WO2023138412A1 - Composés de pyrimidin-2-amine fusionnés utilisés en tant qu'inhibiteurs de cdk20 - Google Patents

Composés de pyrimidin-2-amine fusionnés utilisés en tant qu'inhibiteurs de cdk20 Download PDF

Info

Publication number
WO2023138412A1
WO2023138412A1 PCT/CN2023/071020 CN2023071020W WO2023138412A1 WO 2023138412 A1 WO2023138412 A1 WO 2023138412A1 CN 2023071020 W CN2023071020 W CN 2023071020W WO 2023138412 A1 WO2023138412 A1 WO 2023138412A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
formula
pharmaceutically acceptable
solvate
stereoisomer
Prior art date
Application number
PCT/CN2023/071020
Other languages
English (en)
Inventor
Feng Ren
Xiao DING
Yingtao LIU
Min Zheng
Wei Zhu
Original Assignee
Insilico Medicine Ip Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Insilico Medicine Ip Limited filed Critical Insilico Medicine Ip Limited
Publication of WO2023138412A1 publication Critical patent/WO2023138412A1/fr

Links

Images

Classifications

    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/78—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 2
    • C07D239/84—Nitrogen atoms
    • 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
    • C07D401/02—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
    • 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
    • C07D403/02—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 two hetero rings
    • C07D403/10—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 two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 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
    • C07D403/02—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 two hetero rings
    • C07D403/04—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 two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D403/02—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 two hetero rings
    • C07D403/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems

