WO2012143874A1 - A process for the preparation of morpholino sulfonyl indole derivatives - Google Patents

A process for the preparation of morpholino sulfonyl indole derivatives Download PDF

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Publication number
WO2012143874A1
WO2012143874A1 PCT/IB2012/051958 IB2012051958W WO2012143874A1 WO 2012143874 A1 WO2012143874 A1 WO 2012143874A1 IB 2012051958 W IB2012051958 W IB 2012051958W WO 2012143874 A1 WO2012143874 A1 WO 2012143874A1
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Prior art keywords
compound
formula
acid
reacting
alkyl
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PCT/IB2012/051958
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English (en)
French (fr)
Inventor
Malcolm Mascarenhas
Shashikant Patil
Ravindra Ashok Janrao
Abhijit Roychowdhury
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Piramal Healthcare Limited
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Priority to IN2170MUN2013 priority Critical patent/IN2013MN02170A/en
Priority to US14/112,743 priority patent/US20140046059A1/en
Publication of WO2012143874A1 publication Critical patent/WO2012143874A1/en

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    • 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
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to a process for the preparation of the compounds of formula (I) which are morpholino sulfonyl indole derivatives.
  • the compounds of formula (I) are capable of inhibiting, modulating or regulating Insulin-Like-Growth Factor I Receptors or Insulin Receptors. BACKGROUND OF THE INVENTION
  • PKs Protein kinases
  • PTKs protein tyrosine kinases
  • STKs serine-threonine kinases
  • RTKs receptor tyrosine kinases
  • IGF-IR insulin-like growth factor I receptor
  • IRR insulin receptor related receptor
  • IGF-IR Insulin-like Growth Factor-1 Receptor
  • IGF-1 and IGF-2 are abnormally expressed in numerous tumors, including, but not limited to, breast, prostate, thyroid, lung, hepatoma, colon, brain, neuroendocrine, and others.
  • IGF-IR small molecule inhibitors have been found to inhibit cancer growth in vitro, in vivo and in clinical trials.
  • BMS-754807 effectively inhibits the growth of a broad range of human tumor types in vitro, including mesenchymal (Ewing's, rhabdomyosarcoma, neuroblastoma, and liposarcoma), epothelial (breast, lung, pancreatic, colon, gastric), and hematopoietic (multiple myeloma and leukemia) tumor cell lines.
  • mesenchymal Ewing's, rhabdomyosarcoma, neuroblastoma, and liposarcoma
  • epothelial termed, lung, pancreatic, colon, gastric
  • hematopoietic multiple myeloma and leukemia
  • the present invention relates to a process for the preparation of a compound of formula I, a stereoisomer or pharmaceutically accepatable salt thereof.
  • the present invention relates to a process for the preparation of a compound of formula I, particularly a pharmaceutically acceptable salt namely methane sulfonate of (S)- ethyl 4-(2-carbamoyl-5-chloro-3-(2-(phenoxymethyl) mo holinosulfonyl)-lH-indol-7- ylamino) piperidine-l-carboxylate.
  • the present invention provides a process for the preparation of a compound of the inhibition of IGF-1R or IR.
