WO2018039521A1 - Cénicriviroc deutéré - Google Patents

Cénicriviroc deutéré Download PDF

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Publication number
WO2018039521A1
WO2018039521A1 PCT/US2017/048549 US2017048549W WO2018039521A1 WO 2018039521 A1 WO2018039521 A1 WO 2018039521A1 US 2017048549 W US2017048549 W US 2017048549W WO 2018039521 A1 WO2018039521 A1 WO 2018039521A1
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Prior art keywords
compound
cancer
same
deuterium
pharmaceutically acceptable
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PCT/US2017/048549
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English (en)
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Darren H. WONG
Julie F. Liu
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Concert Pharmaceuticals, Inc.
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Publication of WO2018039521A1 publication Critical patent/WO2018039521A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D225/00—Heterocyclic compounds containing rings of more than seven members having one nitrogen atom as the only ring hetero atom
    • C07D225/04—Heterocyclic compounds containing rings of more than seven members having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D225/06—Heterocyclic compounds containing rings of more than seven members having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with heterocyclic ring 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • A61K31/5517—1,4-Benzodiazepines, e.g. diazepam or clozapine condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • 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

Definitions

  • ADME absorption, distribution, metabolism and/or excretion
  • ADME limitation that affects many medicines is the formation of toxic or biologically reactive metabolites.
  • some patients receiving a drug may experience toxicities, or the safe dosing of such drugs may be limited such that patients receive a suboptimal amount of the active agent.
  • modifying dosing intervals or formulation approaches can help to reduce clinical adverse effects, but often the formation of such undesirable metabolites is intrinsic to the metabolism of the compound.
  • a metabolic inhibitor will be co-administered with a drug that is cleared too rapidly.
  • a drug that is cleared too rapidly.
  • the FDA recommends that these drugs be co-dosed with ritonavir, an inhibitor of cytochrome P450 enzyme 3A4 (CYP3A4), the enzyme typically responsible for their metabolism (see Kempf, D.J. et al., Antimicrobial agents and chemotherapy, 1997, 41(3): 654-60).
  • CYP3A4 cytochrome P450 enzyme 3A4
  • Ritonavir causes adverse effects and adds to the pill burden for HIV patients who must already take a combination of different drugs.
  • the CYP2D6 inhibitor quinidine has been added to dextromethorphan for the purpose of reducing rapid CYP2D6 metabolism of dextromethorphan in a treatment of pseudobulbar affect.
  • Quinidine has unwanted side effects that greatly limit its use in potential combination therapy (see Wang, L. et al., Clinical Pharmacology and
  • cytochrome P450 inhibitors In general, combining drugs with cytochrome P450 inhibitors is not a satisfactory strategy for decreasing drug clearance.
  • the inhibition of a CYP enzyme’s activity can affect the metabolism and clearance of other drugs metabolized by that same enzyme. CYP inhibition can cause other drugs to accumulate in the body to toxic levels.
  • a potentially attractive strategy for improving a drug’s metabolic properties is deuterium modification.
  • Deuterium is a safe, stable, non-radioactive isotope of hydrogen. Compared to hydrogen, deuterium forms stronger bonds with carbon. In select cases, the increased bond strength imparted by deuterium can positively impact the ADME properties of a drug, creating the potential for improved drug efficacy, safety, and/or tolerability.
  • the size and shape of deuterium are essentially identical to those of hydrogen, replacement of hydrogen by deuterium would not be expected to affect the biochemical potency and selectivity of the drug as compared to the original chemical entity that contains only hydrogen.
  • This invention relates to deuterated forms of cenicriviroc, also known as TAK- 652, and by the chemical name (-)-(S)-8-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-(1- propyl-1H-imidazol-5-ylmethylsulfinyl)phenyl]-1,2,3,4-tetrahydro-1-benzazocine-5- carboxamide methanesulfonate, the racemic and (R) forms thereof, free base forms of any of the foregoing and pharmaceutically acceptable salts of the free base forms.
  • the invention provides a compound of Formula I:
  • each of R 1 , R 2a , R 2b and R 3 is independently selected from -CH 3 , -CH 2 D, -CHD 2 , and -CD 3 ;
  • each of Y 1a , Y 1b , Y 2a , Y 2b , Y 3a , Y 3b , Y 4a , Y 4b , Y 5a , Y 5b , Y 6a , Y 6b , Y 7 , Y 8a , Y 8b , Y 9a , Y 9b , Y 10a , Y 10b , Y 11a , Y 11b , Y 12a , Y 12b , Y 13a , Y 13b , Y 14a , Y 14b , Y 15a , Y 15b , Y 16 , Y 17 , Y 18 , Y 19 , Y 20a , Y 20b , Y 21a , Y 21b , Y 22 , and Y 23 is independently selected from hydrogen and deuterium; and when each of R 1 , R 2a , R 2b
  • compositions comprising a compound of this invention, including pharmaceutical compositions comprising a compound of this invention and a pharmaceutically acceptable carrier.
  • This invention also provides the use of such compounds and compositions in methods of treating diseases and conditions that are beneficially treated by administering a CCR5 antagonist, a CCR2 antagonist, or a dual CCR2/CCR5 antagonist.
  • Some exemplary embodiments include a method of treating a disease or condition selected from HIV infection, non-alcoholic steatohepatitis (NASH), primary sclerosing cholangitis, and obesity, the method comprising the step of administering to a subject in need thereof a compound, a pharmaceutically acceptable salt or
  • Some exemplary embodiments include a method of treating cancer, comprising the step of administering to the subject an effective amount of a compound, a pharmaceutically acceptable salt or a pharmaceutically acceptable composition of the present invention, in combination with one or more immune checkpoint inhibitors. Some exemplary embodiments include a method of treating cancer, comprising the step of administering to the subject an effective amount of a compound, a pharmaceutically acceptable salt or a pharmaceutically acceptable composition of the present invention, in combination with one or more focal adhesion kinase (FAK) antagonists. Some exemplary embodiments include a method of treating cancer, comprising the step of administering to the subject an effective amount of a compound, a
  • Cenicriviroc also known as TAK-652, and by the chemical name (-)-(S)-8-[4-(2- butoxyethoxy)phenyl]-1-isobutyl-N-[4-(1-propyl-1H-imidazol-5-ylmethylsulfinyl)phenyl]- 1,2,3,4-tetrahydro-1-benzazocine-5-carboxamide methanesulfonate, is an orally active C-C chemokine receptor type 2 (CCR2) and type 5 (CCR5) antagonist.
