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EP4648799A1 - Conjugués ligand-médicament - Google Patents

Conjugués ligand-médicament

Info

Publication number
EP4648799A1
EP4648799A1 EP24701053.1A EP24701053A EP4648799A1 EP 4648799 A1 EP4648799 A1 EP 4648799A1 EP 24701053 A EP24701053 A EP 24701053A EP 4648799 A1 EP4648799 A1 EP 4648799A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
formula
hydrogen
aryl
compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP24701053.1A
Other languages
German (de)
English (en)
Inventor
Biswajit Samanta
Nakul AKOLKAR
Anil Savajibhai Kumbhani
Jay Prakashchandra Adhyapak
Megha Desai
Anirudh Vitthal BELUBBI
Yogin VAIDYA
R. Jeffrey Neitz
Alan Ashworth
Robert FLAVELL
Morgan DIOLAITI
Junhao LU
Trinadha Rao Chitturi
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sun Pharma Advanced Research Co Ltd
University of California
University of California San Diego UCSD
Original Assignee
Sun Pharma Advanced Research Co Ltd
University of California
University of California San Diego UCSD
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sun Pharma Advanced Research Co Ltd, University of California, University of California San Diego UCSD filed Critical Sun Pharma Advanced Research Co Ltd
Publication of EP4648799A1 publication Critical patent/EP4648799A1/fr
Pending legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/542—Carboxylic acids, e.g. a fatty acid or an amino acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/545—Heterocyclic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D207/04—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 no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—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 no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/14—Ortho-condensed systems
    • C07D491/147—Ortho-condensed systems the condensed system containing one ring with oxygen as ring hetero atom and two rings with nitrogen as ring hetero atom

Definitions

  • the present invention generally relates to novel small molecule PSMA ligand containing drug conjugates that selectively target PSMA expressing tumor cells and cause their death through release of a toxic drug payload. Furthermore, the invention generally relates to the use of such drug conjugates for the treatment of cancer.
  • Prostate cancer is the most common cancer in men and is one among the leading causes of cancer mortality in spite of recent technologies of early diagnosis and treatments. Metastatic prostate cancer further reduces the probabilities of survival of the patient. Androgen deprivation therapy has long been used for the treatment of metastatic prostate cancer.
  • Prostate-specific membrane antigen also known as N-acetyl-L-aspartyl-L-glutamate (NAAG) peptidase or glutamate carboxypeptidase II
  • NAAG N-acetyl-L-aspartyl-L-glutamate
  • PSMA Prostate-specific membrane antigen
  • NAAG N-acetyl-L-aspartyl-L-glutamate
  • the degree of overexpression of PSMA directly correlates with the stage and grade of tumor progression and malignancy in prostate cancer patients [see Silver, David A., et al., Wright Jr, George L., et al., Bostwick, David G., et al.
  • PSMA expression correlates with the development of advanced stage cancer such as metastatic prostate cancer or castration-resistant prostate cancer (CRPC) and also confirms the risk of recurrence after surgical intervention [see Wright Jr, George L., et al., Ross, Jeffrey S., et al., Mitsiades, Constantine S., et al.].
  • PSMA upon binding with an antibody or a ligand has high propensity to internalize. This aspect has been leveraged for the development of radiopharmaceuticals as well as antibody drug conjugates (ADCs) for diagnostics and therapeutics purpose [see Liu, He, et al.].
  • ADCs antibody drug conjugates
  • PSMA-targeted ADCs Some of the PSMA-targeted ADCs reported are MLN2704 (PSMA-antibody MLN591- maytansine conjugate) [see Galsky, Matthew D., et al.], PSMA-ADC (PSMA-antibody- monomethyl auristatin E (MMAE)) conjugate [Ma, Dangshe, et al.], and MEDI3726 (ADCT- 401) [see Song Cho, et al].
  • MLN2704 PSMA-antibody MLN591- maytansine conjugate
  • MMAE PSMA-antibody- monomethyl auristatin E
  • PSMA ligand conjugated to small molecule have strongly surfaced on the horizon of clinical landscape as PSMA-targeting imaging agents, therapies, and/or theranostic agents offering distinctive advantages over ADCs due to their faster in vivo distribution, kinetics, more efficient penetration into solid tumors, and less adverse immunogenic responses. Moreover, they are single synthetic entities with robust reproducibility and low manufacturing cost [see Xiankai Sun et al.].
  • Some of the PSMA ligands conjugated to small molecules have been reported in U.S. patent no 6,479,470 B1, Kozikowski et al, International Published Patent Application No. WO 2006093991 A 1 and U.S. Patent No.6,528,499.
  • the ligands have been radiolabelled and used as imaging agents to detect PSMA expressing cancers.
  • imaging agents have been reported in U.S. Patent No. 7,408,079 B2 and U.S. Patent No.8,487,129 B2. Further there are several reports wherein the PSMA binding ligands have been conjugated with a radiolabelled molecules via linkers.
  • 10,398,791 discloses among others 177 Lu Vipivotide tetraxetan (PLUVICTO ® ), which has been recently approved by US Food and Drug Administration (FDA) for the treatment of adult patients with prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer (mCRPC) who have been treated with androgen receptor (AR) pathway inhibition and taxane-based chemotherapy.
  • PDA US Food and Drug Administration
  • PSMA prostate-specific membrane antigen
  • mCRPC metastatic castration-resistant prostate cancer
  • AR androgen receptor pathway inhibition and taxane-based chemotherapy.
  • Gallium Ga-68 Gozetotide (LOCAMETZ ® ) is disclosed in U.S. Patent No.
  • EP2862857 A 1 , U.S. Patent No. 9,056,841 B2, International Published Patent Application No. WO 2020083853 A 1 and U.S. Patent No.9,861,713 B2 are some of the other patents/applications disclosing radioactive isotope of metals that are coordinated to the chelating groups linked to the PSMA binding ligands. Even though PSMA targeted radiopharmaceuticals for diagnostic and therapeutic purposes are currently aiding the prostate cancer treatment regimen, they suffer from serious drawbacks like off target toxicities, and the requirement of a specialized setup or facility for handling and administering of radioactive substances, besides manufacturability issues.
  • WO 2022108992 discloses a non-radioactive compound with PSMA-targeting ligand, a cleavable linker, and a cytotoxic chemotherapeutic viz. Monomethyl Auristatin E (MMAE).
  • MMAE Monomethyl Auristatin E
  • Such ligand-linker conjugates are also reported in International Published Patent Application No. WO 2021101407 A 1 , Russian Patent No. RU2697519 C1, U.S. Patent Application Nos.11,202,836 B2 and 9,193,763 B2. Therefore, a need remains to develop an agent that is highly selective towards cancerous cells expressing PSMA and is therapeutically effective in the treatment of such cancers.
  • the object of the present invention is to provide an option to develop and fulfill these needs.
  • PSMA binding ligands 2-(3-((S)-5-amino-1-carboxypentyl)ureido) pentanedioic acid, 2-[3-(1,3- dicarboxypropyl)ureido]pentanedioic acid or 2-[3-(1-carboxy-2-mercapto- ethyl)ureido]pentanedioic acid are known as PSMA binding ligands.
  • the present invention generally relates to compounds comprising a PSMA binding ligands conjugated to a cytotoxic or therapeutic agent through a linker.
  • a compound of Formula I or pharmaceutically acceptable salt, stereoisomer or isotope thereof wherein, n is 0, 1, 2, 3 or 4; L is a Ligand; R 1 is selected from a 6 to 14 membered aryl or a 5 to 13 membered heteroaryl containing one, two or three heteroatoms independently selected from nitrogen, oxygen or sulfur; R 1 is unsubstituted or substituted with one or more R5; R 5 , at each occurrence, is independently selected from halogen, —C(O)NH 2 , — C(O)OR 6 , —C 1-3 alkyl, —OR7, and a 6 to 10 membered aryl; wherein, R 6 is hydrogen or C 1-3 alkyl; R7 is hydrogen or C 1-3 alkyl; R 2 is absent or is selected from a 6 to 10 membered cycloalkyl or a 6 to 10 membered aryl; R 3 is hydrogen or —
  • a compound of Formula II or pharmaceutically acceptable salt, stereoisomer or isotope thereof wherein, n is 0, 1, 2, 3 or 4; L is a Ligand; R 1 is selected from a 6 to 14 membered aryl or a 5 to 13 membered heteroaryl containing one, two or three heteroatoms independently selected from nitrogen, oxygen or sulfur; R 1 is unsubstituted or substituted with one or more R 5 ; R5, at each occurrence, is independently selected from halogen, —C(O)NH 2 , —C(O)O R 6 , —C 1-3 alkyl, —OR 7 , and 6 to 10 membered aryl; wherein, R 6 is hydrogen or C 1-3 alkyl; R 7 is hydrogen or C 1-3 alkyl; R 2 is absent or is selected from 6 to 10 membered cycloalkyl or a 6 to 10 membered aryl; R 3 is hydrogen, or —C 1
  • a compound of Formula III or pharmaceutically acceptable salt, stereoisomer or isotope thereof wherein, L is a Ligand; R 4 is selected from a group consisting of —C 1-10 alkyl-, —C 2-6 alkenyl-, —C 1-3 alkyl-O-C 1-3 alkyl—, —C 2-6 alkyl-N(R 8 )—, —C 2-6 alkyl(N(R 8 )(R 8’ ))—, —N(R 8 )-C 2-6 alkyl—, a 3 to 6 membered cycloalkyl and —C 1-2 alkyl-(-OC 2 H 4 ) 1-8 -OC 1-2 alkyl—; wherein, R 8 and R 8 ’ are independently selected from hydrogen, C 1-6 alkyl, -C(O)-C 1-4 alkyl-aryl or -C(O)-(-C 2 H 4 O) 1
  • R 17 is —C(O)NHC 2 H 4 N(CH 3 ) 2 ;
  • R 18 is —C(O)NHC 2 H 4 N(CH 3 ) 2 .
  • R 13 and R 14 along with the nitrogen atom to which they are attached form a 4 to 6 membered heterocyclic ring, wherein 1 or 2 carbons in the heterocyclic ring are optionally replaced with additional heteroatoms independently selected from nitrogen, oxygen and sulfur, and wherein the 4 to 6 membered heterocyclic ring is unsubstituted or substituted with C 1-3 alkyl, —N(CH 3 ) 2 or —CH 2 N(CH 3 ) 2 ;
  • R 22 is selected from hydrogen, —C(O)N(R 23 )R 24 or —(-OC 2 H 4 ) 1-10 -CH 3 ;
  • R 23 is hydrogen;
  • R 24 is selected from —C 1-5 alkyl, —C 2-5 alkenyl, —C 2-5 alkynyl
  • R 4 is selected from a group consisting of —C 1-10 alkyl-, —C 2-6 alkenyl-, —C 1-3 alkyl-O-C 1-3 alkyl—, —C 2-6 alkyl-N(R 8 )—, —C 2-6 alkyl(N(R 8 )(R 8 ’))—, —N(R 8 )-C 2-6 alkyl—, a 3 to 6 membered cycloalkyl and —C 1-2 alkyl-(-OC 2 H 4 ) 1-8 -OC 1-2 alkyl—; wherein, R 8 and R 8’ are independently selected from hydrogen, C 1-6 alkyl, -C(O)-C 1-4 alkyl-aryl or -C(O)-(-C 2 H 4 O) 1-8 -C 1-2 alkyl-N(R)(R’), wherein
  • a compound of Formula V or pharmaceutically acceptable salt, stereoisomer or isotope thereof wherein, L is a Ligand; R 4 is selected from a group consisting of —C 1-10 alkyl-, —C 2-6 alkenyl-, —C 1-3 alkyl-O- C 1-3 alkyl—, —C 2-6 alkyl-N(R 8 )—, —C 2-6 alkyl(N(R 8 )(R 8’ ))—, —N(R 8 )-C 2-6 alkyl—, a 3 to 6 membered cycloalkyl and —C 1-2 alkyl-(-OC 2 H 4 ) 1-8 -OC 1-2 alkyl—; wherein, R 8 and R 8’ are independently selected from hydrogen, C 1-6 alkyl, -C(O)-C 1-4 alkyl-aryl or -C(O)-(-C 2 H 4 O) 1-8 -C 1-2 alkyl—; wherein,
  • L is a Ligand
  • A is an amino acid or a peptide comprising 2-5 amino acids
  • R 11 is selected from —C 1-3 alkyl-OC(O)—**, —C 1-3 alkyl-O-C(O)-N(R 19 )-C 1-5 alkyl-N(R 19 )-C(O)—**, —C 1-3 alkyl-O-C(O)-N[C 1-5 alkyl-N(R 20 R 21 )]-C 1-3 alkyl—**, or —C 1-3 alkyl-O-C(O)-Het 2 -C 1-3 alkyl-N(R 19 )-C(O)—**, wherein ** indicates point of attachment to D;
  • R 19 is selected from H, CH 3 or –C 2 H 4 -O-C 2 H 4 -OH;
  • R 20 is CH 3 ;
  • R 21 is CH 3 ; and Het 2 is
  • a compound of Formula VI, Formula VII or pharmaceutically acceptable salt, stereoisomer or isotope thereof wherein: L is a ligand and D is a cytotoxic agent or therapeutic agent; n is 0, 1, or 2; R 1 is selected from the group consisting of phenyl, indolyl, thiophenyl, quinolinyl and isoquinolinyl; R 1 is unsubstituted or substituted with one or more R5; R5 is selected from halogen, —OH, or a 6 to 10 membered aryl ring; R 2 is cyclohexyl or phenyl; A is a peptide val-cit.
  • a method of treatment of a disease associated with the PSMA expressing cells comprising administering a compound according to any one of the preceding aspects or a medicament comprised thereof.
  • the present invention provides a method of treatment of cancer by administering a medicament comprising a compound selected from the group consisting of a compound of Formula I, a compound of Formula II, a compound of Formula III, a compound of Formula IV, a compound of Formula V, a compound of Formula VI and a compound of Formula VII and a pharmaceutically acceptable excipient.
  • the present invention provides a method of treatment of cancer involving cells that are positive for expression of PSMA, wherein the method comprises administering a compound or a medicament comprising a compound selected from the group consisting of a compound of Formula I, a compound of Formula II, a compound of Formula III, a compound of Formula IV, a compound of Formula V, a compound of Formula VI and a compound of Formula VII.
  • the present invention provides the use of a compound selected from the group consisting of a compound of Formula I, a compound of Formula II, a compound of Formula III, a compound of Formula IV, a compound of Formula V, a compound of Formula VI and a compound of Formula VII for the preparation of a medicament used in the treatment of a disease associated with the PSMA expressing cells.
  • the present invention provides a pharmaceutical composition comprising a compound selected from the group consisting of a compound of Formula I, a compound of Formula II, a compound of Formula III, a compound of Formula IV, a compound of Formula V, a compound of Formula VI and a compound of Formula VII and a pharmaceutically acceptable carrier.
  • the present invention provides a ligand-drug conjugate, wherein the ligand L and the drug D is conjugated via linker of Formula VIII: Formula VIII wherein: n is 0, 1, 2, 3 or 4; R 1 is selected from a 6 to 14 membered aryl or a 5 to 13 membered heteroaryl containing one, two or three heteroatoms independently selected from nitrogen, oxygen or sulfur; R 1 is unsubstituted or substituted with one or more R 5 ; R 5 , at each occurrence, is independently selected from halogen, —C(O)NH 2 , — C(O)OR 6 , —C 1-3 alkyl, —OR 7 , and a 6 to 10 membered aryl; wherein, R 6 is hydrogen or C 1-3 alkyl; R 7 is hydrogen or C 1-3 alkyl; R 2 is absent or is selected from a 6 to 10 membered cycloalkyl or a 6 to 10 membered aryl; R 3 is
  • pharmaceutically acceptable salts refer to derivatives of the disclosed compounds wherein the parent compound is modified by making non-toxic acid or base salts thereof.
  • pharmaceutically acceptable salts include, but are not limited to, mineral acid or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • conventional non-toxic acid salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, malefic, hydroxymaleic, phenylacetic, glutamic, aspartic, benzoic, salicylic, mesylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, malonic, succinic, glutaric, adipic, isethionic and the like.
  • inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like
  • organic acids such as acetic
  • the pharmaceutically acceptable acid addition salts also include salts formed with the addition of one or more equivalents of acids, for example, monohydrochloride, and dihydrochloride salts.
  • isotope refers to the analog of a compound wherein at least one atom in the compound is replaced by its isotope.
  • the compound formed is called an isotope of the original compound.
  • deuterium atom when a hydrogen atom in original compound is replaced by a deuterium atom, the resulting compound is called as “deuterated analog”.
  • the isotope may be a fully or partially isotope substituted derivative.
  • stereoisomers refers to compounds that have identical chemical constitution, but differ with regard to the arrangement of their atoms or groups in space.
  • the compounds of the present invention may contain asymmetric or chiral centers and, therefore, exist in different stereoisomeric forms. It is intended, unless specified otherwise, that all stereoisomeric forms of the compounds of Formula I to Formula VIII as well as mixtures thereof, including racemic mixtures, form part of the present invention.
  • all geometric and positional isomers including E and Z-forms
  • mixtures thereof are also embraced within the scope of the invention.
  • a reference to a compound is intended to cover its stereoisomers and mixture of various stereoisomers.
  • alkyl refers to a saturated hydrocarbon chain radical that includes solely carbon and hydrogen atoms in the backbone, either linear or branched, having from 1 to 10 carbon atoms, both inclusive unless defined otherwise.
  • Suitable non-limiting examples of alkyl groups include, for example, methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-pentyl, n-hexyl.
  • C 1-4 alkyl or “C1 to C4 alkyl” refers to an alkyl chain having 1 to 4 carbon atoms.
  • alkenyl refers to a hydrocarbon chain containing at least one carbon- carbon double bond, and may have (E) or (Z) configuration.
  • An alkenyl group may contain 2 to 8 carbon atoms unless specified otherwise. Unless set forth or recited to the contrary, all alkenyl groups described herein may form part of a straight or branched chain. Suitable non- limiting examples of alkenyl groups include, e.g., ethylene, 2-propenyl (allyl), 2-methyl-2- propenyl and 2-butenyl.
  • alkenyl groups described herein may be unsubstituted or substituted.
  • alkynyl refers to a hydrocarbon chain containing at least one carbon- carbon triple bond. Such group may contain 2 to 5 carbon atoms unless specified otherwise.
  • all alkenyl groups described herein may form part of a straight or branched chain.
  • Non-limiting examples of alkynyl groups are: ethynyl, 2-propynyl, 1-propynyl, 2-butynyl.
  • the alkynyl group of the present invention may be further substituted with the akenyl or alkyl groups as defined above.
  • aryl refers to an aromatic radical having 6 to 14 carbon atoms, including monocyclic, bicyclic or tricyclic aromatic systems.
  • a bicyclic aryl group includes an aromatic ring fused to a saturated, partially unsaturated ring, or aromatic ring.
  • the bicyclic aryl group may be attached to the rest of the molecule at any suitable position including the position on the aromatic ring or saturated or partially unsaturated ring.
  • Typical aryl groups include, but are not limited to, phenyl, naphthyl, indanyl (for e.g. 1-indanyl, 5-indanyl), indenyl, anthracenyl and phenanthrenyl.
  • aryl groups described herein may be unsubstituted or substituted.
  • an aryl group can be substituted with one or more groups independently selected from: C 1-4 alkyl (for example, methyl, ethyl, propyl and butyl) optionally substituted with one more halogen (for example, chloro, fluoro, iodo or bromo); phenyl; 5 to 10 membered heteroaryl ring optionally substituted with one or more groups selected from C 1-4 alkyl; amino group, optionally further substituted with a substituted heteroaryl group; and COOH.
  • C 1-4 alkyl for example, methyl, ethyl, propyl and butyl
  • halogen for example, chloro, fluoro, iodo or bromo
  • phenyl 5 to 10 membered heteroaryl ring optionally substituted with one or more groups selected from C 1-4 alkyl
  • amino group optionally further substituted with a substituted heteroary
  • heteroaryl ring refers to a 5 to 14 membered aromatic heterocyclic ring containing one or more (such as 1, 2 or 3) heteroatoms, each independently selected from nitrogen, oxygen and sulfur.
  • the heteroaryl ring may be a mono-, bi- or tri-cyclic ring system and includes fused ring systems (at least one of which is aromatic).
  • the heteroaryl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure.
  • heteroaryl rings include, but are not limited to, oxazolyl, isoxazolyl, imidazolyl, furyl, indolyl, isoindolyl, pyrrolyl, triazolyl, triazinyl, tetrazoyl, thienyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzofuranyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, benzothienyl, benzopyranyl, carbazolyl, quinolinyl, isoquinolinyl, quinazolinyl, purinyl, quinoxalinyl, quinolinyl, isoquinolinyl, thiadiazolyl, indolizinyl, imidazo[1,2-a]pyridyl and phthalaziny
  • heteroaryl groups described or claimed herein may be unsubstituted or substituted.
  • heterocycloalkyl or “heterocyclic ring” are used interchangeably and refer to an aromatic or non-aromatic cyclic ring containing one, two or three heteroatoms, each independently selected from nitrogen, sulphur or oxygen. Suitable non-limiting examples of heterocycloalkyl groups include those listed under “heteroaryl ring”. Heterocycloalkyl group may further include but are not limited to, pyrrolidinyl, piperidine, piperazinyl, morpholinyl, thiomorpholine and 1,3-oxazine.
  • heterocycloalkyl ring described herein may be unsubstituted or substituted.
  • self-immolative group is a group that has a tendency undergo a cascade of disassembly reactions ultimately leading to release of the active molecule. Such cascade of disassembly reactions are usually triggered due to enzymatic activation of the amino acid or the peptide (A) next to a self-immolative group (Q).
  • Enzymes such as cathepsins and plasmin are non-limiting examples of enzymes that trigger self-immolation of Q of the present invention.
  • cytotoxic agent refers to any agent that exerts a cytotoxic effect on a cell upon contact. Such cytotoxic agents are well known to a person skilled in the art. Examples of cytotoxic agents that may be used in the of the invention include, but are not limited to, alkylating drugs, anthracyclines, pyrimidine derivatives, vinca alkaloids, photodynamic drugs, platinum- containing compounds, taxanes, topoisomerase inhibitors, ribosome inactivating agents (e.g., gelonin), agents that induce DNA damage (e.g., calicheamicin), tubulin inhibitors (e.g., emtansine), anti-mitotic agents (e.g., monomethyl auristatin), or bacterial toxins.
  • alkylating drugs anthracyclines, pyrimidine derivatives, vinca alkaloids, photodynamic drugs, platinum- containing compounds, taxanes, topoisomerase inhibitors, ribosome inactivating agents (e.g.,
  • cytotoxic agents may also be radioisotopes or cytotoxic antibodies.
  • therapeutic agent active ingredient
  • active agent refers to an agent that is administered to treat a condition, disease or illness or the symptoms thereof.
  • a therapeutic agent is an anget known for the treatment of a disease or illness involving cells expressing PSMA.
  • subject or patient are used interchangeably and refer to a subject that may benefit from the present invention such as a mammal (e.g., canine, feline, ovine, porcine, equine, bovine, or human). In one specific embodiment, the patient is human.
