Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
  • A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
  • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/415—1,2-Diazoles
  • A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/42—Oxazoles
  • A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
  • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
  • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
  • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
  • A61P31/14—Antivirals for RNA viruses
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
  • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
  • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D207/24—Oxygen or sulfur atoms
  • C07D207/26—2-Pyrrolidones
  • C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
  • C07D207/267—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to the ring nitrogen atom
• • 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
• • 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
  • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
  • C07K5/06—Dipeptides
  • C07K5/06008—Dipeptides with the first amino acid being neutral
  • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic

Definitions

• the present invention relates to peptidomimetic (or peptide-like) compounds, specifically viral protease inhibitors, for the treatment of viral infections, and methods of preparing and using such compounds.
• SARS-CoV-2 severe acute respiratory syndrome coronavirus 2
• the WHO declared the coronavirus outbreak a public health emergency of international concern.
• Coronaviruses are enveloped, positive-sense, single-stranded RNA viruses.
• Seven human coronaviruses (HCoVs) have been so far identified, namely HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, SARS coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV) and the novel coronavirus (SARS-CoV- 2).
• SARS-CoV While SARS-CoV, MERS-CoV, and SARS-CoV-2 are highly pathogenic, the others generally cause mild to moderate upper-respiratory tract illness and contribute to 15%– 30% cases of common colds in human adults.
• the RNA genome of SARS-CoV-2 is about 30 kilobases in length shares approximately 80% sequence identity with SARS-CoV (Zhou P. et al. "A pneumonia outbreak associated with a new coronavirus of probable bat origin.” Nature 579(7798): 270-273, 2020). It consists six major open-reading frames (ORFs).
• ORF 1a/b which is about two thirds of the whole genome length, directly translates two polyproteins, pp1a and pp1ab, which encodes CNE/30.11.2022 16 nonstructural proteins (nsps) to form the replication transcription complex.
• Nsp3 which encodes papain-like protease (PL pro )
• nsp5 which encodes 3-chymotrypsin-like cysteine protease (3CL pro , also known as main protease, M pro )
• 3CL pro cleaves the polyprotein at 11 distinct sites to generate various nsps that are important for viral replication. Accordingly, inhibitors that block the cleavage function of 3CL pro could inhibit virus replication.
• the present invention provides compounds of formula (I) wherein the variables are as defined herein.
• the present invention provides a process of manufacturing a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, wherein said process is as described in Schemes 1 to 3 below.
• the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, when manufactured according to the processes described herein. In a further aspect, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for use as therapeutically active substance. In a further aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, and a therapeutically inert carrier. In a further aspect, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for use in the treatment or prophylaxis of coronavirus infections.
• the present invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, for use in inhibiting the enzymatic activity of 3C-like proteases.
• Figure 1 shows the crystal structure of example 165a as assessed by single crystal X-ray diffraction.
• Figure 1 shows the crystal structure of example 165a as assessed by single crystal X-ray diffraction.
• alkyl refers to a mono- or multivalent, e.g., a mono- or bivalent, linear or branched saturated hydrocarbon group of 1 to 6 carbon atoms (“C1-6-alkyl”), e.g., 1, 2, 3, 4, 5, or 6 carbon atoms. In other embodiments, the alkyl group contains 1 to 3 carbon atoms, e.g., 1, 2 or 3 carbon atoms.
• Some non-limiting examples of alkyl include methyl, ethyl, propyl, 2-propyl (isopropyl), n-butyl, iso-butyl, sec-butyl, tert-butyl, and 2,2- dimethylpropyl.
• alkyl are methyl, tert- butyl, and 2,2-dimethylpropyl.
• halogen refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I).
• halogen refers to fluoro (F), chloro (Cl) or bromo (Br).
• Particularly preferred, yet non-limiting examples of “halogen” or “halo” are fluoro (F) and chloro (Cl).
• cycloalkyl refers to a saturated or partly unsaturated monocyclic or bicyclic hydrocarbon group of 3 to 10 ring carbon atoms (“C 3-10 -cycloalkyl”). In some preferred embodiments, the cycloalkyl group is a saturated monocyclic hydrocarbon group of 3 to 8 ring carbon atoms.
• “Bicyclic cycloalkyl” refers to cycloalkyl moieties consisting of two saturated carbocycles having two carbon atoms in common, i.e., the bridge separating the two rings is either a single bond or a chain of one or two ring atoms, and to spirocyclic moieties, i.e., the two rings are connected via one common ring atom.
• the cycloalkyl group is a saturated monocyclic hydrocarbon group of 3 to 6 ring carbon atoms, e.g., of 3, 4, 5 or 6 carbon atoms.
• cycloalkyl examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 1- bicyclo[1.1.1]pentanyl, norbornanyl, and 1-bicyclo[2.2.2]octanyl.
• a particularly preferred, yet non-limiting example of cycloalkyl is cyclopropyl.
• the term “cycloalkylalkyl” refers to a cycloalkyl group that is bound to the parent molecule via an alkylene group.
• a particularly preferred, yet non-limiting example of cycloalkylalkyl is 1-bicyclo[1.1.1]pentanylmethyl.
• alkylcycloalkyl refers to a cycloalkyl group, wherein at least one of the hydrogen atoms of the cycloalkyl group has been replaced by an alkyl group.
• alkylcycloalkyl refers to a cycloalkyl group wherein 1, 2 or 3 hydrogen atoms of the cycloalkyl group have been replaced by an alkyl group.
• alkylcycloalkyl is a cycloalkyl group wherein 1 of the hydrogen atoms of the cycloalkyl group have been replaced by an alkyl group, such as 1- methylcyclopropyl.
• aryl refers to a monocyclic, bicyclic, or tricyclic carbocyclic ring system having a total of 6 to 14 ring members (“C6-C14-aryl”), preferably, 6 to 12 ring members, and more preferably 6 to 10 ring members, and wherein at least one ring in the system is aromatic.
• Some non-limiting examples of aryl include phenyl and 9H-fluorenyl (e.g.9H- fluoren-9-yl).
• a particularly preferred, yet non-limiting example of aryl is phenyl.
• arylalkyl refers to an aryl group that is bound to the parent molecule via an alkylene group.
• arylalkyl is benzyl.
• aryloxy refers to an aryl group that is bound to the parent molecule via an oxygen atom.
• a non-limiting example of aryloxy is phenoxy.
• heteroaryl refers to a mono- or multivalent, monocyclic, bicyclic or tricyclic, preferably bicyclic ring system having a total of 5 to 14 ring members, preferably, 5 to 12 ring members, and more preferably 5 to 10 ring members, wherein at least one ring in the system is aromatic, and at least one ring in the system contains one or more heteroatoms.
• heteroaryl refers to a 5-10 membered heteroaryl comprising 1, 2, 3 or 4 heteroatoms independently selected from O, S and N. Most preferably, “heteroaryl” refers to a 5-10 membered heteroaryl comprising 1 to 2 heteroatoms independently selected from O, S and N.
• heteroaryl examples include spiro[cyclopropane-1,3'- indoline] (e.g., spiro[cyclopropane-1,3'-indoline]-1'-yl), 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrazin-2-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrimidin-6-yl, indol-1-yl, 1H-indol-2-yl, 1H-indol-3-yl, 1H-indol-4-yl, 1H-indol-5-yl, 1H-indol-6-yl, 1H-indol-7-yl, 1,2-benzoxazol-3-yl, 1,2-benzoxazol-4-yl, 1,2-benzoxazol-5-yl, 1,2-benzoxazol-6-yl
• heteroaryl are pyridyl, pyrazinyl, pyrimidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl and triazolyl.
• heteroarylalkyl refers to a heteroaryl group that is bound to the parent molecule via an alkylene group.
• a particularly preferred, yet non-limiting example of heteroarylalkyl is pyridylmethyl.
• heterocyclyl or “heterocycloalkyl” refers to a saturated or partly unsaturated mono- or bicyclic, preferably monocyclic ring system of 3 to 14 ring atoms, preferably 3 to 10 ring atoms, more preferably 3 to 8 ring atoms, wherein 1, 2, or 3 of said ring atoms are heteroatoms selected from N, O and S, the remaining ring atoms being carbon.
• 1, 2, or 3 of said ring atoms are heteroatoms selected from N, O and S, the remaining ring atoms being carbon.
• 1 to 2 of said ring atoms are selected from N and O, the remaining ring atoms being carbon.
• Bicyclic heterocyclyl refers to heterocyclic moieties consisting of two cycles having two ring atoms in common, i.e., the bridge separating the two rings is either a single bond or a chain of one or two ring atoms, and to spirocyclic moieties, i.e., the two rings are connected via one common ring atom.
• heterocyclyl groups include azetidinyl, pyrrolidinyl, oxetanyl, 5-azaspiro[2.5]octan-5-yl, piperidyl, 3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl, 2-azaspiro[3.3]heptan-2- yl, 2,6-diazaspiro[3.3]heptanyl, 2-azaspiro[3.5]nonan-2-yl, 1,2-dihydropyridiynl, piperidyl, pyrrolidinyl, and thietanyl.
• haloalkyl refers to an alkyl group, wherein at least one of the hydrogen atoms of the alkyl group has been replaced by a halogen atom, preferably fluoro.
• haloalkyl refers to an alkyl group wherein 1, 2 or 3 hydrogen atoms of the alkyl group have been replaced by a halogen atom, most preferably fluoro.
• Particularly preferred, yet non-limiting examples of haloalkyl are trifluoromethyl, difluoromethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, and 2,2,2-trifluoroethyl.
• carbamoyl refers to a group H2N-C(O)–.
• acyl refers to a group CH 3 -C(O)–.
• pharmaceutically acceptable salt refers to those salts which retain the biological effectiveness and properties of the free bases or free acids, which are not biologically or otherwise undesirable.
• the salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, in particular hydrochloric acid, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcystein and the like.
• inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like
• organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid,
• salts derived from an inorganic base include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium salts and the like.
• Salts derived from organic bases include, but are not limited to salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N- ethylpiperidine, piperidine, polyimine resins and the like.
• the compounds of formula (I) can contain several asymmetric centers and can be present in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, optically pure diastereioisomers, mixtures of diastereoisomers, diastereoisomeric racemates or mixtures of diastereoisomeric racemates.
• the asymmetric carbon atom can be of the "R" or "S" configuration.
• treatment includes: (1) inhibiting the state, disorder or condition (e.g.
• prophylaxis as used herein includes: preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a mammal and especially a human that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition.
• the present invention provides a compound of Formula (I) - 8 - or a pharmaceutically acceptable salt thereof, wherein: L is C 1 -C 6 -alkyl; 1 L is selected from a covalent bond, O, NH, and ; A is selected from C 6 -C 14 -aryl and 3- to 14-membered heteroaryl; R 1 is selected from a group and a group R 2 is selected from hydrogen, C 3 -C 10 -cycloalkyl, C 3 -C 10 -cycloalkyl-C 1 -C 6 -alkyl, C 1 -C 6 -alkyl-C 3 -C 10 -cycloalkyl, C 1 -C 6 -alkyl, C 1 -C 6 -alkyl-S-C 1 -C 6 -alkyl, 3- to 14-membered heteroaryl, (3- to 14-membered heteroaryl)-C1-C6-alkyl;
• the present invention provides a compound of formula (I) as describend herein, or a pharmaceutically acceptable salt thereof, wherein: L is C1-C6-alkyl; R 1 is selected from a group , C 6 -C 14 -aryloxy, and a 3- to 14-membered heteroaryl; wherein said C6-C14-aryloxy and said 3- to 14-membered heteroaryl are optionally substituted with 1 to 2 substituents selected from halogen and halo-C 1 -C 6 -alkyl; and R 2 is selected from hydrogen, C3-C10-cycloalkyl, C3-C10-cycloalkyl-C1-C6-alkyl, C1-C6-alkyl-C3-C10-cycloalkyl, C1-C6-alkyl, C1-C6-alkyl-S-C1-C6-alkyl, 3- to 14-membered heteroaryl, (3- to 14-membered
• the present invention provides a compound of formula (I) as describend herein, or a pharmaceutically acceptable salt thereof, wherein: L is C 1 -C 6 -alkyl; , C 6 -C 14 -aryloxy, and a 3- to 14-membered heteroaryl; wherein said C 6 -C 14 -aryloxy and said 3- to 14-membered heteroaryl are optionally substituted with 1 to 2 substituents selected from halogen and halo-C 1 -C 6 -alkyl; and R 2 is selected from hydrogen, C 3 -C 10 -cycloalkyl, C 3 -C 10 -cycloalkyl-C 1 -C 6 -alkyl, C1-C6-alkyl-C3-C10-cycloalkyl, C1-C6-alkyl, C1-C6-alkyl-S-C1-C6-alkyl, 3- to 14-membered heteroaryl, (3- to 14-member
• the compound of formula (I) of the present invention is a compound of formula (III) (III) or a pharmaceutically acceptable salt thereof, wherein all variables are as defined herein.
• the compound of formula (I) of the present invention is a compound of formula (IV) (IV) or a pharmaceutically acceptable salt thereof, wherein all variables are as defined herein.
• the compound of formula (I) of the present invention is a compound of formula (V) (V) or a pharmaceutically acceptable salt thereof, wherein all variables are as defined herein.
• the compound of formula (I) of the present invention is a compound of formula (VI) (VI) or a pharmaceutically acceptable salt thereof, wherein all variables are as defined herein.
• the compound of formula (I) of the present invention is a compound of formula (VII) (VII) or a pharmaceutically acceptable salt thereof, wherein all variables are as defined herein.
• the compound of formula (I) of the present invention is a compound of formula (VIII) (VIII) or a pharmaceutically acceptable salt thereof, wherein all variables are as defined herein.
• the present invention provides a compound of formula (I) as describend herein, or a pharmaceutically acceptable salt thereof, wherein: L 1 is selected from a covalent bond, O, NH, and ; A is selected from C6-C14-aryl and 3- to 14-membered heteroaryl; A R 1 is selected from a group and a group ;; and R 2 is selected from hydrogen, C3-C10-cycloalkyl, C3-C10-cycloalkyl-C1-C6-alkyl, (3- to 14-membered heteroaryl)-C 1 -C 6 -alkyl, C 1 -C 6 -alkyl, C 6 -C 14 -aryl, C 6 -C 14 - aryl-C 1 -C 6 -alkyl, and C 1 -C 6 -alkyl-S-C 1 -C 6 -alkyl, wherein said C 3 -C 10 - cycloalkyl is optionally substitute
• the present invention provides a compound of formula (I) as describend herein, or a pharmaceutically acceptable salt thereof, wherein: L 1 is selected from a covalent bond, O, NH, and ; A is selected from phenyl, pyridyl, pyrimidinyl; A R 1 is selected from a group and a group ; and R 2 is selected from hydrogen, cyclopropyl, 1-methylcyclopropyl, cyclobutyl, 1- bicyclo[1.1.1]pentanylmethyl, methyl, ethyl, propyl, sec-butyl, tert-butyl, isobutyl, 1-ethylpropyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 2- methylsulfanylethyl, phenyl, benzyl, and pyridylmethyl; or R 1 and R 2 , taken together with the carbon atom to which they are attached, form a phenyl
• the present invention provides a compound of formula (I) as describend herein, or a pharmaceutically acceptable salt thereof, wherein: 1 L is selected from a covalent bond, O, NH, and ; A is selected from phenyl, pyridyl, pyrimidinyl; R 1 is selected from a group and a group R 2 is selected from hydrogen, cyclopropyl, 1-methylcyclopropyl, cyclobutyl, 1- bicyclo[1.1.1]pentanylmethyl, methyl, ethyl, propyl, sec-butyl, tert-butyl, isobutyl, 1-ethylpropyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 2- methylsulfanylethyl, phenyl, benzyl, and pyridylmethyl; or R 1 and R 2 , taken together with the carbon atom to which they are attached, form a phenyl, which is substitute
