MODULATORS OF NLRP3 INFLAMMASOME AND RELATED PRODUCTS AND METHODS BACKGROUND Technical Field The invention relates to modulators of NLRP3 inflamma
some, to products containing the same, as well as to methods of their use and
preparation. Description of the Related Art The NOD‐like receptor protein 3 (NLRP3) is a key protein that interacts with, apoptosis‐associated speck‐like protein (ASC) and procaspase‐1 to form the NLRP3 inflammasome. The activation of the NLRP3 inflammasome produces inf
lammatory mediators, such as interleukin‐1 ^ (IL‐1β) and interleukin‐18 (IL‐18), thereby cont
ributing to the activation of the innate immune syst
em. The dysregulation of innate immunity contributes to
various diseases. The innate immune response protects the host from invading microorganisms. The formation of the NLRP3 inflammasome activates caspase‐1, which leads to the maturation and secretion of IL‐1β and IL‐18, cleavage of gasdermin‐D and, finally the initiation of cell death via pyroptosis. The system is alerted to the presence of
the invading microorganism by cytokine release and is working to resolve the inflammation by elimin
ating the infected cells. However, nonmicrobial compounds of either endogenous or exogenous origin ar
e also effective inducers of NLRP3 inflammation, allergi
c responses, or other forms of inflammation. For example, NLRP3 may be implicated in Parkinson’s dis
ease and/or Alzheimer’s disease, suggesting that misfolded proteins form aggregates that lead to the activation of the NLRP3 inflammasome. Environmental particulates such as inhaled asbestos an
d silica also activate NLRP3 inflammasome, and the high levels of IL‐1β are involved in the development of asbestosis and silicosis, two
progressive pulmonary diseases leading to fibrosis. Emerging studies have revealed the involvement of inc
reased production of IL‐1β and IL‐18 by the NLRP3 inflammasome can contribute to the onset and progress
ion of various diseases such as neuroinflammation‐related disorders, for example, brain infection, acute injury, multiple sclerosis, Alzheimer’s disease, and neurodegenerative diseases; cardiovascular diseases, cardiovascular risk reduction, atherosclerosis, type I
and type II diabetes and related complications, inflammatory skin diseases, acne, hidradenitis suppurativa, asthma, age‐related macular degeneration, or cancer related diseases. Those diso
rders that are immune or inflammatory in nature are usually difficult to diagnose or treat efficientl
y. Accordingly, there is a need in the art for compounds that modulate the NLRP3 inflammasome for the purpose of treating diseases in
which modulation of the NLRP3 inflammasome would be beneficial. The present invention fulfills these needs and provides other advantages as evident from the following description. BRIEF SUMMARY In an embodiment a compound is provided having struc
ture (I): or a pharmaceutically acceptable salt, isomer, hydrate
, solvate or isotope thereof, wherein R
1 , R
2 , R
3 , R
4 , R
5 , R
8 , R
9 , R
10 , R
11 , R
12 , and R
13 are as defined herein. In another embodiment, pharmaceutical compositions are provided comprising a carrier or excipient and a compound having structure
(I), or a pharmaceutically acceptable salt, isomer,
hydrate, solvate or isotope thereof. In a further embodiment, a method is provided for t
reating a NLRP3 inflammasome‐ dependent condition by administering to a subject in need thereof an effective amount of a compounds of structure (I), or a pharmaceutically acc
eptable salt, isomer, hydrate, solvate or isotope thereof, or a pharmaceutical composition comprising th
e same. In some embodiments, the NLRP3 inflammasome‐dependent condition is a neuroinflammatio
n‐related disorder or a neurodegenerative disease. DETAILED DESCRIPTION Definitions As used herein, the following terms have the meaning defined below, unless the context indicates otherwise. Unless the context requires otherwise, throughout the present specification and claims, the word “comprise” and variations thereof
, such as, “comprises” and “comprising” are t
o be construed in an open, inclusive sense, that is as
including, but not limited to”. Reference throughout this specification to “one embo
diment” or “an embodiment” means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment of
the present invention. Thus, the appearances of the phrases “in one embodiment” or “in an embodiment” in various places throughout this specification are not necessarily all referring to th
e same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. Unless defined otherwise, all technical and scientific
terms used herein have the same meaning as is commonly understood by one of skill i
n the art to which this invention belongs. As use
d in the specification and claims, the singular form
one”, “a”, “an” and “the” include plur
al references unless the context clearly dictates otherwise. “Modulating” NLRP3 inflammasome means that the com
pound interacts with NLRP3 in a manner such that it blocks its ATPase function and the downstream formation of the NLRP3 inflammasome complex. In the above context, the compo
und acts to inhibit, or block, activation of the NLRP3 inflammasome and therefore the compound can
also be described as an inhibitor. NLRP3 refers to NOD‐Like Receptor Protein 3. NLRP
3 is a protein‐coding gene, and an exemplary sequence may be found at https://www.uniprot
.org/uniprot/Q96P20. NLRP3 functions as an ATPase that is auto‐inhibited under normal conditions. NLRP3, unlike other inflammasomes, requires a two step activation process, which can be
triggered by a variety of pathogen‐associated molecular patterns (PAMPs) and damage‐associated molecular patterns (DAMPs). The first step primes the NLRP3 inflammasome via recognition of PAMP
s, DAMPs, or pathological species via pattern recoginition receptors (PRRs) (e.g. Toll‐like receptors). Priming increases NLRP3, pro‐IL1 ^, and pro‐ IL18 expression. Activation of NLRP3 is triggered by a second signal, such as ATP, K
+ efflux, other cellular stress, or pathological species, which leads to ATP hydrolysis and activation of the enzyme
. This activation leads to oligmerization of the inflam
masome complex, resulting in auto‐cleavage and activation of caspase‐1. Active caspase‐1 then cle
aves pro‐IL1 ^ and pro‐IL18. Active IL1 ^ and IL18 then are released from the cell through a gasdermin D pore, and release of such cytokines triggers a downstream inflammatory response and cell death via p
yroptosis. “Effective amount” refers to a quantity of a specified agent sufficient to achieve a desired effect in a subject being treated with that
agent. Ideally, an effective amount of an agent i
s an amount sufficient to inhibit or treat the disease
without causing substantial toxicity in the subject.
The effective amount of an agent will be dependent
on the subject being treated, the severity of the affliction, and the manner of administration of the pharmaceutical composition. Methods of determining an effective amount of the disclosed comp
ound sufficient to achieve a desired effect in a subject will be understood by those of skill in the
art in light of this disclosure. “Alkyl” means a saturated or unsaturated straight chain or branched alkyl group having from 1 to 8 carbon atoms, in some embodiments from 1 to 6 carbon atoms, in some embodiments from 1 to 4 carbon atoms, and in some embodiments from 1 to 3 carbon atoms. Examples of saturated straight chain alkyl groups include, but are not limited to, methyl, ethyl, n‐ propyl, n‐butyl, n‐pentyl‐, n‐hexyl, n‐heptyl,
and n‐octyl groups. Examples of branched alkyl gr
oups include, but are not limited to, isopropyl, iso‐but
yl, sec‐butyl, t‐butyl, neopentyl, isopentyl, and
2,2‐ dimethylpropyl groups. “Halo” or “halogen” refers to fluorine, chlo
rine, bromine, and iodine (i.e., F, Cl, Br, and I). “Hydroxyl” refers to −OH. “Cyano” refers to −CN. “Carboxyl” refers to ‐C(O)OH. “Haloalkyl” refers to alkyl as defined above with one or more hydrogen atoms replaced with halogen. Examples of haloalkyl groups
include, but are not limited to, −CF
3 , −CHF
2 , and the like. “Cyanoalkyl” refers to cyano as described above j
oined by way of an alkyl as described above (i.e., ‐alkyl‐CN). Examples of cyanoalkyl gr
oups include, but are not limited to , and the like. “Alkoxy" refers to alkyl as defined above joined by way of an oxygen atom (i.e., −O−alkyl, or in certain embodiments ‐OC
1‐6 alkyl). Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n‐propoxy, n‐butoxy,
isopropoxy, sec‐butoxy, tert‐butoxy, and the like.
"Haloalkoxy" refers to haloalkyl as defined above joi
ned by way of an oxygen atom (i.e., −O−haloalkyl). Examples of haloalkoxy grou
ps include, but are not limited to, −OCF
3 , and the like. “Cycloalkyl” refers to non‐aromatic ring moieties
containing 3 or more ring members. In some embodiments, cycloalkyl includes 3 to 5 ring members. For example, cycloalkyl includes cyclopropyl, cyclobutyl, and cyclopentyl. “Heterocycle” refers to aromatic and non‐aromatic
ring moieties containing 3 or more ring members, of which one or more is a heteroatom
such as, but not limited to, N, O, S, or P. In
some embodiments, heterocyclyl include 3 to 20 ring members, whereas other such gr
oups have 3 to 15 ring members. At least one ring contains a heteroato
m, but every ring in a polycyclic system need not
contain a heteroatom. For example, a dioxolanyl ring and a benzdioxolanyl ring system (methylenedioxyphenyl ring system) are both heterocycly
l groups within the meaning herein. Heterocyclyl groups also include fused ring species including those having fused aromatic and non‐aromatic groups. A heterocyclyl group also includes polycyclic ring systems containing a heteroatom such as, but not limited to,
quinuclidyl, and also includes heterocyclyl groups that have substituents, including but not limited to
alkyl, halo, amino, hydroxy, cyano, carboxy, nitro,
thio, or alkoxy groups, bonded to one of the ring
members. A heterocyclyl group as defined herein can
be a heteroaryl group or a partially or completely
saturated cyclic group including at least one ring heteroatom. Heterocyclyl groups include, but are not limited to, pyrrolidinyl, furanyl, tetrahydrofuranyl, dioxolanyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, dihydrobenzofuranyl, indolyl, dihydroindolyl, azaindolyl,
indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl gro
ups. “Isomer” is used herein to encompass all chiral,
diastereomeric or racemic forms of a structure (also referred to as a stereoisomer, as op
posed to a structural or positional isomer), unless
a particular stereochemistry or isomeric form is specifically indicated. Such compounds can be enriched or resolved optical isomers at any or all asymmetric atoms as are apparent from the depictions, at any degree of enrichment. Both racemic
and diastereomeric mixtures, as well as the individual optical isomers can be synthesized so as to be substantially
free of their enantiomeric or diastereomeric partners, and these are all within the
scope of certain embodiments of the invention. The isomers resulting from the presence of a chiral center comprise a pair of nonsuperimposable‐isomers that are called “enantiome
rs.” Single enantiomers of a pure compound are optically active (i.e., they are capable of rota
ting the plane of plane polarized light and designat
ed R or S). “Isolated optical isomer” means a compound which has been substantial
ly purified from the corresponding optical isomer(s) of the same
formula. For example, the isolated isomer may be at least about 80%, at least 80% or at least 8
5% pure by weight. In other embodiments, the isolate
d isomer is at least 90% pure or at least 98% pure,
or at least 99% pure by weight. “Substantially enantiomerically or diastereomerically” pure means a level of enantiomeric or diastereomeric enrichment of one enant
iomer with respect to the other enantiomer or diastereomer of at least about 80%, and more spe
cifically in excess of 80%, 85%, 90%, 95%, 98%, 99%, 99.5% or 99.9%. The terms “racemate” and “racemic mixture” refer to an equal mixture of two enantiomers. A racemate is labeled “(±)” because
it is not optically active (i.e., will not rotate
plane‐ polarized light in either direction since its constituent enantiomers cancel each other out). All compounds with an asterisk (*) adjacent to a tertiary or quaternary carbon are optically active isomers, which may be purified from the respective r
acemate and/or synthesized by appropriate chiral synthesis. A “hydrate” is a compound that exists in combination with water molecules. The combination can include water in stoichiometric quanti
ties, such as a monohydrate or a dihydrate, or can include water in random amounts. As the term is
used herein a “hydrate” refers to a solid form
; that is, a compound in a water solution, while it
may be hydrated, is not a hydrate as the term is
used herein. A “solvate” is similar to a hydrate except that
a solvent other that water is present. For example, methanol or ethanol can form an “alco
holate”, which can again be stoichiometric or non
stoichiometric. As the term is used herein a “solv
ate” refers to a solid form; that is, a compound
in a solvent solution, while it may be solvated, is not
a solvate as the term is used herein. “Isotope” refers to atoms with the same number o
f protons but a different number of neutrons, and an isotope of a compound of struct
ure (I) includes any such compound wherein one or more atoms are replaced by an isotope of that a
tom. For example, carbon 12, the most common form of carbon, has six protons and six neutrons, whereas carbon 13 has six protons and seven neutrons, and carbon 14 has six protons and eight neutrons. Hydrogen has two stable isotopes, deuterium (one proton and one neutron) and tritium (
one proton and two neutrons). While fluorine has a number of isotopes, fluorine‐19 is longest‐lived. Thus, an isotope of a compound having the structure of structure (I) includes, but not limited
to, compounds of structure (I) wherein one or more
carbon 12 atoms are replaced by carbon‐13 and/or c
arbon‐14 atoms, wherein one or more hydrogen atoms are replaced with deuterium and/or tritium, and
/or wherein one or more fluorine atoms are replaced by fluorine‐19. “Salt” generally refers to an organic compound, s
uch as a carboxylic acid or an amine, in ionic form, in combination with a counter ion. For example, salts formed between acids in their anionic form and cations are referred to as “acid
addition salts”. Conversely, salts formed between bases in the cationic form and anions are referred
to as “base addition salts.” The term “pharmaceutically acceptable” refers an a
gent that has been approved for human consumption and is generally non‐toxic. For e
xample, the term “pharmaceutically acceptable salt” refers to nontoxic inorganic or organic acid and/or base addition salts
(see, e.g., Lit et al., Salt Selection for Basic Drugs, Int. J. Pharm., 33, 201
217, 1986) (incorporated by reference herein). Pharmaceutically acceptable base addition salts of compounds of the invention include, for example, metallic salts including alkali metal, alkaline earth metal, and tra
