WO2024084450A1 - Bicyclic heteroaryl compounds and their derivatives as pkmyt1 inhibitors - Google Patents
Bicyclic heteroaryl compounds and their derivatives as pkmyt1 inhibitors Download PDFInfo
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- WO2024084450A1 WO2024084450A1 PCT/IB2023/060606 IB2023060606W WO2024084450A1 WO 2024084450 A1 WO2024084450 A1 WO 2024084450A1 IB 2023060606 W IB2023060606 W IB 2023060606W WO 2024084450 A1 WO2024084450 A1 WO 2024084450A1
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- BJDYCCHRZIFCGN-UHFFFAOYSA-N pyridin-1-ium;iodide Chemical compound I.C1=CC=NC=C1 BJDYCCHRZIFCGN-UHFFFAOYSA-N 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000010076 replication Effects 0.000 description 1
- 230000028617 response to DNA damage stimulus Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 125000003507 tetrahydrothiofenyl group Chemical group 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 238000011287 therapeutic dose Methods 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 239000006208 topical dosage form Substances 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- IHIXIJGXTJIKRB-UHFFFAOYSA-N trisodium vanadate Chemical compound [Na+].[Na+].[Na+].[O-][V]([O-])([O-])=O IHIXIJGXTJIKRB-UHFFFAOYSA-N 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Definitions
- the present application is directed to bicyclic heteroaryl compounds and their derivatives of formula (I) as PKMYT1 (MYT1) inhibitors, useful for the treatment of cancer and those diseases or conditions involving overexpression/amplification of CCNE1 or inactivating mutation in the FBXW7 gene.
- the disclosure also provides pharmaceutically acceptable compositions comprising compounds of the present application and methods of using said compositions in the treatment of diseases associated with PKMYT1.
- CCNE1 encodes the protein cyclin El, which complexes with cyclin-dependent kinase 2 (CDK2) and drives cells from G1 phase to S phase.
- CDK2 cyclin-dependent kinase 2
- amplification of CCNE1 gene and its deregulation of cyclin El during early stage of tumorigenesis forces cancer cells into S phase prematurely leading to replication stress and DNA damage. As cells move into mitosis with damaged DNA and in the absence of functional p53 leads to genomic instability.
- PKMYT1 a member of the WEE family of serine/threonine-kinases, is an important regulator of CDK1 phosphorylation and is a compelling therapeutic target for the treatment of certain types of DNA damage response cancers due to its strongest dependency in CCNE1- amplified tumours. Absence of functional PKMYT1 in a genetically vulnerable tumor with CCNE1 -amplification, leads to hyperactive CDK1, unscheduled mitosis and catastrophic DNA damage, ultimately resulting in cell death. Selective PKMYT1 inhibition is a promising therapeutic strategy for CCNE1 -amplified cancers taking advantage of the synthetic lethality relationship.
- it comprises compounds of formula (I): wherein, each X 1 to X 6 is independently C or N; wherein a maximum of 3 of X 1 to X 6 are N;
- Ri at each occurrence independently is alkyl, halo or hydroxy; alternatively, two Ri on consecutive ring atoms together get cyclized to form an unsubstituted or alkyl-substituted heteroaryl, or an unsubstituted or alkyl-substituted heterocycloalkyl, having 1 to 3 heteroatoms selected from N, O or S;
- R 2 ’ and R 2 ” each independently hydrogen or alkyl
- R 3 ’ and R 3 ” are each independently hydrogen or alkyl
- R4 is alkyl, halo, hydroxyalkyl, haloalkyl, cyano, -OR 5 , unsubstituted or substituted cycloalkyl, unsubstituted or substituted cycloalkenyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl or unsubstituted or substituted heterocycloalkyl; wherein the substituents on cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocycloalkyl are independently selected from one or more alkyl, halo, haloalkyl, hydroxy, cyano, amino, - COOH or hydroxyalkyl;
- R 5 is selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl or heterocycloalkyl; m is 1, 2, 3 or 4; and n is 0, 1, 2 or 3.
- compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent).
- alkyl alone or in combination with other term(s) means saturated aliphatic hydrocarbon chains, including C1-C10 straight or C1- C10 branched alkyl chains, more preferably, C1-C6 straight or branched alkyl chains.
- alkyl include but are not limited to methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec- butyl, tert-butyl, isopentyl or neopentyl and the like.
- halo or halogen alone or in combination with other term(s) means fluorine, chlorine, bromine or iodine.
- hydroxy or "hydroxyl” alone or in combination with other term(s) means -OH.
- hydroxyalkyl refers to the group HO-alkyl-, wherein alkyl and hydroxy groups are as defined herein.
- cyano refers to -CN.
- haloalkyl means alkyl substituted with one or more halogen atoms, wherein the alkyl groups are as defined above.
- halo is used herein interchangeably with the term “halogen” means F, Cl, Br or I.
- haloalkyl include but are not limited to fluoromethyl, difluoromethyl, chloromethyl, trifluoromethyl, 2,2,2- trifluoroethyl and the like.
- cycloalkyl alone or in combination with other term(s) means -C3-C10 saturated cyclic hydrocarbon ring.
- a cycloalkyl may be a single ring, which typically contains from 3 to 7 carbon ring atoms. Examples of single-ring cycloalkyls include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.
- a cycloalkyl may alternatively be polycyclic or contain more than one ring. Examples of polycyclic cycloalkyls include bridged, fused and spirocyclic carbocyclyls and the like.
- cycloalkenyl alone or in combination with other term(s) means -C3-C10 cyclic hydrocarbon ring with a double bond.
- a cycloalkenyl may be a single ring, which typically contains from 3 to 7 carbon ring atoms. Examples of single-ring cycloalkyls include but are not limited to cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and the like.
- a cycloalkenyl may alternatively be polycyclic or contain more than one ring.
- aryl is unsubstituted or substituted monocyclic, bicyclic or polycyclic aromatic hydrocarbon ring system of about 6 to 14 carbon atoms.
- Examples of a C6- C14 aryl group include, but are not limited to phenyl, naphthyl, anthryl, biphenylenyl and acenaphthyl.
- An aryl group may be unsubstituted or substituted with one or more suitable groups.
- heterocycloalkyl refers to a non-aromatic, saturated or partially saturated monocyclic or polycyclic ring system of 3 to 15 members having at least one heteroatom or heterogroup selected from O, N, S, S(O), S(O)i, or NH with the remaining ring atoms being independently selected from the group consisting of carbon, oxygen, nitrogen and sulfur.
- a monocyclic heterocycloalkyl may typically contain 4 to 7 ring atoms.
- Heterocycloalkyl include, but are not limited to azetidinyl, oxetanyl, imidazolidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, oxapiperazinyl, oxapiperidinyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiophenyl, dihydropyranyl, indolinyl, azepanyl, 1, 2,3,4- tetrahydroisoquinolinyl, 3,4-dihydro-2H-benzo[b][l,4]oxazinyl, and N-oxides thereof.
- a heterocycloalkyl substituent can occur via either a carbon atom or a heteroatom.
- a heterocycloalkyl group can be unsubstituted or substituted with one or more suitable groups by one or more aforesaid groups.
- heteroaryl alone or in combination with other term(s) means a completely unsaturated ring system containing a total of 5 to 14 ring atoms. At least one of the ring atoms is a heteroatom (i.e., oxygen, nitrogen, or sulfur), with the remaining ring atoms/groups being independently selected from the group consisting of carbon, oxygen, nitrogen or sulfur.
- a heteroaryl may be a single-ring (monocyclic) or polycyclic ring system.
- heteroaryl examples include but are not limited to pyridyl, indolyl, benzimidazolyl, benzothiazolyl, pyrrolyl, pyrazolyl, imidazolyl, indolizinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolo[1,2-b]pyridazinyl, pyrrolo[l,2-a]pyrimidinyl, pyrrolo[1,2-a]pyrazinyl, pyrrolo[l,2-c]pyrimidinyl, benzofuranyl, benzo[d]isoxazolyl, benzo[d]oxazolyl, IH-indazolyl and the like.
- heterocyclyl alone or in combination with other term(s) includes both “heterocycloalkyl” and “heteroaryl” groups which are as defined above.
- heterocyclyl include, but are not limited to azetidinyl, pyrrolidinyl, piperidinyl, pyridyl, indolyl, benzimidazolyl, benzothiazolyl and the like.
- heteroatom designates a sulfur, nitrogen or oxygen atom.
- the term "optionally substituted” or “substituted” or “optionally substituted with suitable groups” refers to replacement of one or more hydrogen radicals in a given structure with a radical of a specified substituent including, but not limited to: halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, thiol, alkylthio, arylthio, alkylthioalkyl, arylthioalkyl, alkylsulfonyl, alkylsulfonylalkyl, arylsulfonylalkyl, alkoxy, aryloxy, aralkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino, trifluoromethyl, cyano, nitro, alkylamino, arylamino, alky
- composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
- pharmaceutically acceptable it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
- treat refers to a method of alleviating or abrogating a disease and/or its attendant symptoms.
- prevent refers to a method of preventing the onset of a disease and/or its attendant symptoms or barring a subject from acquiring a disease.
- prevent also include delaying the onset of a disease and/or its attendant symptoms and reducing a subject's risk of acquiring a disease.
- terapéuticaally effective amount refers to the amount of the compound being administered sufficient to prevent development of or alleviate to some extent one or more of the symptoms of the condition or disorder being treated.
- “Pharmaceutically acceptable” means that, which is usefill in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary as well as human pharmaceutical use.
- the phrase "pharmaceutically acceptable excipient” refers to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, solvent, or encapsulating material. Excipients or carriers are generally safe, non-toxic and neither biologically nor otherwise undesirable and include excipients or carriers that are acceptable for veterinary use as well as human pharmaceutical use. In one embodiment, each component is "pharmaceutically acceptable” as defined herein.
- pharmaceutically acceptable salt(s) refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form.
- examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
- the pharmaceutically acceptable salts of the present disclosure include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
- the pharmaceutically acceptable salts of the present disclosure can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.
- such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, alcohols or acetonitrile (ACN) are preferred.
- non-aqueous media like ether, ethyl acetate, alcohols or acetonitrile (ACN) are preferred.
- stereoisomers refers to any enantiomers, diastereoisomers, or geometrical isomers of the compounds of Formula (I), wherever they are chiral or when they bear one or more double bonds. When the compounds of the formula (I) are chiral, they can exist in racemic or in optically active form. It should be understood that the disclosure encompasses all stereochemical isomeric forms, including diastereomeric, enantiomeric and epimeric forms, as well as tZ-isomers and /-isomers and mixtures thereof.
- Individual stereoisomers of compounds can be prepared synthetically from commercially available starting materials which contain chiral centers or by preparation of mixtures of enantiomeric products followed by separation such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, direct separation of enantiomers on chiral chromatographic columns, or any other appropriate method known in the art.
- Starting compounds of particular stereochemistry are either commercially available or can be made and resolved by techniques known in the art.
- the compounds of the present disclosure may exist as geometric isomers. The present disclosure includes all cis and trans, syn and anti, (R) and (S),
- Mechanism (E) and Z) isomers as well as the appropriate mixtures thereof.
- the present disclosure provides bicyclic heteroaryl compounds and their derivatives of formula (I), which are useful for the inhibition of PKMYT1.
- the present disclosure further provides pharmaceutical compositions comprising the said compounds of formula (I), and their derivatives as therapeutic agents.
- the present application provides bicyclic heteroaryl compounds and their derivatives of formula (I), or a pharmaceutically acceptable salt thereof or a stereoisomer thereof; wherein, each X 1 to X 6 is independently C or N; wherein a maximum of 3 of X 1 to X 6 are N;
- Ri at each occurrence independently is alkyl, halo or hydroxy; alternatively, two Ri on consecutive ring atoms together get cyclized to form an unsubstituted or alkyl-substituted heteroaryl, or an unsubstituted or alkyl-substituted heterocycloalkyl, having 1 to 3 heteroatoms selected from N, O or S;
- R 2 ’ and R 2 ” each independently hydrogen or alkyl
- R3’ and R3” are each independently hydrogen or alkyl
- R4 is alkyl, halo, hydroxyalkyl, haloalkyl, cyano, -OR 5 , unsubstituted or substituted cycloalkyl, unsubstituted or substituted cycloalkenyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl or unsubstituted or substituted heterocycloalkyl; wherein the substituents on cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocycloalkyl are independently selected from one or more alkyl, halo, haloalkyl, hydroxy, cyano, amino, - COOH or hydroxyalkyl; R 5 is selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl or heterocycloalkyl; m is 1, 2, 3 or 4; and n is 0, 1, 2 or 3.
- compounds of formula (IA), or pharmaceutically acceptable salts thereof or stereoisomers thereof are provided.
- compounds of formula (IB), or pharmaceutically acceptable salts thereof or stereoisomers thereof are provided.
- compounds of formula (IC), or pharmaceutically acceptable salts thereof or stereoisomers thereof are provided.
- compounds of formula (ID), or pharmaceutically acceptable salts thereof or stereoisomers thereof are provided.
- each X 1 to X 6 is independently C or N; wherein a maximum of 3 of X 1 to X 6 are N;
- Ri at each occurrence independently is alkyl or hydroxy; alternatively, two Ri on consecutive ring atoms together get cyclized to form an unsubstituted or alkyl-substituted heteroaryl, or an unsubstituted or alkyl-substituted heterocycloalkyl, having 1 to 3 heteroatoms selected from N, O or S;
- R 2 ’ and R 2 ” each hydrogen
- R3’ and R3” are each hydrogen
- R4 is alkyl, halo, haloalkyl, cyano or -OR 5 ;
- R5 is selected from hydrogen, alkyl or cycloalkyl;
- m is 1, 2, 3 or 4; and
- n is 0, 1, 2 or 3.
- each X 1 to X 6 is independently C or N; wherein a maximum of 3 of X 1 to X 6 are N;
- Ri at each occurrence independently is alkyl or hydroxy; alternatively, two Ri on consecutive ring atoms together get cyclized to form an unsubstituted or alkyl-substituted heteroaryl, or an unsubstituted or alkyl-substituted heterocycloalkyl, having 1 to 3 heteroatoms selected from N, O or S;
- R 2 ’ and R 2 ” each hydrogen
- R 3 ’ and R 3 ” are each hydrogen;
- R4 is alkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted cycloalkenyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl or unsubstituted or substituted heterocycloalkyl; wherein the substituents on cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocycloalkyl are independently selected from one or more alkyl, halo, haloalkyl, hydroxy, cyano, amino, -COOH and hydroxyalkyl; m is 1, 2, 3 or 4; and n is 0, 1, 2 or 3.
- each X 1 to X 6 is independently C or N; wherein a maximum of 3 of X 1 to X 6 are N;
- Ri at each occurrence independently is alkyl or hydroxy; alternatively, two Ri on consecutive ring atoms together get cyclized to form an unsubstituted or alkyl-substituted heteroaryl, or an unsubstituted or alkyl-substituted heterocycloalkyl, having 1 to 3 heteroatoms selected from N, O or S;
- R 2 ’ and R 2 ” each hydrogen
- R3’ and R3” are each hydrogen
- R4 is alkyl or halo; m is 1, 2, 3 or 4; and n is 0, 1, 2 or 3.
- the present application provides bicyclic heteroaryl compounds and their derivatives of formula (I),
- each X2 to X5 is C; X1 and X6 are each N;
- Ri at each occurrence independently is alkyl, halo or hydroxy; alternatively, two Ri on consecutive ring atoms together get cyclized to form an unsubstituted or alkyl-substituted heteroaryl, or an unsubstituted or alkyl-substituted heterocycloalkyl, having 1 to 3 heteroatoms selected from N, O or S;
- R 2 ’ and R 2 ” each independently hydrogen or alkyl
- R3’ and R3” are each independently hydrogen or alkyl
- R4 is alkyl, halo, hydroxyalkyl, haloalkyl, cyano, -OR 5 , unsubstituted or substituted cycloalkyl, unsubstituted or substituted cycloalkenyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl or unsubstituted or substituted heterocycloalkyl; wherein the substituents on cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocycloalkyl are independently selected from one or more alkyl, halo, haloalkyl, hydroxy, cyano, amino, - COOH or hydroxyalkyl;
- R 5 is selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl or heterocycloalkyl; m is 1, 2, 3 or 4; and n is 0, 1, 2 or 3.
- X2 to X5 are each C.
- X5 and X6 are each N.
- X1 and X6 are each N. In some embodiments, X6 is N.
- Xi to X5 are each C.
- 1 to 3 of X1, X2, X3, X4, X5 or X6 are N.
- a maximum of 3 of X 1 to X 6 are N.
- Ri is hydroxy
- Ri is alkyl
- Ri is methyl
- Ri at each occurrence independently is hydroxy or methyl.
- two Ri on consecutive ring atoms together get cyclized to form an unsubstituted or alkyl-substituted heteroaryl, having 1 to 3 heteroatoms selected from N, O or S.
- two Ri on consecutive ring atoms together get cyclized to form an unsubstituted or alkyl-substituted 5 to 6 membered heteroaryl, having 1 to 3 heteroatoms selected from N, O or S.
- two Ri on consecutive ring atoms together get cyclized to form an unsubstituted or alkyl-substituted heterocycloalkyl, having 1 to 3 heteroatoms selected from N, O or S.
- two Ri on consecutive ring atoms together get cyclized to form an unsubstituted or alkyl-substituted 5 to 6 membered heterocycloalkyl, having 1 to 3 heteroatoms selected from N, O or S.
- two Ri on consecutive ring atoms together get cyclized to form an unsubstituted or alkyl-substituted heterocycloalkyl, or an unsubstituted or alkyl-substituted heteroaryl, the said heterocycloalkyl and heteroaryl independently having 1 to 3 heteroatoms selected from N, O or S; wherein the newly formed heterocyclyl ring system is fused to the existing phenyl ring.
- R2' and R2" are each hydrogen.
- R4 is alkyl. In some embodiments, R4 is methyl.
- R4 is unsubstituted or substituted cycloalkyl; wherein the substituents on cycloalkyl are independently selected from one or more alkyl, halo, haloalkyl, hydroxy, cyano, amino, -COOH and hydroxyalkyl.
- R4 is unsubstituted or substituted aryl; wherein the substituents on aryl are independently selected from one or more alkyl, halo, haloalkyl, hydroxy, cyano, amino, -COOH and hydroxyalkyl.
- R4 is unsubstituted or substituted heteroaryl; wherein the substituents on heteroaryl are independently selected from one or more alkyl, halo, haloalkyl, hydroxy, cyano, amino, -COOH or hydroxyalkyl.
- R4 is unsubstituted or substituted heterocycloalkyl; wherein the substituents on heterocycloalkyl are independently selected from one or more alkyl, halo, haloalkyl, hydroxy, cyano, amino, -COOH or hydroxyalkyl.
- n is 2.
- m is 3.
- m is 4.
- n 0.
- n 1 or 2.
- compounds of formula (I) are provided, wherein Ri is hydroxy or alkyl, m is 3, and R4 is alkyl.
- compounds of formula (I) are provided, wherein Ri at each occurrence is independently hydroxy or alkyl, m is 3 and R4 is alkyl.
- compounds of formula (I) are provided, wherein ring wherein the two open ends marked with at X5 and X6 depict portion of the ring attached with the fused 5 membered heteroaryl ring of compounds of formula (I).
- ring can be represented as
- ring is selected from and
- the present disclosure includes enantiomers, diastereomers, epimers, and atropisomers of the compounds disclosed herein, and mixtures of enantiomers and/or diastereomers thereof including racemic mixtures.
- all possible stereoisomers e.g., enantiomers and/or diastereomers
- enantiomers and/or diastereomers in mixtures and as pure or partially purified compounds are included within the scope of this invention.
- all possible combinations of the stereogenic centers are pure compounds or in mixtures.
- the compounds of formula (I) can be present as two separate rotomers or atropisomers.
- the rotomers or atropisomers contain bonds with hindered rotation such that two separate rotomers or atropisomers, may be separated.
- the separated atropisomers found to have different biological activity which may be advantageous. It is intended that all of the possible atropisomers are included within the scope of this invention.
- the present application provides a compound selected from the group consisting of:
- compound of formula (I) is compound-1;
- compound- 1 exists as atropisomers and depicted by following structures:
- compound of formula (I) is compound-4;
- compound-4 exists as atropisomers and depicted by following structures:
- the compounds of the present invention exist as atropisomers.
- the present disclosure provides a pharmaceutical composition
- a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof or a stereoisomer thereof as described herein and at least one pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent).
- the pharmaceutical composition comprises a therapeutically effective amount of at least one compound described herein.
- the compounds described in the present disclosure may be associated with a pharmaceutically acceptable excipient (such as a carrier or a diluent) or be diluted by a carrier or enclosed within a carrier which can be in the form of a capsule, sachet, paper or other container.
- the compounds of the present disclosure are PKMYT1 inhibitors.
- the compound of formula (I) is a PKMYT1 inhibitor.
- the present disclosure provides pharmaceutical composition for use in treating and/or preventing a disease or condition responsive to the inhibition of PKMYT1 activity.
- the present disclosure provides a pharmaceutical composition
- a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or a stereoisomer thereof and one or more pharmaceutically acceptable carriers or excipients.
- the compounds may also be used in pharmaceutical compositions in which the compound disclosed herein or a pharmaceutically acceptable salt thereof is the only active ingredient.
- the present disclosure provides a method of inhibiting PKMYT1 in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of a compound of the present disclosure.
- the present disclosure provides a method of inhibiting PKMYT1 in a subject, comprising administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer thereof.
- the present disclosure provides a method of treating diseases or conditions mediated by PKMYT1 in a subject comprising administering to the subject in need thereof a therapeutically effective amount of a compound of the present disclosure.
- the present disclosure provides pharmaceutical composition comprising the compound of formula (I), for use in treating a subject suffering from a disease or condition associated with PKMYT1.
- the compounds of the disclosure are typically administered in the form of a pharmaceutical composition.
- Such compositions can be prepared using procedures well known in the pharmaceutical art and comprise at least one compound of the present disclosure.
- the pharmaceutical composition of the present disclosure comprises one or more compounds described herein and one or more pharmaceutically acceptable excipients.
- the pharmaceutically acceptable excipients are approved by regulatory authorities or are generally regarded as safe for human or animal use.
- the pharmaceutically acceptable excipients include, but are not limited to, carriers, diluents, glidants and lubricants, preservatives, buffering agents, chelating agents, polymers, gelling agents, viscosifying agents, solvents and the like.
- the pharmaceutical composition can be administered by oral, parenteral or inhalation routes.
- parenteral administration include administration by injection, percutaneous, transmucosal, transnasal and transpulmonary administrations.
- suitable carriers include, but are not limited to, water, salt solutions, alcohols, polyethylene glycols, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, amylose, magnesium stearate, talc, , agar, pectin, acacia, stearic acid, lower alkyl ethers of cellulose, silicic add, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, fatty acid esters and polyoxyethylene.
- the pharmaceutical composition may also include one or more pharmaceutically acceptable auxiliary agents, wetting agents, suspending agents, preserving agents, buffers, sweetening agents, flavouring agents, colorants or any combination of the foregoing.
- compositions may be in conventional forms, for example, tablets, capsules, solutions, suspensions, injectables or products for topical application. Further, the pharmaceutical composition of the present disclosure may be formulated so as to provide desired release profile.
- Administration of the compounds of the disclosure, in pure form or in an appropriate pharmaceutical composition can be carried out using any of the accepted routes of administration of pharmaceutical compositions.
- the route of administration may be any route which effectively transports the active compound of the present disclosure to the appropriate or desired site of action.
- Suitable routes of administration include, but are not limited to, oral, nasal, buccal, dermal, intradermal, transdermal, parenteral, rectal, subcutaneous, intravenous, intraurethral, intramuscular or topical.