  • CCR2 CCR2
  • CCR5 type 5
  • Cenicriviroc is currently in phase III clinical trials for the treatment of non- alcoholic steatohepatitis (NASH) in adult patients with liver fibrosis, including patients with type 2 diabetes, and in phase II clinical trials for the treatment of HIV infection in
  • antiretroviral treatment na ⁇ ve patients in combination with TRUVADA® (emtricitabine and tenofovir disoproxil fumarate), the treatment of HIV infection in antiretroviral therapy experienced but CCR5 antagonist na ⁇ ve patients, the treatment of obesity in patients with prediabetes or type 2 diabetes and suspected non-alcoholic fatty liver disease, and the treatment of primary sclerosing cholangitis (PSC).
  • Cenicriviroc is also in phase I clinical trials for the treatment of non-alcoholic steatohepatitis (NASH) in combination with pioglitazone. Cenicriviroc is in preclinical studies for the treatment of rheumatoid arthritis.
  • NASH non-alcoholic steatohepatitis
  • Cenicriviroc is in preclinical studies for the treatment of rheumatoid arthritis.
  • the receptors CCR2 and CCR5 are known to bind chemokines CCL2, CCL3, CCL4, CCL5 and CCL8 (CCR2 binds CCL2 and CCR5 binds CCL3, CCL4, CCL5 and CCL8). These chemokines are generated by tumors and attract inhibitory immune cells (e.g., regulatory T cells, tumor associated macrophages and myeloid derived suppressor
  • immune inhibitory cells prevent activated tumoricidal immune cells from efficiently killing cancer cells. While inhibiting either receptor alone may be sufficient for preventing the establishment of an immunosuppressive tumor environment, the combination of the two may more efficiently prevent the accumulation of inhibitor immune cells within the tumor.
  • Immune checkpoint inhibitors are designed to facilitate the generation of an immune response against a tumor. However, many immune checkpoint inhibitors are not efficient in generating an immune response due to the immunosuppressive environment found in a tumor. A combination of a compound of this invention with an immune checkpoint inhibitor may prove beneficial for the treatment of cancer.
  • Focal adhesion kinase or FAK plays a central role in the development and survival of cancer stem cells and it has been found that FAK expression is greater in some highly invasive and metastatic tumors.
  • FAK antagonist therapies are part of a relatively small percentage of the patients with cancer. Not all cancers are impacted by these therapies and not all of the responding population experiences complete or optimal therapy.
  • a combination of a compound of this invention with a FAK inhibitor may prove beneficial for the treatment of cancer.
  • a combination of a compound of this invention with an immune checkpoint inhibitor and a FAK inhibitor may prove beneficial for the treatment of cancer.
  • treat means decrease, suppress, attenuate, diminish, arrest, or stabilize the development or progression of a disease (e.g., a disease or disorder delineated herein), lessen the severity of the disease or improve the symptoms associated with the disease.
  • a disease e.g., a disease or disorder delineated herein
  • Disease means any condition or disorder that damages or interferes with the normal function of a cell, tissue, or organ.
  • the term“subject” includes humans and non-human
  • Non-limiting examples of non-human mammals include mice, rats, guinea pigs, rabbits, dogs, cats, monkeys, apes, pigs, cows, sheep, horses, etc.
  • any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom.
  • the position is understood to have hydrogen at its natural abundance isotopic composition.
  • the position has at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% hydrogen.
  • a position when a position is designated specifically as“H” or“hydrogen”, the position incorporates ⁇ 20% deuterium, ⁇ 10% deuterium, ⁇ 5% deuterium, ⁇ 4% deuterium, ⁇ 3% deuterium, ⁇ 2% deuterium, or ⁇ 1% deuterium. Also unless otherwise stated, when a position is designated specifically as“D” or “deuterium”, the position is understood to have deuterium at an abundance that is at least 3340 times greater than the natural abundance of deuterium, which is 0.015% (i.e., at least 50.1% incorporation of deuterium).
  • isotopic enrichment factor means the ratio between the isotopic abundance and the natural abundance of a specified isotope.
  • a compound of this invention has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).
  • each designated deuterium atom has deuterium incorporation of at least 52.5%.
  • each designated deuterium atom has deuterium incorporation of at least 60%.
  • each designated deuterium atom has deuterium incorporation of at least 67.5%.
  • each designated deuterium atom has deuterium incorporation of at least 75%.
  • each designated deuterium atom has deuterium incorporation of at least 82.5%.
  • each designated deuterium atom has deuterium incorporation of at least 90%.
  • each designated deuterium atom has deuterium incorporation of at least 95%.
  • each designated deuterium atom has deuterium incorporation of at least 97.5%.
  • each designated deuterium atom has deuterium incorporation of at least 99%.
  • each designated deuterium atom has deuterium incorporation of at least 99.5%.
  • isotopologue refers to a species in which the chemical structure differs from a specific compound of this invention only in the isotopic composition thereof.
  • a compound represented by a particular chemical structure containing indicated deuterium atoms will also contain lesser amounts of isotopologues having hydrogen atoms at one or more of the designated deuterium positions in that structure.
  • the relative amount of such isotopologues in a compound of this invention will depend upon a number of factors including the isotopic purity of deuterated reagents used to make the compound and the efficiency of incorporation of deuterium in the various synthesis steps used to prepare the compound.
  • the invention also provides salts of the compounds of the invention.
  • a salt of a compound of this invention is formed between an acid and a basic group of the compound, such as an amino functional group, or a base and an acidic group of the compound, such as a carboxyl functional group.
  • the compound is a pharmaceutically acceptable acid addition salt.
  • the acid addition salt may be a deuterated acid addition salt.
  • A“pharmaceutically acceptable,” as used herein, refers to a component that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and other mammals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.
  • A“pharmaceutically acceptable salt” means any non-toxic salt that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention.
  • A“pharmaceutically acceptable counterion” is an ionic portion of a salt that is not toxic when released from the salt upon administration to a recipient.
  • Acids commonly employed to form pharmaceutically acceptable salts include inorganic acids such as hydrogen bisulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid, as well as organic acids such as para-toluenesulfonic acid, salicylic acid, tartaric acid, bitartaric acid, ascorbic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, para- bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid and acetic acid, as well as related inorganic and organic acids.
  • Such pharmaceutically acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite
  • pharmaceutically acceptable acid addition salts include those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and especially those formed with organic acids such as maleic acid.
  • the acids commonly employed to form pharmaceutically acceptable salts include the above-listed inorganic acids, wherein at least one hydrogen is replaced with deuterium.