  • R a is independently selected from the group consisting of H and C1-C6 alkyl, said alkyl is optionally substituted with one to three substituents selected from R7;
  • Rl is selected from the group consisting of:
  • R 2 is H or Ci-Ce alkyl
  • R 3 is -C(Z)-X-C(0)-Y, -X-Y, -C(Z)-NR 8 R U or heterocyclyl, wherein said heterocyclyl is optionally substituted with one to three substituents selected from the group consisting of Ci- C 6 alkyl, NR 8 C(0)R 10 , C(0)NR 8 R 10 and C(0)OR 12 ;
  • R5 is independently selected from the group consisting of:
  • aryl, heterocyclyl, heterocyclenyl, heteroaryl, alkyl and cycloalkyl is optionally substituted with one to three substituents selected from R7;
  • R7 is independently selected from the group consisting of: C1-C6 alkyl, Halogen, C1-C6 alkoxy, C1-C6 haloalkyl, CN, NH 2 , and NO2;
  • R 8 is independently H or Ci-C alkyl
  • R 9 is selected from the group consisting of C6-Cioaryl, 5-10 membered heterocyclyl, 5-10 membered heterocyclenyl and 5-10 membered heteroaryl, said aryl, heterocyclyl, heterocyclenyl, heteroaryl, is optionally substituted with one to three substituents selected from R7;
  • R 10 is independently selected from the group consisting of C3-Cscycloalkyl, Ci-C 6 alkyl, and C 3 -C 8 cycloalkylCi-C 3 alkyl,
  • R 11 is selected from the group consisting of H, C1-C6 alkyl, C6-Cioaryl, 5-10 membered heterocyclyl, 5-10 membered heterocyclenyl, and C3-Cscycloalkyl, optionally substituted with one to three substituents selected from R 7 ;
  • R 12 is H or Ci-C 6 alkyl
  • X is C 2 -C6 alkylene or Cs-Cscycloalkylene
  • Y is selected from the group consisting of H, OR 12 , CN, heterocyclyl, NR 8 R 10 , wherein said heterocyclyl is optionally substituted with one to three substituents selected from the group consisting of C(0)NR 8 R 10 , NR 8 C(O)R 10 , Ci-C 6 alkyl and C(0)OR 12 ;
  • Z is NH, O or S
  • n 1 or 2;
  • n is independently 0, 1 , 2, 3, 4, 5 or 6;
  • the invention provides a process for the preparation of a compound of formula IA, wherein
  • R 1 is halo
  • R 2 is H
  • R 3 is -C(0)-X-C(0)-Y, -X-Y, -C(S)-NR n R 8 , or heterocyclyl selected from the group consisting of tetrahydro-pyranyl, piperidinyl and pyrrolidinyl, and' wherein the heterocyclyl is optionally substituted with halo, C(0)NR 8 R 10 , Ci-C 6 alkyl, or C(0)OR 12 ;
  • R 8 is H
  • R 9 is phenyl or pyridyl optionally substituted with one to three substituents selected from R ;
  • R 10 is independently selected from the group consisting of C3-Cscycloalkyl, Ci-C 6 alkyl, and C 3 -C 8 cycloalkylCi-C 3 alkyl;
  • R 11 is phenyl optionally substituted with one to three substituents selected from R7;
  • R 12 is C1-C3 alkyl
  • X is C2-C6 alkylene or Cs-Cscycloalkylene
  • Y is selected from the group consisting of H, OR 12 , CN, morpholinyl, and NH 2 , wherein said morpholinyl is optionally substituted with C(0)NR 8 R 10 , Ci-C 6 alkyl, or C(0)OR 12 .
  • the invention provides a process for the preparation of compound of Formula II,
  • R is halo
  • R 13 is selected from the group consisting of H, C(0)NR 8 R 10 , Ci-C 6 alkyl, and C(0)OR 12 ;
  • R 8 is H or C1-C3 alkyl;
  • R 10 is selected from the group consisting of Cs-Cscycloalkyl, Ci-C 6 alkyl, and C 3 - C 8 cycloalkylCi-C 3 alkyl,
  • R 12 is H or C1-C 3 alkyl
  • R is halo
  • s 0, 1, 2, 3, or 4;
  • t 0 or 1.
  • the invention provides a process for the preparation of compound of Formula IIA:
  • R 1 is halo
  • R 13 is C(0)OR 12 ;
  • R 12 is H or C1-C3 alkyl
  • R is halo
  • s 0, 1, 2, 3, or 4;
  • t 0 or 1.
  • the present invention provides a process for the preparation of a compound selected from:
  • alkyl is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
  • Ci-Cio as in “Ci-Cio alkyl” is defined to include groups having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbons in a linear or branched arrangement.
  • Cl-ClO alkyl specifically includes methyl, ethyl, n-propyl, /-propyl, «-butyl, /-butyl, /-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, and so on.
  • alkyl refers to the alkyl portion of the moiety and does not describe the number of atoms in the heterocyclyl portion of the moiety. In an embodiment, if the number of carbon atoms is not specified, the "alkyl” of “alkylaryl”, “alkylcycloalkyl” and “alkylheterocyclyl” refers to C1-C12 alkyl and in a further embodiment, refers to C1-C6 alkyl.
  • cycloalkyl means a monocyclic saturated or unsaturated aliphatic hydrocarbon group having the specified number of carbon atoms.
  • the cycloalkyl is optionally bridged (i.e., forming a bicyclic moiety), for example with a methylene, ethylene or propylene bridge.
