WO2024253416A1 - Dérivés de pyrimidine/pyridine ou leurs sels et compositions pharmaceutiques les comprenant - Google Patents

Dérivés de pyrimidine/pyridine ou leurs sels et compositions pharmaceutiques les comprenant Download PDF

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WO2024253416A1
WO2024253416A1 PCT/KR2024/007677 KR2024007677W WO2024253416A1 WO 2024253416 A1 WO2024253416 A1 WO 2024253416A1 KR 2024007677 W KR2024007677 W KR 2024007677W WO 2024253416 A1 WO2024253416 A1 WO 2024253416A1
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pyridin
methoxyphenyl
fluoro
amino
pyrazol
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Jaewon Jeong
Eun Hye Jung
Soyeon Lee
Hyokjun CHO
Kwan Hoon Hyun
Suhwa KIM
Wonee Chong
Tae Kyun Kim
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Yuhan Corp
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Yuhan Corp
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    • 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
    • C07D401/00—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
    • C07D401/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—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
    • C07D405/14—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 three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings

Definitions

  • the present invention relates to a pyrimidine/pyridine derivative or pharmaceutically acceptable salt thereof having an excellent inhibitory activity against hematopoietic progenitor kinase 1 (HPK1), a process for the preparation thereof, a pharmaceutical composition comprising the same, and a use thereof.
  • HPK1 hematopoietic progenitor kinase 1
  • Antibody-based cancer immunotherapy shows continuous anti-tumor effects in a significant proportion of cancer patients and thus the development of cancer immunotherapy will be one of the effective anti-cancer platforms in the future.
  • Antibody-based cancer immunotherapy has been shown to improve survival rates compared to conventional standard therapies. However, the response rate thereof varies widely depending on tumor types, ranging from 15% in head and neck cancer patients to 87% in leukemia patients (Science 2018;23;359(6382):1350-1355).
  • Such a limitation makes it difficult to utilize cancer immunotherapy as a broad-spectrum anticancer therapy and requires developing the biomarkers that can predict responsiveness (Nature 2017;18;541(7637):321-330; Nat. Rev. Cancer 2019; Mar;19(3):133-150). Therefore, in addition to the cancer immunotherapy, there is an urgent need for alternative approaches that modulate the response of immune cells.
  • Hematopoietic progenitor kinase 1 a member of the MAP4K family, is a serine/threonine kinase and is mainly expressed only in the hematopoietic cell lineage (T cells, B cells, DC cells, mononuclear cells, NK cells, etc.).
  • HPK1 involves in various signaling mechanisms such as JNK, AP-1, and NK- ⁇ B to regulate the function of immune cells (Genes Devel. 1996; 10:2251-2264, EMBO J. 1996; 15:7013-7025, Proc Nat Acad Sci USA. 2009; 106(34):14508-14513).
  • HPK1 plays a role in suppressing excessive activity of T cells through phosphorylation and activation of the T cell receptor adapter protein SLP-76 when the T cell receptor is activated by binding to a ligand (J. Exp. Med. 2007; 204:681).
  • HPK1 inhibits the activity of B cells by interfering with signaling of the B cell receptor through phosphorylation of BLNK protein (J. Biol. Chem. 2012; 287:11037). Therefore, increase in proliferation of T cells and increase in inflammatory cytokines can be observed in HPK1 KO/KD mice in which the function of HPK1 is suppressed.
  • the present inventors carried out various studies to develop a material having an excellent inhibitory activity against HPK1. As a result, the present inventors have found that a pyrimidine/pyridine derivative or pharmaceutically acceptable salt thereof has an excellent inhibitory activity against HPK1. Therefore, the pyrimidine/pyridine derivative or pharmaceutically acceptable salt thereof inhibits HPK1 to activate immune cells and improve the tumor microenvironment in which the immune system is suppressed, thereby being able to be usefully applied to the prevention and treatment of various blood cancers and solid tumors.
  • the present invention provides said pyrimidine/pyridine derivative or pharmaceutically acceptable salt thereof, a process for the preparation thereof, a pharmaceutical composition comprising the same, and a use thereof.
  • a pyrimidine/pyridine derivative or pharmaceutically acceptable salt thereof there is provided a pyrimidine/pyridine derivative or pharmaceutically acceptable salt thereof.
  • a pharmaceutical composition comprising said pyrimidine/pyridine derivative or pharmaceutically acceptable salt thereof as an active ingredient.
  • a therapeutic method comprising administering said pyrimidine/pyridine derivative or pharmaceutically acceptable salt thereof.
  • pyrimidine/pyridine derivative or pharmaceutically acceptable salt thereof for the manufacture of a medicament for inhibiting hematopoietic progenitor kinase 1.
  • the pyrimidine/pyridine derivative or pharmaceutically acceptable salt thereof has an excellent inhibitory activity against HPK1. Therefore, the compound or pharmaceutically acceptable salt thereof according to the present invention can be usefully applied for preventing or treating various blood cancers and solid tumors, through inhibiting the activity of HPK1.
  • the term 'alkyl' refers to an aliphatic hydrocarbon radical, including a straight or branched aliphatic hydrocarbon radical.
  • the C 1 ⁇ C 6 alkyl means aliphatic hydrocarbon having 1 to 6 carbon atoms, including methyl, ethyl, propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, neopentyl, and isopentyl.
  • the term 'hydroxy' refers to the -OH group.
  • the term 'alkoxy' refers to a radical formed by substituting the hydrogen atom in the hydroxyl group with an alkyl, unless otherwise defined.
  • the C 1 ⁇ C 6 alkoxy includes methoxy, ethoxy, propoxy, n-butoxy, n-pentyloxy, isopropoxy, sec-butoxy, tert-butoxy, neopentyloxy, and isopentyloxy.
  • 'halogen' refers to the fluoro, bromo, chloro, or iodo group.
  • the term 'amino' refers to the -NH 2 group.
  • the term 'alkylamino' refers to an amino group substituted with mono- or di-alkyl.
  • the C 1 ⁇ C 6 alkylamino includes an amino group substituted with mono- or di- C 1 ⁇ C 6 alkyl.
  • the term 'aminocarbonyl' refers to a carbonyl group substituted with amino.
  • the term 'alkylcarbonyl' refers to a carbonyl group substituted with alkyl.
  • the term 'hydroxycarbonyl' refers to a carbonyl group substituted with hydroxy.
  • the term 'alkoxycarbonyl' refers to a carbonyl group substituted with alkoxy.
  • the term 'heterocycloalkylcarbonyl' refers to a carbonyl group substituted with heterocycloalkyl.
  • 'sulfonyl' refers to -SO 2 -.
  • 'alkylsulfonyl' refers to a sulfonyl group substituted with alkyl.
  • 'cyano' refers to the -CN.
  • 'cycloalkyl' refers to a cyclic alkyl group, where the 'alkyl' is the same as defined in the above.
  • the cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc., but not limited thereto.
  • heterocycloalkyl refers to a 3- to 12-membered cycloalkyl or spirocycloalkyl group having one to three heteroatoms selected from N, O and S.
