WRN inhibitors and their uses

Abstract

The disclosure provides compounds of Formula I or pharmaceutically acceptable salts thereof, pharmaceutical compositions comprising such compounds, and use of such compounds for treating cancers treatable by inhibition of WRN helicase.

Description

120039.000211 (TYRA041PCT)WRN INHIBITORS AND THEIR USESCROSS REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit of United States Provisional Application No. 63 / 739,888, filed December 30, 2024, the entirety of which is incorporated by reference herein.TECHNICAL FIELD

[0002] The disclosure is directed to compounds that inhibit the Werner Syndrome helicase enzyme (WRN) activity and are therefore useful in treating cancers treatable by inhibition of WRN, including cancers characterized by microsatellite instability (MSI) and / or defective DNA mismatch repair system (dMMR). Also disclosed are pharmaceutical compositions comprising such compounds, methods of making such compounds, and methods of using such compounds.SEQUENCE LISTING

[0003] The sequence listing XML, named 120039 00021 I SL.xml, created on 2025-12-23, and 6000 bytes, is incorporated herein by reference.BACKGROUND

[0004] Cancer is a leading cause of death throughout the world. A limitation of chemotherapy is that the cytotoxic effects of chemotherapeutics are not restricted to cancer cells and adverse side effects, therefore, can occur within normal tissues. Strategies to target cancer cells are therefor needed.

[0005] Microsatellite instability (MSI) is a genomic lesion caused by defects in mismatch repair machinery (dMMR). MSI is present in colorectal cancer, endometrial cancer, gastric cancer and other cancer types. Tumors can be categorized as MSI high (MSI-H), MSI low (MSI-L), or MSS depending on the number of tested microsatellite showing instability. Based on a consensus NCI-Reference Panel (Bethesda, 1998), MSI can be assessed by molecular testing of five microsatellites - including two mononucleotides (BAT25 and BAT26) and three dinucleotides (D2S123, D5S346, D17S250). Tumors are MSI-high (MSI-H) if two or more of the microsatellite markers show instability, MSI-low (MSI-L) if only120039.000211 (TYRA041PCT)one microsatellite marker shows instability, and MS-stable (MSS) if none of the five microsatellite markers show instability.

[0006] WRN (WRN RecQ helicase) is a synthetic lethality vulnerability to cancer cells with high microsatellite instability status (MSI-H). WRN contains an exonuclease domain and an ATP -dependent helicase domain. WRN is localized to the nucleus and unwinds double stranded DNA, particularly secondary structures (fork DNA, holliday junction, G4-quadruaplex, DNA hairpin and cruciform etc.) during DNA replication, damage and repair processes. WRN’s helicase activity is indispensable to the survival of MSI cell lines as helicase -deficient WRN mutant is insufficient to rescue impaired cell viability from WRN knockout or knockdown. The absence of the WRN protein or the inhibition of its helicase activity prevents normal DNA damage and repair processes, leading to increased DNA double-strand breaks (DSB) and subsequent growth arrest and cell death. Thus, WRN inhibitors areSUMMARY

[0007] The disclosure provides compounds of Formula (I):OR5(I),or a pharmaceutically acceptable salt thereof,wherein:~ — is a single bond or a double bond;X is N, or CH;R is:120039.000211 (TYRA041PCT)R1Ais H, C1-C6alkyl, optionally substituted C3-C6cycloalkyl, optionally substituted 3-6 membered heterocycloalkyl, Ci-Csalk-Cs-Cecycloalkyl, Ci-C3alk-3-6 membered heterocycloalkyl, CJ -O-Ci-Cealkyl, 5-11 membered bridged bicyclic cycloalkyl, optionally substituted 5-6 membered heteroaryl, or aryl;R1Bis H; or C1-C6alkyl;or R1Aand R1B, together with the carbon atom to which they are both attached, form a 3-6 membered cycloalkyl ring;R1Cis H, Ci-Csalkyl, Cs-Cscycloalkyl, Cf -O-Ci-Csalkyl; or 5-6 membered heteroaryl;R1Dis H; or Ci-C3alkyl;120039.000211 (TYRA041PCT)or R1Cand R1D, together with the nitrogen atom to which they are both attached, form a 3-6 membered heterocycloalkyl ring;R2is Ci-C3alkyl, C3-C5cycloalkyl, Ci-C3haloalkyl, N(Ci-C3alkyl)2, NH(Ci- C alkyl), optionally substituted 3-6 membered heterocycloalkyl, optionally substituted 5-6 membered heteroaryl, NH-(Ci-C3alk)-N(Ci- C3alkyl)2, NH-(Ci-C3alk)-NH(Ci-C3alkyl), N(Ci-C3alkyl)-(Ci-C3alk)- N(Ci-C3alkyl)2, or N(Ci-C3alkyl)-(Ci-C3alk)-NH(Ci-C3alkyl); NH2;R3is H, CN, Ci-Cealkyl, C3-C6cycloalkyl, -OCi-C6alkyl, -OC3-C6cycloalkyl, -SCi- Cealkyl, -SCs-Cecycloalkyl, -NHCi-Cealkyl, -NHCs-Cecycloalkyl, - NHC(O)Ci-C6alkyl, - NHC(O)C3-C6cycloalkyl, F, Cl,wherein the Ci-Cealkyl or Cs-Cecycloalkyl groups in R3are optionally substituted with one or more halo, Cs-Cscycloalkyl, or C3- Cshalocycloalkyl;R4is H, Ci-Cealkyl, C3-C7cycloalkyl, -OCi-C6alkyl, -OC3-C7cycloalkyl, -OCi- C3alkC3-C7cycloalkyl, -OC3-C7heterocycloalkyl, -SCi-Cealkyl, -SC3- C7cycloalkyl, -NHCi-Cealkyl, -NHC3-C7cycloalkyl, -NH-Ci-Csalk-Cs- C7cycloalkyl, -NHC(O)Ci-C6alkyl, -NHC(O)C3-C7cycloalkyl, -NHC(O)-Ci- C3alk-C3-C7cycloalkyl, C(O)NHC1-C6alkyl, C(O)NHC3-C7cycloalkyl,0711-5, -O-(C5-C9spirocycloalkyl), -O-(3-7-membered heterocycloalkyl), -CH=CH-Ci-C6alkyl, -CH=CH(C3-C7cycloalkyl), -C=C-Ci-C6alkyl, - C=C(C3-C7cycloalkyl), -C≡CC(C1-C3alkyl)2OH, -C≡CC(C1-C3alkyl)3, C=CC(Cl-C3alkyl)2OCl-C6alkylwherein the Ci-Csalk, Ci-Cealkyl, or C3-C7cycloalkyl groups in R4are optionally substituted with one or more halo, D, OH, OMe, CN, aryl, Ci-Cealkyl, OC3-C7cycloalkyl, OCi-C6alkyl, OCi-C6haloalkyl, C3- Cshalocycloalkyl, or Cs-Cscycloalkyl, wherein the Cs-Cscycloalkyl is optionally substituted with one or more halo, Ci-Cealkyl, or -OCi- Cealkyl;120039.000211 (TYRA041PCT)or R3and R4, together with the atoms to which they are attached, form an optionally substituted C5-C6cycloalkyl ring that is fused to Ring A, an optionally substituted 6-membered aryl ring that is fused to Ring A, or an optionally substituted 5-6 membered heteroaryl ring that is fused to ring A,wherein the optionally substituted Cs-Cecycloalkyl ring, optionally substituted 6-membered aryl ring, or optionally substituted 5-6 membered heteroaryl ring formed by R3and R4is optionally substituted with Ci-Cealkyl, C3-C6cycloalkyl, -OCi-C6alkyl, -OC3-C6cycloalkyl, -SCi-C6alkyl, -SC3- Cecycloalkyl, -NHCi-Cealkyl, -NHC3-C6cycloalkyl, -NHC(0)Ci-C6alkyl, - NHC(O)C3-C6cycloalkyl, wherein the Ci-Cealkyl or C3-C6cycloalkyl groups in the optional substituents are themselves optionally substituted with one or more halo, Ci-Cealkyl, Ci-C3haloalkyl, C3-Cscycloalkyl, or C3- Cshalocycloalkyl.R5is optionally substituted aryl, optionally substituted 5-6 membered heteroaryl, optionally substituted C3-Ce cycloalkyl ring, optionally substituted Cs-Ce cycloalkenyl ring, or optionally substituted 5-6 membered heterocycloalkenyl ring;R6is H, D, halo, CN, or Ci-C3alkyl; andR6Ais H or D.DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

[0008] The disclosure may be more fully appreciated by reference to the following description, including the following definitions and examples. Certain features of the disclosed compositions and methods which are described herein in the context of separate aspects, may also be provided in combination in a single aspect. Alternatively, various features of the disclosed compositions and methods that are, for brevity, described in the context of a single aspect, may also be provided separately or in any subcombination.

[0009] Unless otherwise specified, the terms “optionally substituted,” or “substituted” as used herein to describe a substituent defined herein, means that the substituent may, but is not required to be, substituted with one or more of: halo (i.e., -F, -Cl, -120039.000211 (TYRA041PCT)Br, -I), cyano, -OH, -Ci-Cealkyl, Cs-Cecycloalkyl, 3-7 membered heterocycloalkyl, -C3-Cespirocycloalkyl, 3-7 membered spiroheterocycloalkyl, bridged cycloalkyl, bridged heterocycloalkyl, C2-C6alkenyl, C2-C6 alkynyl, Ci-Cehaloalkyl (e.g., -CF3; -CHF2, -CH2CF3, and the like), -Ci-Cealkoxy (e.g., -OCH3, and the like), -Ci-Ce haloalkoxy (e.g., -OCF3; -OCHF2, -OCH2CF3, and the like), Ci-Cealkylthio (e.g., -SCH3; -SCH2CH3, and the like), Ci-C6alkylamino (e.g., -CH2NH2; -CH2CH2NH2, and the like), -NH2, -NH(CI-C6alkyl), -N(Ci-C-6 alkyl)2, -NH(CI-C6alkoxy), -C(O)NHCi-C6alkyl, -C(O)N(CI-C6alkyl)2, -COOH, -Ci- CealkylCOOH. C3-C6cycloalkylCOOH, -C(O)NH2, -Ci-C6alkylCONH2, -C3-C6cycloalkylCONH2, -Ci-CealkylCONHCi-Cealkyl, -Ci-C6alkylCON(Ci-C6alkyl)2, -C(O)Ci- C6alkyl (e.g., -OAc and the like), -C(O)OCi-C6alkyl, -NHCO(CI-C6alkyl), -N(CI-C6alkyl)C(O)(Ci-C6alkyl), -S(O)Ci-C6alkyl, -S(O)2Ci-C6alkyl (e.g., -SO2CH3, and the like), oxo (i.e., =0), 6-12 membered aryl, or 5 to 12 membered heteroaryl groups, -C(O)(Ci-C6haloalkyl), -NHSO2(Ci-C6alkyl), -N(Ci-C6alkyl)SO2(Ci-C6alkyl), or -P(O)(Ci-C6alkyl)2(e.g., -P(O)(CH3)2). In some embodiments, each of the above optional substituents are themselves optionally substituted by one or two of these groups.

[0010] When a range of carbon atoms is used herein, for example, Ci-Ce, all ranges, as well as individual numbers of carbon atoms are encompassed. For example, “C1-C3” includes C1-C3, C1-C2, C2-C3, Ci, C2, and C3. Thus, for example, a “Ci to C4 alkyl” group refers to all alkyl groups having from 1 to 4 carbons (e.g., 1, 2, 3, or 4), that is, CH3-, CH3CH2-, CH3CH2CH2-, (CH3)2CH-, CH3CH2CH2CH2-, CH3CH2CH(CH3)- and (CH3)3C-. A “Ci to Ce alkyl” group refers to all alkyl groups having from 1 to 6 carbons (e.g., 1, 2, 3, 4, 5, or 6).

[0011] As used herein, the term “alkyl” refers to a fully saturated aliphatic hydrocarbon group. The alkyl moiety may be branched or straight chain. Examples of branched alkyl groups include, but are not limited to, iso-propyl, sec-butyl, t-butyl and the like. Examples of straight chain alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl and the like. The alkyl group may have 1 to 30 carbon atoms (whenever it appears herein, a numerical range such as “1 to 30” refers to each integer in the given range; e.g., “1 to 30 carbon atoms” means that the alkyl group may consist of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated). The “alkyl” group may also be a120039.000211 (TYRA041PCT)medium size alkyl having 1 to 12 carbon atoms. The “alkyl” group could also be a lower alkyl having 1 to 6 carbon atoms. An alkyl group may be substituted or unsubstituted. By way of example only, “C1-C5 alkyl” indicates that there are one to five carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched and straight-chained), etc. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl and hexyl. In several embodiments, “Me” is methyl (e.g., CH3).

[0012] As used herein, “cycloalkyl” refers to a completely saturated (no double or triple bonds) mono- or multi- cyclic hydrocarbon ring system. When composed of two or more rings, the rings may be joined together in a fused fashion. Cycloalkyl groups may contain between 3 and 12 carbon atoms. For example, a Cs-Cecycloalkyl group indicates that there three to six carbon atoms in the ring, that is, the ring is a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group. A cycloalkyl group may be unsubstituted or substituted.

[0013] As used herein, the term “spirocycloalkyl ring” refers to a cycloalkyl ring that shares one carbon atom with another cyclic ring. For example, a 3-7 membered spirocycloalkyl ring indicates that there are 3, 4, 5, 6, or 7 carbon atoms in the cycloalkyl ring that shares a single carbon atom in common with another cyclic ring. By way of example, shown below are exemplary 3-7 membered spirocycloalkyl groups attached to a piperidine nng:

[0014] As used herein, “aryl” refers to a carbocyclic (all carbon) monocyclic or multicyclic aromatic ring system (including fused ring systems where two carbocyclic rings share a chemical bond) that has a fully delocalized pi-electron system throughout all the rings. The number of carbon atoms in an aryl group can vary. For example, the aryl group can be a Ce-Cu aryl group, a Ce-Cio aryl group, or a Ce aryl group. Examples of aryl groups120039.000211 (TYRA041PCT)include, but are not limited to, benzene, naphthalene and azulene. An aryl group may be substituted or unsubstituted.

[0015] As used herein, “heteroaryl” refers to a monocyclic or multicyclic aromatic ring system (a ring system with fully delocalized pi-electron system) that contain(s) one or more heteroatoms, that is, an element other than carbon, including but not limited to, nitrogen, oxygen and sulfur. The number of atoms in the ring(s) of a heteroaryl group can vary. For example, the heteroaryl group can contain 4 to 14 atoms in the ring(s), 5 to 10 atoms in the ring(s) or 5 to 6 atoms in the ring(s). Furthermore, the term “heteroaryl” includes fused ring systems where two rings, such as at least one aryl ring and at least one heteroaryl ring, or at least two heteroaryl rings, share at least one chemical bond. Examples of heteroaryl rings include, but are not limited to, furan, furazan, thiophene, benzothiophene, phthalazine, pyrrole, oxazole, benzoxazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, thiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, benzothiazole, imidazole, benzimidazole, indole, indazole, pyrazole, benzopyrazole, isoxazole, benzoisoxazole, isothiazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, purine, pteridine, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, and triazine. Heteroaryl rings may also include bridge head nitrogen atoms. For example but not limited to: pyrazolo[l,5-a]pyridine, imidazo[l,2-a]pyridine, and pyrazolo[l,5-a]pyrimidine. A heteroaryl group may be substituted or unsubstituted.

[0016] As used herein, “heterocycloalkyl” refers to three-, four-, five-, six-, seven-, eight-, nine-, ten-, up to 18-membered monocyclic, bicyclic, and tricyclic ring system wherein carbon atoms together with from 1 to 5 heteroatoms constitute said ring system. A heterocycloalkyl may optionally contain one or more unsaturated bonds situated in such a way, however, that a fully delocalized pi-electron system does not occur throughout all the rings. The heteroatom(s) is an element other than carbon including, but not limited to, oxygen, sulfur, and nitrogen. A heterocycloalkyl may further contain one or more carbonyl or thiocarbonyl functionalities, so as to make the definition include oxo-systems and thiosystems such as lactams, lactones, cyclic imides, cyclic thioimides and cyclic carbamates. When composed of two or more rings, the rings may be joined together in a fused fashion. Additionally, any nitrogens in a heterocycloalkyl may be quatemized. Heterocycloalkyl groups may be unsubstituted or substituted. Examples of such “heterocycloalkyl” groups include but are not limited to, 1,3-dioxin, 1,3-dioxane, 1,4-dioxane, 1,2-di oxolane, 1,3-120039.000211 (TYRA041PCT)dioxolane, 1,4-di oxolane, 1,3-oxathiane, 1,4-oxathiin, 1,3 -oxathiolane, 1,3-dithiole, 1,3-dithiolane, 1,4-oxathiane, tetrahydro- 1,4-thiazine, 2H-l,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, trioxane, hexahydro-1, 3, 5-triazine, imidazoline, imidazolidine, isoxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidine, morpholine, oxirane, piperidine A-Oxide, piperidine, piperazine, pyrrolidine, pyrrolidone, pyrrolidione, 4-piperidone, pyrazoline, pyrazolidine, 2-oxopyrrolidine, tetrahydropyran, 4H-pyran, tetrahydrothiopyran, thiamorpholine, thiamorpholine sulfoxide, thiamorpholine sulfone, and their benzo-fused analogs (e.g., benzimidazolidinone, tetrahydroquinoline, 3, 4-m ethylenedi oxyphenyl).

[0017] As used herein, the term “spiroheterocycloalkyl ring” refers to a heterocycloalkyl ring that shares one carbon atom with another cyclic ring. For example, a 3-7 membered spiroheterocycloalkyl ring indicates that there are 3, 4, 5, 6, or 7 atoms in the heterocycloalkyl ring, and only one of the carbon atoms in that heterocycloalkyl ring is also a member of another cyclic ring. By way of example, shown below are exemplary 3-7 membered spiroheterocycloalkyl groups attached to a piperidine ring:N N H H

[0018] As used herein, the term “bridged bicyclic ring”, refers to a ring system comprising two joined cycloalkyl or heterocycloalkyl rings that share at least three at least three atoms. For example, a 6-9 membered bridged bicyclic ring indicates that there are 6, 7, 8, or 9 atoms in the bridged bicyclic ring. By way of example, shown below are exemplary 6-9 membered bridged bicyclic rings:N N6-membered 7-membered 8-membered 9-membered120039.000211 (TYRA041PCT)

[0019] As used herein, the term “amino” refers to a -NH2 group.

[0020] As used herein, the term “hydroxy” refers to a -OH group.

[0021] As used herein, the term “halogen atom” or “halogen” or “halo” refers to fluorine, chlorine, bromine and iodine.

[0022] The term “pharmaceutically acceptable salt” refers to a salt of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound. In several embodiments, the salt is an acid addition salt of the compound. Pharmaceutical salts can be obtained by reacting a compound with inorganic acids such as hydrohalic acid (e.g., hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid and phosphoric acid. Pharmaceutical salts can also be obtained by reacting a compound with an organic acid such as aliphatic or aromatic carboxylic or sulfonic acids, for example formic, acetic, succinic, lactic, malic, tartaric, citric, ascorbic, nicotinic, methanesulfonic, ethanesulfonic, p-toluensulfonic, salicylic or naphthalenesulfonic acid. Pharmaceutical salts can also be obtained by reacting a compound with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, C1-C7 alkylamine, cyclohexylamine, triethanolamine, ethylenediamine, and salts with amino acids such as arginine and lysine.

[0023] Other pharmaceutically acceptable salts include the trifluoroacetic acid salt.

[0024] It is understood that, in any compound described herein having one or more chiral centers, if an absolute stereochemistry is not expressly indicated, then each center may independently be of R-configuration or S-configuration or a mixture thereof. Thus, the compounds provided herein may be enantiomerically pure, enantiomerically enriched, racemic mixture, diastereomerically pure, diastereomerically enriched, or a stereoisomeric mixture. In addition, it is understood that, in any compound described herein having one or more double bond(s) generating geometrical isomers that can be defined as E or Z, each double bond may independently be E or Z a mixture thereof. It is understood that, in any compound described herein having one or more chiral centers, all possible diastereomers are also envisioned. It is understood that, in any compound described herein all tautomers are envisioned. It is also understood that, in any compound described herein, all isotopes of the included atoms are envisioned. For example, any instance of hydrogen, may include120039.000211 (TYRA041PCT)hydrogen-1 (protium), hydrogen-2 (deuterium), hydrogen-3 (tritium) or other isotopes; any instance of carbon may include carbon-12, carbon-13, carbon-14, or other isotopes; any instance of oxygen may include oxygen-16, oxygen-17, oxygen-18, or other isotopes; any instance of fluorine may include one or more of fluorine- 18, fluorine- 19, or other isotopes; any instance of sulfur may include one or more of sulfur-32, sulfur-34, sulfur-35, sulfur-36, or other isotopes.

[0025] As used herein, “subject,” “host,” “patient,” and “individual” are used interchangeably and shall be given its ordinary meaning and shall include mammals, e.g., a human, a non-human primate, ungulates, canines, felines, equines, mice, rats, and the like. The term “mammal” includes both human and non-human mammals.

[0026] The terms “treatment,” “treating,” “treat” and the like shall be given its ordinary meaning and shall also include herein to generally refer to obtaining a desired pharmacologic and / or physiologic effect. The effect may be prophylactic in terms of completely or partially preventing a disease or symptom thereof and / or may be therapeutic in terms of a partial or complete stabilization or cure for a disease and / or adverse effect attributable to the disease. “Treatment” as used herein shall be given its ordinary meaning and shall also cover any treatment of a disease in a mammal, particularly a human, and includes: (a) preventing the disease or symptom from occurring in a subject which may be predisposed to the disease or symptom but has not yet been diagnosed as having it; (b) inhibiting the disease symptom, e.g., arresting its development; and / or (c) relieving the disease symptom, e.g., causing regression of the disease or symptom.

[0027] The terms “cancer,” “neoplasm,” and “tumor” are used interchangeably herein, shall be given its ordinary meaning and shall also refer to cells which exhibit relatively autonomous growth, so that they exhibit an aberrant growth phenotype characterized by a significant loss of control of cell proliferation. In general, cells of interest for detection or treatment in the present application include precursors, precancerous e.g., benign), malignant, pre-metastatic, metastatic, and non-metastatic cells.

[0028] Terms of approximation such as “about” and “approximately,” as used herein, are intended to indicate that the numerical values to which they apply are variable within a margin of error. In the absence of a recited margin of error, these terms should be understood to mean that range which would encompass ± 10%, preferably ± 5%, the recited value and the range is included.120039.000211 (TYRA041PCT)

[0029] With respect to the use of substantially any plural and / or singular terms herein, those having skill in the art can translate from the plural to the singular and / or from the singular to the plural as is appropriate to the context and / or application. The various singular / plural permutations may be expressly set forth herein for sake of clarity. The indefinite article “a” or “an” does not exclude a plurality. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measures cannot be used to advantage. Any reference signs in the claims should not be construed as limiting the scope.

[0030] In some aspects, the disclosure is directed to compounds of Formula (I):OR5(I),or a pharmaceutically acceptable salts thereof.

[0031] In some embodiments, the disclosure is directed to compounds of Formula (I).

[0032] In other embodiments, the disclosure is directed to pharmaceutically acceptable salts of compounds of Formula (I).

[0033] In some aspects, - in Formula lis a single bond or a double bond.

[0034] In some embodiments, ~ — in Formula lis a single bond.

[0035] In some embodiments, ~ — in Formula lis a double bond.

[0036] In some aspects, X in Formula I is N or CH.

[0037] In some embodiments, X in Formula I is N.

[0038] In some embodiments, X in Formula I is CH.

[0039] In some aspects, R in Formula I is:120039.000211 (TYRA041PCT)

[0040] In some embodiments, R in Formula I is:

[0041] In some embodiments, R in Formula I is:1ARR1BR0

[0042] In some embodiments, R in Formula I is:120039.000211 (TYRA041PCT)

[0043] In some embodiments, R in Formula I is:XNR6R6A

[0044] In some embodiments, R in Formula I is:1A / R RIB R2o R6R6A

[0045] In some embodiments, R in Formula I is:1AR R1B VR2R6A

[0046] In some embodiments, R in Formula I is:

[0047] In some embodiments, R in Formula I is:1AR R1BCN

[0048] In some embodiments, R in Formula I is:1AR R1BCN

[0049] In some embodiments, R in Formula I is:1AR R1BCN

[0050] In some embodiments, R in Formula I is:120039.000211 (TYRA041PCT)R1A

[0051] In some embodiments, R in Formula I is:R2

[0052] In some embodiments, R in Formula I is:1AR R1B1DR^ ^R1C

[0053] In some embodiments, R in Formula I is:

[0054] In some embodiments, R in Formula I is:

[0055] In some aspects, R1Ain Formula I is H, C1-C6alkyl, optionally substituted C3-C6cycloalkyl, optionally substituted 3-6 membered heterocycloalkyl, C1-C3alk-C3-C6cycloalkyl, C1-C3alk-3-6 membered heterocycloalkyl, CH2-O-C1-C6alkyl; 5-11 membered bridged bicyclic cycloalkyl, optionally substituted 5-6 membered heteroaryl, or aryl.

[0056] In some embodiments, R1Ain Formula I is H.

[0057] In some embodiments, R1Ain Formula I is C1-C6alkyl, such as, for example, C6alkyl, C5alkyl, C4alkyl, C3alkyl, C2alkyl, C1alkyl, methyl, ethyl, propyl, and the like.

[0058] In some embodiments, R1Ain Formula I is methyl.

[0059] In some embodiments, R1Ain Formula I is isopropyl.

[0060] In some embodiments, R1Ain Formula I is w-propyl.

[0061] In some embodiments, R1Ain Formula I is / -butyl.

[0062] In some embodiments, R1Ain Formula I is zso-butyl.120039.000211 (TYRA041PCT)

[0063] In some embodiments, R1Ain Formula I is optionally substituted C3-C6cycloalkyl, such as, for example, C3cycloalkyl, C4cycloalkyl, C5cycloalkyl, C6cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like, each optionally substituted.

[0064] In some embodiments, R1Ain Formula I is optionally substituted cyclopropyl.

[0065] In some embodiments, R1Ain Formula I is cyclopropyl substituted with CH2OCH3.

[0066] In some embodiments, R1Ain Formula I is optionally substituted cyclobutyl.

[0067] In some embodiments, R1Ain Formula I is methoxy-substituted cyclobutyl.

[0068] In some embodiments, R1Ain Formula I is optionally substituted cyclopentyl.

[0069] In some embodiments, R1Ain Formula I is optionally substituted cyclohexyl.

[0070] In some embodiments, R1Ain Formula I is optionally substituted 3-6 membered heterocycloalkyl, such as, for example, 1-methylazetidinyl, 1-acetylazetidinyl, 1-(2,2,2-trifluoroethyl)azetidinyl, 1-methylsulfonylazetidinyl, and the like.

[0071] In some embodiments, R1Ain Formula I is optionally substituted oxetanyl.

[0072] In some embodiments, R1Ain Formula I is optionally substituted azetidinyl.

[0073] In some embodiments, R1Ain Formula I is C1-C3alk -C3C6cycloalkyl.

[0074] In some embodiments, R1Ain Formula I is -CFh-cyclopropane.

[0075] In some embodiments, R1Ain Formula I is Ci-C3alk-3-6 membered heterocycloalkyl.

[0076] In some embodiments, R1Ain Formula I is CH2-O-C1-C6alkyl, such as, for example, CH2-O-C1alkyl, CH2-O-C2alkyl, CH2-O-C3alkyl, CH2-O-C4alkyl, CH2-O-C5alkyl, CH2-O-C6alkyl, CH2-O-methyl, CH2-O-ethyl, CH2-O-propyl, and the like.

[0077] In some embodiments, R1Ain Formula I is CH2-O-methyl.

[0078] In some embodiments, R1Ain Formula I is 5-11 membered bridged bicyclic cycloalkyl.

[0079] In some embodiments, R1Ain Formula I is optionally substituted 5-6 membered heteroaryl, such as, for example, 5 membered heteroaryl, 6 membered heteroaryl, pyridinyl, pyrimidinyl, pyridazinyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, and the like.

[0080] In some embodiments, R1Ain Formula I is N-methyl-pyrazolyl.120039.000211 (TYRA041PCT)

[0081] In some aspects, R1Bin Formula I is H, or Ci-Cealkyl.

[0082] In some embodiments, R1Bin Formula I is H.

[0083] In some embodiments, R1Bin Formula I is C1-C6alkyl, such as, for example, C6alkyl, C5alkyl, C4alkyl, C3alkyl, C2alkyl, C1alkyl, methyl, ethyl, propyl, and the like.

[0084] In some embodiments, R1Bin Formula I is methyl.

[0085] In some aspects of the disclosure, R1Aand R1Bin Formula I, together with the carbon atom to which they are both attached, form a 3-6 membered (C3-C6) cycloalkyl ring, such as, for example, C3cycloalkyl, C4cycloalkyl, C5cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, and the like.

[0086] In some aspects of the disclosure, R1Aand R1Bin Formula I, together with the carbon atom to which they are both attached, form cyclopropyl ring.

[0087] In some aspects, R1Cin Formula I is H, C1-C3alkyl, C3-C5cycloalkyl, CH2-O-C1-C3alkyl; or 5-6 membered heteroaryl.

[0088] In some embodiments, R1Cin Formula I is H.

[0089] In some embodiments, R1Cin Formula I is C1-C3alkyl, such as, for example, C3alkyl, C2alkyl, C1alkyl, methyl, ethyl, propyl, and the like.

[0090] In some embodiments, R1Cin Formula I is methyl.

[0091] In some embodiments, R1Cin Formula I is C3-C5cycloalkyl, such as, for example, C3cycloalkyl, C4cycloalkyl, C5cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, and the like.

[0092] In some embodiments, R1Cin Formula I is cyclopropyl.

[0093] In some embodiments, R1Cin Formula I is CH2-O-C1-C3alkyl, such as, for example, CH2-O-C1alkyl, CH2-O-C2alkyl, CH2-O-C3alkyl, CH2-O-methyl, CH2-O-ethyl, CH2-O-propyl, and the like.

[0094] In some embodiments, R1Cin Formula I is 5-6 membered heteroaryl, such as, for example, 5 membered heteroaryl, 6 membered heteroaryl, pyridinyl, pyrimidinyl, pyridazinyl, oxazolyl, thiazolyl, imidazolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, and the like.

[0095] In some aspects, R1Din Formula I is H, or C1-C3alkyl.

[0096] In some embodiments, R1Din Formula I is H.

[0097] In some embodiments, R1Din Formula I is C1-C3alkyl, such as, for example, C3alkyl, C2alkyl, C1alkyl, methyl, ethyl, propyl, and the like.120039.000211 (TYRA041PCT)

[0098] In some embodiments, R1Din Formula I is methyl.

[0099] In some aspects of the disclosure, R1Cand R1Din Formula I, together with the nitrogen atom to which they are both attached, 3-6 membered heterocycloalkyl ring, such as, for example, 3 membered heterocycloalkyl, 4 membered heterocycloalkyl, 5 membered heterocycloalkyl, 6 membered heterocycloalkyl, aziridinyl, azetinyl, pyrrolidinyl, piperidinyl, morpholinyl, oxazolidinyl, oxazetidinyl, isoxazolidinyl, oxaziridinyl, thiomorpholinyl, isothiazolidinyl, thiazolidinyl, and the like.

[0100] In some aspects, R6in Formula I is H, D, halo, CN, or Ci-Csalkyl.

[0101] In some embodiments, R6in Formula I is H.

[0102] In some embodiments, R6in Formula I is D.

[0103] In some embodiments, R6in Formula I is halo, such as, for example, F, Cl, Br, or I.

[0104] In some embodiments, R6in Formula I is Cl.

[0105] In some embodiments, R6in Formula I is F.

[0106] In some embodiments, R6in Formula I is CN.

[0107] In some embodiments, R6in Formula I is C1-C3alkyl, such as, for example, C3alkyl, C2alkyl, C1alkyl, methyl, ethyl, propyl, and the like.

[0108] In some embodiments, R6in Formula I is CH3.

[0109] In some aspects, R6Ain Formula I is H or D.

[0110] In some embodiments, R6Ain Formula I is H.

[0111] In some embodiments, R6Ain Formula I is D.

[0112] In some aspects, R2in Formula I is C1-C3alkyl, C3-C5cycloalkyl, C1-C3haloalkyl, N(C1-C3alkyl)2, NH(Ci-C3alkyl), optionally substituted 3-6 membered heterocycloalkyl, optionally substituted 5-6 membered heteroaryl, NH-(Ci-C3alk)-N(Ci-C3alkyl)2, NH-(Ci-C3alk)-NH(Ci-C3alkyl), N(Ci-C3alkyl)-(Ci-C3alk)-N(Ci-C3alkyl)2, N(Ci-C3alkyl)-(Ci-C3alk)-NH(Ci-C3alkyl), or NH2.

[0113] In some embodiments, R2in Formula I is C1-C3alkyl, such as, for example, C3alkyl, C2alkyl, C1alkyl, methyl, ethyl, propyl, and the like.

[0114] In some embodiments, R2in Formula I is CH3.

[0115] In some embodiments, R2in Formula I is C1-C3haloalkyl.

[0116] In some embodiments, R2in Formula I is C3-C5cycloalkyl.

[0117] In some embodiments, R2in Formula I is N(Ci-C3alkyl)2.120039.000211 (TYRA041PCT)

[0118] In some embodiments, R2in Formula I is N(CH3)2.

[0119] In some embodiments, R2in Formula I is NH(Ci-C3alkyl).

[0120] In some embodiments, R2in Formula I is R2is NHCH3.

[0121] In some embodiments, R2in Formula I is optionally substituted 3-6 membered heterocycloalkyl.

[0122] In some embodiments, R2in Formula I is^'N / v^N- _ )

[0123] In some embodiments, R2in Formula I is'

[0124] In some embodiments, R2in Formula I is optionally substituted 5-6 membered heteroaryl.

[0125] In some embodiments, R2in Formula I is NH-(Ci-C3alk)-N(Ci-C3alkyl)2.

[0126] In some embodiments, R2in Formula I is NH-(Ci-C3alk)-NH(Ci-C3alkyl).

[0127] In some embodiments, R2in Formula I is N(Ci-C3alkyl)-(Ci-C3alk)-N(Ci- C3alkyl)2.

[0128] In some embodiments, R2in Formula I is N(Ci-C3alkyl)-(Ci-C3alk)-NH(Ci-C3alkyl).

[0129] In some embodiments, R2in Formula I is N(CH3)-CH2CH2-N(CH3)2.

[0130] In some embodiments, R2in Formula I is NH2.

[0131] In some aspects, R3in Formula I is H, CN, C1-C6alkyl, C3-C6cycloalkyl, -OC1-C6alkyl, -OC3-C6cycloalkyl, -SC1-C6alkyl, -SC3-C6cycloalkyl, -NHC1-C6alkyl, -NHC3-C6cycloalkyl, -NHC(O)C1-C6alkyl, -NHC(O)C3-C6cycloalkyl, F, or Cl, wherein the C1-C6alkyl or C3-C6cycloalkyl groups in R3are optionally substituted with one or more halo, C3-C5cycloalkyl, or C3-C5halocycloalkyl; and R4is H, C1-C6alkyl, C3-C7cycloalkyl, -OC1-C6alkyl, -OC3-C7cycloalkyl, -OC1-C3alkC3-C7cycloalkyl, -OC3-C7heterocycloalkyl, -SC1-C6alkyl, -SC3-C7cycloalkyl, -NHC1-C6alkyl, -NHC3-C7cycloalkyl, -NH-C1-C3alk-C3-C7cycloalkyl, -NHC(O)C1-C6alkyl, -NHC(O)C3-C7cycloalkyl, -NHC(O)-C1-C3alk-C3- OC7cycloalkyl, C(O)NHCi-C6alkyl, C(O)NHC3-C7cycloalkyl,, -O-(C5-120039.000211 (TYRA041PCT)C9spirocycloalkyl), -O-(3-7-membered heterocycloalkyl), -CH=CH-Ci-C6alkyl, -CH=CH(C3-C7cycloalkyl), -C=C-Ci-C6alkyl, -C=C(C3-C7cycloalkyl), -C≡CC(C1-C3alkyl)2OH, -C≡CC(C1-C3alkyl)3, or C=CC(Ci-C3alkyl)2OCi-C6alkyl, wherein the Ci-C3alk, Ci-C6alkyl, or C3-C7cycloalkyl groups in R4are optionally substituted with one or more halo, D, OH, OMe, CN, aryl, Ci-Cealkyl, OC3-C7cycloalkyl, OCi-Cealkyl, OCi-Cehaloalkyl, C3-Cshalocycloalkyl, or Cs-Cscycloalkyl, wherein the Cs-Cscycloalkyl is optionally substituted with one or more halo, Ci-Cealkyl, or -OCi-Cealkyl.

[0132] In some aspects, R3in Formula I is H, CN, C1-C6alkyl, C3-C6cycloalkyl, -OC1-C6alkyl, -OC3-C6cycloalkyl, -SC1-C6alkyl, -SC3-C6cycloalkyl, -NHC1-C6alkyl, -NHC3-C6cycloalkyl, -NHC(O)C1-C6alkyl, -NHC(O)C3-C6cycloalkyl, F, or Cl; wherein the C1-C6alkyl or C3-C6cycloalkyl groups in R3are optionally substituted with one or more halo, C3-C5cycloalkyl, or C3-C5halocycloalkyl.

[0133] In some embodiments, R3in Formula I is H.

[0134] In some embodiments, R3in Formula I is CN.

[0135] In some embodiments, R3in Formula I is C1-C6alkyl, such as, for example, C6alkyl, C5alkyl, C4alkyl, C3alkyl, C2alkyl, C1alkyl, methyl, ethyl, propyl, and the like.

[0136] In some embodiments, R3in Formula I is methyl.

[0137] In some embodiments, R3in Formula I is C3-C6cycloalkyl, such as, for example, C3cycloalkyl, C4cycloalkyl, C5cycloalkyl, C6cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0138] In some embodiments, R3in Formula I is -OC1-C6alkyl, such as, for example, -OC6alkyl, -OC5alkyl, -OC4alkyl, -OC3alkyl, -OC2alkyl, -OC1alkyl, -Omethyl, -Oethyl, -Opropyl, and the like.

[0139] In some embodiments, R3in Formula I is -OC3-C6cycloalkyl, such as, for example, -OC3cycloalkyl, -OC4cycloalkyl, -OC5cycloalkyl, -OC6cycloalkyl, -Ocyclopropyl, -Ocyclobutyl, -Ocyclopentyl, -Ocyclohexyl, and the like.

[0140] In some embodiments, R3in Formula I is -SC1-C6alkyl, such as, for example, -SC6alkyl, -SC5alkyl, -SC4alkyl, -SC3alkyl, -SC2alkyl, -SC1alkyl, -S-methyl, -S-ethyl, -S-propyl, and the like.

[0141] In some embodiments, R3in Formula I is -SC3-C6cycloalkyl, such as, for example, -SC3cycloalkyl, -SC4cycloalkyl, -SC5cycloalkyl, -SC6cycloalkyl, -S-cyclopropyl, -S-cyclobutyl, -S-cyclopentyl, -S-cyclohexyl, and the like.120039.000211 (TYRA041PCT)

[0142] In some embodiments, R3in Formula I is -NHCi-Cealkyl, such as, for example, -NHCealkyl, -NHCsalkyl, -NHC4alkyl, -NHCsalkyl, -NHC2alkyl, -NHCialkyl, -NH-methyl, -NH-ethyl, -NH-propyl, and the like.

[0143] In some embodiments, R3in Formula I is -NHCs-Cecycloalkyl, such as, for example, -NHCscycloalkyl, -NHC4cycloalkyl, -NHCscycloalkyl, -NHCecycloalkyl, -NH-cyclopropyl, -NH-cyclobutyl, -NH-cyclopentyl, -NH-cyclohexyl, and the like.

[0144] In some embodiments, R3in Formula I is -NHC(O)Ci-C6alkyl, such as, for example, -NHC(O)C6alkyl, -NHC(O)C5alkyl, -NHC(O)C4alkyl, -NHC(O)C3alkyl, -NHC(O)C2alkyl, -NHC(O)C1alkyl, -NHC(O)-methyl, -NHC(O)-ethyl, -NHC(O)-propyl, and the like.

[0145] In some embodiments, R3in Formula I is -NHC(O)C3-C6cycloalkyl, such as, for example, -NHC(O)C3cycloalkyl, -NHC(O)C4cycloalkyl, -NHC(O)C5cycloalkyl, -NHC(O)C6cycloalkyl, -NHC(O)-cyclopropyl, -NHC(O)-cyclobutyl, -NHC(O)-cyclopentyl, -NHC(O)-cyclohexyl, and the like.

[0146] In some aspects of the disclosure, where R3encompasses a Ci-Cealkyl or Cs-Cecycloalkyl group, the Ci-Cealkyl or Cs-Cecycloalkyl group is optionally substituted with one or more halo, Cs-Cscycloalkyl, or Cs-Cshalocycloalkyl.

[0147] In some embodiments, R3in Formula I is a Ci-Cealkyl substituted with one or more F.

[0148] In some embodiments, R3in Formula I is CF3.

[0149] In some embodiments, R3in Formula I is F.

[0150] In some embodiments, R3in Formula I is Cl.

[0151] In some embodiments, R3is H, or Ci-Cealkyl, wherein the Ci-Cealkyl is optionally substituted with Cs-Cscycloalkyl.

[0152] In some embodiments, R3is H.

[0153] In some embodiments, R3is Ci-Cealkyl optionally substituted with C3-Cscycloalkyl.

[0154] In some embodiments, R3is:

[0155] In some embodiments, R3is:120039.000211 (TYRA041PCT)

[0156] In some embodiments, R3is:

[0157] In some aspects, R4in Formula I is H, Ci-Cealkyl, C3-C7cycloalkyl, -OCi- Cealkyl, -OC3-C7cycloalkyl, -OCi-C3alkC3-C7cycloalkyl, -OC3-C7heterocycloalkyl, -SCi- Cealkyl, -SC3-C7cycloalkyl, -NHCi-Cealkyl, -NHC3-C7cycloalkyl, -NH-Ci-C3alk-C3- C7cycloalkyl, -NHC(O)Ci-C6alkyl, -NHC(O)C3-C7cycloalkyl, -NHC(O)-Ci-C3alk-C3- Ov~N C7cycloalkyl, -C(O)NHCi-C6alkyl, C(O)NHC3-C7cycloalkyl,V'1-5, -O-(C5- C9spirocycloalkyl), -O-(3-7-membered heterocycloalkyl), -CH=CH-Ci-C6alkyl, -CH=CH(C3-C7cycloalkyl), -C=C-Ci-C6alkyl, -C=C(C3-C7cycloalkyl), -C≡CC(C1-C3alkyl)2OH, -C≡CC(C1-C3alkyl)3, or -C=CC(Ci-C3alkyl)2OCi-C6alkyl; wherein the Ci-C3alk, Ci-C6alkyl or C3-C7cycloalkyl groups in R4are optionally substituted with one or more halo, D, OH, OMe, CN, aryl, Ci-Cealkyl, OC3-C7cycloalkyl, OCi-Cealkyl, OCi-Cehaloalkyl, C3-Cshalocycloalkyl, Cs-Cscycloalkyl, wherein the Cs-Cscycloalkyl is optionally substituted with one or more halo, Ci-Cealkyl, or -OCi-Cealkyl; or R3and R4, together with the atoms to which they are attached, form an optionally substituted C5-C6cycloalkyl ring that is fused to Ring A, an optionally substituted 6-membered aryl ring that is fused to Ring A, or an optionally substituted 5-6 membered heteroaryl ring that is fused to ring A, wherein the optionally substituted Cs-Cecycloalkyl ring, optionally substituted 6-membered aryl ring, or optionally substituted 5-6 membered heteroaryl ring formed by R3and R4is optionally substituted with Ci-Cealkyl, C3-C6cycloalkyl, -OCi-Cealkyl, -OC3-C6cycloalkyl, -SCi-Cealkyl, -SC3-C6cycloalkyl, -NHCi-Cealkyl, -NHCs-Cecycloalkyl, -NHC(O)Ci-C6alkyl, -NHC(O)C3-C6cycloalkyl, wherein the Ci-Cealkyl or C3-C6cycloalkyl groups in the optional substituents are themselves optionally substituted with one or more halo, Cs-Cscycloalkyl, or Cs-Cshalocycloalkyl.

[0158] In some embodiments, R4in Formula I is H.

[0159] In some embodiments, R4in Formula I is Ci-Cealkyl, such as, for example, Cealkyl, Csalkyl, C4alkyl, C3alkyl, C2alkyl, Cialkyl, methyl, ethyl, propyl, and the like.120039.000211 (TYRA041PCT)

[0160] In some embodiments, R4in Formula I is Cs-Cecycloalkyl, such as, for example, Cscycloalkyl, C4cycloalkyl, Cscycloalkyl, Cecycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0161] In some embodiments, R4in Formula I is -OCi-Cealkyl, such as, for example, -OCealkyl, -OCsalkyl, -OC4alkyl, -OCsalkyl, -OC2alkyl, -OCialkyl, -Omethyl, -Oethyl, -Opropyl, and the like.

[0162] In some embodiments, R4in Formula I is -OC3-C6cycloalkyl, such as, for example, -OCscycloalkyl, -OC4cycloalkyl, -OCscycloalkyl, -OCecycloalkyl, -Ocyclopropyl, -Ocyclobutyl, -Ocyclopentyl, -Ocyclohexyl, and the like.

[0163] In some embodiments, R4in Formula I is -SCi-Cealkyl, such as, for example, -SCealkyl, -SCsalkyl, -SC4alkyl, -SCsalkyl, -SC2alkyl, -SCialkyl, -S-methyl, -S-ethyl, -S-propyl, and the like.

[0164] In some embodiments, R4in Formula I is -SCs-Cecycloalkyl, such as, for example, -SCscycloalkyl, -SC4cycloalkyl, -SCscycloalkyl, -SCecycloalkyl, -S-cyclopropyl, -S-cyclobutyl, -S-cyclopentyl, -S-cyclohexyl, and the like.

[0165] In some embodiments, R4in Formula I is -NHCi-Cealkyl, such as, for example, -NHCealkyl, -NHCsalkyl, -NHC4alkyl, -NHCsalkyl, -NHC2alkyl, -NHCialkyl, -NH-methyl, -NH-ethyl, -NH-propyl, and the like.

[0166] In some embodiments, R4in Formula I is -NHCs-Cecycloalkyl, such as, for example, -NHCscycloalkyl, -NHC4cycloalkyl, -NHCscycloalkyl, -NHCecycloalkyl, -NH-cyclopropyl, -NH-cyclobutyl, -NH-cyclopentyl, -NH-cyclohexyl, and the like.

[0167] In some embodiments, R4in Formula I is -NHC(O)Ci-C6alkyl, such as, for example, -NHC(O)C6alkyl, -NHC(O)C5alkyl, -NHC(O)C4alkyl, -NHC(O)C3alkyl, -NHC(O)C2alkyl, -NHC(O)C1alkyl, -NHC(O)-methyl, -NHC(O)-ethyl, -NHC(O)-propyl, and the like.

[0168] In some embodiments, R4in Formula I is -NHC(O)C3-C6cycloalkyl, such as, for example, -NHC(O)C3cycloalkyl, -NHC(O)C4cycloalkyl, -NHC(O)C5cycloalkyl, -NHC(O)C6cycloalkyl, -NHC(O)-cyclopropyl, -NHC(O)-cyclobutyl, -NHC(O)-cyclopentyl, -NHC(O)-cyclohexyl, and the like.

[0169] In some embodiments, R4in Formula I is -C(O)NHCi-C6alkyl, such as, for example, -C(O)NHC6alkyl, -C(O)NHC5alkyl, -C(O)NHC4alkyl, -C(O)NHC3alkyl, -120039.000211 (TYRA041PCT)C(O)NHC2alkyl, -C(O)NHCialkyl, -C(O)NH-methyl, -C(O)NH-ethyl, -C(O)NH-propyl, and the like.

[0170] In some embodiments, R4in Formula I is -O-(3-7-membered heterocycloalkyl), such as, for example, -O-3 membered heterocycloalkyl, -O-4 membered heterocycloalkyl, -O-5 membered heterocycloalkyl, -O-6 membered heterocycloalkyl, -O-7 membered heterocycloalkyl, -O-aziridinyl, -O-azetinyl, -O-pyrrolidinyl, -O-piperidinyl, -O-morpholinyl, -O-oxazolidinyl, -O-oxazetidinyl, -O-isoxazolidinyl, -O-oxaziridinyl, -O-thiomorpholinyl, -O-isothiazolidinyl, -O-thisazolidinyl, and the like.

[0171] In some embodiments, R4in Formula I is -CH=CH-alkyl.

[0172] In some embodiments, R4in Formula I is -CH=CH(C3-C7cycloalkyl).

[0173] In some embodiments, R4in Formula I is -C≡Calkyl.

[0174] In some embodiments, R4in Formula I is -C≡C(C3-C7cycloalkyl).

[0175] In some embodiments, R4in Formula I is -C≡CC(C1-C3alkyl)2OH.

[0176] In some embodiments, R4in Formula I is C≡CC(C1-C3alkyl)2Oalkyl.

[0177] In some aspects, wherein R4comprises a Ci-Cealkyl or C3-C7cycloalkyl group, that Ci-Cealkyl or C3-C7cycloalkyl group is optionally substituted with one or more halo, OH, OMe, CN, Ci-Cealkyl, Cs-Cscycloalkyl, or Cs-Cshalocycloalkyl.

[0178] In some embodiments, R4is C₁-C₆alkyl optionally substituted with one or more halo, C₃-C₅cycloalkyl, or C₃-C₅halocycloalkyl.

[0179] In some embodiments, R4is C₁-C₆alkyl optionally substituted with one or more halo or C₃-C₅cycloalkyl.

[0180] In some embodiments, R4isF-F

[0181] In some embodiments, R4isF F

[0182] In some embodiments, R4is120039.000211 (TYRA041PCT)

[0183] In some embodiments, R4is

[0184] In some embodiments, R4is -OCi-Cealkyl optionally substituted with one or more halo, or Cs-Cscycloalkyl, wherein the Cs-Cscycloalkyl is optionally substituted with one or more halo.

[0185] In some embodiments, R4is:R,F.0 V 'O

[0186] In some embodiments wherein R4is -OCi-Cealkyl substituted with C3- Cscycloalkyl, the Cs-Cscycloalkyl is not a bridged bicyclic cycloalkyl ring.

[0187] In some embodiments, R4is:

[0188] In some embodiments, R4is:

[0189] In some embodiments,R4

[0190] In some embodiments, R4is:

[0191] In some embodiments, R4is:

[0192] In some embodiments, R4is:

[0193] In some embodiments, R4is:120039.000211 (TYRA041PCT)

[0194] In some embodiments, R4is:

[0195] In some embodiments, R4is:

[0196] In some embodiments, R4is:

[0197] In some embodiments, R4is:

[0198] In some embodiments, R4is:

[0199] In some embodiments, R4is -OC3-C7cycloalkyl optionally substituted with one or more halo or Ci-Cealkyl.

[0200] In some embodiments wherein R4is -OC3-C7cycloalkyl, the C3-C7cycloalkyl is not a bridged bicyclic cycloalkyl ring.

[0201] In some embodiments, R4is:_ F

[0202] In some embodiments, R4is:

[0203] In some embodiments, R4is:

[0204] In some embodiments, R4is:

[0205] In some embodiments, R4is:120039.000211 (TYRA041PCT)

[0206] In some embodiments, R4is:\0F

[0207] In some embodiments, R4is:O'

[0208] In some embodiments, R4is:

[0209] In some embodiments, R4is:fa0

[0210] In some embodiments, R4is:

[0211] In some embodiments, R4is:

[0212] In some embodiments, R4is:O'

[0213] In some embodiments, R4is:O'

[0214] In some embodiments, R4is -SC3-C7cycloalkyl.120039.000211 (TYRA041PCT)

[0215] In some embodiments, R4is:

[0216] In some embodiments, R4is -NHC1-C6alkyl or -NHC3-C7cycloalkyl.

[0217] In some embodiments, R4is:or

[0218] In some embodiments, R4is:

[0219] In some embodiments, R4is:Nh?

[0220] In some embodiments, R4is -NHC(O)Ci-C6alkyl or - NHC(O)C3-C7cycloalkyl, each optionally substituted with one or more halo or Cs-Cecycloalkyl groups.

