Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
  • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
  • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/42—Oxazoles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
  • A61K31/4453—Non condensed piperidines, e.g. piperocaine only substituted in position 1, e.g. propipocaine, diperodon
• • 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
  • 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
  • C07D413/12—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 linked by a chain containing hetero atoms as chain links
• • 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
  • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
• • 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
  • C07D487/08—Bridged systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

• the present disclosure provides substituted piperidines as SMYD protein inhibitors, such as SMYD3 and SMYD2 inhibitors, and therapeutic methods of treating conditions and diseases wherein inhibition of SMYD proteins such as SMYD3 and SMYD2 provides a benefit.
• Epigenetic regulation of gene expression is an important biological determinant of protein production and cellular differentiation and plays a significant pathogenic role in a number of human diseases.
• Epigenetic regulation involves heritable modification of genetic material without changing its nucleotide sequence.
• epigenetic regulation is mediated by selective and reversible modification (e.g., methylation) of DNA and proteins (e.g., histones) that control the conformational transition between transcriptionally active and inactive states of chromatin.
• methyltransferases e.g., SMYD proteins such as SMYD3 and SMYD2
• the present disclosure provides substituted piperidine compounds represented by any one of Formulae I-X below, and the pharmaceutically acceptable salts and solvates thereof, collectively referred to herein as "Compounds of the Disclosure.”
• the present disclosure provides a Compound of the Disclosure and one or more pharmaceutically acceptable carriers.
• the present disclosure provides a method of inhibiting SMYD proteins, such as SMYD3 or SMYD2, or both, in a mammal, comprising administering to the mammal an effective amount of at least one Compound of the Disclosure.
• SMYD proteins such as SMYD3 or SMYD2
• the present disclosure provides methods for treating a disease, disorder, or condition, e.g., cancer, responsive to inhibition of SMYD proteins, such as SMYD3 or SMYD2, or both, comprising administering a therapeutically effective amount of a Compound of the Disclosure.
• a disease, disorder, or condition e.g., cancer
• SMYD proteins such as SMYD3 or SMYD2
• the present disclosure provides the use of Compounds of the Disclosure as inhibitors of SMYD3.
• the present disclosure provides the use of Compounds of the Disclosure as inhibitors of SMYD2.
• the present disclosure provides the use of Compounds of the Dicslosure as inhibitors of SMYD proteins.
• the present disclosure provides a pharmaceutical composition for treating a disease, disorder, or condition responsive to inhibition of SMYD proteins, such as SMYD3 or SMYD2, or both, wherein the pharmaceutical composition comprises a therapeutically effective amount of a Compound of the Disclosure in a mixture with one or more pharmaceutically acceptable carriers.
• the present disclosure provides Compounds of the Disclosure for use in treating cancer in a mammal, e.g., breast, cervical, colon, kidney, liver, head and neck, skin, pancreatic, ovary, esophageal, lung, and prostate cancer.
• a mammal e.g., breast, cervical, colon, kidney, liver, head and neck, skin, pancreatic, ovary, esophageal, lung, and prostate cancer.
• the present disclosure provides a Compound of the Disclosure for use in the manufacture of a medicament for treating cancer in a mammal.
• the present disclosure provides kit comprising a Compound of the Disclosure.
• One aspect of the present disclosure is based on the use of Compounds of the Disclosure as inhibitors of SMYD3.
• the Compounds of the Disclosure are useful for treating diseases, disorders, or conditions, e.g., cancer, responsive to inhibition of SMYD3.
• One aspect of the present disclosure is based on the use of Compounds of the Disclosure as inhibitors of SMYD2.
• the Compounds of the Disclosure are useful for treating diseases, disorders, or conditions, e.g., cancer, responsive to inhibition of SMYD2.
• Compounds of the Disclosure are compounds having Formula I:
• Z is selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, fluoroalkyl, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, (cycloalkylamino)alkyl, (heterocyclo)alkyl, (amino)(hydroxy)alkyl, (amino)(aryl)alkyl, (hydroxy)(aryl)alkyl, (aralkylamino)alkyl, [(cycloalkyl)alkylamino]alky
• R 1 is selected from the group consisting of ethyl, n-propyl, isopropyl, isobutyl, and cyclopropyl;
• R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 5a , and R 5b are each independently selected from the group consisting of hydrogen, halo, C 1-6 alkyl, C 3-12 cycloalkyl, haloalkyl, hydroxyalkyl, optionally substituted C 6-14 aryl, aralkyl, and alkoxycarbonyl; or
• R 2a and R 2b taken together with the carbon atom to which they are attached form a C 3-6 cycloalkyl; and R 3a , R 3b , R 4a , R 4b , R 5a , and R 5b are each independently selected from the group consisting of hydrogen, halo, and C 1-4 alkyl; or
• R 3a and R 3b taken together with the carbon atom to which they are attached form a C 3-6 cycloalkyl; and R 2a , R 2b , R 4a , R 4b , R 5a , and R 5b are each independently selected from the group consisting of hydrogen, halo, and C 1-4 alkyl; or
• R 4a and R 4b taken together with the carbon atom to which they are attached form a C 3-6 cycloalkyl; and R 2a , R 2b , R 3a , R 3b , R 5a , and R 5b are each independently selected from the group consisting of hydrogen, halo, and C 1-4 alkyl; or
• R 5a and R 5b taken together with the carbon atom to which they are attached form a C 3-6 cycloalkyl; and R 2a , R 2b , R 3a , R 3b , R 4a , and R 4b are each independently selected from the group consisting of hydrogen, halo, and C 1-4 alkyl; or
• R 2a and R 5a taken together form a C 1-4 bridge; and R 2b , R 3a , R 3b , R 4a , R 4b , and R 5b are each independently selected from the group consisting of hydrogen, halo, and C 1-4 alkyl; or
• R 3a and R 4a taken together form a C 1-4 bridge; and R 2a , R 2b , R 3b , R 4a , R 5a , and R 5b are each independently selected from the group consisting of hydrogen, halo, and C 1-4 alkyl; or
• R 2a and R 4a taken together form a C 1-4 bridge; and R 2b , R 3a , R 3b , R 4b , R 5a , and R 5b are each independently selected from the group consisting of hydrogen, halo, and C 1-4 alkyl; or [0033] R 3a and R 5a taken form a C 1-4 bridge; and R 2a , R 2b , R 3b , R 4a , R 4b , and R 5b are each independently selected from the group consisting of hydrogen, halo, and C 1-4 alkyl;
• R 6 is selected from the group consisting of hydrogen and C 1-4 alkyl
• R 7 is selected from the group consisting of hydrogen and C 1-4 alkyl
• R 9 is selected from the group consisting of hydrogen and C 1-4 alkyl
• R 10 is selected from the group consisting of (amino)alkyl, (alkylamino)alkyl, and (dialkylamino)alkyl;
• R 11 is selected from the group consisting of hydrogen and C 1-4 alkyl.
• Compounds of the Disclosure are compounds having Formula I, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein R 1 is selected from the group consisting of ethyl and cyclopropyl.
• Compounds of the Disclosure are compounds having Formula I, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein Z is selected from the group consisting of optionally substituted C 1-6 alkyl, fluoroalkyl, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, (cycloalkylamino)alkyl, (heterocyclo)alkyl, (amino)(hydroxy)alkyl, (amino)(aryl)alkyl, (hydroxy)(aryl)alkyl, (aralkylamino)alkyl, alkoxyalkyl, optionally substituted C 6-14 aryl, optionally substituted 4- to 14-membered heterocyclo, optionally substituted 5- to 14-membered heteroaryl, optionally substituted C 3-12 cycloalkyl, aralkyl, and heteroaralkyl, when X is
• Compounds of the Disclosure are compounds having Formula I, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein B is: ;
• R 6 is selected from the group consisting of hydrogen and C 1-4 alkyl; and R 1 , X, and Z are as defined above in connection with Formula I. In another embodiment, R 6 is selected from the group consisting of hydrogen and methyl. In another embodiment, R 6 is hydrogen. [0043] In another embodiment, Compounds of the Disclosure are compounds having Formula I, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein B is:
• R 2a is selected from the group consisting of halo, C 1-6 alkyl, C 3-12 cycloalkyl, haloalkyl, hydroxyalkyl, optionally substituted C 6-14 aryl, aralkyl, and alkoxycarbonyl; and R 1 , X, and Z are as defined above in connection with Formula I.
• B is selected from the rou consistin of:
• R 2a is selected from the group consisting of methyl, ethyl, phenyl, -CF 3 , -CO 2 Et, and -CH 2 OH. In another embodiment, R 2a is -CH 2 Ph.
• Compounds of the Disclosure are compounds having Formula I, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein B is:
• R 3a is selected from the group consisting of halo, C 1-6 alkyl, C 3-12 cycloalkyl, haloalkyl, hydroxyalkyl, optionally substituted C 6-14 aryl, aralkyl, and alkoxycarbonyl; and R 1 , X, and Z are as defined above in connection with Formula I.
• B is selected from the rou consistin of:
• R 3a is selected from the group consisting of methyl, ethyl, propyl, isopropyl, tert-butyl, phenyl, and -CH 2 Ph. In another embodiment, R 3a is -CH 2 Ph.
• Compounds of the Disclosure are compounds having Formula I, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein B is:
• R 2a and R 2b are each independently selected from the group consisting of halo and C 1-6 alkyl; or R 2a and R 2b taken together with the carbon atom to which they are attached form a C 3-6 cycloalkyl; and R 1 , X, and Z are as defined above in connection with Formula I.
• B is selected from the group consisting of:
• B is selected from the group consisting of:
• B is selected from the group consisting of:
• R 2a and R 2b are each independently selected from the group consisting of halo and C 1-4 alkyl. In another embodiment, R 2a and R 2b are selected from the group consisting of fluoro and methyl. [0046] In another embodiment, Compounds of the Disclosure are compounds having Formula I, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein B is:
• R 3a and R 3b are each independently selected from the group consisting of halo and C 1-6 alkyl; or
• R 3a and R 3b taken together with the carbon atom to which they are attached form a C 3-6 cycloalkyl; and R 1 , X, and Z are as defined above in connection with Formula I.
• B is selected from the group consisting of:
• B is selected from the group consisting of:
• B is selected from the group consisting of:
• R 3a and R 3b are each independently selected from the group consisting of halo and C 1-4 alkyl. In another embodiment, R 3a and R 3b are selected from the group consisting of fluoro and methyl. [0047] In another embodiment, Compounds of the Disclosure are compounds having Formula I, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein B is:
• R 3a and R 5a are each independently C 1-6 alkyl; or R 3a and R 5a taken together form a C 1-4 bridge; and R 1 , X, and Z are as defined above in connection with Formula I.
• B is selected from the group consisting of:
• R 3a and R 5a are each independently C 1-4 alkyl. In another embodiment, R 3a and R 5a are each methyl or ethyl.
• Compounds of the Disclosure are compounds having Formula I, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein B is:
• R 1 , X, and Z are as defined above in connection with Formula I.
• B is selected from the group consisting of: .
• Compounds of the Disclosure are compounds having Formula I, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein B is:
• R 2a and R 3a are each independently C 1-6 alkyl; and R 1 , X, and Z are as defined above in connection with Formula I.
• B is:
• R 2a and R 3a are each independently C 1-4 alkyl. In another embodiment, R 2a and R 3a are each methyl or ethyl.
• Compounds of the Disclosure are compounds having Formula I, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein B is:
• R 3a and R 4a are each independently C 1-6 alkyl; or R 3a and R 4a taken together form a C 1-4 bridge; and R 1 , X, and Z are as defined above in connection with Formula I.
• B is:
• R 3a and R 4a are each independently C 1-4 alkyl. In another embodiment, R 3a and R 4a are each methyl or ethyl.
• Compounds of the Disclosure are compounds having Formula I, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein B is selected from the group consisting of:
• B is selected from the rou consistin of:
• B is selected from the rou consistin of:
• Compounds of the Disclosure are compounds having Formula I, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein B is:
• R 2a and R 5a are each independently selected from the group consisting of C 1-6 alkyl and alkoxycarbonyl; or R 2a and R 5a taken together form a C 1-4 bridge; and R 1 , X, and Z are as defined above in connection with Formula I.
• B is:
• R 2a and R 5a are each independently selected from the group consisting of C 1-4 alkyl and alkoxycarbonyl. In another embodiment, R 2a and R 5a are each independently selected from the group consisting of methyl and -CO 2 Me.