Definitions

  • the present disclosure relates to novel fused pyrimidin-2-amine compounds or pharmaceutically acceptable salts, solvate, stereoisomer, or isotopic variant thereof, which are useful as CDK20 inhibitors.
  • the present disclosure further relates to pharmaceutical compositions comprising one or more of such compounds or pharmaceutically acceptable salts, solvate, stereoisomer, or isotopic variant thereof as an active ingredient, and use of such compounds or pharmaceutically acceptable salts, solvate, stereoisomer, or isotopic variant thereof in the treatment of CDK20-associated diseases or conditions, such as hepatocellular carcinoma (HCC) , colorectal cancer, glioblastoma, lung cancer, medulloblastoma, ovarian carcinoma, prostate cancer, renal cell carcinoma, etc.
  • HCC hepatocellular carcinoma
  • colorectal cancer glioblastoma
  • lung cancer medulloblastoma
  • ovarian carcinoma prostate cancer
  • renal cell carcinoma etc.
  • Cyclin-dependent kinase 20 also known as cell cycle-related kinase (CCRK)
  • CCRK cell cycle-related kinase
  • CDK20 is a newly identified member of the cyclin-dependent kinase (CDK) family with increased attraction in recent years due to its functions (both cell cycle-dependent and -independent) in a variety of human tissues 1 .
  • CDK20 is widely expressed at a comparable translational level in many human tissues including brain, lung, liver, pancreas, and gastrointestinal tract 2 .
  • CDK20 is overexpressed in many tumor cell lines as well as tumor samples from patients with different types of cancer such as hepatocellular carcinoma (HCC) , colorectal cancer, glioblastoma, lung cancer, medulloblastoma, ovarian carcinoma, prostate cancer, and renal cell carcinoma 1, 3–6 , indicating its potential role in cancer development, which was proven in numerous basic and preclinical studies by several different research groups.
  • HCC hepatocellular carcinoma
  • CDK20 is also involved in immunosuppression in certain types of tumors.
  • Zhou et al. reported that, by activating the EZH2-NF- ⁇ B pathway, CDK20 expressed in HCC cells increased IL-6 production and induced immunosuppressive MDSC expansion from human peripheral blood mononuclear cells; inhibition of tumorous CDK20 increased IFN- ⁇ + TNF- ⁇ + CD8 + T cell infiltration and upregulated PD-L1 expression level in tumors, providing a greater chance of combination therapy with PD-L1 blockade to eradicate HCC tumors 7 .
  • CDK20-specific inhibitor there is currently no CDK20-specific inhibitor publicly available, and no development of such a reagent has been reported. A major reason for this is perhaps the lack of a 3D structure for the CDK20 protein (with or without its cyclin partner) which may be useful for the design of selective inhibitors. There remains a need to develop new compounds that effectively act as CDK20 inhibitors.
  • novel compounds as CDK20 inhibitors Disclosed herein are novel compounds as CDK20 inhibitors. As a result, the compounds of the present disclosure are particularly useful in the modulation of CDK20 and thus in the treatment of CDK20-associated diseases and conditions.
  • the present disclosure is directed to a compound of Formula (I)
  • the present disclosure is directed to a pharmaceutical composition for treating a CDK20-associated disease or condition, which comprises the compound of Formula (I) or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof as provided herein, and a pharmaceutically acceptable carrier or excipient.
  • the present disclosure is directed to a method of treating a CDK20-associated disease or condition in a subject in need thereof, which comprises administering to the subject a therapeutically effective amount of the compound of Formula (I) or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof as provided herein.
  • the present disclosure is directed to the compound of Formula (I) or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof as provided herein for use in the treatment of a CDK20-associated disease or condition.
  • the present disclosure is directed to use of the compound of Formula (I) or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof as provided herein in the manufacture of a medicament for treating a CDK20-associated disease or condition.
  • kits for treating a CDK20-associated disease or condition which comprises a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof as provided herein, a container, and optionally a package insert or label indicating a treatment.
  • Figure 1 shows predicted binding pose for an exemplary compound of the present disclosure (Compound I-001) with CDK20;
  • Figure 2 shows assay results of an exemplary compound of the present disclosure (Compound I-001) .
  • Embodiment 1 A compound of Formula (I)
  • each of X 1 , X 2 , X 3 , and X 4 is independently N or CR A , in which R A is H or R 1 , with the proviso that no more than two of X 1 , X 2 , X 3 , and X 4 are N;
  • ring A is a 5-or 6-membered aromatic or heteroaromatic ring which contains 0, 1, or 2 heteroatoms selected from the group consisting of N, O, and S, optionally further fused to one or two cyclic rings independently selected from -cycloalkyl, -heterocyclyl, -aryl, -heteroaryl ring;
  • R 1 is H, halo, -CN, -NO 2 , -alkyl, -haloalkyl, -alkenyl, -alkynyl, - (CH 2 ) p -aryl, - (CH 2 ) p -heteroaryl, -cycloalkyl, -heterocyclyl, -aryl, -heteroaryl, -OH, -OR C , -SR C , -COR C , -CO 2 R C , - CONR C R D , -S (O) R C , -SO 2 R C , -SO 3 R C , -SO 2 NR C R D , -P (O) (OR C ) 2 , or -NR C R D , in which each of R C and R D is independently H, -alkyl, -haloalkyl, -alkenyl, -alkynyl, - (
  • R 2 is H, halo, -C 1-6 alkyl, -C 3-6 cycloalkyl, or -C 1-6 haloalkyl;
  • R 3 is R E , -NR E R B , or -CONR E R B , wherein each of R E and R B is independently H, -C 1-6 alkyl, -C 3-6 cycloalkyl, -C 3-6 heterocyclyl, -C 1-6 alkylene-NR F R G , -C 1-6 alkylene-C 3-6 cycloalkyl, or -C 1- 6 alkylene-C 3-6 heterocyclyl, or R E and R B together with the nitrogen to which they are attached form a heterocyclic ring having 3 to 6 carbon atoms, in which each of said C 3-6 heterocyclyl and said heterocyclic ring is monocyclic, fused bicyclic, or spiro bicyclic, contains 1 or 2 heteroatoms selected from the group consisting of N, O and S, and is unsubstituted or substituted by -C 1- 6 alkyl or oxo, and each of R F and R G is independently H or -C
  • R 4 is independently H, -C 1-6 alkyl, -OC 1-6 alkyl, -C 3-6 cycloalkyl, -C 3-6 heterocyclyl, or - (CH 2 ) q -C 3-6 heterocyclyl, in which said C 3-6 heterocyclyl is monocyclic, fused bicyclic, or spiro bicyclic, contains 1 or 2 heteroatoms selected from the group consisting of N, O, and S, and is unsubstituted or further substituted by -C 1-6 alkyl or oxo, and q is 1, 2, or 3; and
  • n 0, 1, 2, 3, or 4.
  • Embodiment 2 The compound of Formula (I) or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof according to embodiment 1, wherein each of X 1 , X 2 , X 3 , and X 4 is independently CR A , in which R A has the same meaning as defined above.
  • Embodiment 3 The compound of Formula (I) or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof according to embodiment 1, wherein one of X 1 , X 2 , X 3 , and X 4 is N, and the remainder of X 1 , X 2 , X 3 , and X 4 are independently CR A , in which R A has the same meaning as defined above.
  • Embodiment 4 The compound of Formula (I) or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof according to any one of the preceding embodiments, wherein ring A is a 5-or 6-membered aromatic or heteroaromatic ring which contains 0, 1, or 2 heteroatoms independently selected from N and S, optionally fused to a 5-or 6-membered -cycloalkyl or heterocyclyl ring.
  • Embodiment 5 The compound of Formula (I) or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof according to any one of the preceding embodiments, wherein ring A is a pyrrole, imidazole, benzene, pyridine, pyrazole, thiazole, isothizole, or 1, 2, 3, 4-tetrahydroisoquinoline ring.
  • Embodiment 6 The compound of Formula (I) or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof according to any one of the preceding embodiments, wherein ring A is a pyrrole ring.
  • Embodiment 7 The compound of Formula (I) or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof according to any one of the preceding embodiments, wherein
  • Embodiment 8 The compound of Formula (I) or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof according to any one of the preceding embodiments, wherein
  • Embodiment 9 The compound of Formula (I) or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof according to any one of the preceding embodiments, wherein n is 0, 1, or 2.
  • Embodiment 10 The compound of Formula (I) or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof according to any one of the preceding embodiments, wherein n is 1, and
  • Embodiment 11 The compound of Formula (I) or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof according to any one of the preceding embodiments, wherein R 1 is independently H, halo, -CN, -NO 2 , -C 1-6 alkyl, -C 1-6 haloalkyl, -C 2- 6 alkenyl, -C 2-6 alkynyl, - (CH 2 ) p -aryl, - (CH 2 ) p -heteroaryl, -C 3-6 cycloalkyl, -C 3-6 heterocyclyl, aryl, heteroaryl, -OH, -OR C , -SR C , -COR C , -CO 2 R C , -CONR C R D , -S (O) R C , -SO 2 R C , -SO 3 R C , -SO 2 NR C R D , -P (O)
  • Embodiment 12 The compound of Formula (I) or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof according to any one of the preceding embodiments, wherein R 1 is independently H, halo, -CN, -C 1-6 alkyl, -C 1-6 haloalkyl, - (CH 2 ) p - (5-to 10-membered aryl) , - (CH 2 ) p - (5-to 10-membered heteroaryl) , -C 3-6 cycloalkyl, -C 3- 6 heterocyclyl, 5-to 10-membered aryl, 5-to 10-membered heteroaryl, -OR C , -SR C , -COR C , -CO 2 R C , -CONR C R D , -S (O) R C , -SO 2 R C , -SO 2 NR C R D , or -NR C R D , in which each of R C and
  • Embodiment 13 The compound of Formula (I) or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof according to any one of the preceding embodiments, wherein R 1 is independently H, halo, -CN, -C 1-3 alkyl, -C 1-3 haloalkyl, -CH 2 -phenyl, -CH 2 -pyridinyl, -O-phenyl, -O-pyridinyl, -OC 1-3 alkyl, 2-oxopyrrolidin-1-yl, -CONHC 1-3 alkyl, -SO 2 C 1-3 alkyl, imidazolopyrimidinyl, tetrahydroimidazolopyridinyl, pyrazolyl, -C 3-6 cycloalkyl, or -C 3-6 heterocycyl, in which said C 3-6 heterocycyl is monocyclic, fused bicyclic or spiro bicyclic
  • Embodiment 14 The compound of Formula (I) or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof according to any one of the preceding embodiments, wherein R 1 is independently H, -Br, -CN, -CH 3 , -CF 3 , pyridin-2-ylmethyl, pyridin-2-yloxy, -OCH 3 , 2-oxopyrrolidin-1-yl, -CONHCH 3 , -SO 2 CH 3 , imidazo [1, 2-a] pyrimidin-3-yl, 5, 6, 7, 8-tetrahydroimidazo [1, 2-a] pyridin-3-yl, pyrazol-4-yl, 3-methyl-pyrazol-4yl, cyclopentyl, or oxetan-3-yl.
  • R 1 is independently H, -Br, -CN, -CH 3 , -CF 3 , pyridin-2-ylmethyl, pyr
  • Embodiment 15 The compound of Formula (I) or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof according to any one of the preceding embodiments, wherein R 2 is H, -C 1-6 alkyl, or -C 3-6 cycloalkyl.
  • Embodiment 16 The compound of Formula (I) or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof according to any one of the preceding embodiments, wherein R 3 is R E , -NHR E , -NR E ’R B ’, -CONHR E , or -CONR E ’R B ’; wherein R E is H, -C 1-6 alkyl, -C 3-6 cycloalkyl, -C 3-6 heterocyclyl, -C 1-6 alkylene-NHC 1-3 alkyl, -C 1-6 alkylene-N (C 1- 3 alkyl) 2 , -C 1-6 alkylene-C 3-6 cycloalkyl, or -C 1-6 alkylene-C 3-6 heterocyclyl, and R E ’a nd R B ’ together with the nitrogen to which they are attached form a heterocyclic ring having 3 to 6 carbon atoms, in which each of said C 3-6 heterocycl
  • Embodiment 17 The compound of Formula (I) or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof according to any one of the preceding embodiments, wherein R 3 is a group represented by the following formula:
  • Embodiment 18 The compound of Formula (I) or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof according to any one of the preceding embodiments, wherein R 3 is a group represented by the following formula:
  • Embodiment 19 The compound of Formula (I) or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof according to any one of the preceding embodiments, wherein R 4 is H, -C 1-6 alkyl, -C 3-6 cycloalkyl, -C 3-6 heterocyclyl, or - (CH 2 ) q -C 3- 6 heterocyclyl, in which said C 3-6 heterocyclyl is monocyclic, fused bicyclic, or spiro bicyclic, contains 1 or 2 heteroatoms selected from the group consisting of N, O, and S, and is unsubstituted or further substituted by -C 1-6 alkyl, and q is 1, 2, or 3.
  • R 4 is H, -C 1-6 alkyl, -C 3-6 cycloalkyl, -C 3-6 heterocyclyl, or - (CH 2 ) q -C 3- 6 heterocyclyl, in which said C 3-6 heterocyclyl is
  • Embodiment 20 The compound of Formula (I) or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof according to any one of the preceding embodiments, wherein R 4 is H, (1-methylpiperidin-4-yl) methyl, or (2, 6-diazaspiro [3.3] heptan-2-yl) ethyl.
  • Embodiment 21 The compound of Formula (I) or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof according to any one of the preceding embodiments, wherein the isotopic variant is a deuterated variant.