  • the heterocycloalkyl includes azetidinyl, pyrrolidinyl, piperidinyl, N-methylpiperidinyl, pyrazolidinyl, morpholinyl, piperazinyl, tetrahydropyranyl, tetrahydrofuranyl, oxazolidin-2-onyl, 2,8-diazaspiro[4.5]decanyl, etc., but not limited thereto.
  • 'aryl' refers to a 3- to 12-membered aromatic ring and may be a single ring or multiple rings.
  • the aryl includes phenyl, naphthyl, biphenyl, etc., but not limited thereto.
  • heteroaryl refers to a 3- to 12-membered aromatic ring having one to three heteroatoms selected from N, O and S and may be a single ring or multiple rings.
  • the heteroaryl includes thienyl, furyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, pyridinyl, pyrimidinyl, quinolinyl, quinazolinyl, quinoxalinyl, [1,2,4]triazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, imidazo[1,2-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridin-6-yl, etc., but not limited thereto.
  • 'substituted' refers to being substituted at one or more substitutable positions.
  • the expression 'C 1 ⁇ C 6 alkyl substituted with halogen' includes a C 1 ⁇ C 6 alkyl group substituted with one or more halogens, for example, 1, 2 or 3 halogens.
  • the present invention provides a pyrimidine/pyridine derivative or pharmaceutically acceptable salt thereof having an excellent inhibitory activity against HPK1, i.e., the following compound of Formula 1 or pharmaceutically acceptable salt thereof:
  • R 1 and R 2 are, independently each other, a C 1 ⁇ C 6 alkyl group; a C 3 ⁇ C 6 cycloalkyl group optionally substituted with hydroxy or amino; or a heterocycloalkyl optionally substituted with hydroxy or amino, or
  • R 1 and R 2 form a heterocycloalkyl together with the nitrogen atom to which they are bonded, wherein the heterocycloalkyl is optionally substituted with one or two groups selected from the group consisting of halogen, amino, hydroxy, C 1 ⁇ C 6 alkyl, C 1 ⁇ C 6 alkoxy, C 1 ⁇ C 6 alkyl substituted with halogen, C 1 ⁇ C 6 alkyl substituted with hydroxy, C 3 ⁇ C 6 cycloalkyl, C 3 ⁇ C 6 cycloalkyl substituted with hydroxy, mono- or di-C 1 ⁇ C 6 alkylamino, aminocarbonyl, C 1 ⁇ C 6 alkylcarbonylamino, and mono- or di-C 1 ⁇ C 6 alkylamino-C 1 ⁇ C 6 alkyl,
  • R 3 is hydrogen, halogen, cyano, nitro, amino, C 1 ⁇ C 3 alkyl, C 1 ⁇ C 3 alkyl substituted with halogen, hydroxycarbonyl, C 1 ⁇ C 3 alkoxycarbonyl, aminocarbonyl, mono- or di-C 1 ⁇ C 3 alkylaminocarbonyl, or C 1 ⁇ C 3 alkylsulfonyl,
  • A is a 5- to 12-membered aryl group; a 5- to 12-membered heteroaryl group having one to three heteroatoms selected from N, O and S; or a 5- to 12-membered heterocycloalkyl group having one to three heteroatoms selected from N, O and S, wherein the aryl group, the heteroaryl group, or the heterocycloalkyl group is optionally substituted with one to three groups selected from the group consisting of halogen, amino, hydroxy, C 1 ⁇ C 6 alkyl, C 1 ⁇ C 6 alkyl substituted with hydroxy, C 1 ⁇ C 6 alkoxy, C 3 ⁇ C 6 cycloalkyl, aldehyde, mono- or di-C 1 ⁇ C 3 alkylamino, mono- or di-C 1 ⁇ C 3 alkylamino-C 1 ⁇ C 6 alkyl, C 1 ⁇ C 6 alkoxycarbonyl, mono- or di-C 1 ⁇ C 6 alkylaminocarbonyl, C
  • L is a bond, -C(O)-, -(CH 2 ) n -, -C(O)NH-, or -C ⁇ C-,
  • n 1, 2, or 3
  • Q is a bond; C 3 ⁇ C 6 cycloalkyl; a 3- to 12-membered heterocycloalkyl having one to three heteroatoms selected from N, O and S; a 5- to 12-membered heteroaryl having one to three heteroatoms selected from N, O and S; or a 5- to 12-membered aryl,
  • n 1, 2, or 3
  • Y is, independently each other, hydrogen, hydroxy, halogen, amino, C 1 ⁇ C 6 alkyl, C 1 ⁇ C 6 alkyl substituted with hydroxy, C 1 ⁇ C 6 alkyl substituted with halogen, C 1 ⁇ C 6 alkyl substituted with mono- or di-C 1 ⁇ C 3 alkylamino, C 1 ⁇ C 6 alkoxy, C 1 ⁇ C 6 alkoxy substituted with C 1 ⁇ C 3 alkoxy, C 1 ⁇ C 6 alkoxy substituted with halogen, C 1 ⁇ C 6 alkoxy substituted with mono- or di-C 1 ⁇ C 3 alkylamino, C 1 ⁇ C 6 alkoxy-C 1 ⁇ C 6 alkyl, C 3 ⁇ C 6 cycloalkyl, C 3 ⁇ C 6 cycloalkyl-C 1 ⁇ C 3 alkyl, C 3 ⁇ C 6 cycloalkyl-C 1 ⁇ C 3 alkyl substituted with halogen, C 1
  • heterocycloalkyl-containing group selected from the group consisting of azetidinyl; azetidinyl-C 1 ⁇ C 6 alkyl; tetrahydropyranyl; tetrahydrofuranyl; pyrrolidinyl; pyrrolidinyl-C 1 ⁇ C 3 alkyl; piperidinyl; piperidinyl-C 1 ⁇ C 3 alkyl; piperidinylcarbonyl; piperidinyloxy; piperazinyl; piperazinyl-C 1 ⁇ C 3 alkyl; piperazinylcarbonyl; oxetanyl; morpholinyl; morpholinyl-C 1 ⁇ C 3 alkyl; and morpholinylcarbonyl, wherein the heterocycloalkyl of the heterocycloalkyl-containing group is optionally substituted with one to four groups selected from the group consisting of halogen, hydroxy, amino, oxo, C 1 ⁇
  • R 1 and R 2 may form piperidine, azetidine, pyrrolidine, piperazine, or 2,8-diazaspiro[4.5]decane together with the nitrogen atom to which they are bonded.
  • R 1 may be a C 1 ⁇ C 6 alkyl group and R 2 may be a C 3 ⁇ C 6 cycloalkyl group substituted with hydroxy.
  • A may be preferably phenyl, pyridinyl, thienyl, [1,2,4]triazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, quinolinyl, quinoxalinyl, or oxazolidinyl.