- Solid oral formulations include, but are not limited to, tablets, capsules (soft or hard gelatin), dragees (containing the active ingredient in powder or pellet form), troches and lozenges.
- Liquid formulations include, but are not limited to, syrups, emulsions and sterile injectable liquids, such as suspensions or solutions.
- Topical dosage forms of the compounds include ointments, pastes, creams, lotions, powders, solutions, eye or ear drops, impregnated dressings and may contain appropriate conventional additives such as preservatives, solvents to assist drug penetration.
- compositions of the present disclosure may be prepared by conventional techniques known in literature.
- Suitable doses of the compounds for use in treating the diseases or disorders described herein can be determined by those skilled in the relevant art.
- Therapeutic doses are generally identified through a dose ranging study in humans based on preliminary evidence derived from the animal studies. Doses must be sufficient to result in a desired therapeutic benefit without causing unwanted side effects.
- Mode of administration, dosage forms and suitable pharmaceutical excipients can also be well used and adjusted by those skilled in the art. All changes and modifications are envisioned within the scope of the present disclosure.
- the compounds as disclosed in the present disclosure are formulated for pharmaceutical administration.
- the disclosure provides the use of the compounds as described above in the treatment and prevention of diseases or conditions responsive to the inhibition of PKMYT1 activity.
- use of the compound or a pharmaceutically acceptable salt thereof, in treating and/or preventing a disease is provided, for which the symptoms thereof are treated, improved, diminished and/or prevented by inhibition of PKMYT1.
- the PKMYT1 mediated disorder and/or disease or condition is cancer.
- compounds of formula (I) for use in the treatment of cancer are provided.
- the subject is a mammal including human.
- the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer thereof, for use as a medicament.
- the disclosure provides the use of the compounds of the present disclosure in the manufacture of a medicament.
- the disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer thereof, for use in the treatment of cancer.
- the disclosure provides the use of the compounds of the present disclosure in the manufacture of a medicament for the treatment of diseases and/or disorder responsive to the inhibition of PKMYT1 activity.
- the disclosure provides the use of the compounds of the present disclosure in the manufacture of a medicament for the treatment of cancer.
- the disorder and/or disease or condition is cancer caused by the overexpression of CCNE1 or having an inactivating mutation in the FBXW7 gene.
- the disorder and/or disease or condition is cancer caused by deficiency in FBXW7 gene.
- the cancer is selected from the group consisting of uterine cancer, ovarian cancer, breast cancer, stomach cancer, glioblastoma, hepatocellular carcinoma, neuroblastoma, prostate cancer, colorectal cancer, lung cancer, esophageal cancer and endometrial cancer.
- the cancers caused by overexpression of CCNE1 include but not limited to uterine cancer, ovarian cancer, breast cancer, stomach cancer, lung cancer, esophageal cancer and endometrial cancer.
- the cancers caused by deficiency in FBXW7 include, e.g., uterine cancer, lung cancer, breast cancer, colorectal cancer and esophageal cancer.
- the disclosure provides a method of treating a disease or disorder mediated by PKMYT1 in a subject comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer thereof.
- the said disease or disorder is cancer.
- the disclosure provides compounds for use as a medicament for treating a subject suffering from diseases or conditions responsive to the inhibition of PKMYT1 activity.
- the disclosure comprises administering to the subject in need thereof a therapeutically effective amount of a compound of the present disclosure along with one or more additional chemotherapeutic agents independently selected from anti-proliferative agents, anti-cancer agents, immunosuppressant agents and pain-relieving agents.
- additional chemotherapeutic agents independently selected from anti-proliferative agents, anti-cancer agents, immunosuppressant agents and pain-relieving agents.
- the method(s) of treatment of the present disclosure generally comprises administering a safe and effective amount of a compound according to formula (I) or a pharmaceutically acceptable salt thereof to a patient (particularly a human) in need thereof.
- compositions of the disclosure are indicated both in the therapeutic and/or prophylactic treatment of the above-mentioned conditions.
- dosage administered will typically vary with the compound employed, the mode of administration, the treatment desired and the disorder or disease indicated.
- the compounds of the present disclosure may be used as single drug or as a pharmaceutical composition in which the compound is mixed with various pharmacologically acceptable materials.
- the compounds of the present disclosure can also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
- the present disclosure also embraces isotopically-labeled variants of the present disclosure which are identical to those recited herein, but for the fact that one or more atoms of the compound are replaced by an atom having the atomic mass or mass number different from the predominant atomic mass or mass number usually found in nature for the atom. All isotopes of any particular atom or element as specified are contemplated within the scope of the compounds of the disclosure and their uses.
- Exemplary isotopes that can be incorporated in to compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine and iodine, such as .
- Isotopically labeled compounds of the present disclosure can generally be prepared by following procedures analogous to those disclosed in the schemes and/or in the examples herein below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
- work-up includes distribution of the reaction mixture between the organic and aqueous phases, separation of layers and drying the organic layer over anhydrous sodium sulphate, filtration and evaporation of the solvent.
- Purification includes purification by silica gel chromatographic techniques, generally using ethyl acetate/petroleum ether mixture of a suitable polarity as the mobile phase.
- intermediate GS2-I was coupled with GSz-2 under the appropriate conditions (CS2CO3 and DMF) to afford GS2-3, which was further reacted with the reactant R4-Lg under appropriate conditions to undergo the Suzuki coupling or Buchwald coupling, to afford intermediate GS2-4.
- the intermediate GS2-4 subjected to thiation under appropriate conditions (P2S5, suitable solvent (toluene or pyridine or 1,4-dioxane), OR Lawesson’s Reagent and sutitable solvent (toluene)), to afford the intermediate GS2-5 via step 2a and step 2b.
- GSi-3 directly affords intermediate GS2-5 via step 2 under appropriate thiation conditions.
- the intermediate GS2-5 was methylated by reacting under suitable conditions (Mel, and acetone) to form intermediate GS2-6 which was further reacted with malononitrile under suitable conditions in presence of an appropriate base and a solvent (NaOtBu, sulfolane, NaH, and THF) to afford GS2-7. Further the intermediate GS2-7 was hydrolysed and was demethylated under appropriate conditions (MeSO3H, H2SO4, and DL- Methionine) to afford the compound of formula (I).
- Step-1 Synthesis of l-(3-methoxy-2,6-dimethylbenzyl)-5-methylpyridin-2(lH)-one (I- 11)
- Step-2 Synthesis of l-(3-methoxy-2,6-dimethylbenzyl)-5-methylpyridine-2(lH)-thione (1-12)
- P2S5 (6.9 g, 15.54 mmol, 2 equiv.)
- sodium bicarbonate 6.5 g, 77.7 mmol, 10 equiv.
- Step-3 Synthesis of l-(3-methoxy-2,6-dimethylbenzyl)-5-methyl-2-(methylthio)pyridin- 1-ium iodide (1-13)
- Step-4 Synthesis of 2-amino-3-(3-methoxy-2,6-dimethylphenyl)-6-methylindolizine-l- carbonitrile (1-14)
- Step-1 Synthesis of 2-(3-methoxy-2,6-dimethylbenzyl)-5,6-dimethylpyridazin-3(2H)-one (1-15)
- Step-2 Synthesis of 2-(3-methoxy-2,6-dimethylbenzyl)-5,6-dimethylpyridazine-3(2H)- thione (1-16)
- Step-3 Synthesis ooff l-(3-methoxy-2,6-dimethylbenzyl)-3,4-dimethyl-6-
- Step-4 Synthesis ooff 6-amino-7-(3-methoxy-2,6-dimethylphenyl)-2,3- dimethylpyrrolo[l,2-b]pyridazine-5-carbonitrile (1-18)
- Step-1 Synthesis of 6-chloro-2-(3-methoxy-2,6-dimethylbenzyl)-5-methylpyridazin- 3(2H)-one (1-19)
- Step-2 Synthesis ooff 6-(cyclohex-l-en-l-yl)-2-(3-methoxy-2,6-dimethylbenzyl)-5- methylpyridazin-3(2H)-one (1-20)
- Intermediate 1-19 (1 g, 3.4 mmol, 1.0 equiv.) in 1,4-dioxane (8 mL) and water (2 mL)
- 1-Cyclohexen-l-yl-boronic acid pinacol ester (2.13 g, 10.25 mmol, 3.0 equiv.)
- sodium carbonate (1.45 g, 10.24 mmol, 4 equiv.
- Step-3 Synthesis ooff 6-(cyclohex-l-en-l-yl)-2-(3-methoxy-2,6-dimethylbenzyl)-5- methylpyridazine-3(2H)-thione (1-21)
- Step-4 Synthesis of 3-(cyclohex-l-en-l-yl)-l-(3-methoxy-2,6-dimethylbenzyl)-4-methyl- 6-(methylthio)pyridazin-l-ium iodide (1-22)
- Step-5 Synthesis of 6-amino-2-(cyclohex-l-en-l-yl)-7-(3-methoxy-2,6-dimethylphenyl)- 3-methylpyrrolo[l,2-b]pyridazine- 5- carbonitrile (1-23)
- Step-1 Synthesis ooff 2-(3-methoxy-2,6-dimethylbenzyl)-5-methyl-6-(pyrrolidin-l- yl)pyridazin-3(2H)-one (1-24)
- Step-2 Synthesis ooff 2-(3-methoxy-2,6-dimethylbenzyl)-5-methyl-6-(pyrrolidin-l- yl)pyridazine-3(2H)-thione (1-25)
- Step-3 Synthesis of l-(3-methoxy-2,6-dimethylbenzyl)-4-methyl-6-(methylthio)-3- (pyrrolidin-l-yl)pyridazin-l-ium (1-26)
- Step-4 Synthesis of 6-amino-7-(3-methoxy-2,6-dimethylphenyl)-3-methyl-2-(pyrrolidin- l-yl)pyrrolo[l,2-b]pyridazine-5-carbonitrile (1-27)
- Step-1 Synthesis of 5,6-dichloro-2-(3-methoxy-2,6-dimethylbenzyl)pyridazin-3(2H)-one (1-28)
- Step-2 Synthesis ooff 6-chloro-5-(4-fluorophenyl)-2-(3-methoxy-2,6- dimethylbenzyl)pyridazin-3(2H)-one (1-29)
- reaction mixture was diluted with EtOAc (4x) and washed with water. Combined organic layers were washed with brine and dried over anhydrous sodium sulphate. The filtered organic layer was concentrated under reduced pressure to give crude product, the resultant crude was purified by combi flash using 20% EtOAc in Hexane as eluent to get the compound 1-29 (0.75 g) as yellow solid.
- Step-3 Synthesis ooff 5-(4-fluorophenyl)-2-(3-methoxy-2,6-dimethylbenzyl)-6- methylpyridazin-3(2H)-one (1-30)
- reaction mixture was diluted with EtOAc (4x) and washed with water. Combined organic layers were washed with brine and dried over anhydrous sodium sulphate. The filtered organic layer was concentrated under reduced pressure to give crude product, the resultant crude was purified by combi flash using 30% EtOAc in Hexane as eluent to get the compound 1-30 (0.38 g) as yellow solid.
- Step-4 Synthesis ooff 5-(4-fluorophenyl)-2-(3-methoxy-2,6-dimethylbenzyl)-6- methylpyridazine-3(2H)-thione (1-31)
- Step-5 Synthesis of 4-(4-fluorophenyl)-l-(3-methoxy-2,6-dimethylbenzyl)-3-methyl-6- (methylthio)pyridazin-l-ium iodide (1-32)
- Step-1 Synthesis ooff 6-(4-fluorophenyl)-2-(3-methoxy-2,6-dimethylbenzyl)-5- methylpyridazin-3(2H)-one (1-34)
- Step-2 Synthesis ooff 6-(4-fluorophenyl)-2-(3-methoxy-2,6-dimethylbenzyl)-5- methylpyridazine-3(2H)-thione (1-35)
- Step-3 Synthesis of 3-(4-fluorophenyl)-l-(3-methoxy-2,6-dimethylbenzyl)-4-methyl-6- (methylthio)pyridazin-l-ium iodide (1-36)
- Step-4 Synthesis of 6-amino-2-(4-fluorophenyl)-7-(3-methoxy-2,6-dimethylphenyl)-3- methylpyrrolo[l,2-b]pyridazine-5-carbonitrile (1-37)
- malononitrile (0.68 g, 10.43 mmol, 4 equiv.)
- NaH 0.3 g, 13.04 mmol, 5 equiv.
- Step-1 Synthesis ooff 6-chloro-5-(cyclopent-l-en-l-yl)-2-(3-methoxy-2,6- dimethylbenzyl)pyridazin-3(2H)-one (1-38)
- reaction mixture was diluted with EtOAc (4x) and washed with water. Combined organic layers were washed with brine and dried over anhydrous sodium sulphate. The filtered organic layer was concentrated under reduced pressure to give crude product, the resultant crude was purified by combi flash using 20% EtOAc in Hexane as eluent to get the compound 1-38 (0.92 g) as yellow solid.
- Step-2 Synthesis of 5-(cyclopent-l-en-l-yl)-2-(3-methoxy-2,6-dimethylbenzyl)-6- methylpyridazin-3(2H)-one (1-39)
- reaction mixture was diluted with EtOAc (4x) and washed with water. Combined organic layers were washed with brine and dried over anhydrous sodium sulphate. The filtered organic layer was concentrated under reduced pressure to give crude product, the resultant crude was purified by combi flash using 30% EtOAc in Hexane as eluent to get the compound 1-39 (0.65 g) as yellow solid.
- Step-3 Synthesis of 5-cyclopentyl-2-(3-methoxy-2,6-dimethylbenzyl)-6-methylpyridazin- 3(2H)-one (1-40)
- MeOH MeOH
- Pd(OH)2 0.52 g, 3.69 mmol, 2 equiv.
- TLC TLC-MS: m/z 327.1 (M+H) +
- Step-4 Synthesis ooff 5-cyclopentyl-2-(3-methoxy-2,6-dimethylbenzyl)-6- methylpyridazine-3(2H)-thione (1-41)
- Step-5 Synthesis of 4-cyclopentyl-l-(3-methoxy-2,6-dimethylbenzyl)-3-methyl-6- (methylthio)pyridazin-l-ium iodide (1-42)
- Step-6 Synthesis ooff 6-amino-3-cyclopentyl-7-(3-methoxy-2,6-dimethylphenyl)-2- methylpyrrolo[l,2-b]pyridazine-5-carbonitrile (1-43)
- malononitrile (0.51 g, 7.69 mmol, 5 equiv.)
- DME 10 mL
- NaH 0.52 g, 21.53 mmol, 14 equiv.
- the resultant reaction mixture was heated to 70 °C and stirred for 16 hours. Progress of the reaction was monitored by TLC. After the completion of reaction, the reaction mixture was cooled to RT, quenched with sat. NH4CI solution and extracted with EtOAc (4x). Combined organic layers were washed with brine and dried over anhydrous sodium sulphate. The filtered organic layer was concentrated to obtain the crude. The resultant crude was purified by combi- flash column chromatography using 30% ethyl acetate in hexane as eluent to afford the intermediate 1-43 (0.31 g) as light-yellow liquid.
- Step-1 Synthesis of 6-chloro-2-(3-methoxy-2,6-dimethylbenzyl)-5-(prop-l-en-2- yl)pyridazin-3(2H)-one (1-44)
- isopropyl boronic acid (0.56 g, 6.9 mmol, 0.9 equiv.)
- sodium carbonate (2.41 g, 22.98 mmol, 3 equiv.
- Step-2 Synthesis of 2-(3-methoxy-2,6-dimethylbenzyl)-6-methyl-5-(prop-l-en-2- yl)pyridazin-3(2H)-one (1-45)
- Step-3 Synthesis of 5-isopropyl-2-(3-methoxy-2,6-dimethylbenzyl)-6-methylpyridazin- 3(2H)-one (1-46)
- MeOH MeOH
- Pd(OH)2 0.67 g, 4.83 mmol, 0.8 equiv.
- Step-4 Synthesis of 5-isopropyl-2-(3-methoxy-2,6-dimethylbenzyl)-6-methylpyridazine- 3(2H)-thione (1-47)
- Step-5 Synthesis ooff 4-isopropyl-l-(3-methoxy-2,6-dimethylbenzyl)-3-methyl-6- (methylthio)pyridazin-l-ium iodide (1-48)
- Step-6 Synthesis of 6-amino-3-isopropyl-7-(3-methoxy-2,6-dimethylphenyl)-2- methylpyrrolo[l,2-b]pyridazine-5-carbonitrile (1-49)
- malononitrile (1.79 g, 27.15 mmol, 5 equiv.)
- DME 20 mL
- NaH 1.95 g, 81.45 mmol, 15 equiv.
- the resultant reaction mixture was heated to 100 °C and stirred for 16 hours. Progress of the reaction was monitored by TLC. After the completion of reaction, the reaction mixture was cooled to RT, quenched with sat. NH4CI solution and extracted with EtOAc (4x). Combined organic layers were washed with brine and dried over anhydrous sodium sulphate. The filtered organic layer was concentrated to obtain the crude. The resultant crude was purified by combi- flash column chromatography using 30% ethyl acetate in hexane as eluent to afford the intermediate 1-49 (0.07 g) as light-yellow liquid.
- Step-1 Synthesis of 6-chloro-2-(3-methoxy-2,6-dimethylbenzyl)-5-(pyrrolidin-l- yl)pyridazin-3(2H)-one (1-50)
- Step-2 Synthesis ooff 2-(3-methoxy-2,6-dimethylbenzyl)-6-methyl-5-(pyrrolidin-l- yl)pyridazin-3(2H)-one (1-51)
- reaction mixture was diluted with EtOAc (4x) and washed with water. Combined organic layers were washed with brine and dried over anhydrous sodium sulphate. The filtered organic layer was concentrated under reduced pressure to give crude product, the resultant crude was purified by combi flash using 50% EtOAc in Hexane as eluent to get the compound 1-51 (1.4 g) as yellow solid.
- Step-3 Synthesis ooff 2-(3-methoxy-2,6-dimethylbenzyl)-6-methyl-5-(pyrrolidin-l- yl)pyridazine-3(2H)-thione (1-52)
- Step-5 Synthesis of 6-amino-7-(3-methoxy-2,6-dimethylphenyl)-2-methyl-3-(pyrrolidin- l-yl)pyrrolo[l,2-b]pyridazine-5-carbonitrile (1-54)
- Step-1 Synthesis of 6-cyclopropyl-2-(3-methoxy-2,6-dimethylbenzyl)-5- methylpyridazin-3(2H)-one (1-55)
- reaction mixture was diluted with EtO Ac (4x) and washed with water. Combined organic layers were washed with brine and dried over anhydrous sodium sulphate. The filtered organic layer was concentrated under reduced pressure to give crude product, the resultant crude was purified by combi flash using 2% EtOAc in Hexane as eluent to get the compound 1-55 (0.63 g) as yellow solid.
- Step-2 Synthesis ooff 6-cyclopropyl-2-(3-methoxy-2,6-dimethylbenzyl)-5- methylpyridazine-3(2H)-thione (1-56)
- Step-3 Synthesis of 3-cyclopropyl-l-(3-methoxy-2,6-dimethylbenzyl)-4-methyl-6- (methylthio)pyridazin-l-ium (1-57)
- Step-4 Synthesis of 6-amino-2-cyclopropyl-7-(3-methoxy-2,6-dimethylphenyl)-3- methylpyrrolo[l,2-b]pyridazine-5-carbonitrile (1-58)
- Step-1 Synthesis of 6-chloro-5-cyclopropyl-2-(3-methoxy-2,6-dhnethylbenzyl)pyridazin- 3(2H)-one (1-59)
- reaction mixture was diluted with EtOAc (4x) and washed with water. Combined organic layers were washed with brine and dried over anhydrous sodium sulphate. The filtered organic layer was concentrated under reduced pressure to give crude product, the resultant crude was purified by combi flash using 20% EtOAc in Hexane as eluent to get the compound intermediate 1-59 (2,8 g) as yellow solid.
- Step-2 Synthesis of 5-cyclopropyl-2-(3-methoxy-2,6-dimethylbenzyl)-6- methylpyridazin-3(2H)-one (1-60)
- intermediate 1-59 2.7 g, 8.47 mmol, 1.0 equiv.
- 1,4-dioxane 40 mL
- trimethylboroxine 3.19 g, 25.41 mmol, 3.0 equiv.
- potassium phosphate tribasic 5.39 g, 25.4 mmol, 3 equiv.
- Step-3 Synthesis of 5-cyclopropyl-2-(3-methoxy-2,6-dimethylbenzyl)-6- methylpyridazine-3(2H)-thione (1-61)
- Step-4 Synthesis of 4-cyclopropyl-l-(3-methoxy-2,6-dimethylbenzyl)-3-methyl-6- (methylthio)pyridazin-l-ium iodide (1-62)
- Step-5 Synthesis of 6-amino-7-(3-methoxy-2,6-dimethylphenyl)-3-methylpyrrolo[l,2- b]pyridazine-5-carbonitrile (1-63)
- Step-1 Synthesis of 5-chloro-2-(3-methoxy-2,6-dimethylbenzyl)pyridazin-3(2H)-one (I- 64)
- Step-2 Synthesis of 5-cyclopropyl-2-(3-methoxy-2,6-dimethylbenzyl)pyridazin-3(2H)- one (1-65)
- reaction mixture was diluted with EtOAc (4x) and washed with water. Combined organic layers were washed with brine and dried over anhydrous sodium sulphate. The filtered organic layer was concentrated under reduced pressure to give crude product, the resultant crude was purified by combi flash using 20% EtOAc in Hexane as eluent to get the compound 1-65 (0.9 g) as yellow solid.
- Step-3 Synthesis of 5-cyclopropyl-2-(3-methoxy-2,6-dimethylbenzyl)pyridazine-3(2H)- thione (1-66)
- the reaction mixture was cooled to RT and poured into water and extracted with EtOAc (4x). Combined organic layers were washed with brine and dried over anhydrous sodium sulphate.
- Step-4 Synthesis ooff 4-cyclopropyl-l-(3-methoxy-2,6-dimethylbenzyl)-6-
- Step-5 Synthesis ooff 6-amino-3-cyclopropyl-7-(3-methoxy-2,6- dimethylphenyl)pyrrolo[l,2-b]pyridazine-5-carbonitrile (1-68)
- Step-1 Synthesis of 2-bromo-l-(3-methoxy-2,6-dimethylbenzyl)-4-methylpyridin-l-ium bromide (1-5)
- Step-2 Synthesis of 2-amino-3-(3-methoxy-2,6-dimethylphenyl)-7-methylindolizine-l- carbonitrile (1-6)
- Step-3 Synthesis of 2-amino-3-(3-hydroxy-2,6-dimethylphenyl)-7-methylindolizme-l- carboxamide (compound 1)
- Example-2 Synthesis ooff 6-amino-7-(3-hydroxy-2,6-dimethylphenyl)-3- methylpyrrolo[l,2-b]pyridazine-5-carboxamide (Compound-4)
- Step-2 Synthesis of 2-(3-methoxy-2,6-dimethylbenzyl)-5-methylpyridazine-3(2H)-thione (1-8)
- Step-3 Synthesis ooff l-(3-methoxy-2,6-dimethylbenzyl)-4-methyl-6-
- Step-4 Synthesis of 6-amino-7-(3-methoxy-2,6-dimethylphenyl)-3-methylpyrrolo[l,2- b]pyridazine-5-carbonitrile (1-10)
- THF THF
- NaH 0.15 g, 6.22 mmol, 2 equiv.
- sulfolane was added to it dropwise at 0 °C.
- reaction mixture was heated to 70 °C and stirred for 16 hours. Progress of the reaction was monitored by TLC. After the completion of reaction, the reaction mixture was cooled to RT, quenched with sat. NH4CI solution and extracted with EtOAc (4x). Combined organic layers were washed with brine and dried over anhydrous sodium sulphate. The filtered organic layer was concentrated to obtain the intermediate 1-10 (0.5 g) as light-yellow liquid.
