NZ722413B2 - Dihydropyrrolopyridine inhibitors of ror-gamma - Google Patents
Dihydropyrrolopyridine inhibitors of ror-gamma Download PDFInfo
- Publication number
- NZ722413B2 NZ722413B2 NZ722413A NZ72241315A NZ722413B2 NZ 722413 B2 NZ722413 B2 NZ 722413B2 NZ 722413 A NZ722413 A NZ 722413A NZ 72241315 A NZ72241315 A NZ 72241315A NZ 722413 B2 NZ722413 B2 NZ 722413B2
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- NZ
- New Zealand
- Prior art keywords
- alkyl
- halo
- compound
- alkoxy
- hydroxy
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Abstract
Provided are novel compounds of Formula (I): pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, which are useful in the treatment of diseases and disorders mediated by RORy. Also provided are pharmaceutical compositions comprising the novel compounds of Formula (I) and methods for their use in treating one or more inflammatory, metabolic, autoimmune and other diseases or disorders. nd methods for their use in treating one or more inflammatory, metabolic, autoimmune and other diseases or disorders.
Description
(12) Granted patent specificaon (19) NZ (11) 722413 (13) B2
(47) Publicaon date: 2021.12.24
(54) DIHYDROPYRROLOPYRIDINE INHIBITORS OF ROR-GAMMA
(51) Internaonal Patent Classificaon(s):
C07D 471/04 A61K 31/437 A61P 29/00
(22) Filing date: (73) Owner(s):
2015.01.30 VITAE PHARMACEUTICALS, LLC
(23) Complete caon filing date: (74) Contact:
2015.01.30 Pizzeys Patent and Trade Mark Attorneys P
ty Ltd
(30) Internaonal Priority Data:
US 61/970,637 2014.03.26 (72) Inventor(s):
US 61/935,162 2014.02.03 DONG, Chengguo
FAN, Yi
(86) Internaonal Applicaon No.: SINGH, Suresh, B.
ZHENG, Yajun
ZHUANG, Linghang
(87) Internaonal Publicaon : DILLARD, Lawrence, Wayne
WO/2015/116904 JIA, Lanqi
YUAN, Jing
CLAREMON, David, A.
LIU, Zhijie
A, Stephen, D.
, Andrew
TICE, Colin, M.
ZHAO, Wei
(57) Abstract:
Provided are novel compounds of Formula (I): pharmaceucally acceptable salts f,
and pharmaceucal composions thereof, which are useful in the treatment of diseases and
disorders mediated by RORy. Also provided are pharmaceucal composions comprising the
novel compounds of Formula (I) and methods for their use in treang one or more inflammatory,
B2 metabolic, autoimmune and other diseases or disorders.
722413
DIHYDROPYRROLOPYRIDINE INHIBITORS OF ROR-GAMMA
RELATED ATIONS
This application claims the benefit of the filing date of US. Provisional Application
No. ,162, filed February 3, 2014, and US. Provisional Application No. 61/970,637, filed
March 26, 2014. The entire contents of the aformentioned ations are incorporated by
reference .
TECHNICAL FIELD OF THE INVENTION
The present invention is directed to novel ic acid receptor—related orphan
receptor gamma ” or “ROR—gamma”) inhibitors, processes for their preparation,
pharmaceutical compositions containing these inhibitors, and their use in the treatment of
inflammatory, metabolic, autoimmune and other diseases mediated by RORy.
BACKGROUND OF THE INVENTION
Retinoic acid receptor—related orphan receptors (RORs) are a subfamily of
transcription factors in the steroid hormone nuclear receptor superfamily (Jetten & J00 (2006)
Adv. Dev. Biol. 2006, 16, 313—355). The ROR family consists of ROR alpha (ROROL), ROR beta
(RORB) and ROR gamma (RORy), each encoded by a separate gene (in human: RORA, RORB
and RORC, respectively; in mouse: ram, rorb and rorc, respectively). RORs contain four
principal domains shared by the ty of nuclear receptors: an N—terminal domain, a highly
conserved DNA—binding domain (DBD) ting of two zinc finger motifs, a hinge domain,
and a ligand binding domain (LBD). Each ROR gene generates several isoforms, differing only
in their N—terminal domains. RORY has two isoforms: RORyl and RORy2 (also known as
RORyt). RORY refers to RORyl and/or RORyt. RORyl is expressed in a variety of tissues
including thymus, muscle, kidney and liver, but RORyt is exclusively expressed in the cells of
the immune system, has a critical role in thymopoiesis and the development of several ary
lymphoid tissues, and is a key regulator of Thl7 cell differentiation (Jetten, 2009, Nucl. Recept.
Signal., 7:e003, doi:10.1621/nrs.07003, Epub 2009 Apr 3).
Thl7 cells are a subset of T helper cells which entially produce the pro—
inflammatory cytokines IL—17A, IL—17F, IL—21 and IL—22. Th17 cells and their effector
molecules, such as IL—17, IL—21, IL—22, GM—CSF and CCL20, are associated with the
pathogenesis of several autoimmune and inflammatory diseases, such as rheumatoid arthritis,
systemic lupus erythematosus, multiple sis, sis, inflammatory bowel disease, allergy
and asthma (Maddur et al., 2012, Am. J. Pathol., 181:8—18). Recent findings t a role for
IL17 and Th17 cells in the pathogenesis of acne (Thiboutot et al., 2014, J. Invest. Dermatol.,
WO 16904 2015/013699
134(2):307—10, doi: 10.1038/jid.2013.400; Agak et al., 2014, J. Invest. Dermatol., 134(2):366—
73, doi: 10.1038/jid.2013.334, Epub 2013 Aug 7). Th17 cells are also potent inducers of
inflammation associated with triosis, a c inflammatory disease (Hirata et al., 2010,
Endocrinol., 68—5476; Hirata et al., 2011, Fertil Steril., (1):113—7, doi:
6/j.fertnstert.2011.04.060, Epub 2011 May 20). Additionally, Th17 cells have a key role
in the mouse mune models of experimental autoimmune encephalomyelitis (EAE),
collagen—induced arthritis (CIA) and adjuvant—induced arthritis (AIA) (Bedoya et al., 2013, Clin.
Dev. Immunol., 2013:986789. Epub 2013 Dec 26. Th17 cells are activated during inflammatory
and autoimmune disease processes and are responsible for recruiting other inflammatory cell
types, particularly neutrophils, to mediate pathology in target tissues (Miossec & Kolls, 2012,
Nature Rev., 11:763—776; Korn et al., 2009, Annu. Rev. Immunol., 27:485—517). Aberrant Th17
cell function has been ated in a variety of autoimmune diseases, including multiple
sclerosis and rheumatoid arthritis. mune disease is believed to arise from the tion
of the equilibrium between effector and regulatory T cells (Solt et al., 2012, ACS Chem. Biol.,
7: 1515—1519, Epub 2012 July 9). The importance of RORyt to Th17 cell differentiation and the
pathogenic role of Th17 cells is evidenced by the fact that RORyt—deficient mice have very few
Th17 cells and have a ion in severity of EAE (Ivanov et al., 2006, Cell, 126:1121—1133).
Circadian rhythms are daily cycles of behavioral and physiological changes that are
regulated by endogenous circadian clocks. A number of studies have established links between
nuclear receptor (including RORy) function and expression, the circadian regulatory circuitry,
and the regulation of s physiological processes (Jetten (2009) op. cit).
Obstructive sleep apnea syndrome (OSAS) is a chronic inflammatory disease
regulated by T lymphocytes. OSAS patients have a significant increase in eral Th17 cell
frequency, IL—17 and RORyt levels (Ye et al., 2012, Mediators Inflamm., 815308, doi:
.1155/2012/815308, Epub 2012 Dec 31).
A number of studies have provided evidence of a role of RORs in cancer. Mice
deficient in the expression of RORY exhibit a high incidence of thymic lymphomas that
metastasize frequently to liver and spleen. High expression of ssociated genes (including
RORy) and high levels of Th17 cells in the tumor microenvironment has been shown to correlate
with a poor prognosis in various cancers, including lung, gastric, breast and colon cancer
(Tosolini et al., 2011, Cancer Res., 71: 1263-1271, doi: 10.1158/0008-5472.CAN-10—2907, Epub
2011 Feb 8; Su et al., 2014, Immunol. Res., 58:118-124, doi: 10.1007/s120268483-y, Epub
2014 Jan 9; Carmi et al., 2011, J. Immunol., 186:3462-3471, doi: 10.4049/jimmunol.1002901,
Epub 2011 Feb 7; Chen et al., 2013, Histopathology, 63:225—233, doi: 10.1111/his.12156, Epub
2013 Jun 6).
RORY has also been identified to have a regulatory role in glucose homeostasis,
and has been implicated in metabolic syndrome, obesity (Meissburger et al., 2011, EMBO Mol.
Med., 3:637—65 1), hepatosteatosis, insulin ance and diabetes.
r support for the role of RORY in the enesis of inflammatory, metabolic,
circadian effect, cancer, and autoimmune diseases and disorders can be found in the following
references: Chang et al., 2012, J. Exp. Pharmacol., 4:141—148; Jetten et al., 2013, Frontiers
Endocrinol., 4:1—8; Huh & n, 2012, Eur. J. Immunol., 42:2232—2237; Martinez et al.,
2008, Ann. NY. Acad. Sci., 1143:188—211; Pantelyushin et al., 2012, J. Clin. Invest., 122:2252—
2256; Jetten & Ueda, 2002, Cell Death Differen., 9:1167—1 171; Solt et al., 2010, Curr. Opin.
Lipidol., 21 :204-21 1.
In light of the role that RORY plays in disease pathogenesis, inhibition of RORY
actiVity and Th17 cell differentiation and actiVity, including IL17 production, will be of
significant therapeutic benefit. It is therefore desirable to prepare compounds that inhibit RORY
actiVity and hence have y in the treatment of inflammatory, autoimmune, metabolic,
circadian effect, cancer, and other diseases mediated by RORy, such as e.g., , atopic
dermatitis, acne, Crohn’s disease, regional enteritis, tive s, Sjogren's syndrome,
uveitis, Behcet's disease, dermatomyositis, multiple sclerosis, ankylosing spondylitis, systemic
lupus erythematosus, derma, psoriasis, psoriatic arthritis, steroid resistant asthma and
rheumatoid arthritis.
SUMMARY OF THE INVENTION
It has now been found that compounds described herein, and ceutically
acceptable compositions thereof, are effective tors of RORY (see e.g., Table 2). Such
compounds include those of Formula (I):
c 2 x L1
y \ M\Cy1
(\—)—N | n
m N/
R3 (I);
or a pharmaceutically acceptable salt thereof, wherein each of R2, R3, R4, X, L1, n, m, Cyl, and
Cy2 are as defined and described herein.
WO 16904
The provided compounds, and pharmaceutically able compositions thereof, are
inverse agonists or antagonists of RORY and are useful for treating a variety of diseases,
disorders or conditions. Such diseases, disorders, or conditions include those described herein.
The provided compounds can be used alone (i.e., as a monotherapy) or in
combination with one or more other therapeutic agent effective for treating any of the indications
described herein.
ED DESCRIPTION OF CERTAIN EMBODIMENTS
1. General DescriQtion of Compounds of the Invention
In certain embodiments, the present invention provides a compound of Formula (1):
2 1
(\—)—N | y
In N/
R3 (1);
or a pharmaceutically acceptable salt thereof, wherein:
R2 and R3 are each independently hydrogen, hydroxy, monocyclic lkyl,
monocyclic heterocyclyl, or (C1—C6)alkyl, wherein the (C1—C6)alkyl is ally substituted with
l to 2 groups independently selected from hydroxy, halo, and cyano;
R4 is en, (C1—C3)alkyl, or :0;
X is —C(O)NH— or —NHC(O)—;
m is 0, l, or 2;
nis 0, l, 2, or 3;
L1 is absent or is SOZ or CR7R8;
Cy1 is absent or is ed from (C1—C3)alkyl, halo(C1—C3)alkyl, aryl, heteroaryl,
heterocyclyl, and cycloalkyl, wherein the aryl, heteroaryl, heterocyclyl, and cycloalkyl are each
optionally tuted with l to 3 groups independently selected from R5;
Cy2 is absent or is selected from (C1—C6)alkoxycarbonyl, phenyl(C1—C3)alkoxycarbonyl,
halophenyl(C1—C3)alkoxycarbonyl, aryl, heteroaryl, clic cycloalkyl, and monocyclic
heterocyclyl, wherein the aryl, heteroaryl, monocyclic lkyl, and moncyclic heterocyclyl
are each optionally substituted with l to 3 groups independently selected from R6;
R5 and R6 are each independently ed from halo, cyano, nitro, amino, hydroxy,
carboxy, (C1—C6)alkyl, heterocyclyl, hydroxy(C1—C6)alkyl, COZH, _3COOH, (C1—
C3)all<ylcarbonyloxy, (C3—C6)cycloalkyl, hydroxy(C3—C6)cycloalkyl, (C4—C7)cycloalkylalkyl, (C2—
C6)alkenyl, halo(C2—C6)all<enyl, hydroxy(C2—C6)alkenyl, (C2—C6)all<ynyl, (C3—C6)cycloall<yl(C2—
C4)a1kyny1, halo(C1—C6)alky1, halo(C3—C6)cycloalky1, halo(C4—C7)cycloa1ky1alky1, (C1—C6)alkoxy,
(C3—C6)cycloalkoxy, (C4—C7)cycloa1ky1alkoxy, halo(C1—C6)alkoxy, halo(C3—C6)cycloalkoxy,
halo(C4—C7)cycloa1ky1alkoxy, (C1—C6)alky1thio, (C3—C6)cycloalkythio, (C4—
C7)cycloa1ky1a1ky1thio, 1—C6)alky1thio, halo(C3—C6)cycloalkythio, halo(C4—
loa1ky1a1ky1thio, (C1—C6)alkylsulfinyl, (C3—C6)cycloa1kylsulfiny1, (C4—
C7)cycloalkylalkylsulfinyl, halo(C1—C6)alkylsulfony1, halo(C3—C6)cycloalkylsulfiny1, halo(C4—
C7)cycloalkylalkylsulfinyl, (C1—C6)a1kylsulfony1, )cycloa1kylsulfony1, (C4—
C7)cycloa1ky1alky1sulfonyl, halo(C1—C6)alkylsulfony1, halo(C3—C6)cycloa1kylsulfony1, halo(C4—
C7)cycloa1ky1alky1sulfonyl, (C1—C6)alky1amino, di(C1—C6)alky1amino, (C1—C6)alkoxy(C1—
C6)alkoxy, halo(C1—C6)alkoxy(C1—C6)alkoxy, (C1—C6)alkoxycarbony1, HZNCO, , (C1-
C6)a1ky1aminocarbony1, di(C1—C6)a1ky1aminocarbony1, (C1—C3)alkoxy(C1—
C3)a1ky1aminocarbony1, heterocyclylcarbonyl, (C1—C6)a1ky1aminosulfonyl, di(C1—
C6)a1ky1aminosulfony1, heterocyclylsulfonyl, (C1—C6)a1ky1carbony1amino, )alky1—
carbonylamino(C1—C6)a1ky1, (C1—C6)a1kylsulfony1amino, (C1—C6)a1kylsulfony1amino(C1—C6)a1ky1,
(C1—C6)alkoxycarbony1(C1—C6)alkoxy, (C1—C6)alkoxy(C1—C6)alkyl, halo(C1—C6)alkoxy(C1—
C6)alky1, hydroxy(C1—C6)alkoxy, aryl, heteroaryl, oxo, amino(C1—C6)alky1, (C1—
C6)a1ky1amino(C1—C6)a1ky1, di(C1—C6)a1ky1amino(C1—C6)alky1 amino(C2—C6)alkoxy, (C1—
C6)a1ky1amino(C2—C6)alkoxy, di(C1—C6)a1ky1amino(C2—C6)alkoxy, (C1—C6)alky1carbony1,
y(C1—C6)a1ky1carbony1, )a1ky1hydroxycarbonyl, (C1—C6)a1ky1hydroxy(C1—C6)a1ky1,
(C3—C6)cycloa1ky1carbony1, (C3—C6)cycloalkylaminocarbonyl, {(C3—C6)cycloalky1} { (C1—
C6)a1ky1}aminocarbony1, di(C3—C6)cycloalkylaminocarbonyl, (C3—C6)cycloalkylaminosulfonyl,
{(C3—C6)cycloalky1}{(C1—C6)a1ky1}aminosu1fony1, di(C3—C6)cycloalky1aminosulfonyl, cyano(C1—
C6)alky1, aminocarbony1(C1—C6)a1ky1, (C1—C6)a1ky1aminocarbony1(C1—C6)a1ky1, di(C1—
C6)a1ky1aminocarbony1(C1—C6)a1ky1, (C3—C6)cycloa1ky1aminocarbony1(C1—C6)alky1, {(C3—
C6)cycloa1ky1} { (C1—C6)a1ky1}aminocarbony1(C1—C6)a1ky1, [(C1—C6)a1ky1(C4—C6)heterocyc1y1](C1—
C6)alky1, and di(C3—C6)cycloa1ky1aminocarbony1(C1—C6)a1ky1; and
R7 and R8 are each independently hydrogen, hydroxy, (C1—C3)a1ky1, hydroxy(C1—C3)alky1,
mono(C1—C3)alky1amino, C3)alky1amino, COZH, _3COOH, moncyclic heterocyclyl,
(C1—C3)a1koxycarbony1, (C1—C3)a1ky1(C1—C3)alkoxycarbony1, halophenyl, halopheny1(C1—
C3)a1ky1, or quinolin—2(1H)one—4y1—methy1; or
R7 and R8, together with the carbon atom to which they are ed, form a 3— to 6—
membered cycloalkyl or heterocyclyl.
PCT/U82015/013699
2. Comgounds and Definitions
The terms “halo” and “halogen” as used herein refer to an atom selected from fluorine
(fluoro, —F), chlorine (chloro, —Cl), bromine (bromo, —Br), and iodine (iodo, —I).
The term “alkyl”, used alone or as a part of a larger moiety such as e.g., “haloalkyl”,
means a saturated monovalent ht or branched arbon radical , unless otherwise
specified, 1—10 carbon atoms and includes, for example, methyl, ethyl, n—propyl, isopropyl, n—
butyl, sec—butyl, isobutyl, tert—butyl, n—pentyl, n—hexyl, n—heptyl, n—octyl, n—nonyl, n—decyl and
the like. “Monovalent” means attached to the rest of the molecule at one point.
The term “haloalkyl” or “halocycloalkyl” include mono, poly, and perhaloalkyl
groups where the ns are independently selected from fluorine, chlorine, and bromine.
The terms “cycloalkyl” and “cycloaliphatic”, used alone or as part of a larger moiety,
refer to a saturated cyclic aliphatic monocyclic or bicyclic ring system, as described herein,
haVing from, unless otherwise specified, 3 to 10 carbon ring atoms. Monocyclic cycloalkyl
groups include, without limitation, cyclopropyl, utyl, cyclopentyl, cyclopentenyl,
cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, and cyclooctyl. It will be understood that
when specified, al substituents on a lkyl or liphatic group may be present on
any substitutable position and, include, e.g., the position at which the cycloalkyl or
cycloaliphatic group is attached.
The term “carbocycle”, cyclyl”, “carbocyclo”, or “carbocyclic” used alone or
as part of a larger moiety refer to saturated, partially saturated, or aromatic ring systems
comprising all carbon atoms haVing, unless otherwise specified, a total of 3 to 10 ring members.
It will be understood that when ied, optional substituents on a carbocycle, carbocyclyl,
carbocyclo, or carbocyclic may be present on any substitutable position and, include, e.g., the
position at which the lkyl is attached.
The term “aryl” used alone or as part of a larger moiety as in “aralkyl”, “aralkoxy”, or
“aryloxyalkyl”, refers to an aromatic carbocyclic ring system , unless otherwise specified,
a total of 6 to 10 ring members. The term “aryl” may be used interchangeably with the term “aryl
ring”, “aryl group”, “aryl ,” or “aryl l”. In n embodiments of the present
disclosure, “aryl” refers to an aromatic ring system which includes, but is not limited to, phenyl
(abbreviated as “Ph”), naphthyl and the like. It will be understood that when specified, optional
substituents on an aryl group may be present on any substitutable position and, include, e.g., the
position at which the aryl is attached.
The term “heteroaryl” used alone or as part of a larger moiety as in “heteroarylalkyl”,
“heteroarylalkoxy”, or "heteroarylaminoalkyl”, refers to a 5—10 —membered aromatic radical
2015/013699
containing 1—4 heteroatoms ed from N, O, and S and includes, for example, thienyl,
furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl,
thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl,
purinyl, naphthyridinyl, and pteridinyl. The term oaryl” may be used hangeably with
the terms “heteroaryl ring”, “heteroaryl group”, or “heteroaromatic”. The terms “heteroaryl” and
“heteroar—”, as used herein, also include groups in which a heteroaromatic ring is fused to one or
more aryl rings, where the radical or point of attachment is on the heteroaromatic ring.
Nonlimiting es e indolyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl,
quinazolinyl, and quinoxalinyl. A heteroaryl group may be mono— or bicyclic. It will be
understood that when specified, optional substituents on a heteroaryl group may be present on
any tutable position and, e, e.g., the position at which the heteroaryl is attached.
The term “heterocyclyl” means a 4—, 5—, 6— and 7—membered saturated or partially
unsaturated cyclic ring containing 1 to 4 heteroatoms independently selected from N, O,
and S. The terms “heterocycle”, “heterocyclyl”, “heterocyclyl ring”, “heterocyclic group”,
“heterocyclic moiety”, and “heterocyclic radical”, are used interchangeably herein. A
heterocyclyl ring can be attached to its pendant group at any heteroatom or carbon atom that
results in a stable structure. Examples of such saturated or partially unsaturated heterocyclic
radicals include, without tion, tetrahydrofuranyl, tetrahydrothienyl, terahydropyranyl,
pyrrolidinyl, idonyl, piperidinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl,
morpholinyl, dihydrofuranyl, dihydropyranyl, dihydropyridinyl, tetrahydropyridinyl,
dihydropyrimidinyl, and tetrahydropyrimidinyl. A heterocyclyl group may be mono— or bicyclic.
Unless otherwise specified, bicyclic heterocyclyl groups include, e.g., unsaturated heterocyclic
radicals fused to another unsaturated heterocyclic radical or aromatic or heteroaryl ring, such as
for e, tetrahydronaphthyridine, indolinone, opyrrolotriazole, imidazopyrimidine,
inone, dioxaspirodecane. It will also be understood that when specified, optional
substituents on a heterocyclyl group may be present on any tutable position and, include,
e.g., the position at which the heterocyclyl is attached.
As used herein the terms “subject” and “patient” may be used interchangeably, and
means a mammal in need of treatment, e.g., companion s (e.g., dogs, cats, and the like),
farm animals (e.g., cows, pigs, horses, sheep, goats and the like) and laboratory animals (e.g.,
rats, mice, guinea pigs and the like). Typically, the subject is a human in need of treatment.
Certain of the disclosed compounds may exist in various stereoisomeric forms.
Stereoisomers are compounds that differ only in their spatial ement. Enantiomers are pairs
of stereoisomers whose mirror images are not superimposable, most commonly because they
2015/013699
contain an trically substituted carbon atom that acts as a chiral . “Enantiomer”
means one of a pair of les that are mirror images of each other and are not
superimposable. reomers are stereoisomers that contain two or more asymmetrically
substituted carbon atoms. The symbol “*” in a structural formula represents the presence of a
chiral carbon center. “R” and “S” represent the configuration of substituents around one or more
chiral carbon atoms. Thus, “R*” and “8*” denote the relative configurations of substituents
around one or more chiral carbon atoms.
“Racemate” or “racemic mixture” means a compound of equimolar quantities of two
enantiomers, wherein such mixtures exhibit no optical activity, i.e., they do not rotate the plane
of polarized light.
“Geometric isomer” means isomers that differ in the orientation of substituent atoms
in relationship to a carbon—carbon double bond, to a cycloalkyl ring, or to a bridged bicyclic
system. Atoms (other than H) on each side of a carbon—carbon double bond may be in an E
(substituents are on opposite sides of the carbon—carbon double bond) or Z (substituents are
oriented on the same side) configuration. “R,” “S,” “S*,” “R*,” “E,” “Z,” “cis,” and “trans,”
indicate configurations relative to the core molecule.
The nds of the invention may be prepared as individual enantiomers by either
enantio—specific synthesis or resolved from an enantiomerically enriched mixture. Conventional
resolution techniques include forming the salt of a free base of each isomer of an enantiomeric
pair using an lly active acid (followed by fractional crystallization and regeneration of the
free base), forming the salt of the acid form of each enantiomer of an enantiomeric pair using an
optically active amine (followed by fractional crystallization and regeneration of the free acid),
forming an ester or amide of each of the enantiomers of an omeric pair using an optically
pure acid, amine or alcohol (followed by chromatographic tion and removal of the chiral
auxiliary), or resolving an enantiomeric mixture of either a starting material or a final product
using various well known chromatographic methods.
When the stereochemistry of a disclosed compound is named or ed by structure,
the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight
pure relative to the other stereoisomers. When a single enantiomer is named or depicted by
structure, the depicted or named enantiomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% by
weight optically pure. Percent optical purity by weight is the ratio of the weight of the
enantiomer over the weight of the enantiomer plus the weight of its l isomer.
When a sed nd is named or depicted by structure without indicating the
chemistry, and the compound has at least one chiral center, it is to be understood that the
name or ure encompasses one enantiomer of compound free from the corresponding optical
isomer, a racemic mixture of the compound and mixtures enriched in one enantiomer relative to
its corresponding optical isomer.
When a sed compound is named or depicted by structure without indicating the
stereochemistry and has at least two chiral centers, it is to be understood that the name or
structure encompasses a reomer free of other diastereomers, a pair of diastereomers free
from other diastereomeric pairs, mixtures of diastereomers, mixtures of diastereomeric pairs,
mixtures of diastereomers in which one diastereomer is enriched relative to the other
reomer(s) and mixtures of diastereomeric pairs in which one diastereomeric pair is
enriched relative to the other diastereomeric pair(s).
The compounds of the invention may be present in the form of pharmaceutically
able salts. For use in medicines, the salts of the nds of the ion refer to non—
toxic “pharmaceutically acceptable salts.” Pharmaceutically acceptable salt forms include
pharmaceutically able acidic/anionic or basic/cationic salts.
Pharmaceutically acceptable basic/cationic salts e, the sodium, potassium,
calcium, magnesium, diethanolamine, n—methyl—D—glucamine, L—lysine, L—arginine, ammonium,
ethanolamine, piperazine and anolamine salts.
Pharmaceutically acceptable acidic/anionic salts include, e.g., the acetate,
benzenesulfonate, benzoate, bicarbonate, bitartrate, carbonate, citrate, dihydrochloride,
gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrobromide, hydrochloride,
malate, e, malonate, te, nitrate, salicylate, stearate, succinate, e, tartrate, and
tosylate.
3. Description of Exemglary Comgounds
In a first embodiment, the present invention provides a compound of Formula (I),
c 2 x L1
y \ M \Cy1
(\—)—N | n
1T1 N/
R3 (1);
or a pharmaceutically acceptable salt thereof, wherein the variables are as described above.
In a second embodiment, the compound of Formula (I) is of Formula (II):
R4 O
c2y AxCW \ N n L1
(\—)—N | H
m /
R3 (H);
or a pharmaceutically acceptable salt thereof, wherein the variables in structural Formula (II) are
as described for Formula (I).
In a third embodiment, the compound of Formula (I) is of Formula (III):
R4 O
Cy2 \ chw
(\—)—N | H
m /
R3 (III);
or a pharmaceutically acceptable salt f, wherein the variables in structural Formula (III)
are as described for Formula (I).
In a fourth embodiment, the compound of Formula (I) is of Formula (IV):
R4 O
Cy? A
R2 (IV);
or a ceutically acceptable salt thereof, n the variables in structural Formula (IV)
are as described for Formula (I).
In a fifth embodiment, the compound of a (I) is of Formula (V):
(V);
or a pharmaceutically able salt thereof, wherein the variables in structural Formula (V) are
as described for Formula (I).