  • A may be optionally substituted with one to three groups selected from the group consisting of halogen, amino, hydroxy, C 1 ⁇ C 6 alkyl, C 1 ⁇ C 6 alkyl substituted with hydroxy, C 1 ⁇ C 6 alkoxy, aldehyde, mono- or di-C 1 ⁇ C 3 alkylamino-C 1 ⁇ C 6 alkyl, C 1 ⁇ C 6 alkoxycarbonyl, mono- or di-C 1 ⁇ C 6 alkylaminocarbonyl, azetidinyl-C 1 ⁇ C 3 alkyl substituted with hydroxy, azetidinylcarbonyl optionally substituted with one or two halogens, pyrrolidinylcarbonyl optionally substituted with one or two halogens, and oxo,
  • A may be particularly preferably phenyl. That is, particularly preferably, the present invention includes a compound of Formula 1a or pharmaceutically acceptable salt thereof:
  • R 1 and R 2 form a heterocycloalkyl together with the nitrogen atom to which they are bonded, wherein the heterocycloalkyl is optionally substituted with one or two groups selected from the group consisting of halogen, amino, hydroxy, C 1 ⁇ C 6 alkyl, C 1 ⁇ C 6 alkoxy, C 1 ⁇ C 6 alkyl substituted with halogen, C 1 ⁇ C 6 alkyl substituted with hydroxy, C 3 ⁇ C 6 cycloalkyl, C 3 ⁇ C 6 cycloalkyl substituted with hydroxy, mono- or di-C 1 ⁇ C 6 alkylamino, aminocarbonyl, C 1 ⁇ C 6 alkylcarbonylamino, and mono- or di-C 1 ⁇ C 6 alkylamino-C 1 ⁇ C 6 alkyl,
  • R 3 is hydrogen, halogen, cyano, nitro, amino, C 1 ⁇ C 3 alkyl, C 1 ⁇ C 3 alkyl substituted with halogen, hydroxycarbonyl, C 1 ⁇ C 3 alkoxycarbonyl, aminocarbonyl, mono- or di-C 1 ⁇ C 3 alkylaminocarbonyl, or C 1 ⁇ C 3 alkylsulfonyl,
  • R 4 is, independently each other, halogen, amino, hydroxy, C 1 ⁇ C 6 alkyl, C 1 ⁇ C 6 alkyl substituted with hydroxy, C 1 ⁇ C 6 alkoxy, C 3 ⁇ C 6 cycloalkyl, aldehyde, mono- or di-C 1 ⁇ C 3 alkylamino, mono- or di-C 1 ⁇ C 3 alkylamino-C 1 ⁇ C 6 alkyl, C 1 ⁇ C 6 alkoxycarbonyl, mono- or di-C 1 ⁇ C 6 alkylaminocarbonyl, C 1 ⁇ C 6 alkylaminocarbonyl substituted with halogen, C 3 ⁇ C 6 cycloalkylaminocarbonyl, C 3 ⁇ C 6 cycloalkylaminocarbonyl substituted with halogen, C 3 ⁇ C 6 cycloalkylaminocarbonyl substituted with hydroxy, heterocycloalkyl-C 1 ⁇ C 3 alkyl optionally substituted
  • o 0, 1, 2, or 3
  • L is a bond, -C(O)-, -(CH 2 ) n -, -C(O)NH-, or -C ⁇ C-,
  • n 1, 2, or 3
  • Q is a bond; C 3 ⁇ C 6 cycloalkyl; a 3- to 12-membered heterocycloalkyl having one to three heteroatoms selected from N, O and S; a 5- to 12-membered heteroaryl having one to three heteroatoms selected from N, O and S; or a 5- to 12-membered aryl,
  • n 1, 2, or 3
  • Y is, independently each other, hydrogen, hydroxy, halogen, amino, C 1 ⁇ C 6 alkyl, C 1 ⁇ C 6 alkyl substituted with hydroxy, C 1 ⁇ C 6 alkyl substituted with halogen, C 1 ⁇ C 6 alkyl substituted with mono- or di-C 1 ⁇ C 3 alkylamino, C 1 ⁇ C 6 alkoxy, C 1 ⁇ C 6 alkoxy substituted with C 1 ⁇ C 3 alkoxy, C 1 ⁇ C 6 alkoxy substituted with halogen, C 1 ⁇ C 6 alkoxy substituted with mono- or di-C 1 ⁇ C 3 alkylamino, C 1 ⁇ C 6 alkoxy-C 1 ⁇ C 6 alkyl, C 3 ⁇ C 6 cycloalkyl, C 3 ⁇ C 6 cycloalkyl-C 1 ⁇ C 3 alkyl, C 3 ⁇ C 6 cycloalkyl-C 1 ⁇ C 3 alkyl substituted with halogen, C 1
  • heterocycloalkyl-containing group selected from the group consisting of azetidinyl; azetidinyl-C 1 ⁇ C 6 alkyl; tetrahydropyranyl; tetrahydrofuranyl; pyrrolidinyl; pyrrolidinyl-C 1 ⁇ C 3 alkyl; piperidinyl; piperidinyl-C 1 ⁇ C 3 alkyl; piperidinylcarbonyl; piperidinyloxy; piperazinyl; piperazinyl-C 1 ⁇ C 3 alkyl; piperazinylcarbonyl; oxetanyl; morpholinyl; morpholinyl-C 1 ⁇ C 3 alkyl; and morpholinylcarbonyl, wherein the heterocycloalkyl of the heterocycloalkyl-containing group is optionally substituted with one to four groups selected from the group consisting of halogen, hydroxy, amino, oxo, C 1 ⁇
  • R 1 and R 2 may form preferably piperidine, azetidine, pyrrolidine, piperazine, or 2,8-diazaspiro[4.5]decane together with the nitrogen atom to which they are bonded.
  • R 4 may be, independently each other, preferably halogen, amino, hydroxy, C 1 ⁇ C 6 alkyl, C 1 ⁇ C 6 alkyl substituted with hydroxy, C 1 ⁇ C 6 alkoxy, aldehyde, mono- or di-C 1 ⁇ C 3 alkylamino-C 1 ⁇ C 6 alkyl, C 1 ⁇ C 6 alkoxycarbonyl, mono- or di-C 1 ⁇ C 6 alkylaminocarbonyl, azetidinyl-C 1 ⁇ C 3 alkyl substituted with hydroxy, azetidinylcarbonyl optionally substituted with one or two halogens, or pyrrolidinylcarbonyl optionally substituted with one or two halogens.
