EP4698518A1 - New alpha4beta7 inhibitors - Google Patents

New alpha4beta7 inhibitors

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Publication number
EP4698518A1
EP4698518A1 EP24717727.2A EP24717727A EP4698518A1 EP 4698518 A1 EP4698518 A1 EP 4698518A1 EP 24717727 A EP24717727 A EP 24717727A EP 4698518 A1 EP4698518 A1 EP 4698518A1
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Prior art keywords
compound
pharmaceutically acceptable
alkyl
acceptable salt
substituted
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EP24717727.2A
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German (de)
French (fr)
Inventor
Maicol BISSARO
Gian Filippo Ruda
Mohamad SABBAH
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Evotec International GmbH
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Evotec International GmbH
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Publication of EP4698518A1 publication Critical patent/EP4698518A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D413/06—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 carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

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  • Chemical & Material Sciences (AREA)
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  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Rheumatology (AREA)
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Abstract

Novel compounds that act as inhibitors of α4β7 integrins are disclosed. Pharmaceutical compositions and methods of use for inhibitors of α4β7 integrins are disclosed. In particular, methods of using the α4β7 inhibtors in the treatment of diseases or conditions associated to inflammatory bowel diseases including ulcerative colitis and Crohn's disease.

Description

Evotec International GmbH
NEW a4p7 INHIBITORS
FIELD OF THE INVENTION
The present disclosure relates to novel compounds that act as inhibitors to integrins, in particular c ? integrins. Additionally, the present disclosure relates to pharmaceutical compositions and methods of using c ? inhibitors in the treatment of diseases or conditions associated to inflammatory bowel diseases including ulcerative colitis and Crohn’s disease.
BACKGROUND OF THE INVENTION
Integrins are involved in numerous cellular processes including cell-cell and cell- extracellular matrix interactions. Upon binding of an extracellular ligand, integrins mediate signal transduction to the cell interior resulting in lymphocyte cell capture, adhesion, and infiltration into the tissue. In fact, integrins are heterodimeric cell surface glycoprotein receptors, composed of non-covalently associated a (alpha) and (beta) subunits.
24 human integrins have been identified using molecular biology and protein chemistry and it is known that they contribute to a diverse set of human diseases, including platelet disorders, atherosclerosis, cancer, osteoporosis, fibrosis, diabetic neuropathy of the kidney, macular degeneration and autoimmune and chronic inflammation diseases.
The a4 integrins, O4 i and O4 ?, play essential roles in lymphocyte migration on most leukocytes, including B and T lymphocytes. O4 i and O4 ? integrin specific adhesion to VCAM-1 (vascular cell adhesion molecule 1) and MAdCAM-1 (mucosal addressing cell adhesion molecule 1) respectively. MAdCAM-1 is an immunoglobulin superfamily adhesion receptor for lymphocytes and is a selective ligand for O4 ? receptor. The MAdCAM-1 is involved in the selective homing of lymphocytes to normal mucosal tissues. In humans, MAdCAM-1 expression has been associated with lymphoid tissues of the gastrointestinal tract and associated lymphoid tissues. The lymphocyte integrin c ? has been shown to mediate memory T cell adhesion to MAdCAM-1. During inflammation, MAdCAM-1 is upregulated in the gut and is believed to play an important role in inflammatory bowel diseases (IBDs), a group of diseases such as ulcerative colitis (UC) and Crohn’s disease (CD). Inhibiting the interactions of integrins with their respective ligands has been proposed as an effective method for treating a variety of autoimmune and inflammatory disease, and blocking the AdCAM-1 interaction has shown therapeutic benefit in inflammatory bowel diseases, such as ulcerative colitis and Crohn’s disease (Hao Li et al., c ? integrin inhibitors: a patent review (2018), Vol. 28, No. 12, 903-917). Currently there are injectable monoclonal antibodies on the market as integrin inhibitors, see for example Natalizumab (Tysabri®) approved for the treatment of highly active relapsing and remitting multiple sclerosis, or Vedolizumab (Entyvio®) approved for both Crohn’s disease and ulcerative colitis. However, orally bioavailable integrin inhibitors are not yet approved.
Thus, there is the need to provide integrin inhibitors, preferably c Py-selective inhibitors useful for the prevention and/or treatment of diseases characterized by MAdCAM-1 upregulation, such as inflammatory bowel diseases.
The present invention relates to compounds of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R1 to R6, Rx and Y are defined herein below.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein:
Rx is hydrogen or methyl;
R1 is -SO2-Ci-6alkyl or -C(O)-R7; wherein R7 is -Ci-ealkyl , substituted with 0 or 1 substituents selected from pyridine, phenyl and cyclopropyl; or R7 is phenyl or a 5-10 membered heterocyclyl each of which is independently substituted with 0, 1 , 2 or 3 instances of R9; each R9 is independently selected from halogen, =0, -Ci-ealkyl, -C(O)- R10, -Ci-ehaloalkyl, -SO2-Ci-6alkyl, -NH-Ci-4alkyl, -N(Ci-4alkyl)2, -C3. ecycloalkyl, -O-R11, phenyl and 4-10 membered heterocycle; and each of R9 is independently substituted with 0, 1 , 2 or 3 instances of R17; R17 is selected from halogen, -Ci-ealkyl, -O-R15, -C(O)-N(Ci-4alkyl)2, - N(R12R13), 4 to 10 membered heterocycle, when R17 is heterocycle, it is further substituted with 0, 1 or 2 groups independently selected from halogen, -Ci-ealkyl, =0, -C(O)-R14, -Ci-ehaloalkyl, -SO2-Ci-6alkyl, -NH- Ci-4alkyl, -N(Ci-4alkyl)2, -Cs-ecycloalkyl, -O-R18;
R10 is independently selected from -Ci-ealkyl, -Ci-ealkyl-Cs- ecycloalkyl and Cs-ecycloalkyl;
R11 is a -C1-6 alkyl, - Ci-ehaloalkyl or 4 to 10 membered heterocycle or -Ci-6 alkyl-N(Ci-6 alkyl)2, and wherein the 4 to 10 membered heterocycle is substituted with 0 or 1 -C1-6 alkyl;
R12 and R13 are independently selected from -Ci-ealkyl, -Ci- ehaloalkyl and cyclopropyl;
R14 is independently selected from -Ci-ealkyl and Cs-ecycloalkyl;
R15 is a -C1-6 alkyl, - Ci-ehaloalkyl, -Ci-e alkyl-N(Ci-e alkyl)2 or 4 to 10 membered heterocycle, when R15 is 4 to 10 membered heterocycle it is substituted with 0 or 1 -Ci-ealkyl;
R18 is a -C1-6 alkyl or -Ci-ehaloalkyl; wherein in each -N(Ci-e alkyl)2 or -N(Ci-4alkyl)2 the two alkyl groups attached to N can be the same or different; or R7 is -NHR19, and R19 is a 4-10 membered heterocycle substituted with 0 or 1 -Ci-e alkyl;
R2 is selected from the group consisting of Br, phenyl, naphthyl, and 5-10 membered heteroaryl, each of which groups can be independently substituted with 0, 1 , 2 or 3 groups independently selected from -CN, -Ci-e alkyl, halogen, -Ci- ehaloalkyl, -O-C1-6 alkyl, phenyl, 5 to 6 membered heteroaryl, -O-Cs-ecycloalkyl, -O- phenyl, and -O-(5 to 6 membered heterocycloalkyl);
Y is -N= or -C(R3)=;
R3 is halogen, -Ci-ehaloalkyl , -C i-4alkyl, -Cs-ecycloalkyl;
R4 is halogen or hydrogen;
R5 is halogen or hydrogen; R6 is -C(O)-O-R8, wherein R8 is hydrogen or -Ci-4alkyl, -Ci-4alkyl-O-C(O)-R16
R16 is -Ci-ealkyl, 3 to 6 cycloalkyl, 4 to 6 membered partially saturated heterocycle, wherein the partially saturated heterocycle is further substituted with one or two groups independently selected from =0 or -Ci- 4alkyl.
In one embodiment, the invention relates to compounds of formula (I), wherein Rx is hydrogen.
In another embodiment, the invention relates to compounds of formula (la) wherein R1 to R6, Rx and Y are as defined herein.
In some embodiments of the compounds of the invention, or a pharmaceutically acceptable salt thereof, R2 is phenyl or 5-10 membered heteroaryl, each of which group is substituted with 1 , 2 or 3 groups independently selected from -CN, -C1-6 alkyl, halogen, -C1- ehaloalkyl.
In some embodiments of the compounds of the invention, or a pharmaceutically acceptable salt thereof, R2 is substituted with 1 , 2 or 3 groups independently selected from -CN, -C1-6 alkyl, halogen, -Ci-ehaloalkyl and R2 is selected from
In some embodiments of the compounds of the invention, or a pharmaceutically acceptable salt thereof, R2 is substituted with 1 , 2 or 3 groups independently selected from methyl, fluorine or -CF3 and is selected from
In some embodiments of the compounds of the invention, or a pharmaceutically acceptable salt thereof, Y is -C(R3)=.
In some embodiments of the compounds of the invention, or a pharmaceutically acceptable salt thereof, R3 is halogen, -CF3, methyl, ethyl, cyclopropyl.
In some embodiments of the compounds of the invention, or a pharmaceutically acceptable salt thereof, Y is is -N=.
In some embodiments of the compounds of the invention, or a pharmaceutically acceptable salt thereof, R4 is halogen or hydrogen.
In some embodiments of the compounds of the invention, or a pharmaceutically acceptable salt thereof, R4 is halogen.
In some embodiments of the compounds of the invention, or a pharmaceutically acceptable salt thereof, R4 is fluorine.
In some embodiments of the compounds of the invention, or a pharmaceutically acceptable salt thereof, R5 is fluorine or hydrogen.
In some embodiments of the compounds of the invention, or a pharmaceutically acceptable salt thereof, R5 is hydrogen.
In some embodiments of the compounds of the invention, or a pharmaceutically acceptable salt thereof, R6 is -C(O)-O-R8, wherein R8 is hydrogen, methyl, ethyl or isopropyl, -O-CH2-O-C(O)-R16or -O-C(CH3)-O-C(O)-R16, wherein R16 is methyl, ethyl, isopropyl, isobutyl, cyclobutyl, cyclopentyl, cyclohexane, neopentyl or (5-methyl-2-oxo-1,3- dioxol-4-yl)methyl.
In some embodiments of the compounds of the invention, or a pharmaceutically acceptable salt thereof, R6 is -C(O)-O-R8, wherein R8 is hydrogen, methyl, ethyl or isopropyl.
In some embodiments of the compounds of the invention, or a pharmaceutically acceptable salt thereof, R6 is -C(O)-O-R8 and R8 is hydrogen.
In some embodiments of the compounds of the invention, or a pharmaceutically acceptable salt thereof, R7 is -Ci-ealkyl , substituted with 0 or 1 phenyl or cyclopropyl; or R7 is phenyl, substituted with 0 or 1 -N(Ci-4alkyl)2, or R7 is 5-10 membered heterocyclyl substituted with 0, 1 , 2 or 3 groups independently selected from R9 and each R9 is independently selected from halogen, =0, -Ci-ealkyl, -C(O)-R10, -Ci- ehaloalkyl, -SCh-Ci-ealkyl, -NH-Ci-4alkyl, -N(Ci-4alkyl)2, -Cs-ecycloalkyl, phenyl, 4 to 7 membered heterocycle, -O-R11; each R9 is independently substituted with 0, 1 or 2 independently selected from R17;
R10 is independently selected from -Ci-ealkyl, Cs-ecycloalkyl and -Ci-ealkyl- Cs-ecycloalkyl;
R11 is a -C1-6 alkyl, -C1-6 alkyl-N(-Ci-6 alkyl)2, - Ci-ehaloalkyl or 4 to 7 membered heterocycle;
R17 is selected from halogen, -O-R15, -C(O)N(Ci-4alkyl)2, -N(R12R13), and 4 to 10 membered heterocycle, when R17 is 4 to 10 membered heterocycle is substituted with 0, 1 or 2 independently selected halogen, -Ci-ealkyl or - Ci-ehaloalkyl;
R12 and R13 are independently selected from -Ci-ealkyl, -Ci-ehaloalkyl and cyclopropyl;
R15 is -Ci-ealkyl, - Ci-ehaloalkyl or 4 to 7 membered heterocycle and when R15 is 4 to 7 membered heterocycle it is substituted with 0 or 1 -Ci-ealkyl; and wherein in each - N(Ci-e alkyl)2 or -N(Ci-4alkyl)2 the two alkyl groups attached to N can be the same or different or R7 is -NHR19, and R19 is 5 membered heteroaryl substituted with 0 or 1 -Ci-ealkyl.
In some embodiments of the compounds of the invention, or a pharmaceutically acceptable salt thereof,
R7 is -Ci-ealkyl, substituted with 0 or 1 phenyl or cyclopropyl; or R7 is phenyl, substituted with 0 or 1 -N(Ci-4alkyl)2, or R7 is 5-10 membered heterocyclyl substituted with 0, 1 , 2 or 3 groups independently selected from R9 and each R9 is independently selected from halogen, =0, -Ci-ealkyl, -C(O)-R10, -Ci- ehaloalkyl, 4 to 7 membered heterocycle,; each R9 is independently substituted with 0, 1 or 2 independently selected from R17;
R10 is -Ci-ealkyl;
R17 is selected from halogen, -N(R12R13), and 4 to 10 membered heterocycle, when R17 is 4 to 10 membered heterocycle is substituted with 0, 1 or 2 independently selected halogen,;
R12 and R13 are instances of -Ci-ealkyl; and wherein in each - N(Ci-6 alkyl)2 or -N(Ci-4alkyl)2 the two alkyl groups attached to N can be the same or different; or R7 is -NHR19, and R19 is a 5 membered heteroaryl further substituted with -Ci- ealkyl.
In some embodiments of the compounds of the invention, or a pharmaceutically acceptable salt thereof, R7 is selected from a group consisting of substituted or unsubstituted
In some embodiments of the compounds of the invention, or a pharmaceutically acceptable salt thereof, R7 is selected from a group consisting of substituted or unsubstituted
In some embodiments of the compounds of the invention, or a pharmaceutically acceptable salt thereof,
R7 is selected from a group consisting of and , each substituted with 0, 1 or 2 substituents independently selected from: -F, -Cl, oxo, -Me, - 'Bu, -'Pr, cyclobutyl, -CH2F, -CHF2, -CH2CF3, -CF3, -OMe, -OCF3, -O-azetidin-3-yl, - N(Me)2, -C(O)Me, -N(Me)2 -C(O)cyclopropyl, 1-Me-azetidin-3-yl, 3-F-azetidin-1-yl, oxetan-3-yl, — C(O)CH2cyclopropyl, -CFkcyclopropyl, -CH2-CH2-azeditin-1-yl, -CH2-CH2- (3-F-azeditin-1-yl), -CH2-CH2-(3-CF3-azeditin-1-yl), -CH2-CH2-(3,3-diF-azeditin-1-yl), - CH2-CH2-(3,3-diMe-azeditin-1-yl),-CH2-azeditin-1-yl, -CH2-(3-F-azeditin-1-yl), -CH2-(1- Me-azetidin-3-yl), -CH2-azetidin-3-yl, -CH2CH2-(3-F-pyrrolidin-1-yl), -CH2CH2OCH3, - CH2C(O)N(Me)2, -CH2CH2N(Me)2, -CH2CH2CH2N(Me)2 -CH2CH2N(Me)CH2CF3, - CH2CH2N(Me)cyclopropyl, 4-F-phenyl and -S(0)2Me. In some embodiments of the compounds of the invention, or a pharmaceutically acceptable salt thereof, wherein the 0, 1 or 2 substituents of R7 are independently selected from: -F, -Cl, oxo, -Me, -N(Me)2, -C(O)Me, 3-F-azetidin-1-yl, oxetan-3-yl, - CH2cyclopropyl, -CH2-CH2-azeditin-1-yl and -CH2CH2N(Me)2.
In some embodiments of the compounds of the invention, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from: -C(O)-CH3, -S(O)2Me,
In some embodiments of the compounds of the invention, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from:
In some embodiments of the compounds of the invention, or a pharmaceutically acceptable salt thereof, wherein each R2 is independently selected from a group consisting of -Br, -CF3,
In some embodiments of the compounds of the invention, or a pharmaceutically acceptable salt thereof, wherein R3 is independently selected from a group consisting of - F, -CF3 and -CH3.
In another embodiment, the invention relates to a compound selected from any one of Examples 1 to 71 described herein.
In another embodiment, the invention relates to a compound selected from any one of Examples 72 to 78 described herein.
In one embodiment the invention relates to a pharmaceutical composition comprising a pharmaceutically effective amount of the compounds of the invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.
In one embodiment the invention relates to the use of the compound of the invention or a pharmaceutically acceptable salt thereof in the preparation of a medicament.
In one embodiment the invention relates to a compound of the invention or a pharmaceutically acceptable salt thereof, for use as a medicament. In certain embodiments, the invention relates to compounds that inhibit c P?- integrin.
In certain embodiments, the invention relates to prodrugs of compounds that inhibit c ?- integrin (/.e., compounds that are converted into c p?- integrin inhibitors under physiological conditions or by enzymatic activity in a mammalian host).
The compounds will be useful for the treatment of inflammatory bowel disease, ulcerative colitis, Crohn’s disease, small intestinal bacterial overgrowth (SI BO), eosinophilic gastrointestinal disease (EGID), enteritis, enteropathy associated with seronegative arthropathies, gut dysbiosis, microscopic or collagenous colitis, cholecystitis, cholangitis, pericholangitis, familial adenomatous polyposis (FAP) associated inflammation gastrointestinal cancer, intestinal graft-versus-host disease (intestinal GVHD), celiac enteritis, chronic pouchitis, checkpoint inhibitor related colitis.
In one embodiment the invention relates to a method of inhibiting the interaction between a c p? integrins and MAdCAM-1 protein in a subject, the method comprising administering to the subject in need thereof a pharmaceutically effective amount of a compound of the invention or its pharmaceutically acceptable salt.
In another embodiment the invention relates to a method of treating inflammatory bowel diseases in a human in need thereof, the method comprising administering to the human a pharmaceutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof.
In another embodiment, the invention relates to a compound of the invention or a pharmaceutically acceptable salt of any of the foregoing, for use in the treatment of inflammatory bowel diseases.
In another embodiment, the invention relates to a compound of the invention or a pharmaceutically acceptable salt of any of the foregoing, for use in the treatment of inflammatory bowel diseases, wherein the inflammatory bowel diseases is ulcerative colitis.
In another embodiment, the invention relates to a compound of the invention or a pharmaceutically acceptable salt of any of the foregoing, for use in the treatment of inflammatory bowel diseases, wherein the inflammatory bowel diseases is Crohn’s disease.
In another embodiment, the invention relates to a method of treating ulcerative colon disease in a human, the method comprising administering to the human in need thereof a pharmaceutically effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof. In another embodiment, the invention relates to a compound of the invention, or a pharmaceutically acceptable salt of any of the foregoing, for use in the treatment of ulcerative colon disease.
In another embodiment, the invention relates to a compound of the invention, or a pharmaceutically acceptable salt of any of the foregoing, for use in the treatment of ulcerative colon disease, wherein the ulcerative colon disease is ulcerative colitis.
In another embodiment, the invention relates to a compound of the invention, or a pharmaceutically acceptable salt of any of the foregoing, for use in the treatment of ulcerative colon disease, wherein the ulcerative colon disease is Crohn’s Disease.
In another embodiment, the invention relates to a kit comprising: a) one or more compositions, each composition comprising a pharmaceutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt of any thereof, and a pharmaceutically acceptable carrier or excipient; and b) instructions for administering the one or more compositions to a human in need thereof.
Terms employed in the specification, description, examples and claims are collected here. These definitions should be read in light of the remainder of the disclosure and understood as by a person of skill in the art. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by a person of ordinary skill in the art.
The terms and phrases are defined below and throughout the specification apply unless stated otherwise.
The articles "a", "an" and "the" include plural referents unless context clearly indicates otherwise and are used herein to refer to one or to more than one (i.e. , to at least one) of the grammatical object of the article. By way of example, "an element" means one element or more than one element.
The phrase "and/or," as used herein in the specification and in the claims, should be understood to mean "either or both" of the elements so conjoined.
In the claims, as well as in the specification above, all transitional phrases such as "comprising," "including," "carrying," "having," "containing," "involving," "holding, "composed of," and the like are to be understood to be open-ended, i.e., to mean including but not limited to. Only the transitional phrases "consisting of' and "consisting essentially of shall be closed or semi-closed transitional phrases, respectively, as set forth in the United States Patent Office Manual of Patent Examining Procedures, Section 2111. 03. Certain compounds contained in compositions of the present invention may exist in particular geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis- and trans-isomers, R- and S-enantiomers, diastereomers, (D )- isomers, (L)isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention. Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention. Unless stereochemistry is explicitly indicated in a structure, the structure is intended to embrace all possible stereoisomers of the compound depicted. If stereochemistry is explicitly indicated for one portion or portions of a molecule, but not for another portion or portions of a molecule, the structure is intended to embrace all possible stereoisomers for the portion or portions where stereochemistry is not explicitly indicated. If, for instance, a particular enantiomer of compound of the present invention is desired, the desired enantiomer can be isolated from the racemic mixture using chiral separation methods known in the art, such as, for example, chiral chromatography. Alternatively, it may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers. Alternatively, where the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomers.
Stereochemistry/Solvates/Hydrates: Unless stated otherwise a structural formula given in the description or in the claims or a chemical name refers to the corresponding compound itself, mixtures of the forms mentioned hereinbefore (if such forms exist) as well as salts, particularly pharmaceutically acceptable salts thereof. The compounds and salts according to the invention may be present in solvated form ( e.g. with pharmaceutically acceptable solvents such as e.g. water, ethanol etc.) or in unsolvated form. Generally, for the purposes of the present invention the solvated forms, e.g. hydrates, are to be regarded as of equal value to the unsolvated forms.
An aliphatic chain comprises the classes of alkyl, alkenyl and alkynyl defined below. As used herein, the term "aliphatic group" refers to an unbranched or linear chain, branched-chain, or cyclic aliphatic hydrocarbon group and includes saturated and unsaturated aliphatic groups, such as an alkyl group, an alkenyl group, or an alkynyl group. The term "alkyl" refers to an unbranched or branched hydrocarbon. For example, an alkyl group can have a specified number of chain carbons, such as 1 to 6 carbon atoms (i.e., Ci-Ce alkyl or C1-6 alkyl). Examples of suitable alkyl groups include, but are not limited to, methyl (Me, --CH3), ethyl (Et, -CH2CH3), 1 -propyl (n-Pr, n-propyl, -CH2CH2CH3), 2- propyl (i-Pr, i-propyl, --CH(CH3)2), 1 -butyl (n-Bu, n-butyl, --CH2CH2CH2CH3), 2-methyl-1- propyl (i-Bu, i-butyl, -CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, -CH(CH3)CH2CH3), 2-methyl- 2-propyl (t-Bu, t-butyl, --C(CH3)3), 1 -pentyl (n-pentyl, --CH2CH2CH2CH2CH3), 2-pentyl (-- CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3- methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1 -butyl (-CH2CH2CH(CH3)2), 2-methyl-1- butyl (-CH2CH(CH3)CH2CH3), 1 -hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (- CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (- C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (- CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (- CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), and 3,3-dimethyl-2- butyl (-CH(CH3)C(CH3)3.
As used herein, the term "alkylene" refers to an alkyl group having the specified number of carbons, for example from 2 to 12 carbon atoms, that contains two points of attachment to the rest of the compound on its longest carbon chain. Non-limiting examples of alkylene groups include methylene -(CH2)-, ethylene -(CH2CH2)-, n-propylene - (CH2CH2CH2)-, isopropylene -(CH2CH(CH3))-, and the like. Alkylene groups can be cyclic or acyclic, branched or unbranched carbon chain moiety, and may be optionally substituted with one or more substituents.
