I 1111111111111111 lllll 111111111111111 111111111111111 11111 1111111111 11111111
`USO 12234236B 1
`
`c12) United States Patent
`
`Liang et al.
`
`US 12,234,236 Bl
`(10) Patent No.:
`Feb.25,2025
`(45) Date of Patent:
`
`(54) GLP-lR AGONIST AND THERAPEUTIC
`METHOD THEREOF
`
`(71) Applicant: Ascletis Pharma (China) Co.,
`Limited, Hong Kong (CN)
`
`(72)
`
`Inventors: Bin Liang, Hong Kong (CN); Jinzi
`Jason Wu, Hong Kong (CN); Bailing
`Yang, Hong Kong (CN)
`
`(73) Assignee: Ascletis Pharma (China) Co.,
`Limited, Hong Kong (CN)
`
`( *) Notice:
`
`Subject to any disclaimer, the term ofthis
`patent is extended or adjusted under 35
`U.S.C. 154(b) by O days.
`
`(21) Appl. No.: 18/884,965
`
`(22) Filed:
`
`Sep. 13, 2024
`
`Related U.S. Application Data
`
`(60) Provisional application No. 63/673,453, filed on Jul.
`19, 2024, provisional application No. 63/603,854,
`filed on Nov. 29, 2023, provisional application No.
`63/545,615, filed on Oct. 25, 2023, provisional
`application No. 63/538,892, filed on Sep. 18, 2023.
`
`(30)
`
`Foreign Application Priority Data
`
`Sep. 14, 2023
`Oct. 23, 2023
`Nov. 24, 2023
`Dec. 8, 2023
`Jan. 31, 2024
`Feb. 22, 2024
`Apr. 2, 2024
`May 11, 2024
`Jul. 17, 2024
`Sep. 4, 2024
`
`(CN) ......................... 202311189557.X
`(CN) ......................... 202311371725.7
`(CN) ......................... 202311582240.2
`(CN) ......................... 202311686034.6
`(CN) ......................... 202410142451.2
`(CN) ......................... 202410202078.5
`(CN) ........................ 202410398964.X
`(CN) ......................... 202410584679.7
`(CN) ........................ 202410963587.X
`(CN) ......................... 202411237048.4
`
`(51)
`
`(2006.01)
`(2006.01)
`(2006.01)
`
`Int. Cl.
`C07D 471104
`A61K 311437
`C07D 519100
`(52) U.S. Cl.
`CPC .......... C07D 471104 (2013.01); A61K 311437
`(2013.01); C07D 519100 (2013.01)
`( 58) Field of Classification Search
`CPC .................................................... C07D 471/04
`USPC .......................................................... 514/300
`See application file for complete search history.
`
`FOREIGN PATENT DOCUMENTS
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`CN
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`101195612 B
`8/2012
`102378574 B
`11/2013
`104080767 A
`10/2014
`103694195 B
`4/2016
`102946882 B
`5/2016
`105622687 B
`3/2018
`109867630 A
`6/2019
`112451515 A
`3/2021
`111548311 B
`4/2021
`107074820 B
`5/2021
`113480534 B
`5/2022
`114478497 A
`5/2022
`114478497 B
`5/2022
`114591296 A
`6/2022
`114634510 A
`6/2022
`114716423 A
`7/2022
`114763352 A
`7/2022
`114790160 A
`7/2022
`114805336 A
`7/2022
`114907351 A
`8/2022
`115279750 A
`11/2022
`115286550 A
`11/2022
`115315426 A
`11/2022
`115697968 B
`11/2022
`(Continued)
`
`OTHER PUBLICATIONS
`
`Analyst and Investor Call to Review Oral GLP-1 Data, The Euro(cid:173)
`pean Association for the Study of Diabetes (EASD) Annual Meet(cid:173)
`ing, Stockholm, Pfizer, (2022), 1-31.
`Griffith et al., A Small-Molecule Oral Agonist of the Human
`Glucagon-like Peptide-1 Receptor, I.Med. Chem., (2022), 65:8208-
`8226.
`Zhao et al., Activation of the GLP-1 receptor by a non-peptidic
`agonist, Nature, (2020), 577:432-456.
`Freeman et al., TTP273, Investigational Oral (Non Peptide) GLP lR
`Agonist: Improved Glycemic Control without Nausea and Vomiting
`in Phase 2, vTv Therapeutics LLC, High Point, NC, USA, p. 1.
`(Continued)
`
`Primary Examiner - Niloofar Rahmani
`(74) Attorney, Agent, or Firm - Nevrivy Patent Law
`Group P.L.L.C.
`
`ABSTRACT
`(57)
`The present disclosure describes GLP-lR modulating com(cid:173)
`pounds that are useful for treating GLP-lR-mediated dis(cid:173)
`eases or conditions,
`
`Formula (I)
`
`(56)
`
`References Cited
`
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`25 Claims, No Drawings
`
`Conjupro EX1001
`Page 1 of 113
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`
`Gustavson et al., TTP273, an Orally-Available Glucagon-Like Peptide(cid:173)
`l(GLP-l)Agonist, Notably Reduces Glycemia in Subjects with
`Type 2 Diabetes Mellitus (T2DM), TransTech Pharma, LLC., (2014),