  • Embodiment 22 The compound of Formula (I) or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof according to embodiment 1, wherein the compound wherein the compound is one of the compounds in Table 1.
  • Embodiment 23 A pharmaceutical composition for treating a CDK20-associated disease or condition, which comprises the compound of Formula (I) or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof according to any one of embodiments 1 to 22, and a pharmaceutically acceptable carrier or excipient.
  • Embodiment 24 The pharmaceutical composition according to embodiment 23, wherein the CDK20-associated disease or condition is a disease or condition selected from the group consisting of hepatocellular carcinoma (HCC) , colorectal cancer, glioblastoma, lung cancer, medulloblastoma, ovarian carcinoma, prostate cancer, and renal cell carcinoma.
  • HCC hepatocellular carcinoma
  • colorectal cancer glioblastoma
  • lung cancer medulloblastoma
  • ovarian carcinoma ovarian carcinoma
  • prostate cancer and renal cell carcinoma.
  • Embodiment 25 The pharmaceutical composition according to embodiment 24, which further comprises a second therapeutic agent useful for treating said disease or condition.
  • Embodiment 26 A method of treating a CDK20-associated disease or condition in a subject in need thereof, which comprises administering to the subject a therapeutically effective amount of the compound of Formula (I) or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof according to any one of embodiments 1 to 22.
  • Embodiment 27 The method according to embodiment 26, wherein the CDK20-associated disease or condition is a disease or condition selected from the group consisting of hepatocellular carcinoma (HCC) , colorectal cancer, glioblastoma, lung cancer, medulloblastoma, ovarian carcinoma, prostate cancer, and renal cell carcinoma.
  • HCC hepatocellular carcinoma
  • colorectal cancer glioblastoma
  • lung cancer medulloblastoma
  • ovarian carcinoma ovarian carcinoma
  • prostate cancer and renal cell carcinoma.
  • Embodiment 28 The method according to embodiment 27, wherein the CDK20-associated disease or condition is hepatocellular carcinoma (HCC) .
  • HCC hepatocellular carcinoma
  • Embodiment 29 A compound of Formula (I) or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof according to any one of embodiments 1 to 22 for use in the treatment of a CDK20-associated disease or condition.
  • Embodiment 30 The compound of Formula (I) or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof according to embodiment 29, wherein the CDK20-associated disease or condition is a disease or condition selected from the group consisting of hepatocellular carcinoma (HCC) , colorectal cancer, glioblastoma, lung cancer, medulloblastoma, ovarian carcinoma, prostate cancer, and renal cell carcinoma.
  • HCC hepatocellular carcinoma
  • colorectal cancer glioblastoma
  • lung cancer medulloblastoma
  • ovarian carcinoma ovarian carcinoma
  • prostate cancer and renal cell carcinoma.
  • Embodiment 31 Use of a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof according to any one of embodiments 1 to 22 in the manufacture of a medicament for treating a CDK20-associated disease or condition.
  • Embodiment 32 The use according to embodiment 31, wherein the CDK20-associated disease or condition is a disease or condition selected from the group consisting of hepatocellular carcinoma (HCC) , colorectal cancer, glioblastoma, lung cancer, medulloblastoma, ovarian carcinoma, prostate cancer, and renal cell carcinoma.
  • HCC hepatocellular carcinoma
  • colorectal cancer glioblastoma
  • lung cancer medulloblastoma
  • ovarian carcinoma ovarian carcinoma
  • prostate cancer and renal cell carcinoma.
  • Embodiment 33 A kit for treating a CDK20-associated disease or condition, which comprises a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof according to any one of embodiments 1 to 22, a container, and optionally a package insert or label indicating a treatment.
  • a kit for treating a CDK20-associated disease or condition which comprises a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof according to any one of embodiments 1 to 22, a container, and optionally a package insert or label indicating a treatment.
  • Embodiment 34 The kit according to embodiment 33, wherein the CDK20-associated disease or condition is a disease or condition selected from the group consisting of hepatocellular carcinoma (HCC) , colorectal cancer, glioblastoma, lung cancer, medulloblastoma, ovarian carcinoma, prostate cancer, and renal cell carcinoma.
  • HCC hepatocellular carcinoma
  • colorectal cancer glioblastoma
  • lung cancer medulloblastoma
  • ovarian carcinoma ovarian carcinoma
  • prostate cancer and renal cell carcinoma.
  • Embodiment 35 The kit according to embodiment 34, which further comprises a second therapeutical agent useful for treating said disease or disorder.
  • C 1-6 is intended to encompass, C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 1-6 , C 1- 5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5 , C 3-4 , C 4-6 , C 4-5 , and C 5-6 .
  • any variable occurs more than one time in any constituent or in Formula (I) or in any other formula depicting and describing the compounds of the present disclosure, its definition at each occurrence is independent of its definition at every other occurrence. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • alkyl refers to a linear or branched chain saturated hydrocarbon group.
  • C i-j alkyl refers to an alkyl having i to j carbon atoms.
  • Alkyl groups may contain 1 to 10 carbon atoms, unless otherwise stated. In certain embodiments, alkyl groups contain 1 to 6 carbon atoms, such as, 1 to 5 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms.
  • alkyl groups include methyl, ethyl, n-and iso-propyl, n-, sec-, iso-, and tert-butyl, neopentyl, and the like.
  • alkylene refers to a divalent substituent that is a monovalent alkyl having one hydrogen atom replaced with a valency.
  • alkenyl refers to a linear or branched-chain hydrocarbon radical having at least one carbon-carbon double bond, and includes radicals having “cis” and “trans” orientations, or alternatively, “E” and “Z” orientations.
  • Alkenyl groups may contain 2 to 10 carbon atoms, unless otherwise stated. In certain embodiments, alkenyl groups may contain 2 to 6 carbon atoms, such as 2 to 5 carbon atoms, 2 to 4 carbon atoms, 2 to 3 carbon atoms. In certain embodiments, alkenyl groups contain 2 carbon atoms.
  • Non-limiting examples of alkenyl groups include ethylenyl (vinyl) , propenyl, butenyl, pentenyl, 1-methyl-2-buten-1-yl, 5-hexenyl, etc.
  • alkynyl refers to a linear or branched hydrocarbon radical having at least one carbon-carbon triple bond.
  • Alkynyl groups may contain 2 to 10 carbon atoms, unless otherwise stated. In certain embodiments, alkynyl groups contain 2 to 8 carbon atoms, 2 to 6 carbon atoms, 2 to 4 carbon atoms, 2 to 3 carbon atoms. In certain embodiments, alkynyl groups contain 2 carbon atoms.
  • Non-limiting examples of alkynyl groups include ethynyl, 1-propynyl, 2-propynyl, etc.
  • cycloalkyl refers to a monovalent non-aromatic, saturated monocyclic and polycyclic ring system, in which all the ring atoms are carbons and which contains at least three ring forming carbon atoms. Cycloalkyl groups may contain 3 to 10 ring forming carbon atoms, unless otherwise stated. In certain embodiments, cycloalkyl groups may contain 3 to 8 ring forming carbon atoms, 3 to 6 ring forming carbon atoms (i.e., C 3 - 6 cycloalkyl) , etc. Particularly, cycloalkyl groups may be monocyclic or bicyclic.
  • bicyclic cycloalkyl groups may include fused, spiro, and bridged cycloalkyl structures. Also included are rings in which 1, 2, or 3 heteroatoms replace carbons. Such groups are termed as “heterocyclyl” or “heterocyclic ring” , which refers to a cycloalkyl group further bearing at least one heteroatom selected from N, O, and S as ring forming atoms.
  • heterocyclyl groups include oxiranyl, pyrrolidinyl, piperidyl, tetrahydropyranyl, piperazinyl, pyrrolidinyl, and morpholinyl. Heterocyclyl groups may be described by using a carbon count.
  • C 3- 9 heterocyclyl refers to a heterocyclyl group which contains three to nine ring forming carbon atoms, and may further contain at least one heteroatom, such as 1, 2, or 3 heteroatoms as ring forming atoms.
  • C 3-6 heterocyclyl refers to a heterocyclyl group which contains three to six ring forming carbon atoms, and may further contain at least one heteroatom, such as 1, 2, or 3 heteroatoms as ring forming atoms.
  • Non-limiting examples of C 3-6 heterocyclyl groups include etc.
  • heterocyclyl groups or heterocyclic rings contain 1 or 2 heteroatoms, as ring forming atoms.
  • heterocyclyl group may be monocyclic or bicyclic, such as fused bicyclic and spiro bicyclic.
  • heterocyclyl and “heterocyclic ring” may be used interchangeably.
  • aryl refers to a mono-, bicyclic, or multicyclic carbocyclic ring system having at least one aromatic rings.
  • Aryl groups may be 6-to 10-membered, unless otherwise stated.
  • aryl groups may contain 6 ring forming carbon atoms. All atoms within a carbocyclic aryl group are carbon atoms.
  • Non-limiting examples of aryl groups include phenyl, naphthyl, 1, 2-dihydronaphthyl, 1, 2, 3, 4-tetrahydronaphthyl, fluorenyl, indanyl, indenyl, etc.
  • the terms “aryl” and “aromatic ring” may be used interchangeably.
  • heteroaryl or “heteroaromatic ring” refers to a monocyclic ring system, or a fused or bridged bicyclic ring system, in which the ring system contains one, two, three, or four heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; and at least one of the rings is an aromatic ring.
  • Heteroaryl groups may be 5-to 10-membered, unless otherwise stated. In certain embodiments, heteroaryl groups may be 5-to 6-membered. In certain embodiments, heteroaryl groups may contain one, two, or three heteroatoms. In certain embodiments, heteroaryl groups may contain one or two heteroatoms.
  • heteroraryl groups may further substituted by alkyl or oxo.
  • heteroaryl groups include benzimidazolyl, benzotriazolyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, furyl, imidazolyl, indolyl, isoindazolyl, isoquinolinyl, isothiazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, purinyl, pyrrolyl, pyridinyl, pyrazinyl, pyrimidinyl, qunazolinyl, quinolinyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, tetrazolyl, dihydroindolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, pyrrol
  • Heteroaryl groups include at least one ring having at least one heteroatom as described above and at least one aromatic ring.
  • a ring having at least one heteroatom may be fused to one, two, or three carbocyclic rings, e.g., an aryl ring, a cyclohexane ring, a cyclohexene ring, a cyclopentane ring, a cyclopentene ring, or another monocyclic heterocyclic ring.
  • Non-limiting examples of fused heteroaryl groups include 1, 2, 3, 5, 8, 8a-hexahydroindolizine, 2, 3-dihydrobenzofuran, 2, 3-dihydroindole, 2, 3-dihydrobenzothiophene, 1, 2, 3, 4-tetrahydroisoquinoline, and 5, 6, 7, 8-tetrahydroimidazo [1, 2-a] pyridine, etc.
  • the terms “heteroaryl” and “heteroaromatic ring” may be used interchangeably.
  • halogen refers to fluoride, chloride, bromide, and iodide.
  • non-limiting examples of halo include fluoride, chloride and bromide, and more particularly fluoride and bromide.
  • haloalkyl refers to an alkyl group substituted with one or more halogen atoms selected from the group consisting of fluoride, chloride, bromide, and iodide.
  • haloalkyl groups include -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CF 3 , -CF 2 CF 3 , etc.
  • substituted when refers to a chemical group, means that the chemical group has one or more hydrogen atoms that is/are removed and replaced by substituents.
  • substituted as used herein has the ordinary meaning known in the art and refers to a chemical moiety that is covalently attached to, or if appropriate, fused to, a parent group. It is to be understood that substitution at a given atom is limited by valency. It is understood that the substituent can be further substituted.
  • the compounds as provided herein are described with reference to both generic formulas and specific compounds.
  • the compounds of the present disclosure may exist in a number of different forms or derivatives, all within the scope of the disclosure. These include, for example, pharmaceutically acceptable salts, tautomers, stereoisomers, racemic mixtures, regioisomers, prodrugs, solvated forms, different crystal forms or polymorphs, and active metabolites, etc.
  • the term “pharmaceutically acceptable salt” includes salts that retain the biological effectiveness of the free acid/base form of the specified compound and that are not biologically or otherwise undesirable.
  • Contemplated pharmaceutically acceptable salt forms include, but are not limited to, mono, bis, tris, tetrakis, and so on.
  • Pharmaceutically acceptable salts are non-toxic in the amounts and concentrations at which they are administered. The preparation of such salts can facilitate the pharmacological use by altering the physical characteristics of a compound without preventing it from exerting its physiological effect. Useful alterations in physical properties may include, for example, increasing the solubility to facilitate administering higher concentrations of the drug.
