(2H)-one (Example 208) was synthesized from 6-(2,2difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)pyrido[3,2-c]pyridazin-3(2H)-one and 525 bromo-3-ethyl-2-methyl-2H-indazole via General Procedure II (Method A, Step G).

^lH NMR (400 MHz, DMSO-^) δ: 8.13 (d, J= 9.2 Hz, 1H), 8.07 (dd, J= 2.0 Hz, 0.8 Hz, 1H), 7.93 (d, J= 8.8 Hz, 2H), 7.68 (dd, J= 9.2 Hz, 0.8 Hz, 1H), 7.48 (dd, J= 8.8 Hz, 1.6 Hz, 1H), 7.41 (t, J_HF~ 74.0 Hz, 1H), 7.31 (d, J= 8.8 Hz, 2H), 7.13 (d, J-9.2 Hz, 1H), 6.47 (tt,

Jhf- 54.4Hz, 3.2 Hz, 1H), 4.65 (tà,J_HF = 15.2 Hz, 3.2 Hz, 2H), 4.20 (s, 3H), 3.17 (q, J = 7.2 Hz, 2H), 1.33 (t, J= 7.2 Hz, 3H).

LC-MS (ESI): m/z 528 [M+H]⁺.

Synthesis of 6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)-8-(hydroxymethyl)2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyridazin-3(2H)-one (Example 209) and 6(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)-8-(difluoromethyl)-2-(2-methyI-2Hindazol-5-yI)pyrido[3,2-c]pyridazin-3(2H)-one (Example 210)

Step A: 6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)-8-(hydroxymethyl)-2-(210 methyl-2H-indazol-5-yl)pyrido[3,2-c]pyridazin-3(2H)-one .

To a solution of 6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)-2-(2-methyl-2Hindazol-5-yl)-8-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)pyrido[3,2-c]pyridazin-3(2H)-one (Example 142, synthesized from (£)-methyl 4-(tetrahydro-2H-pyran-2-yloxy)-3-(4,4,5,5tetramethyl-l,3,2-dioxaborolan-2-yl)but-2-enoate (Ref: Tetrahedron 2012, 68, 3444-3449) via General Procedure I (Method A, Step E-F) (180 mg, 0.3 mmol, 1.0 eq.) in dioxane (3 mL) was added IN HCl (aq.) (1 mL, 1 mmol, 3.3 eq.) at room température. And the resulting mixture was stirred at room température for 2 hrs. Then the reaction was quenched with ice water (20 mL), extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na₂SO4 and concentrated under reduced pressure, the residue was purified by flash column chromatography on silica gel to afford 6-(2,2difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)-8-(hydroxymethyl)-2-(2-methyl-2H-indazol5-yl)pyrido[3,2-c]pyridazin-3(2H)-one (Example 209).

'h NMR (400 MHz, DMSO-rf,) δ (ppm): 8.50 (s, 1H), 8.04 (s, 1H), 7.84 (d, J= 8.4 Hz. 2H), 7.70 (d, J- 9.6 Hz, 1H), 7.49 (d, J= 8.8 Hz, IH), 7.34 (t, J_HF = 74.0 Hz, 1H), 7.24 (d, J = 8.4 Hz, 2H), 6.94 (s, 1H), 6.39 (tt, = 54.4 Hz, 3.2 Hz, 1H), 5.63 (s, 1H), 4.83 (s, 2H), 4.58 (td, J_HF = 15.2 Hz, 3.2 Hz, 2H), 4.22 (s, 3H).

LC-MS (ESI): m/z 530 [M+H]⁺.

Step B: 6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyI)-2-(2-methyI-2H-indazol-5yl)-3-oxo-2,3-dihydropyrido[3,2-c]pyridazine-8-carbaldehyde

To a solution of 6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)-8-(hydroxymethyl)2~(2-methyl-2H-indazol-5-yI)pyrido[3,2-c]pyridazin-3(2H)~one (60 mg, 0.1 mmol, LO eq.) in 0 CHC1₃ (5 mL) was added freshly activated MnO₂ (96 mg, 1.0 mmol, 10.0 eq.) in one portion.

Then the resulting mixture was stirred at room température for 16 hrs. The progress of the reaction was monitored by TLC, After completion, the reaction mixture was filtered through a short pad of Celite®, the filtrate was concentrated under reduced pressure to afford crude 6(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)-2-(2-methyl-2H-indazol-5-yl)-3-oxo’ 2,3-dihydropyrido[3,2-c]pyridazine-8-carbald_ehyde (50 mg) as a yellow solid, which used in next step without further purification. LC-MS: m/z 528 [M+H]⁺.

Step C: 6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)-8-(difluoromethyl)-2-(2methyl-2H-indazol-5-yI)pyrido[3,2-c]pyridazin-3(2H)-one

To a solution of 6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)-2-(2-methyl-2Hindazol-5-yl)-3-oxo-2,3-dihydropyrido[3,2-c]pyridazine-8-carbaldehyde (50 mg, crude) in DCM (3 mL) was added DAST (46 mg) at -60°C. After addition, it was allowed to warm to room température and stirred for additional 16 hrs. After completion of the reaction, ice water (10 mL) was added and extracted with EtOAc (10 mL x 3), The combined organic layers were washed with brine (20 mL), dried over Na₂SO₄ and concentrated under reduced pressure, the residue was purified by RP-prep-HPLC to afford 6-(2,2-difluoroethoxy)-4-(4(difluoromethoxy)phenyl)-8-(difluoromethyl)-2-(2-methyl-2H-indazoI-5-yl)pyrido[3,2c]pyridazin-3(2H)-one (Example 210).

*^H NMR (400 MHz, DMSO-^) δ (ppm): 8.53 (s, 1H), 8.08 (d, J= 2.0 Hz, 1H), 7.86 (d, 8.8 Hz, 2H), 7.73 (d,J=9.2Hz, 1H), 7.51 (dd,J=9.2 Hz, 2.0 Hz, 1H), 7.45 (t, Jh_F — 53.6 Hz, 1H), 7.36 (t, J_HF= 74.0 Hz, 1H), 7.30-7.25 (m, 3H), 6.41 (tt, J_HF = 54.4 Hz, 3.2 Hz, 1H), 4.61 (td, J_HF^ 15.2 Hz, 3.2 Hz, 2H), 4.23 (s, 3H).

LC-MS (ESI): m/z 550 [M+H]⁺.

-1'28^-------i

Synthesis of 6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)-8((dimethylamino)methyl)-2“(2-methyI-2H-indazol-5-yl)pyrido[3,2-c]pyridazm-3(2H)one (Ëxample 211)

Step A: (6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)-2-(2-methyl-2H-indazol-5yl)-3-oxo-2,3-dihydropyrido[3,2-c]pyridazin-8-yl)methyl methanesulfonate

To a solution of 6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)-8-(hydroxymethyl)2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyridazin-3(2H)-one (90 mg, 0.17 mmol, 1.0 eq., Example 209) in DCM (3 mL) was added MsCl (29 mg, 0.25 mmol, 1.47 eq.) and TEA (34 mg, 0.34 mmol, 2.0 eq.) at room température. And the reaction mixture was stirred at room température for 2 hrs. Then the reaction mixture was poured into ice water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na₂SO₄ and concentrated under reduced pressure, The crude residue was purified by flash column chromatography on silica gel to afford (6-(2,2-difluoroethoxy)-4-(4(difluoromethoxy)phenyl)-2-(2-methyl-2H-indazol-5-yl)-3-oxo-2,3-dihydropyrido[3,2c]pyridazin-8-yI)methyl methanesulfonate (90 mg, 87% yield) as a yellow solid. LC-MS: m/z 608 [M+H]⁺.

