WO2025252064A1 - Modulateur de thr-bêta pour le traitement de maladies métaboliques - Google Patents

Modulateur de thr-bêta pour le traitement de maladies métaboliques

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Publication number
WO2025252064A1
WO2025252064A1 PCT/CN2025/098774 CN2025098774W WO2025252064A1 WO 2025252064 A1 WO2025252064 A1 WO 2025252064A1 CN 2025098774 W CN2025098774 W CN 2025098774W WO 2025252064 A1 WO2025252064 A1 WO 2025252064A1
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Prior art keywords
alkyl
group
aryl
independently selected
optionally substituted
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PCT/CN2025/098774
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English (en)
Inventor
Jingzi Jason WU
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Ascletis Pharma China Co Ltd
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Ascletis Pharma China Co Ltd
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    • 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
    • A61K31/664—Amides of phosphorus acids
    • 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
    • A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents

Definitions

  • the present disclosure is related to a method for the treatment of metabolic diseases.
  • Thyroid hormones are critical for normal growth and development and for maintaining metabolic homeostasis (Paul M. Yen Physiological Review, Vol. 81 (3) : pp. 1097-1126 (2001) ) . Circulating levels of thyroid hormones are tightly regulated by feedback mechanisms in the hypothalamus/pituitary/thyroid (HPT) axis. Thyroid dysfunction leading to hypothyroidism or hyperthyroidism clearly demonstrates that thyroid hormones exert profound effects on cardiac function, body weight, metabolism, metabolic rate, body temperature, cholesterol, bone, muscle and behavior.
  • the thyroid hormone receptors are derived from two separate genes, ⁇ and ⁇ . These distinct gene products produce multiple forms of their respective receptors through differential RNA processing.
  • Thyroid hormone receptors ⁇ l, ⁇ l and ⁇ 2 bind thyroid hormone. It has been shown that the thyroid hormone receptor subtypes can differ in their contribution to particular biological responses. Recent studies suggest that TR ⁇ l plays an important role in regulating TRH (thyrotropin releasing hormone) and on regulating thyroid hormone actions in the liver. TR ⁇ 2 plays an important role in the regulation of TSH (thyroid stimulating hormone) . TR ⁇ l plays an important role in regulating heart rate.
  • Obesity or over weight is a common metabolic disease characterized by excessive accumulation of body fat to the extent that it becomes detrimental to health.
  • Obesity is typically associated with a variety of health issues, including but not limited to: cardiovascular diseases: such as coronary heart disease, hypertension, stroke, etc.
  • Metabolic syndrome a cluster of symptoms that includes high blood pressure, high blood sugar, abnormal cholesterol levels, and abdominal obesity.
  • Type 2 diabetes obesity is a significant risk factor for type 2 diabetes.
  • Respiratory problems such as sleep apnea.
  • Certain cancers including breast, colon, and endometrial cancers.
  • Musculoskeletal and joint problems such as osteoarthritis.
  • Psychological impacts such as depression and anxiety.
  • the disclosure provides a therapeutic method involving administering an THR- ⁇ modulator that can target fat, achieve weight loss without muscle loss, realize healthy weight reduction, and at the same time has good tolerability.
  • the THR- ⁇ modulator of the present disclosure is disclosed in PCT patent publication WO2024167961A2, which is incorporated herein by reference in its entirety.
  • One aspect of the present disclosure provides a method for preventing, treating, or ameliorating obesity, comprising administering subcutaneously to a subject in need thereof an effective amount of a THR- ⁇ modulator having formula I, ;
  • G is selected from the group consisting of -O-and -C (X 9 X 8 ) -;
  • T is selected from the group consisting of - (C (R d ) 2 ) m -and -O- (C (R d ) 2 ) m -;
  • n is selected from the group consisting of 0, 1, 2 and 3;
  • X is selected from the group consisting of
  • each of R a and R b is independently selected from the group consisting of CH 3 , CD 3 , Cl, Br, I and CF 3 ;
  • R c is selected from the group consisting of hydrogen, halogen, -CF 3 , -OCF 3 , cyano, optionally substituted -C 1 -C 12 alkyl, optionally substituted -C 2 -C 12 alkenyl, optionally substituted-C 2 -C 12 alkynyl, optionally substituted -C 0-6 alkyl-aryl, optionally substituted -C 0-6 alkyl-cycloalkyl, optionally substituted -C 0-6 alkyl-heterocycloalkyl, and optionally substituted -C 3-8 cycloalkyl;
  • R c is optionally substituted with one to ten substituents each independently selected from the group consisting of halogen, H and D;
  • each of R d is independently selected from the group consisting of hydrogen, halogen, and C 1-6 alkyl;
  • each of R 1 and R 2 is independently selected from the group consisting of H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 6-10 aryl, heteroaryl, C 1-6 alkyl-C 6-10 aryl, and C 1-6 alkyl-heteroaryl, or R 1 and R 2 are combined with the atoms to which they are attached to form a C 3-10 cycloalkyl or a heterocyclyl;
  • R 3 is selected from the group consisting of H, C 1-30 alkyl, C 5-10 cycloalkyl, C 1-30 haloalkyl, C 6-10 aryl, and C 6-10 aryl-C 1-8 alkyl, wherein R 3 is optionally substituted with one or more substituents each independently selected from the group consisting of halo, NH 2 , NO 2 , OH, CN, -C 1-6 alkyl, C 1-6 haloalkyl, and O-C 1-6 alkyl;
  • R 4 is selected from the group consisting of C 6-10 aryl, C 1-6 alkyl-C 6-10 aryl, and 5-10 membered heteroaryl, wherein R 4 is optionally substituted with one or more substituents each independently selected from the group consisting of halo, NH 2 , NO 2 , OH, CN, -C 1-6 alkyl, C 1-6 haloalkyl, and O-C 1-6 alkyl;
  • R 5 is selected from the group consisting of H, -COR 6 , -COOR 6 , CH 2 OC (O) OR 7 , -CONHR 6 , -CONR 7 R 10 , -CONR 6 R 7 , -CH 2 OCOR 6 , -CH 2 OCONHR 6 , and
  • each of R 6 is independently selected from the group consisting of C 1- 30 alkyl, C 1-30 alkenyl, and C 1-30 alkynyl, wherein C 1-30 alkyl, C 1-30 alkenyl, and C 1-30 alkynyl is optionally substituted with one or more substituents each independently selected from the group consisting of halo, -O-C 1-30 alkyl, -S-C 1-30 alkyl, cycloalkyl, heterocyclyl, aryl, and 5-10 membered heteroaryl, wherein each of the -O-C 1-30 alkyl, -S-C 1-30 alkyl, cycloalkyl, heterocyclyl, aryl, and 5-10 membered heteroaryl is optionally substituted with one or more substituents each independently selected from the group consisting of halo and C 1-3 alkyl;
  • R 7 is selected from the group consisting of H, -C 1-30 alkyl, -C 2-30 alkenyl, -C 2-30 alkynyl, -C (O) C 1-30 alkyl, -C (O) C 2-30 alkenyl, -C (O) C 2-30 alkynyl, -C (O) OC 1-30 alkyl, -C (O) OC 2-30 alkenyl, -C (O) OC 2-30 alkynyl, -C (O) NR c C 1-30 alkyl, -C (O) NR c C 2-30 alkenyl, and -C (O) NR c C 2-30 alkynyl, wherein each of the -C 1-30 alkyl, -C 2-30 alkenyl, -C 2-30 alkynyl, -C (O) C 1-30 alkyl, -C (O) C 2-30 alkenyl, and -C (O)
  • R 6 and R 7 are combined with atoms to which they are attached to form a 5-10 membered heterocyclyl, and wherein the 5-10 membered heterocyclyl is optionally substituted with one or more substituents each independently selected from the group consisting of halo, NH 2 , NO 2 , OH, CN, -C 1-6 alkyl, C 1-6 haloalkyl, and O-C 1-6 alkyl;
  • each of R 8 and R 9 is independently selected from the group consisting of H, OH, C 1-6 alkyl, halo, -O-C 1-3 alkyl, -S-C 1-3 alkyl, -C 3-10 cycloalkyl, 3-10 membered heterocyclyl, aryl, and 5-10 membered heteroaryl, wherein each of the C 1-6 alkyl, -O-C 1-3 alkyl, -S-C 1-3 alkyl, -C 3-10 cycloalkyl, 3-10 membered heterocyclyl, aryl, and 5-10 membered heteroaryl can be optionally substituted with one or more substituents each independently selected from the group consisting of OH, halo, -O-C 1-3 alkyl, -S-C 1-3 alkyl, -C 3-10 cycloalkyl, 3-10 membered heterocyclyl, aryl, and 5-10 membered heteroaryl;
  • R 8 and R 9 are combined with the atoms to which they are attached to form a 3-10 membered heterocyclyl, which is optionally substituted with one to four R 6, wherein each R 6 is independently selected from the group consisting of H, halo, C 1-6 alkyl, C 1-6 haloalkyl, and alkoxy;
  • R 10 is selected from the group consisting of H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, - (CH 2 ) n C 3-10 cycloalkyl, - (CH 2 ) n aryl, and - (CH 2 ) n heteroaryl, wherien each of the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, - (CH 2 ) n C 3-10 cycloalkyl, - (CH 2 ) n aryl, and - (CH 2 ) n heteroaryl is optionally substituted with one or more substituents each independently selected from the group consisting of halo, -O-C 1-3 alkyl, -S-C 1-3 alkyl, -C 3-10 cycloalkyl, 3-10 membered heterocyclyl, aryl, and 5-10 membered heteroaryl;
  • X 8 and X 9 is independently selected from the group consisting of H, D and halo;
  • n is selected from the group consisting of 0, 1, 2, and 3;
  • each 5-10 membered heteroaryl mentioned above has one to four heteroatoms, and each is independently selected from the group consisting of N, O, and S;
  • each 3-10 membered heterocyclyl mentioned above has one to four heteroatoms, and each is independently selected from the group consisting of N, O, and S.