In a sixth embodiment, the compound of Formula (I) is of Formula (VI):
2015/013699
(VI);
or a pharmaceutically acceptable salt thereof, wherein the variables in ural Formula (VI)
are as bed for Formula (I).
In a seventh embodiment, the compound of Formula (I) is of Formula (VII):
S2 (VII);
or a pharmaceutically acceptable salt thereof, wherein the variables in structural Formula (VII)
are as described for a (I).
In an eighth embodiment, R2 and R3 in Formulas (I) to (VII) are each independently
hydrogen, hydroxy, or (C1—C3)alkyl, wherein the remainder of the varables are as described in
Formula (I).
In a ninth ment, Cy2 in Formulas (I) to (VII) is present and is selected from
aryl, heteroaryl, monocyclic cycloalkyl, and monocyclic heterocyclyl, each of which is
optionally substituted with l to 2 groups independently selected from R6, wherein the remainder
of the varables are as described in a (I) or the eighth embodiment.
In a tenth embodiment, Cy2 in Formulas (I) to (VII) is phenyl, pyrimidinyl,
cyclohexyl, or pyridinyl, each of which are optionally substituted with l to 2 groups
independently ed from R6, wherein the remainder of the varables are as described in
Formula (I) and the eighth or ninth embodiment.
In an eleventh embodiment, Cy1 in Formulas (I) to (VII) is phenyl, piperidinyl,
tetrahydro—2H—thiopyranyl l,l—dioxide, pyridinyl, zinyl, azetidinyl, imidazolyl,
tetrahydropyranyl, l,4—dioxanyl, pyridazinyl, pyrazolyl, idinyl, cyclohexyl, morpholinyl,
6,7—dihydro—5H—pyrrolo[2,l—c][l,2,4]triazolyl, l,2,3,4—tetrahydro—l,8—naphthyridinyl, 2,3—
dihydro—lH—indenyl, or imidazo[l,2—a]pyrimidinyl, each of which is optionally substituted with l
to 2 groups independently selected from R5, wherein the remainder of the varables are as
described in Formula (I) and the eighth, ninth, or tenth embodiment.
In a twelfth embodiment, Cy1 in Formulas (I) to (VII) is phenyl, piperidinyl,
tetrahydro—2H—thiopyranyl l,l—dioxide, pyridinyl, piperazinyl, azetidinyl, imidazolyl,
tetrahydropyranyl, l,4—dioxanyl, pyridazinyl, pyrazolyl, pyrrolidinyl, cyclohexyl, linyl,
6,7—dihydro—5H—pyrrolo[2,l—c][l,2,4]triazolyl, l,2,3,4—tetrahydro—l,8—naphthyridinyl, 2,3—
dihydro—lH—indenyl, or imidazo[l,2—a]pyrimidinyl, each of which is optionally substituted with l
to 2 groups independently selected from R5, wherein at least one R5 is (C1—C3)alkylsulfonyl or
(C1—C3)alkylaminosulfonyl, and wherein the remainder of the varables are as described in
Formula (I) and the eighth, ninth, tenth, or th embodiment.
In a thirteenth embodiment, R2 in as (I) to (VII) is (C1—C3)alkyl; n is l or 2;
and Cy1 is , pyridinyl, or piperidinyl, each of which is optionally substituted with l to 2
groups independently selected from R5, wherein at least one R5 is (C1—C3)all<ylsulfonyl or (C1—
C3)alkylaminosulfonyl, and n the remainder of the varables are as described in Formula
(I) and the eighth, ninth, tenth, eleventh, or twelfth embodiment.
In a fourteenth embodiment, Cy2 in Formulas (I) to (VII) is cyclohexyl optionally
substituted with l to 2 groups independently selected from R6, wherein the remainder of the
varables are as described in Formula (I) and the eighth, ninth, tenth, eleventh, twelfth, or
thirteenth embodiment.
In a fifteenth embodiment, R5 is selected from halo, (C1—C3)alkyl, 1—C3)alkyl,
cyano, hydroxy(C1—C3)alkyl, (C1—C3)alkoxycarbonyl, (C1—C3)alkylsulfonyl, (C1—C3)alkoxy,
halo(C1—C3)alkoxy, oxo, hydroxy, (C1—C3)alkylcarbonyl, hydroxy(C1—C3)alkylcarbonyl, (C1—
C3)all<ylhydroxycarbonyl, (C1—C3)alkylaminosulfonyl, (C1—C3)alkylaminocarbonyl, di(C1—
C3)alkylamino(C2—C6)alkoxy, (C1—C6)alkoxycarbonyl, [(C1—C3)alkyl(C4—C6)heterocyclyl] (C1—
<yl, and (C1—C3)alkylhydroxy(C1—C3)alkyl; and R6 is selected from halo, (C1—C3)alkyl,
halo(C1—C3)alkyl, cyano, hydroxy(C1—C3)alkyl, (C1—C3)alkoxycarbonyl, )alkylsulfonyl,
(C1—C3)alkoxy, halo(C1—C3)alkoxy, oxo, y, aryl(C1—C3)alkoxycarbonyl, (C1—
C3)all<ylhydroxy(C1—C3)alkyl, heteroaryl, and (C1—C3)alkoxycarbonyl, wherein the remainder of
the varables are as described in Formula (I) and the eighth, ninth, tenth, eleventh, twelfth,
enth, or fourteenth embodiment.
Alternatively, R5 is ed from halo, (C1—C3)alkoxy, hydroxy, )alkyl,
hydroxy(C1—C3)alkyl, halo(C1—C3)alkyl, (C1—C6)alkoxycarbonyl, di(C1—C3)alkylamino(C2—
C6)alkoxy, 3)alkyl(C4—C6)heterocyclyl](C1—C3)alkyl, oxo, (C1—C3)alkylcarbonyl, (C1—
C3)alkylaminosulfonyl, (C1—C3)alkylsulfonyl, and cyano; and
R6 is selected from halo(C1—C3)alkyl, (C1—C3)alkoxy, halo, cyano, (C1—C3)alkoxycarbonyl, (C1—
C3)all<ylhydroxy(C1—C3)alkyl, 2—methyl—2H—tetrazolyl, hydroxy(C1—C3)alkyl, and halo(C1—
C3)alkoxy, wherein the remainder of the varables are as described in Formula (I) and the eighth,
ninth, tenth, eleventh, twelfth, thirteenth, or fourteenth ment. In another alternative, R5 is
selected from halo, cyano, (C1—C3)alkyl, (C1—C3)alkylaminosulfonyl, and (C1—C3)alkylsulfonyl;
and R6 is selected from 1—C3)alkyl, (C1—C3)alkoxy, halo, cyano, (C1—C3)alkoxycarbonyl, 2—
methyl—2H—tetrazolyl, and 1—C3)alkoxy, wherein the remainder of the varables are as
described in Formula (I) and the eighth, ninth, tenth, th, twelfth, thirteenth, or fourteenth
embodiment.
In a sixteenth embodiment, Cy1 in Formulas (I) to (VII) is
Z / S//O
// \R10
0 ;R10 is (C1—C3)alkyl or (C1—C3)alkylamino; and z is CH or N, n the
remainder of the varables are as described in Formula (I) and the eighth, ninth, tenth, eleventh,
twelfth, enth, fourteenth, or fifteenth embodiment.
[005 1] In an seventeenth embodiment, Cy2 in Formulas (I) to (VII) is
H}:- N
/ \ 2— RKM M )2-
; — ; —N ; N_ ; or
Rio:-; R12 is (C1-C3)all<oxycarbonyl, halo, dihalo, (C1—C3)alkoxy, or halo(C1—
C3)alkyl; R13 is halo or halo(C1—C3)alkyl; and R14 is halo, cyano, halo(C1—C3)alkyl, halo(C1—
C3)alkoxy, or 2—methyl—2H—tetrazolyl, wherein the remainder of the varables are as described in
a (I) and the eighth, ninth, tenth, eleventh, twelfth, thirteenth, fifteenth, or sixteenth
embodiment.
In an eighteenth embodiment, R12 to R14 are each CF3, wherein the remainder of the
varables are as described in Formula (I) and the eighth, ninth, tenth, eleventh, twelfth, thirteenth,
fifteenth, sixteenth, or seventeenth embodiment.
In a nineteenth embodiment, R2 in as (I) to (VII) is isopropyl and the
remainder of the variables are as described in Formula (I) and the eighth, ninth, tenth, eleventh,
twelfth, thirteenth, enth, fifteenth, sixteenth, seventeenth, or eighteenth embodiment.
In a eth ment, the compound of Formula (I) is of Formula (X):
WO 16904
2 H CY1
Cy \ WU/
(\—)—N
m |
N/ o
R3 (X);
or a pharmaceutically acceptable salt thereof, wherein L1 is absent; Cy1 is phenyl optionally
substituted with SOZ(C1—C3)alkyl or SOZ(C1—C3)alkylamino; n is 0 or 1; R4 is en or (C1—
C3)all<yl; R2 and R3 are each independently hydrogen or (C1—C6)alkyl; m is 0 or 1; and Cy2 is
phenyl or cyclohexyl, each optionally substituted with halo(C1—C3)alkyl, (C1—C3)alkyl, halo, or
Specific examples of compounds of the invention are provided in the
EXEMPLIFICATION. Pharmaceutically acceptable salts as well as the neutral forms of these
nds are ed in the invention.
In certain embodiments, the present invention provides a method of treating a patient
(e.g., a human) with a disorder mediated by RORY comprising the step of stering to the
patient an effective amount of the compound with any compound described herein, or a
pharmaceutically acceptable salt or composition thereof.
4. Uses, Formulation and Administration
Pharmaceutically able compositions
According to r embodiment, the present invention provides a method of
treating a subject (e.g., a human) with a disorder mediated by RORY using a composition
sing a compound of Formula (I) and a pharmaceutically acceptable carrier, adjuvant, or
vehicle. In n embodiments, the amount of compound of Formula (I) in a ed
composition is such that it is effective as an inverse agonist or antagonist to RORY in a biological
sample or in a subject. In n embodiments, a provided composition is formulated for
administration to a subject in need of such composition. In some embodiments, a provided
composition is formulated for oral administration to a subject.
[005 8] The term “pharmaceutically acceptable r, adjuvant, or vehicle” refers to a non—
toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the
compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or
vehicles that may be used in the itions of this disclosure include, but are not limited to,
ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum
albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, l
glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as
protamine sulfate, disodium en phosphate, potassium en phosphate, sodium
chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose—based
substances, polyethylene , sodium carboxymethylcellulose, polyacrylates, waxes,
polyethylene—polyoxypropylene—block rs, polyethylene glycol and wool fat.
Compositions described herein may be administered orally, parenterally, by
inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir.
The term teral" as used herein es subcutaneous, intravenous, intramuscular, intra—
articular, intra—synovial, intrasternal, intrathecal, epatic, intralesional and intracranial
injection or infusion ques.
Liquid dosage forms for oral administration include, but are not limited to,
pharmaceutically acceptable ons, microemulsions, solutions, suspensions, syrups and
elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents
ly used in the art such as, for e, water or other ts, solubilizing agents and
fiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl
alcohol, benzyl benzoate, propylene glycol, l,3—butylene glycol, dimethylformamide, oils (in
particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol,
tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and es
thereof. Besides inert diluents, the oral itions can also e adjuvants such as wetting
agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
[006l] able preparations, for example, sterile injectable aqueous or oleaginous
suspensions may be formulated according to the known art using suitable dispersing or g
agents and suspending agents. The sterile injectable preparation may also be a sterile injectable
solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for
example, as a solution in l,3—butanediol. Among the acceptable vehicles and solvents that may
be ed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In
addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For
this purpose any bland fixed oil can be employed including synthetic mono— or diglycerides. In
addition, fatty acids such as oleic acid are used in the preparation of injectables.
Injectable formulations can be sterilized, for example, by filtration through a
bacterial—retaining filter, or by incorporating sterilizing agents in the form of sterile solid
compositions which can be dissolved or dispersed in sterile water or other sterile injectable
medium prior to use.
In order to prolong the effect of a provided compound, it is often desirable to slow the
absorption of the compound from subcutaneous or intramuscular injection. This may be
accomplished by the use of a liquid sion of crystalline or amorphous material with poor
water solubility. The rate of absorption of the compound then depends upon its rate of
dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively,
delayed absorption of a parenterally administered compound form is accomplished by dissolving
or suspending the compound in an oil vehicle. able depot forms are made by forming
microencapsule matrices of the compound in biodegradable polymers such as ctide—
ycolide. Depending upon the ratio of compound to polymer and the nature of the
particular polymer employed, the rate of compound release can be controlled. Examples of other
biodegradable rs include rthoesters) and poly(anhydrides). Depot injectable
formulations are also prepared by entrapping the compound in liposomes or mulsions that
are compatible with body tissues.
Solid dosage forms for oral administration include capsules, tablets, pills, powders,
and granules. In such solid dosage forms, the active compound is mixed with at least one inert,
pharmaceutically acceptable excipient or carrier such as sodium citrate or ium phosphate
and/or a) fillers or extenders such as starches, lactose, e, glucose, mannitol, and c
acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin,
polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating
agents such as aga ——agar, calcium carbonate, potato or tapioca starch, alginic acid, certain
silicates, and sodium carbonate, e) solution retarding agents such as in, f) absorption
accelerators such as nary um compounds, g) wetting agents such as, for example,
cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i)
lubricants such as talc, m stearate, magnesium stearate, solid polyethylene glycols, sodium
lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form
may also comprise buffering agents.
Solid compositions of a r type may also be employed as fillers in soft and hard—
filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular
weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, es,
pills, and granules can be prepared with coatings and shells such as enteric coatings and other
coatings well known in the pharmaceutical formulating art. They may optionally contain
opacifying agents and can also be of a composition that they release the active ingredient(s) only,
or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
Examples of embedding compositions that can be used include polymeric substances and waxes.
Solid compositions of a similar type may also be employed as fillers in soft and hard—filled
gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight
polethylene glycols and the like.
ed nds can also be in micro—encapsulated form with one or more
excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and
granules can be prepared with coatings and shells such as enteric coatings, release controlling
coatings and other coatings well known in the pharmaceutical formulating art. In such solid
dosage forms the active compound may be admixed with at least one inert diluent such as
sucrose, lactose or starch. Such dosage forms may also comprise, as is normal ce,
additional nces other than inert diluents, e.g., tableting lubricants and other tableting aids
such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and
pills, the dosage forms may also comprise buffering agents. They may optionally contain
opacifying agents and can also be of a composition that they release the active ingredient(s) only,
or entially, in a certain part of the intestinal tract, ally, in a delayed manner.
Examples of embedding compositions that can be used include polymeric substances and waxes.
Dosage forms for topical or transdermal stration of a compound of this
invention include ointments, pastes, creams, s, gels, powders, solutions, sprays, inhalants
or patches. The active component is admixed under sterile conditions with a pharmaceutically
acceptable carrier and any needed vatives or buffers as may be required. Ophthalmic
formulation, ear drops, and eye drops are also contemplated as being within the scope of this
invention. Additionally, the present invention contemplates the use of ermal patches,
which have the added advantage of providing controlled ry of a compound to the body.
Such dosage forms can be made by dissolving or dispensing the compound in the proper
medium. tion enhancers can also be used to increase the flux of the compound across the
skin. The rate can be controlled by either providing a rate controlling membrane or by
dispersing the compound in a polymer matrix or gel.
Pharmaceutically acceptable compositions provided herein may be formulated for
oral administration. Such formulations may be administered with or t food. In some
embodiments, pharmaceutically acceptable itions of this disclosure are administered
without food. In other embodiments, pharmaceutically acceptable compositions of this
disclosure are administered with food.
The amount of provided compounds that may be combined with carrier materials to
produce a composition in a single dosage form will vary depending upon the patient to be treated
and the particular mode of administration.
It should also be understood that a specific dosage and treatment regimen for any
particular patient will depend upon a variety of s, including age, body weight, general
, sex, diet, time of administration, rate of excretion, drug combination, the judgment of the
treating physician, and the severity of the particular disease being treated. The amount of a
provided compound in the composition will also depend upon the particular nd in the
composition.
Uses of Compounds and Pharmaceutically Acceptable Compositions
[007 1] Compounds and compositions described herein are generally useful for the inhibition
of RORy. Thus, in some embodiments, the present invention provides a method of treating
inflammatory, metabolic and autoimmune diseases or disorders mediated by RORy, comprising
administering a ed compound or composition. More ularly, the compounds and
compositions described herein act as inverse agonists or nists of RORy.
As used herein, the terms “treatment, 79 ‘6treat,” and “treating” refer to ing,
alleviating, delaying the onset of, or inhibiting the progress of a disease or er, or one or
more symptoms thereof, as described herein. In some embodiments, treatment may be
administered after one or more symptoms have developed, i.e., eutic treatment. In other
ments, treatment may be administered in the absence of symptoms. For example,
treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in
light of a history of symptoms and/or in light of genetic or other susceptibility factors), i.e.,
lactic treatment. Treatment may also be continued after symptoms have resolved, for
example to prevent or delay their recurrence.
es and conditions treatable according to the methods of the ion include,
but are not limited to, inflammatory, metabolic and autoimmune diseases or ers mediated
by RORy. These diseases and conditions include, for example, asthma, chronic obstructive
pulmonary disease (COPD), bronchitis, allergic rhinitis, atopic dermatitis, contact dermatitis,
acne, cystic fibrosis, allograft rejection, multiple sis, scleroderma, arthritis, rheumatoid
arthritis, juvenile toid arthritis, osteoarthritis, ankylosing spondylitis, systemic lupus
erythematosus (SLE), psoriasis, Hashimoto's disease, pancreatitis, autoimmune diabetes, type I
diabetes, autoimmune ocular disease, ulcerative colitis, Crohn's disease, regional enteritis,
inflammatory bowel disease (IBD), inflammatory bowel syndrome (IBS), Sjogren's syndrome,
optic neuritis, y, hepatosteatosis, adipose tissue—associated ation, insulin
resistance, type II diabetes, neuromyelitis optica, myasthenia gravis, age related r
degeneration, dry eye, uveitis, Guillain—Barré syndrome, psoriasis, psoriatic arthritis (PsA),
steroid resistant asthma, Graves' disease, scleritis, endometriosis, obstructive sleep apnea
syndrome (OSAS), Behcet's disease, dermatomyositis, polymyocitis, graft versus host disease,
primary biliary cirrhosis, liver fibrosis, non—alcoholic fatty liver disease (NAFLD), sarcoidosis,
y sclerosing cholangitis, autoimmune thyroid disease, autoimmune polyendocrine
syndrome type I, autoimmune polyendocrine syndrome type II, celiac disease, neuromyelitis,
juvenile idiopathic arthritis, systemic sclerosis, myocardial infarction, pulmonary hypertension,
osteoarthritis, cutaneous leishmaniasis, sinonasal polyposis, and cancer, including but not limited
to lung cancer, gastric cancer, breast cancer and colon cancer.
Also included are es or disorders which are implicated by the tion of the
circadian rhythm of individuals and include, e.g., major depression, al ive disorder,
post—traumatic stress disorder (PTSD), bipolar disorder, autism, epilepsy, Alzheimer’s disease
and other central nervous system (CNS) disorders associated with altered sleep and/or circadian
rhythms.
In one embodiment, a human patient is treated with a compound of Formula (I) and a
pharmaceutically acceptable carrier, nt, or vehicle, wherein said compound is t in an
amount to treat or rate one or more of the diseases and conditions d above. In an
alternative embodiment, the diseases and conditions d or ameliorated by a compound of
Formula (I) include, e.g., asthma, atopic dermatitis, acne, Crohn’s disease, regional enteritis,
ulcerative colitis, n's syndrome, uveitis, Behcet's disease, dermatomyositis, multiple
sclerosis, ankylosing spondylitis, systemic lupus erythematosus (SLE), scleroderma, psoriasis,
psoriatic arthritis (PsA), steroid resistant asthma and rheumatoid arthritis in the t.
The invention further relates to a combination therapy for treating or ameliorating a
disease or a disorder described herein. In some embodiments, the combination therapy
comprises administering at least one compound represented by ural Formula I in
combination with one or more agents for treating or ameliorating inflammatory, metabolic and
autoimmune diseases or disorders mediated by RORy. In some embodiments, the combination
y comprises administering at least one compound represented by Structural Formula I in
combination with one or more agents for the treatment of es including asthma, chronic
obstructive pulmonary disease (COPD), itis, ic rhinitis, atopic dermatitis, contact
dermatitis, acne, cystic fibrosis, allograft rejection, le sclerosis, scleroderma, arthritis,
rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, ankylosing spondylitis,
systemic lupus erythematosus (SLE), psoriasis, Hashimoto's disease, pancreatitis, autoimmune
diabetes, type I diabetes, autoimmune ocular disease, ulcerative colitis, Crohn's disease, regional
tis, inflammatory bowel disease (IBD), inflammatory bowel me (IBS), Sjogren's
syndrome, optic neuritis, y, hepatosteatosis, adipose tissue—associated inflammation,
n resistance, type II diabetes, neuromyelitis optica, myasthenia gravis, age related macular
degeneration, dry eye, uveitis, Guillain—Barré syndrome, psoriasis, psoriatic arthritis (PsA),
steroid resistant asthma, Graves' disease, scleritis, major depression, seasonal affective disorder,
PTSD, bipolar disorder, autism, epilepsy, Alzheimer’s, CNS disorders ated with altered
sleep and/or circadian rhythms, triosis, obstructive sleep apnea syndrome ,
Behcet's disease, omyositis, polymyocitis, graft versus host disease, primary y
cirrhosis, liver fibrosis, non—alcoholic fatty liver disease (NAFLD), dosis, primary
sclerosing cholangitis, autoimmune thyroid disease, autoimmune polyendocrine syndrome type I,
autoimmune polyendocrine syndrome type II, celiac disease, neuromyelitis, juvenile idiopathic
arthritis, systemic sclerosis, dial infarction, pulmonary hypertension, osteoarthritis,
cutaneous leishmaniasis, sinonasal polyposis, and cancer, including but not limited to, lung
cancer, gastric cancer, breast cancer and colon cancer.
The compounds according to the invention may also be used in combination with
immunotherapies for the treatment of a disease or disorder disclosed herein.
Combination therapy includes, e.g., co—administration of a compound of the invention
and one or more other agents, tial administration of a compound of the invention and one
or more other , administration of a composition containing a compound of the invention
and one or more other , or simultaneous administration of separate compositions
containing a compound of the invention and one or more other agents.
The ion further provides a method of treating a t, such as a human,
suffering from one of the abovementioned ers or diseases.
The invention further relates to the use of provided compounds for the production of
pharmaceutical compositions which are employed for the treatment and/or prophylaxis and/or
amelioration of the diseases and disorders mentioned .
[008l] Compounds or compositions bed herein may be administered using any amount
and any route of stration effective for treating or lessening the severity of one or more of
the diseases and conditions described herein. The exact amount required will vary from subject
to subject, depending on the species, age, and general condition of the subject, the severity of the
infection, the particular agent, its mode of administration, and the like. Provided compounds are
preferably formulated in unit dosage form for ease of administration and uniformity of dosage.
The expression "unit dosage form" as used herein refers to a physically discrete unit of agent
appropriate for the patient to be treated. It will be understood, however, that the total daily usage
of the compounds and compositions of the present disclosure will be decided by the attending
physician within the scope of sound medical judgment. The specific effective dose level for any
particular patient or organism will depend upon a variety of s including the disorder being
treated and the severity of the disorder; the activity of the specific compound employed; the
specific ition employed; the age, body weight, general health, sex and diet of the patient;
the time of administration, route of administration, and rate of excretion of the specific
compound employed; the duration of the treatment; drugs used in combination or coincidental
with the specific compound employed, and like factors well known in the medical arts.
Pharmaceutically able compositions of this disclosure can be administered to
humans and other animals orally, rectally, parenterally, isternally, aginally,
intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal
spray, or the like, depending on the severity of the infection being d. In certain
embodiments, provided compounds may be administered orally or parenterally at dosage levels
of about 0.01 mg/kg to about 50 mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of
subject body weight per day, one or more times a day, to obtain the desired therapeutic .
The term “biological sample”, as used , includes, t limitation, cell
cultures or extracts thereof, biopsied material obtained from a mammal or ts thereof, and
blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.
The amount of both, a provided compound and onal therapeutic agent (in those
compositions which comprise an additional therapeutic agent as described above) that may be
combined with the carrier materials to produce a single dosage form will vary depending upon
the host treated and the particular mode of administration.
In those compositions which comprise an additional therapeutic agent, that additional
therapeutic agent and the provided compound may act synergistically. Therefore, the amount of
additional therapeutic agent in such compositions will be less than that required in a
monotherapy utilizing only that therapeutic agent.
The amount of additional therapeutic agent present in the compositions of this
disclosure will be no more than the amount that would normally be administered in a
composition comprising that therapeutic agent as the only active agent.
EXEMPLIFICATION
As depicted in the Examples below, in n exemplary embodiments, compounds
are ed according to the following general procedures. It will be appreciated that, although
the general methods depict the synthesis of certain compounds of the t invention, the
following l methods, and other methods known to one of ordinary skill in the art, can be
applied to all compounds and subclasses and species of each of these compounds, as described
herein.
PCT/U82015/013699
GENERAL DESCRIPTION OF SYNTHESIS
The compounds of the present invention can be readily ed according to the
following reaction schemes and examples, or modifications thereof, using readily available
starting materials, reagents and conventional synthesis procedures. Many of the reactions can
also be carried out under microwave (MW) conditions or using tional heating or utilizing
other technologies such as solid phase ts/scavengers or flow chemistry. In these reactions,
it is also possible to make use of variants which are themselves known to those of ordinary skill
in the art, but are not mentioned in greater detail. Furthermore, other methods for preparing
compounds of the invention will be readily apparent to a person of ordinary skill in the art in
light of the following reaction schemes and examples. In cases where synthetic intermediates
and final products contain potentially reactive functional groups, for e amino, hydroxy,
thiol and carboxylic acid groups, that may ere with the d reaction, it may be
advantageous to employ protected forms of the intermediate. Methods for the selection,
introduction and subsequent removal of protecting groups are well known to those skilled in the
art. In the discussion below variables have the meanings indicated above unless otherwise
indicated. The abbreviations used in these experimental details are listed below and additional
ones should be known to a person skilled in the art of synthesis. In addition, one can refer to the
following references for suitable methods of synthesis as described in March, Advanced Organic
try, 3rd n, John Wiley & Sons, 1985, Greene and Wuts, Protective Groups in
Organic Synthesis, 2nd edition, John Wiley & Sons, 1991, and Richard Larock, Comprehensive
Organic Transformations, 4th edition, VCH publishers Inc., 1989.
lly, reagents in the reaction schemes are used in equimolar s; however,
in certain cases it may be desirable to use an excess of one reagent to drive a reaction to
completion. This is especially the case when the excess reagent can be readily removed by
evaporation or extraction. Bases ed to neutralize HCl in reaction mixtures are generally
used in slight to substantial excess (1.05 — 5 lents).
Where NMR data are presented, spectra were obtained on a Varian 400 (400 MHz) or
300 (300 MHz) and are reported as ppm downfield from tetramethylsilane with number of
, multiplicities and ng constants ted parenthetically along with reference to
deuterated solvent.
The invention is illustrated by way of the following es, in which the following
abbreviations may be employed.
