I 1111111111111111 111111111111111 111111111111111 1111111111111111 IIII IIII IIII
`US012037339B2
`
`c12) United States Patent
`Ren et al.
`
`US 12,037,339 B2
`(IO) Patent No.:
`(45) Date of Patent:
`*Jul. 16, 2024
`
`(54) SUBSTITUTED IMIDAZOLES AS GLP-1
`RECEPTOR AGONISTS
`
`(71) Applicant: Eccogene Inc., Cambridge, MA (US)
`
`(72)
`
`Inventors: Zaifang Ren, Shanghai (CN); Xuefeng
`Sun, Shanghai (CN); Jingye Zhou,
`Shanghai (CN)
`
`(73) Assignee: Eccogene Inc., Cambridge, MA (US)
`
`( *) Notice:
`
`Subject to any disclaimer, the term ofthis
`patent is extended or adjusted under 35
`U.S.C. 154(b) by O days.
`
`This patent is subject to a terminal dis(cid:173)
`claimer.
`
`(21) Appl. No.: 17/380,084
`
`(22) Filed:
`
`Jul. 20, 2021
`
`(65)
`
`Prior Publication Data
`
`US 2023/0051320 Al
`
`Feb. 16, 2023
`
`(30)
`
`Foreign Application Priority Data
`
`Jul. 20, 2020
`Jan. 4, 2021
`
`(WO) ................ PCT/CN2020/102955
`(WO) ................ PCT/CN2021/070120
`
`FOREIGN PATENT DOCUMENTS
`
`WO WO 2019/166951 Al
`
`9/2019
`
`OTHER PUBLICATIONS
`
`Jordan, V. C. Nature Reviews: Drug Discovery, 2, 2003, 205.*
`Vippagunta, et al. Advanced Drug Delivery Reviews, 48, 2001, 18.*
`Wolff, Manfred E., Ed. Burger's Medicinal Chemistry and Drug
`Discovery-Fifth Edition, vol. 1: Principles and Practice, New
`York: John Wiley & Sons, 1994, 975-977.*
`
`* cited by examiner
`
`Primary Examiner - Douglas M Willis
`(74) Attorney, Agent, or Firm - COOLEY LLP; Chen
`Chen
`
`(57)
`
`ABSTRACT
`
`The application relates to a compound of Formula (I):
`
`(I)
`
`(51)
`
`Int. Cl.
`A61K 3114166
`C07D 233/04
`C07D 487104
`C07D 519100
`(52) U.S. Cl.
`CPC ......... C07D 487104 (2013.01); C07D 519100
`(2013.01)
`
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`
`( 58) Field of Classification Search
`CPC .......................... A61K 31/4166; C07D 233/04
`USPC ........................................ 514/398; 548/347.1
`See application file for complete search history.
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`or a pharmaceutically acceptable salt, hydrate, solvate, prod(cid:173)
`rug, stereoisomer, or tautomer thereof, which modulates the
`activity of GLP-1 receptor, a pharmaceutical composition
`comprising a compound of Formula (I), and a method of
`treating or preventing a disease in which GLP-1 receptor
`plays a role.
`
`2019/0225604 Al
`
`7/2019 Yoshino et al.
`
`34 Claims, No Drawings
`
`