  • Another aspect of the present disclosure provides a method for preventing, treating, or ameliorating overweight, comprising administering to a subject in need thereof an effective amount of a THR- ⁇ modulator having formula I or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a deuterated compound thereof, prodrugs thereof, or metabolites thereof, wherein the formula I is as defined above.
  • Another aspect of the present disclosure provides a method for weight management or chronic weight management, comprising administering to a subject in need thereof an effective amount of a THR- ⁇ modulator having Formula I or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a deuterated compound thereof, prodrugs thereof, or metabolites thereof, wherein the formula I is as defined above.
  • Another aspect of the present application also relates to a method for weight management or chronic weight management, comprising administering to a subject in need thereof an effective amount of a pharmaceutica composition, wherein the pharmaceutical composition comprises the compound of formula (I) or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a deuterated compound thereof, prodrugs thereof, or metabolites thereof.
  • Another aspect of the present application also relates to a method for weight management or chronic weight management, comprising administering to a subject in need thereof an effective amount of a pharmaceutica composition, wherein the pharmaceutical composition comprises the compound of formula (I) or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a deuterated compound thereof, prodrugs thereof, or metabolites thereof.
  • Fig. 1 shows the body weight changes (%) of mice in G1 (CCl 4 +Vehicle s.c. Q2Wx2) and G2 (CCl 4 + Compound 75-2 (5 mg/kg) s.c. Q2Wx2) .
  • Fig. 2 shows the body weight changes (%) of mice in G1 (CCl 4 +Vehicle s.c. Q2Wx2) and G3 (CCl 4 + Compound 75-2 (15 mg/kg) s.c. single dose) .
  • Fig. 3 shows the body weight changes (%) of mice in G1 (CCl 4 +Vehicle s.c. Q2Wx2) and G4 (CCl 4 + Compound 75-2 (45 mg/kg) s.c. single dose) .
  • Fig. 4 shows the body weight changes of mice at day 28 (the end of dosing medication) in G1 (CCl 4 +Vehicle s.c. Q2Wx2) and G2 (CCl 4 + Compound 75-2 (5 mg/kg) s.c. Q2Wx2) .
  • Fig. 5 shows the body weight changes of mice at day 28 (the end of dosing medication) in G1 (CCl 4 +Vehicle s.c. Q2Wx2) and G3 (CCl 4 + Compound 75-2 (15 mg/kg) s.c. single dose) .
  • Fig. 6 shows the body weight changes of mice at day 28 (the end of dosing medication) in G1 (CCl 4 +Vehicle s.c. Q2Wx2) and G4 (CCl 4 + Compound 75-2 (45 mg/kg) s.c. single dose) .
  • Fig. 7 shows the concentration of Compound 75-2 in white adipose tissues (WAT) in Example 2.
  • Fig. 8 shows Compound 75-2 reduced total fat mass in a dose-dependent fashion in Example 2.
  • Fig. 9 shows Compound 75-2 reduced total body weight in a dose-dependent fashion in Example 2.
  • Fig. 10 shows the body weight (g) of mice over time after taking medication (compound 75-2 or semaglutide) in Example 2.
  • Fig. 11 shows the body weight change (%) of mice over time after taking medication (compound 75-2 or semaglutide) in Example 2.
  • Fig. 12 shows the concentration of Compound 75-2 in white adipose tissues (WAT) in Example 3.
  • Fig. 13 shows Compound 75-2 reduced total fat mass in a dose-dependent fashion in Example 3.
  • Fig. 14 shows Compound 75-2 reduced total body weight in a dose-dependent fashion in Example 3.
  • Fig. 15 shows the body weight (g) of mice over time after taking medication (compound 75-2 or tirzepatide) in Example 3.
  • Fig. 16 shows the body weight change (%) of mice over time after taking medication (compound 75-2 or tirzepatide) in Example 3.
  • Alkyl is a monovalent or divalent linear or branched saturated hydrocarbon radical.
  • an alkyl group can have 1 to 10 carbon atoms (i.e., C 1-10 alkyl) or 1 to 8 carbon atoms (i.e., C 1-8 alkyl) or 1 to 6 carbon atoms (i.e., C 1-6 alkyl) or 1 to 4 carbon atoms (i.e., C 1-4 alkyl) .
  • alkyl groups include, but are not limited to, methyl (Me, -CH 3 ) , ethyl (Et, -CH 2 CH 3 ) , 1-propyl (n-Pr, n-propyl, -CH 2 CH 2 CH 3 ) , 2-propyl (i-Pr, i-Propyl, -CH (CH 3 ) 2 ) , 1-butyl (n-Bu, n-butyl, -CH 2 CH 2 CH 2 CH 3 ) , 2-methyl-1-propyl (i-Bu, i-butyl, -CH 2 CH (CH 3 ) 2 ) , 2-butyl (s-Bu, s-butyl, -CH (CH 3 ) CH 2 CH 3 ) , 2-methyl-2-propyl (t-Bu, t-butyl, -C (CH 3 ) 3 ) , 1-pentyl (n-pentyl, -CH 2 CH 2 CH 3
  • Alkenyl is a monovalent or divalent linear or branched hydrocarbon radical with at least one carbon-carbon double bond.
  • an alkenyl group can have 2 to 8 carbon atoms (i.e., C 2-8 alkenyl) or 2 to 6 carbon atoms (i.e., C 2-6 alkenyl) or 2 to 4 carbon atoms (i.e., C 2-4 alkenyl) .
  • Alkenyl groups can be unsubstituted or substituted.
  • Alkynyl is a monovalent or divalent linear or branched hydrocarbon radical with at least one carbon-carbon triple bond.
  • an alkynyl group can have 2 to 8 carbon atoms (i.e., C 2-8 alkynyl) or 2 to 6 carbon atoms (i.e., C 2-6 alkynyl) or 2 to 4 carbon atoms (i.e., C 2-4 alkynyl) .
  • alkynyl groups include, but are not limited to, acetylenyl (-C ⁇ CH) , propargyl (-CH 2 C ⁇ CH) , and -CH 2 -C ⁇ C-CH 3 .
  • Alkynyl groups can be unsubstituted or substituted.
  • Alkoxy refers to the group -O-alkyl, where alkyl is as defined above.
  • C 1-4 alkoxy refers to an -O-alkyl group having 1 to 4 carbons. Alkoxy groups can be unsubstituted or substituted.
  • Halogen or “Halo” refers to fluoro (-F) , chloro (-Cl) , bromo (-Br) and iodo (-I) .
  • Haloalkyl is an alkyl as defined herein, wherein one or more hydrogen atoms of the alkyl are independently replaced by a halogen, which may be the same or different, such that the alkyl is divalent.
  • the alkyl group and the halogen can be any of those described above.
  • the haloalkyl defines the number of carbon atoms in the alkyl portion, e.g., C 1-4 haloalkyl includes CF 3 , CH 2 F, CHF 2 , CH 2 CF 3 , CH 2 CH 2 CF 3 , CCl 2 CH 2 CH 2 CH 3 , and C (CH 3 ) 2 (CF 2 H) .
  • Haloalkyl groups can be unsubstituted or substituted.
  • Aryl refers to a monovalent or divalent single all carbon aromatic ring or a multiple condensed all carbon ring system wherein the ring is aromatic.
  • an aryl group has 6 to 20 carbon atoms, 6 to 14 carbon atoms, 6 to 12 carbon atoms, or 6 to 10 carbon atoms.
  • Aryl includes a phenyl radical.
  • Aryl also includes multiple condensed ring systems (e.g., ring systems comprising 2, 3 or 4 rings) having about 9 to 20 carbon atoms in which multiple rings are aromatic. The rings of the multiple condensed ring system can be connected to each other via fused bonds when allowed by valency requirements.
  • aryl e.g., 6-10 membered aryl
  • the atom range is for the total ring atoms of the aryl.
  • a 6-membered aryl would include phenyl and a 10-membered aryl would include naphthyl.
  • aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, and the like.
  • Aryl groups can be unsubstituted or substituted.
  • Heteroaryl refers to a single aromatic ring that has at least one atom other than carbon in the ring, wherein the atom is selected from the group consisting of oxygen, nitrogen and sulfur; “5-10 membered heteroaryl” also includes multiple condensed ring systems that have at least one such aromatic ring, which multiple condensed ring systems are further described below. Thus, “5-10 membered heteroaryl” includes single aromatic rings of from about 1 to 6 carbon atoms and about 1-4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur. The sulfur and nitrogen atoms may also be present in an oxidized form provided the ring is aromatic.
  • Exemplary 5-10 membered heteroaryl ring systems include but are not limited to pyridyl, pyrimidinyl, oxazolyl or furyl.
  • “5-10 membered heteroaryl” also includes multiple condensed ring systems (e.g., ring systems comprising 2, 3 or 4 rings) wherein a 5-10 membered heteroaryl group, as defined above, is condensed with one or more rings selected from 5-10 membered heteroaryls (to form for example 1, 8-naphthyridinyl) and aryls (to form, for example, benzimidazolyl or indazolyl) to form the multiple condensed ring system.