Abbreviation Meaning
ACN, MeCN, CH3CN acetonitrile
AIBN azobisisobutyronitrile
aq aqueous
Boc utoxycarbonyl or t—butoxycarbonyl
brine saturated aqueous NaCl
Cbz oxy carbonyl
CeC13 ceric de
C52CO3 cesium carbonate
Cul cuprous iodide
DCM or CH2C12 methylene chloride
DIEA diisopropyl ethyl amine
DMF dimethyl formamide
DMS/Megs dimethyl sulfide
DMSO dimethyl ide
EDCI l—(3—dimethylaminopropyl)—3—ethylcarbodiiimide
hydrochloride
Etl ethyl iodide
Et ethyl
EtzO ethyl ether
EtgsiH triethylsilane
Et3N ylamine
EtOAc AcOEt
, EA, ethyl acetate
EtOH ethanol
FeC13 ferric chloride
h, hr hour(s)
HATU 0—(7—azabenzotriazol— l —yl)—N,N,N’,N’—
tetramethyluronium—heXafluorophosphate
HBTU O—benzotriazole— l —yl—N,N,N’,N ’—tetramethyluronium—
hexafluorophosphate
HCl hydrochloric acid
H20 water
H202 hydrogen peroxide
HPLC high performance liquid chromatography
i—BuOCOCl iso—butoxycarbonyl chloride
ICl iodochloride
K2C03 potassium carbonate
K3PO4 tripotassium phosphate
LC—MS liquid chromatography—mass spectrometry
LDA lithium diiisopropylamide
LiCl lithium chloride
LiOH lithium hydroxide
MCPBA, m-CPBA meta—chloroperoxybenzoic acid
MeOH methanol
Mel methyl iodide
Me methyl
mg milligram
MgSO4 magnesium sulfate (anhydrous)
min minute(s)
mL iters
mmol millimoles
melting point
mass spectrometry
microwave
sodium borohydride
sodium cyanoborohydride
sodium hydride
sodium bicarbonate
sodium hydroxide
sodium methoxide
sodium thiosulfate
sodium dithionate
sodium sulfate
um hydroxide
um ate
ammonium chloride
sodium carbonate
sodium bicarbonate
sodium hydride
N—bromosuccinimide
n—butyllithium
N—methyl—morpholine
N—methyl—pyrrolidin—2—one
OTf trifluoromethanesulfonate
2015/013699
OTs tosylate
PdClzdppf [l, l —bis(diphenylphosphino)ferrocene]
dichloropalladium(ii)
Pd2(dba)3 tris(dibenzylideneacetone)dipalladium(0)
PE eum ether
rt room temperature
sat. saturated
SFC supercritical fluid chromatography
t—BuOK ium tert butoxide
t-BuLi tert butyl lithium
t-BuOOH tert butyl peroxide
TBAF tetrabutylammonium fluoride
TFA trifluoroacetic acid
THF tetrahydrofuran
TLC thin layer chromatography
Ti(OEt)4 titanium tetra de
Zn zinc
Zn(CN)2 zinc cyanide
Compounds ing to Formula (I), can be prepared by reacting an intermediate
compound of Formula (500) with an alkyl or aryl halide, according to reaction Scheme 1, a
reaction that is med in a polar aprotic t, such as, for example, acetonitrile, in the
presence of a suitable base, such as, for example, isopropylethylamine or potassium
carbonate. Alternatively, the final compounds according to Formula (I), can be prepared by
reacting an intermediate compound of Formula (500) with an aldehyde or ketone, according to
reaction Scheme 1, following art—known reductive amination procedure, in the typical solvent,
such as, for example, dichloroethane, dichloromethane, or methanol; in the presence of suitable
reducing reagent, such as sodium cyanoborohydride or sodium triacetoxyborohydride. In
reaction Scheme 1, all variables are defined as in Formula (I) and G1 is a leaving group, such as
for example, bromide, chloride, mesylate (methanesulfonate), tosylate (p—toluenesulfonate), or
iodide.
Scheme 1.
R4 R4
A L\1 X L1 C 2 G1 Cy2 X
\ 1
\ \ 1 y m M C y
HN | M; Cy MmN | n
N/ or ive N
R2 R3 ammination R2 R3
ediate compound of Formula (500) can be can be prepared by deprotecting an
intermediate compound of Formula (501), wherein Pg is a suitable nitrogen ting group
(Greene and Wuts, Protective Groups in Organic Synthesis, 2Ild edition, John Wiley & Sons,
1991), e.g., Pg 2 tert—butoxycarbonyl, removed with trifluoroacetic acid according to Scheme 2.
In reaction Scheme 2, all variables are defined as in Formula (1).
Scheme 2.
X‘M’nL1 L1
de rotection X‘M’n
R2 R3N R2 R3N
Intermediate compound of a (502), wherein X is C(=O)NH, can be prepared
from a carboxylic acid (504) and an amine (503), according to Scheme 3. The reaction is
conveniently carried out in the presence of an activating reagent, for e, N— (3—
dimethylaminopropyl)—N'-ethylcarbodiimide hydrochloride (EDCI) or 0—(7—azabenzotriazol—l—
yl)—N,N,N’,N’— tetramethyluronium hexafluorophosphate (HATU), in an organic solvent, for
example, N,N—dimethylformamide or dichloromethane, optionally in the presence of a base, e.g.,
N,N—diisopropylethylamine or triethylamine, at a temperature, for example in the range from 0 to
60 °C.
Scheme 3.
H2N 0
O R4
n Cyl
503 \
\ Ni’i‘u’
I P _Ng | H n
Pg—N /
/ N
N Base,
3 R2 R3
R2 R ting reagents
Intermediate compound of Formula (505), wherein X is NHC=O, can be prepared
from an intermediate compound of Formula (506) and an amide (507), according to Scheme 4.
The reaction is carried out in the ce of a catalyst, for example,
tris(dibenzylideneacetone)dipalladium (0) (Pd2(dba)3), in an organic solvent, for e,
dioxane or tert—butanol, in the presence of an ve, e.g., potassium phosphate, at a
temperature, for example, in the range from 80 to 150 0C.
PCT/U82015/013699
Scheme 4.
H N /
2 WU
CI 507
\ 0
Pg—N | —>P9N :HWL/Cy
N catalyst, ligand, additive
R2 R3 R2 R3N
506 505
PREPARATION OF INTERMEDIATES
As a representative example, intermediate compound of a (504) wherein R4 is
H, R2 is isopropyl, R3 is H and Pg is tert—butoxycarbonyl, can be ed by following the
reaction steps shown in Scheme 5. An intermediate compound of Formula (504) with variables
R4, R2 and R3 can be prepared readily according to Scheme 5, or modifications f, using
readily available starting materials and ts.
Scheme 5.
PF6'
\N \ \iti/
0' o I CI I
Kok/UMEI O
t—BuOK,DABCO,
o o o
BocHN\)J\ MgCI2 CDI
’ BocHNM NH4OAC E0t \
THF THF
/\ /\ é
OH OMS CI
NaBH4,CaC|2 CI
\ MsCI,Et3N CI CI
\ \
—> | —> | + |
BocHN N/ BocHN BocHN
EtOH
; CH2C|2 N/ N/
; :
/\ /\ /\
\ n-butanol, Pd(OAc)2,
Na“ BocN | dcpp HBF4, CO (1 atm)- \ OH
/ BocN I
THF :' N
‘ N/
/\ DMF 100 C :
Mo(CO)5, Hermann's cat,
Fu's salt, DBU
BocN
MeOH, 160 °C, uwave MeOH/HZO
To a stirred solution of compound Boc—Val—OH (3.11 g, 14.3 mmol) in THF (40 mL)
at rt was added 1,1’—carbonyldiimidazole (3.48 g, 21.5 mmol). The mixture was stirred at rt for 1
h, then ium chloride (1.36 g, 14.3 mmol) and ethyl potassium malonate (2.44 g, 14.3
2015/013699
mmol) were added successively. The mixture was then heated to 50 °C and stirred for 15 h. The
mixture was cooled to rt and quenched with 1 N HCl (100 mL). The aqueous phase was
extracted with EtOAc (3 x 100 mL), then the combined organic layer was washed with brine (50
mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated under
reduced pressure. The residue was ed by silica gel chromatography (eluting with 5%
EtOAc in hexanes) to afford ethyl (S)—4—((tert—butoxycarbonyl)amino)—5—methyl—3—oxohexanoate
(3.53 g, 86% yield) as a yellow oil. LC—MS tR = 0.91 min in 1 min chromatography, MS (ESI)
m/z 288.3 [M + H]+. 1H NMR (CDC13, 400 MHZ): 5 5.08 (d, J: 8.4 HZ, 1H), 4.33 (dd, J: 4.4
HZ, 8.8 HZ, 1H), 4.20 (q, J: 7.2 HZ, 2H), 3.54 (s, 2H), 2.27-2.17 (m, 1H), 1.44 (s, 9H), 1.27 (t, J
= 7.2 HZ, 3H), 1.01 (d, J: 6.8 HZ, 3H), 0.82 (d, J: 6.8 HZ, 3H).
To a e of ethyl (S)—4—((tert—butoxycarbonyl)amino)—5—methyl—3—oxohexanoate
(9.68 g, 33.7 mmol) from above in THF (100 mL) at 0 °C was added potassium tert—butoxide
(3.78 g, 35.4 mmol). The mixture was warmed to rt and stirred for 45 min, at which point 1,4—
diazabicyclo[2.2.2]octane (3.78 g, 33.7 mmol) and 2—chloro—1,3—bis(dimethylamino)trimethinium
rophosphate (15.5 g, 50.5 mmol) were added successively. The mixture was heated to 45
°C and stirred for 3 h, at which point ammonium acetate (5.19 g, 67.4 mmol) was added. The
mixture was then heated to reflux and stirred for 15 h. It was then cooled to rt and concentrated
under reduced pressure. The residue was dry—loaded onto a silica gel column and purified
(eluting with 5% EtOAc in hexanes, gradient to 15%) to yield 6.09 g of ethyl (S)—2—(1—((tert—
butoxycarbonyl)amino)—2—methylpropyl)—5—chloronicotinate (51%). LC—MS tR = 1.14 min in 1
min chromatography, MS (ESI) m/Z 357.3 [M + H]+. 1H NMR (CDClg, 400 MHZ): 5 8.61 (d, J:
2.4 HZ, 1H), 8.18 (d, J: 2.8 HZ, 1H), 5.71 (d, J: 9.6 HZ, 1H), 5.62 (dd, J: 5.2 HZ, 9.6 HZ, 1H),
4.42 (q, J: 7.2 HZ, 2H), 2.08-2.00 (m, 1H), 1.42 (s, 9H), 1.42 (t, J: 7.2 HZ, 3H), 0.93 (d, J:
6.4 HZ, 3H), 0.83 (d, J: 6.4 HZ, 3H).
To a stirred on of ethyl (1—((tert—butoxycarbonyl)amino)—2—methylpropyl)—
—chloronicotinate (6.09 g, 17.1 mmol) at 0 0C in EtOH (70 mL) was added sodium borohydride
(1.30 g, 34.1 mmol). Calcium chloride (1.89 g, 17.1 mmol) was added portionwise while
maintaining the temperature between 0 °C and 5 OC. The ing mixture was stirred at 0 °C for
90 min, then quenched slowly at 0 °C with saturated aqueous um chloride solution (100
mL). The s phase was extracted with EtOAc (3 x 100 mL), then the combined organic
layer was washed with brine (50 mL), dried over anhydrous MgSO4, filtered and concentrated
under reduced pressure. Crude tert—butyl (S)—(1—(5—chloro—3—(hydroxymethyl)pyridin—2—yl)—2—
methylpropyl)carbamate was carried forward without any purification. LC—MS tR = 0.94 min in 1
min chromatography, MS (ESI) m/z 315.3 [M + H]+. 1H NMR (CDCl3, 400 MHZ): 5 8.46 (d, J =
2.4 Hz, 1H), 7.67 (d, J: 2.8 Hz, 1H), 5.34 (d, J: 9.2 Hz, 1H), 4.99 (dd, J: 2.0 Hz, 8.4 Hz, 1H),
4.54 (t, J: 9.2 Hz, 1H), 4.41 (dd, J: 10.0 Hz, 12.4 Hz, 1H), 4.33 (d, J: 10.0 Hz, 1H), 2.18-2.12
(m, 1H), 1.36 (s, 9H), 1.10 (d, J: 6.4 Hz, 3H), 0.69 (d, J: 6.8 Hz, 3H).
To a solution of tert—butyl (S)—(1—(5—chloro—3—(hydroxymethyl)pyridin—2—yl)—2—
methylpropyl)carbamate (5.33 g, 16.9 mmol) in CHzClz (70 mL) at 0 °C was added triethylamine
(3.54 mL, 25.4 mmol) and methanesulfonyl chloride (1.44 mL, 18.6 mmol). The e was
warmed to rt and stirred for 3 h, at which point it was quenched with saturated aqueous sodium
bicarbonate solution (100 mL). The aqueous phase was extracted with ethyl acetate (3 x 100
mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous MgSO4,
filtered and concentrated under reduced pressure. The crude residue (a 3:1 mixture of (S)—(2—(1—
((tert—butoxycarbonyl)amino)—2—methylpropyl)—5—chloropyridin—3—yl)methyl methanesulfonate
and tert—butyl (S)—(1—(5—chloro—3—(chloromethyl)pyridin—2—yl)—2—methylpropyl)carbamate) was
carried forward t any purification. LC—MS tR = 1.01 min in 1 min chromatography, MS
(ESI) m/z 393.3 [M + H]+. 1H NMR (CDC13, 400 MHz): 5 8.53 (d, J: 2.4 Hz, 1H), 7.74 (d, J:
2.8 Hz, 1H), 5.44 (d, J: 12.4 Hz, 1H), 5.37 (d, J: 12.8 Hz, 1H), 5.31 (d, J: 8.4 Hz, 1H), 4.59
(t, J: 9.2 Hz, 1H), 3.13 (s, 3H), 2.13-2.04 (m, 1H), 1.36 (s, 9H), 1.03 (d, J: 6.8 Hz, 3H), 0.77
(d, J = 6.8 Hz, 3H). Characterization data from a purified sample of (S)—(2—(1—((tert—
butoxycarbonyl)amino)—2—methylpropyl)—5—chloropyridin—3—yl)methyl esulfonate.
To a on of (S)—(2—(1—((tert—butoxycarbonyl)amino)—2—methylpropyl)—5—
chloropyridin—3—yl)methyl methanesulfonate and tert—butyl —(5—chloro—3—
omethyl)pyridin—2—yl)—2—methylpropyl)carbamate (3:1 mixture, 6.39 g, 16.9 mmol) in THF
(75 mL) at 0 °C was added sodium hydride (60% dispersion in mineral oil, 811 mg, 20.3 mmol).
The mixture was warmed to rt and stirred for 15 h, at which point it was quenched with saturated
aqueous ammonium chloride solution (100 mL). The aqueous phase was extracted with ethyl
acetate (3 x 100 mL). The combined organic layer was washed with brine (50 mL), dried over
anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue was purified
by silica gel tography (eluting with 5% EtOAc in hexanes, nt to 10%) to give tert—
butyl (S)—3—chloro—7—isopropyl—5,7—dihydro—6H—pyrrolo[3,4—b]pyridine—6—carboxylate (4.31 g,
85% yield over 3 steps) as a yellow oil. LC—MS tR = 1.12 min in 1 min chromatography, MS
(ESI) m/z 297.3 [M + H]+. 1H NMR , 400 MHz, mixture of rotamers): 5 8.43 (s, 1H), 7.56
(s, 0.6H), 7.50 (s, 0.4H), 4.96 (s, 0.4H), 4.87 (s, 0.6H), 4.86 (d, J: 16.0 Hz, 0.6H), 4.74 (d, J:
.6 Hz, 0.4H), 4.52 (d, J: 12.0 Hz, 0.4H), 4.49 (d, J: 15.2 Hz, 0.6H), 2.60—2.51 (m, 0.4H),
2.40—2.36 (m, 0.6H), 1.49 (s, 9H), 1.08 (d, J: 7.2 Hz, 1.2H), 0.99 (d, J: 7.2 Hz, 1.8H), 0.78 (d,
J: 6.8 Hz, 1.8H), 0.72 (d, J: 6.8 Hz, 1.2H).
Potassium carbonate (758 mg, 5.49 mmol) and 4A lar sieves (250 mg) were
placed in a 50 mL round—bottom flask which was then flame dried. Palladium (II) acetate (32.8
mg, 146 umol) and 1,3—bis(dicyclohexylphosphonium)propane bis (tetrafluoroborate) (179 mg,
292 umol) were added to the flask, which was then sealed with a septum. Tert—butyl (S)—3—
chloro—7—isopropyl—5,7—dihydro—6H—pyrrolo[3,4—b]pyridine—6—carboxylate (1.09 g, 3.66 mmol)
was ved in DMF (12 mL) and added to the flask, followed by 1—butanol (3.34 mL, 36.6
mmol). The flask was then evacuated and backfilled with CO three times, with the final time
under a balloon of 1 atm of CO. The flask was heated to 100 °C and stirred for 6 h. The mixture
was then cooled to rt and quenched with 1 N NaOH (25 mL). The mixture was stirred for 30
min, at which point isopropyl acetate (50 mL) was added. The phases were separated, then the
organic phase was extracted with 1 N NaOH (2 x 50 mL), then the combined aqueous layer was
ied to pH = 2 with concentrated HCl. The aqueous layer was then extracted with EtOAc (3
x 25 mL), then the combined organic layer was dried over anhydrous MgSO4, filtered and
concentrated under reduced re. The crude e (S)—6—(tert—butoxycarbonyl)—7—isopropyl—
6,7—dihydro—5H—pyrrolo[3,4—b]pyridine—3—carboxylic acid was carried forward without any
purification.
Alternative ep procedure for (S)—6—(tert—butoxycarbonyl)—7—isopropyl—6,7—
dihydro—5H—pyrrolo[3,4—b]pyridine—3—carboxylic acid: To a solution of tert—butyl (S)—3—chloro—7—
isopropyl—5,7—dihydro—6H—pyrrolo[3,4—b]pyridine—6—carboxylate (158 mg, 532 umol) in MeOH
(2.5 mL) in a MW vial was added molybdenum hexacarbonyl (155 mg, 587 umol) and 1,8—
diazabicyclo[5.4.0]undec—7—ene (279 uL, 1.86 mmol). The mixture was degassed with N2 for 15
min, at which point trans—bis(acetate)bis[o—(di—o—tolylphosphino)benzyl]dipalladium (II) (25.0
mg, 26.6 umol) and tri—tert—butylphosphonium tetrafluoroborate (30.9 mg, 107 umol) were
added. The vial was sealed and heated in the MW at 160 °C for 20 min. After cooling to rt, the
mixture was filtered through Celite with MeOH and concentrated under reduced re. The
residue was purified by silica gel chromatography ng with 10% EtOAc in hexanes, gradient
to 25%) to afford 70.7 mg of t—butyl) 3—methyl (S)—7—isopropyl—5,7—dihydro—6H—
pyrrolo[3,4—b]pyridine—3,6—dicarboxylate (41% yield). LC—MS tR = 1.04 min in 1 min
chromatography, MS (ESI) m/z 321.4 [M + H]+. 1H NMR (CDClg, 400 MHz, mixture of
rotamers): 5 9.10 (s, 1H), 8.17 (s, 0.6H), 8.13 (s, 0.4H), 5.05 (s, 0.4H), 4.95 (s, 0.6H), 4.90 (d, J
= 15.6 Hz, 0.6H), 4.79 (d, J: 15.6 Hz, 0.4H), 4.58 (d, J: 11.2 Hz, 0.4H), 4.54 (d, J: 15.6 Hz,
0.6H), 3.96 (s, 3H), 2.62—2.53 (m, 0.4H), 2.45—2.38 (m, 0.6H), 1.52 (s, 9H), 1.09 (d, J: 6.8 Hz,
1.2H), 0.99 (d, J: 7.2 Hz, 1.8H), 0.79 (d, J: 6.8 Hz, 1.8H), 0.72 (d, J: 6.8 Hz, 1.2H).
To a solution of 6—(tert—butyl) 3—methyl (S)—7—isopropyl—5,7—dihydro—6H—pyrrolo[3,4—
b]pyridine—3,6—dicarboxylate (70.7 mg, 221 umol) in MeOH was added potassium ide
(5.9 M solution in H20, 187 uL, 1.10 mmoL). The mixture was stirred at 40 °C for 1 h, at which
point it was cooled to rt and partitioned between diethyl ether (25 mL) and 1 N NaOH (25 mL).
The organic phase was extracted with 1 N NaOH (2 x 25 mL), then the ed aqueous layer
was acidified to pH = 2 with concentrated HCl. The aqueous layer was then extracted with
EtOAc (3 x 25 mL), then the combined c layer was dried over anhydrous MgSO4, filtered
and concentrated under reduced re. The crude residue (S)—6—(tert—butoxycarbonyl)—7—
isopropyl—6,7—dihydro—5H—pyrrolo[3,4—b]pyridine—3—carboxylic acid was carried forward without
any purification. LC—MS tR = 0.93 min in 1 min chromatography, MS (ESI) m/z 307.4 [M + H]+.
1H NMR (CDC13, 400 MHz, mixture of rotamers): 5 9.19 (s, 1H), 8.23 (s, 0.6H), 8.19 (s, 0.4H),
.09 (s, 0.4H), 4.99 (s, 0.6H), 4.94 (d, J: 15.6 Hz, 0.6H), 4.82 (d, J: 14.4 Hz, 0.4H), 4.60 (d, J
= 8.8 Hz, 0.4H), 4.57 (d, J: 16.0 Hz, 0.6H), 2.65—2.57 (m, 0.4H), 2.49—2.41 (m, 0.6H), 1.53 (s,
9H), 1.10 (d, J: 6.4 Hz, 1.2H), 1.00 (d, J: 6.8 Hz, 1.8H), 0.82 (d, J: 6.8 Hz, 1.8H), 0.75 (d, J
= 6.8 Hz, 1.2H).
(4—(ethylsulfonyl)phenyl)methanamine was prepared following the synthetic route
shown in Scheme 6.
Scheme 6.
Etl, cho3 m-CPBA Us NBS, AIBN
—< >~SH —> —> /\ —>
acetone S/\ CH2C|2 O”Sx‘o CCI4
Br/\©\S/\ HZNS/\/\©\
O MeOH Ol/S\O
] A mixture of ylbenzenethiol (100 g, 0.8 mol) in acetone (1 L) was added
iodoethane (190 g, 1.2 mol) and potassium carbonate (220 g, 1.6 mol). The mixture was stirred at
60 °C overnight. The mixture was filtered and the filtrate was concentrated under reduced
pressure to afford crude ethyl(p—tolyl)sulfane (120 g, 99%) as a yellow solid, which was used for
the next step without further purification.
To a solution of crude p—tolyl)sulfane (35 g, 0.23 mol) in CHZClz (1.5 L) was
added m—chloroperoxybenzoic acid (101 g, 0.59 mol) at 0 OC. The mixture was stirred at rt
overnight. The mixture was filtered. The filtrate was added to saturated aqueous N32803 (500
mL) slowly and then stirred for 0.5 h. After partitioning, the organic layer was washed with
saturated s NaHC03 (500 mL), dried over anhydrous NaZSO4, filtered and concentrated
under reduced pressure to afford crude 1—(ethylsulfonyl)—4—methylbenzene (42.3 g, 100%) as a
pale yellow solid, which was used for the next step without further cation.
To a solution of 1—(ethylsulfonyl)—4—methylbenzene (5 g, 25.7 mmol) in CCl4 (30 mL)
was added N—bromosuccinimide (5.54 g, 30.8 mmol) and azobisisobutyronitrile (0.46 g, 2.57
mmol). The mixture was d at 80 °C overnight. The mixture was filtered and the filtrate was
concentrated under reduced pressure. The residue was added to water (50 mL) and extracted
with EtOAc (3 x 30 mL). The ed organic layers were washed with water (2 x 40 mL) and
brine (50 mL), dried over anhydrous NaZSO4, filtered and trated under reduced pressure to
afford crude l—(bromomethyl)—4—(ethylsulfonyl)benzene (6.62 g, 98%) as a yellow solid, which
was used for the next step without further purification.
To a solution of 1—(bromomethyl)—4—(ethylsulfonyl)benzene (6.62 g, 25.2 mmol) in
MeOH (30 mL) was added 28% aqueous ammonium hydroxide solution (30 mL). The mixture
was stirred at rt overnight. The mixture was then concentrated under reduced pressure. The
residue was purified by basic preparative HPLC separation to afford (4—
sulfonyl)phenyl)methanamine (1.5 g, 30%) as a yellow solid. LC—MS tR = 1.747 min in 0—
30CD_3 min chromatography (Durashell C18, 2.1*30 mm, 3 um), MS (ESI) m/z 200.0 [M + H]+
and 399.0 [2M + H]+. 1H NMR (CDC13, 400 MHz): 5 7.85 (d, J: 8.0 Hz, 2H), 7.53 (d, J: 8.0
Hz, 2H), 3.98 (s, 2H), 3.10 (q, J: 7.6 Hz, 2H), 1.26 (t, J: 7.6 Hz, 3H). Preparative Basic HPLC
Method mobile phase A: water with 0.05% NH3H20 on; mobile phase B: MeCN; flow rate:
mL/min; detection: UV 220 nm / 254 nm; column: Synergi 200 mm x 25 mm x 5 um; column
temperature: 30 0C
Time in min %A %B
0.0 63 37
8.0 33 67
8.10 0 100
.0 0 100
.1 70 30
12 70 30
(S)—N—(4—(ethylsulfonyl)benzyl)—7—isopropyl—6,7—dihydro—5H—pyrrolo[3,4—b]pyridine—
3—carboxamide was prepared ing the synthetic route shown in Scheme 7.
Scheme 7.
HATU i—PrZNEt
BocN
802Et DMF
\ ”/0
BocN ON/\©\ HN I
)lllh,l /
55 8023
(15) CHZCIZ N 802Et
To a solution of (S)—6—(tert—butoxycarbonyl)—7—isopropyl—6,7—dihydro—5H—pyrrolo[3,4—
b]pyridine—3—carboxylic acid (83.3 mg, 281 umol) and (4—(ethylsulfonyl)phenyl)methanamine
(67.1 mg, 337 umol) in DMF (2 mL) at rt was added HATU (160 mg, 421 umol) and
diisopropylethylamine (97.8 uL, 561 umol). The mixture was stirred at rt for 15 h, at which point
it was quenched with saturated s ammonium chloride solution (15 mL). EtOAc (25 mL)
was added, then the phases were separated. The organic layer was washed with brine (15 mL),
dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue was
purified by silica gel chromatography (eluting with 50% EtOAc in hexanes, gradient to 100%) to
afford 98.0 mg tert—butyl ((4—(ethylsulfonyl)benzyl)carbamoyl)—7—isopropyl—5,7—dihydro—
6H—pyrrolo[3,4—b]pyridine—6—carboxylate, (15), (77%). LC—MS tR = 0.92 min in 1 min
chromatography, MS (ESI) m/z 488.5 [M + H]+. 1H NMR (CDgOD, 400 MHz, mixture of
rotamers): 5 8.94 (d, J: 2.0 Hz, 1H), 8.16 (d, J: 12.0 Hz, 1H), 7.89 (dd, J: 2.0 Hz, 8.4 Hz,
2H), 7.64 (d, J: 8.8 Hz, 2H), 4.96 (m, 1H), 4.83 (m, 1H), 4.70 (s, 2H), 4.59 (m, 1H), 3.20 (q, J:
7.2 Hz, 2H), .42 (m, 1H), 1.48 (s, 9H), 1.20 (t, J: 7.2 Hz, 3H), 1.06 (d, J: 7.2 Hz, 1.5H),
1.02 (d, J: 6.8 Hz, 1.5H), 0.80 (d, J: 6.8 Hz, 1.5H), 0.74 (d, J: 6.8 Hz, 1.5H).
To a solution of utyl (S)—3—((4—(ethylsulfonyl)benzyl)carbamoyl)—7—isopropyl—
hydro—6H—pyrrolo[3,4—[9]pyridine—6—carboxylate (98.0 mg, 201 umol) in CH2C12 (4 mL) at
rt was added trifluoroacetic acid (1.5 mL). The solution was stirred for 30 min, then it was
cooled to 0 °C and quenched carefully with saturated sodium bicarbonate solution (20 mL). The
e was warmed to rt, then 1 N NaOH (10 mL) and brine (10 mL) were added. The s
phase was extracted with CH2C12 (5 x 25 mL), then the combined organic layer was dried over
anhydrous MgSO4, filtered and concentrated under reduced pressure. The crude (S)—N—(4—
(ethylsulfonyl)benzyl)—7—isopropyl—6,7—dihydro—5H—pyrrolo[3,4—b]pyridine—3—carboxamide was
carried forward without any purification. LC—MS tR = 0.49 min in 1 min chromatography, MS
(ESI) m/z 388.4 [M + H]+. 1H NMR (CDC13, 400 MHZ): 5 9.06 (t, J: 0.8 Hz, 1H), 8.23 (t, J:
0.8 HZ, 1H), 7.89 (dd, J: 1.6 Hz, 8.4 Hz, 2H), 7.65 (d, J: 8.8 Hz, 2H), 4.85 (d, J: 4.0 Hz, 1H),
4.73 (s, 2H), 4.71 (s, 2H), 3.20 (q, J: 7.6 Hz, 2H), .54 (m, 1H), 1.21 (t, J: 7.6 Hz, 3H),
1.21 (d, J: 6.8 Hz, 3H), 1.07 (d, J: 7.2 Hz, 3H).