`

`2
`
`(I)
`
`US 12,037,339 B2
`
`1
`SUBSTITUTED IMIDAZOLES AS GLP-1
`RECEPTOR AGONISTS
`
`RELATED APPLICATIONS
`
`This application claims the benefit of and priority to
`International Application No. PCT/CN2020/102955, filed
`on Jul. 20, 2020, and International Application No. PCT/
`CN2021/070120, filed on Jan. 4, 2021, the entire contents of 10
`each of which are incorporated herein by reference in their
`entireties.
`
`BACKGROUND
`
`15
`
`Glucagon-like peptide-I (GLP-1) is an incretin of 30 or
`31 amino acids, secreted from L cells in the small intestine.
`GLP-1 exerts a wide range of effects through the GLP-1 20
`receptor, such as promotion of glucose dependent insulin
`secretion, inhibition of glucagon secretion, delay of gastric
`emptying, and suppression of feeding. Accordingly, GLP-1
`analogs display potent effects in HbAlc reduction and 25
`weight loss, and have been developed as effective therapeu(cid:173)
`tic agents for treatment of diabetes and obesity. GLP-1
`analogs also demonstrate efficacy on improving cardiovas-
`cular outcomes and retaining renal functions in diabetic 30
`patients, thus providing therapeutic opportunities for a vari-
`ety of metabolic disorders and related comorbidities.
`Recently, Liraglutide and Semaglutide treatment is shown to
`decrease liver fat and boost NASH resolution in clinical 35
`trials, suggesting potential utility for NASH. However, most
`of these GLP-1 analogs require an invasive subcutaneous
`administration. Semaglutide in specific formulation can be
`administrated via oral route, but still suffers from inconve(cid:173)
`nient dosing regimen and poor bioavailability. Improving
`metabolic stability and bioavailability of GLP-1 analogs is
`challenging, likely due to their peptidic nature.
`
`Currently, there is no approved small molecule GLP-1 45
`receptor agonist for the treatment of diabetes or other
`metabolic disorders where GLP-1 receptor plays a role.
`Thus, there is a need for small molecule GLP-1 receptor
`agonists as therapeutic options for the treatment of these
`disorders. The present application addresses the need.
`
`or a pharmaceutically acceptable salt, solvate, prodrug,
`stereoisomer, or tautomer thereof, wherein A, X, Y, T, L, R2 ,
`and R4 are as described in detail below.
`Another aspect of the application relates to a pharmaceu(cid:173)
`tical composition comprising a compound of Formula (I) or
`a compound described herein, or a pharmaceutically accept(cid:173)
`able salt, solvate, prodrug, stereoisomer, or tautomer thereof,
`and a pharmaceutically acceptable diluent, excipient, or
`earner.
`Another aspect of the application relates to a method of
`treating or preventing a GLP-1 receptor-mediated disease or
`disorder ( e.g., a disease or disorder in which GLP-1 receptor
`plays a role or which is associated with modulation of
`GLP-1 receptor), as described herein ( e.g., diabetes, obesity,
`overweight condition, hyperlipidemia, hypercholesteremia,
`hypertriglyceridemia, atherosclerosis, hypertension, stroke,
`coronary heart disease, congestive heart failure, cardiac
`arrhythmias, diabetic kidney disease, dementia, Parkinson's
`disease, Alzheimer's disease, and liver diseases such as
`NAFLD and NASH). The method comprises administering
`to a subject in need of such a treatment a therapeutically
`effective amount of a compound of Formula (I) or a com(cid:173)
`pound described herein, or a pharmaceutically acceptable
`salt, solvate, prodrug, stereoisomer, or tautomer thereof, or
`40 a therapeutically effective amount of a pharmaceutical com(cid:173)
`position comprising a compound of Formula (I) or a com(cid:173)
`pound described herein, or a pharmaceutically acceptable
`salt, solvate, prodrug, stereoisomer, or tautomer thereof, and
`a pharmaceutically acceptable diluent, excipient, or carrier.
`Another aspect of the application relates to a method of
`modulating ( e.g., activating or stimulating) GLP-1 receptor.
`The method comprises administering to a subject in need of
`such modulation a therapeutically effective amount of a
`compound of Formula (I) or a compound described herein,
`50 or a pharmaceutically acceptable salt, solvate, prodrug,
`stereoisomer, or tautomer thereof, or a therapeutically effec(cid:173)
`tive amount of a pharmaceutical composition comprising a
`compound of Formula (I) or a compound described herein,
`or a pharmaceutically acceptable salt, solvate, prodrug,
`55 stereoisomer, or tautomer thereof, and a pharmaceutically
`acceptable diluent, excipient, or carrier.
`Another aspect of the application relates to a compound of
`Formula (I) or a compound described herein, or a pharma(cid:173)
`ceutically acceptable salt, solvate, prodrug, stereoisomer, or
`60 tautomer thereof, or a pharmaceutical composition compris(cid:173)
`ing a compound of Formula (I) or a compound described
`herein, or a pharmaceutically acceptable salt, solvate, prod(cid:173)
`rug, stereoisomer, or tautomer thereof, and a pharmaceuti(cid:173)
`cally acceptable diluent, excipient, or carrier, for use in a
`65 method of treating or preventing a GLP-1 receptor-mediated
`disease or disorder or of modulating (e.g., activating or
`stimulating) GLP-1 receptor.
`
`SUMMARY
`
`The present application provides novel GLP-1 receptor
`ligands which are useful in the treatment of a disease or
`disorder in which GLP-1 receptor plays a role, such as those
`described herein, including but not limited to diabetes,
`obesity, overweight condition, hyperlipidemia, hypercholes(cid:173)
`teremia, hypertriglyceridemia, atherosclerosis, hyperten(cid:173)
`sion, stroke, coronary heart disease, congestive heart failure,
`cardiac arrhythmias, diabetic kidney disease, dementia, Par(cid:173)
`kinson's disease, Alzheimer's disease, and liver diseases
`such as nonalcoholic fatty liver disease (NAFLD) and
`nonalcoholic steatohepatitis (NASH).
`A first aspect of the application relates to a compound of
`Formula (I):
`
`