  • 5-10 membered heteroaryl to form for example 1, 8-naphthyridinyl
  • aryls to form, for example, benzimidazolyl or indazolyl
  • a 5-10 membered heteroaryl (a single aromatic ring or multiple condensed ring system) can have about 1-20 carbon atoms and about 1-6 heteroatoms within the 5-10 membered heteroaryl ring.
  • tetrazolyl has 1 carbon atom and 4 nitrogen heteroatoms within the ring.
  • the rings of the multiple condensed ring system can be connected to each other via fused bonds when allowed by valency requirements. It is to be understood that the individual rings of the multiple condensed ring system may be connected in any order relative to one another.
  • the point of attachment for a 5-10 membered heteroaryl or 5-10 membered heteroaryl multiple condensed ring system can be at any suitable atom of the 5-10 membered heteroaryl or 5-10 membered heteroaryl multiple condensed ring system including a carbon atom and a heteroatom (e.g., a nitrogen) .
  • a heteroatom e.g., a nitrogen
  • the atom range is for the total ring atoms of the 5-10 membered heteroaryl and includes carbon atoms and heteroatoms.
  • the rings of the multiple condensed ring system may include an aryl ring fused to a heterocyclic ring with saturated or partially unsaturated bonds (e.g., 3, 4, 5, 6 or 7-membered rings) having from about 1 to 6 annular carbon atoms and from about 1 to 3 annular heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur in the ring.
  • a 5-10 membered heteroaryl includes thiazolyl and a 5-10 membered heteroaryl includes quinolinyl.
  • Exemplary 5-10 membered heteroaryls include but are not limited to pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalyl, quinazolyl, benzofuranyl, benzimidazolyl, thianaphthenyl, pyrrolo [2, 3-b] pyridinyl, quinazolinyl-4 (3H) -one, triazolyl, and tetrazolyl.
  • 5-10 membered heteroaryl groups can be unsubstituted or substituted.
  • Cycloalkyl is a monovalent or divalent single all carbon ring or a multiple condensed all carbon ring system wherein the ring in each instance is a non-aromatic saturated or unsaturated ring.
  • a cycloalkyl group has 3 to 12 carbon atoms, 3 to 10 carbon atoms, 3 to 8 carbon atoms, 3 to 6 carbon atoms, 3 to 5 carbon atoms, or 3 to 4 carbon atoms.
  • Exemplary single ring cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, and cyclooctyl.
  • Cycloalkyl also includes multiple condensed ring systems (e.g., ring systems comprising 2 rings) having about 7 to 12 carbon atoms. The rings of the multiple condensed ring system can be connected to each other via fused, spiro, or bridged bonds when allowed by valency requirements.
  • Exemplary multiple ring cycloalkyl groups include octahydropentalene, bicyclo [2.2.
  • Cycloalkyl groups can be unsubstituted or substituted.
  • Heterocyclyl or “heterocycle” or “heterocycloalkyl” as used herein refers to a single saturated or partially unsaturated non-aromatic ring or a non-aromatic multiple ring system that has at least one heteroatom in the ring (i.e., at least one annular (i.e., ring-shaped) heteroatom selected from oxygen, nitrogen, and sulfur) .
  • a heterocyclyl group has from 3 to about 20 annular atoms, for example from 3 to 12 annular atoms, for example from 4 to 12 annular atoms, 4 to 10 annular atoms, or 3 to 8 annular atoms, or 3 to 6 annular atoms, or 3 to 5 annular atoms, or 4 to 6 annular atoms, or 4 to 5 annular atoms.
  • the term includes single saturated or partially unsaturated rings (e.g., 3, 4, 5, 6 or 7-membered rings) having from about 1 to 6 annular carbon atoms and from about 1 to 3 annular heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur in the ring.
  • the rings of the multiple condensed ring (e.g. bicyclic heterocyclyl) system can be connected to each other via fused, spiro and bridged bonds when allowed by valency requirements.
  • Heterocycles include, but are not limited to, azetidine, aziridine, imidazolidine, morpholine, oxirane (epoxide) , oxetane, thietane, piperazine, piperidine, pyrazolidine, piperidine, pyrrolidine, pyrrolidinone, tetrahydrofuran, tetrahydrothiophene, dihydropyridine, tetrahydropyridine, quinuclidine, 2-oxa-6-azaspiro [3.3] heptan-6-yl, 6-oxa-1-azaspiro [3.3] heptan-1-yl, 2-thia-6-azaspiro [3.
  • binding means the specific association of the compound of interest to the thyroid hormone receptor.
  • One method of measuring binding in this disclosure is the ability of the compound to inhibit the association of 125 I-T3 with a mixture of thyroid hormone receptors using nuclear extracts or purified or partially purified thyroid hormone receptor (for example, alpha or beta) in a heterologous assay.
  • energy expenditure means basal or resting metabolic rate as defined by Schoeller et al, JAppl Physiol. 53 (4) : 955-9 (1982) . Increases in the resting metabolic rate can also be measured using increases in O 2 consumption and/or CO 2 efflux and/or increases in organ or body temperature.
  • Compound of the present disclosure includes the THR- ⁇ modulator disclosed herein, for example the THR- ⁇ modulator of the present disclosure includes compound of Formula (I) , (III) , (IV) .
  • Compound of the present disclosure includes the specific compounds as THR modulators disclosed herein.
  • Compound of the present disclosure includes any compound selected from the group consisting of compound 1 to compound 86.
  • Compound of the present disclosure includes any compound selected from the group consisting of compound 75, compound 75-1, compound 75-2, compound 75-3, compound 75-4, compound 75-5, and compound 75-6.
  • salts of compounds of Formula I and its prodrugs derived from the combination of a compound of this disclosure and an organic or inorganic acid or base include acetic acid, adipic acid, benzenesulfonic acid, (+) -7, 7-dimethyl-2-oxobicyclo [2.2.1] heptane-l-methanesulfonic acid, citric acid, 1, 2-ethanedisulfonic acid, dodecyl sulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glucuronic acid, hippuric acid, hydrochloride hemiethanolic acid, HBr, HCl, HI, 2-hydroxyethanesulfonic acid, lactic acid, lactobionic acid, maleic acid, methanesulfonic acid, methylbromide acid, methyl sulfuric acid, 2-naphthalenesulfonic acid, nitric acid,
  • Stepoisomer refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable.
  • the present application contemplates various stereoisomers and mixtures thereof and includes “enantiomers” , which refers to two stereoisomers whose molecules are non-superimposable mirror images of one another.
  • Solvate refers to the result of the interaction of a solvent and a compound. Solvates of salts of the compounds described herein are also provided. Hydrates of the compounds described herein are also provided.
  • Prodrug refers to a derivative of a drug that upon administration to the human body is converted to the parent drug according to some chemical or enzymatic pathway.
  • a prodrug is a biologically inactive derivative of a drug that upon administration to the human body is converted to the biologically active parent drug according to some chemical or enzymatic pathway.
  • administering means to provide a compound or other therapy, remedy or treatment.
  • a health care practitioner can directly provide a compound to an individual in the form of a sample, or can indirectly provide a compound to an individual by providing an oral or written prescription for the compound.
  • an individual can obtain a compound by themselves without the involvement of a health care practitioner.
  • Administration of the compound may or may not involve the individual actually internalizing the compound. In the case where an individual internalizes the compound the body is transformed by the compound in some way.
  • an effective amount refers to the amount of active agent that elicits a biological or medicinal response in a subject, including in a tissue or system of the subject, and that is being sought by a researcher, veterinarian, medical doctor, nutritionist, or other clinician or caregiver or by a subject, which includes one or more of the following:
  • Preventing the condition for example, preventing a condition in a subject that may be predisposed to the condition but does not yet experience or display the pathology or symptomatology of the condition;
  • Inhibiting the condition for example, inhibiting a condition in an individual that is experiencing or displaying the pathology or symptomatology of the condition (i.e., arresting further development of the pathology and/or symptomatology) ;
  • Ameliorating the condition for example, ameliorating a condition in an individual that is experiencing or displaying the pathology or symptomatology of the condition, (i.e., reversing the pathology and/or symptomatology) .
  • prevent, preventing or prevention such as prevention of obesity means prevention of the occurrence or onset of one or more symptoms associated with a particular disorder and does not necessarily mean the complete prevention of a disorder.
  • prevent, preventing and prevention refers to the administration of therapy on a prophylactic or preventative basis to an individual who may ultimately manifest at least one symptom of a disease or condition but who has not yet done so.
  • Such individuals can be identified on the basis of risk factors that are known to correlate with the subsequent occurrence of the disease.
  • prevention therapy can be administered without prior identification of a risk factor, as a prophylactic measure. Delaying the onset of the at least one symptom can also be considered prevention or prophylaxis.
  • treating refers to the administration of therapy to an individual who already manifests at least one symptom of a condition, or who has previously manifested at least one symptom of a condition, or who is identified as at risk of developing a condition.
  • “treating” can include alleviating, abating or ameliorating a condition's symptoms, preventing additional symptoms, ameliorating or preventing the underlying metabolic causes of symptoms, inhibiting the condition, e.g., arresting the development of the condition, relieving the condition, causing regression of the condition, relieving a second condition caused by the first condition, or stopping the symptoms of the condition either prophylacticly and/or therapeutically.
