WO2023098699A1 - Composés et leurs utilisations en tant qu'inhibiteurs de cd38 - Google Patents

Composés et leurs utilisations en tant qu'inhibiteurs de cd38 Download PDF

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WO2023098699A1
WO2023098699A1 PCT/CN2022/135278 CN2022135278W WO2023098699A1 WO 2023098699 A1 WO2023098699 A1 WO 2023098699A1 CN 2022135278 W CN2022135278 W CN 2022135278W WO 2023098699 A1 WO2023098699 A1 WO 2023098699A1
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ring
pyridin
cyclohexyl
alkyl
compound
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PCT/CN2022/135278
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Jianbei XI
Guohuang FAN
Jianfei Wang
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Nanjing Immunophage Biotech Co., Ltd
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Publication of WO2023098699A1 publication Critical patent/WO2023098699A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—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
    • C07D401/04—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 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
    • C07D403/04—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
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D417/02—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 two hetero rings
    • C07D417/04—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 two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/32—Nitrogen atom
    • C07D473/34—Nitrogen atom attached in position 6, e.g. adenine
    • 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
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the present invention relates to novel compounds; methods for the production of the compounds of the invention; pharmaceutical compositions comprising the compounds of the invention; as well as uses and methods for treating a disease mediated by CD38 by administering the compounds of the invention.
  • the compounds of the invention may be used as CD38 inhibitors.
  • CD38 is a protein of 300 amino acids encoded by homologous genes located on chromosomes 4 and 5 in humans and mice, respectively. Within the cell, CD38 is often found localized on the cell surface, but it can also be detected in intracellular compartments such as the endoplasmic reticulum, nuclear membrane and mitochondria. Structurally, CD38 is a single chain glycoprotein with a single transmembrane segment and can topologically behave as a type II or type III membrane protein depending on its membrane orientation. In the most common type II orientation, CD38’s short amino tail faces into the cytosol while CD38’s catalytic domain faces the extracellular environment. A type III orientation, with the catalytic domain facing the cytosol, has been also reported. These two orientations have functional implications, given that CD38’s enzymatic substrates and products would be consumed and produced in the extracellular or the intracellular compartments.
  • CD38 catalyzes the synthesis of nicotinamide (NAM) and ADPR using nicotinamide adenine dinucleotide (NAD + ) as a substrate.
  • NAD + an essential cofactor that regulates energy metabolism, can be converted to cADPR with the release of NAM.
  • cADPR can also be hydrolyzed to ADP-ribose by CD38.
  • CD38 has both ADP-ribosyl cyclase and cADPR hydrolase enzymatic activities.
  • Both ADPR and cADPR act as second messengers controlling several cell functions through calcium (Ca 2+ ) mobilization.
  • CD38 can also act as a receptor to CD31. Through the latter interaction, CD38 could act as an adhesion molecule mediating selectin-like binding of hematopoietic cells to endothelial cells and facilitating their transmigration to tissue.
  • CD38 is a ubiquitous protein expressed in multiple tissues. Nonhematopoietic tissue expression include prostatic epithelial cells, pancreatic islet astrocytes, smooth muscle cells, retinal tubes, kidney, gut, and brain in both mice and humans. However, CD38 is most highly expressed in hematopoietic tissues such as the bone marrow and lymph nodes. Within immune cells, CD38 is highly expressed in B cells, macrophages, dendritic cells (DCs) , innate lymphoid cells (ILC) , natural killer (NK) cells, T cells, neutrophils, and monocytes. Nevertheless, the level of CD38 expression among these populations may differ between human and mouse, as observed in a transcriptional comparison between species.
  • the surface marker and multifunctional enzyme CD38 appear to provide a link between inflammation and age-and disease-related decline in tissue homeostasis and, therefore, represents a critical target for therapeutic intervention.
  • CD38 is expressed predominately on immune cells in response to stimulation by cytokines, endotoxins, and interferon. Expression of the enzyme is regulated by a promoter region containing binding sites for NF-kB, RXR, LXR, and STAT suggesting that it plays a key role in the inflammatory response.
  • CD38 expression causes a substantial decline in cellular NAD + levels, thus altering the availability of substrates for enzymes regulating cellular homeostasis.
  • NAD + homeostasis in parenchymal tissues or the tumor microenvironment; disrupt normal metabolic processes, and undermine tissue integrity.
  • CD38 The important role of CD38 in multiple diseases including neurodegeneration, neuroinflammation, cancer development and autoimmune diseases suggests that targeted inhibition of CD38 is a potential therapeutic approach for the treatment of neurodegenerative diseases, cancer, autoimmune diseases, metabolic disease and other inflammatory diseases.