  • the compounds of the present invention contain an asymmetric sulfur atom (i.e., at the sulfoxide moiety).
  • the compounds of the present invention may also contain an asymmetric carbon atom, for example, as the result of deuterium substitution or otherwise.
  • compounds of this invention can exist as either individual enantiomers, or mixtures of the two enantiomers, individual diastereomers, or mixtures of diastereomers.
  • a compound of the present invention may exist as either a racemic mixture or a scalemic mixture, a mixture of diastereomers, or as individual respective stereoisomers that are substantially free from another possible stereoisomer.
  • “Stereoisomer” refers to both enantiomers and diastereomers.
  • the term“substantially free of other stereoisomers” as used herein means less than 25% of other stereoisomers, preferably less than 10% of other stereoisomers, more preferably less than 5% of other stereoisomers and most preferably less than 2% of other stereoisomers are present.
  • stable compounds refers to compounds which possess stability sufficient to allow for their manufacture and which maintain the integrity of the compound for a sufficient period of time to be useful for the purposes detailed herein (e.g., formulation into therapeutic products, intermediates for use in production of therapeutic compounds, isolatable or storable intermediate compounds, treating a disease or condition responsive to therapeutic agents).
  • Substituted with deuterium refers to the replacement of one or more hydrogen atoms with a corresponding number of deuterium atoms.
  • variable may be referred to generally (e.g.,"each R") or may be referred to specifically (e.g., R 1 , R 2 , R 3 , etc.). Unless otherwise indicated, when a variable is referred to generally, it is meant to include all specific embodiments of that particular variable.
  • each of R 1 , R 2a , R 2b and R 3 is independently selected from -CH 3 , -CH 2 D, -CHD 2 , and -CD 3 ;
  • each of Y 1a , Y 1b , Y 2a , Y 2b , Y 3a , Y 3b , Y 4a , Y 4b , Y 5a , Y 5b , Y 6a , Y 6b , Y 7 , Y 8a , Y 8b , Y 9a , Y 9b , Y 10a , Y 10b , Y 11a , Y 11b , Y 12a , Y 12b , Y 13a , Y 13b , Y 14a , Y 14b , Y 15a , Y 15b , Y 16 , Y 17 , Y 18 , Y 19 , Y 20a , Y 20b , Y 21a , Y 21b , Y 22 , and Y 23 is independently selected from hydrogen and deuterium; and when each of R 1 , R 2a , R 2b
  • At least one of Y 14a , Y 14b , Y 15a , Y 15b , Y 16 , Y 17 , Y 18 , Y 19 , Y 20a , Y 20b , Y 21a , Y 21b , Y 22 , and Y 23 is hydrogen.
  • each of Y 14a , Y 14b , Y 15a , Y 15b , Y 16 , Y 17 , Y 18 , Y 19 , Y 20a , Y 20b , Y 21a , Y 21b , Y 22 , and Y 23 is hydrogen.
  • each of Y 14a , Y 14b , Y 15a , Y 15b , Y 16 , Y 17 , Y 18 , Y 20a , Y 20b , Y 21a , Y 21b , Y 22 , and Y 23 is hydrogen.
  • each Y bound to a common carbon atom is the same (e.g., Y 1a and Y 1b are the same; Y 2a and Y 2b are the same; Y 3a and Y 3b are the same; Y 4a and Y 4b are the same; Y 5a and Y 5b are the same; Y 6a and Y 6b are the same; Y 8a and Y 8b are the same; Y 9a and Y 9b are the same; Y 10a and Y 10b are the same; Y 11a and Y 11b are the same; Y 12a and Y 12b are the same; and Y 13a and Y 13b are the same).
  • each of Y 1a , Y 1b , Y 2a , Y 2b , Y 3a and Y 3b is the same.
  • each of Y 4a , Y 4b , Y 5a and Y 5b is the same.
  • each of Y 8a , Y 8b , Y 9a , Y 9b , Y 10a and Y 10b is the same.
  • each of Y 12a , Y 12b , Y 13a and Y 13b is the same.
  • each of Y 6a , Y 6b , and Y 7 is the same.
  • each of R 1 , R 2a , R 2b and R 3 is independently selected from -CH 3 and -CD 3 .
  • R 2a and R 2b are the same.
  • each of Y 1a and Y 1b is deuterium when R 1 is -CD 3 .
  • each of Y 1a , Y 1b , Y 2a , Y 2b , Y 3a and Y 3b is deuterium when R 1 is -CD 3 .
  • each of Y 1a and Y 1b is hydrogen when R 1 is -CH 3 .
  • each of Y 1a , Y 1b , Y 2a , Y 2b , Y 3a and Y 3b is hydrogen when R 1 is -CH 3 .
  • R 2a and R 2b are -CD 3
  • Y 7 is deuterium.
  • R 2a and R 2b are -CH 3
  • Y 7 is hydrogen.
  • R 2a and R 2b are -CD 3
  • Y 7 is deuterium
  • each of Y 6a and Y 6b is deuterium.
  • R 2a and R 2b are -CH 3
  • Y 7 is hydrogen
  • each of Y 6a and Y 6b is hydrogen
  • each of Y 13a and Y 13b is deuterium when R 3 is -CD 3
  • each of Y 12a , Y 12b , Y 13a and Y 13b is deuterium when R 3 is -CD 3 .
  • each of Y 12a , Y 12b , Y 13a and Y 13b is deuterium when R 3 is -CD 3 .
  • each of Y 13a and Y 13b is hydrogen when R 3 is -CH 3 .
  • each of Y 12a , Y 12b , Y 13a and Y 13b is hydrogen when R 3 is -CH 3 .
  • the compound is an (S) stereoisomer at the sulfoxide moiety having the Formula Ia:
  • the compound is an (R) stereoisomer at the sulfoxide moiety having the Formula Ib:
  • the compound of Formula I, Ia or Ib is a mesylate salt. In other embodiments, the compound of Formula I, Ia or Ib is an oxalate salt. In still other embodiments, the compound of Formula I, Ia or Ib is a free base.