`

`US 12,037,339 B2
`
`3
`Another aspect of the application relates to use of a
`compound of Formula (I) or a compound described herein,
`or a pharmaceutically acceptable salt, solvate, prodrug,
`stereoisomer, or tautomer thereof, or a pharmaceutical com(cid:173)
`position comprising a compound of Formula (I) or a com-
`pound described herein, or a pharmaceutically acceptable
`salt, solvate, prodrug, stereoisomer, or tautomer thereof, and
`a pharmaceutically acceptable diluent, excipient, or carrier,
`in the manufacture of a medicament for treating or prevent-
`ing a GLP-1 receptor-mediated disease or disorder or for 10
`modulating ( e.g., activating or stimulating) GLP-1 receptor.
`The present application provides modulators (e.g., ago(cid:173)
`nists) of GLP-1 receptor that are therapeutic agents in the
`treatment of diseases such as diabetes, obesity, metabolic
`diseases, cardiovascular diseases, liver diseases, NASH,
`kidney diseases, neurodegenerative diseases, and other dis(cid:173)
`eases or disorders associated with the modulation of GLP-1
`receptor.
`The present application further provides compounds and
`compositions with an improved therapeutic profile ( e.g.,
`efficacy, pharmacodynamics, safety) relative to known
`GLP-1 receptor agonists and alternative routes of adminis(cid:173)
`tration, toward the treatment of various types of diseases
`including diabetes, obesity, metabolic diseases, cardiovas-
`cular diseases, liver diseases, NASH, kidney diseases, neu(cid:173)
`rodegenerative diseases, and other diseases associated with
`the modulation of GLP-1 receptor.
`
`5
`
`15
`
`20
`
`25
`
`DETAILED DESCRIPTION
`
`30
`
`Compounds of the Application
`The present application relates to compounds and com(cid:173)
`positions thereof that are capable of modulating the activity
`of GLP-1 receptor. The application features methods of
`treating, preventing, or ameliorating a disease or disorder in 35
`which GLP-1 receptor plays a role by administering to a
`subject in need thereof a therapeutically effective amount of
`a compound of the present application, or a pharmaceuti(cid:173)
`cally acceptable salt, solvate, prodrug, stereoisomer, or
`tautomer thereof. The compounds of the present application 40
`can be used in the treatment of a variety of GLP-1-mediated
`diseases and disorders by stimulating GLP-1 receptor. Acti(cid:173)
`vation or stimulation of GLP-1 receptor provides treatment,
`prevention, or amelioration of diseases including, but not
`limited to, diabetes, obesity, metabolic diseases, cardiovas- 45
`cular diseases, liver diseases, nonalcoholic steatohepatitis
`(NASH), and other diseases associated with the modulation
`of GLP-1 receptor.
`In a first aspect of the application, a compound of Formula
`(I) is described:
`
`50
`
`4
`or a pharmaceutically acceptable salt, solvate, prodrug,
`stereoisomer, or tautomer thereof, wherein:
`
`~----~
`-¥v
`
`X'. __ ,)
`
`4
`
`is
`
`or
`
`R 1 is (CRcRc) 0 _2-C3 -C6 cycloalkyl, (CRcRc)0 _2 -phe(cid:173)
`nyl, or (CRcRc)0 _2 -heteroaryl comprising one 5- or
`6-membered ring and 1-3 heteroatoms selected from N,
`0, and S, wherein the cycloalkyl, phenyl, or heteroaryl
`is optionally substituted with one or more substituents
`independently selected from C 1-C6 alkyl, C 1-C6 haloal(cid:173)
`kyl, C 1 -C6 alkoxy, C 1 -C6 haloalkoxy, OH, halogen,
`NH2 , NH-(C 1 -C6 alkyl), N(C 1 -C6 alkyl) 2 , CN, N02 ,
`and C3 -C6 cycloalkyl, wherein the cycloalkyl is a
`spiro-, bridged-, or mono-cycloalkyl;
`each Re is independently H, C 1-C3 alkyl, or C 1-C3 haloal(cid:173)
`kyl;
`R2 is C3 -C 10 cycloalkyl, phenyl, heterocyclyl comprising
`one or two 5- or 6-membered rings and 1-3 heteroatoms
`selected from N, 0, and S, or heteroaryl comprising one
`or two 5- or 6-membered rings and 1-3 heteroatoms
`selected from N, 0, and S, wherein the cycloalkyl,
`phenyl, heterocyclyl, or heteroaryl is optionally substi(cid:173)
`tuted with one or more substituents independently
`selected from C 1 -C6 alkyl optionally substituted with
`c l -C6 alkoxy, c l -C6 haloalkyl, c l -C6 alkoxy, c l -C6
`haloalkoxy, OH, halogen, NH2 , NH-(C 1 -C6 alkyl),
`N(C 1 -C6 alkyl)2 , CN, and N02 , wherein the cycloalkyl
`is a spiro-, bridged-, or mono-cycloalkyl;
`
`is a bicyclic heteroaryl ring selected from
`
`(I)
`
`55
`
`60
`
`65
`
`