• the present invention provides a compound of formula (I) as describend herein, or a pharmaceutically acceptable salt thereof, wherein: R 1 is a group ; R 2 is selected from C 3 -C 10 -cycloalkyl and C 1 -C 6 -alkyl; and R 1a is selected from C3-C10-cycloalkyl, C1-C6-alkyl and halo-C1-C6-alkyl, wherein said C3-C10-cycloalkyl is optionally substituted with 1 to 2 halogen substituents.
• R 1 is a group
• R 2 is selected from C 3 -C 10 -cycloalkyl and C 1 -C 6 -alkyl
• R 1a is selected from C3-C10-cycloalkyl, C1-C6-alkyl and halo-C1-C6-alkyl, wherein said C3-C10-cycloalkyl is optionally substituted with 1 to 2 halogen substituent
• the present invention provides a compound of formula (I) as describend herein, or a pharmaceutically acceptable salt thereof, wherein: R 1 is a group ; R 2 is selected from cyclopropyl, 1,1-dimethylpropyl, 1-ethylpropyl, sec-butyl and tert-butyl; and R 1a is selected from cyclopropyl, 1-fluorocyclopropyl, 2,2-difluorocyclopropyl, isopropyl, tert-butyl, 1-fluoroethyl, CHFCl, CF 3 , and CHF 2 .
• the present invention provides a compound of formula (I) as describend herein, or a pharmaceutically acceptable salt thereof, wherein R 1 is a group .
• the present invention provides a compound of formula (I) as describend herein, or a pharmaceutically acceptable salt thereof, wherein: R 1 is selected from a group and C 6 -C 14 -aryloxy substituted with 1 to 2 halogen substituents; and R 1a is selected from C3-C10-cycloalkyl, C6-C14-aryl, 3- to 14-membered heteroaryl, C 1 -C 6 -alkyl, and halo-C 1 -C 6 -alkyl, wherein said C 3 -C 10 -cycloalkyl and 3- to 14-membered heteroaryl are oprionally substituted with 1 to 2 substituents selected from halogen, C1-C6-alkyl and halo-C1-C6-alkyl.
• the present invention provides a compound of formula (I) as describend herein, or a pharmaceutically acceptable salt thereof, wherein: R 1 is a group ; and R 1a is selected from C3-C10-cycloalkyl, 3- to 14-membered heteroaryl, C1-C6-alkyl, and halo-C1-C6-alkyl, wherein said 3- to 14-membered heteroaryl is substituted with 1 halo-C1-C6-alkyl substituent.
• the present invention provides a compound of formula (I) as describend herein, or a pharmaceutically acceptable salt thereof, wherein: R 1 is a group ; and R 1a is selected from C 3 -C 10 -cycloalkyl, C 1 -C 6 -alkyl and halo-C 1 -C 6 -alkyl, wherein said C3-C10-cycloalkyl is substituted with 1-2 halogen substituents.
• the present invention provides a compound of formula (I) as describend herein, or a pharmaceutically acceptable salt thereof, wherein: R 1 is a group ; and R 1a is selected from C 3 -C 10 -cycloalkyl, C 1 -C 6 -alkyl and halo-C 1 -C 6 -alkyl, wherein said C3-C10-cycloalkyl is substituted with 1 halogen substituent.
• the present invention provides a compound of formula (I) as describend herein, or a pharmaceutically acceptable salt thereof, wherein: R 1 is a group ; and R 1a is selected from C 1 -C 6 -alkyl and halo-C 1 -C 6 -alkyl.
• the present invention provides a compound of formula (I) as describend herein, or a pharmaceutically acceptable salt thereof, wherein: R 1 is a group ; and R 1a is selected from 2,2-difluorocyclopropyl, 1-fluorocyclopropyl, isopropyl, tert- butyl, CF 3 , and CHF 2 .
• the present invention provides a compound of formula (I) as describend herein, or a pharmaceutically acceptable salt thereof, wherein: R 1 is a group ; and R 1a is selected from 1-fluorocyclopropyl, isopropyl, tert-butyl, CF3, and CHF2.
• R 1 is a group ; and R 1a is selected from 1-fluorocyclopropyl, isopropyl, tert-butyl, CF3, and CHF2.
• the present invention provides a compound of formula (I) as describend herein, or a pharmaceutically acceptable salt thereof, wherein: ; and R 1a is selected from isopropyl, tert-butyl, CF3, and CHF2.
• the present invention provides a compound of formula (I) as describend herein, or a pharmaceutically acceptable salt thereof, wherein .
• the present invention provides a compound of formula (I) as describend herein, or a pharmaceutically acceptable salt thereof, wherein R 1 is a group ; and R 1a is selected from CHF2 and CF3.
• the present invention provides a compound of formula (I) as describend herein, or a pharmaceutically acceptable salt thereof, wherein R 1 is a group ; and R 1a is CF3.
• the present invention provides a compound of formula (I) as describend herein, or a pharmaceutically acceptable salt thereof, wherein R 1 is a group ; and R 1a is CHF 2 .
• the present invention provides a compound of formula (I) as describend herein, or a pharmaceutically acceptable salt thereof, wherein: R 1 is a group ; and R 1a is C3-C10-cycloalkyl, wherein said C3-C10-cycloalkyl is substituted with 1-2 halogen substituents.
• the present invention provides a compound of formula (I) as describend herein, or a pharmaceutically acceptable salt thereof, wherein: R 1 is a group ; and R 1a is selected from 2,2-difluorocyclopropyl and 1-fluorocyclopropyl.
• the present invention provides a compound of formula (I) as describend herein, or a pharmaceutically acceptable salt thereof, wherein: R 1 is a group ; and R 1a is 2,2-difluorocyclopropyl.
• the present invention provides a compound of formula (I) as describend herein, or a pharmaceutically acceptable salt thereof, wherein: R 1 is a group ; and R 1a is 1-fluorocyclopropyl.
• the present invention provides a compound of formula (I) as describend herein, or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from hydrogen, C3-C10-cycloalkyl, and C1-C6-alkyl.
• the present invention provides a compound of formula (I) as describend herein, or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from hydrogen, C3-C10-cycloalkyl, C3-C10-cycloalkyl-C1-C6-alkyl, (3- to 14-membered heteroaryl)-C1-C6-alkyl and C1-C6-alkyl, wherein said C3-C10-cycloalkyl is optionally substituted with 1 C 1 -C 6 -alkyl substituent.
• the present invention provides a compound of formula (I) as describend herein, or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from C 3 -C 10 -cycloalkyl and C 1 -C 6 -alkyl.
• the present invention provides a compound of formula (I) as describend herein, or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from cyclopropyl and tert-butyl.
• the present invention provides a compound of formula (I) as describend herein, or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from cyclopropyl, sec-butyl and tert-butyl.
• the present invention provides a compound of formula (I) as describend herein, or a pharmaceutically acceptable salt thereof, wherein R 2 is C1-C6-alkyl.
• the present invention provides a compound of formula (I) as describend herein, or a pharmaceutically acceptable salt thereof, wherein R 2 is tert-butyl.
• the present invention provides a compound of formula (I) as describend herein, or a pharmaceutically acceptable salt thereof, wherein R 3a is C1-C6-alkyl; R 3b is hydrogen or C1-C6-alkyl; and R 4a and R 4b are both hydrogen; or R 3a and R 3b , taken together with the carbon atom to which they are attached, form a C 3 -C 10 -cycloalkyl; and R 4a and R 4b are both hydrogen; or R 3a and R 4a , taken together with the carbon atoms to which they are attached, form a C 3 -C 10 -cycloalkyl; and R 3b and R 4b are both hydrogen; wherein said C 3 -C 10 - cycloalkyl is optionally substituted with 1 to 2 C 1 -C 6 -alkyl substituents.
• the present invention provides a compound of formula (I) as describend herein, or a pharmaceutically acceptable salt thereof, wherein R 3a and R 3b are both C 1 -C 6 -alkyl; and R 4a and R 4b are both hydrogen; or R 3a and R 3b , taken together with the carbon atom to which they are attached, form a C3-C10-cycloalkyl; and R 4a and R 4b are both hydrogen; or R 3a and R 4a , taken together with the carbon atoms to which they are attached, form a C3-C10-cycloalkyl; and R 3b and R 4b are both hydrogen; wherein said C3-C10- cycloalkyl is optionally substituted with 2 C1-C6-alkyl substituents.
• the present invention provides a compound of formula (I) as describend herein, or a pharmaceutically acceptable salt thereof, wherein: R 3a and R 4a , taken together with the carbon atoms to which they are attached, form a C 3 -C 10 -cycloalkyl; and R 3b and R 4b are both hydrogen; wherein said C 3 -C 10 - cycloalkyl is optionally substituted with 2 C 1 -C 6 -alkyl substituents.
• the present invention provides a compound of formula (I) as describend herein, or a pharmaceutically acceptable salt thereof, wherein R 3a and R 3b are both methyl; and R 4a and R 4b are both hydrogen; or R 3a and R 3b , taken together with the carbon atom to which they are attached, form a cyclopropyl; and R 4a and R 4b are both hydrogen; or R 3a and R 4a , taken together with the carbon atoms to which they are attached, form a cyclopropyl or a cyclopentyl; and R 3b and R 4b are both hydrogen; wherein said cyclopropyl is substituted with 2 methyl substituents.
• the present invention provides a compound of formula (I) as describend herein, or a pharmaceutically acceptable salt thereof, wherein R 3a and R 4a , taken together with the carbon atoms to which they are attached, form a cyclopropyl or a cyclopentyl; and R 3b and R 4b are both hydrogen; wherein said cyclopropyl is substituted with 2 methyl substituents.
• the present invention provides a compound of formula (I) as describend herein, or a pharmaceutically acceptable salt thereof, wherein the group is selected from and .
• the present invention provides a compound of formula (I) as describend herein, or a pharmaceutically acceptable salt thereof, wherein the group is .
• the present invention provides a compound of formula (I) as describend herein, or a pharmaceutically acceptable salt thereof, wherein the group is .
• the present invention provides a compound of formula (I) as describend herein, or a pharmaceutically acceptable salt thereof, wherein the group is .
• the present invention provides a compound of formula (I) as describend herein, or a pharmaceutically acceptable salt thereof, wherein the group is .
• the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein L is C1-C3-alkyl.
• the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein L is CH 2 or CH 2 CH 2 .
• the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein L is CH 2 .
• the present invention provides a compound of formula (I) as describend herein, or a pharmaceutically acceptable salt thereof, wherein: L is C 1 -C 6 -alkyl; and R 5 is selected from 3- to 14-membered heterocycloalkyl and 3- to 14-membered heteroaryl; wherein said 3- to 14-membered heterocycloalkyl is substituted with 1 oxo substituent.
• the present invention provides a compound of formula (I) as describend herein, or a pharmaceutically acceptable salt thereof, wherein: L is C 1 -C 6 -alkyl; and R 5 is 3- to 14-membered heterocycloalkyl substituted with 1 oxo substituent.
• the present invention provides a compound of formula (I) as describend herein, or a pharmaceutically acceptable salt thereof, wherein: L is CH 2 ; and R 5 is pyrrolidinyl substituted with 1 oxo substituent.
• the present invention provides a compound of formula (I) as describend herein, or a pharmaceutically acceptable salt thereof, wherein R 5 is a 3- to 9- membered heterocycloalkyl substituted with 1 oxo substituent.
• the present invention provides a compound of formula (I) as describend herein, or a pharmaceutically acceptable salt thereof, wherein R 5 is a 3- to 8- membered heterocycloalkyl substituted with 1 oxo substituent.
• the present invention provides a compound of formula (I) as describend herein, or a pharmaceutically acceptable salt thereof, wherein R 5 is a 3- to 7- membered heterocycloalkyl substituted with 1 oxo substituent. In one embodiment, the present invention provides a compound of formula (I) as describend herein, or a pharmaceutically acceptable salt thereof, wherein R 5 is a 3- to 6- membered heterocycloalkyl substituted with 1 oxo substituent. In one embodiment, the present invention provides a compound of formula (I) as describend herein, or a pharmaceutically acceptable salt thereof, wherein R 5 is a 4- to 6- membered heterocycloalkyl substituted with 1 oxo substituent.
• the present invention provides a compound of formula (I) as describend herein, or a pharmaceutically acceptable salt thereof, wherein R 5 is a 5- to 6- membered heterocycloalkyl substituted with 1 oxo substituent.
• the present invention provides a compound of formula (I) as describend herein, or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from pyrrolidinyl and piperidyl, each of which is substituted with 1 oxo substituent.
• the present invention provides a compound of formula (I) as describend herein, or a pharmaceutically acceptable salt thereof, wherein R 5 is pyrrolidinyl substituted with 1 oxo substituent.
• the present invention provides a compound of formula (I) as describend herein, or a pharmaceutically acceptable salt thereof, wherein R 5 is piperidyl substituted with 1 oxo substituent.
• the present invention provides a compound of formula (I) as describend herein, or a pharmaceutically acceptable salt thereof, wherein R 5 is .
• the present invention provides a compound of formula (I) as describend herein, or a pharmaceutically acceptable salt thereof, wherein R 5 is .
• the present invention provides a compound of formula (I) as describend herein, or a pharmaceutically acceptable salt thereof, wherein R 5 is .
• the present invention provides a compound of formula (I) as describend herein, or a pharmaceutically acceptable salt thereof, wherein R 5 is .
• the present invention provides a compound of formula (I) as describend herein, or a pharmaceutically acceptable salt thereof, wherein: R 6 is selected from fluoro and chloro; and R 7 is selected from hydrogen and chloro.
• the present invention provides a compound of formula (I) as describend herein, or a pharmaceutically acceptable salt thereof, wherein: R 6 is fluoro; and R 7 is chloro.
• the present invention provides a compound of formula (I) as describend herein, or a pharmaceutically acceptable salt thereof, wherein: L is C 1 -C 6 -alkyl; R 1 is selected from a group and C6-C14-aryloxy substituted with 1 to 2 halogen substituents; R 1a is selected from C3-C10-cycloalkyl, C6-C14-aryl, 3- to 14-membered heteroaryl, C 1 -C 6 -alkyl, and halo-C 1 -C 6 -alkyl, wherein said C 3 -C 10 -cycloalkyl and 3- to 14-membered heteroaryl are oprionally substituted with 1 to 2 substituents selected from halogen, C1-C6-alkyl halo-C1-C6-alkyl; R 2 is selected from hydrogen, C3-C10-cycloalkyl, C3-C10-cycloalkyl-C1-C6-alkyl;
• the present invention provides a compound of formula (I) as describend herein, or a pharmaceutically acceptable salt thereof, wherein: L is C1-C6-alkyl; R 1 is a group ; R 1a is selected from C 3 -C 10 -cycloalkyl, C 1 -C 6 -alkyl and halo-C 1 -C 6 -alkyl, wherein said C 3 -C 10 -cycloalkyl is substituted with 1 halogen substituent; R 2 is selected from C3-C10-cycloalkyl and C1-C6-alkyl; R 3a and R 3b are both C1-C6-alkyl; and R 4a and R 4b are both hydrogen; or R 3a and R 3b , taken together with the carbon atom to which they are attached, form a C3-C10-cycloalkyl; and R 4a and R 4b are both hydrogen; or R 3a and R 4a , taken together with the carbon atom to which they are
• the present invention provides a compound of formula (I) as describend herein, or a pharmaceutically acceptable salt thereof, wherein: L is CH 2 ; R 1 is a group ; R 1a is selected from 1-fluorocyclopropyl, isopropyl, tert-butyl, CF3, and CHF2; R 2 is selected from cyclopropyl, sec-butyl and tert-butyl; R 3a and R 3b are both methyl; and R 4a and R 4b are both hydrogen; or R 3a and R 3b , taken together with the carbon atom to which they are attached, form a cyclopropyl; and R 4a and R 4b are both hydrogen; or R 3a and R 4a , taken together with the carbon atoms to which they are attached, form a cyclopropyl or a cyclopentyl; and R 3b and R 4b are both hydrogen; wherein said cyclopropyl is substituted with 2 methyl
