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WO2025085564A1 - Inhibiteurs de lysine acétyltransférase - Google Patents

Inhibiteurs de lysine acétyltransférase Download PDF

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WO2025085564A1
WO2025085564A1 PCT/US2024/051654 US2024051654W WO2025085564A1 WO 2025085564 A1 WO2025085564 A1 WO 2025085564A1 US 2024051654 W US2024051654 W US 2024051654W WO 2025085564 A1 WO2025085564 A1 WO 2025085564A1
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alkyl
methyl
mmol
compound
optionally substituted
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Tamara Hopkins
Zhihua Ma
Hua Gao
Christopher John DINSMORE
Benjamin Wesley TROTTER
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Kronos Bio Inc
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Kronos Bio Inc
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Priority to PCT/US2025/010315 priority Critical patent/WO2025147670A1/fr
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
    • C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
    • C07D241/40—Benzopyrazines
    • C07D241/42—Benzopyrazines with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
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    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/34—1,4-Oxazines; Hydrogenated 1,4-oxazines condensed with carbocyclic rings
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
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Definitions

  • Lysine acetyltransferases catalyze the transfer of an acetyl group from acetyl CoA (AcCoA) to the ⁇ -amino group on lysine residues of substrate proteins (Lee, K., Workman, J. Nat Rev Mol Cell Biol 8, 284–295 (2007)). Lysine deacetylases (KDACs) catalyze the removal of the acetyl group. Specific protein domains, including bromodomains, can bind proteins in an acetylation-dependent manner (R. Marmorstein and M.-M. Zhou. Cold Spring Harb Perspect Biol 2014;6:a018762).
  • acetyl group can impact protein function, including protein-protein interactions. This is because the acetyl group on the target lysine residue neutralizes the charge of the lysine ⁇ -amino group which is known to impact chromatin compaction in the nucleus.
  • Emerging evidence highlights a diverse set of cofactors and substrate macromolecules that can be regulated by KATs. In addition to transferring acetyl groups, these proteins can also transfer longer chain acyl groups, including crotonyl (from crotonyl CoA), to lysine resides of substrate proteins (Kaczmarska et al. Nat Chem Biol. 2017 Jan; 13(1): 21– 29).
  • KAT ELP3 The function of longer chain acyl group modification is not well understood and this application will focus on acetyl transferase activity of proteins.
  • the KAT ELP3 is known to acetylate non-protein substrates, including transfer RNAs (Lin, TY., Abbassi, N.E.H., Zakrzewski, K. et al. Nat Commun 10, 625 (2019)), further expanding the biological impact of acetyltransferase function.
  • transfer RNAs Lofi, Zakrzewski, K. et al. Nat Commun 10, 625 (2019)
  • the protein activity and its enzymatic inhibition with CoA-competitive KAT inhibitors (KATi) likely encompasses different acyl chain groups and diverse substrates.
  • the human genome encodes at least 12 KATs, consisting of three subfamilies based on amino acid sequence similarity: MYST family, GNAT family and Orphan family.
  • the human KAT proteins p300 and CREB-binding protein (CBP) are paralogs in the Orphan family of human KATs with well-established roles in gene regulation.
  • the p300 protein is encoded by the E1A Binding Protein (EP300) gene (Uniprot ID: Q09472) that is located on human chromosome 22p13.2.
  • the CBP protein is encoded by the CREBBP gene (Uniprot ID: Q92793) that is located on human chromosome 16p13.
  • p300 and CBP are multidomain proteins that consist of an enzymatic KAT domain and multiple protein-protein interaction domains, including a bromodomain and KIX domain.
  • the KAT domain catalyzes acetylation of histones and non-histone proteins where acetylated histones are associated with actively transcribed regions of the genome.
  • the protein-protein interaction domains aid in localizing p300 or CBP to distinct locations in the genome.
  • R 1a is hydrogen, -CN, -C 1 -C 6 alkyl, -CO(C 1 -C 6 alkyl), -CO 2 (C 1 -C 6 alkyl), -CONH 2 , - CONH(C1-C6 alkyl), -CON(C1-C6 alkyl)2, or -SO2(alkyl);
  • R 1b and R 1c are each independently hydrogen, halo, -OH, C1-C6 alkyl, -O-(C1-C6 alkyl), -NH 2 , -NH(C 1 -C 6 alkyl),
  • R 1a is hydrogen; R 1b and R 1c are each independently hydrogen; R 2a is hydrogen; R 2b and R 2c are each independently hydrogen; R 4b is hydrogen; and R 5 is -L-R 6 ; W is N or C-CN; X is CH; Y is CR 10 ; Z is CH; A 1 is NR 1a ; and A 2 is NR 2a , O, or CH 2 .
  • the compound of Formula (I) has the structure of Formula (IIa-2), or Formula (IIb-2), or Formula (IIc-2) or Formula (IIIa-2) 2 ), [0014] In some embodiments, the compound of Formula (I) has the structure of Formula (IIa-2), or Formula (IIb-2), or Formula (IIc-2) or Formula (IIIa-2) 1), (IId-1), or a pharmaceutically acceptable salt thereof.
  • the compound of Formula (I), R 8 , R 9 and R 11 are each independently hydrogen.
  • R 6 is substituted phenyl or R 6 is substituted thiazolyl, pyrazolyl, pyridinyl, pyrimidinyl, or pyridazinyl. In some such embodiments, R 6 is substituted with -COOH, cyano, or alkyl substituted with -COOH or cyano. In some embodiments, R 6 is further substituted with alkyl, halo, hydroxy, oxo, - haloalkyl, or alkoxy.
  • R 4a is phenyl
  • R 10 is 1-methyl-1H-pyrazol-4-yl
  • R 6 is substituted phenyl or R 6 is substituted pyridinyl, and R 6 is substituted with -COOH, cyano, or alkyl substituted with -COOH or cyano.
  • R 6 is substituted with cyano, or alkyl substituted with cyano.
  • W is N and A 2 is O.
  • R 10 is 1-methyl-1H-pyrazol-4-yl.
  • the compound is selected from the group consisting , N N N H N H N N , , [0026] In some embodiments, the compound is selected from the group consisting N N H N , [0028] In some embodiments, A 2 is O or A 2 is NH or A 2 is CH 2 . [0029] In some embodiments, R 10 is hydrogen. In other embodiments, R 10 is halogen. In yet other embodiments, R 10 is 1-methyl-1H-pyrazol-4-yl [0030] In some embodiments, R 6 is phenyl or pyridinyl substituted with – (CH 2 )COOH, -(CH 2 )CN or -CN. [0031] In some embodiments, A 2 is O and R 6 is phenyl substituted with – (CH2)COOH. [0032] In some embodiments, the compound is is [0034] In some embodiments, the compound is [0034] In some embodiments, the compound is [0034] In some embodiments, the compound is
  • N N H N is [0036]
  • the compound is , or a pharmaceutically acceptable salt thereof.
  • the compound is [0038]
  • the compound has the structure of any one of Compounds 101-764, or a pharmaceutically acceptable salt thereof.
  • pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • a method of treating a disease or disorder associated with p300 activity in a subject comprising administering to the subject a therapeutically effective amount of a compound or pharmaceutical composition disclosed herein.
  • non-small cell lung cancer small-cell lung cancer
  • ovarian cancer cervical cancer, gastric cancer, endometrial cancer, esophageal cancer, head and neck cancer, melanoma, neuroendocrine cancer, CNS cancer, brain tumors (e.g., glioma, anaplastic oligodendroglioma, adult glioblastoma multiforme, and adult anaplastic astrocytoma), bone cancer, soft tissue sarcoma, retinoblastomas, neuroblastomas, peritoneal effusions, malignant pleural effusions, mesotheliomas, Wilms tumors, trophoblastic neoplasms, hemangiopericytomas, Kaposi’s sarcomas, myxoid carcinoma, round cell carcinoma, squamous cell carcinomas, esophageal squamous cell carcinomas, oral carcinomas, cancers of the adrenal cortex, and ACTH-producing tumors; the disease or
  • systemic lupus erythematosus myestenia gravis, rheumatoid arthritis, acute disseminated encephalomyelitis, idiopathic thrombocytopenic purpura, multiple sclerosis, Sjoegren’s syndrome, psoriasis, autoimmune hemolytic anemia, asthma, ulcerative colitis, Crohn’s disease, irritable bowel disease, and chronic obstructive pulmonary disease; and the disease or condition is selected from the group consisting of asthma, rheumatoid arthritis, multiple sclerosis, chronic obstructive pulmonary disease, and systemic lupus erythematosus.
  • CBP and p300 KATi with demonstrated anti- proliferative properties in selected cancers, as well as on hematological models. Also provided are methods of treating a subject by administering a therapeutically effective dose of a pharmaceutical composition including the KATi.
  • a pharmaceutical composition including the KATi for a given compound as described herein, if the IUPAC name includes the phrase “S or R” or “R or S,” the compound has a single configuration at that stereocenter, but the configuration is arbitrarily assigned. If the IUPAC name includes the phrase “S and R” or “R and S,” the compound is a mixture of compounds with both R and S configurations at that position.