  • Q may be a bond, C 3 ⁇ C 6 cycloalkyl, tetrahydropyranyl, pyrrolidinyl, phenyl, pyridinyl, pyrazolyl, thiazolyl, imidazo[1,2-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridin-6-yl, 2H-benzo[b][1,4]oxazin-3(4H)-onyl, 3,4-dihydroquinolin-2(1H)-onyl, 3,4-dihydro-2H-benzo[b][1,4]oxazinyl, 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl, 2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-onyl, 1,
  • Y may be, independently each other, hydrogen, hydroxy, halogen, amino, C 1 ⁇ C 6 alkyl, C 1 ⁇ C 6 alkyl substituted with hydroxy, C 1 ⁇ C 6 alkyl substituted with halogen, C 1 ⁇ C 6 alkyl substituted with mono- or di-C 1 ⁇ C 3 alkylamino, C 1 ⁇ C 6 alkoxy, C 1 ⁇ C 6 alkoxy substituted with C 1 ⁇ C 3 alkoxy, C 1 ⁇ C 6 alkoxy substituted with halogen, C 1 ⁇ C 6 alkoxy substituted with mono- or di-C 1 ⁇ C 3 alkylamino, C 1 ⁇ C 6 alkoxy-C 1 ⁇ C 6 alkyl, C 3 ⁇ C 6 cycloalkyl, C 3 ⁇ C 6 cycloalkyl-C 1 ⁇ C 3 alkyl, C 3 ⁇ C 6 cycloo
  • one of Y may be a heterocycloalkyl-containing group selected from the group consisting of azetidinyl; azetidinylmethyl; tetrahydropyranyl; tetrahydrofuranyl; pyrrolidinyl; pyrrolidinylmethyl; pyrrolidinylethyl; piperidinyl; piperidinylmethyl; piperidinylcarbonyl; piperidinyloxy; piperazinyl; piperazinylmethyl; piperazinylcarbonyl; oxetanyl; morpholinyl; morpholinylmethyl; morpholinylethyl; and morpholinylcarbonyl, and the remaining Y may be hydrogen.
  • heterocycloalkyl of the heterocycloalkyl-containing group may be substituted with one to four groups selected from the group consisting of halogen, hydroxy, amino, oxo, C 1 ⁇ C 3 alkyl, C 1 ⁇ C 3 alkyl substituted with hydroxy, and mono- or di-C 1 ⁇ C 3 alkylamino.
  • preferable compounds include the following compound or pharmaceutically acceptable salt thereof selected from the group consisting of:
  • more preferable compounds include the following compound or pharmaceutically acceptable salt thereof selected from the group consisting of:
  • the compound of Formula 1 or pharmaceutically acceptable salt thereof may be in the form of structural isomer such as tautomer and in the form of stereoisomer such as R or S isomer having with asymmetric carbon center(s), cis- or trans-geometrical isomer, or optical isomer (enantiomer). Therefore, the compound of Formula 1 or pharmaceutically acceptable salt thereof includes said all forms, such as a cis- or trans-geometrical isomer, a (R)- or (S)-optical isomer, and a racemic mixture (RS), unless otherwise indicated.
  • structural isomer such as tautomer and in the form of stereoisomer such as R or S isomer having with asymmetric carbon center(s), cis- or trans-geometrical isomer, or optical isomer (enantiomer). Therefore, the compound of Formula 1 or pharmaceutically acceptable salt thereof includes said all forms, such as a cis- or trans-geometrical isomer, a (R
  • the compound of Formula 1 of the present invention may be in a pharmaceutically acceptable salt form.
  • the salt may be a conventional acid addition salt form, which includes e.g., salts derived from an inorganic acid such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, perchloric acid, or hydrobromic acid; and salts derived from an organic acid such as formic acid, acetic acid, propionic acid, oxalic acid, succinic acid, benzoic acid, citric acid, maleic acid, malonic acid, malic acid, tartaric acid, gluconic acid, lactic acid, gentisic acid, fumaric acid, lactobionic acid, salicylic acid, phthalic acid, embonic acid, aspartic acid, glutamic acid, or acetylsalicylic acid.
  • an inorganic acid such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, perchloric acid, or hydrobromic acid
  • the salt includes a salt derived from amino acids such as glycine, alanine, valine, isoleucine, serine, cysteine, cystine, aspartic acid, glutamine, lysine, arginine, tyrosine, and proline.
  • the salt includes a salt derived from sulfonic acids, such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, or toluenesulfonic acid.
  • the present invention includes, within its scope, a process for preparing the compound of Formula 1 or pharmaceutically acceptable salt thereof.
  • the compound of Formula 1 or pharmaceutically acceptable salt thereof according to the present invention may be prepared by a process which comprises preparing a compound of Formula IV from a compound of Formula II, via a compound of Formula III-a or III-b, through Synthesis 1 or Synthesis 2; and reacting the compound of Formula IV with a compound of Formula V through Synthesis 3 to prepare a compound of Formula 1, as shown in the following Reaction Scheme 1:
  • hal is halogen
  • M is -B(OH) 2 or pinacolborane (-BPin)
  • P 1 , P 2 , R 1 , R 2 , L, Q, Y, X, and A are the same as defined in the above.
  • the reaction of Synthesis 1 may be carried out by reacting the commercially available compound of Formula II or III-b with NHR 1 R 2 .
  • the reaction may be carried out with a base such as cesium carbonate (Cs 2 CO 3 ), potassium carbonate (K 2 CO 3 ), triethylamine (TEA), or diisopropylethylamine (DIPEA), in an organic solvent such as dimethylformamide, acetonitrile, dichloromethane, or dimethyl sulfoxide.
  • a base such as cesium carbonate (Cs 2 CO 3 ), potassium carbonate (K 2 CO 3 ), triethylamine (TEA), or diisopropylethylamine (DIPEA)
  • an organic solvent such as dimethylformamide, acetonitrile, dichloromethane, or dimethyl sulfoxide.
  • the reaction may be carried out at room temperature or under heating conditions (60 °C to 110 °C), but is not limited thereto.
  • reaction of Synthesis 2 may be carried out by reacting the compound of Formula II or III-a having the substituent M with Y-Q-L-halide or reacting the compound of Formula II or III-a having the substituent hal with Y-Q-L-B(OH) 2 or pinacolborane.
  • the reaction of Synthesis 2 may be carried out through the Suzuki reaction, using a palladium catalyst.
  • the palladium catalyst includes palladium diacetate (Pd(OAc) 2 ), tetrakis(triphenylphosphine)palladium (Pd(PPh 3 ) 4 ), palladium di[1,1'-bis(diphenylphosphino)ferrocene]dichloride (PdCl 2 (dppf) 2 ), or dichlorobis(triphenylphosphine)palladium(II) (PdCl 2 (PPh 3 ) 2 ), etc.
  • reaction may be carried out in the presence of a base such as cesium carbonate (Cs 2 CO 3 ) or potassium carbonate (K 2 CO 3 ), in an organic solvent such as 1,4-dioxane, tetrahydrofuran, acetonitrile, 1,2-dimethoxyethane, or dimethylformamide and water, at 80 °C to 110 °C.
  • a base such as cesium carbonate (Cs 2 CO 3 ) or potassium carbonate (K 2 CO 3
  • organic solvent such as 1,4-dioxane, tetrahydrofuran, acetonitrile, 1,2-dimethoxyethane, or dimethylformamide and water, at 80 °C to 110 °C.
  • the reaction of Synthesis 2 may be also carried out through the Sonogashira reaction using a palladium and copper catalyst.
  • the palladium and copper catalyst includes e.g., tetrakis(triphenylphosphine)palladium (Pd(PPh 3 ) 4 ), dichlorobis(triphenylphosphine)palladium(II) (PdCl 2 (PPh 3 ) 2 ), and copper(I) iodide (CuI).
  • reaction may be carried out in the presence of a base such as triethylamine (TEA) or diisopropylethylamine (DIPEA), in an organic solvent such as dimethylformamide or tetrahydrofuran, at 60 °C to 110 °C.