[0221] In some embodiments, R4is:O O A P

[0222] In some embodiments, R4is:o

[0223] In some embodiments, R4is:o120039.000211 (TYRA041PCT)

[0224] In some embodiments, R4is:

[0225] In some embodiments, R4is:O

[0226] In some embodiments, R4is:O

[0227] In some embodiments, R4is:O

[0228] In some aspects of in Formula I, R3and R4, together with the atoms to which they are attached, form an optionally substituted C5-C6cycloalkyl ring that is fused to Ring A, an optionally substituted 6-membered aryl ring that is fused to Ring A, or an optionally substituted 5-6 membered heteroaryl ring that is fused to ring A, wherein the optionally substituted Cs-Cecycloalkyl ring, optionally substituted 6-membered aryl ring, or optionally substituted 5-6 membered heteroaryl ring formed by R3and R4is optionally substituted with Ci-Cealkyl, Cs-Cecycloalkyl, -OCi-Cealkyl, -OC3-C6cycloalkyl, -SCi-Cealkyl, -SCs-Cecycloalkyl, -NHCi-Cealkyl, -NHCs-Cecycloalkyl, -NHC(O)Ci-C6alkyl, -NHC(O)C3-C6cycloalkyl, wherein the Ci-Cealkyl or Cs-Cecycloalkyl groups in the optional substituents are themselves optionally substituted with one or more halo, Cs-Cscycloalkyl, or Cs-Cshalocycloalkyl.

[0229] In some aspects, R3and R4, together with the atoms to which they are attached, form an optionally substituted Cs-Cecycloalkyl ring that is fused to Ring A, optionally substituted with Ci-Cealkyl, Cs-Cecycloalkyl, -OCi-Cealkyl, -OC3-C6cycloalkyl, -SCi-Cealkyl, -SCs-Cecycloalkyl, -NHCi-Cealkyl, -NHCs-Cecycloalkyl, -NHC(O)Ci-C6alkyl, - NHC(O)C3-C6cycloalkyl, wherein the Ci-Cealkyl or Cs-Cecycloalkyl groups in the optional120039.000211 (TYRA041PCT)substituents are themselves optionally substituted with one or more halo, Cs-Cscycloalkyl, or Cs-Cshalocycloalkyl.

[0230] In some embodiments, R3and R4, together with the atoms to which they are attached, form an optionally substituted C5-C6cycloalkyl ring that is fused to Ring A. In some embodiments, the compound has the formula IA:OR5(IA).

[0231] In some embodiments, the compound has the formula IA-1:OR5(IA-1).

[0232] In other aspects, R3and R4, together with the atoms to which they are attached, form an optionally substituted 6-membered aryl ring that is fused to Ring A, optionally substituted with Ci-Cealkyl, Cs-Cecycloalkyl, -OCi-Cealkyl, -OC3-C6cycloalkyl, -SCi-Cealkyl, -SCs-Cecycloalkyl, -NHCi-Cealkyl, -NHCs-Cecycloalkyl, -NHC(O)Ci-C6alkyl, - NHC(O)C3-C6cycloalkyl, wherein the Ci-Cealkyl or Cs-Cecycloalkyl groups in the optional substituents are themselves optionally substituted with one or more halo, Cs-Cscycloalkyl, or Cs-Cshalocycloalkyl.

[0233] In some embodiments, R3and R4, together with the atoms to which they are attached, form an optionally substituted 6-membred aryl ring that is fused to Ring A. In some embodiments, the compound has the formula IB:OR5(IB).

[0234] In other aspects, R3and R4, together with the atoms to which they are attached, form an optionally substituted 5-6 membered heteroaryl ring that is fused to ring A, optionally substituted with Ci-Cealkyl, Cs-Cecycloalkyl, -OCi-Cealkyl, -OC3-C6cycloalkyl, -120039.000211 (TYRA041PCT)SCi-Cealkyl, -SCs-Cecycloalkyl, -NHCi-Cealkyl, -NHCs-Cecycloalkyl, -NHC(O)Ci-C6alkyl, - NHC(O)C3-C6cycloalkyl, wherein the Ci-Cealkyl or Cs-Cecycloalkyl groups in the optional substituents are themselves optionally substituted with one or more halo, Cs-Cscycloalkyl, or Cs-Cshalocycloalkyl.

[0235] In some aspects, R3and R4, together with the atoms to which they are attached, form an optionally substituted 5-6 membered heteroaryl ring that is fused to ring A. In some embodiments, the compound has the formula IC:NiXR5(IC),wherein Y is N or CH, andR7is Ci-Cealkyl, Cs-Cecycloalkyl, 3-6-membered heterocycloalkyl, -OCi-Cealkyl, - OCs-Cecycloalkyl, -SCi-Cealkyl, -SCs-Cecycloalkyl, -NHCi-Cealkyl, -NHC3- Cecycloalkyl, -NHC(O)Ci-C6alkyl, - NHC(O)C3-C6cycloalkyl, wherein the Ci- Cealkyl or C3-Cecycloalkyl groups are optionally substituted with one or more halo, Cs-Cscycloalkyl, or Cs-Cshalocycloalkyl.

[0236] In some embodiments of formula IC, Y is N.

[0237] In some embodiments of formula IC, Y is CH.

[0238] In some embodiments of formula IC, R7is C₁-C₆alkyl optionally substituted with one or more halo, C₃-C₅cycloalkyl, or C₃-C₅halocycloalkyl.

[0239] In some embodiments of formula IC, R7is -CH2CH3, -CH(CH3)2, -C(CH3)3, -CF3, -CF2CH3, -CF2CF3, or -CF2CH2CH3.

[0240] In some embodiments of formula IC, R7is Cs-Cecycloalkyl optionally substituted with one or more halo or Ci-Cealkyl.

[0241] In some embodiments of formula IC, R7is120039.000211 (TYRA041PCT), or

[0242] In some embodiments of formula IC, R7is

[0243] In some embodiments of formula IC, R7is

[0244] In some embodiments of formula IC, R7is

[0245] In some embodiments of formula IC, R7is

[0246] In some embodiments of formula IC, R7isF

[0247] In some embodiments of formula IC, R7is

[0248] In some embodiments of formula IC, R7is

[0249] In some embodiments of formula IC, R7is120039.000211 (TYRA041PCT)

[0250] In some embodiments of formula IC, R7is 3-6-membered heterocycloalkyl.

[0251] In some embodiments of formula IC, R7isDN-

[0252] In some embodiments of formula IC, R7is NHC(O)Ci-C6alkyl or -NHC(O)C3-C6cycloalkyl, wherein the Ci-Cealkyl is optionally substituted with one or more halo or Cs-Cecycloalkyl.

[0253] In some embodiments of formula IC, R7is

[0254] In some embodiments of formula IC, R7is

[0255] In some embodiments of formula IC, R7is

[0256] In some embodiments of formula IC, R7is120039.000211 (TYRA041PCT)

[0257] In some embodiments of formula IC, R7is

[0258] In some embodiments of formula IC, R7is

[0259] In some aspects, R5in Formula I is optionally substituted aryl, optionally substituted 5-6 membered heteroaryl, or an optionally substituted C3-C6 cycloalkyl ring.

[0260] In some embodiments, R5in Formula I is an optionally substituted aryl.

[0261] In some embodiments, R5in Formula I is an optionally substituted 5-6 membered heteroaryl.

[0262] In some embodiments, R5in Formula I is an optionally substituted C3-C6 cycloalkyl ring.

[0263] In some embodiments, R5in Formula I is optionally substituted aryl.

[0264] In some embodiments, R5in Formula I is phenyl.

[0265] In some embodiments, R5in Formula I is fluorophenyl.

[0266] In some aspects, the disclosure is directed to a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the compound is:(E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-8-phenyl-2- (trifluoromethyl)pyrimido[4,5-d]pyridazin-5(6H)-one;(S, E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-8-phenyl-2- (trifluoromethyl)pyrimido[4,5-d]pyridazin-5(6H)-one;(R, E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-8-phenyl-2- (trifluoromethyl)pyrimido[4,5-d]pyridazin-5(6H)-one;(E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(l,l-difluoroethyl)-8- phenylpyrimido[4,5-d]pyridazin-5(6H)-one;(R, E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(l,l-difluoroethyl)-8- phenylpyrimido[4,5-d]pyridazin-5(6H)-one;(S, E)-6-( 1 -cyclopropyl -3 -(methylsulfonyl)allyl)-2-( 1, 1 -difluoroethyl)-8- phenylpyrimido[4,5-d]pyridazin-5(6H)-one;120039.000211 (TYRA041PCT)(E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-8-phenyl-2- (trifluoromethyl)pyrimido[4,5-d]pyridazin-5(6H)-one;(S, E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-8-phenyl-2- (trifluoromethyl)pyrimido[4,5-d]pyridazin-5(6H)-one;(R, E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-8-phenyl-2- (trifluoromethyl)pyrimido[4,5-d]pyridazin-5(6H)-one;(E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(l,l-difluoroethyl)-8- phenylpyrimido[4,5-d]pyridazin-5(6H)-one;(R, E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(l,l-difluoroethyl)-8- phenylpyrimido[4,5-d]pyridazin-5(6H)-one;(S, E)-6-( 1 -cyclopropyl -3 -(methylsulfonyl)allyl)-2-( 1, 1 -difluoroethyl)-8- phenylpyrimido[4,5-d]pyridazin-5(6H)-one;(E)-2-cyclobutyl-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-8-phenylpyrimido[4,5- d]pyridazin-5(6H)-one;(R, E)-2-cyclopropyl-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-8- phenylpyrimido[4,5-d]pyridazin-5(6H)-one;(S, E)-2-cyclopropyl-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-8-phenylpyrimido[4,5- d]pyridazin-5(6H)-one;(E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-ethyl-8-phenylpyrimido[4,5- d]pyridazin-5(6H)-one;(E)-2-cyclopentyl-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-8-phenylpyrimido[4,5- d]pyridazin-5(6H)-one;(R, E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(perfluoroethyl)-8- phenylpyrimido[4,5-d]pyridazin-5(6H)-one;(S, E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(perfluoroethyl)-8- phenylpyrimido[4,5-d]pyridazin-5(6H)-one;(R, E)-2-cyclobutyl-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-8-phenylpyrimido[4,5- d]pyridazin-5(6H)-one;(S, E)-2-cyclobutyl-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-8-phenylpyrimido[4,5- d]pyridazin-5(6H)-one;(R, E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-ethyl-8-phenylpyrimido[4,5- d]pyridazin-5(6H)-one;120039.000211 (TYRA041PCT)(S, E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-ethyl-8-phenylpyrimido[4,5- d]pyridazin-5(6H)-one;(R, E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-isopropyl-8-phenylpyrimido[4,5- d]pyridazin-5(6H)-one;(S, E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-isopropyl-8-phenylpyrimido[4,5- d]pyridazin-5(6H)-one;(E)-2-( 1, 1 -difluoroethyl)-6-(4-methyl- 1 -(methyl sulfonyl)pent- 1 -en-3 -y 1 ) - 8 - phenylpyrimido[4,5-d]pyridazin-5(6H)-one;(E)-2-( 1, 1 -difluoroethyl)-6-( 1 -(methyl sulfonyl)pent- 1 -en-3 -yl)-8-phenylpyrimido[4, 5 - d]pyridazin-5(6H)-one;(E)-2-(l,l-difluoroethyl)-6-(4-(methylsulfonyl)but-3-en-2-yl)-8-phenylpyrimido[4,5- d]pyridazin-5(6H)-one;(E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-4-phenyl-5,6,7,8-tetrahydrophthalazin- l(2H)-one;(R, E)-2-cyclopentyl-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-8-phenylpyrimido[4,5- d]pyridazin-5(6H)-one;(S, E)-2-cyclopentyl-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-8-phenylpyrimido[4,5- d]pyridazin-5(6H)-one;(E)-2-(l,l-difluoroethyl)-6-(2-methyl-4-(methylsulfonyl)but-3-en-2-yl)-8- phenylpyrimido[4,5-d]pyridazin-5(6H)-one;(E)-2-(l,l-difluoroethyl)-6-(l-methoxy-4-(methylsulfonyl)but-3-en-2-yl)-8- phenylpyrimido[4,5-d]pyridazin-5(6H)-one;(R, E)-2-(tert-butyl)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-8-phenylpyrimido[4,5- d]pyridazin-5(6H)-one;(S, E)-2-(tert-butyl)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-8-phenylpyrimido[4,5- d]pyridazin-5(6H)-one;(E)-6-(l-cyclobutyl-3-(methylsulfonyl)allyl)-2-(l,l-difluoroethyl)-8- phenylpyrimido[4,5-d]pyridazin-5(6H)-one;(E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-4-phenylphthalazin-l(2H)-one;(S, E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(l-methylcyclopropyl)-8- phenylpyrimido[4,5-d]pyridazin-5(6H)-one;120039.000211 (TYRA041PCT)(R, E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(l-methylcyclopropyl)-8- phenylpyrimido[4,5-d]pyridazin-5(6H)-one;(E)-6-(4-(methylsulfonyl)but-3-en-2-yl)-2-(perfluoroethyl)-8-phenylpyrimido[4,5- d]pyridazin-5(6H)-one;(E)-6-(l-(methylsulfonyl)pent-l-en-3-yl)-2-(perfluoroethyl)-8-phenylpyrimido[4,5- d]pyridazin-5(6H)-one;(E)-6-(l-methoxy-4-(methylsulfonyl)but-3-en-2-yl)-2-(perfluoroethyl)-8- phenylpyrimido[4,5-d]pyridazin-5(6H)-one;(E)-6-(l-cyclobutyl-3-(methylsulfonyl)allyl)-2-(perfluoroethyl)-8- phenylpyrimido[4,5-d]pyridazin-5(6H)-one;(E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(l,l-difluoroethyl)-8-(4- fluorophenyl)pyrimido[4,5-d]pyridazin-5(6H)-one;(E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(l-fluorocyclopropyl)-8- phenylpyrimido[4,5-d]pyridazin-5(6H)-one;(E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(l,l-difluoroethyl)-8-(2- fluorophenyl)pyrimido[4,5-d]pyridazin-5(6H)-one;(E)-6-( 1 -cy clopropyl-3 -(methyl sulfonyl)allyl)-2-( 1, 1 -difluoropropyl)-8 - phenylpyrimido[4,5-d]pyridazin-5(6H)-one;(E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(l,l-difluoroethyl)-8-(3- fluorophenyl)pyrimido[4,5-d]pyridazin-5(6H)-one;(E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-8-phenyl-2-(l- (trifluoromethyl)cyclopropyl)pyrimido[4,5-d]pyridazin-5(6H)-one;(E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(2,2-difluorocyclopropyl)-8- phenylpyrimido[4,5-d]pyridazin-5(6H)-one;(E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(3,3-difluorocyclobutyl)-8- phenylpyrimido[4,5-d]pyridazin-5(6H)-one;(R, E)-2-(azetidin-l-yl)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-8- phenylpyrimido[4,5-d]pyridazin-5(6H)-one;(S, E)-2-(azetidin-l-yl)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-8- phenylpyrimido[4,5-d]pyridazin-5(6H)-one;(R, E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-8-phenyl-2-(pyrrolidin-l- yl)pyrimido[4,5-d]pyridazin-5(6H)-one;120039.000211 (TYRA041PCT)(S, E)-7-(azetidin-l-yl)-3-(l-cyclopropyl-3-(methylsulfonyl)allyl)-l-phenylpyrido[3,4- d]pyridazin-4(3H)-one;(S, E)-7-(azetidin-l-yl)-3-(l-cyclopropyl-3-(methylsulfonyl)allyl)-l-phenylpyrido[3,4- d]pyridazin-4(3H)-one;(R, E)-7-(azetidin-l-yl)-3-(l-cyclopropyl-3-(methylsulfonyl)allyl)-l- phenylpyrido[3,4-d]pyridazin-4(3H)-one;(E)-5-(cyclopentylmethyl)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6- phenylpyridazin-3(2H)-one;(E)-5-(cyclopentyloxy)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6-phenylpyridazin- 3(2H)-one;(E)-2-(l,l-difluoroethyl)-6-(l-(2-(methylsulfonyl)vinyl)cyclopropyl)-8- phenylpyrimido[4,5-d]pyridazin-5(6H)-one;(E)-3-cyclopropyl-3-(2-(l,l-difluoroethyl)-5-oxo-8-phenylpyrimido[4,5-d]pyridazin- 6(5H)-yl)-N, N-dimethylprop- 1 -ene- 1 -sulfonamide;(E)-6-(l-cyclopropyl-3-(morpholinosulfonyl)allyl)-2-(l,l-difluoroethyl)-8- phenylpyrimido[4,5-d]pyridazin-5(6H)-one;(E)-3-cyclopropyl-3-(2-(l,l-difluoroethyl)-5-oxo-8-phenylpyrimido[4,5-d]pyridazin- 6(5H)-yl)-N-methylprop-l -ene- 1 -sulfonamide;(S, E)-6-( 1 -cyclopropyl -3 -(methylsulfonyl)allyl)-2-( 1, 1 -difluoroethyl)-8- phenylpyrido[2,3-d]pyridazin-5(6H)-one;(R, E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(l,l-difluoroethyl)-8- phenylpyrido[2,3-d]pyridazin-5(6H)-one;(E)-5-Cyclobutoxy-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6-phenylpyridazin- 3(2H)-one;(E)-5-(cyclopentyloxy)-2-(4-(methylsulfonyl)but-3-en-2-yl)-6-phenylpyridazin- 3(2H)-one;(E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(cyclopropylmethoxy)-6- phenylpyridazin-3(2H)-one;(E)-7-Cyclopropyl-3-(l-cyclopropyl-3-(methylsulfonyl)allyl)-l-phenylpyrido[3,4- d]pyridazin-4(3H)-one;(E)-5-(Cyclopentylmethyl)-2-(4-(methylsulfonyl)but-3-en-2-yl)-6-phenylpyridazin- 3(2H)-one;120039.000211 (TYRA041PCT)(E)-3-Cyclopropyl-3-(2-(l,l-difluoroethyl)-5-oxo-8-phenylpyrimido[4,5-d]pyridazin- 6(5H)-yl)-N-(2-(dimethylamino)ethyl)-N-methylprop-l-ene-l -sulfonamide; (E)-6-(l-cyclopropyl-3-((4-methylpiperazin-l-yl)sulfonyl)allyl)-2-(l,l-difluoroethyl)- 8-phenylpyrimido[4,5-d]pyridazin-5(6H)-one;(E)- 1 -( 1 -Cy clopropyl-3 -(methyl sulfonyl)allyl)-4-(cy clopropylmethoxy)-5 - phenylpyridin-2(lH)-one;(E)-4-(Cyclopentyloxy)-l-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-phenylpyridin- 2(lH)-one;(E)-5-(Cyclopentyloxy)-2-(3-(methylsulfonyl)allyl)-6-phenylpyridazin-3(2H)-one; (S, E)-5-(cyclopentyloxy)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6- phenylpyridazin-3(2H)-one;(R, E)-5-(cyclopentyloxy)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6- phenylpyridazin-3(2H)-one;(R, E)-5-(cyclopentylmethyl)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6- phenylpyridazin-3(2H)-one;(S, E)-5-(cyclopentylmethyl)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6- phenylpyridazin-3(2H)-one;(E)-5-(cyclobutylmethyl)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6- phenylpyridazin-3(2H)-one;(E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(perfluoropropyl)-6-phenylpyridazin- 3(2H)-one;(E)-4-(cyclopentylmethyl)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6- phenylpyridazin-3(2H)-one;(E)-5-(cyclopentylmethoxy)-2-(4-(methylsulfonyl)but-3-en-2-yl)-6-phenylpyridazin- 3(2H)-one;(E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6-phenyl-5-propoxypyridazin-3(2H)- one;(E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-4-(cyclopropylmethyl)-6- phenylpyridazin-3(2H)-one;(E)-5-(cyclopentylamino)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6- phenylpyridazin-3(2H)-one;120039.000211 (TYRA041PCT)(E)-5-(cyclopentylmethoxy)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6- phenylpyridazin-3(2H)-one;(E)-5-(cyclohexyloxy)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6-phenylpyridazin- 3(2H)-one;(E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(2,2-difluoropropoxy)-6- phenylpyridazin-3(2H)-one;(E)-5-(cyclobutylmethoxy)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6- phenylpyridazin-3(2H)-one;(E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-((3,3-difluorocyclobutyl)methoxy)-6- phenylpyridazin-3(2H)-one;(E)-N-(l-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6-oxo-3-phenyl-l,6- dihydropyridazin-4-yl)pival amide;(E)-N-(l-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6-oxo-3-phenyl-l,6- dihydropyridazin-4-yl)cyclopentanecarboxamide;(E)-5-(cyclopentylthio)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6-phenylpyridazin- 3(2H)-one;(E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-((3-methylcyclopentyl)oxy)-6- phenylpyridazin-3(2H)-one;(E)-4-(cyclobutylmethoxy)-l-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5- phenylpyridin-2(lH)-one;(E)- 1 -( 1 -cy clopropyl-3 -(methyl sulfonyl)allyl)-4-(2,2-difluoropropoxy)-5 - phenylpyridin-2(lH)-one;(E)-l-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-phenyl-4-propoxypyridin-2(lH)-one; (E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-((2,2-difluorocyclobutyl)methoxy)-6- phenylpyridazin-3(2H)-one;(E)-N-(l-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6-oxo-3-phenyl-l,6- dihydropyridazin-4-yl)cyclobutanecarboxamide;(E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-((2,2-difluorocyclopentyl)oxy)-6- phenylpyridazin-3(2H)-one;2-((E)-l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(((lS,2S)-2-methylcyclopentyl)oxy)- 6-phenylpyridazin-3(2H)-one;120039.000211 (TYRA041PCT)(E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(3-methylcyclobutoxy)-6- phenylpyridazin-3(2H)-one;(E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(3,3-dimethylcyclobutoxy)-6- phenylpyridazin-3(2H)-one;(S, E)-6-( 1 -cyclopropyl -3 -(methylsulfonyl)allyl)-2-( 1, 1 -difluoropropyl)-8- phenylpyrimido[4,5-d]pyridazin-5(6H)-one;(R, E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(l,l-difluoropropyl)-8- phenylpyrimido[4,5-d]pyridazin-5(6H)-one;(S, E)-4-(cyclopentyloxy)-l-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-phenylpyridin- 2(lH)-one;(R, E)-4-(cyclopentyloxy)-l-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-phenylpyridin- 2(lH)-one;(E)-5-((cyclobutylmethyl)amino)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6- phenylpyridazin-3(2H)-one;(S, E)-4-cyclobutoxy-l-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-phenylpyridin- 2(lH)-one;(R, E)-4-cyclobutoxy-l-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-phenylpyridin- 2(lH)-one;(S, E)-l-(l-cyclopropyl-3-(methylsulfonyl)allyl)-4-(cyclopropylmethoxy)-5- phenylpyridin-2(lH)-one;(R, E)-l-(l-cyclopropyl-3-(methylsulfonyl)allyl)-4-(cyclopropylmethoxy)-5- phenylpyridin-2(lH)-one;(E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-((3,3-difluorocyclopentyl)oxy)-6- phenylpyridazin-3(2H)-one;(E)-2-cyclopropyl-N-(l-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6-oxo-3-phenyl-l,6- dihydropyridazin-4-yl)-2,2-difluoroacetamide;4-cyclobutoxy-l-(l-cyclopropyl-3-(methylsulfonyl)propyl)-5-phenylpyridin-2(lH)- one;(E)-5-butoxy-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6-phenylpyridazin-3(2H)- one;(E)-N-(l-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6-oxo-3-phenyl-l,6- dihydropyridazin-4-yl)-2,2-difluoropropanamide;120039.000211 (TYRA041PCT)(E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(2-cyclopropylethoxy)-6- phenylpyridazin-3(2H)-one;(E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6-phenyl-5-(pyrrolidine-l- carbonyl)pyridazin-3(2H)-one;(E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-((l-fluorocyclopropyl)methoxy)-6- phenylpyridazin-3(2H)-one;(E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(2,2-difluoropropoxy)-6-(2- fluorophenyl)pyridazin-3 (2H)-one;(E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(2,2-difluoropropoxy)-6-(3- fluorophenyl)pyridazin-3 (2H)-one;(E)-6-(cy cl opent- 1 -en- 1 -y l)-2-( 1 -cyclopropyl-3 -(methylsulfonyl)allyl)-5-(2,2- difluoropropoxy)pyridazin-3(2H)-one;(E)-l-(l-cyclopropyl-3-(methylsulfonyl)allyl)-4-((l-fluorocyclopropyl)methoxy)-5- phenylpyridin-2(lH)-one;(E)-l-(l-cyclopropyl-3-(methylsulfonyl)allyl)-4-((2,2-difluorocyclopropyl)methoxy)- 5 -phenylpyridin-2( 1 H)-one;(E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(2,2-difluoropropoxy)-6-(3,6- dihydro-2H-pyran-4-yl)pyridazin-3(2H)-one;(S, E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(2,2-difluoropropoxy)-6- phenylpyridazin-3(2H)-one;(R, E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(2,2-difluoropropoxy)-6- phenylpyridazin-3(2H)-one;(E)-l-(l-cyclopropyl-3-(methylsulfonyl)allyl)-4-((l-fluorocyclobutyl)methoxy)-5- phenylpyridin-2(lH)-one;(E)-4-((3-chlorocyclobutyl)methoxy)-l-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5- phenylpyridin-2(lH)-one;(E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(2,2-difluorobutoxy)-6- phenylpyridazin-3(2H)-one;(E)-5-(cyclobutoxymethyl)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6- phenylpyridazin-3(2H)-one;(R, E)-5-(cyclobutylmethoxy)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6- phenylpyridazin-3(2H)-one;120039.000211 (TYRA041PCT)(S, E)-5-(cyclobutylmethoxy)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6- phenylpyridazin-3(2H)-one;(S, E)-l-(l-cyclopropyl-3-(methylsulfonyl)allyl)-4-(2,2-difluoropropoxy)-5- phenylpyridin-2(lH)-one;(R, E)-l-(l-cyclopropyl-3-(methylsulfonyl)allyl)-4-(2,2-difluoropropoxy)-5- phenylpyridin-2(lH)-one;1 -((E)- 1 -cy clopropyl-3 -(methyl sulfonyl)allyl)-4-((R)- 1 -cy clopropylethoxy)-5- phenylpyridin-2(lH)-one;1 -((E)- 1 -cy clopropyl-3 -(methyl sulfonyl)allyl)-4-((S)- 1 -cyclopropylethoxy)-5- phenylpyridin-2(lH)-one;(E)-l-(l-cyclopropyl-3-(methylsulfonyl)allyl)-4-((2,2-difluorocyclobutyl)methoxy)-5- phenylpyridin-2(lH)-one;(E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-((2,2-difluorocyclopropyl)methoxy)- 6-phenylpyridazin-3(2H)-one;(E)-4-(cyclobutylmethoxy)-l-(l-cyclopropyl-3-(methylsulfonyl)allyl)-3-fluoro-5- phenylpyridin-2(lH)-one;(E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-4-methyl-6-phenyl-5-((2,2,2- trifluoroethoxy)methyl)pyridazin-3(2H)-one;(E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-((l-fluorocyclobutyl)methoxy)-6- phenylpyridazin-3(2H)-one;(E)-l-(l-cyclopropyl-3-(methylsulfonyl)allyl)-4-(2,2-difluoropropoxy)-3-fluoro-5- phenylpyridin-2(lH)-one;(E)-6-cyclopentyl-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(2,2- difluoropropoxy)pyridazin-3(2H)-one;(E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(isopropoxymethyl)-4-methyl-6- phenylpyridazin-3(2H)-one;(E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(ethoxymethyl)-4-methyl-6- phenylpyridazin-3(2H)-one;(E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-((2,2-difluoroethoxy)methyl)-4- methyl-6-phenylpyridazin-3(2H)-one;5-((S)-l-cyclobutylethoxy)-2-((E)-l-cyclopropyl-3-(methylsulfonyl)allyl)-6- phenylpyridazin-3(2H)-one;120039.000211 (TYRA041PCT)(S, E)-4-(cyclobutylmethoxy)-l-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5- phenylpyridin-2(lH)-one;(R, E)-4-(cyclobutylmethoxy)-l-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5- phenylpyridin-2(lH)-one;(E)-l-(l-cyclopropyl-3-(methylsulfonyl)allyl)-4-(2,2-difluorobutoxy)-5- phenylpyridin-2(lH)-one;(E)-4-cyclobutoxy-l-(l-cyclopropyl-3-(methylsulfonyl)allyl)-3-fluoro-5- phenylpyridin-2(lH)-one;(E)-5-((cyclopentyloxy)methyl)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-4-methyl- 6-phenylpyridazin-3(2H)-one;(E)-5-(cyclobutoxymethyl)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-4-methyl-6- phenylpyridazin-3(2H)-one;5-((R)-l-cyclobutylethoxy)-2-((E)-l-cyclopropyl-3-(methylsulfonyl)allyl)-6- phenylpyridazin-3(2H)-one;(E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-isobutoxy-6-phenylpyridazin-3(2H)- one;(E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6-phenyl-5-(2,2,2- trifluoroethoxy)pyridazin-3(2H)-one;(E)-l-(l-cyclopropyl-3-(methylsulfonyl)allyl)-4-((3-fluorocyclobutyl)methoxy)-5- phenylpyridin-2(lH)-one;(E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6-phenyl-5-(spiro[3.3]heptan-2- yloxy)pyridazin-3(2H)-one;(E)-N-cyclobutyl-l-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6-oxo-3-phenyl-l,6- dihydropyridazine-4-carboxamide;(S, E)-6-( 1 -cyclopropyl -3 -(methylsulfonyl)allyl)-2-( 1, 1 -difluoropropyl)-8- phenylpyrido[2,3-d]pyridazin-5(6H)-one;(R, E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(l,l-difluoropropyl)-8- phenylpyrido[2,3-d]pyridazin-5(6H)-one;(E)-2-( 1 -cy clopropyl-3 -(methyl sulfonyl)allyl)-5 -(3 -hydroxy-3 -methylbut- 1 -yn- 1 -yl)- 6-phenylpyridazin-3(2H)-one;(E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(3,3-difluorocyclobutoxy)-6- phenylpyridazin-3(2H)-one;120039.000211 (TYRA041PCT)(E)-5-((3-chlorocyclobutyl)methoxy)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6- phenylpyridazin-3(2H)-one;(E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(2-fluoro-2-methylpropoxy)-6- phenylpyridazin-3(2H)-one;(E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(neopentyloxy)-6-phenylpyridazin- 3(2H)-one;(E)-2-( 1 -cy clopropyl-3 -(methyl sulfonyl)allyl)-5 -(3,3 -dimethylbut- 1 -yn- 1 -y 1 ) -6 - phenylpyridazin-3(2H)-one;(S, E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(2,2-difluorobutoxy)-6- phenylpyridazin-3(2H)-one;(R, E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(2,2-difluorobutoxy)-6- phenylpyridazin-3(2H)-one;(E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-((3-fluorocyclobutyl)methoxy)-6- phenylpyridazin-3(2H)-one;(E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6-phenyl-5-((tetrahydro-2H-pyran-4- yl)oxy)pyridazin-3 (2H)-one;(E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6-phenyl-5-(prop-l-yn-l-yl)pyridazin- 3(2H)-one;(E)-5-(cyclobutylethynyl)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6- phenylpyridazin-3(2H)-one;2-((E)-l-cyclopropyl-3-(methylsulfonyl)allyl)-6-phenyl-5-(((S)-tetrahydrofuran-3- yl)oxy)pyridazin-3 (2H)-one;(E)-5-(cyclopentylethynyl)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6- phenylpyridazin-3(2H)-one;(E)-5-(cyclobutylmethoxy)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-4-methyl-6- phenylpyridazin-3(2H)-one;2-((E)-l-cyclopropyl-3-(methylsulfonyl)allyl)-6-phenyl-5-(((S)-tetrahydro-2H-pyran- 3 -yl)oxy)pyridazin-3 (2H)-one;2-((E)-l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(((R)-3,3-difluorobutan-2-yl)oxy)-6- phenylpyridazin-3(2H)-one;2-((E)-l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(((S)-3,3-difluorobutan-2-yl)oxy)-6- phenylpyridazin-3(2H)-one;120039.000211 (TYRA041PCT)2-((E)-l-cyclopropyl-3-(methylsulfonyl)allyl)-6-phenyl-5-(((R)-tetrahydro-2H-pyran- 3 -yl)oxy)pyridazin-3 (2H)-one;2-((E)-l-cyclopropyl-3-(methylsulfonyl)allyl)-6-phenyl-5-(((R)-tetrahydrofuran-3- yl)oxy)pyridazin-3 (2H)-one;(E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(3,3-difluorobutoxy)-6- phenylpyridazin-3(2H)-one;(E)-4-(cyclobutylmethoxy)-l-(l-cyclopropyl-3-(methylsulfonyl)allyl)-3-methyl-5- phenylpyridin-2(lH)-one;(E)-5-(cyclobutylmethoxy)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6-phenyl-4- (trifluoromethyl)pyridazin-3(2H)-one;(E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-((l-methylcyclopropyl)methoxy)-6- phenylpyridazin-3(2H)-one;(E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-((l-ethylcyclopropyl)methoxy)-6- phenylpyridazin-3(2H)-one;2-((E)-l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(((trans)-2- methylcyclopropyl)methoxy)-6-phenylpyridazin-3(2H)-one;(E)-4-chloro-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(2,2-difluoropropoxy)-6- phenylpyridazin-3(2H)-one;(S, E)-2-(l-cyclopropyl-3-fluoro-3-(methylsulfonyl)allyl)-5-(2,2-difluoropropoxy)-6- phenylpyridazin-3(2H)-one;(R, E)-2-(l-cyclopropyl-3-fluoro-3-(methylsulfonyl)allyl)-5-(2,2-difluoropropoxy)-6- phenylpyridazin-3(2H)-one;(E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-((l-methylcyclobutyl)methoxy)-6- phenylpyridazin-3(2H)-one;2-((E)-l-cyclopropyl-3-(methylsulfonyl)allyl)-6-phenyl-5-((R)-l- phenylethoxy)pyridazin-3(2H)-one;5-((R)-sec-butoxy)-2-((E)-l-cyclopropyl-3-(methylsulfonyl)allyl)-6-phenylpyridazin- 3(2H)-one;(E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-((l-methoxycyclobutyl)methoxy)-6- phenylpyridazin-3(2H)-one;5-((R)-l-cyclobutylethoxy)-2-((E)-l-cyclopropyl-3-(methylsulfonyl)allyl)-4-methyl- 6-phenylpyridazin-3(2H)-one;120039.000211 (TYRA041PCT)4-((R)-l-cyclobutylethoxy)-l-((E)-l-cyclopropyl-3-fluoro-3-(methylsulfonyl)allyl)-5- phenylpyridin-2(lH)-one;(E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6-phenyl-5-(spiro[3.3]heptan-l- yloxy)pyridazin-3(2H)-one;4-chloro-5-((R)-l-cyclobutylethoxy)-2-((E)-l-cyclopropyl-3-(methylsulfonyl)allyl)-6- phenylpyridazin-3(2H)-one;2-((E)- 1 -cy clopropyl-3 -(methyl sulfonyl)allyl)-5-((R)- 1 -( 1 - methylcyclopropyl)ethoxy)-6-phenylpyridazin-3(2H)-one;(S, E)-l-(l-cyclopropyl-3-fluoro-3-(methylsulfonyl)allyl)-4-(2,2-difluoropropoxy)-5- phenylpyridin-2(lH)-one;(R, E)-l-(l-cyclopropyl-3-fluoro-3-(methylsulfonyl)allyl)-4-(2,2-difluoropropoxy)-5- phenylpyridin-2(lH)-one;2-((E)- 1 -cy clopropyl-3 -(methyl sulfonyl)allyl)-5-((R)- 1 -cy clopropylethoxy)-6- phenylpyridazin-3(2H)-one;2-((E)-l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(((trans)-2- methylcyclobutyl)methoxy)-6-phenylpyridazin-3(2H)-one;1-((E)-l-cyclopropyl-3-fluoro-3-(methylsulfonyl)allyl)-4-(((S)-3,3-difluorobutan-2- yl)oxy)-5 -phenylpy ridin-2( 1 H)-one;2-((S, E)-l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(((R)-3,3-difluorobutan-2-yl)oxy)- 6-phenylpyridazin-3(2H)-one;2-((R, E)-l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(((R)-3,3-difluorobutan-2-yl)oxy)- 6-phenylpyridazin-3(2H)-one;(E)-l-(l-cyclopropyl-3-(methylsulfonyl)allyl-Dl)-4-(2,2-difluoropropoxy)-5- phenylpyridin-2(lH)-one;1 -((E)- 1 -cy clopropyl-3 -fluoro-3 -(methyl sulfonyl)allyl)-4-(((R)-3, 3 -difluorobutan-2- yl)oxy)-5 -phenylpy ridin-2( 1 H)-one;(E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(2,2-difluoropropoxy)-6-(pyridin-3- yl)pyridazin-3(2H)-one;(E)-5-(2-chloro-2,2-difluoroethoxy)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6- phenylpyridazin-3(2H)-one;2-((E)-l-cyclopropyl-3-(methylsulfonyl)allyl)-5-((R)-2-fluoropropoxy)-6- phenylpyridazin-3(2H)-one;120039.000211 (TYRA041PCT)(S, E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl-2-d)-5-(2,2-difluorobutoxy)-6- phenylpyridazin-3(2H)-one;(R, E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl-2-d)-5-(2,2-difluorobutoxy)-6- phenylpyridazin-3(2H)-one;(S, E)-2-(l-cyclobutyl-3-(methylsulfonyl)allyl)-5-(2,2-difluoropropoxy)-6- phenylpyridazin-3(2H)-one;(R, E)-2-(l-cyclobutyl-3-(methylsulfonyl)allyl)-5-(2,2-difluoropropoxy)-6- phenylpyridazin-3(2H)-one;2-((E)-l-cyclopropyl-3-(methylsulfonyl)allyl)-5-((S)-2-fluoropropoxy)-6- phenylpyridazin-3(2H)-one;(E)-5-(2-cyclopropyl-2,2-difluoroethoxy)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)- 6-phenylpyridazin-3(2H)-one;(R, E)-l-(l-cyclopropyl-3-(methylsulfonyl)allyl)-4-(2,2-difluorobutoxy)-5- phenylpyridin-2(lH)-one;(S, E)-l-(l-cyclopropyl-3-(methylsulfonyl)allyl)-4-(2,2-difluorobutoxy)-5- phenylpyridin-2(lH)-one;(S, E)-l-(l-cyclopropyl-3-(methylsulfonyl)allyl-2-d)-4-(2,2-difluorobutoxy)-5- phenylpyridin-2(lH)-one;(R, E)-l-(l-cyclopropyl-3-(methylsulfonyl)allyl-2-d)-4-(2,2-difluorobutoxy)-5- phenylpyridin-2(lH)-one;(S, E)-2-(l-cyclopropyl-3-fluoro-3-(methylsulfonyl)allyl)-5-(2,2-difluorobutoxy)-6- phenylpyridazin-3(2H)-one;(R, E)-2-(l-cyclopropyl-3-fluoro-3-(methylsulfonyl)allyl)-5-(2,2-difluorobutoxy)-6- phenylpyridazin-3(2H)-one;(S, E)-2-(l-cyclobutyl-3-(methylsulfonyl)allyl)-5-(2,2-difluorobutoxy)-6- phenylpyridazin-3(2H)-one;(R, E)-2-(l-cyclobutyl-3-(methylsulfonyl)allyl)-5-(2,2-difluorobutoxy)-6- phenylpyridazin-3(2H)-one;(E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6-phenyl-5-(3,3,3- trifluoropropoxy)pyridazin-3(2H)-one;(E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6-phenyl-5-(4,4,4- trifluorobutoxy)pyridazin-3(2H)-one;120039.000211 (TYRA041PCT)2-((E)- 1 -cy clopropyl-3 -(methylsulfonyl)allyl)-6-phenyl-5-(((R)- 1,1,1 -trifluoropropan- 2-yl)oxy)pyridazin-3(2H)-one;(R, E)-l-(l-cyclopropyl-3-fluoro-3-(methylsulfonyl)allyl)-4-(2,2-difluorobutoxy)-5- phenylpyridin-2(lH)-one;(S, E)-l-(l-cyclopropyl-3-fluoro-3-(methylsulfonyl)allyl)-4-(2,2-difluorobutoxy)-5- phenylpyridin-2(lH)-one;(S, E)-2-(l-cyclopropyl-3-fluoro-3-(methylsulfonyl)allyl-2-d)-5-(2,2-difluorobutoxy)- 6-phenylpyridazin-3(2H)-one;(R, E)-2-(l-cyclopropyl-3-fluoro-3-(methylsulfonyl)allyl-2-d)-5-(2,2-difluorobutoxy)- 6-phenylpyridazin-3(2H)-one;(S, E)-2-(l-cyclopropyl-3-(cyclopropylsulfonyl)allyl)-5-(2,2-difluorobutoxy)-6- phenylpyridazin-3(2H)-one;(R, E)-2-(l-cyclopropyl-3-(cyclopropylsulfonyl)allyl)-5-(2,2-difluorobutoxy)-6- phenylpyridazin-3(2H)-one;(S, E)-l-(l-cyclopropyl-3-fluoro-3-(methylsulfonyl)allyl-2-d)-4-(2,2-difluorobutoxy)- 5 -phenylpyridin-2( 1 H)-one;(R, E)-l-(l-cyclopropyl-3-fluoro-3-(methylsulfonyl)allyl-2-d)-4-(2,2-difluorobutoxy)- 5 -phenylpyridin-2( 1 H)-one;2-((E)- 1 -cy clopropyl-3 -(methylsulfonyl)allyl)-6-phenyl-5-(((S)- 1,1,1 -trifluoropropan- 2-yl)oxy)pyridazin-3(2H)-one;(E)-l-(l-cyclopropyl-3-(methylsulfonyl)allyl-2,3-d2)-4-(2,2-difluoropropoxy)-5- phenylpyridin-2(lH)-one;(S, Z)-2-(3-chloro-l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(2,2-difluorobutoxy)-6- phenylpyridazin-3(2H)-one;(R, Z)-2-(3-chloro-l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(2,2-difluorobutoxy)-6- phenylpyridazin-3(2H)-one;(Z)-5-(2,2-difluorobutoxy)-2-(l-methoxy-4-(methylsulfonyl)but-3-en-2-yl)-6- phenylpyridazin-3(2H)-one;(E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6-phenyl-5-(3,3,3-trifluoro-2- methylpropoxy)pyridazin-3(2H)-one;(S, E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl-2,3-d2)-5-(2,2-difluorobutoxy)-6- phenylpyridazin-3(2H)-one;120039.000211 (TYRA041PCT)(R, E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl-2,3-d2)-5-(2,2-difluorobutoxy)-6- phenylpyridazin-3(2H)-one;(S, E)-2-(l-cyclopentyl-3-(methylsulfonyl)allyl)-5-(2,2-difluorobutoxy)-6- phenylpyridazin-3(2H)-one;(R, E)-2-(l-cyclopentyl-3-(methylsulfonyl)allyl)-5-(2,2-difluorobutoxy)-6- phenylpyridazin-3(2H)-one;(S, E)-l-(l-cyclopropyl-3-(methylsulfonyl)allyl-2,3-d2)-4-(2,2-difluorobutoxy)-5- phenylpyridin-2(lH)-one;(R, E)-l-(l-cyclopropyl-3-(methylsulfonyl)allyl-2,3-d2)-4-(2,2-difluorobutoxy)-5- phenylpyridin-2(lH)-one;(S, E)-2-(l-cyclohexyl-3-(methylsulfonyl)allyl)-5-(2,2-difluorobutoxy)-6- phenylpyridazin-3(2H)-one;(R, E)-2-(l-cyclohexyl-3-(methylsulfonyl)allyl)-5-(2,2-difluorobutoxy)-6- phenylpyridazin-3(2H)-one;(S, E)-5-(2,2-difluorobutoxy)-2-(4-methyl-l-(methylsulfonyl)pent-l-en-3-yl)-6- phenylpyridazin-3(2H)-one;(R, E)-5-(2,2-difluorobutoxy)-2-(4-m ethyl- 1 -(methyl sulfonyl)pent- 1 -en-3 -yl)-6- phenylpyridazin-3(2H)-one;(S, E)-2-(3-chloro-l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(2,2-difluorobutoxy)-6- phenylpyridazin-3(2H)-one;(R, E)-2-(3-chloro-l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(2,2-difluorobutoxy)-6- phenylpyridazin-3(2H)-one;(S, E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(2,2-difluorobutoxy)-6-(3- fluorophenyl)pyridazin-3 (2H)-one;(R, E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(2,2-difluorobutoxy)-6-(3- fluorophenyl)pyridazin-3 (2H)-one;(S, E)-2-(l-cyclopropyl-3-fluoro-3-(methylsulfonyl)allyl)-5-(2,2-difluorobutoxy)-6-(3- fluorophenyl)pyridazin-3 (2H)-one;(R, E)-2-(l-cyclopropyl-3-fluoro-3-(methylsulfonyl)allyl)-5-(2,2-difluorobutoxy)-6- (3-fluorophenyl)pyridazin-3(2H)-one;(E)-5-(2,2-difluorobutoxy)-2-(3-(methylsulfonyl)-l-(oxetan-3-yl)allyl)-6- phenylpyridazin-3(2H)-one;120039.000211 (TYRA041PCT)(E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl-2-d)-5-(2,2-difluorobutoxy-l,l-d2)-6- phenylpyridazin-3(2H)-one;(E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl-2,3-d2)-5-(2,2-difluorobutoxy-l,l-d2)- 6-phenylpyridazin-3(2H)-one;(R, E)-2-(l-cyclopropyl-4-(methylsulfonyl)but-3-en-2-yl)-5-(2,2-difluorobutoxy)-6- phenylpyridazin-3(2H)-one;(S, E)-2-(l-cyclopropyl-4-(methylsulfonyl)but-3-en-2-yl)-5-(2,2-difluorobutoxy)-6- phenylpyridazin-3(2H)-one;(S, E)-5-(2,2-difluorobutoxy)-2-(l-(methylsulfonyl)hex-l-en-3-yl)-6-phenylpyridazin- 3(2H)-one;(R, E)-5-(2,2-difluorobutoxy)-2-(l-(methylsulfonyl)hex-l-en-3-yl)-6-phenylpyridazin- 3(2H)-one;(S, E)-5-(2,2-difluorobutoxy)-2-(5-methyl-l-(methylsulfonyl)hex-l-en-3-yl)-6- phenylpyridazin-3(2H)-one;(R, E)-5-(2,2-difluorobutoxy)-2-(5-methyl-1-(methylsulfonyl)hex-1-en-3-yl)-6-phenylpyridazin-3(2H)-one;(S, E)-2-(l-cyclobutyl-3-(methylsulfonyl)allyl-2-d)-5-(2,2-difluorobutoxy)-6- phenylpyridazin-3(2H)-one;(R, E)-2-(l-cyclobutyl-3-(methylsulfonyl)allyl-2-d)-5-(2,2-difluorobutoxy)-6- phenylpyridazin-3(2H)-one;(R, E)-2-(1-(bicyclo[1.1.1]pentan-1-yl)-3-(methylsulfonyl)allyl)-5-(2,2-difluorobutoxy)-6-phenylpyridazin-3(2H)-one;(S, E)-2-(l-(bicyclo[l.l.l]pentan-l-yl)-3-(methylsulfonyl)allyl)-5-(2,2- difluorobutoxy)-6-phenylpyridazin-3(2H)-one;(S, Z)-2-(3-chloro-l-cyclobutyl-3-(methylsulfonyl)allyl)-5-(2,2-difluorobutoxy)-6- phenylpyridazin-3(2H)-one;(R, Z)-2-(3-chloro-l-cyclobutyl-3-(methylsulfonyl)allyl)-5-(2,2-difluorobutoxy)-6- phenylpyridazin-3(2H)-one;(E)-2-(3-chloro-l-cyclobutyl-3-(methylsulfonyl)allyl)-5-(2,2-difluorobutoxy)-6- phenylpyridazin-3(2H)-one;(S, Z)-2-(3-chloro-l-cyclobutyl-3-(methylsulfonyl)allyl-2-d)-5-(2,2-difluorobutoxy)-6- phenylpyridazin-3(2H)-one;120039.000211 (TYRA041PCT)(R, Z)-2-(3-chloro-l-cyclobutyl-3-(methylsulfonyl)allyl-2-d)-5-(2,2- 276difluorobutoxy)-6-phenylpyridazin-3(2H)-one;(E)-2-(3-chloro-l-cyclobutyl-3-(methylsulfonyl)allyl-2-d)-5-(2,2-difluorobutoxy)-6- phenylpyridazin-3(2H)-one;(R, E)-5-(2,2-difluorobutoxy)-2-(3-(methylsulfonyl)-l-(oxetan-3-yl)allyl)-6- phenylpyridazin-3(2H)-one;(S, E)-5-(2,2-difluorobutoxy)-2-(3-(methylsulfonyl)-l-(oxetan-3-yl)allyl)-6- phenylpyridazin-3(2H)-one;(R, Z)-2-(3-chloro-l-cyclopropyl-3-(methylsulfonyl)allyl-2-d)-5-(2,2-difluorobutoxy)- 6-phenylpyridazin-3(2H)-one;(S, Z)-2-(3-chloro-l-cyclopropyl-3-(methylsulfonyl)allyl-2-d)-5-(2,2-difluorobutoxy)- 6-phenylpyridazin-3(2H)-one;(S, E)-5-(2,2-difluorobutoxy)-2-(4,4-dimethyl-l-(methylsulfonyl)pent-l-en-3-yl)-6- phenylpyridazin-3(2H)-one;(R, E)-5-(2,2-difluorobutoxy)-2-(4,4-dimethyl-l-(methylsulfonyl)pent-l-en-3-yl)-6- phenylpyridazin-3(2H)-one;(E)-2-(3-chloro-l-cyclopropyl-3-(methylsulfonyl)allyl-2-d)-5-(2,2-difluorobutoxy)-6- phenylpyridazin-3(2H)-one; or(E)-5-(2,2-difluorobutoxy)-2-(l-(l-methylcyclopropyl)-3-(methylsulfonyl)allyl)-6- phenylpyridazin-3(2H)-one.

[0267] In some aspects, the disclosure is directed to a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the compound is:(S, E)-2-(l-Cyclopropyl-3-(methylsulfonyl)allyl)-5-(2,2-difluorobutoxy)-6- phenylpyridazin-3(2H)-one;(R, E)-2-(l-Cyclopropyl-3-(methylsulfonyl)allyl)-5-(2,2-difluorobutoxy)-6- phenylpyridazin-3(2H)-one;(R, E)-l-(l-cyclopropyl-3-fluoro-3-(methylsulfonyl)allyl)-4-(2,2-difluoropropoxy)-5- phenylpyridin-2(lH)-one;(S, E)-l-(l-cyclopropyl-3-fluoro-3-(methylsulfonyl)allyl)-4-(2,2-difluoropropoxy)-5- phenylpyridin-2(lH)-one;(S, E)-2-(l-Cyclopropyl-3-fluoro-3-(methylsulfonyl)allyl)-5-(2,2-difluorobutoxy)-6- phenylpyridazin-3(2H)-one;120039.000211 (TYRA041PCT)(R, E)-2-(l-Cyclopropyl-3-fluoro-3-(methylsulfonyl)allyl)-5-(2,2-difluorobutoxy)-6- phenylpyridazin-3(2H)-one;(S, E)-2-(l-cyclobutyl-3-(methylsulfonyl)allyl)-5-(2,2-difluorobutoxy)-6- phenylpyridazin-3(2H)-one;(R, E)-2-(l-cyclobutyl-3-(methylsulfonyl)allyl)-5-(2,2-difluorobutoxy)-6- phenylpyridazin-3(2H)-one;(S, E)-2-(l-cyclobutyl-3-fluoro-3-(methylsulfonyl)allyl-2-d)-5-(2,2-difluorobutoxy)-6- phenylpyridazin-3(2H)-one; or(R, E)-2-(l-cyclobutyl-3-fluoro-3-(methylsulfonyl)allyl-2-d)-5-(2,2-difluorobutoxy)-6- phenylpyridazin-3(2H)-one.

[0268] In other aspects, the disclosure is directed to the following compounds:120039.000211 (TYRA041PCT)120039.000211 (TYRA041PCT)o=s=o

[0269] References herein to Formula (I) or subgenera thereof are meant to encompass the identified formula and any subgenera of those formula disclosed herein.

[0270] Stereoisomers of compounds of Formula (I) are also contemplated by the present disclosure. Thus, the disclosure encompasses all stereoisomers of any compound disclosed or claimed herein, including all enantiomers and diastereomers, or mixtures thereof.

[0271] Pharmaceutically acceptable salts and solvates of the compounds of Formula (I) are also within the scope of the disclosure.