• Compounds of the Disclosure are compounds having Formula I, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein X is absent and R 1 , B, and Z are as defined above in connection with Formula I.
• Compounds of the Disclosure are compounds having Formula I, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein X is selected from the group consisting of: ;
• Compounds of the Disclosure are compounds having Formula I, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein X is selected from the group consisting of:
• Compounds of the Disclosure are compounds having Formula I, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein Z is selected from the group consisting of (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, (heterocyclo)alkyl, (aralkylamino)alkyl, optionally substituted C 6-14 aryl, optionally substituted 4- to 14-membered heterocyclo, optionally substituted 5- to 14-membered heteroaryl, and optionally substituted C 3-12 cycloalkyl.
• Z is selected from the group consisting of (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, (heterocyclo)alkyl, (aralkylamino)alkyl, optionally substituted C 6-14 aryl, optionally substituted 4- to 14-membered heterocyclo, optionally substituted 5- to
• Compounds of the Disclosure are compounds having Formula II:
• R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 5a , and R 5b are each independently selected from the group consisting of hydrogen, halo, C 1-6 alkyl, C 3-12 cycloalkyl, haloalkyl, hydroxyalkyl, optionally substituted C 6-14 aryl, aralkyl, and alkoxycarbonyl; or
• R 2a and R 2b taken together with the carbon atom to which they are attached form a C 3-6 cycloalkyl; and R 3a , R 3b , R 4a , R 4b , R 5a , and R 5b are each independently selected from the group consisting of hydrogen, halo, and C 1-4 alkyl; or
• R 3a and R 3b taken together with the carbon atom to which they are attached form a C 3-6 cycloalkyl; and R 2a , R 2b , R 4a , R 4b , R 5a , and R 5b are each independently selected from the group consisting of hydrogen, halo, and C 1-4 alkyl; or
• R 4a and R 4b taken together with the carbon atom to which they are attached form a C 3-6 cycloalkyl; and R 2a , R 2b , R 3a , R 3b , R 5a , and R 5b are each independently selected from the group consisting of hydrogen, halo, and C 1-4 alkyl; or
• R 5a and R 5b taken together with the carbon atom to which they are attached form a C 3-6 cycloalkyl; and R 2a , R 2b , R 3a , R 3b , R 4a , and R 4b are each independently selected from the group consisting of hydrogen, halo, and C 1-4 alkyl; or
• R 2a and R 5a taken together form a C 1-4 bridge; and R 2b , R 3a , R 3b , R 4a , R 4b , and R 5b are each independently selected from the group consisting of hydrogen, halo, and C 1-4 alkyl; or
• R 3a and R 4a taken together form a C 1-4 bridge; and R 2a , R 2b , R 3b , R 4a , R 5a , and R 5b are each independently selected from the group consisting of hydrogen, halo, and C 1-4 alkyl; or
• R , R 3a , R 3b , R 4b , R 5a , and R 5b are each independently selected from the group consisting of hydrogen, halo, and C 1-4 alkyl; or [0073] R 3a and R 5a taken form a C 1-4 bridge; and R 2a , R 2b , R 3b , R 4a , R 4b , and R 5b are each independently selected from the group consisting of hydrogen, halo, and C 1-4 alkyl;
• R 6 is selected from the group consisting of hydrogen and C 1-4 alkyl
• R 2a , R 3a , R 4a , and R 5a is independently selected from the group consisting of halo, C 1-6 alkyl, C 3-12 cycloalkyl, haloalkyl, hydroxyalkyl, optionally substituted C 6-14 aryl, aralkyl, and alkoxycarbonyl; or b) R 6 is C 1-4 alkyl; and
• R 1 , X, and Z are as defined in connection with Formula I.
• Compounds of the Disclosure are compounds having Formula II, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein Z is selected from the group consisting of optionally substituted C 1-6 alkyl, fluoroalkyl, (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, (cycloalkylamino)alkyl, (heterocyclo)alkyl, (amino)(hydroxy)alkyl, (amino)(aryl)alkyl, (hydroxy)(aryl)alkyl, (aralkylamino)alkyl, alkoxyalkyl, optionally substituted C 6-14 aryl, optionally substituted 4- to 14-membered heterocyclo, optionally substituted 5- to 14-membered heteroaryl, optionally substituted C 3-12 cycloalkyl, aralkyl, and heteroaralkyl, when X is
• Compounds of the Disclosure are compounds having Formula II, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein
• R 2a , R 2b , R 3a , R 3b , R 4a , R 4b , R 5a , and R 5b are each independently selected from the group consisting of hydrogen, halo, C 1-6 alkyl, C 3-12 cycloalkyl, haloalkyl, hydroxyalkyl, optionally substituted C 6-14 aryl, aralkyl, and alkoxycarbonyl; or
• R 2a and R 2b taken together with the carbon atom to which they are attached form a C 3-6 cycloalkyl; and R 3a , R 3b , R 4a , R 4b , R 5a , and R 5b are each independently selected from the group consisting of hydrogen, halo, and C 1-4 alkyl; or
• R 3a and R 3b taken together with the carbon atom to which they are attached form a C 3-6 cycloalkyl; and R 2a , R 2b , R 4a , R 4b , R 5a , and R 5b are each independently selected from the group consisting of hydrogen, halo, and C 1-4 alkyl; or
• R 4a and R 4b taken together with the carbon atom to which they are attached form a C 3-6 cycloalkyl; and R 2a , R 2b , R 3a , R 3b , R 5a , and R 5b are each independently selected from the group consisting of hydrogen, halo, and C 1-4 alkyl; or [0083] R 5a and R 5b taken together with the carbon atom to which they are attached form a C 3-6 cycloalkyl; and R 2a , R 2b , R 3a , R 3b , R 4a , and R 4b are each independently selected from the group consisting of hydrogen, halo, and C 1-4 alkyl; and
• R 1 , R 6 , X, and Z are as defined in connection with Formula I.
• Compounds of the Disclosure are compounds having Formula III:
• Z is selected from the group consisting of (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, (heterocyclo)alkyl, optionally substituted C 6-14 aryl, and optionally substituted 4- to 14-membered heterocyclo.
• Compounds of the Disclosure are compounds having Formula IV:
• Z is selected from the group consisting of (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, (heterocyclo)alkyl, optionally substituted C 6-14 aryl, and optionally substituted 4- to 14-membered heterocyclo.
• Compounds of the Disclosure are compounds having Formula V:
• Z is selected from the group consisting of (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, (heterocyclo)alkyl, optionally substituted C 6-14 aryl, optionally substituted 4- to 14-membered heterocyclo, and optionally substituted C 3-12 cycloalkyl. It will be understood by those of ordinary skill in the art that compounds having Formula V can be drawn in various ways, e.g.,
• Compounds of the Disclosure are compounds having Formula VI:
• Z is selected from the group consisting of (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, (heterocyclo)alkyl, optionally substituted C 6-14 aryl, optionally substituted 4- to 14-membered heterocyclo, and optionally substituted C 3-12 cycloalkyl. It will be understood by those of ordinary skill in the art that compounds having Formula VI can be drawn in various ways, e.g.,
• Compounds of the Disclosure are compounds having Formula VII:
• Z is selected from the group consisting of (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, (heterocyclo)alkyl, optionally substituted C 6-14 aryl, optionally substituted 4- to 14-membered heterocyclo, and optionally substituted C 3-12 cycloalkyl.
• Compounds of the Disclosure are compounds having Formula VIII:
• Z is selected from the group consisting of (amino)alkyl, (alkylamino)alkyl, (dialkylamino)alkyl, (heterocyclo)alkyl, optionally substituted C 6-14 aryl, optionally substituted 4- to 14-membered heterocyclo, and optionally substituted C 3-12 cycloalkyl.
• Compounds of the Disclosure are compounds having Formula IX:
• Compounds of the Disclosure are compounds having Formula X:
• Compounds of the Disclosure are compounds having any one of Formulae I-X, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein R 1 is ethyl.
• Compounds of the Disclosure are compounds having any one of Formulae I-X, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein R 1 is ethyl and Z is selected from the group consisting of (heterocyclo)alkyl, (amino)alkyl-susbstituted phenyl, amino-substituted piperidine, alkylamino-substituted piperidine, dialkylamino-substituted piperidine, and amino-substituted cyclohexyl.
• Compounds of the Disclosure are compounds having any one of Formulae I-X, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein R 1 is n-propyl.
• Compounds of the Disclosure are compounds having any one of Formulae I-X, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein R 1 is n-propyl and Z is selected from the group consisting of (heterocyclo)alkyl, (amino)alkyl-susbstituted phenyl, amino-substituted piperidine, alkylamino-substituted piperidine, dialkylamino-substituted piperidine, and amino-substituted cyclohexyl.
• Compounds of the Disclosure are compounds having any one of Formulae I-X, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein R 1 is isopropyl.
• Compounds of the Disclosure are compounds having any one of Formulae I-X, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein R 1 is isopropyl and Z is selected from the group consisting of (heterocyclo)alkyl, (amino)alkyl-susbstituted phenyl, amino-substituted piperidine, alkylamino-substituted piperidine, dialkylamino-substituted piperidine, and amino-substituted cyclohexyl.
• Compounds of the Disclosure are compounds having any one of Formulae I-X, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein R 1 is isobutyl.
• Compounds of the Disclosure are compounds having any one of Formulae I-X, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein R 1 is isobutyl and Z is selected from the group consisting of (heterocyclo)alkyl, (amino)alkyl-susbstituted phenyl, amino-substituted piperidine, alkylamino-substituted piperidine, dialkylamino-substituted piperidine, and amino-substituted cyclohexyl.
• Compounds of the Disclosure are compounds having any one of Formulae I-X, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein R 1 is cyclopropyl.
• Compounds of the Disclosure are compounds having any one of Formulae I-X, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein R 1 is cyclopropyl and Z is selected from the group consisting of (heterocyclo)alkyl, (amino)alkyl-susbstituted phenyl, amino-substituted piperidine, alkylamino-substituted piperidine, dialkylamino-substituted piperidine, and amino-substituted cyclohexyl.
• Compounds of the Disclosure are compounds having any one of Formulae I-X, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein Z is (heterocyclo)alkyl.
• Compounds of the Disclosure are compounds having any one of Formulae I-X, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein Z is a (heterocyclo)alkyl having the following structure: ;
• R 12 is selected from the group consisting of hydrogen, fluoroalkyl, hydroxyalkyl, aralkyl, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclo, alkoxyalkyl, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl, (cyano)alkyl, (carboxamido)alkyl, (heterocyclo)alkyl, and (heteroaryl)alkyl.
• R 12 is selected from the group consisting of hydrogen, fluoroalkyl, hydroxyalkyl, aralkyl, alkyl, alkoxyalkyl, (amino)alkyl, hydroxyalkylamino, (alkylamino)alkyl, (dialkylamino)alkyl, (heterocyclo)alkyl, and (heteroaryl)alkyl.
• Compounds of the Disclosure are compounds having any one of Formulae I-X, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein Z is selected from the group consisting of:
• Compounds of the Disclosure are compounds having any one of Formulae I-X, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, wherein R 1 is cyclopropyl and Z is selected from the group consisting of:
• Compounds of the Disclosure are compounds of Table 1, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, or a different pharmaceutically acceptable salt thereof.
• the chemical names of the compounds of Table 1 are provided in Table 1A.
• Compounds of the Disclosure are compounds of Table 2, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, or a different pharmaceutically acceptable salt thereof.
• the chemical names of the compounds of Table 2 are provided in Table 2A.
• Compounds of the Disclosure are compounds of Table 3, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, or a different pharmaceutically acceptable salt thereof.
• the chemical names of the compounds of Table 3 are provided in Table 3A.
• Compounds of the Disclosure are compounds of Tables 1 and 2, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, or a different pharmaceutically acceptable salt thereof.
• Compounds of the Disclosure are compounds of Tables 1, 2, and 3, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, or a different pharmaceutically acceptable salt thereof.
• Compounds of the Disclosure are compounds of Tables 1, 1A, 2, 2A, 3, and 3A, and the pharmaceutically acceptable salts or solvates, e.g., hydrates, thereof, or a different pharmaceutically acceptable salt thereof.