  • a base such as triethylamine (TEA) or diisopropylethylamine (DIPEA)
  • DIPEA diisopropylethylamine
  • organic solvent such as dimethylformamide or tetrahydrofuran
  • the reaction of Synthesis 3 may be carried out by reacting the compound of Formula IV with the compound of Formula V, using a palladium catalyst, through the Buchwald-hartwig reaction.
  • the palladium catalyst includes palladium diacetate (Pd(OAc) 2 ), tris(dibenzylideneacetone)dipalladium (Pd 2 (dba) 3 ), tetrakis(triphenylphosphine)palladium (Pd(PPh 3 ) 4 ), or palladium di[1,1'-bis(diphenylphosphino)ferrocene]dichloride (PdCl 2 (dppf) 2 ), etc.
  • the reaction may be carried out using a ligand and a base, in addition to the palladium catalyst.
  • the ligand includes 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (XPhos), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos), (S)-2,2-bis(diphenylphosphino)-1,1-binaphthyl (BINAP), or 1,1'-bis(diphenylphosphino)ferrocene (dppf), etc.
  • XPhos 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl
  • Xantphos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene
  • S 2-bis(diphenylphosphino)-1,1-binaph
  • the base includes cesium carbonate (Cs 2 CO 3 ), potassium carbonate (K 2 CO 3 ), potassium fluoride (KF), potassium phosphate (K 3 PO 4 ), sodium tert-butoxide (NaOtBu), etc.
  • the reaction may be carried out in an organic solvent such as benzene, toluene, 1,4-dioxane, tetrahydrofuran, acetonitrile, 1,2-dimethoxyethane, or dimethylformamide, at 60 °C to 110 °C.
  • the compound of Formula V in the Reaction Scheme 1 may be prepared from e.g., a compound of Formula Va, according to the following Reaction Scheme 2.
  • hal is halogen and X and A are the same as defined in the above.
  • the reaction of Synthesis 4 may be carried out by reacting the compound of Formula Va with A-boronic acid or A-pinacolborane through the Suzuki reaction, using a palladium catalyst.
  • the palladium catalyst includes palladium diacetate (Pd(OAc) 2 ), tetrakis(triphenylphosphine)palladium (Pd(PPh 3 ) 4 ), palladium di[1,1'-bis(diphenylphosphino)ferrocene]dichloride (PdCl 2 (dppf) 2 ), or dichlorobis(triphenylphosphine)palladium(II) (PdCl 2 (PPh 3 ) 2 ), etc.
  • reaction may be carried out in the presence of a base such as cesium carbonate (Cs 2 CO 3 ) or potassium carbonate (K 2 CO 3 ), in an organic solvent such as 1,4-dioxane, tetrahydrofuran, acetonitrile, 1,2-dimethoxyethane, or dimethylformamide and water, at 80 °C to 110 °C.
  • a base such as cesium carbonate (Cs 2 CO 3 ) or potassium carbonate (K 2 CO 3
  • organic solvent such as 1,4-dioxane, tetrahydrofuran, acetonitrile, 1,2-dimethoxyethane, or dimethylformamide and water, at 80 °C to 110 °C.
  • the pyrimidine/pyridine derivative or pharmaceutically acceptable salt thereof according to the present invention i.e., the compound of Formula 1 or pharmaceutically acceptable salt thereof has an excellent inhibitory activity against hematopoietic progenitor kinase 1 (HPK1) and thus can be usefully applied for the prevention or treatment of various diseases mediated by HPK1.
  • HPK1 hematopoietic progenitor kinase 1
  • the present invention includes, within its scope, a pharmaceutical composition for inhibiting hematopoietic progenitor kinase 1 comprising a therapeutically effective amount of the compound of Formula 1 or pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention provides a pharmaceutical composition for preventing or treating the diseases associated with HPK1 such as a cancer including a blood cancer or a solid tumor, for example melanoma, blastoma, sarcoma, lymphoma, leukemia, bladder cancer, brain tumor, breast cancer, cervical cancer, colorectal cancer, esophageal cancer, endometrioma, hepatic cancer, laryngeal cancer, lung cancer, osteosarcoma, ovarian cancer, pancreatic cancer, prostate cancer, renal cancer, thyroid cancer, ependymoma, glioblastoma, bullous cell tumor, neuroblastoma, osteosarcoma, rhabdomyosarcoma, or nephroblasto
  • the pharmaceutical composition of the present invention may comprise a pharmaceutically acceptable carrier, such as diluents, disintegrants, sweeteners, lubricants, or flavoring agents, which is conventionally used in the art.
  • the pharmaceutical composition may be formulated to an oral dosage form such as tablets, capsules, powders, granules, suspensions, emulsions, or syrups; or a parenteral dosage form such as solutions for external use, suspensions for external use, emulsions for external use, gels (e.g., ointment), inhalations, nebulizations, injections, according to conventional methods.
  • the dosage form may be formulated to various forms, e.g., dosage forms for single administration or for multiple administrations.
  • the pharmaceutical composition of the present invention may comprise, for example, a diluent (e.g., lactose, corn starch, etc.); a lubricant (e.g., magnesium stearate); an emulsifying agent; a suspending agent; a stabilizer; and/or an isotonic agent. If necessary, the composition further comprises sweeteners and/or flavoring agents.
  • composition of the present invention may be administered orally or parenterally, including inhalant, intravenous, intraperitoneal, subcutaneous, rectal and topical routes of administration. Therefore, the composition of the present invention may be formulated into various forms such as tablets, capsules, aqueous solutions or suspensions.
  • carriers such as lactose, corn starch, and lubricating agents, e.g. magnesium stearate, are conventionally used.
  • lactose and/or dried corn starch can be used as a diluent.
  • the active ingredient may be combined with emulsifying and/or suspending agents.
  • composition of the present invention may be in the form of an aqueous solution containing pharmaceutically acceptable carriers, e.g., saline having a pH level of 7.4.
  • pharmaceutically acceptable carriers e.g., saline having a pH level of 7.4.
  • the solutions may be introduced into a patient's intramuscular bloodstream by local bolus injection.
  • the compound of Formula 1 or pharmaceutically acceptable salt thereof may be singly or multiply administered in an effective amount ranging from about 1 mg/kg per day to about 1000 mg/kg per day, preferably from about 100 mg/kg per day to about 800 mg/kg per day, to a subject patient.
  • the dosage may be changed according to the patient's age, weight, susceptibility, symptom, or activity of the compound.
  • the present invention includes, within its scope, a method for inhibiting hematopoietic progenitor kinase 1 in a mammal, comprising administering a therapeutically effective amount of the compound of Formula 1 or pharmaceutically acceptable salt thereof to the mammal in need thereof.