  • Diagnosis of a disease or disorder associated with expression of PSMA may be performed by a skilled physician by methods known in the art.
  • the term “subject in need thereof” in the context of the present invention inter alia refers to mammals, particularly human subjects, suffering from a disease or disorder associated with expression of PSMA.
  • the terms “disease” and “disorder” are used interchangeably.
  • the term “cancer” as used herein refers to the diseases caused by uncontrolled cell division and the ability of cells to metastasize, or to establish new growth in additional sites.
  • the terms “malignant”, “malignancy”, “neoplasm”, “tumor”, “cancer” and variations thereof refer to cancerous cells or groups of cancerous cells.
  • the cancer is associated with the expression of PSMA in the cancerous cells or the cancer is associated with the expression of PSMA in the cells that are in a close proximity of cancerous cells.
  • the terms ‘treat’, ‘treating’, ‘treatment’ or forms thereof, as used herein, mean reducing, preventing, curing, reversing, ameliorating, attenuating, alleviating, minimizing, suppressing, or halting the deleterious effects of a disease or a condition or delaying the onset of one or more clinical indications of a disease or disorder.
  • a “therapeutically effective amount” of a compound is an amount which is sufficient to reduce or ameliorate the progression, severity and/or duration of a disease or disorder or ameliorate one or more symptoms of a disease or disorder, prevent the recurrence of a disease or disorder, prevent the development or onset of a disease or disorder, or one or more symptoms thereof.
  • a therapeutically effective amount is an amount of the compound of the present invention administered to the subject to reduce or ameliorate the progression, severity, duration or symptoms of the diseases associated with the expression of PSMA.
  • pharmaceutical composition means a pharmaceutical preparation consisting of drug substance(s) and/or excipient(s) to facilitate dosing or administration and delivery of the content of the drug product to the subject.
  • the drug substance is an active ingredient or a compound containing active ingredient/s.
  • the compounds of Formula I to VII are the drug substances.
  • n 0, 1, 2, 3 or 4;
  • L is a ligand;
  • R 1 is selected from a 6 to 14 membered aryl or a 5 to 13 membered heteroaryl containing one, two or three heteroatoms independently selected from nitrogen, oxygen or sulfur;
  • R 1 is unsubstituted or substituted with one or more R 5 ;
  • R5, at each occurrence, is independently selected from halogen, —C(O)NH 2 , — C(O)OR 6 , —C 1-3 alkyl, —OR 7 , and a 6 to 10 membered aryl;
  • R 6 is hydrogen or C 1-3 alkyl
  • R 7 is hydrogen or C 1-3 alkyl
  • R 2 is absent or is selected from a 6 to 10 membered cycloalkyl or a 6 to 10 membered aryl
  • R 3 is hydrogen or
  • n 0, 1, 2, 3 or 4;
  • L is a ligand;
  • R 1 is selected from a 6 to 14 membered aryl or a 5 to 13 membered heteroaryl containing one, two or three heteroatoms independently selected from nitrogen, oxygen or sulfur;
  • R 1 is unsubstituted or substituted with one or more R 5 ;
  • R5, at each occurrence, is independently selected from halogen, —C(O)NH 2 , — C(O)OR 6 , —C 1-3 alkyl, —OR 7 , and a 6 to 10 membered aryl;
  • R 6 is hydrogen or C 1-3 alkyl
  • R 7 is hydrogen or C 1-3 alkyl
  • R 2 is absent or is selected from a 6 to 10 membered cycloalkyl or a 6 to 10 membered aryl
  • R 3 is hydrogen or —
  • n is 0, wherein R 1 is directly attached to the carbon next to –CO.
  • n is 1, 2, 3 or 4, wherein R 1 is attached to the carbon next to –CO through 1 or 2 or 3 or 4 methylene groups.
  • L is an antigen binding ligand.
  • the ligand is prostate specific membrane antigen (PSMA) binding ligand.
  • L is a ligand of Formula L 1 : wherein, t 1 is 0, 1, 2, 3, or 4; t 2 is 1, 2, 3 or 4; Z is selected from the group consisting of N(R 9 ), Formula Z 1 and Formula Z 2 : wherein: t3 is selected from 1, 2, 3, 4, 5 or 6; t 4 is selected from 1, 2, 3, 4, 5 or 6; Y is -CH 2 - or –NH- and ‘ ’ indicates attachment of Formula L 1 to the rest of the compound of Formula I; R 9 is selected from the group consisting of hydrogen, C 1-5 alkyl, a 6 to 10 membered aryl, a 5 to 10 membered heterocyclyl ring wherein the heterocyclyl ring contains one, two or three heteroatoms independently selected from nitrogen, oxygen or sulfur; and wherein R 9 is unsubstituted or substituted with halogen.
  • t 1 is 3; t 2 is 2; and Z is N(R 9 ), wherein R 9 is hydrogen.
  • t 1 is 3; t 2 is 2; and Z is N(R 9 ), wherein R 9 is phenyl.
  • t 1 is 3; t 2 is 2; and Z is N(R 9 ), wherein phenyl substituted with Cl, Br, or I.
  • t 1 is 0; t 2 is 2; and Z is Z1, wherein t 3 is 1, 2, 3, 4, 5 or 6 and Y is —NH—.
  • t 1 is 1; t 2 is 2 and Z is a compound of Formula Z 2 .
  • R 1 is selected from phenyl, a fused bicyclic or a fused tricyclic aromatic ring. In an embodiment, R 1 is selected from a monocyclic or a fused bicyclic heteroaromatic ring containing at least one heteroatom independently selected from nitrogen, oxygen or sulfur. In an embodiment, R 1 is unsubstituted. In an embodiment, R 1 is substituted with Cl, Br, I, —OH, —C(O)NH 2 , —C(O)OH, — C(O)OCH 3 , —C(O)OC 2 H 5 , —CH 3 , —CH 2 CH 3 , —OCH 3 , —OCH 2 CH 3 or phenyl.
  • R 2 is absent. In an embodiment, R 2 is selected from a monocyclic or a fused bicyclic aromatic or non-aromatic ring. In an embodiment, R 2 is a monocyclic aromatic ring. In an embodiment, R 2 is a monocyclic non-aromatic ring. In an embodiment, when R 2 is absent and R 3 is H. In another embodiment, when R 2 is absent R 3 is —C 1-5 COOH. The skilled person would appreciated that in the absence of R 2 , the carbon atom with R 3 is directly attached to —CO. In an embodiment, when R 2 is selected from a 6 to 10 membered cycloalkyl or a 6 to 10 membered aryl, R 3 is H.
  • the A is an amino acid or a peptide comprising two or more same or different amino acids.
  • the amino acids used for the present invention can be selected from natural or non-natural amino acids. It can be racemic or a stereoisomer. In a particular embodiment, the amino acids used in the present invention are stereoisomers. In another particular embodiment, the amino acids used in the present invention are dextro- rotatory or levo-rotatory.
  • the amino acid is independently selected from the group consisting of alanine (ala), arginine (arg), aspartic acid (asp), cysteine (cys), glutamic acid (glu), glycine (gly), lysine (lys), phenylalanine (phe), serine (ser), threonine (thr), tryptophan (trp), valine (val), ornithine (orn), citrulline (cit), homocitrulline (hct), lanthionine (lan), homocysteine (hcy) or an amino acid having Formula A 1 or Formula A 2 wherein m 1 and m 1 ’ are 0, 1, 2 or 3; m 2 and m 2 ’ are is 0, 1, 2, 3 or 4; R 1 0 is selected from (-C 2 H 4 O)1-24CH 3 , (-C 2 H 4 O)1-24C 1-2 alkyl(N(R 10' )(R 10
  • the amino acid is independently selected from alanine (ala), arginine (arg), aspartic acid (asp), cysteine (cys), glutamic acid (glu), glycine (gly), lysine (lys), phenylalanine (phe), serine (ser), threonine (thr), tryptophan (trp), valine (val), citrulline (cit), homocitrulline (hct), homocysteine (hcy) or amino acid having the Formula A 1 or Formula A 2 wherein: m 1 m 1 ’ are 0, 1 or 2; m 2 is 2; m 2 ’ is 4; R 1 0 is selected from (-C 2 H 4 O) 6-8 CH 3 , (-C 2 H 4 O ) 3C 2 H 4 (NH(C(O)C 3 H 6 -aryl))— , C 3 H 6 -aryl or —CH 2 -Het 1 -(-C
  • a peptide is independently selected from ala-ala, ala- ala-ala, ala-phe, val-ala, val-cit, ala-val-cit, ala(beta)-val-cit, glu-val-cit, glu-cit, glu-val, gly- gly, gly-gly-phe, gly-gly-phe-gly, asp-cit, asp-val-cit and asp-val; or a peptide is selected from the group of compounds having following formula:
  • the self-immolative group Q is of the Formula Q 1 : wherein, R 11 is selected from a group consisting of —C 1-3 alkyl-OC(O)—**, —C 1-3 alkyl-O-C(O)-N(R 19 )-C 1-5 alkyl-N(R 19 )-C(O)—**, —C 1-3 alkyl-O-C(O)-N[C 1-5 alkyl-N(R 20 R 21 )]-C 1-3 alkyl—**, and —C 1-3 alkyl-O-C(O)-Het 2 -C 1-3 alkyl-N(R 19 )-C(O)—**, wherein R 19 is selected from hydrogen, —C 1-3 alkyl or —C 1-3 alkyl-O-C 1-3 alkyl-OH; R 20 is hydrogen or —C 1-3 alkyl; R 21 is hydrogen or —C 1 - 3 alkyl; and
  • R 13 is hydrogen and R 14 is selected from —C 1-5 alkyl, —C 2-5 alkenyl, —C 2-5 alkynyl, —C 1-5 alkyl-N(R 15 )(R 16 ), —C 1-5 alkyl-O-C 1-3 alkyl, —(-C 2 H 4 O) 1-10 C 2 H 5 , —(-C 2 H 4 O) 1-10 -C 2 H 4 -R 17 , —C 1-3 alkyl- Het 3 -(-C 2 H 4 O) 1-10 -C 2 H 4 -R 18 or ; wherein: R 15 is selected from H, —CH 3 or —C 2 H 5 ; R 16 is selected from H, —CH 3 or —C 2 H 5 ; R 15 and R 16 along with the nitrogen atom to which they are attached form a 5 to 6 membered heterocyclic ring, wherein 1 or 2 carbon atoms in the heterocycl
  • R 23 is hydrogen and R 24 is selected from —C 1-5 alkyl, —C 2-5 alkenyl, —C 2-5 alkynyl, —C 1-5 alkyl-N(R 25 )(R 26 ), —C 1-5 alkyl-O-C 1-3 alkyl, —(-C 2 H 4 O) 1-10 C 2 H 5 , —(-C 2 H 4 O) 1-10 -C 2 H 4 -R 27 , —C 1-3 alkyl- Het3-(-C 2 H 4 O) 1-10 -C 2 H 4 -R 28 or wherein R 25 is selected from H, —CH 3 or —C 2 H 5 ; R 26 is selected from H, —CH 3 or —C 2 H 5 ; R 25 and R 26 along with the nitrogen atom to which they are attached form a 5 to 6 membered heterocyclic ring, wherein 1 or 2 carbon atoms in the heterocyclic ring are
  • D is an active ingredient with cytotoxic or therapeutic effect.
  • One of the objects of the present invention is to provide an option for the selective treatment of a disease associated with the PSMA expressing cells or tissues.
  • the compounds of the present invention are designed in such a way that the selectivity of these compounds is due to the ligands and the efficacy for the treatment of disease is arrived at using the drug D.
  • D for the present invention can be any active ingredient that is known or being investigated for the treatment of the pathology associated with PSMA hyperproliferation of cells.
  • PSMA is expressed in various parts of the body, including but not limited to brain cells, renal cells, bladder cells, colon cells and breast cells.
  • the therapeutic agent is a drug that is known for the treatment of cancer.
  • the therapeutic agent is a drug known or being investigated for the treatment of cancer associated with expression of PSMA cells.
  • the therapeutic agent is a drug known or being investigated in the treatment of prostate cancer, lung cancer, renal cell cancer, glioblastoma, pancreatic cancer, bladder cancer, breast cancer, colon cancer, oesophageal cancer, stomach cancer head cancer, neck cancer, head and neck cancer, colorectal cancer, leukaemia/lymphoma, uterine cancer, skin cancer, endocrine cancer, urinary cancer, gastrointestinal cancer, ovarian cancer or cervical cancer.
  • Non-limiting examples of such therapeutic agents are olaparib, rucaparib, talazoparib, niraparib, vellparib; irinotecan, topotecan, exatecan, etoposide, teniposide, dabrafenib, entrectinib, larotrectinib, trametinib, selpercatinib, docetaxel, mobocertinib, infigratinib, tivozanib, tepotinib, pralsetinib, capmatinib, pemigatinib, tucatinib, neratinib, osimertinib, ceritinib, abemaciclib, ribociclib, palbociclib, ripretinib, selumetinib, avapritinib, erdafitinib, lorlatinib, dacomitinib,
  • D is a cytotoxic agent as defined above.
  • cytotoxic agents are microtubule disrupting agents, such as auristatin, for example monomethyl auristatin E (MMAE), monomethyl auristatin F (MMAF), and auristatin F (AF); maytansinoids, for example DM1, DM3, and DM4; DNA damaging agents, such as calicheamicins, duocarmycins, SN-38, and pyrrolo[2,1-c][1,4]benzodi-azepines (PBDs); amanitins, anthracyclines, baccatins, camptothecins, cemadotins, colchicines, colcimids, combretastatins, cryptophycins, discodermolides, doxorubicin, echinomycins, eleutherobins, epothilones, estramustines, le
  • the present invention provides a compound of Formula I, wherein: n is 0, 1 or 2 R 1 is selected from a 6 to 10 membered aryl or a 5 to 13 membered heteroaryl containing one, two or three heteroatoms independently selected from nitrogen, oxygen or sulfur; R 1 is unsubstituted or substituted with one or more R 5 ; R5, at each occurrence, is independently selected from halogen, —OH, —OCH 3 , —OC 2 H 5 or a 6 to 10 membered aryl; R 2 is selected from a group consisting of a 5 to 6 membered cycloalkyl and 6 to 10 membered aryl; R 3 is hydrogen; R 4 is selected from a group consisting of —C 1-10 alkyl-, —C 2-6 alkenyl-, —C 1-3 alkyl-O-C 1-3 alkyl—, —C 2-6 alkyl-N(R 8 )—, —C 2-6 alkyl
  • the present invention provides a compound of Formula I, wherein: n is 1; R 1 is naphthyl; R 2 is cyclohexyl or phenyl; R 3 is hydrogen; R 4 is selected from a group consisting of —C 1-10 alkyl-, —C 2-6 alkenyl-, —C 1-3 alkyl-O-C 1-3 alkyl—, —C 2-6 alkyl-N(R 8 )—, —C 2-6 alkyl(N(R 8 )(R 8 ’))—, —N(R 8 )-C 2-6 alkyl—, a 3 to 6 membered cycloalkyl and —C 1-2 alkyl-(-OC 2 H 4 ) 1-8 -OC 1-2 alkyl—; wherein, R 8 and R 8 ’ are independently selected from hydrogen, C 1-6 alkyl, -C(O)-C 1-4 alkyl-aryl or -C(O)-(
  • R 11 is selected from —C 1-3 alkyl-OC(O)—**, —C 1-3 alkyl-O-C(O)-N(R 19 )-C 1-5 alkyl-N(R 19 )-C(O)—**, —C 1-3 alkyl-O-C(O)-N[C 1-5 alkyl-N(R 20 R 21 )]-C 1-3 alkyl—**, or —C 1-3 alkyl-O-C(O)-Het 2 -C 1-3 alkyl-N(R 19 )-C(O)—**, R 19 is selected from H, CH 3 or –C 2 H 4 -O-C 2 H 4 -OH; R 20 is CH 3 ; R 21 is CH 3 ; and Het 2 is pyrrolidinyl; R 12 is selected from hydrogen, —C(O)N(R 13 )(R 14 ) or —(-OC 2 H 4 ) 1-10 -CH 3 R 13 is hydrogen; R
  • R 4 when R 4 is a 3 to 6 membered cycloalkyl group, it is attached to the adjacent group on both sides through either the same carbon or though different carbons.
  • R 4 when R 4 is a 5 membered cycloalkyl group, it may be attached to the adjacent groups as below:
  • the present invention provides a compound of Formula I, wherein R 4 is selected from a group consisting of —C 2-5 alkyl and a 3 to 6 membered cycloalkyl; and A is selected from the group consisting of cit, val-ala, val-cit, glu-val-cit, gly-gly-phe-gly.
  • the present invention provides a compound of Formula I, wherein: n is 0, 1 or 2; R 1 is selected from the group consisting of phenyl, indolyl, thiophenyl, quinolinyl, and isoquinolinyl; R 1 is unsubstituted or substituted with one or more R 5 ; R5 is selected from halogen, —OH, or 6 to 10 membered aryl ring; R 2 is cyclohexyl or phenyl; R 3 is hydrogen; R 4 is —C 1-10 alkyl; A is val-cit; and Q is of Formula Q 1 , wherein: R 11 is —CH 2 OC(O)—; and R 12 is hydrogen; and R 22 is hydrogen.
  • the present invention provides a compound of Formula I, wherein: n is 0, 1 or 2; R 1 is selected from a 6 to 10 membered aryl; R 2 is absent; R 3 is —CH 2 COOH, —CH 2 CH 2 COOH; R 4 is 3 to 6 membered cycloalkyl; A is Cit; Q is of Formula Q 1 , wherein: R 11 is —CH 2 -O-C(O)-N(CH 3 )-C 2 H 4 -N(CH 3 )-C(O)—; and R 12 is hydrogen; and R 22 is hydrogen.
  • the present invention provides a compound of Formula I, wherein: n is 0, 1 or 2; R 1 is selected from a 6 to 10 membered aryl; R 2 is cyclohexyl or phenyl; R 3 is hydrogen; R 4 is selected from a group consisting of —C 1-10 alkyl- and —C 2-6 alkyl(N(R 8 )(R 8’ ))—; wherein, R 8 and R 8’ are independently selected from hydrogen, C 1-6 alkyl, -C(O)-C 1-4 alkyl-aryl or -C(O)-(-C 2 H 4 O) 1-8 -C 1-2 alkyl-N(R)(R’), wherein said aryl is selected from 6 to 14 membered aryl and is optionally substituted by -C 1-3 alkyl or -OC 1-3 alkyl; wherein R and R’ are independently selected from hydrogen, -C 1-6 alkyl or -C(O)-C
  • n is selected from 0, 1 and 2;
  • R 2 is absent or selected from:
  • R 3 is selected from hydrogen and -C 2 H 4 COOH;
  • A is selected from cit, val-cit, val-ala, gly-gly-phe-gly, glu-val-cit, gly-gly-phe, gly-phe-gly, Formula P1-ala, Formula P3, Formula P4-ala, Formula P5, Formula P9, Formula P12, Formula P13 and Formula P16;
  • Q is selected from:
  • D is a cytotoxic agent or a therapeutic agent selected from Monomethyl auristatin E (MMAE), Rucaparib, Talazoparib, Niraparib, SN-38, Exatecan, Belotecan, Mitomycin C etc.
  • MMAE Monomethyl auristatin E
  • Rucaparib Rucaparib
  • Talazoparib Niraparib
  • SN-38 Exatecan
  • Belotecan Mitomycin C etc.
  • the present disclosure relates to a compound of Formula I or pharmaceutically acceptable salt, stereoisomer or isotope thereof, wherein: L is a ligand of formula: R 1 is n is 1; R 2 is R 3 is hydrogen; R 4 is -C 3 H 6 - A is val-cit; D is Monomethyl auristatin E (MMAE).
  • MMAE Monomethyl auristatin E
  • a compound of Formula II or pharmaceutically acceptable salt, stereoisomer or isotope thereof wherein, n is 0, 1, 2, 3 or 4; L is a Ligand; R 1 is selected from a 6 to 14 membered aryl or a 5 to 13 membered heteroaryl containing one, two or three heteroatoms independently selected from nitrogen, oxygen or sulfur; R 1 is unsubstituted or substituted with one or more R 5 ; R 5 , at each occurrence, is independently selected from halogen, —C(O)NH 2 , —C(O)OR 6 , —C 1-3 alkyl, —OR7, and 6 to 10 membered aryl; wherein, R 6 is hydrogen or C 1-3 alkyl; R 7 is hydrogen or C 1-3 alkyl; R 2 is absent or is selected from 6 to 10 membered cycloalkyl or a 6 to 10 membered aryl; R 3 is hydrogen, or —C 1
  • a compound of Formula II Formula II or pharmaceutically acceptable salt, stereoisomer or isotope thereof wherein: n is 0, 1, 2, 3 or 4; L is a Ligand; R 1 is selected from a 6 to 14 membered aryl or a 5 to 13 membered heteroaryl containing one, two or three heteroatoms independently selected from nitrogen, oxygen or sulfur; R 1 is unsubstituted or substituted with one or more R5; R5, at each occurrence, is independently selected from halogen, —C(O)NH 2 , —C(O)OR 6 , —C 1-3 alkyl, —OR 7 , and a 6 to 10 membered aryl; wherein: R 6 is hydrogen or C 1-3 alkyl; R 7 is hydrogen or C 1-3 alkyl; R 2 is absent or is selected from a 6 to 10 membered cycloalkyl or a 6 to 10 membered aryl; R 3 is hydrogen, or —
  • the ligand in Formula II is of Formula L 1 , wherein t 1 is 3; t 2 is 2; and Z is N(R 9 ), wherein R 9 is hydrogen.
  • L is a ligand of Formula L 1 , wherein t 1 is 3; t 2 is 2; and Z is N(R 9 ), wherein R 9 is phenyl.
  • L is a ligand of Formula L 1 , wherein t 1 is 3; t 2 is 2; and Z is N(R 9 ), wherein phenyl substituted with Cl, Br, or I.
  • the ligand in Formula II is of Formula L 1 , wherein t 1 is 0; t 2 is 2; and Z is Z1, wherein t3 is 1, 2, 3, 4, 5 or 6 and Y is —NH—.
  • the ligand in Formula II is of Formula L 1 , wherein t 1 is 1; t 2 is 2 and Z is the compound of Formula Z2.
  • A is an amino acid selected from the group of consisting of alanine (ala), arginine (arg), aspartic acid (asp), cysteine (cys), glutamic acid (glu), glycine (gly), lysine (lys), phenylalanine (phe), serine (ser), threonine (thr), tryptophan (trp), valine (val), ornithine (orn), citrulline (cit), homocitrulline (hct), lanthionine (lan), homocysteine (hcy) or an amino acid having Formula A 1 or Formula A 2 wherein: m 1 and m 1 ’ are 0, 1, 2 or 3; m 2 and m 2 ’ are is 0, 1, 2, 3 or 4; R 1 0 is selected from (-C 2 H 4 O)1-24CH 3 , (-C 2 H 4 O)1-24C 1-2 alkyl(N(R 10' )
  • A is a peptide selected from the group consisting of ala- ala, ala-ala-ala, ala-phe, val-ala, val-cit, ala-val-cit, ala(beta)-val-cit, glu-val-cit, glu-cit, glu- val, gly-gly, gly-gly-phe, gly-phe-gly, gly-gly-phe-gly, asp-cit, asp-val-cit and asp-val; or the peptide is selected from a group of compounds having following formula:
  • the present invention provides a compound of Formula II, wherein: L is of Formula L 1 , wherein t 1 is 3; t 2 is 2; and Z is N(R 9 ), wherein R 9 is hydrogen.