  • a single IUPAC name may refer to 1, 2, 4, or more individual compounds.
  • the stereochemistry in the chemical structures assigned at a benzylic stereocenter to R 4a (when R 4a is phenyl) is shown relative to the stereochemistry in the chemical structures at the carbon between the R 7 and A 2 positions of Formula I, but is otherwise arbitrarily assigned.
  • the stereochemistry in the chemical structures of the L group methyl substituents was also arbitrarily assigned when L is -(CH2)(CH)(CH3)-.
  • Stereochemistry of substituents in the chemical structures on -(CH2)COOH in R 6 are also arbitrarily assigned, unless otherwise indicated.
  • a 1 is NR 1a or O. In some embodiments, A 1 is NR 1a .
  • a 2 is NR 2a , O, or S. In some embodiments, A 2 is NR 2a . In some embodiments, A 2 is O. In some embodiments, A 2 is S.
  • W is N.
  • X is CR 9 .
  • Y is CR 10 .
  • Z is CR 11 .
  • Some embodiments relate to a compound, having the structure of Formula (IIa-1) (IIa-1), or a pharmaceutically acceptable salt thereof.
  • Some embodiments relate to a compound, having the structure of Formula (IIa-2) (IIa-2), or a pharmaceutically acceptable salt thereof.
  • Some embodiments relate to a compound, having the structure of Formula (IId-1) a pharmaceutically acceptable salt thereof. to a compound, having the structure of Formula (IIe-1) a pharmaceutically acceptable salt thereof. to a compound, having the structure of Formula (IIe-2) a pharmaceutically acceptable salt thereof. to a compound, having the structure of Formula (IIIa-1) (IIIa-1), or a pharmaceutically acceptable salt thereof.
  • Some embodiments relate to a compound, having the structure of Formula (IIIa-2) (IIIa-2), or a pharmaceutically acceptable salt thereof.
  • Some embodiments relate to a compound, having the structure of Formula (IIIb-1) (IIIb-1), or a pharmaceutically acceptable salt thereof.
  • Some embodiments relate to a compound, having the structure of Formula (IIId-1) a pharmaceutically acceptable salt thereof.
  • R 1a is -C1- C 6 alkyl. In some embodiments, R 1a is -CO(C 1 -C 6 alkyl).
  • R 4a and R 4b are each independently hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C 6 -C 10 aryl, optionally substituted 3- to 10-membered cycloalkyl, optionally substituted 3- to 10-membered heteroaryl, or optionally substituted 3- to 10-membered heterocycloalkyl.
  • R 4a is substituted phenyl. In some embodiments, R 4a is phenyl. In some embodiments, R 4a is optionally substituted C 3 -C 10 cycloalkyl.
  • R 4a is optionally substituted 3- to 10-membered heteroaryl. In some embodiments, R 4a is optionally substituted 3- to 10-membered heterocycloalkyl. In some embodiments, R 4a is optionally substituted C 1 -C 6 alkyl.
  • J is O, NH, or CH 2 . In some embodiments, J is NH.
  • R 5 is L-R 6 .
  • L is optionally substituted C1-C10 alkylene. In some embodiments, L is -CH 2 CH 2 - or -CH 2 CH(CH 3 )-.
  • R 6 is optionally substituted phenyl. In some embodiments, R 6 is optionally substituted C3-C10 cycloalkyl. [0078] In some embodiments, R 6 is optionally substituted 3- to 10-membered heteroaryl. In some embodiments, R 6 is optionally substituted thiazolyl, pyrazolyl, pyridinyl, pyrimidinyl, or pyridazinyl. In some embodiments, R 6 is optionally substituted 3- to 10- memebered heterocycloalkyl.
  • each of R 8 , R 9 , R 10 , and R 11 is independently hydrogen, -C1-C6 alkyl, -C1-C6 haloalkyl, -CONH2, -CONH(C1-C6 alkyl), -CON(C1-C6 alkyl)2, C6-C10 aryl, C3-C10 cycloalkyl, 5- to 10-membered heteroaryl, or 4- to 10-membered heterocycloalkyl, wherein said alkyl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl are each optionally substituted with 1, 2, or 3 substituents Q.
  • each of R 8 , R 9 , R 10 , and R 11 is independently selected from the group consisting of hydrogen, halo, -C 1 -C 6 alkyl, -C 1 -C 6 haloalkyl, -CN, -CO 2 H, - CO2(C1-C6 alkyl), -CONH2, -CONH(C1-C6 alkyl), -CON(C1-C6 alkyl)2, -SO2NH2, - SO2NH(C1-C6 alkyl), -SO2N(C1-C6 alkyl)2, C6-C10 aryl, C3-C10 cycloalkyl, 5- to 10-membered heteroaryl, and 4- to 10-membered heterocycloalkyl, wherein said alkyl, aryl, cycloalkyl, heteroaryl and heterocycloalkyl are each optionally substituted with 1, 2, or 3 substituents Q.
  • each of R 9 , R 10 , and R 11 is hydrogen.
  • R 10 is -CONH2, -CONH(C1-C6 alkyl), or -CON(C1- C 6 alkyl) 2 .
  • R 10 is phenyl optionally substituted with 1, 2, or 3 substituents Q.
  • R 10 is 5- to 10-membered heteroaryl optionally substituted with 1, 2, or 3 substituents Q.
  • R 10 is pyrazolyl, pyridinyl, oxazolyl, isoxazolyl, imidazolyl, or indolyl, benzimidazolyl, each optionally substituted with 1, 2, or 3 substituents Q.
  • a compound, or a pharmaceutically acceptable salt thereof having the structure of any one of any one of the compounds described herein.
  • a pharmaceutical composition comprising a compound as described herein and a pharmaceutically acceptable excipient.
  • a droplet includes a plurality of such droplets and reference to “the discrete entity” includes reference to one or more discrete entities, and so forth.
  • the claims may be drafted to exclude any element, e.g., any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology as “solely”, “only” and the like in connection with the recitation of claim elements, or the use of a “negative” limitation.
  • the publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Further, the dates of publication provided may be different from the actual publication dates which may need to be independently confirmed.
  • the term “radical”, such as in “monoradical” or “diradical”, refers to the number groups that a group can connect with.
  • a monoradical group can connect to only a single other group, e.g., the methyl (-CH 3 ) and ethyl (-CH 2 CH 3 ) groups are monoradical groups.
  • the -CH 2 - and -CH 2 CH 2 - groups are diradical groups since they can each connect to two different groups. Since a linker connects two groups, a linker is a diradical group. Connections between groups can also be described by the term “valent”, such as in “monovalent” or “divalent”, which refers to the bond order of the connection.
  • the group -CH3 is a monovalent group since it can form a single covalent bond with another group, e.g., with -OH to form H3COH.
  • the group CH2 is a divalent group since it can form a double bond with another group, e.g., with an oxygen atom to form formaldehyde (CH 2 O).
  • Alkyl refers to monovalent saturated aliphatic hydrocarbyl groups having from 1 to 10 carbon atoms and such as 1 to 6 carbon atoms, or 1 to 5, or 1 to 4, or 1 to 3 carbon atoms.
  • This term includes, by way of example, linear and branched hydrocarbyl groups such as methyl (CH 3 -), ethyl (CH 3 CH 2 -), n-propyl (CH 3 CH 2 CH 2 -), isopropyl ((CH3)2CH-), n-butyl (CH3CH2CH2CH2-), isobutyl ((CH3)2CHCH2-), sec-butyl ((CH3)(CH3CH2)CH-), t-butyl ((CH3)3C-), n-pentyl (CH3CH2CH2CH2CH2-), and neopentyl ((CH 3 ) 3 CCH 2 -).
  • linear and branched hydrocarbyl groups such as methyl (CH 3 -), ethyl (CH 3 CH 2 -), n-propyl (CH 3 CH 2 CH 2 -), isopropyl ((CH3)2CH-), n-butyl (CH3CH2CH2CH2-), iso
  • Alkylene refers to divalent aliphatic hydrocarbyl groups preferably having from 1 to 12 and more preferably 1 to 3 carbon atoms that are either straight-chained or branched. This term includes, by way of example, methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), n-propylene (-CH2CH2CH2-), iso-propylene (-CH2CH(CH3)-), (-C(CH3)2CH2CH2-), (-CH(CH3)CH2-), and the like.
  • Substituted alkylene refers to an alkylene group having from 1 to 3 hydrogens replaced with substituents as described for carbons in the definition of “substituted” below.
  • Alkenyl refers to straight chain or branched hydrocarbyl groups having from 2 to 6 carbon atoms and preferably 2 to 4 carbon atoms and having at least 1 and preferably from 1 to 2 sites of double bond unsaturation. This term includes, by way of example, bivinyl, allyl, and but3en1yl. Included within this term are the cis and trans isomers or mixtures of these isomers.