  • One of the most important strategies targeting CD38 is to develop small molecule inhibitors against CD38, which have demonstrated promising preclinical efficacy.
  • a compound of formula (I) that functions as CD38 inhibitors.
  • a pharmaceutical composition comprising a compound disclosed herein or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, optionally together with a pharmaceutically acceptable excipient.
  • provided herein is a method of treating a disease mediated by CD38 comprising a subject in need thereof a therapeutically effective amount of the compound disclosed herein.
  • provided herein is the use of the compound disclosed herein in the manufacture of a medicament for the treatment of a disease mediated by CD38.
  • a method of inhibiting CD38 function comprising contacting a compound of formula I described above, or a pharmaceutically acceptable salt thereof, with the CD38.
  • the CD38 is in a cell.
  • the contacting occurs in vitro. In yet another embodiment, the contacting occurs in vivo.
  • a 1 is C 1-6 alkyl, phenyl or 5-to 9-membered heteroaryl
  • a 2 is each of which is independently unsubstituted or substituted with one or two substituents selected from halogen, C 1- 6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, cycloalkyl, heterocyclyl, phenyl, heteroaryl, cyano, oxo, -NR a R b , -C (O) R a , -C (O) OR a , -NO 2 , -OR a , -SO 2 R a , -CONR a R b , -NR a COR b , -NR a CO 2 R b , or -NR a SO 2 R b , wherein R a and R b are each independently hydrogen or C 1-4 alkyl; preferably each of which is independently unsubstituted or substituted with oxo, NH 2 , -C (O) CH 3 , or CH 3 , wherein
  • L 1 and L 2 are each independently a direct bond, -C (O) -, or - (CR c R d ) n -, wherein R c and R d are each independently hydrogen, C 1-4 alkyl, hydroxyC 1-4 alkyl, or -C (O) OR e , wherein R e is hydroxy or C 1-4 alkyl, and n is a number of 1, 2, 3 or 4;
  • R is H or C 1-6 alkyl
  • a 3 is a phenyl ring, a 5-to 9-membered heteroaryl ring, a 5-to 9-membered heterocyclyl ring, a C 5- 8 cycloalkyl ring, a C 5-8 cycloalkyl ring further fused with a phenyl ring or with a 5-to 9-membered heteroaryl ring, or a bridged bicyclic cycloalkyl ring, each of said rings is independently unsubstituted or substituted with one or two or three substituents selected from halogen, C 1-6 alkyl, or -OR f , wherein R f is hydrogen, C 1-6 alkyl, or heterocyclyl.
  • a 1 is C 1-6 alkyl, phenyl or 5-to 9-membered heteroaryl.
  • a 1 is a monocyclic 5-to 9-membered heteroaryl comprising from 1 to 3 heteroatoms selected from nitrogen (N) , sulfur (S) and oxygen (O) as the ring member (s) , preferably monocyclic 5-to 6-membered heteroaryl comprising 1 or 2 heteroatoms selected from nitrogen, sulfur and oxygen as the ring member (s) .
  • a 1 is pyridyl, thiazolyl, imidazolyl, pyrazinyl, or pyrazolyl.
  • a 1 is pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, imidazol-1-yl, imidazol-2-yl, imidazol-3-yl, imidazol-4-yl, imidazol-5-yl, pyrazin-2-yl, pyrazin-3-yl, pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, or pyrazol-5-yl.
  • a 1 is pyridin-4-yl, thiazol-5-yl, pyridin-3-yl, 1H-imidazol-1-yl, pyrazin-2-yl, 1H-pyrazol-4-yl, methyl or phenyl.
  • a 2 is
  • a 2 is each of which is independently unsubstituted or substituted with one or two substituents selected from halogen, C 1-6 alkyl, -C 2-6 alkenyl, -C 2-6 alkynyl, cycloalkyl, heterocyclyl, phenyl, heteroaryl, cyano, oxo, -NR a R b , -C (O) R a , -C (O) OR a , -NO 2 , -OR a , -SO 2 R a , -CONR a R b , -NR a COR b , -NR a CO 2 R b , or -NR a SO 2 R b , wherein R a and R b are each independently hydrogen or C 1-4 alkyl; preferably each of which is independently unsubstituted or substituted with oxo, NH 2 , -C (O) CH 3 , or CH 3
  • a 2 is
  • L 1 and L 2 are each independently a direct bond, -C (O) -, or - (CR c R d ) n -, wherein R c and R d are each independently hydrogen, C 1-4 alkyl, hydroxyC 1-4 alkyl, or -C (O) OR e , wherein R e is hydroxy or C 1-4 alkyl, and n is a number of 1, 2, 3 or 4.
  • L 1 is a direct bond or -C (O) -.