  • Pharmaceutically acceptable salts of the compounds of Formula (I) include acid addition and base salts. Suitable acid addition salts can be formed from acids which form non-toxic salts. Non-limiting examples may include the acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulfate/sulfate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphat
  • Suitable base salts are formed from bases which form non-toxic salts.
  • Non-limiting examples may include the aluminium, arginine, benzathine, calcium, choline, diethylamine, bis (2-hydroxyethyl) amine (diolamine) , glycine, lysine, magnesium, meglumine, 2-aminoethanol (olamine) , potassium, sodium, 2-Amino-2- (hydroxymethyl) propane-1, 3-diol (tris or tromethamine) and zinc salts.
  • Hemisalts of acids and bases may also be formed, for example, hemisulfate and hemicalcium salts.
  • suitable salts see, Stahl and Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection, and Use (Wiley-VCH, 2002) .
  • Pharmaceutically acceptable salts of the compound of Formula (I) may be prepared by one or more of three methods: (i) by reacting the compound of Formula (I) with the desired acid or base; (ii) by removing an acid-or base-labile protecting group from a suitable precursor of the compound of Formula (I) or by ring-opening a suitable cyclic precursor, for example, a lactone or lactam, using the desired acid or base; or (iii) by converting one salt of the compound of Formula (I) to another by a reaction with an appropriate acid or base or by means of a suitable ion exchange column.
  • the three reactions may be typically carried out in solution.
  • the resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent.
  • the degree of ionization in the resulting salt may vary from completely ionized to almost non-ionized.
  • solvate refers to a molecular complex comprising the compound of Formula (I) , or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable solvent molecules.
  • hydrate is employed when said solvent is water.
  • the compounds of Formula (I) may have one or more chiral (asymmetric) centers.
  • the present disclosure encompasses all stereoisomeric forms of the compounds of Formula (I) . Centers of asymmetry that are present in the compounds of Formula (I) can all independently of one another have (R) or (S) configuration.
  • bonds to a chiral carbon are depicted as straight lines in the structural formulas of the present disclosure, or when a compound name is recited without an (R) or (S) chiral designation for a chiral carbon, it is understood that both the (R) and (S) configurations of each such chiral carbon and hence each enantiomer or diastereomer and mixtures thereof are embraced within the formula or by the name.
  • the production of specific stereoisomers or mixtures thereof may be identified in the Examples where such stereoisomers or mixtures were obtained, but this in no way limits the inclusion of all stereoisomers and mixtures thereof from being within the scope of the disclosure.
  • the present disclosure includes all possible enantiomers and diastereomers and mixtures of two or more stereoisomers, for example mixtures of enantiomers and/or diastereomers, in all ratios.
  • enantiomers are a subject of the present disclosure in enantiomerically pure form, both as levorotatory and as dextrorotatory antipodes, in the form of racemates and in the form of mixtures of the two enantiomers in all ratios.
  • the present disclosure includes both the cis form and the trans form as well as mixtures of these forms in all ratios.
  • the preparation of individual stereoisomers can be carried out, if desired, by separation of a mixture by customary methods, for example by chromatography or crystallization, by use of stereochemically uniform starting materials for the synthesis or by stereoselective synthesis.
  • a derivatization can be carried out before separation of stereoisomers.
  • the separation of a mixture of stereoisomers can be carried out in an intermediate step during the synthesis of a compound of Formula (I) , or it can be done on a final racemic product.
  • Absolute stereochemistry may be determined by X-ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary, with a reagent containing a stereogenic center of known configuration.
  • absolute stereochemistry may be determined by Vibrational Circular Dichroism (VCD) spectroscopy analysis.
  • VCD Vibrational Circular Dichroism
  • the structures depicted herein are also meant to include the compounds that differ only in the presence of one or more isotopically enriched atoms, in other words, the compounds wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number which predominates in nature. Such compounds are referred to as a “isotopic variant” .
  • the present disclosure is intended to include all pharmaceutically acceptable isotopic variants of the compounds of Formula (I) .
  • isotopes suitable for inclusion in the compounds of the present disclosure include, but not limited to, isotopes of hydrogen, such as 2 H and 3 H; carbon, such as 11 C, 13 C and 14 C; chlorine, such as 36 Cl; fluorine, such as 18 F; iodine, such as 123 I and 125 I; nitrogen, such as 13 N and 15 N; oxygen, such as 15 O, 17 O and 18 O; phosphorus, such as 32 P; and sulfur, such as 35 S.
  • isotopic variants of the compounds of Formula (I) for example those incorporating a radioactive isotope, may be useful in drug and/or substrate tissue distribution studies.
  • Isotopic variants of compounds of Formula (I) can generally be prepared by conventional techniques known to one skilled in the art or by processes analogous to those described in the accompanying examples and synthesis using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed.
  • compositions in accordance with the present disclosure may include those wherein the solvent of crystallization may be isotopically substituted, e.g., D 2 O, d 6 -acetone, d 6 -DMSO.
  • One way of carrying out the present disclosure is to administer a compound of Formula (I) in the form of a prodrug.
  • certain derivatives of a compound of Formula (I) which may have little or no pharmacological activity themselves can, when administered into or onto the body, be converted into a compound of Formula (I) having the desired activity, for example by hydrolytic cleavage, particularly hydrolytic cleavage promoted by an esterase or peptidase enzyme.
  • Such derivatives are referred to as “prodrugs” .
  • Further information on the use of prodrugs may be found in, e.g., T. Higuchi and W. Stella, “Pro-drugs as Novel Delivery Systems” , Vol. 14, ACS Symposium Series, and E. B. Roche (Ed. ) , “Bioreversible Carriers in Drug Design” , Pergamon Press, 1987, American Pharmaceutical Association. Reference can also be made to Nature Reviews/Drug Discovery, 2008, 7, 355, and Current Opinion in Drug Discovery and Development, 2007, 10, 550.
  • Prodrugs in accordance with the present disclosure can, for example, be produced by replacing appropriate functionalities present in the compounds of Formula (I) with certain moieties known to those skilled in the art as “pro-moieties” as described, for example, in H. Bundgaard, “Design of Prodrugs” , Elsevier, 1985, and Y.M. Choi-Sledeski and C.G. Wermuth, “Designing Prodrugs and Bioprecursors” , Practice of Medicinal Chemistry, 4 th Edition, Chapter 28, 657-696, Elsevier, 2015.
  • a prodrug in accordance with the present disclosure may include, but not limited to, (a) an ester or amide derivative of a carboxylic acid in a compound of Formula (I) , if any; (b) an amide, imine, carbamate or amine derivative of an amino group in a compound of Formula (I) ; (c) an oxime or imine derivative of a carbonyl group in a compound of Formula (I) , if any; or (d) a methyl, primary alcohol or aldehyde group that can be metabolically oxidized to a carboxylic acid in a compound of Formula (I) , if any.
  • references to compounds of Formula (I) are taken to include the compounds themselves and prodrugs thereof.
  • the present disclosure includes such compounds of Formula (I) as well as pharmaceutically acceptable salts of such compounds and pharmaceutically acceptable solvates of said compounds and salts.
  • the compounds of the present disclosure may be administered in an amount effective to treat the diseases or conditions as described herein.
  • the compounds of the present disclosure can be administered as compound per se, or alternatively, as a pharmaceutically acceptable salt.
  • the compound of the present disclosure per se or pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof will simply be referred to as the compounds of the disclosure.
  • the compounds of the disclosure are administered by any suitable route in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended.
  • the compounds of the disclosure may be administered orally, rectally, vaginally, parenterally, or topically.
  • the terms “administration” and “administer” refer to absorbing, ingesting, injecting, inhaling, implanting, or otherwise introducing the compound of the disclosure, or a pharmaceutical composition thereof.
  • treatment and “treat” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a “pathological condition” (e.g., a disease, disorder, or condition, or one or more signs or symptoms thereof) described herein.
  • pathological condition e.g., a disease, disorder, or condition, or one or more signs or symptoms thereof
  • treatment may be administered after one or more signs or symptoms of a disease or condition have developed or have been observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of the disease or condition.
  • treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors) . Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence.
  • disease e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors
  • pathological condition e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors
  • Dosage levels for administration can be determined by those skilled in the art by routine experimentation.
  • the dosage regimen for the compounds of the disclosure and/or compositions comprising said compounds is based on a variety of factors, including the type, age, weight, sex, and medical condition of the patient; the severity of the condition; the route of administration; and the activity of the particular compound employed. Thus, the dosage regimen may vary widely. It is not uncommon that the administration of the compounds of the disclosure will be repeated a plurality of times in a day.
  • the compound of the disclosure may be administered in combination with a second therapeutical agent.
  • second therapeutical agents may include an anti-cancer agent.
  • non-limiting examples of second therapeutical agents may include an additional CDK20 inhibitor.
  • the second therapeutical agent can be administered before, after, or at the same time that the compound of the present disclosure is administered.
  • the present disclosure is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of Formula (I) or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof as provided herein, and at least one pharmaceutically acceptable carrier or excipient.
  • the term “pharmaceutically acceptable carrier or excipient” refers to a carrier or excipient which is useful for preparing a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable, and includes carrier or excipient that is acceptable for veterinary use as well as human pharmaceutical use.
  • a “pharmaceutically acceptable carrier or excipient” as used herein includes both one and more than one such carrier or excipient. The particular carrier or excipient used will depend upon the means and purpose for which the compounds of the disclosure is being applied. Suitable carriers and excipients are well known to those skilled in the art and are described in detail in, e.g., Ansel, Howard C, et al., Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems.
  • the formulations may also include one or more of buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents, diluents, and other known additives to provide an elegant presentation of the drug (i.e., the compound or pharmaceutical composition as provided herein) or aid in the manufacturing of the pharmaceutical product (i.e., medicament) .
  • buffers i.e., stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents, diluents, and other known additives to provide an elegant presentation of the drug (i.e., the compound or pharmaceutical composition as provided here
  • compositions of the present disclosure may be in a variety of forms. These include, for example, liquid, semi-solid and solid dosage forms, such as liquid solutions (e.g., injectable and infusible solutions) , dispersions or suspensions, tablets, pills, powders, liposomes, suppositories, etc.
  • liquid solutions e.g., injectable and infusible solutions
  • dispersions or suspensions tablets, pills, powders, liposomes, suppositories, etc.
  • the form depends on the intended mode of administration and therapeutic application.
  • compositions of the present disclosure may be prepared by any of the well-known techniques of pharmacy, such as effective formulation and administration procedures.
  • effective formulations and administration procedures are well known in the art, and are described in standard textbooks.