(5—(ethylsulfonyl)pyridin—2—yl)methanamine was prepared following the synthetic
route shown in Scheme 8.
Scheme 8.
EtSOZNa, L-proline,
BocHN \ CuI.NaOH BocHN \ HCI
| |
N / N / N /
.HzN/fi
Br DMSO 802Et ZHC'
MeOH 802Et
To a flame dried flask equipped with a stir bar was added tert—butyl ((5—
bromopyridin—2—yl)methyl)carbamate (2.92 g, 10.2 mmol), ethane sulfinic acid sodium salt (2.36
g, 20.3 mmol), L—proline (234 mg, 2.03 mmol), copper (I) iodide (194 mg, 1.02 mmol) and
sodium hydroxide (81.3 mg, 2.03 mmol). The flask was purged with N2, then DMSO (35 mL)
was added. The on mixture was heated to 110 °C and stirred for 15 h. The flask was then
cooled to rt and the mixture was partitioned between EtOAc (150 mL) and saturated aqueous
ammonium chloride (150 mL). The c phase was separated, washed with brine (50 mL),
dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue was
ed by silica gel chromatography (eluting with 35% EtOAc in hexanes, gradient to 60%) to
afford 1.81 g tert—butyl ((5—bromopyridin—2—yl)methyl)carbamate (59%). LC—MS tR = 0.74 min in
1 min chromatography, MS (ESI) m/z 301.4 [M + H]+. 1H NMR , 400 MHz): 5 9.02 (dd,
J: 0.8 Hz, 2.0 Hz, 1H), 8.15 (dd, J: 2.4 Hz, 8.4 Hz, 1H), 7.49 (dd, J: 0.8 Hz, 8.4 Hz, 1H),
.49 (broad s, 1H), 4.55 (d, J: 7.0 Hz, 2H), 3.15 (q, J: 7.2 Hz, 2H), 1.47 (s, 9H), 1.31 (t, J:
7.2 Hz, 3H).
To a solution of tert—butyl ((5—bromopyridin—2—yl)methyl)carbamate (1.81 g, 6.03
mmol) in MeOH (40 mL) at 0 °C was added acetyl chloride (4.30 mL, 60.3 mmol) dropwise
over 5 min. The solution was allowed to warm to rt and was stirred for 3 h. The mixture was
concentrated under reduced pressure to yield 1.64 g (5—(ethylsulfonyl)pyridin—2—yl)methanamine
rochloride (~100%). LC—MS tR = 0.25 min in 1 min chromatography, MS (ESI) m/z 201.2
[M + H]+. 1H NMR (CD3OD, 400 MHz): 5 9.09 (d, J: 1.2 Hz, 1H), 8.35 (dd, J: 2.4 Hz, 8.4 Hz,
1H), 7.49 (d, J: 8.4 Hz, 1H), 4.45 (s, 2H), 3.31 (q, J: 7.2 Hz, 2H), 1.26 (t, J: 7.2 Hz, 3H).
\ H \
BocN I I
N/ N /
)IIHI, 802Et
Tert—butyl (S)—3—(((5—(ethylsulfonyl)pyridin—2—yl)methyl)carbamoyl)—7—isopropyl—5,7—
dihydro—6H—pyrrolo[3,4—b]pyridine—6—carboxylate (46): Procedure same as that for tert—butyl (S)—
3—((4—(ethylsulfonyl)benzyl)carbamoyl)—7—isopropyl—5,7—dihydro—6H—pyrrolo[3,4—b]pyridine—6—
carboxylate, using (5—(ethylsulfonyl)pyridin—2—yl)methanamine as a starting material. LC—MS tR
= 0.86 min in 1 min chromatography, MS (ESI) m/z 489.4 [M + H]+. 1H NMR (CDClg, 400
MHz, mixture of rotamers): 5 9.06 (s, 1H), 8.96 (s, 1H), 8.20 (dd, J: 2.0 Hz, 8.4 Hz, 1H), 8.05
(d, J: 7.0 Hz, 1H), 7.56 (d, J: 8.0 Hz, 1H), 7.52 (s, 1H), 4.99 (m, 2H), 4.90 (m, 2H), 4.80 (d, J
= 15.2 Hz, 1H), 4.51 (m, 1H), 3.17 (q, J: 7.6 Hz, 2H), .54 (m, 0.5H), 2.48—2.39 (m,
0.5H), 1.52 (s, 9H), 1.33 (t, J: 7.6 Hz, 3H), 1.10 (d, J: 7.2 Hz, 1.5H), 1.01 (d, J: 6.8 Hz,
1.5H), 0.78 (d, J: 6.8 Hz, 1.5H), 0.73 (d, J: 7.2 Hz, 1.5H).
\ H \
HN- IN/ I
: 802Et
((5—(ethylsulfonyl)pyridin—2—yl)methyl)—7—isopropyl—6,7—dihydro—5H—
pyrrolo[3,4—b]pyridine—3—carboxamide: Procedure same as that for (S)—N—(4—
(ethylsulfonyl)benzyl)—7—isopropyl—6,7—dihydro—5H—pyrrolo[3,4—b]pyridine—3—carboxamide, using
tert—butyl (S)—3—(((5—(ethylsulfonyl)pyridin—2—yl)methyl)carbamoyl)—7—isopropyl—5,7—dihydro—6H—
pyrrolo[3,4—b]pyridine—6—carboxylate as a starting material. LC—MS tR = 0.48 min in 1 min
chromatography, MS (ESI) m/z 389.3 [M + H]+. 1H NMR (CDClg, 400 MHZ): 5 9.06 (dd, J: 0.8
Hz, 2.0 Hz, 1H), 8.93 (t, J: 0.8 Hz, 1H), 8.19 (dd, J: 2.0 Hz, 8.4 Hz, 1H), 8.01 (t, J: 0.8 Hz,
1H), 7.56 (dd, J: 0.8 Hz, 8.0 Hz, 1H), 7.52 (s, 1H), 4.89 (d, J: 5.2 Hz, 2H), 4.35 (dd, J: 1.2
Hz, 4.0 Hz, 1H), 4.32 (d, J: 0.8 Hz, 2H), 3.17 (q, J: 7.6 Hz, 2H), 2.34-2.26 (m, 1H), 1.33 (t, J
= 7.6 Hz, 3H), 1.09 (d, J: 7.2 Hz, 3H), 0.79 (d, J: 6.8 Hz, 3H).
2—(4—(ethylsulfonyl)phenyl)acetamide was prepared following the synthetic route
shown in Scheme 9.
Scheme 9.
HOWNH2 /\0SS"K+ O S\n/OEt 1)aq.KOH,EtOH
NaNo2 HCI 3
HO 2) HCI
l K CO m--CPBA \\//
3 Eon/OSE—>
0 8“
CHZCIZ
00/9 o o
aq. NaOH NH4CI, HATU, Et3N M
—> wsv—» 0
EtOH CH2CI2
HO H2N
A solution of sodium nitrite (18.4 g, 0.267 mol) in water (133 mL) was added
dropwise to a suspension of 2—(4—aminophenyl)acetic acid (40.3 g, 0.267 mol) in water (133 mL)
and conc. HCl (54 mL, 0.65 mol) at 0 0C. After addition, the reaction mixture was stirred at the
same temperature for 45 min. The solution of the cold diazonium salt was then added dropwise
to a mixture of potassium ethyl xanthate (49.3 g, 0.31 mol), water (80 mL) and aqueous sodium
carbonate solution (200 mL, 2 M) at rt. After on, the mixture was d to warm to 45 °C
and stirred at this temperature until gas evolution ceased (about 3 h to overnight). The mixture
was cooled to rt and adjusted to pH = 1 with conc. HCl. The aqueous layer was extracted with
ethyl acetate (3 x 300 mL). The combined organic layers were dried over anhydrous NaZSO4,
filtered and concentrated under reduced re to afford crude 2— (4—
((ethoxycarbonothioyl)thio)phenyl)acetic acid (50 g, 73%) as a dark red liquid, which was used
for next step directly without further cation. 1H NMR ied by pre—TLC, CDC13 300
MHz): 5 7.40 (d, J: 7.5 Hz, 2H), 7.28 (d, J: 7.8 Hz, 2H), 4.54 (q, J: 6.9 Hz, 2H), 3.63 (s, 2H),
1.26 (t, J: 6.9 Hz, 3H).
To a solution of 2—(4—((ethoxycarbonothioyl)thio)phenyl)acetic acid (50.0 g, crude,
0.195 mol) in EtOH (180 mL) was added a solution of KOH (40.5 g, 0.724 mol) in water (180
mL). The mixture was stirred at reflux overnight. The mixture was concentrated under reduced
pressure to remove EtOH. The aqueous phase was adjusted to pH = 1~2 with conc. HCl. The
aqueous phase was then extracted with ethyl e (3 x 200 mL). The combined organic layers
were dried over anhydrous Na2S04, filtered and concentrated under d pressure to afford
crude 2—(4—mercaptophenyl)acetic acid (32.0 g, 98%) as a gray solid, which was used for next
step directly t r purification. 1H NMR (purified by pre—TLC, CD3OD, 400 MHz): 5
7.23 (d, J: 8.4 Hz, 2H), 7.15 (d, J: 8.0 Hz, 2H), 3.54 (s, 2H).
To a solution of 2—(4—mercaptophenyl)acetic acid (32 g, crude, 0.19 mol) in dry DMF
(300 mL) was added potassium carbonate (105 g, 0.76 mol) and iodoethane (118 g, 0.76 mol).
The reaction mixture was stirred at rt overnight. Ethyl acetate (800 mL) and water (600 mL)
were added to the mixture. After partitioning, the aqueous layer was ted with ethyl acetate
(3 x 500 mL). The combined organic layers were washed with brine (2 x 800 mL), dried over
anhydrous NaZSO4, filtered and concentrated under reduced re. The residue was purified
by column chromatography on silica gel (eluting with 30:1 petroleum ether:ethyl acetate) to give
ethyl 2—(4—(ethylthio)phenyl)acetate (15.3 g, 36%) as a yellow oil. LC—MS tR = 0.881 min in 5—
95AB_1.5min chromatography (Welch Xtimate C18, 2.1*30 mm, 3 um), MS (ESI) m/z 224.8
[M+H]+. 1H NMR (CDC13 300 MHz): 5 7.02 (d, J: 8.1 Hz, 2H), 6.94 (d, J: 8.1 Hz, 2H), 3.89
(q, J: 7.2 Hz, 2H), 3.31 (s, 2H), 2.67 (q, J: 7.5 Hz, 2H), 1.07—0.97 (m, 6H).
To a solution of ethyl 2—(4—(ethylthio)phenyl)acetate (7.8 g, 35 mmol) in CHzClz (100
mL) was added m—chloroperoxybenzoic acid (21 g, 123 mmol) in ns at 0 OC. The reaction
mixture was stirred for 16 h at rt. The reaction mixture was filtered. CH2C12 (200 mL) was added
to the filtrate and then the e was ed with saturated aqueous N32803 solution (200
mL). After partitioning, the organic layer was washed with saturated aqueous N32803 solution
(200 mL) and then saturated s N32C03 solution (300 mL). The combined aqueous layers
were extracted with CH2C12 (3 x 400 mL). The combined organic layers were washed with brine
(500 mL), dried over anhydrous N32804, filtered and concentrated under reduced pressure. The
residue was purified by column on silica gel (eluting with 15% EtOAc in petroleum ether,
gradient to 25%) to afford ethyl 2—(4—(ethylsulfonyl)phenyl)acetate (7.0 g, 78%) as a white solid.
LC—MS tR = 0.807 min in 5—95AB_2min chromatography (Welch e C18, 2.1*30 mm, 3
um), MS (ESI) m/z 256.8 [M+H]+. 1H NMR (CDC13 400 MHz): 5 7.87 (d, J: 8.4 Hz, 2H), 7.50
(d, J: 8.0 Hz, 2H), 4.18 (q, J: 6.8 Hz, 2H), 3.72 (s, 2H), 3.11 (q, J: 7.6 Hz, 2H), 1.30-1.25 (m,
6H).
To a on of ethyl 2—(4—(ethylsulfonyl)phenyl)acetate (10.0 g, 39 mmol) in EtOH
(100 mL) was added a solution of NaOH (5.7 g, 142.5 mmol) in water (100 mL). The reaction
mixture was stirred at rt for 16 h. EtOH was removed under reduced pressure. The aqueous layer
was adjusted to pH = 1 with 6 N aq. HCl and ted with ethyl acetate (3 x 100 mL). The
combined organic layers were washed with brine (2 X 100 mL), dried over anhydrous NazSO4,
filtered and trated under reduced pressure to give the desired product 2—(4—
(ethylsulfonyl)phenyl)acetic acid (7.3 g, 82%) as a white solid. LC—MS tR = 0.573 min in 5—
95AB_1.5min chromatography (Welch Xtimate C18, 2.1*30 mm, 3 um), MS (ESI) m/z 228.8
[M+H]+. 1H NMR (CDC13 400 MHz): 5 7.88 (d, J: 8.0 Hz, 2H), 7.50 (d, J: 8.4 Hz, 2H), 3.77
(s, 2H), 3.12 (q, J: 7.6 Hz, 2H), 1.28 (t, J: 7.6 Hz, 3H).
To a mixture of 2—(4—(ethylsulfonyl)phenyl)acetic acid (3 g, 13.2 mmol), Et3N (4.0 g,
39.6 mmol) and HATU (5.93 g, 15.6 mmol) in anhydrous CHzClz (100 mL) was added NH4Cl
(1.54 g, 26.4 mmol). The resulting mixture was d at rt overnight. The mixture was diluted
with CH2C12 (100 mL) and washed with water (3 x 80 mL). The organic layer was dried over
ous NaZSO4, filtered and concentrated under reduced pressure. The residue was purified
by column chromatography on silica gel (eluting with 50% EtOAc in petroleum ether, gradient
to 100%) to afford crude 2—(4—(ethylsulfonyl)phenyl)acetamide. The crude product was added to
petroleum ether/ethyl e (20 mL, 1/ 1), then the mixture was stirred for 0.5 h. The mixture
was ed and the filter cake was dried under vacuum to give 2— (4—
(ethylsulfonyl)phenyl)acetamide (1.5 g, 50%) as a white solid. LC—MS tR = 0.900 min in 0—
30AB_2 min chromatography (Welch Xtimate C18, 2.1*30 mm, 3 um), MS (ESI) m/z 269.0 [M
+ H + CH3CN]+. 1H NMR (DMSO-dg, 400 MHz): 5 7.80 (d, J = 8.0 Hz, 2H), 7.58 (broad s, 1H),
7.51 (d, J: 8.0 Hz, 2H), 7.00 (broad s, 1H), 3.50 (s, 2H), 3.25 (q, J: 7.2 Hz, 2H), 1.08 (t, J:
7.2 Hz, 3H).
BocNS I
N/ msoza
Tert—butyl (S)—3—(2—(4—(ethylsulfonyl)phenyl)acetamido)—7—isopropyl—5,7—dihydro—6H—
pyrrolo[3,4—b]pyridine—6—carboxylate: To a flame—dried Vial equipped with a stir bar was added
tert—butyl (S)—3—chloro—7—isopropyl—5,7—dihydro—6H—pyrrolo[3,4—b]pyridine—6—carboxylate (74.7
mg, 252 nmol), ethylsulfonyl)phenyl)acetamide (68.6 mg, 302 nmol), and potassium
phosphate (64.1 mg, 302 nmol). Tert—butanol (1.5 mL) was added, then the mixture was
degassed with N2 for 15 min. Tris(dibenzylideneacetone)dipalladium (0) (2.3 mg, 252 nmol) and
2—(di—t—butylphosphino)—3,6—dimethoxy—2’,4’,6’—tri—i—propyl—1,1’—biphenyl (4.9 mg, 10.1 umol)
were added to the e, then the Vial was sealed and heated at 110 °C for 15 h. The mixture
was cooled to rt, then partitioned between EtOAc (15 mL) and brine (15 mL). The organic phase
was separated, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure.
The residue was purified by silica gel chromatography (eluting with 10% EtOAc in hexanes,
gradient to 100%) to afford 70.2 mg of Tert—butyl (S)—3—(2—(4—(ethylsulfonyl)phenyl)acetamido)—
7—isopropyl—5,7—dihydro—6H—pyrrolo[3,4—b]pyridine—6—carboxylate (57%). LC—MS tR = 0.90 min
in 1 min chromatography, MS (ESI) m/z 488.5 [M + H]+. 1H NMR , 400 MHz, mixture
ofrotamers): 5 8.58 (s, 0.5H), 8.54 (s, 0.5H), 8.10 (s, 1H), 7.89 (dd, J: 8.0 Hz, 2H), 7.64 (d, J:
8.4 Hz, 2H), 4.77 (d, J: 15.6 Hz, 1H), 4.51 (m, 2H), 3.87 (s, 2H), 3.21 (q, J: 7.2 Hz, 2H), 2.46-
2.37 (m, 1H), 1.52 (s, 9H), 1.22 (t, J: 7.6 Hz, 3H), 1.02 (d, J: 6.8 Hz, 1.5H), 0.99 (d, J: 6.4
Hz, 1.5H), 0.77 (d, J: 7.2 Hz, 1.5H), 0.73 (d, J: 6.8 Hz, 1.5H).
/ O
.- N 802Et
(S)—2—(4—(ethylsulfonyl)phenyl)—N—(7—isopropyl—6,7—dihydro—5H—pyrrolo[3,4—
b]pyridin—3—yl)acetamide: Procedure same as that for (S)—N—(4—(ethylsulfonyl)benzyl)—7—
isopropyl—6,7—dihydro—5H—pyrrolo[3,4—b]pyridine—3—carboxamide, using tert—butyl (S)—3—(2—(4—
(ethylsulfonyl)phenyl)acetamido)—7—isopropyl—5,7—dihydro—6H—pyrrolo[3,4—b]pyridine—6—
carboxylate as a starting material. LC—MS tR = 0.50 min in 1 min chromatography, MS (ESI) m/z
388.3 [M + H]+. 1H NMR (CD3OD, 400 MHz): 5 9.02 (s, 1H), 8.48 (s, 1H), 8.26 (d, J: 2.0 Hz,
1H), 7.84 (m, 2H), 7.66 (d, J: 8.0 Hz, 1H), 7.56 (d, J: 8.4 Hz, 1H), 4.78 (m, 2H), 3.98 (s, 1H),
3.81 (s, 1H), 3.70 (s, 1H), 3.20 (q, J: 7.6 Hz, 2H), 2.65-2.57 (m, 1H), 1.21 (t, J: 7.6 Hz, 3H),
1.21 (d, J: 6.8 Hz, 3H), 1.03 (d, J: 6.8 Hz, 3H).
PREPARATION OF COMPOUNDS OF FORMULA I
Compounds of Formula (I) were prepared according to the general procedures
outlined below.
General ure A: (S)—N—(4—(ethylsulfonyl)benzyl)—7—isopropyl—6—(4—
(trifluoromethyl)benzyl)—6,7—dihydro—5H—pyrrolo[3,4—b]pyridine—3—carboxamide (1).
woo Lamchro802Et
CH3CN 802Et
] (S)—N—(4—(ethylsulfonyl)benzyl)—7—isopropyl—6,7—dihydro—5H—pyrrolo[3,4—b]pyridine—
3—carboxamide (11.3 mg, 29.2 umol), fluoromethyl)benzyl bromide (10.5 mg, 43.9 umol),
and ium carbonate (8.1 mg, 58.6 umol) were stirred together in CH3CN (1 mL) at rt for 2
h. The reaction mixture was quenched with saturated aqueous ammonium chloride on (5
mL) and extracted with EtOAc (10 mL). The organic phase was separated, washed with brine (5
mL), dried over anhydrous MgSO4, filtered and concentrated under d pressure. The
residue was purified by silica gel chromatography (eluting with 50% EtOAc in hexanes, gradient
to 100%), then r purified by reverse—phase HPLC to yield 5.2 mg of the HCl salt of (S)—N—
(4—(ethylsulfonyl)benzyl)—7—isopropyl—6—(4—(trifluoromethyl)benzyl)—6,7—dihydro—5H—pyrrolo[3,4—
b]pyridine—3—carboxamide (1, 31%). LC—MS m/z 546.5 [M + H]+. 1H NMR (CD3OD, 400 MHz):
9.08 (d, J = 1.6 Hz, 1H), 8.28 (s, 1H), 7.89 (d, J = 8.8 Hz, 2H), 7.84 (d, J = 8.0 Hz, 2H), 7.64
(d, J = 8.4 Hz, 2H), 5.03 (d, J = 16.0 Hz, 1H), 4.91 (m, 2H), 4.82 (m, 2H), 4.71 (s, 2H), 3.20 (q, J
= 7.2 Hz, 2H), 2.42-2.29 (m, 1H), 1.21 (t, J = 7.6 Hz, 3H), 1.17 (d, J = 8.0 Hz, 3H), 0.89 (d, J =
6.8 Hz, 3H).
Trans—4—(trifluoromethyl)cyclohexane—1—carbaldehyde (was prepared following the
synthetic route shown in Scheme 10.
Scheme 10.
-, O ID/H
THF -,,,/0H CH2CI2, —78 °c "W0
To a solution of trans—4—(trifluoromethyl)cyclohexane carboxylic acid (789 mg, 4.02
mmol) in THF (12 mL) at rt was added lithium aluminum hydride (1.0 M in THF, 4.02 mL). The
mixture was heated to reflux and d for 3 h. It was then cooled to 0 °C and quenched
successively with water (152 uL), 15% aqueous sodium hydroxide (152 uL), and water (456 uL).
The mixture was then filtered through Celite and concentrated under reduced pressure. The crude
liquid (trans—4—(trifluoromethyl)cyclohexyl)methanol was carried forward without any
purification and without placing under high vacuum due to its lity.
] To a solution of oxalyl chloride (6.2 mL, 87.4 mmol) in anhydrous CHZClz (300 mL)
was added dropwise DMSO (12.5 mL, 0.17 mol) at —78 °C under N2. After the mixture was
stirred at —78 °C for 30 min., a solution of (trans—4—(trifluoromethyl)cyclohexyl)methanol (5.3 g,
29.1 mmol) in CH2C12 (40 mL) was added dropwise while keeping the internal temperature
below —65 0C. After being stirred for 30 min., a on of Et3N (40.5 mL, 0.29 mol) in CHZClZ
(60 mL) was added dropwise slowly, keeping the internal temperature below —65 OC. The
reaction e was stirred at —78 °C for 1 h, and warmed to rt overnight. The mixture was
washed with water (3 x 300 mL) and brine (300 mL), dried over ous Na2S04, filtered and
concentrated under reduced pressure. The residue was purified by column chromatography on
silica (eluting with 15% EtOAc in petroleum ether) to give trans—4—
oromethyl)cyclohexane—1—carbaldehyde (4.6 g, 87%) as a yellow oil.
General procedure B: (S)—N—((5—(ethylsulfonyl)pyridin—2—yl)methyl)—7—isopropyl—6—((trans—4—
(trifluoromethyl)cyclohexyl)methyl)—6,7—dihydro—5H—pyrrolo[3,4—b]pyridine—3—carboxamide (2).
O O
\ N \ O""\\O,NaBH30N,AcoH 3 \ N \
HN | H | ’—N | H |
/ N / N /
_ N/ N SOzEt MeOH 802Et
To a solution of (S)—N—((5—(ethylsulfonyl)pyridin—2—yl)methyl)—7—isopropyl—6,7—
dihydro—5H—pyrrolo[3,4—b]pyridine—3—carboxamide (3.6 g, 9.25 mmol), trans—4—
(trifluoromethyl)cyclohexane—1—carbaldehyde (3.3 g, 18.5 mmol) in anhydrous MeOH (100 mL)
was added acetic acid dropwise until the pH was between 6 and 7. Sodium cyanoborohydride
(1.7 g, 27.75 mmol) was added portionwise at rt. The mixture was heated to 70 °C for 1 h. Upon
WO 16904
completion, the reaction mixture was cooled to rt and concentrated under reduced pressure. The
residue was dissolved in ethyl acetate (100 mL), then the organic phase was washed with water
(3 X 100 mL) and brine (100 mL). The organic layer was dried over anhydrous Na2S04, ed
and concentrated under reduced pressure. The residue was purified by silica gel chromatography
(eluting with 50% EtOAc in heXanes, gradient to 100%), then further purified by a chiral column
using the following ions: instrument: Berger MultiGramTM SFC, Mettler Toledo Co, Ltd;
column: AD 300 mm X 50 mm, 10 um; mobile phase: A: supercritical C02, B: iPrOH (0.05%
lamine), A:B = 60:40 at 200mL/min; column temp: 38 OC; nozzle pressure: 100 bar;
nozzle temp: 60 OC; evaporator temp: 20 OC; trimmer temp: 25 OC; wavelength: 220 nm. Isomer
SFC tR = 2.28 min in 12 min chromatography was isolated as the major isomer, which was then
further purified by reverse—phase HPLC to give (S)—N—((5—(ethylsulfonyl)pyridin—2—yl)methyl)—7—
isopropyl—6—((trans—4—(trifluoromethyl)cycloheXyl)methyl)—6,7—dihydro—5H—pyrrolo[3,4—
b]pyridine—3—carb0Xamide (2, HCl salt) as a light yellow solid. LC—MS tR = 0.69 min in 1 min
tography, MS (ESI) m/z 553.1 [M + H]+. 1H NMR (CD3OD, 400 MHz): 5 9.12 (s, 1H),
9.01 (d, J: 2.0 Hz, 1H), 8.36—8.32 (m, 2H), 7.75 (d, J: 8.0 Hz, 1H), 5.16 (d, J: 15.6 Hz, 1H),
4.89-4.87 (m, 2H), 4.73 (d, J: 15.2 Hz, 1H), 3.42-3.34 (m, 3H), 3.31—3.28 (m, 2H), 2.58—2.51
(m, 1H), 2.20-1.90 (m, 6H), 1.50-1.39 (m, 2H), 1.33 (d, J: 7.2 Hz, 3H), 1.26 (t, J: 7.2 Hz, 3H),
1.24—1.20 (m, 2H), 1.10 (d, J = 6.8 Hz, 3H). HCl preparative HPLC method mobile phase A:
water with 0.05% HCl; mobile phase B: CH3CN; flow rate: 80 mL/min; detection: UV 220 nm/
254 nm; column: PhenomeneX Gemini C18 (250 mm X 50 mm X 5 um); column temperature: 30
Time in min %A %B
0.00 75 25
.00 50 50
.00 0 100
A sample of 2 was converted to the HBr salt by the ing procedure: The HCl
salt of 2 (57.5 mg, 97.7 umol) was dissolved in EtOAc (25 mL) and washed with ted
aqueous sodium bicarbonate (20 mL) and brine (10 mL). The organic phase was dried over
anhydrous MgSO4, ed and trated under reduced pressure. It was then redissolved in
acetonitrile (200 uL), to which was added hydrobromic acid (48 wt% in water, 69 uL) to give a
light yellow clear solution. The solvent was removed under reduced pressure, then more
acetonitrile (300 uL) was added. This procedure was performed iteratively until most of the
water and eXcess HBr was removed, leaving behind a yellow solid. This solid was redissolved in
acetonitrile (6 mL), seeded with an HBr salt crystal (<1 mg), and stirred at rt for 30 min to give a
white solid. The solid was filtered and dried under high vacuum for 3 h to give the HBr salt (40.2
mg, 86%). Melting point 2 171-173 0C. 1H NMR (CD3OD, 400 MHz): 5 9.12 (s, 1 H), 9.07 (s,
1H), 8.46 (d, J = 8.4 Hz, 1H), 8.34 (s, 1H), 7.85 (d, J = 8.4 Hz, 1H), 5.18 (d, J: 14.2 Hz, 1H),
4.94 (m, 1H), 4.87 (s, 2H), 4.75 (d, J: 14.2 Hz. 1H), 3.41 (m, 2H), 3.38 (q, J: 7.6 Hz, 2H), 2.54
(m, 1H), 2.17 (m, 1H), 2.04 (m, 5H), 1.45 (m, 2H), 1.32 (d, J: 7.2 Hz, 3H), 1.27 (t, J: 7.6 Hz,
3H), 1.23 (m, 2H), 1.10 (d, J: 6.4 Hz, 3H).