  • L 2 is a direct bond, -C (O) -, or - (CR c R d ) n -, wherein R c and R d are each independently hydrogen, C 1-4 alkyl, hydroxyC 1-4 alkyl, or -C (O) OR e , wherein R e is hydroxy or C 1-4 alkyl, and n is a number of 1, 2, 3 or 4.
  • L 1 is -C (O) -or a direct bond.
  • L 2 is a direct bond, -C (O) -, -CH 2 -, -CH 2 CH 2 -, -CH (CH 3 ) -, -CH (CH 2 OH) -, or -CH (COOMe) -.
  • L 1 is -C (O) -, and L 2 is a direct bond, -CH 2 -, -CH 2 CH 2 -, -CH (CH 3 ) -, -CH (CH 2 OH) -, or -CH (COOMe) -.
  • L 1 is -C (O) -, and L 2 is a direct bond.
  • L 1 and L 2 are both a direct bond.
  • R is H or C 1-6 alkyl. In some further embodiments, R is H.
  • a 3 is a phenyl ring, a 5-to 9-membered heteroaryl ring, a 5-to 9-membered heterocyclyl ring, a C 5-8 cycloalkyl ring, a C 5-8 cycloalkyl ring further fused with a phenyl ring or with a 5-to 9-membered heteroaryl ring, or a bridged bicyclic cycloalkyl ring, each of said rings is independently unsubstituted or substituted with one or two or three substituents selected from halogen, C 1-6 alkyl, or -OR f , wherein R f is hydrogen, C 1-6 alkyl, or heterocyclyl.
  • a 3 is a monocyclic 5-to 9-membered heteroaryl. In some embodiments, A 3 is a monocyclic 5-to 9-membered heterocyclyl ring comprising from 1 to 3 heteroatoms selected from nitrogen (N) , sulfur (S) and oxygen (O) as the ring member (s) , preferably a monocyclic 5-or 6-membered heterocyclyl ring comprising from 1 to 2 heteroatoms selected from nitrogen (N) , sulfur (S) and oxygen (O) as the ring member (s) , more preferably a pyridinyl ring, e.g., pyridin-2-yl or pyridin-3-yl.
  • a 3 is a C 5 or C 6 cycloalkyl ring, preferably a cyclohexyl ring.
  • a 3 is a C 5 or C 6 cycloalkyl ring further fused with a phenyl ring or with a 5-to 9-membered heteroaryl ring, said fused cycloalkyl ring is unsubstituted or substituted with C 1- 6 alkyl, or -OR f , wherein R f is hydrogen, C 1-6 alkyl, or heterocyclyl, said heterocyclyl ring comprising from 1 to 2 heteroatoms selected from nitrogen (N) , sulfur (S) and oxygen (O) as the ring member (s) .
  • a 3 is a cyclopentyl ring further fused with a phenyl ring, i.e., a dihydroindenyl group, which is unsubstituted or substituted with one or two substituents selected from halogen, C 1- 6 alkyl, or -OR f , wherein R f is hydrogen, C 1-6 alkyl, or heterocyclyl, wherein said heterocyclyl ring is a 5-or 6-membered heterocyclyl comprising from 1 to 2 heteroatoms selected from nitrogen (N) , sulfur (S) and oxygen (O) as the ring member (s) .
  • a 3 is a cyclopentyl ring further fused with a phenyl ring, i.e., a dihydroindenyl group, which is unsubstituted or substituted with hydroxy at the cyclopentyl ring, or substituted with -OR f at the phenyl ring, wherein R f is hydrogen, C 1-6 alkyl, or a 5-or 6-membered heterocyclyl comprising from 1 to 2 heteroatoms selected from nitrogen (N) , sulfur (S) and oxygen (O) as the ring member (s) .
  • a 3 is a cyclopentyl ring further fused with a phenyl ring, i.e., a dihydroindenyl group, which is unsubstituted or substituted with hydroxy at the cyclopentyl ring, or substituted with -OR f at position 5 of the fused ring, wherein R f is hydrogen, C 1-6 alkyl, or a 5-or 6-membered heterocyclyl comprising from 1 to 2 heteroatoms selected from nitrogen (N) , sulfur (S) and oxygen (O) as the ring member (s) .
  • a 3 is a cyclopentyl ring further fused with a phenyl ring, which is a 2, 3-dihydro-1H-indenyl group, e.g., a 2, 3-dihydro-1H-inden-2-yl group.