  • Formulation of pharmaceutical products is discussed in, e.g., Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania, 1975; Liberman, et al., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Kibbe, et al., Eds., Handbook of Pharmaceutical Excipients, 3 rd Edition, American Pharmaceutical Association, Washington, 1999.
  • the present disclosure relates to a kit for treating a CDK20-associated disease or condition, which comprises a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof as provided herein, a container, and optionally a package insert or label indicating a treatment.
  • a kit for treating a CDK20-associated disease or condition which comprises a compound of Formula (I) or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof as provided herein, a container, and optionally a package insert or label indicating a treatment.
  • the present disclosure is directed to a method of treating a CDK20-associated disease or condition in a subject in need thereof, which comprises administering to the subject a therapeutically effective amount of the compound of Formula (I) or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof as provided herein, owning to the CDK20 inhibitor activity of the compound of the present disclosure.
  • the term “subject in need thereof” is a subject having a CDK20-associated disease or condition, or a subject having an increased risk of developing CDK20-associated disease or condition relative to the population at large.
  • the subject is a warm-blooded animal.
  • the warm-blooded animal is a mammal.
  • the warm-blooded animal is a human.
  • the CDK20-associated disease or condition is selected from a group consisting of hepatocellular carcinoma (HCC) , colorectal cancer, glioblastoma, lung cancer, medulloblastoma, ovarian carcinoma, prostate cancer, and renal cell carcinoma.
  • the CDK20-associated disease or condition is hepatocellular carcinoma (HCC) .
  • the method of treating a CDK20-associated disease or condition as described herein may be used as a monotherapy.
  • monotherapy refers to the administration of a single active or therapeutic compound to a subject in need thereof.
  • monotherapy will involve administration of a therapeutically effective amount of one of the compounds of the present disclosure or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof, to a subject in need of such treatment.
  • the method of treating a CDK20-associated disease or condition described herein may involve, in addition to administration of the compound of Formula (I) , combination therapy of one or more additional therapeutic agent (s) , for example, a second therapeutic agent which is an anti-cancer agent.
  • additional therapeutic agent for example, a second therapeutic agent which is an anti-cancer agent.
  • the term “combination therapy” refers to the administration of a combination of multiple active therapeutic agents.
  • the compound of the present disclosure or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof may be administered simultaneously, separately or sequentially to treatment with the one or more additional therapeutic agent (s) .
  • the additional therapeutic agent (s) may be administered separately from the compound of the present disclosure, as part of a multiple dosage regimen.
  • the additional therapeutic agent (s) may be part of a single dosage form, mixed with the compound of the present disclosure in a single composition.
  • the present disclosure is directed to the compound of Formula (I) or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof as provided herein for use in the treatment of a CDK20-associated disease or condition.
  • the present disclosure is directed to use of the compound of Formula (I) or a pharmaceutically acceptable salt, solvate, stereoisomer, or isotopic variant thereof as provided herein in the manufacture of a medicament for treating a CDK20-associated disease or condition.
  • the compounds of the present disclosure may be prepared by the general and specific methods described below, using the common general knowledge of those skilled in the art of synthetic organic chemistry. Such common general knowledge can be found in standard reference books, e.g., Barton and Ollis (Ed. ) , Comprehensive Organic Chemistry, Elsevier; Richard Larock, Comprehensive Organic Transformations: A Guide to Functional Group Preparations, John Wiley and Sons; and Compendium of Organic Synthetic Methods, Vol. I-XII, Wiley-Interscience.
  • the starting materials used herein are commercially available or may be prepared by routine methods known in the art.
  • the compounds of the present disclosure can be readily prepared according to the following reaction schemes and examples, or modifications thereof, using readily available starting materials, reagents, and conventional synthesis procedures. In these reactions, it is also possible to make use of variants which are themselves known to those skilled in the art, but are not mentioned in greater detail. Furthermore, other methods for preparing the compounds of the present disclosure will be readily apparent to those skilled in the art in light of the reaction schemes and examples as described herein. Unless otherwise indicated, all variables are as defined above. In general chemical procedures, all reagents and materials may be purchased from commercial vendors or may be readily prepared by those skilled in the art.
  • Hepatocellular carcinoma is the dominant type of liver cancer, accounting for approximately 75%of the total patient population. The incidence rate of liver cancer is very close to its mortality rate due to very poor prognosis in all regions around the world.
  • PD-L1 inhibitor atezolizumab in combo with bevacizumab has become the new standard-of-care (SoC) first-line treatment for advanced HCC after demonstrating a 42%reduction in the risk of death and a 41%reduction in the risk of disease worsening or death over the previous SoC Nexavar, but there’s still a huge unmet medical need for HCC patients.
  • SoC standard-of-care
  • PandaOmics is one of automated drug discovery AI engines to accelerate and optimize key steps of the early stages of drug discovery. This biocomputational platform combines bioinformatics methods for data analysis, visualization and interpretation with advanced multimodal deep learning approaches for target identification. PandaOmics therapeutic target and biomarker identification system is based on the combination of multiple scores derived from text and OMICs data associating genes with a disease of interest. Text evidence prioritization (Text, Financial and KOL (Key Opinion Leader) score families) singles out the genes, extensively mentioned across scientific literature and grant description.
  • Text evidence prioritization Text, Financial and KOL (Key Opinion Leader) score families
  • OMICs-based scores explore the molecular connection of genes with diseases based on differential expression, gene variants, interactome topology, signaling pathways activation analysis using iPanda algorithm 9 , knockout ⁇ overexpression experiments and more.
  • This kind of approach allows users to unveil the hidden hypotheses that might not be obvious over common general knowledge or simple bioinformatics analysis.
  • AI tools are extremely helpful for efficient target hypothesis generation.
  • the overall scoring approach results in the ranked list of target hypotheses for a given disease which can be subsequently filtered according to their novelty, accessibility by small molecules and antibodies, safety, tissue specificity, crystal structure availability and major biological structures.
  • PandaOmics platform Another unique feature of the PandaOmics platform is the ability to combine the data from different experiments into a single Meta-analysis and leverage the insights from all the datasets together for the precise target prioritization.
  • a Meta-analysis for each of the diseases of interest composed from 10 datasets for HCC (1133 disease samples and 674 healthy controls) .
  • PandaOmics filters After obtaining the ranked list of target hypotheses we applied PandaOmics filters in order to get the list of the most promising targets that satisfy First-in-class (see Methods section) scenarios and share the current unavailability of crystal structure but have structure folds predicted by AlphaFold. The final list of top-20 targets was then manually curated to nominate the most promising candidates.
  • For hepatocellular carcinoma CDK20 was chosen since it had the highest scores aligned with the First-in-class scenario.
  • the proposed therapeutic target CDK20 was passed to Chemistry42 platform for the automated generation of small molecule inhibitors.
  • amide -NH group or pyrrole -NH group may form hydrogen bond interactions with the two acid centers Asp87 and Glu90 in the solvation region. Based on the predicted binding pose, hit expansion upon I-001 is ongoing to further improve the enzymatic activity.
  • Hepatocellular carcinoma Meta-analysis combined the data from ten experiments: GSE36376 30 (Cho et al. 2020) , GSE107170 30, 31 (Cho et al. 2020; Diaz et al. 2018) , GSE102079 32 , GSE45267 32, 33 , GSE133039 34 , GSE104766 35 , GSE77314 35, 36 , GSE60502 37 , E-MTAB-5905 38 and TCGA-LIHC 39 , resulting in 1133 disease samples and 674 healthy controls.
  • Step 1 To a solution of methyl 4-nitro-1H-pyrrole-2-carboxylate (3.0 g, 17.6 mmol) in THF (45 mL) was added LiOH (aq., 2 M, 44.1 mL) . The mixture was stirred at 85°C for 4 hrs. The reaction mixture was neutralized by addition of HCl (aq., 1 M) and then extracted with EtOAc (40 mL ⁇ 3) . The combined organic layers were washed with brine (50 mL ⁇ 2) , dried over anhydrous sodium sulfate, filtered, and concentrated to afford INT-1-1.
  • 1 H NMR 400 MHz, DMSO-d 6 ) ⁇ 13.19 (s, 1H) , 13.08 -12.88 (m, 1H) , 8.01 (s, 1H) , 7.21 (s, 1H) .
  • Step 2 A mixture of INT-1-1 (2.96 g, 18.9 mmol) , DIPEA (9.91 mL, 56.8 mmol, T 3 P (7.84 g, 24.6 mmol, 7.33 mL) and in DCM (30 mL) , followed by the addition of MeNH 2 (1.92 g, 28.4 mmol) . The mixture was stirred at 25°C for 2 hrs. The reaction mixture was diluted with water (30 mL) , and then filtered to give a residue, which was triturated with CH 3 CN at 25 °C. The mixture was filtered to afford INT-1-2. LCMS [M-H] - : 168.0.
  • Step 3 To a solution of INT-1-2 (2.0 g, 11.8 mmol) in MeOH (20 mL) was added Pd/C (0.40 g, 10 wt%) under N 2 atmosphere. The suspension was degassed and purged with H 2 for 3 times. The mixture was stirred under H 2 (15 psi) at 25°C for 12 hrs. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to afford INT-1. LCMS [M+H] + : 140.1.
  • Step 1 To a solution of 2, 4-dichloro-6-methoxyquinazoline (0.30 g, 1.31 mmol) in DCM (5.0 mL) was added zinc powder (256.9 mg, 3.93 mmol) and NH 4 Cl (aq., 44.1 mmol, 5.0 mL) . The mixture was stirred at 40°C for 2 hrs. The resulting mixture was cooled to r.t. and filtered through a Celite pad. The filtrate was extracted with DCM (10 mL ⁇ 2) . The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum to afford I-002-1. LCMS [M+H] + : 195.0.
  • Step 2 To a solution of I-002-1 (50.0 mg, 256.9 ⁇ mol) and INT-1 (35.75 mg, 256.9 ⁇ mol) in DMSO (1 mL) was added K 2 CO 3 (53.3 mg, 385.37 ⁇ mol) . The mixture was stirred at 100°Cfor 4 hrs. The mixture was concentrated and purified by prep-HPLC to afford I-002.
  • Step 1 A mixture of 6-bromo-2-chloroquinazoline (200 mg, 821 ⁇ mol) , 2, 4, 6-trimethyl-1, 3, 5, 2, 4, 6-trioxatriborinane (412 mg, 1.64 mmol, 459 ⁇ L) , Cs 2 CO 3 (803 mg, 2.46 mmol) , Pd(PPh 3 ) 2 Cl 2 (115 mg, 164 ⁇ mol) in H 2 O (0.5 mL) and DME (2 mL) was degassed and purged with N 2 for 3 times, and then the mixture was stirred at 90°C for 4 hrs under N 2 atmosphere. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL ⁇ 3) . The combined organic layers were washed with brine (10 mL) , dried over anhydrous sodium sulfate, filtered, and concentrated to afford I-004-1.
  • LCMS [M+H] + 179.1.
  • Step 2 To a solution of I-004-1 (50.0 mg, 280 ⁇ mol) and INT-1 (38.9 mg, 280 ⁇ mol) in DMSO (1 mL) was added K 2 CO 3 (58.0 mg, 420 ⁇ mol) . The mixture was stirred at 100°C for 2 hrs. The mixture was concentrated and purified by prep-HPLC to afford I-004.
  • Step 1 A mixture of INT-1 (200 mg, 1.44 mmol) and 6-bromo-2-chloroquinazoline (350 mg, 1.44 mmol) in DMSO (10 mL) was added K 2 CO 3 (596 mg, 4.31 mmol) . The mixture was stirred at 90°C for 5 hrs. The reaction mixture was washed by water (2 mL) and then extracted with EtOAc (2 mL ⁇ 3) . The combined organic layers were washed with brine (2 mL ⁇ 2) , dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel chromatography to afford I-005-1. LCMS [M+H] + : 348.0.
  • Step 2 A mixture of I-005-1 (500 mg, 866 ⁇ mol) , Zn (CN) 2 (254 mg, 2.17 mmol, 138 ⁇ L) , Pd 2 (dba) 3 (15.9 mg, 17.3 ⁇ mol) and DPPF (19.2 mg, 34.7 ⁇ mol) in DMF (15 mL) was degassed and purged with N 2 for 3 times. The mixture was stirred at 90°C for 4 hrs under N 2 atmosphere. The reaction mixture was quenched by the addition of water (40 mL) , and then filtered to give a filter residue. The residue was purified by prep-HPLC to afford I-005.