[0272] It is to be appreciated that certain features of the invention which are, for clarity, described herein in the context of separate embodiments, may also be provided in combination in a single embodiment. That is, unless obviously incompatible or specifically excluded, each individual embodiment is deemed to be combinable with any other embodiment s) and such a combination is considered to be another embodiment. Conversely, various features of the invention that are, for brevity, described in the context of a single embodiment, may also be provided separately or in any sub-combination. While an120039.000211 (TYRA041PCT)embodiment may be described as part of a series of steps or part of a more general structure, each said step may also be considered an independent embodiment in itself, combinable with others.Pharmaceutical compositions and methods of administration

[0273] In some aspects, the disclosure is directed to pharmaceutical compositions comprising a compound of the disclosure, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0274] The subject pharmaceutical compositions are typically formulated to provide a therapeutically effective amount of a compound of the present disclosure as the active ingredient, or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof. In some embodiments, the pharmaceutical compositions contain a compound of the present disclosure or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, carriers, including inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants.

[0275] The subject pharmaceutical compositions can be administered alone or in combination with one or more other agents, which are also typically administered in the form of pharmaceutical compositions. Where desired, the one or more compounds of the invention and other agent(s) may be mixed into a preparation or both components may be formulated into separate preparations to use them in combination separately or at the same time.

[0276] In some embodiments, the concentration of one or more compounds provided in the pharmaceutical compositions of the present invention is less than 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% (or a number in the range defined by and including any two numbers above) w / w, w / v or v / v.

[0277] In some embodiments, the concentration of one or more compounds of the invention is greater than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25%, 19%, 18.75%, 18.50%, 18.25% 18%, 17.75%, 17.50%, 17.25% 17%, 16.75%,120039.000211 (TYRA041PCT)16.50%, 16.25%, 16%, 15.75%, 15.50%, 15.25% 15%, 14.75%, 14.50%, 14.25% 14%, 13.75%, 13.50%, 13.25%, 13%, 12.75%, 12.50%, 12.25%, 12%, 11.75%, 11.50%, 11.25% 11%, 10.75%, 10.50%, 10.25% 10%, 9.75%, 9.50%, 9.25%, 9%, 8.75%, 8.50%, 8.25% 8%, 7.75%, 7.50%, 7.25%, 7%, 6.75%, 6.50%, 6.25%, 6%, 5.75%, 5.50%, 5.25%, 5%, 4.75%, 4.50%, 4.25%, 4%, 3.75%, 3.50%, 3.25%, 3%, 2.75%, 2.50%, 2.25%, 2%, 1.75%, 1.50%, 1.25%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% (or a number in the range defined by and including any two numbers above) w / w, w / v, or v / v.

[0278] In some embodiments, the concentration of one or more compounds of the invention is in the range from approximately 0.0001% to approximately 50%, approximately 0.001% to approximately 40%, approximately 0.01% to approximately 30%, approximately 0.02% to approximately 29%, approximately 0.03% to approximately 28%, approximately 0.04% to approximately 27%, approximately 0.05% to approximately 26%, approximately 0.06% to approximately 25%, approximately 0.07% to approximately 24%, approximately 0.08% to approximately 23%, approximately 0.09% to approximately 22%, approximately 0.1% to approximately 21%, approximately 0.2% to approximately 20%, approximately 0.3% to approximately 19%, approximately 0.4% to approximately 18%, approximately 0.5% to approximately 17%, approximately 0.6% to approximately 16%, approximately 0.7% to approximately 15%, approximately 0.8% to approximately 14%, approximately 0.9% to approximately 12%, approximately 1% to approximately 10% w / w, w / v or v / v.

[0279] In some embodiments, the concentration of one or more compounds of the invention is in the range from approximately 0.001% to approximately 10%, approximately 0.01% to approximately 5%, approximately 0.02% to approximately 4.5%, approximately 0.03% to approximately 4%, approximately 0.04% to approximately 3.5%, approximately 0.05% to approximately 3%, approximately 0.06% to approximately 2.5%, approximately 0.07% to approximately 2%, approximately 0.08% to approximately 1.5%, approximately 0.09% to approximately 1%, approximately 0.1% to approximately 0.9% w / w, w / v or v / v.

[0280] In some embodiments, the amount of one or more compounds of the invention is equal to or less than 10 g, 9.5 g, 9.0 g, 8.5 g, 8.0 g, 7.5 g, 7.0 g, 6.5 g, 6.0 g, 5.5 g, 5.0 g, 4.5 g, 4.0 g, 3.5 g, 3.0 g, 2.5 g, 2.0 g, 1.5 g, 1.0 g, 0.95 g, 0.9 g, 0.85 g, 0.8 g, 0.75 g,120039.000211 (TYRA041PCT)0.7 g, 0.65 g, 0.6 g, 0.55 g, 0.5 g, 0.45 g, 0.4 g, 0.35 g, 0.3 g, 0.25 g, 0.2 g, 0.15 g, 0.1 g, 0.09 g, 0.08 g, 0.07 g, 0.06 g, 0.05 g, 0.04 g, 0.03 g, 0.02 g, 0.01 g, 0.009 g, 0.008 g, 0.007 g, 0.006 g, 0.005 g, 0.004 g, 0.003 g, 0.002 g, 0.001 g, 0.0009 g, 0.0008 g, 0.0007 g, 0.0006 g, 0.0005 g, 0.0004 g, 0.0003 g, 0.0002 g, or 0.0001 g (or a number in the range defined by and including any two numbers above).

[0281] In some embodiments, the amount of one or more compounds of the invention is more than 0.0001 g, 0.0002 g, 0.0003 g, 0.0004 g, 0.0005 g, 0.0006 g, 0.0007 g, 0.0008 g, 0.0009 g, 0.001 g, 0.0015 g, 0.002 g, 0.0025 g, 0.003 g, 0.0035 g, 0.004 g, 0.0045 g, 0.005 g, 0.0055 g, 0.006 g, 0.0065 g, 0.007 g, 0.0075 g, 0.008 g, 0.0085 g, 0.009 g, 0.0095 g, 0.01 g, 0.015 g, 0.02 g, 0.025 g, 0.03 g, 0.035 g, 0.04 g, 0.045 g, 0.05 g, 0.055 g, 0.06 g, 0.065 g, 0.07 g, 0.075 g, 0.08 g, 0.085 g, 0.09 g, 0.095 g, 0.1 g,, 0.15 g, 0.2 g,, 0.25 g, 0.3 g,, 0.35 g, 0.4 g,, 0.45 g, 0.5 g, 0.55 g, 0.6 g,, 0.65 g, 0.7 g, 0.75 g, 0.8 g, 0.85 g, 0.9 g, 0.95 g, 1 g, 1-5 g, 2 g, 2.5, 3 g, 3.5, 4 g, 4.5 g, 5 g, 5.5 g, 6 g, 6.5g, 7 g, 7.5g, 8 g, 8.5 g, 9 g, 9.5 g, or 10 g (or a number in the range defined by and including any two numbers above).

[0282] In some embodiments, the amount of one or more compounds of the invention is in the range of 0.0001-10 g, 0.0005-9 g, 0.001-8 g, 0.005-7 g, 0.01-6 g, 0.05-5 g, 0.1-4 g, 0.5-4 g, or 1-3 g.

[0283] In some embodiments, the compounds according to the invention are effective over a wide dosage range. For example, in the treatment of adult humans, dosages from 0.01 to 1000 mg, from 0.5 to 100 mg, from 1 to 50 mg per day, and from 5 to 40 mg per day are examples of dosages that may be used. An exemplary dosage is 10 to 30 mg per day. The exact dosage will depend upon the route of administration, the form in which the compound is administered, the subject to be treated, the body weight of the subject to be treated, and the preference and experience of the attending physician.

[0284] Unless otherwise noted, the amounts of the compounds described herein are set forth on a free base basis. That is, the amounts indicate that amount of the compound administered, exclusive of, for example, solvent (such as in solvates) or counterions (such as in pharmaceutically acceptable salts).

[0285] Described below are non- limiting exemplary pharmaceutical compositions and methods for preparing the same.120039.000211 (TYRA041PCT)Pharmaceutical compositions for oral administration.

[0286] In some embodiments, the invention provides a pharmaceutical composition for oral administration containing a compound of the invention, and a pharmaceutical excipient suitable for oral administration.

[0287] In some embodiments, the invention provides a solid pharmaceutical composition for oral administration containing: (i) an effective amount of a compound of the invention; optionally (ii) an effective amount of a second agent; and (iii) a pharmaceutical excipient suitable for oral administration. In some embodiments, the composition further contains: (iv) an effective amount of a third agent.

[0288] In some embodiments, the pharmaceutical composition may be a liquid pharmaceutical composition suitable for oral consumption. Pharmaceutical compositions of the invention suitable for oral administration can be presented as discrete dosage forms, such as capsules, cachets, or tablets, or liquids or aerosol sprays each containing a predetermined amount of an active ingredient as a powder or in granules, a solution, or a suspension in an aqueous or non-aqueous liquid, an oil-in- water emulsion, or a water-in-oil liquid emulsion. Such dosage forms can be prepared by any of the methods of pharmacy, but all methods include the step of bringing the active ingredient into association with the carrier, which constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation. For example, a tablet can be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free- flowing form such as powder or granules, optionally mixed with an excipient such as, but not limited to, a binder, a lubricant, an inert diluent, and / or a surface active or dispersing agent. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

[0289] This invention further encompasses anhydrous pharmaceutical compositions and dosage forms comprising an active ingredient, since water can facilitate the degradation of some compounds. For example, water may be added (e.g., 5%) in the pharmaceutical arts as a means of simulating long-term storage in order to determine characteristics such as shelf- life or the stability of formulations over time. Anhydrous120039.000211 (TYRA041PCT)pharmaceutical compositions and dosage forms of the invention can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions. Pharmaceutical compositions and dosage forms of the invention which contain lactose can be made anhydrous if substantial contact with moisture and / or humidity during manufacturing, packaging, and / or storage is expected. An anhydrous pharmaceutical composition may be prepared and stored such that its anhydrous nature is maintained.Accordingly, anhydrous compositions may be packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastic or the like, unit dose containers, blister packs, and strip packs.

[0290] An active ingredient can be combined in an intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier can take a wide variety of forms depending on the form of preparation desired for administration. In preparing the compositions for an oral dosage form, any of the usual pharmaceutical media can be employed as carriers, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like in the case of oral liquid preparations (such as suspensions, solutions, and elixirs) or aerosols; or carriers such as starches, sugars, micro-crystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents can be used in the case of oral solid preparations, in some embodiments without employing the use of lactose. For example, suitable carriers include powders, capsules, and tablets, with the solid oral preparations. If desired, tablets can be coated by standard aqueous or nonaqueous techniques.

[0291] Binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, com starch, potato starch, or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose, pre-gelatinized starch, hydroxypropyl methyl cellulose, microcrystalline cellulose, and mixtures thereof.

[0292] Examples of suitable fillers for use in the pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (e.g.,120039.000211 (TYRA041PCT)granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.

[0293] Disintegrants may be used in the compositions of the invention to provide tablets that disintegrate when exposed to an aqueous environment. Too much of a disintegrant may produce tablets which may disintegrate in the bottle. Too little may be insufficient for disintegration to occur and may thus alter the rate and extent of release of the active ingredient(s) from the dosage form. Thus, a sufficient amount of disintegrant that is neither too little nor too much to detrimentally alter the release of the active ingredient(s) may be used to form the dosage forms of the compounds disclosed herein. The amount of disintegrant used may vary based upon the type of formulation and mode of administration, and may be readily discernible to those of ordinary skill in the art. About 0.5 to about 15 weight percent of disintegrant, or about 1 to about 5 weight percent of disintegrant, may be used in the pharmaceutical composition. Disintegrants that can be used to form pharmaceutical compositions and dosage forms of the invention include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pre-gelatinized starch, other starches, clays, other algins, other celluloses, gums or mixtures thereof.

[0294] Lubricants which can be used to form pharmaceutical compositions and dosage forms of the invention include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, or mixtures thereof. Additional lubricants include, for example, a syloid silica gel, a coagulated aerosol of synthetic silica, or mixtures thereof. A lubricant can optionally be added, in an amount of less than about 1 weight percent of the pharmaceutical composition.

[0295] When aqueous suspensions and / or elixirs are desired for oral administration, the active ingredient therein may be combined with various sweetening or flavoring agents, coloring matter or dyes and, if so desired, emulsifying and / or suspending agents, together with such diluents as water, ethanol, propylene glycol, glycerin and various combinations thereof.120039.000211 (TYRA041PCT)

[0296] The tablets can be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate can be employed. Formulations for oral use can also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil.

[0297] Surfactant which can be used to form pharmaceutical compositions and dosage forms of the invention include, but are not limited to, hydrophilic surfactants, lipophilic surfactants, and mixtures thereof. That is, a mixture of hydrophilic surfactants may be employed, a mixture of lipophilic surfactants may be employed, or a mixture of at least one hydrophilic surfactant and at least one lipophilic surfactant may be employed.

[0298] A suitable hydrophilic surfactant may generally have an HLB value of at least 10, while suitable lipophilic surfactants may generally have an HLB value of or less than about 10. An empirical parameter used to characterize the relative hydrophilicity and hydrophobicity of non-ionic amphiphilic compounds is the hydrophilic-lipophilic balance (" HLB" value). Surfactants with lower HLB values are more lipophilic or hydrophobic, and have greater solubility in oils, while surfactants with higher HLB values are more hydrophilic, and have greater solubility in aqueous solutions.

[0299] Hydrophilic surfactants are generally considered to be those compounds having an HLB value greater than about 10, as well as anionic, cationic, or zwitterionic compounds for which the HLB scale is not generally applicable. Similarly, lipophilic (i.e., hydrophobic) surfactants are compounds having an HLB value equal to or less than about 10. However, HLB value of a surfactant is merely a rough guide generally used to enable formulation of industrial, pharmaceutical and cosmetic emulsions.

[0300] Hydrophilic surfactants may be either ionic or non-ionic. Suitable ionic surfactants include, but are not limited to, alkylammonium salts; fusidic acid salts; fatty acid derivatives of amino acids, oligopeptides, and polypeptides; glyceride derivatives of amino acids, oligopeptides, and polypeptides; lecithins and hydrogenated lecithins; lysolecithins and hydrogenated lysolecithins; phospholipids and derivatives thereof; lysophospholipids and derivatives thereof; carnitine fatty acid ester salts; salts of alkylsulfates; fatty acid salts;120039.000211 (TYRA041PCT)sodium docusate; acyl lactylates; mono- and di-acetylated tartaric acid esters of mono- and di-glycerides; succinylated mono- and di-glycerides; citric acid esters of mono- and diglycerides; and mixtures thereof.

[0301] Within the aforementioned group, ionic surfactants include, by way of example: lecithins, lysolecithin, phospholipids, lysophospholipids and derivatives thereof; carnitine fatty acid ester salts; salts of alkyl sulfates; fatty acid salts; sodium docusate; acylactylates; mono- and di-acetylated tartaric acid esters of mono- and di-glycerides; succinylated mono- and di-glycerides; citric acid esters of mono- and di-glycerides; and mixtures thereof.

[0302] Ionic surfactants may be the ionized forms of lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidyl choline, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG-phosphatidylethanolamine, PVP -phosphatidylethanolamine, lactylic esters of fatty acids, stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides, mono / diacetylated tartaric acid esters of mono / diglycerides, citric acid esters of mono / diglycerides,cholyl sarcosine, caproate, caprylate, caprate, laurate, myristate, palmitate, oleate, ricinoleate, linoleate, linolenate, stearate, lauryl sulfate, teracecyl sulfate, docusate, lauroyl carnitines, palmitoyl carnitines, myristoyl carnitines, and salts and mixtures thereof.

[0303] Hydrophilic non-ionic surfactants may include, but are not limited to, alkylglucosides; alkylmaltosides; alkylthioglucosides; lauryl macrogolglycerides; polyoxyalkylene alkyl ethers such as polyethylene glycol alkyl ethers; polyoxyalkylene alkylphenols such as polyethylene glycol alkyl phenols; polyoxyalkylene alkyl phenol fatty acid esters such as polyethylene glycol fatty acids monoesters and polyethylene glycol fatty acids diesters; polyethylene glycol glycerol fatty acid esters; polyglycerol fatty acid esters; polyoxyalkylene sorbitan fatty acid esters such as polyethylene glycol sorbitan fatty acid esters; hydrophilic transesterification products of a polyol with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids, and sterols; polyoxyethylene sterols, derivatives, and analogues thereof; polyoxyethylated vitamins and derivatives thereof; polyoxyethylene-polyoxypropylene block copolymers; and mixtures thereof; polyethylene glycol sorbitan fatty acid esters and hydrophilic transesterification products of a polyol with at least one member of the group consisting of120039.000211 (TYRA041PCT)triglycerides, vegetable oils, and hydrogenated vegetable oils. The polyol may be glycerol, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol, or a saccharide.

[0304] Other hydrophilic-non-ionic surfactants include, without limitation, PEG-10 laurate, PEG- 12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32 dilaurate, PEG- 12 oleate, PEG- 15 oleate, PEG-20 oleate, PEG-20 di oleate, PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG- 15 stearate, PEG-32 distearate, PEG-40 stearate, PEG- 100 stearate, PEG-20 dilaurate, PEG-25 glyceryl trioleate, PEG-32 dioleate, PEG-20 glyceryl laurate, PEG-30 glyceryl laurate, PEG-20 glyceryl stearate, PEG-20 glyceryl oleate, PEG-30 glyceryl oleate, PEG-30 glyceryl laurate, PEG-40 glyceryl laurate, PEG-40 palm kernel oil, PEG-50 hydrogenated castor oil, PEG-40 castor oil, PEG-35 castor oil, PEG-60 castor oil, PEG-40 hydrogenated castor oil, PEG-60 hydrogenated castor oil, PEG-60 corn oil, PEG-6 caprate / capryl ate glycerides, PEG-8 caprate / caprylate glycerides, polyglyceryl- 10 laurate, PEG-30 cholesterol, PEG-25 phyto sterol, PEG-30 soya sterol, PEG-20 trioleate, PEG-40 sorbitan oleate, PEG-80 sorbitan laurate, polysorbate 20, polysorbate 80, POE-9 lauryl ether, POE-23 lauryl ether, POE- 10 oleyl ether, POE-20 oleyl ether, POE-20 stearyl ether, tocopheryl PEG- 100 succinate, PEG-24 cholesterol, polyglyceryl-10 oleate, Tween 40, Tween 60, sucrose monostearate, sucrose mono laurate, sucrose monopalmitate, PEG 10-100 nonyl phenol series, PEG 15-100 octyl phenol series, and pol oxamers.

[0305] Suitable lipophilic surfactants include, by way of example only: fatty alcohols; glycerol fatty acid esters; acetylated glycerol fatty acid esters; lower alcohol fatty acids esters; propylene glycol fatty acid esters; sorbitan fatty acid esters; polyethylene glycol sorbitan fatty acid esters; sterols and sterol derivatives; polyoxyethylated sterols and sterol derivatives; polyethylene glycol alkyl ethers; sugar esters; sugar ethers; lactic acid derivatives of mono- and di-glycerides; hydrophobic transesterification products of a polyol with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids and sterols; oil-soluble vitamins / vitamin derivatives; and mixtures thereof. Within this group, preferred lipophilic surfactants include glycerol fatty acid esters, propylene glycol fatty acid esters, and mixtures thereof, or are hydrophobic transesterification products of a polyol with at least one member of the group consisting of vegetable oils, hydrogenated vegetable oils, and triglycerides.120039.000211 (TYRA041PCT)

[0306] In one embodiment, the composition may include a solubilizer to ensure good solubilization and / or dissolution of the compound of the present invention and to minimize precipitation of the compound of the present invention. This can be especially important for compositions for non-oral use, e.g., compositions for injection. A solubilizer may also be added to increase the solubility of the hydrophilic drug and / or other components, such as surfactants, or to maintain the composition as a stable or homogeneous solution or dispersion.

[0307] Examples of suitable solubilizers include, but are not limited to, the following: alcohols and polyols, such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediols and isomers thereof, glycerol, pentaerythritol, sorbitol, mannitol, transcutol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinylalcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrins and cyclodextrin derivatives; ethers of polyethylene glycols having an average molecular weight of about 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether (glycofurol) or methoxy PEG; amides and other nitrogen-containing compounds such as 2-pyrrolidone, 2-piperidone, ε-caprolactam, N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkylcaprolactam, dimethylacetamide and polyvinylpyrrolidone; esters such as ethyl propionate, tributylcitrate, acetyl tri ethyl citrate, acetyl tributyl citrate, tri ethyl citrate, ethyl oleate, ethyl caprylate, ethyl butyrate, triacetin, propylene glycol monoacetate, propylene glycol diacetate, ε-caprolactone and isomers thereof, δ-valerolactone and isomers thereof, β-butyrolactone and isomers thereof; and other solubilizers known in the art, such as dimethyl acetamide, dimethyl isosorbide, N-methyl pyrrolidones, monooctanoin, diethylene glycol monoethyl ether, and water.

[0308] Mixtures of solubilizers may also be used. Examples include, but not limited to, triacetin, tri ethyl citrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cyclodextrins, ethanol, polyethylene glycol 200-100, glycofurol, transcutol, propylene glycol, and dimethyl isosorbide. Particularly preferred solubilizers include sorbitol, glycerol, triacetin, ethyl alcohol, PEG-400, glycofurol and propylene glycol.

[0309] The amount of solubilizer that can be included is not particularly limited. The amount of a given solubilizer may be limited to a bioacceptable amount, which may be120039.000211 (TYRA041PCT)readily determined by one of skill in the art. In some circumstances, it may be advantageous to include amounts of solubilizers far in excess of bioacceptable amounts, for example to maximize the concentration of the drug, with excess solubilizer removed prior to providing the composition to a subject using conventional techniques, such as distillation or evaporation. Thus, if present, the solubilizer can be in a weight ratio of 10%, 25%o, 50%), 100%o, or up to about 200%> by weight, based on the combined weight of the drug, and other excipients. If desired, very small amounts of solubilizer may also be used, such as 5%>, 2%>, 1%) or even less. Typically, the solubilizer may be present in an amount of about 1%> to about 100%, more typically about 5%> to about 25%> by weight.

[0310] The composition can further include one or more pharmaceutically acceptable additives and excipients. Such additives and excipients include, without limitation, detackifiers, anti-foaming agents, buffering agents, polymers, antioxidants, preservatives, chelating agents, viscomodulators, tonicifiers, flavorants, colorants, odorants, opacifiers, suspending agents, binders, fillers, plasticizers, lubricants, and mixtures thereof.

[0311] In addition, an acid or a base may be incorporated into the composition to facilitate processing, to enhance stability, or for other reasons. Examples of pharmaceutically acceptable bases include amino acids, amino acid esters, ammonium hydroxide, potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, aluminum hydroxide, calcium carbonate, magnesium hydroxide, magnesium aluminum silicate, synthetic aluminum silicate, synthetic hydrocalcite, magnesium aluminum hydroxide, diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine, triethylamine, triisopropanolamine, trimethylamine, tris(hydroxymethyl)aminomethane (TRIS) and the like. Also suitable are bases that are salts of a pharmaceutically acceptable acid, such as acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, oxalic acid, parabromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid, and the like. Salts of polyprotic acids, such as sodium phosphate, disodium hydrogen phosphate, and sodium dihydrogen phosphate can also be used. When the base is a salt, the cation can be any convenient and pharmaceutically acceptable cation, such as ammonium, alkali metals,120039.000211 (TYRA041PCT)alkaline earth metals, and the like. Example may include, but not limited to, sodium, potassium, lithium, magnesium, calcium and ammonium.

[0312] Suitable acids are pharmaceutically acceptable organic or inorganic acids. Examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid, nitric acid, boric acid, phosphoric acid, and the like. Examples of suitable organic acids include acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acids, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid and the like.Pharmaceutical compositions for injection.

[0313] In some embodiments, the invention provides a pharmaceutical composition for injection containing a compound of the present invention and a pharmaceutical excipient suitable for injection. Components and amounts of agents in the compositions are as described herein.

[0314] The forms in which the novel compositions of the present invention may be incorporated for administration by injection include aqueous or oil suspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical vehicles.

[0315] Aqueous solutions in saline are also conventionally used for injection. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and the like (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils may also be employed. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, for the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.

[0316] Sterile injectable solutions are prepared by incorporating the compound of the present invention in the required amount in the appropriate solvent with various other ingredients as enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a120039.000211 (TYRA041PCT)sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, certain desirable methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.Pharmaceutical compositions for topical (e.g. transdermal) delivery.

[0317] In some embodiments, the invention provides a pharmaceutical composition for transdermal delivery containing a compound of the present invention and a pharmaceutical excipient suitable for transdermal delivery.

[0318] Compositions of the present invention can be formulated into preparations in solid, semisolid, or liquid forms suitable for local or topical administration, such as gels, water soluble jellies, creams, lotions, suspensions, foams, powders, slurries, ointments, solutions, oils, pastes, suppositories, sprays, emulsions, saline solutions, dimethylsulfoxide (DMSO)-based solutions. In general, carriers with higher densities are capable of providing an area with a prolonged exposure to the active ingredients. In contrast, a solution formulation may provide more immediate exposure of the active ingredient to the chosen area.

[0319] The pharmaceutical compositions also may comprise suitable solid or gel phase carriers or excipients, which are compounds that allow increased penetration of, or assist in the delivery of, therapeutic molecules across the stratum comeum permeability barrier of the skin. There are many of these penetration- enhancing molecules known to those trained in the art of topical formulation.

[0320] Examples of such carriers and excipients include, but are not limited to, humectants (e.g., urea), glycols (e.g., propylene glycol), alcohols (e.g., ethanol), fatty acids (e.g., oleic acid), surfactants (e.g., isopropyl myristate and sodium lauryl sulfate), pyrrolidones, glycerol monolaurate, sulfoxides, terpenes (e.g., menthol), amines, amides, alkanes, alkanols, water, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.

[0321] Another exemplary formulation for use in the methods of the present invention employs transdermal delivery devices ("patches"). Such transdermal patches may be used to provide continuous or discontinuous infusion of a compound of the present invention in controlled amounts, either with or without another agent.120039.000211 (TYRA041PCT)The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g., U. S. Pat. Nos. 5,023,252, 4,992,445 and 5,001,139. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.Pharmaceutical compositions for inhalation.

[0322] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra. Preferably the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in preferably pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a face mask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices that deliver the formulation in an appropriate manner.Other pharmaceutical compositions.

[0323] Pharmaceutical compositions may also be prepared from compositions described herein and one or more pharmaceutically acceptable excipients suitable for sublingual, buccal, rectal, intraosseous, intraocular, intranasal, epidural, or intraspinal administration. Preparations for such pharmaceutical compositions are well-known in the art. See, e.g., Anderson, Philip O.; Knoben, James E.; Troutman, William G, eds., Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002; Pratt and Taylor, eds., Principles of Drug Action, Third Edition, Churchill Livingston, New York, 1990; Katzung, ed., Basic and Clinical Pharmacology, Ninth Edition, McGraw Hill, 20037ybg; Goodman and Gilman, eds., The Pharmacological Basis of Therapeutics, Tenth Edition, McGraw Hill, 2001; Remingtons Pharmaceutical Sciences, 20th Ed., Lippincott Williams & Wilkins., 2000; Martindale, The Extra Pharmacopoeia, Thirty-Second Edition (The Pharmaceutical Press, London, 1999); all of which are incorporated by reference herein in their entirety.

[0324] Administration of the compounds or pharmaceutical composition of the present invention can be effected by any method that enables delivery of the compounds to the site of action. These methods include oral routes, intraduodenal routes, parenteral injection (including intravenous, intraarterial, subcutaneous, intramuscular, intravascular,120039.000211 (TYRA041PCT)intraperitoneal or infusion), topical (e.g. transdermal application), rectal administration, via local delivery by catheter or stent or through inhalation. Compounds can also be administered intraadiposally or intrathecally.

[0325] The amount of the compound administered will be dependent on the subject being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compound and the discretion of the prescribing physician. However, an effective dosage is in the range of about 0.001 to about 100 mg per kg body weight per day, preferably about 1 to about 35 mg / kg / day, in single or divided doses. For a 70 kg human, this would amount to about 0.05 to 7 g / day, preferably about 0.05 to about 2.5 g / day. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, e.g. by dividing such larger doses into several small doses for administration throughout the day.

[0326] In some embodiments, a compound of the invention is administered in a single dose.

[0327] Typically, such administration will be by injection, e.g., intravenous injection, in order to introduce the agent quickly. However, other routes may be used as appropriate. A single dose of a compound of the invention may also be used for treatment of an acute condition.

[0328] In some embodiments, a compound of the invention is administered in multiple doses. Dosing may be about once, twice, three times, four times, five times, six times, or more than six times per day. Dosing may be about once a month, once every two weeks, once a week, or once every other day. In another embodiment a compound of the invention and another agent are administered together about once per day to about 6 times per day. In another embodiment the administration of a compound of the invention and an agent continues for less than about 7 days. In yet another embodiment the administration continues for more than about 6, 10, 14, 28 days, two months, six months, or one year. In some cases, continuous dosing is achieved and maintained as long as necessary.

[0329] Administration of the compounds of the invention may continue as long as necessary. In some embodiments, a compound of the invention is administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In some embodiments, a compound of the invention is administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, a compound120039.000211 (TYRA041PCT)of the invention is administered chronically on an ongoing basis, e.g., for the treatment of chronic effects.

[0330] An effective amount of a compound of the invention may be administered in either single or multiple doses by any of the accepted modes of administration of agents having similar utilities, including rectal, buccal, intranasal and transdermal routes, by intraarterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant.

[0331] The compositions of the invention may also be delivered via an impregnated or coated device such as a stent, for example, or an artery-inserted cylindrical polymer. Such a method of administration may, for example, aid in the prevention or amelioration of restenosis following procedures such as balloon angioplasty. Without being bound by theory, compounds of the invention may slow or inhibit the migration and proliferation of smooth muscle cells in the arterial wall which contribute to restenosis. A compound of the invention may be administered, for example, by local delivery from the struts of a stent, from a stent graft, from grafts, or from the cover or sheath of a stent. In some embodiments, a compound of the invention is admixed with a matrix. Such a matrix may be a polymeric matrix, and may serve to bond the compound to the stent. Polymeric matrices suitable for such use, include, for example, lactone-based polyesters or copolyesters such as polylactide, polycaprolactonglycolide, polyorthoesters, polyanhydrides, polyaminoacids, polysaccharides, polyphosphazenes, poly (ether-ester) copolymers (e.g. PEO-PLLA); polydimethylsiloxane, poly(ethylene-vinylacetate), acrylate-based polymers or copolymers (e.g. polyhydroxyethyl methylmethacrylate, polyvinyl pyrrolidinone), fluorinated polymers such as polytetrafluoroethylene and cellulose esters. Suitable matrices may be nondegrading or may degrade with time, releasing the compound or compounds. Compounds of the invention may be applied to the surface of the stent by various methods such as dip / spin coating, spray coating, dip-coating, and / or brush-coating. The compounds may be applied in a solvent and the solvent may be allowed to evaporate, thus forming a layer of compound onto the stent. Alternatively, the compound may be located in the body of the stent or graft, for example in microchannels or micropores. When implanted, the compound diffuses out of the body of the stent to contact the arterial wall. Such stents may be prepared by dipping a stent manufactured to contain such micropores or microchannels into a solution of the compound of the invention in a suitable solvent, followed by evaporation of the solvent.120039.000211 (TYRA041PCT)Excess drug on the surface of the stent may be removed via an additional brief solvent wash. In yet other embodiments, compounds of the invention may be covalently linked to a stent or graft. A covalent linker may be used which degrades in vivo, leading to the release of the compound of the invention. Any bio-labile linkage may be used for such a purpose, such as ester, amide or anhydride linkages. Compounds of the invention may additionally be administered intravascularly from a balloon used during angioplasty. Extravascular administration of the compounds via the pericard or via advential application of formulations of the invention may also be performed to decrease restenosis.

[0332] A variety of stent devices which may be used as described are disclosed, for example, in the following references, all of which are hereby incorporated by reference: U. S. Pat. No. 5451233; U. S. Pat. No. 5040548; U. S. Pat. No. 5061273; U. S. Pat. No.5496346; U. S. Pat. No. 5292331; U. S. Pat. No. 5674278; U. S. Pat. No. 3657744; U. S. Pat. No. 4739762; U. S. Pat. No. 5195984; U. S. Pat. No. 5292331; U. S. Pat. No. 5674278; U. S. Pat. No. 5879382; U. S. Pat. No. 6344053.

[0333] The compounds of the invention may be administered in dosages. It is known in the art that due to intersubject variability in compound pharmacokinetics, individualization of dosing regimen is necessary for optimal therapy. Dosing for a compound of the invention may be found by routine experimentation in light of the instant disclosure.

[0334] When a compound of the invention is administered in a composition that comprises one or more agents, and the agent has a shorter half- life than the compound of the invention unit dose forms of the agent and the compound of the invention may be adjusted accordingly.

[0335] The subject pharmaceutical composition may, for example, be in a form suitable for oral administration as a tablet, capsule, pill, powder, sustained release formulations, solution, suspension, for parenteral injection as a sterile solution, suspension or emulsion, for topical administration as an ointment or cream or for rectal administration as a suppository. The pharmaceutical composition may be in unit dosage forms suitable for single administration of precise dosages. The pharmaceutical composition will include a conventional pharmaceutical carrier or excipient and a compound according to the invention as an active ingredient. In addition, it may include other medicinal or pharmaceutical agents, carriers, adjuvants, etc.120039.000211 (TYRA041PCT)

[0336] Exemplary parenteral administration forms include solutions or suspensions of active compound in sterile aqueous solutions, for example, aqueous propylene glycol or dextrose solutions. Such dosage forms can be suitably buffered, if desired.METHODS OF USE

[0337] In some aspects, the disclosure provides methods for decreasing proliferation in a proliferative cell having a microsatellite instability (MSI), comprising decreasing the helicase activity of Werner syndrome ATP-dependent helicase (WRN) in the proliferative cell.

[0338] In some embodiments, decreasing the helicase activity of Werner syndrome ATP-dependent helicase (WRN) in the proliferative cell is achieved by administering a compound of Formula of (I) (or any embodiment thereof disclosed herein) or a pharmaceutically acceptable salt thereof.

[0339] In some embodiments, the proliferative cell is characterized as having MSI low (MSI-L).

[0340] In some embodiments, the proliferative cell is characterized as having high MSI (MSI-H), used interchangeably with MSI-high. Cells can be characterized as MSI, including MSI-L or MSI- H, or as MSS (MS-stable), according to the method known in the art (see, for example, Dudley, Jonathan C., et al., Clinical Cancer Research, 22(4): 813-820, 2016.). MSI-H is used to classify tumors as having a high frequency of MSI. A tumor can be classified as MSI, including MSI-low or MSI-high, using polymerase chain reaction (PCR) and / or immunohistochemistry (IHC) assays. As stated in Dudley et al. (supra), a tumor is classified as MSI-H by PCR if (i) there is a shift (usually downward) in the size of at least two microsatellite loci from a reference panel of five microsatellite loci in tumor relative to normal, where the reference panel can be the “Bethesda Panel,” also referred to herein as the “NCI-Reference Panel (Bethesda, 1998)”, which includes two mononucleotide loci (BAT-25 and BAT-26) and three dinucleotide loci (D2S123, D5S346, and D17S250), or alternatively, the reference panel can be Promega Corporation’s MSI Analysis System, which includes five mononucleotide loci (BAT-25, BAT-26, NR-21, NR-24, and MONO-27); or (ii) there is a shift in the size of 30% or more microsatellite loci from a reference panel of more than five microsatellite loci in tumor relative to normal. The MSI-H phenotype is associated with120039.000211 (TYRA041PCT)germline defects in the mismatch repair genes MLH1, MSH2, MSH6, and PMS2, and is the primary phenotype observed in tumors from patients with HNPCC / Lynch syndrome. A tumor is classified as MSI-H in IHC test if it shows a loss of protein expression for at least 1 of the above 4 mismatch repair genes. Cells can be similarly classified as MSI-H using the tests described herein for tumors.

[0341] In some embodiments, a tumor or cell is classified as MSI-H using PCR to amplify the five microsatellite loci of the “Bethesda Panel” (BAT-25, BAT-26, D2S123, D5S346, and D17S250) from both tumor tissue or cells and normal tissue or cells, wherein the tumor or cell is classified as MSI-H if there is a shift in the size of at least two of the microsatellite loci from the tumor tissue or cells relative to the normal tissue or cells. In some embodiments, the shift in size of the microsatellite loci is a downward shift.

[0342] In some embodiments, a tumor or cell is classified as MSI-H using PCR to amplify the five microsatellite loci of Promega Corporation’s MSI Analysis System (BAT-25, BAT-26, NR- 21, NR-24, and MONO-27) from both tumor tissue or cells and normal tissue or cells, wherein the tumor or cell is classified as MSI-H if there is a shift in the size of at least two of the microsatellite loci from the tumor tissue or cells relative to the normal tissue or cells. In some embodiments, the shift in size of the microsatellite loci is a downward shift.

[0343] In some embodiments, a tumor is classified as MSI-H using IHC to determine the expression level of the MMR proteins MLH1, MSH2, MSH6, and / or PMS2 in both tumor tissue and normal tissue, wherein the tumor is classified as MSI-H if there is a loss of protein expression for at least one of the MMR proteins in the tumor tissue relative to the normal tissue. In some embodiments, the loss of protein expression is a decrease of at least 20% (such as a decrease of 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, or more).

[0344] In contrast, a tumor is classified as MSI-L by PCR if (i) there is a shift in the size of one microsatellite locus from a reference panel of five microsatellite loci in tumor relative to normal, where the reference panel can be the “Bethesda Panel” or Promega Corporation’s MSI Analysis System; or (ii) there is a shift in the size of less than 30% microsatellite loci from a reference panel of more than five microsatellite loci in tumor relative to normal. MSI- L tumors are thought to represent a distinct mutator phenotype with potentially different molecular etiology than MSI-H tumors (Thibodeau, 1998; Wu et al.,120039.000211 (TYRA041PCT)1999, Am J Hum Genetics 65: 1291-1298). Cells can be similarly classified as MSI-L using the tests described herein for tumors.

[0345] Cancers classified as MSI-H include, but not limited to, uterine corpus endometrial carcinoma, colon adenocarcinoma, stomach adenocarcinoma, rectal adenocarcinoma, adenoid cystic carcinoma, uterine carcinosarcoma, cervical squamous cell carcinoma, and endocervical adenocarcinoma.

[0346] In one embodiment, the present disclosure provides use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of comprising the compound, in the manufacture of a medicament for treating cancer. In one embodiment, wherein the cancer is treatable by inhibition of WRN. In one embodiment, the cancer is characterized by MSI-H and / or dMMR.

[0347] In another embodiment, the present disclosure provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of comprising the compound, for use a method of treatment. In another embodiment, the present disclosure provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of comprising the compound, for use in treating cancer. In one embodiment, wherein the cancer is treatable by inhibition of WRN. In one embodiment, the cancer is characterized by MSI-H and / or dMMR.

[0348] In some embodiments, the disclosure provides methods of modulating WRN activity in a subject, wherein the method comprising administering to the patient a therapeutically effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the disclosure.

[0349] In some embodiments, the disclosure provides methods of inhibiting WRN in a subject, wherein the method comprises administering to the patient a therapeutically effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the disclosure.

[0350] In some embodiments, the disclosure provides methods of treating a disorder or disease which can be treated by WRN inhibition in a subject, wherein the method comprises administering to the patient a therapeutically effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the disclosure.120039.000211 (TYRA041PCT)

[0351] In some embodiments, the disclosure provides methods of treating a cancer in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the disclosure.

[0352] In some embodiments of the disclosed methods, the cancer is characterized as microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR).

[0353] In some embodiments of the disclosed methods, the cancer is colorectal, gastric, rectal, prostate, endometrial, adrenocortical, uterine, cervical, endocervical, esophageal, breast, kidney, or ovarian cancer.

[0354] Combination Therapy

[0355] The present disclosure contemplates the use of compounds of Formula (I), or a pharmaceutically acceptable salt thereof in combination with one or more active therapeutic agents (e.g., chemotherapeutic agents) or other prophylactic or therapeutic modalities (e.g., radiation). In such combination therapy, the various active agents frequently have different, complementary mechanisms of action. Such combination therapy may be especially advantageous by allowing a dose reduction of one or more of the agents, thereby reducing or eliminating the adverse effects associated with one or more of the agents.Furthermore, such combination therapy may have a synergistic therapeutic or prophylactic effect on the underlying disease, disorder, or condition.

[0356] As used herein, “combination” is meant to include therapies that can be administered separately, for example, formulated separately for separate administration (e.g., as may be provided in a kit), and therapies that can be administered together in a single formulation (i.e., a “co-formulation”).

[0357] In certain embodiments, the compounds of Formula (I), or a pharmaceutically acceptable salt thereof are administered or applied sequentially, e.g., where one agent is administered prior to one or more other agents. In other embodiments, the compounds of Formula (I), or a pharmaceutically acceptable salt thereof are administered simultaneously, e.g., where two or more agents are administered at or about the same time; the two or more agents may be present in two or more separate formulations or combined into a single formulation (i.e., a coformulation). Regardless of whether the two or more agents are120039.000211 (TYRA041PCT)administered sequentially or simultaneously, they are considered to be administered in combination for purposes of the present disclosure.

[0358] The compounds of Formula (I), or a pharmaceutically acceptable salt thereof may be used in combination with at least one other (active) agent in any manner appropriate under the circumstances.

[0359] In other embodiments, treatment with the at least one active agent and at least one compound of Formula (I), or a pharmaceutically acceptable salt thereof is maintained over a period of time.

[0360] In other embodiments, treatment with the at least one active agent is reduced or discontinued (e.g., when the subject is stable), while treatment with the compound of Formula (I), or a pharmaceutically acceptable salt thereof is maintained at a constant dosing regimen.

[0361] In other embodiments, treatment with the at least one active agent is reduced or discontinued (e.g., when the subject is stable), while treatment with a compound of Formula (I), or a pharmaceutically acceptable salt thereof is reduced (e.g., lower dose, less frequent dosing or shorter treatment regimen).

[0362] In other embodiments, treatment with the at least one active agent is reduced or discontinued (e.g., when the subject is stable), and treatment with the compound of Formula (I), or a pharmaceutically acceptable salt thereof is increased (e.g., higher dose, more frequent dosing or longer treatment regimen).

[0363] In other embodiments, treatment with the at least one active agent is maintained and treatment with the compound of Formula (I), or a pharmaceutically acceptable salt thereof is reduced or discontinued (e.g., lower dose, less frequent dosing or shorter treatment regimen).