  • a 3 is Cyclohexyl, (1r, 4r) -4-hydroxycyclohexyl, (1r, 4r) -4-methoxycyclohexyl, ( (1S, 2S) -1-hydroxy-2, 3-dihydro-1H-inden-2-yl) , (2, 3-dihydro-1H-inden-2-yl) , (5- ( (tetrahydrofuran-3-yl) oxy) -2, 3-dihydro-1H-inden-2-yl) , (5-ethoxy-2, 3-dihydro-1H-inden-2-yl) , (bicyclo [2.2.2] octan-1-yl) , tetrahydro-2H-pyran-4-yl, phenyl or pyridin-3-yl.
  • a 3 is Cyclohexyl, (1r, 4r) -4-hydroxycyclohexyl, (1r, 4r) -4-methoxycyclohexyl, ( (1S, 2S) -1-hydroxy-2, 3-dihydro-1H-inden-2-yl) , (2, 3-dihydro-1H-inden-2-yl) , (5- ( (tetrahydrofuran-3-yl) oxy) -2, 3-dihydro-1H-inden-2-yl) , or (5-ethoxy-2, 3-dihydro-1H-inden-2-yl) .
  • a 1 is 5-to 9-membered heteroaryl
  • a 2 is (wherein the left attaching position is attached to A 1 and the right attaching position is attached to L 1 )
  • L 1 is -C (O) -and L 2 is a direct bond
  • a 3 is a cyclohexyl ring which is unsubstituted or substituted with one or two or three substituents selected from halogen, C 1-6 alkyl, or -OR f , wherein R f is hydrogen, C 1-6 alkyl, or heterocyclyl.
  • a 1 is 5-to 9-membered heteroaryl
  • a 2 is (wherein the left attaching position is attached to A 1 and the right attaching position is attached to L 1 )
  • L 1 is -C (O) -and L 2 is a direct bond
  • a 3 is a C 5 or C 6 cycloalkyl ring further fused with a phenyl ring or with a 5-to 9-membered heteroaryl ring, said fused cycloalkyl ring is unsubstituted or substituted with C 1-6 alkyl, or -OR f , wherein R f is hydrogen, C 1-6 alkyl, or heterocyclyl, said heterocyclyl ring comprising from 1 to 2 heteroatoms selected from nitrogen (N) , sulfur (S) and oxygen (O) as the ring member (s) .
  • a 3 is a cyclopentyl ring further fused with a phenyl ring, i.e., a dihydroindenyl group, which is unsubstituted or substituted with one or two substituents selected from halogen, C 1-6 alkyl, or -OR f , wherein R f is hydrogen, C 1-6 alkyl, or heterocyclyl, wherein said heterocyclyl ring is a 5-or 6-membered heterocyclyl comprising from 1 to 2 heteroatoms selected from nitrogen (N) , sulfur (S) and oxygen (O) as the ring member (s) .
  • a 3 is a cyclopentyl ring further fused with a phenyl ring, i.e., a dihydroindenyl group, which is unsubstituted or substituted with hydroxy at the cyclopentyl ring, or substituted with -OR f at the phenyl ring, wherein R f is hydrogen, C 1-6 alkyl, or a 5-or 6-membered heterocyclyl comprising from 1 to 2 heteroatoms selected from nitrogen (N) , sulfur (S) and oxygen (O) as the ring member (s) .
  • a 3 is a cyclopentyl ring further fused with a phenyl ring, i.e., a dihydroindenyl group, which is unsubstituted or substituted with hydroxy at the cyclopentyl ring, or substituted with -OR f at position 5 of the fused ring, wherein R f is hydrogen, C 1-6 alkyl, or a 5-or 6-membered heterocyclyl comprising from 1 to 2 heteroatoms selected from nitrogen (N) , sulfur (S) and oxygen (O) as the ring member (s) .
  • a 3 is a cyclopentyl ring further fused with a phenyl ring, which is a 2, 3-dihydro-1H-indenyl group, e.g., a 2, 3-dihydro-1H-inden-2-yl group.
  • a 3 is ( (1S, 2S) -1-hydroxy-2, 3-dihydro-1H-inden-2-yl) , (2, 3-dihydro-1H-inden-2-yl) , (5- ( (tetrahydrofuran-3-yl) oxy) -2, 3-dihydro-1H-inden-2-yl) , or (5-ethoxy-2, 3-dihydro-1H-inden-2-yl) .
  • a 1 is 5-to 9-membered heteroaryl
  • a 2 is (wherein the left attaching position is attached to A 1 and the right attaching position is attached to L 1 )
  • L 1 is -C (O) -and L 2 is -CH 2 CH 2 -, -CH (CH 3 ) -, or -CH (CH 2 OH) -
  • a 3 is a phenyl ring, a 5-to 9-membered heteroaryl ring, a 5-to 9-membered heterocyclyl ring, a C 5-8 cycloalkyl ring, each of said rings is independently unsubstituted or substituted with one or two or three substituents selected from halogen, C 1-6 alkyl, or -OR f , wherein R f is hydrogen, C 1-6 alkyl, or heterocyclyl as defined above.