  • R 2a and R 2b are the same; each of Y 1a , Y 1b , Y 2a , Y 2b , Y 3a and Y 3b is the same (designated Y 1 /Y 2 /Y 3 in Table 1); each of Y 4a , Y 4b , Y 5a and Y 5b is the same (designated Y 4 /Y 5 in Table 1); each of Y 6a , Y 6b , and Y 7 is the same (designated Y 6 /Y 7 in Table 1); each of Y 8a , Y 8b , Y 9a , Y 9b , Y 10a and Y 10b is the same (designated Y 8 /Y 9 /Y 10 in Table 1); each of Y 11a and Y 11b is the same (designated Y 11 in Table 1); each of Y 12a , Y 12b , Y 13
  • R 2a and R 2b are the same; each of Y 1a , Y 1b , Y 2a , Y 2b , Y 3a and Y 3b is the same (designated Y 1 /Y 2 /Y 3 in Table 2); each of Y 4a , Y 4b , Y 5a and Y 5b is the same (designated Y 4 /Y 5 in Table 2); each of Y 6a , Y 6b , and Y 7 is the same (designated Y 6 /Y 7 in Table 2); each of Y 8a , Y 8b , Y 9a , Y 9b , Y 10a and Y 10b is the same (designated Y 8 /Y 9 /Y 10 in Table 2); each of Y 11a and Y 11b is the same (designated Y 11 in Table 2); each of Y 12a , Y 12b , Y
  • R 2a and R 2b are the same; each of Y 1a , Y 1b , Y 2a , Y 2b , Y 3a and Y 3b is the same (designated Y 1 /Y 2 /Y 3 in Table 3); each of Y 4a , Y 4b , Y 5a and Y 5b is the same (designated Y 4 /Y 5 in Table 3); each of Y 6a , Y 6b , and Y 7 is the same (designated Y 6 /Y 7 in Table 3); each of Y 8a , Y 8b , Y 9a , Y 9b , Y 10a and Y 10b is the same (designated Y 8 /Y 9 /Y 10 in Table 3); each of Y 11a and Y 11b is the same (designated Y 11 in Table 3); each of Y 12a , Y 12b , Y
  • any atom not designated as deuterium in any of the embodiments set forth herein is present at its natural isotopic abundance.
  • deuterium incorporation at each designated deuterium atom is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, at least 97%, or at least 99%.
  • the level of deuterium incorporation at each Y 1a and Y 1b is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, is at least 97%, or at least 99%.
  • the level of deuterium incorporation at each Y 2a and Y 2b is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, is at least 97%, or at least 99%.
  • the level of deuterium incorporation at each Y 3a and Y 3b is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, is at least 97%, or at least 99%.
  • the level of deuterium incorporation at each Y 4a and Y 4b is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, is at least 97%, or at least 99%.
  • the level of deuterium incorporation at each Y 5a and Y 5b is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, is at least 97%, or at least 99%.
  • the level of deuterium incorporation at each Y 6a and Y 6b is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, is at least 97%, or at least 99%.
  • the level of deuterium incorporation at Y 7 is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, is at least 97%, or at least 99%.
  • the level of deuterium incorporation at each Y 8a and Y 8b is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, is at least 97%, or at least 99%.
  • the level of deuterium incorporation at each Y 9a and Y 9b is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, is at least 97%, or at least 99%.
  • the level of deuterium incorporation at each Y 10a and Y 10b is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, is at least 97%, or at least 99%.
  • the level of deuterium incorporation at each Y 11a and Y 11b is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, is at least 97%, or at least 99%.
  • the level of deuterium incorporation at each Y 12a and Y 12b is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, is at least 97%, or at least 99%.
  • the level of deuterium incorporation at each Y 13a and Y 13b is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, is at least 97%, or at least 99%.
  • the level of deuterium incorporation at R 1 is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, is at least 97%, or at least 99%.
  • the level of deuterium incorporation at each R 2a and R 2b is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, is at least 97%, or at least 99%.
  • the level of deuterium incorporation at R 3 is at least 52.5%, at least 75%, at least 82.5%, at least 90%, at least 95%, is at least 97%, or at least 99%.
  • the present invention also provides deuterated intermediates useful, e.g., in the preparation of the compounds of Formula I, Ia, or Ib, and as provided in the Exemplary Schemes.
  • Such methods can be carried out utilizing corresponding deuterated and, optionally, other isotope-containing reagents and/or intermediates to synthesize the compounds delineated herein, or invoking standard synthetic protocols known in the art for introducing isotopic atoms to a chemical structure.
  • compounds of Formula I can be prepared with greater than about 70%, about 80%, about 90%, about 95%, about 97%, about 98%, or about 99% deuterium incorporation at each position designated as D (see below for details).
  • deuterated intermediate (1) for use in the preparation of compounds of Formula I according to Scheme 1, may be prepared from corresponding deuterated reagents exemplified in Scheme 2.
  • Reagents and conditions (a) NH 2 OH, conc. H 2 SO 4 , heat; (b) MgSO 4 , p-anisaldehyde, heat, NaBH 4 , N aOH; (c) Na 2 CO 3 ; (d) CH 3 I, K 2 CO 3
  • nucleophilic displacement of a fluoride in appropriately deuterated fluorobenzaldehyde intermediate (14) with amino moiety in (13) affords appropriately deuterated aniline intermediate (15) containing aldehyde and carboxylic acid moieties.
  • Esterification of carboxylic acid in (15) using iodomethane in the presence of a mild base such as potassium carbonate produces appropriately deuterated intermediate (1) containing aldehyde and ester moieties.
  • Certain intermediates (16) may be prepared according to published procedures: 4-bromophenol-3,5-d 2 (16a) is prepared according to procedure described by Kirste, B., et al., Chemische Berichte 118(5), 1782-97, (1985); 4-bromophenol-2,6-d 2 (16b) is prepared in accordance with a procedure described by Zhan, M. et al., European Journal of Organic Chemistry 2015(15), 3370-3373, (2015). 4-Bromophenol-2,3,5,6-d 4 (98 atom %D) (16c) is commercially available.
  • Intermediate (4a) is commercially available: isobutyraldehyde-d 7 (98 atom %D).
  • Intermediate (4b), 2-methyl propanal-2-d may be prepared according to a procedure described by Bowen, R. et al., Journal of the Chemical Society, Perkin Transactions 2:
  • Reagent (5a), sodium triacetoxyborodeuteride or NaBD(OAc) 3 for use in the preparation of compounds of Formula I according to Scheme 1, may be prepared according to a procedure described in WO2015189413 from sodium borodeuteride (98 atom %D).
  • appropriately deuterated alkyl iodide intermediate (21) may be prepared by treating appropriately deuterated alcohol intermediate (23) with hydriodic acid (HI) at elevated temperature.
  • Certain intermediates (23) are commercially available: n-butyl-d 9 alcohol (99 atom%D) (23a), n-butyl-2,2,3,3,4,4,4-d 7 alcohol (98 atom%D) (23b), n-butyl-1,1,2,2,3,3-d 6 alcohol (98 atom%D) (23c), n-butyl-1,1,2,2-d 4 alcohol (98 atom%D) (23d), n-butyl-4,4,4-d 3 alcohol (99 atom%D) (23e), and n-butyl-1,1-d 2 alcohol (99 atom %D) (23f).