Step B: 6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)-8-((dimethylamino)methyl)2-(2-methyl-2H-indazol-5-yl)pyrido [3,2-c]pyridazin-3 (2H)-one

To a solution of (6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)-2-(2-methyl-2Hindazol-5-yl)-3-oxo-2,3-dihydropyrido[3,2-c]pyridazin-8-yl)methyl methanesulfonate (50 mg, 0.08 mmol, 1.0 eq.) in DMSO (3 mL) was added NH(Me)₂ HCl sait (33 mg, 0.41 mmol, 5.1 eq.), Nal (23 mg, 0.16 mmol, 2.0 eq.) and NaHCO₃ (14 mg, 0.16 mmol, 2.0 eq.) at room température. And the reaction mixture was stirred at 80 °C for 2 hrs. Then the reaction mixture was poured into ice water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na₂SO₄ and concentrated under reduced pressure. The crude residue was purified by RP-prep-HPLC to give 6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)-8-((dimethylamino)methyl)-2-(2methyl-2H-indazol-5-yl)pyrido[3,2-c]pyridazin-3(2H)-one (Example 211).

^ΧΗ NMR (400 MHz, DMSO-^) δ (ppm) 8.52 (s, 1H), 8.05 (d, J = 2.0 Hz, 1H), 7.84 (d, J= 8.8 Hz, 2H), 7.72 (d, J= 9.2 Hz, 1H), 7.49 (dd, J= 9.2, 2.0 Hz, 1H), 7.36 (t, J_HF = 74.0 Hz, 1H), 7.25 (d, J= 8.8 Hz, 2H), 6.96 (s, 1H), 6.40 (tt, J_HF= 54.4, 3.4 Hz, 1H), 4.23 (s, 3H), 3.77 (s, 2H), 2.29 (s, 6H).

LC-MS (ESI): m/z 557 [M+H]⁺.

Synthesis of 8-ammo-6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)-2-(2-methyl2H-indazol-5-yl)pyrido[3,2-c]pyridazin-3(2H)-one (Example 212)

Step A: 6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)-2-(2-methyl-2H-indazol-5yl)-3-oxo-2,3-dihydropyrido[3,2-c]pyridazine-8-carboxylic acid

To a mixture of 6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)-2-(2-methyl-2Hindazol-5-yl)-3-oxo-2,3-dihydropyrido[3,2-c]pyridazine-8-carbaldehyde (120 mg, 0.23 mmol, 1.0 eq., synthesized as in Example 210 Step B) and HCO₂H (0.1 mL, 2.65 mmol, 11.5 eq.) in H₂O (0,5 mL) was slowly added H₂O₂ (30 wt. % in H₂O, 0.1 mL, 1.14 mmol, 5 eq.) at 4 °C. And the mixture was stirred at room température for 6 hrs. Then the mixture was poured into H₂O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na₂SO₄ and concentrated under reduced pressure, the crude residue was purified by flash column chromatography on silica gel to afford 6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)-2-(2-methyl-2H-indazol-5-yl)3-oxo-2,3-dihydropyrido[3,2-c]pyridazine-8-carboxylic acid (80 mg, 52% yield) as a yellow solid. LC-MS (ESI): m/z 544 [M+H]⁺.

Step B: 8-amino-6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)-2-(2-methyl-2Hindazol-5-yl)pyrido[3,2-c]pyridazin-3(2H)-one

To a solution of 6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)-2-(2-methyl-2Hindazol-5-yl)-3-oxo-2,3-dihydropyrido[3,2-c]pyridazine-8-carboxylic acid (80 mg, 0.15 mmol, 1.5 eq.) in DMF (2 mL) was added TEA (22 mg, 0.22 mmol, 1.45 eq.) and DPPA (61 mg, 0.22 mmol, 1.45 eq.). And the mixture was stirred at room température for 3 hrs. Then 0.3 mL of water was added to the solution and the reaction mixture was stirred at 100 °C ovemight. The reaction was cooled to room température, and poured into H₂O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (20

mL), dried over Na₂SO₄ and concentrated under reduced pressure, the crude residue was purified by RP-Prep-TLC to afford 8-amino-6-(2,2-difluoroethoxy)-4-(4(difluoromethoxy)phenyl)-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyridazin-3(2H)-one (Example 212).

Ή NMR (400 MHz, DMSO-î/₅) δ (ppm): 8.49 (s, 1H), 8.05 (d, J= 1.2 Hz, 1H), 7.83 (d, J= 8.8 Hz, 2H), 7.69 (d, J= 9.2 Hz, 1H), 7.51 (dd, J= 9.2 Hz, 1.6 Hz, 1H), 7.32 (t, J_HF = 74.0 Hz, 1H), 7.23-7.14 (m, 4H), 6.31 (tt, J_HF = 54.0 Hz, 3.6 Hz, 1H), 5.83 (s, 1H), 4.47 (td, J= 14.8 Hz, 3.6 Hz, 2H), 4.22 (s, 3H).

LC-MS (ESI): m/z 515 [M+H]⁺.

Synthesis of 6-(2,2-difluoroethoxy)-2-(2-methyl-2H-indazol-5-yl)-4((trimethylsilyl)ethynyl)pyrido[3,2-cJpyridazin-3(2H)-one (Example 213), 6-(2,2difluoroethoxy)-4-ethynyl-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyridazin-3(2H)one (Example 214) & 4-((lH-pyrazol-3-yl)ethynyl)-6-(2,2-difluoroethoxy)-2-(2-methyl2H-indazol-5-yl)pyrido[3,2-c]pyridazin-3(2H)-one (Example 215)

Pd(PPh₃)₂Cl_z, TEA

Cul, DMF

Step C n-Su₃Sn^=^—TMS

Pd(PPh₃>4, dioxane

Step A

Cs₂CO, ηο^λοηρ₂

Step B

Step A: 6-(2,2-difluoroethoxy)-2-(2-methyl-2H-indazol-5-yl)-4((trimethylsilyl)ethynyl)pyrido[3,2-c]pyridazin-3(2H)-one

A mixture of 4-chloro-6-(2,2-difluoroethoxy)-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2c]pyridazin-3(2H)-one (180 mg, 0.46 mmol, 1.0 eq., Synthesized as in Example 206 Step

A), trimethyl((tributylstannyl)ethynyl)silane (268 mg, 0.69 mmol, 1.5 eq.) and Pd(PPh₃)₄ (58 mg, 0.05 mmol, 0.11 eq.) in dioxane (5 mL) was stirred at 80°C under N₂ atmosphère for 15 hrs. The reaction mixture was concentrated under reduced pressure, the crude residue was purified by flash column chromatography on silica gel to afford 6-(2,2-difluoroethoxy)-2-(2methyl-2H-indazol-5-yl)-4-((trimethylsilyl)ethynyl)pyrido[3,2-c]pyridazin-3(2H)-one (Example 213).