  • L is a ligand of Formula L 1 ,, wherein t 1 is 3; t 2 is 2; and Z is N(R 9 ), wherein R 9 is phenyl.
  • L is a ligand of Formula L 1 , wherein t 1 is 3; t 2 is 2; and Z is N(R 9 ), wherein phenyl substituted with Cl, Br, or I; R 1 is naphthyl; R 2 is a 6 to 10 membered cycloalkyl; R 3 is hydrogen; R 4 is selected from —C 1-10 alkyl- or a 3 to 6 membered cycloalkyl; A is an amino acid or peptide as mentioned in previous embodiments; R 12 is —C(O)N(R 13 )(R 14 ), wherein: R 13 is hydrogen; and R 14 is —C 1-5 alkyl-N(R 15 )(R 16 ), wherein: R 15 is C1 to C3 alkyl; R 16 is C1 to C3 alkyl; and R 22 is hydrogen.
  • the present invention provides a compound of Formula II, wherein: L is a ligand of Formula L 1 , wherein t 1 is 3; t 2 is 2; and Z is N(R 9 ), wherein R 9 is hydrogen.
  • L is a ligand of Formula L 1 , wherein t 1 is 3; t 2 is 2; and Z is N(R 9 ), wherein R 9 is phenyl.
  • L is a ligand of Formula L 1 , wherein t 1 is 3; t 2 is 2; and Z is N(R 9 ), wherein phenyl substituted with Cl, Br, or I; R 1 is naphthyl; R 2 is a 6 to 10 membered cycloalkyl; R 3 is hydrogen; R 4 is selected from —C 1-10 alkyl- or a 3 to 6 membered cycloalkyl; A is an amino acid or peptide as mentioned in previous embodiments; R 12 is —C(O)N(R 13 )(R 14 ), wherein: R 13 is hydrogen; and R 14 is —C 1-5 alkyl-N(R 15 )(R 16 ), wherein: R 15 is C1 to C3 alkyl; and R 16 is C1 to C3 alkyl; R 22 is —C(O)N(R 23 )(R 24 ), wherein: R 23 is hydrogen; and R 24 is —C 1-5 alkyl-
  • the present invention provides a compound of Formula II, wherein: L is of Formula L 1 , wherein t 1 is 3; t 2 is 2; and Z is N(R 9 ), wherein R 9 is hydrogen.
  • L is a ligand of Formula L 1 , wherein t 1 is 3; t 2 is 2; and Z is N(R 9 ), wherein R 9 is phenyl.
  • L is a ligand of Formula L 1 , wherein t 1 is 3; t 2 is 2; and Z is N(R 9 ), wherein phenyl substituted with Cl, Br, or I; R 1 is naphthyl; R 2 is a 6 to 10 membered cycloalkyl; R 3 is hydrogen; R 4 is selected from —C 1-10 alkyl- or —C 2-6 alkyl(N(R 8 )(R 8 ’))—; wherein R 8 and R 8’ are independently selected from hydrogen, -C(O)-C 1-4 alkyl-aryl or -C(O)-(- C 2 H 4 O) 1-8 -C 1-2 alkyl-N(R)(R’), wherein said aryl is selected from 6 to 14 membered aryl and is optionally substituted by -C 1-3 alkyl or -OC 1-3 alkyl, wherein both R 8 and R 8 ’ are not hydrogen; wherein R and R’
  • the present disclosure relates to a compound of Formula II: Formula II or pharmaceutically acceptable salt, stereoisomer or isotope thereof; wherein: L is a ligand, selected from: n is selected from 0, 1 and 2; R 2 is absent or selected from: R 3 is selected from hydrogen and -C 2 H 4 COOH; R 4 is selected from A is selected from cit, val-cit, val-ala, gly-gly-phe-gly, glu-val-cit, gly-gly-phe, gly-phe-gly, Formula P1-ala, Formula P3, Formula P4-ala, Formula P5, Formula P9, Formula P12, Formula P13 and Formula P16;
  • D is a cytotoxic agent or a therapeutic agent selected from Monomethyl auristatin E (MMAE), Rucaparib, Talazoparib, Niraparib, SN-38, Exatecan, Belotecan, Mitomycin C.
  • MMAE Monomethyl auristatin E
  • Rucaparib Rucaparib
  • Talazoparib Niraparib
  • SN-38 Exatecan
  • Belotecan Mitomycin C.
  • the present disclosure relates to a compound of Formula II or pharmaceutically acceptable salt, stereoisomer or isotope thereof, wherein: L is a ligand of formula: R 1 is n is 1; ; R 3 is hydrogen; R 4 is -C3H6- A is val-cit; D is Monomethyl auristatin E (MMAE).
  • a compound of Formula III Formula III or pharmaceutically acceptable salt, stereoisomer or isotope thereof wherein, L is a Ligand; R 4 is selected from a group consisting of —C 1-10 alkyl, —C 2-6 alkenyl, —C 1-3 alkyl-O-C 1-3 alkyl—, —C 2-6 alkyl-N(R 8 )—, —N(R 8 )-C 2-6 alkyl—, a 3 to 6 membered cycloalkyl and —C 1 - 2 alkyl (-OC 2 H 4 ) 1-8 -OC 1-2 alkyl—; wherein, R 8 is hydrogen or C 1-6 alkyl; A is an amino acid or a peptide comprising 2-5 amino acids; R 11 is selected from —C 1-3 alkyl-OC(O)—**, —C 1-3 alkyl-O-C(O)-N(R 19 )-C 1
  • R 17 is —C(O)NHC 2 H 4 N(CH 3 ) 2 ;
  • R 18 is —C(O)NHC 2 H 4 N(CH 3 ) 2 .
  • R 13 and R 14 along with the nitrogen atom to which they are attached form a 4 to 6 membered heterocyclic ring, wherein 1 or 2 carbons in the heterocyclic ring are optionally replaced with additional heteroatoms independently selected from nitrogen, oxygen and sulfur, and wherein the 4 to 6 membered heterocyclic ring is unsubstituted or substituted with C 1-3 alkyl, —N(CH 3 ) 2 or —CH 2 N(CH 3 ) 2 ;
  • R 22 is selected from hydrogen, —C(O)N(R 23 )R 24 or —(-OC 2 H 4 ) 1-10 -CH 3 ;
  • R 23 is hydrogen;
  • R 24 is selected from —CH 3 , —CH 2 -C ⁇ CH, —C 1-3 alkyl-N(R 25
  • a compound of Formula III Formula III or pharmaceutically acceptable salt, stereoisomer or isotope thereof wherein: L is a Ligand; R 4 is selected from a group consisting of —C 1-10 alkyl, —C 2-6 alkenyl, —C 1-3 alkyl-O-C 1-3 alkyl—, —C 2-6 alkyl-N(R 8 )—, —C 2-6 alkyl(N(R 8 )(R 8’ ))—, —N(R 8 )-C 2-6 alkyl—, a 3 to 6 membered cycloalkyl and —C 1-2 alkyl (-OC 2 H 4 ) 1-8 -OC 1-2 alkyl—; wherein: R 8 and R 8’ are independently selected from hydrogen, C 1-6 alkyl, -C(O)-C 1-4 alkyl-aryl or -C(O)-(-C 2 H 4 O) 1-8 -C
  • R 12 is selected from hydrogen, —C(O)N(R 13 )(R 14 ) or —(-OC 2 H 4 ) 1-10 -CH 3 ;
  • R 13 is hydrogen;
  • R 14 is —CH 3 , —CH 2 -C ⁇ CH, —C 1-3 alkyl-N(R 15 )(R 16 ), —C 2 H 4 OCH 3 , —(-C 2 H 4 O)3-8- C 2 H 5 , —(-C 2 H 4 O)5-10-C 2 H 4 -R 17 , —CH 2 -triazole-(-C 2 H 4 O)4-C 2 H 4 -R 18 or
  • R 15 is —CH 3 or —C 2 H 5 ;
  • R 16 is —CH 3 or —C 2 H 5 ; or
  • R 15 and R 16 along with the nitrogen atom to which they are attached form a 5 to 6 membered heterocyclic ring, wherein 1 or 2 carbon atoms in the
  • ligand in Formula III is a lignad of Formula L 1 , wherein t 1 is 3; t 2 is 2; and Z is N(R 9 ), wherein R 9 is hydrogen.
  • L is a ligand of Formula L 1 , wherein t 1 is 3; t 2 is 2; and Z is N(R 9 ), wherein R 9 is phenyl.
  • L is a ligand of Formula L 1 , wherein t 1 is 3; t 2 is 2; and Z is N(R 9 ), wherein phenyl substituted with Cl, Br, or I.
  • the ligand in Formula III is a ligand of Formula L 1 , wherein t 1 is 0; t 2 is 2; and Z is Z1, wherein t3 is 1, 2, 3, 4, 5 or 6 and Y is —NH—.
  • the ligand in Formula III is a ligand of Formula L 1 , wherein t 1 is 1; t 2 is 2 and Z is the compound of Formula Z 2 .
  • A is an amino acid selected from the group consisting of alanine (ala), arginine (arg), aspartic acid (asp), cysteine (cys), glutamic acid (glu), glycine (gly), lysine (lys), phenylalanine (phe), serine (ser), threonine (thr), tryptophan (trp), valine (val), ornithine (orn), citrulline (cit), homocitrulline (hct), lanthionine (lan), homocysteine (hcy) or an amino acid having Formula A 1 or Formula A 2 Formula A 1 Formula A 2 wherein: m 1 and m 1 ’ are 0, 1, 2 or 3; m 2 and m 2 ’ are is 0, 1, 2, 3 or 4; R 10 is selected from (-C 2 H 4 O) 1-24 CH 3 , (-C 2 H 4 O) 1-24 C 1-2 alkyl(N(R 10
  • A is a peptide selected from the group consisting of ala-ala, ala-ala-ala, ala-phe, val-ala, val-cit, ala-val-cit, ala(beta)-val-cit, glu-val-cit, glu-cit, glu-val, gly-gly, gly-gly-phe, gly-phe-gly, gly-gly-phe-gly, asp-cit, asp-val-cit and asp-val; or the peptide is selected from a group of compounds having the following formula:
  • the present invention provides a compound of Formula III, wherein: L is of Formula L 1 , wherein t 1 is 3; t 2 is 2; and Z is N(R 9 ), wherein R 9 is hydrogen.
  • L is ligand of Formula L 1 , wherein t 1 is 3; t 2 is 2; and Z is N(R 9 ), wherein R 9 is phenyl.
  • L is ligand of Formula L 1 , wherein t 1 is 3; t 2 is 2; and Z is N(R 9 ), wherein phenyl substituted with Cl, Br, or I; R 4 is selected from —C 1-10 alkyl- and 3 to 6 membered cycloalkyl; A is selected from the group consisting of cit, val-ala, val-cit, gly-gly-phe-gly, Formula P3, Formula P 5 , Formula P 9 , Formula P 12 , Formula P 13 Formula P 14 Formula P 15 and Formula P 16 ; R 11 is —C 1-3 alkyl-OC(O)—** wherein ** indicates point of attachment to D; R 12 is —C(O)N(R 13 )(R 14 ), wherein: R 13 is hydrogen; R 14 is —C 1-5 alkyl-N(R 15 )(R 16 ), R 15 is C 1-3 alkyl; R 16 is C 1-3 alkyl; and R 22 is hydrogen
  • the present invention provides a compound of Formula III, wherein: L is of Formula L 1 , wherein t 1 is 3; t 2 is 2; and Z is N(R 9 ), wherein R 9 is hydrogen.
  • L is ligand of Formula L 1 , wherein t 1 is 3; t 2 is 2; and Z is N(R 9 ), wherein R 9 is phenyl.
  • L is ligand of Formula L 1 , wherein t 1 is 3; t 2 is 2; and Z is N(R 9 ), wherein phenyl substituted with Cl, Br, or I; R 4 is selected from —C 1-10 alkyl- and 3 to 6 membered cycloalkyl; A is selected from the group consisting of cit, val-ala, val-cit, gly-gly-phe-gly, Formula P3, Formula P5, Formula P9, Formula P12, Formula P13 Formula P14 Formula P15 and Formula P16; R 11 is —C 1-3 alkyl-OC(O)—** wherein ** indicates point of attachment to D; R 12 is —C(O)N(R 13 )(R 14 ), wherein: R 13 is hydrogen; R 14 is —C 1-5 alkyl-N(R 15 )(R 16 ), R 15 is C 1-3 alkyl; R 16 is C 1-3 alkyl; and R 22 is —C(O)
  • L is a ligand, selected from: A is selected from cit, val-cit, val-ala, gly-gly-phe-gly, glu-val-cit, gly-gly-phe, gly-phe-gly, Formula P1-ala, Formula P3, Formula P4-ala, Formula P5, Formula P9, Formula P12, Formula P13 and Formula P16; D is a cytotoxic agent or a therapeutic agent selected from Monomethyl auristatin E (MMAE), Rucaparib, Talazoparib, Niraparib, SN-38, Exatecan, Belotecan, Mitomycin C.
  • MMAE Monomethyl auristatin E
  • the present disclosure relates to a compound of Formula III or pharmaceutically acceptable salt, stereoisomer or isotope thereof, wherein: R 4 is -C3H6-; A is val-cit; D is Monomethyl auristatin E (MMAE).
  • R 4 is -C3H6-; A is val-cit; D is Monomethyl auristatin E (MMAE).
  • a compound of Formula IV or pharmaceutically acceptable salt, stereoisomer or isotope thereof wherein, L is a Ligand; R 4 is selected from a group consisting of —C 1-10 alkyl, —C 2-6 alkenyl, —C 1-3 alkyl-O-C 1-3 alkyl—, —C 2-6 alkyl-N(R 8 )—, —N(R 8 )-C 2-6 alkyl—, a 3 to 6 membered cycloalkyl and —C 1- 2 alkyl (-OC 2 H 4 ) 1-8 -OC 1-2 alkyl—; wherein, R 8 is hydrogen or C 1-6 alkyl; A is an amino acid or a peptide comprising 2-5 amino acids; R 11 is selected from —C 1-3 alkyl-OC(O)—**, —C 1-3 alkyl-O-C(O)-N(R 19 )-C 1-5 alkyl
  • a compound of Formula IV or pharmac eutically acceptable salt, stereoisomer or isotope thereof wherein: L is a Ligand; D is a cytotoxic or therapeutic agent as defined above; R 4 is selected from a group consisting of —C 1-10 alkyl, —C 2-6 alkenyl, —C 1-3 alkyl-O-C 1-3 alkyl—, —C 2-6 alkyl-N(R 8 )—, —C 2-6 alkyl(N(R 8 )(R 8’ ))—, —N(R 8 )-C 2-6 alkyl—, 3 to 6 membered cycloalkyl and —C 1-2 alkyl (-OC 2 H 4 ) 1-8 -OC 1-2 alkyl—; wherein: R 8 and R 8’ are independently selected from hydrogen, C 1-6 alkyl, -C(O)-C 1-4 alkyl-aryl or -C(O)
  • ligand in Formula IV is of Formula L 1 , wherein t 1 is 3; t 2 is 2; and Z is N(R 9 ), wherein R 9 is hydrogen.
  • L is ligand of Formula L 1 , wherein t 1 is 3; t 2 is 2; and Z is N(R 9 ), wherein R 9 is phenyl.
  • L is ligand of Formula L 1 , wherein t 1 is 3; t 2 is 2; and Z is N(R 9 ), wherein phenyl substituted with Cl, Br, or I.
  • ligand in Formula IV is of Formula L 1 , wherein t 1 is 0; t 2 is 2; and Z is Z1, wherein t3 is 1, 2, 3, 4, 5 or 6 and Y is —NH—.
  • ligand in Formula IV is of Formula L 1 , wherein t 1 is 1; t 2 is 2 and Z is the compound of Formula Z 2 .
  • A is an amino acid rom the group of consisting of alanine (ala), arginine (arg), aspartic acid (asp), cysteine (cys), glutamic acid (glu), glycine (gly), lysine (lys), phenylalanine (phe), serine (ser), threonine (thr), tryptophan (trp), valine (val), ornithine (orn), citrulline (cit), homocitrulline (hct), lanthionine (lan), homocysteine (hcy) or an amino acid having Formula A 1 or Formula A 2 wherein: m 1 and m 1 ’ are 0, 1, 2 or 3; m 2 and m 2 ’ are is 0, 1, 2, 3 or 4; R 10 is selected from (-C 2 H 4 O) 1-24 CH 3 , (-C 2 H 4 O) 1-24 C 1-2 alkyl(N(R 10’ )(R
  • A is a peptide selected from the group consisting of ala- ala, ala-ala-ala, ala-phe, val-ala, val-cit, ala-val-cit, ala(beta)-val-cit, glu-val-cit, glu-cit, glu- val, gly-gly, gly-gly-phe, gly-phe-gly, gly-gly-phe-gly, asp-cit, asp-val-cit and asp-val; or the peptide is selected from a group of compounds having the following formula:
  • the present invention provides a compound of Formula IV, wherein: L is a ligand of Formula L 1 , wherein t 1 is 3; t 2 is 2; and Z is N(R 9 ), wherein R 9 is hydrogen.
  • L is a ligand of Formula L 1 , wherein t 1 is 3; t 2 is 2; and Z is N(R 9 ), wherein R 9 is phenyl.
  • L is a ligand of Formula L 1 , wherein t 1 is 3; t 2 is 2; and Z is N(R 9 ), wherein phenyl substituted with Cl, Br, or I;
  • R 4 is selected from —C 2-5 alkyl, —C 2-5 alkyl(N(R 8 )(R 8’ ))— and 3 to 6 membered cycloalkyl;
  • R 8 and R 8 ’ are independently selected from hydrogen, -C(O)-C 1-4 alkyl-aryl or -C(O)-(- C 2 H 4 O) 2-6 -C 1-2 alkyl-N(R)(R’), , wherein said aryl is selected from 6 to 14 membered aryl and is optionally substituted by -C 1-3 alkyl or -OC 1-3 alkyl; wherein R and R’ are independently selected from hydrogen or -C(O)-C 1-4 alkyl-aryl, wherein said aryl is selected from
  • A is selected from cit, val-cit, val-ala, gly-gly-phe-gly, glu-val-cit, gly-gly-phe, gly-phe-gly, Formula P1-ala, Formula P3, Formula P4-ala, Formula P5, Formula P9, Formula P12, Formula P13 and Formula P16;
  • R 11 is selected from -CH 2 -O-C(O)-; selected from:
  • D is a cytotoxic agent or a therapeutic agent selected from Monomethyl auristatin E (MMAE), Rucaparib, Talazoparib, Niraparib, SN-38, Exatecan, Belotecan, Mitomycin C etc.
  • MMAE Monomethyl auristatin E
  • Rucaparib Rucaparib
  • Talazoparib Talazoparib
  • Niraparib Niraparib
  • SN-38 Exatecan
  • Belotecan Mitomycin C etc.
  • the present disclosure relates to a compound of Formula IV or pharmaceutically acceptable salt, stereoisomer or isotope thereof, wherein: R 4 is -C 3 H 6 -; A is val-cit; D is Monomethyl auristatin E (MMAE).
  • a compound of Formula V Formula V or pharmaceutically acceptable salt, stereoisomer or isotope thereof wherein, L is a Ligand; R 4 is selected from a group consisting of —C 1-10 alkyl, —C 2-6 alkenyl, —C 1-3 alkyl-O-C 1- 3 alkyl—, —C 2-6 alkyl-N(R 8 )—, —N(R 8 )-C 2-6 alkyl—, a 3 to 6 membered cycloalkyl and —C 1-2 alkyl (-OC 2 H 4 ) 1-8 -OC 1-2 alkyl—; wherein, R 8 is hydrogen or C 1-6 alkyl; A is an amino acid or a peptide comprising 2-5 amino acids; R 11 is selected from —C 1-3 alkyl-OC(O)—**, —C 1-3 alkyl-O-C(O)-N(R 19 )-C 1-5 alkyl-N
  • a compound of Formula V Formula V or pharmaceutically acceptable salt, stereoisomer or isotope thereof wherein: L and A is as defined in previous embodiments; R 4 is selected from a group consisting of —C 1-10 alkyl, —C 2-6 alkenyl, —C 1-3 alkyl-O-C1- 3 alkyl—, —C 2-6 alkyl-N(R 8 )—, —N(R 8 )-C 2-6 alkyl—, a 3 to 6 membered cycloalkyl and —C 1-2 alkyl (-OC 2 H 4 ) 1-8 -OC 1-2 alkyl—; wherein: R 8 is hydrogen or C 1-6 alkyl; R 11 is selected from —C 1-3 alkyl-OC(O)—**, —C 1-3 alkyl-O-C(O)-N(R 19 )-C 1-5 alkyl-N(R 19 )-C(O)—**, —
  • the present invention provides a compound of Formula V, wherein: L is a ligand of Formula L 1 , wherein t 1 is 3; t 2 is 2; and Z is N(R 9 ), wherein R 9 is hydrogen.
  • L is a ligand of Formula L 1 , wherein t 1 is 3; t 2 is 2; and Z is N(R 9 ), wherein R 9 is phenyl.
  • L is a ligand of Formula L 1 , wherein t 1 is 3; t 2 is 2; and Z is N(R 9 ), wherein R 9 is phenyl substituted with Cl, Br, or I; R 4 is selected from —C 2-5 alkyl and 3 to 6 membered cycloalkyl; A is selected from the group consisting of cit, val-ala, val-cit, glu-val-cit, gly-gly-phe-gly; R 11 is —C 1-3 alkyl-OC(O)—** wherein ** indicates point of attachment to D; R 12 is —C(O)N(R 13 )(R 14 ), wherein: R 13 is hydrogen; R 14 is —C 1-5 alkyl-N(R 15 )(R 16 ), R 15 is C 1-3 alkyl; R 16 is C 1-3 alkyl; and R 22 is —C(O)N(R 23 )R 24 , wherein: R 23 is
  • L is a Ligand
  • A is an amino acid or a peptide comprising 2-5 amino acids
  • R 11 is selected from —C 1-3 alkyl-OC(O)—**, —C 1-3 alkyl-O-C(O)-N(R 19 )-C 1-5 alkyl-N(R 19 )-C(O)—**, —C 1-3 alkyl-O-C(O)-N[C 1-5 alkyl-N(R 20 R 21 )]-C 1-3 alkyl—**, —C 1-3 alkyl-O-C(O)-Het 2 -C 1-3 alkyl-N(R 19 )-C(O)—**, or —C 1-3 alkyl-O-C(O)-N(R 19 )-C 1-5 alkyl-N(R 19 )-C(O)—**; wherein ** indicates point of attachment to D; R 19
  • R 11 is selected from —C 1-3 alkyl-OC(O)—**, —C 1-3 alkyl-O-C(O)-N(R 19 )-C 1-5 alkyl-N(R 19 )-C(O)—**, —C 1-3 alkyl-O-C(O)-N[C 1-5 alkyl-N(R 20 R 21 )]-C 1-3 alkyl—**, or —C 1-3 alkyl-O-C(O)-Het 2 -C 1-3 alkyl-N(R 19 )-C(O)—**, wherein ** indicates point of attachment to D; R 19 is selected from H, CH 3 or –C 2 H 4 -O-C 2 H 4 -OH; R 20 is CH 3 ; R 21 is CH 3 ; and Het 2 is pyrrolidinyl; R 12 is selected from
  • the present invention provides a compound of Formula VI, wherein: L is a ligand of Formula L 1 , wherein t 1 is 3; t 2 is 2; and Z is N(R 9 ), wherein R 9 is hydrogen.