  • the present invention provides a method for treating the diseases associated with HPK1 such as a cancer including a blood cancer or a solid tumor, for example melanoma, blastoma, sarcoma, lymphoma, leukemia, bladder cancer, brain tumor, breast cancer, cervical cancer, colorectal cancer, esophageal cancer, endometrioma, hepatic cancer, laryngeal cancer, lung cancer, osteosarcoma, ovarian cancer, pancreatic cancer, prostate cancer, renal cancer, thyroid cancer, ependymoma, glioblastoma, bullous cell tumor, neuroblastoma, osteosarcoma, rhabdomyosarcoma, or nephroblastoma, comprising administering a therapeutically effective amount of the compound of Formula 1 or pharmaceutically acceptable salt thereof to the mammal in need thereof.
  • a cancer including a blood cancer or a solid tumor for example melanoma, blastoma, sarcoma
  • the present invention also provides a use of the compound of Formula 1 or pharmaceutically acceptable salt thereof for the manufacture of a medicament for inhibiting hematopoietic progenitor kinase 1 in a mammal.
  • the present invention provides a use of the compound of Formula 1 or pharmaceutically acceptable salt thereof for the manufacture of a medicament for preventing or treating the diseases associated with HPK1 such as a cancer including a blood cancer or a solid tumor, for example melanoma, blastoma, sarcoma, lymphoma, leukemia, bladder cancer, brain tumor, breast cancer, cervical cancer, colorectal cancer, esophageal cancer, endometrioma, hepatic cancer, laryngeal cancer, lung cancer, osteosarcoma, ovarian cancer, pancreatic cancer, prostate cancer, renal cancer, thyroid cancer, ependymoma, glioblastoma, bullous cell tumor, neuroblastoma, osteosarcoma, rhabdomyo
  • Step 1 (S)-(6-chloro-4-(3-hydroxypiperidin-1-yl)pyridin-3-yl)(cyclopropyl)methanone
  • Step 2 (S)-(6-((2-chloropyrimidin-4-yl)amino)-4-(3-hydroxypiperidin-1-yl)pyridin-3-yl)(cyclopropyl)methanone (A1-1)
  • the reaction mixture was refluxed under stirring at 110°C overnight. After completion of the reaction, the reaction mixture was cooled to room temperature and then water was added thereto. The aqueous layer was extracted with ethyl acetate. The extracted organic layer was dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated and then purified by silica gel column chromatography to prepare the titled compound (317.0 mg).
  • Step 2 (S)-1-(2-chloro-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyridin-4-yl)piperidin-3-ol (A2-1)
  • the mixed solution was stirred at 80°C for 6 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and then water was added thereto. The aqueous layer was extracted with ethyl acetate. The extracted organic layer was dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated and then purified by silica gel column chromatography to prepare the titled compound (1.61 g).
  • the titled compound was prepared in accordance with the same procedures as in Preparation A2-1, changing the boronic acid reagent to 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine.
  • the titled compound was prepared in accordance with the same procedures as in Preparation A2-1, changing the boronic acid reagent to 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole.
  • the titled compound was prepared in accordance with the same procedures as in Preparation A2-1, changing the boronic acid reagent to 1-(cyclopropylmethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.
  • the titled compound was prepared in accordance with the same procedures as in Preparation A2-1, changing the boronic acid reagent to 1-(2-methoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.
  • the titled compound was prepared in accordance with the same procedures as in Preparation A2-1, changing the boronic acid reagent to 1-(2,2-difluoroethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.
  • the titled compound was prepared in accordance with the same procedures as in Preparation A2-1, changing the boronic acid reagent to 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(trifluoromethyl)-1H-pyrazole.
  • the titled compound was prepared in accordance with the same procedures as in Preparation A2-1, changing the boronic acid reagent to 4-(4-methyl-1-piperazinyl)phenylboronic acid pinacol ester.
  • the titled compound was prepared in accordance with the same procedures as in Preparation A2-1, changing the boronic acid reagent to imidazo[1,2-a]pyridin-6-ylboronic acid.
  • the titled compound was prepared in accordance with the same procedures as in Preparation A2-1, changing the boronic acid reagent to 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,6,6-tetramethyltetrahydropyran-4-yl)pyrazole.
  • Step 1 tert-butyl (S)-(1-(2-chloro-5-iodopyridin-4-yl)piperidin-3-yl)carbamate (A3)
  • Step 2 tert-butyl (S)-(1-(2-chloro-5-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyridin-4-yl)piperidin-3-yl)carbamate (A3-1)
  • the mixed solution was stirred at 100°C for 4 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and then water was added thereto. The aqueous layer was extracted with ethyl acetate. The extracted organic layer was dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated and then purified by silica gel column chromatography to prepare the titled compound (2.3 g).
  • the titled compound was prepared in accordance with the same procedures as in Preparation A3-1, changing the boronic acid reagent to 1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine.
  • the titled compound was prepared in accordance with the same procedures as in Preparation A3-1, changing the boronic acid reagent to 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)pyrazole.
  • the titled compound was prepared in accordance with the same procedures as in Preparation A3-1, changing the boronic acid reagent to 1-(2-methoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole.
  • the titled compound was prepared in accordance with the same procedures as in Preparation A3-1, changing the boronic acid reagent to 1-methyl-3-(trifluoromethyl)pyrazol-4-boronic acid pinacol ester.
  • 1H NMR (CD 3 OD, 400MHz) ⁇ 7.91 (s, 1H), 7.88 (s, 1H), 7.03 (s, 1H), 4.09 (s, 1H), 3.34-3.32 (m, 2H), 3.27-3.23 (m, 1H), 2.71 (t, 1H), 2.38 (t, 1H), 1.90-1.86 (m, 1H), 1.71 (brs, 1H), 1.60-1.54 (m, 2H), 1.44 (s, 9H)
  • the titled compound was prepared in accordance with the same procedures as in Preparation A3-1, changing the boronic acid reagent to N,N-dimethyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)acetamide.
  • the titled compound was prepared in accordance with the same procedures as in Preparation A3-1, changing the boronic acid reagent to 1-(2-(methoxymethoxy)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.
  • the titled compound was prepared in accordance with the same procedures as in Preparation A3-1, changing the boronic acid reagent to 1-(2,2-difluoroethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole.
  • the titled compound was prepared in accordance with the same procedures as in Preparation A3-1, changing the boronic acid reagent to 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(trifluoromethyl)-1H-pyrazole.
  • the titled compound was prepared in accordance with the same procedures as in Preparation A3-1, changing the boronic acid reagent to 4-[2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]ethyl]morpholine.
  • the titled compound was prepared in accordance with the same procedures as in Preparation A3-1, changing the boronic acid reagent to 1-(2-pyrrolidin-1-ylethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole.
  • the titled compound was prepared in accordance with the same procedures as in Preparation A3-1, changing the boronic acid reagent to 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]propanenitrile.
  • the titled compound was prepared in accordance with the same procedures as in Preparation A3-1, changing the boronic acid reagent to tert-butyl 3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)azetidin-1-carboxylate.
  • the titled compound was prepared in accordance with the same procedures as in Preparation A3-1, changing the boronic acid reagent to 2-pyrrolidin-1-yl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine.
  • the titled compound was prepared in accordance with the same procedures as in Preparation A3-1, changing the boronic acid reagent to (4-methylpiperazin-1-yl)-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methanone.