*Η NMR (400 MHz, DMSO-ώ;) δ (ppm): 8.50 (s, 1H), 8.08 (d, J = 9.6 Hz, 1H), 7.98 (d, J= 1.6 Hz, 1H), 7.70 (d, J= 9.2 Hz, 1H), 7.41 (dd, J= 9.2 Hz, 2.0 Hz, 1H), 7.09 (d, J= 9.2 Hz, 1H), 6.54 (tt, J_HF= 54,8 Hz, 3.6 Hz, 1H), 4.82 (td, J_HF= 14.4 Hz, 3.6 Hz, 2H), 4.22 (s, 3H), 0.28 (s, 9H).

LC-MS (ESI): m/z 454 [M+H]⁺.

Step B: 6-(2,2-difluoroethoxy)-4-ethynyl-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2c]pyridazin-3(2H)-one

A mixture of 6-(2,2-difluoroethoxy)-2-(2-methyl-2H-indazol-5-yl)-4((trimethylsilyl)ethynyl)pyrido[3,2-c]pyridazin-3(2H)-one (126 mg, 0.28 mmol, 1.0 eq.) and Cs₂CO₃ (183 mg, 0.56 mmol, 2.0 eq) in 2,2-difluoroethan-l-ol (4 mL) was stirred at room température for 4 hrs. The resulting mixture was poured into H₂O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na₂SO₄ and concentrated under reduced pressure. The crude residue was purified by flash column chromatography on silica gel to afford 6-(2,2-difluoroethoxy)-4-ethynyl-2-(2methyl-2H-indazol-5-yl)pyrido[3,2-c]pyridazin-3(2H)-one (Example 214).

*Η NMR (400 MHz, DMSO-î/₀) δ (ppm): 8.51 (s, 1H), 8.08 (d, J = 9.2 Hz, 1H), 7.99 (d, J= 1.6 Hz, 1H), 7.72 (d,J= 9.6 Hz, 1H), 7.41 (dd,J=9.2Hz, 2.0 Hz, 1H), 7.10 (d,J= 9.2 Hz, 1H), 6.52 (tt, J_HF = 54.4 Hz, 3.2 Hz, 1H), 5.02 (s, 1H), 4.83 (td, J_HF= 14.8 Hz, 3.2 Hz, 2H), 4.23 (s, 3H).

LC-MS (ESI): m/z 382 [M+H]⁺.

StepC: 4-((lH-pyrazol-3-yl)ethynyl)-6-(2,2-difluoroethoxy)-2-(2-methyl-2H-indazol-5yl)pyrido[3,2-c]pyridazin-3(2H)-one

A mixture of 6-(2,2-difluoroethoxy)-4-ethynyl-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2c]pyridazin-3(2H)-one (50 mg, 0.13 mmol, 1.0 eq.), DIPEA (50 mg, 0.39 mmol, 3.0 eq.), Pd(PPh₃)₂Cl₂ (10 mg, 0.013 mmol, 0.1 eq.) and 3-iodo-lH-pyrazole (101 mg, 0.52 mmol, 4.0 eq.) and Cul (25 mg, 0.13 mmol, 1.0 eq.) in DMF (5 mL) was stirred at room température under N₂ atmosphère for 4 hrs. Then the reaction mixture was poured into H₂O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na₂SO₄ and concentrated under reduced pressure. The crude residue was purified by RP-prep-HPLC to afford 4-((lH-pyrazol-3-yl)ethynyl)-6-(2,2-difluoroethoxy)-2(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyridazin-3(2H)-one (Example 215).

³H NMR (400 MHz, DMSO-ck) δ (ppm): 13.39 (br, s, 1H), 8.52 (s, 1H), 8.09 (d, J= 9.2 Hz, 1H), 8.01 (s, 1H), 7.91-7.81 (m, 1H), 7.72 (d, J= 9.2 Hz, 1H), 7.44 (dd, J= 9.2 Hz, 2.0 Hz

1Η), 7.Π (d, J= 9.2Hz, 1H), 6.62 (s, 1H), 6.55 (tt, J_Hf^ 54.4 Hz, 3.2 Hz, 1H), 4.88 (td, J_HF = 14.8 Hz, 3.2 Hz, 2H), 4.23 (s, 3H).

LC-MS (ESI): m/z 448 [M+H]⁺.

Synthesis of 6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)-2-(45 oxocyclohexyl)pyrido[3,2-c]pyridazin-3(2H)-one (Example 216)

A solution of 6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)-2-(l,4dioxaspiro[4.5]dec-7-en-8-yl)pyrido[3,2-c]pyridazin-3(2H)-one (synthesized from 6-(2,2difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)pyrido[3,2-c]pyridazin-3(2H)-one & 1,410 dioxaspiro[4.5]dec-7-en-8-yl trifluoromethanesulfonate via General Procedure II (Method A, Step G)) (10 mg, 0.0197 mmol) and conc. HCl (0.1 mL) in THF (1.5 mL) was stirred at room température for 2 hrs. The reaction was poured into sat. NaHCO₃ aq. (5 mL) and extracted with EA (5 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na₂SO₄ and concentrated under reduced pressure. Then a mixture of the residue and Rh(PPh₃)₃Cl (18 mg, 0.0197 mmol) in toluene (3 mL) was stirred at room température ovemight under H₂ atmosphère. Then the mixture was poured into H₂O (5 mL) and extracted with EtOAc (5 mL x 3). The combined organic layers were washed with brine (10 mL), dried over Na₂SO₄ and concentrated under reduced pressure. The crude residue was purified by RP-prep-HPLC to afford 6-(2,2-difluoroethoxy)-4-(4-(difluoromethoxy)phenyl)20 2-(4-oxocyclohexyl)pyrido[3,2-c]pyridazin-3(2H)-one (Example 216).

’h NMR (400 MHz, DMSO-îA) δ (ppm): 8.02 (d, J= 9.6 Hz, 1H), 7.82 (d, J= 8.8 Hz, 2H), 7.34 (t, J_ΠΡ - 74.0 Hz, 1H), 7.24 (d, J= 8.8 Hz, 2H), 7.02 (d, J = 9.6 Hz, 1H), 6.37 (tt, J_HF = 54.4 Hz, 2.8 Hz, 1H), 5.62 (hept, J= 4.8 Hz, 1H), 4.54 (td, J_HF= 14.8 Hz, 2.8 Hz, 2H), 2.782.63 (m, 2H). 2.45-2.23 (m, 2H), 2.29-2.14 (m, 1H) (HCO₂H sait).

LC-MS (ESI): m/z 466 [M+H]⁺.

Synthesis of 4-(4-(difluoromethoxy)phenyl)-6-ethoxy-2-(2-methyl-2H-mdazol-5y0pyrido|3,2-c]pyridazin-3(2H)-one (Example 217)

A mixture of 6-chloro-4-(4-(difluoromethoxy)phenyl)-2-(2-methyl-2H-indazol-5yl)pyrido[3,2-c]pyridazin-3(2H)-one (synthesized from 4-chloro-2-(2-methyl-2H-indazol-5yl)pyrido[3,2-c]pyridazine-3,6(2H,5H)-dione & 2-(4-(difluoromethoxy)phenyl)-4,4,5,5tetramethyl-l,3,2-dioxaborolane via General Procedure I (Method C, Step E, G) (120 mg, 0.26 mmol, 1.0 eq.) and EtONa (177 mg, 2.6 mmol, 10.0 eq.) in EtOH (8 mL) was stirred at 40°C for 3 hrs. Then the reaction mixture was poured into ice water (10 mL) and extracted with DCM (10 mL x 3). The combined organic layers were dried over Na₂SO₄, concentrated under reduced pressure. The crude residue was purified by RP-prep-HPLC to give 4-(4(difluoromethoxy)phenyl)-6-ethoxy-2-(2-methyl-2H-indazol-5-yl)pyrido[3,2-c]pyridazin3(2H)-one (Example 217).