  • the compound is selected from:
  • the disease mediated by CD38 is neurodegenerative disease selected from dementia, Alzheimer's disease (AD) , Parkinson's disease; tumor selected from glioblastomas, lung cancer, colon cancer, liver cancer, breast cancer, gastric cancer, bladder cancer, melanoma; autoimmune disease selected from diabetes, rheumatoid arthritis (RA) , multiple sclerosis (MS) , systemic lupus erythematosus (SLE) ; inflammatory disease selected from asthma, chronic obstructive pulmonary disease (COPD) , pneumonia, or non-alcoholic steatohepatitis (NASH) .
  • AD Alzheimer's disease
  • Parkinson's disease tumor selected from glioblastomas, lung cancer, colon cancer, liver cancer, breast cancer, gastric cancer, bladder cancer, melanoma
  • autoimmune disease selected from diabetes, rheumatoid arthritis (RA) , multiple sclerosis (MS) , systemic lupus erythematosus (SLE)
  • phase “CD38 inhibitor” includes any and all possible isomers, stereoisomers, enantiomers, diastereomers, tautomers, pharmaceutically acceptable salts, hydrates, solvates, and prodrugs of the CD38 inhibitors described in this invention.
  • alkyl includes a hydrocarbon group selected from linear and branched, saturated hydrocarbon groups comprising from 1 to 18, such as from 1 to 12, further such as from 1 to 10, more further such as from 1 to 8, or from 1 to 6, or from 1 to 4, carbon atoms.
  • alkyl groups comprising from 1 to 6 carbon atoms include, but not limited to, methyl, ethyl, 1-propyl or n-propyl ( “n-Pr” ) , 2-propyl or isopropyl ( “i-Pr” ) , 1-butyl or n-butyl ( “n-Bu” ) , 2-methyl-1-propyl or isobutyl ( “i-Bu” ) , 1-methylpropyl or s-butyl ( “s-Bu” ) , 1, 1-dimethylethyl or t-butyl ( “t-Bu” ) , 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl
  • halogen includes fluoro (F) , chloro (Cl) , bromo (Br) and iodo (I) .
  • haloalkyl includes an alkyl group in which one or more hydrogen is/are replaced by one or more halogen atoms such as fluoro, chloro, bromo, and iodo.
  • haloalkyl include haloC 1-8 alkyl, haloC 1-6 alkyl or halo C 1-4 alkyl, but not limited to -CF 3 , -CH 2 Cl, -CH 2 CF 3 , -CHCl 2 , -CF 3 , and the like.
  • cycloalkyl includes a hydrocarbon group selected from saturated cyclic hydrocarbon groups, comprising monocyclic and polycyclic (e.g., bicyclic and tricyclic) groups including fused, bridged or spiro cycloalkyl.
  • the cycloalkyl group may comprise from 3 to 12, such as from 3 to 10, further such as 3 to 8, further such as 3 to 6, 3 to 5, or 3 to 4 carbon atoms.
  • the cycloalkyl group may be selected from monocyclic group comprising from 3 to 12, such as from 3 to 10, further such as 3 to 8, 3 to 6 carbon atoms.
  • Examples of the monocyclic cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, and cyclododecyl groups.
  • examples of the saturated monocyclic cycloalkyl group include, but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups.
  • the cycloalkyl is a monocyclic ring comprising 3 to 6 carbon atoms (abbreviated as C 3-6 cycloalkyl) , including but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • bicyclic cycloalkyl groups include those having from 7 to 12 ring atoms arranged as a fused bicyclic ring selected from [4, 4] , [4, 5] , [5, 5] , [5, 6] and [6, 6] ring systems, or as a bridged bicyclic ring selected from bicyclo [2.2.1] heptane, bicyclo [2.2.2] octane, and bicyclo [3.2.2] nonane.
  • bicyclic cycloalkyl groups include those arranged as a bicyclic ring selected from [5, 6] and [6, 6] ring systems.
  • heteroaryl includes a group selected from:
  • 5-to 9-membered e.g., 5-, 6-, 7-, 8-or 9-membered
  • aromatic, monocyclic rings comprising at least one heteroatom, for example, from 1 to 4, or, in some embodiments, from 1 to 3, in some embodiments, from 1 to 2, heteroatoms, selected from nitrogen (N) , sulfur (S) and oxygen (O) , with the remaining ring atoms being carbon;
  • - 7-to 12-membered bicyclic rings comprising at least one heteroatom, for example, from 1 to 4, or, in some embodiments, from 1 to 3, or, in other embodiments, 1 or 2, heteroatoms, selected from N, O, and S, with the remaining ring atoms being carbon and wherein at least one ring is aromatic and at least one heteroatom is present in the aromatic ring; and
  • - 11-to 14-membered tricyclic rings comprising at least one heteroatom, for example, from 1 to 4, or in some embodiments, from 1 to 3, or, in other embodiments, 1 or 2, heteroatoms, selected from N, O, and S, with the remaining ring atoms being carbon and wherein at least one ring is aromatic and at least one heteroatom is present in an aromatic ring.