- Step-5 Synthesis of 6-amino-7-(3-hydroxy-2,6-dimethylphenyl)-3-methylpyrrolo[l,2- b]pyridazine-5-carboxamide (compound 4)
- Example-3 Synthesis of 2-amino-3-(3-hydroxy-2,6-dmiethylphenyl)-6-methylindolizine- 1 -carboxamide (Compound 7)
- Step-1 SSyynntthheessiiss of 6-amino-2-cyclopropyl-7-(3-methoxy-2,6-dimethylphenyl)-3- methylpyrrolo[l,2-b]pyridazine-5-carboxamide (1-69)
- Step-2 Synthesis of 6-amino-2-cyclopropyl-7-(3-hydroxy-2,6-dimethylphenyl)-3- methylpyrrolo[l,2-b]pyridazine-5-carboxamide (compound 24)
- HPLC details Exemplary compounds of the present disclosure are analysed for the HPLC purity in any one of the methods A, B, C & D referred herein below: Method A - Column: LUNA OMEGA-PS, C18(150mmx4.6mm, 5p) Mobile phase: C: WATER, B: ACN, Flow rate : 1.0 ml ⁇ min.
- TEMP 40°C GRADIENT : 0/5, 1/5, 6/100, 8/100, 10/5, 12/5, Diluent : ACN:WATER
- Method B Column: ZORBAX, ECLIPSE C18(150mmx4.6mm,4p)
- Mobile phase A: 0.01%TFA IN WATER B: ACN, Flow rate : 1.0 ml ⁇ min.
- TEMP 40°C GRADIENT : 0/5, 1/5, 6/100, 8/100, 10/5, 12/5, Diluent : ACN:WATER
- the inhibitory activity of the test compounds for PKMYT1 was assessed by commercially available ADP Gio assay (Promega cat. no. V9103).
- the human recombinant PKMYT1 full- length human GST-PKMYT1 recombinant protein; ThermoFisher Scientific A33387
- enzyme assay buffer 70 mM HEPES, lOmM MgCh, 0.01% Triton X, 0.01% BSA, 3 ⁇ M sodium orthovanadate, 1.2 mM DTT
- the enzyme-compound mix was added to the plate, spun down briefly, and incubated at 25°C for 30 min.
- ATP solution ADP Gio KIT from Promega
- enzyme assay buffer was added to the plate and incubated for 60 minutes at 30°C, the final ATP concentration was lOpM.
- lOpl of ADP-Glo reagent was added and incubated at room temperature for 60 minutes.
- 20pl of the kinase detection reagent was added and the plate was incubated at room temperature for 60 minutes.
- Luminescence was measured using Victor V multimode plate reader (Perkin Elmer).
- the IC50 and % maximum inhibition of the compounds were estimated by fitting the dose response data to a sigmoidal curve fitting equation using Graph pad Prism software V. 8.
- the compounds were screened by the above-mentioned assay procedure.
- the % inhibition at 0.1 ⁇ M and 1.0 ⁇ M concentration are summarized in the Table-3 below along with IC50 (nM) details in Table-4.
- the IC50 values given herein are in range wherein “A” refers to an IC50 value of less than 10 nM, “B” refers to an IC50 value in between 10-100 nM (both inclusive) and “C” refers to an IC50 value of greater than 100 nM.
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Abstract
The present disclosure provides bicyclic heteroaryl compounds and their derivatives of formula (I), which are therapeutically useful as PKMYT1 inhibitors. (I) These compounds are useful in the treatment and/or prevention of diseases or conditions responsive to the inhibition of PKMYT1 activity. Compounds of the present disclosure are especially useful for treating cancer. The present disclosure also provides processes for preparation of the compounds and pharmaceutical compositions comprising at least one of the compounds of formula (I) or a pharmaceutically acceptable salt or a stereoisomer thereof.
Description
BICYCLIC HETEROARYL COMPOUNDS AND THEIR DERIVATIVES AS
PKMYT1 INHIBITORS
This application claims the benefit of Indian provisional application number 202241060319, filed on 21st October 2022; the specification of which is hereby incorporated by reference in their entirety.
TECHNICAL FIELD
The present application is directed to bicyclic heteroaryl compounds and their derivatives of formula (I) as PKMYT1 (MYT1) inhibitors, useful for the treatment of cancer and those diseases or conditions involving overexpression/amplification of CCNE1 or inactivating mutation in the FBXW7 gene. The disclosure also provides pharmaceutically acceptable compositions comprising compounds of the present application and methods of using said compositions in the treatment of diseases associated with PKMYT1.
BACKGROUND
CCNE1 encodes the protein cyclin El, which complexes with cyclin-dependent kinase 2 (CDK2) and drives cells from G1 phase to S phase. In cancer, amplification of CCNE1 gene and its deregulation of cyclin El during early stage of tumorigenesis forces cancer cells into S phase prematurely leading to replication stress and DNA damage. As cells move into mitosis with damaged DNA and in the absence of functional p53 leads to genomic instability.
PKMYT1, a member of the WEE family of serine/threonine-kinases, is an important regulator of CDK1 phosphorylation and is a compelling therapeutic target for the treatment of certain types of DNA damage response cancers due to its strongest dependency in CCNE1- amplified tumours. Absence of functional PKMYT1 in a genetically vulnerable tumor with CCNE1 -amplification, leads to hyperactive CDK1, unscheduled mitosis and catastrophic DNA damage, ultimately resulting in cell death. Selective PKMYT1 inhibition is a promising therapeutic strategy for CCNE1 -amplified cancers taking advantage of the synthetic lethality relationship.
It is therefore, an object of this disclosure to provide compounds useful in the treatment of such diseases and/or conditions responsive to the inhibition of PKMYT1(MYT1) activity.
SUMMARY
Provided herein are bicyclic heteroaryl compounds and their derivatives of formula (I) and pharmaceutical compositions thereof, which are capable of inhibiting PKMYT1.
In one aspect of the present disclosure, it comprises compounds of formula (I):
wherein, each X1 to X6 is independently C or N; wherein a maximum of 3 of X1 to X6 are N;
Ri at each occurrence independently is alkyl, halo or hydroxy; alternatively, two Ri on consecutive ring atoms together get cyclized to form an unsubstituted or alkyl-substituted heteroaryl, or an unsubstituted or alkyl-substituted heterocycloalkyl, having 1 to 3 heteroatoms selected from N, O or S;
R2’ and R2” each independently hydrogen or alkyl;
R3’ and R3” are each independently hydrogen or alkyl;
R4 is alkyl, halo, hydroxyalkyl, haloalkyl, cyano, -OR5, unsubstituted or substituted cycloalkyl, unsubstituted or substituted cycloalkenyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl or unsubstituted or substituted heterocycloalkyl; wherein the substituents on cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocycloalkyl are independently selected from one or more alkyl, halo, haloalkyl, hydroxy, cyano, amino, - COOH or hydroxyalkyl;
R5 is selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl or heterocycloalkyl; m is 1, 2, 3 or 4; and n is 0, 1, 2 or 3.
Also provided are pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent).
Also provided are processes for the preparation of compounds of formula (I).
Compounds of formula (I) are useful for the inhibition of PKMYT1, and therapeutic use of such compounds is also provided.
DETAILED DESCRIPTION
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in art to which the subject matter herein belongs. As used in the specification and the appended claims, unless specified to the contrary, the following terms have the meaning indicated to facilitate the understanding of the present disclosure.
As used herein, unless otherwise defined the term "alkyl" alone or in combination with other term(s) means saturated aliphatic hydrocarbon chains, including C1-C10 straight or C1- C10 branched alkyl chains, more preferably, C1-C6 straight or branched alkyl chains. Examples of "alkyl" include but are not limited to methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec- butyl, tert-butyl, isopentyl or neopentyl and the like.
As used herein, the term "halo" or "halogen" alone or in combination with other term(s) means fluorine, chlorine, bromine or iodine.
As used herein, the term "hydroxy" or "hydroxyl" alone or in combination with other term(s) means -OH.
As used herein, the term "hydroxyalkyl" refers to the group HO-alkyl-, wherein alkyl and hydroxy groups are as defined herein.
As used herein, the term "cyano" refers to -CN.
As used herein, the term "haloalkyl" means alkyl substituted with one or more halogen atoms, wherein the alkyl groups are as defined above. The term "halo" is used herein interchangeably with the term "halogen" means F, Cl, Br or I. Examples of "haloalkyl" include but are not limited to fluoromethyl, difluoromethyl, chloromethyl, trifluoromethyl, 2,2,2- trifluoroethyl and the like.
As used herein the term "cycloalkyl" alone or in combination with other term(s) means -C3-C10 saturated cyclic hydrocarbon ring. A cycloalkyl may be a single ring, which typically contains from 3 to 7 carbon ring atoms. Examples of single-ring cycloalkyls include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. A cycloalkyl may alternatively be polycyclic or contain more than one ring. Examples of polycyclic cycloalkyls include bridged, fused and spirocyclic carbocyclyls and the like.
As used herein the term "cycloalkenyl" alone or in combination with other term(s) means -C3-C10 cyclic hydrocarbon ring with a double bond. A cycloalkenyl may be a single ring, which typically contains from 3 to 7 carbon ring atoms. Examples of single-ring cycloalkyls include but are not limited to cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and the like. A cycloalkenyl may alternatively be polycyclic or contain more than one ring.
As used herein, the term "aryl" is unsubstituted or substituted monocyclic, bicyclic or polycyclic aromatic hydrocarbon ring system of about 6 to 14 carbon atoms. Examples of a C6- C14 aryl group include, but are not limited to phenyl, naphthyl, anthryl, biphenylenyl and acenaphthyl. An aryl group may be unsubstituted or substituted with one or more suitable groups.
The term "heterocycloalkyl" refers to a non-aromatic, saturated or partially saturated monocyclic or polycyclic ring system of 3 to 15 members having at least one heteroatom or heterogroup selected from O, N, S, S(O), S(O)i, or NH with the remaining ring atoms being independently selected from the group consisting of carbon, oxygen, nitrogen and sulfur. A monocyclic heterocycloalkyl may typically contain 4 to 7 ring atoms. Examples of “Heterocycloalkyl” include, but are not limited to azetidinyl, oxetanyl, imidazolidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl, oxapiperazinyl, oxapiperidinyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiophenyl, dihydropyranyl, indolinyl, azepanyl, 1, 2,3,4- tetrahydroisoquinolinyl, 3,4-dihydro-2H-benzo[b][l,4]oxazinyl, and N-oxides thereof. Attachment of a heterocycloalkyl substituent can occur via either a carbon atom or a heteroatom. A heterocycloalkyl group can be unsubstituted or substituted with one or more suitable groups by one or more aforesaid groups.
As used herein, the term "heteroaryl" alone or in combination with other term(s) means a completely unsaturated ring system containing a total of 5 to 14 ring atoms. At least one of the ring atoms is a heteroatom (i.e., oxygen, nitrogen, or sulfur), with the remaining ring atoms/groups being independently selected from the group consisting of carbon, oxygen, nitrogen or sulfur. A heteroaryl may be a single-ring (monocyclic) or polycyclic ring system. Examples of "heteroaryl" include but are not limited to pyridyl, indolyl, benzimidazolyl, benzothiazolyl, pyrrolyl, pyrazolyl, imidazolyl, indolizinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolo[1,2-b]pyridazinyl, pyrrolo[l,2-a]pyrimidinyl, pyrrolo[1,2-a]pyrazinyl,
pyrrolo[l,2-c]pyrimidinyl, benzofuranyl, benzo[d]isoxazolyl, benzo[d]oxazolyl, IH-indazolyl and the like.
As used herein, the term "heterocyclyl" alone or in combination with other term(s) includes both "heterocycloalkyl" and "heteroaryl" groups which are as defined above. Examples of “Heterocyclyl” include, but are not limited to azetidinyl, pyrrolidinyl, piperidinyl, pyridyl, indolyl, benzimidazolyl, benzothiazolyl and the like.
The term "heteroatom" as used herein designates a sulfur, nitrogen or oxygen atom.
As used in the above definitions, the term "optionally substituted" or “substituted” or “optionally substituted with suitable groups” refers to replacement of one or more hydrogen radicals in a given structure with a radical of a specified substituent including, but not limited to: halo, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, thiol, alkylthio, arylthio, alkylthioalkyl, arylthioalkyl, alkylsulfonyl, alkylsulfonylalkyl, arylsulfonylalkyl, alkoxy, aryloxy, aralkoxy, aminocarbonyl, alkylaminocarbonyl, arylaminocarbonyl, alkoxycarbonyl, aryloxycarbonyl, haloalkyl, amino, trifluoromethyl, cyano, nitro, alkylamino, arylamino, alkylaminoalkyl, arylaminoalkyl, aminoalkylamino, hydroxy, alkoxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, acyl, aralkoxycarbonyl, carboxylic acid, sulfonic acid, sulfonyl, phosphoric acid, aryl, heteroaryl, heterocyclic and aliphatic. It is understood that any substituent may be further substituted.
As used herein, the term "compound(s)" comprises the compounds disclosed in the present disclosure.
As used herein, the term "comprise" or "comprising" is generally used in the sense of include, that is to say permitting the presence of one or more features or components.
As used herein, the term "or" means "and/or" unless stated otherwise.
As used herein, the term "including" as well as other forms, such as "include", includes" and "included" is not limiting.
As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. By "pharmaceutically acceptable" it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
As used herein, the term "treat", "treating" and "treatment" refer to a method of alleviating or abrogating a disease and/or its attendant symptoms.
As used herein, the term "prevent", "preventing" and "prevention" refer to a method of preventing the onset of a disease and/or its attendant symptoms or barring a subject from acquiring a disease. As used herein, "prevent", "preventing" and "prevention" also include delaying the onset of a disease and/or its attendant symptoms and reducing a subject's risk of acquiring a disease.
As used herein, the term "therapeutically effective amount" refers to the amount of the compound being administered sufficient to prevent development of or alleviate to some extent one or more of the symptoms of the condition or disorder being treated.
"Pharmaceutically acceptable" means that, which is usefill in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary as well as human pharmaceutical use.
As used herein, the phrase "pharmaceutically acceptable excipient" refers to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, solvent, or encapsulating material. Excipients or carriers are generally safe, non-toxic and neither biologically nor otherwise undesirable and include excipients or carriers that are acceptable for veterinary use as well as human pharmaceutical use. In one embodiment, each component is "pharmaceutically acceptable" as defined herein. See, e.g., Remington: The Science and Practice of Pharmacy, 21st ed.; Lippincott Williams & Wilkins: Philadelphia, Pa., 2005; Handbook of Pharmaceutical Excipients, 6th ed.; Rowe et al, Eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash Eds.; Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson Ed.; CRC Press LLC: Boca Raton, Fla., 2009.
As used herein, “pharmaceutically acceptable salt(s)” refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts of the present disclosure include the conventional non-toxic salts of the parent compound
formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present disclosure can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, alcohols or acetonitrile (ACN) are preferred.
The term "stereoisomers" refers to any enantiomers, diastereoisomers, or geometrical isomers of the compounds of Formula (I), wherever they are chiral or when they bear one or more double bonds. When the compounds of the formula (I) are chiral, they can exist in racemic or in optically active form. It should be understood that the disclosure encompasses all stereochemical isomeric forms, including diastereomeric, enantiomeric and epimeric forms, as well as tZ-isomers and /-isomers and mixtures thereof. Individual stereoisomers of compounds can be prepared synthetically from commercially available starting materials which contain chiral centers or by preparation of mixtures of enantiomeric products followed by separation such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, direct separation of enantiomers on chiral chromatographic columns, or any other appropriate method known in the art. Starting compounds of particular stereochemistry are either commercially available or can be made and resolved by techniques known in the art. Additionally, the compounds of the present disclosure may exist as geometric isomers. The present disclosure includes all cis and trans, syn and anti, (R) and (S), entgegen (E) and zusammen (Z) isomers as well as the appropriate mixtures thereof.
The present disclosure provides bicyclic heteroaryl compounds and their derivatives of formula (I), which are useful for the inhibition of PKMYT1.
The present disclosure further provides pharmaceutical compositions comprising the said compounds of formula (I), and their derivatives as therapeutic agents.
It will be apparent to those skilled in the art that various modifications and variations can be made to the compounds, compositions, and methods described herein without departing from the scope or spirit of various embodiments disclosed herein. For instance, features illustrated or described as part of one embodiment can be applied to another embodiment to yield a still further embodiment. Thus, it is intended that the present application includes such modifications and variations and their equivalents. Other objects, features, and aspects of the
present application are disclosed in, or are obvious from, the following detailed description. It is to be understood by one of ordinary skill in the art that the present discussion is a description of exemplary embodiments and is not to be construed as limiting the broader aspects of the present disclosure.
The embodiments below are illustrative of the present disclosure and are not intended to limit the claims to the specific embodiments exemplified.
In first embodiment, the present application provides bicyclic heteroaryl compounds and their derivatives of formula (I),
or a pharmaceutically acceptable salt thereof or a stereoisomer thereof; wherein, each X1 to X6 is independently C or N; wherein a maximum of 3 of X1 to X6 are N;
Ri at each occurrence independently is alkyl, halo or hydroxy; alternatively, two Ri on consecutive ring atoms together get cyclized to form an unsubstituted or alkyl-substituted heteroaryl, or an unsubstituted or alkyl-substituted heterocycloalkyl, having 1 to 3 heteroatoms selected from N, O or S;
R2’ and R2” each independently hydrogen or alkyl;
R3’ and R3” are each independently hydrogen or alkyl;
R4 is alkyl, halo, hydroxyalkyl, haloalkyl, cyano, -OR5, unsubstituted or substituted cycloalkyl, unsubstituted or substituted cycloalkenyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl or unsubstituted or substituted heterocycloalkyl; wherein the substituents on cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocycloalkyl are independently selected from one or more alkyl, halo, haloalkyl, hydroxy, cyano, amino, - COOH or hydroxyalkyl;
R5 is selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl or heterocycloalkyl; m is 1, 2, 3 or 4; and n is 0, 1, 2 or 3.
In some embodiments, compounds of formula (IA),
or pharmaceutically acceptable salts thereof or stereoisomers thereof, are provided.
In some embodiments, compounds of formula (IB),
or pharmaceutically acceptable salts thereof or stereoisomers thereof, are provided.
In some embodiments, compounds of formula (IC),
or pharmaceutically acceptable salts thereof or stereoisomers thereof, are provided.
In some embodiments, compounds of formula (ID),
or pharmaceutically acceptable salts thereof or stereoisomers thereof, are provided.
In some embodiments, bicyclic heteroaryl compounds and their derivatives of formula
(I),
or a pharmaceutically acceptable salt thereof or a stereoisomer thereof; wherein, each X1 to X6 is independently C or N; wherein a maximum of 3 of X1 to X6 are N;
Ri at each occurrence independently is alkyl or hydroxy; alternatively, two Ri on consecutive ring atoms together get cyclized to form an unsubstituted or alkyl-substituted heteroaryl, or an unsubstituted or alkyl-substituted heterocycloalkyl, having 1 to 3 heteroatoms selected from N, O or S;
R2’ and R2” each hydrogen;
R3’ and R3” are each hydrogen;
R4 is alkyl, halo, haloalkyl, cyano or -OR5;
R5 is selected from hydrogen, alkyl or cycloalkyl; m is 1, 2, 3 or 4; and n is 0, 1, 2 or 3.
In some embodiments, bicyclic heteroaryl compounds and their derivatives of formula
(I),
or a pharmaceutically acceptable salt thereof or a stereoisomer thereof; wherein, each X1 to X6 is independently C or N; wherein a maximum of 3 of X1 to X6 are N;
Ri at each occurrence independently is alkyl or hydroxy; alternatively, two Ri on consecutive ring atoms together get cyclized to form an unsubstituted or alkyl-substituted heteroaryl, or an unsubstituted or alkyl-substituted heterocycloalkyl, having 1 to 3 heteroatoms selected from N, O or S;
R2’ and R2” each hydrogen;
R3’ and R3” are each hydrogen;
R4 is alkyl, unsubstituted or substituted cycloalkyl, unsubstituted or substituted cycloalkenyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl or unsubstituted or substituted heterocycloalkyl; wherein the substituents on cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocycloalkyl are independently selected from one or more alkyl, halo, haloalkyl, hydroxy, cyano, amino, -COOH and hydroxyalkyl; m is 1, 2, 3 or 4; and n is 0, 1, 2 or 3.
In some embodiments, bicyclic heteroaryl compounds and their derivatives of formula
(I),
or a pharmaceutically acceptable salt thereof or a stereoisomer thereof; wherein, each X1 to X6 is independently C or N; wherein a maximum of 3 of X1 to X6 are N;
Ri at each occurrence independently is alkyl or hydroxy; alternatively, two Ri on consecutive ring atoms together get cyclized to form an unsubstituted or alkyl-substituted heteroaryl, or an unsubstituted or alkyl-substituted heterocycloalkyl, having 1 to 3 heteroatoms selected from N, O or S;
R2’ and R2” each hydrogen;
R3’ and R3” are each hydrogen;
R4 is alkyl or halo; m is 1, 2, 3 or 4; and n is 0, 1, 2 or 3.
In some embodiments, the present application provides bicyclic heteroaryl compounds and their derivatives of formula (I),
or a pharmaceutically acceptable salt thereof or a stereoisomer thereof; wherein, each X2 to X5 is C; X1 and X6 are each N;
Ri at each occurrence independently is alkyl, halo or hydroxy; alternatively, two Ri on consecutive ring atoms together get cyclized to form an unsubstituted or alkyl-substituted heteroaryl, or an unsubstituted or alkyl-substituted heterocycloalkyl, having 1 to 3 heteroatoms selected from N, O or S;
R2’ and R2” each independently hydrogen or alkyl;
R3’ and R3” are each independently hydrogen or alkyl;
R4 is alkyl, halo, hydroxyalkyl, haloalkyl, cyano, -OR5, unsubstituted or substituted cycloalkyl, unsubstituted or substituted cycloalkenyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl or unsubstituted or substituted heterocycloalkyl; wherein the substituents on cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocycloalkyl are independently selected from one or more alkyl, halo, haloalkyl, hydroxy, cyano, amino, - COOH or hydroxyalkyl;
R5 is selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl or heterocycloalkyl; m is 1, 2, 3 or 4; and n is 0, 1, 2 or 3.
In some embodiments, X2 to X5 are each C.
In some embodiments, X5 and X6 are each N.
In some embodiments, X1 and X6 are each N.
In some embodiments, X6 is N.
In some embodiments, Xi to X5 are each C.
In some embodiments, 1 to 3 of X1, X2, X3, X4, X5 or X6 are N.
In some embodiments, a maximum of 3 of X1 to X6 are N.
In some embodiments, Ri is hydroxy.
In some embodiments, Ri is alkyl.
In some embodiments, Ri is methyl.
In some embodiments, Ri at each occurrence independently is hydroxy or methyl.
In some embodiments, two Ri on consecutive ring atoms together get cyclized to form an unsubstituted or alkyl-substituted heteroaryl, having 1 to 3 heteroatoms selected from N, O or S.
In some embodiments, two Ri on consecutive ring atoms together get cyclized to form an unsubstituted or alkyl-substituted 5 to 6 membered heteroaryl, having 1 to 3 heteroatoms selected from N, O or S.
In some embodiments, two Ri on consecutive ring atoms together get cyclized to form an unsubstituted or alkyl-substituted heterocycloalkyl, having 1 to 3 heteroatoms selected from N, O or S.
In some embodiments, two Ri on consecutive ring atoms together get cyclized to form an unsubstituted or alkyl-substituted 5 to 6 membered heterocycloalkyl, having 1 to 3 heteroatoms selected from N, O or S.