  • the following intermediates (23) may be prepared by published procedures: 1-butan-2,2,3,3-d 4 -ol (23g) may be prepared according to a procedure described by Olah, G. et al., Angewandte
  • deuterated intermediates (10), for use in the preparation of compounds of Formula I according to Scheme 1, may be prepared from corresponding deuterated reagents exemplified in Scheme 6.
  • Reagents and conditions (a) m-CPBA; (b) Na 2 S, SDS, AcOH ; (c) Et 3 N; (d) H 2 O 2 , AcOH, NaOH, Na 2 SO 3 [00106]
  • appropriately deuterated aniline intermediate (24) is oxidized with m- chloroperbenzoic acid (m-CPBA) at elevated temperature to furnish appropriately deuterated nitroarene intermediate (25), which is subsequently treated with sodium sulfide in aqueous solution containing surfactant such as sodium dodecyl sulfate (SDS) in a manner analogous to a procedure described in JP 07053507, affording appropriately deuterated aminothiophenol intermediate (26).
  • m-CPBA m- chloroperbenzoic acid
  • SDS sodium dodecyl sulfate
  • hydrochloride salt of appropriately deuterated imidazolyl alkyl halide intermediate (27) in the presence of a base such as triethylamine furnishes appropriately deuterated sulfide intermediate (28).
  • oxidation with oxidizing agent such as with hydrogen peroxide in acetic acid produces racemic and appropriately deuterated sulfoxide intermediate (10).
  • 4-Chloro-benzen-amine-3,5-d 2 , (24c) may be prepared according to a procedure described by Suehiro, T. et al., Bulletin of the Chemical Society of Japan 60(9), 3321-30, (1987).
  • Reagents and conditions (a) KSCN; (b) aq. HNO 3 , NaNO 2 , K 2 CO 3 or HNO 3 /D 2 O, NaNO 2 , K 2 CO 3 ; (c) SOCl 2 [00111]
  • appropriately deuterated acetone intermediate (29) is treated with hydrohalide salt such as hydrochloride salt of appropriately deuterated alkyl amine intermediate (30) in the presence of a thiocyanate such as potassium thiocyanate to furnish appropriately deuterated mercaptoimidazole intermediate (31).
  • 1,3-Dihydroxy-2-propanone-1,1,-d 2 may be prepared from 1,2,3-propane-1, 1-d 2 -triol by analogy to an oxidation procedure described in WO 2014102840.
  • 1,2,3- Propane-1,1-d 2 -triol may be prepared, in turn, according to a procedure described by Hill, A. et al., Chemical Communications (Cambridge) (21), 2361-2362, (1998).
  • Certain intermediates (30) are commercially available: n-propyl-d 7 -amine HCl (98 atom %D) (30a); n-propyl-2,2,3,3,3-d 5 -amine HCl (98 atom % D) (30b); and n-propyl-3,3,3- d 3 -amine HCl (99 atom %D) (30c).
  • the invention also provides pharmaceutical compositions comprising an effective amount of a compound of Formula I, Ia, or Ib (e.g., including any of the formulae herein), or a pharmaceutically acceptable salt of said compound; and a pharmaceutically acceptable carrier.
  • the carrier(s) are“acceptable” in the sense of being compatible with the other ingredients of the formulation and, in the case of a pharmaceutically acceptable carrier, not deleterious to the recipient thereof in an amount used in the medicament.
  • Pharmaceutically acceptable carriers, adjuvants, excipients and vehicles that may be used in the pharmaceutical compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates (e.g., phosphate-buffered saline, etc.), glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.
  • ion exchangers e.g.,
  • the solubility and bioavailability of the compounds of the present invention in pharmaceutical compositions may be enhanced by methods well-known in the art.
  • One method includes the use of lipid excipients in the formulation. See“Oral Lipid- Based Formulations: Enhancing the Bioavailability of Poorly Water-Soluble Drugs (Drugs and the Pharmaceutical Sciences),” David J. Hauss, ed. Informa Healthcare, 2007; and“Role of Lipid Excipients in Modifying Oral and Parenteral Drug Delivery: Basic Principles and Biological Examples,” Kishor M. Wasan, ed. Wiley-Interscience, 2006.
  • Another known method of enhancing bioavailability is the use of an amorphous form of a compound of this invention optionally formulated with a poloxamer, such as LUTROL TM or PLURONIC TM (BASF Corporation), or block copolymers of ethylene oxide and propylene oxide. See U.S. Patent No.7,014,866; and United States Patent Appln.
  • compositions of the invention include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration.
  • the compound of the formulae herein is administered transdermally (e.g., using a transdermal patch or iontophoretic techniques).
  • Other formulations may conveniently be presented in unit dosage form, e.g., tablets, sustained release capsules, and in liposomes, and may be prepared by any methods well known in the art of pharmacy. See, for example, Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins,
  • Such preparative methods include the step of bringing into association with the molecule to be administered ingredients such as the carrier that constitutes one or more accessory ingredients.
  • ingredients such as the carrier that constitutes one or more accessory ingredients.
  • the compositions are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers, liposomes or finely divided solid carriers, or both, and then, if necessary, shaping the product.
  • compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, sachets, or tablets each containing a predetermined amount of the active ingredient; a powder or granules; a solution or a suspension in an aqueous liquid or a non- aqueous liquid; an oil-in-water liquid emulsion; a water-in-oil liquid emulsion; packed in liposomes; or as a bolus, etc.
  • Soft gelatin capsules can be useful for containing such suspensions, which may beneficially increase the rate of compound absorption.
  • carriers that are commonly used include lactose and corn starch.
  • Lubricating agents such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried cornstarch.
  • aqueous suspensions are administered orally, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents may be added.
  • compositions suitable for oral administration include lozenges comprising the ingredients in a flavored basis, usually sucrose and acacia or tragacanth; and pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia.
  • compositions suitable for parenteral administration include aqueous and non- aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
  • the formulations may be presented in unit-dose or multi-dose containers, for example, sealed ampules and vials, and may be stored in a freeze dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.
  • Such injection solutions may be in the form, for example, of a sterile injectable aqueous or oleaginous suspension.
  • This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • suitable vehicles and solvents that may be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant.
  • compositions of this invention may be administered in the form of suppositories for rectal administration.
  • These compositions can be prepared by mixing a compound of this invention with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active components.