  • the total number of S and O atoms in the heteroaryl group exceeds 1, those heteroatoms are not adjacent to one another. In some embodiments, the total number of S and O atoms in the heteroaryl group is not more than 2. In some embodiments, the total number of S and O atoms in the aromatic heterocycle is not more than 1.
  • the heteroaryl group contains more than one heteroatom ring member, the heteroatoms may be the same or different. The nitrogen atoms in the ring (s) of the heteroaryl group can be oxidized to form N-oxides.
  • heteroaryl group or the monocyclic or bicyclic aromatic heterocyclic ring examples include, but are not limited to, (as numbered from the linkage position assigned priority 1) pyridyl (such as 2-pyridyl, 3-pyridyl, or 4-pyridyl) , cinnolinyl, pyrazinyl, 2, 4-pyrimidinyl, 3, 5-pyrimidinyl, 2, 4-imidazolyl, imidazopyridinyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, thiadiazolyl (such as 1, 2, 3-thiadiazolyl, 1, 2, 4-thiadiazolyl, or 1, 3, 4-thiadiazolyl) , tetrazolyl, thienyl (such as thien-2-yl, thien-3-yl) , triazinyl, benzothienyl, furyl or furanyl, benzofuryl, benzoimidazo
  • Heterocyclyl , “heterocycle” or “heterocyclic” are interchangeable and include a non-aromatic heterocyclyl group comprising one or more, e.g., 1 to 3, heteroatoms selected from nitrogen, oxygen or optionally oxidized sulfur as ring members, with the remaining ring members being carbon, including monocyclic, fused, bridged, and spiro ring, i.e., containing monocyclic heterocyclyl, bridged heterocyclyl, spiro heterocyclyl, and fused heterocyclic groups.
  • a non-aromatic heterocyclyl group comprising one or more, e.g., 1 to 3, heteroatoms selected from nitrogen, oxygen or optionally oxidized sulfur as ring members, with the remaining ring members being carbon, including monocyclic, fused, bridged, and spiro ring, i.e., containing monocyclic heterocyclyl, bridged heterocyclyl, spiro heterocyclyl, and fused
  • Exemplary monocyclic 4 to 9-membered heterocyclyl groups include, but not limited to, (as numbered from the linkage position assigned priority 1) pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, imidazolidin-2-yl, imidazolidin-4-yl, pyrazolidin-2-yl, pyrazolidin-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, 2, 5-piperazinyl, pyranyl, morpholinyl, morpholino, morpholin-2-yl, morpholin-3-yl, oxiranyl, aziridin-1-yl, aziridin-2-yl, azocan-1-yl, azocan-2-yl, azocan-3-yl, azocan-4-yl, azocan-5-yl, thiiranyl, azetidin
  • stereoisomer refers to all isomers of individual compounds that differ only in the orientation of their atoms in space.
  • stereoisomer includes mirror image isomers (enantiomers) , mixtures of mirror image isomers (racemates, racemic mixtures) , geometric (cis/trans or syn/anti or E/Z) isomers, and isomers of compounds with more than one chiral center that are not mirror images of one another (diastereoisomers) .
  • Enantiomers refer to two stereoisomers of a compound which are non-superimposable mirror images of one another. Where the compounds disclosed herein possess two or more asymmetric centers, they may additionally exist as diastereomers. Enantiomers and diastereomers fall within the broader class of stereoisomers. All such possible stereoisomers as substantially pure resolved enantiomers, racemic mixtures thereof, as well as mixtures of diastereomers are intended to be included. All stereoisomers of the compounds disclosed herein and/or pharmaceutically acceptable salts thereof are intended to be included. Unless specifically mentioned otherwise, reference to one isomer applies to any of the possible isomers. Whenever the isomeric composition is unspecified, all possible isomers are included.
  • substituents found on such ring system may adopt cis and trans formations.
  • Cis formation means that both substituents are found on the upper side of the 2 substituent placements on the carbon, while trans would mean that they were on opposing sides.
  • the di-substituted cyclic ring system may be cyclohexyl or cyclobutyl ring.
  • reaction products from one another and/or from starting materials.