In some of the above embodiments, two Ri on consecutive ring atoms together get cyclized to form an unsubstituted or alkyl-substituted heterocycloalkyl, or an unsubstituted or alkyl-substituted heteroaryl, the said heterocycloalkyl and heteroaryl independently having 1 to 3 heteroatoms selected from N, O or S; wherein the newly formed heterocyclyl ring system is fused to the existing phenyl ring.
In some embodiments, wherein R2' and R2" are each hydrogen.
In some embodiments, wherein Rs' and R3" are each hydrogen.
In some embodiments, R4 is alkyl.
In some embodiments, R4 is methyl.
In some embodiments, R4 is unsubstituted or substituted cycloalkyl; wherein the substituents on cycloalkyl are independently selected from one or more alkyl, halo, haloalkyl, hydroxy, cyano, amino, -COOH and hydroxyalkyl.
In some embodiments, R4 is unsubstituted or substituted aryl; wherein the substituents on aryl are independently selected from one or more alkyl, halo, haloalkyl, hydroxy, cyano, amino, -COOH and hydroxyalkyl.
In some embodiments, R4 is unsubstituted or substituted heteroaryl; wherein the substituents on heteroaryl are independently selected from one or more alkyl, halo, haloalkyl, hydroxy, cyano, amino, -COOH or hydroxyalkyl.
In some embodiments, R4 is unsubstituted or substituted heterocycloalkyl; wherein the substituents on heterocycloalkyl are independently selected from one or more alkyl, halo, haloalkyl, hydroxy, cyano, amino, -COOH or hydroxyalkyl.
In some embodiments, m is 2.
In some embodiments, m is 3.
In some embodiments, m is 4.
In some embodiments, n is 0.
In some embodiments, n is 1 or 2.
In some embodiments, compounds of formula (I) are provided, wherein Ri is hydroxy or alkyl, m is 3, and R4 is alkyl.
In some embodiments, compounds of formula (I) are provided, wherein Ri at each occurrence is independently hydroxy or alkyl, m is 3 and R4 is alkyl.
In some embodiments, compounds of formula (I) are provided, wherein ring
wherein
the two open ends marked with at X5 and X6 depict portion of the ring attached with the fused 5 membered heteroaryl ring of compounds of formula (I).
In some embodiments, compounds of formula (I) are provided, wherein ring
5
wherein the two open ends marked with at X5
and X6 depict portion of the ring attached with the fused 5 membered heteroaryl ring of compounds of formula (I).
In some embodiments, ring is selected from and
In some embodiments, the present disclosure includes enantiomers, diastereomers, epimers, and atropisomers of the compounds disclosed herein, and mixtures of enantiomers and/or diastereomers thereof including racemic mixtures.
In some embodiments, all possible stereoisomers (e.g., enantiomers and/or diastereomers) in mixtures and as pure or partially purified compounds are included within the scope of this invention.
In some embodiments, all possible combinations of the stereogenic centers are pure compounds or in mixtures.
In some embodiments, the compounds of formula (I) can be present as two separate rotomers or atropisomers.
In some embodiments, the rotomers or atropisomers contain bonds with hindered rotation such that two separate rotomers or atropisomers, may be separated.
In some embodiments, the separated atropisomers found to have different biological activity which may be advantageous. It is intended that all of the possible atropisomers are included within the scope of this invention.
In certain embodiments, the present application provides a compound selected from the group consisting of:
In certain embodiments, the compounds of the present invention exist as atropisomers.
In certain embodiments, the present disclosure provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof or a stereoisomer thereof as described herein and at least one pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent). Preferably, the pharmaceutical composition comprises a therapeutically effective amount of at least one compound described herein. The compounds described in the present disclosure may be associated with a pharmaceutically acceptable excipient (such as a carrier or a diluent) or be diluted by a carrier or enclosed within a carrier which can be in the form of a capsule, sachet, paper or other container.
In some embodiments, the compounds of the present disclosure are PKMYT1 inhibitors.
In some embodiments, the compound of formula (I) is a PKMYT1 inhibitor.
In some embodiments, the present disclosure provides pharmaceutical composition for use in treating and/or preventing a disease or condition responsive to the inhibition of PKMYT1 activity.
In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or a stereoisomer thereof and one or more pharmaceutically acceptable carriers or excipients.
The compounds may also be used in pharmaceutical compositions in which the compound disclosed herein or a pharmaceutically acceptable salt thereof is the only active ingredient.
In some embodiments, the present disclosure provides a method of inhibiting PKMYT1 in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of a compound of the present disclosure.
In some embodiments, the present disclosure provides a method of inhibiting PKMYT1 in a subject, comprising administering to the subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer thereof.
In some embodiments, the present disclosure provides a method of treating diseases or conditions mediated by PKMYT1 in a subject comprising administering to the subject in need thereof a therapeutically effective amount of a compound of the present disclosure.
In some embodiments, the present disclosure provides pharmaceutical composition comprising the compound of formula (I), for use in treating a subject suffering from a disease or condition associated with PKMYT1.
The compounds of the disclosure are typically administered in the form of a pharmaceutical composition. Such compositions can be prepared using procedures well known in the pharmaceutical art and comprise at least one compound of the present disclosure. The pharmaceutical composition of the present disclosure comprises one or more compounds described herein and one or more pharmaceutically acceptable excipients. Typically, the pharmaceutically acceptable excipients are approved by regulatory authorities or are generally regarded as safe for human or animal use. The pharmaceutically acceptable excipients include, but are not limited to, carriers, diluents, glidants and lubricants, preservatives, buffering agents, chelating agents, polymers, gelling agents, viscosifying agents, solvents and the like.
The pharmaceutical composition can be administered by oral, parenteral or inhalation routes. Examples of the parenteral administration include administration by injection, percutaneous, transmucosal, transnasal and transpulmonary administrations.
Examples of suitable carriers include, but are not limited to, water, salt solutions, alcohols, polyethylene glycols, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, amylose, magnesium stearate, talc, , agar, pectin, acacia, stearic acid, lower alkyl ethers of cellulose, silicic add, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, fatty acid esters and polyoxyethylene.
The pharmaceutical composition may also include one or more pharmaceutically acceptable auxiliary agents, wetting agents, suspending agents, preserving agents, buffers, sweetening agents, flavouring agents, colorants or any combination of the foregoing.
The pharmaceutical compositions may be in conventional forms, for example, tablets, capsules, solutions, suspensions, injectables or products for topical application. Further, the pharmaceutical composition of the present disclosure may be formulated so as to provide desired release profile.
Administration of the compounds of the disclosure, in pure form or in an appropriate pharmaceutical composition, can be carried out using any of the accepted routes of administration of pharmaceutical compositions. The route of administration may be any route which effectively transports the active compound of the present disclosure to the appropriate or desired site of action. Suitable routes of administration include, but are not limited to, oral, nasal, buccal, dermal, intradermal, transdermal, parenteral, rectal, subcutaneous, intravenous, intraurethral, intramuscular or topical.
Solid oral formulations include, but are not limited to, tablets, capsules (soft or hard gelatin), dragees (containing the active ingredient in powder or pellet form), troches and lozenges.
Liquid formulations include, but are not limited to, syrups, emulsions and sterile injectable liquids, such as suspensions or solutions.
Topical dosage forms of the compounds include ointments, pastes, creams, lotions, powders, solutions, eye or ear drops, impregnated dressings and may contain appropriate conventional additives such as preservatives, solvents to assist drug penetration.
The pharmaceutical compositions of the present disclosure may be prepared by conventional techniques known in literature.
Suitable doses of the compounds for use in treating the diseases or disorders described herein can be determined by those skilled in the relevant art. Therapeutic doses are generally identified through a dose ranging study in humans based on preliminary evidence derived from the animal studies. Doses must be sufficient to result in a desired therapeutic benefit without causing unwanted side effects. Mode of administration, dosage forms and suitable pharmaceutical excipients can also be well used and adjusted by those skilled in the art. All changes and modifications are envisioned within the scope of the present disclosure.
In some embodiments, the compounds as disclosed in the present disclosure are formulated for pharmaceutical administration.
In some embodiments, the disclosure provides the use of the compounds as described above in the treatment and prevention of diseases or conditions responsive to the inhibition of PKMYT1 activity.
In some embodiments, use of the compound or a pharmaceutically acceptable salt thereof, in treating and/or preventing a disease is provided, for which the symptoms thereof are treated, improved, diminished and/or prevented by inhibition of PKMYT1.
In some embodiments, the PKMYT1 mediated disorder and/or disease or condition is cancer.
In some embodiments, compounds of formula (I) for use in the treatment of cancer are provided.
In some embodiments, the subject is a mammal including human.
In some embodiments, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer thereof, for use as a medicament.
In some embodiments, the disclosure provides the use of the compounds of the present disclosure in the manufacture of a medicament.
In some embodiments, the disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer thereof, for use in the treatment of cancer.
In some embodiments, the disclosure provides the use of the compounds of the present disclosure in the manufacture of a medicament for the treatment of diseases and/or disorder responsive to the inhibition of PKMYT1 activity.
In some embodiments, the disclosure provides the use of the compounds of the present disclosure in the manufacture of a medicament for the treatment of cancer.
In some embodiments, the disorder and/or disease or condition is cancer caused by the overexpression of CCNE1 or having an inactivating mutation in the FBXW7 gene.
In some embodiments, the disorder and/or disease or condition is cancer caused by deficiency in FBXW7 gene.
In some embodiments, the cancer is selected from the group consisting of uterine cancer, ovarian cancer, breast cancer, stomach cancer, glioblastoma, hepatocellular carcinoma,
neuroblastoma, prostate cancer, colorectal cancer, lung cancer, esophageal cancer and endometrial cancer.
In some embodiments, the cancers caused by overexpression of CCNE1 include but not limited to uterine cancer, ovarian cancer, breast cancer, stomach cancer, lung cancer, esophageal cancer and endometrial cancer.
In some embodiments, the cancers caused by deficiency in FBXW7 include, e.g., uterine cancer, lung cancer, breast cancer, colorectal cancer and esophageal cancer.
In some embodiments, the disclosure provides a method of treating a disease or disorder mediated by PKMYT1 in a subject comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or a stereoisomer thereof.
According to the preceding embodiment, the said disease or disorder is cancer.
In some embodiments, the disclosure provides compounds for use as a medicament for treating a subject suffering from diseases or conditions responsive to the inhibition of PKMYT1 activity.
In some embodiments, the disclosure comprises administering to the subject in need thereof a therapeutically effective amount of a compound of the present disclosure along with one or more additional chemotherapeutic agents independently selected from anti-proliferative agents, anti-cancer agents, immunosuppressant agents and pain-relieving agents.
The method(s) of treatment of the present disclosure generally comprises administering a safe and effective amount of a compound according to formula (I) or a pharmaceutically acceptable salt thereof to a patient (particularly a human) in need thereof.
Compounds of the disclosure are indicated both in the therapeutic and/or prophylactic treatment of the above-mentioned conditions. For the above-mentioned therapeutic uses the dosage administered will typically vary with the compound employed, the mode of administration, the treatment desired and the disorder or disease indicated.
The compounds of the present disclosure may be used as single drug or as a pharmaceutical composition in which the compound is mixed with various pharmacologically acceptable materials.
In some embodiments, the compounds of the present disclosure can also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such
compounds. For example, the present disclosure also embraces isotopically-labeled variants of the present disclosure which are identical to those recited herein, but for the fact that one or more atoms of the compound are replaced by an atom having the atomic mass or mass number different from the predominant atomic mass or mass number usually found in nature for the atom. All isotopes of any particular atom or element as specified are contemplated within the scope of the compounds of the disclosure and their uses. Exemplary isotopes that can be incorporated in to compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine and iodine, such as
. Isotopically labeled compounds of
the present disclosure can generally be prepared by following procedures analogous to those disclosed in the schemes and/or in the examples herein below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
EXPERIMENTAL
The present application provides methods for the preparation of compound of formula (I) according to the description provided herein using appropriate methods and/or materials. It is to be understood by those skilled in the art that known variations of the conditions and processes of the following procedures can be used to prepare these intermediates and compounds. Moreover, by utilizing the procedures described in detail, one of ordinary skill in the art can prepare additional compounds of the present disclosure.
Following general guidelines apply to all experimental procedures described here. Until otherwise stated, experiments are performed under positive pressure of nitrogen, temperature described are the external temperature (i.e. oil bath temperature). Reagents and solvents received from vendors are used as such without any further drying or purification. Molarities mentioned here for reagents in solutions are approximate as it was not verified by a prior titration with a standard. All reactions are stirred under magnetic stir bar. Cooling to minus temperature was done by acetone / dry ice or wet ice / salts. Magnesium sulfate and sodium sulfate were used as solvent drying agent after reaction work up and are interchangeable. Removing of solvents under reduced pressure or under vacuum means distilling of solvents in rotary evaporator.
Compounds of this disclosure may be made by synthetic chemical processes, examples of which are shown herein. It is meant to be understood that the order of the steps in the processes may be varied, that reagents, solvents and reaction conditions may be substituted for
those specifically mentioned and that vulnerable moieties may be protected and deprotected, as necessary.
The specifics of the process for preparing compounds of the present disclosure are detailed in the experimental section.
The present disclosure shall be illustrated by means of some examples, which are not construed to be viewed as limiting the scope of the disclosure.
Unless otherwise stated, work-up includes distribution of the reaction mixture between the organic and aqueous phases, separation of layers and drying the organic layer over anhydrous sodium sulphate, filtration and evaporation of the solvent. Purification, unless otherwise mentioned, includes purification by silica gel chromatographic techniques, generally using ethyl acetate/petroleum ether mixture of a suitable polarity as the mobile phase.
Analysis for the compounds of the present disclosure unless mentioned, was conducted in general methods well known to a person skilled in the art. Having described the disclosure with reference to certain preferred embodiments, other embodiments will become apparent to one skilled in the art from consideration of the specification. The disclosure is further defined by reference to the following examples, describing in detail the analysis of the compounds of the disclosure.
It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the disclosure. Some of the intermediates were taken to next step based on TLC results, without further characterization, unless otherwise specified.
GENERAL SYNTHETIC SCHEMES:
Certain compounds of the present invention can be made by following the process as given in General scheme- 1 or 2.
As depicted in the above general scheme- 1, intermediate GSi-1 was coupled with GSi-2 in presence of sulfolane under appropriate conditions to afford GSi-3, which was further reacted with malononitrile in presence of suitable conditions like base and a solvent (NaOtBu, sulfolane, NaH, and THF) to afford GSi-4. The intermediate GSi-4 was hydrolysed and was demethylated under appropriate conditions (MeSOsH, H2SO4, and DL-Methionine) to afford the compound of formula (I).
General Scheme-2:
As depicted in the above general scheme-2, intermediate GS2-I was coupled with GSz-2 under the appropriate conditions (CS2CO3 and DMF) to afford GS2-3, which was further reacted with
the reactant R4-Lg under appropriate conditions to undergo the Suzuki coupling or Buchwald coupling, to afford intermediate GS2-4. The intermediate GS2-4 subjected to thiation under appropriate conditions (P2S5, suitable solvent (toluene or pyridine or 1,4-dioxane), OR Lawesson’s Reagent and sutitable solvent (toluene)), to afford the intermediate GS2-5 via step 2a and step 2b. Alternatively GSi-3 directly affords intermediate GS2-5 via step 2 under appropriate thiation conditions. The intermediate GS2-5 was methylated by reacting under suitable conditions (Mel, and acetone) to form intermediate GS2-6 which was further reacted with malononitrile under suitable conditions in presence of an appropriate base and a solvent (NaOtBu, sulfolane, NaH, and THF) to afford GS2-7. Further the intermediate GS2-7 was hydrolysed and was demethylated under appropriate conditions (MeSO3H, H2SO4, and DL- Methionine) to afford the compound of formula (I).
Alternatively GS2-7 on reacting under the basic hydrolysis condition will afford intermediate GS2-8 which is further demethylated under appropriate conditions (BBr3 and DCM) to afford the compound of formula (I).
SYNTHESIS OF INTERMEDIATES
Step-1: Synthesis of 3-bromo-2,6-dimethylbenzoic acid (1-1)
To a stirred solution of 2,6-dimethylbenzoic acid (49 g, 326.27 mmol, 1.0 equiv.) in TFA (400 mL), was added NBS (58.07 g, 326.27 mmol, 1.0 equiv.) and stirred at 50 °C for 16 hours. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction
mixture was poured into ice-cold water and filtered. The solid obtained was then dried under high vacuum to afford the intermediate 1-1 (70 g) as white solid.
Step-2: Synthesis of 3-methoxy-2,6-dimethylbenzoic acid (1-2)
To a stirred solution of an intermediate 1-1 (70 g, 305.58 mmol, 1.0 equiv.) in DMF (250 mL), was added CuBr (4.38 g, 143.45 mmol, 0.1 equiv.) followed by dropwise addition of NaOMe (25% in MeOH) (198 mL, 916.74 mmol, 3 equiv.) over a period of 35 minutes and stirred at 95 °C for 6 hours. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with EtOAc (3x), washed with IN HC1 (2x) and saturated NH4CI (2x) solution. Combined organic layers were washed with brine and dried over anhydrous sodium sulphate. The filtered organic layer was concentrated to obtain the intermediate 1-2 (51 g) as an off-white solid.
Step-3: Synthesis of (3-methoxy-2,6-dimethylphenyl)methanol (1-3)
To a stirred solution of an intermediate 1-2 (25 g, 180.2 mmol, 1.0 equiv.) in THF (250 mL) LAH solution (2M in THF) (208 mL, 416.2 mmol, 3 equiv.) was added slowly dropwise over period of 30 minutes and stirred at 70 °C for 16 hours. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was quenched with sat. Na2SO4 solution and filtered through celite bed. The filtrate was dried over anhydrous sodium sulphate. The filtered organic layer was concentrated to obtain the intermediate 1-3 (17 g) as an off-white solid.
Step-4: Synthesis of 2-(bromomethyl)-4-methoxy-1,3-dimethylbenzene (1-4)
To a stirred solution of an intermediate 1-3 (17 g, 102.27 mmol, 1.0 equiv.) in diethyl ether (400 mL), BBr3 (10.68 mL, 112.5 mmol, 1.1 equiv.), was added slowly dropwise over period of 1 hour at 0 °C and then stirred at RT for 1 hour. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was extracted with diethyl ether
(3x). Combined organic layers were washed with brine and dried over anhydrous sodium sulphate. The filtered organic layer was concentrated to obtain the intermediate 1-4 (15 g) as an off-white solid.
1HNMR (400 MHz, DMSOd6 ): 57.02 (d, J= 8.4 Hz, 1H), 6.85 (d, J= 8.4 Hz, 1H), 4.69 (s, 2H), 3.75 (s, 3H), 2.25 (s, 3H), 2.20 (s, 3H).
Step-1: Synthesis of l-(3-methoxy-2,6-dimethylbenzyl)-5-methylpyridin-2(lH)-one (I- 11)
To a stirred solution of 5-methylpyridin-2(lH)-one (1 g, 9.16 mmol, 1.0 equiv.) in DMF (20 mL), were added intermediate 1-4 (2.09 g, 9.16 mmol, 1 equiv.), cesium carbonate (8.96 g, 27.48 mmol, 5 equiv.) and stirred at RT for 3 hours. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was poured into ice-cold water and extracted with EtOAc (4x). Combined organic layers were washed with brine and dried over anhydrous sodium sulphate. The filtered organic layer was concentrated under reduced pressure to obtain the intermediate 1-11 (2 g) as an off-white solid.
1HNMR (400 MHz, DMSO-d6): 7.25 (d, J= 2.4 Hz, 1H), 7.10 (d, J= 2.4 Hz, 1H), 6.91 (d, J = 8.0 Hz, 1H), 6.62 (s, 1H), 6.40 (d, J= 9.2 Hz, 1H), 5.05 (s, 2H), 3.79 (s, 3H), 2.15 (s, 3H), 2.06 (s, 3H), 1.90 (s, 3H): LC-MS: m/z 258.1 (M+H)+
Step-2: Synthesis of l-(3-methoxy-2,6-dimethylbenzyl)-5-methylpyridine-2(lH)-thione (1-12)
To a stirred solution of intermediate 1-11 (2 g, 7.77 mmol, 1 equiv.) in pyridine (20 mL), were added P2S5 (6.9 g, 15.54 mmol, 2 equiv.) and sodium bicarbonate (6.5 g, 77.7 mmol, 10 equiv.) at RT. Then the reaction mixture was stirred at 100 °C for 16 hours. Progress of the reaction was monitored by TLC and LC-MS. The reaction mixture was cooled to RT and poured into water and extracted with EtOAc (4x). Combined organic layers were washed with brine and dried over anhydrous sodium sulphate. The filtered organic layer was concentrated under reduced pressure to give crude product, which was purified by combi-flash column chromatography using ethyl acetate in hexane to afford the intermediate 1-12 (0.9 g) as yellow solid.
1HNMR (400 MHz, DMSO-d6): 7.51 (d, J= 8.8 Hz, 1H), 7.21 (d, J= 10.8 Hz, 1H), 7.13 (d, J= 8.4 Hz, 1H), 6.97-6.95 (m, 2H), 5.58 (s, 2H), 3.79 (s, 3H), 2.18 (s, 3H), 2.13 (s, 3H), 2.00 (s, 3H): LC-MS: m/z 274.1 (M+H)+.
Step-3: Synthesis of l-(3-methoxy-2,6-dimethylbenzyl)-5-methyl-2-(methylthio)pyridin- 1-ium iodide (1-13)
To a stirred solution of Intermediate 1-12 (0.9 g, 3.29 mmol, 1 equiv.) in acetone (20 mL), was added lodomethane (0.93 g, 6.58 mmol, 2 equiv.). The resultant reaction mixture was stirred at 60 °C for 2 hours. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to afford the intermediate 1-13 (0.9 g) as yellow solid.
LC-MS: m/z 288.0 (M)+(Salt fragment)
Step-4: Synthesis of 2-amino-3-(3-methoxy-2,6-dimethylphenyl)-6-methylindolizine-l- carbonitrile (1-14)
To a stirred solution of malononitrile (0.4 g, 6.24 mmol, 2 equiv.) in THF (15 mL), was added NaH (0.4 g, 6.24 mmol, 2 equiv.) at 0 °C and stirred at same temperature for 30 minutes. Intermediate 1-13 (0.9 g, 3.12 mmol, 1 equiv.) in sulfolane (5 mL) was added to it dropwise at 0 °C. The resultant reaction mixture was heated to 70 °C and stirred for 16 hours. Progress of the reaction was monitored by TLC. After the completion of reaction, the reaction mixture was cooled to RT, quenched with sat. NH4CI solution and extracted with EtOAc (4x). Combined organic layers were washed with brine and dried over anhydrous sodium sulphate. The filtered organic layer was concentrated to obtain the crude, the resultant crude was purified by combi-
flash column chromatography using ethyl acetate in hexane to afford the intermediate 1-14 (0.3 g) as light-yellow solid.
1HNMR (400 MHz, DMSO-d6 ): 7.35 (d, J= 9.2 Hz, 1H), 7.21 (d, J= 8.4 Hz, 1H), 7.06-7.03 (m, 2H), 6.91 (d, J= 10.0 Hz, 1H), 4.78 (brs, 2H), 3.83 (s, 3H), 2.15 (s, 3H), 1.87 (s, 3H), 1.80 (s, 3H); LC-MS: m/z 306.2 (M+H)+.