[0364] In other embodiments, treatment with the at least one active agent and treatment with the compound of Formula (I), or a pharmaceutically acceptable salt thereof are reduced or discontinued (e.g., lower dose, less frequent dosing or shorter treatment regimen).AspectsAspect 1. A compound of Formula (I):-n -120039.000211 (TYRA041PCT)or5(I),or a pharmaceutically acceptable salt thereof,wherein:~ — is a single bond or a double bond;X is N, or CH;R is:R1Ais H, C1-C3alkyl, C3-C5cycloalkyl, CH2-O-C1-C3alkyl; or 5-6 membered heteroaryl;R1Bis H; or Ci-C3alkyl;or R1Aand R1B, together with the carbon atom to which they are both attached, form a 3-6 membered cycloalkyl ring;120039.000211 (TYRA041PCT)R1Cis H, C1-C3alkyl, C3-C5cycloalkyl, CH2-O-C1-C3alkyl; or 5-6 membered heteroaryl;R1Dis H; or Ci-C3alkyl;or R1Cand R1D, together with the nitrogen atom to which they are both attached, form a 3-6 membered heterocycloalkyl ring;R2is Ci-C3alkyl, Ci-C3haloalkyl, N(Ci-C3alkyl)2, NH(Ci-C3alkyl), optionally substituted 3-6 membered heterocycloalkyl, NH-(Ci-C3alk)- N(Ci-C3alkyl)2, NH-(Ci-C3alk)-NH(Ci-C3alkyl), N(Ci-C3alkyl)-(Ci- C3alk)-N(Ci-C3alkyl)2, or N(Ci-C3alkyl)-(Ci-C3alk)-NH(Ci-C3alkyl); NH2;R3is H, CN, C1-C6alkyl, C3-C6cycloalkyl, -OC1-C6alkyl, -OC3-C6cycloalkyl, -SC1-C6alkyl, -SC3-C6cycloalkyl, -NHC1-C6alkyl, -NHC3-C6cycloalkyl, -NHC(O)C1-C6alkyl, -NHC(O)C3-C6cycloalkyl, F, Cl,wherein the C1-C6alkyl or C3-C6cycloalkyl groups in R3are optionally substituted with one or more halo, C3-C5cycloalkyl, or C3-C5halocycloalkyl;R4is H, Ci-Cealkyl, C3-C7cycloalkyl, -OCi-C6alkyl, -OC3-C7cycloalkyl, -SCi- Cealkyl, -SC3-C7cycloalkyl, -NHCi-Cealkyl, -NHC3-C7cycloalkyl, -NHC(O)Ci- Cealkyl, - NHC(O)C3-C7cycloalkyl, C(O) NHCi-Cealkyl, -O-(3-7-membered heterocycloalkyl), -CH=CHalkyl, -CH=CH(C3-C7cycloalkyl), -C≡Calkyl, - C=C(C3-C7cycloalkyl), -CHCC(Ci-C3alkyl)2OH, CHCC(Ci-C3alkyl)20alkylwherein the C1-C6alkyl or C3-C7cycloalkyl groups in R4are optionally substituted with one or more halo, OH, OMe, CN, C1-C6alkyl, C3-C5cycloalkyl, or C3-C5halocycloalkyl;or R3and R4, together with the atoms to which they are attached, form an optionally substituted C5-C6cycloalkyl ring that is fused to Ring A, an optionally substituted 6-membered aryl ring that is fused to Ring A, or an optionally substituted 5-6 membered heteroaryl ring that is fused to ring A,120039.000211 (TYRA041PCT)wherein the optionally substituted C5-C6cycloalkyl ring, optionally substituted 6-membered aryl ring, or optionally substituted 5-6 membered heteroaryl ring formed by R3and R4is optionally substituted with C1-C6alkyl, C3-C6cycloalkyl, -OC1-C6alkyl, -OC3-C6cycloalkyl, -SC1-C6alkyl, -SC3-C6cycloalkyl, -NHC1-C6alkyl, -NHC3-C6cycloalkyl, -NHC(O)C1-C6alkyl, -NHC(O)C3-C6cycloalkyl, wherein the C1-C6alkyl or C3-C6cycloalkyl groups in the optional substituents are themselves optionally substituted with one or more halo, C3-C5cycloalkyl, or C3-C5halocycloalkyl.R5is optionally substituted aryl, optionally substituted 5-6 membered heteroaryl, optionally substituted C3-C6cycloalkyl ring;R6is H, halo, CN, or Ci-C3alkyl.Aspect 2. The compound of aspect 1, wherein - is a single bond.Aspect 3. The compound of aspect 1, wherein ~ — is a double bond.Aspect 4. The compound of any preceding aspect, wherein R5is optionally substituted aryl.Aspect 5. The compound of aspect 4, wherein R5is phenyl.Aspect 6. The compound of aspect 4, wherein R5is fluorophenyl.Aspect 7. The compound of any one of the preceding aspects, wherein R3is H, or C1-C6alkyl, wherein the C1-C6alkyl is optionally substituted with C3-C5cycloalkyl.Aspect 8. The compound of aspect 7, wherein R3is H.Aspect 9. The compound of aspect 7, wherein R3is C1-C6alkyl optionally substituted with C3-C5cycloalkyl.Aspect 10. The compound of aspect 9, wherein R3is:Aspect 11. The compound of any preceding aspect, wherein R4is H; C1-C6alkyl optionally substituted with one or more halo, C3-C5cycloalkyl, or C3-120039.000211 (TYRA041PCT)C₅halocycloalkyl; -OC₁-C₆alkyl optionally substituted with C₃-C₅cycloalkyl; -OC₃-C₇cycloalkyl optionally substituted with one or more halo, or C₁-C₆alkyl; -SC₁-C₆alkyl, -SC₃-C₆cycloalkyl, -NHC₁-C₆alkyl, -NHC₃-C₆cycloalkyl, -NHC(O)C₁-C₆alkyl, - NHC(O)C₃-C₆cycloalkyl, C(O) NHC₁-C₆alkyl.Aspect 12. The compound of aspect 11, wherein R4is H.Aspect 13. The compound of aspect 11, wherein R4is C₁-C₆alkyl optionally substituted with one or more halo, C₃-C₅cycloalkyl, or C₃-C₅halocycloalkyl.Aspect 14. The compound of aspect 13, wherein R4is C₁-C₆alkyl optionally substituted with one or more halo or C₃-C₅cycloalkyl.Aspect 15. The compound of aspect 14, wherein R4isAspect 16. The compound of aspect 11, wherein R4is -OC₁-C₆alkyl optionally substituted with one or more halo, or C₃-C₅cycloalkyl, wherein the C₃-C₅cycloalkyl is optionally substituted with on or more halo.Aspect 17. The compound of aspect 16, wherein R4is:.0 oo F120039.000211 (TYRA041PCT)Aspect 18. The compound of aspect 11, wherein R4is -OC3-C7cycloalkyl optionally substituted with one or more halo or Ci-Cealkyl.Aspect 19. The compound of aspect 18, wherein R4is:Aspect 20. The compound of aspect 11, wherein R4is -SC3-C7cycloalkyl.Aspect 21. The compound of aspect 20, wherein R4is:Aspect 22. The compound of aspect 11, wherein R4is -NHC₁-C₆alkyl or -NHC₃-C₇cycloalkyl.Aspect 23. The compound of aspect 22, wherein R4is:Aspect 24. The compound of aspect 11, wherein R4is -NHC(O)Ci-C6alkyl or - NHC(O)C3-C7cycloalkyl, each optionally substituted with one or more halo or C3- Cecycloalkyl groups.Aspect 25. The compound of aspect 24, wherein R4is:120039.000211 (TYRA041PCT)Aspect 26. The compound of any one of aspects 1-6, wherein R3and R4, together with the atoms to which they are attached, form an optionally substituted C5-C6cycloalkyl ring that is fused to Ring A; an optionally substituted 6-membered aryl ring that is fused to Ring A; or an optionally substituted 5-6 membered heteroaryl ring that is fused to ring A,wherein the optionally substituted Cs-Cecycloalkyl ring, optionally substituted 6- membered aryl ring, or optionally substituted 5-6 membered heteroaryl ring formed by R3and R4is optionally substituted with C₁-C₆alkyl, C₃-C₆cycloalkyl, -OC₁-C₆alkyl, -OC₃-C₆cycloalkyl, -SC₁-C₆alkyl, -SC₃-C₆cycloalkyl, -NHC₁-C₆alkyl, -NHC₃-C₆cycloalkyl, -NHC(O)C₁-C₆alkyl, - NHC(O)C₃-C₆cycloalkyl, wherein the C₁-C₆alkyl or C₃-C₆cycloalkyl groups in the optional substituents are themselves optionally substituted with one or more halo, C₁-C₆alkyl, C₃-C₅cycloalkyl, or -C₃-C₅halocycloalkyl.Aspect 27. The compound of aspect 26, wherein R3and R4, together with the atoms to which they are attached, form an optionally substituted C5-C6cycloalkyl ring that is fused to Ring A.Aspect 28. The compound of aspect 27, wherein the compound has the formula IA:OR5(IA).Aspect 29. The compound of aspect 28, wherein the compound has the formula IA-1:OR5(IA-1).Aspect 30. The compound of aspect 26, wherein R3and R4, together with the atoms to which they are attached, form an optionally substituted 6-membred aryl ring that is fused to Ring A.120039.000211 (TYRA041PCT)Aspect 31. The compound of aspect 30, wherein the compound has the formula IB:OR5(IB).Aspect 32. The compound of aspect 26, wherein R3and R4, together with the atoms to which they are attached, form an optionally substituted 5-6 membered heteroaryl ring that is fused to ring A.Aspect 33. The compound of aspect 32, wherein the compound has the formula IC:OR5(IC),a. wherein Y is N or CH, andb. R7is Ci-Cealkyl, Cs-Cecycloalkyl, 3-6-membered heterocycloalkyl, -OCi- Cealkyl, -OC3-C6cycloalkyl, -SCi-Cealkyl, -SCs-Cecycloalkyl, -NHC₁-C₆alkyl, -NHC₃-C₆cycloalkyl, -NHC(O)C₁-C₆alkyl, - NHC(O)C₃-C₆cycloalkyl, wherein the C₁-C₆alkyl or C₃-C₆cycloalkyl groups are optionally substituted with one or more halo, C₃-C₅cycloalkyl, or C₃-C₅halocycloalkyl.Aspect 34. The compound of aspect 33, wherein Y is N.Aspect 35. The compound of aspect 33, wherein Y is CH.Aspect 36. The compound of any one of aspects 33-35, wherein R7is C₁-C₆alkyl optionally substituted with one or more halo, C₃-C₅cycloalkyl, or C₃-C₅halocycloalkyl.Aspect 37. The compound of aspect 36, wherein R7is -CH2CH3, -CH(CH)2, -C(CH3)3, - CF3, -CF2CH3, -CF2CF3, or -CF2CH2CH3.Aspect 38. The compound of any one of aspects 33-35, wherein R7is Cs-Cecycloalkyl optionally substituted with one or more halo or Ci-Cealkyl.120039.000211 (TYRA041PCT)Aspect 39. The compound of aspect 38, wherein R7is. orAspect 40. The compound of any one of aspects 33-35, wherein R7is 3-6-membered heterocycloalkyl.Aspect 41. The compound of aspect 40, wherein R7is□n■" 0Aspect 42. The compound of any one of aspects 33-35, wherein R7is NHC(O)C1-C6alkyl or -NHC(O)C3-C6cycloalkyl, wherein the C1-C6alkyl is optionally substituted with one or more halo or C3-C6cycloalkyl.Aspect 43. The compound of aspect 42, wherein R7isAspect 44. The compound of any one of aspects 1-43, wherein R is120039.000211 (TYRA041PCT)Aspect 45. The compound of any one of aspects 1-43, wherein R isAspect 46. The compound of aspect 45, wherein R2is CH3.Aspect 47. The compound of aspect 45, wherein R2is NHCH3.Aspect 48. The compound of aspect 45, wherein R2is N(CH3)2.Aspect 49. The compound of aspect 45, wherein R2isNAspect 50. The compound of aspect 45, wherein R2isNNAspect 51. The compound of aspect 45, wherein R2is N(Ci-C3alkyl)-(Ci-C3alk)-N(Ci- C3alkyl)2.Aspect 52. The compound of aspect 51, wherein R2is N(CH3)-CH2CH2-N(CH3)2.Aspect 53. The compound of any one of aspects 45-52, wherein R1Ais Cs-Cscycloalkyl. Aspect 54. The compound of any one of aspects 45-52, wherein R1Ais Ci-Csalkyl. Aspect 55. The compound of any one of aspects 45-52, wherein R1Ais CH2-O-C1- Csalkyl.Aspect 56. The compound of any one of aspects 45-55, wherein R1Bis C1-C3alkyl. Aspect 57. The compound of any one of aspects 45-55, wherein R1Bis H.Aspect 58. The compound of any one of aspects 45-52, wherein R1Aand R1B, together with the carbon atom to which they are both attached, form a 3-6 membered cycloalkyl ring.Aspect 59. The compound of aspect 58, wherein R1Aand R1B, together with the carbon atom to which they are both attached, form a cyclopropyl ring.120039.000211 (TYRA041PCT)Aspect 60. The compound of any one of aspects 45-59, wherein R6is H.Aspect 61. The compound of any one of aspects 45-59, wherein R6is CH₃.Aspect 62. The compound of aspect 1, or a pharmaceutically acceptable salt thereof, wherein the compound is:(E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-8-phenyl-2- (trifluoromethyl)pyrimido[4,5-d]pyridazin-5(6H)-one;(S, E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-8-phenyl-2- (trifluoromethyl)pyrimido[4,5-d]pyridazin-5(6H)-one;(R, E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-8-phenyl-2- (trifluoromethyl)pyrimido[4,5-d]pyridazin-5(6H)-one;(E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(l,l-difluoroethyl)-8- phenylpyrimido[4,5-d]pyridazin-5(6H)-one;(R, E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(l,l-difluoroethyl)-8- phenylpyrimido[4,5-d]pyridazin-5(6H)-one;(S, E)-6-( 1 -cyclopropyl -3 -(methylsulfonyl)allyl)-2-( 1, 1 -difluoroethyl)-8- phenylpyrimido[4,5-d]pyridazin-5(6H)-one;(E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-8-phenyl-2- (trifluoromethyl)pyrimido[4,5-d]pyridazin-5(6H)-one;(S, E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-8-phenyl-2- (trifluoromethyl)pyrimido[4,5-d]pyridazin-5(6H)-one;(R, E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-8-phenyl-2- (trifluoromethyl)pyrimido[4,5-d]pyridazin-5(6H)-one;(E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(l,l-difluoroethyl)-8- phenylpyrimido[4,5-d]pyridazin-5(6H)-one;(R, E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(l,l-difluoroethyl)-8- phenylpyrimido[4,5-d]pyridazin-5(6H)-one;(S, E)-6-( 1 -cyclopropyl -3 -(methylsulfonyl)allyl)-2-( 1, 1 -difluoroethyl)-8- phenylpyrimido[4,5-d]pyridazin-5(6H)-one;(E)-2-cyclobutyl-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-8- phenylpyrimido[4,5-d]pyridazin-5(6H)-one;120039.000211 (TYRA041PCT)(R, E)-2-cyclopropyl-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-8- phenylpyrimido[4,5-d]pyridazin-5(6H)-one;(S, E)-2-cyclopropyl-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-8- phenylpyrimido[4,5-d]pyridazin-5(6H)-one;(E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-ethyl-8-phenylpyrimido[4,5- d]pyridazin-5(6H)-one;(E)-2-cyclopentyl-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-8- phenylpyrimido[4,5-d]pyridazin-5(6H)-one;(R, E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(perfluoroethyl)-8- phenylpyrimido[4,5-d]pyridazin-5(6H)-one;(S, E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(perfluoroethyl)-8- phenylpyrimido[4,5-d]pyridazin-5(6H)-one;(R, E)-2-cyclobutyl-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-8- phenylpyrimido[4,5-d]pyridazin-5(6H)-one;(S, E)-2-cyclobutyl-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-8- phenylpyrimido[4,5-d]pyridazin-5(6H)-one;(R, E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-ethyl-8-phenylpyrimido[4,5- d]pyridazin-5(6H)-one;(S, E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-ethyl-8-phenylpyrimido[4,5- d]pyridazin-5(6H)-one;(R, E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-isopropyl-8- phenylpyrimido[4,5-d]pyridazin-5(6H)-one;(S, E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-isopropyl-8- phenylpyrimido[4,5-d]pyridazin-5(6H)-one;(E)-2-( 1, 1 -difluoroethyl)-6-(4-methyl- 1 -(methyl sulfonyl)pent- 1 -en-3 -y 1 ) - 8 - phenylpyrimido[4,5-d]pyridazin-5(6H)-one;(E)-2-( 1, 1 -difluoroethyl)-6-( 1 -(methyl sulfonyl)pent- 1 -en-3 -y 1 ) - 8 - phenylpyrimido[4,5-d]pyridazin-5(6H)-one;(E)-2-(l,l-difluoroethyl)-6-(4-(methylsulfonyl)but-3-en-2-yl)-8- phenylpyrimido[4,5-d]pyridazin-5(6H)-one;(E)-2-(l-cy clopropyl-3-(methylsulfonyl)allyl)-4-phenyl-5, 6,7,8- tetrahydrophthalazin- 1 (2H)-one;120039.000211 (TYRA041PCT)(R, E)-2-cyclopentyl-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-8- phenylpyrimido[4,5-d]pyridazin-5(6H)-one;(S, E)-2-cyclopentyl-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-8- phenylpyrimido[4,5-d]pyridazin-5(6H)-one;(E)-2-(l,l-difluoroethyl)-6-(2-methyl-4-(methylsulfonyl)but-3-en-2-yl)-8- phenylpyrimido[4,5-d]pyridazin-5(6H)-one;(E)-2-(l,l-difluoroethyl)-6-(l-methoxy-4-(methylsulfonyl)but-3-en-2-yl)-8- phenylpyrimido[4,5-d]pyridazin-5(6H)-one;(R, E)-2-(tert-butyl)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-8- phenylpyrimido[4,5-d]pyridazin-5(6H)-one;(S, E)-2-(tert-butyl)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-8- phenylpyrimido[4,5-d]pyridazin-5(6H)-one;(E)-6-(l-cyclobutyl-3-(methylsulfonyl)allyl)-2-(l,l-difluoroethyl)-8- phenylpyrimido[4,5-d]pyridazin-5(6H)-one;(E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-4-phenylphthalazin-l(2H)-one; (S, E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(l-methylcyclopropyl)-8- phenylpyrimido[4,5-d]pyridazin-5(6H)-one;(R, E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(l-methylcyclopropyl)-8- phenylpyrimido[4,5-d]pyridazin-5(6H)-one;(E)-6-(4-(methylsulfonyl)but-3-en-2-yl)-2-(perfluoroethyl)-8-phenylpyrimido[4,5- d]pyridazin-5(6H)-one;(E)-6-(l-(methylsulfonyl)pent-l-en-3-yl)-2-(perfluoroethyl)-8- phenylpyrimido[4,5-d]pyridazin-5(6H)-one;(E)-6-(l-methoxy-4-(methylsulfonyl)but-3-en-2-yl)-2-(perfluoroethyl)-8- phenylpyrimido[4,5-d]pyridazin-5(6H)-one;(E)-6-(l-cyclobutyl-3-(methylsulfonyl)allyl)-2-(perfluoroethyl)-8- phenylpyrimido[4,5-d]pyridazin-5(6H)-one;(E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(l,l-difluoroethyl)-8-(4- fluorophenyl)pyrimido[4,5-d]pyridazin-5(6H)-one;(E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(l-fluorocyclopropyl)-8- phenylpyrimido[4,5-d]pyridazin-5(6H)-one;120039.000211 (TYRA041PCT)(E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(l,l-difluoroethyl)-8-(2- fluorophenyl)pyrimido[4,5-d]pyridazin-5(6H)-one;(E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(l,l-difluoropropyl)-8- phenylpyrimido[4,5-d]pyridazin-5(6H)-one;(E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(l,l-difluoroethyl)-8-(3- fluorophenyl)pyrimido[4,5-d]pyridazin-5(6H)-one;(E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-8-phenyl-2-(l- (trifluoromethyl)cyclopropyl)pyrimido[4,5-d]pyridazin-5(6H)-one; (E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(2,2-difluorocyclopropyl)-8- phenylpyrimido[4,5-d]pyridazin-5(6H)-one;(E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(3,3-difluorocyclobutyl)-8- phenylpyrimido[4,5-d]pyridazin-5(6H)-one;(R, E)-2-(azetidin-l-yl)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-8- phenylpyrimido[4,5-d]pyridazin-5(6H)-one;(S, E)-2-(azetidin-l-yl)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-8- phenylpyrimido[4,5-d]pyridazin-5(6H)-one;(R, E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-8-phenyl-2-(pyrrolidin-l- yl)pyrimido[4,5-d]pyridazin-5(6H)-one;(S, E)-7-(azetidin-l-yl)-3-(l-cyclopropyl-3-(methylsulfonyl)allyl)-l- phenylpyrido[3,4-d]pyridazin-4(3H)-one;(S, E)-7-(azetidin-l-yl)-3-(l-cyclopropyl-3-(methylsulfonyl)allyl)-l- phenylpyrido[3,4-d]pyridazin-4(3H)-one;(R, E)-7-(azetidin- 1 -y l)-3 -( 1 -cy clopropyl-3 -(methyl sulfonyl)allyl)- 1 - phenylpyrido[3,4-d]pyridazin-4(3H)-one;(E)-5-(cyclopentylmethyl)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6- phenylpyridazin-3(2H)-one;(E)-5-(cyclopentyloxy)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6- phenylpyridazin-3(2H)-one;(E)-2-(l,l-difluoroethyl)-6-(l-(2-(methylsulfonyl)vinyl)cyclopropyl)-8- phenylpyrimido[4,5-d]pyridazin-5(6H)-one;(E)-3-cyclopropyl-3-(2-(l,l-difluoroethyl)-5-oxo-8-phenylpyrimido[4,5- d]pyridazin-6(5H)-yl)-N, N-dimethylprop- 1 -ene- 1 -sulfonamide;120039.000211 (TYRA041PCT)(E)-6-(l-cyclopropyl-3-(morpholinosulfonyl)allyl)-2-(l,l-difluoroethyl)-8- phenylpyrimido[4,5-d]pyridazin-5(6H)-one;(E)-3-cyclopropyl-3-(2-(l,l-difluoroethyl)-5-oxo-8-phenylpyrimido[4,5- d]pyridazin-6(5H)-yl)-N-methylprop- 1 -ene- 1 -sulfonamide;(S, E)-6-( 1 -cyclopropyl -3 -(methylsulfonyl)allyl)-2-( 1, 1 -difluoroethyl)-8- phenylpyrido[2,3-d]pyridazin-5(6H)-one;(R, E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(l,l-difluoroethyl)-8- phenylpyrido[2,3-d]pyridazin-5(6H)-one;(E)-5-Cyclobutoxy-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6-phenylpyridazin- 3(2H)-one;(E)-5-(cyclopentyloxy)-2-(4-(methylsulfonyl)but-3-en-2-yl)-6-phenylpyridazin- 3(2H)-one;(E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(cyclopropylmethoxy)-6- phenylpyridazin-3(2H)-one;(E)-7-Cyclopropyl-3-(l-cyclopropyl-3-(methylsulfonyl)allyl)-l-phenylpyrido[3,4- d]pyridazin-4(3H)-one;(E)-5-(Cyclopentylmethyl)-2-(4-(methylsulfonyl)but-3-en-2-yl)-6- phenylpyridazin-3(2H)-one;(E)-3-Cyclopropyl-3-(2-(l,l-difluoroethyl)-5-oxo-8-phenylpyrimido[4,5- d]pyridazin-6(5H)-yl)-N-(2-(dimethylamino)ethyl)-N-methylprop-l-ene-l- sulfonamide;(E)-6-( 1 -cy clopropyl-3 -((4-methylpiperazin- 1 -yl)sulfonyl)allyl)-2-( 1,1- difluoroethyl)-8-phenylpyrimido[4,5-d]pyridazin-5(6H)-one;(E)-l-(l-Cyclopropyl-3-(methylsulfonyl)allyl)-4-(cyclopropylmethoxy)-5- phenylpyridin-2(lH)-one;(E)-4-(Cyclopentyloxy)-l-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5- phenylpyridin-2(lH)-one;(E)-5-(Cyclopentyloxy)-2-(3-(methylsulfonyl)allyl)-6-phenylpyridazin-3(2H)-one; (S, E)-5-(cyclopentyloxy)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6- phenylpyridazin-3(2H)-one;(R, E)-5-(cyclopentyloxy)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6- phenylpyridazin-3(2H)-one;120039.000211 (TYRA041PCT)(R, E)-5-(cyclopentylmethyl)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6- phenylpyridazin-3(2H)-one;(S, E)-5-(cyclopentylmethyl)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6- phenylpyridazin-3(2H)-one;(E)-5-(cyclobutylmethyl)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6- phenylpyridazin-3(2H)-one;(E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(perfluoropropyl)-6- phenylpyridazin-3(2H)-one;(E)-4-(cyclopentylmethyl)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6- phenylpyridazin-3(2H)-one;(E)-5-(cyclopentylmethoxy)-2-(4-(methylsulfonyl)but-3-en-2-yl)-6- phenylpyridazin-3(2H)-one; or(E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6-phenyl-5-propoxypyridazin- 3(2H)-one.Aspect 63. A pharmaceutical composition comprising a compound of any one of aspects 1 to 62, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.Aspect 64. A method of modulating WRN activity in a subject, wherein the method comprising administering to the patient a therapeutically effective amount of a compound of any one of aspects 1 to 62 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of aspect 63.Aspect 65. A method of inhibiting WRN in a subject, wherein the method comprises administering to the patient a therapeutically effective amount of a compound of any one of aspects 1 to 62 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of aspect 63.Aspect 66. A method of treating a disorder or disease which can be treated by WRN inhibition in a subject, wherein the method comprises administering to the patient a therapeutically effective amount of a compound of any one of aspects 1 to 62 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of aspect 63.120039.000211 (TYRA041PCT)Aspect 67. A method of treating a cancer in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound of any one of aspects 1 to 62 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of aspect 63.Aspect 68. The method of aspect 67, wherein the cancer is characterized as microsatellite instability -high (MSI-H) or mismatch repair deficient (dMMR).Aspect 69. The method of aspect 67 or aspect 68, wherein the cancer is colorectal, gastric, rectal, prostate, endometrial, adrenocortical, uterine, cervical, endocervical, esophageal, breast, kidney, or ovarian cancer.Examples

[0365] The examples and preparations provided below further illustrate and exemplify the compounds of the present invention and methods of preparing such compounds. It is to be understood that the scope of the present invention is not limited in any way by the scope of the following examples and preparations.Example 1. (E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-8-phenyl-2- (trifluoromethyl)pyrimido[4,5-d]pyridazin-5(6H)-one120039.000211 (TYRA041PCT)A

[0366] Step 1. Ethyl 2-(trifluoromethyl)-4-(trimethylstannyl)pyrimidine-5-carboxylate. To a solution of ethyl 4-chloro-2-(trifluoromethyl)pyrimidine-5-carboxylate (4.0 g, 15.71 mmol, 1.0 eq) in toluene (80 mL) was added hexamethyldistannane (6.18 g, 18.85 mmol, 1.2 eq) and tetrakis(triphenylphosphine)palladium(0) (891 mg, 0.786 mmol, 0.05 eq) and the resulting mixture was stirred at 105 °C for 16 h. The mixture was concentrated under reduced pressure, and the crude material was purified by silica gelchromatography (petroleum ether / ethyl acetate = 30 / 1) to give ethyl 2-(trifluoromethyl)-4-(trimethylstannyl)pyrimidine-5-carboxylate (2.4 g, 40% yield) as colorless oil. LCMS m / z = 385.0 (M + 1).

[0367] Step 2. Ethyl 4-benzoyl-2-(trifluoromethyl)pyrimidine-5-carboxylate. To a solution of ethyl 2-(trifluoromethyl)-4-(trimethylstannyl)pyrimidine-5-carboxylate (3.8 g, 9.92 mmol, 1.0 eq) in toluene (100 mL) was added benzoyl chloride (2.0 eq)and tetrakis(triphenylphosphine)palladium(0) (1.12 g, 0.992 mmol, 0.1 eq), and the resulting mixture was stirred at 105 °C for 16 h. The mixture was then concentrated under reduced pressure, and the residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 20 / 1) to give ethyl 4-benzoyl-2-(trifluoromethyl)pyrimidine-5-carboxylate (930 mg, 29% yield) as colorless oil. LCMS m / z = 325.1 (M + 1).

[0368] Step 3. 8-Phenyl-2-(trifluoromethyl)pyrimido[4,5-d]pyridazin-5(6H)-one. To a solution of ethyl 4-benzoyl-2-(trifluoromethyl)pyrimidine-5-carboxylate (930 mg, 2.87 mmol, 1.0 eq) in ethanol (15 mL) was added hydrazine hydrate (717 mg, 14.34 mmol, 5.0 eq), and the resulting mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with water, and the ethanol removed under reduced pressure. The resulting solid was collected by filtration and washed with water (3 x 3 mL), then dried under vacuum to give 8-phenyl-2-(trifluoromethyl)pyrimido[4,5-d]pyridazin-5(6H)-one (700 mg, 84% yield) as a yellow solid. LCMS m / z = 293.1 (M + 1).

[0369] Step 4. Ethyl 2-cyclopropyl-2-(5-oxo-8-phenyl-2-(trifluoromethyl)pyrimido[4,5-d]pyridazin-6(5H)-yl)acetate.

[0370] To a solution of 8-phenyl-2-(trifluoromethyl)pyrimido[4,5-d]pyridazin-5(6H)-one (700 mg, 2.40 mmol, 1.0 eq) in N, N-dimethylformamide (15 mL) was added ethyl120039.000211 (TYRA041PCT)2-bromo-2-cyclopropylacetate (992 mg, 4.79 mmol, 2.0 eq) and cesium carbonate (2.34 g, 7.19 mmol, 3.0 eq), and the resulting mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with ethyl acetate, washed with water, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate = 5 / 1) to give ethyl 2-cyclopropyl-2-(5 -oxo-8 -phenyl-2-(trifluoromethyl)pyrimido[4, 5 -d]pyridazin-6(5H)-yl)acetate (850 mg, 85% yield) as off-white solid. LCMS m / z = 419.1 (M + 1).

[0371] Step 5. 2-Cyclopropyl-2-(5-oxo-8-phenyl-2-(trifluoromethyl)pyrimido[4,5-d]pyridazin-6(5H)-yl)acetic acid. To a solution of ethyl 2-cyclopropyl-2-(5-oxo-8-phenyl-2-(trifluoromethyl)pyrimido[4,5-d]pyridazin-6(5H)-yl)acetate (800 mg, 1.91 mmol, 1.0 eq) in 1,4-dioxane (10 mL) was added aqueous hydrochloric acid (6 N, 10 mL), and the resulting mixture was stirred at 80 °C for 24 h. After cooling, the reaction mixture was concentrated under reduced pressure and the residue was subjected to reverse phase preparative MPLC (Prep-C18, 20-45 pM, 120 g, Tianjin Bonna-Agela Technologies; gradient elution of 15% acetonitrile in water to 85% acetonitrile in water over a 14 min period, where both solvents contain 0.1% formic acid) to give 2-cyclopropyl-2-(5-oxo-8-phenyl-2-(trifluoromethyl)pyrimido[4,5-d]pyridazin-6(5H)-yl)acetic acid (500 mg, 67% yield) as an off-white solid. LCMS m / z = 391.0 (M + 1).

[0372] Step 6. S-Ethyl 2-cyclopropyl-2-(5-oxo-8-phenyl-2-(trifluoromethyl)pyrimido[4,5-d]pyridazin-6(5H)-yl)ethanethioate. To a solution of 2-cyclopropyl-2-(5-oxo-8-phenyl-2-(trifluoromethyl)pyrimido[4,5-d]pyridazin-6(5H)-yl)acetic acid (200 mg, 0.512 mmol, 1.0 eq) in anhydrous dichloromethane (8 mL) was added thionyl chloride (305 mg, 2.56 mmol, 5.0 eq), and the resulting mixture was stirred at 50 °C for 1 h. The reaction mixture was cooled and concentrated under reduced pressure, then redissolved in anhydrous dichloromethane (10 mL), and ethanethiol (190 mg, 3.06 mmol, 6.0 eq) and N, N-diisopropylethylamine (395 mg, 3.06 mmol, 6.0 eq) were added to the solution. The resulting mixture was stirred at room temperature for 3 h. The mixture was then concentrated under reduced pressure, and crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate = 3 / 1) to give S-ethyl 2-cyclopropyl-2-(5-oxo-8-phenyl-2-(trifluoromethyl)pyrimido[4,5-d]pyridazin-6(5H)-yl)ethanethioate (200 mg, 75% yield) as light yellow solid. LCMS m / z = 435.1 (M + 1).120039.000211 (TYRA041PCT)

[0373] Step 7. 2-Cyclopropyl-2-(5-oxo-8-phenyl-2-(trifluoromethyl)pyrimido[4,5-d]pyridazin-6(5H)-yl)acetaldehyde. To a solution of S-ethyl 2-cyclopropyl-2-(5-oxo-8-phenyl-2-(trifluoromethyl)pyrimido[4,5-d]pyridazin-6(5H)-yl)ethanethioate (180 mg, 0.414 mmol, 1.0 eq) in acetone (5 mL) was added triethylsilane (964 mg, 8.29 mmol, 20eq) and Pd / C (10%, 100 mg), and the resulting mixture was stirred at room temperature for 10 h. The reaction mixture was then filtered and the filtrate was concentrated under reduced pressure to afford 2-cyclopropyl-2-(5-oxo-8-phenyl-2-(trifluoromethyl)pyrimido[4,5-d]pyridazin-6(5H)-yl)acetaldehyde (600 mg) as light brown oil that was used without purification. LCMS m / z = 375.1 (M + 1).

[0374] Step 8. (E)-6-(l-Cyclopropyl-3-(methylsulfonyl)allyl)-8-phenyl-2-(trifluoromethyl)pyrimido[4,5-d]pyridazin-5(6H)-one. To a solution of 2-cyclopropyl-2-(5-oxo-8-phenyl-2-(trifluoromethyl)pyrimido[4,5-d]pyridazin-6(5H)-yl)acetaldehyde (600 mg, crude) and diethyl ((methylsulfonyl)methyl)phosphonate (432 mg, 1.88mmol) in tetrahydrofuran (10 mL) was added potassium carbonate (299 mg, 2.16 mmol), and the resulting mixture was stirred at 60 °C for 2 h. After cooling, the mixture was filtered and concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate = 2 / 1) to give (E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-8-phenyl-2-(trifluoromethyl)pyrimido[4,5-d]pyridazin-5(6H)-one (110 mg, 59% yield) as a white solid. LCMS m / z = 451.2 (M + 1);1H-NMR (400 MHz, DMSO-d6) δ 9.99 (s, 1H), 7.99-7.97 (m, 2H), 7.61-7.55 (m, 3H), 7.06-6.96 (m, 2H), 5.12 (dd, J = 10.0 Hz, 3.6 Hz, 1H), 3.02 (s, 3H), 1.63-1.58 (m, 1H), 0.77-0.72 (m, 2H), 0.59-0.41 (m, 2H).Example 2. (S, E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-8-phenyl-2-(trifluoromethyl)pyrimido[4,5-d]pyridazin-5(6H)-one, and Example 3 (R, E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-8-phenyl-2-(trifluoromethyl)pyrimido[4,5-d]pyridazin-5(6H)-one.

[0375] (E)-6-(l-Cyclopropyl-3-(methylsulfonyl)allyl)-8-phenyl-2-(trifluoromethyl)pyrimido[4,5-d]pyridazin-5(6H)-one from Example 1, step 8, was further purified by Prep-HPLC on a chiral stationary phase by the method outlined below to give (S, E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-8-phenyl-2-(trifluoromethyl)pyrimido[4,5-120039.000211 (TYRA041PCT)d]pyridazin-5(6H)-one, 24.6 mg, 13% yield) as a white solid; LCMS m / z = 451.2 (M + 1);1H-NMR (400 MHz, DMSO-d6) δ 9.99 (s, 1H), 7.99 (dd, J = 6.0 Hz, 2.4 Hz, 2H), 7.60-7.55 (m, 3H), 7.06-6.96 (m, 2H), 5.12 (dd, J= 10.0 Hz, 3.2 Hz, 1H), 3.02 (s, 3H), 1.63-1.58 (m, 1H), 0.78-0.72 (m, 2H), 0.63-0.53 (m, 1H), 0.48-0.37 (m, 1H) and (R, E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-8-phenyl-2-(trifluoromethyl)pyrimido[4,5-d]pyridazin-5(6H)-one, 26.8 mg, 14% yield) as a white solid. LCMS m / z = 451.2 (M + 1);1H-NMR (400 MHz, DMSO-d6) δ 9.99 (s, 1H), 7.99 (dd, J = 5.6 Hz, 2.4 Hz, 2H), 7.61-7.55 (m, 3H), 7.06-6.96 (m, 2H), 5.12 (dd, J= 10.0 Hz, 3.2 Hz, 1H), 3.02 (s, 3H), 1.64-1.58 (m, 1H), 0.78-0.72 (m, 2H), 0.59-0.45 (m, 1H), 0.44-0.35 (m, 1H). The enantiomers were randomly assigned, the absolute configuration was not determined.

[0376] Instrument Model: Prep- HPLC-Flash Brix 1860

[0377] Column Name: phenomenex Lux 5um i-Amylose-1 250x21.2mm

[0378] Mobile Phase: A: n-Hexane; B: Isopropanol

[0379] Isocratic elution: A: B=70:30 (V / V)

[0380] Total Flow: 18 mL / min

[0381] Column temp.: RT

[0382] RT (min) 11 min; 18 min120039.000211 (TYRA041PCT)Example 4. (E)-6-(l-Cyclopropyl-3-(methylsulfonyl)allyl)-2-(l,l-difluoroethyl)-8-phenylpyrimido[4,5-d]pyridazin-5(6H)-one.

[0383] Step 1. 2,2-Difluoropropanamide. To a solution of ethyl 2,2-difluoropropanoate (300.0 g, 2.172 mol, 1.0 eq) in ammonia methanol (500 mL, 7M) was stirred at room temperature for 16 h. The reaction mixture was then concentrated under reduced pressure to afford 2,2-difluoropropanamide (210.0 g, 87% yield) as a white solid. LCMS m / z = 110.0 (M + 1).

[0384] Step 2. 2,2-Difluoropropanimidamide. To a solution of 2,2-difluoropropanamide (210.0 g, 1.921 mol, 1.0 eq) and pyridine (304.5 g, 3.74 mol, 2.0 eq) in di chloromethane (2.0 L) was added trifluoroacetic anhydride (606.5 g, 2.887 mol, 1.5 eq) dropwise at 0 °C. The mixture reaction was stirred at 0 °C for 2 h to afford 2,2-difluoropropanenitrile. Ammonia methanol solution (1.3 L, 9.6 mol, 5.0 eq) was then added120039.000211 (TYRA041PCT)to the reaction mixture dropwise at 0 °C and the reaction was stirred at room temperature for 16 h to provide 2,2-difluoropropanimidamide that was used directly in the next step.

[0385] Step 3. Ethyl 2-(l,l-difluoroethyl)-4-hydroxypyrimidine-5-carboxylate. To a solution of the 2,2-difluoropropanimidamide from step 2 and diethyl 2-(ethoxymethylene)malonate (408.1 g, 1.887 mol, 1.5 eq) in ethanol (1.5 L) was added sodium ethoxide (256.6 g, 3.98 mol, 3.0 eq) at 0 °C. The reaction mixture was then warmed and stirred at 80 °C for 16 h. The mixture was cooled, and the pH was adjusted to ~6 by the addition of aqueous hydrochloric acid (1 M) and was extracted with dichloromethane (3 x 500 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to afford ethyl 2-(l,l-difluoroethyl)-4-hydroxypyrimidine-5-carboxylate (100.0 g, crude) as yellow oil. LCMS m / z = 233.3 (M + 1).

[0386] Step 4. Ethyl 4-chloro-2-(l,l-difluoroethyl)pyrimidine-5-carboxylate. A mixture of ethyl 2-(l,l-difluoroethyl)-4-hydroxypyrimidine-5-carboxylate (70.0 g, 301.5 mmol, 1.0 eq) and phosphorus oxychloride (184.5 g, 1.21 mol, 4.0 eq) in toluene (700 mL) was stirred at 100 °C for 4 h. The mixture was cooled and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10 / 1) to afford ethyl 4-chloro-2-(l,l-difluoroethyl)pyrimidine-5-carboxylate (35.0 g, 10% yield over four steps) as yellow oil. LCMS m / z = 251.2 (M + 1).

[0387] Step 5. Ethyl 4-benzoyl-2-(l,l-difluoroethyl)pyrimidine-5-carboxylate. To a solution of 4-chloro-2-(l,l-difluoroethyl)pyrimidine-5-carboxylate (28.0 g, 117.2 mmol, 1.0 eq), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (25.83 g, 44.69 mmol, 0.4 eq), palladium(II) acetate (5.02 g, 22.34 mmol, 0.2 eq) and 2-((tert-butyldimethylsilyl)oxy)-2-phenyl acetonitrile (35.93 g, 145.2 mmol, 1.3 eq) in tetrahydrofuran (1.5 L) was added lithium bis(trimethylsilyl)amide (152 mL, IM in tetrahydrofuran, 152.36 mmol, 1.3 eq) at -20 °C. The reaction mixture was stirred at room temperature for 16 h. Tetrabutylammonium fluoride (152 mL, IM in tetrahydrofuran, 152.36 mmol, 1.3 eq) was then added and the resulting mixture was stirred at room temperature for 4 h. The mixture was diluted with ethyl acetate (600 mL) and washed with water (3 x 200 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate = 6 / 1) to afford ethyl 4-benzoyl-2-(l,l-difluoroethyl)pyrimidine-5-carboxylate (14.0 g, 39% yield) as yellow oil. LCMS m / z = 321.1 (M + 1).120039.000211 (TYRA041PCT)

[0388] Step 6. 2-(l,l-Difluoroethyl)-8-phenylpyrimido[4,5-d]pyridazin-5(6H)-one. To a solution of ethyl 4-benzoyl-2-(l,l-difluoroethyl)pyrimidine-5-carboxylate (14.0 g, 43.7 mmol, 1.0 eq) in ethanol (150 mL) was added hydrazine hydrate (8.74 g, 174.8 mmol, 4.0 eq) and the reaction mixture was stirred at room temperature for 2 h. The mixture was then diluted with dichloromethane (200 mL) and washed with water (3 x 50 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate = 2 / 1) to afford 2-(l,l-difluoroethyl)-8-phenylpyrimido[4,5-d]pyridazin-5(6H)-one (9.0 g, 71% yield) as a yellow solid. LCMS m / z = 289.3 (M + 1).

[0389] Step 7. Ethyl 2-cyclopropyl-2-(2-(l,l-difluoroethyl)-5-oxo-8-phenylpyrimido[4,5-d]pyridazin-6(5H)-yl)acetate. To a mixture of 2-(l,l-difluoroethyl)-8-phenylpyrimido[4,5-d]pyridazin-5(6H)-one (2.0 g, 6.94 mmol, 1.0 eq) and cesium carbonate (6.74 g, 20.8 mmol, 3.0 eq) in N, N-dimethylformamide (8 mL) was added ethyl 2-bromo-2-cyclopropylacetate (2.87 g, 13.88 mmol, 2.0 eq) and the reaction mixture was stirred at room temperature for 2 h. The mixture was then diluted with dichloromethane (200 mL) and washed with water (3 x 50 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate = 5 / 1) to afford ethyl 2-cyclopropyl-2-(2-(l,l-difluoroethyl)-5-oxo-8-phenylpyrimido[4,5-d]pyridazin-6(5H)-yl)acetate (1.7 g, 59% yield) as yellow oil. LCMS m / z = 451.2 (M + 1).

[0390] Step 8. 2-Cyclopropyl-2-(2-(l,l-difhioroethyl)-5-oxo-8-phenylpyrimido[4,5-d]pyridazin-6(5H)-yl)acetic acid. To a solution of ethyl 2-cyclopropyl-2-(2-(l,l-difhioroethyl)-5-oxo-8-phenylpyrimido[4,5-d]pyridazin-6(5H)-yl)acetate (1.7 g, 4.1 mmol, 1.0 eq) in tetrahydrofuran (20 mL) and water (20 mL) was added lithium hydroxide hydrate (196 mg, 8.2 mmol, 2.0 eq) and the reaction mixture was stirred at room temperature for 2 h. The pH of the mixture was then adjusted to ~5 by addition of aqueous hydrochloric acid (1 M), the solution was extracted with dichloromethane (3 x 300 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give 2-cyclopropyl-2-(2-(l,l-difluoroethyl)-5-oxo-8-phenylpyrimido[4,5-d]pyridazin-6(5H)-yl)acetic acid (1.3 g, 82% yield) as a yellow solid. LCMS m / z = 387.2 (M + 1).120039.000211 (TYRA041PCT)

[0391] Step 9. S-Ethyl 2-cyclopropyl-2-(2-(l,l-difluoroethyl)-5-oxo-8-phenylpyrimido[4,5-d]pyridazin-6(5H)-yl)ethanethioate. To a solution of 2-cyclopropyl-2-(2-(l,l-difluoroethyl)-5-oxo-8-phenylpyrimido[4,5-d]pyridazin-6(5H)-yl)acetic acid (1.3 g, 3.36 mmol, 1.0 eq), ethanethiol (836 mg, 13.46 mmol, 4.0 eq) and 1-[bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (1.92 g, 5.05 mmol, 1.5 eq) in dichloromethane (25 mL) was added N, N-diisopropylethylamine (1.74 g, 13.46 mmol, 4.0 eq) at 0 °C and the mixture was allowed to stir at room temperature for 3 h. The mixture was then diluted dichloromethane (70 mL) and was washed with water (3 x 20 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate = 5 / 1) to provide S-ethyl 2-cyclopropyl-2-(2-(l,l-difluoroethyl)-5-oxo-8-phenylpyrimido[4,5-d]pyridazin-6(5H)-yl)ethanethioate (1.0 g, 69% yield) as a yellow solid. LCMS m / z = 431.2 (M + 1).

[0392] Step 10. 2-Cyclopropyl-2-(2-(1,1-difluoroethyl)-5-oxo-8-phenylpyrimido[4,5-d]pyridazin-6(5H)-yl)acetaldehyde. To a mixture of S-ethyl 2-cyclopropyl-2-(2-(l,l-difluoroethyl)-5-oxo-8-phenylpyrimido[4,5-d]pyridazin-6(5H)-yl)ethanethioate (1.0 g, 2.32 mmol, 1.0 eq) and Pd / C (10%, 500 mg) and in tetrahydrofuran (50 mL) was added triethylsilane (2.69 g, 23.2 mmol, 10.0 eq) at -10 °C and the reaction mixture was stirred at room temperature for 2 h. The mixture was then filtered on celite, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate = 2 / 1) to afford 2-cyclopropyl-2-(2-(l,l-difluoroethyl)-5-oxo-8-phenylpyrimido[4,5-d]pyridazin-6(5H)-yl)acetaldehyde (600 mg, 71% yield) as a white solid. LCMS m / z = 371.4 (M + 1).

[0393] Step 11. (E)-6-(l-Cyclopropyl-3-(methylsulfonyl)allyl)-2-(l,l-difluoroethyl)-8-phenylpyrimido[4,5-d]pyridazin-5(6H)-one. To a solution of 2-cyclopropyl-2-(2-(l,l-difluoroethyl)-5-oxo-8-phenylpyrimido[4,5-d]pyridazin-6(5H)-yl)acetaldehyde (700 mg, 1.89 mmol, 1.0 eq) and potassium carbonate (1.3 g, 9.45 mmol, 5.0 eq) in tetrahydrofuran (15 mL) was added diethyl ((methylsulfonyl)methyl)phosphonate (870 mg, 3.78 mmol, 2.0 eq) and the reaction mixture was stirred at 60 °C for 6 h. The mixture was then diluted with di chloromethane (100 mL) and washed with water (3 x 30 mL). The organic layer was washed with brine (2 x 30 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography120039.000211 (TYRA041PCT)(petroleum ether / ethyl acetate = 2 / 1) to afford (E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(l,l-difluoroethyl)-8-phenylpyrimido[4,5-d]pyridazin-5(6H)-one (600 mg, 71% yield) as a white solid. LCMS m / z = 447.2 (M + 1); ¹H NMR (400 MHz, DMSO-d6) δ 9.90 (s, 1H), 8.04-8.02 (m, 2H), 7.58-7.55 (m, 3H), 7.02-7.01 (m, 2H), 5.11-5.08 (m, 1H), 3.02 (s, 3H), 2.10 (t, J= 18.8 Hz, 3H), 1.64-1.56 (m, 1H), 0.79-0.73 (m, 2H), 0.59-0.53 (m, 1H), 0.45-0.39 (m, 1H).Example 5. (R, E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(l, l-difluoroethyl)-8-phenylpyrimido[4,5-d]pyridazin-5(6H)-one, and Example 6 (S, E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(l,l-difluoroethyl)-8-phenylpyrimido[4,5-d]pyridazin-5(6H)-one.0Y 9^

[0394] (E)-6-(l -Cyclopropyl-3 -(methyl sulfonyl)allyl)-2-( 1, 1 -difluoroethyl)-8-phenylpyrimido[4,5-d]pyridazin-5(6H)-one from Example 4, step 11 was purified by Prep-SFC on a chiral stationary phase with the method outlined below to provide (R, E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(l,l-difluoroethyl)-8-phenylpyrimido[4,5-d]pyridazin-5(6H)-one (252.8 mg, 38% yield) LCMS m / z = 447.3 (M + 1); ¹H NMR (400 MHz, DMSO-d6) δ 9.90 (s, 1H), 8.04-8.02 (m, 2H), 7.59-7.55 (m, 3H), 7.02-7.01 (m, 2H), 5.09 (dd, J= 10.0 Hz, 2.8 Hz, 1H), 3.02 (s, 3H), 2.10 (t, J= 19.2 Hz, 3H), 1.64-1.56 (m, 1H), 0.78-0.73 (m, 2H), 0.60-0.57 (m, 1H), 0.45-0.40 (m, 1H), and (S, E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(l,l-difluoroethyl)-8-phenylpyrimido[4,5-d]pyridazin-5(6H)-one (247.6 mg, 38% yield) LCMS m / z = 447.3 (M + 1); ¹H NMR (400 MHz, DMSO-d6) δ 9.90 (s, 1H), 8.04-8.02 (m, 2H), 7.57-7.56 (m, 3H), 7.02-7.01 (m, 2H), 5.11-5.08 (m, 1H), 3.02 (s, 3H), 2.10 (t, J= 19.2 Hz, 3H), 1.65-1.57 (m, 1H), 0.79-0.73 (m, 2H), 0.61-0.54 (m, 1H), 0.45-0.39 (m, 1H). The enantiomers were randomly assigned; the absolute configuration was not determined.

[0395] Instrument: Waters UPC2 analytical SFC (SFC-H)

[0396] Column: ChiralPak IG, 100×4.6mm I.D., 3μm

[0397] Mobile phase: A for CO2 and B for ethanol (0.05% DEA)

[0398] Gradient: B 5-40 %

[0399] Flow rate: 2.5 mL / min

[0400] Back pressure: 100 bar120039.000211 (TYRA041PCT)