  • suitable non-irritating excipient include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.
  • compositions of this invention may be administered by nasal aerosol or inhalation.
  • Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance
  • Topical administration of the pharmaceutical compositions of this invention is especially useful when the desired treatment involves areas or organs readily accessible by topical application.
  • the pharmaceutical composition should be formulated with a suitable ointment containing the active components suspended or dissolved in a carrier.
  • Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax, and water.
  • the pharmaceutical composition can be formulated with a suitable lotion or cream containing the active compound suspended or dissolved in a carrier.
  • suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.
  • the pharmaceutical compositions of this invention may also be topically applied to the lower intestinal tract by rectal suppository formulation or in a suitable enema formulation. Topically-transdermal patches and iontophoretic administration are also included in this invention.
  • Application of the subject therapeutics may be local, so as to be administered at the site of interest.
  • Various techniques can be used for providing the subject compositions at the site of interest, such as injection, use of catheters, trocars, projectiles, pluronic gel, stents, sustained drug release polymers or other device which provides for internal access.
  • the compounds of this invention may be incorporated into compositions for coating an implantable medical device, such as prostheses, artificial valves, vascular grafts, stents, or catheters.
  • an implantable medical device such as prostheses, artificial valves, vascular grafts, stents, or catheters.
  • Suitable coatings and the general preparation of coated implantable devices are known in the art and are exemplified in US Patent Nos.6,099,562; 5,886,026; and 5,304,121.
  • the coatings are typically biocompatible polymeric materials such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof.
  • the coatings may optionally be further covered by a suitable topcoat of fluorosilicone, polysaccharides, polyethylene glycol, phospholipids or combinations thereof to impart controlled release characteristics to the composition.
  • Coatings for invasive devices are to be included within the definition of pharmaceutically acceptable carrier, adjuvant or vehicle, as those terms are used herein.
  • the invention provides a method of coating an implantable medical device comprising the step of contacting said device with the coating composition described above. It will be obvious to those skilled in the art that the coating of the device will occur prior to implantation into a mammal.
  • the invention provides a method of
  • Implantable drug release devices include, but are not limited to, biodegradable polymer capsules or bullets, non- degradable, diffusible polymer capsules and biodegradable polymer wafers.
  • the invention provides an implantable medical device coated with a compound or a composition comprising a compound of this invention, such that said compound is therapeutically active.
  • the invention provides an implantable drug release device impregnated with or containing a compound or a composition comprising a compound of this invention, such that said compound is released from said device and is therapeutically active.
  • an organ or tissue is accessible because of removal from the subject, such organ or tissue may be bathed in a medium containing a composition of this invention, a composition of this invention may be painted onto the organ, or a composition of this invention may be applied in any other convenient way.
  • a composition of this invention further comprises one or more additional therapeutic agents.
  • the additional therapeutic agent(s) may be selected from any compound or therapeutic agent known to have or that demonstrates advantageous properties when administered with a compound having the same mechanism of action as cenicriviroc (e.g., a CCR5 antagonist).
  • cenicriviroc e.g., a CCR5 antagonist
  • Such agents include, but are not limited to, those described in PCT publications WO2016040860, WO2015187663, WO2015143367, and WO2003014105.
  • the additional therapeutic agent is an agent useful in the treatment of a disease or condition selected from HIV infection, hepatic impairment, NASH, primary sclerosing cholangitis, pre-diabetes, non-alcoholic fatty liver disease and type 2 diabetes.
  • a disease or condition selected from HIV infection, hepatic impairment, NASH, primary sclerosing cholangitis, pre-diabetes, non-alcoholic fatty liver disease and type 2 diabetes.
  • the additional therapeutic agent is selected from a farnesoid X receptor (FXR) agonist, high dose vitamin E (> 400 iU/d), a peroxisome proliferator-activated receptor alpha (PPAR- ⁇ ) agonist, a PPAR- ⁇ agonist, a PPAR- ⁇ agonist, and a chemokine antagonist.
  • FXR farnesoid X receptor
  • PPAR- ⁇ peroxisome proliferator-activated receptor alpha
  • the second agent is selected from obeticholic acid, pioglitazone, 3-[2-[2-chloro-4-[[3-(2,6-dichlorophenyl)-5-(l- methylethyl)-4-isoxazolyl]methoxy]phenyl]ethenyl]benzoic acid (GW4064), 2-methyl-2-[[4- [2- [[(cyclohexylamino)carbonyl](4-cyclohexylbutyl)amino]ethyl]phenyl]thio]-propanoic acid (GW7647), 2-[2,6 dimethyl-4-[3-[4-(methylthio)phenyl]-3-oxo-l(E)- propenyl]phenoxyl]-2-methylpropanoic acid (GFT505), and BX471.
  • the additional therapeutic agent is an antiretroviral agent selected from entry inhibitors, nucleoside reverse transcriptase inhibitors, nucleotide reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors, integrase inhibitors, maturation inhibitors (e.g., GSK2838232), and combinations thereof.
  • the one or more additional antiretroviral agents include, but are not limited to, lamivudine, efavirenz, raltegravir, becon, bevirimat, alpha interferon, zidovudine, abacavir, lopinavir, ritonavir, tenofovir, tenofovir disoproxil or its fumarate salt, tenofovir alafenamide or its fumarate salt, emtricitabine, elvitegravir, cobicistat, darunavir, atazanavir, rilpivirine, dolutegravir, and combinations thereof.
  • the additional therapeutic agent is selected from dolutegravir, midazolam, TRUVADA® (emtricitabine and tenofovir disoproxil fumarate), efavirenz, evogliptin, pioglitazone, a statin (e.g., rosuvastatin, atorvastatin, simvastatin), or evogliptin.
  • TRUVADA® emtricitabine and tenofovir disoproxil fumarate
  • efavirenz evogliptin
  • pioglitazone e.g., a statin (e.g., rosuvastatin, atorvastatin, simvastatin), or evogliptin.
  • the invention provides separate dosage forms of a compound of this invention and one or more of any of the above-described additional therapeutic agents, wherein the compound and additional therapeutic agent are associated with one another.
  • the term“associated with one another,” as used herein, means that the separate dosage forms are packaged together or otherwise attached to one another such that it is readily apparent that the separate dosage forms are intended to be sold and administered together (within less than 24 hours of one another, consecutively or simultaneously).
  • the compound of the present invention is present in an effective amount.
  • the term“effective amount” refers to an amount which, when administered in a proper dosing regimen, is sufficient to treat the target disorder.