• the present invention provides a compound of formula (I) as describend herein, or a pharmaceutically acceptable salt thereof, wherein: L is C1-C6-alkyl; R 1 is a group ; R 1a is selected from C3-C10-cycloalkyl, 3- to 14-membered heteroaryl, C1-C6-alkyl, and halo-C1-C6-alkyl, wherein said 3- to 14-membered heteroaryl is substituted with 1 halo-C 1 -C 6 -alkyl substituent; R 2 is selected from hydrogen, C 3 -C 10 -cycloalkyl, and C 1 -C 6 -alkyl; R 3a is C1-C6-alkyl; R 3b is hydrogen or C1-C6-alkyl; and R 4a and R 4b are both hydrogen; or R 3a and R 3b , taken together with the carbon atom to which they are attached, form a C3-C10-cycloal
• the present invention provides a compound of formula (I) as describend herein, or a pharmaceutically acceptable salt thereof, wherein: L is C1-C6-alkyl; R 1 is a group ; R 1a is selected from C 1 -C 6 -alkyl and halo-C 1 -C 6 -alkyl; R 2 is selected from C 3 -C 10 -cycloalkyl and C 1 -C 6 -alkyl; R 3a and R 3b are both C1-C6-alkyl; and R 4a and R 4b are both hydrogen; or R 3a and R 3b , taken together with the carbon atom to which they are attached, form a C 3 -C 10 -cycloalkyl; and R 4a and R 4b are both hydrogen; or R 3a and R 4a , taken together with the carbon atoms to which they are attached, form a C3-C10-cycloalkyl; and R 3b and R 4b are both hydrogen;
• the present invention provides a compound of formula (I) as describend herein, or a pharmaceutically acceptable salt thereof, wherein: L is CH2; R 1 is a group ; R 1a is selected from isopropyl, tert-butyl, CF3, and CHF2; R 2 is selected from cyclopropyl and tert-butyl; R 3a and R 3b are both methyl; and R 4a and R 4b are both hydrogen; or R 3a and R 3b , taken together with the carbon atom to which they are attached, form a cyclopropyl; and R 4a and R 4b are both hydrogen; or R 3a and R 4a , taken together with the carbon atoms to which they are attached, form a cyclopropyl or a cyclopentyl; and R 3b and R 4b are both hydrogen; wherein said cyclopropyl is substituted with 2 methyl substituents; R 5 is pyrrolidinyl substituted with
• the present invention provides a compound of formula (I) as describend herein, or a pharmaceutically acceptable salt thereof, selected from: N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3- yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2- dimethyl-propyl]-2,2,2-trifluoro-acetamide; N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3- yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabic
• the present invention provides a compound of formula (I) as describend herein, or a pharmaceutically acceptable salt thereof, selected from: N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3- yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2- dimethyl-propyl]-2-methyl-propanamide; N-[(1S)-1-[(6S)-6-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3- yl]methyl]amino]carbamoyl]-5-azaspiro[2.4]heptane-5-carbonyl]-2,2-
• the present invention provides a compound of formula (I) as describend herein, or a pharmaceutically acceptable salt thereof, selected from: N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3- yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2- dimethyl-propyl]-2-methyl-propanamide; N-[(1S)-1-[(6S)-6-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3- yl]methyl]amino]carbamoyl]-5-azaspiro[2.4]heptane-5-carbonyl]-2,2-
• the present invention provides a compound of formula (I) as describend herein, or a pharmaceutically acceptable salt thereof, selected from: N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3- yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2- dimethyl-propyl]-2-methyl-propanamide; N-[(1S)-1-[(6S)-6-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3- yl]methyl]amino]carbamoyl]-5-azaspiro[2.4]heptane-5-carbonyl]-2
• the present invention provides a compound of formula (I) as describend herein, or a pharmaceutically acceptable salt thereof, selected from: N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3- yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2- dimethyl-propyl]-2,2,2-trifluoro-acetamide; N-[(1S)-2-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3- yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-
• the present invention provides a compound of formula (I) as describend herein, or a pharmaceutically acceptable salt thereof, wherein said compound is N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2- oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3- carbonyl]-2,2-dimethyl-propyl]-2-methyl-propanamide.
• the present invention provides a compound of formula (I) as describend herein, or a pharmaceutically acceptable salt thereof, wherein said compound is N-[(1S)-1-[(6S)-6-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2- oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-5-azaspiro[2.4]heptane-5-carbonyl]-2,2- dimethyl-propyl]-2,2,2-trifluoro-acetamide.
• the present invention provides a compound of formula (I) as describend herein, or a pharmaceutically acceptable salt thereof, wherein said compound is N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2- oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3- carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide.
• the present invention provides a compound of formula (I) as describend herein, or a pharmaceutically acceptable salt thereof, wherein said compound is N-[(1S)-1-[(2S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2- oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-4,4-dimethyl-pyrrolidine-1-carbonyl]-2,2- dimethyl-propyl]-2,2,2-trifluoro-acetamide.
• the present invention provides a compound of formula (I) as describend herein, or a pharmaceutically acceptable salt thereof, wherein said compound is N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2- oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3- carbonyl]-2,2-dimethyl-propyl]-2,2-dimethyl-propanamide.
• the present invention provides a compound of formula (I) as describend herein, or a pharmaceutically acceptable salt thereof, wherein said compound is N-[(1S)-2-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2- oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3- yl]-1-cyclopropyl-2-oxo-ethyl]-2,2,2-trifluoro-acetamide.
• the present invention provides a compound of formula (I) as describend herein, or a pharmaceutically acceptable salt thereof, wherein said compound is N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2- oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H- cyclopenta[c]pyrrole-2-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide.
• the present invention provides a compound of formula (I) as describend herein, or a pharmaceutically acceptable salt thereof, wherein said compound is N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2- oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3- carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro-acetamide.
• the present invention provides a compound of formula (I) as describend herein, or a pharmaceutically acceptable salt thereof, wherein said compound is N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2- oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3- carbonyl]-2-methyl-butyl]-2,2,2-trifluoro-acetamide.
• the present invention provides a compound of formula (I) as describend herein, or a pharmaceutically acceptable salt thereof, wherein said compound is N-[(1S,2R)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2- oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3- carbonyl]-2-methyl-butyl]-2,2,2-trifluoro-acetamide.
• the present invention provides a compound of formula (I) as describend herein, or a pharmaceutically acceptable salt thereof, wherein said compound is N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)- 2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H- cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2,2-difluoro-acetamide.
• the present invention provides a compound of formula (I) as describend herein, or a pharmaceutically acceptable salt thereof, wherein said compound is N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2- oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3- carbonyl]-2-methyl-butyl]-1-fluoro-cyclopropanecarboxamide.
• the present invention provides a compound of formula (I) as describend herein, or a pharmaceutically acceptable salt thereof, wherein said compound is (2R)-2-chloro-N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro- acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2-fluoro-acetamide.
• the present invention provides a compound of formula (I) as describend herein, or a pharmaceutically acceptable salt thereof, wherein said compound is (2S)-2-chloro-N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro- acetyl]-[[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2-fluoro-acetamide.
• the present invention provides a compound of formula (I) as describend herein, or a pharmaceutically acceptable salt thereof, wherein said compound is (2R)-N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]- [[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H- cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2-chloro-2-fluoro-acetamide.
• the present invention provides a compound of formula (I) as describend herein, or a pharmaceutically acceptable salt thereof, wherein said compound is (2S)-N-[(1S,2S)-1-[(3S,3aS,6aR)-3-[[[(2S)-2-chloro-2-fluoro-acetyl]- [[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H- cyclopenta[c]pyrrole-2-carbonyl]-2-methyl-butyl]-2-chloro-2-fluoro-acetamide.
• the present invention provides pharmaceutically acceptable salts of the compounds according to formula (I) as described herein.
• the present invention provides compounds according to formula (I) as described herein in their free form (i.e., as free bases or acids).
• the compounds of formula (I) are isotopically-labeled by having one or more atoms therein replaced by an atom having a different atomic mass or mass number. Such isotopically-labeled (i.e., radiolabeled) compounds of formula (I) are considered to be within the scope of this disclosure.
• isotopes that can be incorporated into the compounds of formula (I) include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine, and iodine, such as, but not limited to, 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I, and 125 I, respectively.
• Certain isotopically-labeled compounds of formula (I) for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies.
• the radioactive isotopes tritium, i.e.
• a compound of formula (I) can be enriched with 1, 2, 5, 10, 25, 50, 75, 90, 95, or 99 percent of a given isotope.
• Substitution with heavier isotopes such as deuterium, i.e. 2 H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements.
• Substitution with positron emitting isotopes, such as 11 C, 18 F, 15 O and 13 N can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
• PET Positron Emission Topography
• Isotopically-labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the Examples as set out below using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed. Processes of Manufacturing The preparation of compounds of formula (I) of the present invention may be carried out in sequential or convergent synthetic routes. Syntheses of the invention are shown in the following general schemes. The skills required for carrying out the reaction and purification of the resulting products are known to those persons skilled in the art. The substituents and indices used in the following description of the processes have the significance given herein, unless indicated to the contrary.
• one of the starting materials, intermediates or compounds of formula (I) contain one or more functional groups which are not stable or are reactive under the reaction conditions of one or more reaction steps
• appropriate protective groups as described e.g., in “Protective Groups in Organic Chemistry” by T. W. Greene and P. G. M. Wutts, 5th Ed., 2014, John Wiley & Sons, N.Y.
• Such protective groups can be removed at a later stage of the synthesis using standard methods described in the literature.
• compounds of formula (I) can be obtained as mixtures of diastereomers or enantiomers, which can be separated by methods well known in the art e.g., chiral HPLC, chiral SFC or chiral crystallization. Racemic compounds can e.g., be separated into their antipodes via diastereomeric salts by crystallization with optically pure acids or by separation of the antipodes by specific chromatographic methods using either a chiral adsorbent or a chiral eluent. It is equally possible to separate starting materials and intermediates containing stereogenic centers to afford diastereomerically/enantiomerically enriched starting materials and intermediates.
• the solvent there is no particular restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve the reagents, at least to some extent.
• the described reactions can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. It is convenient to carry out the described reactions in a temperature range between -78 °C to reflux.
• the time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents. However, a period of from 0.5 hours to several days will usually suffice to yield the described intermediates and compounds.
• reaction sequence is not limited to the one displayed in the schemes, however, depending on the starting materials and their respective reactivity, the sequence of reaction steps can be freely altered. If starting materials or intermediates are not commercially available or their synthesis not described in literature, they can be prepared in analogy to existing procedures for close analogues or as outlined in the experimental section. All substituents, in particular, R 1 to R 7 , R 1a , R 3a , R 3b , R 4a , R 4b and L are as defined above and in the claims, unless otherwise indicated.
• Compound of formula III can be prepared by a protection reaction of compound of formula II with di-tert-butyl dicarbonate in the presence of an organic base, such as TEA, DIPEA or DMAP, in a solvent such as DCM, THF, dioxane or a mixed solvent of dioxane and water. Then compound of formula III reacts with benzyl bromide in the presence of a base such as Na2CO3, K2CO3 or Cs2CO3, in a solvent such as DMF or CH3CN, to afford compound of formula IV.
• an organic base such as TEA, DIPEA or DMAP
• a solvent such as DCM, THF, dioxane or a mixed solvent of dioxane and water.
• compound of formula III reacts with benzyl bromide in the presence of a base such as Na2CO3, K2CO3 or Cs2CO3, in a solvent such as DMF or CH3CN, to afford compound of formula IV.
• Compound of formula VI-a can be obtained by a coupling reaction using compound of formula V-1, compound of formula V- a, and coupling reagent(s), such as T3P, HATU, HOPO, PyBOP or EDCI/HOBt, in the presence of an organic base, such TEA, DIEPA or DMAP.
• an acid such as HCl or TFA
• a solvent such as DCM or dioxane or a neat reaction without any solvent.
• Compound of formula VI-a can be obtained by a coupling reaction using compound of formula V-1, compound of formula V- a, and coupling reagent(s), such as T3P, HATU, HOPO, PyBOP or EDCI/HOBt, in the presence of an organic base, such TEA, DIEPA or DMAP.
• Compound of formula VIII can be obtained by a coupling reaction using compound of formula VII-1, compound of formula VII, and coupling reagent(s), such as T 3 P, HATU, PyBOP, HOPO or EDCI/HOBt, in the presence of an organic base, such TEA, DIEPA or DMAP, in a solvent such as THF, EtOAc, DMF or DCM.
• an organic base such as THF, EtOAc, DMF or DCM.
• compound of formula VIII can be obtained by a reaction of compound of formula VII and compound of formula VII-1 in the presence of an organic base such as TEA, DIEPA or DMAP and in a solvent such as MeOH, DCM, THF or DMF. Hydrogenolysis of compound of formula VIII in the presence of Pd/C, Pd(OH)2 or a mixture of Pd/C and Pd(OH)2, and in a solvent such as MeOH can afford compound of formula IX.
• organic base such as TEA, DIEPA or DMAP
• a solvent such as MeOH, DCM, THF or DMF.
• Compound of formula IX reacts with compound of formula IX-1 in the presence of a coupling reagent, such as T3P, HATU, PyBOP, HOPO or EDCI/HOBt, and an organic base such as TEA, DIPEA or DMAP, in a solvent such as THF, EtOAc, DMF or DCM, to afford compound of formula X.