  • the titled compound was prepared in accordance with the same procedures as in Preparation A3-1, changing the boronic acid reagent to 1-(2-methoxy-2-methyl-propyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole.
  • the titled compound was prepared in accordance with the same procedures as in Preparation A3-1, changing the boronic acid reagent to 2-(2-methoxyethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine.
  • the titled compound was prepared in accordance with the same procedures as in Preparation A3-1, changing the boronic acid reagent to N,N-dimethyl-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]propan-1-amine.
  • the titled compound was prepared in accordance with the same procedures as in Preparation A3-1, changing the boronic acid reagent to tert-butyl 3-[[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]methyl]azetidin-1-carboxylate.
  • the titled compound was prepared in accordance with the same procedures as in Preparation A3-1, changing the boronic acid reagent to tert-butyl (R)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)pyrrolidin-1-carboxylate.
  • the titled compound was prepared in accordance with the same procedures as in Preparation A3-1, changing the boronic acid reagent to tert-butyl (S)-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)pyrrolidin-1-carboxylate.
  • the titled compound was prepared in accordance with the same procedures as in Preparation A3-1, changing the boronic acid reagent to N',N'-dimethyl-N-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]ethan-1,2-diamine.
  • the titled compound was prepared in accordance with the same procedures as in Preparation A3-1, changing the boronic acid reagent to tert-butyl 4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]piperazin-1-carboxylate.
  • the titled compound was prepared in accordance with the same procedures as in Preparation A3-1, changing the boronic acid reagent to 1-(2-methoxy-1,1-dimethyl-ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole.
  • the titled compound was prepared in accordance with the same procedures as in Preparation A3-1, changing the boronic acid reagent to 1-[(3,3-difluorocyclobutyl)methyl]-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole.
  • the titled compound was prepared in accordance with the same procedures as in Preparation A3-1, changing the boronic acid reagent to N,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-ethanamine.
  • the titled compound was prepared in accordance with the same procedures as in Preparation A3-1, changing the boronic acid reagent to 1-(fluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole.
  • the titled compound was prepared in accordance with the same procedures as in Preparation A3-1, changing the boronic acid reagent to tert-butyl 4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]piperidin-1-carboxylate.
  • the titled compound was prepared in accordance with the same procedures as in Preparation A3-1, changing the boronic acid reagent to N,N-dimethyl-2-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]oxyethanamine.
  • the titled compound was prepared in accordance with the same procedures as in Preparation A3-1, changing the boronic acid reagent to 1-ethyl-3-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]urea.
  • the titled compound was prepared in accordance with the same procedures as in Preparation A3-1, changing the boronic acid reagent to 4-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydropyrido[3,2-b][1,4]oxazine.
  • the titled compound was prepared in accordance with the same procedures as in Preparation A3-1, changing the boronic acid reagent to 4-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-1,4-benzoxazine.
  • the titled compound was prepared in accordance with the same procedures as in Preparation A3-1, changing the boronic acid reagent to 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4-dihydro-2H-benzo[d][1,3]oxazin-2-one.
  • the titled compound was prepared in accordance with the same procedures as in Preparation A3-1, changing the boronic acid reagent to 4-(2-oxo-1-pyrrolidinyl)phenyl boronic acid pinacol ester.
  • the titled compound was prepared in accordance with the same procedures as in Preparation A3-1, changing the boronic acid reagent to 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-benzo[b][1,4]oxazin-3(4H)-one.
  • the titled compound was prepared in accordance with the same procedures as in Preparation A3-1, changing the boronic acid reagent to 4-methyl-3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-boronic acid pinacol ester.
  • the titled compound was prepared in accordance with the same procedures as in Preparation A3-1, changing the boronic acid reagent to 8-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-2(1H)-one.
  • the titled compound was prepared in accordance with the same procedures as in Preparation A3-1, changing the boronic acid reagent to 1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-2(1H)-one.
  • the titled compound was prepared in accordance with the same procedures as in Preparation A3-1, changing the boronic acid reagent to tert-butyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl]piperazin-1-carboxylate.
  • the titled compound was prepared in accordance with the same procedures as in Preparation A3-1, changing the boronic acid reagent to 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,6,6-tetramethyltetrahydropyran-4-yl)pyrazole.
  • the titled compound was prepared in accordance with the same procedures as in Preparation A3-1, changing the boronic acid reagent to 3,4-dihydro-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2H-1,4-benzoxazine.
  • the titled compound was prepared in accordance with the same procedures as in Preparation A3-1, changing the boronic acid reagent to 4-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrido[3,2-b][1,4]oxazin-3-one.
  • the titled compound was prepared in accordance with the same procedures as in Preparation A3-1, changing the boronic acid reagent to 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4H-pyrido[3,2-b][1,4]oxazin-3-one.
  • the titled compound was prepared in accordance with the same procedures as in Preparation A3-1, changing the boronic acid reagent to 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-1H-1,8-naphthyridin-2-one.
  • the titled compound was prepared in accordance with the same procedures as in Preparation A3-1, changing the boronic acid reagent to 1-(oxetan-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole.
  • the titled compound was prepared in accordance with the same procedures as in Preparation A3-1, changing the boronic acid reagent to methyl 2-methyl-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]propanoate.
  • the titled compound was prepared in accordance with the same procedures as in Preparation A3-1, changing the boronic acid reagent to 3-(dimethylcarbamoyl)phenylboronic acid.
  • the titled compound was prepared in accordance with the same procedures as in Preparation A3-1, changing the boronic acid reagent to 3-methyl-4-trifluoromethoxyphenylboronic acid.
  • the titled compound was prepared in accordance with the same procedures as in Preparation A3-1, changing the boronic acid reagent to tert-butyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]piperidin-1-carboxylate.
  • the titled compound was prepared in accordance with the same procedures as in Preparation A3-1, changing the boronic acid reagent to [4-[4-(2-hydroxyethyl)piperazin-1-carbonyl]phenyl]boronic acid.
  • the titled compound was prepared in accordance with the same procedures as in Preparation A3-1, changing the boronic acid reagent to 4-(trans-4-hydroxycyclohexylcarbamoyl)phenylboronic acid.
  • the titled compound was prepared in accordance with the same procedures as in Preparation A3-1, changing the boronic acid reagent to (3-(dimethylamino)-4-fluorophenyl)boronic acid.
  • the titled compound was prepared in accordance with the same procedures as in Preparation A3-1, changing the boronic acid reagent to (S)-1-(tetrahydrofuran-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.
  • the titled compound was prepared in accordance with the same procedures as in Preparation A3-1, changing the boronic acid reagent to (R)-1-(tetrahydrofuran-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.
  • the titled compound was prepared in accordance with the same procedures as in Preparation A3-1, changing the boronic acid reagent to 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.
  • the titled compound was prepared in accordance with the same procedures as in Preparation A3-1, changing the boronic acid reagent to 1-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.