  • the desired products of each step or series of steps are separated and/or purified (hereinafter separated) to the desired degree of homogeneity by the techniques common in the art.
  • separations involve multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography.
  • Chromatography can involve any number of methods including, for example: reverse-phase and normal phase; size exclusion; ion exchange; high, medium and low pressure liquid chromatography methods and apparatus; small scale analytical; simulated moving bed ( "SMB” ) and preparative thin or thick layer chromatography, as well as techniques of small scale thin layer and flash chromatography.
  • SMB simulated moving bed
  • Diastereomers refer to stereoisomers of a compound with two or more chiral centers but which are not mirror images of one another. Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as by chromatography and/or fractional crystallization.
  • Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher’s acid chloride) , separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereoisomers to the corresponding pure enantiomers.
  • an appropriate optically active compound e.g., chiral auxiliary such as a chiral alcohol or Mosher’s acid chloride
  • Enantiomers can also be separated by use of a chiral HPLC column.
  • a single stereoisomer e.g., a substantially pure enantiomer
  • Racemic mixtures of chiral compounds of the invention can be separated and isolated by any suitable method, including (1) formation of ionic, diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatizing reagents, separation of the diastereomers, and conversion to the pure stereoisomers, and (3) separation of the substantially pure or enriched stereoisomers directly under chiral conditions. See: Wainer, Irving W., Ed. Drug Stereochemistry: Analytical Methods and Pharmacology. New York: Marcel Dekker, Inc., 1993.
  • “Pharmaceutically acceptable salts” refer to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit/risk ratio.
  • a pharmaceutically acceptable salt may be prepared in situ during the final isolation and purification of the compounds disclosed herein, or separately by reacting the free base function with a suitable organic acid or by reacting the acidic group with a suitable base.
  • the free base can be obtained by basifying a solution of the acid salt.
  • an addition salt such as a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds.
  • a pharmaceutically acceptable salt thereof includes salts of at least one compound of Formula (I) , and salts of the stereoisomers of the compound of Formula (I) , such as salts of enantiomers, and/or salts of diastereomers.
  • administration when applied to an animal, human, experimental subject, cell, tissue, organ, or biological fluid, mean contact of an exogenous pharmaceutical, therapeutic, diagnostic agent, or composition to the animal, human, subject, cell, tissue, organ, or biological fluid.
  • Treatment of a cell encompasses contact of a reagent to the cell, as well as the contact of a reagent to a fluid, where the fluid is in contact with the cell.
  • administration and “treatment” also means in vitro and ex vivo treatments, e.g., of a cell, by a reagent, diagnostic, binding compound, or by another cell.
  • subject herein includes any organism, preferably an animal, more preferably a mammal (e.g., rat, mouse, dog, cat, and rabbit) and most preferably a human.
  • an effective amount refers to an amount of the active ingredient, such as a compound that, when administered to a subject for treating a disease, or at least one of the clinical symptoms of a disease or disorder, is sufficient to affect such treatment for the disease, disorder, or symptom.
  • therapeutically effective amount can vary with the compound, the disease, disorder, and/or symptoms of the disease or disorder, severity of the disease, disorder, and/or symptoms of the disease or disorder, the age of the subject to be treated, and/or the weight of the subject to be treated. An appropriate amount in any given instance can be apparent to those skilled in the art or can be determined by routine experiments.
  • “therapeutically effective amount” is an amount of at least one compound and/or at least one stereoisomer thereof, and/or at least one pharmaceutically acceptable salt thereof disclosed herein effective to “treat” as defined herein, a disease or disorder in a subject.
  • the term “therapeutically effective amount” refers to the total amount of the combination objects for the effective treatment of a disease, a disorder or a condition.
  • disease refers to any disease, discomfort, illness, symptoms or indications, and can be interchangeable with the term “disorder” or “condition” .
  • C n-m indicates a range which includes the endpoints, wherein n and m are integers and indicate the number of carbons. Examples include C 1-8 , C 1-6 , and the like.
  • At least one substituent includes, for example, from 1 to 4, such as from 1 to 3, further as 1 or 2, substituents, provided that the theory of valence is met.
  • at least one substituent R 4 disclosed herein includes from 1 to 4, such as from 1 to 3, further as 1 or 2, substituents selected from the list of R 4 as disclosed herein.