  • substituted alkenyl refers to an alkenyl group as defined herein having from 1 to 5 substituents, or from 1 to 3 substituents, selected from alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxy
  • Alkynyl refers to straight or branched monovalent hydrocarbyl groups having from 2 to 6 carbon atoms and preferably 2 to 3 carbon atoms and having at least 1 and preferably from 1 to 2 sites of triple bond unsaturation. Examples of such alkynyl groups include acetylenyl (C ⁇ CH), and propargyl (CH2C ⁇ CH).
  • substituted alkynyl refers to an alkynyl group as defined herein having from 1 to 5 substituents, or from 1 to 3 substituents, selected from alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, al
  • Aryl or “Ar” refers to a monovalent aromatic carbocyclic group of from 6 to 18 carbon atoms having a single ring (such as is present in a phenyl group) or a ring system having multiple condensed rings (examples of such aromatic ring systems include naphthyl, anthryl and indanyl) which condensed rings may or may not be aromatic, provided that the point of attachment is through an atom of an aromatic ring. This term includes, by way of example, phenyl and naphthyl.
  • such aryl groups can optionally be substituted with from 1 to 5 substituents, or from 1 to 3 substituents, selected from acyloxy, hydroxy, thiol, acyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, amino, substituted amino, aminoacyl, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl, carboxylalkyl, cyano, halogen, nitro, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, aminoacyloxy, oxyacylamino, thioalkoxy, substituted thioalkoxy, thioaryloxy, thi
  • Amino refers to a “-NRARB” group in which RA and RB are each independently selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C6-10 aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl, as defined herein.
  • a non-limiting example includes free amino (i.e., -NH2).
  • R is selected from hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyclyl, C6-10 aryl, 5-10 membered heteroaryl, and 3-10 membered heterocyclyl, as defined herein.
  • Cyano or “nitrile” refers to the group –CN.
  • Cycloalkyl refers to cyclic alkyl groups of from 3 to 10 carbon atoms having single or multiple cyclic rings including fused, bridged, and spiro ring systems.
  • suitable cycloalkyl groups include, for instance, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl and the like.
  • Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and the like, or multiple ring structures such as adamantanyl, and the like.
  • substituted cycloalkyl refers to cycloalkyl groups having from 1 to 5 substituents, or from 1 to 3 substituents, selected from alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy,
  • Cycloalkenyl refers to non-aromatic cyclic alkyl groups of from 3 to 10 carbon atoms having single or multiple rings and having at least one double bond and preferably from 1 to 2 double bonds.
  • substituted cycloalkenyl refers to cycloalkenyl groups having from 1 to 5 substituents, or from 1 to 3 substituents, selected from alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy,
  • Cycloalkynyl refers to non-aromatic cycloalkyl groups having single or multiple rings and having at least one triple bond.
  • Halo or “halogen” refers to fluoro, chloro, bromo, and iodo.
  • Heteroaryl refers to an aromatic group of from 1 to 15 carbon atoms, such as from 1 to 10 carbon atoms and 1 to 10 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur within the ring.
  • heteroaryl groups can have a single ring (such as, pyridinyl, imidazolyl or furyl) or multiple condensed rings in a ring system (for example as in groups such as, indolizinyl, quinolinyl, benzofuran, benzimidazolyl or benzothienyl), wherein at least one ring within the ring system is aromatic.
  • any heteroatoms in such heteroaryl rings may or may not be bonded to H or a substituent group, e.g., an alkyl group or other substituent as described herein.
  • the nitrogen and/or sulfur ring atom(s) of the heteroaryl group are optionally oxidized to provide for the N-oxide (N ⁇ O), sulfinyl, or sulfonyl moieties.
  • N ⁇ O N-oxide
  • sulfinyl N-oxide
  • sulfonyl moieties N-oxide (N ⁇ O), sulfinyl, or sulfonyl moieties.
  • This term includes, by way of example, pyridinyl, pyrrolyl, indolyl, thiophenyl, and furanyl.
  • heteroaryl groups can be optionally substituted with 1 to 5 substituents, or from 1 to 3 substituents, selected from acyloxy, hydroxy, thiol, acyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, amino, substituted amino, aminoacyl, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl, carboxylalkyl, cyano, halogen, nitro, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, aminoacyloxy, oxyacylamino, thioalkoxy, substituted thioalkoxy, thioaryloxy, thio
  • Heterocycle refers to a saturated or unsaturated group having a single ring or multiple condensed rings, including fused bridged and spiro ring systems, and having from 3 to 20 ring atoms, including 1 to 10 hetero atoms. These ring atoms are selected from nitrogen, sulfur, or oxygen, where, in fused ring systems, one or more of the rings can be cycloalkyl, aryl, or heteroaryl, provided that the point of attachment is through the non-aromatic ring.
  • the nitrogen and/or sulfur atom(s) of the heterocyclic group are optionally oxidized to provide for the N- oxide, -S(O)-, or –SO2- moieties.
  • any heteroatoms in such heterocyclic rings may or may not be bonded to one or more H or one or more substituent group(s), e.g., an alkyl group or other substituent as described herein.
  • heterocycles and heteroaryls include, but are not limited to, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1,2,3,4-tetrahydroisoquinoline,
  • heterocyclic groups can be optionally substituted with 1 to 5, or from 1 to 3 substituents, selected from alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino,
  • substituted when used to modify a specified group or radical, can also mean that one or more hydrogen atoms of the specified group or radical are each, independently of one another, replaced with the same or different substituent groups as defined below.
  • Each M + may independently be, for example, an alkali ion, such as K + , Na + , Li + ; an ammonium ion, such as + N(R 60 ) 4 ; or an alkaline earth ion, such as [Ca 2+ ] 0.5 , [Mg 2+ ] 0.5 , or [Ba 2+ ] 0.5 (“subscript 0.5 means that one of the counter ions for such divalent alkali earth ions can be an ionized form of a compound of the present disclosure and the other a typical counter ion such as chloride, or two ionized compounds disclosed herein can serve as counter ions for such divalent alkali earth ions, or a doubly ionized compound of the present disclosure can serve as the counter ion for such divalent alkali earth ions).
  • an alkali ion such as K + , Na + , Li +
  • an ammonium ion such as + N(R 60 ) 4
  • -NR 80 R 80 is meant to include -NH2, -NH-alkyl, N-pyrrolidinyl, N-piperazinyl, 4N-methyl-piperazin-1-yl and N- morpholinyl.
  • substituent groups for hydrogens on unsaturated carbon atoms in “substituted” alkene, alkyne, aryl and heteroaryl groups are, unless otherwise specified, -R 60 , halo, -O-M + , -OR 70 , -SR 70 , -S – M + , -NR 80 R 80 , trihalomethyl, -CF 3 , -CN, -OCN, -SCN, -NO, -NO 2 , -N 3 , -SO 2 R 70 , -SO 3 -M + , -SO 3 R 70 , -OSO 2 R 70 , -OSO 3 -M + , -OSO 3 R 70 , -PO 3 -2 (M + ) 2 , -P(O)(OR 70 )O-M + , -P(O)(OR 70 )2, -C(O)R 70 ,
  • substituent groups for hydrogens on nitrogen atoms in “substituted” heteroalkyl and cycloheteroalkyl groups are, unless otherwise specified, -R 60 , -O-M + , -OR 70 , -SR 70 , -S-M + , -NR 80 R 80 , trihalomethyl, -CF3, -CN, -NO, -NO2, -S(O)2R 70 , -S(O)2O-M + , -S(O)2OR 70 , -OS(O)2R 70 , -OS(O)2O-M + , -OS(O)2OR 70 , -P(O)(O-)2(M + )2, -P(O)(OR 70 )O-M + , -P(O)(OR 70 )(OR 70 ), -C(O)R 70 , -
  • a group that is substituted has 1, 2, 3, or 4 substituents, 1, 2, or 3 substituents, 1 or 2 substituents, or 1 substituent.
  • Two substituents may come together with the atom or atoms to which they are attached to form a ring that is spiro or fused with the rest of the compound.
  • substituents that are not explicitly defined herein are arrived at by naming the terminal portion of the functionality followed by the adjacent functionality toward the point of attachment.
  • substituent “arylalkyloxycarbonyl” refers to the group (aryl)-(alkyl)-O-C(O)-.
  • substituents it is understood, of course, that such groups do not contain any substitution or substitution patterns which are sterically impractical and/or synthetically non-feasible.
  • the subject compounds include all stereochemical isomers arising from the substitution of these compounds.
  • salt means a salt which is acceptable for administration to a patient, such as a mammal (salts with counterions having acceptable mammalian safety for a given dosage regime). Such salts can be derived from pharmaceutically acceptable inorganic or organic bases and from pharmaceutically acceptable inorganic or organic acids.
  • “Pharmaceutically acceptable salt” refers to pharmaceutically acceptable salts of a compound, which salts are derived from a variety of organic and inorganic counter ions well known in the art and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, formate, tartrate, besylate, mesylate, acetate, maleate, oxalate, and the like.
  • salt thereof means a compound formed when a proton of an acid is replaced by a cation, such as a metal cation or an organic cation and the like. Where applicable, the salt is a pharmaceutically acceptable salt, although this is not required for salts of intermediate compounds that are not intended for administration to a patient.