"Alkenyl" refers to any cyclic or acyclic, branched or unbranched unsaturated carbon chain moiety having the number of carbon atoms specified, or up to 26 carbon atoms if no limitation on the number of carbon atoms is specified; and having one or more double bonds in the moiety. Alkenyl of 6 to 26 carbon atoms is exemplified by hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodecenyl, tridecenyl, tetradecenyl, pentadecenyl, hexadecenyl, heptadecenyl, octadecenyl, nonadecenyl, eicosenyl, heneicosoenyl, docosenyl, tricosenyl, and tetracosenyl, in their various isomeric forms, where the unsaturated bond(s) can be located anywhere in the moiety and can have either the (Z) or the (E) configuration about the double bond(s).
"Alkynyl" refers to hydrocarbyl moieties of the scope of alkenyl, but having one or more triple bonds in the moiety.
The term "alkoxy" refers to a group having the formula “-O-alkyl,” in which an alkyl group, as defined above, is attached to the parent molecule via an oxygen atom. The alkyl portion of an alkoxy group can have a specified number of carbon chain atoms, such as 1 to 6 carbon atoms (i.e. , Ci-Ce alkoxy or C1-6 alkoxy). Examples of suitable alkoxy groups include, but are not limited to, methoxy (-O-CH3 or --OMe), ethoxy (-OCH2CH3 or --OEt), t- butoxy (-O-C(CH3)3 or --OtBu) and the like.
The term “haloalkyl” refers to a group in which the alkyl group, as defined above, has or more hydrogens replaced by a halogen atom. The alkyl portion of an haloalkyl group can have a specified number of carbon chain atoms, such as 1 to 6 carbon atoms (i.e., -Ci-Ce haloalkyl or -C1-6 haloalkyl). Examples include: -CFH2, -CF2H, -CF3, -CF2CF3, - CHFCF3, -CH2CF3, -CF2CH3, -CHFCH3, -CF2CF2CF3, -CF2CH2CH3 etc.
The term “carbonyl group” refers to C=O, i.e., with the carbon atom bonded to oxygen via a double bond and further bonded to two other atoms. It is indicated as -CO- or -C(O)- herein.
The term “carbocycle” or “carbocyclic group” refers to a chemical ring containing only carbon atoms, including saturated, unsaturated, partially saturated, and aromatic rings. For clarity, “carbocycle” includes “cycloalkyl” and “aryl” as defined herein.
"Cycloalkyl" means mono- or bicyclic or bridged or spirocyclic, or polycyclic saturated carbocyclic rings, each having from 3 to 12 carbon atoms. Likewise and unless specified preferred cycloalkyls have from 3-10 carbon atoms in their ring structure, and more preferably have 3-6 carbons in the ring structure. Cycloalkyl groups may be substituted or unsubstituted. In some embodiments, a preferred cycloalkyl is a monocycle having 3 to 6 carbon atoms.
The term "aryl" as used herein includes 6- to 12-membered substituted or unsubstituted single-ring aromatic groups in which each atom of the ring is carbon . Preferably, aryl groups include 5- to 12-membered rings, more preferably 6- to 10- membered rings The term "aryl" also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, and/or heterocyclyls, wherein the connection point is on the aromatic ring. Aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like. Aryl groups also include di hydrobenzofuran, indoline, isoindoline, quinoline, isoquinoline and the like, wherein the attachment point is on the phenyl ring.
The terms "heterocyclyl", “heterocycle” or "heterocyclic group" refer to 3- to 12- membered ring structures, more preferably 4- to 12-membered rings, more preferably 5- to 10-membered rings, whose ring structures include one to four heteroatoms selected from N, O, S and oxidized forms thereof. Heterocyclyl can be saturated, partially saturated, unsaturated and/or aromatic. Heterocycles can be monocyclic, bicyclic, spirocyclic, or polycyclic. Heterocyclyl groups include, for example, azetidine, aziridine, thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxathiin, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine, phenanthroline, phenazine, phenarsazine, phenothiazine, furazan, phenoxazine, pyrrolidine, oxolane, thiolane, oxazole, piperidine, piperazine, morpholine, lactones, lactams such as azetidinones, pyridone and pyrrolidinones, sultams, sultones, and the like.
For clarity, “heterocyclyl” includes “heteroaryl” and “heterocycloalkyl”.
The heterocyclic ring can be substituted at one or more positions with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, 5 amido, phosphate, phosphonate, phosphinate, carbonyl, carboxyl, silyl, sulfamoyl, sulfinyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, -CF3, -CN, and the like.
It is understood that the general terms for the heterocycles referenced herein include each isomeric form of the heterocycle, such as the term “dithianyl” including 1 ,2 dithianyl, 1 ,3-dithianyl, and 1 ,4-dithianyl groups, the term “thiadiazinyl” including 1 ,2,5 thiadiazinyl and 1 ,3,4-thiadiazinyl groups, the term “azaindolyl” including 4-azaindolyl, 5- azaindolyl, 6-azaindolyl, and 7-azaindolyl groups, and “benzothiophenyl” including benzo[b]thiophenyl and benzo[c]thiophenyl groups.
Similarly, general heterocycle names include each variance in one or more points of unsaturation. For instance, the term “dihydropyrrolyl” refers to “2,3-dihydro-1 H-pyrrolyl” and “2, 5-dihydro-1 H-pyrrolyl” groups.
"Heterocycloalkyl" means saturated heterocyclic rings, each having from 3 to 12 ring members atoms, more preferably 4- to 10-membered rings, more preferably 4- to 7- membered rings, whose ring structures include one to four heteroatoms selected from N, O, S and oxidized forms thereof. Heterocycles can be monocyclic, bicyclic, spirocyclic, or polycyclic. Heterocyclyl groups include, for example, azetidine, oxetane, tetrahydrofuran, pyrrolidine, piperidine, piperazine, morpholine, tetrahydropyran, dioxane, azepane, and the like.
Heterocycloalkyl groups may be substituted or unsubstituted. In some embodiments, a preferred heterocycloalkyl is a monocycle having 4 to 6 ring members, including 1 or 2 hetero atoms.
Partially saturated heterocycle means heterocyclic ring having at least one carboncarbon double bond, preferably one or two or three carbon-carbon double bonds, preferably one or two carbon-carbon double bonds, preferably one carbon-carbon double bond.
Heteroaryl groups include substituted or unsubstituted aromatic 5- to 12- membered ring structures, more preferably 5- to 10-membered rings, whose ring structures include one to four heteroatoms selected from N, O, S and oxidized forms thereof. The term "heteroaryl" also includes polycyclic ring systems having two or more cyclic rings in which two or more atoms are common to two adjoining rings wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls and/or heterocyclyls, wherein the connection point is on an aromatic ring. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like. Heteroaryl groups also include benzofuran, benzothiophene, indole, benzothiazole and the like, regardless of the placement of the attachment point. Aryl and heteroaryl can be monocyclic, bicyclic, or polycyclic.
The term “halogen” refers to an atom selected from the group of elements chlorine, fluorine, bromine, and iodine, i.e., -F, -Cl, -Br, or -I.
The term “oxo” refers to double-bonded oxygen “=O”.
As used herein, the term "nitro" means -NO2; the term "sulfhydryl" means -SH; the term "hydroxyl" means -OH; the term "sulfonyl" means -SO2-; the term "azido" means -N3; the term "cyano" means -CN; the term "isocyanato" means -NCO; the term "thiocyanate" means -SCN; the term "isothiocyanate" means -NCS; and the term "cyanato" means - OCN.
As used herein, the term "substituted" is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. Illustrative substituents include, for example, those described herein above. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this invention, the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. This invention is not intended to be limited in any manner by the permissible substituents of organic compounds. It will be understood that "substitution" or "substituted with" includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. The term "prodrug" as used herein encompasses compounds that, under physiological conditions, are converted into therapeutically active agents. A common method for making a prodrug is to include selected moieties that are hydrolyzed under physiological conditions to reveal the desired molecule. In other embodiments, the prodrug is converted by an enzymatic activity of the mammalian host. Examples of moieties that are hydrolyzed under physiological conditions to reveal the desired molecule include functionalized carboxylic groups, esters of carboxylic acids, which can be converted into the corresponding active molecule under physiological conditions. Examples of moieties that are hydrolyzed under physiological conditions to reveal the desired molecule are e.g.
For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 67th Ed., 1986-87, inside cover.
The terms "therapeutically effective amount" and "pharmaceutically effective amount" refer to an amount that is sufficient to effect treatment, as defined below, when administered to a subject (e.g., a mammal, such as a human) in need of such treatment. The therapeutically or pharmaceutically effective amount will vary depending upon the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art. For example, a "therapeutically effective amount" or a "pharmaceutically effective amount" of a compound of Formula (I), or a pharmaceutically acceptable salt or co-crystal thereof, is an amount sufficient to inhibit, and thereby treat a subject (e.g., a human) suffering an indication, or to ameliorate or alleviate the existing symptoms of the indication.
"Treatment" or "treating" is an approach for obtaining beneficial or desired results including clinical results. Beneficial or desired clinical results may include one or more of the following: (i) inhibiting the disease or condition (e.g., decreasing one or more symptoms resulting from the disease or condition, and/or diminishing the extent of the disease or condition); (ii) slowing or arresting the development of one or more clinical symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or delaying the worsening or progression of the disease or condition, and/or preventing or delaying the spread (e.g., metastasis) of the disease or condition); and/or (iii) relieving the disease, that is, causing the regression of clinical symptoms (e.g., ameliorating the disease state, providing partial or total remission of the disease or condition, enhancing effect of another medication, delaying the progression of the disease, increasing the quality of life, and/or prolonging survival).
The terms “inhibitor” indicates a compound of the invention that selectively binds to c p? integrin preventing the interaction between c ? integrin and MAdCAM-1 protein. Thus “inhibiting” or "inhibition" indicates a decrease in the baseline activity of a biological activity or process regulated by the interaction between c p? integrin and MAdCAM-1 protein. In some embodiments, the inhibition of c p? integrin activity may be compared in the same subject prior to treatment, or other subjects not receiving the treatment. The term “inhibitor” is understood to refer to a compound or agent that, upon administration to a human in need thereof at a pharmaceutically or therapeutically effective dose, provides the inhibitory activity desired.
Numerical values in the specification and claims of this application should be understood to include numerical values which are the same when reduced to the same number of significant figures and numerical values which differ from the stated value by less than the experimental error of conventional measurement technique of the type described in the present application to determine the value.
All ranges disclosed and/or claimed herein are inclusive of the recited endpoint and independently combinable (for example, the ranges of "from 2 to 10" and “2-10” are inclusive of the endpoints, 2 and 10, and all the intermediate values 3, 4, 5, 6, 7, 8, and 9).
By "significant" is meant any detectable change that is statistically significant in a standard parametric test of statistical significance such as Student's T-test, where p<0.05.
Salts: The term "pharmaceutically acceptable" is used herein to denote compounds, materials, compositions and/or formulations which are suitable, according to generally recognised medical opinion, for use in conjunction with human and/or animal tissue and do not have or give rise to any excessive toxicity, irritation or immune response or lead to other problems or complications, i.e. correspond overall to an acceptable risk/benefit ratio. The term "pharmaceutically acceptable salts" relates to derivatives of the chemical compounds disclosed in which the parent compound is modified by the addition of acid or base. Examples of pharmaceutically acceptable salts include (without being restricted thereto) salts of mineral or organic acids in relation to basic functional groups such as for example amines, alkali metal or organic salts of acid functional groups such as for example carboxylic acids, etc. These salts include in particular acetate, ascorbate, benzenesulphonate, benzoate, besylate, bicarbonate, bitartrate, bromide/hydrobromide, Ca-edetate/edetate, camsylate, carbonate, chloride/hydrochloride, citrate, edisylate, ethane disulphonate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycolate, glycollylarsnilate, hexylresorcinate, hydrabamine, hydroxymaleate, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, malate, maleate, mandelate, methanesulphonate, mesylate, methylbromide, methylnitrate, methylsulphate, mucate, napsylate, nitrate, oxalate, pamoate, pantothenate, phenyl acetate, phosphate/diphosphate, polygalacturonate, propionate, salicylate, stearate, subacetate, succinate, sulphamide, sulphate, tannate, tartrate, teoclate, toluenesulphonate, triethiodide, ammonium, benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumin and procaine. Other pharmaceutically acceptable salts may be formed with cations of metals such as aluminium, calcium, lithium, magnesium, potassium, sodium, zinc, etc. (cf. also Pharmaceutical salts, Birge, S.M. et al., J. Pharm. Sci., (1977), 66, 1-19).
As used herein, the terms “isotope” and “isotopic” in reference to a compound as disclosed herein means that one or more atoms of the compound is replaced with an isotope of such one or more atoms. An “isotope” refers to any of two or more forms of a chemical element, having the same number of protons in the nucleus, but having different numbers of neutrons in the nucleus. For example, an isotopic compound includes a compound in which one or more hydrogen atoms (H) has been replaced with one or more deuterium atoms (D). In this example, deuterium is an isotope of hydrogen, and replacing a hydrogen atom with deuterium (at one or more positions) renders the resulting compound an isotopic compound. For example, and in reference to Formula (I), replacing the two methyl groups of the isopropyl moiety (-CH(CH3)2) with fully deuterated methyl groups (-CH(CD3)2) would be an isotopic compound of Formula (I). In addition to replacing hydrogen with deuterium, other stable (non-radioactive) isotope substitutions include replacing carbon 12 with carbon 13, while unstable (radioactive) isotopes include replacing hydrogen with tritium, replacing carbon 12 with carbon 14, replacing iodine 127 with iodine 123 or iodine 125, and the like. Accordingly, all reference herein to isotopic compounds of Formula (I), as well as all reference to the various embodiments thereof, refers to a compound having one or more isotopic substitutions, including (but not limited to) substitutions of one or more hydrogen atoms with one or more deuterium atoms and any occurrence(s) in the compound. To this end, the isotopic compounds disclosed herein provide improved advantages relative to their non-isotopic forms. To this end, isotopic modification provides a means of improving existing drugs and/or as a tool in the design of new drugs. For example, isotopic drug design has proven successful in the context of the deuterium (D) kinetic isotope effect. Due to the twofold higher mass of D compared with H, the C-D bond is much more resistant toward oxidative processes (such as its ability to be catalyzed by CYP450 or by other enzymes involved in metabolism), while retaining very similar steric properties. Therefore, H-D isosteric replacement usually retains the pharmacodynamics of the compound, while improving its pharmacokinetics with a repercussion on half-life and/or of area under the curve values and, ultimately, on dose and/or dosing regimen. For example, drug exposure may be enhanced with isotopic modification, and/or a decrease of clearance. Such benefits are provided to the compounds disclosed hereby by way their isotopic derivation.
Terms such as "subject" and “patient” refer to an animal, such as a mammal, that has been or will be the object of treatment, observation or experiment. The methods described herein may be useful in both human therapy and veterinary applications. In some embodiments, the subject is a mammal; in some embodiments the subject is human; and in some embodiments the subject is chosen from cats and dogs. "Subject in need thereof' or "human in need thereof" refers to a subject, such as a human, who may have or is suspected to have diseases or conditions that would benefit from certain treatment; for example treatment with a compound of Formula (I), or a pharmaceutically acceptable salt or co-crystal thereof, as described herein. This includes a subject who may be determined to be at risk of or susceptible to such diseases or conditions, such that treatment would prevent the disease or condition from developing.
The pharmaceutically acceptable salts of the present invention may be prepared starting from the parent compound which carries a basic or acidic functionality, by conventional chemical methods. Generally, such salts may be synthesised by reacting the free acid or base form of these compounds with a sufficient amount of the corresponding base or acid in water or an organic solvent such as for example ether, ethyl acetate, ethanol, isopropanol, acetonitrile (or mixtures thereof). Salts of acids other than those mentioned above, which are useful for example for purifying or isolating the compounds from the reaction mixtures (e.g. trifluoroacetates), are also to be regarded as part of the invention.
The phrase "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject chemical from one organ or portion of the body, to another organ or portion of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation, not injurious to the patient, and substantially non-pyrogenic. Some examples of materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations. In certain embodiments, pharmaceutical compositions of the present invention are non-pyrogenic, i.e., do not induce significant temperature elevations when administered to a patient.
The compounds of the invention may optionally be present as racemates, but may also be obtained as pure enantiomers, i.e. in the (R) or (S) form. Preferred are the compounds with the specific stereochemistry of formula la.
The invention relates to the compounds in question, optionally in the form of the individual optical isomers, diastereomers, mixtures of diastereomers, mixtures of the individual enantiomers or racemates, in the form of the tautomers as well as in the form of the free bases or the corresponding acid addition salts with pharmacologically acceptable acids -such as for example acid addition salts with hydrohalic acids - for example hydrochloric or hydrobromic acid - or organic acids - such as for example oxalic, fumaric, diglycolic or methanesulphonic acid.
The invention relates to the respective compounds of formulas I in the form of the pharmacologically acceptable salts thereof. These pharmacologically acceptable salts of the compounds of formulae I and la may also be present in the form of their respective hydrates (e.g. Monohydrates, dihydrates, etc.) as well as in the form of their respective solvates.
By a hydrate of the compound according to the formulas I is meant, for the purposes of the invention, a crystalline salt of the compound according to formulas I, containing water of crystallisation. By a solvate of the compound according to formulas I is meant, for the purposes of the invention, a crystalline salt of the compound according to formulas I, which contains solvent molecules (e.g. Ethanol, methanol etc) in the crystal lattice.
COMBINATIONS
The compounds of formula I may be used on their own or in conjunction with other active substances of formula I according to the invention. The compounds of formula I may optionally also be used in conjunction with other pharmacologically active substances. Preferably the active substances used here may be selected for example from among anti-l L17, bispecific antibodies IL23p19/TNF, fecal transplant, aminosalicylates (5-ASA), cox-2 inhibitors, corticosteroids, Azathioprine, Cyclosporine, Tacrolimus, 6-mercaptopurine and/or Antibiotics (such as Ciprofloxacin, Metronidazole, Ampicillin).
FORMULATIONS
The compounds of formula I according to the invention also have properties required for the manufacture of suitable pharmaceutical dosage forms. These properties include for instance properties relevant for sufficient bioavailability of the active ingredient, in particular sufficiently high solubilties thereof such as for instance a solubility that is > 2 pg/ml measured in aqueous solution at pH 6,8.
Suitable forms for administration are for example tablets, capsules, solutions, syrups, emulsions or inhalable powders or aerosols. The content of the pharmaceutically effective compound(s) in each case should be in the range from 0.1 to 90 wt.%, preferably 0.5 to 50 wt.% of the total composition, i.e. in amounts which are sufficient to achieve the dosage range specified hereinafter.
The preparations may be administered orally in the form of a tablet, as a powder, as a powder in a capsule (e.g. a hard gelatine capsule), as a solution or suspension. When administered by inhalation the active substance combination may be given as a powder, as an aqueous or aqueous-ethanolic solution or using a propellant gas formulation.
Preferably, therefore, pharmaceutical formulations are characterised by the content of one or more compounds of formula I according to the preferred embodiments above. It is particularly preferable if the compounds of formula I are administered orally, and it is also particularly preferable if they are administered once or twice a day. Suitable tablets may be obtained, for example, by mixing the active substance(s) with known excipients, for example inert diluents such as calcium carbonate, calcium phosphate or lactose, disintegrants such as corn starch or alginic acid, binders such as starch or gelatine, lubricants such as magnesium stearate or talc and/or agents for delaying release, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate. The tablets may also comprise several layers.
Coated tablets may be prepared accordingly by coating cores produced analogously to the tablets with substances normally used for tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar. To achieve delayed release or prevent incompatibilities the core may also consist of a number of layers. Similarly the tablet coating may consist of a number of layers to achieve delayed release, possibly using the excipients mentioned above for the tablets.
Syrups containing the active substances or combinations thereof according to the invention may additionally contain a sweetener such as saccharine, cyclamate, glycerol or sugar and a flavour enhancer, e.g. a flavouring such as vanillin or orange extract. They may also contain suspension adjuvants or thickeners such as sodium carboxymethyl cellulose, wetting agents such as, for example, condensation products of fatty alcohols with ethylene oxide, or preservatives such as p-hydroxybenzoates.
Capsules containing one or more active substances or combinations of active substances may for example be prepared by mixing the active substances with inert carriers such as lactose or sorbitol and packing them into gelatine capsules. Suitable suppositories may be made for example by mixing with carriers provided for this purpose, such as neutral fats or polyethyleneglycol or the derivatives thereof.
Excipients which may be used include, for example, water, pharmaceutically acceptable organic solvents such as paraffins (e.g. petroleum fractions), vegetable oils (e.g. groundnut or sesame oil), mono- or polyfunctional alcohols (e.g. ethanol or glycerol), carriers such as e.g. natural mineral powders (e.g. kaolins, clays, talc, chalk), synthetic mineral powders (e.g. highly dispersed silicic acid and silicates), sugars (e.g. cane sugar, lactose and glucose), emulsifiers (e.g. lignin, spent sulphite liquors, methylcellulose, starch and polyvinylpyrrolidone) and lubricants (e.g. magnesium stearate, talc, stearic acid and sodium lauryl sulphate).
For oral administration the tablets may, of course, contain, apart from the abovementioned carriers, additives such as sodium citrate, calcium carbonate and dicalcium phosphate together with various additives such as starch, preferably potato starch, gelatine and the like. Moreover, lubricants such as magnesium stearate, sodium lauryl sulphate and talc may be used at the same time for the tableting process. In the case of aqueous suspensions the active substances may be combined with various flavour enhancers or colourings in addition to the excipients mentioned above. It is also preferred if the compounds of formula I are administered by inhalation, particularly preferably if they are administered once or twice a day. For this purpose, the compounds of formula I have to be made available in forms suitable for inhalation. Inhalable preparations include inhalable powders, propellant-containing metered-dose aerosols or propellant-free inhalable solutions, which are optionally present in admixture with conventional physiologically acceptable excipients.
Within the scope of the present invention, the term propellant-free inhalable solutions also includes concentrates or sterile ready-to-use inhalable solutions. The preparations which may be used according to the invention are described in more detail in the next part of the specification.
EXEMPLARY METHODS - INDICATIONS
In certain embodiments, the invention relates to a method of treating a disease or condition selected from the group consisting of inflammatory bowel disease, small intestinal bacterial overgrowth (SIBO), eosinophilic gastrointestinal disease (EGID), enteritis, enteropathy associated with seronegative arthropathies, gut dysbiosis, microscopic or collagenous colitis, cholecystitis, cholangitis, pericholangitis, familial adenomatous polyposis associated inflammation (FAP) gastrointestinal cancer, intestinal graft-versus-host disease (intestinal GVHD), celiac enteritis, chronic pouchitis, checkpoint inhibitor related colitis, comprising the step of: administering to a subject in need thereof a therapeutically effective amount of any one of the aforementioned compounds.
In certain embodiments, the disease or condition is Crohn's disease.
In certain embodiments, the disease or condition is colitis.
In certain embodiments, the disease or condition is ulcerative colitis.
In certain embodiments, the invention relates to any one of the aforementioned methods, wherein the subject is a mammal. In certain embodiments, the invention relates to any one of the aforementioned methods, wherein the subject is human.
Synthesis
The compounds described herein may be prepared by methods known in the art and are exemplified by the following non-limiting descriptions.
Unless otherwise stated, all reactions are typically performed under inert atmosphere (for example under Nitrogen). The following abbreviations are used in the text: s.s. = saturated solution
ON = overnight List of abbreviations
ACN CH3CN, acetonitrile
AcOH Acetic Acid
Boc tert. butoxy carbonyl
DCM dichloromethane
DI PEA diisopropylethyl amine
DMAP dimethyl-pyridin-4-yl-amine
DMF N,N-dimethylformamide
DMSO dimethylsulphoxide
EDTA ethylenediaminetetraacetic acid
EtOAc or ethyl acetate
EA EtOH Ethanol
Et2O Diethyl Ether
FA Formic Acid
FC Flash Chromatography h or hr hour(s)
HATU 1-[Bis(dimethylamino)methylene]-1 H-1,2,3-triazolo[4,5- b]pyridinium 3-oxid
HPLC high performance liquid chromatography
KOAc potassium acetate
LCMS Liquid Chromatography Mass Spectrometry
□HMDS lithium hexamethyl disilazide
M Molar
Min minute(s) mL Millilitre
MS mass spectrometry
N Normal
NMR nuclear resonance spectroscopy
ON or on Overnight
PE petrol ether
PPh3 triphenylphosphine
MeOH Methanol
IPA Isopropyl Alcohol
I nt. Intermediate THF Tetrahydrofuran
DIBAL diisobutylaluminium hydride
RP reversed phase
Rpm rounds per minute
RT or rt room temperature
SFC Supercritical Fluid Chromatography
SCX Strong Cation Exchange resin
STAB Sodium triacetoxy borohydride
TBME tert, butyl methyl ether
TEA triethylamine
T3P Propanephosphonic acid anhydride tert tertiary
TFA trifluoroacetic acid
THF tetra hydrofuran tR retention time [min]
TRIS tris(hydroxymethyl)aminomethane tBuXPhos 2-Di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl wt% weight percent sat. Saturated uPLC ultra performance liquid chromatography
Ar aromatic
Other features and advantages of the present invention will become apparent from the following more detailed Examples which exemplarily illustrate the principles of the invention without restricting its scope.