HBr seed crystals were formed as follows: 2 (5.6 mg) was converted to the free base,
then to the HBr salt, as described above. The resultant yellow solid was dissolved in acetonitrile
(200 uL), then left to stand overnight at rt in a capped vial. ess crystals formed, which
were identified as plate—shaped under a cope.
General procedure C: (S)—N—(4—(ethylsulfonyl)benzyl)—7—isopropyl—6—(4—
(trifluoromethyl)pyrimidin—2—yl)—6,7—dihydro—5H—pyrrolo[3,4—b]pyridine—3—carboxamide (6).
O N O
/ F3C
\>—CI
Moor\ N —N ,i-PerEt N
mm\ N
i-PrOH, 140 °C, uwave SOzEt
/\ /\
To a solution of (S)—N—(4—(ethylsulfonyl)benzyl)—7—isopropyl—6,7—dihydro—5H—
pyrrolo[3,4—b]pyridine—3—carboxamide (27.3 mg, 70.4 umol) in panol (1.5 mL) in a MW
vial was added 2—chloro—5—(trifluoromethyl)pyrimidine (19.3 mg, 106 umol) and
diisopropylethylamine (24.5 uL, 140.7 umol). The vial was sealed and heated in the MW at 140
0C for 2 h. The solvent was then evaporated and the residue was ed by silica gel
chromatography (eluting with 60% EtOAc in hexanes, gradient to 100%), then further purified
by reverse—phase HPLC to yield 7.2 mg of (S)—N—(4—(ethylsulfonyl)benzyl)—7—isopropyl—6—(4—
(trifluoromethyl)pyrimidin—2—yl)—6,7—dihydro—5H—pyrrolo[3,4—b]pyridine—3—carboxamide (6,
19%). LC-MS tR = 0.97 min in 1 min chromatography, MS (ESI) m/z 534.5 [M + H]+. 1H NMR
(CD3OD, 400 MHz): 5 9.34 (t, J: 1.2 Hz, 1H), 8.97 (s, 1H), 8.69 (d, J: 4.8 Hz, 1H), 8.25 (s,
1H), 7.90 (d, J: 8.4 Hz, 2H), 7.65 (d, J: 8.0 Hz, 2H), 7.02 (d, J: 4.8 Hz, 1H), 5.39 (s, 1H),
.14 (d, J: 15.6 Hz, 1H), 4.87 (m, 1H), 4.72 (d, J: 6.0 Hz, 2H), 3.20 (q, J: 7.6 Hz, 2H), 2.79-
2.68 (m, 1H), 1.22 (broad s, 3H), 1.21 (t, J: 7.6 Hz, 3H), 0.69 (broad s, 3H).
] General procedure D: (S)—6—((4—cyanophenyl)sulfonyl)—N—(4—(ethylsulfonyl)benzyl)—
7—isopropyl—6,7—dihydro—5H—pyrrolo[3,4—b]pyridine—3—carboxamide (13).
\ N NC—Q8020| 1 Eth
HN l/ H —» \ N
N SOZEt CH2C|2,rt 0438‘“ IN/ H
/\ s 80E2 t
To a solution of (S)—N—(4—(ethylsulfonyl)benzyl)—7—isopropyl—6,7—dihydro—5H—
pyrrolo[3,4—b]pyridine—3—carboxamide (6.9 mg, 17.8 umol) in CHZClZ (600 uL) was added
triethylamine (5.0 uL, 36.6 umol) and 4—cyanobenzenesulfonyl chloride (5.4 mg, 26.8 umol).
The mixture was stirred at rt for 15 h, at which point it was ed with saturated aqueous
sodium bicarbonate (10 mL). The mixture was extracted with EtOAc (10 mL), then the organic
phase was washed with brine (10 mL), dried over anhydrous MgSO4, filtered and concentrated
under reduced pressure. The residue was purified by reverse—phase HPLC to yield 4.9 mg of (S)—
6—((4—cyanophenyl)sulfonyl)—N—(4—(ethylsulfonyl)benzyl)—7—isopropyl—6,7—dihydro—5H—
pyrrolo[3,4—b]pyridine—3—carboxamide as an HCl salt (13, 46%). LC-MS tR = 0.84 min in 1 min
chromatography, MS (ESI) m/z 553.5 [M + H]+. 1H NMR (CD3OD, 400 MHZ): 5 8.85 (d, J =
2.0 Hz, 1H), 8.09 (d, J: 1.6 Hz, 1H), 8.03 (dd, J: 2.0 Hz, 8.8 Hz, 2H), 7.86 (m, 4H), 7.60 (d, J
= 8.4 Hz, 2H), 4.93 (m, 2H), 4.73 (dt, J: 1.2 Hz, 16.4 Hz, 1H), 4.66 (s, 2H), 3.19 (q, J: 7.6 Hz,
2H), 2.41-2.32 (m, 1H), 1.20 (t, J: 7.6 Hz, 3H), 1.00 (d, J: 7.2 Hz, 3H), 0.96 (d, J: 6.8 Hz,
3H).
General procedure E: benzyl (S)—3—((4—(ethylsulfonyl)benzyl)carbamoyl)—7—
isopropyl—5,7—dihydro—6H—pyrrolo[3,4—b]pyridine—6—carboxylate (16).
O o
\ N BnOCOCI, Et3N, DMAP BnO
\ N
HN | H
/ Hm >_N I
.- N 802Et O
CH2C|2, rt N SOzEt
«5 /\ 16
To a solution of (S)—N—(4—(ethylsulfonyl)benzyl)—7—isopropyl—6,7—dihydro—5H—
pyrrolo[3,4—b]pyridine—3—carboxamide (11.3 mg, 29.2 umol) in CHZClZ (1 mL) was added benzyl
chloroformate (11.7 uL, 3.0 M in e), ylamine (6.1 uL, 43.8 umol) and 4—
dimethylaminopyridine (50 ug, 4.09 umol). The mixture was stirred at rt for 15 h, at which point
it was quenched with saturated s sodium bicarbonate (10 mL). The mixture was extracted
with EtOAc (10 mL), then the organic phase was washed with brine (10 mL), dried over
anhydrous MgSO4, ed and concentrated under reduced pressure. The residue was purified
by silica gel chromatography ng with 30% EtOAc in hexanes, gradient to 100%), then
r purified by reverse—phase HPLC to yield 14.9 mg of benzyl (S)—3—((4—
(ethylsulfonyl)benzyl)carbamoyl)—7—isopropyl—5,7—dihydro—6H—pyrrolo[3,4—b]pyridine—6—
ylate as an HCl salt (16, 91%). LC-MS tR = 0.91 min in 1 min chromatography, MS (ESI)
m/z 522.5 [M + H]+. 1H NMR (CD3OD, 400 MHz): 5 9.00 (s, 1H), 8.34 (s, 1H), 7.87 (dd, J: 1.6
Hz, 6.8 Hz, 2H), 7.63 (d, J: 8.8 Hz, 2H), 7.42 (dd, J: 1.6 Hz, 8.4 Hz, 2H), 7.33 (m, 3H), 5.20
(m, 3H), 4.96 (m, 1H), 4.71 (m, 3H), 3.20 (q, J: 7.6 Hz, 2H), 2.57-2.36 (m, 1H), 1.19 (t, J: 7.6
Hz, 3H), 1.00 (dd, J: 6.8 Hz, 16.0 Hz, 3H), 0.78 (dd, J: 6.8 Hz, 25.6 Hz, 3H).
(7S)—N—(4—(ethylsulfonyl)benzyl)—7—isopropyl—5—methyl—6,7—dihydro—5H—pyrrolo[3,4—
b]pyridine—3—carboxamide was prepared following the synthetic route shown in Scheme 11.
Scheme 11.
0 0
0' NaBH4 CI
EC \ HNMe(OMe)-HCI,MeMgBr \
| |
BOCHN N/ B°CHN
THE-20°C N/ EtOH,O°C
; ;
/\ /'\
0' MsCI EtN \
BocHN / BocHN . N
N l/N 5
CH2C|2
/\ /\ /\
n—butanol, Pd(OAc)2
“©3028 HATU 1,_'Pr NEt dcpp HBF4, CO (1 atm). 2
BocN
DMF 100°C
802Et CH2C|2 Usoza
] To a solution of ethyl (S)—2—(1—((tert—butoxycarbonyl)amino)—2—methylpropyl)—5—
chloronicotinate (104 mg, 291 umol) and N,O—dimethylhydroxylamine hydrochloride (45.5 mg,
466 umol) in THF (1 mL) was added dropwise methylmagnesium bromide (1.4 M in 3:1
toluene:THF, 1.04 mL) at —20 OC. The mixture was stirred at —20 °C for 45 min, at which point it
was quenched carefully with cold ted aqueous ammonium chloride (10 mL). The mixture
was extracted with EtOAc (20 mL), then the organic phase was washed with brine (10 mL),
dried over anhydrous MgSO4, ed and concentrated under reduced pressure. The residue was
purified by silica gel chromatography (eluting with 10% EtOAc in hexanes, gradient to 60%) to
afford 62.3 mg of tert—butyl (S)—(1—(3—acetyl—5—chloropyridin—2—yl)—2—methylpropyl)carbamate
(56% yield). LC-MS tR = 1.08 min in 1 min chromatography, MS (ESI) m/z 327.4 [M + HT".
2015/013699
To a solution of tert—butyl (S)—(1—(3—acetyl—5—chloropyridin—2—yl)—2—
methylpropyl)carbamate (62.3 mg, 191 umol) in EtOH (1 mL) at 0 °C was added sodium
borohydride (7.2 mg, 191 umol) as a solid. The mixture was stirred at 0 °C for 90 min, then it
was quenched with saturated s ammonium chloride (10 mL). The mixture was extracted
with EtOAc (20 mL), then the organic phase was washed with brine (10 mL), dried over
anhydrous MgSO4, filtered and concentrated under reduced pressure. The e was purified
by silica gel chromatography (eluting with 10% EtOAc in hexanes, gradient to 100%) to afford
53.4 mg of tert—butyl ((lS)—1—(5—chloro—3—(1—hydroxyethyl)pyridin—2—yl)—2—
methylpropyl)carbamate (85% yield). LC-MS tR = 1.01 min in 1 min chromatography, MS (ESI)
m/z 329.4 [M + H]+. 1H NMR , 400 MHz, mixture of diastereomers): 5 8.44 (d, J = 2.4
Hz, 0.3H), 8.41 (d, J: 2.4 Hz, 0.7H), 7.86 (d, J: 2.4 Hz, 0.7H), 7.77 (d, J: 2.4 Hz, 0.3H), 5.44
(d, J: 9.6 Hz, 0.7H), 5.31 (m, 0.7H), 5.23 (m, 0.7H), 4.73 (t, J: 8.8 Hz, 0.3H), 4.63 (t, J: 9.6
Hz, 0.3H), 4.56 (s, 0.3H), 2.18—2.12 (m, 0.3H), 2.08—2.00 (m, 0.7H), 1.56 (d, J: 6.8 Hz, 0.9H),
1.52 (d, J: 6.8 Hz, 2.1H), 1.40 (s, 9H), 1.11 (d, J: 6.8 Hz, 0.9H), 1.00 (d, J: 6.8 Hz, 2,1H),
0.80 (d, J: 6.8 Hz, 2.1H), 0.69 (d, J: 6.8 Hz, 0.9H).
1—(2—((S)—1—((tert—butoxycarbonyl)amino)—2—methylpropyl)—5—chloropyridin—3—yl)ethyl
esulfonate. Procedure same as that for (S)—(2—(1—((tert—butoxycarbonyl)amino)—2—
methylpropyl)—5—chloropyridin—3—yl)methyl esulfonate, using tert—butyl ((1S)—1—(5—chloro—
3—(1—hydroxyethyl)pyridin—2—yl)—2—methylpropyl)carbamate as a starting material. LC-MS tR =
1.03 min in 1 min chromatography, MS (ESI) m/z 407.4 [M + H]+.
Tert—butyl (7S)—3—chloro—7—isopropyl—5—methyl—5,7—dihydro—6H—pyrrolo[3,4—
b]pyridine—6—carboxylate. Procedure same as that for tert—butyl (S)—3—chloro—7—isopropyl—5,7—
dihydro—6H—pyrrolo[3,4—b]pyridine—6—carboxylate, using 1—(2—((S)—1—((tert—
butoxycarbonyl)amino)—2—methylpropyl)—5—chloropyridin—3—yl)ethyl methanesulfonate as a
starting material. LC-MS tR = 1.12 min in 1 min chromatography, MS (ESI) m/z 311.4 [M + H]+.
1H NMR , 400 MHz, mixture of diastereomers): 5 8.43 (d, J = 1.6 Hz, 1H), 7.52 (s,
0.7H), 7.46 (s, 0.3H), 5.05—5.00 (m, 1H), 4.94 (s, 0.3H), 4.81 (s, 0.7H), 2.88—2.39 (m, 0.3H),
2.32—2.08 (m, 0.7H), 1.55 (m, 3H), 1.44 (s, 9H), 1.26 (d, J: 7.2 Hz, 0.9H), 1.09 (broad s, 2.1H),
0.81 (broad s, 2.1H), 0.48 (d, J: 7.2 Hz, 0.9H).
(7S)—6—(tert—butoxycarbonyl)—7—isopropyl—5—methyl—6,7—dihydro—5H—pyrrolo[3,4—
b]pyridine—3—carboxylic acid. Procedure same as that for (S)—6—(tert—butoxycarbonyl)—7—
isopropyl—6,7—dihydro—5H—pyrrolo[3,4—b]pyridine—3—carboxylic acid, using utyl (7S)—3—
chloro—7—isopropyl—5—methyl—5,7—dihydro—6H—pyrrolo[3,4—b]pyridine—6—carboxylate as a starting
material. LC-MS tR = 0.99 min in 1 min chromatography, MS (ESI) m/z 321.5 [M + H]+.
utyl (7S)—3—((4—(ethylsulfonyl)benzyl)carbamoyl)—7—isopropyl—5—methyl—5,7—
dihydro—6H—pyrrolo[3,4—b]pyridine—6—carboxylate. Procedure same as that for utyl (S)—3—
((4—(ethylsulfonyl)benzyl)carbamoyl)—7—isopropyl—5,7—dihydro—6H—pyrrolo[3,4—b]pyridine—6—
ylate, using (7S)—6—(tert—butoxycarbonyl)—7—isopropyl—5—methyl—6,7—dihydro—5H—
pyrrolo[3,4—b]pyridine—3—carboxylic acid as a starting material. LC-MS tR = 0.95 min in 1 min
chromatography, MS (ESI) m/z 502.6 [M + H]+. 1H NMR (CD3OD, 400 MHz, mixture of
diastereomers): 5 8.93 (s, 1H), 7.79 (d, J: 8.4 Hz, 2H), 7.50 (d, J: 8.4 Hz, 2H), 7.24 (s, 1H),
.06—4.88 (m, 2H), 4.82—4.70 (m, 2H), 3.06 (q, J: 7.2 Hz, 2H), 2.48-2.26 (m, 1H), 1.59 (d, J:
7.2 Hz, 0.9H), 1.56 (d, J: 7.2 Hz, 2.1H), 1.53 (s, 9H), 1.25 (t, J: 7.2 Hz, 3H), 1.09 (d, J: 7.2
Hz, 0.9H), 0.97 (broad s, 2.1H), 0.83 (broad s, 2.1H), 0.48 (d, J: 7.2 Hz, 0.9H).
(7S)—N—(4—(ethylsulfonyl)benzyl)—7—isopropyl—5—methyl—6,7—dihydro—5H—pyrrolo[3,4—
b]pyridine—3—carboxamide. Procedure same as that for (S)—N—(4—(ethylsulfonyl)benzyl)—7—
isopropyl—6,7—dihydro—5H—pyrrolo[3,4—b]pyridine—3—carboxamide, using tert—butyl (7S)—3—((4—
(ethylsulfonyl)benzyl)carbamoyl)—7—isopropyl—5—methyl—5,7—dihydro—6H—pyrrolo[3,4—b]pyridine—
6—carboxylate as a starting material. LC-MS tR = 0.49 min in 1 min chromatography, MS (ESI)
m/z 402.3 [M + H]+. 1H NMR (CDgOD, 400 MHz, mixture of diastereomers): 5 8.91 (dd, J = 1.2
Hz, 2.0 Hz, 1H), 8.11 (dd, J: 0.8 Hz, 2.0 Hz, 0.4H), 8.07 (dd, J: 1.2 Hz, 1.6 Hz, 0.6H), 7.89 (d,
J: 8.4 Hz, 2H), 7.63 (d, J: 8.4 Hz, 2H), 4.70 (s, 2H), 4.57 (m, 0.4H), 4.48 (m, 0.6H), 4.30 (m,
1H), 3.20 (q, J: 7.2 Hz, 2H), 2.40-2.33 (m, 0.6H), 2.27-2.21 (m, 0.4H), 1.50 (d, J: 6.8 Hz,
1.8H), 1.47 (d, J: 7.2 Hz, 1.2H), 1.20 (t, J: 7.6 Hz, 3H), 1.14 (d, J: 7.2 Hz, 1.8H), 1.08 (d, J:
7.2 Hz, 1.2H), 0.81 (d, J: 6.8 Hz, 1.2H), 0.80 (d, J: 6.8 Hz, 1.8H).
] N—(4—(ethylsulfonyl)benzyl)—7—(tetrahydrofuran—3—yl)—6,7—dihydro—5H—pyrrolo[3,4—
b]pyridine—3—carboxamide was prepared following the synthetic route shown in Scheme 12.
Scheme 12.
KOK/lkOEt EtOOC
HZN COOH BocHN COOH
Boc20 NaOH MgCI2 CDI BocHN
THF/HZO HF
\N \ \N
I OH
0' EtOOC
t—BuOK DABCO CI
NH4OAc BocHN NaBH4. CaClz | TsCI, Et3N
, BocHN N/ _>
EtOH
THF CHZCIZ
H2N/\©\/\©\802Et
6,H'ermann5 cat.
BOON CFu6's salt DBU
BocHN
dioxane 160 °C uwave
\ N \ N
BocN | TFA
N/ HO/\©\
,s\/\ —’ N/ H/\©\,s\/\
O’ \O CH2C|2 O, \O
O 0
To a solution of 2—amino—2—(tetrahydrofuran—3—yl)acetic acid hydrochloride (1 g, 5.52
mmol) in a mixture of THF (15 mL) and water (1.5 mL) was added t—butyl dicarbonate (1.2
g, 5.52 mmol) and sodium hydroxide (0.9 g, 22.1 mmol). The mixture was stirred at rt overnight.
Water (50 mL) was added to the mixture, followed by acidification with 2N aq. HCl solution to
pH: 2. The mixture was ted with ethyl acetate (3 x 20 mL). The ed organic layers
were dried over anhydrous sodium sulfate, filtered, concentrated under reduce pressure to afford
2—((tert—butoxycarbonyl)amino)—2—(tetrahydrofuran—3—yl)acetic acid (1.11 g, 80%) as a colorless
oil, which was used for the next step without further purification. MS: MS (ESI) m/z 268.1180
[M+Na]+.
Ethyl 4—((tert—butoxycarbonyl)amino)—3—oxo—4—(tetrahydrofuran—3—yl)butanoate.
Procedure same as that for ethyl (S)—4—((tert—butoxycarbonyl)amino)—5—methyl—3—oxohexanoate,
using 2—((tert—butoxycarbonyl)amino)—2—(tetrahydrofuran—3—yl)acetic acid as a ng material.
1H NMR (CD3OD, 400 MHz): 5 .13 (m, 3H), 4.00-3.45 (m, 4H), 2.75-2.65 (m, 1H), 2.12-
1.98 (m, 1H), 1.77-1.62 (m, 1H), 1.49 (s 9H), 1.30 (t, J: 7.2 Hz, 3H).
Ethyl 2—(((tert—butoxycarbonyl)amino)(tetrahydrofuran—3—yl)methyl)—5—
chloronicotinate. Procedure same as that for ethyl (1—((tert—butoxycarbonyl)amino)—2—
methylpropyl)—5—chloronicotinate, using ethyl 4—((tert—butoxycarbonyl)amino)—3—oxo—4—
(tetrahydrofuran—3—yl)butanoate as a starting material. 1H NMR (CDgOD, 400 MHz): 5 8.73 (s,
1H), 8.24 (s, 1H), 5.66 (d, J: 8.0 Hz, 1H), 4.61 (s, 1H), 4.45 (q, J: 6.8 Hz, 2H), .86 (m,
1H), 3.82—3.56 (m, 3H), 2.82—2.86 (m, 1H), 1.95 (q, J: 7.2 Hz, 1H) 1.74 (q, J: 6.8 Hz, 1H),
1.44 (t, J: 7.2 Hz, 3H), 1.40 (d, J: 6.8 Hz, 9H).
Tert—butyl ((5 —chloro—3 —(hydroxymethyl)pyridin—2—yl) (tetrahydrofuran—3—
yl)methyl)carbamate. Procedure same as that for tert—butyl (S)—(1—(5—chloro—3—
(hydroxymethyl)pyridin—2—yl)—2—methylpropyl)carbamate, using ethyl 2—(((tert—
2015/013699
butoxycarbonyl)amino)(tetrahydrofuran—3—yl)methyl)—5—chloronicotinate as a starting material.
LCMS: tR = 0.753 min in 5—95AB_1.5min chromatography (MK RP18e 25—2mm), MS (ESI)
m/z 342.9 [M+H]+.
To a solution of tert—butyl ((5—chloro—3—(hydroxymethyl)pyridin—2—
yl)(tetrahydrofuran—3—yl)methyl)carbamate (600 mg, 1.74 mmol) in anhydrous CHzClz (25 mL)
was added Et3N (0.5 mL, 2.62 mmol) and p—toluenesulfonyl chloride (400 mg, 2.1 mmol) at 0
OC. The mixture was stirred at rt for 2 h. The e was then washed with water (3 x 20 mL).
The organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced
pressure and purified by chromatography column on silica gel (eluting with 10% EtOAc in
petroleum ether, gradient to 20%) to afford tert—butoxycarbonyl)amino)(tetrahydrofuran—3—
yl)methyl)—5—chloropyridin—3—yl)methyl 4—methylbenzenesulfonate (470 mg, 54%) as a colorless
oil and tert—butyl ((5 —chloro—3—(chloromethyl)pyridin—2—yl)(tetrahydrofuran—3—
yl)methyl)carbamate (200 mg, 32%) as a white solid. LCMS: tR = 0.947 min in 5—95AB_1.5min
chromatography (MK RP18e 25—2mm), MS (ESI) m/z 519.1 [M+Na]+.
To a solution of tert—butyl ((5—chloro—3—(chloromethyl)pyridin—2—yl)(tetrahydrofuran—
3—yl)methyl)carbamate (470 mg, 0.95 mmol) in anhydrous DMF (5 mL) was added with sodium
hydride (115 mg, 2.84 mmol, 60% in mineral oil) in portions at 0 OC. The mixture was stirred at
rt for 2 h. The mixture was quenched with water (40 mL) and extracted with ethyl e (3 x 20
mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered,
concentrated under d pressure and purified by chromatography column on silica gel
(eluting with 10% EtOAc in petroleum ether) to afford tert—butyl 3—chloro—7—(tetrahydrofuran—3—
yl)—5,7—dihydro—6H—pyrrolo[3,4—b]pyridine—6—carboxylate (285 mg, 91%) as a colorless oil.
LCMS: tR = 0.862 min in 5—95AB_1.5min tography (MK RP—18e 25—2mm), MS (ESI)
m/z 324.9 [M+H]+.1H NMR (CD3OD, 400 MHz): 5 8.47 (s, 1H), 7.83 (d, J: 13.6 Hz, 1H), 5.10
(s, 1H), 4.65—4.50 (m, 1.5H), 3.95 (t, J: 8.0 Hz, 0.5H), 3.85—3.67 (m, 4H), 3.03—2.87 (m, 1H),
.65 (m, 2H), 1.54 (s, 9H).
To a solution of tert—butyl 3—chloro—7—(tetrahydrofuran—3—yl)—5,7—dihydro—6H—
pyrrolo[3,4—b]pyridine—6—carboxylate (60 mg, 0.19 mmol) in a MW Vial in anhydrous dioxane
(0.5 mL) was added molybdenum hexacarbonyl (6 mg, 0.02 mmol), (4—
(ethylsulfonyl)phenyl)methanamine (56 mg, 0.28 mmol) and 1,8—diazabicyclo[5.4.0]undec—7—ene
(90 mg, 0.57 mmol). The mixture was degassed with N2 for 15 min, at which point rt—
butylphosphonium tetrafluoroborate (58 mg, 0.19 mmol) and trans—bis(acetate)bis[o—(di—o—
tolylphosphino)benzyl]dipalladium (II) (10 mg, 0.01 mmol) were added. The Vial was sealed and
heated in the MW at 160 °C for 20 min. The reaction mixture was filtered, then the filtrate was
concentrated under reduced pressure and purified by preparative TLC (eluting with 12% EtOAc
in petroleum ether) to afford tert—butyl (ethylsulfonyl)benzyl)carbamoyl)—7—
(tetrahydrofuran—3—yl)—5,7—dihydro—6H—pyrrolo[3,4—b]pyridine—6—carboxylate (25 mg, 26%) as a
colorless oil. LCMS: tR = 0.761 min in 5—95AB_1.5min chromatography (MK RPl8e 25—2mm),
MS (ESI) m/z 516.2 .1H NMR (CD3OD, 400 MHz): 5 8.96 (s, 1H), 8.20 (d, J: 10.0 Hz,
1H), 8.15-8.00 (m, 1H), 7.91 (d, J: 8.4 Hz, 2H), 7.65 (d, J: 8.0 Hz, 2H), 5.19 (s, 1H), 5.00—
4.90 (m, 2H), 4.75—4.60 (m, 3H), 4.00—3.65 (m, 5H), 3.25 (q, J: 7.2 Hz, 2H), .95 (m, 1H),
.75 (m, 2H), 1.56 (s, 9H), 1.23 (t, J: 7.2 Hz, 3H).
N—(4—(ethylsulfonyl)benzyl)—7—(tetrahydrofuran—3—yl)—6,7—dihydro—5H—pyrrolo[3,4—
b]pyridine—3—carboxamide. Procedure same as that for (S)—N—(4—(ethylsulfonyl)benzyl)—7—
isopropyl—6,7—dihydro—5H—pyrrolo[3,4—b]pyridine—3—carboxamide, using tert—butyl 3—((4—
(ethylsulfonyl)benzyl)carbamoyl)—7—(tetrahydrofuran—3—yl)—5,7—dihydro—6H—pyrrolo[3,4—
b]pyridine—6—carboxylate as a starting material.
] (S)—6—(4—chlorobenzyl)—N—(4—(ethylsulfonyl)benzyl)—7—isopropyl—6,7—dihydro—5H—
pyrrolo[3,4—[9]pyridine—3—carboxamide (9) was prepared following the synthetic route shown in
Scheme 13.
