Classifications

• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

• the invention relates generally to compounds that modulate the activity of CXCR4, pharmaceutical compositions containing said compounds and methods of treating proliferative disorders and disorders of dysregulated apoptosis, such as cancer, utilizing the compounds of the invention.
• Chemokines are a family of about 50 small proteins that modulate cell trafficking and angiogenesis and also play a significant role in the tumor microenvironment (Vicari et al, 2002, Cytokine Growth Factor Rev, 13: 143-154). Depending on their structure, chemokines are classified as C-C chemokines (containing a cysteine-cysteine motif) or C- X-C chemokines (containing a cysteine-X-cysteine motif). Receptors that bind such chemokines thus are classified as members of the CCR family or CXCR family, respectively.
• CXCR4 plays a role in embryogenesis, homeostasis and inflammation. Studies with mice engineered to be deficient in CXCR4 or SDF-1 implicate the CXCR4/SDF-1 pathway in organ vascularization, as well as in the immune and hematopoietic systems (Tachibana et al, 1998, Nature, 393:591-594). Moreover, CXCR4 has been shown to function as a coreceptor for T lymphotrophic HIV-1 isolates (Feng et al, 1996, Science, 272:872-877). CXCR4 also has been shown to be expressed on a wide variety of cancer cell types.
• CXCR4/SDF-1 pathway has been shown to be involved in stimulating the metastatic process in many different neoplasms (Murphy, 2001, N Eng. J Med, 345 : 833-835).
• CXCR4 and SDF-1 have been shown to mediate organ-specific metastasis by creating a chemotactic gradient between the primary tumor site and the metastatic site (Muller et al, 2001, Nature, 410:50-56; Murakami et al, 2002, Cancer Res, 62:7328-7334; Hanahan et al, 2003, Cancer Res, 63:3005-3008).
• R 4 is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, (R 7 )alkyl, ((R 7 )cycloalkyl)alkyl, (((R 7 )cycloalkyl)alkyl, (R 7 )cycloalkyl, or ((R 7 )alkyl)cycloalkyl;
• R 7 is (R 8 )(R 9 )N; or R 7 is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, homopiperidinyl, homopiperazinyl, or octahydropyrrolopyrazinyl, and is substituted with 0-3 halo or alkyl substituents; R 8 is hydrogen or alkyl; R 9 is hydrogen or alkyl;
• R 5 is hydrogen, halo, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, haloalkoxy, (R 7 )alkyl, ((R 7 )cycloalkyl)alkyl, (((R 7 )cycloalkyl)cycloalkyl)alkyl, (R 7 )cycloalkyl, or
• R 8 is hydrogen or alkyl
• R 1 is hydrogen, halo, alkyl, haloalkyl, alkoxy, or haloalkoxy;
• R 5 is hydrogen, halo, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, alkoxy, or haloalkoxy
• R 6 is hydrogen, alkyl, alkoxy, or alkylthio
• R 6 is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, homopiperidinyl, or homopiperazinyl, and is substituted with 0-1 substituents selected from halo, alkyl, (cycloalkyl)alkyl, (tetrahydropyranyl)alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl,
• R 7 alkyl, carboxyalkyl, (alkoxy carbonyl)alkyl, (Ar ⁇ alkyl, diphenylalkyl, cycloalkyl, R 7 , alkylcarbonyl, alkoxy carbonyl, alkylaminocarbonyl, (Ar 2 )aminocarbonyl, alkylsulfonyl, (Ar 2 )sulfonyl, and Ar 2 , and is also substituted with 0-3 halo or alkyl substituents;
• Ar 1 is pyrrolyl, furanyl, thienyl, pyrazolyl, isoxazolyl, isothiazolyl, imidazoyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, phenyl, or biphenyl and is substituted with 0-3 substituents selected from cyano, halo, alkyl, haloalkyl, hydroxy, alkoxy, haloalkoxy, phenoxy, and (R 8 )(R 9 )N; and
• Another aspect of the invention is a compound of formula I where R 6 is alkoxy, or alkylthio.
• Heteroaryl means a 5 to 7 membered monocyclic or 8 to 11 membered bicyclic aromatic ring system with 1 -5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Where a bonding attachment location is not specified, the bonding may be attached at any appropriate location as understood by practitioners in the art. Combinations of substituents and bonding patterns are only those that result in stable compounds as understood by practitioners in the art. Parenthetic and multiparenthetic terms are intended to clarify bonding relationships to those skilled in the art. For example, a term such as ((R)alkyl) means an alkyl substituent further substituted with the substituent R.
• the invention includes all pharmaceutically acceptable salt forms of the compounds.
• compositions, and/or dosage forms which are within the scope of sound medical judgment as understood by practitioners in the field.
• Patient means an animal suitable for therapy as understood by practitioners in the field.
• Compositions for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient.
• a compound of the present invention may also be administered as a bolus, electuary or paste.
• the pharmaceutical compositions may also comprise buffering agents.
• Solid compositions of a similar type may also be employed as fillers in soft and hard shelled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
• a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
• Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface active or dispersing agent.
• Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
• compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner.
• embedding compositions which can be used include polymeric substances and waxes.
• the active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above described excipients.
• Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
• the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 ,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
• inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol
• Dosage forms for topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
• the active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required.
• compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms upon the subject compounds may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the inj ectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.
• adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents.
• compositions containing, for example, 0.1 to 99% (more preferably, 10 to 30%) of active ingredient in combination with a pharmaceutically acceptable carrier.
• a suitable daily dose of a compound of the invention will be that amount of the compound which is the lowest dose effective to produce a therapeutic effect.
• Such an effective dose will generally depend upon the factors described above.
• oral, intravenous, intracerebroventricular and subcutaneous doses of the compounds of this invention for a patient will range from about 0.01 to about 50 mg per kilogram of body weight per day.
• compounds of the invention may be co-formulated with an immuno-oncology agent.
• Immuno-oncology agents include, for example, a small molecule drug, antibody, or other biologic or small molecule.
• biologic immuno-oncology agents include, but are not limited to, cancer vaccines, antibodies, and cytokines.
• the antibody is a monoclonal antibody. In another aspect, the monoclonal antibody is humanized or human.
• the immuno-oncology agent is a LAG-3 antagonist, such as an antagonistic LAG-3 antibody.
• LAG3 antibodies include, for example, BMS-986016 (WO 10/19570, WO 14/08218), or IMP-731 or IMP-321 (WO08/132601, WO09/44273).
• the immuno-oncology agent is a GITR agonist, such as an agonistic GITR antibody.
• GITR antibodies include, for example, BMS-986153, BMS-986156, TRX-518 (WO06/105021, WO09/009116) and MK-4166 (WOl 1/028683).
• the immuno-oncology agent is a CD27 agonist, such as an agonistic CD27 antibody.
• Suitable CD27 antibodies include, for example, varlilumab.
• TNF family of molecules that bind to cognate TNF receptor family members which includes CD40 and CD40L, OX-40, OX-40L, CD70, CD27L, CD30, CD30L, 4-1BBL, CD137 (4-1BB), TRAIL/Apo2-L,
• the immuno-oncology agent is a LAG-3 antagonist, such as an antagonistic LAG-3 antibody.
• LAG3 antibodies include, for example, BMS-986016 (WO 10/19570, WO 14/08218), or IMP-731 or IMP-321 (WO08/132601, WO09/44273).
• Substantially simultaneous administration can be accomplished, for example, by administering to the subject a single dosage form having a fixed ratio of each therapeutic agent or in multiple, single dosage forms for each of the therapeutic agents.
• Sequential or substantially simultaneous administration of each therapeutic agent can be effected by any appropriate route including, but not limited to, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucous membrane tissues.
• the therapeutic agents can be administered by the same route or by different routes.
• a first therapeutic agent of the combination selected may be administered by intravenous injection while the other therapeutic agents of the combination may be administered orally.
• all therapeutic agents may be administered orally or all therapeutic agents may be administered by intravenous injection.
• Compounds 3 can be prepared by coupling fragments 1 and 2 by reductive amination as shown in Scheme 1. Reaction of aldehyde 1 with amine 2 in the presence of a reducing agent such as sodium triacetoxyborohydride provides 3. Such reactions may be run in the presence or absence of an acid, such as acetic acid.
• a reducing agent such as sodium triacetoxyborohydride
• aldehyde 1 may be prepared as illustrated in Scheme 3.
• the mixture was diluted with ethyl acetate, filtered through anhydrous sodium sulfate, and the filtrate concentrated.
• the crude product mixture was purified by a silica gel ISCO 12 g column, eluting with 0 - 100 % of ethyl acetate / DCM over a 15 minute gradient. The appropriate fractions were isolated and concentrated in vacuo to afford the product (60 mg, 18 % yield) as a solid.
• Exemplary compounds of the invention were tested for their ability to induce or inhibit calcium flux in CCRF-CEM cells. Experimental procedures and results are provided below. The exemplified biological assays, which follow, have been carried out with compounds of the invention and/or salts thereof.
• CXCR4-CEM Calcium Flux Assays Human T lymphoblast cells (CCRF-CEM) expressing endogenous CXCR4 receptors were grown in suspension culture and plated in clear bottom 384-well microplates (Greiner bio-one Cat# 789146) in assay buffer
• ECso values were determined.
• the ECso is defined as the concentration of test compound which produces 50% of the maximal response and was quantified using the 4-parameter logistic equation to fit the data.
• Inhibition data for the test compound over a range of concentrations was plotted as percentage inhibition of the test compound as compared to an internal control compound.
• the ICso is defined as the concentration of test compound which inhibits 50% of the maximal response and was quantified using the 4-parameter logistic equation to fit the data. None of the compounds tested demonstrated agonist acitivity in the calcium flux assay. All compounds demonstrated EC50's of >30 uM. In contrast, compounds demonstrated a range of potencies in inhibiting SDF-l a-induced calcium flux as shown in the table below.

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• 2016
  • 2016-12-14 WO PCT/US2016/066575 patent/WO2017106291A1/en not_active Ceased
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