• Compounds of the Disclosure are selected from the group consisting of:
• a Compound of the Disclosure is a compound having Formulae I-X, provided that the compound is not:
• compositions comprising one or more of the following compounds:
• the disclosure relates to a method of inhibiting SMYD proteins, such as SMYD3 or SMYD2, or both, in a subject, comprising administering to a subject in need thereof an effective amount of at least one of the following compounds:
• alkyl refers to a straight- or branched-chain aliphatic hydrocarbon containing one to twelve carbon atoms (i.e., C 1-12 alkyl) or the number of carbon atoms designated (i.e., a C 1 alkyl such as methyl, a C 2 alkyl such as ethyl, a C 3 alkyl such as propyl or isopropyl, etc.).
• the alkyl group is chosen from a straight chain C 1-10 alkyl group.
• the alkyl group is chosen from a branched chain C 3-10 alkyl group.
• the alkyl group is chosen from a straight chain C 1-6 alkyl group. In another embodiment, the alkyl group is chosen from a branched chain C 3-6 alkyl group. In another embodiment, the alkyl group is chosen from a straight chain C 1-4 alkyl group. In another embodiment, the alkyl group is chosen from a branched chain C 3-4 alkyl group. In another embodiment, the alkyl group is chosen from a straight or branched chain C 3-4 alkyl group. In another embodiment, the alkyl group is partially or completely deuterated, i.e., one or more hydrogen atoms of the alkyl group are replaced with deuterium atoms.
• Non-limiting exemplary C 1-10 alkyl groups include methyl (including -CD 3 ), ethyl, propyl, isopropyl, butyl, sec-butyl, tert- butyl, iso-butyl, 3-pentyl, hexyl, heptyl, octyl, nonyl, and decyl.
• Non-limiting exemplary C 1-4 alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, and iso-butyl.
• Non-limiting exemplary C 1-4 groups include methyl, ethyl, propyl, isopropyl, and tert-butyl.
• the term "optionally substituted alkyl" as used by itself or as part of another group means that the alkyl as defined above is either unsubstituted or substituted with one, two, or three substituents independently chosen from nitro, haloalkoxy, aryloxy, aralkyloxy, alkylthio, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, alkoxycarbonyl, and carboxyalkyl.
• the alkyl is a C 1-4 alkyl.
• the optionally substituted alkyl is substituted with two substituents. In another embodiment, the optionally substituted alkyl is substituted with one substituent.
• Non-limiting exemplary optionally substituted alkyl groups include -CH 2 CH 2 NO 2 , -CH 2 CH 2 CO 2 H, -CH 2 CH 2 SO 2 CH 3 , -CH 2 CH 2 COPh, and -CH 2 C 6 H 11 .
• cycloalkyl refers to saturated and partially unsaturated (containing one or two double bonds) cyclic aliphatic hydrocarbons containing one to three rings having from three to twelve carbon atoms (i.e., C 3-12 cycloalkyl) or the number of carbons designated.
• the cycloalkyl group has two rings.
• the cycloalkyl group has one ring.
• the cycloalkyl group is chosen from a C 3-8 cycloalkyl group.
• the cycloalkyl group is chosen from a C 3-6 cycloalkyl group.
• Non-limiting exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, decalin, adamantyl, cyclohexenyl, and spiro[3.3]heptane.
• the term "optionally substituted cycloalkyl" as used by itself or as part of another group means that the cycloalkyl as defined above is either unsubstituted or substituted with one, two, or three substituents independently chosen from halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, aralkylamino, heteroalkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyl, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, alkyl, optionally substituted cycloalkyl, alkenyl, alkyny
• the optionally substituted cycloalkyl is substituted with one, two, or three substituents independently chosen from halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyl, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, alkoxyalkyl, (amino)alkyl, hydroxyalkylamino, (alkyla
• the optionally substituted cycloalkyl is substituted with two substituents. In another embodiment, the optionally substituted cycloalkyl is substituted with one substituent. In one embodiment, the optionally substituted cycloalkyl is substituted with at least one amino, alkylamino, or dialkylamino group.
• amino-substituted cycloalkyl as used by itself or as part of another group means that the optionally susbstituted cycloalkyl as defined above is substituted with at least one amino group. In one embodiment, the amino-substituted cycloalkyl is an amino-substituted cyclohexyl group.
• Non-limiting exemplary optionally substituted cycloalkyl groups include:
• cycloalkenyl as used by itself or part of another group refers to a partially unsaturated cycloalkyl group as defined above.
• the cycloalkenyl has one carbon-to-carbon double bond.
• the cycloalkenyl group is chosen from a C 4-8 cycloalkenyl group.
• Exemplary cycloalkenyl groups include cyclopentenyl and cyclohexenyl.
• the term "optionally substituted cycloalkenyl" as used by itself or as part of another group means that the cycloalkenyl as defined above is either unsubstituted or substituted with one, two, or three substituents independently chosen from halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, aralkylamino, heteroalkyl, haloalkyl, monohydroxyalkyl, dihydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, alkyl, optionally substituted cycloalkyl, alkenyl, alkyl, optionally substituted cycloalky
• the optionally substituted cycloalkenyl is substituted with one, two, or three substituents independently chosen from halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, monohydroxyalkyl, dihydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, alkoxyalkyl, (amino)alkyl, hydroxyalkylamino, (alkyl,
• the optionally substituted cycloalkenyl is substituted with two substituents. In another embodiment, the optionally substituted cycloalkenyl is substituted with one substituent. In another embodiment, the cycloalkenyl is unsubstituted.
• alkenyl refers to an alkyl group as defined above containing one, two or three carbon-to-carbon double bonds.
• the alkenyl group is chosen from a C 2-6 alkenyl group.
• the alkenyl group is chosen from a C 2-4 alkenyl group.
• Non-limiting exemplary alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl, sec-butenyl, pentenyl, and hexenyl.
• alkenyl as used herein by itself or as part of another group means the alkenyl as defined above is either unsubstituted or substituted with one, two or three substituents independently chosen from halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted
• alkynyl refers to an alkyl group as defined above containing one to three carbon-to-carbon triple bonds.
• the alkynyl has one carbon-to-carbon triple bond.
• the alkynyl group is chosen from a C 2-6 alkynyl group.
• the alkynyl group is chosen from a C 2-4 alkynyl group.
• Non-limiting exemplary alkynyl groups include ethynyl, propynyl, butynyl, 2-butynyl, pentynyl, and hexynyl groups.
• the term "optionally substituted alkynyl" as used herein by itself or as part of another group means the alkynyl as defined above is either unsubstituted or substituted with one, two or three substituents independently chosen from halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, or heterocyclo.
• haloalkyl refers to an alkyl group substituted by one or more fluorine, chlorine, bromine and/or iodine atoms.
• the alkyl group is substituted by one, two, or three fluorine and/or chlorine atoms.
• the haloalkyl group is chosen from a C 1-4 haloalkyl group.
• Non-limiting exemplary haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, and trichloromethyl groups.
• fluoroalkyl as used by itself or as part of another group refers to an alkyl group substituted by one or more fluorine atoms.
• the alkyl group is substituted by one, two, or three fluorine atoms.
• the fluoroalkyl group is chosen from a C 1-4 fluoroalkyl group.
• Non-limiting exemplary fluoroalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, 3,3,3-trifluoropropyl, and 4,4,4-trifluorobutyl.
• hydroxyalkyl refers to an alkyl group substituted with one or more, e.g., one, two, or three, hydroxy groups.
• the hydroxyalkyl group is a monohydroxyalkyl group, i.e., substituted with one hydroxy group.
• the hydroxyalkyl group is a dihydroxyalkyl group, i.e., substituted with two hydroxy groups.
• the hydroxyalkyl group is chosen from a C 1-4 hydroxyalkyl group.
• Non-limiting exemplary hydroxyalkyl groups include hydroxymethyl, hydroxyethyl, hydroxypropyl and hydroxybutyl groups, such as 1-hydroxyethyl, 2-hydroxyethyl, 1,2-dihydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 3-hydroxybutyl, 4-hydroxybutyl, 2-hydroxy-1-methylpropyl, and 1,3-dihydroxyprop-2- yl.
• alkoxy refers to an optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl or optionally substituted alkynyl attached to a terminal oxygen atom.
• the alkoxy group is chosen from a C 1-4 alkoxy group.
• the alkoxy group is chosen from a C 1-4 alkyl attached to a terminal oxygen atom, e.g., methoxy, ethoxy, and tert-butoxy.
• alkylthio refers to a sulfur atom substituted by an optionally substituted alkyl group.
• the alkylthio group is chosen from a C 1-4 alkylthio group.
• Non-limiting exemplary alkylthio groups include -SCH 3 , and -SCH 2 CH 3 .
• alkoxyalkyl refers to an alkyl group substituted with an alkoxy group.
• Non-limiting exemplary alkoxyalkyl groups include methoxymethyl, methoxyethyl, methoxypropyl, methoxybutyl, ethoxymethyl, ethoxyethyl, ethoxypropyl, ethoxybutyl, propoxymethyl, iso-propoxymethyl, propoxyethyl, propoxypropyl, butoxymethyl, tert-butoxymethyl, isobutoxymethyl, sec-butoxymethyl, and pentyloxymethyl.
• haloalkoxy as used by itself or as part of another group refers to a haloalkyl attached to a terminal oxygen atom.
• Non-limiting exemplary haloalkoxy groups include fluoromethoxy, difluoromethoxy, trifluoromethoxy, and 2,2,2-trifluoroethoxy.
• heteroalkyl refers to a stable straight or branched chain hydrocarbon radical containing 1 to 10 carbon atoms and at least two heteroatoms, which can be the same or different, selected from O, N, or S, wherein: 1) the nitrogen atom(s) and sulfur atom(s) can optionally be oxidized; and/or 2) the nitrogen atom(s) can optionally be quaternized.
• the heteroatoms can be placed at any interior position of the heteroalkyl group or at a position at which the heteroalkyl group is attached to the remainder of the molecule.
• the heteroalkyl group contains two oxygen atoms.
• the heteroalkyl contains one oxygen and one nitrogen atom. In one embodiment, the heteroalkyl contains two nitrogen atoms.
• Non-limiting exemplary heteroalkyl groups include -CH 2 OCH 2 CH 2 OCH 3 , -OCH 2 CH 2 OCH 2 CH 2 OCH 3 , -CH 2 NHCH 2 CH 2 OCH 2 , -OCH 2 CH 2 NH 2 , -NHCH 2 CH 2 N(H)CH 3 , -CH 2 CH 2 CH 2 N(H)CH 2 CH 2 NH 2 , -CH 2 CH 2 CH 2 N(H)CH 2 CH 2 N(H)CH 3 , -NHCH 2 CH 2 OCH 3, -N(CH 3 )CH 2 CH 2 CH 2 OCH 3 , and -OCH 2 CH 2 OCH 3 .
• aryl refers to a monocyclic or bicyclic aromatic ring system having from six to fourteen carbon atoms (i.e., C 6-14 aryl).
• Non-limiting exemplary aryl groups include phenyl (abbreviated as "Ph"), naphthyl, phenanthryl, anthracyl, indenyl, azulenyl, biphenyl, biphenylenyl, and fluorenyl groups.
• the aryl group is chosen from phenyl or naphthyl.
• the aryl group is phenyl.
• the term "optionally substituted aryl" as used herein by itself or as part of another group means that the aryl as defined above is either unsubstituted or substituted with one to five substituents independently selected from the group consisting of halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, aralkylamino, heteroalkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, heteroaryloxy, aralkyl, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, alkyl, optionally substituted cycloalkyl, alkenyl, alkenyl, alkenyl, alky
• the optionally substituted aryl is substituted with one to five substituents independently selected from the group consisting of halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, heteroaryloxy, aralkyl, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, alkoxyalkyl, (amino)alkyl, hydroxyalkylamino,
• the optionally substituted aryl is an optionally substituted phenyl. In one embodiment, the optionally substituted phenyl has four substituents. In another embodiment, the optionally substituted phenyl has three substituents. In another embodiment, the optionally substituted phenyl has two substituents. In another embodiment, the optionally substituted phenyl has one substituent. In another embodiment, the optionally substituted phenyl has at least one amino, alkylamino, dialkylamino, (amino)alkyl, (alkylamino)alkyl, or (dialkylamino)alkyl substituent.