General Synthesis
Unless stated otherwise, all the reactions are carried out in commercially obtainable apparatus using methods that are commonly used in chemical laboratories. Starting materials that are sensitive to air and/or moisture are stored under protective gas and corresponding reactions and manipulations therewith are carried out under protective gas (nitrogen or argon).
The compounds of formula 1 herein described, can be synthesised as shown in the general route reported in Scheme 1 , via amide coupling of the amino group of biaryl ester 2 and the appropriate amino acid 3. Biaryl amino ester intermediate 2 can be synthesised in a multistep procedure as described in Scheme 2. Starting from commercially available aromatic aldehydes 6, with the chiral auxiliary tert-butlysulfoxamide to generate intermediate 5 which can them undergo metal-catalysed reaction with commercially available aryl and heteroaryl boronates to produce intermediate 4, which can undergo deprotection of the amine to give compound 2.
7 3
Scheme 2
Dimethylcyclopropyl proline Intermediate 3 can be synthesised starting from the amino acid methyl ester 7, via a two-step procedure of amide coupling with acyl chlorides or carboxylates 8, followed by ester hydrolysis.
Alternatively for those compounds where appropriate building blocks are not commercially available, they can be synthesised according to the general routes described herein reported.
Other features and advantages of the present invention will become apparent from the following more detailed Examples which exemplarily illustrate the principles of the invention without restricting its scope.
Analytical LCMS conditions are as follows:
System 1 (S1): ACIDIC IPC METHOD Analytical (MET/uPLC/1704) uHPLC-MS were performed on a Waters Acquity uPLC system using a Waters LIPLC® BEHTM C18 column (2.1 mm x 50 mm, 1.7 pm; temperature 40 °C) and a gradient of 5-100% B (A= 0.1% formic acid in H2O2-H: B= 0.1% formic acid in MeCN) over 1.1 min then 100% B for 0.25 min. A second gradient of 100- 5% B was then applied over 0.05 min and held for 0.1 min with an injection volume of 1 pL at a flow rate of 0.9 mL/min. UV spectra were recorded at 215 nm on a Waters Acquity PDA with a spectrum range of 200-400 nm. Mass spectra were obtained using a Waters QDa. Data were integrated and reported using Waters MassLynx and OpenLynx software, retention times (Rt) are reported in min.
System 2 (S2): BASIC IPC METHOD
Analytical (MET/uPLC/AB2010) (M15) UHPLC-MS were performed in reverse phase using a Waters UPLCTM BEHTM C18 column (2.1 mm x 30 mm, 1.7 pm; temperature 55 °C), with an injection volume of 1 pL at a flow rate of 1.0 mL/min and a gradient of 1 - 100% B over 1.10 min, then 100% B for 0.25 min, where A = 2 mM ammonium bicarbonate in water, buffered to pH 10, and B = acetonitrile. A second gradient of 100 - 1% B was then applied over 0.05 min and held for 0.40 min. UV spectra were recorded at 215 nm; spectrum range: 200 - 400 nm. Mass spectra were obtained using a Waters Quattro Premier XE or a SQD2; ionization mode: electrospray positive or negative. Data were integrated and reported using Waters MassLynx and OpenLynx software, retention times (Rt) are reported in min.
System 3 (S3): ACIDIC FINAL METHOD
Analytical (MET/uPLC/AB101) uHPLC-MS were performed on a Waters Acquity uPLC system using a Phenomenex Kinetex-XB C18 column (2.1 mm x 100 mm, 1.7 pM; temperature: 40 °C) and a gradient of 5-100% B (A = 0.1% formic acid in H2O; B = 0.1% formic acid in MeCN) over 5.3 min then 100% B for 0.5 min. A second gradient of 100-5% B was then applied over 0.02 min and held for 1.18 min with an injection volume of 1 pL at flow rate of 0.6 mL/min. UV spectra were recorded at 215 nm using a Waters Acquity PDA detector spectrum range: 200-400 nm. Mass spectra were obtained using a Waters SQD or Waters Acquity QDA. Data were integrated and reported using Waters MassLynx and OpenLynx software, retention times (Rt) are reported in min.
System 4 (S4): BASIC FINAL METHOD
Analytical (MET/uHPLC/AB105) uPLC-MS were performed on a Waters Acquity uPLC system using a Waters UPLC® BEHTM C18 column (2.1 mm x 100 mm, 1.7 pm column; temperature: 40 °C) and a gradient of 5-100% (A= 2 mM ammonium bicarbonate, buffered to pH 10; B = MeCN) over 5.3 min then 100% B for 0.5 min. A second gradient of 100-5% B was then applied over 0.02 min and held for 1.18 min with an injection volume of 1 pL and at flow rate of 0.6 mL/min. UV spectra were recorded at 215 nm using a Waters Acquity photo diode array detector Spectrum range: 200-400 nm. Mass spectra were obtained using a Waters Quattro Premier XE mass detector. Data were integrated and reported using Waters MassLynx and OpenLynx software, retention times (Rt) are reported in min.
System 5 (S5): NEUTRAL FINAL METHOD
Analytical UHPLC-MS were performed on a Agilent 1260 system using a Agilent Poroshell 120 EC-C18 column (2.1 mm x 50 mm, 1.9 pm; temperature 50 °C) in binary gradient mode (A= 10 mM NH4OAC in H2O: B= ACN) at 0.8 mL/min over 4.5 min (1%B for 0.25 min, then linear increase until 100%B in 2.25 min, then 100% B for 0.40 min before going back to initial conditions in 0.1 min). Default injection volume was 0.2 pL. UV spectra were recorded at 220 and 254 nm on an Agilent PDA with a spectrum range of 190-400 nm. Mass spectra were obtained using a Agilent 6490A QQQ with either positive or negative electrospray ionisation (Agilent Jet Stream source). Data were exploited using the Agilent MassHunter software suite, retention times (Rt) are reported in min.
System 6 (S6): NEUTRAL IPC METHOD
Analytical UHPLC-MS were performed on a Agilent 1260 system using a Agilent Poroshell 120 EC-C18 column (2.1 mm x 50 mm, 1.9 pm; temperature 50 °C) in binary gradient mode (A= 10 mM NH4OAC in H2O: B= ACN) at 0.8 mL/min over 4.2 min (1 %B for 0.25 min, then linear increase until 100%B in 2.25 min, then 100% B for 0.40 min before going back to initial conditions in 0.1 min). Default injection volume was 1 pL. UV spectra were recorded at 220 and 254 nm on an Agilent PDA with a spectrum range of 190-400 nm. Mass spectra were obtained using an Agilent 6120B SQ with simultaneous positive and negative electrospray ionisation. Data were exploited using the Agilent OpenLab software, retention times (Rt) are reported in min.
System 4 (S7): NEUTRAL IPC METHOD
Analytical UHPLC-MS were performed on a Agilent 1260 system using a Agilent Poroshell 120 EC-C18 column (2.1 mm x 50 mm, 2.7 pm; temperature 50 °C) in binary gradient mode (A= 10 mM NH4OAC in H2O: B= ACN) at 1.0 mL/min over 3.8 min (0.5%B for 0.10 min, then linear increase until 100%B in 1.6 min, then 100% B for 0.40 min before going back to initial conditions in 0.1 min). Default injection volume was 1 pL. UV spectra were recorded at 220 and 254 nm on an Agilent PDA with a spectrum range of 190-400 nm. Mass spectra were obtained using a Agilent 6120B SQ with simultaneous positive and negative electrospray ionisation. Data were exploited using the Agilent OpenLab software.
System 9 (S9): ACIDIC IPC METHOD Analytical UHPLC-MS were performed on a Agilent 1290 system using a Agilent Poroshell 120 EC-C18 column (2.1 mm x 50 mm, 1.9 pm; temperature 50 °C) in binary gradient mode (A= 0.1% formic acid in H2O: B= 0.05% formic acid in ACN) at 1.00 mL/min over 2.5 min (1%B for 0.10 min, then linear increase until 100%B in 1.3 min, then 100% B for 0.50 min before going back to initial conditions in 0.1 min). Default injection volume was 1 pL. UV spectra were recorded at 220 and 254 nm on an Agilent PDA with a spectrum range of 190-400 nm. Mass spectra were obtained using a Agilent 6120B SQ with simultaneous positive and negative electrospray ionisation. Data were exploited using the Agilent OpenLab software
Purification methods are as follows:
Compounds were purified using one of the following methods: normal or reverse phase automated flash column chromatography on silica or C-18 silica (e.g. Biotage™ Isolera or Selekt instruments); open access reverse phase prep HPLC (methods detailed below, P1— 4) and custom developed reverse phase prep HPLC method.
Method 1 : ACIDIC EARLY ELUTE METHOD (P1)
Purifications (P1) LC were performed on a Gilson LC system using a Waters Sunfire C18 column (30 mm x 100 mm, 10 pM; temperature: RT) and a gradient of 10- 95% B (A= 0.1% formic acid in H2O; B= 0.1% formic acid in MeCN) over 14.44 min then 95% B for 2.11 min. A second gradient of 95-10% B was then applied over 0.2 min with an injection volume of 1500 pL at flow rate of 40 mL/min. UV spectra were recorded at 215 nm using a Gilson detector.
Method 2: ACIDIC STANDARD METHOD (P2)
Purifications (P2) LC were performed on a Gilson LC system using a Waters Sunfire C18 column (30 mm x 10 mm, 10 pM; temperature: RT) and a gradient of 30-95% B (A= 0.1% formic acid in water; B= 0.1% formic acid in MeCN) over 11.00 min then 95% B for 2.10 min. A second gradient of 95-30% B was then applied over 0.2 min with an injection volume of 1500 pL at flow rate of 40 mL/min. UV spectra were recorded at 215 nm using a Gilson detector.
Method 3: BASIC EARLY ELUTE METHOD (P3)
Purification (P3) LC were performed in reverse phase using a Waters XBridgeTM C18 column (30 mm x 100 mm, 5 pm; temperature: room temperature), with an injection volume of 1500 pL at a flow rate of 40 mL/min at 10% B for 2.00 min then a gradient of 10 - 95% B over 14.00 min and held for 2.00 min, where A = 0.2% NH4OH in water and B = MeCN. A second gradient of 95 - 10% B was then applied over 0.20 min and held for 1.25 min. UV spectra were recorded at 215 nm.
Method 4: BASIC STANDARD METHOD (P4)
Purification (P4) LC were performed in reverse phase using a Waters XBridgeTM C18 column (30 mm * 100 mm, 5 pm; temperature: room temperature), with an injection volume of 1500 pL at a flow rate of 40 mL/min at 30% B for 2.00 min then a gradient of 30 - 95% B over 9.50min and held for 1.97 min, where A = 0.2% NH4OH in water and B = MeCN. A second gradient of 95 - 30% B was then applied over 0.33 min and held for 1.65 min. UV spectra were recorded at 215 nm.
Chiral Separation Methods:
LC Method:
Chiral separation on Gilson LC [Column at RT; isocratic eluent; flow rate: 18mL/min; detector wavelength; 215/254 nm; dilution solvent: IPA; injection volume: 100- 1000pL]
SFC Method:
Chiral separation on Waters Thar SFC [Column at 40°C; isocratic eluent; backpressure: 120bar; flow rate: 15mL/min; dilution solvent: MeOH / Acetonitrile; injection volume: 250pL]
NMR Methods are as follows:
Method 1, NMR (N1)
Unless otherwise stated, 1H NMR spectra were recorded at 500 MHz, 400 MHz or 250 MHz on either a Bruker Avance III HD 500 MHz spectrometer, Bruker Avance III HD 400 MHz spectrometer or Bruker Avance III HD 250 MHz spectrometer respectively. Chemical shifts, 5, are quoted in parts per million (ppm) and are referenced to the residual solvent peak. The following abbreviations are used to denote the multiplicities and general assignments: s (singlet), d (doublet), t (triplet), q (quartet), dd (doublet of doublets), ddd (doublet of doublet of doublets), dt (doublet of triplets), dq (doublet of quartets), hep (heptet), m (multiplet), pent (pentet), td (triplet of doublets), qd (quartet of doublets), app. (apparent) and br. (broad). Coupling constants, J, are quoted to the nearest 0.1 Hz.
Method 2, NMR: (N2)
Unless otherwise stated, 1H NMR spectra were recorded at 300 MHz or 500 MHz on either a Bruker 300 MHz Fourier spectrometer with a dual z-grad 1H/13C probe at 300 K, or a Bruker 500 MHz AVIII HD spectrometer with a N2-cooled z-grad broadband CPP BBO probe at 298 K spectrometer respectively. Chemical shifts, 5, are quoted in parts per million (ppm) and are referenced to the residual solvent peak. The following abbreviations are used to denote the multiplicities and general assignments: s (singlet), d (doublet), t (triplet), q (quartet), dd (doublet of doublets), ddd (doublet of doublet of doublets), dt (doublet of triplets), dq (doublet of quartets), hep (heptet), m (multiplet), pent (pentet), td (triplet of doublets), qd (quartet of doublets), app. (apparent) and br. (broad). Coupling constants, J, are quoted to the nearest 0.1 Hz.
Synthesis
General route 1 (synthesis of biaryl amino esters intermediates 1a-e)
Scheme 3
Intermediate 1a
Step A: (R) -N-[(E) -(5-bromo-2,3-difluorophenyl)methylidene]-2-methylpropane-2- sulfinamide A stirring solution of 5-bromo-2,3-difluorobenzaldehyde (25.00 g, 0.113 mol) and (R)-2-methylpropane-2-sulfinamide (15.08 g, 0.124 mol) in anhydrous THF (300 mL) under N2 at RT was treated dropwise with Ti(OiPr)4 (35 mL, 0.170 mol) then stirred at RT for 1 h, and at 40°C for 1 ,5h. The reaction was poured into a mixture of water (300 mL) and EtOAc (200 mL) and stirred vigorously for 10 mins. The suspension was then sonicated and filtered, washing with EtOAc (200 mL). The organic component was separated, the aqueous was extracted using EtOAc (3 x 100 mL), and the combined organics were washed with brine (2 x 100 mL), dried over MgSO4, filtered, and concentrated to the title compound (33.74 g, 87% Yield) as a solid.
LCMS m/z: 323.9/325.9 [M+HJ+, (ESI+), Rt = 1.08 (S1) 1H NMR (400 MHz, DMSO-d6) 5 [ppm]: 8.61 (s, 1 H), 8.09 (ddd, J = 9.8, 7.1 , 2.5 Hz, 1 H), 7.95 (dt, J = 5.3, 2.2 Hz, 1 H), 1.20 (s, 9H).
Step B ethyl (3S)-3-(5-bromo-2,3-difluorophenyl)-3-{[(R)-2-methylpropane-2- sulfinyl]amino}propanoate
A stirring suspension of zinc dust (activated) (26.91 g, 0.411 mol) in anhydrous THF (350 mL) at 65°C under N2 was treated dropwise with ethyl 2-bromoacetate (29 mL, 0.257 mol) over 20 mins. The solution was stirred at 65°C for 1.5h and allowed to cool and settle for 30 mins. The organozinc solution was added over 5 mins to a stirring solution of (R)-N-[(E)-(5-bromo-2,3-difluorophenyl)methylidene]-2-methylpropane-2-sulfinamide (35.10 g, 0.103 mol) in anhydrous THF (350 mL) under N2 at 65°C, the reaction was then stirred at 65°C for 1 ,5h.
The reaction was cooled and poured into a mixture of TBME (400 mL) and 10% citric acid (600 mL). The organics were separated, and the aqueous extracted with TBME (3 x 150 mL). The combined organics were washed with brine (2 x 150 mL), dried over MgSCL, filtered and concentrated to give crude product which was purified by silica dry flash chromatography (approx. 300 g silica, 0-70% EtOAc in heptane) to afford the title compound (29.40 g, 55% Yield) as an oil.
LCMS m/z: 412.4/414.2 [M+HJ+, (ESI+), Rt = 0.98 (S1) 1H NMR (400 MHz, DMSO-d6) 5 [ppm]: 5 7.74 (ddd, J = 9.6, 6.9, 2.4 Hz, 1H), 7.57 (dt, J = 5.4, 2.1 Hz, 1H), 5.85 (d, J = 7.0 Hz, 1H), 4.95 (d, J = 7.2 Hz, 1H), 4.07 - 3.97 (m, 2H), 3.02 (dd, J = 15.8, 7.2 Hz, 1H), 2.90 (dd, J = 15.8, 7.5 Hz, 1 H), 1.13 (t, J = 7.1 Hz, 3H), 1.06 (s, 9H). (N1)
Step C: ethyl (3S)-3-{4,5-difluoro-2',6'-dimethyl-[1, 1'-biphenyl]-3-yl}-3-{[(R)-2- methylpropane -2 -sulfinyl]amino}propanoate
A solution of ethyl (3S)-3-(5-bromo-2,3-difluorophenyl)-3-{[(R)-2-methylpropane-2- sulfinyl]amino}propanoate (20.00 g, 38.3 mmol), (2,6-dimethylphenyl)boronic acid (11.50 g, 76.6 mmol) and potassium carbonate (15.89 g, 0.115 mol) in 1,4-Dioxane (110 mL) and Water (8 mL) was sparged with N2 for 10 mins. Pd(dppf)Ch (1.57 g, 1.92 mmol) was added, and the reaction was stirred under N2 at 100°C for 4h. The reaction was cooled, poured into water (400 mL) and extracted with EtOAc (4 x 150 mL). The combined organics were washed with brine (2 x 100 mL), dried over MgSCL, filtered and concentrated to the crude product. This was purified by Biotage Isolera™ chromatography (350 g Silica; 10%-100% EtOAc in heptane followed by 0-20% MeOH in EtOAc), to afford the title compound (8.25 g, 44% Yield) as an oil.
LCMS m/z: 438.4 [M+HJ+, (ESI+), Rt = 1.14 (S1)
Step D: ethyl (3S)-3-amino-3-{4,5-difluoro-2',6'-dimethyl-[1, 1'-biphenyl]-3- yljpropanoate hydrochloride
A stirring solution of ethyl (3S)-3-{4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl}-3- {[(R)-2-methylpropane-2-sulfinyl]amino}propanoate (9.63 g, 18.3 mmol) in anhydrous DOM (100 mL) at RT under N2 was treated with HOI [4 M in dioxane] (9.1 mL, 36.5 mmol) and stirred at RT for 2h. The reaction was concentrated in vacuo and the residue purified by FC (50 g silica, 0%-43% MeOH in EtOAc) to intermediate 1a, (7.38 g, 94% Yield) as an solid.
LCMS m/z: 334.1 [M+H]+, (ESI+), Rt = 0.71 (S1) 1H NMR (500 MHz, DMSO-d6) 5 [ppm]: 5 8.80 (s, 3H), 7.42 - 7.35 (m, 1H), 7.35 - 7.27 (m, 1 H), 7.22 - 7.17 (m, 1H), 7.17 - 7.09 (m, 2H), 4.95 - 4.81 (m, 1H), 4.08 - 3.94 (m, 2H), 3.25 - 3.17 (m, 1H), 3.17 - 3.03 (m, 1 H), 2.03 (s, 3H), 1.95 (s, 3H), 1.08 (t, J = 7.1 Hz, 3H). (N1)
Intermediate 1b
Step E ethyl (3S)-3-amino-3-(5-bromo-2,3- difluorophenyl)propanoate hydrochloride
A stirring solution of ethyl (3S)-3-(5-bromo-2,3-difluorophenyl)-3-{[(R)-2- methylpropane-2-sulfinyl]amino}propanoate (0.50 g, 0.958 mmol) from general route 1 step E in anhydrous DCM (10 mL) at RT under N2 was treated with HCI [4 M in dioxane] (1.0 mL, 4.00 mmol) and stirred for 3h. The reaction was then concentrated in vacuo and purified using a silica plug (4 CV DCM flush then 4 CV 1 :1 DCM-MeOH to elute product), filtrate was concentrated to afford the title intermediate 1b as an oil.
LCMS m/z: 308.1/310.1 [M+HJ+, (ESI+), Rt = 0.55 (S1)
The following intermediates were prepared according to the general route 1 reported for intermediate 1a as outlined in Scheme 3, using the corresponding starting materials.
Intermediate 1c
Step A (R) -N-[(E) -[3-bromo-2,6-difluoro-5-(trifluoromethyl)phenyl]methylidene]-2- methylpropane -2 -sulfinamide
Prepared using the route as outlined in Scheme 3, Step A, from ethyl (3S)-3-[3- bromo-2,6-difluoro-5-(trifluoromethyl)phenyl]-3-{[(R)-2-methylpropane-2- sulfinyl]amino}propanoate and 3-bromo-2,6-difluoro-5-(trifluoromethyl)benzaldehyde. LCMS m/z: 392.1 [M+HJ+, (ESI+), Rt = 1.08, (S1)
1H NMR (400 MHz, DMSO-d6) 5 [ppm]: 5 8.58 (s, 1 H), 8.46 (t, J = 7.2 Hz, 1H), 1.25 - 1.13 (m, 9H). (N1)
Step B ethyl (3S)-3-[3-bromo-2,6-difluoro-5-(trifluoromethyl)phenyl]-3-{[(R)-2- methylpropane -2 -sulfinyl]amino}propanoate
Prepared using the route as outlined in Scheme 3, Step B, from (R)-N-[(E)-[3- bromo-2,6-difluoro-5-(trifluoromethyl)phenyl]methylidene]-2-methylpropane-2-sulfinamide. LCMS m/z: 480.1/482.1 [M+HJ+, (ESI+), Rt = 0.89, (S1)
1H NMR (400 MHz, DMSO-d6) 5 [ppm]: 5 8.21 (t, J = 7.2 Hz, 1H), 5.96 (d, J = 5.0 Hz, 1 H), 5.12 (q, J = 6.8 Hz, 1H), 4.01 (q, J = 7.1 Hz, 2H), 3.23 - 2.97 (m, 2H), 1.11 - 1.06 (m, 3H), 1.02 (s, 9H). (N1)
Step C ethyl (3S)-3-[2,4-difluoro-2',4',6'-trimethyl-5-(trifluoromethyl)-[1, -biphenyl]- 3 -yl]-3 -{[ (R) -2 -methylpropane -2 -sulfinyl]amino}propanoate
Prepared using the route as outlined in Scheme 3, Step C, from ethyl (3S)-3-[3- bromo-2,6-difluoro-5-(trifluoromethyl)phenyl]-3-{[(R)-2-methylpropane-2- sulfinyl]amino}propanoate
LCMS m/z: 520.3 [M+HJ+, (ESI+), Rt = 1.20, (S1)
Step D ethyl (3S)-3-amino-3-[2,4-difluoro-2',4',6'-trimethyl-5-(trifluoromethyl)-[1, - biphenyl]-3 -yl]propanoate hydrochloride
Prepared using the route as outlined in Scheme 3, Step D, from ethyl (3S)-3-[2,4- difluoro-2',4',6'-trimethyl-5-(trifluoromethyl)-[1,1'-biphenyl]-3-yl]-3-{[(R)-2-methylpropane-2- sulfinyl]amino}propanoate (EV-SBW001 -785-001)
LCMS m/z: 416.3 [M+HJ+, (ESI+), Rt = 0.91, (S1)
Intermediate 1d Step C ethyl (3S)-3-{[(R)-2-methylpropane-2-sulfinyl]amino]-3-{4,4',5-trifluoro-2',6'- di methyl -[ 1, 1 '-bi phenyl] -3 -yl}propa noate
Prepared using the route as outlined in Scheme 3, Step C, from ethyl (3S)-3-(5- bromo-2,3-difluorophenyl)-3-{[(R)-2-methylpropane-2-sulfinyl]amino}propanoate and 2-(4- fluoro-2,6-dimethylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.