`

`5
`-continued
`
`US 12,037,339 B2
`
`Lis
`
`6
`
`I
`
`N
`,::7 '-
`
`N~(R3)14,
`~
`
`~ X(R3)1-4,
`
`10
`
`F
`
`N
`r / 4 (R3) 14,
`
`10
`
`N~(R3)14,
`
`N:J
`
`N
`
`r/4(R3)1_3,
`
`N\ :J N -
`
`--f4
`
`or phenylenyl, wherein the phenylenyl is optionally
`substituted with one or more substituents indepen(cid:173)
`dently selected from C 1 -C6 alkyl, C 1 -C6 haloalkyl,
`C 1 -C6 alkoxy, C 1 -C6 haloalkoxy, and halogen, or
`wherein when the phenylenyl is substituted with two
`substituents attached to adjacent carbon atoms in the
`phenylenyl ring, the two substituents, together with the
`carbon atoms to which they are attached, may form a 5-
`or 6-membered ring optionally comprising 1-3 heteroa(cid:173)
`toms selected from N, 0, and S;
`Rs and R6 are each independently H, C 1 -C6 alkyl, C 1 -C6
`haloalkyl, C 1 -C6 alkoxy, C 1 -C6 haloalkoxy, OH, or
`halogen, or Rs and R6 , together with the carbon atom to
`which they are attached, form C3 -C6 cycloalkyl option(cid:173)
`ally substituted with one or more substituents indepen(cid:173)
`dently selected from C 1 -C6 alkyl, C 1 -C6 haloalkyl,
`C 1 -C6 alkoxy, C 1 -C6 haloalkoxy, OH, and halogen; and
`T is C(O)OH, (CH2)NHS(0) 2-(C 1 -C6 alkyl), or het(cid:173)
`eroaryl comprising one 5- or 6-membered ring and 1-3
`heteroatoms selected from N, 0, and S, wherein the
`heteroaryl is optionally substituted with C 1 -C6 alkyl,
`c l -C6 haloalkyl, c l -C6 alkoxy, c l -C6 haloalkoxy, OH,
`halogen, or oxo, and when L is
`
`--f4
`
`T is not C(O)OH, or when Lis phenylenyl substituted
`with two substituents attached to adjacent carbon atoms
`in the phenylenyl ring, and the two substituents,
`together with the carbon atoms to which they are
`attached, form a 5- or 6-membered ring, T is H,
`provided that when
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`each R3 is independently halogen, C3 -C10 cycloalkyl, 50
`phenyl, heterocyclyl comprising one or two 3- to
`6-membered rings and 1-3 heteroatoms selected from
`N, 0, and S, or heteroaryl comprising one or two 5- or
`6-membered rings and 1-3 heteroatoms selected from 55
`N, 0, and S, wherein the cycloalkyl, phenyl, heterocy(cid:173)
`clyl, or heteroaryl is optionally substituted with one or
`more substituents independently selected from C 1 -C6
`alkyl, c l -C6 haloalkyl, c l -C6
`alkoxy, c l -C6
`haloalkoxy, OH, halogen, NH2 , NH-(C 1 -C6 alkyl), 60
`N(C 1 -C6 alkyl) 2 , CN, and N02 , wherein the cycloalkyl
`is a spiro-, bridged-, or mono-cycloalkyl, provided that
`at least one R3 is cycloalkyl, phenyl, heterocyclyl, or
`heteroaryl;
`R4 is c l -C6 alkyl, c l -C6 haloalkyl, c l -C6 alkoxy, c l -C6 65
`haloalkoxy, NH-(C 1 -C6 alkyl), N(C1 -C6 alkyl)2 , or
`CN;
`
`X'.. .. _,..i
`
`4
`
`is
`
`~----~
`--¥v
`~,,X;
`
`Tis oxadiazolonyl, each R3 is independently F, hetero(cid:173)
`cyclyl comprising one or two 3- to 6-membered rings
`and 1-3 heteroatoms selected from N, 0, and S, or
`heteroaryl comprising one or two 5- or 6-membered
`
`

`

`US 12,037,339 B2
`
`8
`T is oxadiazolonyl, L is
`
`-f4
`
`and Rs and R6 are each methyl, then R3 is not heteroaryl
`comprising one 6-membered ring and 1-3 heteroatoms
`selected from N, 0, and S; and
`provided that when
`
`N--:-Y
`
`~ x
`
`.
`
`!S
`
`>·
`-f4
`
`Lis
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`Rs and R6 are each H, and R3 is heterocyclyl compris(cid:173)
`ing one 6-membered ring and 1-3 heteroatoms selected
`from N, 0, and S, then R3 is substituted.
`In some embodiments, the compounds of Formula (I)
`45 have the structure of Formula (Ial), (Ia2), (Ia3), (Ia4), (Ia5),
`(Ia6), (Ia7), (Ia8), (Ia9), (Ial 0), or (Iall ):
`
`(Jal)
`
`50
`
`55
`
`60
`
`65
`
`7
`rings and 1-3 heteroatoms selected from N, 0, and S,
`wherein the heterocyclyl or heteroaryl is optionally
`substituted, L is
`
`-f4
`
`and Rs and R6 , together with the carbon atom to which
`they are attached, form C3 -C6 cycloalkyl, then the
`C3 -C 6 cycloalkyl is unsubstituted;
`provided that when
`
`is
`
`----~
`
`X'.. .. _.,/
`
`V~
`
`4
`
`~'')((
`
`T is oxadiazolonyl, L is
`
`-f4
`
`Rs and R6 , together with the carbon atom to which they
`are attached, form unsubstituted C3 -C 6 cycloalkyl, and
`R3 is heterocyclyl comprising one 6-membered ring
`and 1-3 heteroatoms selected from N, 0, and S, then R3
`is substituted;
`provided that when
`
`~----~
`-¥v
`
`X\ __ ,:
`
`4
`
`is
`
`~'')((
`
`