• (amino)alkyl-substituted phenyl as used by itself or as part of another group means that the optionally susbstituted phenyl as defined above is substituted with at least one (amino)alkyl group.
• Non-limiting exemplary substituted aryl groups include 2-methylphenyl, 2-methoxyphenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 3-methylphenyl, 3-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 4-methylphenyl, 4-ethylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 2,6-di-fluorophenyl, 2,6-di-chlorophenyl, 2-methyl, 3-methoxyphenyl, 2-ethyl, 3-methoxyphenyl, 3,4-di- methoxyphenyl, 3,5-di-fluorophenyl 3,5-di-methylphenyl, 3,5-dimethoxy, 4-methylphenyl, 2-fluoro-3-chlorophenyl, 3-chloro-4-fluorophenyl, 2-phenylpropan-2- amine,
• optionally substituted aryl is meant to include groups having fused optionally substituted cycloalkyl and fused optionally substituted heterocyclo rings. Examples include: .
• aryloxy as used by itself or as part of another group refers to an optionally substituted aryl attached to a terminal oxygen atom.
• a non-limiting exemplary aryloxy group is PhO-.
• heteroaryloxy refers to an optionally substituted heteroaryl attached to a terminal oxygen atom.
• aralkyloxy or "arylalkyloxy” as used by itself or as part of another group refers to an aralkyl group attached to a terminal oxygen atom.
• a non-limiting exemplary aralkyloxy group is PhCH 2 O-.
• heteroaryl refers to monocyclic and bicyclic aromatic ring systems having 5 to 14 ring atoms (i.e., a 5- to 14-membered heteroaryl) and 1, 2, 3, or 4 heteroatoms independently chosen from oxygen, nitrogen or sulfur.
• the heteroaryl has three heteroatoms.
• the heteroaryl has two heteroatoms.
• the heteroaryl has one heteroatom.
• the heteroaryl is a 5- to 10-membered heteroaryl.
• the heteroaryl has 5 ring atoms, e.g., thienyl, a 5-membered heteroaryl having four carbon atoms and one sulfur atom.
• the heteroaryl has 6 ring atoms, e.g., pyridyl, a 6-membered heteroaryl having five carbon atoms and one nitrogen atom.
• Non-limiting exemplary heteroaryl groups include thienyl, benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl, benzofuryl, pyranyl, isobenzofuranyl, benzooxazonyl, chromenyl, xanthenyl, 2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, cinnolinyl, quinazolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, ⁇ -carboliny
• the heteroaryl is chosen from thienyl (e.g., thien-2-yl and thien-3-yl), furyl (e.g., 2-furyl and 3-furyl), pyrrolyl (e.g., 1H-pyrrol-2-yl and 1H-pyrrol-3-yl), imidazolyl (e.g., 2H-imidazol-2-yl and 2H- imidazol-4-yl), pyrazolyl (e.g., 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, and 1H-pyrazol-5-yl), pyridyl (e.g., pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl), pyrimidinyl (e.g., pyrimidin-2- yl, pyrimidin-4-yl, and pyrimidin-5-yl), thiazolyl (e.g.
• the term "optionally substituted heteroaryl" as used by itself or as part of another group means that the heteroaryl as defined above is either unsubstituted or substituted with one to four substituents, e.g., one or two substituents, independently chosen from halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, aralkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aralkyl, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, alkyl, optionally substituted cycloalkyl, alkenyl, alkyny
• the optionally substituted heteroaryl is substituted with one to four substituents, e.g., one or two substituents, independently chosen from halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aralkyl, aryloxy, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclo, alkoxyalkyl, (amino)alkyl, hydroxyalkyl,
• the optionally substituted heteroaryl has one substituent.
• the optionally substituted is an optionally substituted pyridyl, i.e., 2-, 3-, or 4-pyridyl. Any available carbon or nitrogen atom can be substituted.
• heterocycle or “heterocyclo” as used by itself or as part of another group refers to saturated and partially unsaturated (e.g., containing one or two double bonds) cyclic groups containing one, two, or three rings having from three to fourteen ring members (i.e., a 3- to 14-membered heterocyclo) and at least one heteroatom.
• Each heteroatom is independently selected from the group consisting of oxygen, sulfur, including sulfoxide and sulfone, and/or nitrogen atoms, which can be quaternized.
• heterocyclo is meant to include cyclic ureido groups such as imidazolidinyl-2-one, cyclic amide groups such as ⁇ -lactam, ⁇ -lactam, ⁇ - lactam and ⁇ -lactam, and cyclic carbamate groups such as oxazolidinyl-2-one.
• heterocyclo is also meant to include groups having fused optionally substituted aryl groups, e.g., indolinyl, indolinyl-2-one, benzo[d]oxazolyl-2(3H)-one.
• the heterocyclo group is chosen from a 4-, 5-, 6-, 7- or 8-membered cyclic group containing one ring and one or two oxygen and/or nitrogen atoms. In one embodiment, the heterocyclo group is chosen from a 5- or 6-membered cyclic group containing one ring and one or two nitrogen atoms. In one embodiment, the heterocyclo group is chosen from a 8-, 9-, 10-, 11-, or 12-membered cyclic group containing two rings and one or two nitrogen atoms. The heterocyclo can be optionally linked to the rest of the molecule through a carbon or nitrogen atom.
• Non-limiting exemplary heterocyclo groups include 2-oxopyrrolidin-3-yl, 2-imidazolidinone, piperidinyl, morpholinyl, piperazinyl, pyrrolidinyl, 8-azabicyclo[3.2.1]octane (nortropane), 6-azaspiro[2.5]octane, 6-azaspiro[3.4]octane, indolinyl, indolinyl-2-one, 1,3-dihydro-2H-benzo[d]imidazol-2- one.
• the term "optionally substituted heterocyclo" as used herein by itself or part of another group means the heterocyclo as defined above is either unsubstituted or substituted with one to four substituents independently selected from the group consisting of halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, aralkylamino, heteroalkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyl, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, alkyl, optionally substituted cycloalkyl, alkenyl, alkynyl, optionally
• Substitution may occur on any available carbon or nitrogen atom, and may form a spirocycle.
• the optionally substituted heterocyclo is substituted with one to four substituents independently selected from the group consisting of halo, nitro, cyano, hydroxy, amino, alkylamino, dialkylamino, aralkylamino, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, aryloxy, aralkyl, aralkyloxy, alkylthio, carboxamido, sulfonamido, alkylcarbonyl, arylcarbonyl, alkylsulfonyl, arylsulfonyl, ureido, guanidino, carboxy, carboxyalkyl, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclo, alkoxyalkyl, (amino)al
• the optionally substituted heterocyclo is substituted with at least one amino, alkylamino, or dialkylamino group.
• amino-substituted heterocyclo as used by itself or as part of another group means that the optionally susbstituted heterocyclo as defined above is substituted with at least one amino group.
• alkylamino-substituted heterocyclo as used by itself or as part of another group means that the optionally susbstituted heterocyclo as defined above is substituted with at least one alkylamino group.
• the amino-substituted or alkylamino- substituted heterocyclo is an amino-substituted or alkylamino-substituted piperidine.
• Non-limiting exemplary optionally substituted heterocyclo groups include:
• amino as used by itself or as part of another group refers to -NH 2 .
• alkylamino as used by itself or as part of another group refers to -NHR 22 , wherein R 22 is C 1-6 alkyl. In one embodiment, R 22 is C 1-4 alkyl.
• Non-limiting exemplary alkylamino groups include -N(H)CH 3 and -N(H)CH 2 CH 3 .
• dialkylamino as used by itself or as part of another group refers to -NR 23a R 23b , wherein R 23a and R 23b are each independently C 1-6 alkyl. In one embodiment, R 23a and R 23b are each independently C 1-4 alkyl.
• Non-limiting exemplary dialkylamino groups include -N(CH 3 ) 2 and -N(CH 3 )CH 2 CH(CH 3 ) 2 .
• hydroxyalkylamino as used by itself or as part of another group refers to -NHR 24 , wherein R 24 is hydroxyalkyl.
• cycloalkylamino as used by itself or as part of another group refers to -NR 25a R 25b , wherein R 25a is optionally substituted cycloalkyl and R 25b is hydrogen or C 1-4 alkyl.
• aralkylamino as used by itself or as part of another group refers to -NR 26a R 26b , wherein R 26a is aralkyl and R 26b is hydrogen or C 1-4 alkyl.
• Non-limiting exemplary aralkylamino groups include -N(H)CH 2 Ph, -N(H)CHPh 2 , and -N(CH 3 )CH 2 Ph.
• (cycloalkyl)alkylamino refers to -NR 26c R 26d , wherein R 26c is (cycloalkyl)alkyl and R 26d is hydrogen or C 1-4 alkyl.
• Non-limiting exemplary (cycloalkyl)alkylamino groups include: .
• (heterocyclo)alkylamino refers to -NR 26e R 26f , wherein R 26e is (heterocyclo)alkyl and R 26f is hydrogen or C 1-4 alkyl.
• Non-limiting exemplary (heterocyclo)alky .
• (amino)alkyl refers to an alkyl group substituted with an amino group.
• the alkyl is a C 1-4 alkyl.
• Non-limiting exemplary (amino)alkyl groups include -CH 2 NH 2 , -C(CH 3 )NH 2 , -C(NH 2 )(H)CH 3 , -CH 2 CH 2 NH 2 , -CH 2 C(NH 2 )(H)CH 3 , -CH 2 CH 2 CH 2 NH 2 , -CH 2 CH 2 CH 2 CH 2 NH 2 , and -CH 2 C(CH 3 ) 2 CH 2 NH 2 .
• (alkylamino)alkyl refers to an alkyl group substituted with an alkylamino group.
• the alkyl is a C 1-4 alkyl.
• a non-limiting exemplary (alkylamino)alkyl group is -CH 2 CH 2 N(H)CH 3 .
• dialkylamino)alkyl refers to an alkyl group substituted by a dialkylamino group.
• the alkyl is a C 1-4 alkyl.
• Non-limiting exemplary (dialkylamino)alkyl groups are -CH 2 CH 2 N(CH 3 ) 2 .
• (cycloalkylamino)alkyl refers to an alkyl group substituted by a cycloalkylamino group.
• the alkyl is a C 1-4 alkyl.
• Non-limiting exemplary (cycloalkylamino)alkyl groups include -CH 2 N(H)cyclopropyl, -CH 2 N(H)cyclobutyl, and -CH 2 N(H)cyclohexyl.
• the term "[(cycloalkyl)alkylamino]alkyl” as used by itself or as part of another group refers to an alkyl group substituted by a (cycloalkyl)alkylamino group.
• the alkyl is a C 1-4 alkyl.
• Non-limiting exemplary ([(cycloalkyl)alkylamino]alkyl groups include:
• the term "[(heterocyclo)alkylamino]alkyl” as used by itself or as part of another group refers to an alkyl group substituted by a (heterocyclo)alkylamino group.
• the alkyl is a C 1-4 alkyl.
• Non-limiting exemplary ([(heterocyclo)alkylamino]alkyl groups include: .
• (aralkylamino)alkyl refers to an alkyl group substituted with an aralkylamino group.
• the alkyl is a C 1-4 alkyl.
• Non-limiting exemplary (aralkylamino)alkyl groups include -CH 2 CH 2 CH 2 N(H)CH 2 Ph and -CH 2 CH 2 CH 2 N(H)CH 2 (4-CF 3 -Ph).
• (cyano)alkyl refers to an alkyl group substituted with one or more cyano, e.g., -CN, groups.
• the alkyl is a C 1-4 alkyl.
• Non-limiting exemplary (cyano)alkyl groups include -CH 2 CH 2 CN, -CH 2 CH 2 CH 2 CN, and -CH 2 CH 2 CH 2 CH 2 CN.
• (amino)(hydroxy)alkyl refers to an alkyl group substituted with one amino, alkylamino, or dialkylamino group and one hydroxy group.
• the alkyl is a C 1-6 alkyl.
• the alkyl is a C 1-4 alkyl.
• Non-limiting exemplary (amino)(hydroxy)alkyl groups include:
• (amino)(aryl)alkyl refers to an alkyl group substituted with one amino, alkylamino, or dialkylamino group and one optionally substituted aryl group.
• the alkyl is a C 1-6 alkyl.
• the optionally substituted aryl group is an optionally substituted phenyl.
• (cycloalkyl)alkyl refers to an alkyl group substituted with one optionally substituted cycloalkyl group.