• a coupling reagent such as T3P, HATU, PyBOP, HOPO or EDCI/HOBt
• an organic base such as TEA, DIPEA or DMAP
• a solvent such as THF, EtOAc, DMF or DCM
• Compound of formula XI then reacts with compound of formula XI-1 in the presence of coupling reagent(s), such as T 3 P, HATU, PyBOP, HOPO or EDCI/HOBt, and a base such as TEA, DIPEA or DMAP, in a solvent such as THF, EtOAc, DMF or DCM, to afford compound of formula I-a.
• coupling reagent(s) such as T 3 P, HATU, PyBOP, HOPO or EDCI/HOBt
• a base such as TEA, DIPEA or DMAP
• compound of formula X can be prepared by using compound of formula V- b as starting material.
• Compound of formula V-b reacts with compound of formula V-1 in the presence of coupling reagent(s), such as T 3 P, HATU, PyBOP, HOPO or EDCI/HOBt, and an organic base such as TEA, DIPEA or DMAP, in a solvent such as DMF or DCM, to afford compound of formula VI-b.
• coupling reagent(s) such as T 3 P, HATU, PyBOP, HOPO or EDCI/HOBt
• an organic base such as TEA, DIPEA or DMAP
• a solvent such as DMF or DCM
• Hydrolyzation of compound of formula VI-b in the presence of a base such as LiOH ⁇ H 2 O, NaOH or KOH, and in a mixed solution of MeOH and H2O can afford compound of formula XII.
• Compound of formula VIII can be obtained by a coupling reaction using compound of formula XII, compound of formula IX-1-a, and coupling reagent(s), such as T3P, HATU, HOPO, PyBOP or EDCI/HOBt, in the presence of an organic base, such as TEA, DIEPA or DMAP, in a solvent such as THF, EtOAc, DMF or DCM.
• an organic base such as TEA, DIEPA or DMAP
• a solvent such as THF, EtOAc, DMF or DCM.
• Hydrogenolysis of compound of formula XIII in the presence of Pd/C, Pd(OH)2 or a mixture of Pd/C and Pd(OH)2 in a solvent such as MeOH can afford compound of formula XIV.
• Compound of formula XIV reacts with compound of formula VII-1 in the presence of coupling reagent(s), such as T3P, HATU, PyBOP, HOPO or EDCI/HOBt, and an organic base such as TEA, DIPEA or DMAP, in a solvent such as DMF or DCM, to afford compound of formula X.
• coupling reagent(s) such as T3P, HATU, PyBOP, HOPO or EDCI/HOBt
• an organic base such as TEA, DIPEA or DMAP
• a solvent such as DMF or DCM
• Scheme 3 IX-1-a II XV XVI V-1 XIII XVII
• PG 1 is as defined in Scheme 1.
• compound of formula I-a can also be prepared by Scheme 3.
• Compound of formula II reacts with benzyl carbonochloridate or benzyl carbonochloridate in the presence of an organic base, such as TEA, DIPEA or DMAP, in a solvent such as DCM, THF, dioxane or a mixed solvent of dioxane and water, to afford compound of formula XV.
• an organic base such as TEA, DIPEA or DMAP
• Compound of formula XV reacts with compound of formula IX-1-a in the presence of a coupling reagent, such as T 3 P, HATU, PyBOP, HOPO or EDCI/HOBt, and an organic base such as TEA, DIPEA or DMAP, in a solvent such as THF, EtOAc, DMF or DCM, to afford compound of formula XVI.
• a coupling reagent such as T 3 P, HATU, PyBOP, HOPO or EDCI/HOBt
• an organic base such as TEA, DIPEA or DMAP
• a solvent such as THF, EtOAc, DMF or DCM
• Hydrogenolysis of compound of formula XVI in the presence of Pd/C, Pd(OH)2 or a mixture of Pd/C and Pd(OH)2 in a solvent such as MeOH, EtOH or THF can afford compound of formula XVII.
• compound of formula XX can obtained by a hydrogenation reaction of compound of formula VI-a in the presence of Pd/C, Pd(OH)2 or a mixture of Pd/C and Pd(OH)2 in a solvent such as MeOH, EtOH or THF.
• Compound of formula XX reacts with compound of formula VII-1 in the presence of an organic base such as TEA, DIPEA or DMAP, in a solvent such as MeOH, DMF or DCM, to afford compound of formula IX.
• an organic base such as TEA, DIPEA or DMAP
• Scheme 5 II-1 IX-1-a II XXI XXII XI-1 XXIII I-b
• LG2 is as defined in Scheme 1.
• Compound of formula XXI can be prepared by a coupling reaction of compound of formula II with compound of formula II-1 in the presence of an organic base such as TEA, DIPEA or DMAP, in a solvent such as DMF or DCM.
• Compound of formula IX-1-a reacts with compound of formula XXI, in presence of coupling reagent(s), such as T3P, HATU, PyBOP, HOPO or EDCI/HOBt, and an organic base, such as TEA, DIEPA or DMAP, in a solvent such as THF, EtOAc, DMF or DCM to afford compound formula XXII.
• coupling reagent(s) such as T3P, HATU, PyBOP, HOPO or EDCI/HOBt
• an organic base such as TEA, DIEPA or DMAP
• Compound of formula XIV can be obtained by a hydrogenation reaction of compound of formula XIII in the presence of Pd/C, Pd(OH)2 or a mixture of Pd/C and Pd(OH)2 in a solvent such as MeOH, EtOH or THF. Then compound of formula XIV is deprotected in the presence of an acid such as HCl or TFA in DCM, dioxane or without any solvent to afford compound formula XXIV.
• PG1 is Boc
• compound of formula XXIV can also be obtained from compound of formula XIII in the same acid condition above mentioned.
• Compound of formula XXIV reacts with compound of formula XI-2 in the presence of coupling reagent(s), such as T3P, HATU, PyBOP, HOPO, EDCI/HOBt or none, and a base such as TEA, DIPEA or DMAP, in a solvent such as THF, EtOAc, DMF or DCM, to afford compound of formula I-c.
• coupling reagent(s) such as T3P, HATU, PyBOP, HOPO, EDCI/HOBt or none
• a base such as TEA, DIPEA or DMAP
• the present invention provides a process of manufacturing a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, comprising: (a) reacting a compound of formula (XI) (XI) wherein R 1a , R 2 , R 3a , R 3b , R 4a , R 4b , R 5 , and L are as defined herein; with a compound of formula (XI-1), (XI-1) wherein R 6 and R 7 are as defined herein and LG2 is a leaving group; in the presence of a coupling reagent and a base; to form a compound of formula (I-a) O R 1a NH 2 O R 5 O N L R R 6 N N 3 a R 4b H R 7 R 3 4a R b R O (I-a) wherein R 1a , R 2 , R 3a , R 3b , R 4a , R 4b , R 5 , R 6 , R 7 , and L are as defined herein;
• said leaving group LG 2 is a halogen, in particular chloro.
• the base used in said process is selected from TEA, DIPEA and DMAP.
• the solvent used in said process is DMF or DCM.
• the coupling reagent is selected from T 3 P, HATU, PyBOP, HOPO and EDCI/HOBt.
• the present invention provides a compound of formula (XI), or a salt thereof, wherein R 1a , R 2 , R 3a , R 3b , R 4a , R 4b , R 5 , and L are as defined herein.
• the present invention provides a compound of formula (XXIII), or a salt th f wherein R 1 , R 3a , R 3b , R 4a , R 4b , R 5 , and L are as defined herein.
• the present invention provides compounds of formula (I), or pharmaceutically acceptable salts thereof, as described herein for use as therapeutically active substance.
• the present invention provides the use of a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, for the treatment or prophylaxis of coronavirus infections.
• the present invention provides the use of a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, for inhibiting the enzymatic activity of 3C-like proteases.
• the present invention provides the use of a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment or prophylaxis of coronavirus infections.
• the present invention provides the use of a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for inhibiting the enzymatic activity of 3C-like proteases.
• the present invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, for use in the treatment or prophylaxis of coronavirus infections.
• the present invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, for use in inhibiting the enzymatic activity of 3C-like proteases.
• the present invention provides a method of treatment or prophylaxis of coronavirus infections, said method comprising administering a therapeutically active amount of a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, to a subject in need.
• the present invention provides a method of inhibiting the enzymatic activity of 3C-like proteases, said method comprising contacting a 3C-like protease with a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof.
• said coronavirus is selected from severe acute respiratory syndrome coronavirus (SARS-CoV), severe acute respiratory syndrome coronavirus 2 (SARS-CoV- 2) and Middle East Respiratory Syndrome Coronavirus (MERS-CoV).
• said coronavirus is severe acute respiratory syndrome coronavirus (SARS-CoV).
• said coronavirus is severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
• said coronavirus is Middle East Respiratory Syndrome Coronavirus (MERS-CoV).
• MERS-CoV Middle East Respiratory Syndrome Coronavirus
• the present invention provides a pharmaceutical composition comprising a compound of formula (I) as described herein and a therapeutically inert carrier.
• the compounds of formula (I) and their pharmaceutically acceptable salts and esters can be used as medicaments (e.g. in the form of pharmaceutical preparations).
• the pharmaceutical preparations can be administered internally, such as orally (e.g. in the form of tablets, coated tablets, dragées, hard and soft gelatin capsules, solutions, emulsions or suspensions), nasally (e.g.
• the administration can also be effected parentally, such as intramuscularly or intravenously (e.g. in the form of injection solutions).
• the compounds of formula (I) and their pharmaceutically acceptable salts and esters can be processed with pharmaceutically inert, inorganic or organic adjuvants for the production of tablets, coated tablets, dragées and hard gelatin capsules. Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts etc. can be used, for example, as such adjuvants for tablets, dragées and hard gelatin capsules.
• Suitable adjuvants for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid substances and liquid polyols, etc.
• Suitable adjuvants for the production of solutions and syrups are, for example, water, polyols, saccharose, invert sugar, glucose, etc.
• Suitable adjuvants for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils, etc.
• Suitable adjuvants for suppositories are, for example, natural or hardened oils, waxes, fats, semi-solid or liquid polyols, etc.
• the pharmaceutical preparations can contain preservatives, solubilizers, viscosity-increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.
• the dosage can vary in wide limits and will, of course, be fitted to the individual requirements in each particular case. In general, in the case of oral administration a daily dosage of about 0.1 mg to 20 mg per kg body weight, preferably about 0.5 mg to 4 mg per kg body weight (e.g. about 300 mg per person), divided into preferably 1-3 individual doses, which can consist, for example, of the same amounts, should be appropriate.
• Silica gel Brand and pore size i) KP-SIL 60 ⁇ , particle size: 40-60 ⁇ m; ii) CAS registry NO: Silica Gel: 63231-67-4, particle size: 47-60 micron silica gel; iii) ZCX from Qingdao Haiyang Chemical Co., Ltd, pore: 200-300 or 300-400.
• intermediates and final compounds were purified by preparative HPLC on reversed phase column using X Bridge TM Perp C18 (5 ⁇ m, OBD TM 30 ⁇ 100 mm) column, X Bridge TM Perp C 18 (20-40 ⁇ m, OBD TM 30 ⁇ 100 mm) column, Welch Ultimate X Bridge TM SiOH 250*50*10um column, SunFire TM Perp C18 (5 ⁇ m, OBD TM 30 ⁇ 100 mm) column, Phenomenex Luna C1875*30 mm*3 ⁇ m column or Phenomenex Synergi C18 150*25 mm*10 ⁇ m column.
• LC/MS spectra were obtained using a Waters UPLC-SQD Mass or SHIMADZU LCMS- 2020. Standard LC/MS conditions were as follows (running time 3 mins): Acidic condition: A: 0.1% formic acid and 1% acetonitrile in H2O; B: 0.1% formic acid in acetonitrile; Basic condition: A: 0.05% NH 3 ⁇ H 2 O in H 2 O; B: acetonitrile.
• Step 2 Preparation of O2-benzyl O3-tert-butyl (1R,2S,5S)-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2,3-dicarboxylate K 2 CO 3 , BnBr DMF
• K 2 CO 3 1,3-bis(trimethoxy)-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid
• K 2 CO 3 (1.51 g, 10.97 mmol
• BnBr (1.22 g, 7.13 mmol).
• Step 5 Preparation of benzyl (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (Intermediate 1) TFA DCM To a solution of benzyl (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl- butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (1.25 g, 2.73 mmol) in DCM (10 mL) was added TFA (10 mL).
• Step 2 Preparation of tert-butyl 3-[(2-benzyloxycarbonylhydrazino)methyl]-2-oxo- pyrrolidine-1-carboxylate i-PrOH, 85 o C, 16 h
• i-PrOH i-PrOH
• benzyl N-aminocarbamate 67.41 g, 405.62 mmol
• Step 3 Preparation of benzyl N-[(2-oxopyrrolidin-3-yl)methylamino]carbamate TFA, DCM
• TFA 500 mL
• the reaction mixture was concentrated in vacuum to afford benzyl N-[(2-oxopyrrolidin-3-yl)methylamino]carbamate (147.0 g) as yellow oil. MS obsd.
• Step 4 Preparation of tert-butyl N-(benzyloxycarbonylamino)-N-[(2-oxopyrrolidin-3- yl)methyl]carbamate Boc 2 O, DIEA EtOH To a solution of benzyl N-[(2-oxopyrrolidin-3-yl)methylamino]carbamate (150.0 g, 569.71 mmol) in EtOH (800 mL) was added DIPEA (220.9 g, 1709 mmol) and Boc2O (149.2 g, 683.66 mmol). The reaction mixture was stirred at 50 °C for 12 h. The mixture was concentrated in vacuum.
• Step 5 Preparation of tert-butyl N-amino-N-[[(3S)-2-oxopyrrolidin-3- yl]methyl]carbamate 1) Pd/C, Pd(OH) 2 H 2 , MeOH 2) SFC To a solution of tert-butyl N-(benzyloxycarbonylamino)-N-[(2-oxopyrrolidin-3- yl)methyl]carbamate (160.0 g, 440.27 mmol) in methanol (1500 mL) was added Pd/C (15.0 g) and Pd(OH)2/C (15.0 g) under N2. The reaction mixture was degassed under vacuum and purged H 2 for 3 times.
• the racemate was split by SFC preparation (Column: Phenomenex-Cellulose-2 (250 mm*50 mm, 10 um); Condition: phase A for CO 2 , phase B for Neu-MeOH: B%: 45-45%; Flow Rate (mL/min): 220; Gradient time: 3.55 min, injections: 440) to afford tert-butyl N-amino-N-[[(3S)-2-oxopyrrolidin-3- yl]methyl]carbamate (41.4 g, Intermediate 9) as a light yellow solid.
• Step 2 Preparation of (2R)-2-chloro-2-fluoro-acetic acid 1) 2) HCl To a solution of 2-chloro-2-fluoro-acetic acid (718.0 g, 3191 mmol) in EtOAc (3000 mL) was added a solution of (S)-1-phenylethanamine (386.7 g, 3191 mmol) in EtOAc (3000 mL) at 0 o C. The mixture was stirred at 0 °C for 2 h and then stood overnight. The reaction mixture was filtered and the filter cake was dissolved in acetone (760 g in 7600 mL) at 80 o C. The resulting solution was slowly cooled to 20 o C and stood overnight.
• Step 1 Preparation of benzyl N-(1H-pyrazol-3-ylmethylamino)carbamate: NaBH 3 CN MeOH, AcOH To a solution of 1H-pyrazole-3-carbaldehyde (5.0 g, 52.03 mmol) (BePharm, CAS number: 3920-50-1) and benzyl carbazate (8.68 g, 52.20 mmol) in methanol (100 mL) was added HOAc (10.0 mL, 174.85 mmol). The mixture was stirred at 25 °C for 3 h.
• Step 2 Preparation of tert-butyl N-(benzyloxycarbonylamino)-N-(1H-pyrazol-3- ylmethyl)carbamate Boc 2 O, DIEA EtOH, 50 o C To a solution of benzyl N-(1H-pyrazol-3-ylmethylamino)carbamate (3.0 g, 12.18 mmol) in EtOH (40 mL) was added DIPEA (6.29 g, 48.67 mmol) and Boc 2 O (5.32 g, 24.38 mmol).
• Step 3 Preparation of tert-butyl N-amino-N-(1H-pyrazol-3-ylmethyl)carbamate Pd/C, Pd(OH) 2 , H 2 MeOH
• Pd/C tert-butyl N-(benzyloxycarbonylamino)-N-(1H-pyrazol-3- ylmethyl)carbamate
• MeOH MeOH
• Step 2 Preparation of 5-(trifluoromethyl)isoxazole-3-carboxylic acid NaOH MeOH/H 2 O
• a solution of ethyl 5-(trifluoromethyl)isoxazole-3-carboxylate (3.75 g, 17.93 mmol) in methanol (40 mL) was added the solution of NaOH (1.58 g, 39.45 mmol) in water (40 mL) at 0 °C.
• the mixture was stirred at 20 °C for 1 h.
• the reaction mixture was concentrated in vacuum to remove MeOH.
• the residue was diluted with EtOAc (80 mL) and washed with 1M HCl (40 mL).
• Step 2 Preparation of 2-(3,5-difluorophenoxy)acetic acid LiOH.H 2 O MeOH/H 2 O To a solution of ethyl 2-(3,5-difluorophenoxy)acetate (150 mg, 0.690 mmol) in MeOH (5 mL) and water (2 mL) was added LiOH ⁇ H 2 O (73 mg, 1.73 mmol).
• Step 3 Preparation of 2-(3,5-difluorophenoxy)acetyl chloride SOCl 2 DCM To a solution of 2-(3,5-difluorophenoxy)acetic acid (110 mg, 0.580 mmol) in DCM (5 mL) was added SOCl 2 (1 mL). The mixture was stirred at 40 °C for 2 h. The mixture was concentrated in vacuum to afford 2-(3,5-difluorophenoxy)acetyl chloride (120 mg, Intermediate 13) as colorless oil.
• Step 3 Preparation of tert-butyl N-[[(1R,2S,5S)-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3- yl]methyl]carbamate H 2 , Pd/C MeOH