[0401] Column temperature: 35°C

[0402] Wavelength: 254 nm

[0403] The following examples in the table were prepared as described above, or with similar methods.Example 1. (E)-6-(l- LCMS m / z = 451.2 (M + cyclopropyl-3- 1); 'H-NMR (400 MHz, DMSO- (m ethyl sulfonyl)ally d6) 89.99 (s, 1H), 7.99-7.97 (m, l)-8-phenyl-2- 2H), 7.61-7.55 (m, 3H), 7.06-6.96 (trifluoromethyl)pyri (m, 2H), 5.12 (dd, J= 10.0 Hz, mido[4,5- 3.6 Hz, 1H), 3.02 (s, 3H), 1.63- d]pyridazin-5(6H)- 1.58 (m, 1H), 0.77-0.72 (m, 2H), one 0.59-0.41 (m, 2H)Example 2. (S, E)-6- LCMS m / z = 451.2 (M +(l-cyclopropyl-3- 1); 'H-NMR (400 MHz, DMSO- (m ethyl sulfonyl)ally d6) 69.99 (s, 1H), 7.99 (dd, J =° Y l)-8-phenyl-2- 6.0 Hz, 2.4 Hz, 2H), 7.60-7.55(trifluoromethyl)pyri (m, 3H), 7.06-6.96 (m, 2H), 5.12 mido[4,5- (dd, J= 10.0 Hz, 3.2 Hz, 1H), 4d]pyridazin-5(6H)- 3.02 (s, 3H), 1.63-1.58 (m, 1H), 4 one 0.78-0.72 (m, 2H), 0.63-0.53 (m,1H), 0.48-0.37 (m, 1H)X- Example 3. (R, E)-6- LCMS m / z = 451.2 (M +(l-cyclopropyl-3- 1); 'H-NMR (400 MHz, DMSO- (m ethyl sulfonyl)ally d6) 69.99 (s, 1H), 7.99 (dd, J= l)-8-phenyl-2- 5.6 Hz, 2.4 Hz, 2H), 7.61-7.55 (trifluoromethyl)pyri (m, 3H), 7.06-6.96 (m, 2H), 5.12 mido[4,5- (dd, J= 10.0 Hz, 3.2 Hz, 1H), d]pyridazin-5(6H)- 3.02 (s, 3H), 1.64-1.58 (m, 1H), one 0.78-0.72 (m, 2H), 0.59-0.45 (m,1H), 0.44-0.35 (m, 1H)Example 4. (E)-6-(l- LCMS m / z = 447.2 (M + cyclopropyl-3- 1); 'H-NMR (400 MHz, DMSO- (m ethyl sulfonyl)ally d6) 69.90 (s, 1H), 8.04-8.02 (m, l)-2-(l,l- 2H), 7.58-7.55 (m, 3H), 7.02-7.01 difluoroethyl)-8- (m, 2H), 5.11-5.08 (m, 1H), 3.02 phenylpyrimido[4,5- (s, 3H), 2.10 (t, J= 18.8 Hz, 3H), d]pyridazin-5(6H)- 1.64-1.56 (m, 1H), 0.79-0.73 (m, one 2H), 0.59-0.53 (m, 1H), 0.45-0.39(m, 1H)120039.000211 (TYRA041PCT)Example 5. (R, E)-6- LCMS m / z = 447.3 (M + (l-cyclopropyl-3- 1); 'H-NMR (400 MHz, DMSO- (m ethyl sulfonyl)ally d6) 69.90 (s, 1H), 8.04-8.02 (m, o Vl)-2-(l,l- 2H), 7.59-7.55 (m, 3H), 7.02-7.01 difluoroethyl)-8- (m, 2H), 5.09 (dd, J= 10.0 Hz, phenylpyrimido[4,5- 2.8 Hz, 1H), 3.02 (s, 3H), 2.10 (t, d]pyridazin-5(6H)- J= 19.2 Hz, 3H), 1.64-1.56 (m, one 1H), 0.78-0.73 (m, 2H), 0.60-0.57(m, 1H), 0.45-0.40 (m, 1H) Example 6. (S, E)-6- LCMS m / z = 447.3 (M + (l-cyclopropyl-3- 1); 'H-NMR (400 MHz, DMSO-0(m ethyl sulfonyl)ally d6) 69.90 (s, 1H), 8.04-8.02 (m, Y l)-2-(l,l- 2H), 7.57-7.56 (m, 3H), 7.02-7.01 difluoroethyl)-8- (m, 2H), 5.11-5.08 (m, 1H), 3.02 4 ■ phenylpyrimido[4,5- (s, 3H), 2.10 (t, J = 19.2 Hz, 3H), d]pyridazin-5(6H)- 1.65-1.57 (m, 1H), 0.79-0.73 (m, one 2H), 0.61-0.54 (m, 1H), 0.45-0.39(m, 1H)Example 7. (E)-2- LCMS m / z = 437.3 (M + cyclobutyl-6-(l- 1); 'H-NMR (400 MHz, DMSO- x «x O / cyclopropyl-3- d6) 69.69 (s, 1H), 8.07-8.05 (m, / O ' (m ethyl sulfonyl)ally 2H), 7.57-7.52 (m, 3H), 7.01-7.00 >4■ l)-8- (m, 2H), 5.08-50.6 (m, 1H), 4.00- $}H ° phenylpyrimido[4,5- 3.92 (m, 1H), 3.01 (s, 3H), 2.44- d]pyridazin-5(6H)- 2.38 (m, 4H), 2.13-2.04 (m, 1H), > one 1.96-1.90 (m, 1H), 1.63-1.56 (m,1H), 0.79-0.71 (m, 2H), 0.59-0.55 (m, 1H), 0.44-0.39 (m, 1H) Example 8. (R, E)-2- LCMS m / z = 423.2 (M + cyclopropyl-6-(l- 1); 'H-NMR (400 MHz, DMSO- cyclopropyl-3- d6) 69.57 (s, 1H), 8.00-7.98 (m, (m ethyl sulfonyl)ally 2H), 7.57-7.50 (m, 3H), 7.03-6.97 l)-8- (m, 2H), 5.08-5.02 (m, 1H), 3.01 phenylpyrimido[4,5- (s, 3H), 2.46-2.39 (m, 1H), 1.62- d]pyridazin-5(6H)- 1.53 (m, 1H), 1.25-1.15 (m, 4H), one 0.79-0.68 (m, 2H), 0.58-0.52 (m,1H), 0.43-0.37 (m, 1H) Example 9. (S, E)-2- LCMS m / z = 423.3 (M + ° Y cyclopropyl-6-(l- 1); 'H-NMR (400 MHz, DMSO- cyclopropyl-3- d6) 69.57 (s, 1H), 8.00-7.98 (m, (m ethyl sulfonyl)ally 2H), 7.57-7.50 (m, 3H), 7.01-6.97 4 ■ l)-8- (m, 2H), 5.08-5.02 (m, 1H), 3.01 phenylpyrimido[4,5- (s, 3H), 2.44-2.39 (m, 1H), 1.62-1.53 (m, 1H), 1.25-1.14 (m, 4H),120039.000211 (TYRA041PCT)d]pyridazin-5(6H)- 0.79-0.68 (m, 2H), 0.58-0.52 (m, one 1H), 0.43-0.37 (m, 1H) Example 10. (E)-6- LCMS m / z = 411.3 (M + (l-cyclopropyl-3- 1); 'H-NMR (400 MHz, DMSO- (m ethyl sulfonyl)ally d6) 69.68 (s, 1H), 8.05-8.03 (m, l)-2-ethyl-8- 2H), 7.57-7.52 (m,3H), 7.01-7.00 phenylpyrimido[4,5- (m, 2H), 5.08-5.06 (m, 1H), 3.12 d]pyridazin-5(6H)- (q, J= 7.6 Hz, 2H), 3.01 (s, 3H), one 1.61-1.58 (m, 1H), 1.35 (t, J= 7.6Hz, 3H), 0.78-0.70 (m, 2H), 0.58- 0.54 (m, 1H), 0.43-0.39 (m, 1H) Example 11. (E)-2- LCMS m / z = 451.3 (M + cyclopentyl-6-(l- 1); 'H-NMR (400 MHz, DMSO- cyclopropyl-3- d6) 69.67 (s, 1H), 8.05-8.02 (m, (m ethyl sulfonyl)ally 2H), 7.57-7.52 (m, 3H), 7.04-6.96 l)-8- (m, 2H), 5.08-5.05 (m, 1H), 3.58- phenylpyrimido[4,5- 3.50 (m, 1H), 3.01 (s, 3H), 2.14- d]pyridazin-5(6H)- 2.06 (m, 2H), 1.96-1.88 (m, 2H), one 1.81-1.74 (m, 4H), 1.66-1.55 (m,1H), 0.79-0.70 (m, 2H), 0.59-0.52 x O / (m, 1H), 0.43-0.37 (m, 1H) 44°^<y ° Example 12. (R, E)- LCMS m / z = 501.3 (M +6-(l-cyclopropyl-3- 1); 'H-NMR (400 MHz, DMSO-0Y (m ethyl sulfonyl)ally d6) 6 10.01 (s, 1H), 8.03-7.95 (m, l)-2- 2H), 7.62-7.52 (m, 3H), 7.07-6.95 (perfluoroethyl)-8- (m, 2H), 5.11 (dd, J= 9.6 Hz, 3.2 phenylpyrimido[4,5- Hz, 1H), 3.02 (s, 3H), 1.68-1.55 d]pyridazin-5(6H)- (m, 1H), 0.82-0.71 (m, 2H), 0.63- one 0.53 (m, 1H), 0.47-0.38 (m, 1H) Example 13. (S, E)- LCMS m / z = 501.3 (M + 6-(l-cyclopropyl-3- 1); 'H-NMR (400 MHz, DMSO- (m ethyl sulfonyl)ally d6) 6 10.01 (s, 1H), 8.03-7.94 (m, l)-2- 2H), 7.61-7.52 (m, 3H), 7.06-6.96 (perfluoroethyl)-8- (m, 2H), 5.11 (dd, J= 10.0 Hz, phenylpyrimido[4,5- 3.6 Hz, 1H), 3.02 (s, 3H), 1.68- d]pyridazin-5(6H)- 1.55 (m, 1H), 0.83-0.69 (m, 2H), one 0.64-0.51 (m, 1H), 0.48-0.36 (m,1H)Example 14. (R, E)- LCMS m / z = 437.3 (M + 2-cyclobutyl-6-(l- 1); 'H-NMR (400 MHz, DMSO- cyclopropyl-3- d6) 69.69 (s, 1H), 8.07-8.05 (m, 0 ' (m ethyl sulfonyl)ally 2H), 7.57-7.53 (m, 3H), 7.01-7.00 l)-8- (m, 2H), 5.08-50.6 (m, 1H), 4.00-phenylpyrimido[4,5- 3.92 (m, 1H), 3.01 (s, 3H), 2.43-120039.000211 (TYRA041PCT)d]pyridazin-5(6H)- 2.38 (m, 4H), 2.13-2.04 (m, 1H), one 1.96-1.91 (m, 1H), 1.62-1.56 (m, L y Z 1H), 0.80-0.69 (m, 2H), 0.59-0.55 t> o° (m, 1H), 0.44-0.39 (m, 1H)f o Example 15. (S, E)- LCMS m / z = 437.3 (M + '(fl.'© / 2-cyclobutyl-6-(l- 1); 'H-NMR (400 MHz, DMSO- cyclopropyl-3- d6) 69.69 (s, 1H), 8.07-8.04 (m, (m ethyl sulfonyl)ally 2H), 7.58-7.52 (m, 3H), 7.01-7.00 l)-8- (m, 2H), 5.08-50.6 (m, 1H), 4.00- phenylpyrimido[4,5- 3.92 (m, 1H), 3.01 (s, 3H), 2.44- ■ d]pyridazin-5(6H)- 2.38 (m, 4H), 2.11-2.04 (m, 1H), one 1.97-1.91 (m, 1H), 1.63-1.56 (m,1H), 0.78-0.70 (m, 2H), 0.59-0.55 (m, 1H), 0.44-0.39 (m, 1H) Example 16. (R, E)- LCMS m / z = 411.3 (M + 6-(l-cyclopropyl-3- 1); 'H-NMR (400 MHz, DMSO- (m ethyl sulfonyl)ally d6) 69.68 (s, 1H), 8.05-8.03 (m, o Vl)-2-ethyl-8- 2H), 7.57-7.52 (m, 3H), 7.01-7.00 phenylpyrimido[4,5- (m, 2H), 5.08-5.06 (m, 1H), 3.12 d]pyridazin-5(6H)- (q, J= 7.6 Hz, 2H), 3.01 (s, 3H), one 1.60-1.58 (m, 1H), 1.35 (t, J= 7.6Hz, 3H), 0.75-0.70 (m, 2H), 0.58- 0.56 (m, 1H), 0.42-0.40 (m, 1H) Example 17. (S, E)- LCMS m / z = 411.3 (M + 6-(l-cyclopropyl-3- 1); 'H-NMR (400 MHz, DMSO- (m ethyl sulfonyl)ally d6) 69.68 (s, 1H), 8.05-8.03 (m, l)-2-ethyl-8- 2H), 7.57-7.52 (m,3H), 7.03-7.01 phenylpyrimido[4,5- (m, 2H), 5.08-5.06 (m, 1H), 3.12 d]pyridazin-5(6H)- (q, J= 7.6 Hz, 2H), 3.01 (s, 3H), one 1.62-1.56 (m, 1H), 1.35 (t, J= 7.6Hz, 3H), 0.78-0.70 (m, 2H), 0.59- 0.56 (m, 1H), 0.44-0.40 (m, 1H) Example 18. (R, E)- LCMS m / z = 425.3 (M + 6-(l-cyclopropyl-3- 1); 'H-NMR (400 MHz, DMSO- (m ethyl sulfonyl)ally d6) 69.70 (s, 1H), 8.08-8.05 (m, 0 VU;(a,,oNNl)-2-isopropyl-8- 2H), 7.57-7.52 (m, 3H), 7.00-6.99 phenylpyrimido[4,5- (m, 2H), 5.08-5.06 (m, 1H), 3.39- d]pyridazin-5(6H)- 3.33 (m, 1H), 3.01 (s, 3H), 1.63- one 1.56 (m, 1H), 1.35 (d, J= 7.2 Hz,6H), 0.78-0.71 (m, 2H), 0.59-0.54 (m, 1H), 0.43-0.38 (m, 1H)120039.000211 (TYRA041PCT)Example 19. (S, E)- LCMS m / z = 425.3 (M + 6-(l-cyclopropyl-3- 1); 'H-NMR (400 MHz, DMSO- (m ethyl sulfonyl)ally d6) 69.70 (s, 1H), 8.08-8.05 (m, l)-2-isopropyl-8- 2H), 7.57-7.52 (m, 3H), 7.00-6.98 phenylpyrimido[4,5- (m, 2H), 5.08-5.06 (m, 1H), 3.39- F d]pyridazin-5(6H)- 3.33 (m, 1H), 3.01 (s, 3H), 1.61- one 1.56 (m, 1H), 1.35 (d, J= 7.2 Hz,6H), 0.78-0.70 (m, 2H), 0.57-0.54 (m, 1H), 0.42-0.38 (m, 1H) Example 20. (E)-2- LCMS m / z = 449.3 (M + (1,1 -difluoroethyl)- 1); 'H-NMR (400 MHz, DMSO- 6-(4-methyl-l- d6) 69.92 (s, 1H), 8.03-8.00 (m, (m ethyl sulfonyl)pent 2H), 7.60-7.53 (m, 3H), 7.05 (d, J -l-en-3-yl)-8- = 15.2 Hz, 1H), 6.96-6.91 (m, phenylpyrimido[4,5- 1H), 5.54-5.50 (m, 1H), 3.01 (s, d]pyridazin-5(6H)- 3H), 2.45-2.40 (m, 1H), 2.1 (t, J= one 2.8 Hz, 3H), 1.07 (d, J= 6.8 Hz,3H), 0.89 (d, J = 6.8 Hz, 3H) Example 21. (E)-2- LCMS m / z =435.3 (M + (1,1 -difluoroethyl)- 1); 'H-NMR (400 MHz, DMSO- 6-(l- d6) 69.91 (s, 1H), 8.01-7.99 (m, (m ethyl sulfonyl)pent 2H), 7.59-7.52 (m, 3H), 6.93 (s, 44 -l-en-3-yl)-8- 2H), 5.81-5.77 (m, 1H), 2.99 (s, JDKH O phenylpyrimido[4,5- 3H), 2.16-2.05 (m, 5H), 0.90 (t, J d]pyridazin-5(6H)- = 7.2 Hz, 3H)oneExample 22. (E)-2- LCMS m / z = 421.2 (M + (1,1 -difluoroethyl)- 1); 'H-NMR (400 MHz, DMSO- 6-(4- d6) 69.91 (s, 1H), 8.04-7.97 (m, (m ethyl sulfony l)but- 2H), 7.60-7.53 (m, 3H), 7.00-6.89 3-en-2-yl)-8- (m, 2H), 6.02-5.94 (m, 1H), 2.99 4 phenylpyrimido[4,5- (s, 3H), 2.11 (t, J = 19.2 Hz, 3H), d]pyridazin-5(6H)- 1.63 (d, 4= 6.8 Hz, 3H) oneExample 23. (E)-2- LCMS m / z = 385.3 (M + (l-cyclopropyl-3- 1); 'H-NMR (400 MHz, DMSO- (m ethyl sulfonyl)ally d6) 67.48-7.45 (m, 5H), 6.95- l)-4-phenyl-5, 6,7,8- 6.87 (m, 2H), 4.95 (dd, J= 10.0 JMtetrahydrophthalazin Hz, 2.8 Hz, 1H), 3.02 (s, 3H), 0 -l(2H)-one 2.56-2.54 (m, 2H), 2.46-2.33 (m,2H), 1.74-1.69 (m, 2H), 1.67-1.55 (m, 2H), 1.52-1.43 (m, 1H), 0.72-0.65 (m, 1H), 0.61-0.55 (m, 1H),120039.000211 (TYRA041PCT)0.53-0.47 (m, 1H), 0.38-0.32 (m, 1H)Example 24. (R, E)- LCMS m / z = 451.3 (M + 2-cyclopentyl-6-(l- 1); 'H-NMR (400 MHz, DMSO- cyclopropyl-3- d6) 89.67 (s, 1H), 8.05-8.03 (m, (m ethyl sulfonyl)ally 2H), 7.56-7.52 (m, 3H), 7.04-6.96 l)-8- (m, 2H), 5.08-5.05 (m, 1H), 3.58- phenylpyrimido[4,5- 3.50 (m, 1H), 3.01 (s, 3H), 2.14- d]pyridazin-5(6H)- 2.06 (m, 2H), 1.96-1.88 (m, 2H), one 1.82-1.66 (m, 4H), 1.64-1.55 (m,1H), 0.78-0.69 (m, 2H), 0.59-0.52 (m, 1H), 0.43-0.37 (m, 1H) Example 25. (S, E)- LCMS m / z = 451.4 (M + 2-cyclopentyl-6-(l- 1); 'H-NMR (400 MHz, DMSO- cyclopropyl-3- d6) 69.67 (s, 1H), 8.05-8.03 (m, (m ethyl sulfonyl)ally 2H), 7.56-7.52 (m, 3H), 7.04-6.96 l)-8- (m, 2H), 5.08-5.05 (m, 1H), 3.58- phenylpyrimido[4,5- 3.50 (m, 1H), 3.01 (s, 3H), 2.14- d]pyridazin-5(6H)- 2.06 (m, 2H), 1.96-1.88 (m, 2H), one 1.81-1.66 (m, 4H), 1.62-1.55 (m,1H), 0.79-0.69 (m, 2H), 0.59-0.52 (m, 1H), 0.43-0.37 (m, 1H) £Example 26. (E)-2- LCMS m / z = 435.2 (M + (1,1 -difluoroethyl)- 1); 'H-NMR (400 MHz, DMSO- 6-(2-methyl-4- d6) 69.87 (s, 1H), 8.07-8.04 (m, (m ethyl sulfony l)but- 2H), 7.56-7.54 (m, 3H), 7.19 (d, J 3-en-2-yl)-8- = 15.6 Hz, 1H), 6.91 (d, J= 15.6 phenylpyrimido[4,5- Hz, 1H), 3.00 (s, 3H), 2.10 (t, J = d]pyridazin-5(6H)- 14.4 Hz, 3H), 1.80 (s, 6H) oneExample 27. (E)-2- LCMS m / z =451.3(M + (1,1 -difluoroethyl)- 1); 'H-NMR (400 MHz, DMSO- 6-(l-methoxy-4- d6) 69.92 (s, 1H), 8.01-7.98 (m, (m ethyl sulfony l)but- 2H), 7.59-7.54 (m, 3H), 7.02 (dd, 3-en-2-yl)-8- J= 16.0 Hz, 2.0 Hz, 1H), 6.91 phenylpyrimido[4,5- (dd, J= 15.2 Hz, 4.4 Hz, 1H), d]pyridazin-5(6H)- 6.14-6.09 (m, 1H), 4.02-3.98 (m, one 1H), 3.90-3.86 (m, 1H), 3.29 (s,3H), 2.99 (s, 3H), 2.10 (t, J= 18.8 Hz, 3H)120039.000211 (TYRA041PCT)Example 28. (R, E)- LCMS m / z = 439.3 (M + 2-(tert-butyl)-6-(l- 1); 'H-NMR (400 MHz, DMSO- o Y cyclopropyl-3- d6) 69.72 (s, 1H), 8.10-8.08 (m, N^ ' N* ^\S° (m ethyl sulfonyl)ally 2H), 7.57-7.50 (m, 3H), 7.04-6.97 t o^ l)-8- (m, 2H), 5.08-5.06 (m, 1H), 3.01 ■ ■ l ■ phenylpyrimido[4,5- (s, 3H), 1.63-1.56 (m, 1H), 1.43 d]pyridazin-5(6H)- (s, 9H), 0.80-0.70 (m, 2H), 0.59- one 0.38 (m, 2H)Example 29. (S, E)- LCMS m / z = 439.3 (M + 2-(tert-butyl)-6-(l- 1); 'H-NMR (400 MHz, DMSO- cyclopropyl-3- d6) 69.72 (s, 1H), 8.10-8.08 (m, (m ethyl sulfonyl)ally 2H), 7.57-7.52 (m, 3H), 7.04-6.97 l)-8- (m, 2H), 5.08-5.06 (m, 1H), 3.01 phenylpyrimido[4,5- (s, 3H), 1.64-1.56 (m, 1H), 1.43 d]pyridazin-5(6H)- (s, 9H), 0.80-0.70 (m, 2H), 0.57- one 0.37 (m, 2H)Example 30. (E)-6- LCMS m / z = 461.3 (M + (l-cyclobutyl-3- 1); 'H-NMR (400 MHz, DMSO- (m ethyl sulfonyl)ally d6) 69.91 (s, 1H), 8.01-7.99 (m, l)-2-(l,l- 2H), 7.60-7.56 (m, 3H), 6.98 (dd, difluoroethyl)-8- J= 15.6 Hz, 1.2 Hz, 1H), 6.83 phenylpyrimido[4,5- (dd, J= 15.2 Hz, 5.2 Hz, 1H), 4d]pyridazin-5(6H)- 5.85-5.81 (m, 1H), 3.09-3.05 (m, one 1H), 2.99 (s, 3H), 2.16-2.05 (m,5H), 1.95-1.75 (m, 4H) Example 31. (E)-2- LCMS m / z = 381.2 (M + (l-cyclopropyl-3- 1); 'H-NMR (400 MHz, DMSO- (m ethyl sulfonyl)ally d6) 68.41-8.39 (m, 1H), 7.96-7.94 A 5LOl)-4- (m, 2H), 7.78-7.75 (m, 1H), 7.67- OM °'^ phenylphthalazin- 7.64 (m, 2H), 7.58-7.57 (m, 3H), l(2H)-one 7.04-6.94 (m, 2H), 5.09-5.06 (m, 0 1H), 3.02 (s, 3H), 1.61-1.52 (m,1H), 0.74-0.65 (m, 2H), 0.54-0.39 (m, 2H)Example 32. (S, E)- LCMS m / z = 437.3 (M + 6-(l-cyclopropyl-3- 1); 'H-NMR (400 MHz, DMSO- (m ethyl sulfonyl)ally d6) 69.59 (s, 1H), 8.08-8.06 (m, l)-2-(l- 2H), 7.54-7.51 (m, 3H), 7.04-6.99 methylcyclopropyl)- (m, 2H), 5.08-5.05 (m, 1H), 3.01 8- (s, 3H), 1.62-1.55 (m, 4H), 1.44- phenylpyrimido[4,5- 1.42 (m, 2H), 1.12-1.10 (m, 2H), d]pyridazin-5(6H)- 0.76-0.69 (m, 2H), 0.59-0.54 (m, one 1H), 0.43-0.39 (m, 1H)120039.000211 (TYRA041PCT)Example 33. (R, E)- LCMS m / z = 437.3 (M + 6-(l-cyclopropyl-3- 1); 'H-NMR (400 MHz, DMSO- (m ethyl sulfonyl)ally d6) 89.59 (s, 1H), 8.08-8.06 (m, o V / l)-2-(l- 2H), 7.56-7.53 (m, 3H), 7.04-6.99 methylcyclopropyl)- (m, 2H), 5.08-5.05 (m, 1H), 3.01 8- (s, 3H), 1.60-1.58 (m, 4H), 1.43- phenylpyrimido[4,5- 1.42 (m, 2H), 1.12-1.11 (m, 2H), d]pyridazin-5(6H)- 0.76-0.70 (m, 2H), 0.58-0.54 (m, one 1H), 0.42-0.39 (m, 1H) Example 43. (E)-6- LCMS m / z = 475.1 (M + (4- 1); 'H-NMR (400 MHz, DMSO- (m ethyl sulfony l)but- d6) 6 10.03 (s, 1H), 7.99-7.93 (m, ^ 3-en-2-yl)-2- 2H), 7.60-7.52 (m, 3H), 7.00-6.90 (perfluoroethyl)-8- (m, 2H), 6.03-5.95 (m, 1H), 3.00 phenylpyrimido[4,5- (s, 3H), 1.64 (d, J= 7.2 Hz, 3H) d]pyridazin-5(6H)- oneExample 44. (E)-6- LCMS m / z = 489.0 (M + (1- 1); 'H-NMR (400 MHz, DMSO- (m ethyl sulfonyl)pent d6) 6 10.02 (s, 1H), 8.01-7.92 (m, -l-en-3-yl)-2- 2H), 7.62-7.51 (m, 3H), 6.98-6.89 (perfluoroethyl)-8- (m, 2H), 5.84-5.75 (m, 1H), 2.99 - Aphenylpyrimido[4,5- (s, 3H), 2.15-2.03 (m, 2H), 0.91 d]pyridazin-5(6H)- (t, J = 7.2 Hz, 3H)oneExample 45. (E)-6- LCMS m / z = 505.0 (M + ( 1 -methoxy -4- 1); 'H-NMR (400 MHz, DMSO- (methylsulfonyl)but- d6) 6 10.03 (s, 1H), 7.97-7.94 (m, 3-en-2-yl)-2- 2H), 7.60-7.56 (m, 3H), 7.05-6.92 (perfluoroethyl)-8- (m, 2H), 6.15-6.10 (m, 1H), 4.01 phenylpyrimido[4,5- (t, J= 10.0 Hz, 1H), 3.95-3.86 d]pyridazin-5(6H)- (m, 1H), 3.29 (s, 3H), 3.00 (s, 3H) oneExample 46. (E)-6- LCMS m / z = 515.0 (M + (l-cyclobutyl-3- 1); 'H-NMR (400 MHz, DMSO- (m ethyl sulfonyl)ally d6) 6 10.02 (s, 1H), 7.97-7.94 (m, l)-2- 2H), 7.57-7.56 (m, 3H), 7.00-6.96 (perfluoroethyl)-8- (m, 1H), 6.96-6.84 (m, 1H), 5.86- phenylpyrimido[4,5- 5.82 (m, 1H), 3.31-3.05 (m, 1H), d]pyridazin-5(6H)- 2.99 (s, 3H), 1.91-1.78 (m, 6H) one120039.000211 (TYRA041PCT)Example 48. (E)-6- LCMS m / z = 465.0 (M + (l-cyclopropyl-3- 1); 'H-NMR (400 MHz, DMSO- (m ethyl sulfonyl)ally d6) δ 9.90 (s, 1H), 8.11-8.07 (m, l)-2-(l,l- 2H), 7.42 (t, J= 8.8 Hz, 2H), difluoroethyl)-8-(4- 7.01-7.00 (m, 2H), 5.12-5.08 (m, fluorophenyl)pyrimi 1H), 3.02 (s, 3H), 2.11 (t, J= 18.8 do[4,5-d]pyridazin- Hz, 3H), 1.63-1.58 (m, 1H), 0.80- 5(6H)-one 0.73 (m, 2H), 0.59-0.56 (m, 1H),0.45-0.40 (m, 1H)Example 53. (E)-6- LCMS m / z = 441.0 (M + (l-cyclopropyl-3- 1); 'H-NMR (400 MHz, DMSO- (m ethyl sulfonyl)ally d6) δ 9.70 (s, 1H), 8.03-8.01 (m, l)-2-(l- 2H), 7.55-7.53 (m,3H), 7.01-7.00 fluorocyclopropyl)- (m, 2H), 5.09-5.06 (m, 1H), 3.02 A?. 8- (s, 3H), 1.80-1.72 (m, 2H), 1.61- phenylpyrimido[4,5- 1.53 (m, 3H), 0.77-0.73 (m,2H), d]pyridazin-5(6H)- 0.71-0.57 (m, 1H), 0.44-0.40 (m, one 1H)Example 54. (E)-6- LCMS m / z = 465.0 (M + (l-cyclopropyl-3- 1); 'H-NMR (400 MHz, DMSO- x «x O / (m ethyl sulfonyl)ally d6) δ 9.90 (s, 1H), 7.66-7.64 (m, l)-2-(l,l- 2H), 7.42-7.41 (m, 2H), 7.01-6.99 difluoroethyl)-8-(2- (m, 2H), 5.08 (dd, J= 9.6 Hz, 3.6 }Q °z fluorophenyl)pyrimi Hz, 1H), 3.01 (s, 3H), 2.02 (t, J= do[4,5-d]pyridazin- 19.2 Hz, 3H), 1.56-1.51 (m, 1H), 5(6H)-one 0.75-0.72 (m, 2H), 0.58-0.55 (m,1H), 0.43-0.40 (m, 1H) Example 55. (E)-6- LCMS m / z = 461.1 (M + (l-cyclopropyl-3- 1); 'H-NMR (400 MHz, DMSO- (m ethyl sulfonyl)ally d6) δ 9.90 (s, 1H), 8.03-8.01 (m, l)-2-(l,l- 2H), 7.59-7.53 (m, 3H), 7.06-6.97 difluoropropyl)-8- (m, 2H), 5.09 (dd, J= 10.0 Hz, phenylpyrimido[4,5- 3.2 Hz, 1H), 3.02 (s, 3H), 2.46- d]pyridazin-5(6H)- 2.33 (m, 2H), 1.66-1.57 (m, 1H), one 0.99 (t, J= 7.6 Hz, 3H), 0.81-0.72(m, 2H), 0.61-0.54 (m, 1H), 0.45- 0.39 (m, 1H)Example 57. (E)-6- LCMS m / z = 465.1 (M + (l-cyclopropyl-3- 1); 'H-NMR (400 MHz, DMSO-N N(m ethyl sulfonyl)ally d6) δ 9.91 (s, 1H), 7.92-7.87 (m, l)-2-(l,l- 2H), 7.65-7.60 (m, 1H), 7.43-7.38 difluoroethyl)-8-(3- (m, 1H), 7.06-6.97 (m, 2H), 5.10 fluorophenyl)pyrimi (dd, J= 10.4 Hz, 3.2 Hz, 1H),3.02 (s, 3H), 2.11 (t, J= 19.2 Hz,120039.000211 (TYRA041PCT)do[4,5-d]pyridazin- 3H), 1.66-1.59 (m, 1H), 0.81-0.72 5(6H)-one (m, 2H), 0.61-0.39 (m, 2H) Example 58. (E)-6- LCMS m / z = 491.0 (M + (l-cyclopropyl-3- 1); 'H-NMR (400 MHz, DMSO- (m ethyl sulfonyl)ally d6) δ 9.68 (s, 1H), 8.06-8.04 (m, ° Y l)-8-phenyl-2-(l- 2H), 7.54-7.52 (m, 3H), 7.00-6.99(trifluoromethyl)cycl (m, 2H), 5.09-5.06 (m, 1H), 3.01 opropyl)pyrimido[4, (s, 3H), 1.75-1.72 (m, 4H), 1.62- 5-d]pyridazin- 1.58 (m, 1H), 0.79-0.70 (m, 2H), 5(6H)-one 0.60-0.55 (m, 1H), 0.44-0.38 (m,1H)Example 59. (E)-6- LCMS m / z = 459.1 (M + (l-cyclopropyl-3- 1); 'H-NMR (400 MHz, DMSO- (m ethyl sulfonyl)ally d6) δ 9.71 (s, 1H), 8.00-7.97 (m, l)-2-(2,2- 2H), 7.58-7.53 (m, 3H), 7.04-7.00 difluorocyclopropyl) (m, 2H), 5.08-5.05 (m, 1H), 3.55- -8- 3.47 (m, 1H), 3.01 (d, J= 5.2 Hz, phenylpyrimido[4,5- 3H), 2.42-2.36 (m, 1H), 2.33-2.24 d]pyridazin-5(6H)- (m, 1H), 1.64-1.55 (m, 1H), 0.80- one 0.69 (m, 2H), 0.61-0.52 (m, 1H), x « o. / 0.44-0.40 (m, 1H)4 > Example 63. (E)-6- LCMS m / z = 473.1 (M + 4 z (l-cyclopropyl-3- 1); 'H-NMR (400 MHz, DMSO- (m ethyl sulfonyl)ally d6) δ 9.74 (s, 1H), 8.04-8.02 (m, u. y l)-2-(3,3- 2H), 7.55-7.54 (m, 3H), 7.05-6.97 difluorocyclobutyl)- (m, 2H), 5.08 (dd, J= 10.0 Hz, 8- 2.0 Hz, 1H), 3.87-3.79 (m, 1H), phenylpyrimido[4,5- 3.17-2.98 (m, 7H), 1.62-1.57 (m, d]pyridazin-5(6H)- 1H), 0.75-0.71 (m, 2H), 0.58-0.52 one (m, 1H), 0.43-0.39 (m, 1H)120039.000211 (TYRA041PCT)Example 34. (R, E)-2-(Azetidin-l-yl)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-8-phenylpyrimido[4,5-d]pyridazin-5(6H)-one, and Example 35 (S, E)-2-(azetidin-l-yl)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-8-phenylpyrimido[4,5-d]pyridazin-5(6H)-one.

[0404] Step 1. Ethyl 4-benzoyl-2-(methylthio)pyrimidine-5-carboxylate. To a solution of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (2.0 g, 8.60 mmol, 1.0 eq), 2-((tert-butyldimethylsilyl)oxy)-2-phenylacetonitrile (4.25 g, 17.19 mmol, 2.0 eq), palladium(II) acetate (193 mg, 0.86 mmol, 0.1 eq) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (994 mg, 1.72 mmol, 0.2 eq) in anhydrous tetrahydrofuran (40 mL) was added lithium bis(trimethylsilyl)amide (11.17 mL, 11.17 mmol, 1.3 eq) at 0 °C, and the reaction mixture was stirred at room temperature for 16 h under nitrogen. Then tetrabutyl ammonium fluoride (17.19 mL, IM in tetrahydrofuran, 17.19 mmol, 2.0 eq) was120039.000211 (TYRA041PCT)added, and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was then diluted with water (200 mL) and extracted with ethyl acetate (2 x 200mL). The combined organic layers were washed with brine (200 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate = 8 / 1) to give ethyl 4-benzoyl-2-(methylthio)pyrimidine-5-carboxylate (1.15 g, 44% yield) as a white solid. LCMS m / z = 303.1 (M + 1).

[0405] Step 2. 2-(Methylthio)-8-phenylpyrimido[4,5-d]pyridazin-5(6H)-one. To a solution of ethyl 4-benzoyl-2-(methylthio)pyrimidine-5-carboxylate (1.15 g, 3.80 mmol, 1.0 eq) in ethanol (10 mL) was added hydrazine hydrate (952 mg, 19.02 mmol, 5.0 eq) at 0 °C and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was then diluted with water, and the ethanol was removed under reduced pressure. The resulting solid was collected by filtration and dried to give 2-(methylthio)-8-phenylpyrimido[4,5-d]pyridazin-5(6H)-one (950 mg, 92% yield) as a light-yellow solid. LCMS m / z = 271.2 (M + 1).

[0406] Step 3. 2-(Azetidin-l-yl)-8-phenylpyrimido[4,5-d]pyridazin-5(6H)-one. To a solution of 2-(methylthio)-8-phenylpyrimido[4,5-d]pyridazin-5(6H)-one (450 mg, 1.66 mmol, 1.0 eq) in dichloromethane (20 mL) was added meta-chloroperoxybenzoic acid (864 mg, 4.99 mmol, 3.0 eq). The resulting mixture was stirred at room temperature for 4 h. Upon completion of the oxidation, triethylamine (736 mg, 7.28 mmol, 5.0 eq) and azetidine (409 mg, 4.37 mmol, 3.0 eq) were added at 0 °C, and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was then diluted with aqueous saturated ammonium chloride (30 mL) and extracted with dichloromethane (2 x 30mL). The combined organic layers were washed with brine (60 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate = 1 / 1) to give 2-(azetidin-l-yl)-8-phenylpyrimido[4,5-d]pyridazin-5(6H)-one (290 mg, 71% yield) as a yellow solid. LCMS m / z = 280.2 (M + 1).

[0407] Step 4. Ethyl 2-(2-(azetidin-l-yl)-5-oxo-8-phenylpyrimido[4,5-d]pyridazin-6(5H)-yl)-2-cyclopropylacetate. To a mixture of 2-(azetidin-l-yl)-8-phenylpyrimido[4,5-d]pyridazin-5(6H)-one (280 mg, 1.00 mmol, 1.0 eq) and cesium carbonate (652 mg, 2.01 mmol, 2.0 eq) in N, N-dimethylformamide (5 mL) was added ethyl 2-bromo-2-120039.000211 (TYRA041PCT)cyclopropylacetate (311 mg, 1.50 mmol, 1.5 eq) and the reaction mixture was stirred at room temperature for 1 h. The mixture was then diluted with ethyl acetate (50 mL) and washed with water (2 x 50 mL), brine (2 x 50 mL), and the organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate = 2 / 1) to give ethyl 2-(2-(azetidin-l-yl)-5-oxo-8-phenylpyrimido[4,5-d]pyridazin-6(5H)-yl)-2-cyclopropylacetate (300 mg, 74% yield) as light-yellow oil. LCMS m / z = 406.3 (M + 1).

[0408] Step 5. 2-(2-(Azetidin-l-yl)-5-oxo-8-phenylpyrimido[4,5-d]pyridazin-6(5H)-yl)-2-cyclopropylacetic acid. To a solution of ethyl 2-(2-(azetidin-l-yl)-5-oxo-8-phenylpyrimido[4,5-d]pyridazin-6(5H)-yl)-2-cyclopropylacetate (290 mg, 0.72 mmol, 1.0 eq) in a mixture of methanol (3 mL), tetrahydrofuran (3 mL) and water (3 mL) was added lithium hydroxide (86 mg, 3.58 mmol, 5.0 eq) at 0 °C. The resulting mixture was stirred at room temperature for 2 h. The volatiles were removed under reduced pressure, and the pH of the mixture was then adjusted to ~6 by addition of IM aqueous hydrochloric acid. The resulting solid was collected by filtration, washed with water (2 x 10 mL), and dried to give 2-(2-(azetidin-l-yl)-5-oxo-8-phenylpyrimido[4,5-d]pyridazin-6(5H)-yl)-2-cyclopropylacetic acid (260 mg) as a light-yellow solid. LCMS m / z = 378.2 (M + 1).

[0409] Step 6. S-Ethyl 2-(2-(azetidin-l-yl)-5-oxo-8-phenylpyrimido[4,5-d]pyridazin-6(5H)-yl)-2-cyclopropylethanethioate. To a solution of 2-(2-(azetidin-l-yl)-5-oxo-8-phenylpyrimido[4,5-d]pyridazin-6(5H)-yl)-2-cyclopropylacetic acid (250 mg, 0.66 mmol, 1.0 eq), N, N-diisopropylethylamine(256 mg, 1.99 mmol, 3.0 eq) and 1-[bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (503 mg, 1.32 mmol, 2.0 eq) in N, N-dimethylformamide (5 mL) was added ethanethiol (82 mg, 1.32 mmol, 2.0 eq). The resulting solution was stirred at room temperature for 1 h. The mixture was then diluted with ethyl acetate (20 mL), washed with water (2 x 20 mL), brine (2 x 20 mL), and the organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate = 5 / 1) to afford S-ethyl 2-(2-(azetidin-l-yl)-5-oxo-8-phenylpyrimido[4,5-d]pyridazin-6(5H)-yl)-2-cyclopropylethanethioate (200 mg, 72% yield) as a light-yellow solid. LCMS m / z = 422.3 (M + 1).

[0410] Step 7. 2-(2-(Azetidin-l-yl)-5-oxo-8-phenylpyrimido[4,5-d]pyridazin-6(5H)-yl)-2-cyclopropylacetaldehyde. To a mixture of S-ethyl 2-(2-(azetidin-l-yl)-5-oxo-8-120039.000211 (TYRA041PCT)phenylpyrimido[4,5-d]pyridazin-6(5H)-yl)-2-cyclopropylethanethioate (190 mg, 0.45 mmol, 1.0 eq) and Pd / C (100 mg) in tetrahydrofuran (3 mL) was added triethylsilane (523 mg, 4.51 mmol, 10.0 eq) at -78 °C. The reaction mixture was then stirred at room temperature for 1 h under nitrogen. The suspension was filtered through Celite and the filter cake was washed with ethyl acetate (2 x 20 mL). The combined filtrates were concentrated under reduced pressure to afford 2-(2-(azetidin-l-yl)-5-oxo-8-phenylpyrimido[4,5-d]pyridazin-6(5H)-yl)-2-cyclopropylacetaldehyde (190 mg) as light-yellow oil. This material was used directly in the next step. LCMS m / z = 362.3 (M + 1).

[0411] Step 8. (E)-2-(Azetidin-l-yl)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-8-phenylpyrimido[4,5-d]pyridazin-5(6H)-one. To a solution of 2-(2-(azetidin-l-yl)-5-oxo-8-phenylpyrimido[4,5-d]pyridazin-6(5H)-yl)-2-cyclopropylacetaldehyde (190 mg) and diethyl ((methylsulfonyl)methyl)phosphonate (242 mg, 1.05 mmol, 2.0 eq) in tetrahydrofuran (3 mL) was added potassium carbonate (218 mg, 1.58 mmol, 3.0 eq) and the resulting mixture was stirred at 60 °C for 4 h. The mixture was then diluted with ethyl acetate (30 mL) and washed with water (2 x 30 mL), brine (30 mL), and the organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by Prep-HPLC (Prep-C18, 5 μM Triart column, 20 × 150 mm, YMC-Actus; gradient elution of 50 % acetonitrile in water to 70% acetonitrile in water over a 9 min period, where both solvents contain 0.05% ammonium hydroxide, to give (E)-2-(azetidin-l-yl)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-8-phenylpyrimido[4,5-d]pyridazin-5(6H)-one (100 mg, 37% yield) as a white solid. LCMS m / z = 438.3 (M + 1)

[0412] Step 9. (R, E)-2-(Azetidin-l-yl)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-8-phenylpyrimido[4,5-d]pyridazin-5(6H)-one, and (S, E)-2-(azetidin-l-yl)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-8-phenylpyrimido[4,5-d]pyridazin-5(6H)-one.

[0413] (E)-2-(Azetidin-l-yl)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-8-phenylpyrimido[4,5-d]pyridazin-5(6H)-one from step 8 was purified by Prep-SFC on a chiral stationary phase with the method below to provide (R, E)-2-(azetidin-l-yl)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-8-phenylpyrimido[4,5-d]pyridazin-5(6H)-one (22.8 mg) LCMS m / z = 438.3 (M + 1); 'H-NMR (400 MHz, DMSO-d6) δ 9.23 (s, 1H), 8.13-7.98 (m, 2H), 7.56-7.40 (m, 3H), 6.97 (d, J = 2.0 Hz, 2H), 5.08-4.92 (m, 1H), 4.32-4.08 (m, 4H), 3.02 (s, 3H), 2.43-2.32 (m, 2H), 1.62-1.47 (m, 1H), 0.81-0.62 (m, 2H), 0.59-0.50 (m, 1H), 0.43-0.34 (m, 1H); and (S, E)-2-(azetidin-l-yl)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-8-120039.000211 (TYRA041PCT)phenylpyrimido[4,5-d]pyridazin-5(6H)-one (26.1 mg) LCMS m / z = 438.3 (M + 1); 'H-NMR (400 MHz, DMSO-d6) δ 9.23 (s, 1H), 8.08-8.02 (m, 2H), 7.52-7.44 (m, 3H), 6.97 (d, J= 1.6 Hz, 2H), 5.03-4.97 (m, 1H), 4.29-4.11 (m, 4H), 3.02 (s, 3H), 2.43-2.32 (m, 2H), 1.59-1.49 (m, 1H), 0.78-0.62 (m, 2H), 0.59-0.49 (m, 1H), 0.43-0.34 (m, 1H). The enantiomers were randomly assigned; the absolute configuration was not determined.

[0414] Instrument: Waters 150 preparative SFC (SFC-26)

[0415] Column: ChiralPak AD, 250x30mm I. D.,10pm

[0416] Mobile phase: A for CO2 and B for Ethanol

[0417] Gradient: B 40 %

[0418] Flow rate: 120 mL / min

[0419] Back pressure: 100 bar

[0420] Column temperature: 38°C

[0421] Wavelength: 220 nm

[0422] Cycle time: ~4 minExample 36. (R, E)-6-(l-Cyclopropyl-3-(methylsulfonyl)allyl)-8-phenyl-2-(pyrrolidin-l-yl)pyrimido[4,5-d]pyridazin-5(6H)-one, and Example 37 (S, E)-7-(azetidin-l-yl)-3-(l-cy cl opropyl-3 -(methyl sulfonyl)allyl)-l-phenylpyrido[3,4-d]pyridazin-4(3H)-one.po'

[0423] This example was prepared following the procedure for Example 34 and 35 using pyrrolidine to give (R, E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-8-phenyl-2-(pyrrolidin-l-yl)pyrimido[4,5-d]pyridazin-5(6H)-one. LCMS m / z = 452.3 (M + 1); *H-NMR (400 MHz, DMSO-d6) δ 9.25 (s, 1H), 8.10-8.07 (m, 2H), 7.52-7.45 (m, 3H), 6.98-6.97 (m, 2H), 5.02-4.99 (m, 1H), 3.66-3.51 (m, 4H), 3.02 (s, 3H), 2.02-1.96 (m, 4H), 1.60-1.51 (m, 1H), 0.77-0.64 (m, 2H), 0.58-0.51 (m, 1H), 0.42-0.36 (m, 1H), and (S, E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-8-phenyl-2-(pyrrolidin-l-yl)pyrimido[4,5-d]pyridazin-5(6H)-one. LCMS m / z = 452.3 (M + 1); 'H-NMR (400 MHz, DMSO-d6) δ 9.25 (s, 1H), 8.09 (dd, J= 7.6 Hz, 1.6 Hz, 2H), 7.53-7.45 (m, 3H), 6.97 (s, 2H), 5.02-4.99 (m, 1H), 3.66-3.51 (m, 4H), 3.02 (s, 3H), 2.00-1.96 (m, 4H), 1.60-1.51 (m, 1H), 0.77-0.64 (m, 2H), 0.58-0.51 (m, 1H), 0.42-0.36 (m, 1H). The enantiomers were randomly assigned; the absolute configuration was not determined.120039.000211 (TYRA041PCT)Exampl e 38. (S, E)-7-(Azetidin- 1 -y 1 )- 3 -( 1 -cy clopropyl-3 -(methyl sulfonyl)allyl)- 1 -phenylpyrido[3,4-d]pyridazin-4(3H)-one, and Example 39 (R, E)-7-(azetidin-l-yl)-3-(l-cy clopropyl-3 -(methyl sulfonyl)allyl)-l-phenylpyrido[3,4-d]pyridazin-4(3H)-one.

[0424] Step 1. 6-Chloro-4-(hydroxy(phenyl)methyl)nicotinic acid. To a solution of 6-chloronicotinic acid (5.00 g, 31.7 mmol, 1.0 eq) and 2,2,6,6-tetramethyl-piperidine (6.72 g, 47.6 mmol, 1.5 eq) in anhydrous tetrahydrofuran (50 mL) was added n-butyllithium (63.5 mL, 159 mmol, 5.0 eq) dropwise at -60 °C under nitrogen. The reaction mixture was stirred for 0.5 h at -60 °C then a solution of benzaldehyde (5.05 g, 47.6 mmol, 1.5 eq) in anhydrous tetrahydrofuran (50 mL) was added dropwise at -60 °C. The reaction mixture was then stirred for 2 h at 0 °C. Methanol was then added slowly (20 mL) at 0 °C. The volatiles were removed under reduced pressure to afford 6-chloro-4-(hydroxy(phenyl)methyl)nicotinic acid (8.0 g) as a brown solid. The material was used without purification. LCMS m / z = 264.2 (M + 1).

[0425] Step 2. 4-Benzoyl-6-chloronicotinic acid. To a solution of 6-chloro-4-(hydroxy(phenyl)methyl)nicotinic acid (6.0 g) in dichloromethane (60 mL) was added 1,1,1-tris(acetyloxy)-l,l-dihydro-l,2-benziodoxol-3-(lH)-one (19.3 g, 45.5 mmol, 2.0 eq) at 0 °C, and the resulting mixture was stirred at room temperature for 16 h. This mixture was used directly in the next step. LCMS m / z = 262.2 (M + 1).

[0426] Step 3. Methyl 4-benzoyl-6-chloronicotinate. To the solution of 4-benzoyl-6-chloronicotinic acid from step 2 (60 mL) was added potassium carbonate (8.3 g, 60 mmol) and methyl iodide (6.5 g, 45.5 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with water (100 mL) and extracted with120039.000211 (TYRA041PCT)di chloromethane (3 x 40 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate = 3 / 1) to afford methyl 4-benzoyl-6-chloronicotinate (3.0 g) as a yellow solid. LCMS m / z = 276.2 (M + 1).

[0427] Step 4. Methyl 6-(azetidin-l-yl)-4-benzoylnicotinate. To a solution of methyl 4-benzoyl-6-chloronicotinate (600 mg, 2.18 mmol, 1.0 eq) in dimethyl sulfoxide (10 mL) was added potassium carbonate (901.02 mg, 6.53 mmol, 3.0 eq) and azetidine (248 mg, 4.36 mmol, 2.0 eq). The reaction mixture was stirred for 16 h at 100 °C. The mixture was cooled and diluted with ethyl acetate (50 mL), and washed with brine (3 x 20 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate = 1 / 1) to afford methyl 6-(azetidin-l-yl)-4-benzoylnicotinate (260 mg, 40% yield) as a yellow solid. LCMS m / z = 297.3 (M + 1).

[0428] Step 5. 7-(Azetidin-l-yl)-l-phenylpyrido[3,4-d]pyridazin-4(3H)-one. To a solution of methyl 6-(azetidin-l-yl)-4-benzoylnicotinate (240 mg, 0.810 mmol, 1.0 eq) in ethanol (5 mL) was added hydrazine hydrate (0.5 mL). The reaction solution was stirred at room temperature for 2 h. The mixture was diluted with water and the solid was collected by filtration and dried to afford 7-(Azetidin-l-yl)-l-phenylpyrido[3,4-d]pyridazin-4(3H)-one (200 mg, 89% yield) as a white solid. LCMS m / z = 279.3 (M + 1).

[0429] Step 6. Ethyl 2-(7-(azetidin-l-yl)-4-oxo-l-phenylpyrido[3,4-d]pyridazin-3(4H)-yl)-2-cyclopropylacetate. To a solution of 7-(azetidin-l-yl)-l-phenylpyrido[3,4-d]pyridazin-4(3H)-one (180 mg, 0.647 mmol, 1.0 eq) and ethyl 2-bromo-2-cyclopropylacetate (201 mg, 970 mmol, 1.5 eq) in N, N-dimethylformamide (5 mL) was added cesium carbonate (420 mg, 1.29 mmol, 2.0 eq) at 0 °C. The reaction mixture was then stirred at room temperature for 2 h. The mixture was diluted with ethyl acetate (20 mL) and washed with brine (3 x 5 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate = 1 / 1) to afford ethyl 2-(7-(azetidin-l-yl)-4-oxo-l-phenylpyrido[3,4-d]pyridazin-3(4H)-yl)-2-cyclopropylacetate (180 mg, 69% yield) as a yellow solid. LCMS m / z = 405.3 (M + 1).

[0430] (S, E)-7-(Azetidin- 1 -y l)-3 -( 1 -cy clopropyl-3 -(methyl sulfonyl)allyl)- 1 -phenylpyrido[3,4-d]pyridazin-4(3H)-one was prepared using ethyl 2-(7-(azetidin-l-yl)-4-oxo-120039.000211 (TYRA041PCT)l-phenylpyrido[3,4-d]pyridazin-3(4H)-yl)-2-cyclopropylacetate from step 6 as described in Example 4 and purified on a chiral stationary phase following the SFC method described for Example 5 and Example 6 to give (S, E)-7-(azetidin-l-yl)-3-(l-cyclopropyl-3- (m ethyl sulfonyl)allyl)-l-phenylpyrido[3,4-d]pyridazin-4(3H)-one. LCMS m / z = 437.4 (M + 1); 'H-NMR (400 MHz, DMSO-d6) δ 9.07 (s, 1H), 7.65-7.64 (m, 2H), 7.56-7.55 (m, 3H), 6.95-6.91 (m, 2H), 6.15 (s, 1H), 4.99-4.96 (m, 1H), 4.06 (t, J= 7.2 Hz, 4H), 3.02 (s, 3H), 2.38-2.35 (m, 2H), 1.50-1.48 (m, 1H), 0.71-0.69 (m, 1H), 0.64-0.62 (m, 1H), 0.53-0.51 (m, 1H), 0.39-0.37 (m, 1H). Also obtained was (R, E)-7-(azetidin-l-yl)-3-(l-cyclopropyl-3- (m ethyl sulfonyl)allyl)-l-phenylpyrido[3,4-d]pyridazin-4(3H)-one. LCMS m / z = 437.4 (M + 1); 'H-NMR (400 MHz, DMSO-d6) δ 9.07 (s, 1H), 7.66-7.64 (m, 2H), 7.56-7.55 (m, 3H), 6.95-6.94 (m, 2H), 6.15 (s, 1H), 4.98-4.96 (m, 1H), 4.06 (t, J =7.2 Hz, 4H), 3.02 (s, 3H), 2.38-2.44 (m, 2H), 1.50-1.48 (m, 1H), 0.72-0.69 (m, 1H), 0.64-0.61 (m, 1H), 0.53-0.51 (m, 1H), 0.39-0.37 (m, 1H). The enantiomers were randomly assigned; the absolute configuration was not determined.Example 40. (E)-5-(Cyclopentylmethyl)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6-phenylpyridazin-3(2H)-one.

[0431] Step 1. 3-Cyclopentyl-N-methoxy-N-methylpropanamide. To a solution of 3 -cyclopentylpropanoic acid (5.0 g, 35.16 mmol, 1.0 eq) in dichloromethane (50 ml) was added CDI (6.8 g, 42.20 mmol, 1.2 eq) at 5 °C and stirred for 1 h, then a mixture of N, O-dimethylhydroxylamine hydrochloride (4.1 g, 42.20 mmol, 1.2 eq) and triethylamine (5.3 g, 52.74 mmol, 1.5 eq) in dichloromethane (100 ml) was added. The reaction mixture was then warmed to room temperature and stirred for 4 h. The mixture was poured into water (50 mL)120039.000211 (TYRA041PCT)and extracted with dichloromethane (2 x 100 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to afford 3-cyclopentyl-N-methoxy-N-methylpropanamide (6.0 g, 92% yield) as yellow liquid. LCMS m / z = 186.3 (M+ 1)

[0432] Step 2. 3 -Cyclopentyl- 1-phenylpropan-l -one. To a solution of 3-cyclopentyl-N-methoxy-N-methylpropanamide (5.5 g, 29.69 mmol, 1.0 eq) in anhydrous tetrahydrofuran (50 mL) was added phenylmagnesium bromide (15.9 ml, 44.53 mmol, 2.8 M in tetrahydrofuran, 1.5 eq) dropwise at 0 °C and the reaction was stirred at 0 °C for 2 h. The mixture was poured into the saturated ammonium chloride solution and extracted with ethyl acetate (2 x 100 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude was purified by silica gel chromatography (petroleum ether) to afford 3 -cyclopentyl- 1-phenylpropan-l -one (3.5 g, 58% yield) as a yellow solid. LCMS m / z = 203.3 (M + 1)

[0433] Step 3. 3-(Cyclopentylmethyl)-4-oxo-4-phenylbut-2-enoic acid. To a solution of 3 -cyclopentyl- 1-phenylpropan-l -one (2.0 g, 9.89 mmol, 1.0 eq) in phosphoric acid (40 ml) was added glyoxalic acid (14.6 g, 98.87 mmol, 10.0 eq, 50% in water). The reaction was then stirred at 120 °C for 48 h. The mixture was poured into ice-water and extracted with di chloromethane (2 x 100 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford 3-(cyclopentylmethyl)-4-oxo-4-phenylbut-2-enoic acid (2.4 g) as a yellow solid. LCMS m / z = 259.3 (M + 1)

[0434] Step 4. Methyl (Z)-3-(cyclopentylmethyl)-4-oxo-4-phenylbut-2-enoate. To a solution of 3-(cyclopentylmethyl)-4-oxo-4-phenylbut-2-enoic acid (2.0 g, 7.74 mmol, 1.0 eq) in acetonitrile (100 ml) was added potassium carbonate (13.2 g, 23.23 mmol, 3.0 eq) and methyl iodide (4.4 g, 30.97 mmol, 4.0 eq). The reaction was stirred at room temperature for 16 h. The mixture was then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 20 / 1) to afford methyl (Z)-3-(cyclopentylmethyl)-4-oxo-4-phenylbut-2-enoate (300 mg, 14% yield) as a yellow solid. LCMS m / z = 273.3 (M + 1)

[0435] Step 5. 5-(Cyclopentylmethyl)-6-phenylpyridazin-3(2H)-one. To a solution of methyl (Z)-3-(cyclopentylmethyl)-4-oxo-4-phenylbut-2-enoate (300 mg, 1.10 mmol, 1.0 eq) in ethanol (10 ml) was added hydrazine hydrate (275 mg, 5.51 mmol, 5.0 eq) and the120039.000211 (TYRA041PCT)reaction was stirred at 80 °C for 2 h. The mixture was cooled and diluted withdi chloromethane (50 mL) washed with brine (2 x 20 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by Prep-TLC (petroleum ether / ethyl acetate = 5 / 1) to afford 5-(cyclopentylmethyl)-6-phenylpyridazin-3(2H)-one (250 mg, 89% yield) as a white solid. LCMS m / z = 255.3 (M +

[0436] Step 6. Ethyl 2-(4-(cyclopentylmethyl)-6-oxo-3-phenylpyridazin-l(6H)-yl)-2-cyclopropylacetate. To a solution of 5-(cyclopentylmethyl)-6-phenylpyridazin-3(2H)-one (250 mg, 0.98 mmol, 1.0 eq) in N, N-dimethylformamide (4 ml) was added cesium carbonate (641 mg, 1.97 mmol, 2.0 eq) and ethyl 2-bromo-2-cyclopropylacetate (305 mg, 1.47 mmol, 1.5 eq) and the reaction was stirred at room temperature for 2 h. The mixture was diluted with ethyl acetate (50 mL) and washed with brine (2 x 20 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by Prep-TLC (petroleum ether / ethyl acetate = 10 / 1) to afford ethyl 2-(4-(cyclopentylmethyl)-6-oxo-3 -phenylpyridazin-l(6H)-yl)-2-cy cl opropyl acetate (300 mg, 80% yield) as yellow oil. LCMS m / z = 381.3 (M + 1)

[0437] (E)-5-(Cyclopentylmethyl)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6-phenylpyridazin-3(2H)-one was prepared using ethyl 2-(4-(cyclopentylmethyl)-6-oxo-3-phenylpyridazin-l(6H)-yl)-2-cyclopropylacetate from step 6 as described in Example 4. LCMS m / z = 413.3 (M + 1); ¹H-NMR (400 MHz, DMSO-d6) δ 7.50-7.46 (m, 5H), 6.92-6.91 (m, 3H), 4.97-4.93 (m, 1H), 3.03 (s, 3H), 2.52-2.51 (m, 2H), 1.87-1.80 (m, 1H), 1.58-1.37 (m, 7H), 1.04-0.96 (m, 2H), 0.72-0.48 (m, 3H), 0.39-0.33 (m, 1H).u! OExample 41. (E)-5-(Cyclopentyloxy)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6-phenylpyridazin-3(2H)-one.120039.000211 (TYRA041PCT)

[0438] Step 1. Ethyl 2-(4-bromo-6-oxo-3-phenylpyridazin-l(6H)-yl)-2-cyclopropylacetate. To a solution of 5-bromo-6-phenylpyridazin-3(2H)-one (1.00 g, 3.98 mmol, 1.0 eq) and ethyl 2-bromo-2-cyclopropylacetate (3.30 g, 15.93 mmol, 4.0 eq) inN, N-dimethylformamide (25 mL) was added cesium carbonate (2.50 g, 7.97 mmol, 2.0 eq) at 0 °C, and the resulting mixture was stirred at room temperature for 4 h. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (2 x 30 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10 / 1) to give ethyl 2-(4-bromo-6-oxo-3-phenylpyridazin-l(6H)-yl)-2-cyclopropylacetate (1.20 g, 80% yield) as light-yellow oil. LCMS m / z = 377.1 (M + 1)

[0439] Step 2. 2-(4-(Cyclopentyloxy)-6-oxo-3-phenylpyridazin-l(6H)-yl)-2-cyclopropylacetic acid. To a solution of ethyl 2-(4-bromo-6-oxo-3-phenylpyridazin-l(6H)-yl)-2-cyclopropylacetate (1.00 g, 2.65 mmol, 1.0 eq) and cyclopentanol (2.28 g, 26.51 mmol, 10.0 eq) in N, N-dimethylformamide (20 mL) was added cesium carbonate (5.18 g, 15.91 mmol, 6.0 eq) and the resulting mixture was stirred for 16 h at 120 °C. The mixture was cooled, and the pH was adjusted to ~5 by addition of aqueous hydrochloric acid (IN). The mixture was then extracted with ethyl acetate (2 x 50 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give 2-(4-(cyclopentyloxy)-6-oxo-3-phenylpyridazin-l(6H)-yl)-2-cyclopropylacetic acid (1.50 g) as light-yellow oil. LCMS m / z = 355.3 (M + 1)

[0440] Step 3. S-Ethyl 2-(4-(cyclopentyloxy)-6-oxo-3-phenylpyridazin-l(6H)-yl)-2-cyclopropylethanethioate.