  • salts of the present compounds include those wherein the compound is protonated by an inorganic or organic acid to form a cation, with the conjugate base of the inorganic or organic acid as the anionic component of the salt.
  • Compounds disclosed herein include all stereoisomers thereof.
  • Stereoisomer and “stereoisomers” refer to compounds that have same atomic connectivity but different atomic arrangement in space. Stereoisomers include cis-trans isomers, E and Z isomers, enantiomers, and diastereomers. [0130] Compounds disclosed herein include all tautomers thereof.
  • pyrazoles imidazoles, benzimidazoles, triazoles, and tetrazoles.
  • the term “or a salt or solvate or stereoisomer thereof” is intended to include all permutations of salts, solvates and stereoisomers, such as a solvate of a pharmaceutically acceptable salt of a stereoisomer of subject compound.
  • Administration and Pharmaceutical Compositions [0132] The disclosed compounds may be used alone or in combination with other treatments. These compounds, when used in combination with other agents, may be administered as a daily dose or an appropriate fraction of the daily dose (e.g., bid). The compounds may be administered after a course of treatment by another agent, during a course of therapy with another agent, administered as part of a therapeutic regimen, or may be administered prior to therapy with another agent in a treatment program.
  • Examples of pharmaceutically acceptable salts include acetate, adipate, besylate, bromide, camsylate, chloride, citrate, edisylate, estolate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hyclate, hydrobromide, hydrochloride, iodide, isethionate, lactate, lactobionate, maleate, mesylate, methylbromide, methylsulfate, napsylate, nitrate, oleate, palmoate, phosphate, polygalacturonate, stearate, succinate, sulfate, sulfosalicylate, tannate, tartrate, terphthalate, tosylate, and triethiodide.
  • compositions containing the active ingredient may be in any form suitable for the intended method of administration.
  • the compounds of a method and/or composition described herein can be provided via oral administration, rectal administration, transmucosal administration, intestinal administration, enteral administration, topical administration, transdermal administration, intrathecal administration, intraventricular administration, intraperitoneal administration, intranasal administration, intraocular administration and/or parenteral administration.
  • oral administration for example, tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs may be prepared.
  • compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation.
  • Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipient which are suitable for manufacture of tablets are acceptable.
  • excipients may be, for example, inert diluents, such as calcium or sodium carbonate, lactose, calcium or sodium phosphate; granulating and disintegrating agents, such as maize starch, or alginic acid; binding agents, such as starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.
  • inert diluents such as calcium or sodium carbonate, lactose, calcium or sodium phosphate
  • granulating and disintegrating agents such as maize starch, or alginic acid
  • binding agents such as starch, ge
  • Formulations for oral use may be also presented as hard gelatin capsules where the active ingredient can be mixed with an inert solid diluent, for example calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient can be mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.
  • Formulations suitable for parenteral administration include aqueous and non-aqueous isotonic sterile injection solutions which may contain, for example, antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the formulations may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze- dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described. [0138] In some embodiments unit dosage formulations contain a daily dose or unit, daily sub-dose, or an appropriate fraction thereof, of a drug.
  • the specific dose level for any particular patient will depend on a variety of factors including the activity of the specific compound employed; the age, body weight, general health, sex and diet of the individual being treated; the time and route of administration; the rate of excretion; other drugs which have previously been administered; and the severity of the particular disease undergoing therapy, as is well understood by those skilled in the art. [0139] The actual dose of the compounds described herein depends on the specific compound, and on the condition to be treated; the selection of the appropriate dose is well within the knowledge of the skilled artisan.
  • a daily dose may be from about 0.1 mg/kg to about 100 mg/kg or more of body weight, from about 0.25 mg/kg or less to about 50 mg/kg, from about 0.5 mg/kg or less to about 25 mg/kg, from about 1.0 mg/kg to about 10 mg/kg of body weight.
  • the dosage range would be from about 7 mg per day to about 7000 mg per day, from about 35 mg per day or less to about 2000 mg per day or more, from about 70 mg per day to about 1000 mg per day.
  • Some embodiments of the present disclosure include methods of treating a disease or disorder associated with p300 activity in a subject, said method comprising administering to the subject a therapeutically effective amount of a compound as described herein or or a pharmaceutical composition as described herein.
  • Some embodiments relate to a method for treating a disease or condition selected from the group consisting of an inflammatory disorder, an allergic disorder, an autoimmune disease, and a cancer in a subject in need thereof, comprising administering a therapeutically effective amount of the compound as described herein or a pharmaceutical composition as described herein to the subject.
  • the disease or condition is a cancer selected from the group consisting of a hematologic malignancy and a solid tumor.
  • the disease or condition is a hematologic malignancy selected from the group consisting of lymphoma, multiple myeloma, or leukemia.
  • the disease or condition is selected from the group consisting of small lymphocytic lymphoma, non-Hodgkin’s lymphoma, indolent non-Hodgkin’s lymphoma, refractory iNHL, mantle cell lymphoma, follicular lymphoma, lymphoplasmacytic lymphoma, marginal zone lymphoma, immunoblastic large cell lymphoma, lymphoblastic lymphoma, Splenic marginal zone B-cell lymphoma (+/- villous lymphocytes), Nodal marginal zone lymphoma (+/- monocytoid B-cells), Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue type, cutaneous T-cell lymphoma, extranodal T-cell lymph
  • the disease or condition is a solid tumor, wherein the solid tumor is from a cancer selected from the group consisting of pancreatic cancer, urological cancer, bladder cancer, colorectal cancer, colon cancer, breast cancer, prostate cancer, renal cancer, hepatocellular cancer, thyroid cancer, gall bladder cancer, lung cancer (e.g.
  • non-small cell lung cancer small-cell lung cancer
  • ovarian cancer cervical cancer, gastric cancer, endometrial cancer, esophageal cancer, head and neck cancer, melanoma, neuroendocrine cancer, CNS cancer, brain tumors (e.g., glioma, anaplastic oligodendroglioma, adult glioblastoma multiforme, and adult anaplastic astrocytoma), bone cancer, soft tissue sarcoma, retinoblastomas, neuroblastomas, peritoneal effusions, malignant pleural effusions, mesotheliomas, Wilms tumors, trophoblastic neoplasms, hemangiopericytomas, Kaposi’s sarcomas, myxoid carcinoma, round cell carcinoma, squamous cell carcinomas, esophageal squamous cell carcinomas, oral carcinomas, cancers of the adrenal cortex, and ACTH-producing tumors.
  • the disease or condition is selected from the group consisting of systemic lupus erythematosus, myestenia gravis, Goodpasture’s syndrome, glomerulonephritis, hemorrhage, pulmonary hemorrhage, atherosclerosis, rheumatoid arthritis, psoriatic arthritis, monoarticular arthritis, osteoarthritis, gouty arthritis, spondylitis, Behçet disease, autoimmune thyroiditis, Reynaud’s syndrome, acute disseminated encephalomyelitis, chronic idiopathic thrombocytopenic purpura, multiple sclerosis, Sjögren’s syndrome, autoimmune hemolytic anemia, tissue graft rejection, hyperacute rejection of transplanted organs, allograft rejection, graft-versus-host disease, diseases involving leukocyte diapedesis, disease states due to leukocyte dyscrasia and metastasis, granulocyte transfusion
  • the disease or condition is selected from the group consisting of systemic lupus erythematosus, myestenia gravis, rheumatoid arthritis, acute disseminated encephalomyelitis, idiopathic thrombocytopenic purpura, multiple sclerosis, Sjoegren’s syndrome, psoriasis, autoimmune hemolytic anemia, asthma, ulcerative colitis, Crohn’s disease, irritable bowel disease, and chronic obstructive pulmonary disease.
  • the disease or condition is selected from the group consisting of asthma, rheumatoid arthritis, multiple sclerosis, chronic obstructive pulmonary disease, and systemic lupus erythematosus.
  • pyrido[2,3-b][1,4]oxazin-3-yl)(phenyl)methyl)-2-(pyridin-4-yl)ethan-1- amine may be prepared according to Procedures C shown in Scheme C, below.
  • Scheme C Preparation of Compounds According to Procedure C: [0159] Additional compounds were prepared according to Procedure C. Their preparation is summarized in Table 3, below. For Compound 201, the corresponding racemic acid was used for the coupling reaction and the resultant diastereomers were separated by SFC following the borane reduction step. Table 3. Compounds prepared according to Procedure C.
  • (S)-3-((R)-(((S)-2-(4-cyanophenyl)propyl)amino)(phenyl)methyl)-N- ethyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-carboxamide may be prepared according to Procedure D shown in Scheme D, below.
  • reaction was stirred at 20 o C for 1 h under H 2 atmosphere (15 psi). LCMS showed starting material was consumed completely and main desired MS was detected.
  • the reaction mixture was filtered through a pad of celite and the celite was rinsed with EtOAc (3 * 10 mL). The filtrate was concentrated under reduced pressure to give a crude product.
  • LCMS showed 42% of peak with starting material remained and 37% of peak with desired MS was detected.