`1-16.
`Reese David, AMG 133 Program Update, Amgen, (2022). 1-15.
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`Sperry et al., Danuglipron, Drugs of the Future, (2022), 47:407-418.
`Pratt et al., Orforglipron (LY3502970), a novel, oral non-peptide
`glucagon-like peptide-1 receptor agonist: A Phase la, blinded,
`placebo-controlled, randomized, singleand multiple-ascending-dose
`study in healthy participants, Diabetes Obes Metab, (2023), 25 :2634-
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`
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`Peptide and Non-peptide Agonists, Molecular Cell, (2020), 80:485-
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`Eccogene Announces US INDApproval for GLP-1 Receptor
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`Adults with Obesity, N Engl J Med, 389:887-888.
`Ma et al., Effect of Food Consumption on the Pharmacokinetics,
`Safety, and Tolerability of Once-Daily Orally Administered Orforglipron
`(LY3502970), a Non-peptide GLP-1 Receptor Agonist, Diabetes
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`Yabe, Daisuke, Twincretin as a potential therapeutic for the man(cid:173)
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`10: 902-905.
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`LY3502970, an orally active nonpeptide agonist, PNAS, (2020),
`117:29959-29967.
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`pharmacotherapies for the treatment of metabolic diseases, Nature
`Reviews, Endocrinology, 15:91-104.
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`glucagonlike peptide-1 receptor agonist: A Phase 1 b, multicentre,
`blinded, placebo-controlled, randomized, multiple-ascending-dose
`study in people with type 2 diabetes, Diabetes Obes Metab., (2023),
`25:2642-2649.
`Dutta et al., Orforglipron, a novel non-peptide oral daily glucagon(cid:173)
`like peptide-1 receptor agonist as an anti-obesity medicine: A
`systematic review and meta-analysis, Obes Sci Pract., (2024), p.
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`2024.
`
`* cited by examiner
`
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`Page 3 of 113
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`US 12,234,236 Bl
`
`1
`GLP-lR AGONIST AND THERAPEUTIC
`METHOD THEREOF
`
`CROSS-REFERENCE TO RELATED
`APPLICATIONS
`
`2
`secondary messenger cyclic adenosine monophosphate
`( cAMP) upon activation. Non-alcoholic steatohepatitis
`(NASH) can be associated with features of metabolic syn(cid:173)
`drome, including obesity, type 2 diabetes, insulin resistance,
`5 and cardiovascular disease.
`GLP-lR agonists are currently being investigated in con(cid:173)
`nection with diabetes, obesity, and NASH. GLP-lR agonists
`include peptides, such as exenatide, liraglutide, and dula(cid:173)
`glutide, that have been approved for the management of type
`10 2 diabetes. Such peptides are predominantly administered by
`subcutaneous injection. Oral GLP-1 agonists are also under
`investigation for treatment of type 2 diabetes. Some GLP-1 R
`agonists, such as liraglutide, dulaglutide, and exenatide, are
`resistant to rapid degradation by dipeptidyl peptidase 4,
`resulting in longer half-lives than endogenous GLP-1.
`There remains a need for compounds, such as agonists of
`GLP-lR, with desirable therapeutic properties, metabolic
`properties, and/or easy administration in the treatment of
`GLP-1 R-mediated diseases and conditions.
`
`15
`
`SUMMARY
`
`One aspect of the present disclosure provides a compound
`of Formula (I), a stereoisomer, a pharmaceutically accept-
`25 able salt, or a deuterated compound thereof:
`
`The present disclosure claims the benefits of the Chinese
`patent application No. 202311189557.X entitled "GLP-lR
`Agonist and Therapeutic Method Thereof' filed Sep. 14,
`2023 with the China National Intellectual Property Admin(cid:173)
`istration, the U.S. provisional application No. 63/538,892
`entitled "GLP-lR Agonist and Therapeutic Method
`Thereof' filed Sep. 18, 2023 with the U.S. Patent and
`Trademark Office, the Chinese patent application No.
`202311371725.7 entitled "GLP-lRAgonist and Therapeutic