nsition metal salts such as, for example, calcium, magnesium, potas
sium, sodium, and zinc salts. Pharmaceutically acceptable base addition salts also include organic s
alts made from basic amines such as, for example, N,N'dibenzylethylenediamine, chloroprocaine, choline, die
thanolamine, ethylenediamine, meglumine (N‐methylglucamine), and procaine. Pharmaceutically acceptable acid addition salts may be
prepared from an inorganic acid or from an organic acid. Examples of inorganic
acids include hydrochloric, hydrobromic, hydriodic, nitric, carbonic, sulfuric, and phosphoric acids. Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, aromatic aliphatic,
heterocyclic, carboxylic, and sulfonic classes of organic acids, examples of which include formic, acet
ic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, 4‐hydroxybenzoic, phenylacetic, mandelic,
hippuric, malonic, oxalic, embonic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, panthothenic, trifluoromethanesulfonic, 2‐ hydroxyethanesulfonic, p‐toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, stearic, alginic, βhydroxybutyric, salicylic, galactaric, and galacturoni
c acid. The compounds of the disclosure (i.e., compounds of
structure (I) and embodiments thereof), or their pharmaceutically acceptable salts m
ay contain one or more centers of geometric asymmetry and may thus give rise to enantiomers, dia
stereomers, and other stereoisomeric forms that are defined, in terms of absolute stereochemistr
y, as (R)‐ or (S)‐ or, as (D)‐ or (L)‐ for
amino acids. Embodiments thus include all such possible isomers, a
s well as their racemic and optically pure forms. Optically active (+) and (‐), (R)‐ and (S)‐, o
r (D)‐ and (L)‐ isomers may be prepared using c
hiral synthons or chiral reagents, or resolved using conventional techniques, for example, chromatography and fractional crystallization. Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Li
kewise, all tautomeric forms are also included. Although pharmaceutically unacceptable salts are not generally useful as medicaments, such salts may be useful, for example a
s intermediates in the synthesis of compounds having the structure of Formula I, for example in t
heir purification by recrystallization. As used herein, the phrase “NLRP3 inflammasome dependent condition” means a condition wherein modulating NLRP3 provides a medical
benefit to the patient or subject. In some embodiments, is provided a method of modulating NLRP3 inflammasome activity by contacting NLRP3 inflammasome with an effective amount of a compound
as described herein, or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, or a pharmaceutical composition comprising the same. In some embodiments, is provided a method of treating a NLRP3 inflammasome dependent condition by administering to a subject in
need thereof an effective amount of a compound as described herein, or a pharmaceutically acceptable
salt, isomer, hydrate, solvate or isotope thereof, or a pharmaceutical composition comprising the same. In certain embodiments, the NLRP3 inflammasome dependent condition is neuroinflammation‐related disorders or neurodegener
ative diseases. In some embodiments, the NLRP3 inflammasome dependent condition is inflammation, an inflammatory disease, an immune disease, cancer, infections including viral infections; central nervous system diseases, metabolic
diseases, cardiovascular diseases, respiratory diseases, liver diseases, renal diseases, ocular disea
ses, skin diseases, psychological diseases or blood diseases. In one embodiment, the NLRP3 inflammasome dependent condition is neuroinflammation‐related disorders or neurodegenerativ
e diseases. In one embodiment, the NLRP3 inflammasome dependent condition is neuroinflammation‐related disorders or neurodegenerativ
e diseases. In one embodiment, the invention provides a method for inhibiting NLRP3 inflammasome with an effective amount of a pharmaceut
ical composition as described herein. In another embodiment, the invention provides a method of treating a NLRP3 inflammasome dependent condition by administering to a
subject in need thereof an effective amount of a pharmaceutical composition as described herein. In certain embodiments, the NLRP3 inflammasome dependent condition is a neuroinflammation‐related disorder(s) or a neurodegenerative disease(s). As used herein the phrase “inflammation” refers to inflammation, including inflammation occurring as a result of an inflammatory disorder, e.g. an autoinflammatory disease
, inflammation occurring as a symptom of a non‐inflam
matory disorder, inflammation occurring as a result of infection, or inflammation secondary to trauma, injury or autoimmunity. Examples of inflammation that may be treated or prevented include inflammatory responses occurring in connection with, or as a result of: (a) a skin condition such as contact hypersensitivity
, bullous pemphigoid, sunburn, psoriasis, atopical dermatitis, contact dermatitis, all
ergic contact dermatitis, seborrhoetic dermatitis, lichen planus, scleroderma, pemphigus, epidermolysis bu
llosa, urticaria, erythemas, or alopecia; (b) a joint condition such as osteoarthritis, systemi
c juvenile idiopathic arthritis, adult‐ onset Still's disease, relapsing polychondritis, rheuma
toid arthritis, juvenile chronic arthritis, crystal induced arthropathy (e.g. pseudo‐gout, gout), or a
seronegative spondyloarthropathy (e.g. ankylosing spondylitis, psoriatic arthritis or Reiter's disease);
(c) a muscular condition such as polymyositis or mya
sthenia gravis; (d) a gastrointestinal tract condition such as inflammatory bowel disease (including Crohn's disease and ulcerative colitis), gastric ulcer
, coeliac disease, proctitis, pancreatitis, eosinopilic
gastro‐enteritis, mastocytosis, antiphospholipid syndro
me, or a food‐related allergy which may have effects remote from the gut (e.g., migraine, rhinitis
or eczema); (e) a respiratory system condition such as chronic obstructive pulmonary disease (COPD), asthma (including bronchial, allergic, intrinsic, extrinsic or dust asthma, and particularly chronic or inveterate asthma, such as late asthma and airways hyper‐responsiveness), bronchitis, rhinitis (including acute rhinitis, allergic rhinitis, atrophic rhinitis, chronic rhinitis, rhinitis caseosa, hypertrophic rhinitis, rhinitis pumlenta, rhinitis sicc
a, rhinitis medicamentosa, membranous rhinitis, seasonal rhinitis e.g. hay fever, and vasomotor rhini
tis), sinusitis, idiopathic pulmonary fibrosis (IPF),
sarcoidosis, farmer's lung, silicosis, asbestosis, adult respiratory distress
syndrome, hypersensitivity pneumonitis, or idiopathic interstitial pneumonia; (f) a vascular condition such as atherosclerosis, Behcet's disease, vasculitides, or Wegener's granulomatosis; (g) an immune condition, e.g. autoimmune condition, such as systemic lupus erythematosus (SLE), Sjogren's syndrome, systemic scler
osis, Hashimoto's thyroiditis, type I diabetes, idiopathic thrombocytopenia purpura, or Graves disease;
(h) an ocular condition such as uveitis, allergic co
njunctivitis, or vernal conjunctivitis; (i) a nervous condition such as multiple sclerosis o
r encephalomyelitis; (j) an infection or infection‐related condition, such as Acquired Immunodeficiency Syndrome (AIDS), acute or chronic bacterial infection, acute or chronic parasitic infection, acute or chronic viral infection, acute or chronic fungal infe
ction, meningitis, hepatitis (A, B or C, or other v
iral hepatitis), peritonitis, pneumonia, epiglottitis, malaria, dengue hemorrhagic fever, leishmaniasis, streptococcal myositis, Mycobacterium tuberculosis, Mycobacterium avium intracellulare, Pneumocystis carinii pneumonia, orchitis/epidydimitis, l
egionella, Lyme disease, influenza A, epstein‐ barr virus, viral encephalitis/aseptic meningitis, or
pelvic inflammatory disease; (k) a renal condition such as mesangial proliferative glomerulonephritis, nep
hrotic syndrome, nephritis, glomerular nephritis, acute renal
failure, uremia, or nephritic syndrome; (l) a lymphatic condition such as Castleman's disease
; (m) a condition of, or involving, the immune system, such as hyper IgE syndrome, lepromatous leprosy, familial hemophagocytic lymphohisti
ocytosis, or graft versus host disease; (n) a hepatic condition such as chronic active hepat
itis, non‐alcoholic steatohepatitis (NASH), alcohol‐induced hepatitis, non‐alcoholic fatty liver disease (NAFLD), alcoholic fatty liver disease (AFLD), alcoholic steatohepatitis (ASH) or pri
mary biliary cirrhosis; (o) a cancer, including those cancers listed herein
below; (p) a burn, wound, trauma, haemorrhage or stroke; (q) radiation exposure; and/or (r) obesity; and/or (s) pain such as inflammatory hyperalgesia. As used herein the phrase “an inflammatory disease” means for example, inflammation occurring as a result of an inflammatory disorder, e.g. an autoinflammatory disease
, such as cryopyrin‐associated periodic syndromes (CAPS
), Muckle‐Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS), familial Mediterranean
fever (FMF), neonatal onset multisystem inflammatory disease (NOMID), Majeed syndrome, pyogenic arthritis, pyoderma
gangrenosum and acne syndrome (PAPA), adult‐onset Still's disease (A
OSD), haploinsufficiency of A20 (HA20), pediatric granulomatous arthritis (PGA), PLCG2‐associated antibody deficiency and immune dysregulation (PLAID), PLCG2‐associated autoinflammatory, antibody deficiency and immune dysregulation (APLAID), or sideroblastic anaemia with with B‐cell immunodeficiency, periodic fevers and developmental delay (SIFD). As used herein the phrase “an immune disease” means for example, auto‐immune diseases, such as acute disseminated encephalitis, Addison's disease, ankylosing spondylitis, antiphospholipid antibody syndrome (APS), anti‐synthet
ase syndrome, aplastic anemia, autoimmune adrenalitis, autoimmune hepatitis, autoimmune oophoritis, autoimmune polyglandular failure, autoimmune thyroiditis, Coeliac disease, Crohn's disease, type 1 diabetes (T1D), Goodpasture's syndrome, Graves' disease, Guillain‐Barre syndrome (GBS), Hashimoto's disease, idiopathic thrombocytopenic purpura, Kawasaki's disease, lupus erythematosus including systemic lupus erythematosus (SLE), multiple sclerosis (MS) including
primary progressive multiple sclerosis (PPMS), secondary progressive multiple sclerosis (SPMS) and relapsing remitting multiple sclerosis (RRMS), myasthenia gravis, opsoclonus myoclonus syndrome (OMS), optic neuritis, Ord's thyroiditis, pemphigus, pernicious anaemia, polyarthritis, primary biliary cirrhosis, rheumatoid arthritis (RA), psoriatic arthritis, juvenile idiopathic arthritis or Still's disease, refractory gouty arthritis, Reiter's syndrome, Sjogren's syndrome, systemic sclerosis a sys
temic connective tissue disorder, Takayasu's arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegener's granulomatosis, alopecia universalis, Beliefs disease, Chagas' disease, dysautonomia, endometriosis, hidradenitis suppurativa (HS), interstitial cystitis, neuromyotonia, psoriasis, sarcoid
osis, scleroderma, ulcerative colitis, Schnitzler syndrome, macrophage activation syndrome, Blau syndrome, giant cell arteritis, vitiligo or vulvodynia. As used herein the phrase “cancer” means for example, lung cancer, renal cell carcinoma, non‐small cell lung carcinoma (NSCLC), Langerhans cell histiocytosis (LCH), myeloproliferative neoplams (MPN), pancreatic cancer, gastric cancer, myelodysplastic syndrome (MDS), leukaemia including acute lymphocytic leukaemia
(ALL) and acute myeloid leukaemia (AML), promyelocytic leukemia (APML, or APL), adrenal cancer, anal cancer, basal a
nd squamous cell skin cancer, bile duct cancer, bladder cancer, bone cancer
, brain and spinal cord tumours, breast cancer, cervical cancer, chronic lymphocytic leukaemia (CLL), chronic myeloid leukaemia (CML), chronic myelomonocytic leukaemia (CMML), colorectal cancer, endometrial cancer, oesophagus cancer, Ewing family of tumours, eye cancer, gallbladder cancer, gastrointestinal carcinoid tumours, gastrointestinal stromal tumour (GIST), gestational tro
phoblastic disease, glioma, Hodgkin lymphoma, Kaposi sarcoma, kidney cancer, laryngeal and hypopharyngeal cancer, liver cancer, lung carcinoid tumour, lymphoma including cutaneous T cell lymphoma,
malignant mesothelioma, melanoma skin cancer, Merkel cell skin cancer, multiple myeloma, nasal cavity and paranasal sinuses cancer, nasopharyngeal cancer, neuroblastoma, non‐Hodgkin lymphoma, non‐small cell lung cancer, oral cavity and oropharyngeal cancer, osteosarcoma, ovarian cancer, penile cancer, pituitary tumours, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, stomach cancer,
testicular cancer, thymus cancer, thyroid cancer including anaplastic thyroid cancer, uterine sarcoma, vaginal cancer, vulvar cancer, Waldenstrom macroglobulinemia, and Wilms tumour
. As used herein the phrase “infections including vir
al infections” means for example, viral infections (e.g. from influenza virus, human immunodeficiency virus (HIV), alphavirus (such as Chikungunya and Ross River virus), flaviviruses (such
as Dengue virus and Zika virus), herpes viruses (such as Epstein Barr Virus, cytomegalovirus, Varicell
a‐zoster virus, and KSHV), poxyiruses (such as vaccinia virus (Modified vaccinia virus Ankara) and M
yxoma virus), adenoviruses (such as Adenovirus 5), or papillomavirus), bacterial infections (e.g. from Staphylococcus aureus, Helicobacter pylori, Bacillus anthracis, Bordatella pertussis, Burkholderia pseudomallei, Corynebacterium diptheriae, Clostridium tetani, Clostridium botulinum, Streptococcus pneumoniae, Streptococcus pyogenes, Listeria monocytogenes, Hemophilus influenzae, Pasteurella multicida, Shigella dysenteriae, Mycobacterium tuberculosis, Mycobacterium leprae, Mycoplasma pneumoniae, Mycoplasma hominis, Neisseria meningitidis, Neisseria gonorrhoeae,
Rickettsia rickettsii, Legionella pneumophila, Klebsiella pneumoniae, Pseudomonas aeruginosa, Propionibacterium acnes, Treponema pallidum, Chlamydia trachomatis, Vibrio cholerae, Salmonella typhimurium, Salmonella typhi, Borrelia burgdorferi or Yersinia pestis), fungal infections (e.
g. from Candida or Aspergillus species), protozoan infections (e.g. from Plasmodium, Babesia, Giardia, Entamoeba, Leishmania or Trypanosomes), helminth infections (e.g. from schistosoma, roundworms,
tapeworms or flukes), and prion infections. As used herein the phrase “central nervous system diseases” means for example, Parkinson's disease, Alzheimer's disease, Frontotemporal
dementia, dementia, motor neuron disease, Huntington's disease, cerebral malaria, brain injury from pneumococcal meningitis, intracranial aneurysms, traumatic brain injury, multiple sclerosis,
and amyotrophic lateral sclerosis. As used herein the phrase “neuroinflammation‐relate
d diseases” means for example, multiple sclerosis, brain infection, acute injury, neurodegenerative disease, Parkinson’s disease
or Alzheimer’s disease. As used herein the phrase “neurodegenerative disease” means for example, Alzheimer’s disease, Parkinson’s disease, multiple