  • the reaction was concentrated under reduced pressure to give a crude product.
  • the crude product was purified by prep-HPLC (Phenomenex luna C18 (250 * 70 mm, 15 um) column; 30 - 60% acetonitrile in an 0.2% formic acid solution in water, 20 min gradient).
  • Step B tert-butyl N-[(R)-[(3R)-2-oxo-1H-pyrido[2,3-b][1,4]oxazin-3-yl]-phenyl- methyl]carbamate (3-nitro-2- pyridyl) - added Fe (1941.41 mg, 34.77 mmol), then the mixture was showed starting material was consumed completely and main desired MS was detected.
  • the reaction mixture was filtered and concentrated under reduced pressure to give a crude product.
  • the mixture was extracted with ethyl acetate (3 * 10 mL).
  • the combined organic layers were dried over anhydrous Na2SO4, then filtered and concentrated under reduced pressure to give a crude product.
  • the mixture was cooled to 25 o C and filtered to removed iron powder. Then evaporate the acetic acid under reduced pressure using a rotary evaporator. Then the crude product was adjusted pH to 8 with sat. NaHCO 3 and filtered. The filter cake was triturated with MeOH (100 mL) at 25 o C for 12 h. The crude product was washed with a small amount of EtOAc, and the filter cake was evaporated the solution on a water bath under reduced pressure using a rotary evaporator and concentrated. The filter was extracted with EtOAc (3*50 mL) and the organic layer was dried over anhydrous Na 2 SO 4 , then filtered and concentrated in vacuum.
  • reaction was stirred at 25 o C for 1 h. LCMS showed the starting material was consumed completely and the main peak with desired MS was detected.
  • the reaction mixture was quenched with MeOH (100 mL) and stirred for 0.5 h. Then the mixture was concentrated under reduced pressure to remove MeOH and THF. The mixture was extracted with EtOAc (100 mL*3) and the combined organic were dried over Na2SO4, filtered and concentrated under reduced pressure to give a crude product.
  • Step I (3S)-3-[(R)-[2-(4-cyanophenyl)propylamino]-phenylmethyl]-N-ethyl-2,3- dihydro- 1H-pyrido[2,3-b][1,4]oxazine-7-carboxamide was added 4-(1-methyl-2-oxo-ethyl)benzonitrile (203.84 mg, 1.28 mmol) and acetic acid (0.05 mL, 0.96 mmol) adjusted to pH 5 ⁇ 6, then the mixture was added NaBH 3 CN (48.28 mg, 0.77 mmol).
  • the reaction mixture was poured into water (50 mL).
  • the aqueous phase was extracted with ethyl acetate (50 mL*2).
  • the combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated in vacuum.
  • the crude product was purified by flash column (ISCO 40 g silica, 50-60 % ethyl acetate in petroleum ether, gradient over 20 min) to give ethyl (2R,3R)-3-(tert-butoxycarbonylamino)-2-[(3-nitro-2-pyridyl)oxy]-3- phenyl-propanoate (3000 mg, 6.9535 mmol, 71.704% yield) was obtained as a yellow solid.
  • Step D tert-butyl N-[(R)-[(3R)-7-(1-methylpyrazol-4-yl)-2-oxo-1H-pyrido[2,3- b][1,4]oxazin-3-yl]-phenyl-methyl]carbamate
  • [5-(1- in acetic acid (10 mL) was added Fe (289.28 mg, 5.18 mmol), then the mixture was stirred at 80 o C for 1 h.
  • LCMS showed the starting material was consumed completely and MS of 96% of desired product was detected.
  • the reaction mixture was concentrated under reduced pressure. Then the crude was adjusted by sat.
  • Step E (3R)-3-[(R)-amino(phenyl)methyl]-7-(1-methylpyrazol-4-yl)-1H-pyrido[2,3- b][1,4]oxazin-2-one oxo-1H- pyrido[2,3-b][1,4]oxazin-3-yl]-phenyl-methyl]carbamate (200 mg, 0.4600 mmol) in HCl/EtOAc (28.21 mL, 112.85 mmol) was stirred at 20 o C for 2 h. LCMS showed the starting material was completely and MS of 61% desired product was detected.
  • Step B 2-[4-[(1R)-2-[[(R)-[(2R)-8-cyano-1,2,3,4-tetrahydroquinoxalin-2-yl]-phenyl- methyl]amino]-1-methyl-ethyl]phenyl]acetic acid/2-[4-[(1S)-2-[[(R)-[(2R)-8-cyano-1,2,3,4- tetrahydroquinoxalin-2-yl]-phenyl-methyl]amino]-1-methyl-ethyl]phenyl]acetic acid SFC IE (250 mm * 30 mm, 10 um); mobile phase: [A: CO2; B: MeOH (0.1%NH3H2O)]; B%: 40.00%-40.00%, 6.50 min).
  • the reaction was stirred at -78 o C for 11 h under N2 atmosphere. LC-MS showed the reactant was consumed completely and desired mass was detected.
  • the reaction mixture was partitioned between NH 4 Cl (80 mL) and EtOAc (80 mL ⁇ 3). The organic phase was separated, washed with brine (150 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue.
  • the residue was purified by flash silica gel chromatography (ISCO@; 80 g SepaFlash@ Silica Flash Column, Eluent of 0 ⁇ 40% Dichloromethane/ Ethyl acetate @ 200 mL/min).
  • Step AB benzyl N-[3-bromo-2-(hydroxymethyl) phenyl] carbamate [0220] (17 g, 73.2 mmol, 1 equiv.) in DCM (160 mL, 0.914 M, 9.412 Vols) was added Pyridine (11.58 g, 11.84 mL, 0.978 g/mL 146.398 mmol, 2 equiv.).
  • Step C.2-[3-[2-[[(S)-[(3S)-5-cyano-1, 2, 3, 4-tetrahydroquinolin-3-yl]-phenyl-methyl] amino] ethyl]-5-fluoro-phenyl] acetic acid (3 g, 13.94 mmol) in methanol (20 mL) and water (10 mL) was added NaOH (5.57 g, 139.37 mmol). The mixture was degassed with N 2 3 times. Then the reaction was warmed to 100 °C and stirred for 12 h. TLC (Petroleum ether: ethyl acetate 3: 1) showed the starting material was consumed completely and one new spot formed.
  • tert-butyl N-[(1S)-3-[(2-formyl-3-pyridyl)amino]-3-oxo-1-phenyl-propyl]carbamate 200 mL was added a solution of tert-butyl N-[(1S)-3-[(2-methyl-3-pyridyl)amino]-3-oxo-1-phenyl- propyl]carbamate (20 g, 56.27 mmol) (parallel 10 g *2) in 1,4-Dioxane (100 mL) at 50 °C and warmed to 110 °C for 12 h.
  • Step F (S)-phenyl-[(3S)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl]methanamine and (S)- phenyl-[(3R)-1,2,3,4-tetrahydro-1,5-naphthyridin-3-yl]methanamine 1,5- naphthyridin-3-yl)methyl]carbamate (180 mg, 0.53 mmol) in EtOAc (1 mL, 0.53 mmol) was added EtOAc/HCl (0.13 mL, 0.53 mmol). The mixture was stirred at 25 °C for 1 h. LCMS showed starting material was consumed completely and 50% of desired mass was detected.
  • reaction mixture was purged with H 2 three times and stirred at 15 o C for 2 h under H 2 (15 psi). LCMS showed starting material was consumed completely and 91% desired MS was detected. The reaction mixture was filtered through a pad of celite and the celite was rinsed with MeOH (20 mL * 3).
  • the reaction mixture was partitioned between H 2 O (100 mL) and EtOAc ⁇ (100 mL ⁇ 3). The organic phase was separated, washed with brine (200 mL), dried over [Na 2 SO 4 ], filtered and concentrated under reduced pressure to give a residue.
  • Step F (1R)-(2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazin-3-yl)(phenyl)methanamine
  • a solution of 3-((R)-amino(phenyl)methyl)-1H-pyrido[2,3-b][1,4]thiazin- 2(3H)-one (190 mg, 0.7 mmol) ⁇ , ⁇ BH 3 .Me 2 S (0.21 mL, 3.5 mmol) ⁇ in ⁇ THF (3 mL) ⁇ was stirred at ⁇ 35 ⁇ o C ⁇ for 2 h.
  • ⁇ LC-MS showed the reactant was consumed completely and desired mass was detected. ⁇ Then the mixture was quenched with MeOH (2 mL), then ⁇ concentrated under reduced pressure to give a residue. ⁇ Then the mixture adjusted by sat.