LCMS m/z: 456.5 [M+HJ+, (ESI+), Rt = 1.01, (S2)
Step D ethyl (3S)-3-amino-3-{4,4',5-trifluoro-2',6'-dimethyl-[1, -biphenyl]-3- yljpropanoate hydrochloride
Prepared using the route as outlined in Scheme 3, Step D, from ethyl (3S)-3-{[(R)-
2-methylpropane-2-sulfinyl]amino}-3-{4,4',5-trifluoro-2',6'-dimethyl-[1,1'-biphenyl]-3- yljpropanoate.
LCMS m/z: 352.3 [M+HJ+, (ESI+), Rt = 0.89, (S2)
Intermediate 1e
Step A - (R)-N -[(E) -(5 -bromo -2 -fluoro -3 -methylphenyl) methylidene] -2- methylpropane -2 -sulf inamide
Prepared using the route as outlined in Scheme 3, Step A, from 5-bromo-2-fluoro-
3-methylbenzaldehyde.
LCMS m/z: 322.1 [M+HJ+, (ESI+), Rt = 1.14, (S1)
1H NMR (400 MHz, DMSO-d6) 5 [ppm]: 8.62 (s, 1 H), 7.95 - 7.87 (m, 1 H), 7.82 - 7.74 (m, 1 H), 2.33 - 2.26 (m, 3H), 1.19 (s, 9H). (N1) Step B - ethyl (3S)-3-(5-bromo-2-fluoro-3-methylphenyl)-3-{[(R)-2-methylpropane-
2 -sulfinyl]amino}propanoate
Prepared using the route as outlined in Scheme 3, Step B, from (R)-N-[(E)-(5- bromo-2-fluoro-3-methylphenyl)methylidene]-2-methylpropane-2-sulfinamide.
LCMS m/z: 408.2 [M+HJ+, (ESI+), Rt = 1.02, (S1)
1H NMR (500 MHz, DMSO-d6) 5 [ppm]: 7.53 - 7.47 (m, 1 H), 7.45 - 7.38 (m, 1 H), 5.73 (d, J = 7.0 Hz, 1 H), 4.91 (q, J = 7.2 Hz, 1 H), 4.01 (q, J = 7.1 Hz, 2H), 2.97 (dd, J = 15.5, 7.4 Hz, 1 H), 2.81 (dd, J = 15.5, 7.4 Hz, 1 H), 2.25 - 2.16 (m, 3H), 1.13 - 1.08 (m, 3H), 1.05 (s, 9H). (N1)
Step E - ethyl (3S)-3-amino-3-(5-bromo-2-fluoro-3-methylphenyl)propanoate hydrochloride
Prepared using the route as outlined in Scheme 3, Step E, from ethyl (3S)-3-(5- bromo-2-fluoro-3-methylphenyl)-3-{[(R)-2-methylpropane-2-sulfinyl]amino}propanoate. LCMS m/z: 304.1 [M+HJ+, (ESI+), Rt = 0.60, (S1)
Intermediate 1f
Step C ethyl (3S)-3-{4,5-difluoro-2',4',6'-trimethyl-[1, 1'-biphenyl]-3-yl}-3-{[(R)-2- methylpropane -2 -sulfinyl]amino}propanoate
Prepared using the route as outlined in Scheme 3, Step C, from ethyl (3S)-3-(5- bromo-2,3-difluorophenyl)-3-{[(R)-2-methylpropane-2-sulfinyl]amino}propanoate and (2,4,6-trimethylphenyl)boronic acid.
LCMS m/z: 452.3 [M+HJ+, (ESI+), Rt = 1.21 , (S1) 1H NMR (400 MHz, CDCh) 6 [ppm]: 56.95 - 6.86 (m, 4H), 5.16 - 5.07 (m, 1H), 4.79 (d, J = 6.2 Hz, 1 H), 4.17 - 4.00 (m, 2H), 3.05 - 2.88 (m, 2H), 2.32 (s, 3H), 1.96 (d, J = 4.8 Hz, 6H), 1.24 - 1.17 (m, 12H). (N1)
Step D ethyl (3S)-3-amino-3-{4,5-difluoro-2',4',6'-trimethyl-[1, -biphenyl]-3- yljpropanoate hydrochloride
Prepared using the route as outlined in Scheme 3, Step D, from ethyl (3S)-3-{4,5- difluoro-2',4',6'-trimethyl-[1,1'-biphenyl]-3-yl}-3-{[(R)-2-methylpropane-2- sulfinyl]amino}propanoate.
LCMS m/z: 348.2 [M+H]+, (ESI+), Rt = 0.84, (S1)
1H NMR (400 MHz, CDCI3) 6 [ppm]: 5 8.94 (s, 3H), 7.08 (s, 1 H), 6.96 (dd, J = 10.1 , 6.7 Hz, 1H), 6.86 (d, J = 5.3 Hz, 2H), 5.02 (s, 1 H), 4.06 (q, J = 6.9 Hz, 2H), 3.25 (d, J = 15.7 Hz, 1 H), 3.07 (d, J = 15.6 Hz, 1H), 2.29 (s, 3H), 1.93 (d, J = 13.0 Hz, 6H), 1.16 (t, J = 6.4 Hz, 3H) (N1)
Intermediate 1g
1st step: ethyl (3S)-3-(5-bromo-2,3-difluorophenyl)-3-{[(tert- butoxy)carbonyl]amino}propanoate
To a solution of intermediate 1b (500 mg, 1.45 mmol) in methyltetrahydrofuran (5ml) was added NEt3 (375 uL, 1.60 mmol) and Boc2O (349 mg, 3.05 mmol). The solution was stirred at RT for 2 hours. The solvent was removed in vacuo to give an oil. Purification by coluimn chromatography (10g silica, 0-40% EtOAc in heptane) afforded the title product (600 mg, 90% yield) as an oil.
LCMS m/z: 309.9 [M-Boc+H]+, (ESI+), Rt = 0.96, (S2)
2nd step: ethyl (3S)-3-{[(tert-butoxy)carbonyl]amino}-3-[2,3-difluoro-5-(4, 4,5,5- tetra methyl -1,3,2 -dioxaborolan -2 -yl)phenyl]propanoate
To a solution of ethyl (3S)-3-(5-bromo-2,3-difluorophenyl)-3-{[(tert- butoxy)carbonyl]amino}propanoate (600 mg, 1.47 mmol) in 1,4-dioxane (12ml) was added KOAc (447 mg, 4.56 mmol), B2Pin2 (450 mg, 1.77 mmol) and Pd (dppf)2Ch (122 mg, 0.15 mmol). The reaction mixture was heated at 80°C for 2 hours. The reaction mixture was concentrated in vacuo to afford a brown gum. Purification by column chromatography (10g silica, 0-50% acetone in heptane then 10% MeOH in acetone) afforded the titled product (520 mg, 89% yield) as an oil.
LCMS m/z: 356.3 [M-Boc+H]+, (ESI+), Rt = 0.79, (S1)
3rd step: ethyl (3S)-3-{[(tert-butoxy)carbonyl]amino}-3-[5-(3,5-dimethylpyridin-4-yl)-
2, 3 -difluorophenyl]propanoate
To a solution of ethyl (3S)-3-{[(tert-butoxy)carbonyl]amino}-3-[2,3-difluoro-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoate ( 950mg, 1.47 mmol) in 1 ,4-dioxane (1.8 mL) and water (1.8 mL) was added K2CO3 (813 mg, 5.88 mmol), 3,5- dimethyl-4-bromopyridine (590 mg, 2.65 mmol) and Pd(dppf)2CI2 (256 mg, 0.3 mmol). Th ereaction was heated at 100°C for 2 hours. The reaction mixture was concentrated in vacuo to afford a brown gum. Purification by column chromatography (10g silica, 0-100% EtOAc in heptane then 10% MeOH in EtOAc) afforded the titled product (800 mg, 52% yield) as an oil.
LCMS m/z: 435.3 [M+HJ+, (ESI+), Rt = 0.91 , (S1)
4th step: ethyl (3S)-3-amino-3-[5-(3,5-dimethylpyridin-4-yl)-2,3- difluorophenyl]propanoate hydrochloride
Prepared using the route as outlined in Scheme 3, Step D, from intermediate 117.
LCMS m/z: 336.4 [M+HJ+, (ESI+), Rt = 0.67 (S1)
General route 2 (synthesis of N-acyl-(6,6-dimethylcyclopropyl)pyrrolidine-2- carboxylate intermediates 2a-b)
Scheme 4
Intermediate 2a
Step A - methyl (1R,2S,5S)-3-benzoyl-6,6-dimethyl-3-azabicyclo[3.1 ,0]hexane-2- carboxylate
To a stirred solution of methyl (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane- 2-carboxylate hydrochloride (96%, 253 mg, 1.18 mmol) and triethylamine (190 pL, 1.36 mmol) in DCM (2.2 mL) was added benzoyl chloride (125 pL, 1.08 mmol at 0 °C). The solution was then allowed to warm to RT over 30 mins and stirred for 1 h. The reaction mixture was diluted with EtOAc (50 mL), washed with HCI (1 M, 50 mL), and brine (50 mL). The organic layer was dried over MgSCL, concentrated in vacuo, and purified by FC (10 g Silica, 0-60% EtOAc in heptane) to afford the title compound (91.0%) (200 mg, 62% Yield) as an oil.
LCMS m/z: 274.2 [M+HJ+, (ESI+), Rt = 0.87 (S1) 1H NMR (400 MHz, DMSO-d6) 5 [ppm]: 5 7.54 - 7.14 (m, 5H), 4.47 (s, 1 H), 3.87 - 3.22 (m, 2H), 3.51 (s, 3H), 1.55 - 1.44 (m, 2H), 1.06 - 0.90 (m, 6H). (N1) Step B - (1R,2S,5S)-3-benzoyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carboxylic acid
To a stirred solution of methyl (1R,2S,5S)-3-benzoyl-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylate (200 mg, 0.549 mmol) from step A in THF (5 mL) and MeOH (0.1 mL) was added 2M LiOH (aq) (1.7 mL, 3.40 mmol). The mix was stirred at 50 °C for 1.5 h. The solution was then allowed to cool for 45 min before water (10 mL) was added and the mixture concentrated in vacuo. The remaining solution was acidified with HCI (1 M) until pH 3 and then extracted with DCM (3 x 15 mL). The combined organic layers were dried over MgSCL and concentrated in vacuo to give intermediate 2a (84.0%) (150 mg, 89% Yield) as an oil.
LCMS m/z: 260.2 [M+HJ+, (ESI+), Rt = 0.74 (S1)
1H NMR (400 MHz, DMSO-d6) 5 [ppm]: 5 12.87 (s, 1 H), 7.45 - 7.40 (m, 4H), 7.28 - 7.21 (m, 1 H), 4.39 (s, 1 H), 3.82 (dd, J = 10.7, 4.9 Hz, 1 H), 3.23 (d, J = 10.8 Hz, 1H), 1.49 - 1.46 (m, 2H), 1.06 - 0.89 (m, 6H). (N1)
The following intermediates were prepared in a manner similar intermediate 2a as outlined in general route 2 (Scheme 4), using the corresponding starting materials.
Intermediate 2b
Step A - methyl (1R,2S,5S)-3-acetyl-6,6-dimethyl-3-azabicyclo[3. 1.0]hexane-2- carboxylate
Prepared using the general route as outlined in Scheme 4, Step A from methyl
(1 R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1 ,0]hexane-2-carboxylate.
LCMS m/z: 212.2 [M+HJ+, (ESI+), Rt = 0.64, (S1)
1H NMR (400 MHz, Chloroform-d) 5 [ppm]: 4.38 (s, 1H), 3.84 (dd, J = 10.2, 5.2 Hz, 1H), 3.75 (s, 3H), 3.46 (d, J = 10.2 Hz, 1 H), 2.03 (s, 3H), 1.54 - 1.40 (m, 2H), 1.05 (s, 3H), 0.96 (s, 3H) (N1)
Step B - (1R,2S,5S)-3-acetyl-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid
Prepared using the general route as outlined in Scheme 4, Step B, from methyl (1 R,2S,5S)-3-acetyl-6,6-dimethyl-3-azabicyclo[3.1 ,0]hexane-2-carboxylate.
LCMS m/z: 324.4 [M+HJ+, (ESI+), Rt = 1.11, (S1)
General route 3 (synthesis of Intermediates 3a-b)
Scheme 5
Intermediate 3a
Step A - ethyl 8-(3-fluoroazetidin-1 -yl)imidazo[1 , 2 -a]pyridine -2 -carboxylate
A suspension of CS2CO3 (593 mg, 1.82 mmol) , ethyl 8-bromoimidazo[1,2- a]pyridine-2-carboxylate (200 mg, 0.728 mmol), 3-fluoroazetidine hydrochloride (122 mg, 1.09 mmol) and XantPhos Pd G3 (69 mg, 0.0728 mmol) in dioxane (4 mL) was purged with nitrogen for 5 min, before being heated at 100 °C for 18 h. The reaction mixture was partitioned between DCM (5 mL) and water (5 mL), the aqueous layer was extracted with DCM (5 mL), and the combined organics were dried using a hydrophobic frit before being concentrated in vacuo to afford a brown solid. The solid was triturated in MeCN (2 mL) and the resulting suspension was filtered. The solid was washed with MeCN (1 mL) to afford ethyl 8-(3-fluoroazetidin-1-yl)imidazo[1,2-a]pyridine-2-carboxylate (90 mg, 46% Yield) as a solid.
LCMS m/z: 264.1 [M+HJ+, (ESI+), Rt = 0.74 (S1) 1H NMR (400 MHz, DMSO-d6) 6 [ppm]: 8.47 (s, 1H), 7.99 - 7.92 (m, 1 H), 6.85 - 6.77 (m, 1 H), 6.11 - 6.04 (m, 1H), 5.63 - 5.34 (m, 1 H), 4.56 - 4.42 (m, 2H), 4.30 (q, J = 7.1 Hz, 2H), 4.24 - 4.10 (m, 2H), 1.31 (t, J = 7.1 Hz, 3H).
Step B - 8-(3-fluoroazetidin-1 -yl)imidazo[1 ,2-a]pyridine-2-carboxylic acid
A solution of ethyl 8-(3-fluoroazetidin-1-yl)imidazo[1,2-a]pyridine-2-carboxylate from step A (90 mg, 0.342 mmol) in LiOH (2 M, aq, 205 pL, 0.410 mmol), THF (1 mL) and Methanol (1 mL) was stirred at 50 °C for 72 h. The reaction mixture was loaded onto a reverse phase samplet, and purified reverse phase FC (12 g C-18, 0-100% MeCN (0.1% formic acid) in water (0.1% formic acid)), to afford 8-(3-fluoroazetidin-1-yl)imidazo[1,2- a]pyridine-2-carboxylic acid intermediate 3a (55 mg, 68% Yield) as a solid.
LCMS m/z: 236.1 [M+HJ+, (ESI+), Rt = 0.47 (S1) 1H NMR (400 MHz, DMSO-d6) 5 [ppm]: 12.65 (br. s, 1H), 8.39 (s, 1 H), 7.95 (dd, J = 6.7, 1.0 Hz, 1 H), 6.83 - 6.74 (m, 1 H), 6.09 - 6.02 (m, 1 H), 5.64 - 5.38 (m, 1 H), 4.49 (dddd, J = 20.9, 10.1, 5.7, 1.5 Hz, 2H), 4.17 (dddd, J = 24.4, 10.1, 3.4, 1.4 Hz, 2H). (N1)
The following intermediates were prepared in a manner similar to intermediate 3a as outlined in Scheme 5, using the corresponding starting materials.
Intermediate 3b
Step A - ethyl 7-(3-fluoroazetidin-1 -yl)imidazo[1 , 2 -a]pyridine -2 -carboxylate
Prepared using the general route 3 as outlined in Scheme 5, Step A from ethyl 7- bromoimidazo[1,2-a]pyridine-2-carboxylate and 3-fluoroazetidine hydrochloride.
LCMS m/z: 264.1 [M+H]+, (ESI+), Rt = 0.49, (S1)
1H NMR (400 MHz, DMSO-d6) 5 [ppm]: 8.34 (d, J = 7.4 Hz, 1 H), 8.24 (s, 1 H), 6.52 - 6.45 (m, 1H), 6.24 (d, J = 2.2 Hz, 1H), 5.51 (dtt, J = 57.5, 6.0, 3.1 Hz, 1 H), 4.34 - 4.18 (m, 4H), 4.00 (dddd, J = 24.2, 9.7, 3.1 , 1.4 Hz, 2H), 1.29 (t, J = 7.1 Hz, 3H). (N1)
Step B - 7-(3-fluoroazetidin-1 -yl)imidazo[1,2-a]pyridine-2-carboxylic acid
Prepared using the general route 3 as outlined in Scheme 5, Step B from ethyl 7- (3-fluoroazetidin-1 -yl)imidazo[1 ,2-a]pyridine-2-carboxylate.
LCMS m/z: 236.1 [M+HJ+, (ESI+), Rt = 0.37, (S1)
1H NMR (400 MHz, DMSO-d6) 5 [ppm]: 8.39 - 8.32 (m, 1 H), 8.06 (s, 1 H), 6.50 (dd, J = 7.4, 2.3 Hz, 1 H), 6.21 (d, J = 2.2 Hz, 1 H), 5.51 (dtt, J = 57.5, 6.0, 3.1 Hz, 1 H), 4.27 (dddd, J = 21.0, 9.9, 5.8, 1.5 Hz, 2H), 4.02 (dddd, J = 24.3, 9.9, 3.1 , 1.4 Hz, 2H). (N1)
General route 10 (synthesis of 1-alkylpyrazole RHS intermediate)
Intermediate 105
Step A: methyl 6-(3-fluoroazetidin-1 -yl)pyrazolo[1 ,5-a]pyridine-3-carboxylate
A suspension of dicaesium carbonate (958 mg, 2.94 mmol), methyl 6- bromopyrazolo[1 ,5-a]pyridine-3-carboxylate (300 mg, 1.18 mmol), 3-fluoroazetidine hydrochloride (1 :1) (197 mg, 1.76 mmol) and XantPhos Pd G3 (112 mg, 0.118 mmol) was purged with nitrogen for 5 minutes before being heated at 100°C for 18 hours. The reaction mixture was partitioned between ethyl acetate (10 mL) and water (10 mL). The resulting suspension was filtered. The solids were washed through with water (5 mL) and ethyl acetate (5 mL) to afford the titled product (130 mg, 0.516 mmol, 44% Yield) as a grey solid.
The filtrate phases were separated and the aqueous layer was extracted with ethyl acetate (10 mL). The combined organics were washed with brine (2 x 10 mL), dried with MgSCL and concentrated in vacuo to afford a brown oil. The oil was triturated in ethyl acetate/MeOH (—2:1 , 5 mL) and was filtered. The solids were washed with ethyl acetate (2 mL) and MeOH (2 mL) to afford the titled product (60 mg, 96% pure, 20% Yield) as an off- white solid. The filtrate was concentrated in vacuo and was purified by column chromatography (10g silica, 0-100% ethyl acetate in heptane) to afford th etotled product (75 mg, 63% pure, 16% Yield) as a white solid.
LCMS m/z: 250.1 [M+H]+, (ESI+), Rt = 0.71 (S1)
1H NMR (400 MHz, DMSO-d6) 5 [ppm]: 8.28 (s, 1H), 8.10 - 8.05 (m, 1H), 7.97 - 7.90 (m, 1 H), 7.14 (dd, J = 9.4, 2.1 Hz, 1 H), 5.61 - 5.40 (m, 1H), 4.21 (dddd, J = 20.5, 9.4, 5.7, 1.3 Hz, 2H), 3.96 (dddd, J = 24.0, 9.4, 3.3, 1.3 Hz, 2H), 3.80 (s, 3H).
Intermediate 106
Step B: 6-(3-fluoroazetidin-1 -yl)pyrazolo[1 ,5-a]pyridine-3-carboxylic acid
A solution of methyl 6-(3-fluoroazetidin-1-yl)pyrazolo[1,5-a]pyridine-3-carboxylate (255 mg, 1.02 mmol) in 2 M aq. lithium hydroxide (1023 uL, 2.05 mmol) , THF (10.2 mL) and Methanol (10.2 mL) was stirred at 40°C for 18 hours. Additional 2M aq. LiOH (3 mL, 3 mmol) was added and the reaction mixture was stirred at 50°C for 6 hours. The reaction mixture was concentrated in vacuo and was purified by reverse phase column chromatography (6 g C-18 silica, 0-100% MeCN I H2O (containing 0.1% formic acid) to afford the titled product (440 mg, 1.03 mmol, 101% Yield) as a white solid.
LCMS m/z: 236.1 [M+H]+, (ESI+), Rt = 0.57 (S1)
1H NMR (400 MHz, DMSO-d6) 5 8.12 [ppm]: (dd, J = 9.4, 0.8 Hz, 1 H), 7.87 (s, 1H), 7.78 (dd, J = 2.0, 0.9 Hz, 1 H), 6.81 (dd, J = 9.4, 2.0 Hz, 1 H), 5.62 - 5.36 (m, 1 H), 4.22 - 4.08 (m, 2H), 3.95 - 3.81 (m, 2H).
General route 11 (synthesis of 1-alkylpyrazole RHS intermediate)
Intermediate 100
Step A: ethyl 1 -{1 -[(tert-butoxy)carbonyl]azetidin-3-yl}-1 H-pyrazole -4 -carboxylate
To a solution of ethyl 1 H-pyrazole-4-carboxylate (200 mg, 1.43 mmol) in Acetonitrile (3 mL) was added tert-butyl 3-iodoazetidine-1 -carboxylate (0.27 mL, 1.43 mmol) and K2CO3 (276 mg, 2.00 mmol). The reaction mixture was heated at 80°C for 20 hours. The reaction was cooled to RT and filtered. The filtrate was concentrated in vacuo to give an oil. Purification by column chromatography (10 g silica, 0 - 50% EtOAc in heptane) afforded the titled product (198 mg, 90% pure, 42% Yield) as a colourless oil.
LCMS m/z: 240.2 [M-butyl+H]+, (ESI+), Rt = 0.87 (S2)
1H NMR (500 MHz, DMSO-d6) 5 [ppm]: 8.47 (d, J = 0.7 Hz, 1 H), 7.97 (s, 1 H), 5.30 - 5.21 (m, 1 H), 4.31 - 4.25 (m, 2H), 4.21 (q, J = 7.1 Hz, 2H), 4.13 (br. s, 2H), 1.40 (s, 9H), 1.26 (t, J = 7.1 Hz, 3H).
Intermediate 101
Step B: 1 -{1 -[(tert-butoxy)carbonyl]azetidin-3-yl}-1H-pyrazole-4-carboxylic acid
To a stirring solution of ethyl 1-(1-tert-butoxycarbonylazetidin-3-yl)pyrazole-4- carboxylate (90%, 198 mg, 0.603 mmol) in THF (2 mL) and Methanol (0.2 mL) was added 2M aq. LiOH (0.40 mL, 0.800 mmol). The reaction mixture was stirred at RT for 22 hours. The reaction mixture was concentrated in vacuo, diluted with water (5ml) and adjusted the pH to 4 using 10% citric acid aqueous solution. The resulting precipitate was extracted with DCM (2 x 20 mL), passed through a hydrophobic frit and concentrated in vacuo to afford the titled product (138 mg, 85% Yield) as a white solid.
LCMS m/z: 266.1 [M+H]+, (ESI+), Rt = 0.64 (S2)
1H NMR (500 MHz, DMSO-d6) 5 [ppm]: 12.40 (br. s, 1 H), 8.38 (d, J = 0.6 Hz, 1 H), 7.92 (s, 1 H), 5.29 - 5.20 (m, 1 H), 4.31 - 4.24 (m, 2H), 4.12 (br. s, 2H), 1.40 (s, 9H).