• the alkyl is a C 1-4 alkyl.
• the cycloalkyl is a C 3-6 cycloalkyl.
• the optionally substituted cycloalkyl group is substituted with an amino or (amino)alkyl group.
• Non-limiting exemplary (cycloalkyl)alkyl groups include:
• (hydroxy)(aryl)alkyl refers to an alkyl group substituted with one hydroxy group and one optionally substituted aryl group.
• the alkyl is a C 1-6 alkyl.
• the optionally substituted aryl group is an optionally substituted phenyl.
• Non-limiting exemplary (hydroxy)(aryl)alkyl groups include: .
• Non-limiting exemplary carboxamido groups include -CONH 2 , -CON(H)CH 3 , CON(CH 3 ) 2 , and -CON(H)Ph.
• (carboxamido)alkyl refers to an alkyl group substituted with a carboxamido group.
• Non-limiting exemplary (carboxamido)alkyl groups include -CH 2 CONH 2 , -C(H)CH 3 -CONH 2 , and -CH 2 CON(H)CH 3 .
• sulfonamido refers to a radical of the formula -SO 2 NR 27a R 27b , wherein R 27a and R 27b are each independently hydrogen, optionally substituted alkyl, or optionally substituted aryl, or R 27a and R 27b taken together with the nitrogen to which they are attached from a 3- to 8-membered heterocyclo group.
• Non-limiting exemplary sulfonamido groups include -SO 2 NH 2 , -SO 2 N(H)CH 3 , and -SO 2 N(H)Ph.
• a non-limiting exemplary alkylcarbonyl group is -COCH 3 .
• a non-limiting exemplary arylcarbonyl group is -COPh.
• alkylsulfonyl as used by itself or as part of another group refers to a sulfonyl group, i.e., -SO 2 -, substituted by any of the above-mentioned optionally substituted alkyl groups.
• a non-limiting exemplary alkylsulfonyl group is -SO 2 CH 3 .
• arylsulfonyl as used by itself or as part of another group refers to a sulfonyl group, i.e., -SO 2 -, substituted by any of the above-mentioned optionally substituted aryl groups.
• a non-limiting exemplary arylsulfonyl group is -SO 2 Ph.
• mercaptoalkyl as used by itself or as part of another group refers to any of the above-mentioned alkyl groups substituted by a–SH group.
• carboxy as used by itself or as part of another group refers to a radical of the formula -COOH.
• carboxyalkyl as used by itself or as part of another group refers to any of the above-mentioned alkyl groups substituted with a -COOH.
• a non-limiting exemplary carboxyalkyl group is -CH 2 CO 2 H.
• the alkoxy group is a C 1-4 alkoxy.
• Non-limiting exemplary alkoxycarbonyl groups are -CO 2 Me and -CO 2 Et.
• aralkyl or “arylalkyl” as used by itself or as part of another group refers to an alkyl group substituted with one, two, or three optionally substituted aryl groups.
• the aralkyl group is a C 1-4 alkyl substituted with one optionally substituted aryl group.
• Non-limiting exemplary aralkyl groups include benzyl, phenethyl, -CHPh 2 , -CH 2 (4-OH-Ph), and -CH(4-F-Ph) 2 .
• the term "(heterocyclo)alkyl" as used by itself or as part of another group refers to an alkyl group substituted with one, two, or three optionally substituted heterocyclo groups.
• the (heterocyclo)alkyl is a C 1-4 alkyl substituted with one optionally substituted heterocyclo group.
• the heterocyclo can be linked to the alkyl group through a carbon or nitrogen atom.
• Non-limiting exemplary (heterocyclo)alkyl groups include:
• the term "(heteroaryl)alkyl” or “heteroaralkyl” as used by itself or as part of another group refers to an alkyl group substituted with one, two, or three optionally substituted heteroaryl groups.
• the (heteroaryl)alkyl group is a C 1-4 alkyl substituted with one optionally substituted heteroaryl group.
• Non-limiting exemplary (heteroaryl)alkyl groups include: , .
• alkylcarbonylamino refers to an alkylcarbonyl group attached to an amino.
• a non-limiting exemplary alkylcarbonylamino group is -NHCOCH 3 .
• C 1-4 bridge refers to a -CH 2 -, -(CH 2 ) 2 - , -(CH 2 ) 3 -, or -(CH 2 ) 4 - group that joins two carbon atoms of a piperidine to form an azabicyclo group.
• R 3a and R 4a of B can be taken together to form a 6-azabicyclo[3.1.1]heptane, 8-azabicyclo[3.2.1]octane, 9-azabicyclo[3.3.1]nonane, or 10-azabicyclo[4.3.1]decane group.
• Each methylene unit of the C 1-4 bridge can be optionally substituted with one or two substituents independently selected from the group consisting of C 1-4 alkyl and halo.
• the present disclosure encompasses any of the Compounds of the Disclosure being isotopically-labelled (i.e., radiolabeled) by having one or more atoms replaced by an atom having a different atomic mass or mass number.
• isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2 H (or deuterium (D)), 3 H, 1 1 C, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 Cl, respectively, e.g., 3 H, 11 C, and 14 C.
• compositions wherein substantially all of the atoms at a position within the Compound of the Disclosure are replaced by an atom having a different atomic mass or mass number.
• Isotopically-labelled Compounds of the Disclosure can be prepared by methods known in the art.
• Compounds of the Disclosure may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms.
• the present disclosure is meant to encompass the use of all such possible forms, as well as their racemic and resolved forms and mixtures thereof.
• the individual enantiomers can be separated according to methods known in the art in view of the present disclosure.
• the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that they include both E and Z geometric isomers. All tautomers are intended to be encompassed by the present disclosure as well.
• stereoisomers is a general term for all isomers of individual molecules that differ only in the orientation of their atoms in space. It includes enantiomers and isomers of compounds with more than one chiral center that are not mirror images of one another (diastereomers). [0200]
• chiral center or “asymmetric carbon atom” refers to a carbon atom to which four different groups are attached.
• enantiomer and “enantiomeric” refer to a molecule that cannot be superimposed on its mirror image and hence is optically active wherein the enantiomer rotates the plane of polarized light in one direction and its mirror image compound rotates the plane of polarized light in the opposite direction.
• racemic refers to a mixture of equal parts of enantiomers and which mixture is optically inactive.
• Compounds of the Disclosure are racemic.
• absolute configuration refers to the spatial arrangement of the atoms of a chiral molecular entity (or group) and its stereochemical description, e.g., R or S.
• enantiomeric excess refers to a measure for how much of one enantiomer is present compared to the other.
• the percent enantiomeric excess is defined as ([D] obs /[D] max )*100, where [D] obs is the optical rotation of the mixture of enantiomers and [D] max is the optical rotation of the pure enantiomer. Determination of enantiomeric excess is possible using a variety of analytical techniques, including NMR spectroscopy, chiral column chromatography or optical polarimetry.
• enantiomerically pure or “enantiopure” refer to a sample of a chiral substance all of whose molecules (within the limits of detection) have the same chirality sense.
• Compounds of the Disclosure are enantiomerically pure.
• enantiomerically enriched or “enantioenriched” refer to a sample of a chiral substance whose enantiomeric ratio is greater than 50:50.
• Compounds of the Disclosure are enantiomerically enriched, e.g., the enantiomeric ratio is about 60:40 or greater, about 70:30 or greater, about 80:20 or greater, about 90:10 or greater, about 95:5 or greater, about 98:2 or greater, or about 99:1 or greater.
• Enantiomerically enriched compounds may be enantiomerically pure.
• the present disclosure encompasses the preparation and use of salts of the Compounds of the Disclosure, including non-toxic pharmaceutically acceptable salts.
• pharmaceutically acceptable addition salts include inorganic and organic acid addition salts and basic salts.
• the pharmaceutically acceptable salts include, but are not limited to, metal salts such as sodium salt, potassium salt, cesium salt and the like; alkaline earth metals such as calcium salt, magnesium salt and the like; organic amine salts such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt and the like; inorganic acid salts such as hydrochloride, hydrobromide, phosphate, sulphate and the like; organic acid salts such as citrate, lactate, tartrate, maleate, fumarate, mandelate, acetate, dichloroacetate, trifluoroacetate, oxalate, formate and the
• pharmaceutically acceptable salt refers to any salt, e.g., obtained by reaction with an acid or a base, of a Compound of the Disclosure that is physiologically tolerated in the target patient (e.g., a mammal, e.g., a human).
• Acid addition salts can be formed by mixing a solution of the particular Compound of the Disclosure with a solution of a pharmaceutically acceptable non-toxic acid such as hydrochloric acid, fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid, oxalic acid, dichloroacetic acid, or the like.
• Basic salts can be formed by mixing a solution of the compound of the present disclosure with a solution of a pharmaceutically acceptable non-toxic base such as sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate and the like.
• solvates typically do not significantly alter the physiological activity or toxicity of the compounds, and as such may function as pharmacological equivalents.
• solvate as used herein is a combination, physical association and/or solvation of a compound of the present disclosure with a solvent molecule such as, e.g. a disolvate, monosolvate or hemisolvate, where the ratio of solvent molecule to compound of the present disclosure is about 2:1, about 1:1 or about 1:2, respectively.
• This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding.
• solvate can be isolated, such as when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid.
• solvate encompasses both solution-phase and isolatable solvates.
• Compounds of the Disclosure can be present as solvated forms with a pharmaceutically acceptable solvent, such as water, methanol, ethanol, and the like, and it is intended that the disclosure includes both solvated and unsolvated forms of Compounds of the Disclosure.
• a pharmaceutically acceptable solvent such as water, methanol, ethanol, and the like
• solvate is a hydrate.
• a "hydrate” relates to a particular subgroup of solvates where the solvent molecule is water.
• Solvates typically can function as pharmacological equivalents. Preparation of solvates is known in the art. See, for example, M.
• a typical, non-limiting, process of preparing a solvate would involve dissolving a Compound of the Disclosure in a desired solvent (organic, water, or a mixture thereof) at temperatures above 20°C to about 25°C, then cooling the solution at a rate sufficient to form crystals, and isolating the crystals by known methods, e.g., filtration.
• Analytical techniques such as infrared spectroscopy can be used to confirm the presence of the solvent in a crystal of the solvate.
• Compounds of the Disclosure are inhibitors of SMYD proteins, such as SMYD3 and SMYD2, a number of diseases, conditions, or disorders mediated by SMYD proteins, such as SMYD3 and SMYD2, can be treated by employing these compounds.
• the present disclosure is thus directed generally to a method for treating a disease, condition, or disorder responsive to the inhibition of SMYD proteins, such as SMYD3 and SMYD2, in an animal suffering from, or at risk of suffering from, the disorder, the method comprising administering to the animal an effective amount of one or more Compounds of the Disclosure.
• the present disclosure is further directed to a method of inhibiting SMYD proteins in an animal in need thereof, the method comprising administering to the animal a therapeutically effective amount of at least one Compound of the Disclosure.
• the present disclosure is further directed to a method of inhibiting SMYD3 in an animal in need thereof, the method comprising administering to the animal a therapeutically effective amount of at least one Compound of the Disclosure.
• the present disclosure is further directed to a method of inhibiting SMYD2 in an animal in need thereof, the method comprising administering to the animal a therapeutically effective amount of at least one Compound of the Disclosure.
• the terms “treat,” “treating,” “treatment,” and the like refer to eliminating, reducing, or ameliorating a disease or condition, and/or symptoms associated therewith. Although not precluded, treating a disease or condition does not require that the disease, condition, or symptoms associated therewith be completely eliminated.
• the terms “treat,” “treating,” “treatment,” and the like may include “prophylactic treatment,” which refers to reducing the probability of redeveloping a disease or condition, or of a recurrence of a previously-controlled disease or condition, in a subject who does not have, but is at risk of or is susceptible to, redeveloping a disease or condition or a recurrence of the disease or condition.
• the term “treat” and synonyms contemplate administering a therapeutically effective amount of a Compound of the Disclosure to an individual in need of such treatment.
• treatment also includes relapse prophylaxis or phase prophylaxis, as well as the treatment of acute or chronic signs, symptoms and/or malfunctions.
• the treatment can be orientated symptomatically, for example, to suppress symptoms. It can be effected over a short period, be oriented over a medium term, or can be a long-term treatment, for example within the context of a maintenance therapy.