  • the term “treating” in reference to a condition includes a reduction in severity of one or more symptoms associated with a particular condition. Therefore, treating a condition does not necessarily mean a reduction in severity of all symptoms associated with a condition and does not necessarily mean a complete reduction in the severity of one or more symptoms associated with a condition. It has been shown that even modest decreases in weight or related parameters such as BMI, waist circumference and percent body fat, can result in improvement of health, for example, lower blood pressure, improved blood lipid profiles, or a reduction in sleep apnea.
  • the term “treating” also includes reducing the rate of increase in severity in a condition already manifested in a subject and/or reducing the rate of occurrence of new related conditions in the subject.
  • subject or “individual” means an animal.
  • animal includes birds and mammals.
  • a mammal includes a mice, dog, cat, cow, horse, goat, sheep, pig or human.
  • the animal is a human.
  • the animal is a male.
  • the animal is a female,
  • the subject of the method of the invention is an adolescent (e.g. 12 to less than 18 years of age, such as 12 to 16 years of age or 12 to less than 16 years of age) .
  • prodrug refers to any compound that when administered to a biological system generates a biologically active compound as a result of spontaneous chemical reaction (s) , enzyme catalyzed chemical reaction (s) , and/or metabolic chemical reaction (s) , or a combination of each.
  • Standard prodrugs are formed using groups attached to functionality, e.g., HO-, HS-, HOOC-, R 2 N-, associated with the drug, that cleave in vivo.
  • Standard prodrugs include but are not limited to carboxylate esters where the group is alkyl, aryl, aralkyl, acyloxyalkyl, alkoxycarbonyloxyalkyl as well as esters of hydroxyl, thiol and amines where the group attached is an acyl group, an alkoxycarbonyl, aminocarbonyl, phosphate or sulfate.
  • the groups illustrated are exemplary, not exhaustive, and one skilled in the art could prepare other known varieties of prodrugs. Such prodrugs of the compounds of the present disclosure fall within this scope. Prodrugs must undergo some form of a chemical transformation to produce the compound that is biologically active or is a precursor of the biologically active compound.
  • the prodrug is biologically active, usually less than the drug itself, and serves to improve drug efficacy or safety through improved oral bioavailability, and/or pharmacodynamic half-life, etc.
  • Prodrug forms of compounds may be utilized, for example, to improve bioavailability, improve subject acceptability such as by masking or reducing unpleasant characteristics such as bitter taste or gastrointestinal irritability, alter solubility such as for intravenous use, provide for prolonged or sustained release or delivery, improve ease of formulation, or provide site-specific delivery of the compound.
  • Prodrugs are described in The Organic Chemistry of Drug Design and Drug Action, by Richard B. Silverman, Academic Press, San Diego, 1992. Chapter 8: "Prodrugs and Drug delivery Systems” pp.
  • the term "enhanced oral bioavailability" refers to an increase of at least 50%of the absorption of the dose of the parent drug, unless otherwise specified. In an additional aspect the increase in oral bioavailability of the prodrug (compared to the parent drug) is at least 100%, that is a doubling of the absorption. Measurement of oral bioavailability usually refers to measurements of the prodrug, drug, or drug metabolite in blood, plasma, tissues, or urine following oral administration compared to measurements following systemic administration of the compound administered orally.
  • thyroid hormone receptors refers to intracellular proteins located in cell nuclei that, following the binding of thyroid hormone, stimulate transcription of specific genes by binding to DNA sequences called thyroid hormone response elements (TREs) .
  • TR regulates the expression of a wide variety of genes involved in metabolic processes (e.g., cholesterol homeostasis and fatty acid oxidation) and growth and development in many tissues, including liver, muscle and heart.
  • TR alpha on chromosome 17
  • TR beta on chromosome 3
  • TR alpha-1 and TR alpha-2 and TR beta-1 and TR beta-2, respectively.
  • TRs are high affinity receptors for thyroid hormones, especially triiodothyronine.
  • compositions a compound useful in the present disclosure. Also provided are pharmaceutical compositions of the present disclosure having an oral bioavailability of least 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%or at least 80%.
  • Metabolic diseases refer to a category of diseases characterized by metabolic disorders due to abnormalities in the body's material or energy metabolism. They are usually diseases involving abnormalities in multiple systems throughout the body. The metabolic diseases herein are specifically related to abnormal fat metabolism, preferably including obesity, overweight, and weight-related conditions.
  • BMI Body Mass Index
  • “Obesity” means, with regard to an individual, one having a BMI ⁇ 30 kg/m 2 .
  • “Overweight” refers to a person's weight exceeding the healthy weight range, and having a 25 kg/m 2 ⁇ BMI ⁇ 30 kg/m 2 .
  • Weight management means behaviors, techniques, and physiological processes that contribute to a person’s ability to attain and maintain a healthy weight.
  • a healthy weight for a particular patient may be determined by consultation with a health care professional;
  • weight management means a reduction in body weight and/or change in body fat composition.
  • Chronic weight management treatment facilitates patient ability to achieve their healthy weight goals.
  • “chronic weight management” means, for example, a subject achieves their healthy weight goal and maintains a weight that is within their healthy weight goal range for a period of time.
  • “chronic weight management” means a subject achieves their healthy weight goal and maintains a weight that is within their healthy weight goal range for at least 13 weeks.
  • a subject achieves their healthy weight goal and maintains a weight within their healthy weight goal range for at least 26 weeks.
  • “chronic weight management” means a subject achieves their healthy weight goal and maintains a weight within their healthy weight goal range for at least 52 weeks.
  • “chronic weight management” means a subject achieves their healthy weight goal and maintains a weight within their healthy weight goal range for at least 104 weeks.
  • treatment of obesity in an individual in need thereof refers to a judgment made by a healthcare practitioner that an individual requires or will benefit from treatment of obesity. This judgment is made based on a variety of factors that are in the realm of a healthcare practitioner's expertise, but that includes the knowledge that the individual has a condition that is treatable by the methods of the disclosure.
  • a body weight a body mass index (BMI)
  • BMI body mass index
  • waist circumference or a body fat percentage of the individual determine if the individual meets a body weight threshold, a BMI threshold, a waist circumference threshold or a body fat percentage threshold.
  • prevention of obesity in an individual in need thereof refers to a judgment made by a healthcare practitioner that an individual requires or will benefit from prevention of obesity. This judgment is made based on a variety of factors that are in the realm of a healthcare practitioner's expertise, but that includes the knowledge that the individual has a condition that is treatable by the methods disclosed herein.
  • an individual in need of prevention of obesity is an individual who is overweight (also called pre-obese) .
  • an individual in need of prevention of obesity is an individual who has a family history of obesity.
  • a body weight a body mass index (BMI)
  • BMI body mass index
  • waist circumference or a body fat percentage of the individual to determine if the individual meets a body weight threshold, a BMI threshold, a waist circumference threshold or a body fat percentage threshold.
  • the term “greater than” is used interchangeably with the symbol >and the term less than is used interchangeably with the symbol ⁇ . Likewise the term less than or equal to is interchangeably with the symbol ⁇ .