• benzyl (1R,2S,5S)-2-[[tert-butoxycarbonyl-[[(3S)-2-oxopyrrolidin-3- yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (2.53 g, 5.04 mmol) in MeOH (30 mL) was added Pd/C (100 mg, 10% purity) under N 2 atmosphere.
• Step 2 Preparation of 1-methylcyclopropanecarbaldehyde DIBAL-H THF To a solution of N-methoxy-N,1-dimethyl-cyclopropanecarboxamide (6.0 g, 41.91 mmol) in THF (60 mL) was added DIBAL-H (50.29 mL, 50.29 mmol, 1 N) dropwise at -70 °C.
• Step 3 Preparation of (2S)-2-[[(1R)-2-hydroxy-1-phenyl-ethyl]amino]-2-(1- methylcyclopropyl)acetonitrile TMSCN
• (R)-(-)-2- phenylglycinol 4.11 g, 29.96 mmol.
• the mixture was stirred at 25 °C for 2 h.
• trimethylsilyl cyanide (4.95 g, 49.90 mmol) was added to the mixture dropwise at 0 °C. Then the mixture was stirred at 0-25 °C for 12 h.
• Step 4 Preparation of (2S)-2-[[(1R)-2-hydroxy-1-phenyl-ethyl]amino]-2-(1- methylcyclopropyl)acetic acid H H N con.HCl N AcOH CN OH H O O OH
• To a solution of (2S)-2-[[(1R)-2-hydroxy-1-phenyl-ethyl]amino]-2-(1- methylcyclopropyl)acetonitrile (4.8 g, 20.84 mmol) in AcOH (10.0 mL) was added 12 N HCl (40.0 mL). The mixture was stirred at 80 °C for 1 h. The mixture was concentrated in vacuum.
• Step 5 Preparation of (2S)-2-amino-2-(1-methylcyclopropyl)acetic acid H 2 , Pd(OH) 2 /C MeOH/AcOH
• the suspension was degassed under vacuum and purged with H 2 for three times.
• the resulting mixture was stirred at 45°C for 16 h under a H2 balloon.
• Step 6 Preparation of (2S)-2-(tert-butoxycarbonylamino)-2-(1- methylcyclopropyl)acetic acid Boc 2 O, Na 2 CO 3 dioxane/H 2 O
• Boc 2 O Na 2 CO 3 dioxane/H 2 O
• Na2CO3 12.8 g, 120.76 mmol
• di-t-butyldicarbonate 5271 mg, 24.15 mmol
• Step 2 Preparation of benzyl (6S)-5-azaspiro[2.4]heptane-6- carboxylate;hydrochloride HCl HCl/dioxane
• a solution of O6-benzyl O5-tert-butyl (6S)-5-azaspiro[2.4]heptane-5,6-dicarboxylate (2.3 g, 6.94 mmol) in 4 N HCl/dioxane (10.0 mL) was stirred at 25 °C for 1 h. The mixture was concentrated in vacuum to afford benzyl (6S)-5-azaspiro[2.4]heptane-6- carboxylate;hydrochloride (1800 mg, Intermediate 17) as yellow oil. MS obsd.
• the reaction was stirred at the same temperature for 15 min under N 2 protection.
• the reaction flask was removed from the dry ice/ethanol bath and placed in an ice-water bath.
• the reaction mixture was stirred at that temperature for 2 h.
• the volatiles were collected via a short path distillation condenser under a dry ice-ethanol environment at 50°C to afford tricyclo[1.1.1.01,3]pentane (7.0 g) in dimethyl ether ( ⁇ 50 mL).
• Boc-3-iodo-l-alanine methyl ester 7.0 g, 21.27 mmol
• Triethylborane (2.82 mL, 2.82 mmol) was added slowly.
• Step 2 Preparation of methyl (2S)-3-(1-bicyclo[1.1.1]pentanyl)-2-(tert- butoxycarbonylamino)propanoate TTMSSH BEt 3 , pentane
• TTMSSH BEt 3 pentane
• Step 3 Preparation of methyl (2S)-3-(1-bicyclo[1.1.1]pentanyl)-2-(tert- butoxycarbonylamino)propanoic acid LiOH.H 2 O THF/H 2 O
• methyl (2S)-3-(1-bicyclo[1.1.1]pentanyl)-2-(tert- butoxycarbonylamino)propanoate (1.03 g, 3.81 mmol) in THF (10 mL) and water (5 mL) was added LiOH ⁇ H 2 O (480 mg, 11.43 mmol). The mixture was stirred at 25 o C for 4 h.
• Step 2 Preparation of 2,2-dimethylbutanal LiAlH 4 -78 o C, THF
• LiAlH4/THF 47.1 mL, 47.1 mmol, 1 N
• H 2 O 1.8 mL
• a aqueous solution of NaOH 1.8 mL, 15%
• Step 3 Preparation of 2-[[(1R)-2-hydroxy-1-phenyl-ethyl]amino]-3,3-dimethyl- pentanenitrile TMSCN, DCM
• 2-dimethylbutanal (3.0 g, 29.95 mmol) in THF (100 mL) was added (R)-(-)-2-phenylglycinol (4.11 g, 29.95 mmol).
• the reaction was stirred at 15 o C for 2h.
• trimethylsilyl cyanide (5.94 g, 59.9 mmol) was added at 0 o C dropwise in 15 min.
• the resulting mixture was stirred at 20 o C for 12 h.
• Step 4 Preparation of (2S)-2-[[(1R)-2-hydroxy-1-phenyl-ethyl]amino]-3,3-dimethyl- pentanoic acid HCl AcOH To a solution of 2-[[(1R)-2-hydroxy-1-phenyl-ethyl]amino]-3,3-dimethyl-pentanoic acid (5.0 g, 18.84 mmol) in acetic acid (10 mL) was added con. HCl (20.0 mL). The reaction was stirred at 80 °C for 12 h.
• Step 5 Preparation of (2S)-2-amino-3,3-dimethyl-pentanoic acid Pd/C, H 2 MeOH
• (2S)-2-[[(1R)-2-hydroxy-1-phenyl-ethyl]amino]-3,3-dimethyl-pentanoic acid 2.5 g, 9.42 mmol
• methanol 60 mL
• acetic acid 40 mL
• Pd(OH) 2 750 mg.
• the suspension was degassed with H2 for 3 times and stirred for 16 h at 20 o C under a H2 balloon.
• Step 6 Preparation of (2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-pentanoic acid Boc 2 O, Na 2 CO 3 THF/H 2 O
• (2S)-2-amino-3,3-dimethyl-pentanoic acid;acetic acid (1.78 g, 8.67 mmol) in THF (40 mL) and water (40 mL) was added Na2CO3 (4.59 g, 43.33 mmol) and (Boc)2O (2.84 g, 12.99 mmol) successively.
• the suspension was stirred at 20 o C for 12 h.
• Step 1 Preparation of tert-butyl N-[(3-amino-3-oxo-propyl)amino]carbamate BocNHNH 2 iPrOH To a solution of tert-butyl hydrazinecarboxylate (10.0 g, 75.67 mmol) in iPrOH (100 mL) was added acrylamide (5.38 g, 75.67 mmol). The reaction mixture was stirred at 70 °C for 3 h.
• Step 2 Preparation of benzyl N-(3-amino-3-oxo-propyl)-N-(tert- butoxycarbonylamino)carbamate CbzOSu DMF
• benzyl (2,5-dioxopyrrolidin-1-yl) carbonate (1.47 g, 5.9 mmol) in DMF (30 mL) at 25 °C.
• DMF dimethyl methyl
• Step 3 Preparation of benzyl N-amino-N-(3-amino-3-oxo-propyl)carbamate;2,2,2- trifluoroacetic acid TFA TFA DCM
• TFA trifluoroacetic acid
• reaction mixture was stirred at 0 o C for 3 h.
• the reaction mixture was warmed to room temperature and diluted with MTBE (20 mL).
• the organic phase was added to a stirred solution of 25% wt. aqueous NaOH/H 2 O (8.64 mL) and TBAB (280.0 mg, 0.870 mmol).
• the mixture stirred at room temperature for 1 h and at 50 o C for 48 h.
• the reaction mixture was cooled to room temperature and washed with 20% brine (10 mL).
• Step 2 Preparation of trans-1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrole-3- carbonitrile TMSCN MeOH/DCM To a solution of 1,3a,4,5,6,6a-hexahydrocyclopenta[c]pyrrole (1.23 g, 11.27 mmol) in DCM (10 mL) was added methanol (1.23 mL) slowly, followed by TMSCN (2.79 g, 28.17 mmol) at 0 o C. The mixture was stirred at 10 o C for 3 h.
• Step 3 Preparation of trans-methyl 1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrole- 3-carboxylate HCl/MeOH
• a solution of (3S,3aS,6aR)-1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrole-3-carbonitrile (1.2 g, 8.81 mmol) in HCl/MeOH (11.0 mL, 4 N) was stirred for 2 h at 25 o C.
• the reaction mixture was concentrated in vacuum to remove HCl/MeOH.
• Step 2 Preparation of methyl (1R,2S,5S)-3-[(2S,3R)-2-amino-3-methyl-pentanoyl]- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate;2,2,2-trifluoroacetic acid TFA DCM
• TFA trifluoroacetic acid
• Step 3 Preparation of benzyl N-[(2-oxo-3-piperidyl)methylamino]carbamate;2,2,2- trifluoroacetic acid O O H O N O N TFA, DCM NH TFA H N NHH N Cbz Cbz
• tert-butyl 3-[(2-benzyloxycarbonylhydrazino)methyl]-2-oxo-piperidine-1- carboxylate (47.3 g, 125.3 mmol) in DCM (320 mL) was added TFA (250.0 mL).
• Step 4 Preparation of tert-butyl N-(benzyloxycarbonylamino)-N-[(2-oxo-3- piperidyl)methyl]carbamate Boc 2 O, DIEA SFC EtOH
• DIPEA 80.9 g, 626.1 mmol
• Boc 2 O 32.9 g, 162.8 mmol
• Step 5 Preparation of tert-butyl N-amino-N-[(2-oxo-3-piperidyl)methyl]carbamate Pd/C, Pd(OH) 2 , H 2 MeOH
• Pd(OH)2 50 mg
• Pd/C 50 mg, 10% purity
• Step 6 Preparation of tert-butyl N-amino-N-[[(3S)-2-oxo-3- piperidyl]methyl]carbamate Pd/C, Pd(OH) 2 , H 2 MeOH
• Pd(OH) 2 a solution of tert-butyl N-(benzyloxycarbonylamino)-N-[[(3S)-2-oxo-3- piperidyl]methyl]carbamate (3.6 g, 9.54 mmol) in methanol (40 mL) was added Pd(OH) 2 (200 mg) and Pd/C (200.0 mg, 10% purity).
• the mixture was degassed with H2 for 3 times and stirred at 25°C for 2 h under H2 balloon.
• Step 7 Preparation of tert-butyl N-amino-N-[[(3R)-2-oxo-3- piperidyl]methyl]carbamate Pd/C, Pd(OH) 2 , H 2 MeOH
• a solution of tert-butyl N-(benzyloxycarbonylamino)-N-[[(3S)-2-oxo-3- piperidyl]methyl]carbamate (3.6 g, 9.54 mmol) in methanol (20 mL) was added Pd(OH) 2 (360 mg) and Pd/C (360 mg, 10% purity).
• the mixture was degassed with H2 for 3 times and stirred at 25°C for 2 h under H 2 balloon.
• Step 1 Preparation of methyl (1R,2S,5S)-3-[(2S,3S)-2-(tert-butoxycarbonylamino)-3- methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate HCl HATU, DIPEA DMF, ACN
• Boc-Ile-OH 96.0 g, 415.06 mmol
• MeCN 1536 mL
• Step 3 Preparation of (1R,2S,5S)-3-[(2S,3S)-2-amino-3-methyl-pentanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid;hydrochloride HCl HCl/dioxane DCM
• (1R,2S,5S)-3-[(2S,3S)-2-(tert-butoxycarbonylamino)-3-methyl- pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (48.1 g, 130.54 mmol) in DCM (500 mL) was added HCl/dioxane (500.0 mL, 2000.0 mmol).
• Step 4 Preparation of (1R,2S,5S)-6,6-dimethyl-3-[(2S,3S)-3-methyl-2-[(2,2,2- trifluoroacetyl)amino]pentanoyl]-3-azabicyclo[3.1.0]hexane-2-carboxylic acid HCl TEA, MeOH
• TEA 79.26 g, 783.24 mmol
• Step 5 Preparation of tert-butyl N-[[(1R,2S,5S)-6,6-dimethyl-3-[(2S,3S)-3-methyl-2- [(2,2,2-trifluoroacetyl)amino]pentanoyl]-3-azabicyclo[3.1.0]hexane-2- carbonyl]amino]-N-[[(3S)-2-oxo-3-piperidyl]methyl]carbamate EDCI, HOPO, DIPEA DMF To a solution of (1R,2S,5S)-6,6-dimethyl-3-[(2S,3S)-3-methyl-2-[(2,2,2- trifluoroacetyl)amino]pentanoyl]-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (150 mg, 0.41 mmol) in DMF (5 mL) was added DIPEA (266 mg, 2.06 mmol).
• Step 7 Preparation of N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]- [[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2,2-trifluoro-acetamide POCl 3 , DIEA, DCM To a solution of (2R)-2-chloro-2-fluoro-acetic acid (126 mg, 0.69 mmol) in DCM (2 mL) was added POCl3 (95 mg, 0.62 mmol).
• Step 2 Preparation of (2S)-4,4-dimethylpyrrolidine-2-carboxylate;2,2,2- trifluoroacetic acid TFA DCM
• TFA trifluoroacetic acid
• reaction mixture was stirred at 25 °C for 1 h.
• the reaction was quenched with water (50 mL) and extracted with EtOAc (80 mL ⁇ 2). The organic layers were washed with brine (50 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuum.
• Step 2 Preparation of (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid H 2 , Pd/C MeOH
• benzyl (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate 1.2 g, 2.64 mmol
• MeOH 20 mL
• Step 3 Preparation of tert-butyl N-[[(1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate
• the reaction mixture was stirred at 25 °C for 12 h.
• the mixture was diluted with EtOAc (100 mL), washed with water (30 mL) and brine (30 mL ⁇ 3).
• the organic phase was dried over Na2SO4, filtered and the filtrate was concentrated.
• Step 4 Preparation of N-((1S)-1-((1R,2S,5S)-6,6-dimethyl-2-(2-(((3S)-2- oxopyrrolidin-3-yl)methyl)hydrazine-1-carbonyl)-3-azabicyclo[3.1.0]hexan-3-yl)-3,3- dimethyl-1-oxobutan-2-yl)-2,2,2-trifluoroacetamide TFA DCM To a solution of tert-butyl N-[[(1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (110 mg, 0.190 m
• Step 2 Preparation of (1R,2S,5S)-3-[(2S)-2-(benzyloxycarbonylamino)-4-methyl- pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid LiOH.H 2 O MeOH/H 2 O
• methyl (1R,2S,5S)-3-[(2S)-2-(benzyloxycarbonylamino)-4-methyl- pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate 330 mg, 0.790 mmol
• THF 3 mL
• water 3 mL
• the mixture was stirred at 25 °C for 12 h.
• the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL ⁇ 3). The combined organic layers were washed with brine (40 mL), dried over Na 2 SO 4 , filtered and concentrated.
• Step 4 Preparation of tert-butyl N-[[(1R,2S,5S)-3-[(2S)-2-amino-4-methyl-pentanoyl]- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin- 3-yl]methyl]carbamate H 2 , Pd/C MeOH To a solution of tert-butyl N-[[(1R,2S,5S)-3-[(2S)-2-(benzyloxycarbonylamino)-4-methyl- pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2- oxopyrrolidin-3-yl]methyl]carbamate (460 mg, 0.750 mmol) in MeOH (6 mL)
• the reaction mixture was stirred at 25 °C for 1 h.
• the mixture was quenched with water (20 mL) and extracted with EtOAc (30 mL ⁇ 2).
• the organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and the filtrate was concentrated.
• Step 6 Preparation of N-[(1S)-1-[(1R,2S,5S)-6,6-dimethyl-2-[[[(3S)-2-oxopyrrolidin- 3-yl]methylamino]carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carbonyl]-3-methyl- butyl]-2,2,2-trifluoro-acetamide TFA DCM To a solution of tert-butyl N-[[(1R,2S,5S)-6,6-dimethyl-3-[(2S)-4-methyl-2-[(2,2,2- trifluoroacetyl)amino]pentanoyl]-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)- 2-oxopyrrolidin-3-yl]methyl]carbamate (310 mg, 0.54 mmol) in DCM (5 mL) was added
• Example 5 N-[(1S)-1-[(1S,2S,5R)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3- yl]methyl]amino]carbamoyl]-3-azabicyclo[3.2.0]heptane-3-carbonyl]-2,2-dimethyl- propyl]-2,2,2-trifluoro-acetamide
• the title compound was prepared in analogy to the procedure described for the preparation of Example 1, by using benzyl (1S,2S,5R)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-3- azabicyclo[3.2.0]heptane-2-carboxylate (Intermidiate 4) instead of benzyl (1R,2S,5S)-3- [(2S)-2-amino-3,3-dimethyl-butanoyl]
• Example 8 N-[(1S)-1-[(2S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3- yl]methyl]amino]carbamoyl]-4,4-dimethyl-pyrrolidine-1-carbonyl]-2,2-dimethyl- propyl]-2,2,2-trifluoro-acetamide
• the title compound was prepared in analogy to the procedure described for the preparation of Example 1, by using benzyl (2S)-1-[(2S)-2-amino-3,3-dimethyl-butanoyl]-4,4- dimethyl-pyrrolidine-2-carboxylate (Intermediate 7) instead of benzyl (1R,2S,5S)-3-[(2S)- 2-amino-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan
• Step 2 Preparation of (1R,2S,5S)-3-[(2S)-2-(bicyclo[1.1.1]pentane-1-carbonylamino)- 3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid H 2 , Pd/C MeOH
• benzyl (1R,2S,5S)-3-[(2S)-2-(bicyclo[1.1.1]pentane-1-carbonylamino)- 3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate 230 mg, 0.51 mmol
• methanol (10 mL) was added Pd/C (100 mg, 10% purity).
• Step 3 Preparation of tert-butyl N-[[(1R,2S,5S)-3-[(2S)-2-(bicyclo[1.1.1]pentane-1- carbonylamino)-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate EDCI, HOPO DIEA, DMF To a solution of (1R,2S,5S)-3-[(2S)-2-(bicyclo[1.1.1]pentane-1-carbonylamino)-3,3- dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (170 mg, 0.470 mmol) in DMF (2 mL) was added EDCI (108 mg, 0.
• the reaction mixture was stirred at 25 °C for 12 h.
• the mixture was diluted with EtOAc (30 mL), washed with water (20 mL) and brine (20 mL ⁇ 3).
• the combined organic phase was dried over Na2SO4, filtered and concentrated.
• Step 4 Preparation of N-[(1S)-1-[(1R,2S,5S)-6,6-dimethyl-2-[[[(3S)-2-oxopyrrolidin- 3-yl]methylamino]carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl- propyl]bicyclo[1.1.1]pentane-1-carboxamide TFA DCM To a solution of tert-butyl N-[[(1R,2S,5S)-3-[(2S)-2-(bicyclo[1.1.1]pentane-1- carbonylamino)-3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (210 mg, 0.37
• Step 5 Preparation of N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]- [[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]bicyclo[1.1.1]pentane-1- carboxamide (Example 15) DIEA, THF To a solution of N-[(1S)-1-[(1R,2S,5S)-6,6-dimethyl-2-[[[(3S)-2-oxopyrrolidin-3- yl]methylamino]carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl- propyl]bicyclo
• Step 2 Preparation of tert-butyl N-[[(1R,2S,5S)-3-[2-(3,5-difluorophenoxy)acetyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3- yl]methyl]carbamate EDCI, HOPO DIEA, DMF To a solution of (1R,2S,5S)-3-[2-(3,5-difluorophenoxy)acetyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid (110 mg, 0.340 mmol) in DMF (10 mL) was added DIPEA (131 mg, 1.01 mmol), tert-butyl N-amino-N-[[(3S)-2-oxopyrrolidin-3- yl]methyl
• the mixture was stirred at 25 °C for 2 h.
• the reaction mixture was diluted with EtOAc (40 ml) and poured into water (50 mL). After separation, the aqueous phase was extracted with EtOAc (30 mL ⁇ 3). The combined organic layers were dried over Na2SO4.
• Step 3 Preparation of (1R,2S,5S)-3-[2-(3,5-difluorophenoxy)acetyl]-6,6-dimethyl-N'- [[(3S)-2-oxopyrrolidin-3-yl]methyl]-3-azabicyclo[3.1.0]hexane-2-carbohydrazide TFA DCM
• TFA DCM To a solution of tert-butyl N-[[(1R,2S,5S)-3-[2-(3,5-difluorophenoxy)acetyl]-6,6-dimethyl- 3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3- yl]methyl]carbamate (120 mg, 0.220 mmol) in DCM (3 mL) was added TFA (1.0 mL).