  • L is a ligand of Formula L 1 , wherein t 1 is 3; t 2 is 2; and Z is N(R 9 ), wherein R 9 is phenyl.
  • L is a ligand of Formula L 1 , wherein t 1 is 3; t 2 is 2; and Z is N(R 9 ), wherein R 9 is phenyl substituted with Cl, Br, or I;
  • A is selected from the group consisting of cit, val-ala, val-cit, gly-gly-phe-gly, Formula P3, Formula P 5 , Formula P 9 and Formula P 12 ;
  • R 11 is —C 1-3 alkyl-OC(O)—** wherein ** indicates the point of attachment to D;
  • R 12 is —C(O)N(R 13 )(R 14 ), wherein: R 13 is hydrogen;
  • R 14 is —C 1-5 alkyl-N(R 15 )(R 16 ), R 15 is C 1-3 alkyl;
  • R 16 is C 1-3 alkyl; and
  • R 22 is hydrogen.
  • the present invention provides a compound of Formula VI, wherein: L is a lignad of Formula L 1 , wherein t 1 is 3; t 2 is 2; and Z is N(R 9 ), wherein R 9 is hydrogen.
  • L is a ligand of Formula L 1 , wherein t 1 is 3; t 2 is 2; and Z is N(R 9 ), wherein R 9 is phenyl.
  • L is a ligand of Formula L 1 , wherein t 1 is 3; t 2 is 2; and Z is N(R 9 ), wherein R 9 is phenyl substituted with Cl, Br, or I;
  • A is selected from the group consisting of cit, val-ala, val-cit, gly-gly-phe-gly, Formula P 3 , Formula P5, Formula P9 and Formula P12;
  • R 11 is —C 1-3 alkyl-OC(O)—** wherein ** indicates the point of attachment to D;
  • R 12 is —C(O)N(R 13 )(R 14 ), wherein: R 13 is hydrogen;
  • R 14 is —C 1-5 alkyl-N(R 15 )(R 16 ), R 15 is C 1-3 alkyl;
  • R 16 is C 1-3 alkyl; and
  • R 22 is —C(O)N(R 23 )(R 24 ), R 23 is hydrogen;
  • R 24 is —C 1
  • the present disclosure relates to a compound of Formula VI: Formula VI or pharmaceutically acceptable salt, stereoisomer or isotope thereof; wherein: L is a ligand, selected from: A is selected from cit, val-cit, val-ala, gly-gly-phe-gly, glu-val-cit, gly-gly-phe, gly-phe-gly, Formula P1-ala, Formula P3, Formula P4-ala, Formula P5, Formula P9, Formula P12, Formula P13 and Formula P16;
  • D is a cytotoxic agent or a therapeutic agent selected from Monomethyl auristatin E (MMAE), Rucaparib, Talazoparib, Niraparib, SN-38, Exatecan, Belotecan, Mitomycin C etc.
  • MMAE Monomethyl auristatin E
  • Rucaparib Rucaparib
  • Talazoparib Talazoparib
  • Niraparib Niraparib
  • SN-38 Exatecan
  • Belotecan Mitomycin C etc.
  • the present disclosure relates to a compound of Formula VI or pharmaceutically acceptable salt, stereoisomer or isotope thereof, wherein: A is val-cit; D is Monomethyl auristatin E (MMAE).
  • a compound of Formula VII, Formula VII or pharmaceutically acceptable salt, stereoisomer or isotope thereof wherein: L is a ligand and D is a cytotoxic agent or therapeutic agent; n is 0, 1, or 2; R 1 is selected from the group consisting of phenyl, indolyl, thiophenyl, quinolinyl and isoquinolinyl; R 1 is unsubstituted or substituted with one or more R5; R 5 is selected from halogen, —OH, or a 6 to 10 membered aryl ring; R 2 is cyclohexyl or phenyl; A is a peptide val-cit.
  • a compound of Formula VII or pharmaceutically acceptable salt, stereoisomer or isotope thereof; wherein: L and D are as defined above; n is 0, 1, or 2; R 1 is selected from the group consisting of phenyl, indolyl, thiophenyl, quinolinyl and isoquinolinyl; R 1 is unsubstituted or substituted with one or more R5; R 5 is selected from halogen, —OH, or a 6 to 10 membered aryl ring; R 2 is cyclohexyl or phenyl; and A is a peptide val-cit.
  • the compound in the compound is a compound of Formula VII, wherein: L is a ligand of Formula L 1 , wherein t 1 is 3; t 2 is 2; and Z is N(R 9 ), wherein R 9 is hydrogen.
  • L is a ligand of Formula L 1 , wherein t 1 is 3; t 2 is 2; and Z is N(R 9 ), wherein R 9 is phenyl.
  • L is a ligand of Formula L 1 , wherein t 1 is 3; t 2 is 2; and Z is N(R 9 ), wherein R 9 is phenyl substituted with Cl, Br, or I; and R 2 is a 6 to 10 membered cycloalkyl.
  • the present disclosure relates to a compound of Formula VII: or pharmaceutically acceptable salt, stereoisomer or isotope thereof; wherein: L is a ligand, selected from: R 1 is selected from:
  • n is selected from 0, 1 and 2;
  • R 2 is absent or selected from: A is selected from val-cit, val-ala, gly-gly-phe-gly, glu-val-cit and Formula P3; D is a cytotoxic agent or a therapeutic agent selected from Monomethyl auristatin E (MMAE), Rucaparib, Talazoparib, Niraparib, SN-38, Exatecan, Belotecan, Mitomycin C etc.
  • MMAE Monomethyl auristatin E
  • Rucaparib Rucaparib
  • Talazoparib Tiraparib
  • SN-38 Exatecan
  • Belotecan Mitomycin C etc.
  • the present invention provides a ligand-drug conjugate, wherein the ligand L and the drug D is conjugated via linker of Formula VIII: wherein: n is 0, 1, 2, 3 or 4; R 1 is selected from a 6 to 14 membered aryl or a 5 to 13 membered heteroaryl containing one, two or three heteroatoms independently selected from nitrogen, oxygen or sulfur; R 1 is unsubstituted or substituted with one or more R5; R 5 , at each occurrence, is independently selected from halogen, —C(O)NH 2 , — C(O)OR 6 , —C 1-3 alkyl, —OR7, and a 6 to 10 membered aryl; wherein, R 6 is hydrogen or C 1-3 alkyl; R7 is hydrogen or C 1-3 alkyl; R 2 is absent or is selected from a 6 to 10 membered cycloalkyl or a 6 to 10 membered aryl; R 3 is hydrogen or —C 1
  • the present invention provides a ligand-drug conjugate; wherein the ligand L and the drug D is conjugated via a linker of Formula VIII: Formula VIII wherein: n is 0, 1, 2, 3 or 4; R 1 is selected from a 6 to 14 membered aryl or a 5 to 10 membered heteroaryl containing one, two or three heteroatoms independently selected from nitrogen, oxygen or sulfur; R 1 is unsubstituted or substituted with one or more R5; R 5 , at each occurrence, is independently selected from halogen, —C(O)NH 2 , —C(O)OR 6 , —C 1-3 alkyl, —OR7, and a 6 to 10 membered aryl; wherein: R 6 is hydrogen or C 1-3 alkyl; R 7 is hydrogen or C 1-3 alkyl; R 2 is absent or is selected from a 6 to 10 membered cycloalkyl or a 6 to 10 membered aryl; R 3 is hydrogen or
  • the A is an amino acid or a peptide comprising two or more of the same or different amino acids.
  • A is as defined in the first aspect.
  • L is an antigen binding ligand.
  • the ligand is prostate specific membrane antigen (PSMA) binding ligand.
  • PSMA prostate specific membrane antigen
  • L is a ligand of Formula L 1 .
  • t 1 is 3; t 2 is 2; and Z is N(R 9 ), wherein R 9 is hydrogen.
  • t 1 is 3; t 2 is 2; and Z is N(R 9 ), wherein R 9 is phenyl.
  • t 1 is 3; t 2 is 2; and Z is N(R 9 ), wherein R 9 is phenyl substituted with Cl, Br, or I.
  • t 1 is 0; t 2 is 2; and Z is Z1, wherein t3 is 1, 2, 3, 4, 5 or 6 and Y is —NH—.
  • t 1 is 1; t 2 is 2 and Z is the compound of Formula Z 2 .
  • the compound is compound of Formula VIII, wherein R 11 is selected from:
  • the compound is a compound of Formula VIII, wherein: R 13 is hydrogen and R 14 is selected from —C 1-5 alkyl, —C 1-5 alkyl-N(R 15 )(R 16 ), —C 1-5 alkyl-O-C 1-3 alkyl, —(- C 2 H 4 O)1-5C 2 H 5 , —(-C 2 H 4 O) 1-10 -C 2 H 4 -R 17 or —C 1-3 alkyl-Het3-(-C 2 H 4 O) 1-10 -C 2 H 4 -R 18 or wherein: R 15 is selected from H, —CH 3 or —C 2 H 5 ; R 16 is selected from H, —CH 3 or —C 2 H 5 ; R 15 and R 16 along with the nitrogen atom to which they are attached form a 5 to 6 membered heterocyclic ring, wherein 1 or 2 carbon atoms in the hetero
  • the compound is a compound of Formula VIII, wherein R 23 is hydrogen and R 24 is selected from —C 1-5 alkyl, —C 1-5 alkyl-N(R 25 )(R 26 ), —C 1-5 alkyl-O-C 1-3 alkyl, —(- C 2 H 4 O) 1-5 C 2 H 5 , —(-C 2 H 4 O) 1-10 -C 2 H 4 -R 27 or —C 1-3 alkyl-Het 4 -(-C 2 H 4 O) 1-10 -C 2 H 4 -R 28 or , wherein: R 25 is selected from H, —CH 3 or —C 2 H 5 ; R 26 is selected from H, —CH 3 or —C 2 H 5 ; or R 25 and R 26 along with the nitrogen atom to which they are attached form a 5 to 6 membered heterocyclic ring, wherein 1 or 2 carbon atoms in the heterocyclic ring are optionally replaced with additional heteroatoms independently selected from nitrogen
  • D is an active ingredient with cytotoxic or therapeutic effect as defined above.
  • the present invention provides a compound of Formula VIII, wherein: n is 0, 1 or 2; R 1 is selected from a 6 to 10 membered aryl or a 5 to 10 membered heteroaryl containing one, two or three heteroatoms independently selected from nitrogen, oxygen or sulfur; R 1 is unsubstituted or substituted with one or more R5; R5, at each occurrence, is independently selected from halogen, —OH, —OCH 3 , —OC 2 H 5 or a 6 to 10 membered aryl; R 2 is selected from a group consisting of a 5 to 6 membered cycloalkyl and a 6 to 10 membered aryl; R 3 is hydrogen; R 4 is selected from a group consisting of —C 1-10 alkyl, —C 2-6 alkenyl, —C 1-3 alkyl-O-C 1-3 alkyl—,
  • the present invention provides a compound of Formula VIII, wherein: n is 1; R 1 is naphthyl; R 2 is cyclohexyl or phenyl; R 3 is hydrogen; R 4 is selected from a group consisting of —C 1-10 alkyl, —C 2-6 alkenyl, —C 1-3 alkyl-O-C 1-3 alkyl—, —C 2-6 alkyl(N(R 8 )(R 8’ ))—, a 3 to 6 membered cycloalkyl and —C 1-2 alkyl(-OC 2 H 4 ) 1- 8-O-C 1-2 alkyl—, wherein R 8 and R 8’ are independently selected from hydrogen, C 1-6 alkyl, -C(O)-C 1-4 alkyl-aryl or -C(O)-(-C 2 H 4 O) 1-8 -C 1-2 alkyl-N(R)(R’), wherein said aryl is selected from 6 to 14
  • the present invention provides a compound of Formula VIII, wherein: R 4 is selected from a group consisting of —C 2-5 alkyl and a 3 to 6 membered cycloalkyl; and A is selected from the group consisting of cit, val-ala, val-cit, glu-val-cit, gly-gly-phe-gly, Formula P1, Formula P13, Formula P14, Formula P15 and Formula P16.
  • the present invention provides a compound of Formula VIII, wherein: n is 0, 1 or 2; R 1 is selected from the group consisting of phenyl, indolyl, thiophenyl, quinolinyl, and isoquinolinyl; R 1 is unsubstituted or substituted with one or more R5; R 5 , at each occurrence, is independently selected from halogen, —OH, or a 6 to 10 membered aryl ring; R 2 is cyclohexyl or phenyl; R 3 is hydrogen; R 4 is —C 1-10 alkyl; A is val-cit; R 11 is —CH 2 OC(O)—; R 12 is hydrogen; and R 22 is hydrogen.
  • the present invention provides a compound of Formula VIII, wherein: n is 0, 1 or 2 R 1 is a 6 to 10 membered aryl; R 2 is absent; R 3 is —CH 2 COOH, —CH 2 CH 2 COOH; R 4 is a 3 to 6 membered cycloalkyl; A is Cit; R 11 is —CH 2 -O-C(O)-N(CH 3 )-C 2 H 4 -N(CH 3 )-C(O)—; R 12 is hydrogen; and R 22 is hydrogen.
  • the present disclosure relates to a compound of Formula VIII: Formula VIII or pharmaceutically acceptable salt, stereoisomer or isotope thereof; wherein: R 1 is selected from: n is selected from 0, 1 and 2; R 2 is absent or selected from: R 3 is selected from hydrogen and -C 2 H 4 COOH; R 4 is selected from A is selected from cit, val-cit, val-ala, gly-gly-phe-gly, glu-val-cit, gly-gly-phe, gly-phe-gly, Formula P1-ala, Formula P3, Formula P4-ala, Formula P5, Formula P9, Formula P12, Formula P13 and Formula P16;
  • D is a cytotoxic agent or a therapeutic agent selected from Monomethyl auristatin E (MMAE), Rucaparib, Talazoparib, Niraparib, SN-38, Exatecan, Belotecan, Mitomycin C etc.
  • MMAE Monomethyl auristatin E
  • Rucaparib Rucaparib
  • Talazoparib Talazoparib
  • Niraparib Niraparib
  • SN-38 Exatecan
  • Belotecan Mitomycin C etc.
  • the present disclosure relates to a compound of Formula II or pharmaceutically acceptable salt, stereoisomer or isotope thereof, wherein: R 3 is hydrogen; R 4 is -C3H6- A is val-cit; D is Monomethyl auristatin E (MMAE).
  • Table 2 shows inhibitory concentration (IC 50 ) that was required to show half-maximal response to inhibit PSMA- expressing PC3 PIP cells and PSMA-negative PC3 flu cells by the compounds of present invention.
  • Table 2 IC 5 0 for cytotoxicity of the compounds against PC3-PIP and PC3 flu cells
  • the inhibitory concentrations (IC 50 ) of the compounds of present invention against PC3 PIP cells were considerably lower than that against PC3 flu cells.
  • the IC 5 0 for PC3 PIP was more than 100 times lower than that for PC3 flu.
  • the IC 50 for PC3 PIP was more than 200 times lower than that for the PC3 flu cells.
  • the IC 5 0 for PC3 PIP was 300 times lower than that for PC3 flu cells.
  • the IC 50 for PC3 PIP was 690 times lower than that for PC3 flu.
  • the IC 5 0 for PC3 PIP was 8935 times lower than that for PC3 flu. This indicated that the compounds of the present invention were highly selective towards inhibition of PSMA-expressing cells as compared to that against PSMA- negative cells. Further, the considerably lower values of the IC 50 for PC3 PIP cells indicate that the compounds show high cytotoxicity at a very low concentration. Especially Compound no 1.16 showed IC 50 value of 0.054 nM, indicating very high efficacy.
  • Cell viability assay to evaluate the anti-proliferative effect of NCEs on the growth of LNCaPWT and LNCaP-PSMA-/- cells Cell lines were cultured in RPMI-1640 (HiMedia) containing 10% FBS (Gibco) and 100U/ml Penicillin, 0.1mg/ml Streptomycin and 0.25 ⁇ g/ml Amphoterecin B. The cells were maintained in a humidified environment at 37 ⁇ C and 5% CO 2 . Cells were seeded at an optimal density in 96-or 384-well plate in RPMI-1640 medium supplemented with 10% FBS. After 24h, the cells were treated with varying concentrations of the compounds or vehicle. The final DMSO concentration was maintained at 0.5%.
  • the present invention provides a method of treatment of a disease that is associated with the expression of PSMA.
  • the present invention provides a method of treatment of cancer.
  • the present invention provides a method of treatment of cancer that is associated with the expression of PSMA.
  • PSMA is a membrane antigen that is expressed in all types of prostate tissues. In prostate cancer tissues the expression is considerably enhanced as compared to the normal tissue. Apart from prostate tissue, PSMA is expressed in other cancer cells such as conventional renal cell, transitional cell of the bladder, testicular-embryonal, neuroendocrine, colon, and breast cancer cells. Specifically PSMA is expressed in the neovasculature of solid tumours.
  • the present invention provides a method of treatment of all such solid tumours or cancers that are associated with PSMA expressing cells.
  • cancers include prostate cancer, lung cancer, renal cell cancer, glioblastoma, pancreatic cancer, bladder cancer, breast cancer, colon cancer, oesophageal cancer, stomach cancer head cancer, neck cancer, head and neck cancer, colorectal cancer, leukemia/lymphoma, uterine cancer, skin cancer, endocrine cancer, urinary cancer, gastrointestinal cancer, ovarian cancer, and cervical cancer.
  • the present invention also provides a method of treating certain benign lesions occurring in the PSMA expressing tissue cells such as conventional renal cell, transitional cell of the bladder, testicular-embryonal, neuroendocrine, colon, and breast cells.
  • a method of treatment of a disease comprising administering to the subject in need thereof a compound of the present invention.
  • the method comprises administering to the subject a compound of Formula I or pharmaceutically acceptable salt, stereoisomer or isotope thereof.
  • the method comprises administering to the subject a compound of Formula II or pharmaceutically acceptable salt, stereoisomer or isotope thereof.
  • the method comprises administering to the subject a compound of Formula III or pharmaceutically acceptable salt, stereoisomer or isotope thereof. In an embodiment, the method comprises administering to the subject a compound of Formula IV or pharmaceutically acceptable salt, stereoisomer or isotope thereof. In an embodiment, the method comprises administering to the subject a compound of Formula V or pharmaceutically acceptable salt, stereoisomer or isotope thereof. In an embodiment, the method comprises administering to the subject a compound of Formula VI or pharmaceutically acceptable salt, stereoisomer or isotope thereof. In an embodiment, the method comprises administering to the subject a compound of Formula VII or pharmaceutically acceptable salt, stereoisomer or isotope thereof.
  • the method comprises administration of the compound of present invention in a therapeutically effective amount.
  • the therapeutically effective amount would depend on several factors including but not limited to the type and stage of the disease; the gender and age of the subject, the way the compound is administered (e.g. oral, parenteral, subcutaneous), and the composition of the compound.
  • a method of treatment of a disease comprising administering to a subject in need thereof a therapeutically effective amount a compound selected from the group consisting of a compound of Formula I, a compound of Formula II, a compound of Formula III, a compound of Formula IV, a compound of Formula V, a compound of Formula VI, a compound of Formula VII or their pharmaceutically acceptable salts, stereoisomers or isotopes.
  • Pharmaceutical Compositions Any of the compounds disclosed herein may be formulated into a composition that additionally comprises one or more suitable pharmaceutically acceptable excipients, including carrier and other compounds that facilitate administration of the compound to a subject.
  • the pharmaceutical compositions may be formulated in a conventional manner using one or more pharmaceutically acceptable excipients.
  • Such pharmaceutical compositions and the processes for preparing the same are described, for example, in Remington: The Science and Practice of Pharmacy, the contents of which are incorporated herein by reference in their entirety.
  • the present invention provides a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt or stereoisomer or isotope thereof, and a pharmaceutically excipient.
  • the present invention provides a pharmaceutical composition comprising a compound of Formula II, or a pharmaceutically acceptable salt or stereoisomer or isotope thereof, and a pharmaceutically excipient.
  • the present invention provides a pharmaceutical composition comprising a compound of Formula III, or a pharmaceutically acceptable salt or stereoisomer or isotope thereof, and a pharmaceutically excipient.
  • the present invention provides a pharmaceutical composition comprising a compound of Formula IV, or a pharmaceutically acceptable salt or stereoisomer or isotope thereof, and a pharmaceutically excipient.
  • the present invention provides a pharmaceutical composition comprising a compound of Formula V, or a pharmaceutically acceptable salt or stereoisomer or isotope thereof, and a pharmaceutically excipient.
  • the present invention provides a pharmaceutical composition comprising a compound of Formula VI, or a pharmaceutically acceptable salt or stereoisomer or isotope thereof, and a pharmaceutically excipient.
  • the present invention provides a pharmaceutical composition comprising a compound of Formula VII, or a pharmaceutically acceptable salt or stereoisomer or isotope thereof, and a pharmaceutically excipient.
  • Suitable doses of the compounds for use in treating any of the diseases, disorders and/or conditions described herein can be determined by those skilled in the relevant art. Doses must be sufficient to result in a desired therapeutic benefit without causing unwanted side effects.
  • the mode of administration, dosage forms, and suitable pharmaceutical excipients can also be understood and is within the knowledge of those skilled in the art.
  • the present invention provides a method of treatment of cancer that is positive for expression of the PSMA comprising administering a pharmaceutical composition comprising a compound of Formula I, or a pharmaceutically acceptable salt or stereoisomer or isotope thereof, and a pharmaceutically excipient.
  • the present invention provides a method of treatment of cancer that is positive for expression of the PSMA comprising administering a pharmaceutical composition comprising a compound of Formula II, or a pharmaceutically acceptable salt or stereoisomer or isotope thereof, and a pharmaceutically excipient.
  • the present invention provides a method of treatment of cancer that is positive for expression of the PSMA comprising administering a pharmaceutical composition comprising a compound of Formula III, or a pharmaceutically acceptable salt or stereoisomer or isotope thereof, and a pharmaceutically excipient.
  • the present invention provides a method of treatment of cancer that is positive for expression of the PSMA comprising administering a pharmaceutical composition comprising a compound of Formula IV, or a pharmaceutically acceptable salt or stereoisomer or isotope thereof, and a pharmaceutically excipient.