`Method Thereof' filed Oct. 23, 2023 with the China
`National Intellectual Property Administration, the U.S. pro(cid:173)
`visional application No. 63/545,615 entitled "GLP-lRAgo(cid:173)
`nist and Therapeutic Method Thereof' filed Oct. 25, 2023
`with the U.S. Patent and Trademark Office, the Chinese 20
`patent application No. 202311582240.2 entitled "GLP-lR
`Agonist and Therapeutic Method Thereof' filed Nov. 24,
`2023 with the China National Intellectual Property Admin(cid:173)
`istration, the U.S. provisional application No. 63/603,854
`entitled "GLP-lR Agonist and Therapeutic Method
`Thereof' filed Nov. 29, 2023 with the U.S. Patent and
`Trademark Office, the Chinese patent application No.
`202311686034.6 entitled "GLP-lRAgonist and Therapeutic
`Method Thereof' filed Dec. 8, 2023, No. 202410142451.2
`entitled "GLP-lR Agonist and Therapeutic Method 30
`Thereof' filed Jan. 31, 2024, No. 202410202078.5 entitled
`"GLP-lR Agonist and Therapeutic Method Thereof' filed
`Feb. 22, 2024, No. 202410398964.X entitled "GLP-lR
`Agonist and Therapeutic Method Thereof' filed Apr. 2,
`2024, No. 202410584679.7 entitled "GLP-lR Agonist and 35
`Therapeutic Method Thereof' filed May 11, 2024, No.
`202410963587.X entitled "GLP-lR Agonist and Therapeu-
`tic Method Thereof' filed Jul. 17, 2024 with the China
`National Intellectual Property Administration, the U.S. pro(cid:173)
`visional application No. 63/673,453 entitled "GLP-lRAgo- 40
`nist and Therapeutic Method Thereof' filed Jul. 19, 2024
`with the U.S. Patent and Trademark Office, and the Chinese
`patent application No. 202411237048.4 entitled "GLP-lR
`Agonist and Therapeutic Method Thereof' filed Sep. 4, 2024
`with the China National Intellectual Property Administra- 45
`tion, which are incorporated herein by their entireties.
`
`Formula (I)
`
`wherein:
`Xis selected from the group consisting ofN and --CR a;
`wherein Ra is selected from the group consisting of
`hydrogen, halogen, and C 1_6 alkyl;
`wherein Y is -C(=O)-;
`wherein each of Z3 , Z4 , Zs, Z6 , Z7 , Zs, Z9 , Z10, Z11 , Z12
`and Z 13 is independently selected from the group con(cid:173)
`sisting of N and C;
`wherein Q 1 is selected from the group consisting ofC 6 _10
`aryl and 5- to IO-membered heteroaryl, wherein C6 _10
`aryl or 5- to IO-membered heteroaryl is optionally
`substituted by one to five substituents independently
`selected from the group consisting of halogen, C 1 _6
`alkyl, C 1 _6 haloalkyl and C 1 _6 alkoxy;
`wherein Q2 is selected from the group consisting of3- to
`12-membered heterocyclic, and 5- to IO-membered
`heteroaryl, wherein 3- to 12-membered heterocyclic,
`and 5- to IO-membered heteroaryl are optionally sub(cid:173)
`stituted by 1-3 substituents independently selected
`from the group consisting of halogen, C 1_6 alkyl, C 1 _6
`haloalkyl, C 1 _6 alkoxy, and -NRQaRQ6
`, or wherein
`two C 1_6 alkyl groups optionally together with the
`carbon atoms to which they are attached form C3 _8
`carbocyclic ring; wherein RQa and RQb are indepen(cid:173)
`dently selected from the group consisting of hydrogen,
`C 1_6 alkyl, C 1 _6 haloalkyl and (C1 _6 alkyl) carbonyl;
`
`FIELD
`
`The present disclosure generally relates to compounds 50
`that bind to and act as agonists or modulators of the
`glucagon-like peptide-I receptor (GLP-lR), as well as the
`use of such compounds for the treatment and/or prevention
`of GLP-lR-mediated diseases and conditions.
`
`55
`
`BACKGROUND
`
`Glucagon-like peptide-I (GLP-1) is a peptide hormone
`secreted from the enteroendocrine cells in the gut in
`response to a meal. GLP-1 is believed to play a role in 60
`regulation of post-prandial glycemia, via directly augment-
`ing meal-induced insulin secretion from the pancreatic beta(cid:173)
`cells, as well as in promoting satiety by delaying the transit
`of food through the gut. GLP-1 mediates intracellular sig(cid:173)
`naling via the GLP-1 receptor (GLP-lR), which belongs to 65
`a family of G-protein coupled receptors that are present on
`the cell membrane and can result in the accumulation of the
`
`Conjupro EX1001
`Page 4 of 113
`
`