Step-1: Synthesis of 2-(3-methoxy-2,6-dimethylbenzyl)-5,6-dimethylpyridazin-3(2H)-one (1-15)
To a stirred solution of 5,6-dimethylpyridazin-3(2H)-one (2 g, 16.11 mmol, 1.0 equiv.) in DMF (20 mL), were added intermediate 1-4 (3.32 g, 14.5 mmol, 0.9 equiv.), cesium carbonate (15.7 g, 40.33 mmol, 3 equiv.) and stirred at RT for 3 hours. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was poured into ice-cold water and extracted with EtOAc (4x). Combined organic layers were washed with brine and dried over anhydrous sodium sulphate. The filtered organic layer was concentrated under reduced pressure to give crude product, which was purified by combi-flash column chromatography using 30% ethyl acetate in hexane to afford the intermediate 1-15 (2.2 g) as an off-white solid.
1HNMR (400 MHz, DMS0-d6 ): 6.98 (d, J= 8.4 Hz, 1H), 6.81 (d, J= 8.4 Hz, 1H), 6.72 (s, 1H), 5.20 (s, 2H), 3.74 (s, 3H), 2.26 (s, 3H), 2.12 (s, 3H), 2.09 (s, 3H), 2.08 (s, 3H): LC-MS: m/z 273.1 (M+H)+
Step-2: Synthesis of 2-(3-methoxy-2,6-dimethylbenzyl)-5,6-dimethylpyridazine-3(2H)- thione (1-16)
To a stirred solution of intermediate 1-15 (2.2 g, 8.07 mmol, 1 equiv.) in toluene (20 mL) was added P2S5 (6.6 g, 14.87 mmol, 1.8 equiv.) at RT. Then the reaction mixture was stirred at 100 °C for 16 hours. Progress of the reaction was monitored by TLC and LC-MS. The reaction mixture was cooled to RT and poured into water and extracted with EtOAc (4x). Combined organic layers were washed with brine and dried over anhydrous sodium sulphate. The filtered organic layer was concentrated under reduced pressure to give crude product, which was purified by combi-flash column chromatography using ethyl acetate in hexane to afford the intermediate 1-16 (1.3 g) as yellow solid.
1HNMR (400 MHz, DMSO-d6 ): 7.65 (s, 1H), 7.01 (d, J= 8.4 Hz, 1H), 6.84 (d, J= 8.4 Hz, 1H), 5.73 (s, 2H), 3.75 (s, 3H), 2.21 (s, 3H), 2.11 (s, 3H), 2.10 (s, 3H), 2.07 (s, 3H): LC-MS: m/z 289.1 (M+H)+
Step-3: Synthesis ooff l-(3-methoxy-2,6-dimethylbenzyl)-3,4-dimethyl-6-
(methylthio)pyridazin-l-ium iodide (1-17)
To a stirred solution of Intermediate 1-16 (1.3 g, 4.51 mmol, 1 equiv.) in acetone, was added lodomethane (1.27 g, 9.01 mmol, 2 equiv.). the resultant reaction mixture was stirred at 60 °C for 4 hours. Progress of the reaction was monitored by TLC. After completion of the reaction, reaction mixture was concentrated under reduced pressure to afford the intermediate 1-17 (1.5 g) as yellow solid.
1HNMR (400 MHz, DMSO-d6 ): 8.37 (s, 1H), 7.10 (d, J= 8.4 Hz, 1H), 6.96 (d, J= 8.4 Hz, 1H), 5.67 (s, 2H), 3.78 (s, 3H), 3.0 (s, 3H), 2.52 (s, 3H), 2.39 (s, 3H), 2.18 (s, 3H), 2.07 (s, 3H): LC-MS: m/z 303.0 (M)+ (Salt fragment)
Step-4: Synthesis ooff 6-amino-7-(3-methoxy-2,6-dimethylphenyl)-2,3- dimethylpyrrolo[l,2-b]pyridazine-5-carbonitrile (1-18)
To a stirred solution of malononitrile (1.63 g, 24.74 mmol, 5 equiv.) in THF (30 mL), was added NaH (1.7 g, 74.14 mmol, 15 equiv.) at 0 °C and stirred at same temperature for 30 minutes. Intermediate 1-17 (1.5 g, 4.94 mmol, 1 equiv.) in sulfolane (15 mL) was added dropwise into the above reaction mixture at 0 °C. The resultant reaction mixture was heated to 80 °C and stirred for 16 hours. Progress of the reaction was monitored by TLC. After the completion of reaction, the reaction mixture was cooled to RT, quenched with sat. NH4CI solution and extracted with EtOAc (4x). Combined organic layers were washed with brine and
dried over anhydrous sodium sulphate. The filtered organic layer was concentrated to obtain the intermediate 1-18 (0.55 g) as light-yellow liquid.
1HNMR (400 MHz, DMSO-d6 ): 7.69 (s, 1H), 7.13 (d, J= 8.4 Hz, 1H), 6.97 (d, J= 8.4 Hz, 1H), 4.91 (brs, 2H), 3.81 (s, 3H), 2.29 (s, 3H), 2.26 (s, 3H), 1.88 (s, 3H), 1.78 (s, 3H); LC- MS: m/z 321.0 (M+H)+.
Step-1: Synthesis of 6-chloro-2-(3-methoxy-2,6-dimethylbenzyl)-5-methylpyridazin- 3(2H)-one (1-19)
To a stirred solution of 6-chloro-5-methylpyridazin-3(2H)-one (1.5 g, 10.37 mmol, 1.0 equiv.) inDMF (15 mL), were added intermediate 1-4 (2.37 g, 10.37 mmol, 1 equiv.), cesium carbonate (10.14 g, 31.12 mmol, 3 equiv.) and stirred at RT for 3 hours. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was poured into ice- cold water and extracted with EtOAc (4x). Combined organic layers were washed with brine and dried over anhydrous sodium sulphate. The filtered organic layer was concentrated under reduced pressure to give crude product, which was washed with diethyl ether and dried under high vacuum to afford intermediate 1-19 (3 g) as an off-white solid.
1HNMR (400 MHz, DMS0-d6 ): 7.01 (d, J= 8.4 Hz, 2H), 6.84 (d, J= 8.0 Hz, 1H), 5.21 (s, 2H), 3.74 (s, 3H), 2.20 (s, 3H), 2.16 (s, 3H), 2.10 (s, 3H): LC-MS: m/z 293.0 (M+H)+
Step-2: Synthesis ooff 6-(cyclohex-l-en-l-yl)-2-(3-methoxy-2,6-dimethylbenzyl)-5- methylpyridazin-3(2H)-one (1-20)
To a stirred solution of intermediate 1-19 (1 g, 3.4 mmol, 1.0 equiv.) in 1,4-dioxane (8 mL) and water (2 mL), were added 1-Cyclohexen-l-yl-boronic acid pinacol ester (2.13 g, 10.25 mmol, 3.0 equiv.), sodium carbonate (1.45 g, 10.24 mmol, 4 equiv.) and degassed the mixture for 5 minutes with argon. Then Pd(dppf)Ch (0.28 g, 0.34 mmol, 0.1 equiv.) was added to the reaction mixture and again degassed for 5 minutes. The resultant reaction mixture was stirred at 80 °C for 16 hours. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with EtOAc (4x) and washed with water. Combined organic layers were washed with brine and dried over anhydrous sodium sulphate. The filtered organic layer was concentrated under reduced pressure to give crude product, the resultant crude was purified by combi flash using 20% EtOAc in Hexane as eluent to get the compound 1-20 (1.1 g) as an off-white solid.
1HNMR (400 MHz, DMSO-d6 ): 7.01-6.98 (m, 1H), 6.83-6.77 (m, 2H), 5.81 (m, 1H), 5.23 (s, 2H), 3.94 (s, 3H), 3.74 (s, 3H), 2.25 (s, 3H), 2.16 (s, 3H), 2.14-2.03 (m, 4H), 1.56-1.54 (m, 4H); LC-MS: m/z 339.2 (M+H)+.
Step-3: Synthesis ooff 6-(cyclohex-l-en-l-yl)-2-(3-methoxy-2,6-dimethylbenzyl)-5- methylpyridazine-3(2H)-thione (1-21)
To a stirred solution of intermediate 1-20 (1 g, 2.95 mmol, 1 equiv.) in toluene (25 mL) was added P2S5 (2.63 g, 5.91 mmol, 2 equiv.) and stirred at 100 °C for 16 hours. Progress of the reaction was monitored by TLC. The reaction mixture was cooled to RT and poured into water and extracted with EtOAc (4x). Combined organic layers were washed with brine and dried over anhydrous sodium sulphate. The filtered organic layer was concentrated under reduced pressure to give crude product, the resultant crude was purified by combi-flash column chromatography using 10% ethyl acetate in hexane as eluent to afford the intermediate 1-210.4 g) as light-yellow liquid.
LC-MS: m/z 355.2 (M+H)+.
Step-4: Synthesis of 3-(cyclohex-l-en-l-yl)-l-(3-methoxy-2,6-dimethylbenzyl)-4-methyl- 6-(methylthio)pyridazin-l-ium iodide (1-22)
To a stirred solution of Intermediate 1-21 (0.3g g, 0.85 mmol, 1 equiv.) in acetone (6 mL), was added iodomethane (1.8 g, 4.23 mmol, 5 equiv.). The resultant reaction mixture was stirred at 70 °C for 16 hours. Progress of the reaction was monitored by TLC. After completion of the
reaction, reaction mixture was concentrated under reduced pressure to afford the intermediate 1-22 (0.3 g) as yellow solid.
LC-MS: m/z 369.1 (M)+ (Salt fragment)
Step-5: Synthesis of 6-amino-2-(cyclohex-l-en-l-yl)-7-(3-methoxy-2,6-dimethylphenyl)- 3-methylpyrrolo[l,2-b]pyridazine- 5- carbonitrile (1-23)
To a stirred solution of malononitrile (0.27 g, 4.05 mmol, 5 equiv.) in THF (3 mL), was added NaH (0.37 g, 16.2 mmol, 20 equiv.) at 0 °C and stirred at same temperature for 30 minutes. Intermediate 1-22 (0.3 g, 0.81 mmol, 1 equiv.) in sulfolane (1.5 mL) was added dropwise to the above reaction mixture at 0 °C. The resultant reaction mixture was heated to 70 °C and stirred for 16 hours. Progress of the reaction was monitored by TLC. After the completion of reaction, the reaction mixture was cooled to RT, quenched with sat. NH4CI solution and extracted with EtOAc (4x). Combined organic layers were washed with brine and dried over anhydrous sodium sulphate. The filtered organic layer was concentrated to obtain the crude. The resultant crude was purified by combi-flash column chromatography using 30% ethyl acetate in hexane as eluent to afford the intermediate 1-23 (0.24 g) as light-yellow liquid.
1HNMR (400 MHz, DMSO-d6 ): 7.74 (s, 1H), 7.14 (d, J= 8.4 Hz, 1H), 6.98 (d, J= 8.4 Hz, 1H), 5.76 (s, 1H), 5.21 (brs, 2H), 3.81 (s, 3H), 2.82 (s, 3H), 2.11-2.10 (m, 4H), 1.89 (s, 3H), 1.81 (s, 3H), 1.65-1.63 (m, 4H); LC-MS: m/z 387.1 (M+H)+.
Synthesis of intermediates 1-24 to 1-27:
Step-1: Synthesis ooff 2-(3-methoxy-2,6-dimethylbenzyl)-5-methyl-6-(pyrrolidin-l- yl)pyridazin-3(2H)-one (1-24)
To a stirred solution of intermediate 1-19 (0.8 g, 2.73 mmol, 1.0 equiv.) in toluene (8 mL), was added pyrrolidine (0.39 g, 5.47 mmol, 2.0 equiv.), cesium carbonate (2.67 g, 8.19 mmol, 3 equiv.) and degassed the mixture for 5 minutes with argon. Then BINAP (0.34 g, 0.54 mmol, 0.2 equiv.) and Pd(OAc)2 were added to the reaction mixture and again degassed for 5 minutes. The resultant reaction mixture was stirred at 80 °C for 16 hours. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with EtOAc (4x) and washed with water. Combined organic layers were washed with brine and dried over anhydrous sodium sulphate. The filtered organic layer was concentrated under reduced pressure to give crude product, the resultant crude was purified by combi flash using 50% EtOAc in Hexane as eluent to get the compound 1-24 (0.8 g) as yellow solid. LC-MS: m/z 328.2 (M+H)+
Step-2: Synthesis ooff 2-(3-methoxy-2,6-dimethylbenzyl)-5-methyl-6-(pyrrolidin-l- yl)pyridazine-3(2H)-thione (1-25)
To a stirred solution of intermediate 1-24 (0.2 g, 0.61 mmol, 1 equiv.) in toluene (2 mL), was added Lawesson’s reagent (0.37 g, 0.91 mmol, 1.5 equiv.) and stirred at 100 °C for 16 hours. Progress of the reaction was monitored by TLC. The reaction mixture was cooled to RT and poured into water and extracted with EtOAc (4x). Combined organic layers were washed with brine and dried over anhydrous sodium sulphate. The filtered organic layer was concentrated under reduced pressure to give crude product, the resultant crude was purified by combi-flash column chromatography using 10% ethyl acetate in hexane as eluent to afford the intermediate 1-25 (0.08 g) as yellow solid.
LC-MS: m/z 344.2 (M+H)+
Step-3: Synthesis of l-(3-methoxy-2,6-dimethylbenzyl)-4-methyl-6-(methylthio)-3- (pyrrolidin-l-yl)pyridazin-l-ium (1-26)
To a stirred solution of Intermediate 1-25 (0.08g, 0.23 mmol, 1 equiv.) in acetone (2 mL), was added iodomethane (0.06 g, 0.46 mmol, 2 equiv.). The resultant reaction mixture was stirred at 70 °C for 2 hours. Progress of the reaction was monitored by TLC. After completion of the reaction, reaction mixture was concentrated under reduced pressure to afford the intermediate 1-26 (0.3 g) as yellow solid.
Step-4: Synthesis of 6-amino-7-(3-methoxy-2,6-dimethylphenyl)-3-methyl-2-(pyrrolidin- l-yl)pyrrolo[l,2-b]pyridazine-5-carbonitrile (1-27)
To a stirred solution of malononitrile (0.6 g, 9.08 mmol, 5.4 equiv.) in THF (6 mL), was added NaH (0.6 g, 26.09 mmol, 15.6 equiv.) at 0 °C and stirred at same temperature for 30 minutes. Intermediate 1-26 (0.6 g, 1.67 mmol, 1 equiv.) in sulfolane (2 mL) was added to it dropwise at 0 °C. The resultant reaction mixture was heated to 70 °C and stirred for 16 hours. Progress of the reaction was monitored by TLC. After the completion of reaction, the reaction mixture was cooled to RT, quenched with sat. NH4CI solution and extracted with EtOAc (4x). Combined organic layers were washed with brine and dried over anhydrous sodium sulphate. The filtered organic layer was concentrated to obtain the crude. The resultant crude was purified by combi- flash column chromatography using 50% ethyl acetate in hexane as eluent to afford the intermediate 1-27 (0.5 g) as light-yellow liquid.
1HNMR (400 MHz, DMSO-d6 ): 7.54 (s, 1H), 7.01 (d, J= 8.4 Hz, 1H), 6.93 (d, J= 8.4 Hz, 1H), 4.64 (s, 2H), 3,78 (s, 3H), 3.22-3.18 (m, 4H), 2.33 (s, 3H), 1.90 (s, 3H), 1.86 (s, 3H), 1.78-1.76 (m, 4H); LC-MS: m/z 376.0 (M+H)+.
Step-1: Synthesis of 5,6-dichloro-2-(3-methoxy-2,6-dimethylbenzyl)pyridazin-3(2H)-one (1-28)
To a stirred solution of 5,6-dichloropyridazin-3(2H)-one (6 g, 36.37 mmol, 1.0 equiv.) in DMF (150 mL), were added intermediate 1-4 (7.5 g, 32.73 mmol, 0.9 equiv.), cesium carbonate (36.5 g, 325.82 mmol, 3 equiv.) and stirred at RT for 3 hours. Progress of the reaction was monitored
by TLC. After completion of the reaction, the reaction mixture was poured into ice-cold water and extracted with EtOAc (4x). Combined organic layers were washed with brine and dried over anhydrous sodium sulphate. The filtered organic layer was concentrated under reduced pressure to give crude product, which was washed with diethyl ether and dried under high vacuum to afford intermediate 1-28 (8.7 g) as yellow solid.
1HNMR (400 MHz, DMSO-d6 ): 7.53 (s, 1H), 7.02 (d, J= 8.4 Hz, 1H), 6.86 (d, J= 8.4 Hz, 1H), 5.22 (s, 2H), 3.75 (s, 3H), 2.24 (s, 3H), 2.10 (s, 3H): LC-MS: m/z 313.0 (M+H)+
Step-2: Synthesis ooff 6-chloro-5-(4-fluorophenyl)-2-(3-methoxy-2,6- dimethylbenzyl)pyridazin-3(2H)-one (1-29)
To a stirred solution of intermediate 1-28 (1 g, 3.19 mmol, 1.0 equiv.) in 1,4-dioxane (13 Ml), were added 4-fluorophenyl boronic acid (0.45 g, 3.19 mmol, 1.0 equiv.), potassium phosphate tribasic (1.36 g, 6.38 mmol, 2 equiv.) and degassed the mixture for 5 minutes with argon. Then Pd(dppf)C12 (0.26 g, 0.31 mmol, 0.1 equiv.) was added to the reaction mixture and again degassed for 5 minutes. The resultant reaction mixture was stirred at 80 °C for 16 hours. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with EtOAc (4x) and washed with water. Combined organic layers were washed with brine and dried over anhydrous sodium sulphate. The filtered organic layer was concentrated under reduced pressure to give crude product, the resultant crude was purified by combi flash using 20% EtOAc in Hexane as eluent to get the compound 1-29 (0.75 g) as yellow solid.
1HNMR (400 MHz, DMSO-d6 ): 8.08 (d, J= 4.4 Hz, 1H), 7.86-7.82 (m, 1H), 7.60-7.53 (m, 1H), 7.35-7.31 (m, 1H), 7.17-7.13 (m, 1H), 7.08-7.03 (m, 1H), 7.88-7.86 (m, 1H), 5.30 (s, 2H), 3.76 (s, 3H), 2.34 (s, 3H), 2.16 (s, 3H): LC-MS: m/z 373.2 (M+H)+
Step-3: Synthesis ooff 5-(4-fluorophenyl)-2-(3-methoxy-2,6-dimethylbenzyl)-6- methylpyridazin-3(2H)-one (1-30)
To a stirred solution of intermediate 1-29 (0.75 g, 2.01 mmol, 1.0 equiv.) in 1,4-dioxane (8 mL), were added trimethylboroxine (0.76 g, 6.03 mmol, 3.0 equiv.), potassium phosphate tribasic (1.28 g, 6.03 mmol, 3 equiv.) and degassed the mixture for 5 minutes with argon. Then Pd(dppf)C12 (0.16 g, 0.2 mmol, 0.1 equiv.) was added to the reaction mixture and again degassed for 5 minutes. The resultant reaction mixture was stirred at 110 °C for 16 hours.
Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with EtOAc (4x) and washed with water. Combined organic layers were washed with brine and dried over anhydrous sodium sulphate. The filtered organic layer was concentrated under reduced pressure to give crude product, the resultant crude was purified by combi flash using 30% EtOAc in Hexane as eluent to get the compound 1-30 (0.38 g) as yellow solid.
1HNMR (400 MHz, DMSO-d6 ): 8.08 (s, 1H), 7.85-7.82 (m, 1H), 7.54-7.51 (m, 1H), 7.33- 7.28 (m, 1H), 7.17-7.12 (m, 1H), 7.03-7.01 (m, 1H), 6.83 (d, J= 8.4 Hz, 1H), 5.29 (s, 2H), 3.75 (s, 3H), 2.36 (s, 3H), 2.20 (s, 3H), 2.05 (s, 3H): LC-MS: m/z 353.2 (M+H)+
Step-4: Synthesis ooff 5-(4-fluorophenyl)-2-(3-methoxy-2,6-dimethylbenzyl)-6- methylpyridazine-3(2H)-thione (1-31)
To a stirred solution of intermediate 1-30 (0.32 g, 0.91 mmol, 1 equiv.) in toluene (5 mL), was added P2S5 (0.6 g, 1.36 mmol, 1.5 equiv.) and stirred at 90 °C for 2 hours. Progress of the reaction was monitored by TLC. The reaction mixture was cooled to RT and poured into water and extracted with EtOAc (4x). Combined organic layers were washed with brine and dried over anhydrous sodium sulphate. The filtered organic layer was concentrated under reduced pressure to give crude product, which was purified by combi-flash column chromatography using 15% ethyl acetate in hexane as eluent to afford the intermediate 1-31 (0.16 g) as yellow solid.
1HNMR (400 MHz, DMSO-d6 ): 7.62-7.57 (m, 3H), 7.34-7.30 (m, 2H), 7.04 (d, J= 8.4 Hz, 1H), 6.87 (d, J= 8.4 Hz, 1H), 5.80 (s, 2H), 3.74 (s, 3H), 2.27 (s, 3H), 2.13 (s, 3H), 2.08 (s, 3H): LC-MS: m/z 369.2 (M+H)+.
Step-5: Synthesis of 4-(4-fluorophenyl)-l-(3-methoxy-2,6-dimethylbenzyl)-3-methyl-6- (methylthio)pyridazin-l-ium iodide (1-32)
To a stirred solution of Intermediate 1-31 (0.16 g, 0.43 mmol, 1 equiv.) in acetone (4 mL), was added iodomethane (2.46 g, 17.36 mmol, 40 equiv.).The resultant reaction mixture was stirred at 60 °C for 4 hours. Progress of the reaction was monitored by TLC. After completion of the reaction, reaction mixture was concentrated under reduced pressure to afford the intermediate 1-32 (0.16 g) as yellow solid.
LC-MS: m/z 383.1 (M)+ (Salt fragment)
Step-6: Synthesis of 6-amino-3-(4-fluorophenyl)-7-(3-methoxy-2,6-dimethylphenyl)-2- methylpyrrolo[l,2-b]pyridazine-5-carbonitrile (1-33)
To a stirred solution of malononitrile (0.2 g, 3.02 mmol, 6.9 equiv.) in THF (2 mL), was added NaH (0.2 g, 8.33 mmol, 20 equiv.) at 0 °C and stirred at same temperature for 30 minutes. Intermediate 1-32 (0.17 g, 0.44 mmol, 1 equiv.) in sulfolane was added dropwise to the above reaction mixture at 0 °C. The resultant reaction mixture was heated to 70 °C and stirred for 16 hours. Progress of the reaction was monitored by TLC. After the completion of reaction, the reaction mixture was cooled to RT, quenched with sat. NH4CI solution and extracted with EtOAc (4x). Combined organic layers were washed with brine and dried over anhydrous sodium sulphate. The filtered organic layer was concentrated to obtain the crude. The resultant crude was purified by combi-flash column chromatography using 30% ethyl acetate in hexane as eluent to afford the intermediate 1-33 (0.02 g) as light-yellow liquid.
LC-MS: m/z 401.1 (M+H)+.