  • the present invention provides a method of treatment of cancer that is positive for expression of the PSMA comprising administering a pharmaceutical composition comprising a compound of Formula V, or a pharmaceutically acceptable salt or stereoisomer or isotope thereof, and a pharmaceutically excipient.
  • the present invention provides a method of treatment of cancer that is positive for expression of the PSMA comprising administering a pharmaceutical composition comprising a compound of Formula VI, or a pharmaceutically acceptable salt or stereoisomer or isotope thereof, and a pharmaceutically excipient.
  • the present invention provides a method of treatment of cancer that is positive for expression of the PSMA comprising administering a pharmaceutical composition comprising a compound of Formula VII, or a pharmaceutically acceptable salt or stereoisomer or isotope thereof, and a pharmaceutically excipient.
  • Pharmaceutical composition of the present invention may be formulated as, for example a tablet, capsule, liquid, gel, syrup, suspension or slurry.
  • the excipients may be selected from those known in the art.
  • Administration according to the present invention may be performed by the routes known to the skilled person. Non-limiting examples of routes of administration are oral administration, intravenous, intramuscular, intraperitoneal, intrathecal, or subcutaneous injection; intra-rectal administration; intranasal administration, ocular administration, or topical administration.
  • the use of the compounds of present invention for the treatment of cancer that is positive for expression of the PSMA.
  • the use of compounds of present invention in the preparation of a medicament for use in the treatment of a cancer that is positive for expression of PSMA can be prepared by the methods that involve several steps including coupling reactions, protections and de-protections, oxidations, reductions, additions, eliminations and such other reactions, which the skilled person is well aware of. Further these steps may be performed by using known methods, for example as documented in the Richard C. Larock, Comprehensive Organic Transformations; Peter G. M. Wuts, Greene’s Protective Groups In Organic Synthesis; George R. Petit.
  • Some of the separation methods may involve purification steps such as treatment with acids and/or bases or with charcoal.
  • the chiral compounds and their chiral intermediates can be optionally separated by known methods, for example, as described in N. L. Allinger in Topics in Stereochemistry; Ganapathy Subramanian, Chiral Separation Techniques: A Practical Approach, as their enantiomers and/or diastereomers.
  • One possible method of enantiomeric separation is the use of chromatography.
  • the methods of purification of the compounds of the present invention and their intermediates may include acid-base or base-acid treatments, distillation, filtration and solvent treatment, chromatographic purification methods such as column chromatography, preparative chromatography etc.
  • the methods of separation and purification listed above are exemplary and vary depending on the nature of the product to be separated. Such variations are well within the understanding of the skilled person.
  • One of the methods of preparation of the compounds of present invention is described below. However the modification and diversions from the given methods are well within the knowledge of the skilled person, who can envision that the compounds may be prepared by several other methods with different starting materials, reagents and conditions.
  • the compound of Formula I can be prepared as per Scheme 1, wherein L, m, R 1 , R 2 , R 3 , R 4 , A, Q and D is as defined above.
  • Scheme 1 AG 1 is an activating group.
  • activating group is a group when reacted with the functional moiety of interest, results in a group that is selectively reactive in certain conditions and stable in other conditions.
  • AG 1 is an activating group that reacts with a –COOH functional moiety and results in an ester like compound. In certain other conditions this ester might remain stable, while when reacting it with the compound of Formula X, it readily forms an amide bond with A.
  • activating groups their selection criteria and their use in the process of preparation of a particular product. For example, to make a carboxylic group (-COOH) active towards certain reagents, it may be converted into an ester or acid chloride.
  • a carboxylic group is reacted with the pre-cursor of the activating group, wherein the skilled person has knowledge about the selection of the pre-cursors of activating group and the reaction conditions under which such pre-cursors of activating group are converted to activated carboxylic groups.
  • pre-cursor of activating group are N-hydroxysuccinimide, pentafluorophenol or those listed in Vincent Gembus et al., Maciej Adamczyk et al. or Yoon- Sik Lee et al.
  • the activating group may also act as a protecting group, wherein the functional moiety to which it is attached may not react while the same functional moiety without this particular activating or protecting group might react and get transformed into another functional moiety.
  • the difference between an activating group and protecting group, factors involved in the selection of any one of these groups and the conditions under which such groups are used in the reactions is within the knowledge of the skilled person.
  • Protecting group as the name suggests is a group that is used to mask a functional group, wherein said functional group is at a risk of getting reacted in a particular medium or getting converted to some other form in the series of reactions.
  • the protecting group when removed results in the functional moiety or group that was present before protection.
  • the present invention relates to compounds that are formed by protection and de-protection of their precursors.
  • the present invention relates to compounds formed by protection and de-protection of the intermediates involved in the preparation of the compounds of the present invention.
  • Such compounds include amino protected intermediates, and carboxyl protected intermediates.
  • the functional groups that are particularly protected are carboxylic groups and amino groups (both primary and secondary).
  • the suitable protecting groups for different functional moieties can be selected, for example, as given in Peter G. M.
  • protecting groups for hydroxyl groups or carboxylic groups include, but are not limited to, benzyl, p-methoxybenzyl (PMB), tert-butyl (t-Bu), methoxymethyl (MOM), methoxyethoxymethyl (MEM), methylthiomethyl (MTM), tetrahydropyranyl (THP), tetrahydrofuranyl (THF), benzyloxymethyl (BOM), trimethylsilyl (TMS), triethylsilyl (TES), tert-butyldimethylsilyl (TBDMS), and triphenylmethyl (trityl, Tr).
  • PMB p-methoxybenzyl
  • t-Bu tert-butyl
  • MOM methoxymethyl
  • MTM methoxyethoxymethyl
  • THF tetrahydrofuranyl
  • BOM benzyloxymethyl
  • TMS trimethylsilyl
  • TES triethylsily
  • protecting groups for amino groups include, but are not limited to, tert- butylcarbonyloxy (Boc), fluorenylmethyocycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), allyoxycarbonyl (Alloc), benzyl, p-methoxybenzyl (PMB), triphenylmethyl (trityl, Tr), trifluoroaceatmide, acetyl (Ac), and benzylidene.
  • Boc tert- butylcarbonyloxy
  • Fmoc fluorenylmethyocycarbonyl
  • Cbz benzyloxycarbonyl
  • Alloc allyoxycarbonyl
  • Tr triphenylmethyl
  • Tr trifluoroaceatmide
  • acetyl Ac
  • benzylidene As per Scheme 1, a compound of Formula IX and Formula X can be condensed to form a compound of Formula I.
  • the condensation can be carried out by combining both the compounds of Formula IX and Formula X in the presence or absence of, preferably in the presence, of a base, including an organic base, for example, triethyl amine, N, N- diisopropylethylamine, N-methyl morpholine, and 4-(dimethylamino)piperidine (DMAP) and inorganic bases for example sodium hydrogen carbonate or potassium carbonate.
  • a base including an organic base, for example, triethyl amine, N, N- diisopropylethylamine, N-methyl morpholine, and 4-(dimethylamino)piperidine (DMAP) and inorganic bases for example sodium hydrogen carbonate or potassium carbonate.
  • a solvent may be optionally used in the condensation of the compound of Formula IX and Formula X.
  • Non-limiting examples of such solvents are N,N-dimethylformamide (DMF), tetrahydrofuran (THF) 1,4-dioxane, dimehyl sulfoxide, acetonitrile, N,N-dimethylacetamide.
  • the reaction conditions such as temperature, pressure or time are variable factors that would depend on and would vary with the different definitions of L, m, R 1 , R 2 , R 3 , R 4 , AG1, A, Q and D.
  • the final product can be separated and purified by the methods given above.
  • the compound of Formula I is prepared using corresponding precursors of Formula IX and Formula X by reacting them together in the presence of a base selected from N,N-diisopropylethylamine or trimethylamine, triethylamine (TEA) and N,N-dimethylformamide (DMF).
  • a base selected from N,N-diisopropylethylamine or trimethylamine, triethylamine (TEA) and N,N-dimethylformamide (DMF).
  • TAA triethylamine
  • DMF N,N-dimethylformamide
  • the compounds of the present invention including the intermediates thereof that may have one or more chiral centres. All the possible chiral isomers (or optical isomers or stereoisomers) formed due to the presence of chiral centre/s in the compounds and their intermediates are well within the scope of the present invention. Such compounds may be prepared as optically active or racemic compounds.
  • the present invention relates to all such isomers, including but not limited to cis and trans geometric isomers, E and Z isomers or mixtures of isomers or in the form of zwitter ions.
  • These isomers can be prepared and separated by the methods well known in the art.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from a parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid.
  • Such reactions are typically carried out in solvents such as water, ether, ethyl acetate, ethanol, isopropanol, acetonitrile, N,N- dimethylformamide, dimethyl sulfoxide or in a mixture of one or more of such solvents. It is within the knowledge of the skilled person to arrive at the intermediates of Formula IX and Formula X. Further, the skilled person will also have understanding about how to arrive at these intermediates with different variables of L, m, R 1 , R 2 , R 3 , R 4 , AG1, A, Q and D. A retrosynthesis of the compound of Formula IX would lead to more than one possible method of preparing it.
  • the compound of Formula IX can be prepared from the compound of Formula XI (Scheme 2) wherein R 1 , R 2 and R 3 are as defined above. Lp is protected L, wherein one or more or sometimes all —COOH in L may be protected as esters.
  • the compound of Formula IX can be prepared by reacting the compound of Formula XI with the precursor of R 4 .
  • the compound of Formula XI can be coupled with a compound selected from: Wherein LG 1 and LG 2 is –OH or a leaving group. It is within the knowledge of the skilled person to appropriately select a leaving group according to the purpose it is required.
  • a leaving can be a halogen selected from F, Cl or Br or it can be a group such as N- hydroxy succinimide, 1-hydroxybenztriazole (HOBt) or pentafluorophenol.
  • PG 1 and PG 2 are the same or different protecting groups.
  • the skilled person has knowledge and understanding about the conversion of the intermediates formed by reaction between Formula XI and the precursors of R 4 to the compound of Formula IX. This may involve de- protection by removal of protecting groups and then reacting with an appropriate reagent comprising an activating group. In another method, the protecting groups PG 1 and PG 2 may be directly replaced with AG1. The de-protection of Lp can be carried out simultaneously or sequentially along with de-protection of PG 1 or PG 2 , which would depend on how the skilled person seems it feasible.
  • the compound of Formula XI can be prepared by the coupling reaction between L p , Fragment 1 and Fragment 2.
  • Fragment 1 and Fragment 2 prior to coupling together, can be seen as unconventional amino acids and therefore synthesis of compound of Formula XI may be carried out by methods known for peptide synthesis such as those disclosed by N. Leo Benoiton in “Chemistry of Peptide Synthesis” and M. Bodanszky, Principles of peptide synthesis. It will be appreciated by the skilled person that the combination of Lp, Fragment 1 and Fragment 2 may be sequential or may be carried out randomly, wherein Fragment 1 and Fragment 2 can be coupled first and the resulting peptide can be coupled with Lp. Fragment 1 and Fragment 2 can be commercially procured or prepared as per methods known in the art.
  • Lp can be prepared by protection of a compound of Formula L 1 , which can be commercially procured or may be prepared as per methods known in the art or that disclosed in Sung-Hyun Moon et al. or in Michael Felber et al.
  • the compound of Formula L 1 , wherein Z is of the Formula Z 1 or Z 2 can be prepared by reacting a compound of Formula L2 or L3 with a substituted maleimide or a diamine compounds, respectively.
  • the choice of the compound of Formula L2 or L3 and the maleimide or diamine compounds would depend on the target compound of Formula L 1 which is within the understanding of the skilled person.
  • the compound of Formula X include A, Q and D.
  • each A, Q and D is a different moiety that may require independent preparation before combining them together.
  • the compound of Formula X may be prepared sequentially from A to D.
  • a or it’s precursor may be combined to form an amide with Fragment 4 in Figure 1 and then the compound of Formula I may be built stepwise.
  • the compound of Formula X can be prepared as given below (Scheme 3): Scheme 3 wherein A p is protected A and AG 2 is an activating group.
  • the free N terminal of A can be protected as N-alkyl or as amide or as carbamates and activating the group with Q may form a carbonate.
  • Reaction between the compounds of Formula XII and D can be carried out for example in the presence of a catalyst such as 1-hydroxybenzotirazole (HOBt) or those given in Yanming Wang et al. and Stephen J. Walsh et al., and a base such as N, N-disiopropylethyl amine, triethyl amine, or pyridine.
  • a catalyst such as 1-hydroxybenzotirazole (HOBt) or those given in Yanming Wang et al. and Stephen J. Walsh et al.
  • a base such as N, N-disiopropylethyl amine, triethyl amine, or pyridine.
  • the compound of Formula XIII prepared as an intermediate may be de-protected in an acidic or basic medium, preferably in the presence of a catalyst to arrive at the compound of Formula X.
  • a and Q can be procured commercially or can be prepared as per known methods.
  • A is a peptide
  • it may be prepared by the methods as known in the art or as disclosed by M Bodanszky in “Principles of Peptide Synthesis”, N. Leo Benoiton in “Chemistry of Peptide Synthesis” or Deboprosad Mondal et al.
  • the NH 2 may be reacted with the appropriate polyethylene glycol derivative, while protecting other reactive sites.
  • NH 2 may be activated using an activating group prior to such reaction.
  • the compound of Formula X can be prepared as per Scheme 4 below: Scheme 4 where, AG 3 is an activating group which may be same or different from AG 2 .
  • R 11A is —C 1-3 alkyl-O-C(O)- and R 11 B is: HN(R 19 )-C 1-5 alkyl-N(R 19 )-C(O)—*, HN[C 1-5 alkyl-N(R 20 R 21 )]-C 1-3 alkyl—*, and Het 2 -C 1-3 alkyl-N(R 19 )-C(O)—*, wherein R 19 , R 20 , R 21 and Het 2 is as defined above.
  • the compounds of the present invention can also include all isotopes of atoms occurring in the intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include tritium and deuterium.
  • Such compounds can be synthesized by means well known in the art, for example by employing starting materials in which one or more hydrogen atoms have been replaced with deuterium.
  • Deuterated analogs may have improved drug metabolism and pharmacokinetics properties, See, for example, Allan B. Foster et al. All of the above listed methods are for illustrative purposes.
  • Examples section set forth below For a more detailed description of the preparation of the compounds of the present invention with detail individual reaction steps, see the Examples section set forth below. Although specific starting materials and reagents are depicted in the Example section, other starting materials and reagents can be easily substituted to provide a variety of derivatives and/or reaction conditions.
  • EDAC 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride
  • EEDQ N-Ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline
  • MDC/DCM Dichromethane DIPEA – N,N-diisopropylethylamine
  • DMF – N,N-dimethylformamide
  • DMAP 4-dimethylaminopyridine
  • HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluoro phosphate HCl –
  • Hydrochloric acid HOBt – 1-Hydroxybenzotriazole
  • HPLC High Performance Liquid Chromatography NaCl – Sodium chloride
  • NHS N-Hydroxysuccinimide RT – Room temperature TBTU – O-(Benzotriazol
  • Formula 1a Formula 1b Formula 1c TBTU (1.98 g, 6.2 mmol) and DIPEA (2.2 mL, 12.9 mmol) were added to a stirred solution of the compound of Formula 1a (2.76 g, 5.7 mmol) and the compound of Formula 1b (1.8 g, 5.2 mmol) in DMF (25 mL) at RT and stirred overnight.
  • the reaction mixture was concentrated under reduced pressure at 50oC, the crude product obtained was purified by column chromatography (silica gel 230-400 mesh, DCM:methanol, 97:3) to get the compound of Formula 1c.
  • Step II Preparation of di-tert-butyl (2S)-2-[[(1S)-5-[[(2S)-2-amino-3-(2-naphthyl) propanoyl]amino]-1-tert-butoxycarbonyl-pentyl]carbamoylamino]pentanedioate (Formula 1d).
  • Formula 1c Formula 1d
  • methanol 50 mL
  • 10% Palladium on charcoal 0.5 g
  • the mixture was stirred under hydrogen pressure at RT for 6 hours.
  • Step III Preparation of di-tert-butyl (2S)-2-[[(1S)-1-tert-butoxycarbonyl-5-[[(2S)-2-[[4-[(9H- fluoren-9-ylmethoxycarbonylamino)methyl]cyclohexanecarbonyl] amino]-3-(2- naphthyl)propanoyl]amino]pentyl]carbamoylamino]pentanedioate (Formula 1e).
  • Formula 1d Formula 1e TBTU (2.16 g, 6.7 mmol) and DIPEA (2.3 mL, 12.9 mmol) were added to a stirred solution of the compound of Formula 1d (3.55 g, 5.2 mmol) and 4-[(9H-fluoren-9- ylmethoxycarbonylamino)methyl]cyclohexanecarboxylic acid (2.55 g, 6.7 mmol) in DMF (35 mL) at RT and stirred overnight. The reaction mixture was concentrated under reduced pressure at 50oC. Water (150 mL) was added to the residue and the resulting mixture was stirred at 55oC for 1 hr. The product obtained was filtered, washed with water and dried.
  • Step IV Preparation of di-tert-butyl (2S)-2-[[(1S)-5-[[(2S)-2-[[4-(aminomethyl) cyclohexanecarbonyl]amino]-3-(2-naphthyl)propanoyl]amino]-1-tert-butoxycarbonyl- pentyl]carbamoylamino]pentanedioate (Formula 1f).
  • Step V Preparation of 5-[[4-[[(1S)-2-[[(5S)-6-tert-butoxy-5-[[(1S)-4-tert-butoxy-1-tert- butoxycarbonyl-4-oxo-butyl]carbamoylamino]-6-oxo-hexyl]amino]-1-(2-naphthyl methyl)-2- oxo-ethyl]carbamoyl]cyclohexyl]methylamino]-5-oxo-pentanoic acid (Formula 1g).
  • Formula 1f Formula 1g DIPEA (0.32 mL, 1.8 mmol) was added to a stirred solution of the compound of Formula 1f (1.0 g, 1.2 mmol) and glutaric anhydride (0.17 g, 1.5 mmol) in acetonitrile (10 mL) under nitrogen atmosphere and then stirred overnight at RT. The reaction mixture was concentrated under reduced pressure at 40oC. Water (10 mL) was added to the residue and the resulting mixture was acidified with an aqueous citric acid solution (20% solution). The mixture was then extracted with ethyl acetate (3x30 mL). Combined organic layers were washed with brine solution and dried over anhydrous sodium sulphate.
  • Step VI Preparation of di-tert-butyl (2S)-2-[[(1S)-1-tert-butoxycarbonyl-5-[[(2S)-2-[[4-[[[5- (2,5-dioxopyrrolidin-1-yl)oxy-5-oxo-pentanoyl]amino]methyl] cyclohexanecarbonyl] amino]- 3-(2-naphthyl)propanoyl]amino]pentyl]carbamoyl-amino]pentanedioate (Formula 1h).
  • Formula 1g Formula 1h NHS (0.23 g, 1.8 mmol) and EDAC (0.38 g, 1.8 mmol) were added sequentially to a stirred solution of the compound of Formula 1g (1.0 g, 1.1 mmol) in DMF (10 mL) at RT and stirred overnight.
  • the reaction mixture was quenched in water (10 mL) and extracted with ethyl acetate (3x20 mL). The combined organic layers were washed with a brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure at 40oC to get the compound of Formula 1h.
  • Step VII Preparation of (2S)-2-[[(1S)-1-carboxy-5-[[(2S)-2-[[4-[[[5-(2,5-dioxopyrrolidin-1- yl)oxy-5-oxo-pentanoyl]amino]methyl]cyclohexanecarbonyl] amino]-3-(2-naphthyl) propanoyl]amino]pentyl]carbamoylamino]pentanedioic acid (Formula 1i).
  • Formula 1h Formula 1i TFA (5.5 mL) was added to a stirred solution of the compound of Formula 1h (0.55 g, 0.53 mmol) in DCM (5.5 mL) at 0-5oC. The reaction mixture was then stirred at RT for 6 hrs. After this time, the reaction mixture was concentrated and degassed under reduced pressure at 30oC. The crude product was leached with diethyl ether (2x2 ml). The diethyl ether layer was decanted off and dried to get the compound of Formula 1i.
  • Step VIII Preparation of ⁇ (S)-1-[(S)-1-(4-hydroxymethyl phenylcarbamoyl)-4-ureido butylcarbamoyl]-2-methyl propyl ⁇ carbamic acid allyl ester (Formula 1k).
  • Formula 1j Formula 1k DIPEA (1.43 mL, 11 mmol) was added to a stirred solution of the compound of Formula 1j (2.1 g, 5 mmol) in mixture of THF (21 mL) and DMF (5 mL).
  • Step IX Preparation of carbonic acid 4-[(S)-2-((S)-2-allyloxycarbonylamino-3-methyl butyrylamino)-5-ureido-pentanoylamino]benzyl 4-nitro phenyl ester (Formula 1l).
  • Formula 1k Formula 1l DIPEA (0.45 mL, 2.5 mmol) was added to a stirred solution of the compound of Formula 1k (0.6 g, 1.2 mmol) in DMF (6 mL) at RT.
  • Bis(4-nitrophenyl)carbonate 0.6 g, 1.9 mmol
  • Step X Preparation of [4-[[(2S)-2-[[(2S)-2-(allyloxycarbonylamino)-3-methyl- butanoyl]amino]-5-ureido-pentanoyl]amino]phenyl]methyl N-[(1S)-1-[[(1S)-1-[[(1S,2R)-4- [(2S)-2-[(1R,2R)-3-[[(1R,2S)-2-hydroxy-1-methyl-2-phenyl-ethyl]amino]-1-methoxy-2- methyl-3-oxo-propyl]pyrrolidin-1-yl]-2-methoxy-1-[(1S)-1-methylpropyl]-4-oxo-butyl]- methyl-carbamoyl]-2-methyl-propyl]carbamoyl]-2-methyl-propyl]-N-methyl-carbamate (Formula 1m
  • Step XI Preparation of [4-[[(2S)-2-[[(2S)-2-amino-3-methyl-butanoyl]amino]-5-ureido- pentanoyl]amino]phenyl]methyl N-[(1S)-1-[[(1S)-1-[[(1S,2R)-4-[(2S)-2-[(1R,2R)-3-[[(1R,2S)- 2-hydroxy-1-methyl-2-phenyl-ethyl]amino]-1-methoxy-2-methyl-3-oxo-propyl]pyrrolidin-1- yl]-2-methoxy-1-[(1S)-1-methylpropyl]-4-oxo-butyl]-methyl
  • Step XII Preparation of Compound No 1.4 Formula 1n Formula 1i
  • Compound no 1.4 DIPEA (0.096 mL, 0.55 mmol) was added to a stirred solution of the compound of Formula 1n (0.076 g, 0.14 mmol) in DMF (1.25 mL), followed by compound of Formula 1i (0.125 g, 0.11 mmol), and stirred at RT for 24 hrs.
  • the reaction mixture was concentrated and degassed under reduced pressure at 50oC.
  • DCM (5 mL) was added to the resulting residue and stirred for 30 min. The solid obtained was filtered, washed with DCM (3x5 mL) and dried under vacuum.