`

`US 12,234,236 Bl
`
`3
`wherein each of Ri, R2 , R3 , Ri', R2 ' and R3 ' is indepen(cid:173)
`dently selected from the group consisting of hydrogen,
`halogen, cl-6 alkyl, cl-6 alkoxy, cl-6 haloalkoxy,
`cycloalkyl and heterocycloalkyl; wherein C 1 _6 alkyl,
`cycloalkyl or heterocycloalkyl is optionally substituted 5
`by one or more substituents independently selected
`from the group consisting of halogen, C 1_6 alkoxy and
`hydroxyl; or
`wherein R2 and R3 together with the carbon atom to which 10
`they are attached form 4- to 8-membered heterocycloal(cid:173)
`kyl;
`each of R4 , Rs and R6 is independently selected from the
`group consisting of hydrogen, halogen and C 1_6 alkyl;
`each of R7 and R8 is independently selected from the
`group consisting of hydrogen and C 1 _6 alkyl, wherein
`C 1_6 alkyl is optionally substituted with one or more
`substituents independently selected from the group
`consisting of halogen and C3 _1s cycloalkyl;
`or R7 and R8 together with the carbon atom to which they
`are attached form C3 _1s carbocyclic ring, wherein the
`C3 _1s carbocyclic ring is optionally substituted by one
`to three C 1_6 alkyl, wherein C 1 _6 alkyl is optionally
`substituted by one or more substituents independently 25
`selected from
`the group consisting of halogen,
`hydroxyl, -NR7 aR76
`, C 1 _6 alkoxy and 3- to 12-mem(cid:173)
`bered heterocyclic, and R7 a and R76 are independently
`selected from the group consisting of hydrogen, C1 _6
`alkyl and (C 1_6 alkyl) carbonyl; and any two C 1 _6 alkyl 30
`optionally together with the carbon atom to which they
`are attached form C3 _1s carbocyclic ring;
`nl is 0, 1, 2 or 3;
`n2 is 0, 1, 2, 3, 4 or 5;
`n3 is O or 1;
`R, is selected from the group consisting of:
`
`15
`
`20
`
`35
`
`40
`
`45
`
`50
`
`a, R96
`f and----C(=O)-NR9gR9
`\ and each ofR9
`-C02 R9
`,
`d and R9g is independently selected from the group 55
`R9
`c, R 9
`consisting of hydrogen, C 1 _6 alkyl and (C 1_6 alkyl) carbonyl,
`wherein C 1_6 alkyl is optionally substituted with one or more
`substituents independently selected from the group consist-
`ing of halogen and C 1 _6 alkoxy;
`R9
`e is selected from the group consisting of hydrogen and
`C 1_6 alkyl optionally substituted by one or more halo(cid:173)
`gen; R9fis selected from the group consisting of hydro(cid:173)
`gen and C 1_6 alkyl; R9
`h is selected from the group
`consisting of hydrogen, C 1_6 alkyl, (C 1 _6 alkyl) carbo- 65
`nyl, cyano and -S(=O)n9-R9
`'; n9 is 0, 1 or 2;
`' is cl-6 alkyl;
`
`R9
`
`60
`
`4
`Z 1 is selected from the group consisting of:
`
`wherein R2 a is selected from the group cons1stmg of
`hydrogen, C 1_6 alkyl and (C 1 _6 alkyl) carbonyl, and
`c is independently selected from the
`each of R26 and R2
`group consisting of hydrogen and C 1 _6 alkyl;
`n4 is 1, 2 or 3;
`each of n5 and n6 is independently an integer selected
`from Oto 10;
`Z2 is 5- to IO-membered heteroaryl, and Z2 is substituted
`with one halogen and one of C3 -C 1s cycloalkyl and
`C 1 -C6 alkyl-C3 -C 1s cycloalkyl; wherein the cycloalkyl
`or alkyl is optionally substituted with one or more
`substituents independently selected from the group
`consisting of halogen, oxo, C 1_6 alkyl, C 1_6 alkoxy and
`(C 1 _6 alkyl) carbonyl, wherein each of alkyl and alkoxy
`is optionally substituted with halogen.
`Another aspect of the present disclosure provides a com(cid:173)
`pound of Formula (III), a stereoisomer, a pharmaceutically
`acceptable salt, or a deuterated compound thereof:
`
`Formula (III)
`
`wherein:
`X is -CRa; Ra is H;
`Y is ----C(=O)-;
`Z3, Z4, Zs, Z6, Zs, Z9, Z10, Z12 and Z 13 are C;
`Z7 and Zu are N;
`Q 1 is C6 _10 aryl, wherein C6 _10 aryl is optionally substi(cid:173)
`tuted with one to five substituents independently
`selected from the group consisting of halogen and C 1 _6
`alkyl;
`
`Conjupro EX1001
`Page 5 of 113
`
`