[0441] To a solution of 2-(4-(Cyclopentyloxy)-6-oxo-3-phenylpyridazin-l(6H)-yl)-2-cyclopropylacetic acid (1 g, crude) and ethanethiol (876 mg, 14.11 mmol, 5.0 eq) in N, N-dimethylformamide (20 mL) were added N, N-diisopropylethylamine (1.46 g, 11.29 mmol, 4.0 eq) and l-[bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (2.14 g, 5.64 mmol, 2.0 eq). The resulting mixture was stirred at room temperature for 6 h. The mixture was then diluted with water (60 mL) and extracted with ethyl acetate (2 x 60 mL). The combined organic layers were dried over sodium sulfate,120039.000211 (TYRA041PCT)filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 4 / 1) to give S-ethyl 2-(4-(cyclopentyloxy)-6-oxo-3-phenylpyridazin-l(6H)-yl)-2-cyclopropylethanethioate (550 mg, 49% yield) as lightyellow oil. LCMS m / z = 399.3 (M + 1)

[0442] Step 4. 2-(4-(Cyclopentyloxy)-6-oxo-3-phenylpyridazin-l(6H)-yl)-2-cyclopropylacetaldehyde. To a solution of S-ethyl 2-(4-(cyclopentyloxy)-6-oxo-3-phenylpyridazin-l(6H)-yl)-2-cyclopropylethanethioate (85 mg, 0.21 mmol, 1.0 eq) and palladium(II) acetate (7.23 mg, 0.031 mmol, 0.15 eq) in acetone (2 ml) was addedtri ethyl silane (247 mg, 2.13 mmol, 10.0 eq) at -70 °C, and the resulting mixture was slowly warmed to 10 °C and stirred for 1 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give 2-(4-(cyclopentyloxy)-6-oxo-3-phenylpyridazin-l(6H)-yl)-2-cyclopropylacetaldehyde (72 mg) as colorless oil. This material was used directly in the next step. LCMS m / z = 339.3 (M + 1)

[0443] Step 5: (E)-5-(Cyclopentyloxy)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6-phenylpyridazin-3(2H)-one. To a solution of 2-(4-(cyclopentyloxy)-6-oxo-3-phenylpyridazin-l(6H)-yl)-2-cyclopropylacetaldehyde (144 mg, crude) and diethyl ((methylsulfonyl)methyl)phosphonate (172 mg, 0.85 mmol, 2.0 eq) in tetrahydrofuran (3 mL) was added potassium carbonate (176 mg, 1.28 mmol, 3.0 eq), and the resulting mixture was stirred at 60 °C for 6 h. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (2 x 30 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (petroleum ether / ethyl acetate = 1 / 1) and further purified by Prep-HPLC (Prep-C18, 5 μM Triart column, 20 x 150 mm, YMC-Actus; gradient elution of 50% acetonitrile in water to 70% acetonitrile in water over a 8 min period, where both solvents contain 0.05% ammonium hydroxide) to give (E)-5-(cyclopentyloxy)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6-phenylpyridazin-3(2H)-one (27.7 mg, 16% yield) as a white solid. LCMS m / z = 415.3 (M + 1); 'H-NMR (400 MHz, DMSO-d6) 7.68-7.65 (m, 2H), 7.46-7.43 (m, 3H), 6.96-6.87 (m, 2H), 6.39 (s, 1H), 4.97-4.92 (m, 2H), 3.03 (s, 3H), 1.96-1.53 (m, 8H), 1.53-1.45 (m, 1H), 0.73-0.49 (m, 3H), 0.38-0.33 (m, 1H).120039.000211 (TYRA041PCT)2-(1,1-dif1uoroethyl)-8-phenylpyrimido[4,5- Methyl 1-(2-(1,1-difluoroethyl)-5-oxo-8-phenylpyrimido[4,5-d]pyridazin-5(6H)-one d]pyridazin-6(5H)-yl)cyclopropane-1-carboxylateExample 42. (E)-2-(l,l-Difluoroethyl)-6-(l-(2-(methylsulfonyl)vinyl)cyclopropyl)-8-phenylpyrimido[4,5-d]pyridazin-5(6H)-one.

[0444] Methyl l-(2-(l,l-difluoroethyl)-5-oxo-8-phenylpyrimido[4,5-d]pyridazin-6(5H)-yl)cyclopropane-l -carboxylate. To a solution of 2-(l,l-difluoroethyl)-8-phenylpyrimido[4,5-d]pyridazin-5(6H)-one from step 8 in Example 4 (800 mg, 2.8 mmol, 1.0 eq) in N, N-dimethylformamide (60 mL) was added cesium carbonate (7.3 g, 22.4 mmol, 8.0 eq) and methyl 2,4-dibromobutanoate (1.4 g, 5.1 mmol, 1.8 eq). The reaction mixture was stirred at 45 °C for 2 h. The reaction mixture was then cooled and filtered. The filtrate was then diluted with water (60 mL) and extracted with ethyl acetate (3 x 60 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate = 50 / 1 to 4 / 1) to afford methyl l-(2-(l,l-difluoroethyl)-5-oxo-8-phenylpyrimido[4,5-d]pyridazin-6(5H)-yl)cyclopropane-l-carboxylate (270 mg, 24% yield) as a light yellow solid. LCMS m / z = 387.2 (M + 1)

[0445] (E)-2-(l,l-difluoroethyl)-6-(l-(2-(methylsulfonyl)vinyl)cyclopropyl)-8-phenylpyrimido[4,5-d]pyridazin-5(6H)-one was then prepared using methyl l-(2-(l,l-difluoroethyl)-5-oxo-8-phenylpyrimido[4,5-d]pyridazin-6(5H)-yl)cyclopropane-l-carboxylate as described for Example 4. LCMS m / z = 433.4 (M + 1); ¹H-NMR (400 MHz, DMSO-d6) δ 9.89 (s, 1H), 8.02-7.91 (m, 2H), 7.62-7.50 (m, 3H), 6.73 (d, J= 15.2 Hz, 1H), 6.65 (d, J= 14.8 Hz, 1H), 2.91 (s, 3H), 2.10 (t, J= 19.2 Hz, 3H), 1.75-1.65 (m, 4H).120039.000211 (TYRA041PCT)Step 1 Step 22-cyclopropyl-2-(2-(1,1 -difluoroethyl)-5-oxo-8-phenylpyrimido[4,5-d]pyridazin-6(5H)-yl)acetaldehydeStep 3Example 47Example 47. (E)-3-Cyclopropyl-3-(2-(l,l-difluoroethyl)-5-oxo-8-phenylpyrimido[4,5-d]pyridazin-6(5H)-yl)-N, N-dimethylprop-l-ene-l-sulfonamide.

[0446] Step 1. Ethyl (E)-3-cyclopropyl-3-(2-(l,l-difluoroethyl)-5-oxo-8-phenylpyrimido[4,5-d]pyridazin-6(5H)-yl)prop-l-ene-l-sulfonate. To a solution of 2-cyclopropyl-2-(2-(l,l-difluoroethyl)-5-oxo-8-phenylpyrimido[4,5-d]pyridazin-6(5H)-yl)acetaldehyde from step 10, Example 4, (390 mg, 1.05 mmol, 1.0 eq) and potassium carbonate (724 mg, 5.26 mmol, 5.0 eq) in tetrahydrofuran (10 mL) was added ethyl (dimethoxyphosphoryl)methanesulfonate (487 mg, 2.10 mmol, 2.0 eq). The reaction mixture was stirred at 60 °C for 6 h. The mixture was cooled and diluted with ethyl acetate (20 mL) and washed with water (10 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate = 2 / 1) to afford ethyl (E)-3-cyclopropyl-3-(2-(l,l-difluoroethyl)-5-oxo-8-phenylpyrimido[4,5-d]pyridazin-6(5H)-yl)prop-l-ene-l-sulfonate (355 mg, 76% yield) as a white solid. LCMS m / z = 477.3 (M + 1)

[0447] Step 2. (E)-3-Cyclopropyl-3-(2-(l,l-difluoroethyl)-5-oxo-8-phenylpyrimido[4,5-d]pyridazin-6(5H)-yl)prop-l-ene-l-sulfonyl chloride. To a solution of ethyl (E)-3-cyclopropyl-3-(2-(l,l-difluoroethyl)-5-oxo-8-phenylpyrimido[4,5-d]pyridazin-6(5H)-yl)prop-l-ene-l -sulfonate (290 mg, 0.61 mmol, 1.0 eq) in acetone (5 mL) was added tetrabutyl ammonium iodide (449 mg, 1.22 mmol, 2.0 eq) and the reaction mixture was stirred at 50 °C for 16 h. The mixture was then concentrated under reduced pressure. The residue120039.000211 (TYRA041PCT)was dissolved in di chloromethane (5 mL) and washed with water (3 x 2 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was then redissolved in dichloromethane (1 mL). In a separate flask containing a solution of triphenylphosphine (307 mg, 1.22 mmol, 2.0 eq) in dichloromethane (4 mL) was added SO2CI2 (181 mg, 1.34 mmol, 2.2 eq) in dichloromethane (1 mL) at 0 °C. This mixture was stirred at room temperature for 30 min and then was added to the initial intermediate in di chloromethane at 0 °C under nitrogen. This resulting solution was stirred for 2 h then used directly in the next step. LCMS m / z = 467.1 (M + 1)

[0448] Step 3. (E)-3-Cyclopropyl-3-(2-(l,l-difluoroethyl)-5-oxo-8-phenylpyrimido[4,5-d]pyridazin-6(5H)-yl)-N, N-dimethylprop-l-ene-l-sulfonamide. To the solution of (E)-3-cyclopropyl-3-(2-(l,l-difhioroethyl)-5-oxo-8-phenylpyrimido[4,5-d]pyridazin-6(5H)-yl)prop-l-ene-l -sulfonyl chloride (0.2 mmol, 2 mL) from step 2 was added dimethylamine (189 mg, 4.2 mmol, 1.0 eq) and N, N-diisopropylethylamine (542 mg, 4.2 mmol, 1.0 eq) in anhydrous dichloromethane (1 mL) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. The mixture was then diluted with dichloromethane (5 mL), and was washed with water (5 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by Prep-HPLC (Prep-C18, 5 μM Triart column, 20 × 150 mm, YMC-Actus; gradient elution of 30 % acetonitrile in water to 55 % acetonitrile in water over an 8 min period, where both solvents contain 0.05% ammonium hydroxide) to give (E)-3-cyclopropyl-3-(2-(l,l-difluoroethyl)-5-oxo-8-phenylpyrimido[4,5-d]pyridazin-6(5H)-yl)-N, N-dimethylprop-l-ene-l-sulfonamide (4.9 mg, 5% yield) as a white solid. LCMS m / z = 476.1 (M + 1); ¹H-NMR (400 MHz, DMSO-d6) δ 9.89 (s, 1H), 8.04-8.00 (m, 2H), 7.59-7.52 (m, 3H), 6.88 (dd, J= 15.6 Hz, 4.8 Hz, 1H), 6.75 (dd, J= 15.2 Hz, 1.2 Hz, 1H), 5.13-5.10 (m, 1H), 2.63 (s, 6H), 2.10 (t, J= 19.6 Hz, 3H), 1.66-1.57 (m, 1H), 0.79-0.70 (m, 2H), 0.60-0.53 (m, 1H), 0.48-0.41 (m, 1H) Example 49. (E)-6-(l-Cyclopropyl-3-(morpholinosulfonyl)allyl)-2-(l,l-difluoroethyl)-8-phenylpyrimido[4,5-d]pyridazin-5(6H)-one.

[0449] This example was synthesized using the procedure for Example 47 using morpholine. LCMS m / z = 518.1 (M + 1); ¹H-NMR (400 MHz, DMSO-d6) δ 9.90 (s, 1H), 8.04-8.01 (m, 2H), 7.58-7.54 (m, 3H), 6.90 (dd, J= 15.2 Hz, 4.4 Hz, 1H), 6.79 (dd, J= 15.2120039.000211 (TYRA041PCT)Hz, 1.6 Hz, 1H), 5.16-5.12 (m, 1H), 3.65-3.56 (m, 4H), 3.04-2.95 (m, 4H), 2.10 (t, J= 19.2 Hz, 3H), 1.67-1.58 (m, 1H), 0.80-0.72 (m, 2H), 0.60-0.53 (m, 1H), 0.49-0.40 (m, 1H).Example 50. (E)-3-Cyclopropyl-3-(2-(l,l-difluoroethyl)-5-oxo-8-phenylpyrimido[4,5-d]pyridazin-6(5H)-yl)-N-methylprop-l-ene-l-sulfonamide.

[0450] This example was synthesized using the procedure for Example 47 using methyl amine. LCMS m / z = 462.0 (M + 1); ¹H-NMR (400 MHz, DMSO-d6) δ 9.89 (s, 1H), 8.04-8.01 (m, 2H), 7.59-7.54 (m, 3H), 7.13-7.09 (m, 1H), 6.83 (dd, J= 15.6 Hz, 5.2 Hz, 1H), 6.67 (dd, J= 15.2 Hz, 1.6 Hz, 1H), 5.13-5.09 (m, 1H), 2.47 (d, J= 4.8 Hz, 3H), 2.10 (t, J = 19.6 Hz, 3H), 1.64-1.55 (m, 1H), 0.79-0.69 (m, 2H), 0.58-0.52 (m, 1H), 0.46-0.40 (m, 1H).Example 51. (S, E)-6-(l-Cyclopropyl-3-(methylsulfonyl)allyl)-2-(l, l-difluoroethyl)-8-phenylpyrido[2,3-d]pyridazin-5(6H)-one, and Example 52 (R, E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(l,l-difluoroethyl)-8-phenylpyrido[2,3-d]pyridazin-5(6H)-one.

[0451] Step 1. Methyl 6-(l,l-difluoroethyl)nicotinate. To a solution of methyl 6-acetylnicotinate (3.0 g, 16.8 mmol, 1.0 eq) in dichloromethane (20 mL) was added di ethylaminosulfur trifluoride (20 mL) and the reaction mixture was stirred at 35 °C for 24 h The mixture was slowly added dropwise into ice water. The pH of the resulting mixture was adjusted to ~7-8 by the addition of saturated aqueous sodium bicarbonate and then extracted with di chloromethane (3 x 50 mL). The combined organic layers were dried over sodium120039.000211 (TYRA041PCT)sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate = 50 / 1 to 20 / 1) to afford methyl 6-(l,l-difluoroethyl)nicotinate (3.0 g, 89% yield) as brown oil. LCMS m / z = 202.2 (M + 1)

[0452] Step 2. 2-(l,l-Difluoroethyl)-5-(methoxycarbonyl)pyridine 1-oxide. To a solution of methyl 6-(l,l-difhioroethyl)nicotinate (2.8 g, 13.9 mmol, 1.0 eq) indi chloromethane (40 mL) was added meta-chloroperoxybenzoic acid (5.63 g, 27.84 mmol, 85% purity, 2.0 eq) at 0 °C and then the reaction mixture was warmed to 45 °C and stirred for 48 h. The mixture was cooled and poured into an aqueous solution of sodium hydrosulfite (aq.) at 0 °C. The pH was adjusted to ~7-8 by addition of saturated aqueous sodium bicarbonate. The mixture was then extracted with dichloromethane (3 x 50 mL) and the combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 20 / 1 to 1 / 1) to afford 2-(l,l-difluoroethyl)-5-(methoxycarbonyl)pyridine 1-oxide (2.5 g, 83% yield) as a white solid. LCMS m / z = 218.2 (M + 1)

[0453] Step 3. Methyl 2-chloro-6-(l,l-difluoroethyl)nicotinate. A solution of 2-(l,l-difluoroethyl)-5-(methoxycarbonyl)pyridine 1-oxide (2.5 g, 11.51 mmol, 1.0 eq) in phosphorus oxychloride (30 mL) was stirred at 100 °C for 8 h. The cooled reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 50 / 1 to 20 / 1) to afford methyl 2-chloro-6-(l,l-difluoroethyl)nicotinate (2.4 g, 88% yield) as colorless oil. LCMS m / z = 236.1 (M + 1)

[0454] Step 4. Methyl 2-benzoyl-6-(l,l-difluoroethyl)nicotinate. To a solution of methyl 2-chloro-6-(l,l-difluoroethyl)nicotinate (2.1 g, 8.91 mmol, 1.0 eq) in tetrahydrofuran (80 mL) was added palladium(II) acetate (400 mg, 1.78 mmol, 0.2 eq), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (2.06 g, 3.57 mmol, 0.4 eq ) and 2-((tert-butyldimethylsilyl)oxy)-2-phenylacetonitrile (4.41g, 17.8 mmol, 2.0 eq) under nitrogen. The mixture was cooled to 0 °C and lithium bis(trimethylsilyl)amide (9.80 mL, IM in tetrahydrofuran, 9.8 mmol, 1.1 eq) was added. The reaction mixture was then stirred at room temperature for 16 h. The mixture was re-cooled to 0 °C and tetrabutylammonium fluoride (4.7 g, 17.8 mmol, 2.0 eq) was added and the resulting solution was stirred at room temperature for 2 h. The mixture was diluted with water (80 mL) and then extracted with ethyl acetate (3 x 80 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel120039.000211 (TYRA041PCT)chromatography (petroleum ether / ethyl acetate = 30 / 1 to 6 / 1) to afford methyl 2-benzoyl-6-(l,l-difluoroethyl)nicotinate (630 mg, 23% yield) as brown oil. LCMS m / z = 306.2 (M + 1)

[0455] Step 5. 2-(l,l-Difluoroethyl)-8-phenylpyrido[2,3-d]pyridazin-5(6H)-one. To a solution of methyl 2-benzoyl-6-(l,l-difluoroethyl)nicotinate (600 mg, 1.97 mmol, 1.0 eq) in ethanol (10 mL) was added hydrazine hydrate (630 mg, 19.7 mmol, 10.0 eq). The reaction mixture was then stirred at 50 °C for 2 h. The reaction mixture was then diluted with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to afford 2-(l,l-difluoroethyl)-8-phenylpyrido[2,3-d]pyridazin-5(6H)-one (500 mg, 88% yield) as a yellow solid. LCMS m / z = 288.2 (M + 1)

[0456] (E)-6-(l -Cyclopropyl-3 -(methyl sulfonyl)allyl)-2-( 1, 1 -difluoroethyl)-8-phenylpyrido[2,3-d]pyridazin-5(6H)-one was prepared using 2-(l,l-difluoroethyl)-8-phenylpyrido[2,3-d]pyridazin-5(6H)-one according to Example 4 and then purified on a chiral stationary phase to afford (S, E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(l,l-difluoroethyl)-8-phenylpyrido[2,3-d]pyridazin-5(6H)-one (56.7 mg, 33%) as a white solid. LCMS m / z = 446.1 (M + 1); ¹H-NMR (400 MHz, DMSO-d6) δ 8.91 (d, J= 8.8 Hz, 1H), 8.21 (d, J= 8.4 Hz, 1H), 8.04-7.95 (m, 2H), 7.59-7.48 (m, 3H), 7.07-6.96 (m, 2H), 5.09 (dd, J = 9.6 Hz, 2.4 Hz, 1H), 3.02 (s, 3H), 2.07 (t, J= 19.2 Hz, 3H), 1.67-1.56 (m, 1H), 0.82-0.67 (m, 2H), 0.60-0.50 (m, 1H), 0.45-0.36 (m, 1H); and (R, E)-6-(l -cyclopropyl-3 -(methylsulfonyl)allyl)-2-(l,l-difluoroethyl)-8-phenylpyrido[2,3-d]pyridazin-5(6H)-one (56.8 mg, 34%) as a white solid. LCMS m / z = 446.0 (M + 1); 'H-NMR (400 MHz, DMSO-d6) 6 8.91 (d, J= 8.4 Hz, 1H), 8.21 (d, J= 8.4 Hz, 1H), 8.03-7.95 (m, 2H), 7.60-7.48 (m, 3H), 7.07-6.96 (m, 2H), 5.10 (dd, J= 9.6 Hz, 2.4 Hz, 1H), 3.02 (s, 3H), 2.07 (t, J= 19.2 Hz, 3H), 1.68-1.56 (m, 1H), 0.82-0.67 (m, 2H), 0.62-0.49 (m, 1H), 0.46-0.35 (m, 1H). The enantiomers were randomly assigned; the absolute configuration was not determined.

[0457] Instrument: Waters UPC2 analytical SFC (SFC-H)

[0458] Column: YMC CHIRAL ART Cellulose-SC, 250x20mm, 5um

[0459] Mobile phase: EtOH-hexane

[0460] Gradient: B 40 % - 40 %

[0461] Flow rate: 2.5 mL / min

[0462] Back pressure: 100 bar

[0463] Column temperature: 35°C120039.000211 (TYRA041PCT)

[0464] Wavelength: 254 nmExample 56. (E)-5-Cyclobutoxy-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6-phenylpyridazin-3(2H)-one.o YA 1 rau. / 9O'

[0465] This example was synthesized using the procedure for Example 41 using cyclobutanol. LCMS m / z =401.1(M + 1); ’H-NMR (400 MHz, DMSO-d6) δ 7.72-7.70 (m, 2H), 7.49-7.45 (m, 3H), 6.91-6.90 (m, 2H), 6.22 (s, 1H), 4.94-4.91 (m, 1H), 4.87-4.80 (m, 1H), 3.03 (s, 3H), 2.50-2.43 (m, 2H), 2.14-2.04 (m, 2H), 1.85-1.77 (m, 1H), 1.70-1.61 (m, 1H), 1.52-1.43 (m, 1H), 0.73-0.66 (m, 1H), 0.63-0.57 (m, 1H), 0.55-0.48 (m, 1H), 0.37-0.31 (m, 1H).

[0466] Example 60. (E)-5-(cyclopentyloxy)-2-(4-(methylsulfonyl)but-3-en-2-yl)-6-phenylpyridazin-3(2H)-one.A01 I 9. O

[0467] This example was synthesized using the procedure for Example 41 using ethyl 2-bromopropanoate. LCMS m / z = 389.1 (M + 1); ¹H-NMR (400 MHz, DMSO-d6) δ 7.65-7.63 (m, 2H), 7.46-7.42 (m, 3H), 6.89-6.77 (m, 2H), 6.39 (s, 1H), 5.83-5.76 (m, 1H), 4.96-4.93 (m, 1H), 3.01 (s, 3H), 1.97-1.89 (m, 2H), 1.77-1.70 (m, 2H), 1.67-1.56 (m, 4H), 1.50 (d, J = 7.2 Hz, 3H).Example 61. (E)-2-(l-Cyclopropyl-3-(methylsulfonyl)allyl)-5-(cyclopropylmethoxy)-6-phenylpyridazin-3(2H)-one.A o YN^X;^s 9'. o'

[0468] This example was synthesized using the procedure for Example 41 using cyclopropylmethanol. LCMS m / z = 401.1 (M + 1); ¹H-NMR (400 MHz, DMSO-d6) δ 7.75-7.72 (m, 2H), 7.47-7.46 (m, 3H), 6.92-6.86 (m, 2H), 6.40 (s, 1H), 4.94 (dd, J= 10.0 Hz, 3.6120039.000211 (TYRA041PCT)Hz, 1H), 3.96 (d, J= 7.2 Hz, 2H), 3.03 (s, 3H), 1.50-1.47 (m, 1H), 1.46-1.23 (m, 1H), 0.59-0.35 (m, 8H).Example 62. (E)-7-Cyclopropyl-3-(l-cyclopropyl-3-(methylsulfonyl)allyl)-l-phenylpyrido[3,4-d]pyridazin-4(3H)-one-011 Y 1 fflx- PO'

[0469] This example was synthesized using the procedure for Example 4 using methyl 4-chloro-6-cyclopropylnicotinate. LCMS m / z = 422.1 (M + 1); ’H-NMR (400 MHz, DMSO-d6) δ 9.40 (s, 1H), 7.70-7.67 (m, 2H), 7.63-7.59 (m, 3H), 7.54 (s, 1H), 6.99-6.95 (m, 2H), 5.05-5.03 (m, 1H), 3.01 (s, 3H), 2.41-2.35 (m, 1H), 1.58-1.49 (m, 1H), 1.08-1.06 (m, 4H), 0.76-0.64 (m, 2H), 0.57-0.50 (m, 1H), 0.42-0.36 (m, 1H).Example 64. (E)-5-(Cy cl opentylmethyl)-2-(4-(m ethyl sulfonyl)but-3 -en-2-yl)-6-phenylpyridazin-3(2H)-one.0I

[0470] This example was synthesized using the procedure for Example 40 using ethyl 2-bromopropanoate. LCMS m / z = 387.1 (M + 1); ¹H-NMR (400 MHz, DMSO-d6) δ 7.47-7.45 (m, 5H), 6.90-6.79 (m, 3H), 5.82-5.79 (m, 1H), 3.01 (s, 3H), 2.50-2.47 (m, 2H), 1.85-1.78 (m, 1H), 1.55-1.37 (m, 9H), 0.99-0.93 (m, 2H).Example 67. (E)-3-Cyclopropyl-3-(2-(l,l-difhioroethyl)-5-oxo-8-phenylpyrimido[4,5-d]pyridazin-6(5H)-yl)-N-(2-(dimethylamino)ethyl)-N-methylprop-l-ene-1 -sulfonamide.

[0471] This example was synthesized using the procedure for Example 47 using Nl, Nl, N2-trimethyl ethane- 1,2-diamine. LCMS m / z = 533.1 (M + 1); ¹H-NMR (400 MHz, DMSO-d6) δ 9.90 (s, 1H), 8.04-8.02 (m, 2H), 7.59-7.53 (m, 3H), 6.88-6.76 (m, 2H), 5.12-5.09 (m, 1H), 3.12-3.00 (m, 2H), 2.68 (s, 3H), 2.39-2.28 (m, 2H), 2.15-2.05 (m, 9H), 1.65-1.55 (m, 1H), 0.79-0.69 (m, 2H), 0.60-0.53 (m, 1H), 0.47-0.41 (m, 1H).120039.000211 (TYRA041PCT)Example 68. (E)-6-(l-Cyclopropyl-3-((4-methylpiperazin-l-yl)sulfonyl)allyl)-2-(l,l-difluoroethyl)-8-phenylpyrimido[4,5-d]pyridazin-5(6H)-one.

[0472] This example was synthesized using the procedure for Example 47 using 1-methylpiperazine. LCMS m / z = 531.2 (M + 1); ’H-NMR (400 MHz, DMSO-d6) δ 9.90 (s, 1H), 8.04-8.01 (m, 2H), 7.56-7.54 (m, 3H), 6.89 (dd, J= 15.6 Hz, 4.8 Hz, 1H), 6.76 (dd, J = 15.6 Hz, 1.6 Hz, 1H), 5.14-5.11 (m, 1H), 3.03-3.01 (m, 4H), 2.33-2.31 (m, 4H), 2.17-2.05 (m, 6H), 1.65-1.56 (m, 1H), 0.79-0.72 (m, 2H), 0.59-0.53 (m, 1H), 0.46-0.40 (m, 1H).ClNHstop 3 step 4Ethyl 2-cyclopropyl-2-(4-(cyclopropylmethoxy)- 2-oxo-5-phenylpyrldln-1(2H)-yl)acetate Example 69. (E)-l-(l-Cyclopropyl-3-(methylsulfonyl)allyl)-4-(cyclopropylmethoxy)-5 -phenylpyridin-2( 1 H)-one.A0Y >9

[0473] Step 1. 5-Bromo-4-(cyclopropylmethoxy)-2-methoxypyridine. To a solution of 5-bromo-4-chloro-2-methoxypyridine (2.0 g, 8.99 mmol, 1.0 eq) and cesium carbonate (7.30 g, 22.48 mmol, 2.5 eq) in N, N-dimethylformamide (40 mL) was added cyclopropylmethanol (1.62 g, 22.48 mmol, 2.5 eq). The reaction mixture was then stirred at 120 °C overnight. The mixture was cooled and diluted with ethyl acetate (50 mL) and washed with water (2 x 50 mL) and brine (2 x 50 mL). The organic layer was then dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1) to give120039.000211 (TYRA041PCT)5-bromo-4-(cyclopropylmethoxy)-2-methoxypyridine (1.5 g, 65% yield) as a light-yellow solid. LCMS m / z = 258.1 (M + 1)

[0474] Step 2. 4-(Cyclopropylmethoxy)-2-methoxy-5-phenylpyridine. To a solution of 5-bromo-4-(cyclopropylmethoxy)-2-methoxypyridine (1.5 g, 5.81 mmol, 1.0 eq), in 1,4-dioxane (15 mL) / water (1.5 mL) was added phenyl boronic acid (1.42 g, 11.62 mmol, 2.0 eq), potassium carbonate (1.60 g, 11.62 mmol, 2.0 eq) and [1,1' bis(diphenylphosphino)ferrocene]palladium(II) dichloride (475 mg, 0.58 mmol, 0.1 eq). The reaction mixture was then stirred under nitrogen at 90 °C for 4 h. The reaction mixture cooled and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate = 15 / 1) to give 4-(cyclopropylmethoxy)-2-methoxy-5-phenylpyridine (1.3 g, 88% yield) as light-yellow oil. LCMS m / z = 256.2 (M + 1)

[0475] Step 3. 4-(Cyclopropylmethoxy)-5-phenylpyridin-2(lH)-one. To a solution of 4-(cyclopropylmethoxy)-2-methoxy-5-phenylpyridine (1.3 g, 5.09 mmol, 1.0 eq) and 4-methylbenzenesulfonic acid (4.38 g, 25.46 mmol, 0.05 eq) in 2-propanol (26 mL) was added lithium chloride (2.19 g, 50.92 mmol, 10.0 eq). The resulting mixture was stirred at 120 °C for 10 h. The mixture was cooled and diluted with ethyl acetate (50 mL), washed with water (2 x 50 mL) and brine (2 x 50 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (dichloromethane / methanol = 10 / 1) to give 4-(cyclopropylmethoxy)-5-phenylpyridin-2(lH)-one (950 mg, 77% yield) as a light-yellow solid. LCMS m / z = 242.2 (M + 1)

[0476] Step 4. Ethyl 2-cyclopropyl-2-(4-(cyclopropylmethoxy)-2-oxo-5-phenylpyridin-l(2H)-yl)acetate. To a solution of 4-(cyclopropylmethoxy)-5-phenylpyridin-2(lH)-one (850 mg, 3.52 mmol, 1.0 eq) in N, N-dimethylformamide (17 mL) was added cesium carbonate (2.30 g, 7.05 mmol, 2.0 eq) and ethyl 2-bromo-2-cyclopropylacetate (1.09 g, 5.28 mmol, 1.5 eq). The reaction solution was stirred at rt for 1 h. The mixture was then diluted with ethyl acetate (30 mL), washed with water (3 x 30 mL) and brine (2 x 30 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate = 1 / 1) to give ethyl 2-cyclopropyl-2-(4-(cyclopropylmethoxy)-2-oxo-5-phenylpyridin-l(2H)-yl)acetate (1.0 g, 77% yield) as light-yellow oil. LCMS m / z = 368.3 (M + 1)120039.000211 (TYRA041PCT)

[0477] (E)-l-(l-Cyclopropyl-3-(methylsulfonyl)allyl)-4-(cyclopropylmethoxy)-5-phenylpyridin-2(lH)-one was then prepared using ethyl 2-cyclopropyl-2-(4-(cyclopropylmethoxy)-2-oxo-5-phenylpyridin-l(2H)-yl)acetate as described in Example 4. LCMS m / z = 400.1 (M + 1); ¹H-NMR (400 MHz, DMSO-d6) δ 7.73 (s, 1H), 7.51-7.44 (m, 2H), 7.43-7.37 (m, 2H), 7.36-7.29 (m, 1H), 6.97 (dd, J= 15.2 Hz, 5.2 Hz, 1H), 6.82 (d, J = 15.2 Hz, 1H), 5.90 (s, 1H), 4.70-4.63 (m, 1H), 3.88 (d, J= 6.8 Hz, 2H), 3.04 (s, 3H), 1.73-1.63 (m, 1H), 1.22-1.11 (m, 1H), 0.78-0.68 (m, 1H), 0.61-0.48 (m, 4H), 0.35-0.25 (m, 3H) Example 70. (E)-4-(Cyclopentyloxy)-l-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-phenylpyridin-2( 1 H)-one.

[0478] This example was synthesized using the procedure for Example 69 using cyclopentanol. LCMS m / z = 414.1 (M + 1); ¹H-NMR (400 MHz, DMSO-d6) δ 7.73 (s, 1H), 7.40-7.36 (m, 4H), 7.35-7.30 (m, 1H), 6.95 (dd, J=15.6 Hz, 5.6 Hz, 1H), 6.82 (dd, J=15.6 Hz, 1.2 Hz, 1H), 5.90 (s, 1H), 4.87-4.68 (m, 1H), 4.67-4.65 (m, 1H), 3.04 (s, 3H), 2.33-1.72 (m, 2H), 1.72-1.55 (m, 7H), 0.76-0.71 (m, 1H), 0.60-0.51 (m, 2H), 0.32-0.28 (m, 1H) Example 71. (E)-5-(Cyclopentyloxy)-2-(3-(methylsulfonyl)allyl)-6-phenylpyridazin-3(2H)-one.

[0479] This example was synthesized using the procedure for Example 41 usingl,2-dibromo-3-(methylsulfonyl)propane. LCMS m / z =375.0 (M + 1); ¹H-NMR (400 MHz, DMSO-d6) δ 7.64-7.61 (m, 2H), 7.46-7.43 (m, 3H), 6.86 (dt, J= 15.4 Hz, 4.4 Hz, 1H), 6.73 (d, J= 15.4 Hz, 1H), 6.42 (s, 1H), 4.98-4.91 (m, 3H), 3.01 (s, 3H), 1.97-1.89 (m, 2H), 1.81-1.72 (m, 2H), 1.66-1.59 (m, 4H).

[0480] The Following examples in the table were prepared as described above, or with similar methods.Example 65. (S, E)- LCMS m / z =415.1 (M +5-(cyclopentyloxy)- 1); 'H-NMR (400 MHz, DMSO- 2-(l-cyclopropyl-3- d6) 67.68-7.66 (m, 2H), 7.48- (m ethyl sulfonyl)ally 7.43 (m, 3H), 6.95-6.86 (m, 2H),l)-6- 6,40 (s, 1H), 4,98-4,92 (m, 2H),120039.000211 (TYRA041PCT)phenylpyridazin- 3.03 (s, 3H), 1.96-1.91 (m, 2H), 3(2H)-one 1.77-1.58 (m, 6H), 1.50-1.46 (m,1H), 0.72-0.51 (m, 3H), 0.37-0.33 (m, 1H)Example 66. (R, E)- LCMS m / z =415.1 (M + 5-(cyclopentyloxy)- 1); 'H-NMR (400 MHz, DMSO- 2-(l-cyclopropyl-3- d6) 67.68-7.65 (m, 2H), 7.48- 0 V(m ethyl sulfonyl)ally 7.43 (m, 3H), 6.95-6.87 (m, 2H), CIXN 6- l)-6- 6.40 (s, 1H), 4.97-4.92 (m, 2H), phenylpyridazin- 3.03 (s, 3H), 1.96-1.91 (m, 2H), 63(2H)-one 1.78-1.58 (m, 6H), 1.52-1.45 (m,1H), 0.74-0.49 (m, 3H), 0.38-0.32 (m, 1H)Example 72. (R, E)- LCMS m / z = 413.1 (M + 5- 1), 'H-NMR (400 MHz, DMSO- o V (cyclopentylmethyl)- d6) 67.50-7.45 (m, 5H), 6.92- vJU 6' ^ 2-(l-cyclopropyl-3- 6.91 (m, 3H), 4.95 (d, J= 9.6 Hz,(m ethyl sulfonyl)ally 1H), 3.03 (s, 3H), 2.54-2.51 (m, 0 l)-6- 2H), 1.87-1.80 (m, 1H), 1.60-1.37 phenylpyridazin- (m, 7H), 1.04-0.96 (m, 2H), 0.72- 3(2H)-one 0.48 (m, 3H), 0.39-0.33 (m, 1H) Example 73. (S, E)- LCMS m / z = 413.1 (M + 5- 1), 'H-NMR (400 MHz, DMSO- ° V (cyclopentylmethyl)- d6) 67.50-7.45 (m, 5H), 6.92- A 1 9YAJCN O 2-(l-cyclopropyl-3- 6.91 (m, 3H), 4.95 (d, J=9.6 Hz,(m ethyl sulfonyl)ally 1H), 3.03 (s, 3H), 2.53-2.51 (m, 0 l)-6- 2H), 1.87-1.80 (m, 1H), 1.58-1.37 phenylpyridazin- (m, 7H), 1.01-0.96 (m, 2H), 0.72- 3(2H)-one 0.48 (m, 3H), 0.39-0.34 (m, 1H) Example 74. (E)-5- LCMS m / z = 399.1 (M + (cyclobutylmethyl)- 1), 'H-NMR (400 MHz, DMSO- 2-(l-cyclopropyl-3- d6) 67.52-7.46 (m, 5H), 6.94-6.86 ° Y (m ethyl sulfonyl)ally (m, 2H), 6.77 (s, 1H), 4.95- A 1*^ 9l)-6- 4.92 (m, 1H), 3.03 (s, 3H), 2.62- COM °phenylpyridazin- 2.55 (m, 2H), 2.43-2.36 (m, 1H), 0 3(2H)-one 1.99-1.92 (m, 2H), 1.83-1.68 (m,2H), 1.60-1.50 (m, 2H), 1.48-1.40 (m, 1H), 0.72-0.55 (m, 2H), 0.54- 0.33 (m, 2H)Example 75. (E)-2- LCMS m / z = 498.9 (M + X ° Y 1 9V IlN(l-cyclopropyl-3- 1), 'H-NMR (400 MHz, DMSO- (m ethyl sulfonyl)ally d6) 67.58 (s, 1H), 7.52-7.38 (m, MS l)-5- 5H), 7.03-6.87 (m, 2H), 4.98-4.93(perfluoropropyl)-6- (m, 1H), 3.01 (s, 3H), 1.49-1.35120039.000211 (TYRA041PCT)phenylpyridazin- (m, 1H), 0.75-0.59 (m, 2H), 0.58- 3(2H)-one 0.48 (m, 1H), 0.43-0.34 (m, 1H) Example 76. (E)-4- LCMS m / z = 413.2 (M + (cyclopentylmethyl)- 1), 'H-NMR (400 MHz, DMSO- 2-(l-cyclopropyl-3- d6) 67.93-7.92 (m, 3H), 7.53- (m ethyl sulfonyl)ally 7.44 (m, 3H), 7.01-6.92 (m, 2H), X o Y i p l)-6- 5.03 (dd, J= 10.0 Hz, 4.0 Hz, II A 6' " phenylpyridazin- 1H), 3.04 (s, 3H), 2.58 (d, J= 7.23(2H)-one Hz, 2H), 2.30-2.22 (m, 1H), 1.71- 01.49 (m, 8H), 1.21-1.17 (m, 1H), 0.76-0.70 (m, 1H), 0.64-0.58 (m, 1H), 0.55-0.48 (m, 1H), 0.39-0.33 (m, 1H)Example 77. (E)-5- LCMS m / z =403.1 (M + (cyclopentylmethox 1), 'H-NMR (400 MHz, DMSO- y)-2-(4- d6) 67.69-7.67 (m, 2H), 7.49-01 (m ethyl sulfony l)but- 7.45 (m, 3H), 6.87 (dd, J= 15.6 < X N JI / 93-en-2-yl)-6- Hz, 4.4 Hz, 1H), 6.79 (d, J= 16.0 cr° i" phenylpyridazin- Hz, 1H), 6.44 (s, 1H), 5.83-5.77 6 3(2H)-one (m, 1H), 3.97 (d, J= 6.8 Hz, 2H),3.01 (s, 3H), 2.31-2.24 (m, 1H), 1.73-1.68 (m, 2H), 1.59-1.49 (m, 7H), 1.32-1.27 (m, 2H) Example 78. (E)-2- LCMS m / z = 389.1 (M + (l-cyclopropyl-3- 1), 'H-NMR (400 MHz, DMSO- (m ethyl sulfonyl)ally d6) 67.73-7.66 (m, 2H), 7.50- l)-6-phenyl-5- 7.42 (m, 3H), 6.96-6.86 (m, 2H), X o Y 1 9 propoxypyridazin- 6.43 (s, 1H), 4.94 (dd, J= 10.0 \z-X o Yli °' 3(2H)-one Hz, 3.6 Hz, 1H), 4.10-4.00 (m,2H), 3.03 (s, 3H), 1.77-1.67 (m, 62H), 1.54-1.43 (m, 1H), 0.94 (t, J = 7.2 Hz, 3H), 0.75-0.66 (m, 1H), 0.65-0.57 (m, 1H), 0.56-0.47 (m, 1H), 0.39-0.30 (m, 1H)o120039.000211 (TYRA041PCT)

[0481] Intermediate 1. 5-Bromo-6-phenyl-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one. To a solution of 5-bromo-6-phenylpyridazin-3(2H)-one (13.0 g, 51.8 mmol) in tetrahydrofuran (300 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (15.8 g, 103.6 mmol, 2.0 eq). After stirring for 0.5 h the solution was cooled to 0 °C and (2-(chloromethoxy)ethyl)trimethylsilane (12.9 g, 77.7 mmol, 1.5 eq) was added. The ice bath was removed, and the reaction mixture was stirred for 5 h. The reaction was then diluted with water (500 mL) and extracted with ethyl acetate (3x100 mL). The combined organic layers were washed with saturated brine (50 mL) and dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10 / 1) to afford 5-bromo-6-phenyl-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (12.0 g, 61% yield) as a yellow solid. LCMS m / z = 381.2 (M+l).o

[0482] Intermediate 2. 5-Bromo-2-(methoxymethyl)-6-phenylpyridazin-3(2H)-one. Bromomethyl methyl ether (6.0 mL, 73.8 mmol, 2.3 eq) was slowly added to a stirred suspension of bromo-6-phenylpyridazin-3(2H)-one (8.0 g, 31.8 mmol, 1 eq), 4-dimethylaminopyridine (80 mg, 0.65 mmol, 0.02 eq) and N, N-diisopropylethylamine (35 mL, 201 mmol, 6.3 eq) in anhydrous dichloromethane (80.0 mL) at 0 °C. Significant vapor evolution occurred during the addition. After the addition was complete, the slurry had transformed into a yellow solution. The reaction was slowly warmed to room temperature and stirred for 16 hours. LCMS analysis indicated -60% conversion. Additional N, N-diisopropylethylamine (12.00 mL, 68.9 mmol, 2.1 eq) was added. The mixture was cooled to 0 °C, and treated again with bromomethyl methyl ether (3.0 mL, 36.9 mmol, 1.1 eq) then warmed to room temperature. After 20 hours, additional bromomethyl methyl ether (3.0 mL, 36.9 mmol, 1.1 eq) was added to the reaction at room temperature. After stirring 20 additional hours, the reaction was diluted with water (50 mL) and extracted with ethyl acetate (2x50 mL). The combined organic layers were diluted with hexane (10 ml) then washed a mixture of with 5% sodium thiosulfate (5 ml) and saturated brine (20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure onto silica gel (30 g). The material120039.000211 (TYRA041PCT)was purified on a Biotage automated chromatography system (Sorbtech 200 g column), eluting with a gradient of 0 to 25% ethyl acetate in hexanes to give 5-bromo-2-(methoxymethyl)-6-phenylpyridazin-3(2H)-one (4.4 g, 47% yield) as an orange wax that slowly solidified. LCMS m / z = 295 (M + 1).o

[0483] Intermediate 3. 5-Bromo-6-phenyl-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one. 3,4-Dihydro-2H-pyran (24 mL, 263 mmol, 9 eq) was slowly added to a slurry of bromo-6-phenylpyridazin-3(2H)-one (7.24 g, 28.8 mmol) and p-toluenesulfonic acid monohydrate (0.82 g, 4.3 mmol, 0.15 eq) in a mixture of tetrahydrofuran (90 mL) and acetonitrile (30 mL) at 50 °C. After stirring overnight, the reaction was cooled to room temperature, diluted with water (100 mL) and extracted with a 9 to 1 mixture of ethyl acetate and hexanes (2x100 mL). The combined organic layers were concentrated under reduced pressure onto silica gel (40 g). The residue was purified on a Biotage automated chromatography system (Yamazen 300 g silica gel column), eluting with a gradient of 0 to 50% ethyl acetate in hexanes. Product containing fractions were concentrated under reduced pressure and dried at 40 °C under vacuum overnight to give 5-bromo-6-phenyl-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (6.4 g, 66% yield) as a tan solid. LCMS m / z = 357 (M + Na).OH

[0484] Intermediate 4. (E)- 1 -Cyclopropyl-3 -(methyl sulfonyl)prop-2-en- 1 -ol.

[0485] Step 1. (E)-3-Cyclopropylprop-2-en-l-ol. IM Diisobutylaluminum hydride in hexanes (235 mL, 235 mmol, 2.2 eq) was added over 15 minutes to a solution of ethyl (E)-3 -cyclopropylacrylate (15 g, 107 mmol, 1 eq) in diethyl ether (200 mL) at -78 °C. The mixture was slowly warmed up to room temperature and stirred for 16 hours. After cooling to 0 °C, methanol (75 mL) was slowly added (Extreme Caution: vigorous gas evolution), followed by saturated potassium sodium tartrate solution (180 mL). After stirring at room temperature for 1 hour, the layers were separated and the organic layer was washed with120039.000211 (TYRA041PCT)saturated brine (150 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give (E)-3-cyclopropylprop-2-en-l-ol (9.2 g, 88% yield) as a colorless oil.

[0486] Step 2. (E)-(3-(Methylsulfonyl)prop-l-en-l-yl)cyclopropane. Dimethyl sulfide (13 mL, 173.4 mmol, 1.85 eq) was added dropwise to a solution of N-chlorosuccinimide (18.8 g, 140.8 mmol, 1.5 eq) in dichloromethane (465 mL) at 0 °C. The resulting white suspension was cooled to -20 °C and a solution of (E)-3-cyclopropylprop-2-en-l-ol (9.2 g, 93.7 mmol, 1 eq) in dichloromethane (230 mL) was added through an addition funnel over 0.5 h while maintaining the temperature between -25 °C and -20 °C. The resulting mixture was stirred at 0 °C for 2 hours and then at room temperature for 70 hours. Sodium methanesulfmate (28.75 g, 281.6 mmol, 3 eq), sodium iodide (1.45 g, 9.7 mmol, 0.1 eq) and dimethyl sulfoxide (140 mL) were sequentially added, and the mixture was heated at 50 °C for 24 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure to remove most of the dichloromethane. The reaction was diluted with ethyl acetate (500 mL) and washed with water (3x150 mL). The combined aqueous layers were extracted with ethyl acetate (2x200 mL). This organic layer was washed with water (3x100 mL). All the organic layers were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified on a Biotage automated chromatography system (Sorbtech 330 g column), eluting with a gradient of 0 to 100% ethyl acetate in hexanes to give (E)-(3-(methylsulfonyl)prop-l-en-l-yl)cyclopropane (12.3 g, 82% yield) as a colorless oil.

[0487] Step 3. (E)-l-Cyclopropyl-3-(methylsulfonyl)prop-2-en-l-ol. Water (500 mL) and sodium bicarbonate (48.4 g, 576.1 mmol, 7.5 eq) were sequentially added to a solution of (E)-(3-(methylsulfonyl)prop-l-en-l-yl)cyclopropane (12.3 g, 76.8 mmol, 1 eq) in acetone (500 mL). Oxone (70.8 g, 115.2 mmol, 3 eq) was added in three portions and the resulting mixture was stirred at room temperature for 2 days. The mixture was diluted with ethyl acetate (1500 mL) and the layers were separated. The aqueous layer was diluted with water (1000 mL) and extracted with ethyl acetate (1000 mL). The combined organic layers were washed with saturated brine (2x500 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified on a Biotage automated chromatography system (Sorbtech 330 g column), eluting with a gradient of 0 to 100% ethyl acetate in hexanes to give (E)-l-cyclopropyl-3-(methylsulfonyl)prop-2-en-l-ol (6.8 g, 50% yield) as a white solid. LCMS m / z = 233 (M+Na), ¹H-NMR (400 MHz, CDCl3) δ 7.05 (dd, J120039.000211 (TYRA041PCT)= 15.0, 3.4 Hz, 1H), 6.74 (dd, J = 15.0, 1.9 Hz, 1H), 3.69 (dq, J = 8.7, 3.3 Hz, 1H), 2.99 (s, 3H), 1.93 (d, J = 3.6 Hz, 1H), 1.03 (dtd, J = 13.1, 8.5, 4.8 Hz, 1H), 0.68 (dd, J = 7.9, 4.0 Hz, 2H), 0.53 - 0.37 (m, 2H).

[0488] Intermediate 5. Diethyl (fluoro(methylsulfonyl)methyl)phosphonate. To a solution of diethyl ((methylsulfonyl)methyl)phosphonate (1.0 g, 4.34 mmol, 1.0 eq) in tetrahydrofuran (20 mL) at -78 °C was added lithium bis(trimethylsilyl)amide (5.64 mL, IM in tetrahydrofuran, 5.64 mmol, 1.3 eq). The mixture was stirred at -78 °C for 0.5 h, and then l-(chloromethyl)-4-fluoro-l,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate), (2.3 g, 6.51 mmol, 1.5 eq) was added. The reaction was slowly warmed to room temperature and stirred for 5 h. The reaction was then cooled to 0 °C and quenched with saturated ammonium chloride solution (50 mL). The mixture was transferred to a separatory funnel and extracted with ethyl acetate (3x50 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate - 10 / 1 to 2 / 1) to afford diethyl (fluoro(methylsulfonyl)methyl)phosphonate (500 mg, 46% yield) as brown oil. LCMS m / z = 249.1 (M + 1).Boc

[0489] Intermediate 6. tert-Butyl (((diethoxyphosphoryl)methyl)(methyl)(oxo)-l6-sulfaneylidene)carbamate.

[0490] Step 1. Diethyl ((methylsulfinyl)methyl)phosphonate. To a solution of diethyl ((methylthio)methyl)phosphonate

[0491] (4.0 g, 20.18 mmol, 1.0 eq) in acetonitrile (40 mL) and water (32 mL) was added sodium periodate (8.71 g, 40.36 mmol, 2.0 eq) at 0 °C. The reaction mixture was stirred at 0 °C for 3 h. The reaction mixture was then poured into water (40 mL) and extracted with ethyl acetate (3x50 mL). The combined organic layers were washed with saturated brine (100 mL), dried over sodium sulfate, filtered and concentrated under reduced120039.000211 (TYRA041PCT)pressure. The crude product was purified by a silica gel chromatography (petroleum ether / ethyl acetate - 3 / 1) to afford diethyl ((methylsulfinyl)methyl)phosphonate (2.0 g, 46% yield) as light-yellow oil. LCMS m / z = 215.1 (M + 1).

[0492] Step 2. tert-Butyl (((diethoxyphosphoryl)methyl)(methyl)(oxo)-l6-sulfaneylidene)carbamate. To a solution of diethyl ((methylsulfinyl)methyl)phosphonate (1.9 g, 8.87 mmol, 1.0 eq) in dichloromethane (40 mL) cooled to 0 °C were added tert-butyl carbamate (2.08 g, 17.74 mmol, 2.0 eq), (diacetoxyiodo)benzene (4.29 g, 13.31 mmol, 1.5 eq), rhodium(II) acetate (124.17 mg, 0.44 mmol, 0.05 eq) and magnesium oxide (1.42 g, 34.33 mmol, 3.9 eq). The cold bath was removed, and the reaction mixture was heated to 50 °C for 3 h. The reaction mixture was then cooled, filtered and concentrated under reduced pressure. The residue was purified by a silica gel chromatography (petroleum ether / ethyl acetate - 3 / 1) to afford tert-butyl (((diethoxyphosphoryl)methyl)(methyl)(oxo)-l6-sulfaneylidene)carbamate (2.0 g, 68% yield) as light-yellow oil. LCMS m / z = 230.1 (M + 1, -BOC).Example 79

[0493] Example 79. (E)-2-(l-Cyclopropyl-3-(methylsulfonyl)allyl)-4- (cyclopropylmethyl)-6-phenylpyridazin-3(2H)-one.120039.000211 (TYRA041PCT)

[0494] Step 1. Diethyl (3-oxo-6-phenyl-2,3,4,5-tetrahydropyridazin-4-yl)phosphonate. To a solution of ethyl 2-(diethoxyphosphoryl)-4-oxo-4-phenylbutanoate (10.0 g, 29.2 mmol, 1.0 eq) in ethanol (60 ml) was added hydrazine hydrate (2.98 g, 87.6 mmol, 3.0 eq) and the reaction mixture heated to 60 °C for 5 h. The reaction mixture was then cooled and concentrated under reduced pressure to remove the ethanol. The residue was taken up in di chloromethane (200 mL) and washed with water (2x50mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate - 5 / 1) to afford diethyl (3-oxo-6-phenyl-2,3,4,5-tetrahydropyridazin-4-yl)phosphonate (5.0 g, 55% yield) as a yellow solid. LCMS m / z = 311.2 (M+l).