sclerosis, or amyotrophic lateral sclerosis. In one embodiment, neurodegenerative diseases are characterized by deep involvement of cell mediating neuroinflammatory process
es. As used herein the phrase “metabolic diseases” me
ans for example, type 2 diabetes (T2D), atherosclerosis, obesity, gout, and pseudo‐gou
t. As used herein the phrase “cardiovascular diseases” means for example, hypertension, ischaemia, reperfusion injury including post‐MI ischemic reperfusion injury, stroke including ischemic stroke, transient ischemic attack, myocardial infarction including recurrent myocardial infarction, heart failure including congesti
ve heart failure and heart failure with preserved ejection fraction, embolism, aneurysms including abdominal aortic aneurysm, cardiovascular risk reduction (CvRR), and pericarditis including Dressler's
syndrome. As used herein the phrase “respiratory diseases” means for example, chronic obstructive pulmonary disorder (COPD), asthma such as
allergic asthma and steroid‐resistant asthma, asbestosis, silicosis, nanoparticle induced inflammation, cystic fibrosis, and idiopathic pulmonary fibrosis. As used herein the phrase “liver diseases” means
for example, non‐alcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH)
including advanced fibrosis stages F3 and F4, alcoholic fatty liver disease (AFLD), and alcohol
ic steatohepatitis (ASH). As used herein the phrase “renal diseases” means
for example, acute kidney disease, hyperoxaluria, chronic kidney disease, oxalate nephropathy, nephrocalcinosis, glomerulonephritis, and diabetic nephropathy; As used herein the phrase “ocular diseases” means
for example, diseases of the ocular epithelium, age‐related macular degeneration (AMD) (d
ry and wet), uveitis, corneal infection, diabetic retinopathy, optic nerve damage, dry eye, and glaucom
a. As used herein the phrase “skin diseases” means for example, dermatitis such as contact dermatitis and atopic dermatitis, contact hype
rsensitivity, sunburn, skin lesions, hidradenitis suppurativa (HS), other cyst‐causing skin diseases,
and acne conglobate. As used herein the phrase “psychological diseases”
means for example, depression, and psychological stress. As used herein the phrase “blood diseases” means
for example, sickle cell disease. As used herein, the term “administration” refers to providing a compound, or a pharmaceutical composition comprising the compound as described herein. The compound or composition can be administered by another person to
the subject or it can be self‐administered by the subject. Non‐limiting examples of routes of a
dministration are oral, parenteral (e.g., intravenous),
or topical. As used herein, the term “treatment” refers to a
n intervention that ameliorates a sign or symptom of a disease or pathological condition. As used herein, the terms “treatment”, “treat
and “treating,” with reference to a disease, pathological condition or symptom, also
refers to any observable beneficial effect of the treatment. The
beneficial effect can be evidenced, for example, by
a delayed onset of clinical symptoms of the disease
in a susceptible subject, a reduction in severity o
f some or all clinical symptoms of the disease, a slo
wer progression of the disease, a reduction in the
number of relapses of the disease, an improvement in
the overall health or well‐being of the subject,
or by other parameters well known in the art that
are specific to the particular disease. A prophylac
tic treatment is a treatment administered to a subject w
ho does not exhibit signs of a disease or exhibits
only early signs, for the purpose of decreasing the risk of developing pathology. A therapeutic treatment is a treatment administered to a subject after signs and symptoms of the disease have developed. As used herein, the term “subject” refers to an animal (e.g., a mammal, such as a human). A subject to be treated according to the
methods described herein may be one who has been diagnosed with a NLRP3 inflammasome dependent conditio
n, such as inflammation, an inflammatory disease, an immune disease, cancer, infections including viral infections; central nervous system diseases, metabolic diseases, cardiovascular diseases, respiratory diseases, liver diseases, renal diseases, ocular diseases, skin diseases, psychological
diseases or blood diseases. Diagnosis may be performed by any method or technique known in the art. One skilled in the art will understand that a subject t
o be treated according to the present disclosure may
have been subjected to standard tests or may have b
een identified, without examination, as one at risk due to the presence of one or more risk facto
rs associated with the disease or condition. The t
erm “patient” may be used interchangeably with the te
rm “subject.” A subject may refer to an adult
or pediatric subject. Compounds As detailed above, the present disclosure provides compounds showing significant activity as NLRP3 inflammasome antagonists (i.e., as
NLRP3 inflammasome inhibitors). Accordingly, in one embodiment, a compound is provide
d having structure (A): or a pharmaceutically acceptable salt, isomer, hydrate
, solvate or isotope thereof, wherein: X is O or NR
15 ; R
1 is H, OH, CF
3 , CHF
2 , C
1‐6 alkyl, C
3‐5 cycloalkyl, CN, F, Cl, OC
1‐6 alkyl or OCF
3 ; R
2 , R
3 , R
4 , and R
5 are independently H, CF
3 , CHF
2 , C
1‐6 alkyl, CN, F, Cl, OCF
3 , OC
1‐6 alkyl or C
3‐5 cycloalkyl; R
8 is H or halo; R
9 is H, C
3‐5 cycloalkyl, or C
1‐6 alkyl optionally substituted with one or more
R
9’ ; R
9’ is OH, F, CHF
2 , CF
3 or C
3‐5 cycloalkyl; R
10 and R
13 are independently H or halo; R
11 and R
12 are each, independently, H, halo, CF
3 , C
1‐6 alkyl, CN, OH or OC
1‐6 alkyl; R
15 is H or C
1‐6 alkyl; n is 1 or 2; wherein if R
1 is F, X is NR
15 and R
2 , R
3 , R
4 , R
5 , R
8 , R
11 and R
12 are each H, then R
9 is not ethyl; and wherein if R
1 is H or CH
3 , then R
9 is not H. Accordingly, in one embodiment, a compound is provide
d having structure (A): or a pharmaceutically acceptable salt, isomer, hydrate
, solvate or isotope thereof, wherein: X is O or NR
15 ; R
1 is H, OH, CF
3 , CHF
2 , C
1‐6 alkyl, C
3‐5 cycloalkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OC
1‐ 6 alkyl or OCF
3 ; R
2 , R
3 , R
4 , and R
5 are independently H, CF
3 , CHF
2 , C
1‐6 alkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OCF
3 , OC
1‐6 alkyl or C
3‐5 cycloalkyl; R
8 is H or halo; R
9 is H, C
3‐5 cycloalkyl, or C
1‐6 alkyl optionally substituted with one or more
R
9’ ; R
9’ is OH, F, CHF
2 , CF
3 or C
3‐5 cycloalkyl; R
10 and R
13 are independently H or halo; R
11 and R
12 are each, independently, H, halo, CF
3 , C
1‐6 alkyl, CN, OH or OC
1‐6 alkyl; R
15 is H, C
1‐6 alkyl, or C
3‐5 cycloalkyl; n is 1 or 2; wherein if R
1 is F, X is NR
15 and R
2 , R
3 , R
4 , R
5 , R
8 , R
11 and R
12 are each H, then R
9 is not ethyl; and wherein if R
1 is H or CH
3 , then R
9 is not H. Accordingly, in one embodiment, a compound is provide
d having structure (A): or a pharmaceutically acceptable salt, isomer, hydrate
, solvate or isotope thereof, wherein: X is O or NR
15 ; R
1 is H, OH, CF
3 , CHF
2 , C
1‐6 alkyl, C
3‐5 cycloalkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OC
1‐ 6 alkyl or OCF
3 ; R
2 and R
5 are independently H, CF
3 , CHF
2 , C
1‐6 alkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OCF
3 , OC
1‐6 alkyl or C
3‐5 cycloalkyl; R
3 and R
4 are independently H, CF
3 , C
1‐6 alkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OCF
3 , or C
3‐5 cycloalkyl; R
8 is H or halo; R
9 is H, C
3‐5 cycloalkyl, or C
1‐6 alkyl optionally substituted with one or more
R
9’ ; R
9’ is OH, F, CHF
2 , CF
3 or C
3‐5 cycloalkyl; R
10 and R
13 are independently H or halo; R
11 and R
12 are each, independently, H, halo, CF
3 , C
1‐6 alkyl, CN, OH or OC
1‐6 alkyl; R
15 is H, C
1‐6 alkyl, or C
3‐5 cycloalkyl; n is 1 or 2; wherein if R
1 is F, X is NR
15 and R
2 , R
3 , R
4 , R
5 , R
8 , R
11 and R
12 are each H, then R
9 is not ethyl; and wherein if R
1 is H or CH
3 , then R
9 is not H. Accordingly, in one embodiment, a compound is provide
d having structure (A): or a pharmaceutically acceptable salt, isomer, hydrate
, solvate or isotope thereof, wherein: X is O or NR
15 ; R
1 is OH, CF
3 , CHF
2 , C
1‐6 alkyl, C
3‐5 cycloalkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OC
1‐6 alkyl or OCF
3 ; R
2 and R
5 are independently H, CF
3 , CHF
2 , C
1‐6 alkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OCF
3 , OC
1‐6 alkyl or C
3‐5 cycloalkyl; R
3 and R
4 are independently H, CF
3 , C
1‐6 alkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OCF
3 , or C
3‐5 cycloalkyl; R
8 is H or halo; R
9 is H, C
3‐5 cycloalkyl, or C
1‐6 alkyl optionally substituted with one or more
R
9’ ; R
9’ is OH, F, CHF
2 , CF
3 or C
3‐5 cycloalkyl; R
10 and R
13 are independently H or halo; R
11 and R
12 are each, independently, H, halo, CF
3 , C
1‐6 alkyl, CN, OH or OC
1‐6 alkyl; R
15 is H, C
1‐6 alkyl, or C
3‐5 cycloalkyl; n is 1 or 2; wherein if R
1 is F, X is NR
15 and R
2 , R
3 , R
4 , R
5 , R
8 , R
11 and R
12 are each H, then R
9 is not ethyl; and wherein if R
1 is CH
3 , then R
9 is not H. In one embodiment, a compound is provided having str
ucture (A’): or a pharmaceutically acceptable salt, isomer, hydrate
, solvate or isotope thereof, wherein: (1) X is O or NR
15 ; R
1 is F; R
2 , R
3 , R
4 , and R
5 are independently H, CF
3 , CHF
2 , C
1‐6 alkyl, CN, F, Cl, OCF
3 , OC
1‐6 alkyl or C
3‐5 cycloalkyl; R
8 is H or halo; R
9 is H, C
3‐5 cycloalkyl, methyl or C
3‐6 alkyl optionally substituted with one or more
R
9’ ; R
9’ is OH, F, CHF
2 , CF
3 or C
3‐5 cycloalkyl; R
10 and R
13 are independently H or halo; R
11 and R
12 are each, independently, H, halo, CF
3 , C
1‐6 alkyl, CN, OH or OC
1‐6 alkyl; R
15 is H or C
1‐6 alkyl; n is 1 or 2; (2) X is O or NR
15 ; R
1 is H or methyl; R
2 , R
3 , R
4 , and R
5 are independently H, CF
3 , CHF
2 , C
1‐6 alkyl, CN, F, Cl, OCF
3 , OC
1‐6 alkyl or C
3‐5 cycloalkyl; R
8 is H or halo; R
9 is C
3‐5 cycloalkyl, or C
1‐6 alkyl optionally substituted with one or more
R
9’ ; R
9’ is OH, F, CHF
2 , CF
3 or C
3‐5 cycloalkyl; R
10 and R
13 are independently H or halo; R
11 and R
12 are each, independently, H, halo, CF
3 , C
1‐6 alkyl, CN, OH or OC
1‐6 alkyl; R
15 is H or C
1‐6 alkyl; n is 1 or 2; or (3) X is O or NR
15 ; R
1 is OH, CF
3 , CHF
2 , C
2‐6 alkyl, C
3‐5 cycloalkyl, CN, Cl, OC
1‐6 alkyl or OCF
3 ; R
2 , R
3 , R
4 , and R
5 are independently H, CF
3 , CHF
2 , C
1‐6 alkyl, CN, F, Cl, OCF
3 , OC
1‐6 alkyl or C
3‐5 cycloalkyl; R
8 is H or halo; R
9 is H, C
3‐5 cycloalkyl, or C
1‐6 alkyl optionally substituted with one or more
R
9’ ; R
9’ is OH, F, CHF
2 , CF
3 or C
3‐5 cycloalkyl; R
10 and R
13 are independently H or halo; R
11 and R
12 are each, independently, H, halo, CF
3 , C
1‐6 alkyl, CN, OH or OC
1‐6 alkyl; R
15 is H or C
1‐6 alkyl; and n is 1 or 2. In one embodiment, a compound is provided having str
ucture (A’): or a pharmaceutically acceptable salt, isomer, hydrate
, solvate or isotope thereof, wherein: (1) X is O or NR
15 ; R
1 is F; R
2 , R
3 , R
4 , and R
5 are independently H, CF
3 , CHF
2 , C
1‐6 alkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OCF
3 , OC
1‐6 alkyl or C
3‐5 cycloalkyl; R
8 is H or halo; R
9 is H, C
3‐5 cycloalkyl, methyl or C
3‐6 alkyl optionally substituted with one or more
R
9’ ; R
9’ is OH, F, CHF
2 , CF
3 or C
3‐5 cycloalkyl; R
10 and R
13 are independently H or halo; R
11 and R
12 are each, independently, H, halo, CF
3 , C
1‐6 alkyl, CN, OH or OC
1‐6 alkyl; R
15 is H, C
1‐6 alkyl or C
3‐5 cycloalkyl; n is 1 or 2; (2) X is O or NR
15 ; R
1 is H or methyl; R
2 , R
3 , R
4 , and R
5 are independently H, CF
3 , CHF
2 , C
1‐6 alkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OCF
3 , OC
1‐6 alkyl or C
3‐5 cycloalkyl; R
8 is H or halo; R
9 is C
3‐5 cycloalkyl, or C
1‐6 alkyl optionally substituted with one or more
R
9’ ; R
9’ is OH, F, CHF
2 , CF
3 or C
3‐5 cycloalkyl; R
10 and R
13 are independently H or halo; R
11 and R
12 are each, independently, H, halo, CF
3 , C
1‐6 alkyl, CN, OH or OC
1‐6 alkyl; R
15 is H, C
1‐6 alkyl or C
3‐5 cycloalkyl; n is 1 or 2; or (3) X is O or NR
15 ; R
1 is OH, CF
3 , CHF
2 , C
2‐6 alkyl, C
3‐5 cycloalkyl, CN, C
1‐6 cyanoalkyl, Cl, C(O)OH, OC
1‐6 alkyl or OCF
3 ; R
2 , R
3 , R
4 , and R
5 are independently H, CF
3 , CHF
2 , C
1‐6 alkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OCF
3 , OC
1‐6 alkyl or C
3‐5 cycloalkyl; R
8 is H or halo; R
9 is H, C
3‐5 cycloalkyl, or C
1‐6 alkyl optionally substituted with one or more
R
9’ ; R
9’ is OH, F, CHF
2 , CF
3 or C
3‐5 cycloalkyl; R
10 and R
13 are independently H or halo; R
11 and R
12 are each, independently, H, halo, CF
3 , C
1‐6 alkyl, CN, OH or OC
1‐6 alkyl; R
15 is H, C
1‐6 alkyl, or C
3‐5 cycloalkyl; and n is 1 or 2. In one embodiment, a compound is provided having str
ucture (A’): or a pharmaceutically acceptable salt, isomer, hydrate
, solvate or isotope thereof, wherein: (1) X is O or NR
15 ; R
1 is F; R
2 , R
3 , R
4 , and R
5 are independently H, CF
3 , CHF
2 , C
1‐6 alkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OCF
3 , OC
1‐6 alkyl or C
3‐5 cycloalkyl; R
8 is H or halo; R
9 is H, C
3‐5 cycloalkyl, methyl or C
3‐6 alkyl optionally substituted with one or more
R
9’ ; R
9’ is OH, F, CHF
2 , CF
3 or C
3‐5 cycloalkyl; R
10 and R
13 are independently H or halo; R
11 and R
12 are each, independently, H, halo, CF
3 , C
1‐6 alkyl, CN, OH or OC
1‐6 alkyl; R
15 is H, C
1‐6 alkyl or C
3‐5 cycloalkyl; n is 1 or 2; (2) X is O or NR
15 ; R
1 is H or methyl; R
2 and R
5 are independently H, CF
3 , CHF
2 , C
1‐6 alkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OCF
3 , OC
1‐6 alkyl or C
3‐5 cycloalkyl; R
3 and R
4 are independently H, CF
3 , C
1‐6 alkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OCF
3 or C
3‐5 cycloalkyl; R
8 is H or halo; R
9 is C
3‐5 cycloalkyl, or C
1‐6 alkyl optionally substituted with one or more
R
9’ ; R
9’ is OH, F, CHF
2 , CF
3 or C
3‐5 cycloalkyl; R
10 and R
13 are independently H or halo; R
11 and R
12 are each, independently, H, halo, CF
3 , C
1‐6 alkyl, CN, OH or OC
1‐6 alkyl; R
15 is H, C
1‐6 alkyl or C
3‐5 cycloalkyl; n is 1 or 2; or (3) X is O or NR
15 ; R
1 is OH, CF
3 , CHF
2 , C
2‐6 alkyl, C
3‐5 cycloalkyl, CN, C
1‐6 cyanoalkyl, Cl, C(O)OH, OC
1‐6 alkyl or OCF
3 ; R
2 and R
5 are independently H, CF
3 , CHF
2 , C
1‐6 alkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OCF
3 , OC
1‐6 alkyl or C
3‐5 cycloalkyl; R
3 and R
4 are independently H, CF
3 , C
1‐6 alkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OCF
3 or C
3‐5 cycloalkyl; R
8 is H or halo; R
9 is H, C
3‐5 cycloalkyl, or C
1‐6 alkyl optionally substituted with one or more
R
9’ ; R
9’ is OH, F, CHF
2 , CF
3 or C
3‐5 cycloalkyl; R
10 and R
13 are independently H or halo; R
11 and R
12 are each, independently, H, halo, CF
3 , C
1‐6 alkyl, CN, OH or OC
1‐6 alkyl; R
15 is H, C
1‐6 alkyl, or C
3‐5 cycloalkyl; and n is 1 or 2. In one embodiment, a compound is provided having str
ucture (A’): or a pharmaceutically acceptable salt, isomer, hydrate
, solvate or isotope thereof, wherein: (1) X is O or NR
15 ; R
1 is F; R
2 , R
3 , R
4 , and R
5 are independently H, CF
3 , CHF
2 , C
1‐6 alkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OCF