  • the cycloalkyl may be fused with an aryl group such as phenyl, and it is understood that the cycloalkyl substituent is attached via the cycloalkyl group.
  • cycloalkyl includes cyclopropyl, methyl-cyclopropyl, 2,2-dimethyl-cyclobutyl, 2- ethyl-cyclopentyl, cyclohexyl, cyclopentenyl, cyclobutenyl and so on.
  • alkyl refers to
  • alkyl refers to C1-C6 alkyl.
  • cycloalkyl refers to C3-C10 cycloalkyl and in a further embodiment, “cycloalkyl” refers to C3-C7 cycloalkyl.
  • examples of "alkyl” include methyl, ethyl, n-propyl, /-propyl, «-butyl, /-butyl and /-butyl.
  • alkylene means a hydrocarbon diradical group having the specified number of carbon atoms.
  • alkylene includes -CH2-, -CH2CH2- and the like.
  • alkylene refers to Ci- C12 alkylene and in a further embodiment, “alkylene” refers to C1-C6 alkylene.
  • alkenyl refers to a non-aromatic hydrocarbon radical, straight, branched or cyclic, containing from 2 to 10 carbon atoms and at least one carbon to carbon double bond. Preferably one carbon to carbon double bond is present, and up to four non-aromatic carbon-carbon double bonds may be present.
  • C2-C6 alkenyl means an alkenyl radical having from 2 to 6 carbon atoms.
  • Alkenyl groups include ethenyl, propenyl, butenyl, 2-methylbutenyl and cyclohexenyl. The straight, branched or cyclic portion of the alkenyl group may contain double bonds and may be substituted if a substituted alkenyl group is indicated.
  • alkenylene means a diradical group of an alkenyl group that is defined above.
  • alkynyl refers to a hydrocarbon radical straight, branched or cyclic, containing from 2 to 10 carbon atoms and at least one carbon to carbon triple bond. Up to three carbon-carbon triple bonds may be present.
  • C2-C6 alkynyl means an alkynyl radical having from 2 to 6 carbon atoms.
  • Alkynyl groups include ethynyl, propynyl, butynyl, 3-methylbutynyl and so on.
  • the straight, branched or cyclic portion of the alkynyl group may contain triple bonds and may be substituted if a substituted alkynyl group is indicated.
  • substituents may be defined with a range of carbons that includes zero, such as (Co-C6)alkylene-aryl. If aryl is taken to be phenyl, this definition would include phenyl itself as well as -CH2PI1, -CH2CH2PI1, CH(CH3)CH2CH(CH3)Ph, and so on.
  • Aryl is intended to mean any stable monocyclic, bicyclic or tricyclic carbon ring of up to 7 atoms in each ring, wherein at least one ring is aromatic.
  • aryl elements include phenyl, naphthyl, tetrahydronaphthyl, indanyl and biphenyl.
  • the aryl substituent is bicyclic and one ring is non-aromatic, it is understood that attachment is via the aromatic ring.
  • aryl is an aromatic ring of 6 to 14 carbons atoms, and includes a carbocyclic aromatic group fused with a 5-or 6-membered cycloalkyl group such as indan.
  • carbocyclic aromatic groups include, but are not limited to, phenyl, naphthyl, e.g. 1 -naphthyl and 2-naphthyl; anthracenyl, e.g. 1-anthracenyl, 2-anthracenyl; phenanthrenyl; fluorenonyl, e.g. 9-fluorenonyl, indanyl and the like.
  • heteroaryl represents a stable monocyclic, bicyclic or tricyclic ring of up to 7 atoms in each ring, wherein at least one ring is aromatic and contains carbon and from 1 to 4 heteroatoms selected from the group consisting of O, N and S.
  • heteroaryl refers to a monocyclic, bicyclic or tricyclic aromatic ring of 5- to 14-ring atoms of carbon and from one to four heteroatoms selected from O, N, or S.
  • heteroaryl is also understood to include the N-oxide derivative of any nitrogen-containing heteroaryl. In cases where the heteroaryl substituent is bicyclic and one ring is non-aromatic or contains no heteroatoms, it is understood that attachment is via the aromatic ring or via the heteroatom containing ring, respectively.