  • An effective amount of a compound of this invention can range from about 1 mg/day to about 2000 mg/day, from about 5 mg/day to about 1000 mg/day, from about 10 mg/day to about 500 mg/day, or from about 25 mg/day to about 200 mg/day.
  • An effective amount of a compound of this invention can range from about 10 mg/day to about 200 mg/day, from about 10 mg/day to about 100 mg/day, from about 25 mg/day to about 150 mg/day, or from about 25 mg/day to about 100 mg/day.
  • Effective doses will also vary, as recognized by those skilled in the art, depending on the diseases treated, the severity of the disease, the route of administration, the sex, age and general health condition of the subject, excipient usage, the possibility of co-usage with other therapeutic treatments such as use of other agents and the judgment of the treating physician. For example, guidance for selecting an effective dose can be determined by reference to the prescribing information for cenicriviroc.
  • an effective amount of the additional therapeutic agent is between about 20% and 100% of the dosage normally utilized in a monotherapy regime using just that agent.
  • an effective amount is between about 70% and 100% of the normal
  • Certain aspects of the invention provide a method of antagonizing the activity of CCR2 in a cell, comprising contacting a cell with one or more compounds of Formula I, Ia or Ib herein, or a salt (e.g., pharmaceutically acceptable salt) thereof.
  • the cell is contacted in vitro.
  • the cell is contacted in vivo.
  • the cell is contacted ex vivo.
  • Certain aspects of the invention provide a method of treating a disease that is beneficially treated by cenicriviroc in a subject in need thereof, comprising the step of administering to the subject an effective amount of a compound or a composition of this invention.
  • the subject is a patient in need of such treatment.
  • the subject is a human.
  • Certain aspects of the invention provide a method of antagonizing the activity of CCR5 in a cell, comprising contacting a cell with one or more compounds of Formula I, Ia or Ib herein, or a salt (e.g., pharmaceutically acceptable salt) thereof.
  • Certain aspects of the invention provide a method of antagonizing the activity of both CCR2 and CCR5 in a cell, comprising contacting a cell with one or more compounds of Formula I, Ia or Ib herein, or a salt (e.g., pharmaceutically acceptable salt) thereof.
  • Certain aspects of the invention provide a method of treating a disease that is beneficially treated by administration of a CCR2 antagonist, a CCR5 antagonist, or a dual CCR2/CCR5 antagonist to a subject in need thereof, comprising administering to the subject an effective amount of a compound, a pharmaceutically acceptable salt or a composition of this invention.
  • the subject is a patient in need of such treatment.
  • diseases are well known in the art and are disclosed in, but not limited to the following published applications: WO2016040860, WO2015187663, WO2015143367,
  • Such diseases include, but are not limited to, cirrhosis, hepatic fibrosis, kidney fibrosis, hepatic non- alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), primary sclerosing cholangitis (PSC), emerging cirrhosis, graft-versus-host disease, HIV infection, rheumatoid arthritis, autoimmune disease, allergies, ischemic brain cell disorder, cardiac infarction, chronic nephritis, arteriosclerosis, alcoholic liver disease, HIV/HCV co-infection, HBV infection, HCV infection, metabolic syndrome, obesity, type 2 diabetes, and prediabetes.
  • diseases include, but are not limited to, cirrhosis, hepatic fibrosis, kidney fibrosis, hepatic non- alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), primary sclerosing cholangitis (PSC
  • the method of this invention is used to treat a disease or condition selected from HIV infection, non-alcoholic steatohepatitis (NASH), primary sclerosing cholangitis (PSC), and obesity in a subject in need thereof.
  • a disease or condition selected from HIV infection, non-alcoholic steatohepatitis (NASH), primary sclerosing cholangitis (PSC), and obesity in a subject in need thereof.
  • Certain aspects of this invention provide a method of treating cancer, comprising administering to a subject in need thereof an effective amount of a compound, a
  • checkpoint inhibitors include, but are not limited to, inhibitors of programmed cell death protein 1 (PD-1), programed cell death-ligand 1 (PD-L1), programed cell death 1-ligand 2 (PD-L2), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), lymphocyte-activation gene 3 (LAG-3), and cluster of differentiation 276 gene (CD276 also known as B7-H3).
  • PD-1 programmed cell death protein 1
  • PD-L1 programed cell death-ligand 1
  • PD-L2 programed cell death 1-ligand 2
  • CTL-4 cytotoxic T-lymphocyte-associated protein 4
  • LAG-3 lymphocyte-activation gene 3
  • CD276 cluster of differentiation 276 gene
  • inhibitors include, but are not limited to, PD-1inhibitors: nivolumab, pembrolizumab and AMP-224; PD-L1 inhibitors: MDX-1105, atezolizumab, and durvalumab; CTLA-4 inhibitors: ipilimumab and
  • tremelimumab LAG-3 protein or fusion protein: IMP-321
  • CD276 inhibitor enoblituzumab
  • pidilizumab pidilizumab and MGD009.
  • Certain aspects of this invention provide a method of treating cancer, comprising administering to a subject in need thereof an effective amount of a compound, a pharmaceutically acceptable salt or a composition of this invention in combination with one or more FAK inhibitors.
  • FAK inhibitors include, but are not limited to, BI 853529, GSK2256098, NVP-226, PF-573,228, PF-562,271 (VS-6062), VS-4718, VS-6063, VS-5095, Y15, CFAK-C4, INT2-31, M13, and R2.
  • Certain aspects of this invention provide a method of treating cancer, comprising administering to a subject in need thereof an effective amount of a compound, a
  • the invention provides a method of treating a cancer selected from skin cancer, basal cell carcinoma, melanoma, renal carcinoma, urothelial cancer, bladder cancer, pancreatic cancer, colorectal cancer, breast cancer, prostate cancer, head and neck cancer, digestive/gastrointestinal cancer, esophageal cancer, gastric cancer, respiratory/thoracic cancer, laryngeal cancer, lung cancer, small cell lung cancer, non-small cell lung cancer, genitourinary cancer, female reproductive system cancer, ovarian cancer, thyroid cancer, endometrial cancer, cervical cancer, glioblastoma multiforme, malignant pleural mesothelioma, squamous cell carcinoma, myelodysplastic syndrome, multiple myeloma, myeloid leukemia, lymphoma, lymphocytic leukemia, non-Hodgkin's lymphoma, endocrine cancer, neurologic cancer, sarcoma, osteosarcoma, liver cancer,
  • the cancer is selected from pancreatic cancer, colorectal cancer, breast cancer, head and neck cancer, melanoma, renal carcinoma, non-small cell lung cancer, Hodgkin’s lymphoma and bladder cancer. In one embodiment, the cancer is selected from head and neck cancer, melanoma, renal carcinoma, non-small cell lung cancer, Hodgkin’s lymphoma and bladder cancer.