3 , OC
1‐6 alkyl or C
3‐5 cycloalkyl; R
8 is H or halo; R
9 is H, C
3‐5 cycloalkyl, methyl or C
3‐6 alkyl optionally substituted with one or more
R
9’ ; R
9’ is OH, F, CHF
2 , CF
3 or C
3‐5 cycloalkyl; R
10 and R
13 are independently H or halo; R
11 and R
12 are each, independently, H, halo, CF
3 , C
1‐6 alkyl, CN, OH or OC
1‐6 alkyl; R
15 is H, C
1‐6 alkyl or C
3‐5 cycloalkyl; n is 1 or 2; (2) X is O or NR
15 ; R
1 is H or methyl; R
2 and R
5 are independently H, CF
3 , CHF
2 , C
1‐6 alkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OCF
3 , OC
1‐6 alkyl or C
3‐5 cycloalkyl; R
3 and R
4 are independently H, CF
3 , C
1‐6 alkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OCF
3 or C
3‐5 cycloalkyl; R
8 is H or halo; R
9 is C
3‐5 cycloalkyl, or C
1‐6 alkyl optionally substituted with one or more
R
9’ ; R
9’ is OH, F, CHF
2 , CF
3 or C
3‐5 cycloalkyl; R
10 and R
13 are independently H or halo; R
11 and R
12 are each, independently, H, halo, CF
3 , C
1‐6 alkyl, CN, OH or OC
1‐6 alkyl; R
15 is H, C
1‐6 alkyl or C
3‐5 cycloalkyl; n is 1 or 2; (3) X is O or NR
15 ; R
1 is CF
3 or Cl; R
2 and R
5 are independently H, CF
3 , CHF
2 , C
1‐6 alkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OCF
3 , OC
1‐6 alkyl or C
3‐5 cycloalkyl; R
3 and R
4 are independently H, CF
3 , C
1‐6 alkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OCF
3 or C
3‐5 cycloalkyl; R
8 is H or halo; R
9 is H, C
3‐5 cycloalkyl, or C
1‐6 alkyl optionally substituted with one or more
R
9’ ; R
9’ is OH, F, CHF
2 , CF
3 or C
3‐5 cycloalkyl; R
10 and R
13 are independently H or halo; R
11 and R
12 are each, independently, H, halo, CF
3 , C
1‐6 alkyl, CN, OH or OC
1‐6 alkyl; R
15 is H, C
1‐6 alkyl, or C
3‐5 cycloalkyl; and n is 1 or 2; or (4) X is O or NR
15 ; R
1 is OH, CHF
2 , C
2‐6 alkyl, C
3‐5 cycloalkyl, CN, C
1‐6 cyanoalkyl, C(O)OH, OC
1‐6 alkyl or OCF
3 ; R
2 , R
3 , R
4 , and R
5 are independently H, CF
3 , CHF
2 , C
1‐6 alkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OCF
3 , OC
1‐6 alkyl or C
3‐5 cycloalkyl; R
8 is H or halo; R
9 is H, C
3‐5 cycloalkyl, or C
1‐6 alkyl optionally substituted with one or more
R
9’ ; R
9’ is OH, F, CHF
2 , CF
3 or C
3‐5 cycloalkyl; R
10 and R
13 are independently H or halo; R
11 and R
12 are each, independently, H, halo, CF
3 , C
1‐6 alkyl, CN, OH or OC
1‐6 alkyl; R
15 is H, C
1‐6 alkyl, or C
3‐5 cycloalkyl; and n is 1 or 2. In one embodiment, a compound is provided having str
ucture (A’): or a pharmaceutically acceptable salt, isomer, hydrate
, solvate or isotope thereof, wherein: (1) X is O or NR
15 ; R
1 is F; R
2 , R
3 , R
4 , and R
5 are independently H, CF
3 , CHF
2 , C
1‐6 alkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OCF
3 , OC
1‐6 alkyl or C
3‐5 cycloalkyl; R
8 is H or halo; R
9 is H, C
3‐5 cycloalkyl, methyl or C
3‐6 alkyl optionally substituted with one or more
R
9’ ; R
9’ is OH, F, CHF
2 , CF
3 or C
3‐5 cycloalkyl; R
10 and R
13 are independently H or halo; R
11 and R
12 are each, independently, H, halo, CF
3 , C
1‐6 alkyl, CN, OH or OC
1‐6 alkyl; R
15 is H, C
1‐6 alkyl or C
3‐5 cycloalkyl; n is 1 or 2; (2) X is O or NR
15 ; R
1 is methyl; R
2 and R
5 are independently H, CF
3 , CHF
2 , C
1‐6 alkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OCF
3 , OC
1‐6 alkyl or C
3‐5 cycloalkyl; R
3 and R
4 are independently H, CF
3 , C
1‐6 alkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OCF
3 or C
3‐5 cycloalkyl; R
8 is H or halo; R
9 is C
3‐5 cycloalkyl, or C
1‐6 alkyl optionally substituted with one or more
R
9’ ; R
9’ is OH, F, CHF
2 , CF
3 or C
3‐5 cycloalkyl; R
10 and R
13 are independently H or halo; R
11 and R
12 are each, independently, H, halo, CF
3 , C
1‐6 alkyl, CN, OH or OC
1‐6 alkyl; R
15 is H, C
1‐6 alkyl or C
3‐5 cycloalkyl; n is 1 or 2; or (3) X is O or NR
15 ; R
1 is OH, CF
3 , CHF
2 , C
2‐6 alkyl, C
3‐5 cycloalkyl, CN, C
1‐6 cyanoalkyl, Cl, C(O)OH, OC
1‐6 alkyl or OCF
3 ; R
2 and R
5 are independently H, CF
3 , CHF
2 , C
1‐6 alkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OCF
3 , OC
1‐6 alkyl or C
3‐5 cycloalkyl; R
3 and R
4 are independently H, CF
3 , C
1‐6 alkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OCF
3 or C
3‐5 cycloalkyl; R
8 is H or halo; R
9 is H, C
3‐5 cycloalkyl, or C
1‐6 alkyl optionally substituted with one or more
R
9’ ; R
9’ is OH, F, CHF
2 , CF
3 or C
3‐5 cycloalkyl; R
10 and R
13 are independently H or halo; R
11 and R
12 are each, independently, H, halo, CF
3 , C
1‐6 alkyl, CN, OH or OC
1‐6 alkyl; R
15 is H, C
1‐6 alkyl, or C
3‐5 cycloalkyl; and n is 1 or 2. In one embodiment, a compound is provided having str
ucture (B): or a pharmaceutically acceptable salt, isomer, hydrate
, solvate or isotope thereof, wherein: R
1 is H, OH, CF
3 , CHF
2 , C
1‐6 alkyl, C
3‐5 cycloalkyl, CN, F, Cl, OC
1‐6 alkyl or OCF
3 ; R
2 , R
3 , R
4 , and R
5 are independently H, CF
3 , CHF
2 , C
1‐6 alkyl, CN, F, Cl, OCF
3 , OC
1‐6 alkyl or C
3‐5 cycloalkyl; R
8 is H or halo; R
9 is H, C
3‐5 cycloalkyl, or C
1‐6 alkyl optionally substituted with one or more
R
9’ ; R
9’ is OH, F, CHF
2 , CF
3 or C
3‐5 cycloalkyl; R
10 and R
13 are independently H or halo; R
11 and R
12 are each, independently, H, halo, CF
3 , C
1‐6 alkyl, CN, OH or OC
1‐6 alkyl; R
15 is H or C
1‐6 alkyl; n is 1 or 2; wherein if R
1 is F and R
2 , R
3 , R
4 , R
5 , R
8 , R
11 and R
12 are each H, then R
9 is not ethyl; and wherein if R
1 is H or CH
3 , then R
9 is not H. In one embodiment, a compound is provided having str
ucture (B): or a pharmaceutically acceptable salt, isomer, hydrate
, solvate or isotope thereof, wherein: R
1 is H, OH, CF
3 , CHF
2 , C
1‐6 alkyl, C
3‐5 cycloalkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OC
1‐ 6 alkyl or OCF
3 ; R
2 , R
3 , R
4 , and R
5 are independently H, CF
3 , CHF
2 , C
1‐6 alkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OCF
3 , OC
1‐6 alkyl or C
3‐5 cycloalkyl; R
8 is H or halo; R
9 is H, C
3‐5 cycloalkyl, or C
1‐6 alkyl optionally substituted with one or more
R
9’ ; R
9’ is OH, F, CHF
2 , CF
3 or C
3‐5 cycloalkyl; R
10 and R
13 are independently H or halo; R
11 and R
12 are each, independently, H, halo, CF
3 , C
1‐6 alkyl, CN, OH or OC
1‐6 alkyl; R
15 is H, C
1‐6 alkyl or C
3‐5 cycloalkyl; n is 1 or 2; wherein if R
1 is F and R
2 , R
3 , R
4 , R
5 , R
8 , R
11 and R
12 are each H, then R
9 is not ethyl; and wherein if R
1 is H or CH
3 , then R
9 is not H. In one embodiment, a compound is provided having str
ucture (B): or a pharmaceutically acceptable salt, isomer, hydrate
, solvate or isotope thereof, wherein: R
1 is H, OH, CF
3 , CHF
2 , C
1‐6 alkyl, C
3‐5 cycloalkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OC
1‐ 6 alkyl or OCF
3 ; R
2 and R
5 are independently H, CF
3 , CHF
2 , C
1‐6 alkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OCF
3 , OC
1‐6 alkyl or C
3‐5 cycloalkyl; R
3 and R
4 are independently H, CF
3 , C
1‐6 alkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OCF
3 or C
3‐5 cycloalkyl; R
8 is H or halo; R
9 is H, C
3‐5 cycloalkyl, or C
1‐6 alkyl optionally substituted with one or more
R
9’ ; R
9’ is OH, F, CHF
2 , CF
3 or C
3‐5 cycloalkyl; R
10 and R
13 are independently H or halo; R
11 and R
12 are each, independently, H, halo, CF
3 , C
1‐6 alkyl, CN, OH or OC
1‐6 alkyl; R
15 is H, C
1‐6 alkyl or C
3‐5 cycloalkyl; n is 1 or 2; wherein if R
1 is F and R
2 , R
3 , R
4 , R
5 , R
8 , R
11 and R
12 are each H, then R
9 is not ethyl; and wherein if R
1 is H or CH
3 , then R
9 is not H. In one embodiment, a compound is provided having str
ucture (B): or a pharmaceutically acceptable salt, isomer, hydrate
, solvate or isotope thereof, wherein: R
1 is OH, CF
3 , CHF
2 , C
1‐6 alkyl, C
3‐5 cycloalkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OC
1‐6 alkyl or OCF
3 ; R
2 and R
5 are independently H, CF
3 , CHF
2 , C
1‐6 alkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OCF
3 , OC
1‐6 alkyl or C
3‐5 cycloalkyl; R
3 and R
4 are independently H, CF
3 , C
1‐6 alkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OCF
3 or C
3‐5 cycloalkyl; R
8 is H or halo; R
9 is H, C
3‐5 cycloalkyl, or C
1‐6 alkyl optionally substituted with one or more
R
9’ ; R
9’ is OH, F, CHF
2 , CF
3 or C
3‐5 cycloalkyl; R
10 and R
13 are independently H or halo; R
11 and R
12 are each, independently, H, halo, CF
3 , C
1‐6 alkyl, CN, OH or OC
1‐6 alkyl; R
15 is H, C
1‐6 alkyl or C
3‐5 cycloalkyl; n is 1 or 2; wherein if R
1 is F and R
2 , R
3 , R
4 , R
5 , R
8 , R
11 and R
12 are each H, then R
9 is not ethyl; and wherein if R
1 is H or CH
3 , then R
9 is not H. In one embodiment, a compound is provided having str
ucture (B’): or a pharmaceutically acceptable salt, isomer, hydrate
, solvate or isotope thereof, wherein: (1) R
1 is F; R
2 , R
3 , R
4 , and R
5 are independently H, CF
3 , CHF
2 , C
1‐6 alkyl, CN, F, Cl, OCF
3 , OC
1‐6 alkyl or C
3‐5 cycloalkyl; R
8 is H or halo; R
9 is H, C
3‐5 cycloalkyl, methyl or C
3‐6 alkyl optionally substituted with one or more
R
9’ ; R
9’ is OH, F, CHF
2 , CF
3 or C
3‐5 cycloalkyl; R
10 and R
13 are independently H or halo; R
11 and R
12 are each, independently, H, halo, CF
3 , C
1‐6 alkyl, CN, OH or OC
1‐6 alkyl; R
15 is H or C
1‐6 alkyl; n is 1 or 2; (2) R
1 is H or methyl; R
2 , R
3 , R
4 , and R
5 are independently H, CF
3 , CHF
2 , C
1‐6 alkyl, CN, F, Cl, OCF
3 , OC
1‐6 alkyl or C
3‐5 cycloalkyl; R
8 is H or halo; R
9 is C
3‐5 cycloalkyl, or C
1‐6 alkyl optionally substituted with one or more
R
9’ ; R
9’ is OH, F, CHF
2 , CF
3 or C
3‐5 cycloalkyl; R
10 and R
13 are independently H or halo; R
11 and R
12 are each, independently, H, halo, CF
3 , C
1‐6 alkyl, CN, OH or OC
1‐6 alkyl; R
15 is H or C
1‐6 alkyl; n is 1 or 2; or (3) R
1 is OH, CF
3 , CHF
2 , C
2‐6 alkyl, C
3‐5 cycloalkyl, CN, Cl, OC
1‐6 alkyl or OCF
3 ; R
2 , R
3 , R
4 , and R
5 are independently H, CF
3 , CHF
2 , C
1‐6 alkyl, CN, F, Cl, OCF
3 , OC
1‐6 alkyl or C
3‐5 cycloalkyl; R
8 is H or halo; R
9 is H, C
3‐5 cycloalkyl, or C
1‐6 alkyl optionally substituted with one or more
R
9’ ; R
9’ is OH, F, CHF
2 , CF
3 or C
3‐5 cycloalkyl; R
10 and R
13 are independently H or halo; R
11 and R
12 are each, independently, H, halo, CF
3 , C
1‐6 alkyl, CN, OH or OC
1‐6 alkyl; R
15 is H or C
1‐6 alkyl; and n is 1 or 2. In one embodiment, a compound is provided having str
ucture (B’): or a pharmaceutically acceptable salt, isomer, hydrate
, solvate or isotope thereof, wherein: (1) R
1 is F; R
2 , R
3 , R
4 , and R
5 are independently H, CF
3 , CHF
2 , C
1‐6 alkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OCF
3 , OC
1‐6 alkyl or C
3‐5 cycloalkyl; R
8 is H or halo; R
9 is H, C
3‐5 cycloalkyl, methyl or C
3‐6 alkyl optionally substituted with one or more
R
9’ ; R
9’ is OH, F, CHF
2 , CF
3 or C
3‐5 cycloalkyl; R
10 and R
13 are independently H or halo; R
11 and R
12 are each, independently, H, halo, CF
3 , C
1‐6 alkyl, CN, OH or OC
1‐6 alkyl; R
15 is H, C
1‐6 alkyl, C
3‐5 cycloalkyl; n is 1 or 2; (2) R
1 is H or methyl; R
2 , R
3 , R
4 , and R
5 are independently H, CF
3 , CHF
2 , C
1‐6 alkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OCF
3 , OC
1‐6 alkyl or C
3‐5 cycloalkyl; R
8 is H or halo; R
9 is C
3‐5 cycloalkyl, or C
1‐6 alkyl optionally substituted with one or more
R
9’ ; R
9’ is OH, F, CHF
2 , CF
3 or C
3‐5 cycloalkyl; R
10 and R
13 are independently H or halo; R
11 and R
12 are each, independently, H, halo, CF
3 , C
1‐6 alkyl, CN, OH or OC
1‐6 alkyl; R
15 is H, C
1‐6 alkyl or C
3‐5 cycloalkyl; n is 1 or 2; or (3) R
1 is OH, CF
3 , CHF
2 , C
2‐6 alkyl, C
3‐5 cycloalkyl, CN, C
1‐6 cyanoalkyl, Cl, C(O)OH, OC
1‐6 alkyl or OCF
3 ; R
2 , R
3 , R
4 , and R
5 are independently H, CF
3 , CHF
2 , C
1‐6 alkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OCF
3 , OC
1‐6 alkyl or C
3‐5 cycloalkyl; R
8 is H or halo; R
9 is H, C
3‐5 cycloalkyl, or C
1‐6 alkyl optionally substituted with one or more
R
9’ ; R
9’ is OH, F, CHF
2 , CF
3 or C
3‐5 cycloalkyl; R
10 and R
13 are independently H or halo; R
11 and R
12 are each, independently, H, halo, CF
3 , C
1‐6 alkyl, CN, OH or OC
1‐6 alkyl; R
15 is H, C
1‐6 alkyl or C
3‐5 cycloalkyl; and n is 1 or 2. In one embodiment, a compound is provided having str
ucture (B’): or a pharmaceutically acceptable salt, isomer, hydrate
, solvate or isotope thereof, wherein: (1) R
1 is F; R
2 , R
3 , R
4 , and R
5 are independently H, CF
3 , CHF
2 , C
1‐6 alkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OCF
3 , OC
1‐6 alkyl or C
3‐5 cycloalkyl; R
8 is H or halo; R
9 is H, C
3‐5 cycloalkyl, methyl or C
3‐6 alkyl optionally substituted with one or more
R
9’ ; R
9’ is OH, F, CHF
2 , CF
3 or C
3‐5 cycloalkyl; R
10 and R
13 are independently H or halo; R
11 and R
12 are each, independently, H, halo, CF
3 , C
1‐6 alkyl, CN, OH or OC
1‐6 alkyl; R
15 is H, C
1‐6 alkyl, C
3‐5 cycloalkyl; n is 1 or 2; (2) R
1 is H or methyl; R
2 and R
5 are independently H, CF
3 , CHF
2 , C
1‐6 alkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OCF
3 , OC
1‐6 alkyl or C
3‐5 cycloalkyl; R
3 and R
4 are independently H, CF
3 , C
1‐6 alkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OCF
3 or C
3‐5 cycloalkyl; R
8 is H or halo; R
9 is C
3‐5 cycloalkyl, or C
1‐6 alkyl optionally substituted with one or more
R
9’ ; R
9’ is OH, F, CHF
2 , CF
3 or C
3‐5 cycloalkyl; R
10 and R
13 are independently H or halo; R
11 and R
12 are each, independently, H, halo, CF
3 , C
1‐6 alkyl, CN, OH or OC
1‐6 alkyl; R
15 is H, C
1‐6 alkyl or C
3‐5 cycloalkyl; n is 1 or 2; or (3) R
1 is OH, CF
3 , CHF
2 , C
2‐6 alkyl, C
3‐5 cycloalkyl, CN, C
1‐6 cyanoalkyl, Cl, C(O)OH, OC
1‐6 alkyl or OCF
3 ; R
2 and R
5 are independently H, CF
3 , CHF
2 , C
1‐6 alkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OCF
3 , OC
1‐6 alkyl or C
3‐5 cycloalkyl; R
3 and R
4 are independently H, CF
3 , C
1‐6 alkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OCF
3 or C
3‐5 cycloalkyl; R
8 is H or halo; R
9 is H, C
3‐5 cycloalkyl, or C
1‐6 alkyl optionally substituted with one or more
R
9’ ; R
9’ is OH, F, CHF
2 , CF
3 or C
3‐5 cycloalkyl; R
10 and R
13 are independently H or halo; R
11 and R
12 are each, independently, H, halo, CF
3 , C
1‐6 alkyl, CN, OH or OC
1‐6 alkyl; R
15 is H, C
1‐6 alkyl or C
3‐5 cycloalkyl; and n is 1 or 2. In one embodiment, a compound is provided having str
ucture (B’): or a pharmaceutically acceptable salt, isomer, hydrate
, solvate or isotope thereof, wherein: (1) R
1 is F; R
2 , R
3 , R
4 , and R
5 are independently H, CF
3 , CHF
2 , C
1‐6 alkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OCF
3 , OC
1‐6 alkyl or C
3‐5 cycloalkyl; R
8 is H or halo; R
9 is H, C
3‐5 cycloalkyl, methyl or C
3‐6 alkyl optionally substituted with one or more
R
9’ ; R
9’ is OH, F, CHF
2 , CF
3 or C
3‐5 cycloalkyl; R
10 and R
13 are independently H or halo; R
11 and R
12 are each, independently, H, halo, CF
3 , C
1‐6 alkyl, CN, OH or OC
1‐6 alkyl; R
15 is H, C
1‐6 alkyl, C
3‐5 cycloalkyl; n is 1 or 2; (2) R
1 is H or methyl; R
2 and R
5 are independently H, CF
3 , CHF
2 , C
1‐6 alkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OCF
3 , OC
1‐6 alkyl or C
3‐5 cycloalkyl; R
3 and R
4 are independently H, CF
3 , C
1‐6 alkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OCF
3 or C
3‐5 cycloalkyl; R
8 is H or halo; R
9 is C
3‐5 cycloalkyl, or C