Scheme 13.
o O O
EtO \ TFA
BocHN HNbL/j/CI
N/ HZNEtOfij/CI
CH2C|2 N/ W N/
; 5
/\ A /\
C| CI
0 o
r ,NaH
CI CI
—. Q \ + Q \
THF,O°C N | N |
/ /
N OHN
H2N/\©\ CI
3023
Mo(CO)6, Hermann's cat, 0 O
Fu 3 salt, DBU
\ N
—> N | H
dioxane, 160 °C, uwave N
:. 802Et
/\ 9
Ethyl (S)—2—(1—amino—2—methylpropyl)—5—chloronicotinate. Procedure same as that for
(S)—N—(4—(ethylsulfonyl)benzyl)—7—isopropyl—6,7—dihydro—5H—pyrrolo[3,4—b]pyridine—3—
carboxamide, using ethyl (S)—2—(1—((tert—butoxycarbonyl)amino)—2—methylpropyl)—5—
2015/013699
chloronicotinate as a starting material. LCMS: tR = 0.59 min in in 1 min chromatography, MS
(ESI) m/z 257.3 [M + H]+.
A solution of ethyl (1—amino—2—methylpropyl)—5—chloronicotinate (282 mg, 1.10
mmol) was heated in toluene (5 mL) at 100 °C for 15 h. The solvent was removed in vacuo to
yield crude (S)—3—chloro—7—isopropyl—6,7—dihydro—5H—pyrrolo[3,4—b]pyridin—5—one, which was
carried forward without further purification. LCMS: tR = 0.73 min in in 1 min chromatography,
MS (ESI) m/z 211.2 [M + H]+.1H NMR (CD3OD, 400 MHz): 5 8.70 (d, J: 2.8 Hz, 1H), 8.07 (d,
J: 2.0 Hz, 1H), 6.75 (broad s, 1H), 4.55 (dd, J: 1.2 Hz, 3.6 Hz, 1H), 2.49-2.41 (m, 1H), 1.23
(d, J: 7.2 Hz, 3H), 0.74 (d, J: 6.8 Hz, 3H).
To a degassed solution of (S)—3—chloro—7—isopropyl—6,7—dihydro—5H—pyrrolo[3,4—
b]pyridin—5—one (42.2 mg, 200 umol) in THF (2 mL) at 0 °C was added sodium hydride (60%
dispersion in mineral oil, 9.6 mg, 240 umol). The mixture was d at 0 °C for 30 min, at
which point 4—chlorobenzyl bromide (49.3 mg, 240 umol) was added. The mixture was allowed
to warm to rt and was stirred for 15 h. The mixture was ed with saturated aqueous
ammonium chloride (10 mL) and extracted with EtOAc (10 mL). The organic phase was washed
with brine (10 mL), dried over anhydrous MgSO4, filtered and concentrated under d
pressure. The e was purified by silica gel chromatography (eluting with 5% EtOAc in
hexanes, gradient to 50%) to afford (S)—3—chloro—6—(4—chlorobenzyl)—7—isopropyl—6,7—dihydro—
5H—pyrrolo[3,4—b]pyridin—5—one (19.6 mg, 29%) and 3—chloro—6—(4—chlorobenzyl)—7—hydroxy—7—
isopropyl—6,7—dihydro—5H—pyrrolo[3,4—b]pyridin—5—one (20.1 mg, 29%). LCMS: tR = 1.09 min in
in 1 min chromatography, MS (ESI) m/z 335.3 [M + H]+. 1H NMR (CDgOD, 400 MHz): 5 8.74
(d, J: 2.0 Hz, 1H), 8.17 (d, J: 2.4 Hz, 1H), 7.37-7.32 (m, 4H), 5.16 (d, J: 15.6 Hz, 1H), 4.47
(d, J: 15.2 Hz, 1H), 4.40 (d, J: 3.2 Hz, 1H), 2.56-2.48 (m, 1H), 1.27 (d, J: 7.2 Hz, 3H), 0.48
(d, J: 7.2 Hz, 3H).
General procedure F: (S)—6—(4—chlorobenzyl)—N—(4—(ethylsulfonyl)benzyl)—7—
isopropyl—6,7—dihydro—5H—pyrrolo[3,4—b]pyridine—3—carboxamide (9).
SOZEt
CFu'5 salt DBU6,H'ermann5 cat.
wI H
dioxane 160 °C uwave N 802Et
] Procedure same as that for tert—butyl 3—((4—(ethylsulfonyl)benzyl)carbamoyl)—7—
(tetrahydrofuran—3—yl)—5,7—dihydro—6H—pyrrolo[3,4—b]pyridine—6—carboxylate (Scheme 12), using
(S)—3—chloro—6—(4—chlorobenzyl)—7—isopropyl—6,7—dihydro—5H—pyrrolo[3,4—b]pyridin—5—one as a
starting material. LCMS: tR = 0.92 min in in 1 min chromatography, MS (ESI) m/z 526.4 [M +
H]+.1H NMR (CD3OD, 400 MHz): 5 9.22 (d, J=2.0 Hz, 1H), 8.57 (d, J: 2.0 Hz, 1H), 7.90 (dd,
J: 2.0 Hz, 6.8 Hz, 2H), 7.66 (d, J: 8.8 Hz, 2H), 7.36 (m, 4H), 5.19 (d, J: 15.6 Hz, 1H), 4.73
(s, 2H), 4.48 (m, 2H), 3.20 (q, J: 7.2 Hz, 2H), 2.60-2.52 (m, 1H), 1.29 (d, J: 7.2 Hz, 3H), 1.21
(t, J: 7.2 Hz, 3H), 0.49 (d, J: 6.8 Hz, 3H).
(S)—7—isopropyl—6—(4—(trifluoromethyl)benzyl)—6,7—dihydro—5H—pyrrolo[3,4—
b]pyridine—3—carboxylic acid was prepared following the tic route shown in Scheme 14.
Scheme 14.
O O
\ HC| FC4<3 >—\
OMe \ OMe Bra K2003
BocN I HN I
/ /
N dioxane/MeOH N
~ :- CH3CN
/\ /\
F3C F3C
O O
LIOH, N328203
\ OMe \ OH
N | N
/ HZO/MeOH I
N 5 N
/\ /\
To a solution of 6—(tert—butyl) 3—methyl (S)—7—isopropyl—5,7—dihydro—6H—pyrrolo[3,4—
b]pyridine—3,6—dicarboxylate (296 mg, 0.92 mmol) in MeOH (3 mL) was added HCl (4 mL, 4.0
M in dioxane). The mixture was stirred for 30 min at rt for 30 min. The reaction mixture was
concentrated to dryness to give methyl (S)—7—isopropyl—6,7—dihydro—5H—pyrrolo[3,4—b]pyridine—3—
ylate as the HCl salt. LC-MS tR = 0.56 min in 2 min chromatography, MS (ESI) m/z 221
[M + H]+.
t—butyl) 3—methyl (S)—7—isopropyl—5,7—dihydro—6H—pyrrolo[3,4—b]pyridine—3,6—
dicarboxylate. ure same as that for (S)—N—(4—(ethylsulfonyl)benzyl)—7—isopropyl—6—(4—
(trifluoromethyl)benzyl)—6,7—dihydro—5H—pyrrolo[3,4—b]pyridine—3—carboxamide, using methyl
(S)—7—isopropyl—6,7—dihydro—5H—pyrrolo[3,4—b]pyridine—3—carboxylate as a starting material. LC-
MS tR = 1.45 min in 2 min chromatography, MS (ESI) m/z 379 [M + H]+.
To a solution of 6—(tert—butyl) 3—methyl (S)—7—isopropyl—5,7—dihydro—6H—pyrrolo[3,4—
b]pyridine—3,6—dicarboxylate (216 mg, 674 umol) in MeOH (4 mL) was added 10% s
NaZSZOg (3 drops) and aqueous lithium hydroxide (1.2 mL, 2.0 M). The mixture was stirred for 3
h at rt. The reaction mixture was then concentrated, and the residue was ed by preparative
HPLC to give 230 mg of (S)—7—isopropyl—6—(4—(trifluoromethyl)benzyl)—6,7—dihydro—5H—
pyrrolo[3,4—b]pyridine—3—carboxylic acid as the TFA salt. LC-MS tR = 1.22 min in 2 min
chromatography, MS (ESI) m/z 365 [M + H]+. 1H NMR (CD3OD, 400 MHz): δ 9.14, (s, 1H),
8.35 (s 1H), 7.84-7.81 (m, 4H), 4.81-4.58 (m, 5H), 2.38 (m, 1H), 1.13 (d, J = 6.8 Hz, 3H),
0.91 (d, J = 6.8 Hz, 3H).
General procedure G: tert-butyl (S)isopropyl((4-
(methoxycarbonyl)benzyl)carbamoyl)-5,7-dihydro-6H-pyrrolo[3,4-b]pyridinecarboxylate.
O O
H2N HATU, i-Pr2NEt
OH N
BocN + OMe BocN H
N DMF N
Tert-butyl isopropyl((4-(methoxycarbonyl)benzyl)carbamoyl)-5,7-
dihydro-6H-pyrrolo[3,4-b]pyridinecarboxylate. Procedure same as that for tert-butyl (S)
((4-(ethylsulfonyl)benzyl)carbamoyl)isopropyl-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine
carboxylate, using methyl 4-(aminomethyl)benzoate as a starting material. LC-MS tR = 1.61
min in 2 min chromatography, MS (ESI) m/z 454.
((7-isopropyl(4-(trifluoromethyl)benzyl)-6,7-dihydro-5H-pyrrolo[3,4-
b]pyridinecarboxamido)methyl)benzoic acid was prepared ing the synthetic route
shown in Scheme 15.
Scheme 15.
O O
N HCl N
BocN H HN H
O O
N dioxane/MeOH N
O O
N H
O 65
N H
N 147
Methyl (S)((7-isopropyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine
carboxamido)methyl)benzoate. Procedure same as that for methyl (S)isopropyl-6,7-
dihydro-5H-pyrrolo[3,4-b]pyridinecarboxylate, using tert-butyl (S)isopropyl((4-
(methoxycarbonyl)benzyl)carbamoyl)—5,7—dihydro—6H—pyrrolo[3,4—b]pyridine—6—carboxylate as a
starting material. LC-MS tR = 0.73 min in 2 min chromatography, MS (ESI) m/z 354.
Methyl (S)—4—((7—isopropyl—6—(4—(trifluoromethyl)benzyl)—6,7—dihydro—5H—
pyrrolo[3,4—b]pyridine—3—carboxamido)methyl)benzoate (65). Procedure same as that for (S)—N—
(4—(ethylsulfonyl)benzyl)—7—isopropyl—6—(4—(trifluoromethyl)benzyl)—6,7—dihydro—5H—pyrrolo[3,4—
b]pyridine—3—carboxamide, using methyl (S)—4—((7—isopropyl—6,7—dihydro—5H—pyrrolo[3,4—
b]pyridine—3—carboxamido)methyl)benzoate as a starting al. LC-MS tR = 1.34 min in 2
min chromatography, MS (ESI) m/z 512 [M + H]+.
General procedure H: (S)—4—((7—isopropyl—6—(4—(trifluoromethyl)benzyl)—6,7—
dihydro—SH—pyrrolo[3,4—b]pyridine—3—carboxamido)methyl)benzoic acid (147). Procedure same
as that for (S)—7—isopropyl—6—(4—(trifluoromethyl)benzyl)—6,7—dihydro—5H—pyrrolo[3,4—b]pyridine—
3—carboxylic acid, using methyl (S)—4—((7—isopropyl—6—(4—(trifluoromethyl)benzyl)—6,7—dihydro—
SH—pyrrolo[3,4—b]pyridine—3—carboxamido)methyl)benzoate as a starting material. LC-MS tR =
1.20 min in 2 min chromatography, MS (ESI) m/z 498 [M + H]+.
The following compounds in Table 1 were prepared ing to the methods
described .
Table 1.
Cmpd 1
Structure LCMS H-NMR Starting Material
(CD30D) 6 9.36 (t,
J = 1.2 Hz, 1H),
9.05 (s, 1H), 8.23
(s, 1H), 7.89 (d, J =
8.4 Hz, 2H), 7.63
Q (d, J = 8.4 Hz, 2H),
o 7.59 (d, J = 8.4 Hz,
2H), 7.52 (d, J =
3 \ ”U
N l 8.4 Hz, 2H), 4.90
, H)+
,s'\/ (m, 1H), 4.74 (m,
/7\ 0' 4H), 4.57 (s, 2H),
3.20 (q, J = 7.6 Hz,
2H), 2.42-2.29 (m,
1H), 1.21 (t, J = 7.6
Hz, 3H), 1.13 (d,
6.8 Hz, 3H), 0.90
d, J = 6.8 Hz, 3H.
(00300) 6 9.36 (t,
J = 1.2 Hz, 1H),
9.03 (s, 1H), 8.21
(s, 1H), 7.88 (d, J =
8.8 Hz, 2H), 7.86
o (d, J = 8.4 Hz, 2H),
4 503.5 7.78 (d, J = 8.8 Hz,
N (M+H)+ 2H), 7.63 (d,J=
N’ ”D7 o., 8.4 Hz, 2H), 4.84
/\ 0" (d, J = 15.6 Hz,
1H), 4.71 (m, 3H),
4.59 (m, 3H), 3.20
(q, J = 7.6 Hz, 2H),
2.43-2.32
m, 1H ,
1.21 (t, J = 7.2 Hz,
3H), 1.12 (d, 6.8
Hz, 3H), 0.92 (d, J
= 6.8 Hz, 3H
(CD30D) 6 9.36 (t,
J = 1.2 Hz,1H),
9.04 (s, 1H), 8.23
(s, 1H), 7.89 (d, J =
8.8 Hz, 2H), 7.64
(d, J = 8.4 Hz, 4H),
7.27 (d, J = 8.4 Hz,
544.4 2H), 6.92 (t, J =
73.6 Hz, 1H), 4.90
(M+H)+
(m, 2H), 4.72 (m,
3H), 4.56 (m, 2H),
3.20 (q, J = 7.6 Hz,
2H), 2.40-2.29 (m,
1H),1.21 (t, J = 7.6
,1.12(d,
6.8 Hz, 3H), 0.90
d, J = 6.8 Hz, 3H.
(CD30D) 6 9.06 (s,
1H), 8.26 (s, 1H),
7.89 (d, J = 8.4 Hz,
2H), 7.66 (m, 4H),
7.26 (d, J = 8.4 Hz,
2H), 4.96 (d, J =
.6 Hz, 1H), 4.82
(m, 2H), 4.73 (d, J
496.5 = 6.0 Hz, 2H), 4.64
(M+H)+ (d, J = 13.2 Hz,
1H), 4.59 (d, J =
13.2 Hz, 1H), 3.20
(q, J = 7.6 Hz, 2H),
2.42-2.33 (m, 1H),
1.21 (t, J = 7.2 Hz,
3H), 1.12 (d, 6.8
Hz, 3H), 0.87 (d, J
= 6.8 Hz, 3H
(CD30D) 6 8.97 (d,
J = 2.0 Hz,1H),
8.68 (s, 2H), 8.25
(t, J = 0.8 Hz, 1H),
7.89 (dd, J = 1.6
Hz, 8.4 Hz, 2H),
7.65 (d, J = 8.4 Hz,
2H), 5.39 (dd, J =
2.0 Hz, 3.2 Hz, 1H),
534.4
.15 (d, J = 16.4
(M+H)+
Hz, 1H), 4.88 (d, J
=16.4 Hz, 1H),
4.72 (s, 2H), 3.20
(q, J = 7.2 Hz, 2H),
2.80-2.71 (m, 1H),
1.22 (d, J = 6.8 Hz,
3H), 1.21 (t, J = 7.2
Hz, 3H), 0.64 (d, J
= 6.8 Hz, 3H
W0 2015/116904
(CD30D) 6 9.02 (d,
J = 7.6 Hz,1H),
8.99 (s, 1H), 8.26
(s, 1H), 7.90 (dd, J
= 2.0 Hz, 6.8 Hz,
2H), 7.65 (d, J =
8.8 Hz, 2H), 5.44
(d, J = 9.2 Hz,1H),
F F 5.22 (dd, J = 10.0
F o Hz, 16.8 Hz, 1H),
o 4.93 (d, J = 16.4
mom”N 606.6
Hz, 1H), 4.72 (s,
/‘0 ‘N .. N/ (M+H)+
s 2H), 4.36 (q, J =
’\ 7.2 Hz, 2H), 3.20
(q, J = 7.6 Hz, 2H),
2.81-2.70 (m, 1H),
1.37 (t, J = 7.2 Hz,
3H), 1.21 (t, J = 7.6
Hz, 3H), 0.88 (dd, J
= 7.2 Hz, 13.2 Hz,
3H), 0.69 (dd, J =
7.2 Hz, 17.6 Hz,
(CD30D) 6 9.23 (d,
J :24 Hz, 1H),
8.53 (d, J = 2.4 Hz,
1H), 7.90 (dd, J =
2.0 Hz, 6.8 Hz, 2H),
7.65 (d, J = 8.4 Hz,
CI 2H), 7.49 (d, J =
8.4 Hz, 2H), 7.32
0 O (dd, J = 2.0 Hz, 6.8
11 \ 542.5 Hz, 2H), 4.80 (d, J
N | (M+H)+ = 14.0 Hz, 1H),
4.73 (m, 2H), 4.61
(d, J = 15.2 Hz,
1H), 3.20 (q, J =
7.2 Hz, 2H), 2.48-
2.41 (m,1H),1.27
(d, 6.8 Hz, 3H),
1.20 (t, J = 7.2 Hz,
3H), 0.39 (d, J =
7.2 Hz, 3H .
(CD30D) 6 9.02 (s,
1H), 8.75 (s, 1H),
8.40 (s, 1H), 7.90
(dd, J = 1.6 Hz, 6.8
Hz, 2H), 7.66 (d, J
F F = 8.4 Hz, 2H), 5.51
F o (t, J = 2.8 Hz, 1H),
N (d, J =16.4 5.21
12 woo” 564.5
Hz, 1H), 4.93 (m, Reduction of 10
HO —N N’ (M+H)+
1H), 4.73 (s, 2H),
’\ 4.67 (s, 2H), 3.20
(q, J = 7.2 Hz, 2H),
2.78-2.66 (m, 1H),
1.21 (t, J = 7.2 Hz,
3H), 1.17 (d, J =
.6 Hz, 3H), 0.78
d, J = 5.6 Hz, 3H.
(CD30D) 6 9.09 (d,
F F
o J: 2.0 Hz, 1H),
F Oxidation of
8.93
N (s, 1H), 8.59 12 followed by
14 / \FNCEYL 578.5 (s, 1H), 7.90 (dd, J
HO —N N’ (M+H)+ :16 Hz, 6.8 Hz, methyl
2H), 7.67 (d, J = rd
/\ 8.4 Hz, 2H), 5.64 addition
dd, J = 3.2 Hz, 7.0
2015/013699
Hz, 1H), 5.28 (d, J
= 16.4 Hz, 1H),
.13 (q, J = 6.4 Hz,
1H), 4.95 (d, J =
.6 Hz, 1H), 4.74
(s, 2H), 3.20 (q, J =
7.6 Hz, 2H), 2.76-
2.66 (m, 1H),1.47
(d, J = 6.4 Hz, 3H),
1.21 (t, J = 7.2 Hz,
3H), 1.13 (d, 6.8
Hz, 3H), 0.81 (dd, J
= 6.8 Hz, 3H
(CD30D) 6 9.39 (brs,
1H), 9.09 (s, 1H),
8.28 (s, 1H), 7.96
CI (d, J: 8.4 Hz, 2H),
0 7.70-7.60 (m, 4H),
7.56 (d, J: 8.0 Hz,
17 \ 498.0
N I, 00 2H), 5.05-4.95 (m,
. (M+H)+
N 2H), 4.75-4.60 (m,
s 0&0
/\ 5H), 3.13 (s, 3H),
2.39-2.35 (m, 1H),
1.16 (d, J: 6.8 Hz,
3H), 0.90 (d, J=
6.8 Hz, 3H .
(CD30D) 6 9.08 (d, J
= 1.6 Hz, 1H), 8.27
(s, 1H), 7.96 (dd, J
CI =1.6,6.8 Hz, 2H),
7.67-7.63 (m, 4H),
7.55 (d, J: 8.4 Hz,
18 498.0
2H), 5.10-4.95 (m,
(M+H)+
2H), 4.75-4.60 (m,
5H), 3.13 (s, 3H),
2.38-2.34 (m, 1H),
1.14 (d, J: 6.8 Hz,
3H), 0.90 (d, J=
7.2 Hz, 3H .
(CD30D) 6 9.07 (d, J
:16 Hz, 1H), 8.27
(s, 1H), 7.96 (dd, J
= 2.0, 6.8 Hz, 2H),
7.88 (dd, J: 8.8,
22.4 Hz, 4H), 7.65
19 489.1
(d, J: 8.4 Hz, 2H),
(M+H)+
4.85-4.65 (m, 7H),
N I:”\ 3.13 (s, 3H), 2.42-
O 2.37(m,1H),1.16
(d, J: 6.8 Hz, 3H),
0.91 (d, J: 6.8 Hz,
3H .
(CD30D) 6 9.08 (s,
1H), 8.30 (s, 1H),
F F 7.95 (d, J: 8.4 Hz,
2H), 7.91 (s, 4H),
7.66 (d, J: 8.4 Hz,
2H), 5.07 (d, J=
489.0
\ 15.6 Hz, 1H), 4.90-
, N
—N | (M+H)+
/ H/\©\ p 4.70 (m, 3H), 4.72
g N .,3\/ (s, 3H), 3.13 (s,
/\ 0 3H), 2.42-2.37 (m,
1H),1.16(d,J=
6.8 Hz, 3H), 0.90
(d, J: 6.8 Hz, 3H).
(CD30D) 6 9.08 (s,
1H), 8.30 (s, 1H),
7.95 (d, J= 8.4 Hz,
2H), 7.91 (s, 4H),
7.66 (d, J= 8.4 Hz,
2H), 5.07 (d, J=
21 489.0
.6 Hz, 1H), 4.90-
(M+H)+
4.70 (m, 3H), 4.72
(s, 3H), 3.13 (s,
3H), 2.42-2.37 (m,
1H), 1.16 (d, J:
6.8 Hz, 3H), 0.90
d, J= 6.8 Hz, 3H.
(CD3OD) 5 9.09 (d, J
= 2.0 Hz, 1H), 8.30
(s, 1H), 7.95 (d, J:
8.0 Hz, 2H), 8.88
(q, J= 8.4 Hz, 4H),
7.66 (d, J= 8.4 Hz,
22 532.1
2H), 5.04 (d, J=
(M+H)+
.2 Hz, 2H), 4.85-
N as: 4.70 (m, 5H), 3.13
o 0
(s, 3H), 2.41-2.37
(m, 1H), 1.17 (d, J
= 6.8 Hz, 3H), 0.90
d, J= 6.8 Hz, 3H .
(CD30D) 5 9.08 (s,
1H), 8.71 (cl, J: 2.4
Hz, 1H), 8.32 (s,
1H), 8.00 (dd, J:
2.4, 8.4 Hz, 1H),
7.95 (d, J= 8.4 Hz,
O 2H), 7.66 (d, J:
\ / 8.4 Hz, 2H), 7.62
23 \ 499.1
N I (d, J= 8.8 ,
/ H
/ (M+H)+
.15
N d’S‘b (d, J= 16.0
/\ Hz, 2H), 4.85-4.75
(m, 3H), 4.73 (s,
2H), 3.13 (s, 3H),
2.62-2.54 (m, 1H),
1.22 (d, J= 7.2 Hz,
3H), 0.96 (d, J=
6.8 Hz, 3H .
(CD3OD) 5 9.08 (d, J
= 1.6 Hz, 1H), 8.31
(s, 1H), 7.95 (d, J:
8.4 Hz, 2H), 7.75
F (dd, J= 4.8, 8.4 Hz,
2H), 7.66 (d, J=
o 8.4 Hz, 2H), 7.28 (t,
24 \ 482.1
N J= 8.4 Hz, 2H),
N I, 90, (M+H)+ 5.10-5.03 (m, 2H),
i 093.0 4.90-4.70 (m, 4H),
/\ 4.59 (d, J= 12.8
Hz, 1H), 3.13 (s,
3H), 2.37-2.30 (m,
1H), 1.11 (d, J:
6.4 Hz, 3H), 0.87
d, J= 6.8 Hz, 3H .
CI (CD30D) 6 8.96 (s,
1H), 8.22 (d, J :
11.6 Hz, 1H), 7.89
o (d, J = 8.8 Hz, 2H),
556.6
o \ N 7.64 (d, J = 8.8 Hz,
I HUS) H (M+H)+
, 2H), 7.42 (d, J :
O N
s ..S\/ 8.8 Hz, 2H), 7.38
/\ 0 (d, J = 8.8 Hz, 2H),
2015/013699
(m, 1H), 4.85 (m,
2H), 4.71 (s, 2H),
3.20 (q, J = 7.2 Hz,
2H), 2.58-2.39 (m,
1H),1.21 (t, J = 7.2
Hz, 3H), 1.03 (dd,
6.8 Hz, 16.8 Hz,
3H), 0.75 (dd, J =
6.8 Hz, 18.8 Hz,
(CD30D) 6 9.30 (s,
2H), 9.09 (s, 1H),
8.30 (s, 2H), 7.89
F F (dd, J = 2.0 Hz, 8.4
F”H Hz, 2H), 7.65 (d, J
= 8.4 Hz, 2H), 4.95
26 NL<N (m, 3H), 4.82 (m,
548.5
2H), 4.71 (s, 2H),
l (M+H)+
3.20 (q, J = 7.2 Hz,
2H), 2.62-2.53 (m,
«1 1H), 1.25 (d, J =
6.8 Hz, 3H), 1.21 (t,
J = 7.6 Hz, 3H),
0.98 (d, J = 6.8 Hz,
3H .