  • Heteroaryl groups within the scope of this definition include but are not limited to acridinyl, carbazolyl, cinnolinyl, quinoxalinyl, pyrrazolyl, indolyl, benzotriazolyl, furanyl, thienyl, benzothienyl, benzofuranyl, quinolinyl, isoquinolinyl, oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrahydroquinoline.
  • heteroaryl examples include, but are not limited to pyridyl, e.g., 2-pyridyl (also referred to as -pyridyl), 3-pyridyl (also referred to as ⁇ -pyridyl) and 4-pyridyl (also referred to as ( ⁇ - pyridyl); thienyl, e.g., 2-thienyl and 3-thienyl; furanyl, e.g., 2-furanyl and 3-furanyl; pyrimidyl, e.g., 2-pyrimidyl and 4-pyrimidyl; imidazolyl, e.g., 2-imidazolyl; pyranyl, e.g., 2- pyranyl and 3-pyranyl; pyrazolyl, e.g., 4-pyrazolyl and 5-pyrazolyl; thiazolyl, e.g., 2- thiazolyl, 4-thiazolyl and 5-thiazolyl
  • heteroaryl may also include a “fused polycyclic aromatic", which is a heteroaryl fused with one or more other heteroaryl or nonaromatic heterocyclic ring.
  • fused polycyclic aromatic examples include, quinolinyl and isoquinolinyl, e.g.
  • Heterocyclyl means a non-aromatic saturated monocyclic, bicyclic, tricyclic or spirocyclic ring system comprising up to 7 atoms in each ring.
  • the heterocyclyl contains 3 to 14, or 5 to 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example, nitrogen, oxygen, phosphor or sulfur, alone or in combination. There are no adjacent oxygen and/or sulfur atoms present in the ring system.
  • Preferred heterocyclyls contain about 5 to about 6 ring atoms.
  • the heterocycle may be fused with an aromatic aryl group such as phenyl or heterocyclenyl.
  • heterocyclyl means that at least a nitrogen, oxygen or sulfur atom, respectively, is present as a ring atom.
  • the nitrogen or sulfur atom of the heterocyclyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.
  • suitable monocyclic heterocyclyl rings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1 ,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, lactam, lactone, and the like.
  • heteroatoms contained in a specified heterocyclyl group the expression, "having one to x heteroatoms selected from the group of N, O, P and S" (wherein x is a specified integer), for example, means that each heteroatom in the specified heterocyclyl is independently selected from the specified selection of heteroatoms. Attachment of a heterocyclyl substituent can occur via a carbon atom or via a heteroatom.
  • Heterocyclenyl means a non-aromatic monocyclic, bicyclic, tricyclic or spirocyclic ring system comprising up to 7 atoms in each ring.
  • the heterocyclenyl contains 3 to 14, or 5 to 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur atom, alone or in combination, and which contains at least one carbon-carbon double bond or carbon-nitrogen double bond. There are no adjacent oxygen and/or sulfur atoms present in the ring system.
  • Preferred heterocyclenyl rings contain about 5 to about 6 ring atoms.
  • the prefix aza, oxa or thia before the heterocyclenyl root name means that at least a nitrogen, oxygen, phosphor or sulfur atom respectively is present as a ring atom.
  • the nitrogen or sulfur atom of the heterocyclenyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S- dioxide.
  • heterocyclenyl groups include 1,2,3,4- tetrahydropyridinyl, 1,2-dihydropyridinyl, 1 ,4-dihydropyridinyl, 1,2,3,6-tetrahydropyridinyl, 1,4,5,6-tetrahydropyrimidinyl, 2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl, dihydroimidazolyl, dihydrooxazolyl, dihydrooxadiazolyl, dihydrothiazolyl, 3,4-dihydro-2H- pyranyl, dihydrofuranyl, fluorodihydrofuranyl, 7-oxabicyclo[2.2.1]heptenyl, dihydrothiophenyl, dihydrothiopyranyl, and the like.
  • heteroatoms contained in a specified heterocyclenyl group the expression, "having one to x heteroatoms selected from the group of N, O, P and S" (wherein x is a specified integer), for example, means that each heteroatom in the specified heterocyclenyl is independently selected from the specified selection of heteroatoms.
  • alkylaryl group is an alkyl group substituted with an aryl group, for example, a phenyl group. Suitable aryl groups are described herein and suitable alkyl groups are described herein. The bond to the parent moiety is through the aryl group.