`

`6
`
`Formula (IV)
`
`US 12,234,236 Bl
`
`5
`Q2 is 3- to 12-membered heterocyclic; wherein 3- to
`12-membered heterocyclic is optionally substituted
`with 1-3 substituents independently selected from the
`group consisting of halogen and C 1 _6 alkyl, or wherein 5
`two C 1 _6 alkyl groups optionally together with the
`carbon atoms to which they are attached form C3 _8
`carbocyclic ring;
`
`wherein each of Ri, R2 , Ri', and R2 ' is independently
`selected from the group consisting of hydrogen and
`cl-6 alkyl;
`R3 and R3 ' are independently selected from the group 15
`consisting of hydrogen and C 1_6 alkyl;
`
`each of R7 and R8 is independently selected from the
`group consisting of hydrogen and C 1 _6 alkyl; or R7 and 20
`R8 together with the carbon atom to which they are
`attached form C3 _15 carbocyclic ring, wherein the C3 _15
`carbocyclic ring is optionally substituted by one to
`three cl-6 alkyl;
`
`25
`
`nl is O or 1;
`
`n2 is O or 1;
`
`n3 is 1;
`
`and R9
`a is H;
`Z1 is
`
`wherein:
`each of X, Z4 and Z6 is independently selected from the
`group consisting of N and CH;
`R21 is selected from the group consisting of halogen, C 1 _3
`alkyl, and C3 _8 cycloalkyl;
`R22 is selected from the group consisting of C3 _8 cycloal(cid:173)
`kyl and C 1 _6 alkyl-C3 _8 cycloalkyl; and R22 is optionally
`substituted with substituents independently selected
`from the group consisting of halogen, -OH, C 1_6 alkyl,
`and cl-6 alkoxy;
`ml is 0, 1, 2 or 3.
`Yet still another aspect of the present disclosure provides
`a compound of Formula (V), a stereoisomer, a pharmaceu-
`35 tically acceptable salt, or a deuterated compound thereof:
`
`30
`
`Formula (V)
`
`Z2 is 5- to 10-membered heteroaryl, and Z2 is substituted
`with one halogen and one of C3 -C 15 cycloalkyl and 55
`C 1 -C6 alkyl-C3 -C 15 cycloalkyl; wherein the cycloalkyl
`or alkyl is optionally substituted with one or more
`substituents independently selected from the group
`consisting of halogen, oxo, C 1_6 alkyl, C 1_6 alkoxy and 60
`(C 1 _6 alkyl) carbonyl, wherein each of alkyl and alkoxy
`is optionally substituted with halogen.
`
`Still another aspect of the present disclosure provides a
`compound of Formula (IV), a stereoisomer, a pharmaceuti(cid:173)
`cally acceptable salt, or a deuterated compound thereof:
`
`65
`
`wherein:
`each of X, Z4 and Z6 is independently selected from the
`group consisting of N and CH;
`Q2 is selected from the group consisting of
`
`and
`
`Conjupro EX1001
`Page 6 of 113
`
`