[0495] Step 2. 4-(Cyclopropylmethyl)-6-phenylpyridazin-3(2H)-one. To a solution of diethyl (3-oxo-6-phenyl-2,3,4,5-tetrahydropyridazin-4-yl)phosphonate (3.0 g, 9.67 mmol, 1.0 eq) in tetrahydrofuran (60 ml) was added sodium hydride (515 mg, 60% in mineral oil, 21.3 mmol, 2.2 eq) at 0 °C and the mixture was stirred for 0.5 h. Cyclopropanecarbaldehyde (2.03 g, 29.1 mmol, 3.0 eq) was then added and then mixture stirred at room temperature for 2 h. The reaction was quenched with saturated ammonium chloride (30 mL) and water (30 mL). The mixture was extracted with ethyl acetate (2x50 mL) and the combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10 / 1) to afford 4-(cyclopropylmethyl)-6-phenylpyridazin-3(2H)-one (13.0 g, 76% yield) as a yellow solid. LCMS m / z = 227.2 (M+l).

[0496] Step 3. Ethyl 2-cyclopropyl-2-(5-(cyclopropylmethyl)-6-oxo-3-phenylpyridazin-l(6H)-yl)acetate. To a solution of 4-(cyclopropylmethyl)-6-phenylpyridazin-3(2H)-one (250 mg, 1.1 mmol, 1.0 eq) and ethyl 2-bromo-2-cyclopropylacetate (343 mg, 1.66 mmol, 1.5 eq) in N, N-dimethylformamide (5 ml) was added cesium carbonate (1.08 g, 3.31 mmol, 3.0 eq) and the reaction was stirred at room temperature for 3 h. The mixture was then diluted with the saturated ammonium chloride (50 mL) and extracted with ethyl acetate (2x50 mL). The combined organic layers were washed with saturated brine (50 mL), dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate - 5 / 1) to afford ethyl 2-cyclopropyl-2-(5-(cyclopropylmethyl)-6-oxo-3-phenylpyridazin-l(6H)-yl)acetate (220 mg, 56% yield) as a yellow solid. LCMS m / z = 253.3 (M+l).120039.000211 (TYRA041PCT)

[0497] Step 4. S-Ethyl 2-cyclopropyl-2-(5-(cyclopropylmethyl)-6-oxo-3-phenylpyridazin-l(6H)-yl)ethanethioate.

[0498] To a solution of ethyl 2-cyclopropyl-2-(5-(cyclopropylmethyl)-6-oxo-3-phenylpyridazin-l(6H)-yl)acetate (220 mg, 0.62 mmol, 1.0 eq) in tetrahydrofuran (6 ml) and water (3 ml) was added lithium hydroxide monohydrate (75 mg, 3.12 mmol, 5.0 eq) and the reaction mixture was stirred at room temperature for 8 h. The mixture was then diluted with water (5 mL) and IM aqueous hydrochloric acid added (pH ~ 4). The mixture was extracted with ethyl acetate (3x20 mL) and the combined organic layers were washed with saturated brine (10 mL), dried over sodium sulfate and concentrated under reduced pressure to give 2-cyclopropyl-2-(5-(cyclopropylmethyl)-6-oxo-3-phenylpyridazin-l(6H)-yl)acetic acid (180 mg) as a yellow solid. LCMS m / z = 325.2 (M+l).

[0499] 2-Cyclopropyl-2-(5-(cyclopropylmethyl)-6-oxo-3-phenylpyridazin-l(6H)-yl)acetic acid (180 mg, 0.55 mmol, 1.0 eq) was taken up in dichloromethane (5 ml) and N, N-diisopropylethylamine (358 mg, 2.77 mmol, 5.0 eq), l-[bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (633 mg, 1.66 mmol, 3.0 eq) and ethanethiol (276 mg, 3.35 mmol, 8.0 eq) were added. The reaction mixture was stirred at room temperature for 3 h. The reaction was quenched with the addition of saturated ammonium chloride (20 mL) and extracted with dichloromethane (2x30 mL). The combined organic layers were washed with saturated brine (20 mL), dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate - 5 / 1) to afford S-ethyl 2-cyclopropyl-2-(5-(cyclopropylmethyl)-6-oxo-3-phenylpyridazin-l(6H)-yl)ethanethioate (110 mg, 54% yield over two steps) as a yellow solid. LCMS m / z = 369.3 (M+l).

[0500] Step 5. 2-Cyclopropyl-2-(5-(cyclopropylmethyl)-6-oxo-3-phenylpyridazin-l(6H)-yl)acetaldehyde. To a solution of S-ethyl 2-cyclopropyl-2-(5-(cyclopropylmethyl)-6-oxo-3 -phenylpyridazin-l(6H)-yl)ethanethioate (110 mg, 0.30 mmol, 1.0 eq) in tetrahydrofuran (30 mL) was added palladium on carbon (10% Pd / C, 20 mg) andtri ethyl silane (277 mg, 2.39 mmol, 8.0 eq). The reaction mixture was stirred at room temperature for 1 h. The mixture was then filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate -2 / 1) to afford 2-cyclopropyl-2-(5-(cyclopropylmethyl)-6-oxo-3-phenylpyridazin-l(6H)-yl)acetaldehyde (50 mg, 54% yield) as a yellow solid. LCMS m / z = 309.2 (M+l).120039.000211 (TYRA041PCT)

[0501] Step 6. (E)-2-(l-Cyclopropyl-3-(methylsulfonyl)allyl)-4-(cyclopropylmethyl)-6-phenylpyridazin-3(2H)-one.

[0502] To a solution of 2-cyclopropyl-2-(5-(cyclopropylmethyl)-6-oxo-3-phenylpyridazin-l(6H)-yl)acetaldehyde (50 mg, 0.16 mmol, 1.0 eq) and diethyl ((methylsulfonyl)methyl)phosphonate (75 mg, 0.32 mmol, 2.0 eq) in tetrahydrofuran (5 ml) was added potassium carbonate (67 mg, 0.49 mmol, 3.0 eq) and the reaction mixture was stirred at 60 °C for 4 h. The mixture was cooled, saturated ammonium chloride (20 mL) added and then extracted with ethyl acetate (2x20 mL). The combined organic layers were washed with saturated brine (20 mL), dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by Prep-HPLC (Prep-C18, 5 μM Triart column, 20 x 150 mm, YMC-Actus; gradient elution of 54 % acetonitrile in water to 66% acetonitrile in water over a 8 min period, where both solvents contain 0.05% ammonium hydroxide) to give (E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-4-(cyclopropylmethyl)-6-phenylpyridazin-3(2H)-one (26.6 mg, 43 % yield) as an off-white solid. LCMS m / z = 385.1 (M+l), ¹H-NMR (400 MHz, DMSO-d6) δ 7.99 (s, 1H), 7.93 (d, J = 7.2 Hz, 2H), 7.54-7.47 (m, 3H), 6.98-6.97 (m, 2H), 5.05 (dd, J = 9.6 Hz, 3.2 Hz, 1H), 3.04 (s, 3H), 2.48-2.46 (m, 2H), 1.62-1.55 (m, 1H), 1.15-1.09 (m, 1H), 0.75-0.70 (m, 1H), 0.65-0.61 (m, 1H), 0.56-0.49 (m, 3H), 0.50-0.45 (m, 1H), 0.25-0.22 (m, 2H).120039.000211 (TYRA041PCT)Example 94

[0503] Example 94. (E)-N-(l-(l-Cyclopropyl-3-(methylsulfonyl)allyl)-6-oxo-3-phenyl- 1,6-dihydropyridazin-4-yl)cyclobutanecarboxamide.

[0504] Step 1. 5-Azido-2-(methoxymethyl)-6-phenylpyridazin-3(2H)-one. To a solution of 5-bromo-2-(methoxymethyl)-6-phenylpyridazin-3(2H)-one (3.0 g, 10.2 mmol, 1.0 eq) in N, N-dimethylformamide (30 mL) was added sodium azide (793 mg, 12.2 mmol, 1.2 eq). The mixture was stirred at room temperature for 2 h. The reaction mixture was then diluted with ethyl acetate (150 mL) and washed with saturated brine (3x40 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The isolated material was purified by silica gel chromatography (petroleum ether / dichloromethane - 2 / 1) to afford 5-azido-2-(methoxymethyl)-6-phenylpyridazin-3(2H)-one (2.2 g, 84% yield) as a brown solid. LCMS m / z = 258.2 (M+l).

[0505] Step 2. 5-Amino-2-(methoxymethyl)-6-phenylpyridazin-3(2H)-one. To a solution of 5-azido-2-(methoxymethyl)-6-phenylpyridazin-3(2H)-one (2.2 g, 8.55 mmol, 1.0120039.000211 (TYRA041PCT)eq) in methanol (50 mL) was added palladium on carbon (10% Pd / C, 904 mg, 8.55 mmol, 1.0 eq). The flask was charged with hydrogen gas three times, and the mixture was stirred for 3 h under an atmosphere of hydrogen. The reaction was then filtered and concentrated under reduced pressure. The material was purified by silica gel chromatography (petroleum ether / dichloromethane - 2 / 3) to afford 5-amino-2-(methoxymethyl)-6-phenylpyridazin-3(2H)-one (1.8 g, 82% yield) as a yellow solid. LCMS m / z = 232.2 (M+l).

[0506] Step 3. N-(l-(Methoxymethyl)-6-oxo-3 -phenyl- 1,6-dihy dropyridazin-4-yl)cyclobutanecarboxamide.

[0507] To a solution of 5-amino-2-(methoxymethyl)-6-phenylpyridazin-3(2H)-one (200 mg, 0.86 mmol, 1.0 eq) and cyclobutanecarboxylic acid (173 mg, 1.73 mmol, 2.0 eq) in di chloromethane (4 mL) and pyridine (2 mL) was added phosphorous oxychloride (662 mg, 4.32 mmol, 5.0 eq) at 0 °C. The cold bath was removed, and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was then diluted with dichloromethane (20 mL) and saturated aqueous sodium bicarbonate (20 mL) was added. The layers were separated, and the organic layer was extracted with dichloromethane (2x20 mL). The combined organic layers were washed with saturated brine (2x40 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate - 1 / 1) to afford N-(l-(methoxymethyl)-6-oxo-3-phenyl-l,6-dihydropyridazin-4-yl)cyclobutanecarboxamide (220 mg, 74% yield) as a lightyellow solid. LCMS m / z = 314.2 (M+l).

[0508] Step 4. N-(6-Oxo-3-phenyl-l,6-dihydropyridazin-4-yl)cyclobutanecarboxamide. To a solution of N-(l-(methoxymethyl)-6-oxo-3-phenyl-l,6-dihydropyridazin-4-yl)cyclobutanecarboxamide (200 mg, 0.64 mmol, 1.0 eq) indi chloromethane (4 mL) was added boron tribromide (2 mmol / L in dichloromethane, 4 mL) at 0 °C. The cold bath was removed, and the resulting mixture was stirred at room temperature for 16 h. The reaction was cooled to 0 °C and methanol (4 mL) and ammonium hydroxide (4 mL) were then added and the resulting mixture was stirred for 1 h. The reaction mixture was then diluted with dichloromethane (20 mL) and saturated aqueous sodium bicarbonate (20 mL) was added. The layers were separated, and the organic layer was extracted with di chloromethane (2x20 mL). The combined organic layers were washed with saturated brine (2x40 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatograph (dichloromethane / methanol -120039.000211 (TYRA041PCT)20 / 1) to afford N-(6-oxo-3-phenyl-l,6-dihydropyridazin-4-yl)cyclobutanecarboxamide (150 mg, 87% yield) as a light-yellow solid. LCMS m / z = 270.2 (M+l).

[0509] Step 5. Ethyl 2-(4-(cyclobutanecarboxamido)-6-oxo-3-phenylpyridazin-l(6H)-yl)-2-cyclopropylacetate. To a mixture of N-(6-oxo-3-phenyl-l,6-dihydropyridazin-4-yl)cyclobutanecarboxamide (140 mg, 0.52 mmol, 1.0 eq) and cesium carbonate (338 mg, 1.04 mmol, 2.0 eq) in N, N-dimethylformamide (3 mL) was added ethyl 2-bromo-2-cyclopropylacetate (215 mg, 1.04 mmol, 2.0 eq). The reaction mixture was stirred at room temperature for 1 h. The reaction was then diluted with ethyl acetate (20 mL), washed with water (3x20 mL) and saturated brine (2x20 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The isolated material was purified by silica gel chromatography (petroleum ether / ethyl acetate - 1 / 1) to afford ethyl 2-(4-(cyclobutanecarboxamido)-6-oxo-3-phenylpyridazin-l(6H)-yl)-2-cyclopropylacetate (150 mg, 73% yield) as a light-yellow solid. LCMS m / z = 396.3 (M+l).

[0510] Step 6. S-Ethyl 2-(4-(cyclobutanecarboxamido)-6-oxo-3-phenylpyridazin-l(6H)-yl)-2-cyclopropylethanethioate.

[0511] To a solution of ethyl 2-(4-(cyclobutanecarboxamido)-6-oxo-3-phenylpyridazin-l(6H)-yl)-2-cyclopropylacetate (150 mg, 0.38 mmol, 1.0 eq) in tetrahydrofuran (3 mL) and water (3 mL) at 0 °C was added lithium hydroxide monohydrate (80 mg, 1.90 mmol, 5.0 eq). The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure to remove most of the tetrahydrofuran. IM hydrochloric acid was then added (pH~4) and the mixture was extracted with di chloromethane (2x10 mL). The combined organic layers were washed with saturated brine (20 mL), dried over sodium sulfate and concentrated and concentrated under reduced pressure to give a light-yellow solid (100 mg). LCMS m / z = 368.3 (M+l). A portion of the material (70 mg, 0.19 mmol, 1.0 eq) was taken up in N, N-dimethylformamide (2 mL) and N, N-diisopropylethylamine (74 mg, 0.57 mmol, 3.0 eq) and 1-[bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (145 mg, 0.38 mmol, 2.0 eq) were added. The mixture was stirred for 10 min. Then a solution of ethanethiol (40 mg, 0.57 mmol, 3.0 eq) in N, N-dimethylformamide (1 mL) was added and the mixture was stirred for 1 h. The reaction was then diluted with ethyl acetate (10 mL) and washed with water (3x10 mL) and saturated brine (2x10 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under120039.000211 (TYRA041PCT)reduced pressure. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate - 1 / 1) to afford S-ethyl 2-(4-(cyclobutanecarboxamido)-6-oxo-3-phenylpyridazin-l(6H)-yl)-2-cyclopropylethanethioate (70 mg, 89% yield) as a light-yellow solid. LCMS m / z = 412.3 (M+l).

[0512] Step 7. N-(l-(l-Cyclopropyl-2-oxoethyl)-6-oxo-3-phenyl-l,6-dihydropyridazin-4-yl)cyclobutanecarboxamide. To a solution of S-ethyl 2-(4-(cyclobutanecarboxamido)-6-oxo-3-phenylpyridazin-l(6H)-yl)-2-cyclopropylethanethioate (70 mg, 0.17 mmol, 1.0 eq) in tetrahydrofuran (2 mL) and acetone (0.2 mL) cooled to 0 °C was added palladium on carbon (10% Pd / C, 35 mg) and triethylsilane (197 mg, 1.70 mmol, 10.0 eq). The reaction mixture was then stirred at room temperature for 2 h. The mixture was filtered through celite and the filter cake was washed with ethyl acetate (2x10 mL). The filtrate and combined washings were concentrated under reduced pressure to give N-(l-(l-cy cl opropyl-2-oxoethyl)-6-oxo-3 -phenyl- l,6-dihydropyridazin-4-yl)cy cl obutanecarb oxami de (60 mg) as a light-yellow solid. LCMS m / z = 352.3 (M+l).

[0513] Step 8. (E)-N-(l-(l-Cyclopropyl-3-(methylsulfonyl)allyl)-6-oxo-3-phenyl-l,6-dihydropyridazin-4-yl)cyclobutanecarboxamide. To a solution of N-(l-(l-cyclopropyl-2-oxoethyl)-6-oxo-3-phenyl-l,6-dihydropyridazin-4-yl)cyclobutanecarboxamide (60 mg) and diethyl ((methylsulfonyl)methyl)phosphonate (118 mg, 0.51 mmol) in tetrahydrofuran (2 mL) was added potassium carbonate (71 mg, 0.51 mmol). The resulting mixture was then heated to 60 °C for 4 h. The reaction mixture was then cooled, diluted with ethyl acetate (20 mL) and washed with water (2x10 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by Prep-HPLC (Prep-C18, 5 μM Triart column, 20 × 150 mm, YMC-Actus; gradient elution of 50 % acetonitrile in water to 70% acetonitrile in water over a 9 min period, where both solvents contain 0.05% ammonium hydroxide) to give (E)-N-(l-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6-oxo-3-phenyl-l,6-dihydropyridazin-4-yl)cyclobutanecarboxamide (14.0 mg, 19% yield) as a white solid. LCMS m / z = 428.1 (M+l), ¹H-NMR (400 MHz, DMSO-d6) δ 9.05 (s, 1H), 7.56-7.48 (m, 5H), 7.45 (s, 1H), 6.96-6.87 (m, 2H), 4.93 (dd, J= 9.6 Hz, 2.8 Hz, 1H), 3.29-3.19 (m, 1H), 3.03 (s, 3H), 2.22-2.10 (m, 2H), 2.08-1.98 (m, 2H), 1.95-1.84 (m, 1H), 1.81-1.70 (m, 1H), 1.52-1.39 (m, 1H), 0.74-0.65 (m, 1H), 0.64-0.47 (m, 2H), 0.42-0.31 (m, 1H).120039.000211 (TYRA041PCT)step 1 step 2Example 103

[0514] Example 103. (E)-5-((Cyclobutylmethyl)amino)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6-phenylpyridazin-3(2H)-one.

[0515] Step 1. 5-((Cyclobutylmethyl)amino)-2-(methoxymethyl)-6-phenylpyridazin-3(2H)-one. To a solution of 5-bromo-2-(methoxymethyl)-6-phenylpyridazin-3(2H)-one (600 mg, 2.03 mmol, 1.0 eq), cyclobutylmethanamine (1.7 g, 20.33 mmol, 10.0 eq) in toluene (10 mL) was added sodium tert-butoxide (585 mg, 6.09 mmol, 3.0 eq), 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl (379 mg, 0.81 mmol, 0.4 eq) and dipalladium-tris(dibenzylideneacetone)chloroform complex (421 mg, 0.41 mmol, 0.2 eq). The reaction was purged with nitrogen mixture and heated to 90 °C for 1 h. The mixture was cooled, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (dichloromethane / methanol - 30 / 1) to afford 5-((cyclobutylmethyl)amino)-2-(methoxymethyl)-6-phenylpyridazin-3(2H)-one (300 mg, 49% yield) as a brown solid. LCMS m / z = 300.1 (M+l).

[0516] Step 2. 5-((Cyclobutylmethyl)amino)-6-phenylpyridazin-3(2H)-one. To a solution of 5-((cyclobutylmethyl)amino)-2-(methoxymethyl)-6-phenylpyridazin-3(2H)-one (300 mg, 1.00 mmol, 1.0 eq) in methanol (10 mL) was added hydrochloric acid (6.0 M, 10 ml). The mixture was stirred at 85 °C for 24 h. The reaction was cooled and diluted with water (10 mL) and saturated sodium bicarbonate was added slowly (~pH 8). The mixture was then extracted with ethyl acetate (2x50 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (dichloromethane / methanol = 15 / 1) to afford 5-120039.000211 (TYRA041PCT)((cyclobutylmethyl)amino)-6-phenylpyridazin-3(2H)-one (240 mg, 94% yield) as a brown solid. LCMS m / z = 256.1 (M+l).

[0517] (E)-N-(l-(l -Cyclopropyl -3-(methylsulfonyl)allyl)-6-oxo-3-phenyl-l, 6-dihydropyridazin-4-yl)cyclobutanecarboxamide was then obtained from ethyl 2-bromo-2-cyclopropylacetate and 5-((cyclobutylmethyl)amino)-6-phenylpyridazin-3(2H)-one. LCMS m / z = 256.1 (M+l), ¹H-NMR (400 MHz, DMSO-d6) δ 7.55-7.48 (m, 5H), 6.90-6.81 (m, 2H), 5.82 (t, J = 5.6 Hz, 1H), 5.66 (s, 1H), 4.87 (dd, J = 10.0 Hz, 4.0 Hz, 1H), 3.31 (s, 3H), 3.10 (t, J = 6.4 Hz, 2H), 2.63-2.55 (m, 1H), 2.02-1.94 (m, 2H), 1.86-1.77 (m, 2H), 1.72-1.63 (m, 2H), 1.44-1.35 (m, 1H), 0.69-0.62 (m, 1H), 0.57-0.48 (m, 2H), 0.35-0.30 (m, 1H).step 5Example 118

[0518] Example 118. (E)-6-(Cyclopent-l-en-l-yl)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(2,2-difluoropropoxy)pyridazin-3(2H)-one.

[0519] Step 1. 5,6-Dichloro-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one. To a solution of 5,6-dichloropyridazin-3(2H)-one (3.0 g, 18.2 mmol, 1.0 eq) in tetrahydrofuran (30 mL) was added l,8-diazabicyclo[5.4.0]undec-7-ene (6.87 g, 27.3 mmol, 1.5 eq) and (2-(chloromethoxy)ethyl)trimethylsilane (4.55 g, 27.3 mmol, 1.5 eq) at 0 °C. The reaction mixture was stirred at room temperature for 16 h. The mixture was then diluted with di chloromethane (100 mL) and washed with water (3x100 mL). The organic layer was dried120039.000211 (TYRA041PCT)over sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate - 7 / 1) to afford 5,6-dichloro-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (3.8 g, 71% yield) as colorless oil. LCMS m / z = 295.3 (M+l).

[0520] Step 2. 6-Chloro-5-(2,2-difluoropropoxy)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one. To a solution of 2,2-difluoropropan-l-ol (1.85 g, 19.3 mmol, 1.5 eq) in tetrahydrofuran (40 mL) was added sodium hydride (463 mg, 19.3 mmol, 1.5 eq) at 0 °C and the mixture was stirred at 0 °C for 0.5 h. 5,6-Dichloro-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (3.8 g, 12.9 mmol, 1.0 eq) was then added and the mixture was stirred at 0 °C for 2 h. The reaction mixture was then diluted with di chloromethane (100 mL) and washed with water (3x20 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate - 1 / 1) to afford 6-chloro-5-(2,2-difluoropropoxy)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (3.0 g, 66% yield) as colorless oil. LCMS m / z = 355.3 (M+l).

[0521] Step 3. 6-(Cyclopent-l-en-l-yl)-5-(2,2-difluoropropoxy)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one.

[0522] To a solution of 6-chloro-5-(2,2-difluoropropoxy)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (1.5 g, 4.23 mmol, 1.0 eq) and cyclopent-1-en-l-ylboronic acid (567 mg, 5.08 mmol, 1.2 eq) in 1,4-dioxane (20 mL) and water (2 mL) was added potassium carbonate (1.75g, 12.7 mmol, 3.0 eq) and 1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane complex (345 mg, 0.42 mmol, 0.1 eq). The reaction mixture was heated to 90 °C for 16 h. The reaction mixture was cooled, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10 / 1) to afford 6-(cyclopent-l-en-l-yl)-5-(2,2-difluoropropoxy)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (1.3 g, 80% yield) as a brown solid. LCMS m / z = 387.3 (M+l).

[0523] Step 4. 6-(Cyclopent-l-en-l-yl)-5-(2,2-difluoropropoxy)pyridazin-3(2H)-one. A solution of 6-(cyclopent-l-en-l-yl)-5-(2,2-difluoropropoxy)-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (1.3 g, 3.37 mmol, 1.0 eq) in hydrochloric acid- 1,4-dioxane solution (20 mL, 4M) was stirred for 6 h at 0 °C. The reaction mixture was then concentrated, and the residue was taken up in water (20 mL) and saturated sodium120039.000211 (TYRA041PCT)bicarbonate solution was added (pH = 7~8). This mixture was then extracted with ethyl acetate (2x40 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to afford 6-(cyclopent-l-en-l-yl)-5-(2,2-difluoropropoxy)pyridazin-3(2H)-one (600 mg, 69.6%) as a white solid. LCMS m / z = 257.2 (M+l).

[0524] Step 5. (E)-6-(Cyclopent-l-en-l-yl)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(2,2-difluoropropoxy)pyridazin-3(2H)-one. To a solution of 6-(cyclopent-l-en-l-yl)-5-(2,2-difluoropropoxy)pyridazin-3(2H)-one (120 mg, 0.47 mmol, 1.0 eq), triphenylphosphine (246 mg, 0.94 mmol, 2.0 eq) and (E)-l-cyclopropyl-3-(methylsulfonyl)prop-2-en-l-ol (107 mg, 0.61 mmol, 1.3 eq) in dichloromethane (5 mL) was added diisopropyl azodicarboxylate (142 mg, 0.70 mmol, 1.5 eq) at 0 °C and the reaction mixture was stirred at 0 °C for 2 h. The reaction was then diluted with dichloromethane (20 mL) and washed with water (2x10 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by Pre-HPLC (Prep-C18, 5 μM Triart column, 20 × 150 mm, YMC-Actus; gradient elution of 45% acetonitrile in water to 70% acetonitrile in water over a 5 min period, where both solvents contain 0.05% ammonium hydroxide) to afford (E)-6-(cyclopent-l-en-l-yl)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(2,2-difluoropropoxy)pyridazin-3(2H)-one (10.9 mg, 6% yield) as a white solid. LCMS m / z = 415.0 (M+l), ¹H-NMR (400 MHz, DMSO-d6) δ 6.87-6.86 (m, 2H), 6.74-6.72 (m, 1H), 6.45 (s, 1H), 4.92 (dd, J = 9.6 Hz, 2.8 Hz, 1H), 4.47 (t, J = 12.4 Hz, 2H), 3.02 (s, 3H), 2.70-2.67 (m, 2H), 2.57-2.54 (m, 2H), 1.86-1.80 (m, 2H), 1.75 (t, J = 19.2 Hz, 2H), 1.42-1.39 (m, 1H), 0.69-0.67 (m, 1H), 0.59-0.58 (m, 1H), 0.49-0.47 (m, 1H), 0.33-0.31 (m, 1H).o o o, SEM SEMstep 1 step 2step 3OF / \ F °[IExample 126120039.000211 (TYRA041PCT)

[0525] Example 126. (E)-2-(l-Cyclopropyl-3-(methylsulfonyl)allyl)-5-(2,2-difluorobutoxy)-6-phenylpyridazin-3(2H)-one.

[0526] Step 1. 5-(2,2-Difluorobutoxy)-6-phenyl-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one. To a solution of 2,2-difluorobutan-l-ol (2.67 g, 15.73 mmol, 2.0 eq) in N, N-dimethylformamide (50 mL) was added sodium hydride (629.36 mg, 15.73 mmol, 2.0 eq, 60% dispersion in mineral oil) at 0 °C, the reaction was stirred at 0 °C for 0.5 h. 5-Bromo-6-phenyl-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (3.0 g, 7.87 mmol, 1.0 eq) was then added to the reaction, and the mixture was stirred at room temperature for 2 h. Upon completion, the mixture was poured into water (100 mL) and extracted with ethyl acetate (2x200 mL). The combined organic layers were washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The isolated material was purified by silica gel chromatography (petroleum ether / ethyl acetate - 2 / 1) to afford 5-(2,2-difluorobutoxy)-6-phenyl-2-((2- (trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (2.7 g, 84% yield) as colorless oil. LCMS m / z = 411.3 (M+l).

[0527] Step 2. 5-(2,2-Difluorobutoxy)-6-phenylpyridazin-3(2H)-one. To a solution of 5-(2,2-difluorobutoxy)-6-phenyl-2-((2-(trimethylsilyl)ethoxy)methyl)pyridazin-3(2H)-one (3.0 g, 7.31 mmol, 1.0 eq) in di chloromethane (30 mL) was added trifluoroacetic acid (10 mL). The resulting mixture was stirred for 3 h. Methanol (30 mL) and ammonium hydroxide (20 mL) were then added, and the mixture was stirred for another 0.5 h. The mixture was poured into water (30 mL) and extracted with ethyl acetate (2x30 mL). The combined organic layers were washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (dichloromethane / methanol - 20 / 1) to afford 5-(2,2-difluorobutoxy)-6-phenylpyridazin-3(2H)-one (2.0 g, 78% yield) as a yellow solid. LCMS m / z = 281.3 (M+l).

[0528] Step 3. (E)-2-(l-Cyclopropyl-3-(methylsulfonyl)allyl)-5-(2,2-difluorobutoxy)-6-phenylpyridazin-3(2H)-one. To a solution of 5-(2,2-difluorobutoxy)-6-phenylpyridazin-3(2H)-one (1.56 g, 5.57 mmol, 1.0 eq) and (E)-l-cyclopropyl-3-(methylsulfonyl)prop-2-en-l-ol (1.28 g, 7.24 mmol, 1.3 eq) in dichloromethane (20 mL) were added triphenylphosphine (2.2 g, 8.35 mmol, 1.5 eq) and diisopropyl azodicarboxylate (1.46 g, 7.24 mmol, 1.3 eq). The mixture was stirred for 2 h at 0 °C. Upon completion, the mixture was diluted with water (30 mL) and the layers separated. The aqueous was extracted with120039.000211 (TYRA041PCT)di chloromethane (2x20 mL) and the combined organic layers were washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The isolated material was purified by Prep-HPLC (Prep-C18, 20-45M, 120 g, Tianjin Bonna-Agela Technologies; gradient elution of 50% acetonitrile in water to 60% acetonitrile in water over a 8 min period, where both solvents contain 0.05% ammonium hydroxide) to afford (E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(2,2-difluorobutoxy)-6-phenylpyridazin-3(2H)-one (500 mg, 21% yield) as a white solid. LCMS m / z = 439.0 (M + 1), ’H-NMR (400 MHz, DMSO-d6) 7.70-7.67 (m, 2H), 7.50-7.46 (m, 3H), 6.92-6.91 (m, 2H), 6.20 (s, 1H), 4.96 (dd, J = 10.0 Hz, 2.8 Hz, 1H), 4.46 (t, J= 12.4 Hz, 2H), 3.03 (s, 3H), 2.07-1.87 (m, 2H), 1.53-1.46 (m, 1H), 0.98 (t, J= 7.6 Hz, 3H), 0.71-0.52 (m, 3H), 0.38-0.32 (m, 1H).

[0529] (E)-2-(l-Cyclopropyl-3-(methylsulfonyl)allyl)-5-(2,2-difluorobutoxy)-6-phenylpyridazin-3(2H)-one was further purified on a chiral stationary phase to afford two isomers. The isomers were randomly assigned; the absolute configurations were not determined.Instrument Model: Prep- HPLC-Flash Brix 1860Column Name: YMC CHIRAL ART Cellulose-SC, 250x20mm, 5umMobile Phase: A: n-Hexane; B: isopropanolIsocratic elution: A:B=20:20（V / V）Total Flow: 20 mL / minColumn temp.: RTRT(min): 12 min;18 minRunning Time: 25 min

[0530] Isomer A, Example 165. LCMS m / z = 439.1 (M + 1), ¹H-NMR (400 MHz, DMSO-d6) δ 7.72-7.66 (m, 2H), 7.51-7.44 (m, 3H), 6.97-6.88 (m, 2H), 6.62 (s, 1H), 4.95 (dd, J= 9.6 Hz, 2.8 Hz, 1H), 4.46 (t, J= 12.4 Hz, 2H), 3.03 (s, 3H), 2.03-1.86 (m, 2H), 1.55-1.44 (m, 1H), 0.96 (t, J= 7.2 Hz, 3H), 0.76-0.67 (m, 1H), 0.66-0.58 (m, 1H), 0.57-0.48 (m, 1H), 0.39-0.31 (m, 1H)

[0531] Isomer B, Example 166. LCMS m / z = 439.1 (M + 1), ¹H-NMR (400 MHz, DMSO-d6) δ 7.72-7.66 (m, 2H), 7.51-7.45 (m, 3H), 6.96-6.88 (m, 2H), 6.62 (s, 1H), 4.95 (dd, J= 10.0 Hz, 3.2 Hz, 1H), 4.46 (t, J= 12.0 Hz, 2H), 3.03 (s, 3H), 2.02-1.86 (m, 2H), 1.55-1.44 (m, 1H), 0.96 (t, J= 7.2 Hz, 3H), 0.76-0.67 (m, 1H), 0.66-0.58 (m, 1H), 0.57-0.47 (m, 1H), 0.39-0.30 (m, 1H)120039.000211 (TYRA041PCT)Example 127

[0532] Example 127. (E)-5-(Cyclobutoxymethyl)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6-phenylpyridazin-3(2H)-one.

[0533] Step 1. 5-(Hydroxymethyl)-6-phenylpyridazin-3(2H)-one. To a solution of 5-(hydroxymethyl)-6-phenyl-4,5-dihydropyridazin-3(2H)-one (500 mg, 2.45 mmol, 1.0 eq) in acetonitrile (10 mL) was added copper (II) chloride (656 mg, 4.90 mmol, 2.0 eq). The reaction mixture was heated to 80 °C for 1 h. The mixture was then cooled and diluted with ethyl acetate (30 mL). The mixture was washed with water (2x30 mL) and saturated brine (2x30 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (dichloromethane / methanol - 15 / 1) to give 5-(hydroxymethyl)-6-phenylpyridazin-3(2H)-one (450 mg, 91% yield) as a light-yellow solid. LCMS m / z = 203.2 (M+l).

[0534] Step 2. 5-(Bromomethyl)-6-phenylpyridazin-3(2H)-one. To a solution of 5-(hydroxymethyl)-6-phenylpyridazin-3(2H)-one (450 mg, 2.23 mmol, 1.0 eq) indi chloromethane (9 mL) was added phosphorus tribromide (1.81 g, 6.68 mmol, 3.0 eq) at 0 °C and the reaction mixture was stirred then at 35 °C for 6 h. The reaction was quenched with methanol (6 mL) at 0 °C and then concentrated under reduced pressure. The residue was taken up in di chloromethane (20 mL) and saturated aqueous sodium bicarbonate was added (pH ~7). The layers were separated and the aqueous layer extracted with di chloromethane (2x20 mL). The combined organic layers were washed with saturated brine (2x20 mL), dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (dichloromethane / methanol - 15 / 1) to give 5-120039.000211 (TYRA041PCT)(bromomethyl)-6-phenylpyridazin-3(2H)-one (250 mg, 42% yield) as a yellow solid. LCMS m / z = 265.1 (M+l).

[0535] Step 3. 5-(Cyclobutoxymethyl)-6-phenylpyridazin-3(2H)-one. To a solution of cyclobutanol (125 mg, 1.74 mmol, 2.0 eq) in N, N-dimethylformamide (3 mL) was added sodium hydride (69 mg, 60% in mineral oil, 1.74 mmol, 2.0 eq) at 0 °C. This mixture was stirred at room temperature for 0.5 h. 5-(Bromomethyl)-6-phenylpyridazin-3(2H)-one (230 mg, 0.87 mmol, 1.0 eq) in N, N-dimethylformamide (2 mL) was then added at 0 °C and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was then poured into a mixture of ice and saturated ammonium chloride (10 mL) and ethyl acetate (10 mL). The layers were separated, and the aqueous layer was then extracted with ethyl acetate (2x10 mL). The combined organic layers were washed with water (20 mL), saturated brine (20 mL), dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (dichloromethane / methanol - 20 / 1) to give 5-(cyclobutoxymethyl)-6-phenylpyridazin-3(2H)-one (90 mg, 40% yield) as a light-yellow solid. LCMS m / z = 257.2 (M+l).

[0536] Step 4. (E)-5-(Cyclobutoxymethyl)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6-phenylpyridazin-3(2H)-one.

[0537] To a solution of 5-(cyclobutoxymethyl)-6-phenylpyridazin-3(2H)-one (80 mg, 0.31 mmol, 1.0 eq), (E)-l-cyclopropyl-3-(methylsulfonyl)prop-2-en-l-ol (83 mg, 0.47 mmol, 1.5 eq) and triphenylphosphine (123 mg, 0.47 mmol, 1.5 eq) in tetrahydrofuran (2 mL) was added diisopropyl azodicarboxylate (95 mg, 0.47 mmol, 1.5 eq). The resulting mixture was stirred at room temperature for 1 h. The mixture was then diluted with dichloromethane (10 mL) and washed with water (2x10 mL) and saturated brine (10 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (dichloromethane / methanol - 20 / 1) to give (E)-5-(cyclobutoxymethyl)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6-phenylpyridazin-3(2H)-one (100 mg, 60% purity). The material was further purified by Prep-HPLC (Prep-C18, 5 μM Triart column, 20 × 150 mm, YMC-Actus; gradient elution of 50 % acetonitrile in water to 70% acetonitrile in water over a 9 min period, where both solvents contain 0.05% ammonium hydroxide) to give (E)-5-(cyclobutoxymethyl)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6-phenylpyridazin-3(2H)-one (12.2 mg, 9% yield) as a white solid. LCMS m / z = 415.1 (M+l), ¹H-NMR (400 MHz, DMSO-d6) δ 7.57-7.46 (m, 5H), 6.99 (s, 1H), 6.93-6.90 (m, 2H), 5.00-120039.000211 (TYRA041PCT)4.94 (m, 1H), 4.28-4.13 (m, 2H), 4.00-3.91 (m, 1H), 3.03 (s, 3H), 2.16-2.05 (m, 2H), 1.86-1.74 (m, 2H), 1.67-1.56 (m, 1H), 1.53-1.36 (m, 2H), 0.74-0.58 (m, 2H), 0.56-0.47 (m, 1H), 0.40-0.32 (m, 1H).oExample 136

[0538] Example 136. (E)-4-(Cyclobutylmethoxy)-l-(l-cyclopropyl-3-(methylsulfonyl)allyl)-3-fluoro-5-phenylpyridin-2(lH)-one.

[0539] Step 1. 5-Bromo-4-chloro-3-fluoro-2 -methoxypyridine. To a solution of 5-bromo-3-fluoro-2 -methoxypyridine (8.0 g, 38.83 mmol, 1.0 eq) in tetrahydrofuran (200 mL) was added lithium diisopropylamide (2 M, 39 mL, 77.7 mmol, 2.0 eq) at -78 °C, the resulting mixture was stirred at -78 °C for 1 h. Perchloroethane (1.72 g, 7.28 mmol, 1.3 eq) was then added, the resulting mixture was stirred at -78 °C for 3 h. The reaction mixture was quenched with water (200 mL) and warmed to room temperature. The mixture was extracted with ethyl acetate (3x200 mL) and the combined organic layers were washed with saturated brine (600 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (petroleum ether / dichloromethane - 2 / 1) to give 5-bromo-4-chl oro-3 -fluoro-2-methoxypyri dine (7.5 g, 80% yield) as a white solid. LCMS m / z = 240.1 (M+l).

[0540] Step 2. 4-Chloro-3-fluoro-2-methoxy-5-phenylpyridine. To a solution of 5-bromo-4-chloro-3-fluoro-2-methoxypyridine (4.0 g, 16.6 mmol, 1.0 eq) in 1,4-dioxane (500mL) and water (25 ml) was added potassium carbonate (4.6 g, 33.3 mmol, 2.0 eq), 1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane complex (243 mg, 3.3 mmol, 0.02 eq) and phenylboronic acid (3.04 g, 24.9 mmol, 1.5 eq). The reaction120039.000211 (TYRA041PCT)mixture was purged with nitrogen and stirred at 90 °C for 2 h. The reaction was cooled, diluted with water (200 mL), and extracted with ethyl acetate (3x200 mL). The combined organic layers were washed with saturated brine (600 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (petroleum ether / dichloromethane - 30 / 1) to give 4-chl oro-3 -fluoro-2-methoxy-5-phenylpyridine (3.1 g, 78% yield) as a white solid. LCMS m / z = 238.2 (M+l).

[0541] Step 3. 4-(Cyclobutylmethoxy)-3-fluoro-2-methoxy-5-phenylpyridine. To a solution of 4-chl oro-3 -fluoro-2-methoxy-5 -phenylpyridine (800 mg, 3.37 mmol, 1.0 eq) in N, N-dimethylformamide (10 mL) was added cesium carbonate (2.2 g, 6.73 mmol, 2.0 eq) and cyclobutylmethanol (579 mg, 6.73 mmol, 2.0 eq) and the mixture was heated to 80 °C for 20 h. The mixture was cooled, diluted with water (10 mL), and extracted with ethyl acetate (3x20 mL). The combined organic layers were washed with saturated brine (30 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate - 3 / 1) to give 4-(cyclobutylmethoxy)-3-fluoro-2-methoxy-5 -phenylpyridine (500 mg) as colorless oil. LCMS m / z = 288.1 (M+l).

[0542] Step 4. 4-(Cyclobutylmethoxy)-3-fluoro-5-phenylpyridin-2(lH)-one. To a solution of 4-(cyclobutylmethoxy)-3-fluoro-2-methoxy-5-phenylpyridine (500 mg, 1.74 mmol, 1.0 eq) in N, N-dimethylformamide (10 mL) was added p-toluenesulfonic acid monohydrate (453 mg, 8.70 mmol, 5.0 eq) and lithium chloride (369 mg, 8.70 mmol, 5.0 eq) and the mixture was heated at 110 °C for 2 h. The reaction was cooled, diluted with water (20 mL), and extracted with ethyl acetate (3x20...

Claims

120039.000211 (TYRA041PCT)What is claimed:

1. A compound of Formula (I):OR6(I),or a pharmaceutically acceptable salt thereof,wherein:- is a single bond or a double bond;X is N, or CH;R is:120039.000211 (TYRA041PCT)R1Ais H, C1-C6alkyl, optionally substituted C3-C6cycloalkyl, optionally substituted 3-6 membered heterocycloalkyl, C1-C3alk-C3-C6cycloalkyl, C1-C3alk-3-6 membered heterocycloalkyl, CH2-O-C1-C6alkyl, 5-11 membered bridged bicyclic cycloalkyl, optionally substituted 5-6 membered heteroaryl, or aryl;R1Bis H; or C1-C6alkyl;or R1Aand R1B, together with the carbon atom to which they are both attached, form a 3-6 membered cycloalkyl ring;R1Cis H, Ci-C3alkyl, C3-C5cycloalkyl, CH2-O-C1-C3alkyl; or 5-6 membered heteroaryl;R1Dis H; or Ci-C3alkyl;or R1Cand R1D, together with the nitrogen atom to which they are both attached, form a 3-6 membered heterocycloalkyl ring;R2is C1-C3alkyl, C3-C5cycloalkyl, C1-C3haloalkyl, N(C1-C3alkyl)2, NH(C1-C3alkyl), optionally substituted 3-6 membered heterocycloalkyl, optionally substituted 5-6 membered heteroaryl, NH-(C1-C3alk)-N(C1-C3alkyl)2, NH-(C1-C3alk)-NH(C1-C3alkyl), N(C1-C3alkyl)-(C1-C3alk)-N(C1-C3alkyl)2, or N(C1-C3alkyl)-(C1-C3alk)-NH(C1-C3alkyl); NH2;R3is H, CN, C1-C6alkyl, C3-C6cycloalkyl, -OC1-C6alkyl, -OC3-C6cycloalkyl, -SC1-C6alkyl, -SC3-C6cycloalkyl, -NHC1-C6alkyl, -NHC3-C6cycloalkyl, -NHC(O)C1-C6alkyl, -NHC(O)C3-C6cycloalkyl, F, Cl,wherein the C1-C6alkyl or C3-C6cycloalkyl groups in R3are optionally substituted with one or more halo, C3-C5cycloalkyl, or C3-C5halocycloalkyl;R4is H, C1-C6alkyl, C3-C7cycloalkyl, -OC1-C6alkyl, -OC3-C7cycloalkyl, -OC1-C3alkC3-C7cycloalkyl, -OC3-C7heterocycloalkyl, -SC1-C6alkyl, -SC3-C7cycloalkyl, -NHC1-C6alkyl, -NHC3-C7cycloalkyl, -NH-C1-C3alk-C3-C7cycloalkyl, -NHC(O)C1-C6alkyl, -NHC(O)C3-C7cycloalkyl, -NHC(O)-C1-120039.000211 (TYRA041PCT)C3alk-C3-C7cycloalkyl, C(O)NHC1-C6alkyl, C(O)NHC3-C7cycloalkyl,OM-i-s, -O-(C5-C9spirocycloalkyl), -O-(3-7-membered heterocycloalkyl), -CH=CH-Ci-C6alkyl, -CH=CH(C3-C7cycloalkyl), -C=C-Ci-C6alkyl, - C=C(C3-C7cycloalkyl), -C≡CC(C1-C3alkyl)2OH, -C=CC(C!-C3alkyl)3, C=CC(Cl-C3alkyl)2OCl-C6alkylwherein the C1-C3alk, C1-C6alkyl, or C3-C7cycloalkyl groups in R4are optionally substituted with one or more halo, D, OH, OMe, CN, aryl, C1-C6alkyl, OC3-C7cycloalkyl, OC1-C6alkyl, OC1-C6haloalkyl, C3-C5halocycloalkyl, or C3-C5cycloalkyl, wherein the C3-C5cycloalkyl is optionally substituted with one or more halo, C1-C6alkyl, or -OC1-C6alkyl;or R3and R4, together with the atoms to which they are attached, form an optionally substituted C5-C6cycloalkyl ring that is fused to Ring A, an optionally substituted 6-membered aryl ring that is fused to Ring A, or an optionally substituted 5-6 membered heteroaryl ring that is fused to ring A,wherein the optionally substituted C5-C6cycloalkyl ring, optionally substituted 6-membered aryl ring, or optionally substituted 5-6 membered heteroaryl ring formed by R3and R4is optionally substituted with C1-C6alkyl, C3-C6cycloalkyl, -OC1-C6alkyl, -OC3-C6cycloalkyl, -SC1-C6alkyl, -SC3-C6cycloalkyl, -NHC1-C6alkyl, -NHC3-C6cycloalkyl, -NHC(O)C1-C6alkyl, -NHC(O)C3-C6cycloalkyl, wherein the C1-C6alkyl or C3-C6cycloalkyl groups in the optional substituents are themselves optionally substituted with one or more halo, C1-C6alkyl, C1-C3haloalkyl, C3-C5cycloalkyl, or C3-C5halocycloalkyl.R5is optionally substituted aryl, optionally substituted 5-6 membered heteroaryl, optionally substituted C3-Ce cycloalkyl ring, optionally substituted Cs-Ce cycloalkenyl ring, or optionally substituted 5-6 membered heterocycloalkenyl ring;120039.000211 (TYRA041PCT)R6is H, D, halo, CN, or C1-C3alkyl; andR6Ais H or D.

2. The compound of claim 1, wherein R3is H, CN, Ci-Cealkyl, Cs-Cecycloalkyl, -OCi- Cealkyl, -OC3-C6cycloalkyl, -SCi-Cealkyl, -SCs-Cecycloalkyl, -NHCi-Cealkyl, - NHCs-Cecycloalkyl, -NHC(O)Ci-C6alkyl, - NHC(O)C3-C6cycloalkyl, F, Cl,wherein the C1-C6alkyl or C3-C6cycloalkyl groups in R3are optionally substituted with one or more halo, C3-C5cycloalkyl, or C3-C5halocycloalkyl; andR4is H, Ci-Cealkyl, C3-C7cycloalkyl, -OCi-C6alkyl, -OC3-C7cycloalkyl, -OCi- C3alkC3-C7cycloalkyl, -OC3-C7heterocycloalkyl, -SCi-Cealkyl, -SC3- C7cycloalkyl, -NHCi-Cealkyl, -NHC3-C7cycloalkyl, -NH-Ci-Csalk-Cs- C7cycloalkyl, -NHC(O)Ci-C6alkyl, -NHC(O)C3-C7cycloalkyl, -NHC(O)-Ci- C3alk-C3-C7cycloalkyl, C(O)NHC1-C6alkyl, C(O)NHC3-C7cycloalkyl, ov—M-i-s, -O-(C5-C9spirocycloalkyl), -O-(3-7-membered heterocycloalkyl), -CH=CH-Ci-C6alkyl, -CH=CH(C3-C7cycloalkyl), -C=C-Ci-C6alkyl, - C=C(C3-C7cycloalkyl), -C≡CC(C1-C3alkyl)2OH, -C≡CC(C1-C3alkyl)3, C=CC(Cl-C3alkyl)2OCl-C6alkylwherein the C1-C3alk, C1-C6alkyl, or C3-C7cycloalkyl groups in R4are optionally substituted with one or more halo, D, OH, OMe, CN, aryl, C1-C6alkyl, OC3-C7cycloalkyl, OC1-C6alkyl, OC1-C6haloalkyl, C3-C5halocycloalkyl, or C3-C5cycloalkyl, wherein the C3-C5cycloalkyl is optionally substituted with one or more halo, C1-C6alkyl, or -OC1-C6alkyl.

3. The compound of claim 1 or claim 2, wherein - is a single bond.

4. The compound of claim 1 or claim 2, wherein - is a double bond.

5. The compound of any preceding claim, wherein R5is optionally substituted aryl.

6. The compound of claim 5, wherein R5is phenyl.120039.000211 (TYRA041PCT)7. The compound of claim 5, wherein R5is fluorophenyl.

8. The compound of any one of claims 1-4, wherein R5is optionally substituted 5-6 membered heteroaryl.

9. The compound of claim 8, wherein R5is thiophenyl or pyridinyl.

10. The compound of any one of claims 1-4, wherein R5is an optionally substituted C3-C6 cycloalkyl ring.

11. The compound of claim 10, wherein R5is cyclopentanyl.

12. The compound of any one of claims 1-4, wherein R5is an optionally substituted C5-C6 cycloalkenyl ring.

13. The compound of claim 12, wherein R5is cyclopentenyl.

14. The compound of any one of claims 1-4, wherein R5is an optionally substituted 5-6 membered heterocycloalkenyl ring.

15. The compound of claim 14, wherein R5is a dihydropyranyl ring.

16. The compound of any one of the preceding claims, wherein R3is H, F, or C1-C6alkyl, wherein the C1-C6alkyl is optionally substituted with one or more halo or C3-C5cycloalkyl.

17. The compound of claim 16, wherein R3is H.

18. The compound of claim 16, wherein R3is F.

19. The compound of claim 16, wherein R3is C₁-C₆alkyl optionally substituted with one or more halo or C₃-C₅cycloalkyl.

20. The compound of claim 19, wherein R3is:

21. The compound of claim 19, wherein R3is CH3 or CF3.

22. The compound of any preceding claim, wherein R4is H; C1-C6alkyl optionally substituted with one or more halo, OC3-C7cycloalkyl, OC1-C6alkyl, OC1-C6haloalkyl, C3-C5cycloalkyl, or C3-C5halocycloalkyl; -OC1-C6alkyl optionally substituted with one or more halo, D, aryl, or C3-C5cycloalkyl, wherein the C3-C5cycloalkyl is120039.000211 (TYRA041PCT)optionally substituted with one or more halo, C1-C6alkyl, or -OC1-C6alkyl; -OC3-C7cycloalkyl optionally substituted with one or more halo or C1-C6alkyl; -SC1-C6alkyl; -SC3-C6cycloalkyl; -NHC1-C6alkyl; -NHC3-C6cycloalkyl; -NHC(O)C1-C6alkyl; -NHC(O)C3-C6cycloalkyl; C(O)NHC1-C6alkyl; -C(O)NHC3-C7cycloalkyl;C=CC(Cl-C3alkyl)2OH; -C≡CC(C1-C3alkyl)3; or C=CC(Ci-C3alkyl)2O-Ci-C6alkyl.

23. The compound of claim 22, wherein R4is H.

24. The compound of claim 22, wherein R4is C1-C6alkyl optionally substituted with one or more halo, OC3-C7cycloalkyl, OC1-C6alkyl, OC1-C6haloalkyl, C3-C5cycloalkyl, or C3-C5halocycloalkyl.

25. The compound of claim 24, wherein R4is C₁-C₆alkyl optionally substituted with one or more halo or C₃-C₅cycloalkyl.

26. The compound of claim 25, wherein R4is27. The compound of claim 24, wherein R4is C1-C6alkyl optionally substituted with one or more OC1-C6alkyl, OC1-C6haloalkyl, or OC3-C7cycloalkyl.

28. The compound of claim 27, wherein R4is120039.000211 (TYRA041PCT)29. The compound of claim 22, wherein R4is -OC1-C6alkyl optionally substituted with one or more halo, D, aryl, or C3-C5cycloalkyl, wherein the C3-C5cycloalkyl is optionally substituted with one or more halo, C1-C6alkyl, or -OC1-C6alkyl.

30. The compound of claim 29, wherein R4is:120039.000211 (TYRA041PCT)31. The compound of claim 22, wherein R4is -OC3-C7cycloalkyl optionally substituted with one or more halo or Ci-Cealkyl.

32. The compound of claim 31, wherein R4is:

33. The compound of claim 22, wherein R4is -O-(C5-C9spirocycloalkyl).

34. The compound of claim 33, wherein R4is:

35. The compound of claim 22, wherein R4is -O-3-7 membered heterocycloalkyl optionally substituted with one or more halo or C1-C6alkyl.