'H NMR (400 MHz, DMSO-^₆) δ: 8.49 (s, 1H), 8.04 (d, J= 1.2 Hz, 1H), 7.97 (d, J= 9.2 Hz, 1H), 7.86 (d, J = 8.8 Hz, 2H), 7.70 (d, J = 9.2 Hz, 1H), 7.45 (dd, 9.2 Hz, 2.0 Hz, 1H), 7.34 (t, J_HF= 74.0, 1H), 7.24 (d, J= 8.8 Hz, 2H), 6.95 (d, J= 9.6 Hz, 1H), 4.34 (q, J= 7.2 Hz, 2H), 4.22 (s, 3H), 1.32 (t, J= 7.2 Hz, 3H).

LC-MS (ESI): m/z 464 [M+H]⁺.

Synthesis of 5-(6-(2,2-difluoroethoxy)-2-(2-methyl-2H-indazol-5-yl)-3-oxo-2,3dihydropyrido[3,2-c]pyridazin-4-yl)-lH-indole-3-carbonitrile (Example 331)

¹ 2

To a solution of7-(2,2-difluoroethoxy)-3-(2-methyl-2H-indazol-5-yl)-l-(1-((2(trimethylsilyl)ethoxy)methyl)-lH-indazol-5-yl)-3,4-dihydropyrido[2,3-d]pyrimidin-2(lH)one (54 mg, 0.09 mmol, 1.0 eq) (synthesized from 4-chloro-2-(2-methyl-2H-indazol-5yl)pyrido[3,2-c]pyridazine-3,6(2H,5H)-dione & 5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2yl)-l-((2-(trimethylsilyI)ethoxy)methyl)-lH-indole-3-carbonitrile (Ref: WO2018215316) via

General Procedure I (Method A, Step E & F)) in DCM (3 mL) was added TFA (1 mL), the reaction mixture was stirred at room température for 3 hrs. Then the reaction mixture was concentrated under reduced pressure, the residue was re-dissolved in MeOH (2 mL) and conc. NH₄OH (1 mL), the resulting mixture was stirred at room température ovemight. After completion, the reaction mixture was concentrated under reduced pressure, the residue was purified by RP-Prep-HPLC to give 5-(6-(2,2-difluoroethoxy)-2-(2-methyl-2H-indazol-5-yl)3-oxo-2,3-dihydropyrido[3,2-c]pyridazin-4-yl)-lH-indole-3-carbonitrile (Example 331). ^lH NMR (400 MHz, DMSO-J₆) δ (ppm): δ 12.29 (s, 1H), 8.50 (s, 1H), 8.29 (s, 1H), 8.12 (d, J= 0.9 Hz, 1H), 8.10-8.01 (m, 2H), 7.75 (dd, J= 8.6 Hz, 1.5 Hz, 1H), 7.71 (d, J= 9.2 Hz, 1H), 7.60 (d, J= 8.7 Hz, 1H), 7.49 (dd, J= 9.1 Hz, 2.0 Hz, 1H), 7.06 (d, J= 9.4 Hz, 1H), 6.38 (tt, Jhf = 54.5 Hz, J= 3.3 Hz, 1H), 4.54 (td, J_Hf = 15.0 Hz, J= 3.4 Hz, 2H), 4.22 (s, 3H).

LC-MS (ESI): m/z 498 [M+H]⁺.

Synthesis of 5-(6-(ethylamino)-2-(2-methyl-2H-indazol-5-yl)-3-oxo-2,3dihydropyrido[3,2-c]pyrïdazm-4-yl)-lH-mdole-3-carbonitrile (Example 332)

To a solution of 5-(6-(ethylamino)-2-(2-methyl-2H-indazol-5-yl)-3-oxo-2,3dihydropyrido[3,2-c]pyridazin-4-yl)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-indole-3carbonitrile (100 mg, 0.17 mmol) (synthesized from 4-chloro-2-(2-methyl-2H-indazol-5yl)pyrido[3,2-c]pyridazine-3,6(2H,5H)-dione&5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2yl)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-indole-3-carbonitrile (Ref: WO2018215316) via General Procedure I (Method A, Step E; Method D, Step I)) in DCM (6 mL) was added TFA (6 mL), the reaction mixture was stirred at room température for 12 hrs. Then the reaction mixture was concentrated under reduced pressure, the residue was re-dissolved with MeOH (4 mL) and conc. NH₄OH (2 mL), the resulting mixture was stirred at room température for additional 6 hrs. After completion, the reaction mixture was concentrated under reduced pressure, the residue was purified by RP-prep-HPLC to give 5-(613 (ethylamino)-2-(2-methyl-2H-indazol-5-yl)-3-oxo-2,3-dihydropyrido[3,2-c]pyridazin-4-yl)lH-indole-3-carbonitrile (Example 332).

NMR (400 MHz, DMSO<Z₆) (ppm): δ 12.17 (s, 1H), 8.45 (s, 1H), 8.27 (s, 1H), 8.22 (s, 1H), 8.16 (s, 1H), 7.96 (s, 1H), 7.76 (d, J= 9.0 Hz, 1H), 7.66 (d, J= 9.1 Hz, 1H), 7.64 (d, J= 9.1 Hz, 1H), 7.51 (d, J= 8.9 Hz, 1H), 7.43 (d, J= 8.9 Hz, 1H), 6.78 (d, 9.3 Hz, 1H), 4.21 (s, 3H), 3.31 (q, J= 7.1 Hz, 2H), 1.14 (t, 7.1 Hz, 3H).

LC-MS (ESI): m/z 461 [M+H]⁺.

Biochemical Assay

Mat2A protein was expressed by recombinant baculovirus in SF9 infected cells using the Bac to Bac System cloned into the pFASTBACl vector (Invitrogen, Carlsbad, CA). Recombinant MAT2A was isolated from the cell lysate of 150 g of infected cells using HP Ni sepharose column chromatography. Recombinant MAT2A homodimer was eluted with 250 and 500 mM imidazole, and fractions containing MAT2A were identified by sodium dodecyl sulfate polyacrylamide gel electrophoresis and pooled.

For détermination of the inhibitory potency of compounds against the MAT2A homodimer, protein was diluted to 4 pg/mL in assay buffer (50 mM Tris, pH 8.0, 50 mM KC1, 15 mM MgCl₂, 0.3 mM EDTA, 0.005% [w/v] bovine sérum albumin [BSA]). Test compound was prepared in 100% dimethyl sulfoxide (DMSO) at 50^x the desired final concentration. A 1 pL volume of compound dilution was added to 40 pL of enzyme dilution and the mixture was allowed to equilibrate for 60 minutes at 25 °C. The enzymatic assay was initiated by the addition of 10 pL of substrate mix (500 pM ATP, pH 7.0, 400 pM L-methionine in lx assay buffer), and the mixture was incubated for a further 60 minutes at 25 °C. The reaction was halted and the liberated phosphate released by the enzyme in stoichiometric amounts by the production of S-adenosyl méthionine (SAM) was measured using the PiColorLock Gold kit (Innova Biosciences, UK). Absolute product amounts were determined by comparison to a standard curve of potassium phosphate buffer, pH 8.0.