1‐6 alkyl optionally substituted with one or more
R
9’ ; R
9’ is OH, F, CHF
2 , CF
3 or C
3‐5 cycloalkyl; R
10 and R
13 are independently H or halo; R
11 and R
12 are each, independently, H, halo, CF
3 , C
1‐6 alkyl, CN, OH or OC
1‐6 alkyl; R
15 is H, C
1‐6 alkyl or C
3‐5 cycloalkyl; n is 1 or 2; (3) R
1 is CF
3 or Cl; R
2 and R
5 are independently H, CF
3 , CHF
2 , C
1‐6 alkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OCF
3 , OC
1‐6 alkyl or C
3‐5 cycloalkyl; R
3 and R
4 are independently H, CF
3 , C
1‐6 alkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OCF
3 or C
3‐5 cycloalkyl; R
8 is H or halo; R
9 is H, C
3‐5 cycloalkyl, or C
1‐6 alkyl optionally substituted with one or more
R
9’ ; R
9’ is OH, F, CHF
2 , CF
3 or C
3‐5 cycloalkyl; R
10 and R
13 are independently H or halo; R
11 and R
12 are each, independently, H, halo, CF
3 , C
1‐6 alkyl, CN, OH or OC
1‐6 alkyl; R
15 is H, C
1‐6 alkyl or C
3‐5 cycloalkyl; and n is 1 or 2; or (4) R
1 is OH, CHF
2 , C
2‐6 alkyl, C
3‐5 cycloalkyl, CN, C
1‐6 cyanoalkyl, C(O)OH, OC
1‐6 alkyl or OCF
3 ; R
2 , R
3 , R
4 , and R
5 are independently H, CF
3 , CHF
2 , C
1‐6 alkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OCF
3 , OC
1‐6 alkyl or C
3‐5 cycloalkyl; R
8 is H or halo; R
9 is H, C
3‐5 cycloalkyl, or C
1‐6 alkyl optionally substituted with one or more
R
9’ ; R
9’ is OH, F, CHF
2 , CF
3 or C
3‐5 cycloalkyl; R
10 and R
13 are independently H or halo; R
11 and R
12 are each, independently, H, halo, CF
3 , C
1‐6 alkyl, CN, OH or OC
1‐6 alkyl; R
15 is H, C
1‐6 alkyl or C
3‐5 cycloalkyl; and n is 1 or 2. In one embodiment, a compound is provided having str
ucture (B’): or a pharmaceutically acceptable salt, isomer, hydrate
, solvate or isotope thereof, wherein: (1) R
1 is F; R
2 , R
3 , R
4 , and R
5 are independently H, CF
3 , CHF
2 , C
1‐6 alkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OCF
3 , OC
1‐6 alkyl or C
3‐5 cycloalkyl; R
8 is H or halo; R
9 is H, C
3‐5 cycloalkyl, methyl or C
3‐6 alkyl optionally substituted with one or more
R
9’ ; R
9’ is OH, F, CHF
2 , CF
3 or C
3‐5 cycloalkyl; R
10 and R
13 are independently H or halo; R
11 and R
12 are each, independently, H, halo, CF
3 , C
1‐6 alkyl, CN, OH or OC
1‐6 alkyl; R
15 is H, C
1‐6 alkyl, C
3‐5 cycloalkyl; n is 1 or 2; (2) R
1 is methyl; R
2 and R
5 are independently H, CF
3 , CHF
2 , C
1‐6 alkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OCF
3 , OC
1‐6 alkyl or C
3‐5 cycloalkyl; R
3 and R
4 are independently H, CF
3 , C
1‐6 alkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OCF
3 or C
3‐5 cycloalkyl; R
8 is H or halo; R
9 is C
3‐5 cycloalkyl, or C
1‐6 alkyl optionally substituted with one or more
R
9’ ; R
9’ is OH, F, CHF
2 , CF
3 or C
3‐5 cycloalkyl; R
10 and R
13 are independently H or halo; R
11 and R
12 are each, independently, H, halo, CF
3 , C
1‐6 alkyl, CN, OH or OC
1‐6 alkyl; R
15 is H, C
1‐6 alkyl or C
3‐5 cycloalkyl; n is 1 or 2; or (3) R
1 is OH, CF
3 , CHF
2 , C
2‐6 alkyl, C
3‐5 cycloalkyl, CN, C
1‐6 cyanoalkyl, Cl, C(O)OH, OC
1‐6 alkyl or OCF
3 ; R
2 and R
5 are independently H, CF
3 , CHF
2 , C
1‐6 alkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OCF
3 , OC
1‐6 alkyl or C
3‐5 cycloalkyl; R
3 and R
4 are independently H, CF
3 , C
1‐6 alkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OCF
3 or C
3‐5 cycloalkyl; R
8 is H or halo; R
9 is H, C
3‐5 cycloalkyl, or C
1‐6 alkyl optionally substituted with one or more
R
9’ ; R
9’ is OH, F, CHF
2 , CF
3 or C
3‐5 cycloalkyl; R
10 and R
13 are independently H or halo; R
11 and R
12 are each, independently, H, halo, CF
3 , C
1‐6 alkyl, CN, OH or OC
1‐6 alkyl; R
15 is H, C
1‐6 alkyl or C
3‐5 cycloalkyl; and n is 1 or 2. In one embodiment, a compound is provided having str
ucture (C): or a pharmaceutically acceptable salt, isomer, hydrate
, solvate or isotope thereof, wherein: R
1 is H, OH, CF
3 , CHF
2 , C
1‐6 alkyl, C
3‐5 cycloalkyl, CN, F, Cl, OC
1‐6 alkyl or OCF
3 ; R
2 , R
3 , R
4 , and R
5 are independently H, CF
3 , CHF
2 , C
1‐6 alkyl, CN, F, Cl, OCF
3 , OC
1‐6 alkyl or C
3‐5 cycloalkyl; R
8 is H or F; R
9 is H, C
3‐5 cycloalkyl, or C
1‐6 alkyl optionally substituted with one or more
R
9’ ; R
9’ is OH, F, CHF
2 , CF
3 or C
3‐5 cycloalkyl; R
10 and R
13 are independently H or F; R
11 and R
12 are each, independently, H, F, Cl, CF
3 , C
1‐6 alkyl, CN, OH or OC
1‐6 alkyl; n is 1 or 2; wherein if R
1 is F and R
2 , R
3 , R
4 , R
5 , R
8 , R
11 and R
12 are each H, then R
9 is not ethyl; and wherein if R
1 is H or CH
3 , then R
9 is not H. In one embodiment, a compound is provided having str
ucture (C): or a pharmaceutically acceptable salt, isomer, hydrate
, solvate or isotope thereof, wherein: R
1 is H, OH, CF
3 , CHF
2 , C
1‐6 alkyl, C
3‐5 cycloalkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OC
1‐ 6 alkyl or OCF
3 ; R
2 , R
3 , R
4 , and R
5 are independently H, CF
3 , CHF
2 , C
1‐6 alkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OCF
3 , OC
1‐6 alkyl or C
3‐5 cycloalkyl; R
8 is H or F; R
9 is H, C
3‐5 cycloalkyl, or C
1‐6 alkyl optionally substituted with one or more
R
9’ ; R
9’ is OH, F, CHF
2 , CF
3 or C
3‐5 cycloalkyl; R
10 and R
13 are independently H or F; R
11 and R
12 are each, independently, H, F, Cl, CF
3 , C
1‐6 alkyl, CN, OH or OC
1‐6 alkyl; n is 1 or 2; wherein if R
1 is F and R
2 , R
3 , R
4 , R
5 , R
8 , R
11 and R
12 are each H, then R
9 is not ethyl; and wherein if R
1 is H or CH
3 , then R
9 is not H. In one embodiment, a compound is provided having str
ucture (C): or a pharmaceutically acceptable salt, isomer, hydrate
, solvate or isotope thereof, wherein: R
1 is H, OH, CF
3 , CHF
2 , C
1‐6 alkyl, C
3‐5 cycloalkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OC
1‐ 6 alkyl or OCF
3 ; R
2 and R
5 are independently H, CF
3 , CHF
2 , C
1‐6 alkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OCF
3 , OC
1‐6 alkyl or C
3‐5 cycloalkyl; R
3 and R
4 are independently H, CF
3 , C
1‐6 alkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OCF
3 or C
3‐5 cycloalkyl; R
8 is H or F; R
9 is H, C
3‐5 cycloalkyl, or C
1‐6 alkyl optionally substituted with one or more
R
9’ ; R
9’ is OH, F, CHF
2 , CF
3 or C
3‐5 cycloalkyl; R
10 and R
13 are independently H or F; R
11 and R
12 are each, independently, H, F, Cl, CF
3 , C
1‐6 alkyl, CN, OH or OC
1‐6 alkyl; n is 1 or 2; wherein if R
1 is F and R
2 , R
3 , R
4 , R
5 , R
8 , R
11 and R
12 are each H, then R
9 is not ethyl; and wherein if R
1 is H or CH
3 , then R
9 is not H. In one embodiment, a compound is provided having str
ucture (C): or a pharmaceutically acceptable salt, isomer, hydrate
, solvate or isotope thereof, wherein: R
1 is OH, CF
3 , CHF
2 , C
1‐6 alkyl, C
3‐5 cycloalkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OC
1‐6 alkyl or OCF
3 ; R
2 and R
5 are independently H, CF
3 , CHF
2 , C
1‐6 alkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OCF
3 , OC
1‐6 alkyl or C
3‐5 cycloalkyl; R
3 and R
4 are independently H, CF
3 , C
1‐6 alkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OCF
3 or C
3‐5 cycloalkyl; R
8 is H or F; R
9 is H, C
3‐5 cycloalkyl, or C
1‐6 alkyl optionally substituted with one or more
R
9’ ; R
9’ is OH, F, CHF
2 , CF
3 or C
3‐5 cycloalkyl; R
10 and R
13 are independently H or F; R
11 and R
12 are each, independently, H, F, Cl, CF
3 , C
1‐6 alkyl, CN, OH or OC
1‐6 alkyl; n is 1 or 2; wherein if R
1 is F and R
2 , R
3 , R
4 , R
5 , R
8 , R
11 and R
12 are each H, then R
9 is not ethyl; and wherein if R
1 is H or CH
3 , then R
9 is not H. In one embodiment, a compound is provided having str
ucture (C’): or a pharmaceutically acceptable salt, isomer, hydrate
, solvate or isotope thereof, wherein: (1) R
1 is F; R
2 , R
3 , R
4 , and R
5 are independently H, CF
3 , CHF
2 , C
1‐6 alkyl, CN, F, Cl, OCF
3 , OC
1‐6 alkyl or C
3‐5 cycloalkyl; R
8 is H or F; R
9 is H, C
3‐5 cycloalkyl, methyl or C
3‐6 alkyl optionally substituted with one or more
R
9’ ; R
9’ is OH, F, CHF
2 , CF
3 or C
3‐5 cycloalkyl; R
10 and R
13 are independently H or F; R
11 and R
12 are each, independently, H, F, Cl, CF
3 , C
1‐6 alkyl, CN, OH or OC
1‐6 alkyl; n is 1 or 2; (2) R
1 is H or methyl; R
2 , R
3 , R
4 , and R
5 are independently H, CF
3 , CHF
2 , C
1‐6 alkyl, CN, F, Cl, OCF
3 , OC
1‐6 alkyl or C
3‐5 cycloalkyl; R
8 is H or F; R
9 is C
3‐5 cycloalkyl, or C
1‐6 alkyl optionally substituted with one or more
R
9’ ; R
9’ is OH, F, CHF
2 , CF
3 or C
3‐5 cycloalkyl; R
10 and R
13 are independently H or F; R
11 and R
12 are each, independently, H, F, Cl, CF
3 , C
1‐6 alkyl, CN, OH or OC
1‐6 alkyl; n is 1 or 2; or (3) R
1 is OH, CF
3 , CHF
2 , C
2‐6 alkyl, C
3‐5 cycloalkyl, CN, Cl, OC
1‐6 alkyl or OCF
3 ; R
2 , R
3 , R
4 , and R
5 are independently H, CF
3 , CHF
2 , C
1‐6 alkyl, CN, F, Cl, OCF
3 , OC
1‐6 alkyl or C
3‐5 cycloalkyl; R
8 is H or F; R
9 is H, C
3‐5 cycloalkyl, or C
1‐6 alkyl optionally substituted with one or more
R
9’ ; R
9’ is OH, F, CHF
2 , CF
3 or C
3‐5 cycloalkyl; R
10 and R
13 are independently H or F; R
11 and R
12 are each, independently, H, F, Cl, CF
3 , C
1‐6 alkyl, CN, OH or OC
1‐6 alkyl; and n is 1 or 2. In one embodiment, a compound is provided having str
ucture (C’): or a pharmaceutically acceptable salt, isomer, hydrate
, solvate or isotope thereof, wherein: (1) R
1 is F; R
2 , R
3 , R
4 , and R
5 are independently H, CF
3 , CHF
2 , C
1‐6 alkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OCF
3 , OC
1‐6 alkyl or C
3‐5 cycloalkyl; R
8 is H or F; R
9 is H, C
3‐5 cycloalkyl, methyl or C
3‐6 alkyl optionally substituted with one or more
R
9’ ; R
9’ is OH, F, CHF
2 , CF
3 or C
3‐5 cycloalkyl; R
10 and R
13 are independently H or F; R
11 and R
12 are each, independently, H, F, Cl, CF
3 , C
1‐6 alkyl, CN, OH or OC
1‐6 alkyl; n is 1 or 2; (2) R
1 is H or methyl; R
2 , R
3 , R
4 , and R
5 are independently H, CF
3 , CHF
2 , C
1‐6 alkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OCF
3 , OC
1‐6 alkyl or C
3‐5 cycloalkyl; R
8 is H or F; R
9 is C
3‐5 cycloalkyl, or C
1‐6 alkyl optionally substituted with one or more
R
9’ ; R
9’ is OH, F, CHF
2 , CF
3 or C
3‐5 cycloalkyl; R
10 and R
13 are independently H or F; R
11 and R
12 are each, independently, H, F, Cl, CF
3 , C
1‐6 alkyl, CN, OH or OC
1‐6 alkyl; n is 1 or 2; or (3) R
1 is OH, CF
3 , CHF
2 , C
2‐6 alkyl, C
3‐5 cycloalkyl, CN, C
1‐6 cyanoalkyl, Cl, C(O)OH, OC
1‐6 alkyl or OCF
3 ; R
2 , R
3 , R
4 , and R
5 are independently H, CF
3 , CHF
2 , C
1‐6 alkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OCF
3 , OC
1‐6 alkyl or C
3‐5 cycloalkyl; R
8 is H or F; R
9 is H, C
3‐5 cycloalkyl, or C
1‐6 alkyl optionally substituted with one or more
R
9’ ; R
9’ is OH, F, CHF
2 , CF
3 or C
3‐5 cycloalkyl; R
10 and R
13 are independently H or F; R
11 and R
12 are each, independently, H, F, Cl, CF
3 , C
1‐6 alkyl, CN, OH or OC
1‐6 alkyl; and n is 1 or 2. In one embodiment, a compound is provided having str
ucture (C’): or a pharmaceutically acceptable salt, isomer, hydrate
, solvate or isotope thereof, wherein: (1) R
1 is F; R
2 , R
3 , R
4 , and R
5 are independently H, CF
3 , CHF
2 , C
1‐6 alkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OCF
3 , OC
1‐6 alkyl or C
3‐5 cycloalkyl; R
8 is H or F; R
9 is H, C
3‐5 cycloalkyl, methyl or C
3‐6 alkyl optionally substituted with one or more
R
9’ ; R
9’ is OH, F, CHF
2 , CF
3 or C
3‐5 cycloalkyl; R
10 and R
13 are independently H or F; R
11 and R
12 are each, independently, H, F, Cl, CF
3 , C
1‐6 alkyl, CN, OH or OC
1‐6 alkyl; n is 1 or 2; (2) R
1 is H or methyl; R
2 and R
5 are independently H, CF
3 , CHF
2 , C
1‐6 alkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OCF
3 , OC
1‐6 alkyl or C
3‐5 cycloalkyl; R
3 and R
4 are independently H, CF
3 , C
1‐6 alkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OCF
3 or C
3‐5 cycloalkyl; R
8 is H or F; R
9 is C
3‐5 cycloalkyl, or C
1‐6 alkyl optionally substituted with one or more
R
9’ ; R
9’ is OH, F, CHF
2 , CF
3 or C
3‐5 cycloalkyl; R
10 and R
13 are independently H or F; R
11 and R
12 are each, independently, H, F, Cl, CF
3 , C
1‐6 alkyl, CN, OH or OC
1‐6 alkyl; n is 1 or 2; or (3) R
1 is OH, CF
3 , CHF
2 , C
2‐6 alkyl, C
3‐5 cycloalkyl, CN, C
1‐6 cyanoalkyl, Cl, C(O)OH, OC
1‐6 alkyl or OCF
3 ; R
2 and R
5 are independently H, CF
3 , CHF
2 , C
1‐6 alkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OCF
3 , OC
1‐6 alkyl or C
3‐5 cycloalkyl; R
3 and R
4 are independently H, CF
3 , C
1‐6 alkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OCF
3 or C
3‐5 cycloalkyl; R
8 is H or F; R
9 is H, C
3‐5 cycloalkyl, or C
1‐6 alkyl optionally substituted with one or more
R
9’ ; R
9’ is OH, F, CHF
2 , CF
3 or C
3‐5 cycloalkyl; R
10 and R
13 are independently H or F; R
11 and R
12 are each, independently, H, F, Cl, CF
3 , C
1‐6 alkyl, CN, OH or OC
1‐6 alkyl; and n is 1 or 2. In one embodiment, a compound is provided having str
ucture (C’): or a pharmaceutically acceptable salt, isomer, hydrate
, solvate or isotope thereof, wherein: (1) R
1 is F; R
2 , R
3 , R
4 , and R
5 are independently H, CF
3 , CHF
2 , C
1‐6 alkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OCF
3 , OC
1‐6 alkyl or C
3‐5 cycloalkyl; R
8 is H or F; R
9 is H, C
3‐5 cycloalkyl, methyl or C
3‐6 alkyl optionally substituted with one or more
R
9’ ; R
9’ is OH, F, CHF
2 , CF
3 or C
3‐5 cycloalkyl; R
10 and R
13 are independently H or F; R
11 and R
12 are each, independently, H, F, Cl, CF
3 , C
1‐6 alkyl, CN, OH or OC
1‐6 alkyl; n is 1 or 2; (2) R
1 is H or methyl; R
2 and R
5 are independently H, CF
3 , CHF
2 , C
1‐6 alkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OCF
3 , OC
1‐6 alkyl or C
3‐5 cycloalkyl; R
3 and R
4 are independently H, CF
3 , C
1‐6 alkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OCF
3 or C
3‐5 cycloalkyl; R
8 is H or F; R
9 is C
3‐5 cycloalkyl, or C
1‐6 alkyl optionally substituted with one or more
R
9’ ; R
9’ is OH, F, CHF
2 , CF
3 or C
3‐5 cycloalkyl; R
10 and R
13 are independently H or F; R
11 and R
12 are each, independently, H, F, Cl, CF
3 , C
1‐6 alkyl, CN, OH or OC
1‐6 alkyl; n is 1 or 2; (3) R
1 is CF
3 or Cl; R
2 and R
5 are independently H, CF
3 , CHF
2 , C
1‐6 alkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OCF
3 , OC
1‐6 alkyl or C
3‐5 cycloalkyl; R
3 and R
4 are independently H, CF
3 , C
1‐6 alkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OCF
3 or C
3‐5 cycloalkyl; R
8 is H or F; R
9 is H, C
3‐5 cycloalkyl, or C
1‐6 alkyl optionally substituted with one or more
R
9’ ; R
9’ is OH, F, CHF
2 , CF
3 or C
3‐5 cycloalkyl; R
10 and R
13 are independently H or F; R
11 and R
12 are each, independently, H, F, Cl, CF
3 , C
1‐6 alkyl, CN, OH or OC
1‐6 alkyl; and n is 1 or 2; or (4) R
1 is OH, CHF
2 , C
2‐6 alkyl, C
3‐5 cycloalkyl, CN, C
1‐6 cyanoalkyl, C(O)OH, OC
1‐6 alkyl or OCF
3 ; R
2 , R
3 , R
4 , and R
5 are independently H, CF
3 , CHF
2 , C
1‐6 alkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OCF
3 , OC
1‐6 alkyl or C
3‐5 cycloalkyl; R
8 is H or F; R
9 is H, C
3‐5 cycloalkyl, or C
1‐6 alkyl optionally substituted with one or more
R
9’ ; R
9’ is OH, F, CHF
2 , CF
3 or C
3‐5 cycloalkyl; R
10 and R
13 are independently H or F; R
11 and R
12 are each, independently, H, F, Cl, CF
3 , C
1‐6 alkyl, CN, OH or OC
1‐6 alkyl; and n is 1 or 2; or In one embodiment, a compound is provided having str