`

`US 12,234,236 Bl
`
`7
`R,, is selected from the group consisting of halogen, C 1 _6
`alkyl, C 1 _6 haloalkyl and C1 _6 alkoxy;
`mis 0, 1, 2 or 3;
`2 is selected from the group consisting of C3 _8 cycloal(cid:173)
`~
`kyl and C 1 _6 alkyl-C3 _8 cycloalkyl; and R22 is optionally 5
`substituted with substituents independently selected
`from the group consisting of halogen, hydroxyl, C 1 _6
`alkyl and C 1_6 alkoxy.
`Yet still another aspect of the present disclosure provides
`a compound of Formula (VIII), a stereoisomer, a pharma- 10
`ceutically acceptable salt, or a deuterated compound thereof:
`
`8
`Rqm and Rqn are each independently selected from the
`group consisting of H, methyl, and ethyl, or Rqm and
`Rqn together with the carbon atom to which they are
`attached to form a C3 _6 cycloalkyl.
`Yet still another aspect of the present disclosure provides
`a compound of Formula (IX), a stereoisomer, a pharmaceu(cid:173)
`tically acceptable salt, or a deuterated compound thereof:
`
`Formula (IX)
`
`Formula (VIII)
`
`15
`
`30
`
`35
`
`40
`
`wherein:
`each of X, Z4 and Z6 is independently selected from the
`group consisting of N and CH;
`Rm is selected from the group consisting ofH, C 1_6 alkyl,
`cl-6 haloalkyl, cl-6 alkoxy and cl-6 haloalkoxy;
`R,, 1 and Rn3 are each independently selected from the
`group consisting of hydrogen, halogen, C1 _6 alkyl, C 1 _6
`haloalkyl, cl-6 alkoxy, and cl-6 haloalkoxy; Rn2 is 45
`selected from halogen;
`R3 is selected from the group consisting of hydrogen,
`halogen, cl-6 alkyl, cl-6 haloalkyl, cl-6 alkoxy and
`C 1_6 haloalkoxy;
`1 is selected from the group consisting of hydrogen, 50
`halogen, C 1 _3 alkyl and C3 _8 cycloalkyl;
`2 Selected from the group consisting of
`
`~
`
`~
`
`wherein:
`each of X, Z4 and Z6 is independently selected from the
`group consisting of N and CH;
`Z2 is selected from the group consisting of
`
`R10 o= j
`
`)=o,
`N
`\
`R11
`
`R10
`
`W I
`
`m
`
`o'
`
`and
`
`Rn is selected from the group consisting of halogen, C 1 _6
`alkyl, C 1 _6 haloalkyl and C 1 _6 alkoxy;
`mis 0, 1, 2 or 3.
`Yet still another aspect of the present disclosure provides
`a compound of Formula (X), a stereoisomer, a pharmaceu(cid:173)
`tically acceptable salt, or a deuterated compound thereof:
`
`Conjupro EX1001
`Page 7 of 113
`
`

`

`US 12,234,236 Bl
`
`9
`
`Formula (X)
`
`10
`C 1_6 alkoxy, wherein two C 1_6 alkyl groups optionally
`together with the carbon atoms to which they are
`attached form a C3 _8 carbocyclic ring;
`X 1 , X2 , and X3 are independently selected from the group
`consisting of N and C;
`X4 , and X5 are independently selected from the group
`consisting of N and C;
`Rm is selected from the group consisting of H, C1 _6 alkyl,
`cl-6 haloalkyl, cl-6 alkoxy and cl-6 haloalkoxy;
`R22 is selected from the group consisting of C3 _8 cycloal(cid:173)
`kyl and C 1_6 alkyl-C3 _8 cycloalkyl.
`Yet still another aspect of the present disclosure provides
`15 a compound, a stereoisomer, a pharmaceutically acceptable
`salt, or a deuterated compound thereof, selected from the
`group consisting of:
`
`25
`
`20
`
`wherein:
`each of X, Z4 and Z6 is independently selected from the
`group consisting of N and CH;
`mis 0, 1, 2 or 3;
`RP is selected from the group consisting of -CH2-P
`(=O)R2 mRzn and-P(=O)OR2 mOR2 n;
`Rq is selected from the group consisting of halogen,
`-NH-C 1_6 alkyl, -C 1_6 alkyl, -O----C 1 _6 alkyl, 3- to
`12-membered heterocyclic, ----C3 -C 15 cycloalkyl and
`C 1-C6 alkyl-C3 -C 15 cycloalkyl;
`wherein each of Rzm and R2 n is independently selected 30
`from the group consisting of hydrogen, C 1_6 alkyl and
`C6 _10 aryl; or wm and R2n together with the phospho(cid:173)
`rous atom to which they are attached form 5- to
`8-membered heterocycloalkyl, wherein the heterocy(cid:173)
`cloalkyl is optionally substituted with 1-3 C 1 _6 alkyl.
`Yet still another aspect of the present disclosure provides
`a compound of Formula (XI), a stereoisomer, a pharmaceu(cid:173)
`tically acceptable salt, or a deuterated compound thereof:
`
`40
`
`Formula (XI)
`
`4
`
`wherein:
`Q 1 is C6 _10 aryl, and the C6 _10 aryl is optionally substituted
`with one to five substituents selected from the group
`consisting of halogen, C 1_6 alkyl, C 1 _6 haloalkyl and
`cl-6 alkoxy;
`Q2 is selected from the group consisting of3- to 12-mem(cid:173)
`bered heterocyclic, and 5- to IO-membered heteroaryl,
`wherein 3- to 12-membered heterocyclic, and 5- to
`IO-membered heteroaryl are optionally substituted by
`1-3 substituents independently selected from the group
`consisting of halogen, C 1_6 alkyl, C 1_6 haloalkyl, and
`
`Conjupro EX1001
`Page 8 of 113
`
`