Spécifie compounds disclosed herein were tested in the foregoing assay and they were determined to inhibit MAT2A with an IC₅q according to the foliowing scores: (A) less than 100 nM (> 40% maximum inhibition), (B) between 100 nM and 1 pM (> 40% maximum inhibition), and (C) between 1 pM and 10 pM (> 40% maximum inhibition), as shown in Table 2 below.

Cellular Assay of target engagement (SAM)

-136-3——”.........

Measurement of MAT2A activity in cells was made by direct quantitation of the abundance of the product of its enzymatic activity, SAM. Cancer cells were treated with candidate MAT2A inhibitors for a suitable incubation period, and the cells were then lysed using a reagent which quenched any further enzyme activity. Soluble métabolites including SAM 5 were collected and SAM itself was directly measured from the lysate using quantitative LCMS/MS.

A typical assay was performed using an HCT116 human colon carcinoma cell line which was genetically engineered to delete the MTAP gene (commercially available from Horizon Discovery). This cell line was utilized because it was determined that loss of the MTAP gene 10 predicts sensitivity to MAT2A inhibitors. Cells were plated in 96-well dishes at appropriate cell density. Following 24 hours, cells were then treated with the candidate MAT2A inhibitor. Prior to addition to cells, the compound was first serially diluted in 100% DMSO, typically as a 3-fold serial dilution starting at 500* top dose with 10 dose points including DMSO only control. Compound was then transferred to a working stock plate in cell culture 15 media by adding 5 pL of compound in DMSO to 495 pL of cell culture media. This working stock was then added to cells via a further 5-fold dilution, by adding 25 pL of working stock to 100 pL of cells in culture media. Following compound addition, cells were incubated at 37 °C / 5% CO₂ for 72 hrs.

To quantitate SAM levels following compound treatment, cells were gently washed once in 20 ammonium carbonate buffer (75mM at pH 7.4), placed on dry ice, and lysed with métabolite extraction buffer (80% cold methanol and 20% water (v/v) with acetic acid at IM final concentration with 200 ng/mL deuterated d₃-SAM as internai control). Following centrifugation at 4 °C at 3,200 rpm for 30 minutes, the supematant was collected and stored at -80 °C until analysis by Liquid Chromatography with tandem Mass Spectrometry (LC25 MS/MS). LC-MS/MS analysis was performed using an API6500 Mass Spectrometer (Sciex, Framingham, MA, USA) operating in positive ion spray mode and equipped with a Waters UPLC Acquity (Waters, Milford, MA, USA) BEH Amide column. Multiple Reaction Monitoring data was acquired for SAM and the d₃-SAM standard, using a mass transition pair at m/z 399.2^250.1 and 402.2^250.1, respectively. In a typical LC-MS/MS analysis, 30 the initial flow rate was 0.5 ml/min of 25% mobile phase A (acetonitrile and water at 5:95 (v/v) with 1% formic acid and 10 mM ammonium acetate) and 75% mobile phase B (acetonitrile and water at 95:5 (v/v) with 1% formic acid and 10 mM ammonium acetate), 0.2-0.5 minutes with 75% - 35% mobile phase B, 25%-65% mobile phase A, at 0.5 min 65% mobile phase A and 35% mobile phase B, 1.0—1.1 minutes with 35% -75% mobile phase B,

65%-25% mobile phase A, at 1.1min 25% mobile phase A and 75% mobile phase B with a total run time of 1.5 minutes.

Spécifie compounds disclosed herein were tested in the foregoing assay and they were determined to inhibit SAM with an IC50 according to the following scores: (A) less than 100 nM (> 60% maximum inhibition), (B) between 100 nM and 1 μΜ (> 60% maximum inhibition), (C) greater than or equal to 1 μΜ (> 60% maximum inhibition), and (NT) not tested, as shown in Table 2 below.

Assay for Inhibition of Cellular Prolifération

Test compound impact on cancer cell growth was assessed by treating cancer cells with compound for 4 days and then measuring prolifération using an ATP-based cell prolifération readout (Cell Titer Glo, Promega Corporation).

In a typical assay an isogenic pair of HCT116 human colon carcinoma cell lines which vary only in MTAP délétion status (HCT116 MTAP+/+ and HCT116 MTAP-/-) were plated in 96-well dishes at appropriate cell density. Following 24 hours, cells were then treated with the candidate MAT2A inhibitor. Prior to addition to cells, the compound was first serially diluted in 100% DMSO, typically as a 3-fold serial dilution starting at 500x top dose with 10 dose points including DMSO only control. Compound was then transferred to a working stock plate in cell culture media by adding 5 pL of compound in DMSO to 495 pL of cell culture media. This working stock was then added to cells via a further 5-fold dilution, by adding 25 pL of working stock to 100 pL of cells in culture media. Following compound addition, cells were incubated at 37 °C / 5% CO2 for 4 days.

To measure inhibition of cellular prolifération, cells were allowed to equilibrate to room température for 30 minutes, and were then treated with 125 pL of Cell Titer Glo reagent. The plate was then covered with aluminum foil and shaken for 15 minutes to ensure complété mixing and full cell lysis. Luminescent signal was then measured using a plate-based luminometer Veritas version 1.9.2 using ATP standard curve to confîrm assay reproducibility from run to run. This luminescence measure was converted to a prolifération index by subtracting from each data point the ATP luminescence signal measured from a bank (no cells) well and dividing by the ATP luminescence signal measured in 0.2% DMSO control well adjusted for signal in blank well. Compound activity was then represented as a percentage change in prolifération relative to a within-plate DMSO control against loglO of compound concentration in molar (M) units.

Spécifie compounds disclosed herein were tested in the foregoing assay and they were determined to inhibit cellular prolifération with an IC50 according to the following scores: (A) less than 100 nM (> 30% maximum inhibition for MTAP > 10% maximum inhibition for MTAP +/+), (B) between 100 nM and 1 μΜ (> 30% maximum inhibition for MTAP > 10% maximum inhibition for MTAP +/+), (C) greater than or equal to 1 μΜ, and (NT) not tested, as shown in Table 2 below.

Table 2

Example	Enzyme Inhibition	Cell 72 h SAM Inhibition (MTAP -/-)	4 Day Relative Growth Inhibition (MTAP -A)	4 Day Relative Growth Inhibition (MTAP +/+)
___101	A	A	B	C
102	A	A	B	C
103	A	A	A	c
104	A	B	B	c
105	A	B	B	c
___106	A	A	A	B
_ 107	A	A	A	C
108	A	A	A	C
109	A	A	A	C
110	A	A	A	B
111	A	A	A	C
112	A	B	B	C
113	A	A	B	C
____114	A	A	A	C
115	A	A	A	B
116	A	A	A	C
117	A	A	A	C
118	B	NT	NT	NT
119	A	A	A	C
120	A	A	A	C
_ 121	A	A	A	c
122	A	B	A	c
123	A	A	A	B
124	A	A	A	B
125	A	A	A	B
126	A	A	A	C
127	A	A	A	C
128	A	A	A	C
129	A	A	A	C
130	A	A	A	B
131	A	B	C	C
132	A	B	__ B	C