  • Step 1 A mixture of pyrrolidin-2-one (83.9 mg, 986 ⁇ mol) , 7-bromo-2-chloroquinazoline (200 mg, 821 ⁇ mol) , Xantphos (157 mg, 271 ⁇ mol) , Pd 2 (dba) 3 (120 mg, 131 ⁇ mol) and K 3 PO 4 (976 mg, 4.60 mmol) in toluene (5.0 mL) was degassed and purged with N 2 for 3 times. The mixture was stirred at 60°C for 16 hrs under N 2 atmosphere. The reaction mixture was diluted with water (10 mL) and extracted with DCM (5.0 mL ⁇ 3) . The combined organic layers were washed with brine (10 mL) , dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give I-007-1.
  • Step 2 To a solution of I-007-1 (50.0 mg, 202 ⁇ mol) and INT1-1 (28.1 mg, 202 ⁇ mol) in DMSO (1 mL) was added K 2 CO 3 (41.9 mg, 303 ⁇ mol) . The mixture was stirred at 100°C for 3 hrs. The mixture was purified by prep-HPLC to afford I-007.
  • Step 2 To a solution of I-008-2 (200 mg, 959 ⁇ mol) in DCM (1 mL) was added T 3 P (1.22 g, 1.92 mmol, 1.14 mL, 50.0%purity) and DIEA (501 ⁇ L 2.88 mmol, ) and methylamine hydrochloride (77.7 mg, 1.15 mmol) . The mixture was stirred at 25°C for 2 hrs. The reaction mixture was quenched by the addition of water (3 mL) at 25°C and extracted with DCM (5 mL ⁇ 3) . The combined organic layers were washed with brine (15 mL) , dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give I-008-2. LCMS [M+H] + : 222.3.
  • Step 3 To a solution of I-008-2 (50.0 mg, 0.226 mmol) in DMSO (1 mL) was added INT-1 (31.4 mg, 0.226 mmol) and K 2 CO 3 (46.8 mg, 0.338 mmol) . The mixture was stirred at 100°Cfor 2 hrs. The reaction was concentrated and purified by prep-HPLC to afford I-008.
  • Step 1 A mixture of 7-bromo-2-chloroquinazoline (244 mg, 1.01 mmol) and INT-1 (140 mg, 1.01 mmol) in DMSO (5.0 mL) was stirred at 25°C for 1 hr, followed by the addition of KF (87.6 mg, 1.51 mmol) . The resulting mixture was stirred at 120°C for 2 hrs. The mixture was cooled to 25°C and pour it into water (10 mL) . The mixture was put in ultrasound bath for 10 min and filtered to afford I-009-1. LCMS [M+H] + : 346.0.
  • Step 2 A mixture of I-009-1 (60.0 mg, 133 ⁇ mol) , copper (II) trifluoroacetate (38.6 mg, 133 ⁇ mol) , methylsulfinyloxysodium (85.7 mg, 839 ⁇ mol) , N, N'-dimethylethane-1, 2-diamine (8.22 mg, 93.3 ⁇ mol, 10.0 ⁇ L) in DMSO (1 mL) was stirred at 140°C for 2 hrs. The reaction mixture was diluted with EtOAc (5 mL) and filtered. The filtrate was diluted with water (3.0 mL) and extracted with EtOAc (15 mL ⁇ 3) .
  • Step 1 A mixture of I-009-2 (130 mg, 288 ⁇ mol) , 4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (112 mg, 577 ⁇ mol) , XPhos (27.5 mg, 57.7 ⁇ mol) , Pd (dppf) Cl 2 (21.1 mg, 28.8 ⁇ mol) and Cs 2 CO 3 (282 mg, 866 ⁇ mol) in dioxane (5 mL) and H 2 O (1 mL) was degassed and purged with N 2 for 3 times, and then the mixture was stirred at 100°C for 12 hrs under N 2 .
  • Step 1 To a solution of methyl 4-amino-1H-pyrrole-2-carboxylate (1.08 g, 6.99 mmol) in DMF (25 mL) was added K 2 CO 3 (1.45 g, 10.48 mmol) , 2-chloroquinazoline (1.15 g, 6.99 mmol) . The mixture was stirred at 80°C for 16 hrs. The reaction mixture was washed with water (30 mL) and extracted with EtOAc (15 mL ⁇ 3) . The combined organic layers were washed with brine (30 mL ⁇ 2) , dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel chromatography to afford I-014-1.
  • Step 2 To a solution of I-014-1 (1.3 g, 4.61 mmol) in THF (46 mL) was added aqueous LiOH (1 M, 46 mL) . The mixture was stirred at 85°C for 12 hrs. The reaction mixture was neutralized by HCl (1 M) and then extracted with EtOAc (40 mL ⁇ 3) . The combined organic layers were washed with brine (50 mL) , dried over anhydrous sodium sulfate, and concentrated to give I-014-2. LCMS [M-H] + : 253.0.
  • Step 3 To a solution of I-014-2 (100 mg, 393 ⁇ mol) in DMF (1 mL) was added N', N'-dimethylethane-1, 2-diamine (36.4 mg, 412.9 ⁇ mol, 45.1 uL) , HOBt (58.46 mg, 432.66 ⁇ mol) , EDCI (82.94 mg, 432.66 ⁇ mol) and DIPEA (101.6 mg, 786.65 ⁇ mol, 137.02 ⁇ L) . The resulting mixture was degassed and purged with N 2 for 3 times and stirred at 25°C for 16 hrs under N 2 atmosphere.
  • Step 1 A mixture of 7-bromo-2-chloroquinazoline (300 mg, 1.23 mmol) , imidazo [1, 2-a]pyrimidine (176 mg, 1.48 mmol) , Pd (OAc) 2 (27.7 mg, 0.123 mmol) , tetrabutylammonium chloride (68.5 mg, 0.246 mmol) and K 2 CO 3 (511 mg, 3.70 mmol) in DMF (3 mL) was degassed and purged with N 2 for 3 times. The mixture was stirred at 100°C for 2 hrs under N 2 atmosphere. The mixture was filtrated and washed with water (3 mL ⁇ 3) . The organic phase was concentrated under vacuum to give I-034-1. LCMS [M+H] + : 282.2.
  • Step 2 To a solution of I-034-1 (50.0 mg, 0.359 mmol) in DMSO (1 mL) was added INT-1 (100 mg, 0.355 mmol) and K 2 CO 3 (73.6 mg, 0.532 mmol) . The mixture was stirred at 100°Cfor 1 hr. The mixture was concentrated and purified by prep-HPLC to afford I-034.
  • Step 1 A mixture of I-009-1 (20.0 mg, 0.0580 mmol) , bis (pinacolato) diboron (29.3 mg, 0.116 mmol) , Pd (dppf) Cl 2 (4.23 mg, 0.06 mmol) and KOAc (17.0 mg, 0.173 mmol) in dioxane (1 mL) was degassed and purged with N 2 for 3 times. The mixture was stirred at 100°C for 12 hrs under N 2 atmosphere. The mixture was concentrated to give I-035-1. LCMS [M+H] + : 312.1.
  • Step 2 A mixture of I-035-1 (22.8 mg, 0.073 mmol) , 3-bromo-5, 6, 7, 8-tetrahydroimidazo [1, 2-a] pyridine (22.1 mg, 0.110 mmol) , Pd (dppf) Cl 2 (5.36 mg, 0.07 mmol) , and Cs 2 CO 3 (71.7 mg, 0.220 mmol) in dioxane (1 mL) and H 2 O (0.4 mL) was degassed and purged with N 2 for 3 times. The mixture was stirred at 100°C for 12 hrs under N 2 atmosphere. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL ⁇ 3) .
  • Step 1 To a solution of 5-nitroisothiazole-3-carboxylic acid (300 mg, 1.72 mmol) , MeNH 2 (107 mg, 3.44 mmol) and DIEA (1.13 mL, 6.89 mmol) in DMF (6.0 mL) was added HATU (1310 mg, 3.44 mmol) . The mixture was stirred at 20°C for 12 hrs. The reaction mixture was added water (5.0 mL) , then extracted with EtOAc (10 mL ⁇ 3) . The combined organic layers were washed with brine (5.0 mL) , dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by pre-TLC to afford I-038-1. LCMS [M+H] + : 188.1.
  • Step 2 To a solution of I-038-1 (340 mg, 1.54 mmol) in EtOH (4.0 mL) was added NH 4 Cl (247 mg, 4.62 mmol) in H 2 O (1 mL) , followed by the addtion of iron powder (430 mg, 7.71 mmol) . The mixture was stirred at 25°C for 6 hrs. The reaction mixture was filtered and then extracted with EtOAc (3.0 mL ⁇ 3) . The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give I-038-2. LCMS [M+Na] + : 180.1.
  • Step 3 To a solution of I-038-2 (200 mg, 1.27 mmol) and INT-2 (420 mg, 1.27 mmol) in dioxane (5.0 mL) was added Pd 2 (dba) 3 (116 mg, 0.127 mmol) , Xantphos (147 mg, 0.254 mmol) and Cs 2 CO 3 (829 mg, 2.54 mmol) under N 2 atomosphere. The reaction mixture was stirred at 120°C for 2 hrs under microwave irratation. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure and purified by prep-HPLC to afford I-038.
  • Pd 2 (dba) 3 116 mg, 0.127 mmol
  • Xantphos 147 mg, 0.254 mmol
  • Cs 2 CO 3 829 mg, 2.54 mmol
  • Step 1 To a solution of 4- ( (methylamino) methyl) aniline (500 mg, 3.67 mmol) in THF (5.0mL) was added Boc 2 O (0.843 mL, 3.671 mmol) at 0°C. The reaction mixture was warmed to room temperature and stirred for 2 h. The reaction mixture was concentrated to afford I-039-1.
  • Step 2 To a mixture of I-039-1 (100 mg, 0.423 mmol) and 7-bromo-2-chloroquinazoline (124mg, 0.508 mmol) in DMSO (1 mL) was added potassium fluoride (36.9mg, 0.635 mmol) . The resulting mixture was stirred at 120°C for 2 hrs. The reaction mixture was concentrated under reduced pressure and purified by prep-TLC to afford I-039-2. LCMS [M+H] + : 443.2.
  • Step 3 A mixture of I-039-2 (200 mg, 0.056 mmol) , 2-methylpropan-2-yl 4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrazole-1-carboxylate (151.3 mg, 0.514 mmol) , Pd (dppf) Cl 2 (31.4 mg, 0.043 mmol) and K 2 CO 3 (177.7 mg, 1.286 mmol) in THF (2.0 mL) and H 2 O (0.4 mL) was stirred at 80°C for 2 h under N 2 atmosphere. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL ⁇ 3) . The combined organic layers were washed with brine (20 mL) , dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by prep-HPLC to afford I-039-3.
  • Step 4 To a solution of I-039-3 (100 mg, 0.303 mmol) in MeOH (5.0 mL) was added HCl/MeOH (3 mL) . The mixture was stirred at 20°C for 2 hrs. The reaction was concentrated under reduced pressure and purified by prep-HPLC to afford I-039.
  • Step 1 To a solution of 4-amino-N-methylbenzamide (300 mg, 1.20 mmol) in 2-methylpropan-2-ol (15 mL) was added INT-2 (661 mg, 1.72 mmol) and TsOH (516 mg, 2.0 mmol) . The mixture was stirred at 100°C for 2 hrs. The reaction was filtered and washed with EtOAc (10 mL) to afford I-040-1.
  • Step 2 A solution of I-040-1 (100 mg, 0.19 mmol) in MeOH/HCl (10 mL) was stirred at 25°C for 1 hr. The reaction was concentrated under vacuum and purified by prep-HPLC to give I-040.
  • Step 1 A mixture of INT-4 (400 mg, 1.27 mmol) , 3-amino-N-methylbenzamide (209 mg, 1.39 mmol) and K 2 CO 3 (526 mg, 3.81 mmol) in DMSO (2 mL) was stirred at 100°C for 2 hrs. The mixture was filtered and the filtrate was concentrated under reduced pressure to give I-041-1.
  • Step 2 A solution of I-041-1 (400 mg, 0.933 mmol) in HCl/MeOH (5.0 mL) was stirred at 25°C for 2 hrs. The reaction mixture was concentrated and purified by pre-HPLC to afford I-041.
  • Step 1 To a solution of 5-nitroisothiazole-3-carboxylic acid (200 mg, 1.15 mmol) in DMF (2 mL) was added HATU (524 mg, 1.38 mmol) and DIPEA (0.570 mL, 3.45 mmol) and MeNH 2 ⁇ HCl (93.1 mg, 1.38 mmol) . The mixture was stirred at 25°C for 2 hrs. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (5.0 mL ⁇ 3) . The combined organic layers were washed with brine (10 mL) , dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give I-042-1. LCMS [M+H] + : 188.3.
  • Step 2 To a solution of I-042-1 (200 mg, 1.07 mmol) in EtOH (2 mL) and H 2 O (0.40 mL) was added iron powder (298 mg, 5.34 mmol) and NH 4 Cl (171 mg, 3.21 mmol) . The mixture was stirred at 20°C for 6 hrs. The mixture was filtrated, and the filtrate was concentrated under vacuum to give I-042-2.
  • Step 3 A mixture of INT-4 (100 mg, 0.318 mmol) , I-042-2 (49.9 mg, 0.318 mmol) , Pd (OAc) 2 (7.13 mg, 0.032 mmol) , Xantphos (36.8 mg, 0.064 mmol) and Cs 2 CO 3 (207 mg, 0.635 mmol) in dioxane (1 mL) was degassed and purged with N 2 for 3 times. The mixture was stirred at 110°C for 1 hr under N 2 atmosphere via microwave irritation. The mixture was filtrated to give I-042-3. LCMS [M+H] + : 436.3.
  • Step 4 To a solution of I-042-3 (50.0 mg, 0.115 mmol) in MeOH (1 mL) was added HCl (6 M, 0.096 mL, 0.574 mmol) . The mixture was stirred at 25°C for 16 hrs. The mixture was filtrated, and the obtained solid was purified by prep-HPLC to afford I-042.
  • Step 1 To a solution of I-039-1 (100 mg, 0.423 mmol) in DMSO (1.0 mL) was added INT-4 (133 mg, 0.423 mmol) and K 2 CO 3 (146 mg, 1.06 mmol) . The mixture was stirred at 100°C for 2 hrs under N 2 atmosphere. The reaction was diluted with water (10 mL) and extracted with EtOAc (8 mL ⁇ 3) . The combined organic phases were washed with brine and dried over anhydrous sodium sulfate, concentrated, and purified by prep-HPLC to give I-043-1. LCMS [M+H] + : 515.3.
  • Step 2 A solution of I-043-1 (180 mg, 0.340 mmol) in HCl /MeOH (5.0 mL) was stirred at 25°C for 2 hrs. The reaction was concentrated and purified by prep-HPLC to give I-043.
  • 1 H NMR 400 MHz, CD 3 OD
  • Step 1 To a solution of tert-butyl 6-hydroxy-2-azaspiro [3.3] heptane-2-carboxylate (2.00 g, 9.37 mmol) and PPh 3 (3.69 g, 14.0 mmol) in THF (25mL) was added DIAD (2.84 g, 14.0 mmol) at 0°C under N 2 atmosphere. The mixture was stirred at 25°C for 18 hrs. The mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL ⁇ 3) . The combined organic layers were washed with brine (100 mL) , dried over Na 2 SO 4 , and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel chromatography to afford I-044-1. LCMS [M+H] + : 309.1.
  • Step 2 To a solution of I-044-1 (2.50 g, 8.10 mmol) in THF (20 mL) was added LiAlH 4 (1.08 g, 28.3 mmol) under N 2 atmosphere. The mixture was stirred at 25°C for 8 hrs. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL ⁇ 3) . The combined organic layers were washed with brine (100 mL) , dried over Na 2 SO 4 , and filtered. The filtrate was concentrated and purified by silica gel chromatography to give I-044-2.
  • Step 3 To a mixture of I-044-2 (200 mg, 1.47 mmol) ) and INT-4 (260 mg, 1.47 mmol) in DMSO (15 mL) was added conc. HCl (12 M, 0.12 mL, 1.47 mmol) . The mixture was stirred at 80°C for 3 hrs. The reaction mixture was concentrated under reduced pressure and purified by prep-HPLC to afford I-044.
  • Step 1 To a solution of (4-iodophenyl) methanamine (10.0 g, 42.9 mmol) and TEA (8.95 mL, 64.4 mmol) in THF (100 mL) was added Boc 2 O (14.8 mL, 64.4 mmol) at 0°C. The mixture was stirred at 25°C for 18 hrs. The reaction mixture was diluted with water (300 mL) and extracted with EtOAc (100 mL ⁇ 3) . The combined organic layers were washed with brine (100 mL) , dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give I-045-1. LCMS [M+H- t Bu] + : 278.0.
  • Step 2 To a stirred suspension of NaH (0.60 g, 15.07 mmol) in THF (30 mL) was added I-045-1 (2.0 g, 6.0 mmol) at 0°C, followed by the addition of CH 3 I (2.13 g, 15.0 mmol) . The mixture was stirred at 25°C for 18 hrs. The reaction mixture was quenched with aqueous NaHCO 3 (50 mL) , extracted with EtOAc (50 mL ⁇ 3) . The combined organic layers were washed with brine (50 mL) , dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give I-045-2. LCMS [M+H- t Bu] + : 291.9.