`

`US 12,234,236 Bl
`
`11
`-continued
`
`12
`-continued
`
`10
`
`25
`
`50
`
`55
`
`65
`
`FF
`
`\
`
`o-N
`
`N
`
`N
`
`N f ' F
`
`-
`
`1 ~ ~N
`
`#
`
`/
`N
`\
`
`-
`o...._N
`
`f \ o;
`
`\
`
`,,_..,N f ' F
`
`N
`
`N
`
`::::::,.....
`
`-
`
`I ~ ~N
`
`#
`
`/
`N
`\
`
`Conjupro EX1001
`Page 9 of 113
`
`

`

`US 12,234,236 Bl
`
`13
`-continued
`
`11
`
`14
`-continued
`
`20
`
`25
`
`15
`
`16
`
`17
`
`Conjupro EX1001
`Page 10 of 113
`
`

`

`US 12,234,236 Bl
`
`15
`-continued
`
`16
`-continued
`
`10
`
`15
`
`20
`
`25
`
`23
`
`45
`
`25
`
`26
`
`27
`
`Conjupro EX1001
`Page 11 of 113
`
`

`

`17
`-continued
`
`US 12,234,236 Bl
`
`28
`
`0
`
`18
`-continued
`
`49
`
`48
`
`31
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`cqN-Q-C
`' <~,--l '
`'CCN N h.
`
`Yet still an th o er aspect of th
`:~ompound or a pharmaceuti:J;esent disclosure provides
`erem the compound .
`1
`y acceptable salt th
`f
`is se ected from th
`ereo '
`of:
`e group consisting
`
`Conjupro EX1001
`Page 12 of 113
`
`

`

`US 12,234,236 Bl
`
`19
`-continued
`
`20
`-continued
`
`13
`
`20
`
`Q
`
`<;.
`f
`-
`0-N
`
`'
`
`25
`
`18
`
`30
`
`35
`
`\
`
`N
`
`N
`\N
`
`,:,,-
`::::,...
`
`f
`
`'
`
`F
`
`.-9
`
`/
`N
`
`I~ '\
`~
`
`40
`
`45
`
`19
`
`and
`
`21
`
`65
`
`Yet still another aspect of the present disclosure provides
`a compound, selected from the group consisting of:
`
`Conjupro EX1001
`Page 13 of 113
`
`

`

`22
`22
`-continued
`-continued
`
`19
`
`US 12,234,236 Bl
`US 12,234,236 Bl
`
`21
`21
`
`Zz
`
`25
`
`13
`
`18
`
`
`
`21
`
`Conjupro EX1001
`Page 14 of 113
`
`Conjupro EX1001
`Page 14 of 113
`
`

`

`23
`-continued
`
`US 12,234,236 Bl
`
`65
`
`24
`sure and the appended claims. "The" is used in the claims in
`the singular form to include objects in the plural unless the
`context explicitly states otherwise. Thus, for example, ref(cid:173)
`erence to an extended-release tablet comprising "pharma-
`5 ceutically acceptable excipi