Example	Enzyme Inhibition	Cell 72 h SAM Inhibition (MTAP -/-)	4 Day Relative Growth Inhibition (MTAP -/-)	4 Day Relative Growth Inhibition (MTAP+/+)
133	A	A	B	C
134	A	B	C	C
135	A	A	B	c
136	A	B	B	c
137	A	A	A	c
138	A	A	A	c
139	A	A	A	B
140	A	B	A	C
141	A	A	B	C
142	A	B	B	c
143	A	A	A	c
144	A	A	A	c
145	A	A	A	c
146	A	A	A	c
147	A	B	B	c
148	A	B	B	c
149	A	A	B	c
150	A	A	A	c
151	A	A	A	c
152	A	A	A	B
153	B	C	C	c
154	A	A	A	c
155	A	A	A	c
156	A	A	A	c
__157	A	B	B	c
158	A	A	A	c
159	A	A	A	c
160	A	A	A	c
161	A	A	A	c
___162	A	A	A	c
163	A	C	C	c
___164	B	NT	NT	NT
165	A	A	A	B
166	A	A	A	C
167	A	A	A	c
168	A	A	B	c
___169	A	A	A	A
170	A	A	B	C
171	A	A	A	c
172	A	A	A	c
173	A	A	A	B
174	A	A	A	C
175	A	A	A	B

Example	Enzyme Inhibition	Cell 72 h SAM Inhibition (MT AP -/-)	4 Day Relative Growth Inhibition (MTAP-/-)	4 Day Relative Growth Inhibition (MTAP +/+)
176	A	A	B	B
177	A	A	A	B
_ 178	A	A	A	B
___179	A	A	B	C
180	A	A	A	C
_ 181	C	NT	NT	NT
182	A	A	A	B
___183	A	A	A	B
_ 184	A	A	B	C
185	B	NT	NT	NT
186	B	NT	NT	NT
187	A	B	C	C
188	A	B	B	C
189	A	B	B	c
_ 190	C	NT	NT	NT
___191	B	B	C	C
___192	A	A	B	B
193	A	B	B	C
194	A	B	A	C
195	A	A	C	C
196	A	A	A	c
197	A	A	A	c
198	A	A	A	c
___199	A	A	A	c
200	A	A	A	c
201	A	A	A	c
202	A	A	A	c
203	A	A	A	B
204	A	NT	NT	NT
205	A	A	A	C
___206	A	B	B	C
207	A	A	B	c
208	A	A	A	B
209	A	A	A	C
210	A	A	B	c
___211	A	B	B	c
212	A	A	A	B
213	B	. NT	C	C
214	B	C	C	C
215	A	C	B	C
216	B	NT	NT	NT
217	A	A	A	B
301	A	_______A 1	A	C

Example	Enzyme Inhibition	Cell 72 h 1 4 Day Relative	4 Day Relative Growth Inhibition (MTAP +/+)
SAM Inhibition (MT AP-/-)	Growth Inhibition (MT AP -/-)
302	A	A	A	C
303	A	A	A	C
304	A	A	B	B
305	A	A	A	C
306	A	NT	NT	NT
307	A	A	A	C
___308	A	NT	NT	NT
309	A	A	A	C
310	A	A	A	C
311	A	NT	NT	NT
___312	A	NT	NT	NT
313	A	A	A	B
314	A	NT	NT	NT
315	A	A	A	C
316	A	A	A	C
317	A	A	A	c
318	A	A	A	c
___319	A	A	A	c
320	A	NT	NT	NT
321	A	A	A	C
3.22	A	NT	NT	NT
323	A	A	A	A
324	A	NT	NT	NT
325	A	NT	NT	NT
326	A	NT	NT	NT
327	A	A	A	C
328	B	NT	NT	NT
329	B	NT	NT	NT
330	A	NT	NT	NT
331	A	A	A	C
332	A	NT	NT	NT

Claims (36)

1. A compound according to Formula I:

R⁴

R² wherein

L is O, S, NR, or a bond;

R is H or Ci-C₆-alkyl;

R¹ is selected from the group consisting of C_rC₆-alkyl, C₂-C₆-alkenyl, C₃-C₆-carbocyclyl, (Ci-C₆-alkyl)(C₃-C₆-carbocyclyl), and -(Ci-C₆-alkyl)(C₃-C₆-cycloalkenyl) wherein any alkyl in R¹ is straight or branched, and

R¹ is optionally substituted by 1 - 6 halo or 1 - 6 deuterium;

or when L is NR, then R and R¹ in combination with L represent a 3- to 6-membered heterocycloalkyl (wherein 1-4 ring members are independently selected from N, O, and S) optionally substituted by one or more R^A;

R and R are independently selected from the group consisting of (C₂-C₆)alkynyl, C₆-Ci₀aryl, C₃-C₆-carbocyclyl, 5- to 10-membered heteroaryl (wherein 1-4 heteroaryl members are independently selected from N, O, and S), and 3- to 14-membered heterocycloalkyl (wherein 1-4 heterocycloalkyl members are independently selected from N, O, and S), wherein R² and R³ are independently and optionally substituted by one or more substituents that are selected from the group consisting of R^A, OR^A, halo, -N=NR^a, NR^aR^b, -(C[-C6-alkyl)NR^AR^B, -C(O)OR^A, -C(O)NR^AR^B, -OC(O)R^A, -Si(Cr C₆-alkyl)₃ and -CN;

R⁴ is selected from the group consisting of H, C_rC₆-alkyl (optionally substituted by one or more halo, hydroxy or 3- to 14-membered heterocycloalkoxy (wherein 1-4 heterocycloalkoxy members are independently selected from N, O, and S)), -O(Ci-C₆alkyl) (optionally substituted by one or more halo), -OH, halo, -CN, -(Ci-C₆alkyl)NR^AR^B, and -NR^AR^B;

R⁵ is selected from the group consisting of H, C_rC₆-alkyl, C]-C₆-alkoxy, C₂-C₆-alkenyl, C₂C₆-alkynyl, halo, -CN, and -NR^CR^D;

R^A and R^b are independently selected from the group consisting of H, -CN, -hydroxy, oxo, C_rC₆-alkyl, Ci-C₆-alkoxy, C₂-C₆-alkenyl, C₂-C₆-alkynyl, -NH₂, -SiOXHCrCé-alkyl), S(0)o-₂-(C6-Cio-aryl), -C(O)(Ci-Cg-alkyl), -C(O)(C₃-Ci4-carbocyclyl), -C3-C14carbocyclyl, -(Ci-C₆-alkyl)(C₃-Ci₄-carbocyclyl), C₆-Cio-aryl, 3- to 14-membered

143 heterocycloalkyl and -(Ci-Cs-alkyl)-(3- to 14-membered heterocycloalkyl) (wherein 1-4 heterocycloalkyl members are independently selected from N, O, and S), and 5- to 10membered heteroaryl (wherein 1 -4 heteroaryl members are independently selected from N, O, and S);

wherein each alkyl, alkoxy, alkenyl, alkynyl, aryl, carbocyclyl, heterocycloalkyl, and heteroaryl moiety of R^A and R^B is optionally substituted with one or more substituents selected from the group consisting of deuterium, hydroxy, halo, NR’2 (wherein each R’ is independently selected from the group consisting of Cf Cô-alkyl, C2-Cg-alkenyl, C2-Câ-alkynyl, Cg-Cio-aryl, 3- to 14-membered heterocycloalkyl and -(C]-C6-alkyl)-(3- to 14-membered heterocycloalkyl) (wherein 1-4 ring members are independently selected from N, O, and S), and 5to 10-membered heteroaryl (wherein 1-4 heteroaryl members are independently selected from N, O, and S), -NHC(O)(OCrC6-alkyl), -NO2, -CN, oxo, -C(O)OH, -C(O)O(Ci-C6-alkyl), -Ci-C6-alkyl(Ci-C6-alkoxy), -C(O)NH2, Ci-C6-alkyl, C(O)Ci-C6-alkyl, -OCi-C6-alkyl, -Si(Ci-C6-alkyl)3, -S(O)0.2-(Ci-C6-alkyl), C6Cw-aryl, -(Ci-Ce-alkylXCg-Cio-aryl), 3- to 14-membered heterocycloalkyl, and (Ci-Cô-alkyl)-(3- to 14-membered heterocycle) (wherein 1-4 heterocycle members are independently selected from N, O, and S), and -O(C6-C14-aryl), wherein each alkyl, alkenyl, aryl, and heterocycloalkyl substituent in R^A and R is optionally substituted with one or more substituents selected from the group consisting of hydroxy, -OCh-Cé-alkyl, halo, -NH2, -(Ci-C₆alkyl)NH₂, -C(O)OH, CN, and oxo;

R^c and R^D are each independently selected from H and C]-C₆-alkyl; or a pharmaceutically acceptable sait thereof.