  • Step 3 A mixture of 7-bromoquinazolin-2-amine (2.50 g, 11.2 mmol) , 4, 4, 5, 5-tetramethyl-2- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1, 3, 2-dioxaborolane (3.12 g, 12.2 mmol) , KOAc (3.29 g, 33.5 mmol) , Pd (dppf) Cl 2 (0.41 g, 0.558 mmol) in dioxane (25 mL) was degassed and purged with N 2 for 3 times. The mixture was stirred at 80°C for 2 hrs under N 2 atmosphere.
  • Step 4 A mixture of I-045-3 (500 mg, 1.84 mmol) , 3-bromo-5, 6, 7, 8-tetrahydroimidazo [1, 2-a] pyridine (532 mg, 2.65 mmol) , Pd (dppf) Cl 2 (96.8 mg, 0.132 mmol) , K 3 PO 4 (1.68 g, 7.94 mmol) in dioxane (5 mL) and H 2 O (1 mL) was degassed and purged with N 2 for 3 times. The mixture was stirred at 100°C for 2 hrs under N 2 atmosphere. The mixture was poured into water (10 mL) and filtrated. The filtrate was extracted with EtOAc (10 mL ⁇ 3) . The combined organic layers were washed with brine (10 mL) , dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give I-045-4. LCMS [M+H] + : 266.3.
  • Step 5 A mixture of I-045-4 (200 mg, 0.482 mmol) , I-045-2 (184 mg, 0.531 mmol) , CuI (9.19 mg, 0.048 mmol) , K 2 CO 3 (200 mg, 1.45 mmol) and methyl [ (1R, 2R) -2- (methylamino) cyclohexyl] amine (13.7 mg, 0.096 mmol) in DMF (1 mL) was degassed and purged with N 2 for 3 times. The mixture was stirred at 100°C for 2 hrs under N 2 atmosphere. The reaction mixture was diluted with NH 4 Cl (5 mL) and extracted with EtOAc (5 mL ⁇ 3) . The combined organic layers were washed with brine (5 mL) , dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give I-045-5.
  • Step 6 A mixture of I-045-5 (5.0 mg, 10.3 ⁇ mol) in HCl/MeOH (2 mL) was stirred at 25°Cfor 1 hr under N 2 atmosphere. The reaction was filtered, concentrated under reduced pressure and purified by prep-HPLC to afford I-045.
  • Step 1 To a solution of tert-butyl 6-amino-2-azaspiro [3.3] heptane-2-carboxylate (896 mg, 4.22 mmol ) , 2-fluoro-4-nitropyridine (600 mg, 4.22 mmol) in DMF (12 mL) was added K 2 CO 3 (1.45 g, 10.5 mmol) . The mixture was stirred at 90°C for 12 hrs. The reaction mixture was diluted with water (20 mL) and extracted with DCM (25 mL ⁇ 3) . The combined organic layers were washed with brine (20 mL) , dried over Na 2 SO 4 , and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel chromatography to afford I-048-1.
  • Step 2 To a solution of I-048-1 (1.00 g, 2.99 mmol) in MeOH (15 mL) was added Pd/C 10%(0.06 g, 0.598 mmol) under N 2 atmosphere. The suspension was degassed and purged with H 2 for 3 times. The mixture was stirred under H 2 (15 psi) at 25°C for 2 hr. The reaction mixture was filtered and concentrated under reduced pressure to give I-048-2.
  • Step 3 A mixture of I-048-2 (450 mg, 1.47 mmol) ) and INT-3 (465 mg, 1.47 mmol) in dioxane (15 mL) and added Pd (dba) 3 (676 mg, 0.73 mmol) , Xantphos (342 mg, 0.591 mmol) and Cs 2 CO 3 (1.44 g, 4.43 mmol) was degassed and purged with N 2 for 3 times. The mixture was stirred at 100°C for 3 hrs under N 2 . The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (30 mL ⁇ 3) . The combined organic layers were washed with brine (100 mL) , dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel chromatography to afford I-048-3.
  • Step 4 To a solution of I-048-3 (100 mg, 9.27 mmol) in H 2 O (5.0 mL) was added HCl (12 M, 4.0 mL) . The mixture was stirred at 25°C for 5 hrs. The reaction mixture was concentrated under reduced pressure to give I-048-4. LCMS [M+H] + : 399.3.
  • Step 5 A mixture of I-048-4 (50.0 mg, 0.125 mmol) , formaldehyde (16.9 ⁇ L, 0.62 mmol) , AcOH (35.9 ⁇ L, 0.627 mmol) and NaBH 3 CN (7.89 mg, 0.125 mmol) was degassed and purged with N 2 for 3 times. The mixture was stirred at 25°C for 5 hrs under N 2 atmosphere. The combined organic layers were washed with brine (20 mL) , dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by HPLC to give I-048.
  • Step 1 A mixture of 6-bromo-1, 2, 3, 4-tetrahydroisoquinoline (887 mg, 5.19 mmol) , 6-bromo-1, 2, 3, 4-tetrahydroisoquinoline (1.0 g, 4.72 mmol) , NaBH (OAc) 3 (1.10 g, 5.19 mmol) , acetic acid (28.3 mg, 471 ⁇ mol, 26.9 ⁇ L) in DCM (10 mL) was degassed and purged with N 2 for 3 times. The mixture was stirred at 20°C for 8 hrs under N 2 atmosphere. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (30mL ⁇ 3) . The combined organic layers were washed with brine (5 mL) , dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give I-049-1.
  • LCMS [M+H] + 367.3.
  • Step 2 A mixture of I-049-1 (350 mg, 1.19 mmol) , INT-5 (522 mg, 1.42 mmol) , Cs 2 CO 3 (1.16 g, 3.56 mmol) , Xantphos (274 mg, 474.03 ⁇ mol, 0.4 eq) and Pd 2 (dba) 3 (217 mg, 237 ⁇ mol, 0.2 eq) in dioxane (1 mL) was degassed and purged with N 2 for 3 times. The mixture was stirred at 140°C for 5 hrs under N 2 atmosphere. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc mL (30mL ⁇ 3) .
  • Step 3 A solution of I-049-2 (200 mg, 2.18 mmol) in HCl/dioxane (1 M, 21.78 mL) was stirred at 25°C for 5 hrs under N 2 atmosphere. The reaction was concentrated under reduced pressure to give I-049-3. LCMS [M+H] + : 398.4.
  • Step 4 A mixture of I-049-3 (60.0 mg, 2.84 mmol) , paraformaldehyde (60.0 mg, 3.41 mmol) , NaBH (OAc) 3 (63.20 mg, 3.13 mmol) , AcOH (7.08 mg, 284 ⁇ mol, 16.2 ⁇ L) in DCM (10 mL) was degassed and purged with N 2 for 3 times. The mixture was filtered, concentrated, and purified by prep-HPLC to afford I-049.
  • Step 1 To a solution of 4-iodobenzoyl chloride (3.0 g, 11.2 mmol) in DCM (20.0 mL) was added 1-methylpiperidin-4-amine (1.29 g, 11.2 mmol) and TEA (4.69 mL, 33.7 mmol) . The resulting reaction was stirred at 25°C for 3 hrs. The mixture was filtered, and the filtrate was concentrated under reduced pressure to afford I-050-1.
  • Step 2 A mixture of I-050-1 (489 mg, 1.42 mmol) , INT-3 (420 mg, 1.42 mmol) , CuI (270 mg, 1.42 mmol) , Cs 2 CO 3 (138 mg, 4.266 mmol) and methyl [ (1R, 2R) -2- (methylamino) cyclohexyl] amine (101 mg, 0.711 mmol) were dissolved in DMF (10.0 mL) and heated at 100°Cfor 12 hrs. The reaction mixture was filtered, added with water (10 mL) , and extracted with EtOAc (15 mL ⁇ 3) .
  • Step 3 A solution of I-050-2 (300 mg, 0.586 mmol) in HCl/MeOH (10.0 mL) was stirred at 25°C for 1 hr. The reaction mixture was concentrated under reduced pressure to give I-050.
  • Step 1 To a solution of 4-bromo-3-methoxybenzaldehyde (10.0 g, 46.5 mmol) in toluene (100 mL) was added 2-amino-1, 1-dimethoxyethane (5.38 g, 51.1 mmol) and MgSO 4 (8.40 g, 69.8 mmol) . The mixture was stirred at 100°C for18 hrs. The reaction mixture was filtered and concentrated under reduced pressure to give I-051-1.
  • Step 2 To a solution of I-051-1 (9.0 g, 29.8 mmol) in PPA (50 mL) and the mixture was stirred at 140°C for 3 hrs. The reaction mixture was diluted with water (500 mL) and extracted with DCM (200 mL ⁇ 3) . The combined organic layers were washed with brine (500 mL) , dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give I-051-2.
  • Step 3 To a solution of I-051-2 (2.70 g, 11.3 mmol) in MeOH (1 mL) was added CH 3 I (2.74 g, 19.3 mmol) . The mixture was stirred at 25°C for 16 hrs. The reaction mixture was concentrated under reduced pressure to give I-051-3. LCMS [M+H] + : 252.0.
  • Step 4 To a solution of I-051-3 (4.0 g, 10.5 mmol) in MeOH (40 mL) was added NaBH 4 (1.20 g, 31.7 mmol) at 0°C. The mixture was stirred at 25°C for 16 hrs. The reaction mixture was quenched by saturated NH 4 Cl (40 mL) and extracted with EtOAc (50 mL ⁇ 3) . The combined organic layers were washed with brine (100 mL) , dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give I-051-4.
  • Step 5 A mixture of I-051-4 (50.0 mg, 0.20 mmol) , INT-3 (69.2 mg, 0.23 mmol) , Cs2CO3 (190 mg, 0.59 mmol) , Pd 2 (dba) 3 (17.9 mg, 0.02 mmol) and Xantphos (22.5 mg, 0.039 mmol) in dioxane (2 mL) was degassed and purged with N 2 for 3 times. The mixture was stirred at 100 °C for 3 hrs under N 2 atmosphere. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL ⁇ 3) .
  • Step 6 A mixture of I-051-5 (30.0 mg, 0.064 mmol) in HCl/MeOH (5 mL) was stirred at 25°C for 2 hrs. The reaction mixture was freeze-dried under reduced pressure to give I-051.
  • Step 1 To a solution of 7-bromo-2-chloroquinazoline (140 mg, 575 ⁇ mol) in i-PrOH (5.0 mL) was added 3-amino-N-methylbenzamide (104 mg, 690 ⁇ mol) and TsOH (198 mg, 1.15 mmol) at 20°C. The mixture was stirred at 100°C for 2 hrs. The mixture was concentrated under vacuum. The crude product was triturated with EtOAc (10 mL) at 25°C for 30 mins, and then was filtered to give I-054-1. LCMS [M+H] + : 357.0.
  • Step 2 A mixture of I-054-1 (100 mg, 280 ⁇ mol) , 4- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (54.3 mg, 280 ⁇ mol) , K 3 PO 4 (178 mg, 840 ⁇ mol) , Pd (dppf) Cl 2 (20.5 mg, 28.0 ⁇ mol) in dioxane (1 mL) and H 2 O (0.25 mL) was degassed and purged with N 2 for 3 times. The mixture was stirred at 100°C for 2 hrs under N 2 atmosphere. The mixture was filtrated, and the cake was diluted with DMSO (2 mL) .
  • kinase-tagged T7 phage strains were prepared in an E. coli host derived from the BL21 strain. E. coli were grown to log-phase and infected with T7 phage and incubated with shaking at 32°C until lysis. The lysates were centrifuged and filtered to remove cell debris. The remaining kinases were produced in HEK-293 cells and subsequently tagged with DNA for qPCR detection. Streptavidin-coated magnetic beads were treated with biotinylated small molecule ligands for 30 minutes at room temperature to generate affinity resins for kinase assays.
  • Binding reactions were assembled by combining kinases, liganded affinity beads, and test compounds in 1x binding buffer (20%SeaBlock, 0.17x PBS, 0.05%Tween 20, 6 mM DTT) .
  • Test compounds were prepared as 111X stocks in 100%DMSO. Kds were determined using an 11-point 3-fold compound dilution series with three DMSO control points.
  • All compounds for Kd measurements are distributed by acoustic transfer (non-contact dispensing) in 100%DMSO.
  • the compounds were then diluted directly into the assays such that the final concentration of DMSO was 0.9%.
  • All reactions performed in polypropylene 384-well plate. Each was a final volume of 0.02 ml.
  • the assay plates were incubated at room temperature with shaking for 1 hour and the affinity beads were washed with wash buffer (1x PBS, 0.05%Tween 20) .
  • the beads were then re-suspended in elution buffer (1x PBS, 0.05%Tween 20, 0.5 ⁇ M nonbiotinylated affinity ligand) and incubated at room temperature with shaking for 30 minutes.
  • SBDD structure-based drug discovery
  • CDK20 kinase activity assay
  • a radiometric protein kinase assay ( ActivityAssay, available as a service product from Reaction Biology Corp. ) was used for measuring the kinase activity of the CDK20 kinases. This assay was performed in 96-well FlashPlates TM from PerkinElmer (Boston, MA, USA) in a 50 ⁇ l reaction volume. The reaction cocktail was pipetted in four steps in the following order: a. 25 ⁇ l of assay buffer (standard buffer/ [ ⁇ - 33 P] -ATP) ; b. 10 ⁇ l of ATP solution (in H 2 O) ; c.5 ⁇ l of test compound (in 10 %DMSO) ; d. 10 ⁇ l of enzyme/substrate mixture.
  • the assay for CDK20 kinase contained 70 mM HEPES-NaOH pH 7.5, 3 mM MgCl 2 , 3 mM MnCl 2 , 3 ⁇ M Na-orthovanadate, 1.2 mM DTT, 50 ⁇ g/ml PEG 20000 , 1.0 ⁇ M ATP, [ ⁇ - 33 P] -ATP (approx. 7 ⁇ 10 5 cpm per well) , 200 ng/50 ⁇ l kinase protein, and substrate was 4.0 ug/50 ⁇ l. The compounds were dissolved to 1 ⁇ 10 -3 M in volumes of 100%DMSO.
  • the 1 ⁇ 10 -3 M stock solutions were subjected to a serial, semi-logarithmic dilution using 100 %DMSO as a solvent.
  • the final volume of the assay was 50 ⁇ L All compounds were tested at 10 final assay concentrations in the range from 1 ⁇ 10 -5 M to 3 ⁇ 10 -10 M.
  • the final DMSO concentration in the reaction cocktails was 1 %in all cases.
  • the "low control” was defined as the value reflects unspecific binding of radioactivity to the plate in the absence of a protein kinase but in the presence of the substrate.
  • the "high control” was defined as the full activity in the absence of any inhibitor. The difference between high and low control was taken as 100 %activity. As part of the data evaluation the low control value from a particular plate was subtracted from the high control value as well as from all 80 "compound values" of the corresponding plate.
  • the residual activities for each concentration and the compound IC 50 values were calculated using Quattro Workflow V3.1.1 (Quattro Research GmbH, Kunststoff, Germany; www. quattro-research. com) .
  • the fitting model for the IC 50 determinations was "Sigmoidal response (variable slope) " with parameters "top” fixed at 100 %and "bottom” at 0 %.
  • the fitting method used was a least-squares fit.
  • the assay results shows that the compounds listed in Table 3 exhibited IC 50 values (CDK20/CycT1) in the range from 10 nM to 10 ⁇ M, even in the range from 10 nM to 1 ⁇ M for compounds I-008, I-034, I-037, I-038, I-042, I-044, I-045, I-051, I-052, and I-053, and even more in the range from 10 nM to 100 nM for compounds I-11, I-035, I-036, I-039, I-040, I-046, I-047, I-048, I-049, and I-050.
  • Mok, M. CCRK is a novel signalling hub exploitable in cancer immunotherapy. Pharmacol. Ther. 186, 138–151 (2016) .
  • CCRK cell cycle-related kinase