  • Example 1 N-cyclohexyl-4-oxo-2- (pyridin-4-yl) -3, 4-dihydrothieno [3, 2-d] pyrimidine-7-carboxamide (Compound 1) and 4-amino-N-cyclohexyl-2- (pyridin-4-yl) thieno [3, 2-d] pyrimidine-7-carboxamide (Compound 2)
  • Methyl 4-aminothiophene-3-carboxylate (3.5 g, 22.266 mmol) , isonicotinonitrile (5.1 g, 49.98 mmol) and THF (100 mL) were added to a 250 mL one-neck round-bottom flask. The mixture was stirred and cooled to 0 ⁇ 10°C. A solution of t-BuOK (6.2 g, 55.7 mmol) in THF (50 mL) was added drop wise. After addition, the mixture was warmed up to room temperature and stirred for an hour. The resulting mixture was quenched with water (100 mL) and the pH of the mixture was adjusted to 8 ⁇ 9 with HCl (2.0 M, aqueous) .
  • N- (2, 3-dihydro-1H-inden-2-yl) -4-oxo-2- (pyridin-4-yl) -3, 4-dihydrothieno [3, 4-d] pyrimidine-7-carboxamide (1.0 g, 4.36 mmol) and DMF (30 mL) were added to a 100 mL one-neck round-bottom flask at room temperature. NBS (1.24 g, 7.0 mmol) was added, the mixture was stirred at room temperature for 2 hours. The resulting mixture was diluted with water (200 mL) . The mixture was extracted with EtOAc (200 mL*3) .
  • the resulting mixture was purified by prep-HPLC (Basi method: Waters 2767/2545/2489/Qda, Column name: Inertsil ODS-3 10um 20*250 nm, Mobile Phase A: 0.1%NH 4 OH in water, Mobile Phase B: CH 3 CN, Flow: 20 mL/min: Column temp: RT) to afford the titled compound (3.97 mg, 3.7%yield) .
  • the resulting mixture was purified by prep-HPLC (Waters 2767/2545/2489, Waters Xbridge C18 10um OBD 19*250 mm, Mobile Phase A: 0.1%NH 4 OH in water, Mobile Phase B: CH 3 CN, Flow: 20 mL/min, Column temp: RT) to afford the titled compound (26.43 mg, 41.6%yield) .
  • Step 1 6-bromo-4-chloro-7- (phenylsulfonyl) -7H-pyrrolo [2, 3-d] pyrimidine.
  • Step 3 tert-butyl 3- (cyclohexylamino) -5- (thiazol-5-yl) -1H-indazole-1-carboxylate.
  • Example 13 4- ( ( (1r, 4r) -4-methoxycyclohexyl) amino) -1-methyl-6- (1H-pyrazol-4-yl) quinolin-2 (1H) -one
  • Step 6 4- ( ( (1r, 4r) -4-methoxycyclohexyl) amino) -1-methyl-6- (1H-pyrazol-4-yl) quinolin- 2 (1H) -one
  • Step 1 tert-butyl 5-bromo-3- (cyclohexanecarboxamido) -1H-indazole-1-carboxylate.
  • Step 1 methyl 2-oxo-2, 3-dihydro-1H-benzo [d] imidazole-5-carboxylate.
  • a dilution of the test compounds 4 ⁇ of the desired final concentration in sucrose buffer (0.25 M sucrose, 40 mM tris base) was prepared. Also, a blank sample was prepared with 50 ⁇ l of sucrose buffer and no test compounds.
  • a CD38 inhibitor 78c (as disclosed in J. Med. Chem. 2015, 58, 3548-3571) was used as a control for the CD38 activity and the compounds disclosed herein were tested.
  • 2.5X rhCD38 enzyme working fluid (10818-H08H, Sino Biological Inc, 0.125 ng/ ⁇ l; BSA, 500 ng/ ⁇ l) in sucrose buffer (0.25 M sucrose, 40 mM tris base) was prepared.
  • 2.5x substrate working fluid ( ⁇ -NAD, N2630-25MG, Sigma-Aldrich, 125 ⁇ M) in sucrose buffer (0.25 M sucrose, 40 mM tris base) was also prepared.
  • the dynamic reading was performed at 25°C with excitation light of 300 nm and emission light of 410 nm on the enzyme marker. The readings were recorded for a total of 1 hour, and the data were analyzed with the point reading time of 20min.
  • the microplate reader records fluorescence. Individual excel files containing fluorescence data are exported and the results are plotter against various drug concentrations and analyzed in GraphPad Prism 7.0 for concentration curve generation.

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Abstract

La présente invention concerne des composés de formule I qui peuvent être utilisés en tant qu'inhibiteurs de CD38; des procédés de production des composés de l'invention; des compositions pharmaceutiques comprenant les composés de l'invention; ainsi que des utilisations et des méthodes de traitement d'une maladie médiée par CD38 par administration des composés de l'invention.
PCT/CN2022/135278 2021-12-01 2022-11-30 Composés et leurs utilisations en tant qu'inhibiteurs de cd38 WO2023098699A1 (fr)

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