  • One aspect of the present disclosure provides a method for preventing, treating, or ameliorating obesity, comprising administering subcutaneously to a subject in need thereof an effective amount of a THR- ⁇ modulator having formula I,
  • G is selected from the group consisting of -O-and -C (X 9 X 8 ) -;
  • T is selected from the group consisting of - (C (R d ) 2 ) m -and -O- (C (R d ) 2 ) m -;
  • n is selected from the group consisting of 0, 1, 2 and 3;
  • X is selected from the group consisting of
  • each of R a and R b is independently selected from the group consisting of CH 3 , CD 3 , Cl, Br, I and CF 3 ;
  • R c is selected from the group consisting of hydrogen, halogen, -CF 3 , -OCF 3 , cyano, optionally substituted -C 1 -C 12 alkyl, optionally substituted -C 2 -C 12 alkenyl, optionally substituted-C 2 -C 12 alkynyl, optionally substituted -C 0-6 alkyl-aryl, optionally substituted -C 0-6 alkyl-cycloalkyl, optionally substituted -C 0-6 alkyl-heterocycloalkyl, and optionally substituted -C 3-8 cycloalkyl;
  • R c is optionally substituted with one to ten substituents each independently selected from the group consisting of halogen, H and D;
  • each of R d is independently selected from the group consisting of hydrogen, halogen, and C 1-6 alkyl;
  • each of R 1 and R 2 is independently selected from the group consisting of H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 6-10 aryl, heteroaryl, C 1-6 alkyl-C 6-10 aryl, and C 1-6 alkyl-heteroaryl, or R 1 and R 2 are combined with the atoms to which they are attached to form a C 3-10 cycloalkyl or a heterocyclyl;
  • R 3 is selected from the group consisting of H, C 1-30 alkyl, C 5-10 cycloalkyl, C 1-30 haloalkyl, C 6-10 aryl, and C 6-10 aryl-C 1-8 alkyl, wherein R 3 is optionally substituted with one or more substituents each independently selected from the group consisting of halo, NH 2 , NO 2 , OH, CN, -C 1-6 alkyl, C 1-6 haloalkyl, and O-C 1-6 alkyl;
  • R 4 is selected from the group consisting of C 6-10 aryl, C 1-6 alkyl-C 6-10 aryl, and 5-10 membered heteroaryl, wherein R 4 is optionally substituted with one or more substituents each independently selected from the group consisting of halo, NH 2 , NO 2 , OH, CN, -C 1-6 alkyl, C 1-6 haloalkyl, and O-C 1-6 alkyl;
  • R 5 is selected from the group consisting of H, -COR 6 , -COOR 6 , CH 2 OC (O) OR 7 , -CONHR 6 , -CONR 7 R 10 , -CONR 6 R 7 , -CH 2 OCOR 6 , -CH 2 OCONHR 6 , and
  • each of R 6 is independently selected from the group consisting of C 1- 30 alkyl, C 1-30 alkenyl, and C 1-30 alkynyl, wherein C 1-30 alkyl, C 1-30 alkenyl, and C 1-30 alkynyl is optionally substituted with one or more substituents each independently selected from the group consisting of halo, -O-C 1-30 alkyl, -S-C 1-30 alkyl, cycloalkyl, heterocyclyl, aryl, and 5-10 membered heteroaryl, wherein each of the -O-C 1-30 alkyl, -S-C 1-30 alkyl, cycloalkyl, heterocyclyl, aryl, and 5-10 membered heteroaryl is optionally substituted with one or more substituents each independently selected from the group consisting of halo and C 1-3 alkyl;
  • R 7 is selected from the group consisting of H, -C 1-30 alkyl, -C 2-30 alkenyl, -C 2-30 alkynyl, -C (O) C 1-30 alkyl, -C (O) C 2-30 alkenyl, -C (O) C 2-30 alkynyl, -C (O) OC 1-30 alkyl, -C (O) OC 2-30 alkenyl, -C (O) OC 2-30 alkynyl, -C (O) NR c C 1-30 alkyl, -C (O) NR c C 2-30 alkenyl, and -C (O) NR c C 2-30 alkynyl, wherein each of the -C 1-30 alkyl, -C 2-30 alkenyl, -C 2-30 alkynyl, -C (O) C 1-30 alkyl, -C (O) C 2-30 alkenyl, and -C (O)
  • R 6 and R 7 are combined with atoms to which they are attached to form a 5-10 membered heterocyclyl, and wherein the 5-10 membered heterocyclyl is optionally substituted with one or more substituents each independently selected from the group consisting of halo, NH 2 , NO 2 , OH, CN, -C 1-6 alkyl, C 1-6 haloalkyl, and O-C 1-6 alkyl;
  • each of R 8 and R 9 is independently selected from the group consisting of H, OH, C 1-6 alkyl, halo, -O-C 1-3 alkyl, -S-C 1-3 alkyl, -C 3-10 cycloalkyl, 3-10 membered heterocyclyl, aryl, and 5-10 membered heteroaryl, wherein each of the C 1-6 alkyl, -O-C 1-3 alkyl, -S-C 1-3 alkyl, -C 3-10 cycloalkyl, 3-10 membered heterocyclyl, aryl, and 5-10 membered heteroaryl can be optionally substituted with one or more substituents each independently selected from the group consisting of OH, halo, -O-C 1-3 alkyl, -S-C 1-3 alkyl, -C 3-10 cycloalkyl, 3-10 membered heterocyclyl, aryl, and 5-10 membered heteroaryl;
  • R 8 and R 9 are combined with the atoms to which they are attached to form a 3-10 membered heterocyclyl, which is optionally substituted with one to four R 6, wherein each R 6 is independently selected from the group consisting of H, halo, C 1-6 alkyl, C 1-6 haloalkyl, and alkoxy;
  • R 10 is selected from the group consisting of H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, - (CH 2 ) n C 3-10 cycloalkyl, - (CH 2 ) n aryl, and - (CH 2 ) n heteroaryl, wherien each of the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, - (CH 2 ) n C 3-10 cycloalkyl, - (CH 2 ) n aryl, and - (CH 2 ) n heteroaryl is optionally substituted with one or more substituents each independently selected from the group consisting of halo, -O-C 1-3 alkyl, -S-C 1-3 alkyl, -C 3-10 cycloalkyl, 3-10 membered heterocyclyl, aryl, and 5-10 membered heteroaryl;
  • X 8 and X 9 is independently selected from the group consisting of H, D and halo;
  • n is selected from the group consisting of 0, 1, 2, and 3;
  • each 5-10 membered heteroaryl mentioned above has one to four heteroatoms, and each is independently selected from the group consisting of N, O, and S;
  • each 3-10 membered heterocyclyl mentioned above has one to four heteroatoms, and each is independently selected from the group consisting of N, O, and S.
  • Another aspect of the present disclosure provides a method for preventing, treating, or ameliorating overweight, comprising administering to a subject in need thereof an effective amount of a THR- ⁇ modulator having formula I or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a deuterated compound thereof, prodrugs thereof, or metabolites thereof, wherein the formula I is as defined above.
  • Another aspect of the present disclosure provides a method for preventing, treating, or ameliorating overweight, comprising administering to a subject in need thereof an effective amount of a THR- ⁇ modulator having formula I or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a deuterated compound thereof, prodrugs thereof, or metabolites thereof, wherein the formula I is as defined above.
  • Another aspect of the present disclosure provides a method for weight management or chronic weight management, comprising administering to a subject in need thereof an effective amount of a THR- ⁇ modulator having Formula I or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a deuterated compound thereof, prodrugs thereof, or metabolites thereof, wherein the formula I is as defined above.
  • THR- ⁇ modulator having Formula I or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a deuterated compound thereof, prodrugs thereof, or metabolites thereof in the preparation of a medicament for the treatment of obesity or overweight, wherein the formula I is as defined above.
  • THR- ⁇ modulator having Formula I or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a deuterated compound thereof, prodrugs thereof, or metabolites thereof in the preparation of a medicament for weight management or chronic weight management, wherein the formula I is as defined above.
  • THR- ⁇ modulator having formula I or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a deuterated compound thereof, prodrugs thereof, or metabolites thereof used for preventing, treating, or ameliorating obesity or overweight, wherein the THR- ⁇ modulator is administered to a subject in need thereof, wherein the formula I is as defined above.
  • THR- ⁇ modulator having formula I or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a deuterated compound thereof, prodrugs thereof, or metabolites thereof used for weight management or chronic weight management, wherein the THR- ⁇ modulator is administered to a subject in need thereof, wherein the formula I is as defined above.
  • Another aspect of the present application also relates to a method for weight management or chronic weight management, comprising administering to a subject in need thereof an effective amount of a pharmaceutica composition, wherein the pharmaceutical composition comprises the compound of formula (I) or a stereoisomer thereof, a pharmaceutically acceptable salt thereof, a deuterated compound thereof, prodrugs thereof, or metabolites thereof.
  • the THR- ⁇ modulator is a compound having formula III:
  • each of R a and R b is independently selected from the group consisting of CH 3 , CD 3 , Cl, Br, I and CF 3 ;
  • each R c is selected from the group consisting of hydrogen, halogen, -CF 3 , -OCF 3 , cyano, optionally substituted -C 1 -C 12 alkyl, optionally substituted -C 2 -C 12 alkenyl, optionally substituted-C 2 -C 12 alkynyl, optionally substituted-C 0-6 alkyl-aryl, optionally substituted -C 0-6 alkyl-cycloalkyl, optionally substituted -C 0-6 alkyl-heterocycloalkyl, optionally substituted -C 3-8 cycloalkyl;
  • R c is optionally substituted with one to ten substituents each independently selected from the group consisting of halogen, H and D;
  • each of X 8 , X 9 , Z 1 and Z 2 is independently selected from the group consisting of H, D and halo;
  • Z 3 is independently selected from the group consisting of Oand-CH 2 -;
  • each of R 1 and R 2 is independently selected from the group consisting of H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 6-10 aryl, heteroaryl, C 1-6 alkyl-C 6-10 aryl, and C 1-6 alkyl-heteroaryl, or R 1 and R 2 are combined with the atoms to which they are attached to form a C 3-10 cycloalkyl or a heterocyclyl;
  • R 3 is selected from the group consisting of H, C 1-30 alkyl, C 5-10 cycloalkyl, C 1-30 haloalkyl, C 6-10 aryl, and C 6-10 aryl-C 1-8 alkyl, wherein R 3 is optionally substituted with one or more substituents each independently selected from the group consisting of halo, NH 2 , NO 2 , OH, CN, -C 1-6 alkyl, C 1-6 haloalkyl, and O-C 1-6 alkyl;
  • R 4 is selected from the group consisting of C 6-10 aryl, C 1-6 alkyl-C 6-10 aryl, and 5-10 membered heteroaryl, wherein R 4 is optionally substituted with one or more substituents each independently selected from the group consisting of halo, NH 2 , NO 2 , OH, CN, -C 1-6 alkyl, C 1-6 haloalkyl, and O-C 1-6 alkyl;
  • R 5 is selected from the group consisting of H, -COR 6 , -CONHR 6 , -COOR 6 , -CONR 6 R 7 , -CH 2 OCOR 6 , and -CH 2 OCONHR 6 ;
  • each of R 6 and R 7 is independently selected from the group consisting of C 1-30 alkyl, C 1-30 alkenyl and C 1-30 alkynyl, wherein the C 1-30 alkyl, the C 1-30 alkenyland the C 1-30 alkynyl is optionally substituted with one or more substituents each independently selected from the group consisting of halo, NH 2 , NO 2 , OH, CN, O-C 1-6 alkyl, C 6-10 aryl, and heteroaryl; or R 6 and R 7 are combined with atoms to which they are attached to form a 5-10 membered heterocyclyl, and wherein the 5-10 membered heterocyclyl is optionally substituted with one or more substituents each independently selected from the group consisting of halo, NH 2 , NO 2 , OH, CN, -C 1-6 alkyl, C 1-6 haloalkyl, and O-C 1-6 alkyl.