  • alkylheteroaryl group is an alkyl group substituted with a heteroaryl group. Suitable heteroaryl groups are described herein and suitable alkyl groups are described herein. The bond to the parent moiety is through the heteroaryl group.
  • alkylheterocyclyl group is an alkyl group substituted with a heterocyclyl group. Suitable heterocyclyl groups are described herein and suitable alkyl groups are described herein. The bond to the parent moiety is through the heterocyclyl group.
  • alkylheterocyclenyl group is an alkyl group substituted with a heterocyclenyl group. Suitable heterocyclenyl groups are described herein and suitable alkyl groups are described herein. The bond to the parent moiety is through the heterocyclenyl group.
  • alkylcycloalkyl group is an alkyl group substituted with a cycloalkyl group. Suitable cycloalkyl groups are described herein and suitable alkyl groups are described herein. The bond to the parent moiety is through the cycloalkyl group.
  • arylalkyl group is an aryl group substituted with an alkyl group, for example, a phenyl group. Suitable aryl groups are described herein and suitable alkyl groups are described herein. The bond to the parent moiety is through the alkyl group.
  • heteroarylalkyl group is a heteroaryl group substituted with an alkyl group. Suitable heteroaryl groups are described herein and suitable alkyl groups are described herein. The bond to the parent moiety is through the alkyl group.
  • heterocyclylalkyl group is a heterocyclyl group substituted with an alkyl group. Suitable heterocyclyl groups are described herein and suitable alkyl groups are described herein. The bond to the parent moiety is through the alkyl group.
  • heterocyclenylalkyl group is a heterocyclenyl group substituted with an alkyl group. Suitable heterocyclenyl groups are described herein and suitable alkyl groups are described herein. The bond to the parent moiety is through the alkyl group.
  • a “cycloalkylalkyl group” is a cycloalkyl group substituted with an alkyl group. Suitable cycloalkyl groups are described herein and suitable alkyl groups are described herein. The bond to the parent moiety is through the alkyl group.
  • An “aryloxy group” is an aryl group that is attached to a compound via an oxygen (e.g., phenoxy).
  • alkoxy group is a straight chain or branched C1-C12 or cyclic C3-C12 alkyl group that is connected to a compound via an oxygen atom.
  • alkoxy groups include but are not limited to methoxy, ethoxy and propoxy.
  • arylalkoxy group is an arylalkyl group that is attached to a compound via an oxygen on the alkyl portion of the arylalkyl (e.g., phenylmethoxy).
  • arylamino group is an aryl group that is attached to a compound via a nitrogen.
  • alkylamino group is an alkyl group that is attached to a compound via a nitrogen.
  • an "arylalkylamino group” is an arylalkyl group that is attached to a compound via a nitrogen on the alkyl portion of the arylalkyl.
  • alkylsulfonyl group is an alkyl group that is attached to a compound via the sulfur of a sulfonyl group.
  • substituents When a moiety is referred to as “unsubstituted” or not referred to as “substituted” or “optionally substituted”, it means that the moiety does not have any substituents. When a moiety is referred to as substituted, it denotes that any portion of the moiety that is known to one skilled in the art as being available for substitution can be substituted.
  • the phrase "optionally substituted with one or more substituents” means, in one embodiment, one substituent, two substituents, three substituents, four substituents or five substituents.
  • the substitutable group can be a hydrogen atom that is replaced with a group other than hydrogen (i.e., a substituent group). Multiple substituent groups can be present.
  • substituents When multiple substituents are present, the substituents can be the same or different and substitution can be at any of the substitutable sites. Such means for substitution are well known in the art.
  • groups that are substituents are: alkyl, alkenyl or alkynyl groups (which can also be substituted, with one or more substituents), alkoxy groups (which can be substituted), a halogen or halo group (F, CI, Br, I), hydroxy, nitro, oxo, -CN, -COH, -COOH, amino, azido, N-alkylamino or ⁇ , ⁇ -dialkylamino (in which the alkyl groups can also be substituted), N-arylamino or ⁇ , ⁇ -diarylamino (in which the aryl groups can also be substituted), esters (-C(O)-OR, where R can be a group such as alky
  • protecting groups When a functional group in a compound is termed "protected", this means that the group is in modified form to preclude undesired side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those with ordinary skill in the art as well as by reference to standard textbooks such as, for example, T. W. Greene et al, Protective Groups in organic Synthesis (1991), Wiley, New York.