36. The compound of claim 35, wherein R4is37. The compound of claim 22, wherein R4is -SC3-C7cycloalkyl.

38. The compound of claim 37, wherein R4is:

39. The compound of claim 22, wherein R4is -NHC1-C6alkyl or -NHC3-C7cycloalkyl.

40. The compound of claim 39, wherein R4is:120039.000211 (TYRA041PCT)41. The compound of claim 22, wherein R4is -NHC(O)Ci-C6alkyl or - NHC(O)C3-C7cycloalkyl, each optionally substituted with one or more halo or C3-C6cycloalkyl groups.

42. The compound of claim 41, wherein R4is:

43. The compound of claim 22, wherein R4is -C(O)NHC3-C7cycloalkyl or44. The compound of claim 43, wherein R4is:O45. The compound of claim 22, wherein R4is -C=C-Ci-C6alkyl, -C≡C(C3-C7cycloalkyl), -C≡CC(C1-C3alkyl)2OH, -C≡CC(C1-C3alkyl)3.

46. The compound of claim 45, wherein R4is:

47. The compound of any one of claims 1, or 3-15, wherein R3and R4, together with the atoms to which they are attached, form an optionally substituted C5-C6cycloalkyl ring that is fused to Ring A; an optionally substituted 6-membered aryl ring that is fused to120039.000211 (TYRA041PCT)Ring A; or an optionally substituted 5-6 membered heteroaryl ring that is fused to ring A,wherein the optionally substituted Cs-Cecycloalkyl ring, optionally substituted 6- membered aryl ring, or optionally substituted 5-6 membered heteroaryl ring formed by R3and R4is optionally substituted with C₁-C₆alkyl, C₃-C₆cycloalkyl, -OC₁-C₆alkyl, -OC₃-C₆cycloalkyl, -SC₁-C₆alkyl, -SC₃-C₆cycloalkyl, -NHC₁-C₆alkyl, -NHC₃-C₆cycloalkyl, -NHC(O)C₁-C₆alkyl, - NHC(O)C₃-C₆cycloalkyl, wherein the C₁-C₆alkyl or C₃-C₆cycloalkyl groups in the optional substituents are themselves optionally substituted with one or more halo, C₁-C₆alkyl, C₃-C₅cycloalkyl, or -C₃-C₅halocycloalkyl.

48. The compound of claim 47, wherein R3and R4, together with the atoms to which they are attached, form an optionally substituted C5-C6cycloalkyl ring that is fused to Ring A.

49. The compound of claim 48, wherein the compound has the formula IA:OR5(IA).

50. The compound of claim 49, wherein the compound has the formula IA-1:OR5(IA-1).

51. The compound of claim 47, wherein R3and R4, together with the atoms to which they are attached, form an optionally substituted 6-membred aryl ring that is fused to Ring A.

52. The compound of claim 51, wherein the compound has the formula IB:120039.000211 (TYRA041PCT)53. The compound of claim 47, wherein R3and R4, together with the atoms to which they are attached, form an optionally substituted 5-6 membered heteroaryl ring that is fused to ring A.

54. The compound of claim 53, wherein the compound has the formula IC:OR5(IC),wherein Y is N or CH, andR7is C1-C6alkyl, C3-C6cycloalkyl, 3-6-membered heterocycloalkyl, -OC1-C6alkyl, -OC3-C6cycloalkyl, -SC1-C6alkyl, -SC3-C6cycloalkyl, -NHC1-C6alkyl, -NHC3-C6cycloalkyl, -NHC(O)C1-C6alkyl, - NHC(O)C3-C6cycloalkyl, wherein the C1-C6alkyl or C3-C6cycloalkyl groups are optionally substituted with one or more halo, C1-C6alkyl, C1-C6haloalkyl, C3-C5cycloalkyl, or C3-C5halocycloalkyl.

55. The compound of claim 54, wherein Y is N.

56. The compound of claim 54, wherein Y is CH.

57. The compound of any one of claims 54-56, wherein R7is C₁-C₆alkyl optionally substituted with one or more halo, C₃-C₅cycloalkyl, or C₃-C₅halocycloalkyl.

58. The compound of claim 57, wherein R7is -CH2CH3, -CH(CH3)2, -CH3, -CF3, -CF2CH3, -CF2CF3, or -CF2CH2CH3.

59. The compound of any one of claims 54-56, wherein R7is C3-C6cycloalkyl optionally substituted with one or more halo, C1-C6alkyl, or C1-C6haloalkyl.

60. The compound of claim 59, wherein R7is120039.000211 (TYRA041PCT)F61. The compound of any one of claims 54-56, wherein R7is 3-6-membered heterocycloalkyl.

62. The compound of claim 61, wherein R7is63. The compound of any one of claims 54-56, wherein R7is NHC(O)C1-C6alkyl or -NHC(O)C3-C6cycloalkyl, wherein the C1-C6alkyl is optionally substituted with one or more halo or C3-C6cycloalkyl.

64. The compound of claim 63, wherein R7is65. The compound of any one of claims 1-64, wherein R is66. The compound of any one of claims 1-64, wherein R is120039.000211 (TYRA041PCT)67. The compound of any one of claims 1-64, wherein R is Or2R1BO%ZOR6R6A68. The compound of any one of claims 1-64, wherein R isR R1BR6A69. The compound of any one of claims 1-64, wherein R isOR6A70. The compound of any one of claims 1-64, wherein R is71. The compound of any one of claims 1-64, wherein R is1BIXNR6R6A120039.000211 (TYRA041PCT)72. The compound of claim 70 or claim 71, wherein R1Dis H.

73. The compound of claim 70 or claim 71, wherein R1Dis CH3.

74. The compound of any one of claims 1-64, wherein R is1AR75. The compound of any one of claims 66-74, wherein R2is CH3.

76. The compound of any one of claims 66-74, wherein R2is CH2CH3.

77. The compound of any one of claims 66-74, wherein R2is cyclopropyl78. The compound of any one of claims 66-74, wherein R2is NHCH3.

79. The compound of any one of claims 66-74, wherein R2is N(CH3)2.

80. The compound of any one of claims 66-74, wherein R2is81. The compound of any one of claims 66-74, wherein R2is82. The compound of any one of claims 66-74, wherein R2is N(Ci-C3alkyl)-(Ci-C3alk)- N(Ci-C3alkyl)2.

83. The compound of any one of claims 66-74, wherein R2is N(CH3)-CH2CH2-N(CH3)2.

84. The compound of any one of claims 66-83, wherein R1Ais C3-C6cycloalkyl.

85. The compound of claim 84, wherein R1Ais cyclopropyl.

86. The compound of claim 84, wherein R1Ais cyclobutyl.

87. The compound of claim 84, wherein R1Ais cyclopentyl.

88. The compound of claim 84, wherein R1Ais cyclohexyl.

89. The compound of any one of claims 66-83, wherein R1Ais 3-6 memberedheterocycloalkyl.120039.000211 (TYRA041PCT)90. The compound of claim 89, wherein R1Ais oxetanyl.

91. The compound of any one of claims 66-83, wherein R1Ais C1-C6alkyl.

92. The compound of claim 91, wherein R1Ais isopropyl or n-propyl.

93. The compound of claim 91, wherein R1Ais tert-butyl or isobutyl.

94. The compound of any one of claims 66-83, wherein R1Ais C1-C3alk-C3-C6cycloalkyl.

95. The compound of claim 94, wherein R1Ais -CH2-cyclopropyl.

96. The compound of any one of claims 66-83, wherein R1Ais CH2-O-C1-C3alkyl.

97. The compound of any one of claims 66-96, wherein R1Bis C1-C3alkyl.

98. The compound of any one of claims 66-96, wherein R1Bis H.

99. The compound of any one of claims 66-83, wherein R1Aand R1B, together with the carbon atom to which they are both attached, form a 3-6 membered cycloalkyl ring.

100. The compound of claim 99, wherein R1Aand R1B, together with the carbon atom to which they are both attached, form a cyclopropyl ring.

101. The compound of any one of claims 66-100, wherein R6is H.

102. The compound of any one of claims 66-100, wherein R6is D.

103. The compound of any one of claims 66-100, wherein R6is CH3.

104. The compound of any one of claims 66-100, wherein R6is F.

105. The compound of any one of claims 66-100, wherein R6is Cl.

106. The compound of any one of claims 66-105, wherein R6Ais H.

107. The compound of any one of claims 66-105, wherein R6Ais D.

108. The compound of claim 1, wherein the compound of Formula I is:120039.000211 (TYRA041PCT)or a pharmaceutically acceptable salt thereof,wherein:R1Ais C3-C6cycloalkyl,R4is -OC1-C6alkyl optionally substituted with one or more halo, or C3-C5cycloalkyl;R6is H or F; andR6Ais H or D.

109. The compound of claim 108, wherein R1Ais cyclopropyl.

110. The compound of claim 108, wherein R1Ais cyclobutyl.

111. The compound of any one of claims 108-110, wherein R6is H.

112. The compound of any one of claims 108-110, wherein R6is F.

113. The compound of any one of claims 108-112, wherein R4is -OC1-C6alkyl substituted with one or more F.

114. The compound of claim 113, wherein R4is:

115. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is:120039.000211 (TYRA041PCT)(E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-8-phenyl-2- (trifluoromethyl)pyrimido[4,5-d]pyridazin-5(6H)-one;(S, E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-8-phenyl-2- (trifluoromethyl)pyrimido[4,5-d]pyridazin-5(6H)-one;(R, E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-8-phenyl-2- (trifluoromethyl)pyrimido[4,5-d]pyridazin-5(6H)-one;(E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(l,l-difluoroethyl)-8- phenylpyrimido[4,5-d]pyridazin-5(6H)-one;(R, E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(l,l-difluoroethyl)-8- phenylpyrimido[4,5-d]pyridazin-5(6H)-one;(S, E)-6-( 1 -cyclopropyl -3 -(methylsulfonyl)allyl)-2-( 1, 1 -difluoroethyl)-8- phenylpyrimido[4,5-d]pyridazin-5(6H)-one;(E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-8-phenyl-2- (trifluoromethyl)pyrimido[4,5-d]pyridazin-5(6H)-one;(S, E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-8-phenyl-2- (trifluoromethyl)pyrimido[4,5-d]pyridazin-5(6H)-one;(R, E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-8-phenyl-2- (trifluoromethyl)pyrimido[4,5-d]pyridazin-5(6H)-one;(E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(l,l-difluoroethyl)-8- phenylpyrimido[4,5-d]pyridazin-5(6H)-one;(R, E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(l,l-difluoroethyl)-8- phenylpyrimido[4,5-d]pyridazin-5(6H)-one;(S, E)-6-( 1 -cyclopropyl -3 -(methylsulfonyl)allyl)-2-( 1, 1 -difluoroethyl)-8- phenylpyrimido[4,5-d]pyridazin-5(6H)-one;(E)-2-cyclobutyl-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-8-phenylpyrimido[4,5- d]pyridazin-5(6H)-one;(R, E)-2-cyclopropyl-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-8- phenylpyrimido[4,5-d]pyridazin-5(6H)-one;(S, E)-2-cyclopropyl-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-8-phenylpyrimido[4,5- d]pyridazin-5(6H)-one;(E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-ethyl-8-phenylpyrimido[4,5- d]pyridazin-5(6H)-one;120039.000211 (TYRA041PCT)(E)-2-cyclopentyl-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-8-phenylpyrimido[4,5- d]pyridazin-5(6H)-one;(R, E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(perfluoroethyl)-8- phenylpyrimido[4,5-d]pyridazin-5(6H)-one;(S, E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(perfluoroethyl)-8- phenylpyrimido[4,5-d]pyridazin-5(6H)-one;(R, E)-2-cyclobutyl-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-8-phenylpyrimido[4,5- d]pyridazin-5(6H)-one;(S, E)-2-cyclobutyl-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-8-phenylpyrimido[4,5- d]pyridazin-5(6H)-one;(R, E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-ethyl-8-phenylpyrimido[4,5- d]pyridazin-5(6H)-one;(S, E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-ethyl-8-phenylpyrimido[4,5- d]pyridazin-5(6H)-one;(R, E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-isopropyl-8-phenylpyrimido[4,5- d]pyridazin-5(6H)-one;(S, E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-isopropyl-8-phenylpyrimido[4,5- d]pyridazin-5(6H)-one;(E)-2-( 1, 1 -difluoroethyl)-6-(4-methyl- 1 -(methyl sulfonyl)pent- 1 -en-3 -y 1 ) - 8 - phenylpyrimido[4,5-d]pyridazin-5(6H)-one;(E)-2-( 1, 1 -difluoroethyl)-6-( 1 -(methyl sulfonyl)pent- 1 -en-3 -yl)-8-phenylpyrimido[4, 5 - d]pyridazin-5(6H)-one;(E)-2-(l,l-difluoroethyl)-6-(4-(methylsulfonyl)but-3-en-2-yl)-8-phenylpyrimido[4,5- d]pyridazin-5(6H)-one;(E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-4-phenyl-5,6,7,8-tetrahydrophthalazin- l(2H)-one;(R, E)-2-cyclopentyl-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-8-phenylpyrimido[4,5- d]pyridazin-5(6H)-one;(S, E)-2-cyclopentyl-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-8-phenylpyrimido[4,5- d]pyridazin-5(6H)-one;(E)-2-(l,l-difluoroethyl)-6-(2-methyl-4-(methylsulfonyl)but-3-en-2-yl)-8- phenylpyrimido[4,5-d]pyridazin-5(6H)-one;120039.000211 (TYRA041PCT)(E)-2-(l,l-difluoroethyl)-6-(l-methoxy-4-(methylsulfonyl)but-3-en-2-yl)-8- phenylpyrimido[4,5-d]pyridazin-5(6H)-one;(R, E)-2-(tert-butyl)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-8-phenylpyrimido[4,5- d]pyridazin-5(6H)-one;(S, E)-2-(tert-butyl)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-8-phenylpyrimido[4,5- d]pyridazin-5(6H)-one;(E)-6-(l-cyclobutyl-3-(methylsulfonyl)allyl)-2-(l,l-difluoroethyl)-8- phenylpyrimido[4,5-d]pyridazin-5(6H)-one;(E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-4-phenylphthalazin-l(2H)-one;(S, E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(l-methylcyclopropyl)-8- phenylpyrimido[4,5-d]pyridazin-5(6H)-one;(R, E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(l-methylcyclopropyl)-8- phenylpyrimido[4,5-d]pyridazin-5(6H)-one;(E)-6-(4-(methylsulfonyl)but-3-en-2-yl)-2-(perfluoroethyl)-8-phenylpyrimido[4,5- d]pyridazin-5(6H)-one;(E)-6-(l-(methylsulfonyl)pent-l-en-3-yl)-2-(perfluoroethyl)-8-phenylpyrimido[4,5- d]pyridazin-5(6H)-one;(E)-6-(l-methoxy-4-(methylsulfonyl)but-3-en-2-yl)-2-(perfluoroethyl)-8- phenylpyrimido[4,5-d]pyridazin-5(6H)-one;(E)-6-(l-cyclobutyl-3-(methylsulfonyl)allyl)-2-(perfluoroethyl)-8- phenylpyrimido[4,5-d]pyridazin-5(6H)-one;(E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(l,l-difluoroethyl)-8-(4- fluorophenyl)pyrimido[4,5-d]pyridazin-5(6H)-one;(E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(l-fluorocyclopropyl)-8- phenylpyrimido[4,5-d]pyridazin-5(6H)-one;(E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(l,l-difluoroethyl)-8-(2- fluorophenyl)pyrimido[4,5-d]pyridazin-5(6H)-one;(E)-6-( 1 -cy clopropyl-3 -(methyl sulfonyl)allyl)-2-( 1, 1 -difluoropropyl)-8 - phenylpyrimido[4,5-d]pyridazin-5(6H)-one;(E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(l,l-difluoroethyl)-8-(3- fluorophenyl)pyrimido[4,5-d]pyridazin-5(6H)-one;120039.000211 (TYRA041PCT)(E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-8-phenyl-2-(l- (trifluoromethyl)cyclopropyl)pyrimido[4,5-d]pyridazin-5(6H)-one;(E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(2,2-difluorocyclopropyl)-8- phenylpyrimido[4,5-d]pyridazin-5(6H)-one;(E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(3,3-difluorocyclobutyl)-8- phenylpyrimido[4,5-d]pyridazin-5(6H)-one;(R, E)-2-(azetidin-l-yl)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-8- phenylpyrimido[4,5-d]pyridazin-5(6H)-one;(S, E)-2-(azetidin-l-yl)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-8- phenylpyrimido[4,5-d]pyridazin-5(6H)-one;(R, E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-8-phenyl-2-(pyrrolidin-l- yl)pyrimido[4,5-d]pyridazin-5(6H)-one;(S, E)-7-(azetidin-l-yl)-3-(l-cyclopropyl-3-(methylsulfonyl)allyl)-l-phenylpyrido[3,4- d]pyridazin-4(3H)-one;(S, E)-7-(azetidin-l-yl)-3-(l-cyclopropyl-3-(methylsulfonyl)allyl)-l-phenylpyrido[3,4- d]pyridazin-4(3H)-one;(R, E)-7-(azetidin-l-yl)-3-(l-cyclopropyl-3-(methylsulfonyl)allyl)-l- phenylpyrido[3,4-d]pyridazin-4(3H)-one;(E)-5-(cyclopentylmethyl)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6- phenylpyridazin-3(2H)-one;(E)-5-(cyclopentyloxy)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6-phenylpyridazin- 3(2H)-one;(E)-2-(l,l-difluoroethyl)-6-(l-(2-(methylsulfonyl)vinyl)cyclopropyl)-8- phenylpyrimido[4,5-d]pyridazin-5(6H)-one;(E)-3-cyclopropyl-3-(2-(l,l-difluoroethyl)-5-oxo-8-phenylpyrimido[4,5-d]pyridazin- 6(5H)-yl)-N, N-dimethylprop- 1 -ene- 1 -sulfonamide;(E)-6-(l-cyclopropyl-3-(morpholinosulfonyl)allyl)-2-(l,l-difluoroethyl)-8- phenylpyrimido[4,5-d]pyridazin-5(6H)-one;(E)-3-cyclopropyl-3-(2-(l,l-difluoroethyl)-5-oxo-8-phenylpyrimido[4,5-d]pyridazin- 6(5H)-yl)-N-methylprop-l -ene- 1 -sulfonamide;(S, E)-6-( 1 -cyclopropyl -3 -(methylsulfonyl)allyl)-2-( 1, 1 -difluoroethyl)-8- phenylpyrido[2,3-d]pyridazin-5(6H)-one;120039.000211 (TYRA041PCT)(R, E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(l,l-difluoroethyl)-8- phenylpyrido[2,3-d]pyridazin-5(6H)-one;(E)-5-Cyclobutoxy-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6-phenylpyridazin- 3(2H)-one;(E)-5-(cyclopentyloxy)-2-(4-(methylsulfonyl)but-3-en-2-yl)-6-phenylpyridazin- 3(2H)-one;(E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(cyclopropylmethoxy)-6- phenylpyridazin-3(2H)-one;(E)-7-Cyclopropyl-3-(l-cyclopropyl-3-(methylsulfonyl)allyl)-l-phenylpyrido[3,4- d]pyridazin-4(3H)-one;(E)-5-(Cyclopentylmethyl)-2-(4-(methylsulfonyl)but-3-en-2-yl)-6-phenylpyridazin- 3(2H)-one;(E)-3-Cyclopropyl-3-(2-(l,l-difluoroethyl)-5-oxo-8-phenylpyrimido[4,5-d]pyridazin- 6(5H)-yl)-N-(2-(dimethylamino)ethyl)-N-methylprop-l-ene-l -sulfonamide; (E)-6-(l-cyclopropyl-3-((4-methylpiperazin-l-yl)sulfonyl)allyl)-2-(l,l-difluoroethyl)- 8-phenylpyrimido[4,5-d]pyridazin-5(6H)-one;(E)- 1 -( 1 -Cy clopropyl-3 -(methyl sulfonyl)allyl)-4-(cy clopropylmethoxy)-5 - phenylpyridin-2(lH)-one;(E)-4-(Cyclopentyloxy)-l-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-phenylpyridin- 2(lH)-one;(E)-5-(Cyclopentyloxy)-2-(3-(methylsulfonyl)allyl)-6-phenylpyridazin-3(2H)-one; (S, E)-5-(cyclopentyloxy)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6- phenylpyridazin-3(2H)-one;(R, E)-5-(cyclopentyloxy)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6- phenylpyridazin-3(2H)-one;(R, E)-5-(cyclopentylmethyl)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6- phenylpyridazin-3(2H)-one;(S, E)-5-(cyclopentylmethyl)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6- phenylpyridazin-3(2H)-one;(E)-5-(cyclobutylmethyl)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6- phenylpyridazin-3(2H)-one;120039.000211 (TYRA041PCT)(E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(perfluoropropyl)-6-phenylpyridazin- 3(2H)-one;(E)-4-(cyclopentylmethyl)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6- phenylpyridazin-3(2H)-one;(E)-5-(cyclopentylmethoxy)-2-(4-(methylsulfonyl)but-3-en-2-yl)-6-phenylpyridazin- 3(2H)-one;(E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6-phenyl-5-propoxypyridazin-3(2H)- one;(E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-4-(cyclopropylmethyl)-6- phenylpyridazin-3(2H)-one;(E)-5-(cyclopentylamino)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6- phenylpyridazin-3(2H)-one;(E)-5-(cyclopentylmethoxy)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6- phenylpyridazin-3(2H)-one;(E)-5-(cyclohexyloxy)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6-phenylpyridazin- 3(2H)-one;(E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(2,2-difluoropropoxy)-6- phenylpyridazin-3(2H)-one;(E)-5-(cyclobutylmethoxy)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6- phenylpyridazin-3(2H)-one;(E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-((3,3-difluorocyclobutyl)methoxy)-6- phenylpyridazin-3(2H)-one;(E)-N-(l-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6-oxo-3-phenyl-l,6- dihydropyridazin-4-yl)pival amide;(E)-N-(l-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6-oxo-3-phenyl-l,6- dihydropyridazin-4-yl)cyclopentanecarboxamide;(E)-5-(cyclopentylthio)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6-phenylpyridazin- 3(2H)-one;(E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-((3-methylcyclopentyl)oxy)-6- phenylpyridazin-3(2H)-one;(E)-4-(cyclobutylmethoxy)-l-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5- phenylpyridin-2(lH)-one;120039.000211 (TYRA041PCT)(E)- 1 -( 1 -cy clopropyl-3 -(methyl sulfonyl)allyl)-4-(2,2-difluoropropoxy)-5 - phenylpyridin-2(lH)-one;(E)-l-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-phenyl-4-propoxypyridin-2(lH)-one; (E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-((2,2-difluorocyclobutyl)methoxy)-6- phenylpyridazin-3(2H)-one;(E)-N-(l-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6-oxo-3-phenyl-l,6- dihydropyridazin-4-yl)cyclobutanecarboxamide;(E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-((2,2-difluorocyclopentyl)oxy)-6- phenylpyridazin-3(2H)-one;2-((E)-l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(((lS,2S)-2-methylcyclopentyl)oxy)- 6-phenylpyridazin-3(2H)-one;(E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(3-methylcyclobutoxy)-6- phenylpyridazin-3(2H)-one;(E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(3,3-dimethylcyclobutoxy)-6- phenylpyridazin-3(2H)-one;(S, E)-6-( 1 -cyclopropyl -3 -(methylsulfonyl)allyl)-2-( 1, 1 -difluoropropyl)-8- phenylpyrimido[4,5-d]pyridazin-5(6H)-one;(R, E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(l,l-difluoropropyl)-8- phenylpyrimido[4,5-d]pyridazin-5(6H)-one;(S, E)-4-(cyclopentyloxy)-l-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-phenylpyridin- 2(lH)-one;(R, E)-4-(cyclopentyloxy)-l-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-phenylpyridin- 2(lH)-one;(E)-5-((cyclobutylmethyl)amino)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6- phenylpyridazin-3(2H)-one;(S, E)-4-cyclobutoxy-l-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-phenylpyridin- 2(lH)-one;(R, E)-4-cyclobutoxy-l-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-phenylpyridin- 2(lH)-one;(S, E)-l-(l-cyclopropyl-3-(methylsulfonyl)allyl)-4-(cyclopropylmethoxy)-5- phenylpyridin-2(lH)-one;120039.000211 (TYRA041PCT)(R, E)-l-(l-cyclopropyl-3-(methylsulfonyl)allyl)-4-(cyclopropylmethoxy)-5- phenylpyridin-2(lH)-one;(E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-((3,3-difluorocyclopentyl)oxy)-6- phenylpyridazin-3(2H)-one;(E)-2-cyclopropyl-N-(l-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6-oxo-3-phenyl-l,6- dihydropyridazin-4-yl)-2,2-difluoroacetamide;4-cyclobutoxy-l-(l-cyclopropyl-3-(methylsulfonyl)propyl)-5-phenylpyridin-2(lH)- one;(E)-5-butoxy-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6-phenylpyridazin-3(2H)- one;(E)-N-(l-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6-oxo-3-phenyl-l,6- dihydropyridazin-4-yl)-2,2-difluoropropanamide;(E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(2-cyclopropylethoxy)-6- phenylpyridazin-3(2H)-one;(E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6-phenyl-5-(pyrrolidine-l- carbonyl)pyridazin-3(2H)-one;(E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-((l-fluorocyclopropyl)methoxy)-6- phenylpyridazin-3(2H)-one;(E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(2,2-difluoropropoxy)-6-(2- fluorophenyl)pyridazin-3 (2H)-one;(E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(2,2-difluoropropoxy)-6-(3- fluorophenyl)pyridazin-3 (2H)-one;(E)-6-(cy cl opent- 1 -en- 1 -y l)-2-( 1 -cyclopropyl-3 -(methylsulfonyl)allyl)-5-(2,2- difluoropropoxy)pyridazin-3(2H)-one;(E)-l-(l-cyclopropyl-3-(methylsulfonyl)allyl)-4-((l-fluorocyclopropyl)methoxy)-5- phenylpyridin-2(lH)-one;(E)-l-(l-cyclopropyl-3-(methylsulfonyl)allyl)-4-((2,2-difluorocyclopropyl)methoxy)- 5 -phenylpyridin-2( 1 H)-one;(E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(2,2-difluoropropoxy)-6-(3,6- dihydro-2H-pyran-4-yl)pyridazin-3(2H)-one;(S, E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(2,2-difluoropropoxy)-6- phenylpyridazin-3(2H)-one;120039.000211 (TYRA041PCT)(R, E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(2,2-difluoropropoxy)-6- phenylpyridazin-3(2H)-one;(E)-l-(l-cyclopropyl-3-(methylsulfonyl)allyl)-4-((l-fluorocyclobutyl)methoxy)-5- phenylpyridin-2(lH)-one;(E)-4-((3-chlorocyclobutyl)methoxy)-l-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5- phenylpyridin-2(lH)-one;(E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(2,2-difluorobutoxy)-6- phenylpyridazin-3(2H)-one;(E)-5-(cyclobutoxymethyl)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6- phenylpyridazin-3(2H)-one;(R, E)-5-(cyclobutylmethoxy)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6- phenylpyridazin-3(2H)-one;(S, E)-5-(cyclobutylmethoxy)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6- phenylpyridazin-3(2H)-one;(S, E)-l-(l-cyclopropyl-3-(methylsulfonyl)allyl)-4-(2,2-difluoropropoxy)-5- phenylpyridin-2(lH)-one;(R, E)-l-(l-cyclopropyl-3-(methylsulfonyl)allyl)-4-(2,2-difluoropropoxy)-5- phenylpyridin-2(lH)-one;1 -((E)- 1 -cy clopropyl-3 -(methyl sulfonyl)allyl)-4-((R)- 1 -cy clopropylethoxy)-5- phenylpyridin-2(lH)-one;1 -((E)- 1 -cy clopropyl-3 -(methyl sulfonyl)allyl)-4-((S)- 1 -cyclopropylethoxy)-5- phenylpyridin-2(lH)-one;(E)-l-(l-cyclopropyl-3-(methylsulfonyl)allyl)-4-((2,2-difluorocyclobutyl)methoxy)-5- phenylpyridin-2(lH)-one;(E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-((2,2-difluorocyclopropyl)methoxy)- 6-phenylpyridazin-3(2H)-one;(E)-4-(cyclobutylmethoxy)-l-(l-cyclopropyl-3-(methylsulfonyl)allyl)-3-fluoro-5- phenylpyridin-2(lH)-one;(E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-4-methyl-6-phenyl-5-((2,2,2- trifluoroethoxy)methyl)pyridazin-3(2H)-one;(E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-((l-fluorocyclobutyl)methoxy)-6- phenylpyridazin-3(2H)-one;120039.000211 (TYRA041PCT)(E)-l-(l-cyclopropyl-3-(methylsulfonyl)allyl)-4-(2,2-difluoropropoxy)-3-fluoro-5- phenylpyridin-2(lH)-one;(E)-6-cyclopentyl-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(2,2- difluoropropoxy)pyridazin-3(2H)-one;(E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(isopropoxymethyl)-4-methyl-6- phenylpyridazin-3(2H)-one;(E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(ethoxymethyl)-4-methyl-6- phenylpyridazin-3(2H)-one;(E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-((2,2-difluoroethoxy)methyl)-4- methyl-6-phenylpyridazin-3(2H)-one;5-((S)-l-cyclobutylethoxy)-2-((E)-l-cyclopropyl-3-(methylsulfonyl)allyl)-6- phenylpyridazin-3(2H)-one;(S, E)-4-(cyclobutylmethoxy)-l-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5- phenylpyridin-2(lH)-one;(R, E)-4-(cyclobutylmethoxy)-l-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5- phenylpyridin-2(lH)-one;(E)-l-(l-cyclopropyl-3-(methylsulfonyl)allyl)-4-(2,2-difluorobutoxy)-5- phenylpyridin-2(lH)-one;(E)-4-cyclobutoxy-l-(l-cyclopropyl-3-(methylsulfonyl)allyl)-3-fluoro-5- phenylpyridin-2(lH)-one;(E)-5-((cyclopentyloxy)methyl)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-4-methyl- 6-phenylpyridazin-3(2H)-one;(E)-5-(cyclobutoxymethyl)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-4-methyl-6- phenylpyridazin-3(2H)-one;5-((R)-l-cyclobutylethoxy)-2-((E)-l-cyclopropyl-3-(methylsulfonyl)allyl)-6- phenylpyridazin-3(2H)-one;(E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-isobutoxy-6-phenylpyridazin-3(2H)- one;(E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6-phenyl-5-(2,2,2- trifluoroethoxy)pyridazin-3(2H)-one;(E)-l-(l-cyclopropyl-3-(methylsulfonyl)allyl)-4-((3-fluorocyclobutyl)methoxy)-5- phenylpyridin-2(lH)-one;120039.000211 (TYRA041PCT)(E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6-phenyl-5-(spiro[3.3]heptan-2- yloxy)pyridazin-3(2H)-one;(E)-N-cyclobutyl-l-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6-oxo-3-phenyl-l,6- dihydropyridazine-4-carboxamide;(S, E)-6-( 1 -cyclopropyl -3 -(methylsulfonyl)allyl)-2-( 1, 1 -difluoropropyl)-8- phenylpyrido[2,3-d]pyridazin-5(6H)-one;(R, E)-6-(l-cyclopropyl-3-(methylsulfonyl)allyl)-2-(l,l-difluoropropyl)-8- phenylpyrido[2,3-d]pyridazin-5(6H)-one;(E)-2-( 1 -cy clopropyl-3 -(methyl sulfonyl)allyl)-5 -(3 -hydroxy-3 -methylbut- 1 -yn- 1 -yl)- 6-phenylpyridazin-3(2H)-one;(E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(3,3-difluorocyclobutoxy)-6- phenylpyridazin-3(2H)-one;(E)-5-((3-chlorocyclobutyl)methoxy)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6- phenylpyridazin-3(2H)-one;(E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(2-fluoro-2-methylpropoxy)-6- phenylpyridazin-3(2H)-one;(E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(neopentyloxy)-6-phenylpyridazin- 3(2H)-one;(E)-2-( 1 -cy clopropyl-3 -(methyl sulfonyl)allyl)-5 -(3,3 -dimethylbut- 1 -yn- 1 -y 1 ) -6 - phenylpyridazin-3(2H)-one;(S, E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(2,2-difluorobutoxy)-6- phenylpyridazin-3(2H)-one;(R, E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(2,2-difluorobutoxy)-6- phenylpyridazin-3(2H)-one;(E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-((3-fluorocyclobutyl)methoxy)-6- phenylpyridazin-3(2H)-one;(E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6-phenyl-5-((tetrahydro-2H-pyran-4- yl)oxy)pyridazin-3 (2H)-one;(E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6-phenyl-5-(prop-l-yn-l-yl)pyridazin- 3(2H)-one;(E)-5-(cyclobutylethynyl)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6- phenylpyridazin-3(2H)-one;120039.000211 (TYRA041PCT)2-((E)-l-cyclopropyl-3-(methylsulfonyl)allyl)-6-phenyl-5-(((S)-tetrahydrofuran-3- yl)oxy)pyridazin-3 (2H)-one;(E)-5-(cyclopentylethynyl)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6- phenylpyridazin-3(2H)-one;(E)-5-(cyclobutylmethoxy)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-4-methyl-6- phenylpyridazin-3(2H)-one;2-((E)-l-cyclopropyl-3-(methylsulfonyl)allyl)-6-phenyl-5-(((S)-tetrahydro-2H-pyran- 3 -yl)oxy)pyridazin-3 (2H)-one;2-((E)-l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(((R)-3,3-difluorobutan-2-yl)oxy)-6- phenylpyridazin-3(2H)-one;2-((E)-l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(((S)-3,3-difluorobutan-2-yl)oxy)-6- phenylpyridazin-3(2H)-one;2-((E)-l-cyclopropyl-3-(methylsulfonyl)allyl)-6-phenyl-5-(((R)-tetrahydro-2H-pyran- 3 -yl)oxy)pyridazin-3 (2H)-one;2-((E)-l-cyclopropyl-3-(methylsulfonyl)allyl)-6-phenyl-5-(((R)-tetrahydrofuran-3- yl)oxy)pyridazin-3 (2H)-one;(E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(3,3-difluorobutoxy)-6- phenylpyridazin-3(2H)-one;(E)-4-(cyclobutylmethoxy)-l-(l-cyclopropyl-3-(methylsulfonyl)allyl)-3-methyl-5- phenylpyridin-2(lH)-one;(E)-5-(cyclobutylmethoxy)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6-phenyl-4- (trifluoromethyl)pyridazin-3(2H)-one;(E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-((l-methylcyclopropyl)methoxy)-6- phenylpyridazin-3(2H)-one;(E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-((l-ethylcyclopropyl)methoxy)-6- phenylpyridazin-3(2H)-one;2-((E)-l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(((trans)-2- methylcyclopropyl)methoxy)-6-phenylpyridazin-3(2H)-one;(E)-4-chloro-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(2,2-difluoropropoxy)-6- phenylpyridazin-3(2H)-one;(S, E)-2-(l-cyclopropyl-3-fluoro-3-(methylsulfonyl)allyl)-5-(2,2-difluoropropoxy)-6- phenylpyridazin-3(2H)-one;120039.000211 (TYRA041PCT)(R, E)-2-(l-cyclopropyl-3-fluoro-3-(methylsulfonyl)allyl)-5-(2,2-difluoropropoxy)-6- phenylpyridazin-3(2H)-one;(E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-((l-methylcyclobutyl)methoxy)-6- phenylpyridazin-3(2H)-one;2-((E)-l-cyclopropyl-3-(methylsulfonyl)allyl)-6-phenyl-5-((R)-l- phenylethoxy)pyridazin-3(2H)-one;5-((R)-sec-butoxy)-2-((E)-l-cyclopropyl-3-(methylsulfonyl)allyl)-6-phenylpyridazin- 3(2H)-one;(E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-((l-methoxycyclobutyl)methoxy)-6- phenylpyridazin-3(2H)-one;5-((R)-l-cyclobutylethoxy)-2-((E)-l-cyclopropyl-3-(methylsulfonyl)allyl)-4-methyl- 6-phenylpyridazin-3(2H)-one;4-((R)-l-cyclobutylethoxy)-l-((E)-l-cyclopropyl-3-fluoro-3-(methylsulfonyl)allyl)-5- phenylpyridin-2(lH)-one;(E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6-phenyl-5-(spiro[3.3]heptan-l- yloxy)pyridazin-3(2H)-one;4-chloro-5-((R)-l-cyclobutylethoxy)-2-((E)-l-cyclopropyl-3-(methylsulfonyl)allyl)-6- phenylpyridazin-3(2H)-one;2-((E)- 1 -cy clopropyl-3 -(methyl sulfonyl)allyl)-5-((R)- 1 -( 1 - methylcyclopropyl)ethoxy)-6-phenylpyridazin-3(2H)-one;(S, E)-l-(l-cyclopropyl-3-fluoro-3-(methylsulfonyl)allyl)-4-(2,2-difluoropropoxy)-5- phenylpyridin-2(lH)-one;(R, E)-l-(l-cyclopropyl-3-fluoro-3-(methylsulfonyl)allyl)-4-(2,2-difluoropropoxy)-5- phenylpyridin-2(lH)-one;2-((E)- 1 -cy clopropyl-3 -(methyl sulfonyl)allyl)-5-((R)- 1 -cy clopropylethoxy)-6- phenylpyridazin-3(2H)-one;2-((E)-l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(((trans)-2- methylcyclobutyl)methoxy)-6-phenylpyridazin-3(2H)-one;1-((E)-l-cyclopropyl-3-fluoro-3-(methylsulfonyl)allyl)-4-(((S)-3,3-difluorobutan-2- yl)oxy)-5 -phenylpy ridin-2( 1 H)-one;2-((S, E)-l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(((R)-3,3-difluorobutan-2-yl)oxy)- 6-phenylpyridazin-3(2H)-one;120039.000211 (TYRA041PCT)2-((R, E)-l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(((R)-3,3-difluorobutan-2-yl)oxy)- 6-phenylpyridazin-3(2H)-one;(E)-l-(l-cyclopropyl-3-(methylsulfonyl)allyl-Dl)-4-(2,2-difluoropropoxy)-5- phenylpyridin-2(lH)-one;1 -((E)- 1 -cy clopropyl-3 -fluoro-3 -(methyl sulfonyl)allyl)-4-(((R)-3, 3 -difluorobutan-2- yl)oxy)-5 -phenylpy ridin-2( 1 H)-one;(E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(2,2-difluoropropoxy)-6-(pyridin-3- yl)pyridazin-3(2H)-one;(E)-5-(2-chloro-2,2-difluoroethoxy)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6- phenylpyridazin-3(2H)-one;2-((E)-l-cyclopropyl-3-(methylsulfonyl)allyl)-5-((R)-2-fluoropropoxy)-6- phenylpyridazin-3(2H)-one;(S, E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl-2-d)-5-(2,2-difluorobutoxy)-6- phenylpyridazin-3(2H)-one;(R, E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl-2-d)-5-(2,2-difluorobutoxy)-6- phenylpyridazin-3(2H)-one;(S, E)-2-(l-cyclobutyl-3-(methylsulfonyl)allyl)-5-(2,2-difluoropropoxy)-6- phenylpyridazin-3(2H)-one;(R, E)-2-(l-cyclobutyl-3-(methylsulfonyl)allyl)-5-(2,2-difluoropropoxy)-6- phenylpyridazin-3(2H)-one;2-((E)-l-cyclopropyl-3-(methylsulfonyl)allyl)-5-((S)-2-fluoropropoxy)-6- phenylpyridazin-3(2H)-one;(E)-5-(2-cyclopropyl-2,2-difluoroethoxy)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)- 6-phenylpyridazin-3(2H)-one;(R, E)-l-(l-cyclopropyl-3-(methylsulfonyl)allyl)-4-(2,2-difluorobutoxy)-5- phenylpyridin-2(lH)-one;(S, E)-l-(l-cyclopropyl-3-(methylsulfonyl)allyl)-4-(2,2-difluorobutoxy)-5- phenylpyridin-2(lH)-one;(S, E)-l-(l-cyclopropyl-3-(methylsulfonyl)allyl-2-d)-4-(2,2-difluorobutoxy)-5- phenylpyridin-2(lH)-one;(R, E)-l-(l-cyclopropyl-3-(methylsulfonyl)allyl-2-d)-4-(2,2-difluorobutoxy)-5- phenylpyridin-2(lH)-one;120039.000211 (TYRA041PCT)(S, E)-2-(l-cyclopropyl-3-fluoro-3-(methylsulfonyl)allyl)-5-(2,2-difluorobutoxy)-6- phenylpyridazin-3(2H)-one;(R, E)-2-(l-cyclopropyl-3-fluoro-3-(methylsulfonyl)allyl)-5-(2,2-difluorobutoxy)-6- phenylpyridazin-3(2H)-one;(S, E)-2-(l-cyclobutyl-3-(methylsulfonyl)allyl)-5-(2,2-difluorobutoxy)-6- phenylpyridazin-3(2H)-one;(R, E)-2-(l-cyclobutyl-3-(methylsulfonyl)allyl)-5-(2,2-difluorobutoxy)-6- phenylpyridazin-3(2H)-one;(E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6-phenyl-5-(3,3,3- trifluoropropoxy)pyridazin-3(2H)-one;(E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6-phenyl-5-(4,4,4- trifluorobutoxy)pyridazin-3(2H)-one;2-((E)- 1 -cy clopropyl-3 -(methylsulfonyl)allyl)-6-phenyl-5-(((R)- 1,1,1 -trifluoropropan- 2-yl)oxy)pyridazin-3(2H)-one;(R, E)-l-(l-cyclopropyl-3-fluoro-3-(methylsulfonyl)allyl)-4-(2,2-difluorobutoxy)-5- phenylpyridin-2(lH)-one;(S, E)-l-(l-cyclopropyl-3-fluoro-3-(methylsulfonyl)allyl)-4-(2,2-difluorobutoxy)-5- phenylpyridin-2(lH)-one;(S, E)-2-(l-cyclopropyl-3-fluoro-3-(methylsulfonyl)allyl-2-d)-5-(2,2-difluorobutoxy)- 6-phenylpyridazin-3(2H)-one;(R, E)-2-(l-cyclopropyl-3-fluoro-3-(methylsulfonyl)allyl-2-d)-5-(2,2-difluorobutoxy)- 6-phenylpyridazin-3(2H)-one;(S, E)-2-(l-cyclopropyl-3-(cyclopropylsulfonyl)allyl)-5-(2,2-difluorobutoxy)-6- phenylpyridazin-3(2H)-one;(R, E)-2-(l-cyclopropyl-3-(cyclopropylsulfonyl)allyl)-5-(2,2-difluorobutoxy)-6- phenylpyridazin-3(2H)-one;(S, E)-l-(l-cyclopropyl-3-fluoro-3-(methylsulfonyl)allyl-2-d)-4-(2,2-difluorobutoxy)- 5 -phenylpyridin-2( 1 H)-one;(R, E)-l-(l-cyclopropyl-3-fluoro-3-(methylsulfonyl)allyl-2-d)-4-(2,2-difluorobutoxy)- 5 -phenylpyridin-2( 1 H)-one;2-((E)- 1 -cy clopropyl-3 -(methylsulfonyl)allyl)-6-phenyl-5-(((S)- 1,1,1 -trifluoropropan- 2-yl)oxy)pyridazin-3(2H)-one;120039.000211 (TYRA041PCT)(E)-l-(l-cyclopropyl-3-(methylsulfonyl)allyl-2,3-d2)-4-(2,2-difluoropropoxy)-5- phenylpyridin-2(lH)-one;(S, Z)-2-(3-chloro-l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(2,2-difluorobutoxy)-6- phenylpyridazin-3(2H)-one;(R, Z)-2-(3-chloro-l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(2,2-difluorobutoxy)-6- phenylpyridazin-3(2H)-one;(Z)-5-(2,2-difluorobutoxy)-2-(l-methoxy-4-(methylsulfonyl)but-3-en-2-yl)-6- phenylpyridazin-3(2H)-one;(E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-6-phenyl-5-(3,3,3-trifluoro-2- methylpropoxy)pyridazin-3(2H)-one;(S, E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl-2,3-d2)-5-(2,2-difluorobutoxy)-6- phenylpyridazin-3(2H)-one;(R, E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl-2,3-d2)-5-(2,2-difluorobutoxy)-6- phenylpyridazin-3(2H)-one;(S, E)-2-(l-cyclopentyl-3-(methylsulfonyl)allyl)-5-(2,2-difluorobutoxy)-6- phenylpyridazin-3(2H)-one;(R, E)-2-(l-cyclopentyl-3-(methylsulfonyl)allyl)-5-(2,2-difluorobutoxy)-6- phenylpyridazin-3(2H)-one;(S, E)-l-(l-cyclopropyl-3-(methylsulfonyl)allyl-2,3-d2)-4-(2,2-difluorobutoxy)-5- phenylpyridin-2(lH)-one;(R, E)-l-(l-cyclopropyl-3-(methylsulfonyl)allyl-2,3-d2)-4-(2,2-difluorobutoxy)-5- phenylpyridin-2(lH)-one;(S, E)-2-(l-cyclohexyl-3-(methylsulfonyl)allyl)-5-(2,2-difluorobutoxy)-6- phenylpyridazin-3(2H)-one;(R, E)-2-(l-cyclohexyl-3-(methylsulfonyl)allyl)-5-(2,2-difluorobutoxy)-6- phenylpyridazin-3(2H)-one;(S, E)-5-(2,2-difluorobutoxy)-2-(4-methyl-l-(methylsulfonyl)pent-l-en-3-yl)-6- phenylpyridazin-3(2H)-one;(R, E)-5-(2,2-difluorobutoxy)-2-(4-m ethyl- 1 -(methyl sulfonyl)pent- 1 -en-3 -yl)-6- phenylpyridazin-3(2H)-one;(S, E)-2-(3-chloro-l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(2,2-difluorobutoxy)-6- phenylpyridazin-3(2H)-one;120039.000211 (TYRA041PCT)(R, E)-2-(3-chloro-l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(2,2-difluorobutoxy)-6- phenylpyridazin-3(2H)-one;(S, E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(2,2-difluorobutoxy)-6-(3- fluorophenyl)pyridazin-3 (2H)-one;(R, E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl)-5-(2,2-difluorobutoxy)-6-(3- fluorophenyl)pyridazin-3 (2H)-one;(S, E)-2-(l-cyclopropyl-3-fluoro-3-(methylsulfonyl)allyl)-5-(2,2-difluorobutoxy)-6-(3- fluorophenyl)pyridazin-3 (2H)-one;(R, E)-2-(l-cyclopropyl-3-fluoro-3-(methylsulfonyl)allyl)-5-(2,2-difluorobutoxy)-6- (3-fluorophenyl)pyridazin-3(2H)-one;(E)-5-(2,2-difluorobutoxy)-2-(3-(methylsulfonyl)-l-(oxetan-3-yl)allyl)-6- phenylpyridazin-3(2H)-one;(S, E)-5-(2,2-difluorobutoxy)-2-(4,4-dimethyl-l-(methylsulfonyl)pent-l-en-3-yl)-6- phenylpyridazin-3(2H)-one;(R, E)-5-(2,2-difluorobutoxy)-2-(4,4-dimethyl-l-(methylsulfonyl)pent-l-en-3-yl)-6- phenylpyridazin-3(2H)-one;(E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl-2-d)-5-(2,2-difluorobutoxy-l,l-d2)-6- phenylpyridazin-3(2H)-one;(E)-2-(l-cyclopropyl-3-(methylsulfonyl)allyl-2,3-d2)-5-(2,2-difluorobutoxy-l,l-d2)- 6-phenylpyridazin-3(2H)-one;(R, E)-2-(l-cyclopropyl-4-(methylsulfonyl)but-3-en-2-yl)-5-(2,2-difluorobutoxy)-6- phenylpyridazin-3(2H)-one;(S, E)-2-(l-cyclopropyl-4-(methylsulfonyl)but-3-en-2-yl)-5-(2,2-difluorobutoxy)-6- phenylpyridazin-3(2H)-one;(S, E)-5-(2,2-difluorobutoxy)-2-(l-(methylsulfonyl)hex-l-en-3-yl)-6-phenylpyridazin- 3(2H)-one;(R, E)-5-(2,2-difluorobutoxy)-2-(l-(methylsulfonyl)hex-l-en-3-yl)-6-phenylpyridazin- 3(2H)-one;(S, E)-5-(2,2-difluorobutoxy)-2-(5-methyl-l-(methylsulfonyl)hex-l-en-3-yl)-6- phenylpyridazin-3(2H)-one; or(R, E)-5-(2,2-difluorobutoxy)-2-(5-methyl-1-(methylsulfonyl)hex-1-en-3-yl)-6-phenylpyridazin-3(2H)-one;120039.000211 (TYRA041PCT)(S, E)-2-(l-cyclobutyl-3-(methylsulfonyl)allyl-2-d)-5-(2,2-difluorobutoxy)-6- phenylpyridazin-3(2H)-one;(R, E)-2-(l-cyclobutyl-3-(methylsulfonyl)allyl-2-d)-5-(2,2-difluorobutoxy)-6- phenylpyridazin-3(2H)-one;(R, E)-2-(1-(bicyclo[1.1.1]pentan-1-yl)-3-(methylsulfonyl)allyl)-5-(2,2-difluorobutoxy)-6-phenylpyridazin-3(2H)-one;(S, E)-2-(l-(bicyclo[l.l.l]pentan-l-yl)-3-(methylsulfonyl)allyl)-5-(2,2- difluorobutoxy)-6-phenylpyridazin-3(2H)-one;(S, Z)-2-(3-chloro-l-cyclobutyl-3-(methylsulfonyl)allyl)-5-(2,2-difluorobutoxy)-6- phenylpyridazin-3(2H)-one;(R, Z)-2-(3-chloro-l-cyclobutyl-3-(methylsulfonyl)allyl)-5-(2,2-difluorobutoxy)-6- phenylpyridazin-3(2H)-one;(E)-2-(3-chloro-l-cyclobutyl-3-(methylsulfonyl)allyl)-5-(2,2-difluorobutoxy)-6- phenylpyridazin-3(2H)-one;(S, Z)-2-(3-chloro-l-cyclobutyl-3-(methylsulfonyl)allyl-2-d)-5-(2,2-difluorobutoxy)-6- phenylpyridazin-3(2H)-one;(R, Z)-2-(3-chloro-l-cyclobutyl-3-(methylsulfonyl)allyl-2-d)-5-(2,2- 276difluorobutoxy)-6-phenylpyridazin-3(2H)-one;(E)-2-(3-chloro-l-cyclobutyl-3-(methylsulfonyl)allyl-2-d)-5-(2,2-difluorobutoxy)-6- phenylpyridazin-3(2H)-one;(R, E)-5-(2,2-difluorobutoxy)-2-(3-(methylsulfonyl)-l-(oxetan-3-yl)allyl)-6- phenylpyridazin-3(2H)-one;(S, E)-5-(2,2-difluorobutoxy)-2-(3-(methylsulfonyl)-l-(oxetan-3-yl)allyl)-6- phenylpyridazin-3(2H)-one;(R, Z)-2-(3-chloro-l-cyclopropyl-3-(methylsulfonyl)allyl-2-d)-5-(2,2-difluorobutoxy)- 6-phenylpyridazin-3(2H)-one;(S, Z)-2-(3-chloro-l-cyclopropyl-3-(methylsulfonyl)allyl-2-d)-5-(2,2-difluorobutoxy)- 6-phenylpyridazin-3(2H)-one;(E)-2-(3-chloro-l-cyclopropyl-3-(methylsulfonyl)allyl-2-d)-5-(2,2-difluorobutoxy)-6- phenylpyridazin-3(2H)-one; or(E)-5-(2,2-difluorobutoxy)-2-(l-(l-methylcyclopropyl)-3-(methylsulfonyl)allyl)-6- phenylpyridazin-3(2H)-one.120039.000211 (TYRA041PCT)116. A pharmaceutical composition comprising a compound of any one of claims 1 to 115, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

117. A method of modulating WRN activity in a subject, wherein the method comprising administering to the patient a therapeutically effective amount of a compound of any one of claims 1 to 115 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 116.

118. A method of inhibiting WRN in a subject, wherein the method comprises administering to the patient a therapeutically effective amount of a compound of any one of claims 1 to 115 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 116.

119. A method of treating a disorder or disease which can be treated by WRN inhibition in a subject, wherein the method comprises administering to the patient a therapeutically effective amount of a compound of any one of claims 1 to 115 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 116.

120. A method of treating a cancer in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a compound of any one of claims 1 to 115 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 116.

121. The method of claim 120, wherein the cancer is characterized as microsatellite instability -high (MSI-H) or mismatch repair deficient (dMMR).

122. The method of claim 120 or claim 121, wherein the cancer is colorectal, gastric, rectal, prostate, endometrial, adrenocortical, uterine, cervical, endocervical, esophageal, breast, kidney, or ovarian cancer.

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