2. The compound according to claim 1, wherein:

R⁴ is selected from the group consisting of H, Ci-C₆-alkyl (optionally substituted by one or more halo, hydroxy or 3- to 14-membered heterocycloalkoxy (wherein 1-4 heterocycloalkoxy members are independently selected from N, O, and S)), -O(Ci-C₆alkyl), -(Ci-C6-alkyl)NR^AR^B, and -NR^AR^B (wherein R^A and R^B are independently selected from H and Ci-C^-alkyl); and

R⁵ is selected from the group consisting of H, Ci-C₆-alkyl, Ci-C₆-alkoxy, and -NR^CR^D.

3. The compound according to claim 1 or 2, wherein at least one of R⁴ and R⁵ is H.

4. The compound according to any one of daims 1 to 3, wherein R⁴ is H.

4·

5. The compound according to any one of claims 1 to 4, wherein R⁵ is H.

6. The compound according to any one of claims 1 to 5, wherein each of R⁴ and R⁵ is H.

7. The compound according to any one of claims 1 to 6, wherein R² is optionally substituted

C₆-C[o-aryl or optionally substituted 5- to 10-membered heteroaryl.

8. The compound according to claim 7, wherein R² is optionally substituted C₆-Ci₀-aryl.

9. The compound according to claim 8, wherein R² is optionally substituted phenyl.

10. The compound according to claim 7, wherein R² is optionally substituted 5- to 10- membered heteroaryl, and wherein 1 ring member is N.

11. The compound according to claim 10, wherein R² is optionally substituted 5- or 6membered heteroaryl.

12. The compound according to claim 10 or 11, wherein R² is optionally substituted 6membered heteroaryl.

13. The compound according to any one of claims 10 to 12, wherein R² is optionally substituted pyridyl.

14. The compound according to any one of claims 1 to 12, wherein R³ is optionally substituted 3- to 14-membered heterocycloalkyl or optionally substituted 5- to 10membered heteroaryl.

15. The compound according to claim 14, wherein R³ is selected from the group consisting of benzothiazolyl, benzoisothiazolyl, benzoxazolyl, pyridinyl, pyridinonyl, pyridazinyl, benzimidazolyl, benzotriazolyl, indazolyl, quinoxalinyl, quinolinyl, quinazolinyl, imidazopyridinyl, pyrazolopyridinyl, triazolopyridinyl, cinnolinyl, isoxazolyl, pyrazolyl, benzofuranyl, dihydrobenzofuranyl, dihydrobenzodioxinyl, and tetrahydrobenzodioxinyl, each of which may be optionally substituted.

16. The compound according to any one of claims 1 to 12, wherein R³ is optionally substituted Ce-Cjo-aryl.

17. The compound according to claim 16, wherein R³ is optionally substituted phenyl.

18. The compound according to any one of claims 1 to 6, wherein R² is optionally substituted phenyl and R³ is optionally substituted 3- to 14-membered heterocycloalkyl or optionally substituted 5- to 10-membered heteroaryl.

19. The compound according to any one of claims 1 to 18, wherein L is O or NR.

5

20. The compound according to claim 19, wherein R¹ is optionally substituted Ci-C₆-alkyl or optionally substituted C₃-C₆-carbocyclyl.

21. The compound according to claim 19 or 20, wherein R¹ is Ci-C₃-alkyl that is optionally substituted by 1 - 3 F.

22. The compound according to claim 1, wherein

10 L is O or NR and R is H;

R* is Ci-C₃-alkyl that is optionally substituted by 1 - 3 F;

R is optionally substituted 3- to 14-membered heterocycloalkyl or optionally substituted 5to 10-membered heteroaryl (wherein 1 heterocycloalkyl or heteroaryl member is N) or optionally substituted Cg-Cio-aryl;

15 R³ is optionally substituted 3- to 14-membered heterocycloalkyl or optionally substituted 5to 10-membered heteroaryl wherein 1 to 3 heterocycloalkyl or heteroaryl members are independently selected from N, O, and S; and each of R⁴ and R⁵ is H.

23. The compound according to claim 22, wherein L is NR.

The compound according to claim 1 or a pharmaceutically acceptable sait thereof, wherein the compound is selected from the following table:

107 Λ ^zy ο > ο I Μ 165 —N 7 | Q^y^pj^gX^yxF 0 ^F ochf₂

108 —Ν ] ] Ο^Υ^νΜ^ΟΗΡ;, 0 ocd₃ 166 -ν η η ₀^y M'oMîHFs 0 ochf₂

109 CXI LL T O < O \ / CO )-----( j-----< LL yy ΛΛ o 'z ¹ . 167 tv LL T O O z/v· \ F '/A /=^ Q z ν—ά /Vo

110 < O V 2 \ f CO )—< _t—v Q ² 7—(\ /)—O . Z 1 168 z—x 7—A ² - \_/ A z Λ f O )

111 1 Z f,—x y—z o—ç y—/ z a \_/ a x —' )—( H -7 \ h> Z t) \\ // „ 169 ÇQ s '- 'N yx N^O^C H F₂ ochf₂

112 1— O /T^ \ ² f O Φ s 170 ₀^y<_N^₀^_CHF2 0 ochf₂

113 —N ] | Ο^γ N 0 0 Cl 171 S 1 CD °γ O YA / o—u y—6 z O \—/ 0 // x — )—\ J¹ £ λ \\ // o ) o I -η KJ

114 Y 2 Λ \\ // o > O X 6J 172 MeO—/ Il Q^Y^Yo^GI-F;, ochf₂

115 /=\ °w A—w s v 0 y // CD /----Ç y/ O 173 ohPH ^Zz “ \_/ y 0 z Λ \\ // o > o X Π rj

116 tri U- O < O /Y \ ² /=/ z y—0 /—° Y 'z 1 174 g I œ 4 Y οΥγτ % \\ // o > o X ro

117 XA-.Q Cl 175 N;-ZV —N ] | r^N'^NY/ d₃co J J J Ο^γΝ O^CHF₂ 0 ochf₂

ocf₃ ochf₂

—N J ] 128 ⁰ _M6 Ml ocf₃ —N ] | 129 ° J ^N' O^CH₂F ₁₈₇ 0 ochf₂ —N 1_3β ° jC^N' θ^⁰^² 188 fil OMe f\K ^^ΝΎ1 ΝΜ^γ^F ιΊ ^F ochf₂ /Ο,Λ yL F U ochf₂ m_n._n_ Ν^Ο'^γ ^F F M ochf₂ ^NYt^‘Y-i —N /\ ΥΊ. Y 131 0 ochf₂ —N J | ochf₂ 0 _n ^k^N'^N^ 189 F Q ochf₂ ^Ci\X<Y, ΪΧ'^ΝγΥ ^3 Υ\<γ·\ y-L ^_F 190 OYN A. F Q ochf₂ ......