General route 4 (synthesis of intermediates 4a-b)
Scheme 6
Intermediate 4a ethyl (3S)-3-(5-bromo-2,3 -difluorophenyl) -3-{[(1R,2S,5S)-6,6 -dimethyl -3-(1 -methyl -
HATLI (726 mg, 1.91 mmol) was added to a solution of intermediate 1b (470 mg, 0.955 mmol), intermediate 12 (282 mg, 1.05 mmol), and DIPEA (1.7 mL, 9.55 mmol) in DCM (10 mL) at RT and stirred for 16h. The reaction was diluted with water (30 mL) and extracted with DCM (3 x 15 mL). The organic components were dried over MgSCL, filtered, and concentrated to afford the crude material which was purified by FC (50 g Silica; 10%-100% EtOAc in heptane then 20% MeOH in EtOAc) to afford a crude oil. This was re-purified by basic reverse-phase FC (30g C18-D; 10%-100% MeCN (0.1 % ammonium hydroxide) in Water to afford the title intermediate (245 mg, 45% Yield) as an oil.
LCMS m/z: 553.5/555.3 [M+HJ+, (ESI+), Rt = 0.86 (S1)
The following intermediates were prepared in a manner similar intermediate 4a as outlined in Scheme 6 using the corresponding starting materials.
Intermediate 4b ethyl (3S) -3-(5-bromo-2-fluoro-3-methylphenyl) -3-{[(1R,2S,5S) -6, 6-dimethyl-3-(1 -
Prepared using the route as outlined to general route 4, from intermediate 1e and (1 R,2S,5S)-6,6-dimethyl-3-(1-methyl-1 H-imidazole-4-carbonyl)-3-azabicyclo[3.1.0]hexane- 2-carboxylic acid. LCMS m/z: 549.5/550.3 [M+H]+, (ESI+), Rt = 0.86 (S1)
Intermediate 4c ethyl (3S) -3-(5-bromo-2,3-difluorophenyl) -3-{[(1R,2S,5S) -3-{imidazo[1,2- a ]pyrazine -2 -carbonyl] -6, 6 -dimethyl -3 -azabicyclo[3. 1.0]hexan -2 -yl]formamido]propanoate
Prepared using the route as outlined to general route 4, from intermediate 1 b and intermediate 12c (1 R,2S,5S)-3-{imidazo[1 ,2-a]pyrazine-2-carbonyl}-6,6-dimethyl-3- azabicyclo[3.1 ,0]hexane-2-carboxylic acid.
LCMS m/z: 592.2 [M+H]+, (ESI+), Rt = 0.89 (S1)
General route 5 (Suzuki coupling synthesis of intermediate 5a)
Scheme 7
Intermediate 5a ethyl (3S) -3-{[(1R,2S,5S) -6,6-dimethyl-3-( 1 -methyl-1H-imidazole-4 -carbonyl) -3- azabicyclo[3. 1.0]hexan -2 -yl]formamido] -3 -{4 -fluoro -2 4 5, 6' -tetra methyl -[ 1, 1 '-biphenyl] -3 - yljpropanoate
A suspension of intermediate 4a (115 mg, 0.205 mmol), (2,4,6- trimethylphenyl)boronic acid (50 mg, 0.305 mmol) and K2CO3 (85 mg, 0.615 mmol) in Dioxane (1 .5 mL) and water (0.05 mL) in a pressure vial was sparged with N2 for 3 mins then Pd(dppf)Ch (15 mg, 0.0205 mmol) was added. The reaction was stirred at 100 °C under N2 for 2 h. To the reaction mixture was added EtOAc (5 mL) and water (10 mL). The aqueous was extracted with EtOAc (3 x 5 mL), and the combined organics were washed with brine (10 mL), dried over MgSO4, and concentrated in vacuo to afford the title intermediate 5a (200 mg, 56% Yield) as an oil.
LCMS m/z: 589.4 [M+HJ+, (ESI+), Rt = 1.08 (S1)
General route 6 (amide coupling with biaryl amino ester, synthesis of intermediates 6a-e)
Scheme 8
Intermediate 6a tert-butyl (1R,2S,5S) -2-{[(1S)-1 -{4,5-difluoro-2', 6'-dimethyl-[1, 1 ' -bi phenyl] -3 -yl} -3-
DIPEA (6.4 mL, 36.5 mmol) was added to a solution of (1 R,2S,5S)-3-[(tert- butoxy)carbonyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (3.91 g, 15.3 mmol), intermediate 1a (90%, 6.00 g, 14.6 mmol), and HATLI (6.11 g, 16.1 mmol) in DCM (100 mL), and stirred at RT for 2 h. Water (50 mL) was added and the resulting aqueous layer extracted with DCM (50 mL). The combined organics were dried using a hydrophobic frit and concentrated in vacuo. The residual material was purified via FC (100 g, eluting with 0-50% EtOAc in heptane), to afford the title intermediate (6.40 g, 77% Yield) as a glass.
LCMS m/z: 471.5 [M+HJ+, (ESI+), Rt = 1.26 (S1) 1H NMR (400 MHz, CDCI3) 6 [ppm]: 5 7.80 - 7.27 (m, 1 H), 7.18 - 7.10 (m, 1H), 7.10 - 7.02 (m, 2H), 6.95 - 6.81 (m, 2H), 5.71 - 5.59 (m, 1H), 4.15 - 3.96 (m, 3H), 3.71 - 3.40 (m, 2H), 2.99 - 2.79 (m, 2H), 2.02 - 1.97 (m, 3H), 1.97 - 1.93 (m, 3H), 1.60 - 1.50 (m, 1 H), 1.33 - 1.13 (m, 13H), 1.04 - 0.98 (m, 3H), 0.89 - 0.85 (m, 3H). (N1)
The following intermediates were prepared in a manner similar intermediate 6a as outlined in Scheme 8, using the corresponding starting materials.
Intermediate 6b tert -butyl (1 R, 2 S, 5S) -2 -{[(1S)-1 -[2, 4 -di fluoro -2', 4 6' -tri methyl -5 -(trifluoromethyl) - [1, 1 ' -biphenyl] -3 -yl] -3 -ethoxy -3 -oxopropyl]carbamoyl] -6, 6 -dimethyl -3- azabicyclo[3. 1.0]hexane -3 -Carboxylate
Prepared according to the general route 6, reported in Scheme 7, starting from ethyl (3S)-3-amino-3-[2,4-difluoro-2',4',6'-trimethyl-5-(trifluoromethyl)-[1,T-biphenyl]-3- yl]propanoate hydrochloride (synthesised according to general route 1) and (1R,2S,5S)-3- [(tert-butoxy)carbonyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid synthesised according to general route 5.
LCMS m/z: 675.5 [M+HJ+, (ESI+), Rt = 1.28 (S1)
Intermediate 6c ethyl (3S) -3-{[(1R,2S,5S) -3-benzoyl-6,6-dimethyl-3-azabicyclo[3. 1.0]hexan-2-
Prepared according to the general route 6, reported in Scheme 7, starting from intermediate 1a (synthesised according to general route 1) and (1 R,2S,5S)-3-benzoyl-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid synthesised according to general route 5.
LCMS m/z: 575.4 [M+HJ+, (ESI+), Rt = 1.17 (S1)
1H NMR (400 MHz, DMSO-d6) 5 [ppm]: 5 8.71 - 8.43 (m, 1 H), 7.51 - 6.93 (m, 10H), 5.63 - 5.39 (m, 1H), 4.43 - 3.89 (m, 1 H), 4.07 - 3.94 (m, 2H), 3.88 - 3.55 (m, 2H), 3.25 - 2.79 (m, 2H), 2.67 - 2.57 (m, 1H), 2.00 - 1.88 (m, 6H), 1.42 - 1.31 (m, 1H), 1.13 - 1.07 (m, 3H), 0.95 - 0.79 (m, 6H). (N1)
Intermediate 6d ethyl (3S) -3-{[(1R,2S,5S) -3-acetyl-6,6-dimethyl-3-azabicyclo[3. 1.0]hexan-2- yl]formamido] -3 -{4, 5 -di fluoro -2', 6' -dimethyl -[ 1, 1 '-biphenyl] -3 -ylfpropanoate
Prepared according to the general route 6, reported in Scheme 7, starting from intermediate 1a (synthesised according to general route 1) and (1R,2S,5S)-3-acetyl-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (synthesised according to general route 2).
LCMS m/z: 513.3 [M+H]+, (ESI+), Rt = 4.12 (S3)
1H NMR (500 MHz, CDCI3) 6 [ppm]: 7.77 (d, J = 8.4 Hz, 1 H), 7.21 - 7.13 (m, 1 H), 7.10 - 7.06 (m, 2H), 6.96 - 6.86 (m, 2H), 5.72 - 5.60 (m, 1H), 4.33 (s, 1H), 4.09 - 4.01 (m, 2H), 3.86 - 3.74 (m, 1H), 3.46 (d, J = 10.5 Hz, 1H), 2.94 - 2.83 (m, 2H), 2.01 (s, 3H), 2.00 (s, 3H), 2.00 (s, 3H), 1.59 (d, J = 7.6 Hz, 1 H), 1.46 (dd, J = 7.6, 5.2 Hz, 1H), 1.18 (t, J = 7.1 Hz, 3H), 1.02 (s, 3H), 0.90 (s, 3H). (N1)
Intermediate 6e tert-butyl (1R,2S,5S)-2-{[(1S)-3-ethoxy-3-oxo-1 -{4,4', 5-trifluoro-2',6'-dimethyl-[1, 1'-
Prepared using the route as outlined in general route 5 from intermediate 1d and (1 R,2S,5S)-3-[(tert-butoxy)carbonyl]-6,6-dimethyl-3-azabicyclo[3.1 ,0]hexane-2-carboxylic acid. LCMS m/z: 611.3 [M+HJ+, (ESI+), Rt = 1.19 (S1)
1H NMR (400 MHz, DMSO-d6) 5 [ppm]: 7.85 - 7.28 (m, 1H), 6.93 - 6.70 (m, 4H), 5.71 - 5.59 (m, 1 H), 4.14 - 3.95 (m, 3H), 3.71 - 3.43 (m, 2H), 3.03 - 2.79 (m, 2H), 2.02 - 1.91 (m, 6H), 1.41 - 1.27 (m, 7H), 1.21 - 1.14 (m, 7H), 1.04 - 1.00 (m, 3H), 0.87 (d, J = 5.3 Hz, 3H). (N1)
Intermediate 6f tert-butyl (1R,2S,5S) -2-{[(1S)-1 -{4,5-difluoro-2',4', 6'-trimethyl-[1, 1 ' -bi phenyl] -3 -yl} -3- ethoxy-3 -oxopropyl]carbamoyl] -6, 6 -dimethyl -3 -azabicyclo[3. 1.0]hexane -3 -carboxylate,
Prepared using the route as outlined in general route 5 from intermediate 1f and (1 R,2S,5S)-3-[(tert-butoxy)carbonyl]-6,6-dimethyl-3-azabicyclo[3.1 ,0]hexane-2-carboxylic acid. LCMS m/z: 585.5 [M+HJ+, (ESI+), Rt = 1.09 (S2)
1H NMR (500 MHz, DMSO-d6) 5 [ppm]: 8.60 - 8.52 (m, 1 H), 7.20 - 7.08 (m, 1 H), 7.00 (d, J = 5.7 Hz, 1 H), 6.95 - 6.88 (m, 2H), 5.59 - 5.49 (m, 1 H), 4.06 - 3.95 (m, 2H), 3.89 (d, J = 20.4 Hz, 1H), 3.48 (ddd, J = 19.0, 11.0, 5.2 Hz, 1 H), 3.27 (t, J = 10.5 Hz, 1H), 2.88 - 2.78 (m, 2H), 2.24 (s, 3H), 1.93 (s, 2H), 1.90 (t, J = 5.1 Hz, 4H), 1.29 (s, 3H), 1.26 (dd, J = 7.4, 5.2 Hz, 1 H), 1.18 (s, 6H), 1.11 (q, J = 7.3 Hz, 3H), 1.04 (d, J = 7.5 Hz, 1H), 0.91 (d, J = 2.3 Hz, 3H), 0.84 (s, 3H). (N1)
General route 7 (Boc deprotection, synthesis of intermediates 7a-c)
Scheme 9
Intermediate 7a ethyl (3S)-3-{4,5-difluoro-2',6'-dimethyl-[1, 1'-biphenyl]-3-yl}-3-{[(1R,2S,5S)-6,6- di methyl -3 -azabicyclo[3. 1.0]hexan -2 -yl]formamido}propanoate hydrochloride HCI (4 M, dioxane, 11 mL, 45.6 mmol) was added to a solution of intermediate 6a (6.40 g, 11.2 mmol) in DCM (80 mL), and stirred at RT for 18 h. The reaction mixture was concentrated in vacuo to afford the crude oil which was purified using an SCX cartridge (70 g), eluting with MeOH, and NH3 in MeOH (7 M). The methanol solution was loaded onto a second SCX cartridge (70 g), eluting with NH3 in MeOH (7 M) to afford the title intermediate 7a (4.93 g, 92% Yield) as a sticky glass.
LCMS m/z: 471.2 [M+HJ+, (ESI+), Rt = 0.91 (S1)
1H NMR (400 MHz, CDCI3) 6 [ppm]: 5 8.81 (d, J = 9.2 Hz, 1 H), 7.21 - 7.10 (m, 1H), 7.08 (d, J = 7.5 Hz, 2H), 6.88 (ddd, J = 10.0, 7.4, 2.0 Hz, 1 H), 6.87 - 6.80 (m, 1 H), 5.61 (dt, J = 9.3, 6.1 Hz, 1 H), 4.13 - 3.99 (m, 2H), 3.58 - 3.46 (m, 1 H), 3.19 (dd, J = 11.4, 4.9 Hz, 1 H), 3.02 - 2.82 (m, 3H), 1.99 (d, J = 6.2 Hz, 6H), 1.68 (d, J = 7.1 Hz, 1H), 1.24 (dd, J = 7.1, 4.7 Hz, 1 H), 1.19 (t, J = 7.1 Hz, 3H), 1.03 (s, 3H), 0.97 (s, 2H). (N1)
The following intermediates were prepared in a manner similar 7a as outlined in Scheme 9, using the corresponding starting materials.
Intermediate 7b ethyl (3S) -3 -[2, 4 -di fluoro -2', 4 ', 6' -tri methyl -5 -(tri fluoromethyl) -[ 1, 1 '-bi phenyl] -3 -yl]-3 - {[(1R, 2S, 5S) -6, 6 -dimethyl -3 -azabicyclo[3.1.0]hexan -2 -yl]formamido}propanoate hydrochloride
Prepared according to the general route 7 as outlined in Scheme 9, starting from intermediate 6b, synthesised according to general route 5.
LCMS m/z: 553.3 [M+HJ+, (ESI+), Rt = 1.02, (S1)
Intermediate 7c ethyl (3S) -3 -{[ (1 R, 2 S, 5S) -6, 6 -dimethyl -3 -azabicyclo[3. 1.0]hexan -2 -yl]formamido] -3 - Prepared according to the general route 7 as outlined in Scheme 9, starting from intermediate 6e.
LCMS m/z: 489.3 [M+H]+, (ESI+), Rt = 2.77, (S3)
1H NMR (400 MHz, DMSO-d6) 5 [ppm]: 9.90 (s, 1 H), 9.52 (d, J = 7.6 Hz, 1 H), 8.92 (s, 1 H), 7.25 (ddd, J = 11.0, 7.3, 2.0 Hz, 1H), 7.11 - 7.04 (m, 1 H), 7.01 (d, J = 9.8 Hz, 2H), 5.56 (q, J = 7.5 Hz, 1 H), 4.10 - 3.97 (m, 3H), 3.57 - 3.53 (m, 1 H), 3.35 (s, 2H), 3.06 (d, J = 12.2 Hz, 1H), 2.96 (dd, J = 7.6, 2.8 Hz, 2H), 1.97 (d, J = 13.4 Hz, 6H), 1.73 - 1.60 (m, 1H), 1.29 (dd, J = 7.9, 1.7 Hz, 1 H), 1.11 (t, J = 7.1 Hz, 3H), 1.05 (s, 3H), 0.94 (s, 3H).] (N1)
Intermediate 7d ethyl (3S) -3-{4, 5-difluoro-2',4',6'-trimethyl-[1, 1'-biphenyl]-3-yl}-3-{[(1R,2S,5S) -6,6- di methyl -3 -azabicyclo[3. 1.0]hexan -2 -yl]formamido}propa noate hydrochloride,
Prepared according to the general route 7 as outlined in Scheme 9, starting from intermediate 1f.
LCMS m/z: 485.4 [M+HJ+, (ESI+), Rt = 3.02, (S3)
1H NMR (500 MHz, DMSO-d6) 5 [ppm]: 9.37 (s, 2H), 8.96 (s, 1 H), 7.25 - 7.12 (m, 1 H), 7.02 (d, J = 5.6 Hz, 1 H), 6.93 (d, J = 8.2 Hz, 2H), 5.54 (q, J = 7.6 Hz, 1 H), 4.09 - 3.98 (m, 2H), 3.97 (s, 1 H), 3.55 - 3.49 (m, 1H), 3.06 (d, J = 12.3 Hz, 1H), 2.99 - 2.87 (m, 2H), 2.25 (s, 3H), 1.93 (s, 3H), 1.90 (s, 3H), 1.64 (t, J = 7.0 Hz, 1H), 1.32 - 1.27 (m, 1 H), 1.14 - 1.07 (m, 3H), 1.04 - 0.99 (m, 3H), 0.94 (d, J = 1.6 Hz, 3H). (N1)
General route 8 (coupling between carboxylic acid and intermediates 7a-c for the synthesis of intermediates 8a-m)
Scheme 10
Intermediate 8a ethyl (3S)-3-{4,5-difluoro-2',6'-dimethyl-[1,1'-biphenyl]-3-yl}-3-{[(1R,2S,5S)-6,6- di methyl -3 -(2 -methyl - 1, 3 -oxazole -4 -carbonyl) -3 -azabicyclo[3.1.0]hexan -2 - yl]formamido}propanoate
DI PEA (85 pL, 0.488 mmol) was added to a mixture of 2-methyl-1,3-oxazole-4- carboxylic acid (28 mg, 0.220 mmol), intermediate 7a (90 mg, 0.191 mmol), and HATLI (80 mg, 0.210 mmol) in DCM (1 mL) and the reaction was stirred at RT for 2 h. Water (2 mL) and DCM (2 mL) were added. The layers were separated, and the aqueous layer extracted with DCM (3x2 mL). The organic components were dried using a hydrophobic frit and concentrated in vacuo, and the resulting oil purified by FC (10 g silica, 0-100% EtOAc in heptane) to afford the intermediate 8a (115 mg, 91% Yield) as a solid.
LCMS m/z: 580.6 [M+HJ+, (ESI+), Rt= 1.14 (S1)
1H NMR (400 MHz, DMSO-d6) 5 [ppm]: 58.76-8.53 (m, 1H), 8.36-8.22 (m, 1H), 7.24- 6.98 (m, 5H), 5.61 -5.41 (m, 1H), 5.08-4.21 (m, 1H), 4.07-3.93 (m, 3H), 3.67-3.57 (m, 1H), 2.89-2.70 (m, 2H), 2.46-2.31 (m, 3H), 2.06- 1.77 (m, 6H), 1.50-1.41 (m, 1H), 1.33-0.97 (m, 4H), 0.96-0.78 (m, 6H). (N1)
The following intermediates in Table 1 were prepared in a manner similar intermediate 8a as outlined in Scheme 10, using the corresponding starting materials.
Table 1
Synthetis of other intermediates
Intermediate 9a
Scheme 11
Step A: ethyl (3S)-3-{4,5-difluoro-2',6'-dimethyl-[1, 1'-biphenyl]-3-yl}-3-{[(1R,2S,5S)-
6, 6 -dimethyl -3 -{ 1 H, 2H, 3H, 4H -pyrrol o[ 1,2 -a ]pyrazine -6 -carbonyl} -3 -azabicyclo[ 3. 1.0]hexan -
2 -yl]formamido}propanoate hydrochloride
HCI (4 M, dioxane, 0.40 mL, 1.60 mmol) was added to a solution of tert-butyl 6- [(1R,2S,5S)-2-{[(1S)-1-{4,5-difluoro-2',6'-dimethyl-[1,T-biphenyl]-3-yl}-3-ethoxy-3- oxopropyl]carbamoyl}-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-1 H,2H,3H,4H- pyrrolo[1,2-a]pyrazine-2-carboxylate (139 mg, 0.162 mmol) in DCM (1 mL) for 2 h. The solvents were removed under reduced pressure to afford ethyl (3S)-3-{4,5-difluoro-2',6'- dimethyl-[1,T-biphenyl]-3-yl}-3-{[(1R,2S,5S)-6,6-dimethyl-3-{1H,2H,3H,4H-pyrrolo[1,2- a]pyrazine-6-carbonyl}-3-azabicyclo[3.1.0]hexan-2-yl]formamido}propanoate hydrochloride (136 mg, 100% Yield) as a foam.
LCMS m/z: 619.5 [M+HJ+, (ESI+), Rt = 0.92 (S1) 1H NMR (500 MHz, CDCI3) 6 [ppm]: 5 7.78 (d, J = 8.5 Hz, 1 H), 7.19 - 7.14 (m, 1H), 7.09 - 7.02 (m, 3H), 6.90 - 6.84 (m, 2H), 6.65 (d, J = 4.1 Hz, 1 H), 6.04 (d, J = 4.0 Hz, 1 H), 5.67 - 5.63 (m, 1 H), 4.81 - 4.73 (m, 1H), 4.63 (s, 1H), 4.41 - 4.36 (m, 2H), 4.24 - 4.16 (m, 1H), 4.04 - 3.95 (m, 3H), 3.78 (d, J = 10.8 Hz, 1H), 3.49 - 3.42 (m, 2H), 2.91 - 2.85 (m, 2H), 1.99 (s, 3H), 1.95 (s, 4H), 1.59 (d, J = 7.5 Hz, 1H), 1.52 - 1.49 (m, 1H), 1.12 (t, J = 7.0 Hz, 3H), 1.02 (s, 3H), 0.87 (s, 3H) (N1)
Step B: ethyl (3S)-3-{4,5-difluoro-2',6'-dimethyl-[1, 1'-biphenyl]-3-yl}-3-{[(1R,2S,5S)- 6, 6 -dimethyl -3 -{2 -methyl - 1H, 2H, 3H, 4H-pyrrolo[ 1,2 -a ]pyrazine -6 -carbonyl} -3 - azabicyclo[3. 1.0]hexan -2 -yl]formamido}propanoate
To a stirred solution of ethyl (3S)-3-{4,5-difluoro-2',6'-dimethyl-[1 , 1 '-biphenyl]-3-yl}- 3-{[(1 R,2S,5S)-6,6-dimethyl-3- {1 H,2H,3H,4H-pyrrolo[1,2-a]pyrazine-6-carbonyl}-3-azabicyclo[3.1.0]hexan-2- yl]formamido}propanoate hydrochloride
(78%, 136 mg, 0.161 mmol) in DCE (0.8 mL) was added aqueous formaldehyde (37%, 0.10 mL, 1.34 mmol). The reaction was vigorously stirred for 5 min at room temperature before the addition of STAB (137 mg, 0.646 mmol) then stirred at RT for 2.5 h and then diluted with DCM (1 mL) and NaHCCh (1 M, aq) was added until solution remained basic. The aqueous component was extracted with DCM (2 * 10 mL). The combined organic components were dried (hydrophobic frit), and concentrated to afford the title intermediate 9a (156 mg, 99% Yield) as an oil.