`

`9
`-continued
`
`US 12,037,339 B2
`
`(la2)
`
`10
`-continued
`
`(1wN~1),
`
`1-R, Jlyjj (la5)
`
`0~
`
`/L
`T
`
`5
`
`10
`
`15
`
`20
`
`0
`
`N~
`3 I
`(1
`
`NAN_,.,,.R2,
`
`\=1
`
`O ~N ' A",
`
`I;
`
`2
`
`NA
`\
`NH
`
`a-{
`
`0
`
`Ri
`
`t£6N✓R,
`
`N
`
`Ri
`
`(la6)
`
`(la7)
`
`(la3) 25 1-R, Jlyjj
`
`(1wN~1),
`
`30
`
`NH
`
`-7"
`
`N
`
`'b--{
`
`0
`
`(la4)
`
`0
`
`NAN_,.,,.R2,
`
`3 C \=1
`
`NH
`
`-7"
`
`N
`
`'b--{
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`0~
`
`L
`
`NA
`\
`NH
`
`a-{
`
`0
`
`(1wN~/),
`
`1-R, Jlv)j
`
`N
`
`Ri
`
`0
`
`NH
`
`-7"
`
`N
`
`'b--{
`
`0
`
`0
`
`

`

`US 12,037,339 B2
`
`11
`-continued
`
`12
`-continued
`
`(laS)
`
`(!all)
`
`A ~ I ~\,
`0 v 5 j
`\=1
`
`N
`
`N
`
`F
`
`N~
`3 I
`
`( ~ OJp
`
`L
`
`NANH
`
`b--{
`
`0
`
`or
`
`10
`
`15
`
`20
`
`A ~ I ~\,
`0 y ; j
`\=1
`
`N
`
`N
`
`F
`
`N~
`
`3 I (
`
`N
`
`(Ia9)
`
`25 or a pharmaceutically acceptable salt, solvate, prodrug,
`stereoisomer, or tautomer thereof, wherein:
`
`each R7 is independently C1 -C6 alkyl, C 1 -C6 haloalkyl,
`C 1 -C6 alkoxy, C 1 -C6 haloalkoxy, OH, or halogen; and
`
`each R11 is independently C 1 -C6 alkyl, C 1 -C6 haloalkyl,
`C 1 -C6 alkoxy, C 1 -C6 haloalkoxy, OH, halogen, NH2 ,
`NH-(C 1 -C6 alkyl), N(C 1 -C6 alkyl)2 , CN, NO2 , or
`C3 -C6 cycloalkyl.
`
`In some embodiments, the compounds of Formula (I)
`have the structure of Formula (Ibl), (Ib2), (Ib3), (Ib4), (Ib5),
`(Ib6), (Ib7), (Ib8), (Ib9), (Ibl0), or (Ibll):
`
`30
`
`35
`
`40
`
`45
`
`(!bl)
`
`(lal0) 5o
`
`55
`
`60
`
`65
`
`

`

`US 12,037,339 B2
`
`13
`-continued
`
`14
`-continued
`
`(Ib2)
`
`10
`
`15
`
`20
`
`(Ib3) 25
`
`R1
`
`/
`
`0
`
`N--N Av)
`C(NwN ~ 1 >
`
`/
`
`(Ib5)
`
`(Ib6)
`
`/Ri
`
`0
`
`NAN_,,R2,
`
`\=1
`
`ctN--N
`
`N
`
`Ri
`
`NH
`
`~
`
`N
`
`'a-{
`
`0
`
`Q (R , - ) , ,
`
`(Ib4)
`
`ctN--N
`
`Ri
`
`N
`
`NAN_,,R2,
`
`\=1
`
`NH
`
`~ N
`
`'a-{
`
`0
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`0~
`
`L
`
`NA
`\
`NH
`
`a-{
`
`0
`
`o v)/ (lb7)
`l 1
`~
`C(NC) ~I>
`
`N--N
`
`N
`
`RJ
`
`NH
`
`~ N
`
`'a-{
`
`0
`
`

`

`US 12,037,339 B2
`
`15
`-continued
`
`16
`-continued
`
`(IbS)
`
`(Ibll)
`
`or
`
`10
`
`15
`
`(Ib9)
`
`25
`
`20 or a pharmaceutically acceptable salt, solvate, prodrug,
`stereoisomer, or tautomer thereof, wherein:
`each R7 is independently C1 -C6 alkyl, C 1 -C6 haloalkyl,
`C 1 -C6 alkoxy, C 1 -C6 haloalkoxy, OH, or halogen; and
`each R11 is independently C 1 -C6 alkyl, C 1 -C6 haloalkyl,
`C 1 -C6 alkoxy, C 1 -C6 haloalkoxy, OH, halogen, NH2 ,
`NH-(C 1 -C6 alkyl), N(C 1 -C6 alkyl)2 , CN, 0 2 , or C3 -C6
`cycloalkyl.
`For each of the formulae described herein, where appli-
`30 cable:
`In some embodiments,
`
`N:::::," NH
`
`'a-{
`
`0
`
`35
`
`40
`
`45
`
`(Ibl0) 5o
`
`In some embodiments, is
`
`55
`
`In some embodiments, R1 is (CRcRc)0 _2 -phenyl substi-
`tuted with one or more substituents independently selected
`from straight-chain C 1 -C6 alkyl or branched C3 -C6 alkyl
`(e.g., methyl, ethyl, propyl, i-propyl, n-butyl,
`i-butyl,
`s-butyl, t-butyl, pentyl, or hexyl), straight-chain C 1 -C6
`60 haloalkyl or branched C3 -C6 haloalkyl (e.g., methyl, ethyl,
`propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or
`hexyl, each of which is substituted with one or more halogen
`( e.g., F, Cl)), straight-chain C 1 -C6 alkoxy or branched C3 -C6
`alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy,
`65 i-butoxy, s-butoxy, t-butoxy, pentoxy, or hexyloxy), straight(cid:173)
`chain C 1 -C6 haloalkoxy or branched C3 -C6 haloalkoxy ( e.g.,
`methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy,
`
`