  • variable e.g., aryl, heterocycle, R 2 , etc.
  • its definition on each occurrence is independent of its definition at every other occurrence.
  • the present invention also encompasses within its scope a process for the preparation of the pharmaceutically acceptable salt of the compounds of formula (I). It is well known that for use in medicine, the compounds of Formula I may be required to be provided as their pharmaceutically acceptable salts.
  • suitable “pharmaceutically acceptable salts” refers to salts prepared form pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium and sodium salts.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as arginine, betaine caffeine, choline, N, Nl- dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine tripropylamine, tromethamine and the like.
  • basic ion exchange resins such as arginine, betaine
  • salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids.
  • acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid and the like.
  • the acids are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric or tartaric acids.
  • the compounds of formula (I) are potentially internal salts or zwitterions, since under physiological conditions a deprotonated acidic moiety in the compound, such as a carboxyl group, may be anionic, and this electronic charge might then be balanced off internally against the cationic charge of a protonated or alkylated basic moiety, such as a quaternary nitrogen atom.
  • X is (C 3 -C 8 )-cycloalkylene
  • Y is H
  • Step la Diazotising the compound of formula 1 (which is commercially available or may be prepared by methods, well-known in the art
  • R 1 is as defined in formula I, by reacting it with sodium nitrite (NaNC ) and HCl at a temperature range of -10 to 5 °C, followed by a dropwise addition of the diazotized mixture to an alkaline solution of the reagent, ethyl 2-methyl-3-oxobutanoate in a base selected from potassium hydroxide (KOH) or sodium hydroxide (NaOH) in a solvent such as methanol or ethanol at a temperature range of -20 °C to -15 °C to afford the compound of formula 2;
  • KOH potassium hydroxide
  • NaOH sodium hydroxide
  • Step lb Cyclising the compound of formula 2 by reaction with a Lewis acid such as ZnC3 ⁇ 4, AICI 3 , BF 3 , P 2 O5 or polyphosphoric acid at a temperature range of 80 - 120 °C for 5-12 h to afford the compound of formula 3; wherein R is as defined in formula I.
  • a Lewis acid such as ZnC3 ⁇ 4, AICI 3 , BF 3 , P 2 O5 or polyphosphoric acid
  • Step lc Sulphonating the compound of formula 3 by reaction with sulphuric acid and acetic anhydride at a temperature range of 0-30 °C for 10-20 h to afford the compound of formula 4;
  • Step Id Reacting the compound of formula 4 with oxalyl chloride or thionyl chloride in the presence of an organic base selected from triethylamine or pyridine in a solvent selected from DMF, methylene dichloride or a mixture thereof at a temperature range of 25-50 °C for 1-6 h to prepare the corresponding sulphonyl chloride of the compound of formula 4, which is further reacted with the intermediate of formula E;
  • R 9 is as defined in formula I; at room temperature in presence of an organic base selected from pyridine or triethylamine in a solvent selected from dichloromethane or chloroform at room temperature (25-30 °C) for 2-12 h to afford the compound of formula 5;
  • R 1 and R 9 are as defined in formula I.
  • Step le Reducing the compound of formula 5 by reaction with a reducing agent selected from Fe and NH 4 CI, Zn and HCl or SnCi 2 for 2-8 h in a suitable solvent selected from methanol, ethanol, THF, water or a mixture thereof, to afford the compound of formula 6;
  • a reducing agent selected from Fe and NH 4 CI, Zn and HCl or SnCi 2 for 2-8 h in a suitable solvent selected from methanol, ethanol, THF, water or a mixture thereof, to afford the compound of formula 6;
  • R 1 and R 9 are as defined in formula I.
  • R 1 and R 9 are as defined in formula I.
  • Step lg Reacting the compound of formula 7 with the reagent of formula F;
  • R 3 is an optionally substituted heterocyclyl or -X-Y wherein X is (C3-C8)- cycloalkylene and Y is H, as defined in Formula I; in presence of trifluoroacetic acid in a suitable base such as sodium triacetoxy borohydride and optionally, Hunig's base; in a suitable solvent selected from dichloromethane or ethyl acetate at room temperature for 0.5 - 2 h to afford the compound of formula I;
  • a suitable base such as sodium triacetoxy borohydride and optionally, Hunig's base
  • Step lh Reaction of the compound of formula I obtained in Step lg with an acid to afford corresponding pharmaceutically acceptable salt of the compound of formula I of Step lg.