LCMS m/z: 633.5 [M+HJ+, (ESI+), Rt = 0.94 (S1)
1H NMR (500 MHz, CDCI3) 6 [ppm]: 5 7.76 (d, J = 8.4 Hz, 1 H), 7.17 - 7.13 (m, 1H), 7.07 - 7.05 (m, 2H), 6.90 - 6.85 (m, 2H), 6.58 (d, J = 3.9 Hz, 1 H), 5.84 (d, J = 3.9 Hz, 1H), 5.66 - 5.61 (m, 1 H), 4.70 (s, 1 H), 4.50 - 4.44 (m, 1 H), 3.99 - 3.90 (m, 4H), 3.60 (s, 1 H), 2.88 - 2.83 (m, 2H), 2.74 - 2.68 (m, 2H), 2.44 (s, 3H), 2.00 (s, 3H), 1.95 (s, 3H), 1.68 - 1.57 (m, 4H), 1.09 (t, J = 7.2 Hz, 3H), 1.02 (s, 3H), 0.83 (s, 3H). (N1)
Intermediate 103
Step D: ethyl (3S)-3-{[(1R,2S,5S)-3-[1 -(azetidin-3-yl)-1H-pyrazole-4-carbonyl]-6,6- di methyl -3 -azabicyclo[3. 1.0]hexan -2 -yl]formamido] -3 -{4, 5 -difluoro -2 6' -dimethyl -[ 1, 1 '- biphenyl] -3 -yl} pro pa noate
To a stirring solution of tert-butyl 3-[4-[(1 R,2S,5S)-2-[[(1S)-1-[5-(2,6- dimethylphenyl)-2,3-difluoro-phenyl]-3-ethoxy-3-oxo-propyl]carbamoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-3-carbonyl]pyrazol-1-yl]azetidine-1 -carboxylate (90%, 180 mg, 0.225 mmol) in DCM (1.8 mL) was added TFA (0.19 mL, 2.48 mmol). The reaction mixture was stirred at rt under nitrogen for 18 hours. The reaction mixture was concentrated in vacuo, sonicated with EtOAc and concentrated in vacuo. Purification by SCX chromatography (25g SCX, 0-100% 7M NH3 in MeOH) afforded the titled product (134 mg, 83% pure, 80% Yield) as a colourless gum.
LCMS m/z: 620.1 [M+H]+, (ESI+), Rt = 0.83 (S2)
Intermediate 104
Step E: ethyl (3S)-3-{4,5-difluoro-2',6'-dimethyl-[1, 1'-biphenyl]-3-yl}-3-{[(1R,2S,5S)-
6,6-dimethyl-3-[ 1-(1 -methylazetidin-3-yl)-1H-pyrazole-4-carbonyl]-3- azabicyclo[3. 1.0]hexan -2 -yl]formamido}propanoate
To a stirring solution of ethyl (3S)-3-[[(1R,2S,5S)-3-[1-(azetidin-3-yl)pyrazole-4-carbonyl]- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-3-[5-(2,6-dimethylphenyl)-2,3- difluoro-phenyl]propanoate (83%, 134 mg, 0.179 mmol) in DCE (0.85 mL) was added aqueous formaldehyde (37%, 0.11 mL, 1.44 mmol). The reaction was stirred vigorously under nitrogen for 5 mins at RT before STAB (152 mg, 0.718 mmol) was added. The reaction was stirred at room temperature under nitrogen for 2 hours. The residue was diluted with DCM (20 ml) and saturated NaHCC>3(aq) was added until it remained basic. The organic layer was separated and the aqueous layer was further extracted with DCM (2 x 20 ml). The combined organic layers were dried (hydrophobic frit) and concentrated in vacuo to afford the titled product (132 mg, 55% pure, 64% Yield) as a yellow gum.
LCMS m/z: 634.4 [M+H]+, (ESI+), Rt = 0.89 (S2)
1H (500 MHz, DMSO-d6) 5 [ppm]: 8.83 - 8.55 (m, 1H), 8.26 - 7.94 (m, 1H), 7.85 - 7.51 (m, 1 H), 7.27 - 6.98 (m, 5H), 5.53 (q, J = 7.8 Hz, 1 H), 5.02 - 4.87 (m, 1 H), 4.38 - 4.28 (m, 1 H), 4.04 - 3.94 (m, 3H), 3.76 - 3.53 (m, 3H), 3.40 - 3.35 (m, 2H), 2.89 - 2.75 (m, 2H), 2.33 - 2.26 (m, 3H), 1.98 - 1.90 (m, 6H), 1.55 - 1.44 (m, 1 H), 1.34 - 1.19 (m, 1H), 1.13 - 1.04 (m, 3H), 0.95 - 0.89 (m, 3H), 0.83 - 0.79 (m, 3H). Intermediate 110
2, 5 -dimethyl -4 -(4, 4, 5, 5 -tetra methyl -1,3,2 -dioxaborolan -2 -yl) -2 H -indazole
To a degassed suspension of 4-bromo-2,5-dimethyl-indazole (300.0 mg, 1.33 mmol) 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1 ,3,2-dioxaborolane (B2Pin2) (507.599 mg, 2.0 mmol) , potassium acetate (392.596 mg, 4.0 mmol) in 1 ,4-Dioxane (4.1 mL) and 1 drop of DMF was added Pd(dppf)2Ch (81.133 mg, 0.11 mmol). The reaction was heated at 150 °C under MW irradiation for 15 minutess. The reaction mixture was passed through a thiol cartridge and washed with EtOAc (2 x 10 mL). The solvent was concentrated in vacuo to afford the titled product (410 mg, 71 % pure, 80% Yield) as a black oil.
LCMS m/z: 273.2 [M+H]+, (ESI+), Rt = 1.00 (S2)
Intermediate 111
(1R,2S,5S)-3 -{imidazo[ 1,2 -a ]pyrazine -2 -carbonyl} -6, 6 -dimethyl -3 - azabicyclo[3. 1.0]hexane -2 -carboxylic acid
A stirring solution of imidazo[1 ,2-a]pyrazine-2-carboxylic acid (542.518 mg, 3.21 mmol) and HATLI (1.44 g, 3.79 mmol) in DMF (10 mL) was stirred for 30 minutes. Methyl (1 R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate hydrochloride (600 mg, 2.92 mmol) and N-ethyl-N-(propan-2-yl)propan-2-amine (5.08 mL, 29.2 mmol) were added and the reacton mixture was stirred at RT for 17 hours. The reaction was diluted with water (40 mL) and the organic layer was separated. The aqueous layer was extracted with EtOAc (4 x 10 mL) and the combined organic layers were washed with saturated aq. LiCI solution, dried over MgSO4, and concentrated in vacuo to give an orange oil. The crude oil was dissolved in THF (6.0 mL) and treated with lithium hydroxide (140 mg, 5.83 mmol) at RT for 18 hours. The reaction was acidified with citric acid (10 mL) to pH 3, and extracted with IPC/CHCI3 1 :3 (4 x 10 mL). The combined organic layers were concentrated in vacuo to afford the titled product (1.15 g, 77% pure, 101% yield) as a clear oil.
LCMS m/z: 301.0 [M+H]+, (ESI+), Rt = 0.27 (S2)
Intermediate 10a ethyl (3S)-3-{4,5-difluoro-2',6'-dimethyl-[1, 1'-biphenyl]-3-yl}-3-{[(1R,2S,5S)-6,6- di methyl -3 -[(1 -methyl-1H-pyrazol-4-yl)carbamoyl]-3-azabicyclo[3. 1.0]hexan-2- yl]formamido}propanoate
A stirring solution of 1-methyl-1 H-pyrazol-4-amine (0.049 mL, 0.574 mmol) and N- ethyl-N-(propan-2-yl)propan-2-amine (200 pL, 1.15 mmol) in THF (2 mL) under N2 at 0° C was treated with 4-nitrophenyl chloroformate (116 mg, 0.574 mmol) then allowed to warm to RT stirring for 2h. A solution of intermediate 7a (90%, 100 mg, 0.191 mmol) in anhydrous THF (1 mL) was added and the reaction was stirred at 50 °C for 4h.
The reaction was concentrated, resuspended in EtOAc (30 mL) and washed sequentially with water (2 x 15 mL), sat. NaHCCh solution (4 x 10 mL) then brine (20 mL), dried over MgSCL, filtered and concentrated to the title intermediate 10a (254 mg, 100% Yield) as a oil.
LCMS m/z: 594.4 [M+HJ+, (ESI+), Rt = 1.01 (S1)
Intermediate 11a
Scheme 12
Step A: methyl (1R,2S,5S)-6,6-dimethyl-3-(1H-pyrazole-4-carbonyl)-3- azabicyclo[3.1.0]hexane -2 -carboxylate
To a stirred solution of methyl (1R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1.0]hexane- 2-carboxylate hydrochloride (350 mg, 1.70 mmol) and 1 H-pyrazole-4-carboxylic acid (98%, 200 mg, 1.75 mmol) in DCM (25 mL) was added DIPEA (1.0 mL, 5.73 mmol) followed by HATLI (800 mg, 2.10 mmol). The resulting mixture was stirred at RT for 18 h and then allowed to stand at RT for 3 days. The reaction mixture was washed with water (20 mL), the resulting aqueous layer was extracted with DCM (2 x 20 mL), and the combined organic components dried over Na2SO4 and concentrated in vacuo to give the crude oil. This was purified by FC (50 g silica, 0 - 100% EtOAc in heptane, followed by 0 - 10% MeOH in EtOAc) to afford methyl (1R,2S,5S)-6,6-dimethyl-3-(1 H-pyrazole-4- carbonyl)-3-azabicyclo[3.1.0]hexane-2-carboxylate (497 mg, 100% yield ) as an oil. LCMS m/z: 264.2 [M+HJ+, (ESI+), Rt = 0.64 (S1)
Step B: methyl (1R,2S,5S)-6,6-dimethyl-3-[1 -(oxetan-3-yl)-1H-pyrazole-4- carbonyl]-3 -azabicyclo[3.1.0]hexane -2 -carboxylate
To a stirred suspension of methyl (1R,2S,5S)-6,6-dimethyl-3-(1 H-pyrazole-4- carbonyl)-3-azabicyclo[3.1.0]hexane-2-carboxylate from step A (490 mg, 1.73 mmol) and 3-bromooxetane (262 mg, 1.91 mmol) in anhydrous DMF (7 mL) was added CS2CO3 (1.21 g, 3.71 mmol) and the resulting mixture stirred at 90° C for 2 h. The reaction mixture was allowed to cool to rt, diluted with water (30 mL) and extracted into EtOAc (3 x 20 mL). The combined organic components were washed with water (20 mL), brine (30 mL), dried over Na2SC>4 and concentrated in vacuo. The crude material was purified by FC (25 g silica column, 0 - 100% EtOAc in heptane, 0 - 10% MeOH in EtOAc gradient) to afford methyl (1 R,2S,5S)-6,6-dimethyl-3-[1-(oxetan-3-yl)-1 H-pyrazole-4-carbonyl]-3- azabicyclo[3.1.0]hexane-2-carboxylate (188 mg, 28% yield) as an oil.
LCMS m/z: 320.2 [M+HJ+, (ESI+), Rt = 0.64 (S1)
1H NMR (400 MHz, CDCh) 6 [ppm]: 5 8.07 - 8.05 (m, 1 H), 7.96 - 7.91 (m, 1H), 5.49 - 5.40 (m, 1 H), 5.07 - 5.01 (m, 4H), 4.65 - 4.51 (m, 1H), 4.10 (dd, J = 9.8, 5.4 Hz, 1H), 3.80 - 3.73 (m, 4H), 1.62 - 1.54 (m, 1 H), 1.52 - 1.47 (m, 1 H), 1.09 - 1.06 (m, 3H), 0.98 - 0.94 (m, 3H).(N1)
Step C: (1R,2S,5S)-6,6 -dimethyl -3-[1-( oxetan -3-yl)-1H -pyrazole -4 -carbonyl] -3 -
To a stirred solution of methyl (1R,2S,5S)-6,6-dimethyl-3-[1-(oxetan-3-yl)-1 H- pyrazole-4-carbonyl]-3-azabicyclo[3.1.0]hexane-2-carboxylate (180 mg, 0.468 mmol) from step B in THF (5 mL) and MeOH (0.4 mL) was added LiOH (2M, aq, 1.2 mL, 2.40 mmol). The mixture was stirred at RT for 1.5 h and then concentrated in vacuo. The residue was suspended in MeCN (10 mL) and concentrated in vacuo to give a crude residue. This was partitioned between EtOAc (20 mL) and citric acid (aq, 10% w/w, 20 mL). The aqueous layer was extracted with EtOAc (2 x 20 mL), and the combined organic components were dried over Na2SO4 and concentrated in vacuo to afford (1 R,2S,5S)-6,6-dimethyl-3-[1- (oxetan-3-yl)-1 H-pyrazole-4-carbonyl]-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (intermediate 11a) (128 mg, 81% yield) as a gum. LCMS m/z: 306.2 [M+H]+, (ESI+), Rt = 0.56 (S1)
1H NMR (400 MHz, CDCI3) 6 [ppm]: 5 8.10 (s, 1 H), 7.93 (s, 1 H), 5.47 (p, J = 6.8 Hz, 1 H), 5.06 (d, J = 6.9 Hz, 4H), 4.68 (s, 1 H), 4.04 (dd, J = 10.1 , 5.4 Hz, 1 H), 3.80 (d, J = 10.1 Hz, 1 H), 1.89 (d, J = 7.7 Hz, 1 H), 1.64 (dd, J = 7.7, 5.4 Hz, 1 H), 1.11 (s, 3H), 0.93 (s, 3H). (N1)
General route 12 (coupling of dimenthylbicyclopropyl proline with carboxylic acids) Intermediate 12a
Scheme 13
Step A: methyl (1R,2S,5S)-6,6-dimethyl-3-(1 -methyl-1H-imidazole-4-carbonyl)-3-
DIPEA (6.4 mL, 36.5 mmol) was added to a solution of methyl (1 R,2S,5S)-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate hydrochloride (2.21 g, 17.5 mmol), and HATLI (6.10 g, 16.0 mmol) in DCM (45 mL) and stirred at RT for 5 h. The reaction mixture was diluted with EtOAc (5 mL) and water (5 mL). The aqueous was extracted with EtOAc (3 x 5 mL) and the combined organic components washed with brine (10 mL), dried over MgSCL, and concentrated in vacuo to give a crude residue which was purified by FC (50 g Silica column, 10 - 100% EtOAc in Heptane, then 100% MeOH), to afford methyl (1 R,2S,5S)-6,6-dimethyl-3-(1-methyl-1 H-imidazole-4-carbonyl)-3- azabicyclo[3.1.0]hexane-2-carboxylate (4.60 g, 100% Yield) as an oil.
LCMS m/z: 306.2 [M+H]+, (ESI+), Rt = 0.56 (S1)
Step B: ( 1R,2S,5S) -6,6-dimethyl-3-( 1 -methyl-1 H-imidazole-4-carbonyl) -3- azabicyclo[3. 1.0]hexane -2 -carboxylic acid
To a stirred solution of methyl (1R,2S,5S)-6,6-dimethyl-3-(1-methyl-1 H-imidazole- 4-carbonyl)-3-azabicyclo[3.1.0]hexane-2-carboxylate (4.60 g, 14.6 mmol) from step A in THF (44 mL) was added 2M LiOH (aq) (42 mL, 84.6 mmol) and the mixture stirred at 45 °C for 1 h before cooling. Water (10 mL) was added and the mixture concentrated in vacuo to remove the organics. The solution was acidified with HCI (1 M) until pH 3 and extracted with DCM (3 x 15 mL). The organic components were concentrated in vacuo and purified reverse phase FC (50 g, Silica C18, 15 CVs, 10 - 100% [0.1% NH3 in water] in [0.1% NH3 in MeCN]). The product was dissolved in water (20 mL), acidified to pH3, extracted with DCM (5 x 15 mL), dried using MgSCL, and concentrated in vacuo to afford intermediate 12a (1.60 g, 41% Yield) as an oil.
LCMS m/z: 264.2 [M+HJ+, (ESI+), Rt = 0.44 (S1) 1H NMR (400 MHz, DMSO-d6) 5 [ppm]: 5 12.54 (br s, 1 H), 7.68 - 7.56 (m, 2H), 4.33 - 4.23 (m, 1 H), 3.70 - 3.62 (m, 4H), 3.61 - 3.52 (m, 1H), 1.58 - 1.50 (m, 1H), 1.41 - 1.32 (m, 1 H), 1.05 - 0.98 (m, 3H), 0.92 - 0.85 (m, 3H). (N1)
The following intermediates were prepared in a manner similar Int 12a as outlined in Scheme 13, using the corresponding starting materials.
Intermediate 12b methyl (1R, 2S, 5S) -3 -{imidazo[ 1, 2 -a ]pyrazine -2 -carbonyl} -6, 6 -dimethyl -3 - azabicyclo[3.1.0]hexane -2 -carboxylate
Prepared according to the general route 12 as outlined in Scheme 13, starting from methyl (1 R,2S,5S)-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylate hydrochloride) and imidazo[1,2-a]pyrazine-2- carboxylic acid.
LCMS m/z: 315.2 [M+H]+, (ESI+), Rt = 0.70, (S1)
Intermediate 12c (1R,2S,5S)-3 -{imidazo[ 1,2 -a Jpyrazine -2 -carbonyl} -6, 6 -dimethyl -3 - azabicyclo[3. 1.0]hexane -2 -carboxylic acid
Prepared according to the general route 12 as outlined in scheme 12, starting from methyl (1 R,2S,5S)-3-{imidazo[1 ,2-a]pyrazine-2-carbonyl}-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylate.
LCMS m/z: 301.2 [M+HJ+, (ESI+), Rt = 0.58, (S1)
1H NMR (400 MHz, DMSO-d6) 5 [ppm]: 9.20 - 8.99 (m, 1 H), 8.63 - 8.57 (m, 1 H), 8.52 (dd, J = 9.9, 0.8 Hz, 1 H), 7.96 (t, J = 4.9 Hz, 1 H), 4.43 - 4.32 (m, 1 H), 4.23 - 4.08 (m, 1 H), 3.77 - 3.61 (m, 2H), 1 .69 - 1 .57 (m, 1 H), 1 .52 - 1 .41 (m, 1 H), 1 .09 - 1 .01 (m, 3H), 1 .01 - 0.89 (m, 3H).
Intermediate 13a
Scheme 14
To a stirring mixture of ethyl 1 H-pyrazole-3-carboxylate (500 mg, 3.57 mmol) and CsCC>3 (1.74 g, 5.35 mmol) in MeCN (10 mL) under a nitrogen atmosphere, was added 2- (bromomethyl)-1 ,3-dioxolane (97%, 419 pL, 3.93 mmol), and the reaction was stirred at RT for 44 h. The reaction was heated to 60 °C for 1 h, and then 80°C for 3 h, then cooled and filtered through a pad of celite. The filter cake was washed with EtOAc (100 mL), the filtrate was collected and concentrated in vacuo to give the crude oil. This was purified by FC (25 g, silica, 0-80% EtOAc in Heptane) to afford the title compound (223 mg, 27% Yield) as an oil.
LCMS m/z: 227.3 [M+HJ+, (ESI+), Rt = 0.62 (S1)
1H NMR (400 MHz, DMSO-d6) 5 [ppm]: 7.81 (d, J = 2.4 Hz, 1 H), 6.74 (d, J = 2.4 Hz, 1H), 5.19 (t, J = 4.2 Hz, 1H), 4.34 (d, J = 4.3 Hz, 2H), 4.26 (q, J = 7.1 Hz, 2H), 3.87 - 3.77 (m, 4H), 1.28 (t, J = 7.1 Hz, 3H).
To a solution of ethyl 1-[(1,3-dioxolan-2-yl)methyl]-1 H-pyrazole-3-carboxylate from step A ( 70 mg, 0.306 mmol) in THF (1.5 mL) was added HCI (2M, 1.5 mL, 3.00 mmol), the reaction was stirred at RT for 2 h. HCI (12M, 50 pL, 0.600 mmol) was added and the reaction heated to 40 °C and stirred for a further 30 min, then heated to 50 °C and stirred for 2 h. Further HCI (12M, 150 pL, 1.80 mmol) was added and the reaction stirred at 50 °C for 17 h, followed by further HCI (12M, 150 pL, 1.80 mmol) and the reaction stirred at 50 °C for 3 h. The reaction was cooled to RT before extracting with DCM (3 x 2 mL), the organics were combined, dried using a phase separator, and concentrated in vacuo. The aqueous layer was neutralised (pH 7) with saturated NaHCCh, extracted with DCM (3 x 5 mL), organics were dried using a phase separator, and the combined organics concentrated to afford ethyl 1-(2-oxoethyl)-1 H-pyrazole-3-carboxylate (EV-HYY001-793- 001) (49 mg, 53% Yield) as an oil.
LCMS m/z: 201.1 [M+HJ+, (ESI+), Rt = 0.37 (S2)
To a solution of ethyl 1-(2-oxoethyl)-1 H-pyrazole-3-carboxylate from step B (161 mg, 0.307 mmol) in THF-Anhydrous (1.5 mL) was added acetic acid (19 pL, 0.332 mmol) and azetidine (31 pL, 0.460 mmol), and was stirred at RT for 20 min before addition of STAB (98 mg, 0.462 mmol). The reaction was stirred at RT for 3 h, and then left standing at RT for 2 days. The reaction mixture was diluted with MeOH and purified using an SCX cartridge (1 g), eluting with NH3 in MeOH (3.5 M), which was concentrated in vacuo and the resulting product dried in a vacuum oven to afford a mixture (1:1) of ethyl 1-[2- (azetidin-1-yl)ethyl]-1 H-pyrazole-3-carboxylate and 1-[2-(azetidin-1-yl)ethyl]-1 H-pyrazole- 3-carboxylic acid (8.8 mg, 13.7% Yield) as a gum.
LCMS m/z: 224.2 [M+H]+, (ESI+), Rt = 0.51 (S2)
1H N MR (400 MHz, DMSO-d6) 6 [ppm]: 7.88 - 7.81 (m, 1 H), 6.70 (d, J = 2.3 Hz, 1 H), 4.25 (q, J = 7.1 Hz, 2H), 4.10 (t, J = 6.2 Hz, 2H), 3.07 - 3.02 (m, 4H), 2.73 (t, J = 6.2 Hz, 2H), 1.95 - 1.87 (m, 2H), 1.28 (t, J = 7.1 Hz, 3H).
Step D 1 -[2-(azetidin-1 -yl)ethyl]-1 H -pyrazole -3 -carboxylate lithium
To a solution of ethyl 1-[2-(azetidin-1-yl)ethyl]-1 H-pyrazole-3-carboxylate ( 27 mg, 0.106 mmol) in THF (0.5 mL) and MeOH (50 pL) was added LiOH (2M, 265 pL, 0.530 mmol), the reaction was stirred at RT for 1.5 h; then concentrated to dryness to afford 1- [2-(azetidin-1-yl)ethyl]-1 H-pyrazole-3-carboxylate lithium (intermediate 13) (35 mg, 100% Yield) as a solid.
LCMS m/z: 196.1 [M+HJ+, (ESI+), Rt = 0.14 (S2) 1H NMR (400 MHz, DMSO-d6) 5 [ppm]: 7.53 (d, J = 2.2 Hz, 1 H), 6.28 (d, J = 2.2 Hz, 1 H), 3.93 (t, J = 6.4 Hz, 2H), 3.05 (t, J = 7.0 Hz, 4H), 2.70 (t, J = 6.4 Hz, 2H), 1.91 (p, J = 6.9 Hz, 2H).
Intermediate 14a
Scheme 15
Step A - ethyl 1 -[2-(dimethylamino)ethyl]-1 H-imidazole-5-carboxylate
Ethyl 1 H-imidazole-4-carboxylate (500 mg, 3.57 mmol) was dissolved in DMF (17.8 mL), then (2-chloroethyl)dimethylamine hydrochloride (2.06 g, 14.3 mmol), and CS2CO3 (2.32 g, 7.14 mmol) was added successively. The mixture was heated in the microwave at 150 °C for 3 h, after which the mixture was quenched with water, and extracted twice with EtOAc. The combined organics were washed with brine, dried with Na2SO4, and concentrated in vacuo. The crude residue was purified by FC (24 g Silica, eluting with a gradient of 0-5% MeOH in DCM), to afford a mixture of the two isomers (including ethyl 1- [2-(dimethylamino)ethyl]-1 H-imidazole-5-carboxylate) as a gum (210mg, 23% Yield).