  • Example 2 Preparation of Compound No 1.6 Step I: Preparation of ⁇ 4-[(2S)-5-(carbamoylamino)-2-[(2S)-3-methyl-2- ⁇ [(prop-2-en-1- yloxy)carbonyl] amino ⁇ butanamido]pentanamido]phenyl ⁇ methyl N-[(4- ⁇ 6-fluoro-9-oxo- 3,10-diazatricyclo[6.4.1.04,13]trideca-1,4,6,8(13)-tetraen-2-yl ⁇ phenyl)methyl]-N-methyl carbamate (Formula 2a) Formula 1l Formula 2a DIPEA (0.22 mL, 1.3 mmol) was added to a stirred solution of the compound of Formula 1l (0.4 g, 0.64 mmol) and Rucaparib (0.21 g, 0.64 mmol) in DMF (5 mL) at RT, and the mixture was stirred for 2 hrs.
  • Step II Preparation of ⁇ 4-[(2S)-2-[(2S)-2-amino-3-methylbutanamido]-5-(carbamoylamino) pentanamido]phenyl ⁇ methyl N-[(4- ⁇ 6-fluoro-9-oxo-3,10-diazatricyclo [6.4.1.04,13]trideca- 1,4,6,8(13)-tetraen-2-yl ⁇ phenyl)methyl]-N-methylcarbamate (Formula 2b) Palladium tetrakis(triphenylphosphine) ( 0.04 g, 0.035 mmol) was added to a stirred solution of the compound of Formula 2a (0.38 g, 0.47 mmol) in a mixture of DCM
  • Formula 1i Formula 2b Compound No 1.6
  • the compound of Formula 2b (0.1 g, 0.11 mmol) was added to a stirred solution the compound of Formula 1i (0.08 g, 0.15 mmol) and triethylamine (0.16 mL, 1.13 mmol) in DMF (2 mL) at RT and the mixure was stirred for 4 hrs. Additionally the compound of Formula 1i (0.23 g, 0.27 mmol) was added to the reaction mixture, and the resulting mixture was stirred for 4 hrs more. The reaction mixture was concentrated and degassed under reduced pressure at 50oC. DCM (5 mL) was added to the residue and the mixture was stirred at RT for 30 min.
  • Example 3 Preparation of Compound No 1.13 Step I : Preparation of (11S,12R)-3-( ⁇ [2-(dimethylamino)ethyl]amino ⁇ methyl)-7-fluoro-11-(4- fluorophenyl)-12-(1-methyl-1H-1,2,4-triazol-5-yl)-2,3,10-triazatricyclo[7.3.1.05,13] trideca- 1,5,7,9(13)-tetraen-4-one (Formula 3a).
  • N,N-Dimethylethylenediamine (1.7 mL, 15.8 mmol) was added to a stirred solution of talazoparib (0.5 g, 1.3 mmol) and formaldehyde solution (37% aqueous solution, 0.75 mL, 10.5 mmol) in ethanol (5 mL) at RT, and the mixture was further stirred in a sealed tube. The mixture was then heated in the sealed tube at 80oC for 5 hrs. After 5 hrs the reaction mixture was concentrated and degassed under reduced pressure at 80oC. n-Hexane (10 mL) was added to the residue, and the resulting mixture was stirred at RT for 30 min.
  • Step II Preparation of ⁇ 4-[(2S)-5-(carbamoylamino)-2-[(2S)-3-methyl-2- ⁇ [(prop-2-en-1- yloxy)carbonyl] amino ⁇ butanamido]pentanamido]phenyl ⁇ methyl N-[2-(dimethylamino) ethyl]-N- ⁇ [(11S,12R)-7-fluoro-11-(4-fluorophenyl)-12-(1-methyl-1H-1,2,4-triazol-5-yl)-4- oxo-2,3,10-triazatricyclo[7.3.1.05,13]trideca-1,5,7,9(13)-tetraen-3-yl]methyl ⁇ carbamate (Formula 3b).
  • Step III Preparation of ⁇ 4-[(2S)-2-[(2S)-2-amino-3-methylbutanamido]-5- (carbamoylamino)pentanamido]phenyl ⁇ methyl N-[2-(dimethylamino)ethyl]-N- ⁇ [(11S,12R)- 7-fluoro-11-(4-fluorophenyl)-12-(1-methyl-1H-1,2,4-triazol-5-yl)-4-oxo-2,3,10-triazatricyclo [7.3.1.05,13]trideca-1,5,7,9(13)-tetraen-3-yl]methyl ⁇ carbamate (Formula 3c) Formula 3b Formula 3c Palladium tetrakis(triphenylphosphine) ( 0.024 g, 0.021 mmol) was added to a stirred solution of the compound of Formula 3b ( 0.27 g, 0.28 mmol) in a
  • Step IV Preparation of (2S)-2-( ⁇ [(1S)-1-carboxy-5-[(2S)-3-(naphthalen-2-yl)-2- ⁇ [(1R,4R)-4- [(4- ⁇ [(1S)-1- ⁇ [(1S)-4-(carbamoylamino)-1-( ⁇ 4-[( ⁇ [2-(dimethyl amino)ethyl]( ⁇ [(11S,12R)-7- fluoro-11-(4-fluorophenyl)-12-(1-methyl-1H-1,2,4-triazol-5-yl)-4-oxo-2,3,10- triazatricyclo[7.3.1.05,13]trideca-1,5,7,9(13)-tetraen-3- yl]methyl ⁇ )carbamoyl ⁇ oxy)methyl]phenyl ⁇ carbamoyl)butyl] carbamoyl ⁇ -2- methylpropyl]carbamoyl ⁇ butana
  • Formula 1i Formula 3c Compound No 1.13
  • the compound of Formula 3c (0.1 g, 0.11 mmol) was added to a stirred solution of the compound of Formula 1i (0.19 g, 0.22 mmol) and triethylamine (0.16 mL, 1.13 mmol) in DMF (2 mL) at RT, and the resulting mixture was stirred for 4 hrs.
  • An additional amount of the compound of Formula 1i (0.04 g, 0.075 mmol) was added to the reaction mixture, and the mixture was stirred for further 4 hrs.
  • the reaction mixture was then concentrated and degassed under reduced pressure at 50oC.
  • DCM (5 mL) was added to the residue and the mixture was stirred at RT for 30 min.
  • Example 4 Preparation of Compound no 1.8 Step I: Preparation of di-tert-butyl (2S)-2-[[(1S)-1-tert-butoxycarbonyl-5-[[(2S)-2-[[4-[[(1- ethoxy carbonylcyclobutanecarbonyl)amino]methyl]cyclohexanecarbo-nyl]amino]-3-(2- naphthyl)propanoyl]amino]pentyl]carbamoylamino] pentanedioate (Formula 4a).
  • Formula 1f Formula 4a EEDQ (0.18 g, 0.73 mmol) was added to a stirred solution of the compound of Formula 1f (0.4 g, 0.48 mmol) and 1-ethoxycarbonylcyclobutanecarboxylic acid (0.093 g, 0.53 mmol) in a mixture of DCM (4 mL) and methanol (2 mL). The mixture was stirred overnight at RT then concentrated at 40oC under reduced pressure. Diethyl ether (10 mL) was added to the crude product and the resulting mixture was stirred at RT for 30 min. The solid obtained was filtered, washed with diethyl ether and dried under reduced pressure to get the compound of Formula 4a.
  • Step II Preparation of 1-[[4-[[(1S)-2-[[(5S)-6-tert-butoxy-5-[[(1S)-4-tert-butoxy-1-tert- butoxycarbonyl-4-oxo-butyl]carbamoylamino]-6-oxo-hexyl]amino]-1-(2-naphthyl methyl)-2- oxo-ethyl]carbamoyl]cyclohexyl]methylcarbamoyl] cyclobutanecarboxylic acid (Formula 4b) Formula 4a Formula 4b A solution of lithium hydroxide (0.058 g, 1.39 mmol) in water (3 mL) was added to a stirred solution of the compound of Formula 4a (0.34 g, 0.34 mmol) in ethanol (7 mL) at RT.
  • Step III Preparation of di-tert-butyl (2S)-2-[[(1S)-1-tert-butoxycarbonyl-5-[[(2S)-2-[[4-[[[1- (2,5-dioxopyrrolidin-1-yl)oxycarbonylcyclobutanecarbonyl]amino] methyl]cyclohexanecarbonyl]amino]-3-(2-naphthyl)propanoyl]amino]pentyl] carbamoylamino] pentanedioate (Formula 4c).
  • Formula 4b Formula 4c NHS (0.053 g, 0.46 mmol) followed by EEDQ (0.088 g, 0.46 mmol) was added to a stirred solution of the compound of Formula 4b (0.25 g, 0.26 mmol) in DMF (4 mL). The reaction mixture was stirred overnight at RT. After this time, the reaction mixture was diluted with DCM (30 mL). The organic layer was washed with water (2 x 15 mL) followed by brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure at 50oC to get the compound of Formula 4c.
  • Step IV Preparation of (2S)-2-[[(1S)-1-carboxy-5-[[(2S)-2-[[4-[[[1-(2,5-dioxopyrrolidin-1-yl) oxycarbonylcyclobutanecarbonyl]amino]methyl] cyclohexanecarbonyl]amino]-3-(2- naphthyl)propanoyl]amino]pentyl] carbamoylamino]pentanedioic acid (Formula 4d) Formula 4c Formula 4d TFA (1.5 mL) was added to a stirred solution of the compound of Formula 4c (0.3 g, 0.29 mmol) in DCM (3.0 mL) at RT.
  • Step V Preparation of Compound number 1.8 Formula 4d Formula 4e
  • the compound of Formula 4e was prepared by a similar method as that for the compound of Formula 1n. Triethylamine (0.2 mL, 1.46 mmol) was added to a stirred solution of the compound of Formula 4e (0.15 g, 0.14 mmol) in DMF (3 mL).
  • Example 5 Preparation of Compound No 1.3 Step I: Preparation of di-tert-butyl (2S)-2-[[(1S)-5-[[(2S)-2-[[(2S)-2-amino-5-tert-butoxy-5- oxo-pentanoyl]amino]-3-(2-naphthyl)propanoyl]amino]-1-tert-butoxycarbonyl- pentyl]carbamoylamino]pentanedioate (Formula 5d).
  • Formula 5a Formula 5b Formula 5c Formula 5d EEDQ (0.3 g, 1.5 mmol) was added to a stirred solution of the compound of Formula 5b (0.5 g, 1.2 mmol) and 1-hydroxy benzotriazole (0.21 g, 1.5 mmol) in DMF (5 mL), and the mixture was stirred at RT for 2 hrs.
  • a solution of the compound of Formula 5a (0.8 g, 1.2 mmol) in DMF (5 mL) was added to the reaction mixture, and the mixture was stirred overnight. Piperidine (2 mL) was added to the reaction mixture and this mixture was stirred for 2 hrs at RT. The reaction mixture was concentrated at 50oC under reduced pressure.
  • Step II Preparation of di-tert-butyl (2S)-2-[[(1S)-1-tert-butoxycarbonyl-5-[[(2S)-2-[[(2S)-5- tert-butoxy-2-[[1-[[(1S)-1-[[4-(hydroxymethyl)phenyl]carbamoyl]-4-ureido-butyl] carbamoyl]cyclobutanecarbonyl]amino]-5-oxo-pentanoyl]amino]-3-(2-naphthyl) propanoyl]amino]pentyl]carbamoylamino]pentanedioate (Formula 5f) .
  • Formula 5d Formula 5e Formula 5f EEDQ (0.28 g, 1.1 mmol) was added to a stirred solution of the compound of Formula 5d (0.5 g, 0.57 mmol) and the compound of Formula 5e (0.26 g, 0.63 mmol) in a mixture of DCM (5 mL) and methanol (2.5 mL). The reaction mixture was stirred overnight at RT and then concentrated at 40oC under reduced pressure. Diethyl ether (10 mL) was added to the crude product and the resulting mixture was stirred at RT for 30 min. The solid obtained was filtered, washed with diethyl ether and dried under reduced pressure.
  • Step III Preparation of 1,5-di-tert-butyl (2S)-2-( ⁇ [(2S)-1-(tert-butoxy)-6-[(2S)-2-[(2S)-5- (tert-butoxy)-2-[(1- ⁇ [(1S)-4-(carbamoylamino)-1-[(4- ⁇ [( ⁇ 2-[( ⁇ [(19S)-10,19-diethyl-7- hydroxy-14,18-dioxo-17-oxa-3,13-diazapentacyclo[11.8.0.02,11.04,9.015,20]henicosa- 1(21),2(11),3,5,7,9,15(20)-heptaen-19-yl]oxy ⁇ carbonyl)(methyl)amino]ethyl ⁇ (methyl) carbamo
  • Formula 5f Formula 5g DIPEA (0.1 mL, 0.43 mmol) followed by bis(4-nitrophenyl)carbonate (0.065 g, 0.21 mmol) was added to a stirred solution of the compound of Formula 5f (0.18 g, 0.14 mmol) in DMF (2 mL) under nitrogen atmosphere at RT. The reaction mixture was stirred for 5 hrs then concentrated under reduced pressure at 55oC.
  • reaction mixture was stirred for 1 hr, diluted with DCM (500 mL), washed with aqueous 0.1 N HCl solution (3x50 mL) and dried over anhydrous sodium sulphate. Removal of DCM under reduced pressure at 40oC resulted in the crude product, which was purified by column chromatography (silica gel 230- 400 mesh, ethyl acetate : DCM, 10:90) to get the compound of Formula 6a.
  • Step II Preparation of (19S)-19- ⁇ [(2- ⁇ [(tert-butoxy)carbonyl](methyl)amino ⁇ ethyl) (methyl)carbamoyl]oxy ⁇ -10,19-diethyl-14,18-dioxo-17-oxa-3,13-diazapentacyclo [11.8.0.02,11.04,9.015,20]henicosa-1(21),2(11),3,5,7,9,15(20)-heptaen-7-yl tert-butyl carbonate (Formula 6b) Formula 6a Formula 6b A solution of the compound of Formula 6a (3.5 g, 5.3 mmol) in DMF (17.5 mL) was added to a stirred solution of tert-butyl N-methyl-N-[2-(methylamino)ethyl]carbamate (1.1 g, 5.85 mmol) and DIPEA (1.4 mL, 07.98 mmol) in acetonit
  • Formula 6b Formula 6c HCl (4M) in 1,4-dioxane (1.65 mL) was added to a stirred solution of the compound of Formula 6b (0.33 g, 0.47 mmol) in 1,4-dioxane (1.0 mL) at RT. The reaction mixture was stirred for 5 hrs and then was concentrated and degassed under reduced pressure at 35oC to get the compound of Formula 6c (0.25 g), which was used for the next step without purification.
  • Step V Preparation of (19S)-10,19-diethyl-7-hydroxy-14,18-dioxo-17-oxa-3,13- diazapentacyclo[11.8.0.02,11.04,9.015,20]henicosa-1(21),2(11),3,5,7,9,15(20)-heptaen-19-yl N- (2- ⁇ [( ⁇ 4-[(2S)-2-[(2S)-2- ⁇ [(benzyloxy)carbonyl]amino ⁇ -3-methylbutanamido]-5- (carbamoylamino)pentanamido]phenyl ⁇ methoxy)carbonyl] (methyl)amino ⁇ ethyl)-N- methylcarbamate (Formula 6f).
  • Step VI Preparation of (19S)-10,19-diethyl-7-hydroxy-14,18-dioxo-17-oxa-3,13- diazapentacyclo [11.8.0.02,11.04,9.015,20]henicosa-1(21),2(11),3,5,7,9,15(20)-heptaen-19-yl N- (2- ⁇ [( ⁇ 4-[(2S)-2-[(2S)-2-amino-3-methylbutanamido]-5-(carbamoylamino) pentanamido]phenyl ⁇ methoxy)carbonyl](methyl)amino ⁇ ethyl)-N-methylcarbamate (Formula 6g).
  • Step VII Preparation of Compound no 1.2 Formula 1i Formula 6g
  • Compound no 1.2 DIPEA (0.12 mL, 0.69 mmol) was added to a stirred solution of the compound of Formula 6g (0.12 g, 0.12 mmol) in DMF (3 mL).
  • the compound of Formula 1i (0.12 g, 0.14 mmol) was added to the mixture, and the resulting mixture was stirred at RT for 24 hrs. After 24 hrs the reaction mixture was concentrated and degassed under reduced pressure at 50oC.
  • DCM (5 mL) was added to the residue and stirred at RT for 30 min. The product obtained was filtered, washed with DCM (3x5 mL) and dried under vacuum.
  • Step II Preparation of (S)-4-allyloxycarbonylamino-4-[2-(2- ⁇ 2-[2-(2- ⁇ 2-[2-(2-(2- ⁇ 2-[2-(2- methoxyethoxy)ethoxy]ethoxy ⁇ ethoxy)ethoxy]ethoxy ⁇ ethoxy)ethylcarbamoyl]butyric acid tert-butyl ester (Formula 7a).
  • Step III Preparation of (S)-4-allyloxycarbonylamino-4-[2-(2- ⁇ 2-[2-(2- ⁇ 2-[2-(2- ⁇ 2-[2-(2- methoxyethoxy)ethoxy]ethoxy ⁇ ethoxy)ethoxy]ethoxy ⁇ ethoxy)ethylcarbamoyl]butyric acid (Formula 7b).
  • Formula 7a Formula 7b TFA (4 mL) was added dropwise to a stirred solution of the compound of Formula 7a (1.0 gm, 1.53 mmol) in DCM (14 mL) at 0oC, the mixture was stirred for 15 mins. The reaction mixture was then stirred at RT for 2 hours.
  • Step IV Preparation of [(S)-1-(3-oxo-1, 3-dihydro-isobenzofuran-5-ylcarbamoyl)-4-ureido- butyl]carbamic acid tert-butyl ester.
  • EEDQ (6.8 gm, 27.27 mmol) was added to a stirred solution of (S)-2-tert- butoxycarbonylamino-5-ureido pentanoic acid (5.0 gm, 18.18 mmol) and 6-amino-3H- isobenzofuran-1-one (3.0 gm, 20.0 mmol) in a mixture of DCM (60 mL) and methanol (30 mL). The reaction mixture was stirred overnight at RT and then concentrated under reduced pressure at 45oC. Ethyl acetate (5 mL) was added to the residue, and the resulting mixture was stirred for 2 hrs.
  • Step V Preparation of (S)-2-amino-5-ureido-pentanoic acid(3-oxo-1,3-dihydro- isobenzofuran-5-yl)amide trifluoroacetate.
  • Step VI Preparation of ⁇ (S)-2-methyl-1-[(S)-1-(3-oxo-1, 3-dihydro-isobenzofuran-5- ylcarbamoyl)-4-ureido-butylcarbamoyl]-propyl ⁇ -carbamic acid allyl ester (Formula 7c).
  • reaction mixture was quenched in water (50 mL) and the aqueous layer was extracted with ethyl acetate (3x100 mL). The combined organic layers were washed with a brine solution (1x50 mL) and was dried over anhydrous sodium sulphate and concentrated under reduced pressure at 50oC to get the crude product (5.8 gm), which was purified by column chromatography (silica gel 230-400 mesh; DCM: methanol, 95:05) to get the compound of Formula 7c.
  • Step VII Preparation of ((S)-1- ⁇ (S)-1-[3-(3-dimethylamino-propylcarbamoyl)-4- hydroxymethyl-phenylcarbamoyl]-4-ureido-butylcarbamoyl ⁇ -2-methyl-propyl)-carbamic acid allyl ester (Formula 7d).
  • Formula 7c Formula 7d N',N'-dimethylpropane-1,3-diamine (1.5 mL) was added to the compound of Formula 7c (0.5 gm, 0.84 mmol) at RT and this mixture was heated under stirring at 85oC for 2 hrs.
  • Step VIII Preparation of ((S)-1- ⁇ (S)-1-[3-(3-dimethylaminopropylcarbamoyl)-4-( ⁇ [4-(8- fluoro-6-oxo-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-2-yl)- benzyl]methylcarbamoyloxy ⁇ methyl)phenylcarbamoyl]-4-ureidobutylcarbamoyl ⁇ -2- methylpropyl) carbamic acid allyl ester (Formula 7e).
  • Formula 7d Formula 7e DIPEA (0.36 mL, 2.0 mmol) was added to a stirred solution of the compound of Formula 7d (0.3 g, 0.5 mmol) in DMF (3 mL) at RT.
  • Bis(4-nitrophenyl)carbonate (0.32 g, 1.0 mmol) was added to the reaction mixture and the resulting mixture was stirred for 2 hrs. After this time the reaction mixture was concentrated under reduced pressure at 55oC. The residue was triturated with diethyl ether (5 mL). Diethyl ether was decanted and the resulting residue was dried under reduced pressure to get the crude product.
  • Step X Preparation of ⁇ 4-[(2S)-5-(carbamoylamino)-2-[(2S)-3-methyl-2-[(4S)-4- [(2,5,8,11,14,17,20,23-octaoxapentacosan-25-yl)carbamoyl]-4- ⁇ [(prop-2-en-1-yloxy) carbonyl]amino ⁇ butanamido]butanamido]pentanamido]-2- ⁇ [3-(dimethylamino)propyl] carbamoyl ⁇ phenyl ⁇ methyl N-[(4- ⁇ 6-fluoro-9-oxo-3,10-diazatricyclo[6.4.1.04,13]trideca- 1,4,6,8(13)-tetraen-2-yl ⁇ phenyl)methyl]-N-methylcarbamate (Formula 7g).
  • Step XI Preparation of ⁇ 4-[(2S)-2-[(2S)-2-[(4S)-4-amino-4-[(2,5,8,11,14,17,20,23- octaoxapentacosan-25-yl)carbamoyl]butanamido]-3-methylbutanamido]-5- (carbamoylamino)pentanamido]-2- ⁇ [3-(dimethylamino)propyl]carbamoyl ⁇ phenyl ⁇ methyl N- [(4- ⁇ 6-fluoro-9-oxo-3,10-diazatricyclo[6.4.1.04,13]trideca-1,4,6,8(13)-tetraen-2-yl ⁇ phenyl) methyl]-N-methylcarbamate (Formula 7h).
  • Formula 7g Palladium tetrakis(triphenylphosphine) ( 0.007 g, 0.006 mmol) was added to a stirred solution of the compound of Formula 7g ( 0.11 g, 0.076 mmol) in a mixture of DCM (0.77 mL) and methanol (0.33 mL) at RT. Morpholine (0.053 mL, 0.608 mmol) was added to the reaction mixture. and the mixture was stirred for 2.0 hr. Following this period, the reaction mixture was concentrated under reduced pressure at 35oC.
  • Step XII Preparation of the Compound no 1.56
  • the compound of Formula 7h (0.09 gm, 0.066 mmol) was added to a stirred solution of the compound of Formula 1i (0.075 g, 0.086 mmol) in DMF (1.0 mL) and TEA (0.093 ml, 0.66 mmol) and continued stirring the mixture at RT for 14 hrs.
  • the reaction mixture was then concentrated and degassed under reduced pressure at 50oC.