  • Step lj Reaction of the compound of formula 7 with the compound of formula (R 3 ) 2 0,
  • Step lk Reaction of the compound of formula I obtained in Step lj with an acid to obtain a pharmaceutically acceptable salt of the compound of formula I of Step lj.
  • Step lm Reaction of the compound of formula 7 with the compound of formula R 3 -halide; wherein R 3 is -X-Y wherein X and Y are as defined in formula I, in presence of a base selected from anhydrous sodium carbonate, potassium carbonate, triethylamine or pyridine to afford the compound of formula I.
  • Step In Reaction of the compound of formula I obtained in Step lm with an acid to obtain a pharmaceutically acceptable salt of the compound of formula I of Step lm.
  • the acid used in steps (lh), (lk) and (In) is selected from acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid or p- toluenesulfonic acid.
  • Scheme 2 describes the detailed process for the preparation of the compound of formula E used in Step Id of Scheme 1 above, the steps comprising:
  • R 9 is as defined in formula I.
  • R 9 is as defined in formula I.
  • Scheme 1A provides for the preparation of compounds 34 and 34a, which are representative examples of the Compound of formula I or formula IIA, wherein R 1 is
  • Scheme 1A describes the detailed process for the preparation of compounds 34 and 34a as the representative examples of the Compound of formula I, the steps comprising:
  • Step la Diazotising the compound 1;
  • Step lb Cyclising the compound 2 by reaction with a Lewis acid such as ZnC3 ⁇ 4, AICI 3 , BF 3 , P 2 O5 or polyphosphoric acid at a temperature range of 80 - 120 °C for 5-12 h to afford the compound 3;
  • a Lewis acid such as ZnC3 ⁇ 4, AICI 3 , BF 3 , P 2 O5 or polyphosphoric acid
  • cyclization is carried out using polyphosphoric acid as the Lewis acid at a temperature range of 100 - 110 °C for 8-9 h.
  • Step lc Sulphonating the compound 3 by reaction with sulphuric acid and acetic anhydride at a temperature range of 0-30 °C for 10-20 h to afford the compound 4;
  • Step le Reducing the compound 5 by reaction with a reducing agent selected from Fe and NH 4 CI, Zn and HC1 or SnCi 2 for 2-8 h in a suitable solvent selected from methanol, ethanol, THF, water or a mixture thereof, to afford the compound 6.
  • a reducing agent selected from Fe and NH 4 CI, Zn and HC1 or SnCi 2 for 2-8 h in a suitable solvent selected from methanol, ethanol, THF, water or a mixture thereof, to afford the compound 6.
  • reduction of the compound 5 is carried out using Fe and NH 4 C1 as the reducing agent in a mixture of THF, water and ethanol as solvent at a temperature range of 70 - 80 °C for 2-4 h.
  • the residual iron and iron oxides obtained along with compound 6 during reduction using Fe and NH 4 C1 were removed by using EDTA and chloroform.
  • Step lg Reacting the compound of formula 7 with the reagent F;
  • Step lh Reacting the compound 34 of Step lg, in the form of a free base with methanesulphonic acid in THF as solvent at room temperature for about 30 min to 2 h to afford the corresponding methanesulfonate salt.
  • Scheme 2A provides for the preparation of compound E used in Step Id of Scheme 1A above.
  • Scheme 2A provides the detailed process for the preparation of the Compound E used in Step Id of Scheme 1A, the steps comprising:
  • the titled compound was obtained in a two step procedure.
  • the ethyl ester intermediate ((S)- ethyl 3-(2-carbamoyl-5-chloro-3-(2-(phenoxymethyl)mo holinosulfonyl)-lH-indol-7-yl amino)propanoate) was obtained by condensation of compound 7 of example 6 (0.075 g, 0.161 mol) with ethyl bromopropionate (0.033 g, 0.185 mol) in the presence of potassium carbonate under refluxing conditions.