(CD30D) 6 9.08 (d,
J = 1.6 Hz,1H),
9.03 (s, 1H), 8.32
(d,J=1.6 Hz,1H),
8.26 (dd, J = 2.0
Hz, 8.0 Hz, 1H),
7.89 (d, J = 8.4 Hz,
2H), 7.77 (d, J =
8.0 Hz, 1H), 7.65
27 N/ 547.5 (d, J = 8.4 Hz, 2H),
(M+H)+ 5.18 (d, J = 15.6
Hz, 1H), 4.97 (s,
2H), 4.92 (m, 2H),
4.72 (s, 2H), 3.20
(q, J = 7.6 Hz, 2H),
2.68-2.59 (m, 1H),
1.24 (d, J = 7.2 Hz,
3H), 1.21 (t, J = 7.6
Hz, 3H), 0.96 (d, J
= 6.8 Hz, 3H
(CD30D) 6 9.11 (s,
1H), 8.32 (s, 1H),
7.90 (d, J = 8.8 Hz,
2H), 7.65 (d, J =
CI 8.4 Hz, 2H), 7.59
(m, 4H), 5.25-4.83
(m, 2H), 4.73 (s,
28 526.3 2H), 4.62 (m, 1H),
(M+H)+ 4.15 (m, 1H), 3.20
(q, J = 7.2 Hz, 2H),
2.21-2.10 (m, 1H),
1.47 (d, J = 6.4 Hz,
3H), 1.21 (t, J = 7.2
Hz, 3H), 0.95 (m,
3H), 0.79 (d, J =
6.8 Hz, 3H .
(CD30D) 6 9.07 (d,
J = 2.0 ,
8.22 (s, 1H), 7.89
(dd, J = 2.0 Hz, 6.8
Hz, 2H), 7.71 (d, J
= 6.8 Hz, 2H), 7.64
CI (d, J = 8.0 Hz, 2H),
7.57 (m, 2H), 5.21
0 (q, J = 6.8 Hz,1H),
29 \ N 526.3 4.99 (d, J = 3.2 Hz,
N |
, HUD (M+H)+ 1H), 4.82 (d, J =
s‘ N ,S\/ 3.6 Hz, 1H), 4.72
/\ O (m, 3H), 3.20 (q, J
= 7.2 Hz, 2H), 2.16-
2.09(m,1H),1.75
(d, J = 6.8 Hz, 3H),
1.29 (d, J = 6.8 Hz,
3H), 1.21 (t, J = 7.2
Hz, 3H), 0.86 (d, J
= 6.8 Hz, 3H
(CD30D) 6 9.11 (s,
1H), 8.32 (s, 1H),
7.87 (m, 6H), 7.66
F F (d, J = 8.0 Hz, 2H),
.35 (m, 1H), 4.83
(m, 1H), 4.73 (s,
E 2H), 4.63 (m, 1H),
. 560.6
\ N 4.28 (m, 1H), 3.21
N | (M+H)+
/ H/\©\,Q (q, J = 7.2 Hz, 2H),
: N ,,S\/ 2.23-2.11 (m, 1H),
/\ o 1.97 (d, J = 6.8 Hz,
3H), 1.21 (t, J = 7.2
Hz, 3H), 0.97 (m,
3H), 0.80 (d, J =
6.8 Hz, 3H .
(CD30D) 6 9.08 (d,
J = 1.2 Hz,1H),
8.24 (s, 1H), 7.95
(d, J = 8.4 Hz, 2H),
F F 7.89 (m, 4H), 7.64
(d, J = 8.8 Hz, 2H),
.24 (m, 1H), 5.01
o (d, J = 2.8 Hz,1H),
31 560.6
\ N 4.88 (m, 2H), 4.71
N ' (M+H)+
, an (s, 2H), 3.20 (q, J =
i N 55¢ 7.6 Hz, 2H), 2.18-
/\ 0 2.10(m,1H),1.75
(d, J = 6.8 Hz, 3H),
1.28 (d, J = 6.8 Hz,
3H), 1.21 (t, J = 7.6
Hz, 3H), 0.87 (d, J
= 6.8 Hz, 3H
(CD30D) 6 9.23 (d,
J = 2.0 ,
8.59 (d, J: 2.4 Hz,
1H), 7.90 (d, J =
8.8 Hz, 2H), 7.65
FF (m, 4H), 7.55 (d, J
= 8.8 Hz, 2H), 5.26
O o (d, J = 15.6 Hz,
32 560.5 1H), 4.74 (s, 2H),
\ N
N I/ H (M+H)+ 4.63 (d, J = 16.4
N Hz, 1H), 4.53 (d, J
/\ = 3.2 Hz, 1H), 3.20
(q, J = 7.2 Hz, 2H),
2.60-2.52 (m, 1H),
1.30 (d, J = 6.8 Hz,
3H), 1.21 (t, J = 7.6
Hz, 3H), 0.50 (d, J
= 6.8 Hz, 3H
(CD30D) 6 9.12 (s,
1H), 9.10 (d, J: 1.2
Hz, 1H), 8.53 (dd, J
= 2.0 Hz, 8.4 Hz,
1H), 8.34 (s, 1H),
FF 7.93 (d, J = 8.0 Hz,
F 2H), 7.91 (d, J =
6.4 Hz, 1H), 7.84
O (d, J = 8.0 Hz, 2H),
33 547.5
\ N 5.07 (d, J =15.6
N l/ H (M+H)+
Hz, 1H), 4.84 (m,
: N 3H), 4.73 (d, J =
/\ 12.8 Hz, 1H), 3.35
(q, J = 7.2 Hz, 2H),
2.42-2.29 (m, 1H),
1.28 (t, J = 7.2 Hz,
3H), 1.15 (d, J =
6.8 Hz, 3H), 0.89
d, J = 6.8 Hz, 3H.
(CD30D) 6 9.13
(dd, J: 1.6 Hz, 3.6
Hz, 2H), 8.59 (dd, J
= 2.0 Hz, 8.4 Hz,
1H), 8.35 (s, 1H),
7.98 (d, J = 8.0 Hz,
1H), 7.70 (d, J =
CI 8.8 Hz, 2H), 7.54
0 (d, J = 8.8 Hz, 2H),
.07 (d, J = 15.2
34 \ 513.5
N l/ Hz, 1H), 4.87 (m,
H (M+H)+
N 2H), 4.73 (d, J =
13.2 Hz, 1H), 4.60
(d, J =12.8 Hz,
1H), 3.37 (q, J =
7.6 Hz, 2H), 2.41-
2.25 (m, 1H),1.29
(t, J = 7.6 Hz, 3H),
1.12 (d, J = 6.4 Hz,
3H), 0.88 (d, J =
6.8 Hz, 3H .
(CD30D) 6 9.11 (d,
J: 2.0 Hz, 2H),
8.56, (dd, J = 2.0
Hz, 8.4 Hz, 1H),
N\\ 8.33 (s, 1H), 8.01-
7.79 (m, 5H), 5.07
(d, J = 15.2 Hz,
504.5 1H), 4.91-4.80 (m,
NI, (M+H)+ 3H), 4.72 (d, J =
14.4 Hz, 1H), 3.36
: N
/\ (q, J = 7.2 Hz, 2H),
2.64-2.53 (m, 1H),
1.28 (t, J = 7.2 Hz,
3H), 1.15 (d, J =
6.8 Hz, 3H), 0.89
d, J = 7.2 Hz, 3H.
(CD30D) 5 9.09 (s,
1H), 9.04 (s, 1H), 8.33
(s, 1H), 8.28 (d, J:
8.0 Hz, 2H), 7.95
FF (d, J: 8.4 Hz, 2H),
7.80 (d, J: 8.0 Hz,
2H), 7.66 (d, J:
36 N/ 533.1 8.4 Hz, 2H), 5.20
NI/ (M+H)+ (d, J: 15.6 Hz,
1H), 5.25-4.93 (m,
s N
/\ 4H), 4.73 (s, 2H),
3.13 (s, 3H), 2.68-
2.63 (m, 1H), 1.25
(d, J: 6.8 Hz, 3H),
0.98 (d, J: 6.8 Hz,
3H .
(CD3OD) 5 9.43 (t, J
= 6.0 Hz, 1H), 9.07
(d, J: 18.8 Hz,
FF 2H), 8.33-8.25 (m,
F 2H), 7.96 (d, J:
8.4 Hz, 2H), 7.76
\ (d, J: 8.0,1H),
37 N/ 533.0
\ 7.66 (d, J: 8.4 Hz,
NI/ (M+H)+
2H), 5.20-4.92 (m,
N 5H), 4.73 (d, J:
6.0, 2H), 3.13 (s,
3H), .61 (m,
1H),1.25(d,J=
7.2 Hz, 3H), 0.98
d, J: 6.8 Hz, 3H.
(CD30D) 5 9.08 (s,
1H), 8.31 (s, 1H), 8.26
(d, J= 8.0 Hz, 2H),
7.90 (d, J= 8.0 Hz,
2H), 7.86 (d, J=
\N.N‘.N 8.0 Hz, 2H), 7.65
N‘ (d, J= 8.0 Hz, 2H),
.10 (d, J= 15.2
O Hz, 1H), 4.99-4.96
38 560.1
\ (m, 1H), 4.85-4.77
N (M+H)+
N I H (m, 2H), 4.73-4.67
s: N (m, 3H), 4.46 (s,
/\ 3H), 3.22 (q, J:
7.6 Hz, 2H), 2.38-
2.32 (m, 1H), 1.22
(t, J= 7.6 Hz, 3H),
1.14 (d, J= 6.4 Hz,
3H), 0.90 (d, J=
6.8 Hz, 3H .
(c0300) 5 9.10 (d, J
= 2.0 Hz, 1H), 9.05
(s, 1H), 8.46 (dd, J
= 2.0, 8.0 Hz, 1H),
F F 8.31 (s, 1H), 7.99
(d, J= 8.0 Hz,1H),
O 7.91 (d, J= 8.4 Hz,
\ /
39 547.1 2H), 7.66 (d, J:
\ N
N I (M+H)+ 8.0 Hz, 2H), 5.06-
/ 4.98 (m, 2H), 4.86-
:5 N
4.81
/\ (m, 3H), 4.73
(s, 2H), 3.22 (q, J:
7.6 Hz, 2H), 2.52-
2.48 (m, 1H),1.23-
1.19 (m, 6H), 0.94
(d, J= 6.8 Hz, 3H).
(CD30D) 5 9.08 (s,
1H), 8.99 (s, 1H), 8.36
(d, J= 7.6 Hz, 1H),
F F 8.26 (s, 1H), 7.98
F (d, J= 8.0 ,
—N 7.91 (d, J= 8.0 Hz,
40 \ / 547.1 2H), 7.66 (d, J=
\ N 8.4 Hz, 2H), 5.01-
N I (M+H)+
I H 4.96 (m, 1H), 4.82-
N 4.68 (m, 6H), 3.22
(q, J: 7.2 Hz, 2H),
2.52-2.48 (m, 1H),
1.23-1.19 (m, 6H),
0.47 (d, J= 6.8 Hz,
(CD30D) 6 9.09 (d,
J= 1.6 Hz,1H),
8.30 (d, J= 1.2 Hz,,
1H), 7.91 (d, J:
8.4 Hz, 2H), 7.67
FF (d, J= 8.4 Hz, 2H),
F 5.14 (d, J= 14.4
O Hz, 1H), 4.74 (s,
41 552.1 3H), 3.52 (d, J:
\ N
N I, 90 (M+H)+ 5.6 Hz, 2H), 3.22
s N 55 (q, J: 7.6 Hz, 2H),
O 2.54-2.52 (m, 1H),
2.22-2.19 (m, 2H),
1.83-1.60 (m, 8H),
1.33 (d, J= 6.8 Hz,
4H), 1.22 (d, J:
7.2 Hz, 3H), 1.11
d, J= 6.4 Hz, 3H.
) 6 9.08 (s,
1H), 8.29, (s, 1H),
7.90 (d, J = 7.6 Hz,
2H), 7.65 (d, J =
7.6 Hz, 2H), 5.16
(d, J =14.4 Hz,
FF 1H), 4.73 (d, J :
14.4 Hz, 1H), 4.72
0 (s, 2H), 3.41 (m,
42 \ N 1H), 3.20 (q, J : 520.6
N | (M+H)+ 7.2 Hz, 2H), 2.58-
N H/\©\O
: "3 2.47 (m, 1H), 2.20-
/\ o 2.06 (m, 3H), 2.05-
1.95 (m, 4H), 1.92-
1.8 (m,2H),1.58-
1.32
, 2H),
( ) (s,
1H), 9.00, (d, J :
2.0 Hz, 1H), 8.32
(s, 1H), 8.30 (d, J =
2.0 Hz, 1H), 7.72
(d, J = 8.4 Hz,1H),
.17 (d, J = 15.6
FF Hz, 1H), 4.83 (s,
0 2H), 4.74 (d, J =
14.8 Hz, 1H), 3.46
43 \ \ 521.5
N l, ' (m, 1H), 3.30 (q, J
H O
N/ (M+H)+
. = 7.6 Hz, 2H), 2.60-
s: N
2.49 (m, 1H), 2.20-
/\ o
2.06 (m, 3H), 2.05-
1.95 (m, 4H), 1.92-
1.82 (m, 2H), 1.58-
1.41 (m,2H),1.33
(d, J = 6.8 Hz, 3H),
1.27 (t, J = 7.6 Hz,
3H), 1.10 (d, J =
6.8 Hz, 3H .
) 5 9.08 (s,
1H), 8.28 (s, 1H), 7.90
(d, J= 8.4 Hz, 2H),
7.65 (d, J= 8.4 Hz,
2H), 5.16-5.05 (m,
1H), 4.72 (s, 3H),
3.68 (s, 3H), 3.44-
44 542.1 3.29 (m, 2H), 3.21
(M+H)+ (q, J: 7.6 Hz, 2H),
2.52-2.33 (m, 2H),
2.13-1.83 (m, 6H),
1.57-1.44 (m, 2H),
1.31 (d, J= 6.4 Hz,
4H), 1.21 (t, J= 7.6
Hz, 4H), 1.09 (d, J
= 6.4 Hz, 3H
(CD30D) 6 9.42 (t,
J= 6.0 Hz,1H),
9.10 (s, 1H), 8.30
(s, 1H), 7.91 (d, J:
8.4 Hz, 2H), 7.66
(d, J= 8.4 Hz, 2H),
.13-5.08 (m, 2H),
4.77-4.62 (m, 4H),
45 \ 514.2
N 3.41-3.37 (m,
N I ),
/ H (M+H)+ 3.26-3.17 (m,
N ),
2.56-2.48 (m, )
2.21-2.13 (m, ),
2.03-1.92 (m, 3H),
1.32 (d, J= 7.2 Hz,
3H), 1.28-1.19 (m,
6H), 1.10 (d, J:
6.8 Hz, 3H .
(c0300) 5 9.24 (d, J
= 2.0 Hz, 1H), 8.99
(d, J= 1.6 ,
8.55 (d, J= 2.0 Hz,
1H), 8.27 (dd, J:
2.4, 8.4 Hz, 1H),
F F 7.69 (d, J= 8.4 Hz,
F 1H), 4.83 (s, 2H),
4.71 (d, J= 3.2 Hz,
O O 1H), 3.88 (dd, J:
47 567.53
"a \ N 9.2, 13.8 Hz, 1H),
_N I H (M+H)+
/ 3.30 (q, J: 7.6 Hz,
s“ 2H), 3.16 (dd, J:
’\ 5.2, 13.8 Hz, 1H),
2.62-2.58 (m, 1H),
2.33-1.71 (m, 6H),
1.38 (d, J= 6.8 Hz,
3H), 1.35-1.04 (m,
4H), 1.25 (t, J= 7.6
Hz, 3H), 0.53 (d, J
= 6.8 Hz, 3H
(CD30D) 5 9.01 (s,
1H), 8.21 (s, 1H), 7.86
N (dd, J= 8.4, 10.4
\\Q Hz, 4H), 7.76 (d, J
= 8.0 Hz, 2H), 7.62
(d, J= 8.4 Hz, 2H),
48 \ N 531.1 4.75-4.50 (m, 6H),
N | H (M+H)+ 4.00-3.68 (m, 5H),
3.18 (q, J: 7.6 Hz,
2H), 3.00-2.90 (m,
1H), 2.10-2.04 (m,
1H), 1.98-1.85 (m,
1H), 1.19 (t, J= 7.6
Hz, 3H .
(CD30D) 5 9.08 (s,
1H), 8.30 (s, 1H),
7.89 (d, J: 8.4 Hz,
2H), 7.65 (d, J=
8.4 Hz, 2H), 4.72
(s, 2H), 4.12-4.05
(m, 2H), 3.65-3.60
(m, 2H), 3.50-3.40
49 QN| 567.1 (m, 2H), 3.30-3.25
(M+H)+ (m, 5H), 3.20 (q, J
= 7.2 Hz, 2H), 2.60-
2.50 (m, 1H), 2.34-
2.20(m,3H),1.82-
1.73 , 1.32
(d, J: 7.2 Hz, 3H),
1.21 (t, J: 7.6 Hz,
3H),1.15-1.00(m,
3H .
(CD30D) 5 8.98 (s,
1H), 8.17 (s, 1H), 7.85
N (dd, J: 8.4, 14.4
b Hz, 4H), 7.76 (d, J
= 8.0 Hz, 2H), 7.62
(d, J: 8.4 Hz, 2H),
50 \ 531.1 4.80-4.40 (m, 6H),
N I (M+H)+ 4.00-3.65 (m, 5H),
3.18 (q, J: 7.6 Hz,
2H), 3.00-2.88 (m,
1H), 2.25-2.13 (m,
1H), 2.13-2.00 (m,
1H), 1.19 (t, J: 7.6
Hz, 3H .
(CD30D) 6 9.00 (s,
1H), 8.19 (s, 1H),
Nb; 7.84 (t, J: 8.0 Hz,
4H), 7.78 (d, J=
8.0 Hz, 2H), 7.62
(d, J: 8.0 Hz, 2H),
51 \ 531.1 4.80-4.45 (m, 6H),
N I (M+H)+ 4.00-3.65 (m, 5H),
3.18 (q, J: 7.6 Hz,
2H), 3.00-2.88 (m,
1H), 2.27-2.13 (m,
1H), 2.10-1.98 (m,
1H),1.19(t,J= 7.6
Hz, 3H .
(CD30D) 5 8.99 (s,
1H), 8.19 (s, 1H), 7.85
(dd, J: 8.0, 17.6
Hz, 4H), .70
(m, 2H), 7.62 (d, J
= 8.4 Hz, 2H), 4.70-
52 531.1 4.35 (m, 6H), 3.95-
(M+H)+ 3.65 (m, 5H), 3.18
(q, J: 7.6 Hz, 2H),
3.00-2.88 (m, 1H),
2.12-2.06 (m, 1H),
2.00-1.87 (m, 1H),
1.19 (t, J: 7.6 Hz,
(CD30D) 5 9.12 (s,
1H), 9.01 (cl, J: 2.0
Hz, 1H), 8.36-8.32
(m, 2H), 7.75 (d, J
= 8.0 Hz, 1H), 5.16
FF (d, J= 15.6 Hz,
1H), 4.89-4.87 (m,
2H), 4.73 (d, J:
.2 Hz, 1H), 3.42-
53 553.1
a, \ N \ 3.34 (m, 3H), 3.31-
‘N I (M+H)+
, Hmr 3.28 (m, 2H), 2.58-
N ”3:0 2.51 (m, 1H), 2.20-
0 1.90 (m, 6H) 1.50-
1.39 , 1.33
(d, J= 7.2 Hz, 3H),
1.26 (t, J= 7.2 Hz,
3H),1.24-1.20 (m,
2H), 1.10 (d, J:
6.8 Hz, 3H .
(CD30D) 5 9.11 (s,
1H), 9.01 (s, 1H), 8.35
(dd, J = 2.0, 8.4 Hz,
1H), 8.31 (s,1H),
7.75 (d, J= 8.4 Hz,
1H), 7.62 (d, J:
1.2 Hz, 1H), 7.50
F (dd, J= 1.6, 8.5 Hz,
1H), 7.37 (d, J:
8.0 Hz, 1H), 5.01
54 559.50
\ N \ (d,J=15.6 Hz,
(M+H)+
1H), 4.84 (s, 2H),
4.68 (dd, J= 12.8,
/\ 00
24.0 Hz, 2H), 3.34
(s, 2H), 3.30 (q, J:
7.6 Hz, 2H), 2.38
(broad s, 1H), 1.25
(t, J= 7.6 Hz, 3H),
1.16 (d, J= 6.0 Hz,
3H), 0.90 (d, J:
6.8 Hz, 3H .
(CD30D) 6 8.60 (s,
1H), 8.33 (s, 1H),
7.89 (d, J = 8.4 Hz,
2H), 7.64 (d, J :
8.4 Hz, 2H), 4.95
F F (m, 1H), 4.62 (m,
4H), 3.89 (s, 2H),
3.21 (q, J = 7.2 Hz,
55 552.7 2H), 2.48-2.38 (m,
\ N7(\©\
_N | (M+H)+ 1H), 2.24-2.12 (m,
/ o [p
1H), 2.11-1.86 (m,
g N ,,3\/
/\ 0 5H), 1.48-1.38 (m,
2H), 1.37-1.24 (m,
2H), 1.29 (d, J
6.8 Hz, 3H), 1.22 (t,
J = 7.6 Hz, 3H),
1.06 (d, J = 6.8 Hz,
3H .
(CD30D) 6 8.69 (s,
CI 1H), 8.31 (s,1H),
7.89 (d, J = 8.4 Hz,
H 2H), 7.64 (d, J :
56 \ NYU 512.8 8.8 Hz, 4H), 7.52
N |
, 0 P (M+H)+ (d, J = 8.8 Hz, 2H),
g N 55¢ 4.95 (d, J =15.6
/\ 0 Hz, 1H), 4.72 (m,
2H), 4.66 (d, J :
14.4 Hz, 1H ,4.54
(d, J = 12.8 Hz,
1H), 3.90 (s, 2H),
3.21 (q, J = 7.2 Hz,
2H), 2.38-2.23 (m,
1H), 1.22 (t, J = 7.2
Hz, 3H), 1.08 (d, J
= 6.0 Hz, 3H), 0.86
d, J = 6.8 Hz, 3H .
(CD30D) 6 8.66 (s,
1H), 8.30 (s, 1H),
7.90-7.82 (m, 6H),
7.65-7.56 (m, 2H),
4.94 (d, J = 15.6
Hz, 1H), 4.71 (m,
57 N 503.7 2H), 4.64 (m, 2H),
I (M+H)+ 3.90 (s, 2H), 3.21
N/ O I". (q, J = 7.2 Hz, 2H),
2.39-2.27 (m, 1H),
1.22 (t, J = 7.2 Hz,
3H), 1.04 (d, J =
6.8 Hz, 3H), 0.87
d, J = 6.8 Hz, 3H.
(CD30D) 6 8.67 (s,
1H), 8.31 (s,1H),
7.90-7.81 (m, 6H),
7.67-7.56 (m, 2H),
4.95 (d, J =15.6
Hz, 1H), 4.73 (m,
58 N 546.5 3H), 4.65 (m, 1H),
| (M+H)+ 3.90 (s, 2H), 3.21
N/ o (q, J = 7.2 Hz, 2H),
2.38-2.25 (m, 1H),
1.22 (t, J = 7.2 Hz,
3H), 1.04 (d, J =
7.2 Hz, 3H), 0.87
d, J = 6.8 Hz, 3H .
) 6 9.11
(d, J = 1.6 Hz,1H),
9.03 (d, J = 2.0 Hz,
1H), 8.36-8.25 (m,
2H), 7.89 (dd, J =
8.0, 24.0 Hz, 4H),
7.78 (d, J = 8.4 Hz,
1H), 5.38 (q, J =
59 561.1 7.2 Hz, 1H), 5.08-
(M+H)+ 5.03 (m, 1H), 4.85-
4.65 (m, 4H), 3.32-
3.29 (m, 2H), 2.40-
2.35(m,1H),1.68
(d, J = 7.2 Hz, 3H),
1.28 (t, J = 7.2 Hz,
3H), 1.16 (d, J =
6.8 Hz, 3H), 0.90
d, J = 6.8 Hz, 3H .
(CD30D) 6 9.12
(d, J = 1.6 Hz,1H),
9.02 (d, J :16 Hz,
1H), .25 (m,
2H), 7.88 (q, J =
8.0 Hz, 4H), 7.75
(d, J = 8.0 Hz,1H),
O 5.38 (q, J = 7.2 Hz,
60 561.1 1H), 5.05-4.95 (m,
\ N \
N I I
H (M+H)+ 1H), 4.85-4.71 (m,
, N /
N .,Sf\ 4H), 3.31-3.28 (m,
/\ o o 2H), 2.45-2.35 (m,
1H), 1.67 (d, J =
6.8 Hz, 3H), 1.28 (t,
J = 7.2 Hz, 3H),
1.17 (d, J = 6.8 Hz,
3H), 0.90 (d, J =
6.8 Hz, 3H .
F F
61 510.5
N I (M+H)+
/ H/\OS:ON
: N b
F F p
F 8:0
62 524.5
\ N
N I (M+H)+
/ H
63 539.5
(M+H)+
64 479.5
(M+H)+
JLJ<o
547.7
N | H (M+H)+
2015/013699
67 547.5
\ N
N I. MO (M+H)+
: N .3.“
/\ 00
68 \
533.6
l, H/Y‘NO N
N (M+H)+
: N \g
/\ K
69 495.6
N {Iv-NN I, (M+H)+
: N—
F FF
0TI 1»
7o 552.6
\ N
N I/ IN Z
H (M+H)+
OH OI
g N
F OH
71 532.6
\ N
N I, H (M+H)+ H2N
s CI
72 526.6
N I/ HN’XC‘O (M+H)+
73 458.5
N I, M \,N (M+H)+
- N
WO 16904
74 O 547.7
N |\ H NJ< (M+H)+
/ o
75 518.6
\ N
N I/ l (M+H)+
: ’n’
/\ O
76 458.53
\ N //
N I, H/\C—\NN (M+H)+
o (\o
77 477.55
\ NNNQ
N I/ H (M+H)+
78 N 455.41
\ N \
N I, H |/ (M+H)+
£- N
O O
489.55
N I/ H \? (M+H)+
_.- N
80 528.56
\ N
N I/ H (M+H)+
j N
0 Nd
81 566.46
\ N
N I/ H (M+H)+
WO 16904
82 458.5
\ N (M+H)+
é N ‘N
83 456.49
\ N \ N
N I/ H | . (M+H)+
s: N
84 456.49
\ N
N I/ H (M+H)+
85 464.45
\ N
N l/ H (M+H)+
: N
86 484.5
\ N/ng/
N | (M+H)+
87 510.5
N | HE N (M+H)+
88 554.7
\ N
N l/ H (M+H)+
s‘ N
89 524.6
\ N
N I, (M+H)+
s‘ N
WO 16904
90 476.6
Nl/ (M+H)+
s.-N
91 546.6
Nl/ (M+H)+
92 512.6
NI/ (M+H)+
s.-N
93 621.6
NI/ (M+H)+
94 485.5
Nl/ (M+H)+
95 561.6
NI, (M+H)+
96 472.51
\ N/\/\N \
NI, H SN (M+H)+
s.-N
0 /
97 469.55
\ N \N
NI/ H (M+H)+
2015/013699
98 N03 541.66
(M+H)+
g- N O
/\ R
o (\N’
99 490.59
N I/ (M+H)+
S= N
100 475.57
\ N (M+H)+
N ‘
O /N
101 485.45
\ N OH
N l/ H (M+H)+
102 o/\//:/NS\/ 539.5
\ N
N I/ H (M+H)+
Fh o
0 NJLO/
103 Na/L 539.5
N l/ H (M+H)+
s N
104 525.5
\ N
N I, H/TN./\ (M+H)+
: 0"S‘b
WO 16904
105 491.5
\ N
N I, H/\C\N (M+H)+
: If)"
106 /" 539.5
\ N
N l/ ,
H N,,S:O (M+H)+
N O
107 ’ 505.6
(M+H)+
108 517.6
/III
\ N
N l/ H H (M+H)+
N ‘
/\ O
109 553.5
\ N
N l/ H (M+H)+
i N 3.
110 519.6
N:(YLNl/ H/U (M+H)+
N o\
g ‘n’
/\ O
111 554.5
\ N
N. IN, H/U.S.N\H (M+H)+
112 533.6
\ N OH
N l, H (M+H)+
s 1%
/\ O
WO 16904
113 519.6
\N OH
Nl/H (M+H)+
/\ O
114 503.6
N I, H/U (M+H)+
sN ‘n/
/\ O
115 455.5
\N \
N I, H IN (M+H)+
116 030 532.5
Nam;\N \
(M+H)+
117 F 446.4
N| (M+H)+
, ”NF
118 534.5
N l/ Hno (M+H)+
S‘N OJ
119 546.5
waffll\N (M+H)+
s=N Br
120 N 482.5
N HIIJ\ I, (M+H)+
é-N N
WO 16904
F F
O NH O
121 557.5
HN2 G
N I: H (M+H)+
= N CI
Cl
F F
122 406.4
\ J\ J\ G
N l (M+H)+
, N H2N
F F
123 562.4
N I (M+H)+
, HLQ
N Br
F F
124 F 428.4
N | N/Y
H (M+H)+
/ F
125 496.5
\ N'
N I H (M+H)+
l (SH
F F
125 544.6
\ 0\ N
N | (M+H)+
/ H
s: N
F F
127 532.6
N |\ H O (M+H)+
/ "Ir/A /
i— O
WO 16904
128 604.5
(M+H)+
129 485.6
\ N
N l/ (M+H)+
: N I/\§N
130 496.5
\ N
NI H (M+H)+
/ OH
131 496.5
\ N
NI I (M+H)+
/ H OH
132 496.5
NI (M+H)+
(CD30D) 6 9.02 (s,
1H), 8.24 (s, 1H),
8.18 (s, 1H), 7.90
FF (s, 1H), 7.82 (m,
4H),4.96 (d, J =
16.0 Hz, 1H), 4.91
133 536.46 (m, 2H), 4.78 (s,
N l/ (M+H)+ 2H), 4.52 (s, 2H),
3.58 (q, J = 7.6 Hz,
: N
’\ 2H), 2.38 (m, 1H),
1.21 (t, J = 7.6 Hz,
3H), 1.17 (d, J =
8.0 Hz, 3H), 0.89
d, J = 6.8 Hz, 3H.