• terapéuticaally effective amount refers to an amount of the active ingredient(s) that is(are) sufficient, when administered by a method of the disclosure, to efficaciously deliver the active ingredient(s) for the treatment of condition or disease of interest to an individual in need thereof.
• the therapeutically effective amount of the agent may reduce (i.e., retard to some extent and preferably stop) unwanted cellular proliferation; reduce the number of cancer cells; reduce the tumor size; inhibit (i.e., retard to some extent and preferably stop) cancer cell infiltration into peripheral organs; inhibit (i.e., retard to some extent and preferably stop) tumor metastasis; inhibit, to some extent, tumor growth; modulate protein methylation in the target cells; and/or relieve, to some extent, one or more of the symptoms associated with the cancer.
• the administered compound or composition prevents growth and/or kills existing cancer cells, it may be cytostatic and/or cytotoxic.
• the term "container” means any receptacle and closure therefore suitable for storing, shipping, dispensing, and/or handling a pharmaceutical product.
• insert means information accompanying a pharmaceutical product that provides a description of how to administer the product, along with the safety and efficacy data required to allow the physician, pharmacist, and patient to make an informed decision regarding use of the product.
• the package insert generally is regarded as the "label" for a pharmaceutical product.
• SMYD proteins such as SMYD3 and SMYD2
• SMYD3 and SMYD2 can be used in treating diseases and conditions such as proliferative diseases, wherein inhibition of SMYD proteins, such as SMYD3 and SMYD2 provides a benefit.
• the Compounds of the Disclosure can be used to treat a "SMYD protein mediated disorder" (e.g., a SMYD3-mediated disorder or a SMYD2-mediated disorder).
• a SMYD protein mediated disorder is any pathological condition in which a SMYD protein is know to play a role.
• a SMYD-mediated disorder is a proliferative disease.
• inhibiting SMYD proteins is the inhibition of the activity of one or more activities of SMYD proteins such as SMYD3 and SMYD2.
• the activity of the SMYD proteins such as SMYD3 and SMYD2 is the ability of the SMYD protein such as SMYD3 or SMYD2 to transfer a methyl group to a target protein (e.g., histone). It should be appreciated that the activity of the one or more SMYD proteins such as SMYD3 and SMYD2 may be inhibited in vitro or in vivo.
• Examplary levels of inhibition of the activity one or more SMYD proteins such as SMYD3 and SMYD2 include at least 10% inhibition, at least 20% inhibition, at least 30% inhibition, at least 40% inhibition, at least 50% inhibition, at least 60% inhibition, at least 70% inhibition, at least 80% inhibition, at least 90% inhibition, and up to 100% inhibition.
• the SMYD (SET and MYND domain) family of lysine methyltransferases (KMTs) plays pivotal roles in various cellular processes, including gene expression regulation and DNA damage response.
• the family of human SMYD proteins consists of SMYD1, SMYD2, SMYD3, SMYD4 and SMYD5.
• SMYD1, SMYD2, and SMYD3 share a high degree of sequence homology and, with the exception of SMYD5, human SMYD proteins harbor at least one C-terminal tetratrico peptide repeat (TPR) domain.
• TPR tetratrico peptide repeat
• SMYD3 is a protein methyltransferase found to be expressed at high levels in a number of different cancers (Hamamoto, R., et al., Nat. Cell Biol., 6(8):731-40 (2004)). SMYD3 likely plays a role in the regulation of gene transcription and signal transduction pathways critical for survival of breast, liver, prostate and lung cancer cell lines (Hamamoto, R., et al., Nat.
• RNAi-based technologies have shown that ablation of SMYD3 in hepatocellular carcinoma cell lines greatly reduces cell viability and that its pro-survival role is dependent on its catalytic activity (Hamamoto, R., et al., Nat. Cell Biol., 6(8):731-40 (2004); Van Aller, G.S., et al., Epigenetics, 7(4):340-3 (2012)).
• SMYD3 has also been shown to be a critical mediator of transformation resulting from gain of function mutations in the oncogene, KRAS for both pancreatic and lung adenocarcinoma in mouse models.
• SMYD3 function has also been shown to play a role in immunology and development. For instance, de Almeida reported that SMYD3 plays a role in generation of inducible regulatory T cells (iTreg) cells.
• iTreg inducible regulatory T cells
• SMYD3-/- mice demonstrated exacerbation of RSV- induced disease related to enhanced proinflammatory responses and worsened pathogenesis within the lung (de Almeida et al. Mucosal Immunol. 2015 Feb 11. doi: 10.1038/mi.2015.4. [Epub ahead of print]).
• SMYD2 (SET and MYND domain-containing protein 2) was first characterized as protein that is a member of a sub-family of SET domain containing proteins which catalyze the site-specific transfer of methyl groups onto substrate proteins.
• SMYD2 was initially shown to have methyltransferase activity towards lysine 36 on histone H3 (H3K36) but has subsequently been shown to have both histone and non-histone methyltrasferase activity.
• SMYD2 has been implicated in the pathogenesis of multiple cancers. It has been shown to be over-expressed, compared to matched normal samples, in tumors of the breast, cervix, colon, kidney, liver, head and neck, skin, pancreas, ovary, esophagus and prostate, as well as hematologic malignancies such as AML, B- and T-ALL, CLL and MCL, suggesting a role for SMYD2 in the biology of these cancers. More specifically, studies using genetic knock-down of SMYD2 have demonstrated anti-proliferative effects in esophageal squamous cell carcinoma (ESCC), bladder carcinoma and cervical carcinoma cell lines.
• ESCC esophageal squamous cell carcinoma
• SMYD2 has also been implicated in immunology. For instance, Xu et al. have shown that SMYD2 is a negative regulator of macrophage activation by suppressing Interleukin-6 and TNF-alpha production. (Xu et al., J Biol Chem. 2015 Feb 27;290(9):5414-23).
• the present disclosure provides a method of treating cancer in a patient comprising administering a therapeutically effective amount of a Compound of the Disclosure. While not being limited to a specific mechanism, in some embodiemtns, Compounds of the Disclorure can treat cancer by inhibiting SMYD proteins, such as SMYD3 and SMYD2.
• treatable cancers include, but are not limited to, adrenal cancer, acinic cell carcinoma, acoustic neuroma, acral lentigious melanoma, acrospiroma, acute eosinophilic leukemia, acute erythroid leukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, acute monocytic leukemia, acute promyelocytic leukemia, adenocarcinoma, adenoid cystic carcinoma, adenoma, adenomatoid odontogenic tumor, adenosquamous carcinoma, adipose tissue neoplasm, adrenocortical carcinoma, adult T-cell leukemia/lymphoma, aggressive NK-cell leukemia, AIDS-related lymphoma, alveolar rhabdomyosarcoma, alveolar soft part sarcoma, ameloblastic fibroma, anaplastic large cell
• the cancer is breast, cervix, colon, kidney, liver, head and neck, skin, pancreas, ovary, esophagus, or prostate cancer.
• the cancer is a hematologic malignancy such as acute myeloid leukemia (AML), B- and T-acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), or mantle cell lymphoma (MCL).
• AML acute myeloid leukemia
• ALL B- and T-acute lymphoblastic leukemia
• CLL chronic lymphocytic leukemia
• MCL mantle cell lymphoma
• the cancer is esophageal squamous cell carcinoma (ESCC), bladder carcinoma, or cervical carcinoma.
• ESCC esophageal squamous cell carcinoma
• bladder carcinoma esophageal squamous cell carcinoma
• cervical carcinoma esophageal squamous cell carcinoma
• the cancer is a leukemia, for example a leukemia selected from acute monocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia and mixed lineage leukemia (MLL).
• the cancer is NUT-midline carcinoma.
• the cancer is multiple myeloma.
• the cancer is a lung cancer such as small cell lung cancer (SCLC).
• SCLC small cell lung cancer
• the cancer is a neuroblastoma.
• the cancer is Burkitt's lymphoma.
• the cancer is cervical cancer.
• the cancer is esophageal cancer.
• the cancer is ovarian cancer.
• the cancer is colorectal cancer.
• the cancer is prostate cancer.
• the cancer is breast cancer.
• the present disclosure provides a therapeutic method of modulating protein methylation, gene expression, cell proliferation, cell differentiation and/or apoptosis in vivo in the cancers mentioned above by administering a therapeutically effective amount of a Compound of the Disclosure to a subject in need of such therapy.
• Compounds of the Disclosure can be administered to a mammal in the form of a raw chemical without any other components present.
• Compounds of the Disclosure can also be administered to a mammal as part of a pharmaceutical composition containing the compound combined with a suitable pharmaceutically acceptable carrier.
• a suitable pharmaceutically acceptable carrier can be selected from pharmaceutically acceptable excipients and auxiliaries.
• pharmaceutically acceptable carrier or “pharmaceutically acceptable vehicle” encompasses any of the standard pharmaceutical carriers, solvents, surfactants, or vehicles. Suitable pharmaceutically acceptable vehicles include aqueous vehicles and nonaqueous vehicles. Standard pharmaceutical carriers and their formulations are described in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 19th ed. 1995.
• compositions within the scope of the present disclosure include all compositions where a Compound of the Disclosure is combined with one or more pharmaceutically acceptable carriers.
• the Compound of the Disclosure is present in the composition in an amount that is effective to achieve its intended therapeutic purpose. While individual needs may vary, a determination of optimal ranges of effective amounts of each compound is within the skill of the art.
• a Compound of the Disclosure can be administered to a mammal, e.g., a human, orally at a dose of from about 0.0025 to about 1500 mg per kg body weight of the mammal, or an equivalent amount of a pharmaceutically acceptable salt or solvate thereof, per day to treat the particular disorder.
• a useful oral dose of a Compound of the Disclosure administered to a mammal is from about 0.0025 to about 50 mg per kg body weight of the mammal, or an equivalent amount of the pharmaceutically acceptable salt or solvate thereof.
• the dose is typically about one-half of the oral dose.
• a unit oral dose may comprise from about 0.01 mg to about 1 g of the Compound of the Disclosure, e.g., about 0.01 mg to about 500 mg, about 0.01 mg to about 250 mg, about 0.01 mg to about 100 mg, 0.01 mg to about 50 mg, e.g., about 0.1 mg to about 10 mg, of the compound.
• the unit dose can be administered one or more times daily, e.g., as one or more tablets or capsules, each containing from about 0.01 mg to about 1 g of the compound, or an equivalent amount of a pharmaceutically acceptable salt or solvate thereof.
• a pharmaceutical composition of the present disclosure can be administered to any patient that may experience the beneficial effects of a Compound of the Disclosure.
• mammals e.g., humans and companion animals, although the disclosure is not intended to be so limited.
• the patient is a human.
• a pharmaceutical composition of the present disclosure can be administered by any means that achieves its intended purpose.
• administration can be by the oral, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, intranasal, transmucosal, rectal, intravaginal or buccal route, or by inhalation.
• the dosage administered and route of administration will vary, depending upon the circumstances of the particular subject, and taking into account such factors as age, gender, health, and weight of the recipient, condition or disorder to be treated, kind of concurrent treatment, if any, frequency of treatment, and the nature of the effect desired.
• a pharmaceutical composition of the present disclosure can be administered orally.
• a pharmaceutical composition of the present disclosure can be administered orally and is formulated into tablets, dragees, capsules, or an oral liquid preparation.
• the oral formulation comprises extruded multiparticulates comprising the Compound of the Disclosure.
• a pharmaceutical composition of the present disclosure can be administered rectally, and is formulated in suppositories.
• composition of the present disclosure can be administered by injection.
• composition of the present disclosure can be administered transdermally.
• composition of the present disclosure can be administered by inhalation or by intranasal or transmucosal administration.
• composition of the present disclosure can be administered by the intravaginal route.
• a pharmaceutical composition of the present disclosure can contain from about 0.01 to 99 percent by weight, e.g., from about 0.25 to 75 percent by weight, of a Compound of the Disclosure, e.g., about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, or about 75% by weight of a Compound of the Disclosure.
• a Compound of the Disclosure e.g., about 1%, about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, or about 75% by weight of a Compound of the Disclosure.
• a pharmaceutical composition of the present disclosure is manufactured in a manner which itself will be known in view of the instant disclosure, for example, by means of conventional mixing, granulating, dragee-making, dissolving, extrusion, or lyophilizing processes.