• Step 4 Preparation of (1R,2S,5S)-N'-[(2R)-2-chloro-2-fluoro-acetyl]-3-[2-(3,5- difluorophenoxy)acetyl]-6,6-dimethyl-N'-[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3- azabicyclo[3.1.0]hexane-2-carbohydrazide (Example 17) DIEA, THF To a solution of (1R,2S,5S)-3-[2-(3,5-difluorophenoxy)acetyl]-6,6-dimethyl-N'-[[(3S)-2- oxopyrrolidin-3-yl]methyl]-3-azabicyclo[3.1.0]hexane-2-carbohydrazide (60 mg, 0.140 mmol) in THF (14 mL) was added DIPEA (179 mg, 1.39 mmol
• the mixture was stirred at 25 °C for 2 h.
• the mixture was diluted with water (40 mL) and extracted with ethyl acetate (50 mL ⁇ 2).
• the combined organic phase was washed with brine (50 mL ⁇ 2), dried over anhydrous Na 2 SO 4 , filtered and concentrated in vacuum.
• Step 2 Preparation of tert-butyl N-[[(1R,2S,5S)-3-[(2S)-2-amino-3-phenyl- propanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2- oxopyrrolidin-3-yl]methyl]carbamate H 2 , Pd/C MeOH To a solution of tert-butyl N-[[(1R,2S,5S)-3-[(2S)-2-(benzyloxycarbonylamino)-3-phenyl- propanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2- oxopyrrolidin-3-yl]methyl]carbamate (350 mg, 0.540 mmol) in methanol (8
• Step 3 Preparation of tert-butyl N-[[(1R,2S,5S)-6,6-dimethyl-3-[(2S)-3-phenyl-2- [(2,2,2-trifluoroacetyl)amino]propanoyl]-3-azabicyclo[3.1.0]hexane-2- carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate O H F N F F O H N H 2 N O O O TFAA, Et H N 3N O O O N N O N DCM H N N O H H O H H H H H H H To a solution of tert-butyl N-[[(1R,2S,5S)-3-[(2S)-2-amino-3-phenyl-propanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-
• the reaction mixture was stirred at 25 °C for 1 h.
• the mixture was diluted with water (80 mL) and extracted with EtOAc (60 mL ⁇ 3).
• the organic layers were washed with brine (80 mL) and dried over anhydrous sodium sulfate.
• Step 1 Preparation of benzyl (6S)-5-[(2S)-2-(tert-butoxycarbonylamino)-2-(1- methylcyclopropyl)acetyl]-5-azaspiro[2.4]heptane-6-carboxylate HCl HATU, DIPEA, DMF ACN
• (2S)-2-(tert-butoxycarbonylamino)-2-(1-methylcyclopropyl)acetic acid 900 mg, 3.93 mmol, Intermediate 16
• DMF 2 mL
• ACN 10 mL
• benzyl (6S)-5-azaspiro[2.4]heptane-6- carboxylate;hydrochloride (2033 mg, 5.89 mmol, Intermediate 17).
• Step 3 Preparation of (6S)-5-[(2S)-2-amino-2-(1-methylcyclopropyl)acetyl]-5- azaspiro[2.4]heptane-6-carboxylic acid;hydrochloride HCl HCl/dioxane DCM To a solution of (6S)-5-[(2S)-2-(tert-butoxycarbonylamino)-2-(1- methylcyclopropyl)acetyl]-5-azaspiro[2.4]heptane-6-carboxylic acid (790 mg, 2.24 mmol) in DCM (5 mL) was added 4 N HCl/dioxane (5.0 mL).
• Step 4 Preparation of (6S)-5-[(2S)-2-(1-methylcyclopropyl)-2-[(2,2,2- trifluoroacetyl)amino]acetyl]-5-azaspiro[2.4]heptane-6-carboxylic acid HCl TEA, MeOH
• Step 5 Preparation of tert-butyl N-[[(6S)-5-[(2S)-2-(1-methylcyclopropyl)-2-[(2,2,2- trifluoroacetyl)amino]acetyl]-5-azaspiro[2.4]heptane-6-carbonyl]amino]-N-[[(3S)-2- oxopyrrolidin-3-yl]methyl]carbamate EDCI, HOPO, DIPEA DMF To a solution of (6S)-5-[(2S)-2-(1-methylcyclopropyl)-2-[(2,2,2- trifluoroacetyl)amino]acetyl]-5-azaspiro[2.4]heptane-6-carboxylic acid (760 mg, 2.18 mmol) in DMF (5 mL) was added EDCI (502 mg, 2.62 mmol), DIPEA (846 mg, 6.50 mmol) and HOPO (291
• Step 6 Preparation of 2,2,2-trifluoro-N-[(1S)-1-(1-methylcyclopropyl)-2-oxo-2-[(6S)- 6-[[[(3S)-2-oxopyrrolidin-3-yl]methylamino]carbamoyl]-5-azaspiro[2.4]heptan-5- yl]ethyl]acetamide TFA DCM To a solution of tert-butyl N-[[(6S)-5-[(2S)-2-(1-methylcyclopropyl)-2-[(2,2,2- trifluoroacetyl)amino]acetyl]-5-azaspiro[2.4]heptane-6-carbonyl]amino]-N-[[(3S)-2- oxopyrrolidin-3-yl]methyl]carbamate (330 mg, 0.590 mmol) in DCM (4 mL) was added TFA (2.0 mL
• DIPEA (10.2 g, 79.16 mmol) was added into above solution to afford a yellow solution.
• the mixture was stirred at 25 o C for 12h.
• the mixture was diluted with EtOAc (400 mL), washed with brine (60 mL ⁇ 4), dried over Na2SO4, filtered and concentrated in vacuum.
• Step 2 Preparation of (3S,3aS,6aR)-2-[(2S)-2-(benzyloxycarbonylamino)-3,3- dimethyl-butanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylic acid LiOH.H 2 O THF/H 2 O
• Step 3 Preparation of tert-butyl N-[[(3S,3aS,6aR)-2-[(2S)-2- (benzyloxycarbonylamino)-3,3-dimethyl-butanoyl]-3,3a,4,5,6,6a-hexahydro-1H- cyclopenta[c]pyrrole-3-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3- yl]methyl]carbamate EDCI, HOPO DIPEA, DMF To a solution of (3S,3aS,6aR)-2-[(2S)-2-(benzyloxycarbonylamino)-3,3-dimethyl- butanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylic acid (5.9 g, 14.66 mmol) in DMF (60 mL) was added
• the mixture was stirred at 25 o C for 1 h.
• the mixture was diluted in DCM (30 mL) and washed with 1 N HCl (30 mL). After separation, the aqueous phase was extracted with DCM (30 ml ⁇ 2).
• Step 6 Preparation of N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(3S)-2-oxopyrrolidin-3- yl]methylamino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2- carbonyl]-2,2-dimethyl-propyl]acetamide;hydrochloride TFA DCM HCl To a solution of tert-butyl N-[[(3S,3aS,6aR)-2-[(2S)-2-acetamido-3,3-dimethyl-butanoyl]- 3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carbonyl]amino]-N-[[(3S)-2- oxopyrrolidin-3-yl]methyl]carbamate (500 mg, 0.
• Example 33 The title compound was prepared in analogy to the procedure described for the preparation of Example 29, by using isobutyryl chloride instead of acetic anhydride to afford N-[(1S)- 1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3- yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2- carbonyl]-2,2-dimethyl-propyl]-2-methyl-propanamide (Example 33) as a white solid.
• Step 2 Preparation of (1R,2S,5S)-3-[(2S,3R)-2-(tert-butoxycarbonylamino)-3-methyl- pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid LiOH.H 2 O THF/H 2 O
• methyl (1R,2S,5S)-3-[(2S,3R)-2-(tert-butoxycarbonylamino)-3-methyl- pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate 760 mg, 1.99 mmol
• THF 20 mL
• Step 3 Preparation of (1R,2S,5S)-3-[(2S,3R)-2-amino-3-methyl-pentanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid;hydrochloride O NH 2 HCl O NH O HC O O l/dioxane N O DCM N OH OH H H H H H To a solution of (1R,2S,5S)-3-[(2S,3R)-2-(tert-butoxycarbonylamino)-3-methyl- pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (600 mg, 1.63 mmol) in DCM (20 mL) was added HCl/dioxane (20 mL, 4 N).
• Step 4 Preparation of (1R,2S,5S)-6,6-dimethyl-3-[(2S,3R)-3-methyl-2-[(2,2,2- trifluoroacetyl)amino]pentanoyl]-3-azabicyclo[3.1.0]hexane-2-carboxylic acid HCl TEA, MeOH
• Step 5 Preparation of tert-butyl N-[[(1R,2S,5S)-6,6-dimethyl-3-[(2S,3R)-3-methyl-2- [(2,2,2-trifluoroacetyl)amino]pentanoyl]-3-azabicyclo[3.1.0]hexane-2- carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate EDCI, HOPO, DIPEA DMF To a solution of (1R,2S,5S)-6,6-dimethyl-3-[(2S,3R)-3-methyl-2-[(2,2,2- trifluoroacetyl)amino]pentanoyl]-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (500 mg, 1.37 mmol) in DMF (8 mL) was added DIPEA (709 mg, 5.49 mmol),
• Example 67 The title compound was prepared in analogy to the procedure described for the preparation of Example 64, by using Boc-L-4-pyridylalanine (Bide, CAS number: 37535-57-2) instead of Boc-L-isoleucine to afford N-[(1S)-2-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro- acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexan-3-yl]-2-oxo-1-(4-pyridylmethyl)ethyl]-2,2,2-trifluoro- acetamide (Example 67) as a white solid.
• Example 68 The title compound was prepared in analogy to the procedure described for the preparation of Example 64, by using (2S)-2-(tert-butoxycarbonylamino)-2-(1- methylcyclopropyl)acetic acid (Intermediate 16) instead of Boc-L-isoleucine to afford N- [(1S)-2-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3- yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexan-3-yl]-1-(1- methylcyclopropyl)-2-oxo-ethyl]-2,2,2-trifluoro-acetamide (Example 68) as a white solid.
• Step 1 Preparation of benzyl (3S,3aS,6aR)-2-[(2S)-2- (benzyloxycarbonylamino)butanoyl]-3,3a,4,5,6,6a-hexahydro-1H- cyclopenta[c]pyrrole-3-carboxylate TFA HATU, DIPEA DMF
• DIPEA DIPEA
• Step 2 Preparation of (3S,3aS,6aR)-2-[(2S)-2-aminobutanoyl]-3,3a,4,5,6,6a- hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylic acid H 2 , Pd(OH) 2 /C, Pd/C MeOH
• benzyl (3S,3aS,6aR)-2-[(2S)-2-(benzyloxycarbonylamino)butanoyl]- 3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylate 1.5 g, 3.25 mmol
• THF 15 mL
• Pd/C 150.0 mg, 10% purity
• Pd(OH)2 150.0 mg
• Step 3 Preparation of (3S,3aS,6aR)-2-[(2S)-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]- 3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylic acid TEA, MeOH
• 3S,3aS,6aR 2-[(2S)-2-aminobutanoyl]-3,3a,4,5,6,6a-hexahydro-1H- cyclopenta[c]pyrrole-3-carboxylic acid (758 mg, 3.15 mmol) in methanol (6 mL) was added Et3N (958 mg, 9.46 mmol).
• Step 4 Preparation of tert-butyl N-[[(3S,3aS,6aR)-2-[(2S)-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3- carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate EDCI, HOPO, DIPEA DMF To a solution of (3S,3aS,6aR)-2-[(2S)-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]- 3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylic acid (1.1 g, 3.22 mmol) in DMF (20 mL) was added DIPEA (1.67
• Step 5 Preparation of N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(3S)-2-oxopyrrolidin-3- yl]methylamino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2- carbonyl]propyl]-2,2,2-trifluoro-acetamide TFA DCM To a solution of tert-butyl N-[[(3S,3aS,6aR)-2-[(2S)-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3- carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate (1.61 g, 2.
• Example 86 The title compound was prepared in analogy to the procedure described for the preparation of Example 64, by using (2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-pentanoic acid (Intermediate 25) instead of Boc-L-isoleucine to afford N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)- 2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-butyl]-2,2,2-trifluoro- acetamide (Example 86) as a white solid.
• Step 1 Preparation of methyl (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3,3- dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate HCl HATU, DIPEA DMF, ACN
• HATU HCl
• Step 2 Preparation of (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl- butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid LiOH.H 2 O THF/H 2 O
• Step 3 Preparation of (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid;hydrochloride HCl HCl/dioxane DCM To a solution of (1R,2S,5S)-3-[(2S)-2-(tert-butoxycarbonylamino)-3,3-dimethyl-butanoyl]- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (68.0 g, 184.55 mmol) in DCM (180 mL) was added HCl/dioxane (230.68 mL, 4 N).
• Step 4 Preparation of (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid HCl TEA, MeOH
• (1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl-butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carboxylic acid hydrochloride (56.0 g, 183.72 mmol) in methanol (180 mL) was added triethylamine (153.6 mL, 1102.33 mmol) and ethyl trifluoroacetate (70.5 g, 496.05 mmol) dropwise.
• the reaction was warmed to 50 o C and stirred for 16 h. The mixture was concentrated to remove MeOH. The residue was dissolved in EtOAc (400 mL) and washed with 0.5 N HCl (300 mL). The aqueous phase was extracted with EtOAc (300 mL ⁇ 3). The combined organic phase was washed with brine (100 mL), dried over Na2SO4, filtered and concentrated. The residue was triturated in PE (300 mL) for 10 min. The suspension was filtered.
• Step 5 Preparation of benzyl N-(3-amino-3-oxo-propyl)-N-[[(1R,2S,5S)-3-[(2S)-3,3- dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carbonyl]amino]carbamate EDCI, HOPO, DIPEA DMF To a solution of (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (540 mg, 1.48 mmol) in DMF (5 mL) was added DIPEA (1149 mg, 8.89 mmol), EDCI (341 mg, 1.78
• reaction mixture was stirred at 20 °C for 12 h and the mixture was purified by prep-HPLC (TFA condition, column: Phenomenex Luna C18150*25mm*10um;mobile phase: [water(TFA)-ACN]; B%: 42%-72%,1min) to afford benzyl N-(3-amino-3-oxo- propyl)-N-[[(1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]carbamate (500 mg) as colorless oil.
• Example 88a and Example 88b (3S,3aS,6aR)-N'-[(2R)-2-chloro-2-fluoro-acetyl]-2-[2-(3-fluorophenoxy)acetyl]-N'- [[(3S)-2-oxopyrrolidin-3-yl]methyl]-3,3a,4,5,6,6a-hexahydro-1H- cyclopenta[c]pyrrole-3-carbohydrazide and (3R,3aR,6aS)-N'-[(2R)-2-chloro-2-fluoro- acetyl]-2-[2-(3-fluorophenoxy)acetyl]-N'-[[(3S)-2-oxopyrrolidin-3-yl]methyl]- 3,3a,4,5,6,6a-hexahydro-1H-cyclopent
• Step 2 Preparation of trans-2-[2-(3-fluorophenoxy)acetyl]-3,3a,4,5,6,6a-hexahydro- 1H-cyclopenta[c]pyrrole-3-carboxylic acid LiOH.H 2 O THF/H 2 O
• To a solution of trans-methyl 2-[2-(3-fluorophenoxy)acetyl]-3,3a,4,5,6,6a-hexahydro-1H- cyclopenta[c]pyrrole-3-carboxylate (350 mg, 1.09 mmol) in THF (5 mL) was added the solution of LiOH ⁇ H 2 O (91 mg, 2.18 mmol) in water (2 mL).
• Step 3 Preparation of trans-tert-butyl N-[[2-[2-(3-fluorophenoxy)acetyl]- 3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carbonyl]amino]-N-[[(3S)-2- oxopyrrolidin-3-yl]methyl]carbamate HOPO, EDCI, DIPEA DMF
• HOPO EDCI
• DIPEA DMF To a solution of trans-2-[2-(3-fluorophenoxy)acetyl]-3,3a,4,5,6,6a-hexahydro-1H- cyclopenta[c]pyrrole-3-carboxylic acid (250 mg, 0.810 mmol) in DMF (2 mL) was added HOPO (108 mg, 0.980 mmol), EDCI (187 mg, 0.980 mmol), DIPEA (315 mg, 2.4 mmol)
• Step 5 Preparation of (3S,3aS,6aR)-N'-[(2R)-2-chloro-2-fluoro-acetyl]-2-[2-(3- fluorophenoxy)acetyl]-N'-[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3,3a,4,5,6,6a- hexahydro-1H-cyclopenta[c]pyrrole-3-carbohydrazide and (3R,3aR,6aS)-N'-[(2R)-2- chloro-2-fluoro-acetyl]-2-[2-(3-fluorophenoxy)acetyl]-N'-[[(3S)-2-oxopyrrolidin-3- yl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carbohydrazide (Example 88a and 88
• Step 2 Preparation of trans-methyl 2-[2-(3,5-difluorophenoxy)acetyl]-3,3a,4,5,6,6a- hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylate K 2 CO 3 , DMF
• K 2 CO 3 To a solution of trans-methyl 2-(2-chloroacetyl)-3,3a,4,5,6,6a-hexahydro-1H- cyclopenta[c]pyrrole-3-carboxylate (272 mg, 1.11 mmol) in DMF (10 mL) was added K 2 CO 3 (306 mg, 2.21 mmol) and 3,5-difluorophenol (144 mg, 1.11 mmol).
• Step 3 Preparation of trans-2-[2-(3,5-difluorophenoxy)acetyl]-3,3a,4,5,6,6a- hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylic acid LiOH.H 2 O THF/H 2 O
• Step 5 Preparation of trans-2-[2-(3,5-difluorophenoxy)acetyl]-N'-[[(3S)-2- oxopyrrolidin-3-yl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3- carbohydrazide TFA DCM
• TFA DCM To a solution of trans-tert-butyl N-[[2-[2-(3,5-difluorophenoxy)acetyl]-3,3a,4,5,6,6a- hexahydro-1H-cyclopenta[c]pyrrole-3-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3- yl]methyl]carbamate (252 mg, 0.470 mmol) in DCM (5 mL) was added TFA (5.0 mL).
• Step 2 Preparation of (1R,2S,5S)-3-[(2S)-2-(benzyloxycarbonylamino)-3,3-dimethyl- butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid LiOH.H 2 O MeOH/H 2 O
• methyl (1R,2S,5S)-3-[(2S)-2-(benzyloxycarbonylamino)-3,3-dimethyl- butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate 5.57 g, 13.38 mmol
• THF 30 mL
• H2O 15 mL
• the mixture was stirred at 25°C for 2 h.
• the resulting mixture was diluted with water (80 mL) and extracted with EtOAc (50 mL ⁇ 2).
• the mixture was extracted with EtOAc (80 mL ⁇ 3).
• Step 3 Preparation of tert-butyl N-[[(1R,2S,5S)-3-[(2S)-2-(benzyloxycarbonylamino)- 3,3-dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N- [[(3S)-2-oxopyrrolidin-3-yl]methyl]carbamate EDCI, HOPO DIEA, DMF To a solution of (3S,3aS,6aR)-2-[(2S)-2-(benzyloxycarbonylamino)pentanoyl]- 3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carboxylic acid (5.38 g, 13.86 mmol) in DMF (8 mL) was added DIPEA (7.2 g, 55.44 mmol).
• Step 4 Preparation of tert-butyl N-[[(1R,2S,5S)-3-[(2S)-2-amino-3,3-dimethyl- butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2- oxopyrrolidin-3-yl]methyl]carbamate H 2 , Pd(OH) 2 MeOH To a solution of tert-butyl N-[[(1R,2S,5S)-3-[(2S)-2-(benzyloxycarbonylamino)-3,3- dimethyl-butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)- 2-oxopyrrolidin-3-yl]methyl]carbamate (2.5 g, 4.07 mmol)