`

`US 12,037,339 B2
`
`17
`s-butoxy, t-butoxy, pentoxy, or hexyloxy, each of which is
`substituted with one or more halogen (e.g., F, Cl)), OH,
`halogen ( e.g., F, Cl, Br, or I), NH2 , NH-(C 1 -C6 alkyl) ( e.g.,
`methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl,
`( e.g., methyl, 5
`t-butyl, pentyl, or hexyl), N(C 1 -C6 alkyl)2
`ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl,
`pentyl, or hexyl), CN, NO2 , and C3 -C6 cycloalkyl ((e.g.,
`cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl).
`In some embodiments, R1 is (CRcRc)0 _2 -phenyl substi(cid:173)
`tuted with one or more substituents independently selected 10
`from straight-chain C1 -C4 alkyl or branched C3 -C4 alkyl
`(e.g., methyl, ethyl, propyl, i-propyl, n-butyl,
`i-butyl,
`s-butyl, or t-butyl), straight-chain C 1 -C4 haloalkyl or
`branched C3 -C4 haloalkyl (e.g., methyl, ethyl, propyl, i-pro- 15
`pyl, n-butyl, i-butyl, s-butyl, or t-butyl, each of which is
`substituted with one or more halogen (e.g., F, Cl)), straight(cid:173)
`chain C 1-C4 alkoxy or branched C3 -C4 alkoxy (e.g.,
`methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy,
`s-butoxy, or t-butoxy), straight-chain C 1-C4 haloalkoxy or 20
`branched C3 -C4 haloalkoxy ( e.g., methoxy, ethoxy, propoxy,
`i-propoxy, n-butoxy, i-butoxy, s-butoxy, or t-butoxy, each of
`which is substituted with one or more halogen (e.g., F, Cl)),
`OH, halogen ( e.g., F, Cl, Br, or I), NH2 , NH-(C 1 -C4 alkyl)
`(e.g., methyl, ethyl, propyl, i-propyl, n-butyl,
`i-butyl, 25
`( e.g., methyl, ethyl,
`s-butyl, or t-butyl), N(C 1 -C4 alkyl)2
`propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl), CN,
`NO2 , and C3 -C6 cycloalkyl ((e.g., cyclopropyl, cyclobutyl,
`cyclopentyl, or cyclohexyl).
`In some embodiments, R1 is (CRcRc)0 _2 -phenyl substi- 30
`tuted with one or more substituents independently selected
`from straight-chain C1 -C4 alkyl or branched C3 -C4 alkyl
`(e.g., methyl, ethyl, propyl, i-propyl, n-butyl,
`i-butyl,
`s-butyl, or t-butyl), straight-chain C 1 -C4 haloalkyl or
`branched C3 -C4 haloalkyl (e.g., methyl, ethyl, propyl, i-pro- 35
`pyl, n-butyl, i-butyl, s-butyl, or t-butyl, each of which is
`substituted with one or more halogen (e.g., F, Cl)), straight(cid:173)
`chain C 1-C4 alkoxy or branched C3 -C4 alkoxy (e.g.,
`methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy,
`s-butoxy, or t-butoxy), straight-chain C 1-C4 haloalkoxy or 40
`branched C3 -C4 haloalkoxy ( e.g., methoxy, ethoxy, propoxy,
`i-propoxy, n-butoxy, i-butoxy, s-butoxy, or t-butoxy, each of
`which is substituted with one or more halogen (e.g., F, Cl)),
`and halogen (e.g., F, Cl, Br, or I).
`In some embodiments, R1 is (CRcRc)0 _2 -phenyl substi- 45
`tuted with one, two, or three substituents as described herein.
`In some embodiments, R1 is (CRcRc)0 _2 -phenyl substi(cid:173)
`tuted with one, two, or three substituents selected from
`methyl, methoxy, CF 3 , F, and Cl.
`In some embodiments, R1 is (CRcRc)0 _1-phenyl substi- 50
`tuted with one or more substituents as described herein.
`In some embodiments, R1 is (CRcRc)0 _1-phenyl substi(cid:173)
`tuted with one, two, or three substituents as described herein.
`In some embodiments, R1 is (CRcRc)0 _1-phenyl substi(cid:173)
`tuted with one, two, or three substituents selected from
`methyl, methoxy, CF 3 , F, and Cl.
`In some embodiments, R1 is phenyl substituted with one
`or more substituents as described herein.
`In some embodiments, R1 is phenyl substituted with one,
`two, or three substituents as described herein.
`In some embodiments, R1 is phenyl substituted with one,
`two, or three substituents selected from methyl, methoxy,
`CF 3 , F, and Cl.
`In some embodiments, R1 is CRcRcphenyl substituted
`with one or more substituents as described herein.
`In some embodiments, R1 is CRcRcphenyl substituted
`with one, two, or three substituents as described herein.
`
`18
`In some embodiments, R1 is CRcRcphenyl substituted