ucture (C’): (C’) or a pharmaceutically acceptable salt, isomer, hydrate
, solvate or isotope thereof, wherein: (1) R
1 is F; R
2 , R
3 , R
4 , and R
5 are independently H, CF
3 , CHF
2 , C
1‐6 alkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OCF
3 , OC
1‐6 alkyl or C
3‐5 cycloalkyl; R
8 is H or F; R
9 is H, C
3‐5 cycloalkyl, methyl or C
3‐6 alkyl optionally substituted with one or more
R
9’ ; R
9’ is OH, F, CHF
2 , CF
3 or C
3‐5 cycloalkyl; R
10 and R
13 are independently H or F; R
11 and R
12 are each, independently, H, F, Cl, CF
3 , C
1‐6 alkyl, CN, OH or OC
1‐6 alkyl; n is 1 or 2; (2) R
1 is methyl; R
2 and R
5 are independently H, CF
3 , CHF
2 , C
1‐6 alkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OCF
3 , OC
1‐6 alkyl or C
3‐5 cycloalkyl; R
3 and R
4 are independently H, CF
3 , C
1‐6 alkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OCF
3 or C
3‐5 cycloalkyl; R
8 is H or F; R
9 is C
3‐5 cycloalkyl, or C
1‐6 alkyl optionally substituted with one or more
R
9’ ; R
9’ is OH, F, CHF
2 , CF
3 or C
3‐5 cycloalkyl; R
10 and R
13 are independently H or F; R
11 and R
12 are each, independently, H, F, Cl, CF
3 , C
1‐6 alkyl, CN, OH or OC
1‐6 alkyl; n is 1 or 2; or (3) R
1 is OH, CF
3 , CHF
2 , C
2‐6 alkyl, C
3‐5 cycloalkyl, CN, C
1‐6 cyanoalkyl, Cl, C(O)OH, OC
1‐6 alkyl or OCF
3 ; R
2 and R
5 are independently H, CF
3 , CHF
2 , C
1‐6 alkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OCF
3 , OC
1‐6 alkyl or C
3‐5 cycloalkyl; R
3 and R
4 are independently H, CF
3 , C
1‐6 alkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OCF
3 or C
3‐5 cycloalkyl; R
8 is H or F; R
9 is H, C
3‐5 cycloalkyl, or C
1‐6 alkyl optionally substituted with one or more
R
9’ ; R
9’ is OH, F, CHF
2 , CF
3 or C
3‐5 cycloalkyl; R
10 and R
13 are independently H or F; R
11 and R
12 are each, independently, H, F, Cl, CF
3 , C
1‐6 alkyl, CN, OH or OC
1‐6 alkyl; and n is 1 or 2. In one embodiment, a compound is provided having str
ucture (D): or a pharmaceutically acceptable salt, isomer, hydrate
, solvate or isotope thereof, wherein: R
1 is H, OH, CF
3 , CHF
2 , C
1‐6 alkyl, C
3‐5 cycloalkyl, CN, F, Cl, OC
1‐6 alkyl or OCF
3 ; R
2 , R
3 , R
4 , and R
5 are independently H, CF
3 , CHF
2 , C
1‐6 alkyl, CN, F, Cl, OCF
3 , OC
1‐6 alkyl or C
3‐5 cycloalkyl; R
8 is H or F; R
9 is H, C
3‐5 cycloalkyl, or C
1‐6 alkyl optionally substituted with one or more
R
9’ ; R
9’ is OH, F, CHF
2 , CF
3 or C
3‐5 cycloalkyl; R
10 and R
13 are independently H or F; R
11 and R
12 are each, independently, H, F, Cl, CF
3 , C
1‐6 alkyl, CN, OH or OC
1‐6 alkyl; and n is 1 or 2. In one embodiment, a compound is provided having str
ucture (D): or a pharmaceutically acceptable salt, isomer, hydrate
, solvate or isotope thereof, wherein: R
1 is H, OH, CF
3 , CHF
2 , C
1‐6 alkyl, C
3‐5 cycloalkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OC
1‐ 6 alkyl or OCF
3 ; R
2 , R
3 , R
4 , and R
5 are independently H, CF
3 , CHF
2 , C
1‐6 alkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OCF
3 , OC
1‐6 alkyl or C
3‐5 cycloalkyl; R
8 is H or F; R
9 is H, C
3‐5 cycloalkyl, or C
1‐6 alkyl optionally substituted with one or more
R
9’ ; R
9’ is OH, F, CHF
2 , CF
3 or C
3‐5 cycloalkyl; R
10 and R
13 are independently H or F; R
11 and R
12 are each, independently, H, F, Cl, CF
3 , C
1‐6 alkyl, CN, OH or OC
1‐6 alkyl; and n is 1 or 2. In one embodiment, a compound is provided having str
ucture (I): (I) or a pharmaceutically acceptable salt, isomer, hydrate
, solvate or isotope thereof, wherein: R
1 is H, CF
3 , C
1‐6 alkyl, C
3‐5 cycloalkyl, CN, F, Cl, OC
1‐6 alkyl or OCF
3 ; R
2 , R
3 , R
4 , and R
5 are independently H, CF
3 , C
1‐6 alkyl, CN, F, Cl or OC
1‐6 alkyl; R
8 is H or F; R
9 is H, C
3‐5 cycloalkyl, or C
1‐6 alkyl optionally substituted with one or more
R
9’ ; R
9’ is OH, F, CF
2 , CF
3 , or C
3‐5 cycloalkyl; R
10 and R
13 are independently H or F; R
11 is H, CF
3 , C
1‐6 alkyl or CN; R
12 is H, Cl or C
1‐6 alkyl; wherein if R
1 is F and R
2 , R
3 , R
4 , R
5 , R
8 , R
11 and R
12 are each H, then R
9 is not ethyl; and wherein if R
1 is H, then R
12 is not methyl or H. In one embodiment, a compound is provided having str
ucture (I): or a pharmaceutically acceptable salt, isomer, hydrate
, solvate or isotope thereof, wherein: R
1 is H, CF
3 , C
1‐6 alkyl, C
3‐5 cycloalkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OC
1‐6 alkyl or OCF
3 ; R
2 , R
3 , R
4 , and R
5 are independently H, CF
3 , C
1‐6 alkyl, CN, F, Cl, C(O)OH or OC
1‐6 alkyl; R
8 is H or F; R
9 is H, C
3‐5 cycloalkyl, or C
1‐6 alkyl optionally substituted with one or more
R
9’ ; R
9’ is OH, F, CF
2 , CF
3 , or C
3‐5 cycloalkyl; R
10 and R
13 are independently H or F; R
11 is H, CF
3 , C
1‐6 alkyl or CN; R
12 is H, Cl or C
1‐6 alkyl; wherein if R
1 is F and R
2 , R
3 , R
4 , R
5 , R
8 , R
11 and R
12 are each H, then R
9 is not ethyl; and wherein if R
1 is H, then R
12 is not methyl or H. In one embodiment, a compound is provided having str
ucture (I): or a pharmaceutically acceptable salt, isomer, hydrate
, solvate or isotope thereof, wherein: R
1 is H, CF
3 , C
1‐6 alkyl, C
3‐5 cycloalkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OC
1‐6 alkyl or OCF
3 ; R
2 and R
5 are independently H, CF
3 , C
1‐6 alkyl, CN, F, Cl, C(O)OH or OC
1‐6 alkyl; R
3 and R
4 are independently H, CF
3 , C
1‐6 alkyl, OC
2‐6 alkyl, CN, F, Cl or C(O)OH; R
8 is H or F; R
9 is H, C
3‐5 cycloalkyl, or C
1‐6 alkyl optionally substituted with one or more
R
9’ ; R
9’ is OH, F, CF
2 , CF
3 , or C
3‐5 cycloalkyl; R
10 and R
13 are independently H or F; R
11 is H, CF
3 , C
1‐6 alkyl or CN; R
12 is H, Cl or C
1‐6 alkyl; wherein if R
1 is F and R
2 , R
3 , R
4 , R
5 , R
8 , R
11 and R
12 are each H, then R
9 is not ethyl; and wherein if R
1 is H, then R
12 is not methyl or H. In one embodiment, a compound is provided having str
ucture (I): or a pharmaceutically acceptable salt, isomer, hydrate
, solvate or isotope thereof, wherein: R
1 is CF
3 , C
1‐6 alkyl, C
3‐5 cycloalkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OC
1‐6 alkyl or OCF
3 ; R
2 and R
5 are independently H, CF
3 , C
1‐6 alkyl, CN, F, Cl, C(O)OH or OC
1‐6 alkyl; R
3 and R
4 are independently H, CF
3 , C
1‐6 alkyl, OC
2‐6 alkyl, CN, F, Cl or C(O)OH; R
8 is H or F; R
9 is H, C
3‐5 cycloalkyl, or C
1‐6 alkyl optionally substituted with one or more
R
9’ ; R
9’ is OH, F, CF
2 , CF
3 , or C
3‐5 cycloalkyl; R
10 and R
13 are independently H or F; R
11 is H, CF
3 , C
1‐6 alkyl or CN; R
12 is H, Cl or C
1‐6 alkyl; wherein if R
1 is F and R
2 , R
3 , R
4 , R
5 , R
8 , R
11 and R
12 are each H, then R
9 is not ethyl; and wherein if R
1 is H, then R
12 is not methyl or H. In one embodiment, a compound is provided having str
ucture (I): or a pharmaceutically acceptable salt, isomer, hydrate
, solvate or isotope thereof, wherein: R
1 is H, CF
3 , C
1‐6 alkyl, C
3‐5 cycloalkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OC
1‐6 alkyl or OCF
3 ; R
2 and R
5 are independently H, CF
3 , C
1‐6 alkyl, CN, F, Cl, C(O)OH or OC
1‐6 alkyl; R
3 and R
4 are independently H, CF
3 , C
1‐6 alkyl, CN, F, Cl or C(O)OH; R
8 is H or F; R
9 is H, C
3‐5 cycloalkyl, or C
1‐6 alkyl optionally substituted with one or more
R
9’ ; R
9’ is OH, F, CF
2 , CF
3 , or C
3‐5 cycloalkyl; R
10 and R
13 are independently H or F; R
11 is H, CF
3 , C
1‐6 alkyl or CN; R
12 is H, Cl or C
1‐6 alkyl; wherein if R
1 is F and R
2 , R
3 , R
4 , R
5 , R
8 , R
11 and R
12 are each H, then R
9 is not ethyl; and wherein if R
1 is H, then R
12 is not methyl or H. In one embodiment, a compound is provided having str
ucture (I): or a pharmaceutically acceptable salt, isomer, hydrate
, solvate or isotope thereof, wherein: R
1 is CF
3 , C
1‐6 alkyl, C
3‐5 cycloalkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OC
1‐6 alkyl or OCF
3 ; R
2 and R
5 are independently H, CF
3 , C
1‐6 alkyl, CN, F, Cl, C(O)OH or OC
1‐6 alkyl; R
3 and R
4 are independently H, CF
3 , C
1‐6 alkyl, CN, F, Cl or C(O)OH; R
8 is H or F; R
9 is H, C
3‐5 cycloalkyl, or C
1‐6 alkyl optionally substituted with one or more
R
9’ ; R
9’ is OH, F, CF
2 , CF
3 , or C
3‐5 cycloalkyl; R
10 and R
13 are independently H or F; R
11 is H, CF
3 , C
1‐6 alkyl or CN; R
12 is H, Cl or C
1‐6 alkyl; wherein if R
1 is F and R
2 , R
3 , R
4 , R
5 , R
8 , R
11 and R
12 are each H, then R
9 is not ethyl; and wherein if R
1 is H, then R
12 is not methyl or H. In one embodiment, a compound is provided having str
ucture (I’): or a pharmaceutically acceptable salt, isomer, hydrate
, solvate or isotope thereof, wherein: (1) R
1 is F; R
2 , R
3 , R
4 , and R
5 are independently H, CF
3 , CHF
2 , C
1‐6 alkyl, CN, F, Cl or OC
1‐6 alkyl; R
8 is H or F; R
9 is H, C
3‐5 cycloalkyl, methyl or C
3‐6 alkyl optionally substituted with one or more
R
9’ ; R
9’ is OH, F, CF
2 , CF
3 , or C
3‐5 cycloalkyl; R
10 and R
13 are independently H or F; R
11 is H, CF
3 , OCH
3 , C
1‐6 alkyl or CN; R
12 is H, CF
3 , OH, Cl or C
1‐6 alkyl; n is 1 or 2; (2) R
1 is H or methyl; R
2 , R
3 , R
4 , and R
5 are independently H, CF
3 , CHF
2 , C
1‐6 alkyl, CN, F, Cl or OC
1‐6 alkyl; R
8 is H or F; R
9 is C
3‐5 cycloalkyl, or C
1‐6 alkyl optionally substituted with one or more
R
9’ ; R
9’ is OH, F, CF
2 , CF
3 , or C
3‐5 cycloalkyl; R
10 and R
13 are independently H or F; R
11 is H, CF
3 , C
1‐6 alkyl or CN; R
12 is H, Cl or C
1‐6 alkyl; n is 1 or 2; or (3) R
1 is CF
3 , CHF
2 , C
2‐6 alkyl, C
3‐5 cycloalkyl, CN, Cl, OC
1‐6 alkyl or OCF
3 ; R
2 , R
3 , R
4 , and R
5 are independently H, CF
3 , CHF
2 , C
1‐6 alkyl, CN, F, Cl or OC
1‐6 alkyl; R
8 is H or F; R
9 is H, C
3‐5 cycloalkyl, or C
1‐6 alkyl optionally substituted with one or more
R
9’ ; R
9’ is OH, F, CF
2 , CF
3 , or C
3‐5 cycloalkyl; R
10 and R
13 are independently H or F; R
11 is H, CF
3 , OCH
3 , C
1‐6 alkyl or CN; R
12 is H, CF
3 , OH, Cl or C
1‐6 alkyl; and n is 1 or 2. In one embodiment, a compound is provided having str
ucture (I’): or a pharmaceutically acceptable salt, isomer, hydrate
, solvate or isotope thereof, wherein: (1) R
1 is F; R
2 , R
3 , R
4 , and R
5 are independently H, CF
3 , CHF
2 , C
1‐6 alkyl, CN, F, Cl, C(O)OH or OC
1‐6 alkyl; R
8 is H or F; R
9 is H, C
3‐5 cycloalkyl, methyl or C
3‐6 alkyl optionally substituted with one or more
R
9’ ; R
9’ is OH, F, CF
2 , CF
3 , or C
3‐5 cycloalkyl; R
10 and R
13 are independently H or F; R
11 is H, CF
3 , OCH
3 , C
1‐6 alkyl or CN; R
12 is H, CF
3 , OH, Cl or C
1‐6 alkyl; n is 1 or 2; (2) R
1 is H or methyl; R
2 , R
3 , R
4 , and R
5 are independently H, CF
3 , CHF
2 , C
1‐6 alkyl, CN, F, Cl, C(O)OH or OC
1‐6 alkyl; R
8 is H or F; R
9 is C
3‐5 cycloalkyl, or C
1‐6 alkyl optionally substituted with one or more
R
9’ ; R
9’ is OH, F, CF
2 , CF
3 , or C
3‐5 cycloalkyl; R
10 and R
13 are independently H or F; R
11 is H, CF
3 , C
1‐6 alkyl or CN; R
12 is H, Cl or C
1‐6 alkyl; n is 1 or 2; or (3) R
1 is CF
3 , CHF
2 , C
2‐6 alkyl, C
3‐5 cycloalkyl, CN, C
1‐6 cyanoalkyl, Cl, C(O)OH, OC
1‐6 alkyl or OCF
3 ; R
2 , R
3 , R
4 , and R
5 are independently H, CF
3 , CHF
2 , C
1‐6 alkyl, CN, F, Cl, C(O)OH or OC
1‐6 alkyl; R
8 is H or F; R
9 is H, C
3‐5 cycloalkyl, or C
1‐6 alkyl optionally substituted with one or more
R
9’ ; R
9’ is OH, F, CF
2 , CF
3 , or C
3‐5 cycloalkyl; R
10 and R
13 are independently H or F; R
11 is H, CF
3 , OCH
3 , C
1‐6 alkyl or CN; R
12 is H, CF
3 , OH, Cl or C
1‐6 alkyl; and n is 1 or 2. In one embodiment, a compound is provided having str
ucture (I’): or a pharmaceutically acceptable salt, isomer, hydrate
, solvate or isotope thereof, wherein: (1) R
1 is F; R
2 , R
3 , R
4 , and R
5 are independently H, CF
3 , CHF
2 , C
1‐6 alkyl, CN, F, Cl, C(O)OH or OC
1‐6 alkyl; R
8 is H or F; R
9 is H, C
3‐5 cycloalkyl, methyl or C
3‐6 alkyl optionally substituted with one or more
R
9’ ; R
9’ is OH, F, CF
2 , CF
3 , or C
3‐5 cycloalkyl; R
10 and R
13 are independently H or F; R
11 is H, CF
3 , OCH
3 , C
1‐6 alkyl or CN; R
12 is H, CF
3 , OH, Cl or C
1‐6 alkyl; n is 1 or 2; (2) R
1 is H or methyl; R
2 and R
5 are independently H, CF
3 , C
1‐6 alkyl, CN, F, Cl, C(O)OH or OC
1‐6 alkyl; R
3 and R
4 are independently H, CF
3 , C
1‐6 alkyl, CN, F, Cl or C(O)OH; R
8 is H or F; R
9 is C
3‐5 cycloalkyl, or C
1‐6 alkyl optionally substituted with one or more
R
9’ ; R
9’ is OH, F, CF
2 , CF
3 , or C
3‐5 cycloalkyl; R
10 and R
13 are independently H or F; R
11 is H, CF
3 , C
1‐6 alkyl or CN; R
12 is H, Cl or C
1‐6 alkyl; n is 1 or 2; or (3) R
1 is CF
3 , CHF
2 , C
2‐6 alkyl, C
3‐5 cycloalkyl, CN, C
1‐6 cyanoalkyl, Cl, C(O)OH, OC
1‐6 alkyl or OCF
3 ; R
2 and R
5 are independently H, CF
3 , C
1‐6 alkyl, CN, F, Cl, C(O)OH or OC
1‐6 alkyl; R
3 and R
4 are independently H, CF
3 , C
1‐6 alkyl, CN, F, Cl or C(O)OH; R
8 is H or F; R
9 is H, C
3‐5 cycloalkyl, or C
1‐6 alkyl optionally substituted with one or more
R
9’ ; R
9’ is OH, F, CF
2 , CF
3 , or C
3‐5 cycloalkyl; R
10 and R
13 are independently H or F; R
11 is H, CF
3 , OCH
3 , C
1‐6 alkyl or CN; R
12 is H, CF
3 , OH, Cl or C
1‐6 alkyl; and n is 1 or 2. In one embodiment, a compound is provided having str
ucture (I’): or a pharmaceutically acceptable salt, isomer, hydrate
, solvate or isotope thereof, wherein: (1) R
1 is F; R
2 , R
3 , R
4 , and R
5 are independently H, CF
3 , CHF
2 , C
1‐6 alkyl, CN, F, Cl, C(O)OH or OC
1‐6 alkyl; R
8 is H or F; R
9 is H, C
3‐5 cycloalkyl, methyl or C
3‐6 alkyl optionally substituted with one or more
R
9’ ; R
9’ is OH, F, CF
2 , CF
3 , or C
3‐5 cycloalkyl; R
10 and R
13 are independently H or F; R
11 is H, CF
3 , OCH
3 , C
1‐6 alkyl or CN; R
12 is H, CF
3 , OH, Cl or C
1‐6 alkyl; n is 1 or 2; (2) R
1 is H or methyl; R
2 and R
5 are independently H, CF
3 , C
1‐6 alkyl, CN, F, Cl, C(O)OH or OC
1‐6 alkyl; R
3 and R
4 are independently H, CF
3 , C
1‐6 alkyl, CN, F, Cl or C(O)OH; R
8 is H or F; R
9 is C
3‐5 cycloalkyl, or C
1‐6 alkyl optionally substituted with one or more
R
9’ ; R
9’ is OH, F, CF
2 , CF
3 , or C
3‐5 cycloalkyl; R
10 and R
13 are independently H or F; R
11 is H, CF
3 , C
1‐6 alkyl or CN; R
12 is H, Cl or C
1‐6 alkyl; n is 1 or 2; (3) R
1 is CF
3 or Cl; R
2 and R
5 are independently H, CF
3 , C
1‐6 alkyl, CN, F, Cl, C(O)OH or OC
1‐6 alkyl; R
3 and R
4 are independently H, CF
3 , C
1‐6 alkyl, CN, F, Cl or C(O)OH; R
8 is H or F; R
9 is H, C
3‐5 cycloalkyl, or C
1‐6 alkyl optionally substituted with one or more
R
9’ ; R
9’ is OH, F, CF
2 , CF
3 , or C
3‐5 cycloalkyl; R
10 and R
13 are independently H or F; R
11 is H, CF
3 , OCH
3 , C
1‐6 alkyl or CN; R
12 is H, CF
3 , OH, Cl or C
1‐6 alkyl; and n is 1 or 2; or (4) R
1 is CHF
2 , C
2‐6 alkyl, C
3‐5 cycloalkyl, CN, C
1‐6 cyanoalkyl, C(O)OH, OC
1‐6 alkyl or OCF
3 ; R
2 , R
3 , R
4 , and R
5 are independently H, CF
3 , CHF
2 , C
1‐6 alkyl, CN, F, Cl, C(O)OH or OC
1‐6 alkyl; R
8 is H or F; R
9 is H, C
3‐5 cycloalkyl, or C
1‐6 alkyl optionally substituted with one or more
R
9’ ; R
9’ is OH, F, CF
2 , CF
3 , or C
3‐5 cycloalkyl; R
10 and R
13 are independently H or F; R
11 is H, CF
3 , OCH
3 , C
1‐6 alkyl or CN; R
12 is H, CF
3 , OH, Cl or C
1‐6 alkyl; and n is 1 or 2. In one embodiment, a compound is provided having str
ucture (I’): or a pharmaceutically acceptable salt, isomer, hydrate
, solvate or isotope thereof, wherein: (1) R
1 is F; R
2 , R
3 , R
4 , and R