  • Example 8 Preparation of Compound no 1.51 Step I: Preparation of O1-benzyl O5-tert-butyl (2S)-2-(benzyloxycarbonylamino) pentanedioate.
  • Step II Preparation of (4S)-5-benzyloxy-4-(benzyloxycarbonylamino)-5-oxo-pentanoic acid.
  • TFA 11 mL
  • O1-benzyl O5-tert-butyl (2S)-2- (benzyloxycarbonylamino) pentanedioate 2.2 gm, 5.15 mmol
  • DCM 33.0 mL
  • reaction mixture was stirred at RT for 3 hrs and then concentrated and degassed completely under reduced pressure at 35oC to get the crude product (2.5 gm), which was purified by column chromatography (silica gel 230-400 mesh; ethyl acetate: n-hexane, 50:50) to get (4S)-5- benzyloxy-4-(benzyloxycarbonylamino)-5-oxo-pentanoic acid.
  • Step IV Preparation of (2S)-2-amino-5-[2-[2-[2-[2-[2-[2-[2-[2-(2-methoxyethoxy) ethoxy]ethoxy]ethoxy]ethylamino]-5-oxo-pentanoic acid (Formula 8b).
  • Formula 8a Formula 8b Palladium on carbon (10%, 50% wet, 0.68 g) was added to a stirred solution of the compound of Formula 8a (3.4 g, 4.61 mmol) in methanol (34 mL) at RT. The reaction mixture was stirred at RT under hydrogen gas pressure for 2 hrs. After 2 hrs the reaction mixture was filtered through Celite ® bed and washed with excess methanol. The combined filtrates were concentrated under reduced pressure at 45oC to get the compound of Formula 8b, which is used for the next step without further purification.
  • Step V Preparation of (2S)-2-(allyloxycarbonylamino)-5-[2-[2-[2-[2-[2-[2-[2-[2-(2- methoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethylamino]-5-oxo-pentanoic acid (Formula 8c).
  • Formula 8b Formula 8c Allyl chloroformate (0.43 mL, 4.1 mmol) was added dropwise to a stirred solution of the compound of Formula 8b (1.9 gm, 3.7 mmol) in a mixture of THF (30 ml), water (30 mL) and potassium carbonate (0.84 g, 5.56 mmol) at 0oC.
  • Step VI Preparation of [4-[[(2S)-2-[[(2S)-2-[[(2S)-2-(allyloxycarbonylamino)-5-[2-[2-[2-[2-[2-[2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethylamino]-5-oxo- pentanoyl]amino]-3-methyl-butanoyl]amino]-5-ureido-pentanoyl]amino]-2-[3- (dimethylamino)propylcarbamoyl]phenyl]methyl N-[(1S)-1-[[(1S)-1-[[(1S,2R)-4-[(2S)-2- [(1R,2R)-3-[[(1R,2S)-2-hydroxy-1-methyl-2-phenyl-ethyl]amino]-1-
  • Step VII Preparation of [4-[[(2S)-2-[[(2S)-2-[[(2S)-2-amino-5-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethoxy]ethylamino]-5-oxo- pentanoyl]amino]-3-methyl-butanoyl]amino]-5-ureido-pentanoyl]amino]-2-[3- (dimethylamino)propylcarbamoyl]phenyl]methyl N-[(1S)-1-[[(1S)-1-[[(1S,2R)-4-[(2S)-2- [(1R,2R)-3-[[(1R,2S)-2-hydroxy-1-methyl-2-phenyl-ethyl]amino]-1-methoxy-2-methyl-3-
  • Step VIII Preparation of Compound no 1.51 Compound no 1.51
  • the compound of Formula 8f (0.05 gm, 0.029 mmol) was added to a stirred solution of the compound of Formula 1i (0.037 g, 0.043 mmol) in DMF (1.0 mL) and TEA (0.04 ml, 0.29 mmol).
  • Step II Preparation of 9H-fluoren-9-ylmethyl N-[2-[4-(hydroxymethyl)anilino]-2-oxo- ethyl]carbamate (Formula 9b).
  • Step III Preparation of 2-amino-N-[4-(hydroxymethyl)phenyl]acetamide (Formula 9c).
  • Formula 9b Formula 9c Piperidine (7.4 mL, 74.5 mmol) was added to a stirred solution of the compound of Formula 9b (6.0 g, 14.9 mmol) in DMF (30 mL). The reaction mixture was stirred at room temperature for 1 hr and then concentrated under reduced pressure at 50oC. Diethyl ether (60 mL) was added to the residue, and the resulting mixture was stirred at room temperature for 30 min.
  • Step IV Preparation of 9H-fluoren-9-ylmethyl N-[(1S)-1-benzyl-2-[[2-[4-(hydro- xylmethyl)anilino]-2-oxo-ethyl]amino]-2-oxo-ethyl]carbamate (Formula 9d).
  • Step V Preparation of (2S)-2-amino-N-[2-[4-(hydroxymethyl)anilino]-2-oxo-ethyl]-3-phenyl- propanamide (Formula 9e).
  • Formula 9d Formula 9e Piperidine (0.87 mL, 8.8 mmol) was added to a stirred solution of the compound of Formula 9d (1.0 g, 1.76 mmol) in DMF (5 mL). The reaction mixture was stirred at RT for 1 hr and then concentrated under reduced pressure at 50oC.
  • Step VI Preparation of allyl N-[2-[[2-[[(1S)-1-benzyl-2-[[2-[4-(hydroxymethyl)anilino]-2- oxo-ethyl]amino]-2-oxo-ethyl]amino]-2-oxo-ethyl]amino]-2-oxo-ethyl]carbamate (Formula 9f).
  • Formula 9a Formula 9e Formula 9f EEDQ (1.6 g, 4.6 mmol) was added to a stirred solution of the compound of Formula 9a (0.5 g, 2.3 mmol) and the compound of Formula 9e (0.75 g, 2.3 mmol) in a mixture of DCM (5 mL) and methanol (2.5 mL). The reaction mixture was stirred overnight at room temperature and then concentrated at 40oC under reduced pressure. Diethyl ether (10 mL) was added to the crude product, and the resulting mixture was stirred at RT for 30 min. The product obtained was filtered, washed with diethyl ether and dried under reduced pressure to get the compound of Formula 9f, which was used for the next step without purification.
  • Step VII Preparation of [4-[[2-[[(2S)-2-[[2-[[2-(allyloxycarbonylamino) acetyl]amino]acetyl]amino]-3-phenyl-propanoyl]amino]acetyl]amino]phenyl] methyl (4- nitrophenyl) carbonate (Formula 9g).
  • Formula 9f Formula 9g DIPEA (0.6 mL, 3.4 mmol) was added to a stirred solution of the compound of Formula 9f (0.6 g, 1.14 mmol) in DMF (6 mL) at RT.
  • Step VIII Preparation of [4-[[2-[[(2S)-2-[[2-[[2-(allyloxycarbonylamino) acetyl]amino] acetyl]amino]-3-phenyl-propanoyl]amino]acetyl]amino]phenyl] methyl N-[(1S)-1-[[(1S)-1- [[(1S,2R)-4-[(2S)-2-[(1R,2R)-3-[[(1R,2S)-2-hydroxy-1-methyl-2-phenyl-ethyl]amino]-1- methoxy-2-methyl-3-oxo-propyl]pyrrolidin-1-yl]-2-methoxy-1-[(1S)-1-methylpropyl]-4-oxo- butyl]-methyl-carbamoyl]-2-methyl-propyl]carbamoyl]-2-methyl-propyl]-N
  • Formula 9g Formula 9h HOBt (45 mg) and DIPEA (0.22 mL, 1.28 mmol) was added to a stirred solution of the compound of Formula 9g(0.44 g, 0.64 mmol) and monomethyl auristatin E (0.46 g, 0.64 mmol) in DMF (4.4 mL) at room temperature. The reaction mixture was stirred for 48 hrs and then concentrated under reduced pressure at 55oC. The crude material obtained was purified by column chromatography (silica gel 230-400 mesh; DCM : methanol : aqueous ammonia 88:10:2) to get the compound of Formula 9h.
  • Step IX Preparation of [4-[[2-[[(2S)-2-[[2-[(2-aminoacetyl)amino]acetyl]amino]-3-phenyl- propanoyl]amino]acetyl]amino]phenyl]methyl N-[(1S)-1-[[(1S)-1-[[(1S, 2R)-4-[(2S)-2- [(1R,2R)-3-[[(1R,2S)-2-hydroxy-1-methyl-2-phenyl-ethyl]amino]-1-methoxy-2-methyl-3- oxo-propyl]pyrrolidin-1-yl]-2-methoxy-1-[(1S)-1-methyl propyl]-4-oxo-butyl]-methyl- carbamoyl]-2-methyl-propyl]carbamoyl]-2-methyl-propyl]-N-methyl-carbamate (Formula
  • Step X Preparation of Compound no 1.16
  • DIPEA 0.11 mL, 0.82 mmol
  • Example 10 Preparation of Compound no 1.9 Step I: Preparation of tert-butyl 2-[2-[2-(2-tert-butoxy-2-oxo-ethoxy)ethoxy]ethoxy] acetate (Formula 10a).
  • Formula 10b Formula 10c TEA (3.25 mL, 23.4 mmol) was added to a stirred solution of the compound of Formula 10b (2.0 gm, 9.0 mmol) in acetone (14 mL) at RT. The reaction mixture was stirred for 15 min and then cooled to 0-5oC. Benzyl bromide (1.12 mL, 9.46 mmol) was added dropwise to the reaction mixture at 0-5oC, and the reaction mixture was stirred for 15 min and then the overnight at RT. After the completion of reaction, the reaction mixture was filtered, washed with acetone (3x20 mL) and then the combined filtrates were concentrated under reduced pressure at 45oC. Water (20 mL) was added to the residue.
  • Step IV Preparation of di-tert-butyl (2S)-2-[[(1S)-5-[[(2S)-2-[[4-[[[2-[2-[2-(2-benzyloxy-2- oxo-ethoxy)ethoxy]ethoxy]acetyl]amino]methyl]cyclohexane carbonyl]amino]-3-(2- naphthyl)propanoyl]amino]-1-tert-butoxycarbonyl-pentyl]carbamoylamino] pentanedioate (Formula 10d).
  • Formula 1f Formula 10c Formula 10d TBTU (0.07 g, 0.21 mmol) and DIPEA (0.07 mL, 0.4 mmol) was added to a stirred solution containing the compound of Formula 1f (0.13 g, 0.16 mmol) and the compound of Formula 10c (0.05 g, 0.16 mmol) in DMF (2 mL) at RT.
  • the reaction mixture was stirred overnight and then concentrated under reduced pressure at 50oC to give the crude product which was purified by column chromatography (silica gel 230-400 mesh, DCM:methanol, 95:5) to get the compound of Formula 10d.
  • Step V Preparation of 2-[2-[2-[2-[[4-[[(1S)-2-[[(5S)-6-tert-butoxy-5-[[(1S)-4-tert-butoxy-1- tert-butoxycarbonyl-4-oxo-butyl]carbamoylamino]-6-oxo-hexyl]amino] -1-(2- naphthylmethyl)-2-oxo-ethyl]carbamoyl]cyclohexyl]methylamino]-2-oxo- ethoxy]ethoxy]ethoxy] acetic acid Formula 10e.
  • Formula 10d Palladium on carbon (10%, 50% wet, 0.03 g) was added to a stirred solution of the compound of Formula 10d (0.15 g, 0.134 mmol) in methanol (2.5 mL) at RT. Hydrogen gas was purged through the reaction mixture at RT and then the reaction mixture was stirred for 1 hr. After this time, the reaction mixture was filtered through Celite® bed and washed with excess methanol. The combined filtrates were concentrated under reduced pressure at 45oC to get the compound of Formula 10e (0.115 gm), which is used for the next step without further purification.
  • Step VI Preparation of di-tert-butyl (2S)-2-[[(1S)-1-tert-butoxycarbonyl-5-[[(2S)-2-[[4-[[[2- [2-[2-[2-(2,5-dioxopyrrolidin-1-yl)oxy-2-oxo-ethoxy]ethoxy]ethoxy] acetyl]amino]methyl]cyclohexanecarbonyl]amino]-3-(2-naphthyl)propanoyl] amino]pentyl]carbamoyl amino]pentanedioate.
  • Step VII Preparation of (2S)-2-[[(1S)-1-carboxy-5-[[(2S)-2-[[4-[[[2-[2-[2-[2-[2-(2,5- dioxopyrrolidin-1-yl)oxy-2-oxo-ethoxy]ethoxy]ethoxy]acetyl]amino]methyl] cyclohexane carbonyl]amino]-3-(2-naphthyl)propanoyl]amino]pentyl]carbamoyl amino] pentanedioic acid Formula 10g.
  • Formula 10f Formula 10g TFA (0.5 mL) was added to a stirred solution of the compound of Formula 10f (0.1 g, 0.089 mmol) in DCM (2 mL) at 0-5oC. The reaction mixture was then stirred at RT for 6 hrs. After completion of reaction the reaction mixture was concentrated and degassed under reduced pressure at 30oC. The crude product was leached with diethyl ether (2x2 ml). The diethyl ether layer was decanted and dried to get the compound of Formula 10g, which was used for next step as such.
  • Step VI Preparation of Compound no 1.9
  • Compound no 1.9 TEA (0.06 mL, 0.45 mmol) was added to a stirred solution of the compound of Formula 1n (0.05 g, 0.045 mmol) in DMF (1 mL) and the resulting mixture was stirred for clear solution.
  • the compound of Formula 10g (0.055 g, 0.057 mmol) was added to the reaction mixture, and the resulting mixture was stirred at RT for 24 hrs. . After this time, the reaction mixture was concentrated and degassed under reduced pressure at 50oC. DCM (5 mL) was added to the residue and the resulting mixture was stirred at RT for 30 min.
  • N, N-diisopropylethylamine (0.7 mL, 3.86 mmol) is added to stirred solution of 4-(4- methoxyphenyl)butanoic acid (0.3 gm, 1.54 mmol), tert-butyl 3-[2-[2-[2-(2- aminoethoxy)ethoxy]ethoxy]ethoxy]propanoate (0.5 gm, 1.54 mmol) and 1- [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluoro phosphate (HATU, 0.7 gm, 1.85 mmol) in N, N-dimethylformamide (10 mL) at room temperature and stirred overnight.
  • HATU 1- [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluoro phosphate
  • Reaction mixture is quenched with D. M. water (1x20 mL) and extracted with ethyl acetate (3x30 mL). Combined organic layer is washed with 0.5 N HCl solution (1x20 mL) followed by saturated sodium bicarbonate solution (1x20 mL), D. M. water (1x20 mL) and brine solution (1x20 mL).
  • Step II Preparation of 3-[2-[2-[2-[2-[4-(4-methoxyphenyl)butanoylamino]ethoxy] ethoxy]ethoxy]propanoic acid.
  • Trifluoroacetic acid (2.25 mL) is added to a stirred solution of tert-butyl 3-[2-[2-[2-[2-[4-(4- methoxyphenyl)butanoylamino]ethoxy]ethoxy]ethoxy]propanoate (0.75 gm, 1.51 mmol) in dichloromethane (7.5 mL) at 0-5oC and stirred for 10 min. Reaction mixture is then allowed to attain room temperature and stirred for 3 hrs. Reaction mixture is concentrated under reduced pressure at 35oC. Diethyl ether (20 ml) is added to the residue and stirred for 30 min. Diethyl ether is then decant off.
  • Step III Preparation diethyl 3-[3-[2-[2-[2-[4-(4-methoxyphenyl)butanoylamino] ethoxy]ethoxy]ethoxy]propanoylamino]pentanedioate.
  • N, N-diisopropylethylamine (0.63 mL, 3.68 mmol) is added to stirred solution of diethyl 3- aminopentanedioate (0.3 gm, 1.48 mmol), 3-[2-[2-[2-[2-[4-(4-methoxy phenyl)butanoylamino]ethoxy]ethoxy]ethoxy]propanoic acid (0.65 gm, 1.48 mmol) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluoro phosphate (HATU, 0.67 gm, 1.77 mmol) in N, N-dimethylformamide (10 mL) at room temperature and stirred overnight.
  • HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hex
  • Reaction mixture is quenched with D. M. water (1x20 mL) and extracted with ethyl acetate (3x30 mL). Combined organic layer is washed with 0.5 N HCl solution (1x20 mL) followed by saturated sodium bicarbonate solution (1x20 mL), D. M. water (1x20 mL) and brine solution (1x20 mL).
  • Step III Preparation of 3-[3-[2-[2-[2-[4-(4-methoxyphenyl)butanoylamino] ethoxy]ethoxy]ethoxy]propanoylamino]pentanedioic acid.
  • Step IV Preparation of N-[2-[2-[2-[3-[(2, 6-dioxotetrahydropyran-4-yl)amino]-3-oxo- propoxy]ethoxy]ethoxy]ethyl]-4-(4-methoxyphenyl)butanamide.
  • N, N′- Dicyclohexylcarbodiimide (DCC, 0.24 gm, 1.16 mmol) is added to a stirred solution of 3-[3-[2-[2-[2-[2-[4-(4-methoxyphenyl)butanoylamino]ethoxy]ethoxy]ethoxy]ethoxy] propanoylamino]pentanedioic acid (0.53 gm, 0.93 mmol) in tetrahydrofuran (10 mL) at room temperature and stirred overnight.
  • DCC N, N′- Dicyclohexylcarbodiimide
  • N, N′-Dicyclohexylcarbodiimide (DCC, 0.24 gm, 1.16 mmol) followed by molecular sieves (4A 0 , 0.5 gm) and tetrahydrofuran (10 mL) are added to the reaction mixture at room temperature and stirred for 8 hrs. Reaction mixture is filtered through celite bed and washed with tetrahydrofuran (3x10 mL).
  • Step V Preparation of 5-[[4-[[(1S)-2-[[(5S)-6-tert-butoxy-5-[[(1S)-4-tert-butoxy-1-tert- butoxycarbonyl-4-oxo-butyl]carbamoylamino]-6-oxo-hexyl]amino]-1-(2-naphthyl methyl)-2- oxo-ethyl]carbamoyl]cyclohexyl]methylamino]-3-[3-[2-[2-[2-[2-[2-[2-[4-(4-methoxy phenyl)butanoylamino]ethoxy]ethoxy]ethoxy]propanoylamino]-5-oxo-pentanoic acid.
  • N, N - Diisopropylethylamine (0.3 mL, 1.82 mmol) is added to a stirred solution of di-tert- butyl (2S)-2-[[(1S)-5-[[(2S)-2-[[4-(aminomethyl)cyclohexanecarbonyl]amino]-3-(2-naphthyl) propanoyl]amino]-1-tert-butoxycarbonyl-pentyl]carbamoylamino]pentanedioate (0.6 g, 0.73 mmol) and N-[2-[2-[2-[2-[2-[2-[2-[2-[2-[3-[(2, 6-dioxotetrahydropyran-4-yl)amino]-3-oxo-propoxy]ethoxy] ethoxy]ethyl]-4-(4-methoxyphenyl)butanamide (0.5 g, 0.87 mmol, by
  • Step VI Preparation of di-tert-butyl (2S)-2-[[(1S)-1-tert-butoxycarbonyl-5-[[(2S)-2-[[4-[[[3- [3-[2-[2-[2-[2-[4-(4-methoxyphenyl)butanoylamino]ethoxy]ethoxy]ethoxy] propanoylamino]-5-oxo-5-(2,3,4,5,6-pentafluorophenoxy)pentanoyl]amino]methyl] cyclohexanecarbonyl]amino]-3-(2-naphthyl)propanoyl]amino]pentyl]carbamoylamino] pentanedioate.
  • Pentafluorophenol (0.1 g, 0.57 mmol) followed by 1-ethyl-3-(3- dimethylaminopropyl)carbodiimide hydrochloride (0.11 g, 0.57 mmol) are added to a stirred solution of 5-[[4-[[(1S)-2-[[(5S)-6-tert-butoxy-5-[[(1S)-4-tert-butoxy-1-tert-butoxycarbonyl- 4-oxo-butyl]carbamoylamino]-6-oxo-hexyl]amino]-1-(2-naphthylmethyl)-2-oxo-ethyl] carbamoyl]cyclohexyl]methylamino]-3-[3-[2-[2-[2-[2-[2-[4-(4-methoxyphenyl)butanoylamino] ethoxy]ethoxy]ethoxy]propanoylamino]
  • Step VII Preparation of (2S)-2-[[(1S)-1-carboxy-5-[[(2S)-2-[[4-[[[3-[3-[2-[2-[2-[2-[4-(4- methoxyphenyl)butanoylamino]ethoxy]ethoxy]ethoxy]propanoylamino]-5-oxo-5- (2,3,4,5,6-pentafluorophenoxy)pentanoyl]amino]methyl]cyclohexanecarbonyl]amino]-3-(2- naphthyl)propanoyl]amino]pentyl]carbamoylamino]pentanedioic acid.
  • Trifluoroacetic acid (3.5 mL) is added to stirred solution of di-tert butyl (2S)-2-[[(1S)-1-tert butoxycarbonyl-5-[[(2S)-2-[[4-[[[3-[3-[2-[2-[2-[2-[4-(4-methoxyphenyl)butanoylamino] ethoxy]ethoxy]ethoxy]ethoxy]propanoylamino]-5-oxo-5-(2,3,4,5,6-pentafluorophenoxy) pentanoyl]amino]methyl]cyclohexanecarbonyl]amino]-3-(2-naphthyl)propanoyl]amino] pentyl]carbamoylamino]pentanedioate (0.7 g, 0.45 mmol) in dichloromethane (7 mL) at 0-5 0 C.
  • Step VIII Preparation of (2S)-2-[[(1S)-1-carboxy-5-[[(2S)-2-[[4-[[[5-[[(1S)-1-[[(1S)-1-[[3-[2- (dimethylamino)ethylcarbamoyl]-4-[[[(1S)-1-[[(1S)-1-[[(1S,2R)-4-[(2S)-2-[(1R,2R)-3- [[(1R,2S)-2-hydroxy-1-methyl-2-phenyl-ethyl]amino]-1-methoxy-2-methyl-3-oxo- propyl]pyrrolidin-1-yl]-2-methoxy-1-[(1S)-1-methylpropyl]-4-oxo-butyl]-methyl- carbamoyl]-2-methyl-propyl]carbamoyl]-2-methyl-propyl]-methyl-carbamo
  • Triethylamine (0.09 mL, 0.61 mmol) is added to a stirred solution of [4-[[(2S)-2-[[(2S)-2- amino-3-methyl-butanoyl]amino]-5-ureido-pentanoyl]amino]-2-[2-(dimethylamino)ethyl carbamoyl]phenyl]methyl N-[(1S)-1-[[(1S)-1-[[(1S,2R)-4-[(2S)-2-[(1R,2R)-3-[[(1R,2S)-2- hydroxy-1-methyl-2-phenyl-ethyl]amino]-1-methoxy-2-methyl-3-oxo-propyl]pyrrolidin-1- yl]-2-methoxy-1-[(1S)-1-methylpropyl]-4-oxo-butyl]-methyl-carbamoyl]-2-methyl-
  • N, N-Diisopropylethylamine (0.35 mL, 2.03 mmol) is added to stirred solution of allyl N-[(1S)- 1-[[(1S)-1-[[3-[3-(dimethylamino)propylcarbamoyl]-4-(hydroxymethyl)phenyl]carbamoyl]- 4-ureido-butyl]carbamoyl]-2-methyl-propyl]carbamate (0.4 g, 0.68 mmol) in tetrahydrofuran (4 mL) at room temperature.