`with one, two, or three substituents selected from methyl,
`CF 3 , F, and Cl.
`In some embodiments, R1 is (CRcRc) 0 _2----C3 -C6 cycloal(cid:173)
`kyl ( e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
`bicyclobutanyl, bicyclopentanyl, or bicyclohexanyl) option(cid:173)
`ally substituted with one or more substituents independently
`selected from straight-chain C 1 -C6 alkyl or branched C3 -C6
`alkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl,
`s-butyl, t-butyl, pentyl, or hexyl), straight-chain C 1 -C6
`haloalkyl or branched C3 -C6 haloalkyl (e.g., methyl, ethyl,
`propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or
`hexyl, each of which is substituted with one or more halogen
`( e.g., F, Cl)), straight-chain C 1 -C6 alkoxy or branched C3 -C6
`alkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy, n-butoxy,
`i-butoxy, s-butoxy, t-butoxy, pentoxy, or hexyloxy), straight(cid:173)
`chain C 1 -C6 haloalkoxy or branched C3 -C6 haloalkoxy ( e.g.,
`methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy,
`s-butoxy, t-butoxy, pentoxy, or hexyloxy, each of which is
`substituted with one or more halogen (e.g., F, Cl)), OH,
`halogen ( e.g., F, Cl, Br, or I), NH2 , NH-(C 1 -C6 alkyl) ( e.g.,
`methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl,
`( e.g., methyl,
`t-butyl, pentyl, or hexyl), N(C 1 -C6 alkyl) 2
`ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl,
`pentyl, or hexyl), CN, NO2 , and C3 -C6 cycloalkyl ((e.g.,
`cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl).
`In some embodiments, R1 is (CRcRc) 0 _2----C3 -C6 cycloal(cid:173)
`kyl ( e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
`bicyclobutanyl, bicyclopentanyl, or bicyclohexanyl) option(cid:173)
`ally substituted with one or more substituents independently
`selected from straight-chain C 1 -C4 alkyl or branched C3 -C4
`alkyl (e.g., methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl,
`s-butyl, or t-butyl), straight-chain C 1 -C4 haloalkyl or
`branched C3 -C4 haloalkyl (e.g., methyl, ethyl, propyl, i-pro(cid:173)
`pyl, n-butyl, i-butyl, s-butyl, or t-butyl, each of which is
`substituted with one or more halogen (e.g., F, Cl)), straight(cid:173)
`chain C 1-C4 alkoxy or branched C3 -C4 alkoxy (e.g.,
`methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy,
`s-butoxy, or t-butoxy), straight-chain C 1 -C4 haloalkoxy or
`branched C3 -C4 haloalkoxy (e.g., methoxy, ethoxy, propoxy,
`i-propoxy, n-butoxy, i-butoxy, s-butoxy, or t-butoxy, each of
`which is substituted with one or more halogen (e.g., F, Cl)),
`OH, halogen (e.g., F, Cl, Br, or I), NH2 , NH-(C 1-C4 alkyl)
`(e.g., methyl, ethyl, propyl, i-propyl, n-butyl,
`i-butyl,
`( e.g., methyl, ethyl,
`s-butyl, or t-butyl), N(C 1 -C4 alkyl)2
`propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl), CN,
`NO2 , and C3 -C6 cycloalkyl ((e.g., cyclopropyl, cyclobutyl,
`cyclopentyl, or cyclohexyl).
`In some embodiments, R1 is (CRcRc) 0 _2----C3 -C6 cycloal(cid:173)
`kyl ( e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
`bicyclobutanyl, bicyclopentanyl, or bicyclohexanyl) option(cid:173)
`ally substituted with one, two, or three substituents as
`55 described herein.
`In some embodiments, R1 is (CRcRc) 0 _2----C3 -C6 cycloal(cid:173)
`kyl ( e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
`bicyclobutanyl, bicyclopentanyl, or bicyclohexanyl) option(cid:173)
`ally substituted with one, two, or three substituents selected
`60 from methyl, methoxy, CF 3 , F, and Cl.
`In some embodiments, R1 is (CRcRc) 0 _1----C3 -C6 cycloal(cid:173)
`kyl ( e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
`bicyclobutanyl, bicyclopentanyl, or bicyclohexanyl) option(cid:173)
`ally substituted with one or more substituents as described
`65 herein.
`In some embodiments, R1 is (CRcRc) 0 _1----C3 -C6 cycloal(cid:173)
`kyl ( e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
`
`