• pharmaceutical compositions for oral use can be obtained by combining the active compound with solid excipients, optionally grinding the resulting mixture and processing the mixture of granules, after adding suitable auxiliaries, if desired or necessary, to obtain tablets or dragee cores.
• Suitable excipients include fillers such as saccharides (for example, lactose, sucrose, mannitol or sorbitol), cellulose preparations, calcium phosphates (for example, tricalcium phosphate or calcium hydrogen phosphate), as well as binders such as starch paste (using, for example, maize starch, wheat starch, rice starch, or potato starch), gelatin, tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and/or polyvinyl pyrrolidone.
• saccharides for example, lactose, sucrose, mannitol or sorbitol
• cellulose preparations for example, calcium phosphates (for example, tricalcium phosphate or calcium hydrogen phosphate)
• binders such as starch paste (using, for example, maize starch, wheat starch, rice starch, or potato starch), gelatin, tragacanth, methyl cellulose, hydroxypropylmethyl
• one or more disintegrating agents can be added, such as the above-mentioned starches and also carboxymethyl-starch, cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate.
• Auxiliaries are typically flow-regulating agents and lubricants such as, for example, silica, talc, stearic acid or salts thereof (e.g., magnesium stearate or calcium stearate), and polyethylene glycol.
• Dragee cores are provided with suitable coatings that are resistant to gastric juices.
• concentrated saccharide solutions can be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures.
• cellulose preparations such as acetylcellulose phthalate or hydroxypropylmethyl-cellulose phthalate
• Dye stuffs or pigments can be added to the tablets or dragee coatings, for example, for identification or in order to characterize combinations of active compound doses.
• Examples of other pharmaceutical preparations that can be used orally include push-fit capsules made of gelatin, or soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol.
• the push-fit capsules can contain a compound in the form of granules, which can be mixed with fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers, or in the form of extruded multiparticulates.
• the active compounds are preferably dissolved or suspended in suitable liquids, such as fatty oils or liquid paraffin.
• stabilizers can be added.
• Possible pharmaceutical preparations for rectal administration include, for example, suppositories, which consist of a combination of one or more active compounds with a suppository base.
• Suitable suppository bases include natural and synthetic triglycerides, and paraffin hydrocarbons, among others. It is also possible to use gelatin rectal capsules consisting of a combination of active compound with a base material such as, for example, a liquid triglyceride, polyethylene glycol, or paraffin hydrocarbon.
• Suitable formulations for parenteral administration include aqueous solutions of the active compound in a water-soluble form such as, for example, a water-soluble salt, alkaline solution, or acidic solution.
• a suspension of the active compound can be prepared as an oily suspension.
• Suitable lipophilic solvents or vehicles for such as suspension may include fatty oils (for example, sesame oil), synthetic fatty acid esters (for example, ethyl oleate), triglycerides, or a polyethylene glycol such as polyethylene glycol-400 (PEG-400).
• An aqueous suspension may contain one or more substances to increase the viscosity of the suspension, including, for example, sodium carboxymethyl cellulose, sorbitol, and/or dextran.
• the suspension may optionally contain stabilizers.
• kits which comprise a Compound of the Disclosure (or a composition comprising a Compound of the Disclosure) packaged in a manner that facilitates their use to practice methods of the present disclosure.
• the kit includes a Compound of the Disclosure (or a composition comprising a Compound of the Disclosure) packaged in a container, such as a sealed bottle or vessel, with a label affixed to the container or included in the kit that describes use of the compound or composition to practice the method of the disclosure.
• the compound or composition is packaged in a unit dosage form.
• the kit further can include a device suitable for administering the composition according to the intended route of administration.
• a suitable sulfonyl chloride Z-SO 2 Cl
• a suitable acide chloride Z-COCl
• a suitable base such as TEA or DIPEA
• a suitable solvent such as dichloromethane, acetonitrile, or DMF
• a suitable coupling reagent such as HATU and a suitable base such as TEA or DIPEA
• a suitable solvent such as dichloromethane, acetonitrile, or DMF.
• Step 1 Synthesis of ethyl 4-cyclopropyl-2,4-dioxobutanoate
• Step 2 Synthesis of ethyl 5-cyclopropylisoxazole-3-carboxylate
• Step 2 Synthesis of (2S)-tert-butyl 4-(5-cyclopropylisoxazole-3-carboxamido)-2- methylpiperidine-1-carboxylate
• Step 3 Synthesis of tert-butyl (2S,4S)-4-(5-cyclopropyl-1,2-oxazole-3-amido)-2- methylpiperidine-1-carboxylate and tert-butyl (2S,4R)-4-(5-cyclopropyl-1,2-oxazole-3- amido)-2-methylpiperidine-1-carboxylate
• Step 4 Synthesis of 5-cyclopropyl-N-((2S,4S)-2-methylpiperidin-4-yl)isoxazole- 3-carboxamide hydrochloride and 5-cyclopropyl-N-((2S,4R)-2-methylpiperidin-4- yl)isoxazole-3-carboxamide hydrochloride
• Step 2 Synthesis of (2R,4R)-tert-butyl 4-(5-cyclopropylisoxazole-3- carboxamido)-2-methylpiperidine-1-carboxylate and (2R,4S)-tert-butyl 4-(5- cyclopropylisoxazole-3-carboxamido -2-meth l i eridine-1-carbox late
• Prep-SFC 350 Column, CHIRALPAK AD-H SFC, 5x25cm,5um; mobile phase, CO 2 (50%), methanol(50%); Detector, uv 220nm. This was resulted in 7.48 g (54%) of tert-butyl (2R,4R)-4-(5-cyclopropyl-1,2-oxazole-3-amido)-2-methylpiperidine-1-carboxylate as light yellow oil.
• Step 3 Synthesis of 5-cyclopropyl-N-((2R,4R)-2-methylpiperidin-4- yl)isoxazole-3-carboxamide h drochloride
• Step 4 Synthesis of 5-cyclopropyl-N-((2R,4S)-2-methylpiperidin-4-yl)isoxazole- 3-carboxamide hydrochloride
• Step 1 Synthesis of tert-butyl 4-amino-2-benzylpiperidine-1-carboxylate
• the resulting mixture was concentrated under vacuum.
• the resulting solution was diluted with 200 mL of EA.
• the resulting mixture was washed with 3x200 mL of brine (sat.).
• the organic phase was collected and dried over anhydrous sodium sulfate and concentrated under vacuum.
• the residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10). The collected fractions were combined and concentrated under vacuum.
• the trans mixture was purified by Prep-SFC with the following conditions (prep SFC 350): Column, Phenomenex Lux 5u Cellulose-4250*50mm00G-4491-V0- AX664184-1; mobile phase, CO 2 (50%) and MeOH(50%) ,Detector, uv 220 nm.
• Step 3 Synthesis of N-((2R,4R)-2-benzylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide h drochloride
• Step 1 Synthesis of (1R,5S,E)-tert-butyl 3-(hydroxyimino)-9- azabicyclo[3.3.1]nonane-9-carboxylate
• Step 2 Synthesis of (1R,3s,5S)-tert-butyl 3-amino-9-azabicyclo[3.3.1]nonane-9- carboxylate and (1R,3r,5S)-tert-butyl 3-amino-9-azabicyclo[3.3.1]nonane-9-carboxylate
• Step 3 Synthesis of (1R,3s,5S)-tert-butyl 3-(5-cyclopropylisoxazole-3- carboxamido)-9-azabicyclo[3.3.1]nonane-9-carboxylate and (1R,3r,5S)-tert-butyl 3-(5- cyclopropylisoxazole-3-carboxamido)-9-azabicyclo[3.3.1]nonane-9-carboxylate
• the resulting solution was stirred for 3 h at room temperature.
• the resulting solution was diluted with 400 mL of DCM.
• the resulting mixture was washed with 2x400 mL of H 2 O.
• the residue was purified on a silica gel column with dichloromethane/methanol (20:1).
• Step 4 Synthesis of (1R,3s,5S)-tert-butyl 3-(5-cyclopropylisoxazole-3- carboxamido)-9-azabicyclo[3.3.1]nonane-9-carboxylate and (1R,3r,5S)-tert-butyl 3-(5- cyclopropylisoxazole-3-carboxamido)-9-azabicyclo[3.3.1]nonane-9-carboxylate
• Step 5 Synthesis of N-((1R,3r,5S)-9-azabicyclo[3.3.1]nonan-3-yl)-5- cyclopropylisoxazole-3-carboxamide
• Step 6 Synthesis of N-((1R,3s,5S)-9-azabicyclo[3.3.1]nonan-3-yl)-5- cyclopropylisoxazole-3-carboxamide
• (1R,3s,5S)-tert-butyl 3-(5- cyclopropylisoxazole-3-carboxamido)-9-azabicyclo[3.3.1]nonane-9-carboxylate 8.0 g, 21.25 mmol, 1.00 equiv
• dichloromethane 100 mL
• Step 1 Synthesis of tert-butyl 3-amino-8-azabicyclo[3.2.1]octane-8-carboxylate [0291] Into a 2000-mL 3-necked round-bottom flask was placed HCOONH 4 (42 g, 666.03 mmol, 30.00 equiv), acetic acid (1.3 g, 21.65 mmol, 1.00 equiv) and methanol (1.5 L). Then NaBH 3 CN (2.8 g, 44.56mmol, 2.00 equiv) was added into batch wise.
• Step 2 Synthesis of tert-butyl (1R,3r,5S)-3-(5-cyclopropyl-1,2-oxazole-3- amido)-8-azabicyclo[3.2.1]octane-8-carboxylate and tert-butyl (1R,3s,5S)-3-(5- cyclopropyl-1,2-oxazole-3-amido)-8-azabicyclo[3.2.1]octane-8-carboxylate
• Step 3 Sytnthesis of N-((1R,3r,5S)-8-aza-bicyclo[3.2.1]octan-3-yl)-5- cyclopropylisoxazole-3-carboxamide hydrochloride and N-((1R,3s,5S)-8-aza- bicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamide hydrochloride
• Step 1 Synthesis of ethyl (2E)-2-cyano-3-(4-hydroxyphenyl)prop-2-enoate
• Step 2 Synthesis of ethyl 3-[[(tert-butoxy)carbonyl]amino]-2-[(4- hydroxyphenyl)methyl] propanoate
• Step 3 Synthesis of ethyl 3-[[(tert-butoxy)carbonyl]amino]-2-[(4-hydroxy-3- iodophenyl)methyl]propanoate
• Step 4 Synthesis of ethyl 3-[[(tert-butoxy)carbonyl]amino]-2-[[4-hydroxy-3- (prop-1-en-2-yl)phenyl]methyl]propanoate
• the resulting solution was stirred overnight at 100 o C.
• the resulting solution was diluted with 40 mL of NH 4 Cl (sat. aq.).
• the resulting solution was extracted with 4x40 mL of ethyl acetate and the organic layers combined.
• the resulting mixture was washed with 4x50 mL of NH 4 Cl (sat. aq.).
• the resulting mixture was concentrated under vacuum.
• the residue was purified on a silica gel column with ethyl acetate/petroleum ether (1:5).
• Step 5 Synthesis of ethyl 3-[[(tert-butoxy)carbonyl]amino]-2-[[4-hydroxy-3- (propan-yl)phenyl]methyl]propanoate
• Step 6 Synthesis of 3-[[(tert-butoxy)carbonyl]amino]-2-[[4-hydroxy-3-(propan- 2-yl)phenyl]methyl]propanoic acid
• Step 7 Synthesis of tert-butyl N-[3-[4-(5-cyclopropyl-1,2-oxazole-3- amido)piperidin-1-yl]-2-[[4-hydroxy-3-(propan-2-yl)phenyl]methyl]-3- oxopropyl]carbamate
• Step 8 Synthesis of tert-butyl N-[(2S)-3-[4-(5-cyclopropyl-1,2-oxazole-3- amido)piperidin-1-yl]-2-[[4-hydroxy-3-(propan-2-yl)phenyl]methyl]-3- oxopropyl]carbamate
• Step 9 Synthesis of N-[1-[(2S)-3-Amino-2-[[4-hydroxy-3-(propan-2- yl)phenyl]methyl] propanoyl]piperidin-4-yl]-5-cyclopropyl-1,2-oxazole-3-carboxamide hydrochloride salt
• Step 1 Synthesis of tert-butyl 2,5-dimethylpyridin-4-ylcarbamate
• Step 2 Synthesis of tert-butyl 2,5-dimethylpiperidin-4-ylcarbamate
• Step 3 Synthesis of tert-butyl 1-((1R,4R)-4-(1,3-dioxoisoindolin-2- yl)cyclohexanecarbonyl) -2,5-dimethylpiperidin-4-ylcarbamate
• Step 4 Synthesis of 2-((1R,4R)-4-(4-Amino-2,5-dimethylpiperidine-1- carbonyl)cyclohexyl) isoindoline-1,3-dione h drochloride
• Step 5 Synthesis of 5-Cyclopropyl-N-(1-((1R,4R)-4-(1,3-dioxoisoindolin-2- yl)cyclohexanecarbonyl)-2,5-dimethylpiperidin-4-yl)isoxazole-3-carboxamide
• Step 7 Synthesis of N-((2R,4S,5R)-1-((1r,4R)-4-Aminocyclohexanecarbonyl)- 2,5-dimethylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide
• Step 1 Synthesis of tert-butyl 4-amino-3-methylpiperidine-1-carboxylate
• Step 2 Synthesis of tert-butyl 4-(5-cyclopropylisoxazole-3-carboxamido)-3- methylpiperidine-1-carboxylate
• the resulting solution was diluted with 50 mL of H 2 O.