  • Step 1 (S)-1-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-4-yl)piperidin-3-ol (A4)
  • Step 2 (S)-1-(6-chloro-6'-(tetrahydro-2H-pyran-4-yl)-[3,3'-bipyridin]-4-yl)piperidin-3-ol (A4-1)
  • the mixed solution was stirred at 80°C for 4 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and then water was added thereto. The aqueous layer was extracted with ethyl acetate. The extracted organic layer was dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated and then purified by silica gel column chromatography to prepare the titled compound (20.1 mg).
  • the titled compound was prepared in accordance with the same procedures as in Preparation A4-1, changing the bromine reagent to (5-bromopyridin-2-yl)(4-methylpiperazin-1-yl)methanone.
  • the titled compound was prepared in accordance with the same procedures as in Preparation A4-1, changing the bromine reagent to (5-bromopyridin-2-yl)(morpholino)methanone.
  • Step 1 tert-butyl (S)-(1-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-4-yl)piperidin-3-yl)carbamate
  • Step 2 tert-butyl (S)-(1-(6-chloro-6'-(tetrahydro-2H-pyran-4-yl)-[3,3'-bipyridin]-4-yl)piperidin-3-yl)carbamate (A5-1)
  • the mixed solution was stirred at 80°C for 4 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and then water was added thereto. The aqueous layer was extracted with ethyl acetate. The extracted organic layer was dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated and then purified by silica gel column chromatography to prepare the titled compound (51.0 mg).
  • the mixed solution was stirred at 80°C for 4 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and then water was added thereto. The aqueous layer was extracted with ethyl acetate. The extracted organic layer was dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated and then purified by silica gel column chromatography to prepare the titled compound (491.7 mg).
  • the titled compound was prepared in accordance with the same procedures as in Preparation A6-1, changing the ethyne reagent to 1-(2,2-difluoroethyl)-4-ethynyl-1H-pyrazole.
  • the titled compound was prepared in accordance with the same procedures as in Preparation A6-1, changing the ethyne reagent to 4-ethynyl-1-(2,2,2-trifluoroethyl)pyrazole.
  • the mixed solution was stirred at 80°C for 4 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and then water was added thereto. The aqueous layer was extracted with ethyl acetate. The extracted organic layer was dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated and then purified by silica gel column chromatography to prepare the titled compound (120.4 mg).
  • 2,4-Dichloro-5-iodo-pyrimidine 500 mg, 1.82 mmol was dissolved in anhydrous acetonitrile (10.0 mL) and the (S)-3-hydroxypiperidine hydrochloride (275.3 mg, 2.00 mmol) and diisopropylethylamine (1.6 mL, 11.65 mmol) were added dropwise thereto.
  • the reaction mixture was stirred 50°C for 4 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and then water was added thereto. The aqueous layer was extracted with ethyl acetate. The extracted organic layer was dried over anhydrous magnesium sulfate and then filtered.
  • Step 2 (S)-1-(2-chloro-5-(1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidin-4-yl)piperidin-3-ol (A9-1)
  • the mixed solution was stirred at 80°C for 6 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and then water was added thereto. The aqueous layer was extracted with ethyl acetate. The extracted organic layer was dried over anhydrous magnesium sulfate and then filtered. The filtrate was concentrated and then purified by silica gel column chromatography to prepare the titled compound (50.0 mg).
  • Step 1 tert-butyl (S)-(1-(3-bromo-6-chloropyridazin-4-yl)piperidin-3-yl)carbamate (A10)
  • Step 2 tert-butyl (S)-(1-(6-chloro-3-(1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)pyridazin-4-yl)piperidin-3-yl) carbamate (A10-1)
  • Methyl-4,6-dichloronicotinate (1.0 g, 4.85 mmol) was dissolved in anhydrous dimethylformamide (20.0 mL) and then (S)-3-hydroxypiperidine hydrochloride (734.7 mg, 5.34 mmol) and diisopropylethylamine (1.7 mL, 9.71 mmol) were added dropwise thereto.
  • the reaction mixture was stirred at 50°C for 4 hours. After completion of the reaction, the reaction mixture was cooled to room temperature. Water was added to the reaction mixture and the aqueous layer was extracted with ethyl acetate. The extracted organic layer was dried over anhydrous magnesium sulfate and then filtered.
  • Step 1 2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-4-yl)-4-fluoropyridine (B1)
  • Step 2 tert-butyl (S)-(1-(2-chloro-5-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyridin-4-yl)piperidin-3-yl)(methyl)carbamate (B1-1)

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Abstract

La présente invention concerne un nouveau dérivé de pyrimidine/pyridine ou un sel pharmaceutiquement acceptable de celui-ci, un procédé de préparation de celui-ci, une composition pharmaceutique le comprenant et une utilisation de celui-ci. Le dérivé de pyrimidine/pyridine ou un sel pharmaceutiquement acceptable de celui-ci peut être utilement appliqué pour prévenir ou traiter divers cancers du sang ou divreses tumeurs solides par l'intermédiaire d'une excellente activité inhibitrice contre le progéniteur hématopoïétique kinase 1 (HPK1).
PCT/KR2024/007677 2023-06-09 2024-06-05 Dérivés de pyrimidine/pyridine ou leurs sels et compositions pharmaceutiques les comprenant Pending WO2024253416A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004089286A2 (fr) * 2003-04-04 2004-10-21 Irm Llc Nouveaux composes et compositions utilises comme inhibiteurs de la proteine kinase
WO2010129053A2 (fr) * 2009-05-05 2010-11-11 Dana Farber Cancer Institute Inhibiteurs d'egfr et procédés de traitement de troubles
WO2021159993A1 (fr) * 2020-02-14 2021-08-19 Pharmablock Sciences (Nanjing) , Inc. Inhibiteurs de la kinase associée au récepteur de l'interleukine 1 (irak)/tyrosine kinase du récepteur de type fms (flt3), leurs produits pharmaceutiques et leurs procédés
WO2022246025A1 (fr) * 2021-05-20 2022-11-24 Dana-Farber Cancer Institute, Inc. Inhibiteurs et agents de dégradation de protéine pip4k
WO2023027518A1 (fr) * 2021-08-27 2023-03-02 Yuhan Corporation Composés aminopyridine substitués en tant qu'inhibiteurs d'egfr

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004089286A2 (fr) * 2003-04-04 2004-10-21 Irm Llc Nouveaux composes et compositions utilises comme inhibiteurs de la proteine kinase
WO2010129053A2 (fr) * 2009-05-05 2010-11-11 Dana Farber Cancer Institute Inhibiteurs d'egfr et procédés de traitement de troubles
WO2021159993A1 (fr) * 2020-02-14 2021-08-19 Pharmablock Sciences (Nanjing) , Inc. Inhibiteurs de la kinase associée au récepteur de l'interleukine 1 (irak)/tyrosine kinase du récepteur de type fms (flt3), leurs produits pharmaceutiques et leurs procédés
WO2022246025A1 (fr) * 2021-05-20 2022-11-24 Dana-Farber Cancer Institute, Inc. Inhibiteurs et agents de dégradation de protéine pip4k
WO2023027518A1 (fr) * 2021-08-27 2023-03-02 Yuhan Corporation Composés aminopyridine substitués en tant qu'inhibiteurs d'egfr

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