`

`US 12,037,339 B2
`
`19
`bicyclobutanyl, bicyclopentanyl, or bicyclohexanyl) option(cid:173)
`ally substituted with one, two, or three substituents as
`described herein.
`In some embodiments, R1 is (CReRc)0 _1----C3 -C6 cycloal(cid:173)
`kyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 5
`bicyclobutanyl, bicyclopentanyl, or bicyclohexanyl) option(cid:173)
`ally substituted with one, two, or three substituents selected
`from methyl, methoxy, CF 3 , F, and Cl.
`In some embodiments, R1 is cyclohexyl or bicyclopenta(cid:173)
`nyl, each of which is optionally substituted with one or more 10
`substituents as described herein.
`In some embodiments, R1 is cyclohexyl or bicyclopenta(cid:173)
`nyl, each of which is optionally substituted with one, two, or
`three substituents as described herein.
`In some embodiments, R1 is cyclohexyl or bicyclopenta(cid:173)
`nyl, each of which is optionally substituted with one, two, or
`three substituents selected from methyl, methoxy, CF 3 , F,
`and Cl.
`In some embodiments, R1 is (CReRc)0 _2 -heteroaryl com(cid:173)
`prising one 5- or 6-membered ring and 1-3 heteroatoms
`selected from N, 0, and S, optionally substituted with one or
`more substituents independently selected from straight(cid:173)
`chain C 1-C6 alkyl or branched C3 -C6 alkyl (e.g., methyl,
`ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, 25
`pentyl, or hexyl), straight-chain C 1 -C6 haloalkyl or branched
`C3 -C6 haloalkyl (e.g., methyl, ethyl, propyl, i-propyl,
`n-butyl, i-butyl, s-butyl, t-butyl, pentyl, or hexyl, each of
`which is substituted with one or more halogen (e.g., F, Cl)),
`straight-chain C 1 -C6 alkoxy or branched C3 -C6 alkoxy ( e.g.,
`methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy,
`s-butoxy, t-butoxy, pentoxy, or hexyloxy), straight-chain
`C 1-C6 haloalkoxy or branched C3 -C6 haloalkoxy (e.g.,
`methoxy, ethoxy, propoxy, i-propoxy, n-butoxy, i-butoxy,
`s-butoxy, t-butoxy, pentoxy, or hexyloxy, each of which is
`substituted with one or more halogen (e.g., F, Cl)), OH,
`halogen ( e.g., F, Cl, Br, or I), NH2 , NH-(C 1 -C6 alkyl) ( e.g.,
`methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl,
`( e.g., methyl,
`t-butyl, pentyl, or hexyl), N(C 1 -C6 alkyl)2
`ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl,
`pentyl, or hexyl), CN, N02 , and C3 -C6 cycloalkyl ((e.g.,
`cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl).
`In some embodiments, R1 is (CReRc)0 _2 -heteroaryl com(cid:173)
`prising one 5- or 6-membered ring and 1-3 heteroatoms
`selected from N, 0, and S, optionally substituted with one or
`more substituents independently selected from straight(cid:173)
`chain C 1 -C 4 alky 1 or branched C3 -C 4 alky 1 (e.g., methy 1,
`ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, or t-butyl),
`straight-chain C 1 -C4 haloalkyl or branched C3 -C4 haloalkyl
`(e.g., methyl, ethyl, propyl, i-propyl, n-butyl,
`i-butyl,
`s-butyl, or t-butyl, each of which is substituted with one or
`more halogen ( e.g., F, Cl)), straight-chain C 1 -C4 alkoxy or
`branched C3 -C4 alkoxy (e.g., methoxy, ethoxy, propoxy,
`i-propoxy, n-butoxy,
`i-butoxy, s-butoxy, or t-butoxy),
`straight-chain C 1 -C4 haloalkoxy or branched C3 -C4
`haloalkoxy (e.g., methoxy, ethoxy, propoxy, i-propoxy,
`n-butoxy, i-butoxy, s-butoxy, or t-butoxy, each of which is
`substituted with one or more halogen (e.g., F, Cl)), OH,
`halogen ( e.g., F, Cl, Br, or I), NH2 , NH-(C 1 -C4 alkyl) ( e.g.,
`methyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, s-butyl, or
`t-butyl), N(C 1 -C4 alkyl)2 ( e.g., methyl, ethyl, propyl, i-pro(cid:173)
`pyl, n-butyl, i-butyl, s-butyl, or t-butyl), CN, N02 , and
`C3 -C6 cycloalkyl ((e.g., cyclopropyl, cyclobutyl, cyclopen-
`tyl, or cyclohexyl).
`In some embodiments, R1 is (CReRc)0 _2 -heteroaryl com(cid:173)
`prising one 5-membered ring and 1-3 heteroatoms selected
`from N, 0, and S, optionally substituted as described herein.
`
`20
`In some embodiments, R1 is (CReRc) 0 _1-heteroaryl com(cid:173)
`prising one 5-membered ring and 1-3 heteroatoms selected
`from N, 0, and S, optionally substituted as described herein.
`In some embodiments, R1 is heteroaryl comprising one
`5-membered ring and 1-3 heteroatoms selected from N, 0,
`and S, optionally substituted as described herein.
`In some embodiments, R1 is (CReRc) 0 _2 -heteroaryl com(cid:173)
`prising one 6-membered ring and 1-3 heteroatoms selected
`from N, 0, and S, optionally substituted as described herein.
`In some embodiments, R1 is (CReRc) 0 _1-heteroaryl com(cid:173)
`prising one 6-membered ring and 1-3 heteroatoms selected
`from N, 0, and S, optionally substituted as described herein.
`In some embodiments, R1 is heteroaryl comprising one
`6-membered ring and 1-3 heteroatoms selected from N, 0,
`15 and S, optionally substituted as described herein