  • the ethyl ester intermediate ((S)-ethyl 3-(2-carbamoyl- 5-chloro-3-(2-(phenoxymethyl)mo holinosulfonyl)-lH-indol-7-ylamino)propanoate) (0.080 g, 0.141 mol) was dissolved in ethanol (3 mL), and subjected to hydrolysis with 1M NaOH (8.5 mg) for 4 h to afford the desired compound. Upon completion, ethanol was evaporated. The aqueous layer was filtered through celite and subsequently acidified. The acidified layer was then filtered and purified using column chromatography (silica gel, 5% MeOH in chloroform) to afford the title compound.
  • the titled compound was obtained in a two step procedure.
  • the first step was to obtain the same ethyl ester intermediate ((S)-ethyl 3-(2-carbamoyl-5-chloro-3-(2- (phenoxymethyl)morpholinosulfonyl)-lH-indol-7-ylamino)propanoate)) as described in example 21.
  • This ester intermediate was reacted with saturated isopropanolic ammonia in sealed tube at 110 °C for about 16 h to afford the titled compound.
  • IPA/ammonia was evaporated and the title compound was obtained after purification using column chromatography (silica gel, 0-5% MeOH in CHCI 3 ).
  • the title compound was prepared analogous to the compound 20 of example 25 by reaction of the compound 7 of example 6 (0.075 g, 0.161 mmol) with ethyl 4-formylbenzoate (0.039 g, 0.242 mmol), the crude compound obtained was purified using column chromatography (silica gel, 2 % MeOH in chloroform).
  • the title compound was prepared analogous to the compound 20 of example 25 by reaction of the compound 7 of example 6 (0.075 g, 0.161 mmol) with t-butyl(l- formylcyclopentyl)carbamate (0.051 g, 0.242 mol), to obtain the N-Boc protected intermediate of the title compound, which was treated with TFA in dichloromethane (1 : 1, v/v) to afford the amine, which was purified using column chromatography (silica gel, 2 % MeOH in chloroform).
  • the title compound was prepared analogous to the compound 20 of example 25 by reaction of the compound 7 of example 6 (0.075 g, 0.161 mmol) with 4-formylbenzoic acid (0.036 g, 0.242 mmol) to obtain a crude material, which was purified by column chromatography (silica gel, 2 % MeOH in chloroform).
  • the title compound was prepared analogous to the compound 20 of example 25 by reaction of the compound 7 of example 6 (0.075 g, 0.161 mmol) with N-(tert-butyl)-4-oxopiperidine- 1-carboxamide (0.048 g, 0.242 mmol) to obtain a crude material which was purified by column chromatography (Reverse phase C-18, 50 to 30 % water in acetonitrile).
  • the title compound was prepared analogous to the compound 20 of example 25 by reaction of the compound 7 of example 6 (0.075 g, 0.161 mmol) with N-cyclohexyl-4-oxopiperidine- 1-carboxamide (0.072 g, 0.323 mmol) to obtain a crude material which was purified by column chromatography (Reverse phase C-18, 50 to 30 % water in acetonitrile).
  • the title compound was prepared analogous to the compound 20 of example 25 by reaction of the compound 7 of example 6 (0.075 g, 0.161 mmol) with N-(cyclohexylmethyl)-4- oxopiperidine-l-carboxamide (0.076 g, 0.323 mmol) to obtain a crude material which was purified by column chromatography (Reverse phase C-18, 50 to 30 % water in acetonitrile).
  • the title compound was prepared analogous to the compound 20 of example 25 by reaction of the compound 7 of example 6 (0.075 g, 0.161 mmol) with l-isobutylpiperidin-4-one (0.037 g, 0.242 mmol) to obtain a crude material which was purified by column chromatography (silica gel, 2 % MeOH in chloroform).
  • the title compound was prepared analogous to the compound 20 of example 25 by reaction of the compound 7 of example 6 (0.075 g, 0.161 mmol) with pyrrolidin-3-one (0.020 g, 0.242 mmol) to obtain a crude material which was purified by column chromatography (silica gel, 2 % MeOH in chloroform).
  • the title compound was prepared analogous to the compound 20 of example 25 by reaction of the compound 7 of example 6 (0.075 g, 0.161 mmol) with t-butyl 4-oxopiperidine-l- carboxylate (0.048 g, 0.242 mol), to obtain the N-Boc protected intermediate of the title compound, which was treated with TFA in dichloromethane (1 :1, v/v) at room temperature for 4 h to afford the crude title compound, which was purified using column chromatography (silica gel, 0-5 % MeOH in chloroform).

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