  • Step H 4-(2-(((R)-((S)-2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazin-3- yl)(phenyl)methyl)amino)ethyl)benzonitrile and 4-(2-(((R)-((R)-2,3-dihydro-1H-pyrido[2,3- b][1,4]thiazin-3-yl)(phenyl)methyl)amino)ethyl)benzonitrile [0258] 4-(2-(((1R)-(2,3-dihydro-1H-pyrido[2,3-b][1,4]thiazin-3- yl)(phenyl)methyl)amino) ethyl)benzonitrile was purified by ⁇ SFC (base condition, column: DAICEL CHIRALPAK IC(250mm*30mm,
  • Step E methyl 2-(3-acetylphenyl)-2-methyl-propanoate (2 g, 7.78 mmol) in Toluene (15 mL) was added tributyl(1-ethoxyvinyl)stannane (4.24 mL, 12.54 mmol) and Pd(PPh3)2Cl2 (272.99 mg, 0.39 mmol), the mixture was degassed and purged with N2 atmosphere for 3 times. The reaction was allowed to warm to 100 o C and continuously stirred at 100 o C for 12 h under N 2 atmosphere. LC-MS showed the reactant was consumed completely.
  • reaction mixture was cooled to 25 °C and was added 1 M HCl (5 mL, 5 mmol), the reaction was continuously stirred at 25 °C for 2 h, whereupon LC-MS showed desired mass was detected.
  • the reaction was quenched with aq. KF (12 mL) slowly at 25 °C. Then diluted with H 2 O (10 mL) and extracted with EtOAc (30 mL). The combined organic layers were washed with saturated NaCl solution (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue.
  • reaction mixture was concentrated under reduced pressure to get a residue, and the reaction mixture was dissolved in MeOH (2 mL) and purified by Prep.-HPLC (column: Phenomenex Luna 80*30 mm*3 um; mobile phase: [water (FA)-ACN]; B%: 13% - 53%, 6 min).
  • the reaction mixture was diluted with H2O (10 mL) and extracted with ethyl acetate (10 mL ⁇ 3). The organic phase was washed with brine (10 mL ⁇ 1), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0 ⁇ 60% Ethyl acetate/Petroleum ether gradient @ 80 mL/min).
  • Step F (R)-N-[(R)-(2-fluorophenyl)-[(3S)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl]methyl]-2-methyl-propane-2-sulfinamide -2-oxo-3,4- dihydro-1H-pyrido[2,3-b]pyrazin-3-yl]methyl]-2-methyl-propane-2-sulfinamide (100 mg, 0.27 mmol) in THF (2 mL) at 0 °C was added BH3.THF (0.8 mL, 0.8 mmol) under N2 atmosphere. The reaction was continuously stirred at 20 o C over 2 h.
  • Step G (R)-(2-fluorophenyl)-[(3S)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl]methanamine -[(3S)-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl]methyl]-2-methyl-propane-2-sulfinamide (70 mg, 0.19 mmol) in HCl/EtOAc (0.5 mL, 2 mmol) was stirred at 25 o C for 0.5 h. LC-MS showed the reactant remained and desired mass was formed. The reaction mixture filtered and concentrated under reduced pressure to give a residue.
  • Compound was purified by Prep.-HPLC (neutral condition, column: Waters Xbridge BEH C18 100*30mm*10um; mobile phase: [A: H 2 O (10mM NH 4 HCO 3 ); B: ACN]; B%: 20.00%-50.00%, 8.00mins).
  • Compound (R)-(2- fluorophenyl)-[(3S)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl]methanamine (15 mg, 0.05 mmol, 30.1% yield) was obtained as a yellow solid.
  • Step H 2-[3-[2-[[(R)-(2-fluorophenyl)-[(3S)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl]methyl]amino]ethyl]phenyl]-2-methyl-propanoic acid [2,3- b]pyrazin-3-yl]methanamine (15 mg, 0.08 mmol) in Methanol (3 mL) were added 2-methyl- 2-[3-(2-oxoethyl)phenyl]propanoic acid (7.98 mg, 0.04 mmol), AcOH (6.97 mg, 0.12 mmol) and NaBH 3 CN (4.88 mg, 0.08 mmol), the mixture was stirred at 20 o C for 1 h.
  • the reaction mixture was quenched by addition NH 4 Cl (30 mL) at 0 °C, diluted with H 2 O (40 mL) and extracted with EtOAc (50 mL ⁇ 3). The organic phase was separated, washed with brine (50 mL), dried over [Na2SO4], filtered and concentrated under reduced pressure to give a residue.
  • the residue was purified by flash silica gel chromatography. (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0 ⁇ 10% Ethyl acetate/Petroleum ether gradient @ 80 mL/min).
  • the reaction was stirred at 80 °C for 2 h under N 2 atmosphere. LCMS showed the reactant was consumed completely and desired mass was formed.
  • the reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (50 mL ⁇ 3). The organic phase was separated, washed with brine (50 mL), dried over [Na 2 SO 4 ], filtered and concentrated under reduced pressure to give a residue.
  • the residue was purified by flash silica gel chromatography. (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 5 ⁇ 10% Ethyl acetate/Petroleum ether gradient @ 80 mL/min).
  • Step B 4-(2,4-difluoro-5-(2-methoxyvinyl)phenyl)isoxazole benzene (0.8 g, 3.21 mmol) in THF (8 mL) and Water (2 mL) were added 4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)isoxazole (751.73 mg, 3.85 mmol), K 3 PO 4 (1361.98 mg, 6.42 mmol) and Catacxium A-Pd-G2 (214.78 mg, 0.32 mmol) and degassed and purged with N23 times. The reaction was stirred at 80 °C for 2 h under N2 atmosphere.
  • Step B methyl 1-(3-acetylphenyl)cyclopropanecarboxylate 1-[3-(1- ethoxyvinyl)phenyl]cyclopropanecarboxylate (4.5 g, 18.27 mmol) in 1,4-Dioxane (10 mL) was added HCl (4.5 mL, 4.5 mmol) (1M in H2O). The mixture was stirred at 25 o C for 0.5 h.
  • methyl 2-(3-acetylphenyl)-2-methyl-propanoate [0296] To a stirred solution of methyl 2-(3-bromophenyl)-2-methyl-propanoate (5 g, 19.45 mmol) in Toluene (50 mL) were added tributyl(1-ethoxyvinyl)stannane (10.53 g, 29.17 mmol) and Pd(PPh3)2Cl2 (682.44 mg, 0.97 mmol) at 25 °C. The mixture was degassed with N2 for 3 times. Then the reaction was warmed to 100 °C and stirred for 12 h under N2. LCMS showed starting material was consumed completely and main desired mass was detected.
  • Step E 2-methyl-2-[3-[(1S)-1-methyl-2-[[(R)-phenyl-[(3R)-1,2,3,4-tetrahydropyrido[2,3- b]pyrazin-3-yl]methyl]amino]ethyl]phenyl]propanoic acid and 2-methyl-2-[3-[(1R)-1-methyl-
  • Step E 1-[3-[(1R)-1-methyl-2-[[(R)-phenyl-[(3R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl]methyl]amino]ethyl]phenyl]cyclobutanecarboxylic acid [(3R)- 1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl]methyl]amino]ethyl]phenyl]cyclobutanecarboxylate (25 mg, 0.05 mmol) in Methanol (0.5 mL), THF (0.5 mL), Water (0.5 mL) was added LiOH.H 2 O (11.15 mg, 0.27 mmol), then the mixture was stirred at 50 o C for 2 h.
  • Step C methyl 3-(3-(1-methoxyprop-1-en-2-yl)phenyl)oxetane-3-carboxylate (1.35 g, 3.93 mmol) in THF (10 mL) was added t-BuOK (3.93 mL, 1M in THF 3.93mmol) at 0 o C under N 2 . The mixture was stirred at 0 o C for 1h. A solution of methyl 3-(3- acetylphenyl)oxetane-3-carboxylate (460 mg, 1.96 mmol) in THF (1 mL) was added to previous mixture at 0 o C. The resulting mixture was stirred at 25 o C for 2 h.
  • the crude product was purified by prep-HPLC(column: Waters Xbridge BEH C18 100*25mm*10um;mobile phase: [A: H 2 O(10mM NH 4 HCO 3 );B: ACN];B%: 20.00%- 50.00%,8.00min) to get 3-[3-[1-methyl-2-[[(R)-phenyl-[(3R)-1,2,3,4-tetrahydropyrido[2,3- b]pyrazin-3-yl]methyl]amino]ethyl]phenyl]oxetane-3-carboxylic acid (50.6 mg, 0.11 mmol, 36.26% yield) as a white solid.
  • Step G 3-[3-[(1S)-1-methyl-2-[[(R)-phenyl-[(3R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl]methyl]amino]ethyl]phenyl]oxetane-3-carboxylic acid and 3-[3-[(1R)-1-methyl-2-[[(R)- phenyl-[(3R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl]methyl]amino]ethyl]phenyl]oxetane-3-carboxylic acid [0326] 3-[3-[1-methyl-2-[[(R)-phenyl-[(3R)-1,2,3,4-tetrahydropyrido[2,3- b]pyrazin-3-yl]methyl]amino]ethyl]phenyl]ox
  • Step B 4-[5-(2-methoxy-1-methyl-vinyl)-3-pyridyl]isoxazole (3 g, 13.15 mmol) in THF (32 mL) and Water (8 mL) was added 4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)isoxazole (2.82 g, 14.47 mmol), K 3 PO 4 (5.58 g, 26.31 mmol) and Catacxium A-Pd-G2 (0.44 g, 0.66 mmol).