  • Identifying a subject in need of such treatment can be in the judgment of a subject or a health care professional and can be subjective (e.g. opinion) or objective (e.g. measurable by a test or diagnostic method).
  • any of the above methods of treatment further comprises co-administering to the subject in need thereof one or more additional therapeutic agents.
  • additional therapeutic agent may be made from any additional therapeutic agent set forth above for use in combination compositions comprising a compound of this invention and an additional therapeutic agent.
  • the combination therapies of this invention include co- administering a compound of Formula I, or a pharmaceutically acceptable salt thereof, and an additional therapeutic agent selected from dolutegravir, midazolam, TRUVADA®
  • evogliptin e.g., rosuvastatin, atorvastatin, simvastatin
  • evogliptin e.g., rosuvastatin, atorvastatin, simvastatin
  • the term“co-administered,” as used herein, means that the additional therapeutic agent may be administered together with a compound of this invention as part of a single dosage form (such as a composition of this invention comprising a compound of the invention and an additional therapeutic agent as described above) or as separate, multiple dosage forms. Alternatively, the additional agent may be administered prior to, consecutively with, or following the administration of a compound of this invention. In such combination therapy treatment, both the compounds of this invention and the additional therapeutic agent(s) are administered by conventional methods.
  • composition of this invention comprising both a compound of the invention and an additional therapeutic agent to a subject does not preclude the separate administration of that same therapeutic agent, any other additional therapeutic agent or any compound of this invention to said subject at another time during a course of treatment.
  • the effective amount of the compound of this invention is less than its effective amount would be where the additional therapeutic agent is not administered. In another embodiment, the effective amount of the additional therapeutic agent is less than its effective amount would be where the compound of this invention is not administered. In this way, undesired side effects associated with high doses of either agent may be minimized. Other potential advantages (including without limitation improved dosing regimens and/or reduced drug cost) will be apparent to those of skill in the art.
  • the invention provides the use of a compound of Formula I, Ia or Ib, or a pharmaceutically acceptable salt of any of the foregoing, alone or together with one or more of the above-described additional therapeutic agents in the manufacture of a medicament, either as a single composition or as separate dosage forms, for treatment in a subject of a disease, disorder or symptom set forth above.
  • Another aspect of the invention is a compound of Formula I, Ia or Ib, or a pharmaceutically acceptable salt of any of the foregoing, for use in the treatment in a subject of a disease, disorder or symptom thereof delineated herein.
  • Microsomal Assay Human liver microsomes (20 mg/mL) are obtained from Xenotech, LLC (Lenexa, KS). ⁇ -nicotinamide adenine dinucleotide phosphate, reduced form (NADPH), magnesium chloride (MgCl 2 ), and dimethyl sulfoxide (DMSO) are purchased from Sigma-Aldrich.
  • 7.5 mM stock solutions of test compounds are prepared in DMSO.
  • the 7.5 mM stock solutions are diluted to 12.5-50 ⁇ M in acetonitrile (ACN).
  • ACN acetonitrile
  • the 20 mg/mL human liver microsomes are diluted to 0.625 mg/mL in 0.1 M potassium phosphate buffer, pH 7.4, containing 3 mM MgCl 2 .
  • the diluted microsomes are added to wells of a 96-well deep-well polypropylene plate in triplicate.
  • a 10 ⁇ L aliquot of the 12.5-50 ⁇ M test compound is added to the microsomes and the mixture is pre-warmed for 10 minutes. Reactions are initiated by addition of pre-warmed NADPH solution.
  • the final reaction volume is 0.5 mL and contains 0.5 mg/mL human liver microsomes, 0.25-1.0 ⁇ M test compound, and 2 mM NADPH in 0.1 M potassium phosphate buffer, pH 7.4, and 3 mM MgCl 2 .
  • the reaction mixtures are incubated at 37 °C, and 50 ⁇ L aliquots are removed at 0, 5, 10, 20, and 30 minutes and added to shallow-well 96-well plates which contain 50 ⁇ L of ice- cold ACN with internal standard to stop the reactions.
  • the plates are stored at 4 °C for 20 minutes after which 100 ⁇ L of water is added to the wells of the plate before centrifugation to pellet precipitated proteins.

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Abstract

Cette invention concerne des formes deutérées de cénicriviroc, racémiques et leurs formes (R), des formes de base libres de l'un quelconque des précédents et des sels pharmaceutiquement acceptables des formes de base libres. Dans un aspect, l'invention concerne un composé de formule I : ou un stéréoisomère de celui-ci, ou un sel pharmaceutiquement acceptable de l'un ou l'autre des éléments précédents, chaque Y et chaque R étant tels que définis dans l'application.
PCT/US2017/048549 2016-08-26 2017-08-25 Cénicriviroc deutéré WO2018039521A1 (fr)

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Publication number Priority date Publication date Assignee Title
WO2020021215A1 (fr) 2018-07-27 2020-01-30 Inventiva Derives deuteres du lanifibranor
WO2020181163A1 (fr) * 2019-03-06 2020-09-10 Tobira Therapeutics, Inc. Formulation lipidique de cénicriviroc

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WO2016011316A1 (fr) * 2014-07-17 2016-01-21 Chdi Foundation, Inc. Méthodes et compositions pour le traitement de troubles liés au vih

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US20110200592A1 (en) * 2005-07-22 2011-08-18 Olson William C Methods For Reducing Viral Load in HIV-1 Infected Patients
WO2016011316A1 (fr) * 2014-07-17 2016-01-21 Chdi Foundation, Inc. Méthodes et compositions pour le traitement de troubles liés au vih

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DATABASE PUBCHEM 2 February 2015 (2015-02-02), "(-)-8-(4-(2-butoxyethoxy)phenyl)-N-(4-(((1-propylimidazol-5-yl)methyl)sulfinyl)phenyl)-1,2,3,4-tetrahydro-1-benzazocine-5-carboxamide", XP055469098, Database accession no. 223915294 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020021215A1 (fr) 2018-07-27 2020-01-30 Inventiva Derives deuteres du lanifibranor
EP4331584A1 (fr) 2018-07-27 2024-03-06 Inventiva Derives deuteres du lanifibranor
WO2020181163A1 (fr) * 2019-03-06 2020-09-10 Tobira Therapeutics, Inc. Formulation lipidique de cénicriviroc

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