134 520.56
NI (M+H)+
WO 16904
I O
O O
135 593.61 NH
| G
(M+H)+ H2N
136 579.47
135 H
(M+H)+
137 532.62 HgN \
(M+H)+ o
138 530.5
(M+H)+
139 518.5
(M+H)+
140 590.5
(M+H)+
WO 16904
(CD30D) 5 9.12 (s,
1H), 8.90 (s, 1H), 8.32
(s, 1H), 8.17 (d, J:
8.4 Hz, 1H), 7.90
(d, J : 8.0 Hz, 2H),
7.84 (d, J: 8.0 Hz,
2H), 7.65 (d, J:
8.4 Hz, 1H), 5.05
(d, J: 15.6 Hz,
1H), 4.77 (dd, J:
141 NflN%H Eff): 13.2,30.0Hz,2H),
3.34(s,2H),3.26
, N/ N/,,S_.’\ (q, J: 7.6 Hz, 2H),
/\ 00
2.37 (broad s, 1H),
1.84 (dd, J= 4.4,
7.6 Hz, 2H), 1.52
(dd, J= 4.4, 7.6 Hz,
2H), 1.23 (t, J= 7.6
Hz, 3H), 1.16 (d, J
= 6.0, 3H), 0.89 (d,
J= 6.8 Hz, 3H .
(CD30D) 5 9.11 (s,
1H), 8.87 (s, 1H), 8.33
(d, J= 8.0 Hz, 2H),
7.90 (d, J= 8.0 Hz,
2H), 7.84 (d, J=
8.0 Hz, 2H), 5.04
(d, J= 15.6 Hz,
1H), 4.89-4.82 (m,
142 Nflfifi0 561.55 2H), 4.87 (s, 2H),
(M+H)+ 4.76 (dd, J: 13.2,
N’ N / ,sf\
28.8 Hz, 2H),3.33
/\ o o (q, J: 7.6 Hz, 2H),
2.58 (s, 3H), 2.36
(bs, 1H), 1.26 (t, J
= 7.6 Hz, 3H), 1.14
(d, J= 6.0 Hz, 3H),
0.88 (d, J: 6.8 Hz,
(CD30D) 5 9.12 (5,
1H), 8.72 (d,J 7.6
Hz, 1H), 8.35 (s,
1H), 7.92 (d, J:
7.6 Hz, 1H), 7.92
(d, J: 8.0 Hz, 2H),
7.83 (d, J: 8.0 Hz,
2H), 5.07 (d, J:
.2 Hz, 1H),4.91-
143 561 52
\ N \ (M+H)+ 4.71 (m, 4H), 4.77
N I I
/ H
N / (dd, J: 12.4, 35.4
N /\
:~' ISeO Hz, 2H), 3.41 (q, J
/\ O
: 7.6 Hz, 2H), 3.06
(s, 3H), 2.36 (br,J=d0a
3, 1H), 1.28 (t
7.6 Hz, 3H), 1.14
(d, J: 5.2 Hz, 3H),
0.88 (d J: 6.8 Hz,
(CD30D) 5 9.08 (s,
1H), 8.81 (s, 1H), 8.28
(s, 1H), 8.12 (d, J:
O F
8.8 Hz, 1H), 7.91
\ N \ (Sn/ISEHE): (d, J : 8.0 Hz, 2H),
N I I
/ N / 7.83 (d, J: 8.0 Hz,
3 N 01.3.1 2H), 5.04 (d, J:
/\ O
14.4 Hz, 1H), 4.91-
(s, 2H), 4.76 (dd, J
= 12.4, 33.4 Hz,
2H), 3.33 (q, J:
7.6 Hz, 2H), 2.35
(broad s, 1H), 1.25
(t, J: 7.6 Hz, 3H),
1.13 (d, J: 5.2 Hz,
3H), 0.87 (d, J:
6.8 Hz, 3H .
HO O
145 518.55
\ N 137
N I H -
: N
F F
O OH
146 506.58
\ N O 134
(M+H)+-
= N
s O
F F
148 504.6
\ N 127
N l, (M+H)+-
N Hm.
g "”n’
/\ o
F F
149 O 509.5
I: OH
\ N 10/ (M+H)+
N I
/ H
s: N
150 513.6
\ N \
N I I
H (M+H)+
N / O\
g N’
/\ O
F F
151 499.6
\ N \ 150
N l I (M+H)+-
, H N / OH
s: N
/\ O
WO 16904
F F
FAQ O O“s"o
N. \
152 /\/C/ 525-6
N | j ” (M+H)+
; N
F F
153 5115-
\ N
N I <M+H>+
. HMS/“C
g N
d, ¢O
154 o 0 525.5
\ 1",
-n(0X11
155 480.5
/ /
2 12 z_ \ (M+H)+
Z\ //
)Ill z
F F
156 577.5
\ n CII, N I, (M+H)+
157 m, 561.6
N |\ (M+H)+
, H
N 0 ”11/
/\ A0 0
F F CN
158 0 509.5
(M+H)+
\ N
N I
/ H
OH OH
: H2N
WO 16904
(CD30D) 6 9.13 (d,
J: 2.0 Hz, 1H),
8.32 (d, J: 3.2 Hz,
1H), 8.29 (s, 1H),
F F 8.07 (d, J: 8.8 Hz,
F 1H), 7.92-7.85 (m,
0 4H), .04 (m,
159 N, 548.1 3H), 4.89-4.85 (m,
N H | (M+H)+ 1H), 4.80-4.76 (m,
3H), 3.60 (q, J:
/‘\ 0"S\/ 7.2 Hz, 2H), 2.42-
2.38 (m, 1H),1.33
(t, J: 7.2 Hz, 3H),
1.17 (d, J: 6.8 Hz,
3H), 0.91 (d, J:
7.2 Hz, 3H .
BIOLOGICAL ASSAYS
Radio-Ligand RORy Binding Assay (Assay 1)
] Compounds of the present invention were tested for ability to bind to RORY in a cell—
free competition assay with commercially available radio—ligand (RL), 25—hydroxy [26,27—3H]—
cholesterol (PerkinElmer, Cat. # NET674250UC), for a ligand binding site on a recombinant
RORY Ligand Binding Domain (LBD) protein expressed as a Glutathione—S—Transferase
(GST) fusion. The assay was performed in 96—well SPA plates (PerkinElmer, Cat. # 1450—401) in
50 mM HEPES buffer, pH 7.4, ning 150 mM NaCl, 5 mM MgClg, 10% (v/v) glycerol, 2
mM CHAPS, 0.5 mM B—octylglucopyranoside and 5 mM DTT. Tested compounds were
dissolved in DMSO, and semi—log (3.162X) serial dilutions of the compounds were prepared in
the same solvent. Two uL of the DMSO solutions were mixed with 28 uL of 8.6 nM 25—
hydroxy [26,27—3H]— cholesterol and 50 uL of 24 nM RORY LED. The plate was shaken at 700
rpm for 20 min and incubated for 10 min at rt, after which 40 uL of poly—Lys YSi SPA beads
(PerkinElmer, Cat. # RPNQ0010) were added to e 50 ug of the beads per well. The plate
was incubated on an orbital shaker for 20 min and then for 10 min without agitation at rt. SPA
signal for tritium beta radiation was registered on PerkinElmer Microbeta plate reader. Percent
inhibition values were calculated based on the high signal obtained with DMSO control and the
low signal observed with 10 uM rd RORY inverse agonist T09013l7 (SigmaAldrich, Cat.
# . The percent inhibition vs. concentration data were fit into a four—parameter model,
and IC50 values were calculated from the fit as the concentrations corresponding to the inflection
points on the dose—response curves. Inhibitory constants (Ki) were calculated using the
following equation, where [RL] is the concentration in the assay and KD is a dissociation
nt of roxy [26,27—3H]— cholesterol:
RORyt SXRORE Assay in Jurkat Cells (Assay 2)
] Compounds of the t invention were tested for RORY inverse t activity in
a cell—based, transcriptional activity assay. Secreted c® luciferase was used as a reporter
for transcriptional activity of the full—length RORyt in Jurkat cells (ATCC, Cat. # TIE—152). A
reporter plasmid was constructed by inserting 5 repeats of the ROR Response Element (RORE)
AAAGTAGGTCA (SEQ ID NO: 1) into a commercially available promoterless plasmid
pNL1.3[sechuc] (Promega, Cat. # N1021) using KpnI and I restriction sites. The
expression plasmid for RORyt was purchased (Geneocopoeia, Cat. # EX—T6988—M02). Jurkat
cells (30 million cells) were transfected with 11 u g of EX—T6988—M02 and 26 ug of the reporter
plasmid in OptiMEM® media using Lipofectamine® LTX and PlusTM reagents (Life
Technologies, Cat. # 15338—100). After 5—6 hrs of incubation at 37 °C/5% C02, the cells were
collected, resuspended in phenol—red free RPMI media containing 10% (v/v) delipidated FBS
(Hyclone, Cat. # SH30855.03) and dispensed into l clear bottom tissue culture plates
(CoStar, Cat. # 3603), at 80,000 cells per well. Tested compounds were added to the cells in the
same media (final concentration of DMSO was 0.1% , and the plates were incubated at 37
°C/5% C02 for 16—18 hrs. Luciferase ty in the conditioned supernatants was determined
with NanoGlo® assay reagents (Promega, Cat.# N1130). Percent inhibition values were
calculated based on the fully inhibited and non—inhibited (DMSO) controls, and the values were
regressed against concentrations of the tested compounds to derive IC50 values using a four—
parameter near fitting model.
The results of assays 1 and 2 are shown in Table 2.
Table 2:
Compound RORy RORytSX Compound RORy RORytSX
# Binding IC50 # Binding IC50
Ki Range* Ki Range*
Range* (nM) (nM)
(nM)
1 +++ +++
2 +++ +++
3 +++ +++
4 +++ +++
+++ +++
6 +++ +
7 +++ ++
8 +++ +
WO 16904
9 +++ ++
+++
11 ++ \D ++++++
12 ++ +++ \D
13 \D
14 ++
+++ \DUI ++
16 ++
17 +++ +++ \D\l
+++ +++ 100
21 ++ ++ 101
22 +++ +++ 102 ++
23 ++ 103
24 +++ 104 ++
+++ ++ 105 +
26 ++ 106 ++
27 +++ ++ 107 ++
28 +++ +++ 108
29 +++ +++ 109 +++ +
+++ +++ 110 +
31 +++ +++ 111 ++
32 +++ ++ 112 +
33 +++ +++ 113 ++
34 +++ +++ 114 +
+++ ++ 115 ++
36 ++ 116 ++
37 117
38 +++ ++ 118
39 +++ +++ 119
40 ++ 120
41 +++ 121
42 +++ 122
43 +++ 123 ++
44 +++ 124
45 +++ 125
46 +++ 126
47 +++ 127 ++
48 128 ++
49 +++ 129 ++
50 130
51 ++ 131 ++
52 ++ 132 ++
53 ++ 133 + + ++
54 +++ +++ 134
55 +++ +++ 135
56 +++ ++ 136
57 +++ +++ 137
58 +++ +++
59 +++ +++
60 ++
61 +
62 +
63 +++ ++
64 +++ ++
65 ++
66 +
67 +++ +++
68 +
69 +
70 +
71 ++
72 ++
73 +
74 +
75 +
76 ++
77 +
78 ++
79 +
80 +
>l<+ means > 1000 nM; ++ means 100 nM — 1000 nM; +++ means < 100 nM.
] While we have described a number of embodiments of this invention, it is apparent
that our basic examples may be altered to provide other embodiments that utilize the compounds
and s of this invention. Therefore, it will be appreciated that the scope of this invention is
to be defined by the appended claims rather than by the specific embodiments that have been
represented by way of example.
The contents of all references (including literature references, issued patents,
published patent applications, and co—pending patent applications) cited hout this
application are hereby expressly incorporated herein in their entireties by reference. Unless
ise defined, all technical and scientific terms used herein are accorded the meaning
commonly known to one with ordinary skill in the art.
Listing of
Claims (25)
1. A compound of Formula (I): (I); or a pharmaceutically acceptable salt thereof, wherein R2 is (C1-C3)alkyl; R3 is hydrogen, hydroxy, monocyclic cycloalkyl, monocyclic heterocyclyl, or (C1- C6)alkyl, wherein the (C1-C6)alkyl is optionally tuted with 1 to 2 groups independently selected from hydroxy, halo, and cyano; R4 is hydrogen, (C1-C3)alkyl, or =O; X is –C(O)NH- or –NHC(O)-; m is 0, 1, or 2; n is 0, 1, 2, or 3; L1 is absent or is SO2 or CR7R8; Cy1 is phenyl, dinyl, tetrahydro-2H-thiopyranyl 1,1-dioxide, pyridinyl, zinyl, azetidinyl, imidazolyl, tetrahydropyranyl, 1,4-dioxanyl, pyridazinyl, pyrazolyl, pyrrolidinyl, cyclohexyl, morpholinyl, 6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazolyl, 1,2,3,4-tetrahydro-1,8- naphthyridinyl, 2,3-dihydro-1H-indenyl, or imidazo[1,2-a]pyrimidinyl, each of which is ally substituted with 1 to 2 groups independently selected from R5, wherein at least one R5 is (C1-C3)alkylsulfonyl or (C1-C3)alkylaminosulfonyl when Cy1 is phenyl or pyridiyl; Cy2 is selected from (C1-C6)alkoxycarbonyl, phenyl(C1-C3)alkoxycarbonyl, halophenyl(C1-C3)alkoxycarbonyl, aryl, heteroaryl, monocyclic cycloalkyl, and monocyclic heterocyclyl, n the aryl, heteroaryl, monocyclic lkyl, and moncyclic heterocyclyl are each ally substituted with 1 to 3 groups independently selected from R6; R5 and R6 are each independently selected from halo, cyano, nitro, amino, hydroxy, carboxy, )alkyl, heterocyclyl, hydroxy(C1-C6)alkyl, CO2H, (CH2)1-3COOH, (C1- C3)alkylcarbonyloxy, (C3-C6)cycloalkyl, hydroxy(C3-C6)cycloalkyl, (C4-C7)cycloalkylalkyl, (C2- C6)alkenyl, halo(C2-C6)alkenyl, hydroxy(C2-C6)alkenyl, (C2-C6)alkynyl, )cycloalkyl(C2- C4)alkynyl, halo(C1-C6)alkyl, halo(C3-C6)cycloalkyl, halo(C4-C7)cycloalkylalkyl, (C1-C6)alkoxy, (C3-C6)cycloalkoxy, (C4-C7)cycloalkylalkoxy, halo(C1-C6)alkoxy, 3-C6)cycloalkoxy, halo(C4-C7)cycloalkylalkoxy, )alkylthio, (C3-C6)cycloalkythio, (C4-C7)cycloalkylalkylthio, halo(C1-C6)alkylthio, halo(C3-C6)cycloalkythio, 4-C7)cycloalkylalkylthio, (C1- C6)alkylsulfinyl, (C3-C6)cycloalkylsulfinyl, (C4-C7)cycloalkylalkylsulfinyl, halo(C1- ylsulfonyl, halo(C3-C6)cycloalkylsulfinyl, halo(C4-C7)cycloalkylalkylsulfinyl, (C1- C6)alkylsulfonyl, (C3-C6)cycloalkylsulfonyl, (C4-C7)cycloalkylalkylsulfonyl, halo(C1- C6)alkylsulfonyl, halo(C3-C6)cycloalkylsulfonyl, halo(C4-C7)cycloalkylalkylsulfonyl, (C1- C6)alkylamino, di(C1-C6)alkylamino, (C1-C6)alkoxy(C1-C6)alkoxy, halo(C1-C6)alkoxy(C1- C6)alkoxy, (C1-C6)alkoxycarbonyl, H2NCO, H2NSO2, (C1-C6)alkylaminocarbonyl, di(C1- C6)alkylaminocarbonyl, (C1-C3)alkoxy(C1-C3)alkylaminocarbonyl, heterocyclylcarbonyl, (C1- ylaminosulfonyl, di(C1-C6)alkylaminosulfonyl, heterocyclylsulfonyl, (C1- C6)alkylcarbonylamino, (C1-C6)alkylcarbonylamino(C1-C6)alkyl, (C1-C6)alkylsulfonylamino, (C1-C6)alkylsulfonylamino(C1-C6)alkyl, (C1-C6)alkoxycarbonyl(C1-C6)alkoxy, (C1- C6)alkoxy(C1-C6)alkyl, halo(C1-C6)alkoxy(C1-C6)alkyl, hydroxy(C1-C6)alkoxy, aryl, heteroaryl, oxo, C1-C6)alkyl, (C1-C6)alkylamino(C1-C6)alkyl, di(C1-C6)alkylamino(C1-C6)alkyl amino(C2-C6)alkoxy, (C1-C6)alkylamino(C2-C6)alkoxy, di(C1-C6)alkylamino(C2-C6)alkoxy, (C1- C6)alkylcarbonyl, hydroxy(C1-C6)alkylcarbonyl, (C1-C6)alkylhydroxycarbonyl, (C1- C6)alkylhydroxy(C1-C6)alkyl, (C3-C6)cycloalkylcarbonyl, (C3-C6)cycloalkylaminocarbonyl, {(C3-C6)cycloalkyl}{(C1-C6)alkyl}aminocarbonyl, di(C3-C6)cycloalkylaminocarbonyl, (C3- loalkylaminosulfonyl, {(C3-C6)cycloalkyl}{(C1-C6)alkyl}aminosulfonyl, di(C3- C6)cycloalkylaminosulfonyl, cyano(C1-C6)alkyl, aminocarbonyl(C1-C6)alkyl, (C1- C6)alkylaminocarbonyl(C1-C6)alkyl, di(C1-C6)alkylaminocarbonyl(C1-C6)alkyl, (C3- C6)cycloalkylaminocarbonyl(C1-C6)alkyl, {(C3-C6)cycloalkyl}{(C1-C6)alkyl}aminocarbonyl(C1- C6)alkyl, [(C1-C6)alkyl(C4-C6)heterocyclyl](C1-C6)alkyl, and di(C3- C6)cycloalkylaminocarbonyl(C1-C6)alkyl; and R7 and R8 are each independently hydrogen, hydroxy, )alkyl, hydroxy(C1-C3)alkyl, mono(C1-C3)alkylamino, C3)alkylamino, CO2H, (CH2)1-3COOH, moncyclic heterocyclyl, (C1-C3)alkoxycarbonyl, (C1-C3)alkyl(C1-C3)alkoxycarbonyl, halophenyl, halophenyl(C1- C3)alkyl, or quinolin-2(1H)one-4yl-methyl; or R7 and R8, together with the carbon atom to which they are attached, form a 3- to 6- membered cycloalkyl or heterocyclyl.
2. The compound of Claim 1, wherein the compound is of Formula (II): (II); or a pharmaceutically acceptable salt thereof.
3. The compound of Claim 1 or 2, wherein the compound is of a (III): (III); or a pharmaceutically able salt thereof.
4. The compound of any one of Claims 1 to 3, wherein the compound is of Formula (IV): (IV); or a pharmaceutically able salt thereof.
5. The compound of any one of Claims 1 to 4, wherein the compound is of Formula (V) or (VI): (V); or (VI); or a pharmaceutically acceptable salt thereof.
6. The compound of any one of Claims 1 to 5, wherein the compound is of Formula (VII): (VII); or a pharmaceutically acceptable salt thereof.
7. The compound of any one of Claims 1 to 6, n R3 is hydrogen, hydroxy, or (C1- C3)alkyl.
8. The compound of any one of Claims 1 to 7, wherein Cy2 is selected from aryl, heteroaryl, monocyclic cycloalkyl, and monocyclic heterocyclyl, each of which is optionally tuted with 1 to 2 groups independently selected from R6.
9. The compound of any one of Claims 1 to 8, wherein Cy2 is phenyl, pyrimidinyl, cyclohexyl, or pyridinyl, each of which are optionally substituted with 1 to 2 groups independently selected from R6.
10. The compound of any one of Claims 1 to 9, wherein n is 1 or 2; and Cy1 is phenyl, pyridinyl, or piperidinyl, each of which is optionally substituted with 1 to 2 groups ndently selected from R5, wherein at least one R5 is (C1-C3)alkylsulfonyl or (C1- C3)alkylaminosulfonyl.
11. The compound of any one of Claims 1 to 10, wherein Cy2 is cyclohexyl optionally substituted with 1 to 2 groups independently selected from R6.
12. The compound of any one of Claims 1 to 11, wherein R5 is selected from halo, (C1-C3)alkyl, halo(C1-C3)alkyl, cyano, hydroxy(C1-C3)alkyl, )alkoxycarbonyl, (C1-C3)alkylsulfonyl, (C1-C3)alkoxy, halo(C1-C3)alkoxy, oxo, hydroxy, (C1-C3)alkylcarbonyl, hydroxy(C1-C3)alkylcarbonyl, )alkylhydroxycarbonyl, (C1- C3)alkylaminosulfonyl, (C1-C3)alkylaminocarbonyl, di(C1-C3)alkylamino(C2-C6)alkoxy, (C1- C6)alkoxycarbonyl, [(C1-C3)alkyl(C4-C6)heterocyclyl](C1-C3)alkyl, and (C1-C3)alkylhydroxy(C1- C3)alkyl; and R6 is selected from halo, (C1-C3)alkyl, halo(C1-C3)alkyl, cyano, hydroxy(C1-C3)alkyl, )alkoxycarbonyl, (C1-C3)alkylsulfonyl, (C1-C3)alkoxy, 1-C3)alkoxy, oxo, hydroxy, aryl, (C1-C3)alkylhydroxy(C1-C3)alkyl, heteroaryl, and (C1-C3)alkoxycarbonyl.
13. The compound of any one of Claims 1 to 12, wherein R5 is selected from halo, (C1-C3)alkoxy, hydroxy, (C1-C3)alkyl, hydroxy(C1-C3)alkyl, halo(C1-C3)alkyl, (C1-C6)alkoxycarbonyl, di(C1-C3)alkylamino(C2-C6)alkoxy, [(C1-C3)alkyl(C4- C6)heterocyclyl](C1-C3)alkyl, oxo, (C1-C3)alkylcarbonyl, )alkylaminosulfonyl, (C1- ylsulfonyl, and cyano; and R6 is selected from halo(C1-C3)alkyl, (C1-C3)alkoxy, halo, cyano, (C1-C3)alkoxycarbonyl, (C1-C3)alkylhydroxy(C1-C3)alkyl, hydroxy(C1-C3)alkyl, and halo(C1-C3)alkoxy.
14. The compound of any one of Claims 1 to 13, wherein R5 is selected from halo, cyano, (C1-C3)alkyl, (C1-C3)alkylaminosulfonyl, and (C1-C3)alkylsulfonyl; and R6 is selected from halo(C1-C3)alkyl, (C1-C3)alkoxy, halo, cyano, (C1-C3)alkoxycarbonyl, and 1-C3)alkoxy.
15. The compound of any one of Claims 1 to 14, wherein Cy1 is ; R10 is (C1-C3)alkyl or (C1-C3)alkylamino; and Z is CH or N.
16. The compound of any one of Claims 1 to 15, wherein Cy2 is ; ; ; ; or ; R12 is (C1-C3)alkoxycarbonyl, halo, dihalo, )alkoxy, or halo(C1-C3)alkyl; R13 is halo or halo(C1-C3)alkyl; and R14 is halo, cyano, halo(C1-C3)alkyl, or halo(C1-C3)alkoxy.
17. The nd of Claim 16, wherein R12 to R14 are each CF3.
18. The compound of any one of Claims 1 to 17, wherein R2 is isopropyl.
19. The compound of Claim 1, wherein the compound is of the Formula: or a pharmaceutically acceptable salt thereof.
20. The compound of Claim 1, wherein the compound is selected from any one of the following formulae or a pharmaceutically acceptable salt thereof Structure N H O N S S N H O O N SO2Et N H O N S N H N S N H N S O N N H O O N S N H N O N S N H N S N H N S N H N S O O ’3 \ N \ /\ OQ 100100 O O N S O O N S N H N N S N H S O N O NI/ HM) é~N SI\ /\ 00 NI/ O §N Y : N/ N—\ N l/ N MN N '/ N HEN/{0% 103103 N H N N (11,, 2 IZ \ OH II“, II”, 2 IZ 105105 O N N H \ N N l/ HKCNA N d’S‘b N l/ HKCNON N ‘n/\ \ N N| HrN’§s 00 s N/ NI HEN/NO s N/ \ ///,,, N| H H é N/ /\ O \ N N I/ H N :,sf\ /\ Oo 107107 N H N \ N I;\ N l/ H N N O 0NH \ N N l/ H = N 5 CI \ N"= N l/ H EH l/ H/UN O S: N ”(QAO/ \ Nas S N (”S t N 109109 Nl/HOH Nl/HEH Nl/HOH 110110 N O N H N OH 112112 N H N S
21. A nd selected from any one of the following formulae or a pharmaceutically acceptable salt thereof / OH sN \\ = N F FF NI/ H F OH NI/ H gN CI \ N o/ NI/ H \N \ N l/ H l/ 114114 N|\N 0 Nd \ N N l/ H s‘ N 0 00 N I/ H S: N O /N| \ N N l/ H 5‘ N H [01 115115 'l'l 'l'l “H “H TI TI 'l'l “H “H 116116 117117 N/ O \ N N I/ HO O O \ N OH N l/ H i N \ N/x/ N I/ H 5: N \ N \ NI ' N/ N/ O\ /\ O \ N \ N I/ I N/ OH 5 N /\ O 118118 N H N
22. A pharmaceutical composition comprising a compound of any one of Claims 1 to 21, or a ceutically acceptable salt thereof, and a ceutically acceptable carrier.
23. The use of a therapeutically effective amount of a compound according to any one of Claims 1 to 21, or a ceutically able salt thereof in the manufacture of a medicament for the treatment of one or more diseases or disorders that are responsive to the inhibition of ROR gamma in a subject,
24. The use of Claim 23, wherein the disease or disorder is selected from asthma, chronic obstructive pulmonary disease (COPD), bronchitis, allergic rhinitis, atopic dermatitis, contact dermatitis, acne, cystic fibrosis, allograft rejection, multiple sclerosis, scleroderma, arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, sing spondylitis, systemic lupus erythematosus (SLE), psoriasis, Hashimoto's disease, pancreatitis, autoimmune diabetes, type I es, autoimmune ocular disease, ulcerative colitis, Crohn's disease, regional tis, inflammatory bowel disease (IBD), inflammatory bowel syndrome (IBS), Sjögren's me, optic neuritis, obesity, hepatosteatosis, adipose tissue-associated inflammation, insulin ance, type II diabetes, neuromyelitis optica, myasthenia gravis, age related macular degeneration, dry eye, uveitis, Guillain-Barré syndrome, sis, psoriatic arthritis (PsA), steroid resistant asthma, Graves' disease, scleritis, major depression, seasonal affective disorder, PTSD, bipolar disorder, autism, epilepsy, Alzheimer’s, CNS disorders associated with altered sleep and/or circadian s, endometriosis, obstructive sleep apnea syndrome , Behçet's disease, dermatomyositis, polymyocitis, graft versus host disease, primary biliary cirrhosis, liver fibrosis, non-alcoholic fatty liver disease (NAFLD), sarcoidosis, primary sclerosing cholangitis, autoimmune thyroid disease, autoimmune polyendocrine syndrome type I, mune polyendocrine syndrome type II, celiac disease, neuromyelitis, juvenile idiopathic arthritis, systemic sclerosis, myocardial tion, pulmonary hypertension, osteoarthritis, cutaneous leishmaniasis, sal polyposis, and cancer.
25. The use of Claim 24, wherein the disease or er is selected from , atopic dermatitis, acne, s disease, regional tis, ulcerative colitis, Sjögren's syndrome, uveitis, Behçet's disease, dermatomyositis, multiple sclerosis, ankylosing spondylitis, systemic lupus erythematosus (SLE), scleroderma, psoriasis, psoriatic arthritis (PsA), steroid resistant asthma, and rheumatoid arthritis.
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
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US201461935162P | 2014-02-03 | 2014-02-03 | |
US61/935,162 | 2014-02-03 | ||
US201461970637P | 2014-03-26 | 2014-03-26 | |
US61/970,637 | 2014-03-26 | ||
PCT/US2015/013699 WO2015116904A1 (en) | 2014-02-03 | 2015-01-30 | Dihydropyrrolopyridine inhibitors of ror-gamma |
Publications (2)
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NZ722413A NZ722413A (en) | 2021-08-27 |
NZ722413B2 true NZ722413B2 (en) | 2021-11-30 |
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