• reaction mixture was stirred at 25°C for 12 h.
• the reaction mixture was poured into EtOAc (150 mL) and washed with 1 N HCl (50 mL ⁇ 2), 5% aqueous solution of K2CO3 (50 mL ⁇ 2) and brine (50 mL).
• Step 6 Preparation of N-[(1S)-1-[(1R,2S,5S)-6,6-dimethyl-2-[[[(3S)-2-oxopyrrolidin- 3-yl]methylamino]carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl- propyl]-3,3-difluoro-cyclobutanecarboxamide;hydrochloride TFA DCM HCl To a solution of tert-butyl N-[[(1R,2S,5S)-3-[(2S)-2-[(3,3- difluorocyclobutanecarbonyl)amino]-3,3-dimethyl-butanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3- y
• Step 7 Preparation of N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]- [[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-3,3-difluoro- cyclobutanecarboxamide DIEA, THF To a solution of N-[(1S)-1-[(1R,2S,5S)-6,6-dimethyl-2-[[[(3S)-2-oxopyrrolidin-3- yl]methylamino]carbamoyl]-3-azabicyclo[3.1.0]hexan
• Example 91 The title compound was prepared in analogy to the procedure described for the preparation of Example 90, by using 1-fluorocyclobutanecarboxylic acid intead of 3,3- difluorocyclobutanecarboxylic acid to afford N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2- fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-1-fluoro- cyclobutanecarboxamide (Example 91) as a white solid.
• Example 92 The title compound was prepared in analogy to the procedure described for the preparation of Example 90, by using (1S)-2,2-difluorocyclopropanecarboxylic acid intead of 3,3- difluorocyclobutanecarboxylic acid to afford (1S)-N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2- chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2-difluoro- cyclopropanecarboxamide (Example 92) as a white solid.
• Example 98 N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3- yl]methyl]amino]carbamoyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-2- carbonyl]-2,2-dimethyl-propyl]-3,3-difluoro-cyclobutanecarboxamide
• the title compound was prepared in analogy to the procedure described for the preparation of Example 29, by using 3,3-difluorocyclobutanecarboxylic acid and T3P intead of acetic anhydride to afford N-[(1S)-1-[(3S,3aS,6aR)-3-[[[(2R)-2-chloro-2-fluoro-acetyl]-
• Step 2 Preparation of (1R,2S,5S)-3-[(2S,3S)-2-(benzyloxycarbonylamino)-3-methyl- pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid LiOH.H 2 O THF/H 2 O
• To a solution of methyl (1R,2S,5S)-3-[(2S,3S)-2-(benzyloxycarbonylamino)-3-methyl- pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (3.0 g, 7.2 mmol) in THF (20 mL) was added a solution of LiOH.H2O (605 mg, 14.42 mmol) in water (20 mL) at 0°C.
• Step 3 Preparation of tert-butyl N-[[(1R,2S,5S)-3-[(2S,3S)-2- (benzyloxycarbonylamino)-3-methyl-pentanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3- yl]methyl]carbamate EDCI, HOPO DIEA, DMF To a solution of (1R,2S,5S)-3-[(2S,3S)-2-(benzyloxycarbonylamino)-3-methyl-pentanoyl]- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (2.42 g, 6.01 mmol) in DMF (30 mL) was added DIPEA (3.89 g, 30.06 mmol), EDCI (1.
• tert-butyl N-amino-N-[[(3S)-2-oxopyrrolidin-3- yl]methyl]carbamate (1.65 g, 7.2 mmol) was added to the mixture at 0°C.
• the reaction mixture was stirred at 25 °C for 12 h.
• the mixture was diluted with brine (50 mL) and acidified with 1N HCl (10 mL).
• the mixture was extracted with EtOAc (50 mL ⁇ 3).
• the combined organic phase was washed with brine (100 mL), dried over Na 2 SO 4 , filtered and concentrated under vacuum.
• Step 4 Preparation of tert-butyl N-[[(1R,2S,5S)-3-[(2S,3S)-2-amino-3-methyl- pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2- oxopyrrolidin-3-yl]methyl]carbamate H 2 , Pd/C MeOH To a solution of tert-butyl N-[[(1R,2S,5S)-3-[(2S,3S)-2-(benzyloxycarbonylamino)-3- methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2- oxopyrrolidin-3-yl]methyl]carbamate (2.48 g, 4.04 m
• Step 6 Preparation of N-[(1S,2S)-1-[(1R,2S,5S)-6,6-dimethyl-2-[[[(3S)-2- oxopyrrolidin-3-yl]methylamino]carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carbonyl]- 2-methyl-butyl]-1-fluoro-cyclobutanecarboxamide;hydrochloride TFA DCM HCl To a solution of tert-butyl N-[[(1R,2S,5S)-3-[(2S,3S)-2-[(1- fluorocyclobutanecarbonyl)amino]-3-methyl-pentanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-
• Step 7 Preparation of N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]- [[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-1-fluoro- cyclobutanecarboxamide DIEA, THF To a solution of N-[(1S,2S)-1-[(1R,2S,5S)-6,6-dimethyl-2-[[[(3S)-2-oxopyrrolidin-3- yl]methylamino]carbamoyl]-3-azabicyclo[3.1.0]hexane-3
• Example 106 N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3- yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2- methyl-butyl]-1-fluoro-cyclopropanecarboxamide
• the title compound was prepared in analogy to the procedure described for the preparation of Example 105, by using 1-fluorocyclopropanecarboxylic acid intead of 1- fluorocyclobutanecarboxylic acid, and (2S)-2-chloro-2-fluoro-acetyl chloride (Intermediate 28) intead of (2R)-2-chlor
• Example 10 The title compound was prepared in analogy to the procedure described for the preparation of Example 105, by using 2,2-difluoroacetic acid intead of 1-fluorocyclobutanecarboxylic acid, and (2S)-2-chloro-2-fluoro-acetyl chloride (Intermediate 28) intead of (2R)-2- chloro-2-fluoro-acetyl chloride (Intermediate 10) to afford N-[(1S,2S)-1-[(1R,2S,5S)-2- [[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3- yl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2- methyl-butyl]-2,2-difluoro-acetamide (Example 109) as a white
• Example 110 The title compound was prepared in analogy to the procedure described for the preparation of Example 105, by using isobutyryl chloride without coupling reagent intead of 1- fluorocyclobutanecarboxylic acid, and (2S)-2-chloro-2-fluoro-acetyl chloride (Intermediate 28) intead of (2R)-2-chloro-2-fluoro-acetyl chloride (Intermediate 10) to afford N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2S)-2-chloro-2-fluoro-acetyl]-[[(3S)-2- oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2-methyl-propanamide (Example 110) as a white solid
• Example 111 Rac-2,2-difluoro-N-[(1S,2S)-2-methyl-1-[(1R,2S,5S)-6,6-dimethyl-2-[[[(2S)-2-chloro-2- fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-3- azabicyclo[3.1.0]hexane-3-carbonyl]butyl]cyclopropanecarboxamide
• the title compound was prepared in analogy to the procedure described for the preparation of Example 105, by using 2,2-difluorocyclopropanecarboxylic acid intead of 1- fluorocyclobutanecarboxylic acid, and (2S)-2-chloro-2-fluoro-acetyl chloride (Intermediate 28) intead of (2R)
• Step 3 Preparation of (1R,2S,5S)-3-[(2S,3R)-2-(benzyloxycarbonylamino)-3-methyl- pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid LiOH.H 2 O THF/H 2 O
• methyl (1R,2S,5S)-3-[(2S,3R)-2-(benzyloxycarbonylamino)-3-methyl- pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate (3.6 g, 8.64 mmol) in a mixed solvent of THF (15 mL) and water (15 mL) was added LiOH.H 2 O (726 mg, 17.3 mmol) at 0°C.
• Step 4 Preparation of tert-butyl N-[[(1R,2S,5S)-3-[(2S,3R)-2- (benzyloxycarbonylamino)-3-methyl-pentanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3- yl]methyl]carbamate EDCI, HOPO DIEA, DMF To a solution of (1R,2S,5S)-3-[(2S,3R)-2-(benzyloxycarbonylamino)-3-methyl-pentanoyl]- 6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (3.3 g, 8.2 mmol) in DMF (30 mL) was added DIPEA (5.3 g, 41.03 mmol).
• Step 5 Preparation of tert-butyl N-[[(1R,2S,5S)-3-[(2S,3R)-2-amino-3-methyl- pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2- oxopyrrolidin-3-yl]methyl]carbamate H 2 , Pd/C MeOH To a solution of tert-butyl N-[[(1R,2S,5S)-3-[(2S,3R)-2-(benzyloxycarbonylamino)-3- methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2- oxopyrrolidin-3-yl]methyl]carbamate (4.68 g, 7.63 m
• Step 8 Preparation of N-[(1S,2R)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]- [[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2-difluoro-acetamide DIEA, THF To a solution of N-[(1S,2R)-1-[(1R,2S,5S)-6,6-dimethyl-2-[[[(3S)-2-oxopyrrolidin-3- yl]methylamino]carbamoyl]-3-azabicyclo[3.1.0]hexane-3-carbon
• Example 116 The title compound was prepared in analogy to the procedure described for the preparation of Example 112, by using (2R)-2-fluoropropanoic acid and T 3 P intead of (2,2- difluoroacetyl) 2,2-difluoroacetate to afford (2R)-N-[(1S,2R)-1-[(1R,2S,5S)-2-[[[(2R)-2- chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3-yl]methyl]amino]carbamoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2-fluoro- propanamide (Example 116) as a white solid.
• Step 2 Preparation of (1R,2S,5S)-3-[(2S,3R)-2-(cyclopropanecarbonylamino)-3- methyl-pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid H N O H N O O LiOH.
• Step 3 Preparation of tert-butyl N-[[(1R,2S,5S)-3-[(2S,3R)-2- (cyclopropanecarbonylamino)-3-methyl-pentanoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxopyrrolidin-3- yl]methyl]carbamate EDCI, HOPO DIEA, DMF To a solution of (1R,2S,5S)-3-[(2S,3R)-2-(cyclopropanecarbonylamino)-3-methyl- pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (670 mg, 1.99 mmol) in DMF (10 mL) was added DIPEA (772 mg, 5.97 mmol), HOPO (288 mg, 2.
• Example 138 N-[(1S)-1-[(2S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxopyrrolidin-3- yl]methyl]amino]carbamoyl]-4,4-dimethyl-pyrrolidine-1-carbonyl]-2-ethyl-butyl]-1- fluoro-cyclopropanecarboxamide
• the title compound was prepared in analogy to the procedure described for the preparation of Example 15, by using benzyl (2S)-1-[(2S)-2-amino-3-ethyl-pentanoyl]-4,4-dimethyl- pyrrolidine-2-carboxylate;hydrochloride (Intermediate 32) instead of benzyl (1R,2S,5S)- 3-[(2S)-2-amino-3,3-
• reaction mixture was stirred at 25 °C for 1 h.
• the reaction was quenched with water (50 mL) and extracted with EtOAc (80 mL ⁇ 2). The organic layers were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuum.
• Step 2 Preparation of (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid H 2 , Pd/C MeOH
• benzyl (1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylate 1.2 g, 2.64 mmol
• MeOH 20 mL
• Step 3 Preparation of tert-butyl N-[[(1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2- trifluoroacetyl)amino]butanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2- carbonyl]amino]-N-[[(3R)-2-oxo-3-piperidyl]methyl]carbamate and tert-butyl N- [[(1R,2S,5S)-3-[(2S)-3,3-dimethyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N-[[(3S)-2-oxo-3- piperidyl]methyl]carbamate 1)EDCI, HOPO DIEA, D
• Step 4 Preparation of N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]- [[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-3-carbonyl]-2,2-dimethyl-propyl]-2,2,2-trifluoro-acetamide and N-[(1S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3R)-2-oxo-3- piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3- carbonyl]-2,2-dimethyl-propyl]-2,2,2-
• Example 165a and 165b N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3- piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3- carbonyl]-2-methyl-butyl]-2,2,2-trifluoro-acetamide and N-[(1S,2S)-1-[(1R,2S,5S)-2- [[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3R)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]- 6,6-dimethyl-3-azabicyclo[3.
• Step 3 Preparation of (1R,2S,5S)-3-[(2S,3S)-2-amino-3-methyl-pentanoyl]-6,6- dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid;hydrochloride HCl HCl/dioxane DCM
• (1R,2S,5S)-3-[(2S,3S)-2-(tert-butoxycarbonylamino)-3-methyl- pentanoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (48.1 g, 130.54 mmol) in DCM (500 mL) was added HCl/dioxane (500.0 mL, 2000.0 mmol).
• Step 4 Preparation of (1R,2S,5S)-6,6-dimethyl-3-[(2S,3S)-3-methyl-2-[(2,2,2- trifluoroacetyl)amino]pentanoyl]-3-azabicyclo[3.1.0]hexane-2-carboxylic acid HCl TEA, MeOH
• TEA 79.26 g, 783.24 mmol
• Step 5 Preparation of tert-butyl N-[[(1R,2S,5S)-6,6-dimethyl-3-[(2S,3S)-3-methyl-2- [(2,2,2-trifluoroacetyl)amino]pentanoyl]-3-azabicyclo[3.1.0]hexane-2- carbonyl]amino]-N-[[(3S)-2-oxo-3-piperidyl]methyl]carbamate and tert-butyl N- [[(1R,2S,5S)-6,6-dimethyl-3-[(2S,3S)-3-methyl-2-[(2,2,2- trifluoroacetyl)amino]pentanoyl]-3-azabicyclo[3.1.0]hexane-2-carbonyl]amino]-N- [[(3R)-2-oxo-3-piperidyl]methyl]carbamate EDCI, HOPO, DIPEA
• Step 6 Preparation of N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]- [[(3S)-2-oxo-3-piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3- azabicyclo[3.1.0]hexane-3-carbonyl]-2-methyl-butyl]-2,2,2-trifluoro-acetamide and N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3R)-2-oxo-3- piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3- carbonyl]-2-methyl-butyl]-2,2,2-
• Example 166a and 166b N-[(1S,2S)-1-[(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3S)-2-oxo-3- piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo[3.1.0]hexane-3- carbonyl]-2-methyl-butyl]-1-fluoro-cyclopropanecarboxamide and N-[(1S,2S)-1- [(1R,2S,5S)-2-[[[(2R)-2-chloro-2-fluoro-acetyl]-[[(3R)-2-oxo-3- piperidyl]methyl]amino]carbamoyl]-6,6-dimethyl-3-azabicyclo
• Example 168a and Example 168b were prepared as white solids.
• DFC DICEL CHIRALPAK IC (250 mm*50 mm,10 um); Condition Neu-ETOH Begin B 25, End B 25 Gradient Time (min) 3.7; 100%B Hold Time (min) FlowRate (mL/min) 60; Injections 35) to afford Example 168a and Example 168b as white solids.
• Example 178 (1R,2S,5S)-3-[2-[3,5-bis(trifluoromethyl)phenyl]acetyl]-N'-[(2R)-2-chloro-2-fluoro- acetyl]-6,6-dimethyl-N'-[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3- azabicyclo[3.1.0]hexane-2-carbohydrazide
• the title compound was prepared in analogy to the procedure described for the preparation of Example 177, by using 3,5-bis(trifluoromethyl)phenylacetic acid instead of 3,5- bis(trifluoromethyl)benzoic acid to afford (1R,2S,5S)-3-[2-[3,5- bis(trifluoromethyl)phenyl]acetyl]-N'-[(2R)-2-chloro-2-fluoro-acety
• Example 180 The title compound was prepared in analogy to the procedure described for the preparation of Example 177, by using (E)-3-[3,5-bis(trifluoromethyl)phenyl]prop-2-enoic acid instead of 3,5-bis(trifluoromethyl)benzoic acid to afford (1R,2S,5S)-3-[(E)-3-[3,5- bis(trifluoromethyl)phenyl]prop-2-enoyl]-N'-[(2R)-2-chloro-2-fluoro-acetyl]-6,6- dimethyl-N'-[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3-azabicyclo[3.1.0]hexane-2- carbohydrazide (Example 180) as a white solid.
• Example 181 The title compound was prepared in analogy to the procedure described for the preparation of Example 177, by using (E)-3-(3,5-difluorophenyl)prop-2-enoic acid instead of 3,5- bis(trifluoromethyl)benzoic acid to afford (1R,2S,5S)-N'-[(2R)-2-chloro-2-fluoro-acetyl]- 3-[(E)-3-(3,5-difluorophenyl)prop-2-enoyl]-6,6-dimethyl-N'-[[(3S)-2-oxopyrrolidin-3- yl]methyl]-3-azabicyclo[3.1.0]hexane-2-carbohydrazide (Example 181) as a white solid.
• Step 3 Preparation of (3S,3aS,6aR)-N'-[(2R)-2-chloro-2-fluoro-acetyl]-2-[(2S)-2-[(6- fluoropyrimidin-4-yl)amino]-3,3-dimethyl-butanoyl]-N'-[[(3S)-2-oxopyrrolidin-3- yl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carbohydrazide DIEA, THF
• 3S,3aS,6aR 2-[(2S)-2-[(6-fluoropyrimidin-4-yl)amino]-3,3-dimethyl- butanoyl]-N'-[[(3S)-2-oxopyrrolidin-3-yl]methyl]-3,3a,4,5,6,6a-hexahydr
• Example 183 The title compound was prepared in analogy to the procedure described for the preparation of Example 182, by using 4-chloro-5-fluoropyrimidine instead of 4,6-difluoropyrimidine to afford (3S,3aS,6aR)-N'-[(2R)-2-chloro-2-fluoro-acetyl]-2-[(2S)-2-[(5- fluoropyrimidin-4-yl)amino]-3,3-dimethyl-butanoyl]-N'-[[(3S)-2-oxopyrrolidin-3- yl]methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carbohydrazide (Example 183) as a white solid.
• Example 184 The title compound was prepared in analogy to the procedure described for the preparation of Example 182, by using pyridine-N-oxide instead of 4,6-difluoropyrimidine in the presence of PyBop to afford (3S,3aS,6aR)-N'-[(2R)-2-chloro-2-fluoro-acetyl]-2-[(2S)- 3,3-dimethyl-2-(2-pyridylamino)butanoyl]-N'-[[(3S)-2-oxopyrrolidin-3-yl]methyl]- 3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrole-3-carbohydrazide (Example 184) as a white solid.
• Step 2 Preparation of (2S)-1-[(2S,3S)-2-(tert-butoxycarbonylamino)-3-methyl- pentanoyl]-4,4-dimethyl-pyrrolidine-2-carboxylic acid LiOH.H 2 O THF/H 2 O