Step-1: Synthesis ooff 6-(4-fluorophenyl)-2-(3-methoxy-2,6-dimethylbenzyl)-5- methylpyridazin-3(2H)-one (1-34)
To a stirred solution of intermediate 1-19 (2 g, 6.83 mmol, 1.0 equiv.) in 1,4-dioxane (25 mL) and water (5 mL), were added (4-fluorophenyl)boronic acid (1.43 g, 10.25 mmol, 1.5 equiv.), potassium carbonate (3.78 g, 27.32 mmol, 4 equiv.) and degassed the mixture for 5 minutes with argon. Then Pd(dppf)Ch (0.56 g, 0.68 mmol, 0.1 equiv.) was added to the reaction mixture
and again degassed for 5 minutes. The resultant reaction mixture was stirred at 80 °C for 16 hours. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with EtO Ac (4x) and washed with water. Combined organic layers were washed with brine and dried over anhydrous sodium sulphate. The filtered organic layer was concentrated under reduced pressure to give crude product, the resultant crude was purified by combi flash using 25% EtOAc in Hexane as eluent to get the compound 1-34 (2.3 g) as yellow solid. LC-MS: m/z 353.3 (M+H)+
Step-2: Synthesis ooff 6-(4-fluorophenyl)-2-(3-methoxy-2,6-dimethylbenzyl)-5- methylpyridazine-3(2H)-thione (1-35)
To a stirred solution of intermediate 1-34 (1.8 g, 5.12 mmol, 1 equiv.) in toluene (20 mL), was added Lawesson’s reagent (3.09 g, 7.66 mmol, 1.5 equiv.) and stirred at 90 °C for 2 hours. Progress of the reaction was monitored by TLC. The reaction mixture was cooled to RT and poured into water and extracted with EtOAc (4x). Combined organic layers were washed with brine and dried over anhydrous sodium sulphate. The filtered organic layer was concentrated under reduced pressure to give crude product, which was purified by combi-flash column chromatography using 25% ethyl acetate in hexane as eluent to afford the intermediate 1-35 (1.4 g) as yellow solid.1HNMR (400 MHz, DMSO-d6 ): 7.85 (s, 1H), 7.85-7.38 (m, 2H), 7.28-7.23 (m, 2H), 7.04- 6.99 (d, J= 8.4 Hz, 1H), 6.82 (d, J= 8.4 Hz, 1H), 5.82 (s, 2H), 3.72 (s, 3H), 2.25 (s, 3H), 2.15 (s, 3H), 2.07 (s, 3H): LC-MS: m/z 369.2 (M+H)+.
Step-3: Synthesis of 3-(4-fluorophenyl)-l-(3-methoxy-2,6-dimethylbenzyl)-4-methyl-6- (methylthio)pyridazin-l-ium iodide (1-36)
To a stirred solution of Intermediate 1-35 (1.4g, 3.8 mmol, 1 equiv.) in acetone (20 mL), was added iodomethane (2.7 g, 18.9 mmol, 5 equiv.). the resultant reaction mixture was stirred at 70 °C for 3 hours. Progress of the reaction was monitored by TLC. After completion of the reaction, reaction mixture was concentrated under reduced pressure to afford the crude intermediate 1-36 (3.02 g) as yellow solid.
LC-MS: m/z 383.2 (M)+(Salt fragment)
Step-4: Synthesis of 6-amino-2-(4-fluorophenyl)-7-(3-methoxy-2,6-dimethylphenyl)-3- methylpyrrolo[l,2-b]pyridazine-5-carbonitrile (1-37)
To a stirred solution of malononitrile (0.68 g, 10.43 mmol, 4 equiv.) in THF (15 mL), was addedNaH (0.3 g, 13.04 mmol, 5 equiv.) at 0 °C and stirred at same temperature for 30 minutes. Intermediate 1-36 (3 g, 7.82 mmol, 1 equiv.) in sulfolane (15 mL) was added dropwis into the above reaction mixture e at 0 °C. The resultant reaction mixture was heated to 70 °C and stirred for 16 hours. Progress of the reaction was monitored by TLC. After the completion of reaction, the reaction mixture was cooled to RT, quenched with sat. NH4CI solution and extracted with EtOAc (4x). Combined organic layers were washed with brine and dried over anhydrous sodium sulphate. The filtered organic layer was concentrated to obtain the crude. The resultant crude was purified by combi-flash column chromatography using 35% ethyl acetate in hexane as eluent to afford the intermediate 1-37 (0.13 g) as light-yellow liquid. LC-MS: m/z 401.4 (M+H)+.
Step-1: Synthesis ooff 6-chloro-5-(cyclopent-l-en-l-yl)-2-(3-methoxy-2,6- dimethylbenzyl)pyridazin-3(2H)-one (1-38)
To a stirred solution of intermediate 1-28 (2 g, 6.39 mmol, 1.0 equiv.) in DME (40 mL) and water (8 ml), were added cyclopent- 1-en-l-ylboronic add (1.11 g, 5.75 mmol, 0.9 equiv.),
sodium carbonate (2.03 g, 19.16 mmol, 3 equiv.) and degassed the mixture for 5 minutes with argon. Then Pd(dppf)Ch (0.52 g, 0.63 mmol, 0.1 equiv.) was added to the reaction mixture and again degassed for 5 minutes. The resultant reaction mixture was stirred at 75 °C for 4 hours. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with EtOAc (4x) and washed with water. Combined organic layers were washed with brine and dried over anhydrous sodium sulphate. The filtered organic layer was concentrated under reduced pressure to give crude product, the resultant crude was purified by combi flash using 20% EtOAc in Hexane as eluent to get the compound 1-38 (0.92 g) as yellow solid.
1HNMR (400 MHz, DMSO-d6 ): 7.05 (d, J= 8.44 Hz, 1H), 6.85 (d, J= 8.4 Hz, 1H), 6.82 (d, J= 8.4 Hz, 1H), 6.67-6.69 (m, 1H), 5.21 (s, 2H), 3.73 (s, 3H), 2.65-2.49 (m, 2H), 2.49-2.47 (m, 2H), 2.23 (s, 3H), 2.09 (s, 3H), 1.95-1.85 (m, 2H): LC-MS: m/z 345.0 (M+H)+
Step-2: Synthesis of 5-(cyclopent-l-en-l-yl)-2-(3-methoxy-2,6-dimethylbenzyl)-6- methylpyridazin-3(2H)-one (1-39)
To a stirred solution of intermediate 1-38 (0.9 g, 2.61 mmol, 1.0 equiv.) in 1,4-dioxane (10 mL), were added trimethylboroxine (0.98 g, 7.83 mmol, 3.0 equiv.), potassium phosphate tribasic (1.66 g, 7.83 mmol, 3 equiv.) and degassed the mixture for 5 minutes with argon. Then Pd(dppf)C12 (0.21 g, 0.26 mmol, 0.1 equiv.) was added to the reaction mixture and again degassed for 5 minutes. The resultant reaction mixture was stirred at 100 °C for 16 hours. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with EtOAc (4x) and washed with water. Combined organic layers were washed with brine and dried over anhydrous sodium sulphate. The filtered organic layer was concentrated under reduced pressure to give crude product, the resultant crude was purified by combi flash using 30% EtOAc in Hexane as eluent to get the compound 1-39 (0.65 g) as yellow solid.
1HNMR (400 MHz, DMSO-d6 ): 6.99 (d, J= 8.4 Hz, 1H), 6.81 (d, J= 8.4 Hz, 1H), 6.68 (s, 1H), 6.30-6.29 (m, 1H), 5.23 (s, 2H), 3.74 (s, 3H), 2.63-2.59 (m, 2H), 2.58-2.56 (m, 2H), 2.27 (s, 3H), 2.20 (s, 3H), 2.13 (s, 3H), 1.93-1.87 (m, 2H): LC-MS: m/z 325.1 (M+H)+
Step-3: Synthesis of 5-cyclopentyl-2-(3-methoxy-2,6-dimethylbenzyl)-6-methylpyridazin- 3(2H)-one (1-40)
To a stirred solution of intermediate 1-39 (0.6 g, 1.85 mmol, 1 equiv.) in MeOH (10 mL), was added Pd(OH)2 (0.52 g, 3.69 mmol, 2 equiv.) and then stirred at RT for 16 hours under hydrogen atmosphere. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through celite bed. Concentrated the filterate under reduced pressure to give crude product, 1-40 (0.5 g) as yellow solid. LC-MS: m/z 327.1 (M+H)+
Step-4: Synthesis ooff 5-cyclopentyl-2-(3-methoxy-2,6-dimethylbenzyl)-6- methylpyridazine-3(2H)-thione (1-41)
To a stirred solution of intermediate 1-40 (0.5 g, 1.53 mmol, 1 equiv.) in toluene (15 mL), was added Lawesson’s reagent (0.93 g, 2.29 mmol, 1.5 equiv.) and stirred at 90 °C for 1 hours. Progress of the reaction was monitored by TLC. The reaction mixture was cooled to RT and poured into water and extracted with EtOAc (4x). Combined organic layers were washed with brine and dried over anhydrous sodium sulphate. The filtered organic layer was concentrated under reduced pressure to give crude product, which was purified by combi-flash column chromatography using 20% ethyl acetate in hexane as eluent to afford the intermediate 1-41 (0.45 g) as yellow solid.
1HNMR (400 MHz, DMSO-d6 ): 7.55 (s, 1H), 7.02 (d, J= 8.4 Hz, 1H), 6.84 (d, J= 8.4 Hz, 1H), 5.74 (s, 2H), 3.75 (s, 3H), 2.95-2.90 (m, 1H), 2.24 (s, 3H), 2.20 (s, 3H), 2.06 (s, 3H), 1.99-1.94 (m, 2H), 1.75-1.71 (m, 2H), 1.69-1.64 (m, 2H), 1.59-1.48 (m, 2H): LC-MS: m/z 343.1 (M+H)+.
Step-5: Synthesis of 4-cyclopentyl-l-(3-methoxy-2,6-dimethylbenzyl)-3-methyl-6- (methylthio)pyridazin-l-ium iodide (1-42)
To a stirred solution of Intermediate 1-41 (0.45g, 1.31 mmol, 1 equiv.) in acetone (15 mL), was added iodomethane (3.7 g, 26.28 mmol, 20 equiv.). the resultant reaction mixture was stirred at 60 °C for 4 hours. Progress of the reaction was monitored by TLC. After completion of the reaction, reaction mixture was concentrated under reduced pressure to afford the intermediate 1-42 (0.63 g) as yellow solid.
LC-MS: m/z 357.1 (M)+ (Salt fragment)
Step-6: Synthesis ooff 6-amino-3-cyclopentyl-7-(3-methoxy-2,6-dimethylphenyl)-2- methylpyrrolo[l,2-b]pyridazine-5-carbonitrile (1-43)
To a stirred solution of malononitrile (0.51 g, 7.69 mmol, 5 equiv.) in DME (10 mL), was added NaH (0.52 g, 21.53 mmol, 14 equiv.) at 0 °C and stirred at same temperature for 30 minutes. Intermediate 1-42 (0.55 g, 1.54 mmol, 1 equiv.) was added to it portionwise at 0 °C. The resultant reaction mixture was heated to 70 °C and stirred for 16 hours. Progress of the reaction was monitored by TLC. After the completion of reaction, the reaction mixture was cooled to RT, quenched with sat. NH4CI solution and extracted with EtOAc (4x). Combined organic layers were washed with brine and dried over anhydrous sodium sulphate. The filtered organic layer was concentrated to obtain the crude. The resultant crude was purified by combi- flash column chromatography using 30% ethyl acetate in hexane as eluent to afford the intermediate 1-43 (0.31 g) as light-yellow liquid.
LC-MS: m/z 375.1 (M+H)+.
Step-1: Synthesis of 6-chloro-2-(3-methoxy-2,6-dimethylbenzyl)-5-(prop-l-en-2- yl)pyridazin-3(2H)-one (1-44)
To a stirred solution of intermediate 1-28 (2.4 g, 7.66 mmol, 1.0 equiv.) in DME (100 mL) and water (18 ml), were added isopropyl boronic acid (0.56 g, 6.9 mmol, 0.9 equiv.), sodium carbonate (2.41 g, 22.98 mmol, 3 equiv.) and degassed the mixture for 5 minutes with argon. Then Pd(dppf)C12 (0.62 g, 0.76 mmol, 0.1 equiv.) was added to the reaction mixture and again degassed for 5 minutes. The resultant reaction mixture was stirred at 100 °C for 16 hours. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with EtOAc (4x) and washed with water. Combined organic layers were washed with brine and dried over anhydrous sodium sulphate. The filtered organic layer was concentrated under reduced pressure to give crude product, the resultant crude was purified by combi flash using 20% EtOAc in Hexane as eluent to get the compound 1-44 (1.8 g) as an off- white solid.
1HNMR (400 MHz, DMSO-d6 ): 7.03 (d, J= 8.4 Hz, 1H), 6.92 (s, 1H), 6.86 (d, J= 8.4 Hz, 1H), 5.35 (d, J= 2.8 Hz, 1H), 5.24 (s, 2H), 5.35 (d, J= 2.8 Hz, 1H), 3.75 (s, 3H), 2.25 (s, 3H), 2.12 (s, 3H), 2.0 (s, 3H): LC-MS: m/z 319.0 (M+H)+
Step-2: Synthesis of 2-(3-methoxy-2,6-dimethylbenzyl)-6-methyl-5-(prop-l-en-2- yl)pyridazin-3(2H)-one (1-45)
To a stirred solution of intermediate 1-44 (2.23 g, 6.99 mmol, 1.0 equiv.) in 1,4-dioxane (30 mL) and water (10 mL), were added trimethylboroxine (2.63 g, 20.98 mmol, 3.0 equiv.), potassium phosphate tribasic (4.45 g, 20.98 mmol, 3 equiv.) and degassed the mixture for 5 minutes with argon. Then Pd(dppf)Ch (0.57 g, 0.69 mmol, 0.1 equiv.) was added to the reaction mixture and again degassed for 5 minutes. The resultant reaction mixture was stirred at 100 °C for 16 hours. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with EtOAc (4x) and washed with water. Combined organic layers were washed with brine and dried over anhydrous sodium sulphate. The filtered organic layer was concentrated under reduced pressure to give crude product, the resultant crude was purified by combi flash using 40% EtOAc in Hexane as eluent to get the compound 1-45 (1.8 g) as yellow solid.
1HNMR (400 MHz, DMSO-d6 ): 6.99 (d, J= 8.4 Hz, 1H), 6.82 (d, J= 8.4 Hz, 1H), 6.68 (s, 1H), 5.28 (d, J= 2.8 Hz, 1H), 5.23 (s, 2H), 5.04 (s, 1H), 3.74 (s, 3H), 2.28 (s, 3H), 2.14 (s, 3H), 2.10 (s, 3H), 1.97 (s, 3H): LC-MS: m/z 299.0 (M+H)+
Step-3: Synthesis of 5-isopropyl-2-(3-methoxy-2,6-dimethylbenzyl)-6-methylpyridazin- 3(2H)-one (1-46)
To a stirred solution of intermediate 1-45 (1.8 g, 6.04 mmol, 1 equiv.) in MeOH (20 mL), was added Pd(OH)2 (0.67 g, 4.83 mmol, 0.8 equiv.) and then stirred at RT for 16 h under hydrogen atmosphere. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through celite bed. The filtrate was concentrated under reduced pressure to give crude product, 1-46 (1.5 g) as yellow solid.
1HNMR (400 MHz, DMSO-d6 ): 6.99 (d, J= 8.4 Hz, 1H), 6.81 (d, J= 8.4 Hz, 1H), 6.71 (d, J = 8.4 Hz, 1H), 5.20 (s, 2H), 3.74 (s, 3H), 2.82-2.75 (m, 1H), 2.27 (s, 3H), 2.14 (s, 3H), 2.12 (s, 3H), 1.13 (d, J= 6.8 Hz, 6H).
Step-4: Synthesis of 5-isopropyl-2-(3-methoxy-2,6-dimethylbenzyl)-6-methylpyridazine- 3(2H)-thione (1-47)
To a stirred solution of intermediate 1-46 (1.5 g, 4.99 mmol, 1 equiv.) in toluene (15 mL), was added Lawesson’s reagent (3.11 g, 7.68 mmol, 1.5 equiv.) and stirred at 90 °C for 1 hours. Progress of the reaction was monitored by TLC. The reaction mixture was cooled to RT and poured into water and extracted with EtOAc (4x). Combined organic layers were washed with brine and dried over anhydrous sodium sulphate. The filtered organic layer was concentrated under reduced pressure to give crude product, which was purified by combi-flash column chromatography using 20% ethyl acetate in hexane as eluent to afford the intermediate 1-47 (1.2 g) as yellow solid.
1HNMR (400 MHz, DMSO-d6 ): 7.58 (s, 1H), 7.02 (d, J= 8.4 Hz, 1H), 6.85 (d, J= 8.4 Hz, 1H), 5.74 (s, 2H), 3.82 (s, 3H), 2.86-2.82 (m, 1H), 2.20 (s, 3H), 2.18 (s, 3H), 2.08 (s, 3H), 1.18 (d, J= 6.8 Hz, 6H): LC-MS: m/z 317.0 (M+H)+.
Step-5: Synthesis ooff 4-isopropyl-l-(3-methoxy-2,6-dimethylbenzyl)-3-methyl-6- (methylthio)pyridazin-l-ium iodide (1-48)
To a stirred solution of Intermediate 1-47 (1.2g, 3.8 mmol, 1 equiv.) in acetone (15 mL), was added iodomethane (0.8 g, 5.68 mmol, 1.5 equiv.). The resultant reaction mixture was stirred at 60 °C for 4 hours. Progress of the reaction was monitored by TLC. After completion of the reaction, reaction mixture was concentrated under reduced pressure to afford the intermediate 1-48 (1.8 g) as yellow solid.
Step-6: Synthesis of 6-amino-3-isopropyl-7-(3-methoxy-2,6-dimethylphenyl)-2- methylpyrrolo[l,2-b]pyridazine-5-carbonitrile (1-49)
To a stirred solution of malononitrile (1.79 g, 27.15 mmol, 5 equiv.) in DME (20 mL) was added, NaH (1.95 g, 81.45 mmol, 15 equiv.) at 0 °C and stirred at same temperature for 30 minutes. Intermediate 1-48 (1.8 g, 5.43 mmol, 1 equiv.) was added to it portionwise at 0 °C. The resultant reaction mixture was heated to 100 °C and stirred for 16 hours. Progress of the reaction was monitored by TLC. After the completion of reaction, the reaction mixture was cooled to RT, quenched with sat. NH4CI solution and extracted with EtOAc (4x). Combined organic layers were washed with brine and dried over anhydrous sodium sulphate. The filtered organic layer was concentrated to obtain the crude. The resultant crude was purified by combi- flash column chromatography using 30% ethyl acetate in hexane as eluent to afford the intermediate 1-49 (0.07 g) as light-yellow liquid.
1HNMR (400 MHz, DMSO-d6 ): 7.28 (s, 1H), 7.04 (d, J= 8.4 Hz, 1H), 6.87 (d, J= 8.4 Hz, 1H), 5.48 (s, 2H), 3.73 (s, 3H), 2.93-2.91 (m, 1H), 2.18 (s, 6H), 2.02 (s, 3H), 1.18 (d, J= 6.8 Hz, 6H); LC-MS: m/z 349.0 (M+H)+.
Step-1: Synthesis of 6-chloro-2-(3-methoxy-2,6-dimethylbenzyl)-5-(pyrrolidin-l- yl)pyridazin-3(2H)-one (1-50)
To a stirred solution of intermediate 1-28 (2 g, 6.4 mmol, 1.0 equiv.) in DMF (15 mL), were added pyrrolidine (0.68 g, 7.06 mmol, 1.1 equiv.), potassium carbonate (2.65 g, 19.16 mmol, 3 equiv.) and then stirred the reaction mixture at RT for 16 hours. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was poured into ice
water and then filtered the obtained solid. The resultant solid was dried under high vacuum to afford the compound 1-50 (2.3 g) as yellow solid.
1HNMR (400 MHz, DMSO-d6 ): 6.99 (d, J= 8.4 Hz, 1H), 6.82 (d, J= 8.3 Hz, 1H), 5.73 (s, 1H), 5.14 (s, 2H), 3.74 (s, 3H), 3.44-3.41 (m, 4H), 2.25 (s, 3H), 2.12 (s, 3H), 1.87-1.84 (m, 4H): LC-MS: m/z 348.2 (M+H)+
Step-2: Synthesis ooff 2-(3-methoxy-2,6-dimethylbenzyl)-6-methyl-5-(pyrrolidin-l- yl)pyridazin-3(2H)-one (1-51)
To a stirred solution of intermediate 1-50 (2.3 g, 6.6 mmol, 1.0 equiv.) in 1,4-dioxane (30 mL), were added trimethylboroxine (2.07 g, 16.53 mmol, 2.5 equiv.), potassium phosphate tribasic (4.21 g, 19.83 mmol, 3 equiv.) and degassed the mixture for 5 minutes with argon. Then Pd(dppf)C12 (0.54 g, 0.66 mmol, 0.1 equiv.) was added to the reaction mixture and again degassed for 5 minutes. The resultant reaction mixture was stirred at 110 °C for 16 hours. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with EtOAc (4x) and washed with water. Combined organic layers were washed with brine and dried over anhydrous sodium sulphate. The filtered organic layer was concentrated under reduced pressure to give crude product, the resultant crude was purified by combi flash using 50% EtOAc in Hexane as eluent to get the compound 1-51 (1.4 g) as yellow solid.
1HNMR (400 MHz, DMSO-d6 ): 6.97 (d, J= 8.4 Hz, 1H), 6.79 (d, J= 8.4 Hz, 1H), 5.53 (s, 1H), 5.11 (s, 2H), 3.74 (s, 3H), 3.36-3.34 (m, 4H), 2.27 (s, 6H), 2.15 (s, 3H), 1.87-1.84 (m, 4H): LC-MS: m/z 328.1 (M+H)+
Step-3: Synthesis ooff 2-(3-methoxy-2,6-dimethylbenzyl)-6-methyl-5-(pyrrolidin-l- yl)pyridazine-3(2H)-thione (1-52)
To a stirred solution of intermediate 1-51 (3 g, 9.16 mmol, 1 equiv.) in toluene (15 mL), was added Lawesson’s reagent (5.56 g, 13.74 mmol, 1.5 equiv.) and stirred at 100 °C for 7 hours. Progress of the reaction was monitored by TLC. The reaction mixture was cooled to RT and poured into water and extracted with EtOAc (4x). Combined organic layers were washed with brine and dried over anhydrous sodium sulphate. The filtered organic layer was concentrated under reduced pressure to give crude intermediate 1-52 (3.4 g) as yellow solid. LC-MS: m/z 344.05 (M+H)+
Step-4: Synthesis of l-(3-methoxy-2,6-dimethylbenzyl)-3-methyl-6-(methylthio)-4- (pyrrolidin-l-yl)pyridazin-l-ium iodide (1-53)
To a stirred solution of Intermediate 1-52 (3 g, 8.73 mmol, 1 equiv.) in acetone (10 mL), was added iodomethane (1.46 g, 12.73 mmol, 1 equiv.).The resultant reaction mixture was stirred at 70 °C for 2 hours. Progress of the reaction was monitored by TLC. After completion of the reaction, reaction mixture was concentrated under reduced pressure to afford the intermediate 1-53 (2.5 g) as yellow solid.
LC-MS: m/z 358.0 (M)+(Salt fragment)
Step-5: Synthesis of 6-amino-7-(3-methoxy-2,6-dimethylphenyl)-2-methyl-3-(pyrrolidin- l-yl)pyrrolo[l,2-b]pyridazine-5-carbonitrile (1-54)
To a stirred solution of malononitrile (2.3 g, 34.8 mmol, 5 equiv.) in DME (20 mL), was added NaH (2.4 g, 104.59 mmol, 15 equiv.) at 0 °C and stirred at same temperature for 30 minutes. Intermediate 1-53 (2.5 g, 6.97 mmol, 1 equiv.) was added to it portionwise at 0 °C. The resultant reaction mixture was heated to 70 °C and stirred for 12 hours. Progress of the reaction was monitored by TLC. After the completion of reaction, the reaction mixture was cooled to RT, quenched with sat. NH4CI solution and extracted with EtOAc (4x). Combined organic layers were washed with brine and dried over anhydrous sodium sulphate. The filtered organic layer was concentrated to obtain the crude. The resultant crude was purified by combi-flash column chromatography using 60% ethyl acetate in hexane as eluent to afford the intermediate 1-54 (0.86 g) as light-yellow liquid.
LC-MS: m/z 376.1 (M+H)+.