  • Bis(4-nitrophenyl)carbonate 0.35 g, 1.15 mmol is added to the reaction mixture and stirred for 5 hrs.
  • Reaction mixture is concentrated under reduced pressure at 40oC .
  • Diethyl ether (20 mL) is added to the residue and stirred at room temperature for 45 min. Diethyl ether is decanted off. This process is repeated thrice and then the residue is dried to get [4-[[(2S)-2-[[(2S)-2-(allyloxycarbonylamino)-3-methyl-butanoyl]amino]-5-ureido- pentanoyl]amino]-2-[3-(dimethylamino)propylcarbamoyl]phenyl]methyl (4-nitrophenyl) carbonate (0.75 g), which is used for the next step without further purification.
  • Step II Preparation of [4-[[(2S)-2-[[(2S)-2-(allyloxycarbonylamino)-3-methyl-butanoyl] amino]-5-ureido-pentanoyl]amino]-2-[3-(dimethylamino)propylcarbamoyl]phenyl] methyl N- [(1S)-1-[[(1S)-1-[[(1S,2R)-4-[(2S)-2-[(1R,2R)-3-[[(1R,2S)-2-hydroxy-1-methyl-2-phenyl- ethyl]amino]-1-methoxy-2-methyl-3-oxo-propyl]pyrrolidin-1-yl]-2-methoxy-1-[(1S)-1- methylpropyl]-4-oxo-butyl]-methyl-carbamoyl]-2-methyl-propyl]carbamoyl]-2-
  • Step III Preparation of [4-[[(2S)-2-[[(2S)-2-amino-3-methyl-butanoyl]amino]-5-ureido- pentanoyl]amino]-2-[3-(dimethylamino)propylcarbamoyl]phenyl]methyl N-[(1S)-1-[[(1S)-1- [[(1S,2R)-4-[(2S)-2-[(1R,2R)-3-[[(1R,2S)-2-hydroxy-1-methyl-2-phenyl-ethyl] amino]-1- methoxy-2-methyl-3-oxo-propyl]pyrrolidin-1-yl]-2-methoxy-1-[(1S)-1-methyl propyl]-4- oxo-butyl]-methyl-carbamoyl]-2-methyl-propyl]carbamoyl]-2-methyl-propyl]-2-methyl
  • Step XI Preparation of [4-[[(2S)-2-[[(2S)-2-[[(2S)-2-(allyloxycarbonylamino)-5-[2-[2-[2-[2- [4-(4-methoxyphenyl)butanoylamino]ethoxy]ethoxy]ethylamino]-5-oxo- pentanoyl]amino]-3-methyl-butanoyl]amino]-5-ureido-pentanoyl]amino]-2-[3- (dimethylamino)propylcarbamoyl]phenyl]methyl N-[(1S)-1-[[(1S)-1-[[(1S,2R)-4-[(2S)-2- [(1R,2R)-3-[[(1R,2S)-2-hydroxy-1-methyl-2-phenyl-ethyl]amino]-1
  • Step XII Preparation of [4-[[(2S)-2-[[(2S)-2-[[(2S)-2-amino-5-[2-[2-[2-[2-[4-(4- methoxyphenyl)butanoylamino]ethoxy]ethoxy]ethylamino]-5-oxo-pentanoyl] amino]- 3-methyl-butanoyl]amino]-5-ureido-pentanoyl]amino]-2-[3-(dimethylamino) propylcarbamoyl]phenyl]methyl N-[(1S)-1-[[(1S)-1-[[(1S,2R)-4-[(2S)-2-[(1R,2R)-3- [[(1R,2S)-2-hydroxy-1-methyl-2-phenyl-ethyl]amino]-1-methoxy-2-methyl-3-oxo- prop
  • Step XIII Preparation of (2S)-2-[[(1S)-1-carboxy-5-[[(2S)-2-[[4-[[[5-[[(1S)-1-[[(1S)-1-[[(1S)- 1-[[3-[3-(dimethylamino)propylcarbamoyl]-4-[[[(1S)-1-[[(1S)-1-[[(1S,2R)-4-[(2S)-2- [(1R,2R)-3-[[(1R,2S)-2-hydroxy-1-methyl-2-phenyl-ethyl]amino]-1-methoxy-2-methyl-3- oxo-propyl]pyrrolidin-1-yl]-2-methoxy-1-[(1S)-1-methylpropyl]-4-oxo-butyl]-methyl- carbamoyl]-2-methyl-propyl]carbamoyl]-2-methyl-
  • Step II Preparation of (2, 5-dioxopyrrolidin-1-yl) 2-[[2-(allyloxycarbonylamino)acetyl] amino]acetate.
  • N-Hydroxysuccinimide (1.86 g, 16.2 mmol) followed by 1-ethyl-3-(3-dimethylamino propyl)carbodiimide hydrochloride (3.1 g, 16.2 mmol) is added to stirred solution of 2-[[2- (allyloxycarbonylamino)acetyl]amino]acetic acid (2.0 g, 9.26 mmol) in N, N-dimethyl formamide (20 mL) at room temperature and stirred overnight. Reaction mixture is diluted with dichloromethane (100 mL). Combined organic layer is washed with D. M.
  • Step III Preparation of (2S)-2-[[2-[[2-(allyloxycarbonylamino)acetyl]amino] acetyl] amino]- 3-phenyl-propanoic acid.
  • reaction mixture (19.2 mL) is added dropwise to the reaction mixture at 0-5oC and stirred for 15 min. Reaction mixture is then allowed to attain room temperature and stirred overnight. Reaction mixture is again cooled to 0-5oC and acidified up to pH ⁇ 4 using 2N HCl solution. It is then extracted with ethyl acetate (3x50 mL).
  • Step IV Preparation of (2,5-dioxopyrrolidin-1-yl) (2S)-2-[[2-[[2-(allyloxycarbonylamino) acetyl]amino]acetyl]amino]-3-phenyl-propanoate N-Hydroxysuccinimide (1.96 g, 17.1 mmol) followed by 1-ethyl-3-(3-dimethylamino propyl)carbodiimide hydrochloride (3.26 g, 17.1 mmol) is added to stirred solution of (2S)-2- [[2-[[2-(allyloxycarbonylamino)acetyl]amino]acetyl]amino]-3-phenyl-propanoic acid (3.55 g, 9.76 mmol) in N, N-dimethyl formamide (35 mL) at room temperature and stirred overnight.
  • N-dimethyl formamide 35 mL
  • Reaction mixture is diluted with dichloromethane (150 mL). Combined organic layer is washed with D. M. water (1x50 mL) followed by brine solution (1x50 mL), dried over anhydrous sodium sulphate and concentrated under reduced pressure at 40oC to get (2,5- dioxopyrrolidin-1-yl) (2S)-2-[[2-[[2-(allyloxycarbonylamino)acetyl]amino]acetyl]amino]-3- phenyl-propanoate (4.7 gm), whichisused for the next step without purification.
  • Step V Preparation of 2-[[(2S)-2-[[2-[[2-(allyloxycarbonylamino)acetyl]amino]acetyl] amino]-3-phenyl-propanoyl]amino]acetic acid.
  • (2S)-2-[[2-[[2-(allyloxycarbonylamino)acetyl]amino]acetyl] amino]-3-phenyl-propanoate (4.7 gm, 10.2 mmol) is dissolved in a mixture of N, N-dimethyl formamide (33.7 mL) and tetrahydrofuran (47 mL) at room temperature and stirred.
  • Reaction mixture is cooled to 0-5oC.
  • a previously stirred clear solution of glycine (0.76 gm, 10.2 mmol) and triethylamine (1.42 mL, 10.2 mmol) in D. M. water (33.7 mL) is added dropwise to the reaction mixture at 0-5oC and stirred for 15 min. Reaction mixture is then allowed to attain room temperature and stirred overnight. Reaction mixture is again cooled to 0-5oC and acidified up to pH ⁇ 4 using 2N HCl solution. It is then extracted with ethyl acetate (3x100 mL).
  • Step VI Preparation of allyl N-[2-[[2-[[(1S)-1-benzyl-2-oxo-2-[[2-oxo-2-[(3-oxo-1H- isobenzofuran-5-yl)amino]ethyl]amino]ethyl]amino]-2-oxo-ethyl]amino]-2-oxo- ethyl]carbamate.
  • N-Ethoxycarbonyl-2-ethoxy-1, 2-dihydroquinoline (EEDQ, 1.24 g, 5.03 mmol) is added to a stirred solution of 2-[[(2S)-2-[[2-[[2-(allyloxycarbonylamino)acetyl]amino]acetyl]amino]-3- phenyl-propanoyl]amino]acetic acid (1.55 g, 3.7 mmol) and 6-amino-3H-isobenzofuran-1-one (0.5 gm, 3.36 mmol) in a mixture of dichloromethane (16 mL) and methanol (8 mL) and stirred overnight at room temperature.
  • Reaction mixture is concentrated at 40oC under reduced pressure. Diethyl ether (25 mL) is added to the crude product and stirred at room temperature for 30 min. Solid thus obtained is filtered, washed with diethyl ether. A mixture of ethyl acetate : n-hexane (75:25) is added to the solid residue and stirred at room temperature for 30 min.
  • Step VII Preparation of allyl N-[2-[[2-[[(1S)-1-benzyl-2-[[2-[3-[3-(dimethylamino) propylcarbamoyl]-4-(hydroxymethyl)anilino]-2-oxo-ethyl]amino]-2-oxo-ethyl]amino]-2-oxo- ethyl]amino]-2-oxo-ethyl]carbamate.
  • N', N'-Dimethylpropane-1,3-diamine (2.1 mL) is added to allyl N-[2-[[2-[[(1S)-1-benzyl-2- oxo-2-[[2-oxo-2-[(3-oxo-1H-isobenzofuran-5-yl)amino]ethyl]amino]ethyl]amino]-2-oxo- ethyl]amino]-2-oxo-ethyl]carbamate (0.7 gm, 1.81 mmol) at room temperature and then the reaction mixture is heated at 85oC for 2 hours.
  • Reaction mixture is concentrated under reduced pressure at 50oC to get crude product, which is purified by column chromatography (silica gel 230-400 mesh; dichloromethane: methanol: ammonia, 83:15:2) to get allyl N-[2-[[2-[[(1S)-1- benzyl-2-[[2-[3-[3-(dimethylamino) propylcarbamoyl]-4-(hydroxymethyl)anilino]-2-oxo- ethyl]amino]-2-oxo-ethyl]amino]-2-oxo-ethyl]amino]-2-oxo-ethyl]amino]-2-oxo-ethyl]carbamate (0.6 gm).
  • Step VIII Preparation of [4-[[2-[[(2S)-2-[[2-[[2-(allyloxycarbonylamino)acetyl]amino] acetyl]amino]-3-phenyl-propanoyl]amino]acetyl]amino]-2-[3-(dimethylamino)propyl carbamoyl]phenyl]methyl (4-nitrophenyl) carbonate.
  • N, N-Diisopropylethylamine (0.48 mL, 2.75 mmol) is added to stirred solution of allyl N-[2- [[2-[[(1S)-1-benzyl-2-[[2-[3-[3-(dimethylamino)propylcarbamoyl]-4-(hydroxymethyl) anilino]-2-oxo-ethyl]amino]-2-oxo-ethyl]amino]-2-oxo-ethyl]amino]-2-oxo-ethyl]amino]-2-oxo-ethyl]carbamate (0.6 g, 0.92 mmol) in tetrahydrofuran (6 mL) at room temperature.
  • Bis(4-nitrophenyl)carbonate ( 0.5 g, 1.61 mmol) is added to the reaction mixture and stirred for 5 hrs. Reaction mixture is concentrated under reduced pressure at 40 0 C. Diethyl ether (20 mL) is added to the residue and stirred at room temperature for 45 min. Diethyl ether is decanted off.
  • Step IX Preparation of [4-[[2-[[(2S)-2-[[2-[[2-(allyloxycarbonylamino)acetyl]amino] acetyl]amino]-3-phenyl-propanoyl]amino]acetyl]amino]-2-[3-(dimethylamino)propyl carbamoyl]phenyl]methyl N-[(1S)-1-[[(1S)-1-[[(1S,2R)-4-[(2S)-2-[(1R,2R)-3-[[(1R,2S)-2- hydroxy-1-methyl-2-phenyl-ethyl]amino]-1-methoxy-2-methyl-3-oxo-propyl]pyrrolidin-1- yl]-2-methoxy-1-[(1S)-1-methylpropyl]-4-oxo-butyl]-methyl-carbamoyl]-2-me
  • Step X Preparation of [4-[[2-[[(2S)-2-[[2-[(2-aminoacetyl)amino]acetyl]amino]-3-phenyl- propanoyl]amino]acetyl]amino]-2-[3-(dimethylamino)propylcarbamoyl]phenyl] methyl N- [(1S)-1-[[(1S)-1-[[(1S,2R)-4-[(2S)-2-[(1R,2R)-3-[[(1R,2S)-2-hydroxy-1-methyl-2-phenyl- ethyl]amino]-1-methoxy-2-methyl-3-oxo-propyl]pyrrolidin-1-yl]-2-methoxy-1-[(1S)-1- methylpropyl]-4-oxo-butyl]-methyl-carbamoyl]-2-methyl-methyl-
  • Step XI Preparation of N-[2-[2-[2-(2-azidoethoxy)ethoxy]ethoxy]ethyl]-4-(4-methoxy phenyl)butanamide.
  • N N-Diisopropylethylamine (1.8 mL, 10.3 mmol) is added to stirred solution of 4-(4- methoxyphenyl)butanoic acid (0.8 gm, 4.12 mmol), 2-[2-[2-(2-azidoethoxy)ethoxy]ethoxy] ethanamine (1.0 gm, 4.53 mmol)
  • Synthesis reference Journal of Organic Chemistry, 1991, vol. 56, # 13, p.
  • Step XII Preparation of N-[2-[2-[2-(2-aminoethoxy)ethoxy]ethoxy]ethyl]-4-(4-methoxy phenyl)butanamide.
  • Triphenyl phosphine (0.96 gm, 4.02 mmol) is added to a stirred solution of N-[2-[2-[2-(2- azidoethoxy)ethoxy]ethoxy]ethyl]-4-(4-methoxy phenyl) butanamide (1.32 gm, 3.35 mmol) in tetrahydrofuran (20 mL) at room temperature and stirred overnight.
  • Step XIII Preparation of benzyl (2S)-2-(benzyloxycarbonylamino)-5-[2-[2-[2-[2-[4-(4- methoxyphenyl)butanoylamino]ethoxy]ethoxy]ethylamino]-5-oxo-pentanoate.
  • N, N-Diisopropylethylamine (0.84 mL, 4.89 mmol) is added to stirred solution of N-[2-[2-[2- (2-aminoethoxy)ethoxy]ethoxy]ethyl]-4-(4-methoxyphenyl)butanamide (0.72 gm, 1.95 mmol), (4S)-5-benzyloxy-4-(benzyloxycarbonylamino)-5-oxo-pentanoic acid (0.8 gm, 2.15 mmol) and O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU, 0.94 gm, 2.93 mmol) in N, N-dimethylformamide (8 mL) at room temperature and stirred for 5 hrs.
  • Step XIV Preparation of (2S)-2-amino-5-[2-[2-[2-[2-[4-(4-methoxyphenyl)butanoylamino] ethoxy]ethoxy]ethylamino]-5-oxo-pentanoic acid 10% Palladium on charcoal (50% wet) (0.24 g) is added to a stirred solution of benzyl (2S)-2- (benzyloxycarbonylamino)-5-[2-[2-[2-[2-[2-[4-(4-methoxyphenyl)butanoylamino]ethoxy] ethoxy]ethylamino]-5-oxo-pentanoate (1.2 g, 1.66 mmol) in methanol (10 mL).
  • Reaction mixture is stirred under hydrogen pressure applied through a balloon filled with hydrogen gas at room temperature for 3 hrs.
  • Reaction mixture is filtered through celite bed and washed with methanol (2x50 mL). Combined filtrate is concentrated under reduced pressure to get (2S)-2-amino-5-[2-[2-[2-[2-[4-(4-methoxyphenyl)butanoylamino]ethoxy]ethoxy] ethylamino]-5-oxo-pentanoic acid (0.72 gm), which is used for the next step without purification.
  • Step XV Preparation of (2S)-2-(allyloxycarbonylamino)-5-[2-[2-[2-[2-[4-(4-methoxy phenyl)butanoylamino]ethoxy]ethoxy]ethylamino]-5-oxo-pentanoic acid.
  • Step XVI Preparation of [4-[[(2S)-2-[[(2S)-2-[[(2S)-2-(allyloxycarbonylamino)-5-[2-[2-[2-[2-[2-[2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethyl amino]-5- oxo-pentanoyl]amino]-3-methyl-butanoyl]amino]-5-ureido-pentanoyl]amino]-2-[3- (dimethylamino)propylcarbamoyl]phenyl]methyl N-[(1S)-1-[[(1S)-1-[[(1S,2R)-4-[(2S)-2- [(1R,2R)-3-[[(1R,2S)-2-hydroxy-1-methyl-2-phenyl-ethyl]amino]-1
  • Step XVII Preparation of [4-[[2-[[(2S)-2-[[2-[[2-[[[(2S)-2-amino-5-[2-[2-[2-[4-(4- methoxyphenyl)butanoylamino]ethoxy]ethoxy]ethylamino]-5-oxo-pentanoyl] amino]acetyl]amino]acetyl]amino]-3-phenyl-propanoyl]amino]acetyl]amino]-2-[3- (dimethylamino)propylcarbamoyl]phenyl]methyl N-[(1S)-1-[[(1S)-1-[[(1S,2R)-4-[(2S)-2- [(1R,2R)-3-[[(1R,2S)-2-hydroxy-1-methyl-2-phenyl-ethyl]amino]-1-me
  • Step XVIII Preparation of (2S)-2-[[(1S)-5-[[(2S)-2-[[4-[[[5-[[(1S)-1-[[2-[[2-[[(1S)-1-benzyl- 2-[[2-[3-[3-(dimethylamino)propylcarbamoyl]-4-[[[(1S)-1-[[(1S)-1-[[(1S,2R)-4-[(2S)-2- [(1R,2R)-3-[[(1R,2S)-2-hydroxy-1-methyl-2-phenyl-ethyl]amino]-1-methoxy-2-methyl-3- oxo-propyl]pyrrolidin-1-yl]-2-methoxy-1-[(1S)-1-methylpropyl]-4-oxo-butyl]-methyl- carbamoyl]-2-methyl-propyl]carbamoyl]-2-methyl
  • Compound no. 1.80 was made in an analogous manner as the synthetic procedures provided above in Example 13; 1.80: mass (m/z) 830.34 [M+3H]3+
  • Example 14 Biological Studies PC3-PIP cell lines were a generous gift from the Pomper Lab at Johns Hopkins University (USA). Cells were selected by bleomycin and sorted by FACS. Cells were seeded at 1000 cells/well in 96-well plates, 24 hrs prior to the addiction of the compounds. All compounds were diluted three times from 10 ⁇ M into 7 concentrations that varied from 0.01 nM to 1000 nM. The concentration ranges were further optimized after first test data to cover the best concentration ranges.

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Abstract

La présente invention concerne de manière générale des conjugués ligand-médicament de formule I : ou des sels, stéréoisomères ou isotopes pharmaceutiquement acceptables de ceux-ci. L'invention concerne en outre l'utilisation du composé de formule I, pour le traitement du cancer.
EP24701053.1A 2023-01-10 2024-01-09 Conjugués ligand-médicament Pending EP4648799A1 (fr)

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US6528499B1 (en) 2000-04-27 2003-03-04 Georgetown University Ligands for metabotropic glutamate receptors and inhibitors of NAALADase
CA2367787C (fr) 1999-04-28 2011-07-26 Alan P. Kozikowski Ligands pour recepteurs metabotropes du glutamate
CA2473289C (fr) 2002-01-10 2014-07-29 The Johns Hopkins University Composes d'uree asymetriques utiles en tant qu'agents d'imagerie naaladase et psma
WO2006093991A1 (fr) 2005-03-02 2006-09-08 The Cleveland Clinic Foundation Composes se liant a l'antigene membranaire specifique de la prostate (psma) et utilisations associees
PT2097111E (pt) 2006-11-08 2015-11-03 Molecular Insight Pharm Inc Heterodímeros de ácido glutámico
PL2187965T3 (pl) 2007-08-17 2020-05-18 Purdue Research Foundation Koniugaty wiążący psma ligand-łącznik i sposoby ich zastosowania
DK3222615T3 (da) 2008-08-01 2022-06-20 Univ Johns Hopkins Psma-bindende stoffer og anvendelser deraf
PL3964502T3 (pl) 2009-03-19 2024-10-28 The Johns Hopkins University Związki do kierunkowania w psma i ich zastosowania
EP2862857A1 (fr) 2013-10-18 2015-04-22 Deutsches Krebsforschungszentrum Inhibiteurs marqués de l'antigène membranaire spécifique de la prostate (PSMA), leur utilisation comme agents d'imagerie et agents pharmaceutiques pour le traitement du cancer de la prostate
MY194484A (en) 2013-10-18 2022-11-30 Deutsches Krebsforsch Labeled Inhibitors of Prostate Specific Membrane Antigen (PSMA), Their use as Imaging Agents and Pharmaceutical Agents for the Treatment of Prostate Cancer
WO2016062370A1 (fr) 2014-10-20 2016-04-28 Deutsches Krebsforschungszentrum Inhibiteurs à marquage 18f- de l'antigène membranaire spécifique de la prostate (psma), leur utilisation comme agents d'imagerie et agents pharmaceutiques pour le traitement du cancer de la prostate
RU2697519C1 (ru) 2018-10-15 2019-08-15 Общество с ограниченной ответственностью "Изварино Фарма" Средство пептидной природы, включающее псма-связывающий лиганд на основе производного мочевины, способ его получения и применение для получения конъюгата с лекарственным и диагностическим агентом
DE102018126558A1 (de) 2018-10-24 2020-04-30 Helmholtz-Zentrum Dresden - Rossendorf E.V. Markierungsvorläufer mit Quadratsäure-Kopplung
RU2729192C1 (ru) 2019-11-22 2020-08-05 Общество с ограниченной ответственностью "Изварино Фарма" Конъюгат монометил ауристатина е для получения композиции для лечения рака предстательной железы
JP2023547105A (ja) * 2020-10-20 2023-11-09 ザ ボード オブ リージェンツ オブ ザ ユニバーシティー オブ テキサス システム 炎症促進性プロドラッグ
WO2022108992A1 (fr) 2020-11-17 2022-05-27 The Johns Hopkins University Promédicament ciblant l'antigène membranaire spécifique de la prostate (psma) pour tuer sélectivement des cellules exprimant le psma

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