Landscapes

• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Medicinal Chemistry (AREA)
• General Health & Medical Sciences (AREA)
• Pharmacology & Pharmacy (AREA)
• Animal Behavior & Ethology (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Epidemiology (AREA)
• Virology (AREA)
• Molecular Biology (AREA)
• Communicable Diseases (AREA)
• Oncology (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Biochemistry (AREA)
• Biophysics (AREA)
• Genetics & Genomics (AREA)
• Proteomics, Peptides & Aminoacids (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Peptides Or Proteins (AREA)

Priority Applications (4)

Applications Claiming Priority (6)

Related Child Applications (1)

Publications (1)

Family

ID=84688511

Family Applications (1)

Country Status (7)

Cited By (4)

Citations (2)

• 2022
  • 2022-12-07 JP JP2024534299A patent/JP2024545135A/ja active Pending
  • 2022-12-07 EP EP22830839.1A patent/EP4444711A1/en active Pending
  • 2022-12-07 CN CN202280080782.7A patent/CN118525014A/zh active Pending
  • 2022-12-07 WO PCT/EP2022/084782 patent/WO2023104882A1/en not_active Ceased
  • 2022-12-08 TW TW111147190A patent/TW202334113A/zh unknown
  • 2022-12-12 AR ARP220103392A patent/AR127929A1/es unknown
• 2024
  • 2024-06-06 US US18/736,151 patent/US20250059171A1/en active Pending

Patent Citations (2)

Non-Patent Citations (10)

Also Published As

Similar Documents

Legal Events