  • Step A 3-(3-acetylphenyl)propanoic acid mmol, 1 equiv.) in dioxane (40 mL, 0.44 M, 10 Vols) was added tributyl(1-ethoxyethenyl)stannane (9.46 g, 8.85 mL, 1.07 g/mL, 26.19 mmol, 1.5 equiv.) and Pd(PPh3)2Cl2 (612.82 mg, 0.87 mmol, 0.05 equiv.) at 15 o C. The mixture was degassed with N 2 for 3 times. Then the reaction was warmed to 100 o C and stirred for 12 h under N2.
  • the reaction mixture was degassed with N 2 for three times and stirred at 15 o C for 1 h under N2 atmosphere. LCMS showed starting material was consumed completely and 77% peak with desired mass was detected.
  • the mixture was diluted with water (5 mL) and the mixture was adjusted pH ⁇ 6 by adding 1N HCl, and extracted with EtOAc (10 ⁇ 3 mL). The organic layer was washed with brine (10 mL), dried over anhydrous Na 2 SO 4 , then filtered and concentrated in vacuo.
  • the reaction mixture was degassed with N 2 three times and heated to 80 o C and stirred for 2 h under N2 atmosphere. LCMS showed starting material was consumed completely and 45% peak with desired mass was detected.
  • the reaction was cooled to 20 o C.
  • the mixture was diluted with water (5 mL) and extracted with ethyl acetate (3 ⁇ 3 mL). The organic layer was washed with brine (10 mL), dried over anhydrous Na 2 SO 4 , then filtered and concentrated in vacuo.
  • reaction mixture was degassed with N2 for three times, and then the mixture was heated to 50 o C and stirred for 2 h under N2 atmosphere.
  • LCMS showed starting material was consumed completely and one main peak with desired mass was detected.
  • the reaction was cooled to 20 o C and adjusted by 1 M HCl to pH ⁇ 5-6 at 0 o C.
  • the mixture was diluted with water (5 mL) and extracted with ethyl acetate (3 ⁇ 3 mL). The organic layer was washed with brine (10 mL), dried over anhydrous Na 2 SO 4 , then filtered and concentrated in vacuo.
  • the residue was purified by prep-HPLC (column: Waters Xbridge BEH C18 100 * 30 mm * 10um; mobile phase: [A: H2O (10mM NH4HCO3); B: ACN]; B%: 15.00%-45.00%, 8.00min).
  • HPLC purification The residue was lyophilized to give 3-[4-(2- ⁇ [(R)-phenyl((3R)-1H,2H,3H,4H-pyrido[2,3- b]pyrazin-3-yl)methyl]amino ⁇ ethyl)pyridin-2-yl]propanoic acid (20.2 mg, 0.05 mmol, Yield 12.69%) as a yellow solid.
  • Step C 1-[(3-acetylphenyl)methyl]cyclopropane-1-carboxylic acid 1- was added tributyl(1-ethoxyethenyl)stannane (7.01 g, 6.56 mL, 1.069 g/cm3, 19.40 mmol, 1.5 equiv.) and Pd(PPh3)2Cl2 (0.454 g, 0.647 mmol, 0.05 equiv.) at 15 o C. The mixture was degassed with N 2 for 3 times. Then the reaction was warmed to 100 o C and stirred for 12 h under N 2 . LCMS showed starting material was consumed completely and a new peak was detected.
  • the reaction was cooled to 15 o C and then was added 1N HCl (20 mL) at 0 °C, then the mixture was stirred at 50 °C for 30 min, then the mixture was added sat. aq. KF (50 mL) at 0 °C, then the mixture was stirred at 20 °C for 3 h, then filtered and extracted with ethyl acetate (3 * 10 mL), then filtered and concentrated under reduced pressure to give a crude product.
  • the crude product was purified by flash column (ISCO 10 g silica, 0 -30 % ethyl acetate in petroleum ether, gradient over 20 min).
  • the reaction mixture was degassed with N2 for three times, and then the mixture was stirred at 15 °C for 1 h under N 2 atmosphere.
  • LCMS showed starting material was consumed completely and 67% peak with desired mass was detected.
  • the mixture was diluted with water (5 mL) and the mixture was adjusted pH ⁇ 6 by adding 1 M HCl, and extracted with EtOAc (10 ⁇ 3 mL). The organic layer was washed with brine (10 mL), dried over anhydrous Na2SO4, then filtered and concentrated in vacuum.
  • Step A ethyl(2S,3S)-3-(tert-butoxycarbonylamino)-2-[(3-nitro-2-pyridyl)amino]-3-phenyl- propanoate
  • 2-amino-3-(tert- butoxycarbonylamino)-3-phenyl-propanoate 2000 mg, 6.4857 mmol
  • 2-chloro-3-nitro-pyridine 1131.1 mg, 7.1343 mmol
  • TEA 2.7294 mL, 19.457 mmol
  • the mixture was cooled to 25 o C, 40 mL of water was added and extracted with Ethyl acetate (15 mL*2). The combined organic layers were washed with brine (15 mL) and dried over Na 2 SO 4 . The combined organic layer was concentrated to dryness to give residue.
  • the crude product was purified by flash column (ISCO 20 g silica, 0-40 % ethyl acetate in petroleum ether, gradient over 20 min).
  • the reaction mixture was cooled to room temperature and poured into water (50 mL) .
  • the aqueous phase was extracted with ethyl acetate (50 mL*2).
  • the combined organic phase was dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum.
  • the crude product was purified by flash column (ISCO 40 g silica, 50-60 % ethyl acetate in petroleum ether, gradient over 20 min) to give methyl (2R,3R)-3-(tert- butoxycarbonylamino)-2-[(3-nitro-2-pyridyl)amino]-3-phenyl-propanoate (850 mg, 2.04 mmol, 72.39% yield) as a yellow solid.
  • tert-butyl (((2S,5R)-5-isopropyl-3,6-dimethoxy-2,5-dihydropyrazin-2-yl)(6- methoxypyridin-2-yl)methyl)carbamate (6.43 g, 34.92 mmol) in THF (8 mL) was added 2.5 M n-BuLi (15.24 mL, 38.09 mmol) at -78 o C for 0.5 h under N 2 , and then tert-butyl (E)-((6-methoxypyridin-2-yl)methylene)carbamate (7.5 g, 31.74 mmol) was added at -78 o C for 1 h under N2.
  • NE tert-butyl N-[benzenesulfonyl-(2-fluorophenyl)methyl]carbamate
  • Na2SO4 13.99 g, 98.52 mmol
  • Cs2CO3 32.39 g, 98.52 mmol
  • dihydropyrazine (10 g, 54.28 mmol) was n- mmol) at -78 o C dropwise under N2, and the suspension was stirred at -78 o C for 30 min under N2.
  • the reaction mixture was extracted between EtOAc (30 mL ⁇ 3) and H 2 O 40 mL. The organic phase was separated, washed with brine (30 mL), dried over [Na2SO4], filtered and concentrated under reduced pressure to give a residue. The residue was concentrated under reduced pressure to get a residue, and the residue was purified by flash silica gel chromatography. (ISCO®; 20 g Sepa Flash Silica Flash Column, Eluent of 0 ⁇ 20% Ethyl acetate/Petroleum ether gradient @ 80 mL/min).
  • the reaction was stirred at 80 o C for 8 hours. LCMS showed the reactant was consumed completely and desired mass was formed.
  • the mixture was basified pH to 8 with NaHCO3, the reaction mixture was extracted between EtOAc (20 mL ⁇ 3) and H2O 20 mL. The organic phase was separated, washed with brine (20 mL), dried over [Na2SO4], filtered and concentrated under reduced pressure to give a residue.
  • Step I 4-(2-(((R)-(2-fluorophenyl)((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)ethyl) and 4-(2-(((R)-(2-fluorophenyl)((S)-1,2,3,4- tetrahydropyrido[2,3-b] 3-yl)methyl)amino)ethyl) (formate salt) pyrazin- 3-yl]methanamine (70 mg, 0.27 mmol), 4-(2-oxoethyl)benzonitrile (8.43 mg, 0.06 mmol) and AcOH (0.1 mL) in Methanol (2 mL) was stirred for 0.5 h, and then NaBH3CN (2.43 mg, 0.04 mmol) was added to the mixture.
  • reaction mixture was diluted with H2O (5 mL) and extracted with EtOAc (5 mL ⁇ 3). The combined organic layers were washed with brine (5 mL ⁇ 1), dried over [Na 2 SO 4 ], filtered and concentrated under reduced pressure to give a residue, and the residue was purified by flash silica gel chromatography (ISCO@; 20 g SepaFlash@ Silica Flash Column, Eluent of 25 ⁇ 40% Ethyl acetate/Petroleum ethergradient @ 100 mL/min).
  • the reaction was stirred at 25 o C for 0.5 h, then iodoethane (1.34 mL, 16.74 mmol) was added to the mixture.
  • the reaction was stirred at 25 o C for 1.5 h under N 2 .