5 are independently H, CF
3 , CHF
2 , C
1‐6 alkyl, CN, F, Cl, C(O)OH or OC
1‐6 alkyl; R
8 is H or F; R
9 is H, C
3‐5 cycloalkyl, methyl or C
3‐6 alkyl optionally substituted with one or more
R
9’ ; R
9’ is OH, F, CF
2 , CF
3 , or C
3‐5 cycloalkyl; R
10 and R
13 are independently H or F; R
11 is H, CF
3 , OCH
3 , C
1‐6 alkyl or CN; R
12 is H, CF
3 , OH, Cl or C
1‐6 alkyl; n is 1 or 2; (2) R
1 is methyl; R
2 and R
5 are independently H, CF
3 , C
1‐6 alkyl, CN, F, Cl, C(O)OH or OC
1‐6 alkyl; R
3 and R
4 are independently H, CF
3 , C
1‐6 alkyl, CN, F, Cl or C(O)OH; R
8 is H or F; R
9 is C
3‐5 cycloalkyl, or C
1‐6 alkyl optionally substituted with one or more
R
9’ ; R
9’ is OH, F, CF
2 , CF
3 , or C
3‐5 cycloalkyl; R
10 and R
13 are independently H or F; R
11 is H, CF
3 , C
1‐6 alkyl or CN; R
12 is H, Cl or C
1‐6 alkyl; n is 1 or 2; or (3) R
1 is CF
3 , CHF
2 , C
2‐6 alkyl, C
3‐5 cycloalkyl, CN, C
1‐6 cyanoalkyl, Cl, C(O)OH, OC
1‐6 alkyl or OCF
3 ; R
2 and R
5 are independently H, CF
3 , C
1‐6 alkyl, CN, F, Cl, C(O)OH or OC
1‐6 alkyl; R
3 and R
4 are independently H, CF
3 , C
1‐6 alkyl, CN, F, Cl or C(O)OH; R
8 is H or F; R
9 is H, C
3‐5 cycloalkyl, or C
1‐6 alkyl optionally substituted with one or more
R
9’ ; R
9’ is OH, F, CF
2 , CF
3 , or C
3‐5 cycloalkyl; R
10 and R
13 are independently H or F; R
11 is H, CF
3 , OCH
3 , C
1‐6 alkyl or CN; R
12 is H, CF
3 , OH, Cl or C
1‐6 alkyl; and n is 1 or 2. In another embodiment, a compound is provided having
the following structure: or a pharmaceutically acceptable salt, isomer, hydrate
, solvate or isotope thereof, wherein: R
1 is CF
3 , C
1‐6 alkyl, C
3‐5 cycloalkyl, CN, F, or OCF
3 ; R
9 is C
1‐6 alkyl optionally substituted with one or more
R
9’ ; and wherein R
9’ is F or C
3‐5 cycloalkyl. In another embodiment, a compound is provided having
the following structure: or a pharmaceutically acceptable salt, isomer, hydrate
, solvate or isotope thereof, wherein: R
1 is CF
3 , C
1‐6 alkyl, C
3‐5 cycloalkyl, CN, C
1‐6 cyanoalkyl, F, C(O)OH or OCF
3 ; R
9 is C
1‐6 alkyl optionally substituted with one or more
R
9’ ; and wherein R
9’ is F or C
3‐5 cycloalkyl. In one embodiment, a compound is provided having the
following structure: or a pharmaceutically acceptable salt, isomer, hydrate
, solvate or isotope thereof. In one embodiment, a compound is provided having the
following structure: or a pharmaceutically acceptable salt, isomer, hydrate
, solvate or isotope thereof, wherein: R
1 is CF
3 or F. In one embodiment, a compound is provided having the
following structure: or a pharmaceutically acceptable salt, isomer, hydrate
, solvate or isotope thereof. In one embodiment, a compound is provided having the
following structure: or a pharmaceutically acceptable salt, isomer, hydrate
, solvate or isotope thereof, wherein: R
1 is CF
3 or F. In another embodiment, a compound is provided having
the following structure: or a pharmaceutically acceptable salt, isomer, hydrate
, solvate or isotope thereof, wherein: X is O or NR
15 ; R
1 is H, OH, CHF
2 , C
1‐6 alkyl, C
3‐5 cycloalkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OC
1‐6 alkyl or OCF
3 ; R
2 and R
5 are independently H, CF
3 , CHF
2 , C
1‐6 alkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OCF
3 , OC
1‐6 alkyl or C
3‐5 cycloalkyl; one of R
3 or R
4 is CHF
2 and the other is H, CF
3 , CHF
2 , C
1‐6 alkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OCF
3 , OC
1‐6 alkyl or C
3‐5 cycloalkyl; R
8 is H or halo; R
9 is H, C
3‐5 cycloalkyl, or C
1‐6 alkyl optionally substituted with one or more
R
9’ ; R
9’ is OH, F, CHF
2 , CF
3 or C
3‐5 cycloalkyl; R
10 and R
13 are independently H or halo; R
11 and R
12 are each, independently, H, halo, CF
3 , C
1‐6 alkyl, CN, OH or OC
1‐6 alkyl; R
15 is H, C
1‐6 alkyl or C
3‐5 cycloalkyl; n is 1 or 2; wherein if R
1 is F, X is NR
15 and R
2 , R
3 , R
4 , R
5 , R
8 , R
11 and R
12 are each H, then R
9 is not ethyl; and wherein if R
1 is H or CH
3 , then R
9 is not H. Accordingly, in one embodiment, a compound is provide
d having structure (II): or a pharmaceutically acceptable salt, isomer, hydrate
, solvate or isotope thereof, wherein: X is O or NR
15 ; R
1 is OH, CF
3 , CHF
2 , C
1‐6 alkyl, C
3‐5 cycloalkyl, CN, F, Cl, OC
1‐6 alkyl or OCF
3 ; R
2 , R
3 , R
4 , and R
5 are independently H, CF
3 , CHF
2 , C
1‐6 alkyl, CN, F, Cl, OCF
3 or OC
1‐6 alkyl; R
8 is H or halo; R
9 is C
3‐5 cycloalkyl, or C
1‐6 alkyl optionally substituted with one or more
R
9’ ; R
9’ is OH, F, CHF
2 , CF
3 or C
3‐5 cycloalkyl; R
10 and R
13 are independently H or halo; R
11 and R
12 are each, independently, H, halo, CF
3 , C
1‐6 alkyl, CN, OH or OC
1‐6 alkyl; R
15 is H or C
1‐6 alkyl; and wherein if R
1 is F and R
2 , R
3 , R
4 , R
5 , R
8 , R
11 and R
12 are each H, then R
9 is not tert‐butyl. Accordingly, in one embodiment, a compound is provide
d having structure (II): or a pharmaceutically acceptable salt, isomer, hydrate
, solvate or isotope thereof, wherein: X is O or NR
15 ; R
1 is OH, CF
3 , CHF
2 , C
1‐6 alkyl, C
3‐5 cycloalkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OC
1‐6 alkyl or OCF
3 ; R
2 , R
3 , R
4 , and R
5 are independently H, CF
3 , CHF
2 , C
1‐6 alkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OCF
3 or OC
1‐6 alkyl; R
8 is H or halo; R
9 is C
3‐5 cycloalkyl, or C
1‐6 alkyl optionally substituted with one or more
R
9’ ; R
9’ is OH, F, CHF
2 , CF
3 or C
3‐5 cycloalkyl; R
10 and R
13 are independently H or halo; R
11 and R
12 are each, independently, H, halo, CF
3 , C
1‐6 alkyl, CN, OH or OC
1‐6 alkyl; R
15 is H or C
1‐6 alkyl; and wherein if R
1 is F and R
2 , R
3 , R
4 , R
5 , R
8 , R
11 and R
12 are each H, then R
9 is not tert‐butyl. In one embodiment, a compound is provided having str
ucture (II’): or a pharmaceutically acceptable salt, isomer, hydrate
, solvate or isotope thereof, wherein: (1) R
1 is F; X is O or NR
15 ; R
2 , R
3 , R
4 , and R
5 are independently H, CF
3 , CHF
2 , C
1‐6 alkyl, CN, F, Cl or OC
1‐6 alkyl; R
8 is H or halo; R
9 is H, C
3‐5 cycloalkyl, methyl or C
3‐6 alkyl optionally substituted with one or more
R
9’ ; R
9’ is OH, F, CF
2 , CF
3 , or C
3‐5 cycloalkyl; R
10 and R
13 are independently H or halo; R
11 is H, CF
3 , OCH
3 , C
1‐6 alkyl or CN; R
12 is H, CF
3 , OH, Cl or C
1‐6 alkyl; R
15 is H or C
1‐6 alkyl; (2) R
1 is OH, CF
3 , CHF
2 , C
1‐6 alkyl, C
3‐5 cycloalkyl, CN, F, Cl, OC
1‐6 alkyl or OCF
3; X is O or NR
15 ; R
2 , R
3 , R
4 , and R
5 are independently H, CF
3 , CHF
2 , C
1‐6 alkyl, CN, F, Cl or OC
1‐6 alkyl; R
8 is H or halo; R
9 is H, C
3‐5 cycloalkyl, or C
1‐6 alkyl optionally substituted with one or more
R
9’ ; R
9’ is OH, F, CF
2 , CF
3 , or C
3‐5 cycloalkyl; R
10 and R
13 are independently H or halo; R
11 is H, CF
3 , OCH
3 , C
1‐6 alkyl or CN; R
12 is H, CF
3 , OH, Cl or C
1‐6 alkyl; and R
15 is H or C
1‐6 alkyl. In one embodiment, a compound is provided having str
ucture (II’): or a pharmaceutically acceptable salt, isomer, hydrate
, solvate or isotope thereof, wherein: (1) R
1 is F; X is O or NR
15 ; R
2 , R
3 , R
4 , and R
5 are independently H, CF
3 , CHF
2 , C
1‐6 alkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH or OC
1‐6 alkyl; R
8 is H or halo; R
9 is H, C
3‐5 cycloalkyl, methyl or C
3‐6 alkyl optionally substituted with one or more
R
9’ ; R
9’ is OH, F, CF
2 , CF
3 , or C
3‐5 cycloalkyl; R
10 and R
13 are independently H or halo; R
11 is H, CF
3 , OCH
3 , C
1‐6 alkyl or CN; R
12 is H, CF
3 , OH, Cl or C
1‐6 alkyl; R
15 is H or C
1‐6 alkyl; (2) R
1 is OH, CF
3 , CHF
2 , C
1‐6 alkyl, C
3‐5 cycloalkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OC
1‐6 alkyl or OCF
3; X is O or NR
15 ; R
2 , R
3 , R
4 , and R
5 are independently H, CF
3 , CHF
2 , C
1‐6 alkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH or OC
1‐6 alkyl; R
8 is H or halo; R
9 is H, C
3‐5 cycloalkyl, or C
1‐6 alkyl optionally substituted with one or more
R
9’ ; R
9’ is OH, F, CF
2 , CF
3 , or C
3‐5 cycloalkyl; R
10 and R
13 are independently H or halo; R
11 is H, CF
3 , OCH
3 , C
1‐6 alkyl or CN; R
12 is H, CF
3 , OH, Cl or C
1‐6 alkyl; and R
15 is H or C
1‐6 alkyl. In one embodiment, a compound is provided having the
following structure (IIa’): or a pharmaceutically acceptable salt, isomer, hydrate
, solvate or isotope thereof, wherein: R
1 is CF
3 or F. In some embodiments, X is O. In other embodiments, X is NR
15 . In some embodiments, when X is NR
15 ; R
1 is CH
3 , CF
3 , or Cl; and one of R
3 or R
4 is CHF
2 or OCH
3 then either (1) the other of R
3 or R
4 is not H or (2) R
2 or R
5 is not H. In some embodiments, when X is NH; R
1 is CH
3 , CF
3 , or Cl; and one of R
3 or R
4 is CHF
2 or OCH
3 then either (1) the other of R
3 or R
4 is not H or (2) R
2 or R
5 is not H. In some embodiments, R
11 is H, halo, CF
3 , C
1‐6 alkyl, CN, OH or OC
1‐6 alkyl. In some embodiments, R
12 is H, halo, CF
3 , C
1‐6 alkyl, CN, OH or OC
1‐6 alkyl. In some embodiments, R
11 and R
12 are each, independently, is H, halo, CF
3 , C
1‐6 alkyl, CN, OH or OC
1‐6 alkyl. In some embodiments, R
11 and R
12 are each, independently, is H, halo, CF
3 , C
1‐6 alkyl, CN, OH or OC
1‐6 alkyl. In another embodiment, R
11 and R
12 are not H. In some embodiments, R
11 is F, CF
3 , C
1‐6 alkyl, OH, OC
1‐6 alkyl or CN and R
12 is H. In some embodiments, R
11 is F, CF
3 , C
1‐6 alkyl, OC
1‐6 alkyl or CN and R
12 is H. In some embodiments, R
11 is methyl and R
12 is H. In some embodiments, R
11 is OH and R
12 is H. In some embodiments, R
11 is CF
3 and R
12 is H. In some embodiments, R
11 is CF
3 , C
1‐6 alkyl, or CN and R
12 is H. In other embodiments, R
11 is H and R
12 is F, CF
3 , CN, OC
1‐6 alkyl, Cl or C
1‐6 alkyl. In some embodiments, R
11 is H and R
12 is methyl. In some embodiments, R
11 is H and R
12 is CF
3 . In other embodiments, R
11 is H and R
12 is Cl or C
1‐6 alkyl. In yet other embodiments, both R
11 and R
12 are H. In some embodiments, both R
11 and R
12 are not H. In some embodiments, R
11 or R
12 is OH. In some embodiments, R
11 is methyl and R
12 is OH. In some embodiments, R
11 or R
12 is OCH
3 . In some embodiments, R
1 is H, OH, CF
3 , CHF
2 , C
1‐6 alkyl, C
3‐5 cycloalkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OC
1‐6 alkyl or OCF
3 . In some embodiments, R
1 is OH, CF
3 , CHF
2 , C
1‐6 alkyl, C
3‐5 cycloalkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OC
1‐6 alkyl or OCF
3 . In some embodiments, R
1 is H, OH, CHF
2 , C
2‐6 alkyl, C
3‐5 cycloalkyl, CN, C
1‐6 cyanoalkyl, F, C(O)OH, OC
1‐6 alkyl or OCF
3 . In some embodiments, R
1 is OH, CHF
2 , C
2‐6 alkyl, C
3‐5 cycloalkyl, CN, C
1‐6 cyanoalkyl, F, C(O)OH, OC
1‐6 alkyl or OCF
3 . In some embodiments, R
1 is H, OH, CHF
2 , C
3‐5 cycloalkyl, CN, C
1‐6 cyanoalkyl, F, C(O)OH, OC
1‐6 alkyl or OCF
3 . In some embodiments, R
1 is OH, CHF
2 , C
3‐5 cycloalkyl, CN, C
1‐6 cyanoalkyl, F, C(O)OH, OC
1‐6 alkyl or OCF
3 . In other embodiments, R
1 is H, CF
3 , C
1‐6 alkyl, C
3‐5 cycloalkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OC
1‐6 alkyl or OCF
3 . In other embodiments, R
1 is CF
3 , C
1‐6 alkyl, C
3‐5 cycloalkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OC
1‐6 alkyl or OCF
3 . In other embodiments, R
1 is CF
3 , C
1‐6 alkyl, C
3‐5 cycloalkyl, CN, C
1‐6 cyanoalkyl, F, C(O)OH or OCF
3 . In other embodiments, R
1 is CF
3 , CN, C
1‐6 cyanoalkyl, F or OCF
3 . In certain embodiments, R
1 is CF
3 , or F. In some embodiments, R
1 is H. In one embodiment, R
1 is CF
3 . In one embodiment, R
1 is CHF
2 . In another embodiment, R
1 is F. In some embodiments, R
1 is Cl. In other embodiments, R
1 is OCF
3 . In some embodiments, R
1 is CN. In other embodiments, R
1 is OH. In some embodiments, R
1 is C(O)OH. In some embodiments, R
1 is C
1‐6 alkyl. In certain embodiments, R
1 is methyl. In certain embodiments, R
1 is ethyl. In cerain embodiments, R
1 is isopropyl. In some embodiments, R
1 is C
1‐6 cyanoalkyl. In certain embodiments, R
1 is . In some embodiments, R
1 is OC
1‐6 alkyl. In certain embodiments, R
1 is OCH
3 . In some embodiments, R
1 is C
3‐5 cycloalkyl. In certain embodiments, R
1 is cyclopropyl. In certain embodiments, R
1 is cyclobutyl. In some embodiments, R
2 and R
5 are independently H, CF
3 , CHF
2 , C
1‐6 alkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OCF
3 , OC
1‐6 alkyl or C
3‐5 cycloalkyl; and R
3 and R
4 are independently H, CF
3 , C
1‐6 alkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OCF
3 , OC
2‐6 alkyl or C
3‐5 cycloalkyl. In some embodiments, R
2 and R
5 are independently H, CF
3 , CHF
2 , C
1‐6 alkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OCF
3 , OC
1‐6 alkyl or C
3‐5 cycloalkyl; and R
3 and R
4 are independently H, CF
3 , C
1‐6 alkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OCF
3 or C
3‐5 cycloalkyl. In some embodiments, R
2 , R
3 , R
4 , and R
5 are independently H, CF
3 , CHF
2 , C
1‐6 alkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OCF
3 , OC
1‐6 alkyl or C
3‐5 cycloalkyl. In some embodiments, R
2 , R
3 , R
4 , and R
5 are independently H, CF
3 , C
1‐6 alkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OCF
3 , OC
2‐6 alkyl or C
3‐5 cycloalkyl. In some embodiments, R
2 , R
3 , R
4 , and R
5 are independently H, CF
3 , C
1‐6 alkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OCF
3 , or C
3‐5 cycloalkyl. In other embodiments, R
2 , R
3 , R
4 , and R
5 are independently H, CF
3 , CHF
2 , C
1‐6 alkyl, CN, F, Cl, C(O)OH, OCF
3 , OC
1‐6 alkyl or C
3‐5 cycloalkyl. In certain embodiments, R
2 , R
3 , R
4 , and R
5 are independently H, CF
3 , C
1‐6 alkyl, CN, F, Cl, C(O)OH or OC
1‐6 alkyl. In one embodiment, R
2 and R
5 are independently H, C
1‐6 alkyl, F, Cl, CF
3 or CN. In some embodiments, R
2 is H, CF
3 , CHF
2 , C
1‐6 alkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OCF
3 , OC
1‐6 alkyl or C
3‐5 cycloalkyl. In other embodiments, R
2 is H, CF
3 , CHF
2 , C
1‐6 alkyl, CN, F, Cl, C(O)OH, OCF
3 , OC
1‐6 alkyl or C
3‐5 cycloalkyl. In certain embodiments, R
2 is H, CF
3 , C
1‐6 alkyl, CN, F, Cl, C(O)OH or OC
1‐6 alkyl. In one embodiment, R
2 is H. In other embodiments, R
2 is C
1‐6 alkyl. In certain embodiments, R
2 is methyl. In certain embodiments, R
2 is ethyl. In certain embodiments, R
2 is isopropyl.In some embodiments, R
2 is C
1‐6 cyanoalkyl. In certain embodiments, R
2 is . In some embodiments, R
2 is F. In yet another embodiment, R
2 is Cl. In some embodiments, R
2 is Br. In yet another embodiment, R
2 is I. In one embodiment, R
2 is CF
3 . In another embodiment, R
2 is CHF
2 . In some embodiments, R
2 is OCF
3 . In yet other embodiments, R
2 is OC
1‐6 alkyl. In certain embodiments, R
2 is OCH
3 . In another embodiment, R
2 is CN. In certain embodiments, R
2 is C(O)OH. In some embodiments, R
2 is C
3‐5 cycloalkyl. In certain embodiments, R
2 is cyclopropyl. In certain embodiments, R
2 is cyclobutyl. In some embodiments, R
5 is H, CF
3 , CHF
2 , C
1‐6 alkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OCF
3 , OC
1‐6 alkyl or C
3‐5 cycloalkyl. In other embodiments, R
5 is H, CF
3 , CHF
2 , C
1‐6 alkyl, CN, F, Cl, C(O)OH, OCF
3 , OC
1‐6 alkyl or C
3‐5 cycloalkyl. In certain embodiments, R
5 is H, CF
3 , C
1‐6 alkyl, CN, F, Cl, C(O)OH or OC
1‐6 alkyl. In some embodiments, R
5 is H. In yet other embodiments, R
5 is C