  • Z 3 is O.
  • each of Z 1 and Z 2 is H.
  • R 4 is selected from the group consisting of C 6-10 aryl, C 1-6 alkyl-C 6-10 aryl, and 5-10 membered heteroaryl, wherein R 4 is optionally substituted with one or more substituents each independently selected from the group consisting of halo, -C 1-6 alkyl, C 1-6 haloalkyl, and O-C 1-6 alkyl.
  • R 3 is selected from the group consisting of C 1-30 alkyl, and C 5-10 cycloalkyl.
  • R c is independently selected from the group consisting of C 1-6 alkyl, C 0-6 alkyl-aryl, C 0-6 alkyl-cycloalkyl, C 0-6 alkyl-heterocycloalkyl, and C 3-8 cycloalkyl; wherein the R c is optionally substituted with halo.
  • the THR- ⁇ modulator is a compound having formula IV,
  • each of R 1 and R 2 is independently selected from the group consisting of H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 6-10 aryl, heteroaryl, C 1-6 alkylC 6-10 aryl, and C 1-6 alkyl-heteroaryl, or R 1 and R 2 are combined with the atoms to which they are attached to form a C 3-10 cycloalkyl or a heterocyclyl;
  • R 3 is selected from the group consisting of H, C 1-30 alkyl, C 5-10 cycloalkyl, C 1-30 haloalkyl, C 6-10 aryl, and C 6-10 aryl-C 1-8 alkyl, wherein R 3 is optionally substituted with one or more substituents each independently selected from the group consisting of halo, NH 2 , NO 2 , OH, CN, -C 1-6 alkyl, C 1-6 haloalkyl, and O-C 1-6 alkyl;
  • R 4 is selected from the group consisting of C 6-10 aryl, C 1-6 alkyl-C 6-10 aryl, and 5-10 membered heteroaryl, wherein R 4 is optionally substituted with one or more substituents each independently selected from the group consisting of halo, NH 2 , NO 2 , OH, CN, -C 1-6 alkyl, C 1-6 haloalkyl, and O-C 1-6 alkyl;
  • R 5 is selected from the group consisting of H, -COR 6 , -CONHR 6 , -COOR 6 , -CONR 6 R 7 , -CH 2 OCOR 6 , and -CH 2 OCONHR 6 ;
  • each of X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 and X 9 is independently selected from the group consisting of H, D and halo,
  • each of Z 1 and Z 2 is independently selected from the group consisting of H, D and halo;
  • Ra and Rb is independently selected from the group consisting of CH 3 , CD 3 , Cl, Br, I and CF 3 ;
  • each of R 6 and R 7 is independently selected from the group consisting of C 1-30 alkyl, C 1-30 alkenyland C 1-30 alkynyl, wherein the C 1-30 alkyl, the C 1-30 alkenyl and the C 1-30 alkynyl is optionally substituted with one or more substituents each independently selected from the group consisting of halo, NH 2 , NO 2 , OH, CN, O-C 1-6 alkyl, C 6-10 aryl, and heteroaryl; or R 6 and R 7 are combined with atoms to which they are attached to form a 5-10 membered heterocyclyl, and wherein the 5-10 membered heterocyclyl is optionally substituted with one or more substituents each independently selected from the group consisting of halo, NH 2 , NO 2 , OH, CN, -C 1-6 alkyl, C 1-6 haloalkyl, and O-C 1-6 alkyl.
  • each of Z 1 and Z 2 is H.
  • R 4 is selected from the group consisting of C 6-10 aryl, C 1-6 alkyl-C 6-10 aryl, and 5-10 membered heteroaryl, wherein R 4 is optionally substituted with one or more substituents each independently selected from the group consisting of halo, -C 1-6 alkyl, C 1-6 haloalkyl, and O-C 1-6 alkyl.
  • R 3 is selected from the group consisting of C 1-30 alkyl, and C 5-10 cycloalkyl.
  • THR- ⁇ modulator is a compound having formula V
  • R 1 and R 2 is independently selected from the group consisting of H, C 1-6 alkyl, C 6-10 aryl, heteroaryl, C 1-6 alkyl-C 6-10 aryl, and C 1-6 alkyl-heteroaryl;
  • R 3 is selected from the group consisting of H, C 1-30 alkyl, and C 5-10 cycloalkyl;
  • R 4 is selected from the group consisting of C 6-10 aryl, C 1-6 alkyl-C 6-10 aryl, and 5-10 membered heteroaryl, wherein R 4 is optionally substituted with one or more substituents each independently selected from the group consisting of halo, -C 1-6 alkyl, C 1-6 haloalkyl, and O-C 1-6 alkyl.
  • R 4 is selected from the group consisting of C 6-10 aryl, C 1-6 alkyl-C 6-10 aryl, and 5-10 membered heteroaryl, wherein R 4 is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, C 1-6 alkyl, C 1-6 haloalkyl, and O-C 1-6 alkyl.
  • R 3 is selected from the group consisting of C 1-30 alkyl and C 5-10 cycloalkyl.
  • THR- ⁇ modulator is a compound having formula VI
  • R 1 and R 2 is independently selected from the group consisting of H, C 1-6 alkyl, C 6-10 aryl , heteroaryl, C 1-6 alkyl-C 6-10 aryl, and C 1-6 alkyl-heteroaryl; wherein the alkyl, aryl and heteroaryl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, C 1-6 alkyl and C 1-6 haloalkyl;
  • R 3 is selected from the group consisting of H, C 1-30 alkyl, and C 5-10 cycloalkyl;
  • R 4 is selected from the group consisting of C 6-10 aryl, C 1-6 alkyl-C 6-10 aryl, and 5-10 membered heteroaryl, wherein R 4 is optionally substituted with one or more substituents each independently selected from the group consisting of halo, -C 1-6 alkyl, C 1-6 haloalkyl, and O-C 1-6 alkyl;
  • p is an integer from 0-3.
  • the R 3 is selected from the group consisting of C 1-6 alkyl and C 5-10 cycloalkyl.
  • the R 3 is selected from the group consisting of C 7-30 alkyl and C 5-10 cycloalkyl.
  • the R 4 is C 6-10 aryl; and the C 6-10 aryl is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, C 1-6 alkyl.
  • the THR- ⁇ modulator is selected from the group consisting of
  • the THR- ⁇ modulator is selected from the group consisting of
  • the THR- ⁇ modulator is selected from the group consisting of
  • the THR- ⁇ modulator is selected from the group consisting of
  • the THR- ⁇ modulator is selected from the group consisting of
  • the THR- ⁇ modulator is administered once daily, once weekly, once every two weeks, once monthly, once every two months, once every three months, once every six months, or once annually.
  • the THR- ⁇ modulator is administered once weekly, once every two weeks, once monthly, or once every two months.
  • the THR- ⁇ modulator is administered at a dose of about 0.1 mg to about 3 g, or about 1 mg to about 50 mg, or about 50 to about 250 mg, or about 150 to about 500 mg, or about 150 to about 250 mg, or about 250 mg to about 1 g, or about 100 mg to about 2 g, or about 500 mg to about 2 g, or about 500 mg to about 1 g, or about 100 mg to about 300 mg, about 5 mg to about 25 mg, about 20 mg to about 100 mg, about 5 mg to about 100 mg, about 5 mg to about 500 mg, about 50 mg to about 300 mg, about 100 mg to about 200 mg, about 100 mg to about 500 mg, or about 5 mg to about 50 mg.
  • the THR- ⁇ modulator is administered subcutaneously, intravenously, intramuscularly, intraperitoneally, orally, or via inhalation.
  • the THR- ⁇ modulator is administered Subcutaneous injection.
  • the subject is human.
  • the subject before the administration of the THR- ⁇ modulator, the subject has a BMI of 25 kg/m 2 or greater.
  • the subject before the administration of the THR- ⁇ modulator, the subject has a BMI of 27 kg/m 2 or greater.
  • the subject before the administration of the THR- ⁇ modulator, the subject has a BMI of 30 kg/m 2 or greater.
  • the subject before the administration of the THR- ⁇ modulator, the subject is obesity or overweight.
  • the subject before the administration of the THR- ⁇ modulator, the subject has a weight-related condition, preferablythe, weight-related condition is selected from the group consisting of high blood pressure, type 2 diabetes and high cholesterol.
  • administering to a subject in need thereof an effective amount of a THR- ⁇ modulator is for a minimum of 13 weeks.
  • administering to a subject in need thereof an effective amount of a THR- ⁇ modulator is for a minimum of 26 weeks.
  • administering to a subject in need thereof an effective amount of a THR- ⁇ modulator is for a minimum of 52 weeks.
  • administering to a subject in need thereof an effective amount of a THR- ⁇ modulator is for a minimum of 104 weeks.
  • Another aspect of the present disclosure provides a method for weight management or chronic weight management, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition, wherein the pharmaceutical composition comprises the compound selected from the group consisting of
  • Another aspect of the present disclosure provides a method for preventing, treating, or ameliorating obesity or overweight, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition, wherein the pharmaceutical composition comprises the compound selected from the group consisting of
  • Yet still another aspect of the present disclosure provides a pharmaceutical composition comprising the THR- ⁇ modulator of the present disclosure, and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition comprising a THR- ⁇ modulator selected from the group consisting of
  • the pharmaceutical composition comprising a THR- ⁇ modulator selected from the group consisting of
  • the pharmaceutical composition of the present disclosure is used for preventing, treating, or ameliorating obesity or overweight.