Abstract

La présente invention concerne des composés de formule (I) ou des sels pharmaceutiquement acceptables, un solvate, un stéréoisomère ou un variant isotopique de ceux-ci, utiles en tant qu'inhibiteurs de CDK20, des compositions pharmaceutiques les comprenant, et leur utilisation dans le traitement de maladies ou d'états associés à CDK20 tels que le carcinome hépatocellulaire (HCC), le cancer colorectal, le glioblastome, le cancer du poumon, le médulloblastome, le carcinome ovarien, le cancer de la prostate, le carcinome à cellules rénales, etc
PCT/CN2023/071020 2022-01-20 2023-01-06 Composés de pyrimidin-2-amine fusionnés utilisés en tant qu'inhibiteurs de cdk20 WO2023138412A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CNPCT/CN2022/072865 2022-01-20
CN2022072865 2022-01-20

Publications (1)

Publication Number Publication Date
WO2023138412A1 true WO2023138412A1 (fr) 2023-07-27

Family

ID=87347788

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2023/071020 WO2023138412A1 (fr) 2022-01-20 2023-01-06 Composés de pyrimidin-2-amine fusionnés utilisés en tant qu'inhibiteurs de cdk20

Country Status (1)

Country Link
WO (1) WO2023138412A1 (fr)

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006039718A2 (fr) * 2004-10-01 2006-04-13 Amgen Inc Composes bicycliques azotes d'aryle et leurs procedes d'utilisation
WO2008020203A1 (fr) * 2006-08-17 2008-02-21 Astrazeneca Ab Dérivés de pyridinylquinazolinamine et leur utilisation comme inhibiteurs de b-raf
WO2008068507A2 (fr) * 2006-12-08 2008-06-12 Astrazeneca Ab Composés chimiques 576
CN101454294A (zh) * 2006-04-06 2009-06-10 诺华公司 用于pdk1抑制的喹唑啉
CN101652352A (zh) * 2006-12-22 2010-02-17 诺瓦提斯公司 用于抑制pdk1的喹唑啉类
CN102123991A (zh) * 2008-06-20 2011-07-13 诺瓦提斯公司 用于治疗增殖性疾病的2-芳基氨基喹唑啉类化合物

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006039718A2 (fr) * 2004-10-01 2006-04-13 Amgen Inc Composes bicycliques azotes d'aryle et leurs procedes d'utilisation
CN101454294A (zh) * 2006-04-06 2009-06-10 诺华公司 用于pdk1抑制的喹唑啉
WO2008020203A1 (fr) * 2006-08-17 2008-02-21 Astrazeneca Ab Dérivés de pyridinylquinazolinamine et leur utilisation comme inhibiteurs de b-raf
US20100216791A1 (en) * 2006-08-17 2010-08-26 Astrazeneca Pyridinylquinazolinamine derivatives and their use as b-raf inhibitors
WO2008068507A2 (fr) * 2006-12-08 2008-06-12 Astrazeneca Ab Composés chimiques 576
CN101652352A (zh) * 2006-12-22 2010-02-17 诺瓦提斯公司 用于抑制pdk1的喹唑啉类
CN102123991A (zh) * 2008-06-20 2011-07-13 诺瓦提斯公司 用于治疗增殖性疾病的2-芳基氨基喹唑啉类化合物

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DATABASE Registry 26 August 2021 (2021-08-26), ANONYMOUS: "L22: 2-Quinazolinamine, 6-bromo-N-[1-(l-methyl-4-piperidinyl)-lH-pyrazol-4-yl]", XP009548007, Database accession no. RN 2682115-60-0 *

Similar Documents

Publication Publication Date Title
JP6856614B2 (ja) １，４−二置換ピリダジン誘導体およびｓｍｎ欠損に関連する状態を処置するためのその使用
KR102219441B1 (ko) 메틸 변형 효소 조절제, 이의 조성물 및 용도
JP6617155B6 (ja) チロシンキナーゼ阻害剤およびそれを含む医薬組成物
JP6047556B2 (ja) Ｌｒｒｋ２キナーゼ活性の阻害剤
JP7168773B2 (ja) イソインドリン化合物、その調製方法、医薬組成物および使用
WO2022061251A1 (fr) Composés et procédés pour la modulation de kras et leurs indications
JP2021525717A (ja) 治療用化合物
CA3182507A1 (fr) Inhibiteurs de la proteine kras g12c et leurs utilisations
JP7219902B2 (ja) ブルトン型チロシンキナーゼ阻害剤
EP3694330B1 (fr) Dérivés d'indazolyl-spiro [2.2]pentane-carbonitrile en tant qu'inhibiteurs de lrrk2, compositions pharmaceutiques et leurs utilisations
JP6966425B2 (ja) 抗がん剤としての複素環式の限定された三環系スルホンアミド
EP2922850A1 (fr) Composés hétérocycliques et leurs procédés d'utilisation
AU2014400628A1 (en) Aminopyridazinone compounds as protein kinase inhibitors
CN103732596A (zh) 新的吡咯并嘧啶衍生物
JP2017528475A (ja) Ｒａｆキナーゼ阻害剤としての化合物および組成物
EA016108B1 (ru) [2,6]нафтиридины, применимые в качестве ингибиторов протеинкиназы
AU2015276699A1 (en) Pyridino[1,2-a]pyrimidone analogue used as PI3K inhibitor
WO2016058501A1 (fr) Composé 5-méthyl-2-(pyridine-2-ylamino)-8h-pyridino[2,3-d]pyrimidine-7-one
JP2016508135A (ja) カゼインキナーゼ１ｄ／ｅ阻害剤としての新規なピラゾール置換のイミダゾピラジン
CN115991706A (zh) Pim激酶抑制剂
WO2016079669A1 (fr) Dérivés d'aminopyrimidine marqués
WO2023138412A1 (fr) Composés de pyrimidin-2-amine fusionnés utilisés en tant qu'inhibiteurs de cdk20
CN109476643B (zh) 作为jak抑制剂的吡唑基氨基苯并咪唑衍生物
WO2019170055A1 (fr) Composés ayant une activité inhibitrice de kinase cdk4/6, composition pharmaceutique de ceux-ci et utilisation de ceux-ci
AU2022255486A1 (en) Nek7 inhibitors

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 23742727

Country of ref document: EP

Kind code of ref document: A1