LCMS m/z: 212.2 [M+HJ+, (ESI+), Rt = 1.56 (S7)
Step B - Lithium 1 -[2-(dimethylamino)ethyl]-1H-imidazole-5-carboxylic acid
Ethyl 1-[2-(dimethylamino)ethyl]-1 H-imidazole-5-carboxylate (209 mg, 0.811 mmol) from step A was dissolved in THF (9 mL) at RT. LiOH hydrate (170 mg, 4.06 mmol) in water (3 mL) was added, and the mixture stirred for 16 h. The mixture was concentrated in vacuo to afford intermediate 14 (153mg, 49% Yield).
No mass ion observed, Rt = 0.18 (S6)
Intermediate 16a
7 -methyl -5H,6H, 7H,8H-imidazo[ 1 ,2-a]pyrazine-2-carboxylic acid,
HCI (4 M in dioxane, 1.4 mL, 5.60 mmol) was added to a solution of 7-tert-butyl 2- methyl 5H,6H,7H,8H-imidazo[1,2-a]pyrazine-2,7-dicarboxylate (150 mg, 0.523 mmol) in DCM (4.9 mL). The resulting mixture was stirred for 3 h at RT under N2. The reaction mixture was concentrated to afford 7-methyl-5H,6H,7H,8H-imidazo[1,2-a]pyrazine-2- carboxylic acid (EV-YQP001 -022-001) (120 mg, 99% Yield) as a solid. LCMS m/z: 182.1 [M+H]+, (ESI+), Rt = 0.27 (S1)
1H NMR (400 MHz, DMSO-d6) 6 [ppm]: 9.82 (br. s, 2H), 7.98 (s, 1 H), 4.38 (s, 2H), 4.27 (t,
J = 5.7 Hz, 2H), 3.75 (s, 3H), 3.61 (d, J = 5.8 Hz, 2H). (N1)
Step B - methyl 7-methyl-5H,6H, 7H,8H-imidazo[1,2-a]pyrazine-2-carboxylate
To a stirred solution of 7-methyl-5H,6H,7H,8H-imidazo[1 ,2-a]pyrazine-2-carboxylic acid (60 mg, 0.273 mmol) from step A, and acetic acid (125 pL, 2.19 mmol) in DCE (2 mL) and was added paraformaldehyde (52 mg, 1 .68 mmol) and the mixture stirred for 2 h at RT. Sodium cyanoborohydriide (106 mg, 1.69 mmol) was added and the mixture stirred for a further 3 h. The reaction was cooled and quenched by stirring with sodium bicarbonate (saturated aq, 2 mL). The organic phase was separated using a phase separator. The aqueous component was extracted with DCM (2 x 2 mL) and the combined organic components concentrated in vacuo to afford the crude residue, which was purified by FC (11 g KP-silica, 0-15% EtOAc in heptane) to afford methyl 7-methyl-5H,6H,7H,8H- imidazo[1 ,2-a]pyrazine-2-carboxylate (28 mg, 44% Yield) as a semi solid.
LCMS m/z: 196.3 [M+HJ+, (ESI+), Rt = 0.52 (S1) 1H NMR (400 MHz, CD3CN) 5 [ppm]: 7.68 (s, 1 H), 4.29 - 4.20 (m, 2H), 4.13 - 3.98 (m, 2H), 3.78 (s, 3H), 3.56 - 3.36 (m, 2H), 2.82 (s, 3H). (N1)
Step C - ethyl (3S)-3-{[(1R,2S,5S)-6,6-dimethyl-3-{7-methyl-5H,6H, 7H,8H- imidazo[ 1, 2 -a ]pyrazine -2 -carbonyl} -3 -azabicyclo[3. 1.0]hexan -2 -yl]formamido} -3 -{4, 4', 5- trifluoro-2', 6' -dimethyl-} 1, 1 '-bi phenyl] -3 -yl}propa noate
To a solution of methyl 7-methyl-5H,6H,7H,8H-imidazo[1 ,2-a]pyrazine-2- carboxylate from step B in THF (1 mL) was added LiOH (2 M, aq, 75 pL, 0.150 mmol) and the solution was stirred at RT for 1h. The reaction was then concentrated in vacuo to give the crude intermediate. This was dissolved with intermediate 7c (60 mg, 0.0937 mmol) in DCM (1 mL), followed by addition of DI PEA (40 pL, 0.229 mmol) and HATU (44 mg, 0.116 mmol), and the resulting mixture was stirred at RT for 48 h. Water (1 mL) was added to the reaction mixture, which was then separated using a phase separator. The retained aqueous was extracted with DCM (2 x 2 mL) and the combined organic components concentrated in vacuo. The residue was purified by FC (11g KP-Silica, 0-10% MeOH in DCM) to afford intermediate 16a (40 mg, 25% Yield) as a solid.
LCMS m/z: 652.5 [M+HJ+, (ESI+), Rt = 3.02 (S3)
Intermediate 17a
Step A methyl (1R,2S,5S)-3-[(2R)-1 -acetylpyrrolidine-2-carbonyl]-6,6-dimethyl-3- azabicyclo[ 3.1.0] hexane -2 -carboxylate
To a solution of (2R)-1-acetylpyrrolidine-2-carboxylic acid (80 mg, 0.509 mmol) and methyl (1 R,2S,5S)-6,6-dimethyl-3-azabicyclo[3.1 ,0]hexane-2-carboxylate hydrochloride (100 mg, 0.467 mmol) in DCM (9 mL) was added DIPEA (203 pL, 1.16 mmol) followed by HATLI (195 mg, 0.513 mmol). The reaction was stirred at RT for 3 h. The reaction was washed with water (10 mL) and passed through a phase separator. The organic component was collected and concentrated in vacuo to afford a crude oil. This was purified by flash column chromatography on silica (10 g, 0 -100% EtOAc in heptane followed by 0-40% MeOH in EtOAc), to afford a gum. The gum was further purified by basic reverse phase column chromatography (C18 silica 6 g, 10-100% MeCN (+0.1% ammonia) in water (+0.1% ammonia)) to afford methyl (1 R,2S,5S)-3-[(2R)-1- acetylpyrrolidine-2-carbonyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate 100 mg, 69% Yield) as a gum.
LCMS m/z: 309.2 [M+HJ+, (ESI+), Rt = 0.56 (S2)
1H NMR (400 MHz, DMSO-d6) 5 [ppm]: 4.62 - 4.46 (m, 1H), 4.23 - 4.08 (m, 1 H), 3.95 - 3.87 (m, 1 H), 3.67 - 3.60 (m, 3H), 3.58 - 3.46 (m, 3H), 2.39 - 2.27 (m, 1H), 2.17 - 2.03 (m, 1 H), 1.97 - 1.88 (m, 3H), 1.78 - 1.65 (m, 2H), 1.62 - 1.53 (m, 1H), 1.46 - 1.34 (m, 1 H), 1.05 - 1.03 (m, 3H), 0.94 - 0.90 (m, 3H). (N1)
Step B (1R, 2S, 5S) -3 -[ (2R) - 1 -acetylpyrrolidine -2 -carbonyl] -6, 6 -dimethyl -3 - azabicyclo[3.1.0]hexane -2 -carboxylic acid
To a stirred solution of methyl (1R,2S,5S)-3-[(2R)-1-acetylpyrrolidine-2-carbonyl]- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (100 mg, 0.321 mmol) in THF (1.5 mL) and methanol (0.2 mL) was added LiOH (2 M, aq, 803 pL, 1.61 mmol) and the reaction was stirred at RT for 1 hr. The reaction was concentrated in vacuo, then diluted with water (2 mL). The mixture was acidified to approximately pH 0-1) using HCI (2M, aq), extracted with EtOAc (3 x 5 mL), the organics were combined, dried over Na2SO4, filtered, and concentrated in vacuo to afford intermediate 17 (1 R,2S,5S)-3-[(2R)-1- acetylpyrrolidine-2-carbonyl]-6,6-dimethyl-3-azabicyclo[3.1 ,0]hexane-2-carboxylic acid (74 mg, 64% Yield) as a glass.
LCMS m/z: 295.3 [M+HJ+, (ESI+), Rt = 0.61 (S1) 1H NMR (400 MHz, CDCI3) 6 [ppm]: 4.47 (dd, J = 7.9, 5.5 Hz, 1 H), 4.44 - 4.41 (m, 1 H), 4.17 (dd, J = 10.2, 5.5 Hz, 1 H), 3.71 - 3.62 (m, 1 H), 3.58 - 3.46 (m, 2H), 2.26 - 2.19 (m, 1 H), 2.17 - 2.13 (m, 1H), 2.11 (s, 3H), 2.02 - 1.89 (m, 2H), 1.78 (d, J = 7.5 Hz, 1H), 1.51 (dd, J = 7.5, 5.4 Hz, 1 H), 1.07 (s, 3H), 0.94 (s, 3H). (N1)
Examplar compounds
Scheme for general route 1 : (Hydrolysis of carboxyl ester)
Example 1, (3S)-3-{4,5 lifluoro-2',6' limethyl-[1, 1'-biphenyl]-3-yl}-3-{[(1R,2S,5S)-
6,6-dimethyl-3-(2-methyl-1,3-oxazole-4-carbonyl) -3-azabicyclo[3.1.0]hexan-2- yl]formamido}propanoic acid LiOH (2M, aq, 0.20 mL, 0.400 mmol) was added to a solution of intermediate 8a (110 mg, 0.180 mmol) in THF (1 mL), and the mixture stirred at RT for 18 h. The reaction was concentrated in vacuo to remove the organics and the resulting aqueous was acidified to pH 1 with HCI (aq, 2M, 0.3 mL). Water (1.5 mL) and EtOAc (3 mL) were added and the aqueous layer extracted with EtOAc (2 x 3 mL), and the combined organic components were washed with water (1 mL), brine (1 mL), dried over MgSO4, filtered, and concentrated in vacuo to afford a crude oil. This was purified using prep HPLC (P2) to afford the title compound (67 mg, 65% Yield) as a solid.
LCMS m/z: 552.5 [M+HJ+, (ESI+), Rt = 3.81 (S3) 1H NMR (400 MHz, DMSO-d6) 5 [ppm]: 12.41 (br. s, 1 H), 8.78 - 8.54 (m, 1 H), 8.28 (s, 1 H), 7.23 - 7.07 (m, 4H), 7.00 (t, J = 6.3 Hz, 1 H), 5.54 - 5.38 (m, 1H), 5.10 - 4.26 (m, 1H), 4.08 - 3.88 (m, 1H), 3.68 - 3.55 (m, 1H), 2.78 - 2.63 (m, 2H), 2.45 - 2.30 (m, 3H), 2.00 - 1.85 (m, 6H), 1.50 - 1.27 (m, 1H), 1.22 - 0.98 (m, 1H), 0.96 - 0.77 (m, 6H). (N1)
The examples in Table 2 were synthesised according to general route 1 as exemplified by Example 1 using the corresponding intermediates, and were purified using one of the methods listed above (P1-5). Diastereomers were either separated during the final purification or by chiral separation methods as required. Examples were afforded as the title compound or salt thereof.
Table 2
Scheme for general route 2: (combined amide coupling and ester hydrolysis to carboxylate)
Example 22, Step a: (3S)-3-{4,5-difluoro-2',6'-dimethyl-[1, 1'-biphenyl]-3-yl}-3- {[(1R,2S,5S) -6,6-dimethyl-3-(5-methylpyrazine-2-carbonyl) -3-azabicyclo[3. 1 ,0]hexan-2- yl]formamido]propanoic acid
To a stirred solution of intermediate 7a (26 mg, 0.188 mmol) in DCM (5 mL) was added DIPEA (100 pL, 0.573 mol), followed by HATLI (80 mg, 0.210 mmol). The resulting mixture was stirred in a sealed tube at RT for 2 h, after which it was concentrated in vacuo and the residue dissolved in THF (3.5 mL) and MeOH (0.3 mL). LiOH (2M, aq, 0.50 mL, 1.00 mmol) was added, and the reaction stirred for 1 h at RT. The reaction mixture was concentrated in vacuo, the residue dissolved in water (3 mL), and acidified to pH1 using HCI (2 M, aq). The resulting precipitate was collected by filtration, air dried, and then purified by prep HPLC (P2) to afford the title compound (72 mg, 71% yield) as a solid. LCMS m/z: 563.2 [M+HJ+, (ESI+), Rt = 3.71 (S3)
1H NMR (500 MHz, DMSO-d6) 5 [ppm]: 12.39 (br. s, 1 H), 8.81 - 8.33 (m, 3H), 7.20 - 7.13 (m, 2H), 7.13 - 7.07 (m, 2H), 7.05 - 6.94 (m, 1 H), 5.53 - 5.26 (m, 1H), 4.83 - 4.39 (m, 1 H), 3.99 - 3.67 (m, 2H), 2.79 - 2.52 (m, 5H), 1.97 - 1.87 (m, 6H), 1.44 - 1.34 (m, 1 H), 1.22 - 0.99 (m, 1H), 0.95 - 0.88 (m, 6H). (N1)
The examples in Table 3 were synthesised according to general route 2 as exemplified by Example 22 using the corresponding starting materials and were purified using one of the methods listed above (P1-5). Diastereomers were either separated during the final purification or by chiral separation methods as required. Examples were afforded as the title compound or salt thereof.
Table 3
Scheme for general route 3: (Telescoped acylchloride amide formation and hydrolysis)
DIPEA (0.037 mL, 0.213 mmol) was added to a solution of intermediate 7a (100%, 50 mg, 0.106 mmol) in DCM (5 mL), followed by methanesulfonyl chloride (13 mg, 0.117 mmol), and the reaction stirred at rt for 18 h. Further methanesulfonyl chloride (13 mg, 0.117 mmol) and DIPEA (0.037 mL, 0.213 mmol) were added, and the reaction stirred for 4 h at rt. The reaction was then concentrated in vacuo, the residue dissolved in THF (5 mL), and LiOH (2M, aq, 0.27 mL, 0.531 mmol) added at rt. After 3 h HCI (2M) was added to adjust pH1 , and the reaction extracted with DCM (2 x 25 ml). The combined organic components were dried using a phase separator, and concentrated in vacuo to give the residual, which was purified by prep HPLC (P2) to afford the title compound (27 mg, 49% Yield) as a powder.
LCMS m/z: 521.2[M+H]+, (ESI+), Rt = 3.75, (S3) 1H NMR (500 MHz, DMSO-d6) 5 [ppm]: 12.46 (s, 1 H), 8.96 - 8.67 (m, 1H), 7.22 - 7.15 (m, 2H), 7.14 - 7.08 (m, 2H), 6.99 (d, J = 5.7 Hz, 1 H), 5.52 (dd, J = 7.6, 7.6 Hz, 1H), 4.08 (s, 1H), 3.59 (dd, J = 9.0, 5.1 Hz, 1 H), 3.31 - 3.27 (m, 1H), 2.87 (s, 3H), 2.75 (d, J = 7.5 Hz, 2H), 1.95 (d, J = 18.5 Hz, 6H), 1.41 (dd, J = 7.5, 5.1 Hz, 1 H), 1.02 (s, 3H), 0.96 (d, J = 7.6 Hz, 1 H), 0.90 (s, 3H). (N1)
The examples in Table 4 were synthesised according to general route 3 as exemplified by Example 48 using the corresponding starting materials, and were purified using one of the methods listed above (P1-5). Diastereomers were either separated during the final purification or by chiral separation methods as required. Examples were afforded as the title compound or salt thereof.
Table 4 Scheme for general route 4: (one pot Suzuki and hydrolysis)
Example 52, (3S)-3-{4,5-difluoro-2',4',6'-trimethyl-[1, 1'-biphenyl]-3-yl}-3- {[(1R,2S,5S) -6,6-dimethyl-3-( 1 -methyl-1 H-imidazole-4-carbonyl) -3-azabicyclo[3. 1.0]hexan- 2-yl]formamido}propanoic acid
A solution of intermediate 4a (65 mg, 0.117 mmol), (2,4,6-trimethylphenyl)boronic acid (21 mg, 0.129 mmol) and K3PO4 (76 mg, 0.359 mmol) in 1,4-Dioxane (0.7 mL) and Water (94 pL) was purged with N2 for 5 mins, before addition of (Pd(dppf)CI2 (13 mg, 0.0155 mmol), and stirred at 90 °C for 2 h and cooled to rt. The mixture was diluted with EtOAc (15 mL), washed with water (15 mL), and the aqueous components extracted with EtOAc (3 x 10 mL). The combined organics were washed with brine (15 mL), dried (MgSO4), and concentrated in vacuo. To the dry residue was added THF (1 mL) and LiOH (2M, 0.30 mL, 0.593 mmol) and stirred for 18 h at RT. The reaction mixture was acidified to pH1 with HCI (1M, aq), sonicated, and the resulting precipitate was collected by filtration. The solid was purified high pH HPLC (P3) to afford the title compound (19 mg, 28% Yield) as a solid
LCMS m/z: 565.3[M+H]+, (ESI+), Rt = 2.38, (S3) 1H NMR (500 MHz, DMSO-d6) 5 [ppm]: 9.13 - 8.79 (m, 1 H), 7.54 - 7.34 (m, 1H), 7.64 - 7.17 (m, 1 H), 7.10 - 7.00 (m, 1H), 6.99 - 6.88 (m, 3H), 5.43 - 5.26 (m, 1H), 5.25 - 4.27 (m, 1 H), 4.35 - 3.95 (m, 1H), 3.74 - 3.53 (m, 4H), 2.68 - 2.49 (m, 2H), 2.26 (s, 3H), 1.94 - 1.82 (m, 6H), 1.45 - 0.99 (m, 2H), 0.96 - 0.80 (m, 6H). (N1)
The examples in Table 5 were synthesised according to general route 4 as exemplified by Example 52 using the corresponding starting materials, and were purified using one of the methods listed above (P1-5). Diastereomers were either separated during the final purification or by chiral separation methods as required. Examples were afforded as the title compound or salt thereof. Table 5
Examples - Integrins cell adhesion assays a4b7 Cell Adhesion assay:
A transparent non-binding v bottom plate is used for dispensing the compounds from a stock solution of 10 mM. The compounds are dispensed in is reconstituted in 250 mL PBS to give 200 mg/mL solution. This is then further diluted to give 6 mg/mL in 5 mL of carbonate buffer (150 mL stock + 4850 mL carbonate buffer). On the black high binding maxisorp plate 50 mL of this protein solution is added to the compound wells and 50 mL of carbonate buffer is added to control wells and left to incubate overnight at 4°C. This plate is referred to as Plate 2. RPMI8866 cells are a half log dilution series and normalised to 0.1 % DMSO. This plate is referred to as Plate 1. Recombinant human MAdCAM (stock: 50 mg protein) reconstituted in plating media (50 mM HEPES, 3 mM MgCI2, 1 mM CaCI2, 1% BSA in PBS) with 1 :1000 of calcein AM at the density of 75000 cells/well. The cells are added to the above prepared compound plate (Platel) and incubated for an hour at 370 C and 5% CO2. The protein coated plate (Plate2) is washed with PBS and is blocked for two hours with 4% BSA prior to the addition of 100 mL of cell suspension using Via Flo (96well format). It is left to incubate for an hour at 370 C and 5% CO2. The supernatant from this plate is aspirated and is spun at 450g for 30 sec to remove unbound cells. The plate with the remaining adherent cells is then read in a fluorescent read out mode with an excitation wavelength of 485 nm and emission wavelength of 385 nm. a4b 1 Cell Adhesion assay:
A transparent non-binding v bottom plate is used for dispensing the compounds from a stock solution of 10 mM. The compounds are dispensed in a half log dilution series and normalised to 0.1% DMSO. Recombinant human VCAM (stock: 100 mg protein) is reconstituted in 1000 mL PBS to give 100 mg/mL solution. This is then further diluted to give 3 mg/mL in 5 mL of carbonate buffer (150 mL stock + 4850 mL carbonate buffer). On the black high binding maxisorp plate 50 mL of this protein solution is added to the compound wells and 50 mL of carbonate buffer is added to control wells and left to incubate overnight at 4°C. Jurkat cells are reconstituted in plating media (50 mM HEPES, 3 mM MgCh, 1 mM CaCh, 1% BSA in PBS) with 1 :1000 of calcein AM at the density of 50000 cells/well. The cells are added to the above prepared compound plate and incubated for an hour at 37° C and 5% CO2. The protein coated plate is washed with PBS prior to the addition of 100 mL of cell suspension using Via Flo (96well format) and is left to incubate for an hour at 37° C and 5% CO2. The supernatant from this plate is aspirated and is spun at 450g for 30 sec to remove unbound cells. The plate with the remaining adherent cells is then read in a fluorescent read out mode with an excitation wavelength of 485 nm and emission wavelength of 385 nm.
Activities for the compounds of the present invention are reported in
Table 6 and described as follow: C= IC50 > 1 pM; B= 1 pM > IC50 SO.01 pM; A= IC50 < 0.01 pM. Table 6 Series A Cell adhesion assays Activities ranges C= IC50 > 1 pM; B= 1 pM > IC50
>0.01 pM; A= IC50 < 0.01 pM
SELECTED EMBODIMENTS
Embodiment 1 . A compound of Formula I, or a pharmaceutically acceptable salt thereof: wherein:
Rx is hydrogen or methyl;
R1 is -SO2-Ci-6alkyl or -C(O)-R7; wherein R7 is -Ci-ealkyl , substituted with 0 or 1 substituents selected from pyridine, phenyl and cyclopropyl; or R7 is phenyl or a 5-10 membered heterocyclyl each of which is independently substituted with 0, 1 , 2 or 3 instances of R9; each R9 is independently selected from halogen, =0, -Ci-ealkyl, -C(O)- R10, -Ci-ehaloalkyl, -SO2-Ci.6alkyl, -NH-Ci-4alkyl, -N(Ci-4alkyl)2, -C3. ecycloalkyl, -O-R11, phenyl and 4-10 membered heterocycle; and each of R9 is independently substituted with 0, 1 , 2 or 3 instances of R17; R17 is selected from halogen, -Ci-ealkyl, -O-R15, -C(O)-N(Ci-4alkyl)2, - N(R12R13), 4 to 10 membered heterocycle, wherein when R17 is heterocycle, it is further substituted with 0, 1 or 2 groups independently selected from halogen, -Ci-ealkyl, =0, -C(O)-R14, -Ci-ehaloalkyl, -SO2- Ci.6alkyl, -NH-Ci.4alkyl, -N(Ci-4alkyl)2, -C3.6cycloalkyl, -O-R18;
R10 is independently selected from -Ci-ealkyl, -Ci-ealkyl-C3. ecycloalkyl and C3-6cycloalkyl;
R11 is a -C1-6 alkyl, - Ci-ehaloalkyl or 4 to 10 membered heterocycle or -Ci-6 alkyl-N(Ci-6 alkyl)2, and wherein the 4 to 10 membered heterocycle is substituted with 0 or 1 -C1-6 alkyl;
R12 and R13 are independently selected from -Ci-ealkyl, -Ci- ehaloalkyl and cyclopropyl;
R14 is independently selected from -Ci-ealkyl and C3-ecycloalkyl;
R15 is a -C1-6 alkyl, - Ci-ehaloalkyl, -Ci-e alkyl-N(Ci-e alkyl)2 or 4 to 10 membered heterocycle, when R15 is 4 to 10 membered heterocycle it is substituted with 0 or 1 -Ci-ealkyl; R18 is a -C1-6 alkyl or -Ci-ehaloalkyl; wherein in each -N(Ci-6 alkyl)2 or -N(Ci-4alkyl)2 the two alkyl groups attached to N can be the same or different; or R7 is -NHR19, and R19 is a 4-10 membered heterocycle substituted with 0 or 1 -C1-6 alkyl;
R2 is selected from the group consisting of Br, phenyl, naphthyl, and 5-10 membered heteroaryl, each of which can be independently substituted with 0, 1 , 2 or 3 groups independently selected from -CN, -C1-6 alkyl, halogen, -Ci-ehaloalkyl, - O-C1-6 alkyl, phenyl, 5 to 6 membered heteroaryl, -O-Cs-ecycloalkyl, -O-phenyl, and -O-(5 to 6 membered heterocycloalkyl);
Y is -N= or -C(R3)=;
R3 is halogen, -Ci-ehaloalkyl , -C i-4alkyl, -Cs-ecycloalkyl;
R4 is halogen or hydrogen;
R5 is halogen or hydrogen;
R6 is -C(O)-O-R8, wherein R8 is hydrogen or -Ci-4alkyl, -Ci-4alkyl-O-C(O)-R16
R16 is -Ci-ealkyl, 3 to 6 cycloalkyl, 4 to 6 membered partially saturated heterocycle, wherein the partially saturated heterocycle is further substituted with one or two groups independently selected from =0 or -C1- 4alkyl.