  • the pharmaceutical composition of the present disclosure is used for weight management or chronic weight management.
  • the pharmaceutical composition comprising the compound, the stereoisomer, the pharmaceutically acceptable salt, or the deuterated compound thereof of the present disclosure may be prepared with one or more pharmaceutically acceptable excipients, the excipients may be selected in accordance with conventional practice. Tablets may contain excipients, including flow aids, fillers, binders, and the like. Aqueous compositions may be prepared in a sterile form and may generally be isotonic when intended to be delivered by means other than oral administration.
  • the compositions may comprise excipients, such as those set forth in Rowe et al, Handbook of Pharmaceutical Excipients, 6th edition, American Pharmacists Association, 2009. Excipients may include ascorbic acid and other antioxidants, chelating agents such as ethylenediaminetetraacetic acid, carbohydrates such as dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid, and the like.
  • the compositions are provided in solid dosage forms, including solid oral dosage forms.
  • the pharmaceutical composition may be prepared by any of the methods well known in the art of pharmacy, including oral administration. Such methods include the step of bringing into association the active ingredient (e.g., a compound of the present disclosure or a pharmaceutical salt thereof) with one or more pharmaceutically acceptable excipients.
  • the active ingredient e.g., a compound of the present disclosure or a pharmaceutical salt thereof
  • the pharmaceutical compositions are prepared by unifor mly and intimately bringing into association the active ingredient with liquid excipients or finely divided solid excipients or both, and then, if desired, shaping the product.
  • Techniques and formulations generally are found in Remington: The Science and Practice of Pharmacy, 21st Edition, Lippincott Wiliams and Wilkins, Philadelphia, Pa., 2006.
  • the pharmaceutical compositions of the present disclosure are presented in unit dosage form, including but not limited to capsules, sachets, or tablets, each containing a predetermined amount of the active ingredient.
  • the pharmaceutical composition is a tablet.
  • the pharmaceutical composition disclosed herein comprises one or more of the compound, the stereoisomer, the pharmaceutically acceptable salt, or the deuterated compound thereof of the present disclosure, as well as pharmaceutically acceptable excipients and, optionally, other therapeutic agents.
  • the pharmaceutical compositions containing the active ingredient may be in any form suitable for the intended method of administration. When intended for oral use, for example, tablets, lozenges, ingots, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups, or elixirs may be prepared.
  • compositions for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, and such compositions may contain one or more excipients, including sweeteners, flavoring agents, coloring agents, and preservatives, to provide palatable formulations. Tablets containing the active ingredient with a non-toxic pharmaceutically acceptable excipient are acceptable and said excipient is suitable for the production of tablets.
  • excipients may be, for example, inert diluents, such as calcium or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, povidone, calcium or sodium phosphate; granulating and disintegrating agents, such as maize starch, or alginic acid; binding agents, such as cellulose, microcrystalline cellulose, starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.
  • inert diluents such as calcium or sodium carbonate, lactose, lactose monohydrate, croscarmel
  • a dosage form for oral administration to humans may contain approximately 1 to 1000 mg of active material formulated with an appropriate and convenient amount of a pharmaceutically acceptable excipient.
  • the pharmaceutically acceptable excipient varies from about 5%to about 95%of the total compositions (weight: weight) .
  • the pharmaceutical composition of the present disclosure does not contain an agent that affects the rate at which the active ingredient is metabolized.
  • pharmaceutical compositions comprising a compound of the present disclosure in one aspect do not comprise an agent that would affect (e.g., slow, hinder or retard) the metabolism of a compound of the present disclosure or any other active ingredient administered separately, sequentially or simultaneously with a compound of the present disclosure.
  • any of the methods, kits, articles of manufacture, and the like detailed herein in one aspect do not comprise an agent that would affect (e.g., slow, hinder or retard) the metabolism of a compound of the present disclosure or any other active ingredient administered separately, sequentially or simultaneously with a compound of the present disclosure.
  • the above-described pharmaceutical compositions are for use in humans or animals.
  • the present disclosure also includes compounds of the present disclosure which are administered as a single active ingredient of a pharmaceutically acceptable composition that may be prepared by conventional methods known in the art, for example, by combining the active ingredient to a pharmaceutically acceptable, therapeutically inert organic and/or inorganic carrier or excipient, or by mixing therewith.
  • the present disclosure provided herein are uses of the compounds of the present disclosure as a second or other active ingredient, said second or other active ingredient being synergistic with other active ingredients in known drugs, or the compounds of the present disclosure being administered with such drugs.
  • the compounds of the present disclosure may also be used in the form of a prodrug or other suitably modified form that releases the active ingredient in vivo.
  • the compounds of the disclosure may be prepared using methods disclosed herein and routine modifications thereof which will be apparent given the disclosure herein and methods well known in the art. Conventional and well-known synthetic methods may be used in addition to the teachings herein.
  • the synthesis of typical compounds of Formula I, or a pharmaceutically acceptable salt thereof, e.g., compounds having structures described by one or more of Formula I, or other formulas or compounds disclosed herein, may be accomplished as described in the following examples.
  • Typical embodiments of compounds in accordance with the present application may be synthesized using the general reaction schemes and/or examples described below. It will be apparent given the description herein that the general schemes may be altered by substitution of the starting materials with other materials having similar structures to result in products that are correspondingly different. Descriptions of syntheses follow to provide numerous examples of how the starting materials may vary to provide corresponding products. Starting materials are typically obtained from commercial sources or synthesized using published methods for synthesizing compounds which are embodiments of the present application, inspection of the structure of the compound to be synthesized will provide the identity of each substituent group The identity of the final product will generally render apparent the identity of the necessary starting materials by a simple process of inspection, given the examples herein. Group labels (e.g., R1, R2) used in the reaction schemes herein are for illustrative purposes only and unless otherwise specified do not necessarily match by name or function the labels used elsewhere to describe compounds of Formula I or aspects or fragments thereof.
  • Group labels e.g., R1, R2
  • the compounds of this disclosure can be prepared from readily available starting materials using, for example, the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc. ) are given; other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.
  • protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions.
  • Suitable protecting groups for various functional groups as well as suitable conditions for protecting and deprotecting particular functional groups are well known in the art. For example, numerous protecting groups are described in T. W. Greene and G. M. Wuts (1999) Protecting Groups in Organic Synthesis, 3rd Edition, Wiley, New York, and references cited therein.
  • the compounds of the present aapplication may contain one or more chiral centers. Accordingly, if desired, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers or as stereoisomer-enriched mixtures. All such stereoisomers (and enriched mixtures) are included within the scope of this disclosure, unless otherwise indicated. Pure stereoisomers (or enriched mixtures) may be prepared using, for example, optically active starting materials or stereoselective reagents well-known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, chiral resolving agents, and the like.
  • the starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof.
  • many of the starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA) .
  • Others may be prepared by procedures or obvious modifications thereof, described in standard reference texts such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley, and Sons, 1991) , Rodd's Chemistry of Carbon Compounds, Volumes 1-5, and Supplemental (Elsevier Science Publishers, 1989) organic Reactions, Volumes 1-40 (John Wiley, and Sons, 1991) , March's Advanced Organic Chemistry, (John Wiley, and Sons, 5thEdition, 2001) , and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989) .
  • solvent inert organic solvent or “inert solvent” refer to a solvent inert under the conditions of the reaction being described in conjunction therewith (including, for example, benzene, toluene, acetonitrile, tetrahydrofuran ( “THF” ) , N, N-dimethylformamide ( “DMF” ) , chloroform, methylene chloride (or dichloromethane) , diethyl ether, methanol, pyridine and the like) .
  • the solvents used in the reactions of the present application are inert organic solvents, and the reactions are carried out under an inert gas, preferably nitrogen.
  • q.s. means adding a quantity sufficient to achieve a stated function, e.g., to bring a solution to the desired volume (i.e., 100%) .
  • Pentan-3-ol (28 g, 318 mmol) was added to a solution of Int A-1 (60 g, 317 mmol) , Imidazole (21 g, 323 mmol) , HATU (180 g, 473 mmol) and TEA (64 g, 633 mmol) in DMF/DCM (500ml/500ml) , and stirred overnight at RT. The reaction was concentrated in vacuo to remove the DCM. The residue was added into water and stirred for 1 h. The mixture was filtrated to obtain a solid. The solid was dried to obtain Int A-2 (80.0g, yield 97.3%) .
  • the Int A-2 (50 g, 193 mmol) was dissolved into the solution of HCl in dioxane (4 M, 500 ml) at 0-5°C, and stirred for 1 h. The reaction was concentrated in vacuo to obtain a solid. The solid was added into DCM (500 ml) and saturated sodium carbonate solution (500 ml) , and stirred for 15 mins. The organic layer was separated and concentrated in vacuo to obtain Int A (27.0 g, yield 87.9%) .
  • n-BuLi (4.3 ml, 2.5 M in hexane) was added to a solution of Int E-4 (1.9 g, 7.16 mmol) in THF (20 ml) at -78°C and stirred for 30 min. Then 2, 6-dimethyl-4- ( (triisopropylsilyl) oxy) benzaldehyde (2.31 g, 7.52 mmol) was added dropwisely and for stirred 1 h at -78°C. The mixture reaction was quenched with saturated NH 4 Cl solution (20 ml) and EtOAc (40 ml) was added into the mixture reaction.