  • LC-MS showed the reactant was consumed completely and desired mass was detected.
  • the reaction was successful.
  • the reaction mixture was poured into ice saturated NH4Cl solution (10 mL).
  • the mixture was diluted with H 2 O (30 mL) and extracted with EtOAc (30 mL ⁇ 3).
  • the organic phase was separated, washed with brine (10 mL ⁇ 1).
  • the combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated to give a residue.
  • Step B 2-(3-(2-ethoxyvinyl) phenyl) butanoic acid
  • Step D 2-(3-(2-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)ethyl)phenyl)butanoic acid
  • Step E (R)-2-(3-(2-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)ethyl)phenyl)butanoic acid & (S)-2-(3-(2-(((R)-phenyl((R)-1,2,3,4- tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)ethyl)phenyl)butanoic acid yl]methyl]amino]ethyl]phenyl]butanoic acid (80 mg, 0.19 mmol) was purified by SFC separation (basic condition, column: DAICEL CHIRALPAK IG (250mm*30mm,10um); mobile phase: [A: CO2, B: IPA(0.1% NH3H2O); B%: 50.00%-50.00%, 9.00min
  • the reaction was stirred at 25 o C for 1 h. LC-MS showed the reactant was consumed completely and desired mass was detected.
  • the reaction was added HCl (1M) adjust pH to 5 ⁇ 6, and the reaction mixture was diluted with H2O (200 mL), and extracted with ethyl acetate (200 mL ⁇ 3). The combined organic phase was washed with brine (200 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated give a residue.
  • the residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0 ⁇ 10% Ethyl acetate/Petroleum ether gradient @ 80 mL/min).
  • the reaction was combined with another batch for work up and purification.
  • the reaction mixture was filtered.
  • the filtrate was diluted with water (100 mL), and then extracted with ethyl acetate (100 mL ⁇ 3).
  • the combined organic layers were washed with saturated brine (100 mL), dried over anhydrous Na2SO4.
  • the reaction mixture was concentrated under reduced pressure to get a residue.
  • the residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0 ⁇ 20% Ethyl acetate/Petroleum ether gradient @ 120 mL/min).
  • the reaction was stirred at 80 o C for 2 h, whereupon LC-MS showed the reactant was consumed completely and desired mass was detected.
  • the reaction was concentrated to dryness.
  • the residue was diluted with H2O (20 mL) and extracted with ethyl acetate (20 mL ⁇ 3). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated give a residue.
  • the residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0 ⁇ 10% Ethyl acetate/Petroleum ether gradient @ 80 mL/min).
  • Step E 3-methoxy-2-(3-(2-oxoethyl)phenyl)propanoic acid -3-methoxy- (0.3 mL, 3.6 mmol).
  • the reaction was stirred at 0 o C for 0.5 h, whereupon TLC showed the reactant was consumed completely and one spot was detected.
  • the reaction was concentrated to dryness.
  • the residue was diluted with H 2 O (2 mL) and extracted with ethyl acetate (2 mL ⁇ 3). The combined organic phase was washed with brine (2 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated give a residue.
  • the reaction was allowed to warm to 25 o C and continuously stirred at 25 o C for 1 h, whereupon LC-MS showed the reactant was consumed completely and desired mass was detected.
  • the reaction was concentrated to dryness.
  • the reaction was concentrated to dryness.
  • the residue was diluted with H2O (2 mL) and extracted with ethyl acetate (2 mL ⁇ 3). The combined organic phase was washed with brine (2 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated give a residue.
  • Step E 2-[3-[2-[[(R)-phenyl-[(3R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl]methyl]amino]ethyl]-4-(trifluoromethyl)phenyl]acetic acid H N N H 2 H O pyrazin- 3-yl]methanamine (40 mg, 0.17 mmol) in Methanol (1 mL) were added CH3COOH (9.99 mg, 0.17 mmol) and NaBH3CN (31.38 mg, 0.5 mmol) at 0 o C.
  • the mixture was stirred at 25 o C for 1.5 h. TLC indicated the reactant was consumed completely and one new spot formed.
  • the reaction mixture was quenched by addition saturated aqueous NH4Cl (20 mL) at 0 o C slowly under N2 atmosphere, and stirred at 20 o C for 15 mins. The reaction was concentrated to dryness. The residue was diluted with H 2 O (20 mL) and extracted with ethyl acetate (20 mL ⁇ 3). The combined organic phase was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated give a residue.
  • Step B (E)-2-(5-(2-ethoxyvinyl)-2-methylphenyl)propanoic acid acid (0.9 g, 3.70 mmol, 1 -2-ethoxyethenyl] -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane (0.88 g, 4.44 mmol, 1.2 equiv.), K 2 CO 3 (1.02 g, 7.40 mmol, 2 equiv.) and Pd(pddf)Cl2 (0.14 g, 0.19 mmol, 0.05 equiv.). The reaction was degassed and purged with N2 for 3 times, and then the mixture was stirred at 90 o C for 2 h under N 2 atmosphere.
  • Step C 2-(2-methyl-5-(2-oxoethyl)phenyl)propanoic acid propanoic acid (500 mg, 2.13 mmol, 1 equiv.) in CH3CN (2 mL) was added HCl (0.1 mL, 12 M, 1 equiv.). The mixture was stirred at 20 o C for 0.5 h. TLC indicated the reactant was consumed completely and one new spot formed. The residue was diluted with H 2 O (3 mL) and extracted with ethyl acetate (3 mL ⁇ 3). The combined organic phase was washed with brine (3 mL), dried over anhydrous Na2SO4, filtered and concentrated give a residue.
  • Step E (S)-2-(2-methyl-5-(2-(((R)-phenyl((R)-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3- yl)methyl)amino)ethyl)phenyl)propanoic
  • R -2-(2-methyl-5-(2-(((R)-phenyl((R)- 1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-3-yl)methyl)amino)ethyl)phenyl)propanoic acid (10 mM NH 4 HCO 3 ); B: ACN]; B%: 25.00%-55.00%, 8.00 min).
  • the suspension was degassed and purged with N 2 for 3 times.
  • the reaction was stirred at 80 o C for 3 h.
  • LC-MS showed the reactant remained and desired mass was detected.
  • the reaction was concentrated to dryness.
  • the residue was diluted with H 2 O (50 mL) and extracted with ethyl acetate (50 mL ⁇ 3).
  • the combined organic phase was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated give a residue.
  • the residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0 ⁇ 40% Ethyl acetate/Petroleum ether gradient @ 80 mL/min).
  • Step C 2-[2,4-difluoro-5-[(E)-2-methoxyvinyl]phenyl]acetic acid in THF (2 mL) were 5-[(E)-2- methoxyvinyl]phenyl]acetic acid (300 mg, 1.31mmol) at -78 o C under N 2 atmosphere. The mixture was stirred at -78 o C for 0.5 h under N2 atmosphere. The mixture was added CH3I (279.91 mg, 1.97 mmol) at -78 o C, the mixture was stirred at 25 o C for 1.5 h under N2 atmosphere. TLC indicated reactant was consumed completely and one new spot formed.
  • the reaction mixture was quenched by addition NH 4 Cl 10 (mL), then the mixture was diluted with H2O (10 mL) and extracted with ethyl acetate (10 mL ⁇ 3). The combined organic phase was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0 ⁇ 47% Ethyl acetate/Petroleum ether gradient @ 80 mL/min).
  • Step E 2-[2,4-difluoro-3-methyl-5-[2-[[(R)-phenyl-[(3R)-1,2,3,4-tetrahydropyrido[2,3- b]pyrazin-3-yl]methyl]amino]ethyl]phenyl]acetic acid b]pyrazin- 3-yl]methanamine (60.0 mg, 0.25 mmol) in Methanol (0.5 mL) were added 2-[2,4-difluoro-3- methyl-5-(2-oxoethyl)phenyl]acetic acid (68.37 mg, 0.3 mmol) and Acetic acid (0.1 mL) for 10 mins.
  • Step B 2-[4-cyclopropyl-3-[(E)-2-ethoxyvinyl]phenyl]acetic acid (2100 mg, , , mg, 17.45 mmol), RuPhos Pd G3 (583.8 mg, 0.70 mmol) in Toluene (40 mL) and water (10 mL) was degassed and purged with N 2 for 3 times, the mixture was stirred at 110 °C for 12 h under N2 atmosphere. LC-MS showed the reactant was consumed completely and desired mass was detected. The mixture was adjusted pH to 3 with aqueous solution of hydrochloric acid (1mol/L), diluted with H 2 O (100 mL) and extracted with EtOAc (100 mL ⁇ 3).

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Abstract

L'invention concerne des inhibiteurs de la protéine de liaison à CREB (CBP) et de la lysine acétyltransférase p300 (KATi). L'invention concerne également des méthodes de traitement d'un sujet par administration d'une quantité thérapeutiquement efficace d'une composition pharmaceutique contenant les KATi.
PCT/US2024/051654 2023-10-16 2024-10-16 Inhibiteurs de lysine acétyltransférase Pending WO2025085564A1 (fr)

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