Synthesis of intermediates 1-55 to 1-58:
Step-1: Synthesis of 6-cyclopropyl-2-(3-methoxy-2,6-dimethylbenzyl)-5- methylpyridazin-3(2H)-one (1-55)
To a stirred solution of intermediate 1-19 (1.5 g, 5.12 mmol, 1.0 equiv.) in 1,4-dioxane (20 mL) and water (10 mL), were added cyclopropyl boronic acid (0.88 g, 10.25 mmol, 2.0 equiv.), potassium carbonate (1.42 g, 10.24 mmol, 2 equiv.) and degassed the mixture for 5 minutes with argon. Then Pd(dppf)C12 (0.42 g, 0.5 mmol, 0.1 equiv.) was added to the reaction mixture and again degassed for 5 minutes. The resultant reaction mixture was stirred at 80 °C for 16 hours. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with EtO Ac (4x) and washed with water. Combined organic layers were washed with brine and dried over anhydrous sodium sulphate. The filtered organic layer was concentrated under reduced pressure to give crude product, the resultant crude was purified by combi flash using 2% EtOAc in Hexane as eluent to get the compound 1-55 (0.63 g) as yellow solid.
1HNMR (400 MHz, DMSO-d6 ): 7.27 (s, 1H), 7.01 (d, J= 1.2 Hz, 1H), 6.83 (d, J= 2.4 Hz, 1H), 5.22 (s, 2H), 3.74 (s, 3H), 2.23 (s, 3H), 2.15 (s, 3H), 2.06 (s, 3H), 0.75-0.72 (m, 1H), 0.49-0.40 (m, 2H), 0.39-0.31 (m, 2H): LC-MS: m/z 299.0 (M+H)+
Step-2: Synthesis ooff 6-cyclopropyl-2-(3-methoxy-2,6-dimethylbenzyl)-5- methylpyridazine-3(2H)-thione (1-56)
To a stirred solution of intermediate 1-55 (0.63 g, 2.11 mmol, 1 equiv.) in pyridine (8 mL), was added P2S5 (1.87 g, 4.22 mmol, 1.5 equiv.) and stirred at 100 °C for 16 hours. Progress of the reaction was monitored by TLC. The reaction mixture was cooled to RT and poured into
water and extracted with EtOAc (4x). Combined organic layers were washed with brine and dried over anhydrous sodium sulphate. The filtered organic layer was concentrated under reduced pressure, the resultant crude was purified by combi flash using 10% EtOAc in Hexane as eluent to get the compound to give intermediate 1-56 (0.3 g) as yellow solid.
1HNMR (400 MHz, DMSO-d6 ): 7.64 (s, 1H), 7.02 (d, J= 8.4 Hz, 1H), 6.86 (d, J= 8.4 Hz, 1H), 5.64 (s, 2H), 3.75 (s, 3H), 2.24 (s, 3H), 2.15 (s, 3H), 2.00 (s, 3H), 1.93-1.88 (m, 1H), 0.78-0.75 (m, 2H), 0.39-0.37 (m, 2H); LC-MS: m/z 315.1 (M+H)+.
Step-3: Synthesis of 3-cyclopropyl-l-(3-methoxy-2,6-dimethylbenzyl)-4-methyl-6- (methylthio)pyridazin-l-ium (1-57)
To a stirred solution of intermediate 1-56 (0.3g g, 0.95 mmol, 1 equiv.) in acetone (5 mL), was added iodomethane (1.34 g, 9.54 mmol, 1 equiv.).The resultant reaction mixture was stirred at 70 °C for 16 hours. Progress of the reaction was monitored by TLC. After completion of the reaction, reaction mixture was concentrated under reduced pressure to afford the intermediate 1-57 (0.32 g) as yellow solid.
LC-MS: m/z 329.5 (M)+ (Salt fragment)
Step-4: Synthesis of 6-amino-2-cyclopropyl-7-(3-methoxy-2,6-dimethylphenyl)-3- methylpyrrolo[l,2-b]pyridazine-5-carbonitrile (1-58)
To a stirred solution of malononitrile (0.24 g, 3.64 mmol, 4 equiv.) in THF (3 mL), was added NaH (0.17 g, 7.2 mmol, 8 equiv.) at 0 °C and stirred at same temperature for 30 minutes. Intermediate 1-57 (0.3 g, 0.91 mmol, 1 equiv.) in sulfolane (1 mL) was added dropwise into the above reaction mixture at 0 °C. The resultant reaction mixture was heated to 80 °C and stirred for 16 hours. Progress of the reaction was monitored by TLC. After the completion of reaction, the reaction mixture was cooled to RT, quenched with sat. NH4CI solution and extracted with EtOAc (4x). Combined organic layers were washed with brine and dried over anhydrous sodium sulphate. The filtered organic layer was concentrated to obtain the crude. The resultant crude was purified by combi-flash column chromatography using 30% ethyl acetate in hexane as eluent to afford the intermediate 1-58 (0.27 g) as light-yellow liquid.
1HNMR (400 MHz, DMSO-d6 ): 7.67 (s, 1H), 7.12 (d, J= 8.4 Hz, 1H), 6.96 (d, J= 8.0 Hz, 1H), 4.93 (brs, 2H), 3.81 (s, 3H), 2.41 (s, 3H), 2.07-2.04 (m, 1H), 1.85 (s, 3H), 1.78 (s, 3H), 0.85-0.82 (m, 2H), 0.63-0.60 (m, 2H); LC-MS: m/z 347.1 (M+H)+.
Synthesis of intermediates 1-59 to 1-63:
Step-1: Synthesis of 6-chloro-5-cyclopropyl-2-(3-methoxy-2,6-dhnethylbenzyl)pyridazin- 3(2H)-one (1-59)
To a stirred solution of intermediate 1-28 (8 g, 4.79 mmol, 1.0 equiv.) in 1,4-dioxane (200 mL), were added cyclopropyl boronic acid (2.19 g, 25.54 mmol, 1.0 equiv.), potassium phosphate tribasic (10.84 g, 51.08 mmol, 2 equiv.) and degassed the mixture for 5 minutes with argon. Then Pd(dppf)C12 (2.08 g, 2.55 mmol, 0.1 equiv.) was added to the reaction mixture and again degassed for 5 minutes. The resultant reaction mixture was stirred at 60 °C for 16 hours. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with EtOAc (4x) and washed with water. Combined organic layers were washed with brine and dried over anhydrous sodium sulphate. The filtered organic layer was concentrated under reduced pressure to give crude product, the resultant crude was purified by combi flash using 20% EtOAc in Hexane as eluent to get the compound intermediate 1-59 (2,8 g) as yellow solid.
THNMR (400 MHz, DMSO-d6 ): 7.02 (d, J= 8.4 Hz, 1H), 6.85 (d, J= 8.0 Hz, 1H), 6.65 (s, 1H), 5.21 (s, 2H), 3.75 (s, 3H), 2.24 (s, 3H), 2.10 (s, 3H), 1.87-1.83 (m, 1H), 1.06-1.01 (m, 2H), 0.87-0.83 (m, 2H): LC-MS: m/z 318.9 (M+H)+
Step-2: Synthesis of 5-cyclopropyl-2-(3-methoxy-2,6-dimethylbenzyl)-6- methylpyridazin-3(2H)-one (1-60)
To a stirred solution of intermediate 1-59 (2.7 g, 8.47 mmol, 1.0 equiv.) in 1,4-dioxane (40 mL), were added trimethylboroxine (3.19 g, 25.41 mmol, 3.0 equiv.), potassium phosphate tribasic (5.39 g, 25.4 mmol, 3 equiv.) and degassed the mixture for 5 minutes with argon. Then Pd(dppf)C12 (0.69 g, 0.84 mmol, 0.1 equiv.) was added to the reaction mixture and again degassed for 5 minutes. The resultant reaction mixture was stirred at 110 °C for 16 hours. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with EtOAc (4x) and washed with water. Combined organic layers were washed with brine and dried over anhydrous sodium sulphate. The filtered organic layer was concentrated under reduced pressure to give crude product, the resultant crude was purified by combi flash using 30% EtOAc in Hexane as eluent to get the compound 1-60 (1.9 g) as yellow solid.
1HNMR (400 MHz, DMSO-d6 ): 6.98 (d, J= 8.4 Hz, 1H), 6.80 (d, J= 8.0 Hz, 1H), 6.42 (s, 1H), 5.19 (s, 2H), 3.73 (s, 3H), 2.26 (s, 3H), 2.22 (s, 3H), 2.12 (s, 3H), 1.82-1.72 (m, 1H), 0.96-0.92 (m, 2H), 0.74-0.72 (m, 2H): LC-MS: m/z 299.1 (M+H)+
Step-3: Synthesis of 5-cyclopropyl-2-(3-methoxy-2,6-dimethylbenzyl)-6- methylpyridazine-3(2H)-thione (1-61)
To a stirred solution of intermediate 1-60 (1.5 g, 5.03 mmol, 1 equiv.) in toluene (15 mL) was added Lawesson’s reagent (3.05 g, 7.54 mmol, 1.5 equiv.) and stirred at 100 °C for 7 hours. Progress of the reaction was monitored by TLC. The reaction mixture was cooled to RT and poured into water and extracted with EtOAc (4x). Combined organic layers were washed with brine and dried over anhydrous sodium sulphate. The filtered organic layer was concentrated under reduced pressure to give crude product, which was purified by combi-flash column chromatography using 10% ethyl acetate in hexane as eluent to afford the intermediate 1-61 (1.4 g) as yellow solid.
1HNMR (400 MHz, DMSO-d6 ): 7.26 (s, 1H), 7.02 (d, J= 8.0 Hz, 1H), 6.84 (d, J= 8.4 Hz, 1H), 5.74 (s, 2H), 3.75 (s, 3H), 2.24 (s, 3H), 2.20 (s, 3H), 2.06 (s, 3H), 1.83-1.78 (m, 1H), 1.03-1.00 (m, 2H), 0.83-0.82 (m, 2H); LC-MS: m/z 315.1 (M+H)+.
Step-4: Synthesis of 4-cyclopropyl-l-(3-methoxy-2,6-dimethylbenzyl)-3-methyl-6- (methylthio)pyridazin-l-ium iodide (1-62)
To a stirred solution of Intermediate 1-61 (1.3 g, 4.13 mmol, 1 equiv.) in acetone (20 mL), was added iodomethane (0.59 g, 4.13 mmol, 1 equiv.). the resultant reaction mixture was stirred
at 70 °C for 2 hours. Progress of the reaction was monitored by TLC. After completion of the reaction, reaction mixture was concentrated under reduced pressure to afford the intermediate 1-62 (1.4 g) as yellow solid.
1HNMR (400 MHz, DMSO-d6 ): 7.53 (s, 1H), 7.09 (d, J= 8.4 Hz, 1H), 6.96 (d, J= 8.4 Hz, 1H), 5.64 (s, 2H), 3.78 (s, 3H), 3.33 (s, 3H), 3.01 (s, 3H), 2.22-2.20 (m, 1H), 2.20 (s, 3H), 2.06 (s, 3H), 1.37-1.34 (m, 2H), 1.30-1.27 (m, 2H): LC-MS: m/z 329.1 (M)+ (Salt fragment)
Step-5: Synthesis of 6-amino-7-(3-methoxy-2,6-dimethylphenyl)-3-methylpyrrolo[l,2- b]pyridazine-5-carbonitrile (1-63)
To a stirred solution of malononitrile (1.4 g, 21.24 mmol, 5 equiv.) in THF (50 mL), was added NaH (1.46 g, 63.73 mmol, 15 equiv.) at 0 °C and stirred at same temperature for 30 minutes. Intermediate 1-62 (1.4g, 4,25 mmol, 1 equiv.) in sulfolane was added dropwise into the above reaction mixture at 0 °C. The resultant reaction mixture was heated to 70 °C and stirred for 12 hours. Progress of the reaction was monitored by TLC. After the completion of reaction, the reaction mixture was cooled to RT, quenched with sat. NH4CI solution and extracted with EtOAc (4x). Combined organic layers were washed with brine and dried over anhydrous sodium sulphate. The filtered organic layer was concentrated to obtain the crude. The resultant crude was purified by combi-flash column chromatography using 30% ethyl acetate in hexane as eluent to afford the intermediate 1-63 (1.34 g) as light-yellow solid.
1HNMR (400 MHz, DMSO-d6 ): 7.37 (s, 1H), 7.13 (d, J= 8.4 Hz, 1H), 6.97 (d, J= 8.4 Hz, 1H), 4.92 (brs, 2H), 3.81 (s, 3H), 2.41 (s, 3H), 1.92-1.90 (m, 1H), 1.87 (s, 3H), 1.80 (s, 3H), 0.98-0.93 (m, 2H), 0.81-0.76 (m, 2H); LC-MS: m/z 347.1 (M+H)+.
Synthesis of intermediates 1-64 to 1-68:
Step-1: Synthesis of 5-chloro-2-(3-methoxy-2,6-dimethylbenzyl)pyridazin-3(2H)-one (I- 64)
To a stirred solution of 5-chloropyridazin-3(2H)-one (1 g, 7.66 mmol, 1.0 equiv.) in DMF (15 mL), were added intermediate 1-4 (1.58 g, 6.89 mmol, 0.9 equiv.), cesium carbonate (7.48 g, 22.98 mmol, 3 equiv.) and stirred at RT for 3 hours. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was poured into ice-cold water and extracted with EtOAc (4x). Combined organic layers were washed with brine and dried over anhydrous sodium sulphate. The filtered organic layer was concentrated under reduced pressure to give crude product, which was washed with diethyl ether and dried under high vacuum to afford intermediate 1-64 (1.75 g) as an off-white solid.
1HNMR (400 MHz, DMSO-d6 ): 7.97 (d, J= 2.4 Hz, 1H), 7.28 (d, J= 2.4 Hz, 1H), 6.99 (d, J = 8.4 Hz, 1H), 6.82 (d, J= 8.4 Hz, 1H), 5.24 (s, 2H), 3.74 (s, 3H), 2.19 (s, 3H), 2.06 (s, 3H).
Step-2: Synthesis of 5-cyclopropyl-2-(3-methoxy-2,6-dimethylbenzyl)pyridazin-3(2H)- one (1-65)
To a stirred solution of intermediate 1-64 (1.7 g, 6.09 mmol, 1.0 equiv.) in DME (20 mL) and water (5 mL) were added cyclopropyl boronic acid (0.63 g, 7.31 mmol, 1.2 equiv.), sodium carbonate (1.94 g, 18.3 mmol, 2 equiv.) and degassed the mixture for 5 minutes with argon. Then Pd(dppf)C12 (0.5 g, 0.6 mmol, 0.1 equiv.) was added to the reaction mixture and again degassed for 5 minutes. The resultant reaction mixture was stirred at 90 °C for 16 hours. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was diluted with EtOAc (4x) and washed with water. Combined organic layers were washed with brine and dried over anhydrous sodium sulphate. The filtered organic layer was concentrated under reduced pressure to give crude product, the resultant crude was purified by combi flash using 20% EtOAc in Hexane as eluent to get the compound 1-65 (0.9 g) as yellow solid.
1HNMR (400 MHz, DMSO-d6 ): 7.60 (d, J= 2.4 Hz, 1H), 6.99 (d, J= 8.4 Hz, 1H), 6.82 (d, J = 8.4 Hz, 1H), 6.13 (s, 1H), 5.21 (s, 2H), 3.74 (s, 3H), 2.19 (s, 3H), 2.06 (s, 3H), 1.81-1.78 (m, 1H), 1.02-0.98 (m, 2H), 0.84-0.82 (m, 2H).
Step-3: Synthesis of 5-cyclopropyl-2-(3-methoxy-2,6-dimethylbenzyl)pyridazine-3(2H)- thione (1-66)
To a stirred solution of intermediate 1-65 (0.9 g, 3.16 mmol, 1 equiv.) in toluene (15 mL), was added Lawesson’s reagent (1.92 g, 4.74 mmol, 1.5 equiv.) and stirred at 100 °C for 7 hours. Progress of the reaction was monitored by TLC. The reaction mixture was cooled to RT and poured into water and extracted with EtOAc (4x). Combined organic layers were washed with brine and dried over anhydrous sodium sulphate. The filtered organic layer was concentrated under reduced pressure to give crude product, which was purified by combi-flash column chromatography using 10% ethyl acetate in hexane as eluent to afford the intermediate 1-66 (0.63 g) as yellow solid.
1HNMR (400 MHz, DMSO-d6 ): 7.98 (s, 1H), 7.60 (s, 1H), 7.01 (d, J= 8.4 Hz, 1H), 6.84 (d, J= 8.4 Hz, 1H), 5.71 (s, 2H), 3.74 (s, 3H), 2.19 (s, 3H), 2.06 (s, 3H), 1.81-1.78 (m, 1H), 1.02-0.98 (m, 2H), 0.84-0.82 (m, 2H).LC-MS: m/z 301.2 (M+H)+.
Step-4: Synthesis ooff 4-cyclopropyl-l-(3-methoxy-2,6-dimethylbenzyl)-6-
(methylthio)pyridazin-l-ium iodide (1-67)
To a stirred solution of Intermediate 1-66 (0.6g, 2.01 mmol, 1 equiv.) in acetone (10 mL), was added iodomethane (0.85 g, 5.99 mmol, 3 equiv.). the resultant reaction mixture was stirred at 70 °C for 2 hours. Progress of the reaction was monitored by TLC. After completion of the reaction, reaction mixture was concentrated under reduced pressure to afford the intermediate 1-67 (0.6 g) as yellow solid.
1HNMR (400 MHz, DMSO-d6): 8.78 (s, 1H), 8.16 (s, 1H), 7.08 (d, J = 8.4 Hz, 1H), 6.84 (d, J = 8.4 Hz, 1H), 5.71 (s, 2H), 3.74 (s, 3H), 3.04 (s, 3H), 2.28-2.26 (m, 1H), 2.12 (s, 3H), 2.02 (s, 3H), 1.44-1.42 (m, 2H), 1.32-1.28 (m, 2H); LC-MS: m/z 315.2 (M>4- (Salt fragment)
Step-5: Synthesis ooff 6-amino-3-cyclopropyl-7-(3-methoxy-2,6- dimethylphenyl)pyrrolo[l,2-b]pyridazine-5-carbonitrile (1-68)
To a stirred solution of malononitrile (0.62 g, 9.51 mmol, 5 equiv.) in THF (10 mL), was added NaH (0.65 g, 28.53 mmol, 15 equiv.) at 0 °C and stirred at same temperature for 30 minutes. Intermediate 1-67 (0.6 g, 1.91 mmol, 1 equiv.) in sulfolane (5 mL) was added dropwise into the above reaction mixture at 0 °C. The resultant reaction mixture was heated to 80 °C and stirred for 16 hours. Progress of the reaction was monitored by TLC. After the completion of reaction, the reaction mixture was cooled to RT, quenched with sat. NH4CI solution and extracted with EtOAc (4x). Combined organic layers were washed with brine and dried over anhydrous sodium sulphate. The filtered organic layer was concentrated to obtain the crude.
The resultant crude was purified by combi-flash column chromatography using 50% ethyl acetate in hexane as eluent to afford the intermediate 1-68 (0.26 g) as light-yellow liquid.
1HNMR (400 MHz, DMSO-d6 ): 8.00 (d, J= 2.0 Hz, 1H), 7.53 (d, J= 2.0 Hz, 1H)„ 7.13 (d, J = 8.4 Hz, 1H), 6.98 (d, J= 8.4 Hz, 1H), 5.08 (s, 2H), 3.80 (s, 3H), 2.02-1.98 (m, 1H), 1.86 (s, 3H), 1.78 (s, 3H), 1.03-0.99 (m, 2H), 0.88-0.86 (m, 2H); LC-MS: m/z 333.0 (M+H)+.
Example-1: Synthesis of 2-amino-3-(3-hydroxy-2,6-dimethylphenyl)-7-methylindolizine- 1 -carboxamide (Compound-1)
Step-1: Synthesis of 2-bromo-l-(3-methoxy-2,6-dimethylbenzyl)-4-methylpyridin-l-ium bromide (1-5)
To a stirred solution of 2-bromo-4-methylpyridine (2 g, 11.62 mmol, 1.0 equiv.) in sulfolane (5 mL), was added intermediate 1-4 (2.9 g, 12.78 mmol, 1.1 equiv.) and stirred at 80 °C for 16 hours. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was directly taken for next step without workup. Formation of product (1-5) was confirmed by LC-MS data.
LC-MS: m/z 319.95 (M)+ (Salt fragment)
Step-2: Synthesis of 2-amino-3-(3-methoxy-2,6-dimethylphenyl)-7-methylindolizine-l- carbonitrile (1-6)
To a stirred solution of malononitrile (1.16 g, 17.57 mmol, 1 equiv.) in THF (15 mL), was added sodium tert-butoxide (2.5 g, 26.36 mmol, 1.5 equiv.) at 0 °C and stirred at same temperature for 30 minutes. Then the reaction mixture from step-1 was added to it dropwise at
0 °C and heated the resultant reaction mixture to 100 °C for 16 hours. The reaction mixture was cooled to RT. The resultant reaction mixture was added to the stirred suspension of NaH (1.68 g, 70 mmol, 4 equiv.) in THF at 0 °C, heated to 70 °C and stirred for 6 hours at the same temperature. Progress of the reaction was monitored by TLC and LC-MS. After the completion of reaction, the reaction mixture was cooled to RT and quenched with sat. NH4CI solution and extracted with EtOAc (4x). Combined organic layers were washed with brine and dried over anhydrous sodium sulphate. The filtered organic layer was concentrated to obtain the intermediate 1-6 (1.3 g) as light yellow solid.
1HNMR (400 MHz, DMSO-d6 ): 7.23-7.16 (m, 3H), 7.03 (d, J= 8.4 Hz, 1H), 6.56 (d, J = 8.8 Hz, 1H), 4.73 (s, 2H), 3.82 (s, 3H), 2.33 (s, 3H), 1.88 (s, 3H), 1.79 (s, 3H): LC-MS: m/z 306.2 (M+H)+
Step-3: Synthesis of 2-amino-3-(3-hydroxy-2,6-dimethylphenyl)-7-methylindolizme-l- carboxamide (compound 1)
To the stirred solution of methanesulfonic acid (6 mL), sulfuric acid (3 mL) and water (0.2 mL), was added Intermediate 1-6 (1.2 g, 3.71 mmol, 1 equiv.) at 0 °C. Then allowed the reaction mixture to cool to RT and stirred for 2 hours. Later, DL-Methionine was added to the reaction mixture portion wise at RT and then stirred at 40 °C for 16 hours. Progress of the reaction was monitored by TLC. After completion of the reaction, reaction mixture was poured into ice-cold water, neutralised with aqueous ammonia solution, and then extracted with EtOAc (3x). Combined organic layers were washed with brine and dried over anhydrous sodium sulphate. The filtered organic layer was concentrated under reduced pressure to give crude product, which was purified by combi-flash column chromatography using ethyl acetate in hexane to afford the pure product compound 1 (0.4 g) as an off-white solid.
1HNMR (400 MHz, DMSO-d6 ): 9.22 (s, 1H), 7.64 (s, 1H), 7.11 (d, J = 7.2 Hz, 1H), 7.02 (d, J= 8.0 Hz, 1H), 6.85 (d, J= 8.0 Hz, 1H), 6.81 (s, 2H), 6.46 (dd, J= 6.8, 1.6 Hz, 1H), 4.82 (s, 2H), 2.30 (s, 3H) 1.84 (s, 3H), 1.76 (s, 3H); LC-MS: m/z 310.1 (M+H)+; Chiral HPLC: 49.79% + 50.21%.
Atropisomers of compound-1 (compound 2 and compound 3) were separated using chiral HPLC (column: chiral pak-IG (250 x21.2 mm) 5μ, mobile phase: A % = n-Hexane B % = Ethanol).