  • Potassium carbonate (3.30 g, 23.85 mmol) was added to a solution of 4- [ (4- (methoxymethoxy) -3- (propan-2-yl) phenyl) methyl] -3, 5-dimethylphenol (5 g, 15.90 mmol ) , and diethyl [ (4-methylbenzenesulfonyl) oxy] methanephosphonate (5.12 g, 15.9 mmol) in acetonitrile (30 ml) , and stirred for 4 h at 80-85°C. After cooling, water and ethyl acetate were added to the mixture.
  • TMSBr (3.30 g, 21.6 mmol) was add dropwise to a solution of diethyl [ (4- [ (4- (methoxymethoxy) -3- (propan-2-yl) phenyl) methyl] -3, 5-dimethylphenoxy) methyl] phosphonate (5 g, 10.76 mmol ) in dichloromethane (25 ml) and stirred for 4 h at 10-15°C. Water was added dropwise to the mixture. The organic layer was separated and concentrated under reduced pressure to obtain compound A (3.6g, yield 92%) .
  • Oxalyl chloride (8.6 g, 67.7 mmol) was added dropwisely to a solution of Int F (10 g, 22.7 mmol) and DMF (166 mg, 2.27 mmol) in DCM (100 ml) and stirred for 2 h at room temperature.
  • the reaction mixture was concentrated to dryness to afford an oil.
  • the oil was dissolved into DCM (100 ml) , followed by addition of pentan-3-yl L-alaninate (18.05 g, 113.5 mmol) and stirred for 2 h at room tempreature.
  • the compound 75-1 was purified by chiral column (Welch XT C18 150 mm*21.2 mm, 5 um) to afford compound 75-2 ( 31 PNMR: 22.00) , (1.5 g) and compound 75-3 ( 31 PNMR: 21.19) (1.2 g) .
  • the reaction was quenched by the addition of water (50 mL) at 25 °C.
  • the resulting mixture was extrated with EA (3 x 100 mL) .
  • the combined organic layers were washed with brine (2 x 50 mL) , dried over anhydrous Na 2 SO 4 . After filtration, the filtrate was concentrated under reduced pressure.
  • Example 1 evaluated the therapeutic efficacy of the compound of the present disclosure in a NASH model.
  • mice were randomly divided into 4 groups according to their body weight, 10 mice in each group. Mice of each group were subcutaneously injected with 5%CCl 4 solution twice a week according to 2.5 mL/kg body weight.
  • the mice in the G1 group were given Solvent (100%MCT) as Vehicle, G2 group was subcutaneously injected with the compound of the present disclosure (5 mg/kg, Q2W ⁇ 2) , G3 group was subcutaneously injected with the compound of the present disclosure (15 mg/kg, single dose) , and G4 group was subcutaneously injected with the compound of the present disclosure (45 mg/kg, single dose) .
  • the body weight of the mice were measured every day after taking medication.
  • Figs. 1 to 3 show that the body weight of mice in G2, G3 and G4 group began to reduce at day 2 after taking medication (compound 75-2) and continued to reduce to maximum levels around days 21-23. The reduction of body weight of mice maintained until the end of dosing medication (compound 75-2) at day 28. These results demonstrate that compound 75-2 helps subject achieve healthy weight goals, and can be used for weight management and chronic weight management.
  • Figs. 4 to 6 show that the body weight decreased 9.4%in vehicle control group; decreased 17.7%in 5 mg/kg Compound 75-2 treatment group; decreased 17.3%in 15 mg/kg Compound 75-2 treatment group; decreased 24.7%in 45mg/kg Compound 75-2 treatment group.
  • Example 2 In vivo tissue distribution and efficacy of the compound of the present disclosure in a diet-induced obese (DIO) mouse model
  • mice Five-week-old male mice (C57BL/6J) [Gem Pharmatech] were fed a high-fat diet (D12492 [Research Diets, Inc. ] ) with ad libitum fresh water and housed three to four mice per cage in a controlled environment (20-24 °C, 30%-70%relative humidity) with a 12-h dark/light cycle. After 15-16 weeks of feeding, the mice had obesity (mean starting weight about 49 g [range 45.0-53.2 g] ) . Mice were grouped according to body weight and body fat percentage before the DIO studies. All operations and managements were carried out in strict accordance with the SOP institutional guidelines.
  • the healthy non-obese mice were set as blank vehicle control group. The details of dosing information were shown as below.
  • Fig. 7 shows that Compound 75-2 in white adipose tissues (WAT) were significantly higher than in the blood plasma. Compound 75-2 was undetectable in the blood plasma, suggesting that it is an adipose-targeting drug.
  • WAT white adipose tissues
  • Fig. 8 shows that Compounds 75-2 reduced total fat mass in a dose-dependent fashion.
  • Fig. 9 shows that Compound 75-2 reduced total body weight in a dose-dependent fashion.
  • Fig. 10 and Fig. 11 show that the body weight of mice began to decrease obviously after taking medication (compound 75-2) .
  • the reduction of body weight of mice maintained until the end of dosing medication (compound 75-2) , while the body weight started to rebounded from Day19 in semaglutide-treated group.
  • the body weight of mice treated with 45 mg/kg of compound 75-2 was similar to that of healthy, non-obese mice.
  • Example 3 In vivo tissue distribution and efficacy of the compound of the present disclosure in a diet-induced obese (DIO) mouse model
  • mice Five-week-old male mice (C57BL/6J) [Gem Pharmatech] were fed a high-fat diet (D12492 [Research Diets, Inc. ] ) with ad libitum fresh water and housed three to four mice per cage in a controlled environment (20-24 °C, 30%-70%relative humidity) with a 12-h dark/light cycle. After 15-16 weeks of feeding, the mice had obesity (mean starting weight about 49 g [range 45.0-53.2 g] ) . Mice were grouped according to body weight and body fat percentage before the DIO studies. All operations and managements were carried out in strict accordance with the SOP institutional guidelines.
  • the healthy non-obese mice were set as blank vehicle control group. The details of dosing information were shown as below.
  • Fig. 12 shows that Compound 75-2 in white adipose tissues were significantly higher than in the blood plasma. Compound 75-2 was undetectable in the blood plasma, suggesting that it is an adipose-targeting drug.
  • Fig. 13 shows that Compounds 75-2 reduced total fat mass in a dose-dependent fashion.
  • Fig. 14 shows that Compound 75-2 reduced total body weight in a dose-dependent fashion.
  • Fig. 15 and Fig. 16 show that the body weight of mice began to decrease after taking medication (compound 75-2) in a dose-dependent manner. The reduction of body weight of mice maintained until the end of dosing medication (compound 75-2) .
  • Example 4 Phase I single subcutaneous injection studies in healthy subjects with elevated low-density lipoprotein cholesterol (LDL-C) (Part I) and in patients with obesity (Part II)
  • LDL-C low-density lipoprotein cholesterol
  • Part I Single ascending dose (SAD) study of the compound of the present disclosure monotherapy in subjects with elevated low-density lipoprotein cholesterol (LDL-C) : Study objectives include safety, tolerability, target engagement and pharmacokinetics in subjects with elevated LDL-C receiving SAD of ultra-long-acting the compound of the present disclosure monotherapy via subcutaneous (SQ) injections. After the single SQ injections, healthy subjects are examined and followed up for 8 weeks.
  • Part I study consists of three cohorts (10 mg, 30 mg and 90 mg) . Each of 10 mg and 30 mg cohorts has six subjects (four subjects treated with the compound of the present disclosure and two subjects treated with matching placebo) . 90 mg cohort has eight subjects (six subjects treated with the compound of the present disclosure and two subjects treated with matching placebo) .
  • Study objectives include safety, tolerability, pharmacokinetics and preliminary efficacy in patients with obesity (BMI: 30-40 kg/m 2 ) receiving 90 mg single dose the compound of the present disclosure thereof monotherapy via SQ injections. After the single SQ injections, patients are examined and followed up for 12 weeks. 90 mg cohort has eight patients with obesity (six patients treated with the compound of the present disclosure and two patients treated with matching placebo) .
  • Compound 75-2 after single subcutaneous injections in healthy subjects with elevated LDL-C (10 mg, 30 mg, 90 mg) and patients with obesity (90 mg) , showed clinically significant placebo-adjusted mean reductions in LDL-C and total cholesterol (TC) .
  • Compound 75-2 after single subcutaneous injections (90 mg) in patients with obesity, demonstrated benefits of the treatment of obesity and weight management.

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Abstract

L'invention concerne une méthode de prévention, de traitement ou d'atténuation de l'obésité ou du surpoids, et un procédé de gestion du poids ou de gestion de poids chronique, comprenant l'administration à un sujet qui en a besoin d'une quantité efficace d'un modulateur de THR-β.
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114907401A (zh) * 2021-02-08 2022-08-16 江苏天士力帝益药业有限公司 一种亚甲基双苯酚类磷配体衍生物，它们的制备与治疗用途
WO2024167961A2 (fr) 2023-02-07 2024-08-15 Gannex, Llc Promédicaments d'analogues de l'hormone thyroïdienne, procédés de fabrication et d'utilisation correspondants

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CN114907401A (zh) * 2021-02-08 2022-08-16 江苏天士力帝益药业有限公司 一种亚甲基双苯酚类磷配体衍生物，它们的制备与治疗用途
WO2024167961A2 (fr) 2023-02-07 2024-08-15 Gannex, Llc Promédicaments d'analogues de l'hormone thyroïdienne, procédés de fabrication et d'utilisation correspondants

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