• the resulting solution was extracted with 3x50 mL of ethyl acetate and the organic layers combined.
• the resulting mixture was washed with 3x150 mL of brine (sat.).
• the mixture was dried over anhydrous sodium sulfate.
• the residue was purified on a silica gel column with ethyl acetate/petroleum ether (1/5). This resulted in 6 g (52%) of tert-butyl 4-(5-cyclopropylisoxazole-3-carboxamido)-3- methylpiperidine-1-carboxylateas yellow solid.
• Step 3 Synthesis of (3S,4R)-tert-butyl 4-(5-cyclopropylisoxazole-3- carboxamido)-3-methylpi eridine-1-carbox late
• Step 4 Synthesis of 5-cyclopropyl-N-((3S,4R)-3-methylpiperidin-4-yl)isoxazole- 3-carboxamide
• Step 5 Synthesis of 5-cyclopropyl-N-((3S,4R)-1-(3-(1,3-dioxoisoindolin-2- yl)propylsulfonyl)-3-meth l i eridin-4- l isoxazole-3-carboxamide
• Step 6 Synthesis of N-((3S,4R)-1-(3-aminopropylsulfonyl)-3-methylpiperidin-4- yl)-5-cyclopropylisoxazole-3-carboxamide
• the crude product (100 mg) was purified by Prep-HPLC with the following conditions : Column: X Bridge C18, 19*150 mm, 5 um; Mobile Phase A:Water/NH 4 HCO 3 10mmol, Mobile Phase B: ACN; Flow rate: 30 mL/min; Gradient: 30%B to 85%B in 10 min; Detector,254nm This resulted in 66.4 mg (30%) of N-[(3R,4S)-1-[(3- aminopropane)sulfonyl]-3-methylpiperidin-4-yl]-5-cyclopropyl-1,2-oxazole-3- carboxamide as a white solid.
• Step 1 Synthesis of 5-cyclopropyl-N-(9-[[3-(1,3-dioxo-2,3-dihydro-1H-isoindol- 2-yl)propane]sulfonyl]-9-azabicyclo[3.3.1]nonan-3-yl)-1,2-oxazole-3-carboxamide
• Step 2 Synthesis of N-[9-[(3-aminopropane)sulfonyl]-9-azabicyclo[3.3.1]nonan- 3-yl]-5-cyclopropyl-1,2-oxazole-3-carboxamide hydrochloride salt
• Step 1 Synthesis of tert-butyl 4-[2-[(2S,4S)-2-benzyl-4-(5-cyclopropyl-1,2- oxazole-3-amido)pi eridin-1- l -2-oxoeth l i eridine-1-carbox late
• Step 2 Synthesis of N-((2S,4S)-2-benzyl-1-(2-(piperidin-4-yl)acetyl)piperidin-4- yl)-5-cyclopropylisoxazole-3-carboxamide hydrochloride
• Step 1 Synthesis of N-((1R,3r,5S)-8-(3-chloropropylsulfonyl)-8-aza- bicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamide
• Step 2 Synthesis of 5-cyclopropyl-N-((1S,3r,5R)-8-(3-(1,3-dioxoisoindolin-2- yl)propylsulfonyl)-8-aza-bicyclo[3.2.1]octan-3-yl)isoxazole-3-carboxamide
• Step 3 Synthesis of N-((1S,3r,5R)-8-(3-aminopropylsulfonyl)-8-aza- bicyclo[3.2.1]octan-3-yl)-5-cyclopropylisoxazole-3-carboxamide
• Step 1 Synthesis of 5-cyclopropyl-N-((1R,3s,5S)-8-(vinylsulfonyl)-8- azabicyclo[3.2.1]octan-3-yl)isoxazole-3-carboxamide
• Step 2 Synthesis of 5-cyclopropyl-N-((1R,3s,5S)-8-((2-(pyrrolidin-1- yl)ethyl)sulfonyl)-8-azabicyclo 3.2.1 octan-3- l isoxazole-3-carboxamide
• the crude product (89mg) was purified by Prep-HPLC with the following conditions(1#- Waters 2767-1): Column, X-bridge Prep phenyl 5um,19*150mmh Prep C012(T)186003581138241113.01; mobile phase, Phase A:water with 0.5% NH 4 HCO 3 ,Phase B:CH 3 CN .Water with 0.5% NH 4 HCO 3 and CH 3 CN (80% CH 3 CN up to 95% in 13 min ,hold 95% in 1min ,down to 80% in 1 min); Detector, uv254nm.
• Step 3 Synthesis of (2S,4S)-tert-butyl 4-(5-cyclopropylisoxazole-3- carboxamido)-2-methylpiperidine-1-carboxylate
• the diastereomeric product was further purified by Chiral-HPLC with the following conditions: Column name: CHIRALPAK AD-H, 4.6*150mm,5um,Co-Solvent: EtOH(0.1%DEA), %Co-Solvent: Hexane,25.000, Detector: 220nm.
• the resulting solution was concentrated under vacuum. This resulted in 9.8 g (70%) of tert-butyl (2S,4S)-4-(5-cyclopropyl-1,2-oxazole-3-amido)-2-methylpiperidine-1-carboxylate as colorless oil.
• Step 4 Synthesis of 5-cyclopropyl-N-((2S,4S)-2-methylpiperidin-4-yl)isoxazole- 3-carboxamide hydrochloride
• Step 5 Synthesis of N-((2S,4S)-1-(3-chloropropylsulfonyl)-2-methylpiperidin-4- yl)-5-cyclopropylisoxazole-3-carboxamide
• Step 6 Synthesis of N-((2S,4S)-1-(3-(benzylamino)propylsulfonyl)-2- methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide
• Step 1 Synthesis of N-((2S,4S)-1-(6-chloropyridin-3-ylsulfonyl)-2- methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide
• Step 2 Synthesis of 5-cyclopropyl-N-((2S,4S)-2-methyl-1-(6-(2- morpholinoethylamino) pyridin-3-ylsulfonyl)piperidin-4-yl)isoxazole-3-carboxamide dihydrochloride
• Step 1 Synthesis of tert-butyl 4-(5-cyclopropyl-1,2-oxazole-3-amido)-2- methylpiperidine-1-carboxylate
• Step 2 Synthesis of 5-cyclopropyl-N-(2-methylpiperidin-4-yl)-1,2-oxazole-3- carboxamide hydrochloride
• a solution of tert-butyl 4-(5-cyclopropyl-1,2-oxazole-3-amido)-2- methylpiperidine-1-carboxylate (1.55 g, 4.44 mmol) in DCM (50ml) was treated with 4M HCl in dioxane (15 ml) at rt for ⁇ 4h.
• LCMS analysis showed complete reaction. The solvent was evaporated to dryness to yield 1.12 g (88%) of the amine as HCl salt as a white solid.
• Step 3 Synthesis of benzyl 4-( ⁇ [4-(5-cyclopropyl-1,2-oxazole-3-amido)-2- methylpiperidin-1-yl]sulfonyl ⁇ methyl)piperidine-1-carboxylate
• Step 4 Synthesis of 5-cyclopropyl-N-[2-methyl-1-(piperidin-4- ylmethanesulfonyl) piperidin-4-yl]-1,2-oxazole-3-carboxamide
• Step 5 Chiral separation of 5-cyclopropyl-N-[2-methyl-1-(piperidin-4- ylmethanesulfon l i eridin-4- l -1,2-oxazole-3-carboxamide
• Step 1 Synthesis of benzyl 4-(((1S,3r,5R)-3-(5-cyclopropylisoxazole-3- carboxamido)-8-aza-bicyclo[3.2.1]octan-8-ylsulfonyl)methyl)piperidine-1-carboxylate
• Step 2 Synthesis of 5-cyclopropyl-N-((1R, 3rR, 5S)-8-(piperidin-4- ylmethylsulfonyl)-8-aza-bicyclo [3.2.1] octan-3-yl) isoxazole-3-carboxamide
• Step 2 Synthesis of 5-cyclopropyl-N-[(2S,4S)-1-[1,4-dioxa-8- azaspiro[4.5]decane-8-sulfon l -2-meth l i eridin-4- l -1,2-oxazole-3-carboxamide O N O
• Step 3 Synthesis of 5-cyclopropyl-N-((2S,4S)-2-methyl-1-(4-oxopiperidin-1- ylsulfonyl)piperidin-4-yl isoxazole-3-carboxamide
• Step 4 Synthesis of N-((2S,4S)-1-(4-aminopiperidin-1-ylsulfonyl)-2- methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide trifluoroacetic acid
• Step 1 Synthesis of N-((2S,4S)-1-(4-bromophenylsulfonyl)-2-methylpiperidin-4- yl)-5-cyclopropylisoxazole-3-carboxamide
• Step 2 Synthesis of 5-cyclopropyl-N-((2S,4S)-2-methyl-1-(4-(prop-1-en-2- yl)phenylsulfonyl)piperidin-4- l isoxazole-3-carboxamide
• the resulting solution was stirred at 90 o C overnight.
• the reaction mixture was diluted with 10 mL of H 2 O andextracted with 3x50 mL of ethyl acetate.
• Theorganic layers were combined and dried over anhydrous sodium sulfate and concentrated under vacuum.
• the residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (1:10-1:2).
• Step 3 Synthesis of N-((2S,4S)-1-(4-(2-(2-chloroacetamido)propan-2- yl)phenylsulfonyl)-2-methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide
• the reaction mixture was diluted with of ice-water and the pH of the solution was adjusted to 7 with sodium carbonate (sat. aq.).
• the resulting solution was extracted with 3x50 mL of dichloromethane and the organic layers combined and dried over anhydrous sodium sulfate.
• the residue was chromatographed on a silica gel column with dichloromethane/methanol (20:1). This resulted in 580 mg (99%) of N-((2S,4S)-1-(4-(2- (2-chloroacetamido)propan-2-yl)phenylsulfonyl)-2-methylpiperidin-4-yl)-5- cyclopropylisoxazole-3-carboxamide as a white solid.
• Step 4 Synthesis of N-((2S,4S)-1-(4-(2-aminopropan-2-yl)phenylsulfonyl)-2- methylpiperidin-4-yl)-5-cyclopropylisoxazole-3-carboxamide
• Step 1 Synthesis of (2S,4S)-4-(5-cyclopropylisoxazole-3-carboxamido)-2- methylpiperidine-1-sulfonyl chloride
• Step 2 Synthesis of tert-butyl 8-((2S,4S)-4-(5-cyclopropylisoxazole-3- carboxamido)-2-methylpiperidin-1-ylsulfonyl)-3,8-diaza-bicyclo[3.2.1]octane-3- carboxylate
• Step 3 Synthesis of 5-cyclopropyl-N-[(2S,4S)-1-[3,8-diazabicyclo[3.2.1]octane- 8-sulfonyl]-2-methylpiperidin-4-yl]-1,2-oxazole-3-carboxamide
• Step 1 Synthesis of 5-cyclopropyl-N-((1R,3r,5S)-8-(4-oxocyclohexylsulfonyl)- 8-aza-bicyclo[3.2.1]octan-3-yl)isoxazole-3-carboxamide

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