Embodiment 2. The compound of embodiment 1 , or a pharmaceutically acceptable salt thereof, with Formula la wherein R1 to R6, and Y are as defined in embodiment 1.
Embodiment 3. The compound of embodiment 1 , or a pharmaceutically acceptable salt thereof wherein:
Rx is hydrogen.
Embodiment 4. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein:
R2 is phenyl or 5-10 membered heteroaryl, each of which group is substituted with 1 , 2 or 3 groups independently selected from -CN, -C1-6 alkyl, halogen, -Ci- ehaloalkyl. Embodiment 5. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein:
R2 is substituted with 1 , 2 or 3 groups independently selected from -CN, -C1-6 alkyl, halogen, -Ci-ehaloalkyl and R2 is selected from
Embodiment 6. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein:
R2 is substituted with 1 , 2 or 3 groups independently selected from methyl, fluorine
Embodiment 7. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein Y is -N=.
Embodiment 8. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein Y is -C(R3)=.
Embodiment 9. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein
R3 is halogen, -CF3, methyl, ethyl, cyclopropyl;
Embodiment 10. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein
R4 is halogen or hydrogen.
Embodiment 11 . The compound of embodiment 10, wherein R4 is halogen.
Embodiment 12. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R4 is fluorine.
Embodiment 13. The compound of any one of embodiments 1-7, wherein R5 is fluorine or hydrogen.
Embodiment 14. The compound of any one of embodiments 1-7, wherein R5 is hydrogen. Embodiment 15. The compound of any one of the preceding embodiments, wherein R6 is -C(O)-O-R8, wherein R8 is hydrogen, methyl, ethyl or isopropyl, -O-CH2-O- C(O)-R16 or -O-C(CH3)-O-C(O)-R16, wherein R16 is methyl, ethyl, isopropyl, isobutyl, cyclobutyl, cyclopentyl, cyclohexane, neopentyl or (5-methyl-2-oxo-1 ,3-dioxol-4- yl)methyl.
Embodiment 16. The compound of any one of embodiments 1-8, wherein R6 is - C(O)-O-R8, wherein R8 is hydrogen, methyl, ethyl or isopropyl.
Embodiment 17. The compound of embodiment 9, wherein R8 is hydrogen.
Embodiment 18. The compound of anyone of the preceding embodiments, wherein R7 is -Ci-ealkyl, substituted with 0 or 1 phenyl or cyclopropyl; or R7 is phenyl, substituted with 0 or 1 -N(Ci-4alkyl)2, or R7 is 5-10 membered heterocyclyl substituted with 0, 1 , 2 or 3 groups independently selected from R9 and each R9 is independently selected from halogen, =0, -Ci-ealkyl, -C(O)-R10, -Ci- ehaloalkyl, -SCh-Ci-ealkyl, -NH-Ci-4alkyl, -N(Ci-4alkyl)2, -Cs-ecycloalkyl, phenyl, 4 to 7 membered heterocycle, -O-R11; each R9 is independently substituted with 0, 1 or 2 independently selected from R17;
R10 is independently selected from -Ci-ealkyl, Cs-ecycloalkyl and -Ci-ealkyl- Cs-ecycloalkyl;
R11 is a -C1-6 alkyl, -C1-6 alkyl-N(-Ci-6 alkyl)2, - Ci-ehaloalkyl or 4 to 7 membered heterocycle;
R17 is selected from halogen, -O-R15, -C(O)N(Ci-4alkyl)2, -N(R12R13), and 4 to 10 membered heterocycle, when R17 is 4 to 10 membered heterocycle is substituted with 0, 1 or 2 independently selected halogen, -Ci-ealkyl or - Ci-ehaloalkyl;
R12 and R13 are independently selected from -Ci-ealkyl, -Ci-ehaloalkyl and cyclopropyl;
R15 is -Ci-ealkyl, - Ci-ehaloalkyl or 4 to 7 membered heterocycle and when R15 is 4 to 7 membered heterocycle it is substituted with 0 or 1 -Ci-ealkyl; and wherein in each - N(Ci-e alkyl)2 or -N(Ci-4alkyl)2 the two alkyl groups attached to N can be the same or different or R7 is -NHR19, and R19 is 5 membered heteroaryl substituted with 0 or 1 -Ci-ealkyl.
Embodiment 19. The compound of anyone of the preceding embodiments, wherein R7 is -Ci-ealkyl, substituted with 0 or 1 phenyl or cyclopropyl; or R7 is phenyl, substituted with 0 or 1 -N(Ci-4alkyl)2, or R7 is 5-10 membered heterocyclyl substituted with 0, 1 , 2 or 3 groups independently selected from R9 and each R9 is independently selected from halogen, =0, -Ci-ealkyl, -C(O)-R10, -Ci- ehaloalkyl, 4 to 7 membered heterocycle,; each R9 is independently substituted with 0, 1 or 2 independently selected from R17;
R10 is -Ci-ealkyl;
R17 is selected from halogen, -N(R12R13), and 4 to 10 membered heterocycle, when R17 is 4 to 10 membered heterocycle is substituted with 0, 1 or 2 independently selected halogen,;
R12 and R13 are instances of -Ci-ealkyl; and wherein in each - N(Ci-6 alkyl)2 or -N(Ci-4alkyl)2 the two alkyl groups attached to N can be the same or different; or R7 is -NHR19, and R19 is a 5 membered heteroaryl further substituted with -Ci- ealkyl.
Embodiment 20. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R7 is selected from a group consisting of substituted or unsubstituted and
Embodiment 21 . The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R7 is selected from a group consisting of substituted or unsubstituted
Embodiment 22. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R7 is selected from a group consisting of and , each substituted with 0, 1 or 2 substituents independently selected from: -F, -Cl, oxo, -Me, -'Bu, -'Pr, cyclobutyl, -CH2F, - CHF2, -CH2CF3, -CF3, -OMe, -OCF3, -O-azetidin-3-yl, -N(Me)2, -C(O)Me, - N(Me)2 -C(O)cyclopropyl, 1-Me-azetidin-3-yl, 3-F-azetidin-1-yl, oxetan-3-yl, — C(O)CH2cyclopropyl, -CFkcyclopropyl, -CH2-CH2-azeditin-1-yl, -CH2-CH2-(3-F- azeditin-1-yl), -CH2-CH2-(3-CF3-azeditin-1-yl), -CH2-CH2-(3,3-diF-azeditin-1-yl), - CH2-CH2-(3,3-diMe-azeditin-1-yl),-CH2-azeditin-1-yl, -CH2-(3-F-azeditin-1-yl), -CH2- (1-Me-azetidin-3-yl), -CH2-azetidin-3-yl, -CH2CH2-(3-F-pyrrolidin-1-yl), - CH2CH2OCH3, -CH2C(O)N(Me)2, -CH2CH2N(Me)2, -CH2CH2CH2N(Me)2 - CH2CH2N(Me)CH2CF3, -CH2CH2N(Me)cyclopropyl, 4-F-phenyl and -S(O)2Me.
Embodiment 23. The compound of embodiment 21 or 22, wherein the 0, 1 or 2 substituents are independently selected from: -F, -Cl, oxo, -Me, -N(Me)2, - C(O)Me, 3-F-azetidin-1-yl, oxetan-3-yl, -CF^cyclopropyl, -CH2-CH2-azeditin-1-yl and -CH2CH2N(Me)2.
Embodiment 24. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from: -C(O)-CH3, -S(O)2Me,
Embodiment 25. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein each R2 is independently selected from a group consisting of -Br, -CF3, Embodiment 26. The compound of any one of the preceding embodiments, or a pharmaceutically acceptable salt thereof, wherein R3 is independently selected from a group consisting of -F, -CFs and -CH3.
Embodiment 27. A compound, or a pharmaceutically acceptable salt thereof, selected from
Embodiment 28. A pharmaceutical composition comprising a pharmaceutically effective amount of a compound selected from any of the preceding embodiments or a pharmaceutically acceptable salt of any of the foregoing, and a pharmaceutically acceptable carrier or excipient.
Embodiment 29. The use of a compound selected from any of the preceding embodiments, or a pharmaceutically acceptable salt of any of the foregoing, in the preparation of a medicament.
Embodiment 30. A compound selected from any of the preceding embodiments, or a pharmaceutically acceptable salt thereof, for use as a medicament.
Embodiment 31. A method of inhibiting the interaction between a c ? integrins and MAdCAM-1 protein in a subject, the method comprising administering to the subject in need thereof a pharmaceutically effective amount of a compound selected from any of the preceding embodiments, a compound selected from any of the preceding embodiments, or a pharmaceutically acceptable salt thereof.
Embodiment 32. A method of treating inflammatory bowel diseases in a human in need thereof, the method comprising administering to the human a pharmaceutically effective amount of a compound selected from any one of embodiments 1 to 27, or a pharmaceutically acceptable salt thereof.
Embodiment 33. A compound selected from any of the preceding embodiments, a compound selected from any one of embodiments 1 to 27, or a pharmaceutically acceptable salt thereof, for use in the treatment of inflammatory bowel diseases.
Embodiment 34. The method of Embodiment 32 or 33, wherein the inflammatory bowel diseases is ulcerative colitis.
Embodiment 35. The method of Embodiment 32 or 33, wherein the inflammatory bowel diseases is Crohn’s disease. Embodiment 36. A method of treating ulcerative colon disease in a human, the method comprising administering to the human in need thereof a pharmaceutically effective amount of a compound selected from any one of Embodiments 1-27 or a pharmaceutically acceptable salt thereof.
Embodiment 37. A compound selected from any one of embodiments 1 to 27, or a pharmaceutically acceptable salt thereof, for use in the treatment of ulcerative colon disease.
Embodiment 38. The method of Embodiment 37, wherein the ulcerative colon disease is ulcerative colitis.
Embodiment 39. The method of Embodiment 37, wherein the ulcerative colon disease is Crohn’s Disease.
Embodiment 40. A kit comprising: a) one or more compositions, each composition comprising a pharmaceutically effective amount of a compound selected from any one of Embodiments 1-27 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient; and b) instructions for administering the one or more compositions to a human in need thereof.

Claims

Claims
1 . A compound of Formula I, or a pharmaceutically acceptable salt thereof: wherein:
Rx is hydrogen or methyl;
R1 is -SO2-Ci-6alkyl or -C(O)-R7; wherein R7 is -Ci-ealkyl , substituted with 0 or 1 substituents selected from pyridine, phenyl and cyclopropyl; or R7 is phenyl or a 5-10 membered heterocyclyl each of which is independently substituted with 0, 1 , 2 or 3 instances of R9; each R9 is independently selected from halogen, =0, -Ci-ealkyl, -C(O)- R10, -Ci-ehaloalkyl, -SO2-Ci.6alkyl, -NH-Ci-4alkyl, -N(Ci-4alkyl)2, -C3. ecycloalkyl, -O-R11, phenyl and 4-10 membered heterocycle; and each of R9 is independently substituted with 0, 1 , 2 or 3 instances of R17; R17 is selected from halogen, -Ci-ealkyl, -O-R15, -C(O)-N(Ci-4alkyl)2, - N(R12R13), 4 to 10 membered heterocycle, when R17 is heterocycle, it is further substituted with 0, 1 or 2 groups independently selected from halogen, -Ci-ealkyl, =0, -C(O)-R14, -Ci-ehaloalkyl, -SO2-Ci-6alkyl, -NH- Ci-4alkyl, -N(Ci-4alkyl)2, -Cs-ecycloalkyl, -O-R18;
R10 is independently selected from -Ci-ealkyl, -Ci-ealkyl-Cs- ecycloalkyl and Cs-ecycloalkyl;
R11 is a -C1-6 alkyl, - Ci-ehaloalkyl or 4 to 10 membered heterocycle or -Ci-6 alkyl-N(Ci-6 alkyl)2, and wherein the 4 to 10 membered heterocycle is substituted with 0 or 1 -C1-6 alkyl;
R12 and R13 are independently selected from -Ci-ealkyl, -Ci- ehaloalkyl and cyclopropyl;
R14 is independently selected from -Ci-ealkyl and Cs-ecycloalkyl;
R15 is a -C1-6 alkyl, - Ci-ehaloalkyl, -C1-6 alkyl-N(Ci-e al ky l)2 or 4 to 10 membered heterocycle, when R15 is 4 to 10 membered heterocycle it is substituted with 0 or 1 -Ci-ealkyl; R18 is a -C1-6 alkyl or -Ci-ehaloalkyl; wherein in each -N(Ci-6 alkyl)2 or -N(Ci-4alkyl)2 the two alkyl groups attached to N can be the same or different; or R7 is -NHR19, and R19 is a 4-10 membered heterocycle substituted with 0 or 1 -C1-6 alkyl;
R2 is selected from the group consisting of Br, phenyl, naphthyl, and 5-10 membered heteroaryl, each of which groups can be independently substituted with 0, 1 , 2 or 3 groups independently selected from -CN, -C1-6 alkyl, halogen, -Ci- ehaloalkyl, -O-C1-6 alkyl, phenyl, 5 to 6 membered heteroaryl, -O-Cs-ecycloalkyl, -O- phenyl, and -O-(5 to 6 membered heterocycloalkyl);
Y is -N= or -C(R3)=;
R3 is halogen, -Ci-ehaloalkyl , -C i-4alkyl, -Cs-ecycloalkyl;
R4 is halogen or hydrogen;
R5 is halogen or hydrogen;
R6 is -C(O)-O-R8, wherein R8 is hydrogen or -Ci-4alkyl, -Ci-4alkyl-O-C(O)-R16
R16 is -Ci-ealkyl, 3 to 6 cycloalkyl, 4 to 6 membered partially saturated heterocycle, wherein the partially saturated heterocycle is further substituted with one or two groups independently selected from =0 or -C1- 4alkyl.
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, with Formula la wherein R1 to R6, Rx and Y are as defined in claim 1
3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof wherein: Rx is hydrogen.
4. The compound of any one of the proceeding claims, or a pharmaceutically acceptable salt thereof, wherein:
R2 is phenyl or 5-10 membered heteroaryl, each of which group is substituted with 1 , 2 or 3 groups independently selected from -CN, -C1-6 alkyl, halogen, -Ci- ehaloalkyl.
5. The compound of any one of the proceeding claims, or a pharmaceutically acceptable salt thereof, wherein:
R2 is substituted with 1 , 2 or 3 groups independently selected from -CN, -C1-6 alkyl, halogen, -Ci-ehaloalkyl and R2 is selected from
The compound of any one of the proceeding claims, or a pharmaceutically acceptable salt thereof, wherein:
R2 is substituted with 1 , 2 or 3 groups independently selected from methyl, fluorine or -CF3 and is selected from
7. The compound of any one of the proceeding claims, or a pharmaceutically acceptable salt thereof, weherein Y is -N=.
8. The compound of any one of the proceeding claims, or a pharmaceutically acceptable salt thereof, wherein Y is -C(R3)=.
9. The compound of any one of the proceeding claims, or a pharmaceutically acceptable salt thereof, wherein
R3 is halogen, -CF3, methyl, ethyl, cyclopropyl;
10. The compound of any one of the proceeding claims, or a pharmaceutically acceptable salt thereof, wherein R4 is halogen or hydrogen.
11. The compound of claim 10, wherein R4 is halogen.
12. The compound of any one of the proceeding claims, or a pharmaceutically acceptable salt thereof, wherein R4 is fluorine.
13. The compound of any one of claims 1-7, wherein R5 is fluorine or hydrogen.
14. The compound of any one of claims 1-7, wherein R5 is hydrogen.
15. The compound of any one of the proceeding claims, wherein R6 is -C(O)-O-R8, wherein R8 is hydrogen, methyl, ethyl or isopropyl, -O-CH2-O-C(O)-R16 or -O- C(CH3)-O-C(O)-R16, wherein R16 is methyl, ethyl, isopropyl, isobutyl, cyclobutyl, cyclopentyl, cyclohexane, neopentyl or (5-methyl-2-oxo-1 ,3-dioxol-4-yl)methyl.
16. The compound of any one of claims 1-8, wherein R6 is -C(O)-O-R8, wherein R8 is hydrogen, methyl, ethyl or isopropyl.
17. The compound of claim 9, wherein R8 is hydrogen.
18. The compound of anyone of the proceeding claims, wherein R7 is -Ci-ealkyl, substituted with 0 or 1 phenyl or cyclopropyl; or R7 is phenyl, substituted with 0 or 1 -N(Ci-4alkyl)2, or R7 is 5-10 membered heterocyclyl substituted with 0, 1 , 2 or 3 groups independently selected from R9 and each R9 is independently selected from halogen, =0, -Ci-ealkyl, -C(O)-R10, -Ci- ehaloalkyl, -SCh-Ci-ealkyl, -NH-Ci-4alkyl, -N(Ci-4alkyl)2, -Cs-ecycloalkyl, phenyl, 4 to 7 membered heterocycle, -O-R11; each R9 is independently substituted with 0, 1 or 2 independently selected from R17;
R10 is independently selected from -Ci-ealkyl, Cs-ecycloalkyl and -Ci-ealkyl- Cs-ecycloalkyl;
R11 is a -C1-6 alkyl, -C1-6 alkyl-N(-Ci-6 alkyl)2, - Ci-ehaloalkyl or 4 to 7 membered heterocycle;
R17 is selected from halogen, -O-R15, -C(O)N(Ci-4alkyl)2, -N(R12R13), and 4 to 10 membered heterocycle, when R17 is 4 to 10 membered heterocycle is substituted with 0, 1 or 2 independently selected halogen, -Ci-ealkyl or - Ci-ehaloalkyl;
R12 and R13 are independently selected from -Ci-ealkyl, -Ci-ehaloalkyl and cyclopropyl;
R15 is -Ci-ealkyl, - Ci-ehaloalkyl or 4 to 7 membered heterocycle and when R15 is 4 to 7 membered heterocycle it is substituted with 0 or 1 -Ci-ealkyl; and wherein in each - N(Ci-e alkyl)2 or -N(Ci-4alkyl)2 the two alkyl groups attached to N can be the same or different or R7 is -NHR19, and R19 is 5 membered heteroaryl substituted with 0 or 1 -Ci-ealkyl.
19. The compound of anyone of the proceeding claims, wherein R7 is -Ci-ealkyl, substituted with 0 or 1 phenyl or cyclopropyl; or R7 is phenyl, substituted with 0 or 1 -N(Ci-4alkyl)2, or R7 is 5-10 membered heterocyclyl substituted with 0, 1 , 2 or 3 groups independently selected from R9 and each R9 is independently selected from halogen, =0, -Ci-ealkyl , -C(O)-R10, -Ci- ehaloalkyl, 4 to 7 membered heterocycle,; each R9 is independently substituted with 0, 1 or 2 independently selected from R17;
R10 is -Ci.6alkyl;
R17 is selected from halogen, -N(R12R13), and 4 to 10 membered heterocycle, when R17 is 4 to 10 membered heterocycle is substituted with 0, 1 or 2 independently selected halogen,;
R12 and R13 are instances of -Ci-ealkyl; and wherein in each - N(Ci-6 alkyl)2 or -N(Ci-4alkyl)2 the two alkyl groups attached to N can be the same or different; or R7 is -NHR19, and R19 is a 5 membered heteroaryl further substituted with -Ci- ealkyl.
20. The compound of any one of the proceeding claims, or a pharmaceutically acceptable salt thereof, wherein R7 is selected from a group consisting of substituted or unsubstituted and
21. The compound of any one of the proceeding claims, or a pharmaceutically acceptable salt thereof, wherein R7 is selected from a group consisting of substituted or unsubstituted
22. The compound of any one of the proceeding claims, or a pharmaceutically acceptable salt thereof, wherein R7 is selected from a group consisting of and , each substituted with 0, 1 or 2 substituents independently selected from: -F, -Cl, oxo, -Me, -'Bu, -'Pr, cyclobutyl, -CH2F, - CHF2, -CH2CF3, -CF3, -OMe, -OCF3, -O-azetidin-3-yl, -N(Me)2, -C(O)Me, - N(Me)2 -C(O)cyclopropyl, 1-Me-azetidin-3-yl, 3-F-azetidin-1-yl, oxetan-3-yl, — C(O)CH2cyclopropyl, -CFkcyclopropyl, -CH2-CH2-azeditin-1-yl, -CH2-CH2-(3-F- azeditin-1-yl), -CH2-CH2-(3-CF3-azeditin-1-yl), -CH2-CH2-(3,3-diF-azeditin-1-yl), - CH2-CH2-(3,3-diMe-azeditin-1-yl),-CH2-azeditin-1-yl, -CH2-(3-F-azeditin-1-yl), -CH2- (1-Me-azetidin-3-yl), -CH2-azetidin-3-yl, -CH2CH2-(3-F-pyrrolidin-1-yl), - CH2CH2OCH3, -CH2C(O)N(Me)2, -CH2CH2N(Me)2, -CH2CH2CH2N(Me)2 - CH2CH2N(Me)CH2CF3, -CH2CH2N(Me)cyclopropyl, 4-F-phenyl and -S(O)2Me.
23. The compound of claim 21 or 22, wherein the 0, 1 or 2 substituents are independently selected from: -F, -Cl, oxo, -Me, -N(Me)2, -C(O)Me, 3-F-azetidin- 1-yl, oxetan-3-yl, -CFkcyclopropyl, -CH2-CH2-azeditin-1-yl and -CH2CH2N(Me)2.
24. The compound of any one of the proceeding claims, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from: -C(O)-CH3, -S(O)2Me,
25. The compound of any one of the proceeding claims, or a pharmaceutically acceptable salt thereof, wherein R1 is selected from:
26. The compound of any one of the proceeding claims, or a pharmaceutically acceptable salt thereof, wherein each R2 is independently selected from a group consisting of -Br, -CF3,
27. The compound of any one of the proceeding claims, or a pharmaceutically acceptable salt thereof, wherein R3 is independently selected from a group consisting of -F, -CFsand -CH3.
28. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, selected from Structure
29. A compound of claim 1 , or a pharmaceutically acceptable salt thereof, selected from
30. A pharmaceutical composition comprising a pharmaceutically effective amount of a compound selected from any of the preceding claims or a pharmaceutically acceptable salt of any of the foregoing, and a pharmaceutically acceptable carrier or excipient.
31. The use of a compound of any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament. 32. A compound of any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, for use as a medicament.
33. A method of inhibiting the interaction between a c ? integrins and MAdCAM-1 protein in a subject, the method comprising administering to the subject in need thereof a pharmaceutically effective amount of a compound of any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof.
34. A method of treating inflammatory bowel diseases in a human in need thereof, the method comprising administering to the human a pharmaceutically effective amount of a compound of any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof.
35. A compound selected from any of the preceding claims, a compound of any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, for use in the treatment of inflammatory bowel diseases.
36. The method of claim 33 or 34, wherein the inflammatory bowel diseases is ulcerative colitis.
37. The method of claim 33 or 34, wherein the inflammatory bowel diseases is Crohn’s disease.
38. A method of treating ulcerative colon disease in a human, the method comprising administering to the human in need thereof a pharmaceutically effective amount of a compound of any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof.
39. A compound of any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, for use in the treatment of ulcerative colon disease.
40. The method of Claim 38, wherein the ulcerative colon disease is ulcerative colitis.
41. The method of Claim 38, wherein the ulcerative colon disease is Crohn’s Disease.
42. A kit comprising: a) one or more compositions, each composition comprising a pharmaceutically effective amount of a compound of any one of claims 1 to 29 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient; and b) instructions for administering the one or more compositions to a human in need thereof.
EP24717727.2A 2023-04-17 2024-04-16 New alpha4beta7 inhibitors Pending EP4698518A1 (en)

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