Compound-2 (Isomer-1 of compound-1):
1HNMR (400 MHz, DMSO-d6 ): 9.22 (s, IH), 7.64 (s, IH), 7.11 (d, J = 6.8 Hz, IH), 7.02 (d, J = 8.0 Hz, IH), 6.85 (d, J= 8.0 Hz, IH), 6.81 (s, 2H), 6.46 (dd, J= 7.0, 1.4 Hz, IH), 4.82 (s, 2H), 2.30 (s, 3H) 1.83 (s, 3H), 1.76 (s, 3H); LC-MS: m/z 310.1 (M+H)+ ; Chiral HPLC: 99.89%.
Compound-3 (Isomer-2 of compound-1):
1HNMR (400 MHz, DMSO-d6 ): 9.22 (s, IH), 7.64 (s, IH), 7.11 (d, J = 7.2 Hz, IH), 7.02 (d, J = 8.4 Hz, IH), 6.85 (d, J= 8.4 Hz, IH), 6.81 (s, 2H), 6.46 (dd, J= 6.8, 1.6 Hz, IH), 4.82 (s, 2H), 2.30 (s, 3H) 1.83 (s, 3H), 1.76 (s, 3H); LC-MS: m/z 310.2 (M+H)+ ; Chiral HPLC: 100%.
Example-2: Synthesis ooff 6-amino-7-(3-hydroxy-2,6-dimethylphenyl)-3- methylpyrrolo[l,2-b]pyridazine-5-carboxamide (Compound-4)
Step-1: Synthesis of 5-methylpyridazin-3(2H)-one (1-7)
To a stirred solution of 5-methylpyridazin-3(2H)-one (1 g, 9.08 mmol, 1.0 equiv.) in DMF (10 mL), were added intermediate 1-4 (2.08 g, 9.08 mmol, 1 equiv.), cesium carbonate (8.9 g, 27.24 mmol, 3 equiv.) and stirred at RT for 3 hours. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was poured into ice-cold water and extracted with EtOAc (4x). Combined organic layers were washed with brine and dried over anhydrous sodium sulphate. The filtered organic layer was concentrated under reduced pressure to give crude product, which was washed with diethyl ether and dried under high vacuum to afford intermediate 1-7 (0.9 g) as yellow solid.
1HNMR (400 MHz, DMSO-d6 ): 7.68 (d, J= 2.4 Hz, 1H), 6.99 (d, J= 8.4 Hz, 1H), 6.82 (d, J = 8.4 Hz, 1H), 6.75-6.74 (m, 1H), 5.27 (s, 2H), 3.74 (s, 3H), 2.20 (s, 3H), 2.15 (s, 3H), 2.06 (s, 3H): LC-MS: m/z 259.1 (M+H)+
Step-2: Synthesis of 2-(3-methoxy-2,6-dimethylbenzyl)-5-methylpyridazine-3(2H)-thione (1-8)
To a stirred solution of intermediate 1-7 (1.2 g, 4.75 mmol, 1 equiv.) in 1,4-dioxane (12 mL), were added P2S5 (4.22 g, 9.49 mmol, 2 equiv.) and NaHCCh (3.98 g, 47.46 mmol, 10 equiv.) at RT. Then the reaction mixture was stirred at 100 °C for 16 hours. Progress of the reaction was monitored by TLC and LC-MS. The reaction mixture was cooled to RT and poured into water and extracted with EtOAc (4x). Combined organic layers were washed with brine and dried over anhydrous sodium sulphate. The filtered organic layer was concentrated under reduced pressure to give crude product, which was purified by combi-flash column chromatography using ethyl acetate in hexane to afford the intermediate 1-8 (0.9 g) as yellow solid.
1HNMR (400 MHz, DMSO-d6 ): 8.10 (d, J= 2.4 Hz, 1H), 7.72 (d, J= 1.2 Hz, 1H), 7.02 (d, J = 8.4 Hz, 1H), 6.86 (d, J= 8.4 Hz, 1H), 5.71 (s, 2H), 3.75 (s, 3H), 2.14 (s, 3H), 2.13 (s, 3H), 2.08 (s, 3H): LC-MS: m/z 275.1 (M+H)+.
Step-3: Synthesis ooff l-(3-methoxy-2,6-dimethylbenzyl)-4-methyl-6-
(methylthio)pyridazin-l-ium iodide (1-9)
To a stirred solution of Intermediate 1-8 (0.9 g, 3.28 mmol, 1 equiv.) in acetone, was added lodomethane (0.93 g, 6.55 mmol, 2 equiv.). the resultant reaction mixture was stirred at 60 °C for 2 hours. Progress of the reaction was monitored by TLC. After completion of the reaction, reaction mixture was concentrated under reduced pressure to afford the intermediate 1-9 (1 g) as yellow solid.
1HNMR (400 MHz, DMSO-d6 ): 8.96 (d, J= 2.0 Hz, 1H), 8.46 (s, 1H), 7.13 (d, J= 8.4 Hz, 1H), 6.98 (d, J= 8.8 Hz, 1H), 5.71 (s, 2H), 3.78 (s, 3H), 3.0 (s, 3H), 2.56 (s, 3H), 2.14 (s, 3H), 2.03 (s, 3H): LC-MS: m/z 289.2 (M)+(Salt fragment)
Step-4: Synthesis of 6-amino-7-(3-methoxy-2,6-dimethylphenyl)-3-methylpyrrolo[l,2- b]pyridazine-5-carbonitrile (1-10)
To a stirred solution of malononitrile (0.41 g, 6.22 mmol, 2 equiv.) in THF (15 mL) , was added NaH (0.15 g, 6.22 mmol, 2 equiv.) at 0 °C and stirred at same temperature for 30 minutes. Intermediate 1-9 (0.9 g, 3.11 mmol, 1 equiv.) in sulfolane was added to it dropwise at 0 °C. The resultant reaction mixture was heated to 70 °C and stirred for 16 hours. Progress of the reaction was monitored by TLC. After the completion of reaction, the reaction mixture was cooled to RT, quenched with sat. NH4CI solution and extracted with EtOAc (4x). Combined organic layers were washed with brine and dried over anhydrous sodium sulphate. The filtered organic layer was concentrated to obtain the intermediate 1-10 (0.5 g) as light-yellow liquid.
1HNMR (400 MHz, DMSO-d6 ): 8.03 (d, J= 2.0 Hz, 1H), 7.73-7.72 (m, 1H), 7.14 (d, J= 8.4 Hz, 1H), 6.98 (d, J= 8.4 Hz, 1H), 5.09 (s, 2H), 3.81 (s, 3H), 2.33 (s, 3H), 1.87 (s, 3H), 1.78 (s, 3H); LC-MS: m/z 307.2 (M+H)+.
Step-5: Synthesis of 6-amino-7-(3-hydroxy-2,6-dimethylphenyl)-3-methylpyrrolo[l,2- b]pyridazine-5-carboxamide (compound 4)
To the stirred solution of methane sulfonic acid (0.6 mL), sulfuric acid (0.4 mL) and water (0.1 mL), was added Intermediate 1-10 (0.5 g, 1.63 mmol, 1 equiv.) at 0 °C. Then allowed the reaction mixture to RT and stirred for 2 hours. DL-Methionine (1.2 g, 8.16 mmol, 5 equiv.) was added to this reaction mixture portion wise at RT and then stirred at 40 °C for 16 hours. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was poured into ice-cold water, neutralised with aqueous ammonia solution and then extracted with EtOAc (3x). Combined organic layers were washed with brine and dried over anhydrous sodium sulphate. The filtered organic layer was concentrated under reduced pressure to give crude product, which was purified by combi-flash column chromatography using ethyl acetate in hexane to afford the pure product compound 4 (0.12 g) as yellow solid.
1HNMR (400 MHz, DMSO-d6 ): 9.10 (s, 1H), 8.03 (d, J = 2.8 Hz, 1H), 7.92 (d, J= 2.4 Hz, 1H), 6.98 (s, 2H), 6.95 (d, J= 8.0 Hz, 1H), 6.81 (d, J= 8.4 Hz, 1H), 5.09 (s, 2H), 2.30 (s, 3H), 1.83 (s, 3H), 1.75 (s, 3H); LC-MS: m/z 311.1 (M+H)+ ; Chiral HPLC : 50.35% + 49.65%.
Atropisomers of compound-4 (compound-5 and compound-6) were separated using chiral HPLC (column: chiral pak-IG (250 x21.2mm) 5μ, mobile phase: A % = n-Hexane B % = Ethanol).
Compound 5 (Isomer- 1 of compound 4):
1HNMR (400 MHz, DMSO-d6 ): 9.07 (s, 1H), 8.03 (d, J = 2.8 Hz, 1H), 7.92 (d, J= 2.0 Hz, 1H), 6.98 (s, 2H), 6.95 (d, J= 8.0 Hz, 1H), 6.81 (d, J= 8.4 Hz, 1H), 5.09 (s, 2H), 2.30 (s, 3H), 1.83 (s, 3H), 1.75 (s, 3H); LC-MS: m/z 311.2 (M+H)+; Chiral HPLC: 100%.
Compound 6 (Isomer-2 of compound 4):
1HNMR (400 MHz, DMSO-d6 ): 9.10 (s, 1H), 8.03 (d, J= 2.8 Hz, 1H), 7.92 (d, J= 2.4 Hz, 1H), 6.98 (s, 2H), 6.95 (d, J= 8.0 Hz, 1H), 6.81 (d, J= 8.4 Hz, 1H), 5.09 (s, 2H), 2.30 (s, 3H), 1.83 (s, 3H), 1.75 (s, 3H); LC-MS: m/z 311.2 (M+H)+ ; Chiral HPLC: 100%.
Example-3: Synthesis of 2-amino-3-(3-hydroxy-2,6-dmiethylphenyl)-6-methylindolizine- 1 -carboxamide (Compound 7)
To the stirred solution of methanesulfonic acid (0.6 mL), sulfuric acid (0.4 mL) and water (0.02 mL), was added Intermediate 1-14 (0.3 g, 0.98 mmol, 1 equiv.) at 0 °C. Then allowed the reaction mixture to RT and stirred for 2 hours. DL-Methionine (0.29 g, 1.9 mmol, 2 equiv.) was added to this reaction mixture portion wise at RT and then stirred at 40 °C for 16 hours. Progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was poured into ice-cold water, neutralised with aqueous ammonia solution, and then extracted with EtOAc (3x). Combined organic layers were washed with brine and dried over anhydrous sodium sulphate. The filtered organic layer was concentrated under reduced pressure to give crude product, which was purified by combi-flash column chromatography using ethyl acetate in hexane to afford the pure product compound 7 (0.11 g) as an off-white solid.
1HNMR (400 MHz, DMSO-d6 ): 9.26 (s, 1H), 7.76 (d, J= 8.8 Hz, 1H), 7.04-6.99 (m, 2H), 6.87-6.77 (m, 4H), 4.81 (s, 2H), 2.14 (s, 3H), 1.83 (s, 3H), 1.76 (s, 3H); LC-MS: m/z 308.05 (M-H)+ ; Chiral HPLC: 49.97% + 50.03%.
Atropisomers of compound 7 (compound 8 and compound 9) were separated using chiral HPLC (column: chiral pak-IG (250 x21.2mm) 5μ, mobile phase: A % = n-Hexane B % = Ethanol).
Compound 8 (Isomer- 1 of compound 7):
1HNMR (400 MHz, DMSO-d6 ): 9.24 (s, 1H), 7.76 (d, J= 8.8 Hz, 1H), 7.04-6.99 (m, 2H), 6.87-6.77 (m, 4H), 4.81 (s, 2H), 2.14 (s, 3H), 1.83 (s, 3H), 1.76 (s, 3H); LC-MS: m/z 310.0 (M+H)+ ; Chiral HPLC: 100%.
Compound 9 (Isomer-2 of compound 7):
1HNMR (400 MHz, DMSO-d6 ): 9.26 (s, 1H), 7.76 (d, J= 8.8 Hz, 1H), 7.04-6.99 (m, 2H), 6.87-6.77 (m, 4H), 4.81 (s, 2H), 2.14 (s, 3H), 1.83 (s, 3H), 1.76 (s, 3H); LC-MS: m/z 310.0 (M+H)+ ; Chiral HPLC: 100%.
Example-4: Synthesis of 6-amino-2-cyclopropyl-7-(3-hydroxy-2,6-dimethylphenyl)-3- methylpyrrolo[l,2-b]pyridazine-5-carboxamide (Compound 24)
Step-1: SSyynntthheessiiss of 6-amino-2-cyclopropyl-7-(3-methoxy-2,6-dimethylphenyl)-3- methylpyrrolo[l,2-b]pyridazine-5-carboxamide (1-69)
To a stirred solution of Intermediate 1-58 (0.24 g, 0.69 mmol, 1 equiv.) in EtOH (3.6 mL) and water (1.2 mL), were added lithium hydroxide monohydrate (0.23g, 5.54 mmol, 8 equiv.), and 30% hydrogen peroxide (0.43g, 12.64 mmol, 18.2 equiv.) at 0 °C and then stirred at 70 °C for 16 hours. Progress of the reaction was monitored by TLC. After the completion of reaction, the reaction mixture was cooled to RT, and extracted with EtOAc (4x). Combined organic layers were washed with brine and dried over anhydrous sodium sulphate. The filtered organic layer was concentrated to obtain the crude. The resultant crude was purified by combi-flash column chromatography using 70% ethyl acetate in hexane as eluent to afford the intermediate 1-69 (80 mg) as light-yellow liquid.LC-MS: m/z 365.2 (M+H)+.
Step-2: Synthesis of 6-amino-2-cyclopropyl-7-(3-hydroxy-2,6-dimethylphenyl)-3- methylpyrrolo[l,2-b]pyridazine-5-carboxamide (compound 24)
To a stirred solution of Intermediate 1-69 (0.07 g, 0.19 mmol, 1 equiv.) in DCM (5 mL), was added BBn (0.5 g, 1.9 mmol, 10 equiv.) at 0 °C and then stirred at same RT for 16 hours. The reaction mixture was diluted with DCM (12 mL) and poured into ice water and then neutralised with aqueous ammonia solution. The organic layer was washed with brine and dried over anhydrous sodium sulphate. The filtered organic layer was concentrated to obtain the crude. The resultant crude was purified by combi-flash column chromatography using 80% ethyl acetate in DCM to get the compound 24 (6 mg) as pale brown solid.
1HNMR (400 MHz, DMSO-d6 ): 9.14 (s, 1H), 7.98 (s, 1H), 6.95-6.91 (m, 3H), 6.79 (d, J= 8.0 Hz, 1H), 4.99 (s, 2H), 2.39 (s, 3H), 2.04-1.98 (m, 1H), 1.82 (s, 3H), 1.74 (s, 3H), 0.86- 0.78 (m, 2H), 0.63-0.61 (m, 2H); LC-MS: m/z 351.2 (M+H)+.
HPLC details: Exemplary compounds of the present disclosure are analysed for the HPLC purity in any one of the methods A, B, C & D referred herein below:
Method A - Column: LUNA OMEGA-PS, C18(150mmx4.6mm, 5p) Mobile phase: C: WATER, B: ACN, Flow rate : 1.0 ml\min. TEMP : 40°C GRADIENT : 0/5, 1/5, 6/100, 8/100, 10/5, 12/5, Diluent : ACN:WATER
Method B - Column: ZORBAX, ECLIPSE C18(150mmx4.6mm,4p) Mobile phase: A: 0.01%TFA IN WATER B: ACN, Flow rate : 1.0 ml\min. TEMP : 40°C GRADIENT : 0/5, 1/5, 6/100, 8/100, 10/5, 12/5, Diluent : ACN:WATER
Method C - Column: KINETEX EVO, C18(150mmx4.6mm,5pm, 100 A) Mobile phase: A : 0.01%TFA IN WATER B: ACETONITRILE, How rate : 1.0 ml\min.TEMP : 40°C GRADIENT : 0/5, 1/5, 6/100, 8/100, 10/5, 12/5, Diluent: : ACN:WATER
Method D - Column: Agilent POROSHELL C18(150mmx4.6mm, 4p) Mobile phase: A: 0.01%TFA IN WATER B: ACETONITRILE, How rate : 1.0 ml\min.TEMP : 40°C GRADIENT : 0/5, 1/5, 6/100, 8/100, 10/5, 12/5, Diluent : ACN:WATER
Chiral HPLC method: Exemplary compounds of the present disclosure are analysed for the chiral purity in the method referred herein:
Column: CHIRALPAK IG (250mmx4.6mm, 5μ) Mobile phase: A: n-HEXANE, B :EtOH, How rate : 1.0 ml\min.TEMP : 25°C, ISOCRATIC : 70:30, Diluent : ETHANOL
Although the present application has been illustrated by certain of the preceding examples, it is not to be construed as being limited thereby; but rather, the present application encompasses the generic area as hereinbefore disclosed. For example, the compounds in the below table-2 which can be prepared by following similar procedure as described in above SchemesZExamples with suitable modifications known to the one ordinary skilled in the art are also included in the scope of the present application:
Biochemical Assay:
The inhibitory activity of the test compounds for PKMYT1 was assessed by commercially available ADP Gio assay (Promega cat. no. V9103). The human recombinant PKMYT1 (full- length human GST-PKMYT1 recombinant protein; ThermoFisher Scientific A33387), was diluted in enzyme assay buffer (70 mM HEPES, lOmM MgCh, 0.01% Triton X, 0.01% BSA, 3μM sodium orthovanadate, 1.2 mM DTT) in a lOpl volume and added to 384-well plates (Cat# 781075, Greiner) to a final concentration of 5nM. The enzyme-compound mix was added to the plate, spun down briefly, and incubated at 25°C for 30 min. ATP solution (ADP Gio KIT from Promega) diluted in enzyme assay buffer was added to the plate and incubated for 60 minutes at 30°C, the final ATP concentration was lOpM. After 60-minute incubation, lOpl of ADP-Glo reagent was added and incubated at room temperature for 60 minutes. Following this, 20pl of the kinase detection reagent was added and the plate was incubated at room temperature for 60 minutes. Luminescence was measured using Victor V multimode plate reader (Perkin Elmer). The IC50 and % maximum inhibition of the compounds were estimated by fitting the dose response data to a sigmoidal curve fitting equation using Graph pad Prism software V. 8.
The compounds were screened by the above-mentioned assay procedure. The % inhibition at 0.1μM and 1.0μM concentration are summarized in the Table-3 below along with IC50 (nM) details in Table-4. The IC50 values given herein are in range wherein “A” refers to an IC50 value of less than 10 nM, “B” refers to an IC50 value in between 10-100 nM (both inclusive) and “C” refers to an IC50 value of greater than 100 nM.
Incorporation bv Reference
All publications and patents mentioned herein are hereby incorporated by reference in their entirety as if each individual publication or patent were specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.
Equivalents
While specific embodiments of the subject disclosure have been discussed, the above specification is illustrative and not restrictive. Many variations of the disclosure will become apparent to those skilled in the art upon review of this specification and the claims below. The full scope of the disclosure should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations.
Claims
1. A compound of formula (I)
or a pharmaceutically acceptable salt thereof or a stereoisomer thereof; wherein, each X1 to X6 is independently C or N; wherein a maximum of 3 of X1 to X6 are N;
Ri at each occurrence independently is alkyl, halo or hydroxy; alternatively, two Ri on consecutive ring atoms together get cyclized to form an unsubstituted or alkyl-substituted heteroaryl, or an unsubstituted or alkyl-substituted heterocycloalkyl, having 1 to 3 heteroatoms selected from N, O or S;
R2’ and R2” each independently is hydrogen or alkyl;
R3’ and R3” each independently is hydrogen or alkyl;
R4 is alkyl, halo, hydroxyalkyl, haloalkyl, cyano, -OR5, unsubstituted or substituted cycloalkyl, unsubstituted or substituted cycloalkenyl, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl or unsubstituted or substituted heterocycloalkyl; wherein the substituents on cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocycloalkyl are independently selected from one or more alkyl, halo, haloalkyl, hydroxy, cyano, amino, - COOH or hydroxyalkyl;
R5 is selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl or heterocycloalkyl; m is 1, 2, 3 or 4; and n is 0, 1, 2 or 3.
2. The compound as claimed in claim 1, having a formula (IA):
5. The compound as claimed in claim 1, having a formula (ID):
6. The compound as claimed in claim 1 to 5, wherein Ri is hydroxy.
The compound as claimed in claim 1 to 5, wherein Ri is alkyl.
8. The compound as claimed in claim 1 to 5, wherein Ri is hydroxy or methyl.
9. The compound as claimed in claim 1 to 5, wherein R2' and R2" are each hydrogen.
10. The compound as claimed in claim 1 to 5, wherein R3' and R3" are each hydrogen.
11. The compound as claimed in claim 1 to 5, wherein R4 is alkyl.
12. The compound as claimed in claim 1 to 5, wherein m is 3.
13. The compound as claimed in claim 1 to 5, wherein m is 4.
14. The compound as claimed in claim 1 to 5, wherein n is 0.
15. The compound as claimed in claim 1 to 5, wherein n is 1 or 2.
17. A pharmaceutical composition comprising the compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipient (such as a pharmaceutically acceptable carrier or diluent).
18. The compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt or a stereoisomer thereof, for use as a medicament.
19. The compound of any one of claims 1 to 16, for use in the treatment of a cancer.
20. The compound of claim 19, wherein the cancer is caused by the overexpression of CCNE1 or having an inactivating mutation in the FBXW7 gene.
21. The compound of claim 19, wherein the cancer is selected from uterine cancer, ovarian cancer, breast cancer, stomach cancer, glioblastoma, hepatocellular carcinoma, neuroblastoma, prostate cancer, colorectal cancer, lung cancer, esophageal cancer and endometrial cancer.
22. A method of inhibiting PKMYT1 in a subject, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt or a stereoisomer thereof.
23. A method of treating diseases or conditions mediated by PKMYT1 in a subject comprising administering to the subject in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt or a stereoisomer thereof.
24. The method of claim 23, wherein the disease or condition mediated by PKMYT1 is cancer caused by the overexpression of CCNE1 or having an inactivating mutation in the FBXW7 gene.
25. The method of claim 24, wherein the cancer caused by overexpression of CCNE1 is uterine cancer, ovarian cancer, breast cancer, stomach cancer, lung cancer, esophageal cancer and endometrial cancer.
26. The method of claim 24, wherein the cancer caused by deficiency in FBXW7 is uterine cancer, lung cancer, breast cancer, colorectal cancer and esophageal cancer.
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Citations (4)
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WO2000033837A2 (en) * | 1998-12-07 | 2000-06-15 | Smithkline Beecham Corporation | Myt1 kinase inhibitors |
WO2021195782A1 (en) * | 2020-04-01 | 2021-10-07 | Repare Therapeutics Inc. | Methods of using myt1 inhibitors |
US20230122909A1 (en) * | 2021-10-04 | 2023-04-20 | Repare Therapeutics Inc. | Compounds, pharmaceutical compositions, and methods of preparing compounds and of their use |
WO2023249563A1 (en) * | 2022-06-23 | 2023-12-28 | Engine Biosciences Pte. Ltd. | Compounds and method for pkmyt1 inhibition |
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WO2000033837A2 (en) * | 1998-12-07 | 2000-06-15 | Smithkline Beecham Corporation | Myt1 kinase inhibitors |
WO2021195782A1 (en) * | 2020-04-01 | 2021-10-07 | Repare Therapeutics Inc. | Methods of using myt1 inhibitors |
US20230122909A1 (en) * | 2021-10-04 | 2023-04-20 | Repare Therapeutics Inc. | Compounds, pharmaceutical compositions, and methods of preparing compounds and of their use |
WO2023249563A1 (en) * | 2022-06-23 | 2023-12-28 | Engine Biosciences Pte. Ltd. | Compounds and method for pkmyt1 inhibition |
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