133 -N T η O^ y 191 ^F-XX ^n-VY qXxX^ F Γί ^f ochf₂

134 J ζΓΊ\ Z 7--<\ Z \__/ 0__Z' z Λ \\ // o > O 192 cx_v, x\xk >f q y n ο y XX F O ochf₂

135 0 ochf₂ 193 H IX N. fl ^-yx Jx F rj ochf₂

136 CD „ 0 r—x y—z o—ç y—C z o ^χ_/ Λ y Tl 2-- )---< CO / \ z /) \\ // 194 N^XX —N ] ] ^^Vy-y^F G^y^ N^O^CH f₂ 0 ochf₂

137 Ν^χΧ —N ] | '^^Λ _Ν-^Νγγ XJ ' 0 ochf₂ 195 NîXX —N I ] ^^^N'^N<px^F qXXîX n'^; '0’\ 0 ochf₂

ochf₂

25. The compound according to claim 1 or a pharmaceutically acceptable sait thereof, wherein the compound is selected from the following table:

A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of daims 1 to 25 or a pharmaceutically acceptable sait thereof, and a pharmaceutically acceptable carrier.

A compound according to any one of daims 1 to 25, or a pharmaceutically acceptable sait thereof, for use in treating a cancer in a subject suffering therefrom.

The compound according to claim 27, or a pharmaceutically acceptable sait thereof, wherein the cancer is an MTAP-deleted cancer.

The compound according to daim 27 or 28, or a pharmaceutically acceptable sait thereof, wherein the cancer is selected from the group consisting of mesothelioma, neuroblastoma, rectum carcinoma, colon carcinoma, familiary adenomatous polyposis carcinoma and hereditary non-polyposis colorectal cancer, esophageal carcinoma, labial carcinoma, larynx carcinoma, hypopharynx carcinoma, tongue carcinoma, salivary gland carcinoma, gastric carcinoma, adenocarcinoma, medullary thyroidea carcinoma, papillary thyroidea carcinoma, rénal carcinoma, kidney parenchym carcinoma, ovarian carcinoma, cervix carcinoma, uterine corpus carcinoma, endometrium carcinoma, chorion carcinoma, pancreatic carcinoma, prostate carcinoma, bladder carcinoma, testis carcinoma, breast carcinoma, urinary carcinoma, melanoma, brain tumors, lymphoma, head and neck cancer, acute lymphatic leukemia (ALL), chronic lymphatic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), hepatocellular carcinoma, gall bladder carcinoma, bronchial carcinoma, small cell lung carcinoma, non-small cell lung carcinoma, multiple myeloma, basalioma, teratoma, retinoblastoma, choroidea melanoma, seminoma, rhabdomyo

?

sarcoma, osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma, Ewing sarcoma, and plasmocytoma.

30. The compound according to claim 27 or 28, or a phamiaceutically acceptable sait thereof, wherein the cancer is selected from the group consisting of B-cell acute lymphocytic leukemia (B-ALL), mesothelioma, lymphoma, pancreatic carcinoma, lung cancer, gastric cancer, esophageal cancer, bladder carcinoma, brain cancer, head and neck cancer, melanoma, and breast cancer.

31. The compound according to claim 30, or a pharmaceutically acceptable sait thereof, wherein the cancer is a lung cancer selected from the group consisting of non-small cell lung cancer, small cell lung cancer, adenocarcinoma of the lung, and squamous cell carcinoma of the lung.

32, The compound according to claim 30, or a phamiaceutically acceptable sait thereof, wherein the cancer is triple négative breast cancer (TNBC).

33. The compound according to claim 30, or a pharmaceutically acceptable sait thereof, wherein the cancer is a brain tumor selected from the group consisting of glioma, glioblastoma, astrocytoma, meningioma, medulloblastoma, peripheral neuroectodermal tumors, and craniopharyngioma.

34. The compound according to any one of claims 27 to 29, or a pharmaceutically acceptable sait thereof, wherein the cancer is a lymphoma selected from the group consisting of mantle cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, Burkitt lymphoma, diffuse large B-cell lymphoma (DLBCL), and adult T-cell leukemia/lymphoma.

35. Use of a compound according to any one of claims 1 to 25, or a pharmaceutically acceptable sait thereof, for the manufacture of a médicament for treating cancer.

36. The use according to claim 35, or a pharmaceutically acceptable sait thereof, wherein the cancer is an MTAP-deleted cancer.

37. The use cording to claim 35 or 36, or a pharmaceutically acceptable sait thereof, wherein the cancer is selected from the group consisting of mesothelioma, neuroblastoma, rectum carcinoma, colon carcinoma, familiary adenomatous polyposis carcinoma and hereditary non-polyposis colorectal cancer, esophageal carcinoma, labial carcinoma, larynx carcinoma, hypopharynx carcinoma, tongue carcinoma, salivary gland carcinoma, gastric carcinoma, adenocarcinoma, medullary thyroidea carcinoma, papillary thyroidea carcinoma, rénal carcinoma, kidney parenchym carcinoma, ovarian carcinoma, cervix carcinoma, uterine corpus carcinoma, endometrium carcinoma, chorion carcinoma, pancreatic carcinoma, prostate carcinoma, bladder carcinoma, testis carcinoma, breast carcinoma, urinary carcinoma, melanoma, brain tumors, lymphoma, head and neck cancer, acute lymphatic leukemia (ALL), chronic lymphatic leukemia (CLL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), hepatocellular carcinoma, gall bladder carcinoma, bronchial carcinoma, small cell lung carcinoma, non-small cell lung carcinoma, multiple myeloma, basalioma, teratoma, retinoblastoma, choroidea melanoma, seminoma, rhabdomyo sarcoma, osteosarcoma, chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma, Ewing sarcoma, and plasmocytoma.

38. The use according to claim 35 or 36, or a pharmaceutically acceptable sait thereof, wherein the cancer is selected from the group consisting of B-cell acute lymphocytic leukemia (BALL), mesothelioma, lymphoma, pancreatic carcinoma, lung cancer, gastric cancer, esophageal cancer, bladder carcinoma, brain cancer, head and neck cancer, melanoma, and breast cancer. ·

39. The use according to claim 38, or a pharmaceutically acceptable sait thereof, wherein the cancer is a lung cancer is selected from the group consisting of non-small cell lung cancer, small cell lung cancer, adenocarcinoma of the lung, and squamous cell carcinoma of the lung.

40. The use according to claim 38, or a pharmaceutically acceptable sait thereof, wherein the cancer is triple négative breast cancer (TNBC).

Λ Μ*

41. The use according to claim 38, or a pharmaceutically acceptable sait thereof, wherein the cancer is a brain tumor selected from the group consisting of glioma, glioblastoma, astrocytoma, meningioma, médulloblastome, peripheral neuroectodermal tumors, and craniopharyngioma.

42. The use according to claim 38, or a phannaceutically acceptable sait thereof, wherein the cancer is a lymphoma selected from the group consisting of mantle cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, Burkitt lymphoma, diffuse large B-cell lymphoma (DLBCL), and adult T-cell leukemia/lymphoma.