1‐6 alkyl. In certain embodiments, R
5 is methyl. In certain embodiments, R
5 is ethyl. In certain embodiments, R
5 is isopropyl.In some embodiments, R
5 is C
1‐6 cyanoalkyl. In certain embodiments, . In one embodiment, R
5 is F. In another embodiment, R
5 is Cl. In one embodiment, R
5 is Br. In another embodiment, R
5 is I. In some embodiments, R
5 is CF
3 . In another embodiment, R
5 is CHF
2 . In yet other embodiments, R
5 is OCF
3 . In yet other embodiments, R
5 is CN. In some embodiments, R
5 is OC
1‐6 alkyl. In certain embodiments, R
5 is OCH
3 . In certain embodiments, R
5 is C(O)OH. In some embodiments, R
5 is C
3‐5 cycloalkyl. In certain embodiments, R
5 is cyclopropyl. In certain embodiments, R
5 is cyclobutyl. In one embodiment, R
3 are R
4 are independently H, CF
3 , C
1‐6 alkyl, CN, F or Cl. In some embodiments, R
3 is H, CF
3 , CHF
2 , C
1‐6 alkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OCF
3 , OC
1‐6 alkyl or C
3‐5 cycloalkyl. In other embodiments, R
3 is H, CF
3 , CHF
2 , C
1‐6 alkyl, CN, F, Cl, C(O)OH, OCF
3 , OC
1‐6 alkyl or C
3‐5 cycloalkyl. In certain embodiments, R
3 is H, CF
3 , C
1‐6 alkyl, CN, F, Cl, C(O)OH or OC
1‐6 alkyl. In one embodiment, R
3 is H. In another embodiment, R
3 is CF
3 . In another embodiment, R
3 is CHF
2 . In some embodiments, R
3 is C
1‐6 alkyl. In certain embodiments, R
3 is methyl. In certain embodiments, R
3 is ethyl. In certain embodiments, R
3 is isopropyl.In some embodiments, R
3 is C
1‐6 cyanoalkyl. In certain embodiments, . In other embodiments, R
3 is CN. In yet other embodiments, R
3 is F. In one embodiment, R
3 is Cl. In one embodiment, R
3 is Br. In one embodiment, R
3 is I. In some embodiments, R
3 is OC
1‐6 alkyl. In certain embodiments, R
3 is OCH
3 . In certain embodiments, R
3 is C(O)OH. In some embodiments, R
3 is C
3‐5 cycloalkyl. In certain embodiments, R
3 is cyclopropyl. In certain embodiments, R
3 is cyclobutyl. In some embodiments, R
4 is H, CF
3 , CHF
2 , C
1‐6 alkyl, CN, C
1‐6 cyanoalkyl, F, Cl, C(O)OH, OCF
3 , OC
1‐6 alkyl or C
3‐5 cycloalkyl. In other embodiments, R
4 is H, CF
3 , CHF
2 , C
1‐6 alkyl, CN, F, Cl, C(O)OH, OCF
3 , OC
1‐6 alkyl or C
3‐5 cycloalkyl. In certain embodiments, R
4 is H, CF
3 , C
1‐6 alkyl, CN, F, Cl, C(O)OH or OC
1‐6 alkyl. In one embodiment, R
4 is H. In another embodiment, R
4 is CF
3 . In another embodiment, R
4 is CHF
2 . In some embodiments, R
4 is C
1‐6 alkyl. In certain embodiments, R
4 is methyl. In certain embodiments, R
4 is ethyl. In certain embodiments, R
4 is isopropyl.In some embodiments, R
4 is C
1‐6 cyanoalkyl. In certain embodiments, R
4 is . In one embodiment, R
4 is CN. In another embodiment, R
4 is F. In yet another embodiment, R
4 is Cl. In another embodiment, R
4 is Br. In yet another embodiment, R
4 is I. In some embodiments, R
4 is OC
1‐6 alkyl. In certain embodiments, R
4 is OCH
3 . In certain embodiments, R
4 is C(O)OH. In some embodiments, R
4 is C
3‐5 cycloalkyl. In certain embodiments, R
4 is cyclopropyl. In certain embodiments, R
4 is cyclobutyl. In one embodiment, R
8 is H. In another embodiment, R
8 is F. In another embodiment, R
8 is Cl. In another embodiment, R
8 is Br. In another embodiment, R
8 is I. In some embodiments, R
9 is H, C
3‐5 cycloalkyl, or C
1‐6 alkyl optionally substituted with one or more R
9’ . In some embodiments, R
9 is C
3‐5 cycloalkyl, or C
1‐6 alkyl optionally substituted with one or more R
9’ . In one embodiment, R
9 is H. In another embodiment, R
9 is not H. In yet another embodiment, R
9 is C
1‐6 alkyl. In certain embodiments, R
9 is methyl. In certain embodiments, R
9 is CD
3 . In certain embodiments, R
9 is ethyl. In certain embodiments, R
9 is isopropyl. In one embodiment, R
9 is C
1‐6 alkyl optionally substituted with one or more
F. In certain embodiments, R
9 is ‐CH
2 CH
2 F. In certain embodiments, R
9 is ‐CH
2 CHF
2 . In certain embodiments, R
9 is ‐CH
2 CF
3 . In some embodiments, R
9 is C
3‐5 cycloalkyl. In certain embodiments, R
9 is cyclopropyl. In some embodiments, R
9 is C
1‐6 alkyl optionally substituted with one or more
C
3‐5 cycloalkyl. In certain embodiments, R
9 is In some embodiments, R
9 is C
1‐6 alkyl optionally substituted with one or more
OH. In certain embodiments, R
9 is In another embodiment, R
10 and R
13 are both H. In one embodiment, R
10 and R
13 are both halo. In another embodiment, R
10 is H and R
13 is halo. In one embodiment, R
10 and R
13 are both F. In another embodiment, R
10 is H and R
13 is F. In some embodiments, R
10 is H. In some embodiments, R
10 is F. In some embodiments, R
10 is Cl. In some embodiments, R
10 is Br. In some embodiments, R
10 is I. In some embodiments, R
13 is H. In some embodiments, R
13 is F. In some embodiments, R
13 is Cl. In some embodiments, R
13 is Br. In some embodiments, R
13 is I. In some embodiments, R
15 is H. In other embodiments, R
15 is C
1‐6 alkyl. In certain embodiments, R
15 is methyl. In certain embodiments, R
15 is ethyl. In certain embodiments, R
15 is isopropyl. In certain embodiments, R
15 is C
3‐5 cycloalkyl. In certain embodiments, R
15 is cyclopropyl. In certain embodiments, R
15 is cyclobutyl. In certain embodiments, R
15 is cyclopentyl. In certain embodiments, n is 1. In certain embodiments, n is 2. In one embodiment, a compound is selected from one
one of the compounds listed in Table 1, or a pharmaceutically acceptable salt, i
somer, hydrate, solvate or isotope thereof. Table 1 Representative compounds having Structure (I)
97 Pharmaceutical Compositions In certain embodiments, the invention provides a phar
maceutical composition comprising a compound of structure (I), or a pharmac
eutically acceptable salt, isomer, hydrate, solvate or isotope thereof, together with at least one pharmaceutically acceptable carrier, diluent, or excipient. For example, the active compou
nd will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier
which can be in the form of an ampoule, capsule, sachet, paper, or other container. When the active
compound is mixed with a carrier, or when the carrier serves as a diluent, it can be solid,
semi‐solid, or liquid material that acts as a vehi
cle, excipient, or medium for the active compound. The active compound can be adso
rbed on a granular solid carrier, for example contained in a s
achet. Some examples of suitable carriers are water, salt solutions, alcohols, polyethylene glycols,
polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid, or
lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose, and polyvinylpyrrolidone. Similar
ly, the carrier or diluent can include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax. As used herein, the term “pharmaceutical composition
” refers to a composition containing one or more of the compounds described he
rein, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt t
hereof, formulated with a pharmaceutically acceptable carrier, which can also include other addi
tives, and manufactured or sold with the approval of a governmental regulatory agency as part of a therapeutic regimen for the treatment of disease in a mammal. Pharmaceutical compositions can be formulated, for example, for oral administration in unit dosage form
(e.g., a tablet, capsule, caplet, gelcap, or syrup); for topical administration (e.g., as a cream, gel, lotion, or ointment); for intravenous administration (e.g., as a sterile solution free of particulate emboli and in a solvent system suitable for intravenous use); for administration to a pediatric subject (e.g., solution, syrup, suspension, elixir, powder for reconstitution as suspe
nsion or solution, dispersible/effervescent tablet, chewable tablet, lollipop, freezer pops, troches, oral thin strips, orally disintegrating tablet, orally disintegrating strip, and sprinkle oral powder or granules); or in any other formulation described herein. Conventional procedures a
nd ingredients for the selection and preparation of suitable formulations are described, fo
r example, in Remington: The Science and Practice of Pharmacy, 21st Ed., Gennaro, Ed., Lippenc
ott Williams & Wilkins (2005) and in The United States Pharmacopeia: The National Formulary (US
P 36 NF31), published in 2013. In some embodiments, the pharmaceutical composition comprising a compound of structure (I) or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, with at least one pharmaceutically acceptable carrier, diluent, or excipient further comprises a second therapeutic agent. As used herein, the term “pharmaceutically acceptable carrier” refers to any ingredient other than the disclosed compounds, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof (e.g., a carrier capable of suspending or dissolving the active compound) and having the properties of being nontoxic and non‐ inflammatory in a patient. Excipients may include, for example: antiadherents, antioxidants, binders, coatings, compression aids, disintegrants, dye
s (colors), emollients, emulsifiers, fillers (diluents), film formers or coatings, flavors, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, sorbents, suspending or
dispersing agents, sweeteners, or waters of hydration. Exemplary excipients include, but are not limited to: butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, crosslinked polyvinyl pyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose,
lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methyl paraben, microcrystalline cellulose, polyethylene glycol, polyvinyl pyrrolidone, povidone, pregelatinized starch, propyl paraben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethyl cellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stea
ric acid, stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylito
l. The formulations can be mixed with auxiliary agents
which do not deleteriously react with the active compounds. Such additives can
include wetting agents, emulsifying and suspending agents, salt for influencing osmotic pressure, buffers and/or coloring
substances, preserving agents, sweetening agents, or flavoring agents. The compositions can also be sterilized if desired. The route of administration can be any route which
effectively transports the active compound of the invention to the appropriate
or desired site of action, such as oral, nasal, pulmonary, buccal, subdermal, intradermal, transdermal,
or parenteral, including intravenous, subcutaneous and/or intramuscular. In one embodiment,
the route of administration is oral. In another embodiment, the route of administration is to
pical. Dosage forms can be administered once a day, or mor
e than once a day, such as twice or thrice daily. Alternatively, dosage forms
can be administered less frequently than daily, such as every other day, or weekly, if found
to be advisable by a prescribing physician or drug’s prescribing information. Dosing regimens include, for example, dose titration to the extent necessary or useful for the indication to be
treated, thus allowing the patient’s body to adapt to the treatment, to minimize or avoid unwanted side effects associated with the treatment, and/or to maximize the therapeutic effect
of the present compounds. Other dosage forms include delayed or controlled‐release forms. Suitable dosage regimens and/or forms include those set out, for example, in the latest edition of the Physicians' Desk Reference, incorporated herein by reference. In one embodiment, the invention provides an oral ph
armaceutical composition comprising structure (I) or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, together with at least one pharmaceu
tically acceptable oral carrier, diluent, or excipient. In another embodiment, the invention provid
es a topical pharmaceutical composition comprising a compound of structure (I) or a pharmace
utically acceptable salt, isomer, hydrate, solvate or isotope thereof, together with at least one pharmaceutically acceptable topical carrier, diluent, or excipient. In another embodiment, there are provided methods of
making a composition of a compound described herein including formulating a compound of the invention with a pharmaceutically acceptable carrier or diluent. In some embodiments, the pharmaceutically acceptable carrier or diluent is suitable for oral a
dministration. In some such embodiments, the methods can further include the step of formulating
the composition into a tablet or capsule. In other embodiments, the pharmaceutically acceptable carrier or diluent is suitable for parenteral administration. In some such embodiments, t
he methods further include the step of lyophilizing the composition to form a lyophilized preparation. In some embodiments, the composition is formulated into a pediatric dosage for
m suitable for treating a pediatric subject. In certain embodiments, the invention provides a comp
ound having structure (I) or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof. Such compounds can be synthesized using standard synthetic
techniques known to those skilled in the art. For example, compounds of the present invention can be synthesized using appropriately modified synthetic procedures set forth
in the following Examples and Reaction Schemes. To this end, the reactions, processes, and synthetic
methods described herein are not limited to the specific conditions described
in the following experimental section, but rather are intended as a guide to one with suitable
skill in this field. For example, reactions may be carried out in any suitable solvent, or other reagents to perform the transformation[s] necessary. Generally, suitable solvents are protic or aprotic
solvents which are substantially non‐reactive with the reactants, the intermediates or products at the temperatures at whic
h the reactions are carried out (i.e., temperatures whi
ch may range from the freezing to boiling temperatures). A given reaction may be carried out i
n one solvent or a mixture of more than one solvent. Depending on the particular reaction, su
itable solvents for a particular work‐up following the reaction may be employed. All reagents, for which the synthesis is not describ
ed in the experimental part, are either commercially available, or are known compo
unds or may be formed from known compounds by known methods by a person skilled in t
he art. The compounds and intermediates produced according to the methods of the invention m
ay require purification. Purification of organic compounds is well known to a person skilled
in the art and there may be several ways of purifying the same compound. In some cases, no purification may be necessary. In some cases, the compounds may be purified by crystallization. In some cases, impurities may be stirred out using a suitable solvent. In some cases, the compounds may be purified by chromatography, particularly flash column chromatography
, using purpose‐made or prepacked silica gel cartridges and eluents such as gradients of solvents such as heptane, ether, ethyl acetate, acetonitrile, ethanol and the like. In some cases, the compounds may be purified
by preparative HPLC using methods as described. Purification methods as described herein may provide compounds of the present invention which possess a sufficiently basic
or acidic functionality in the form of a salt, such as, in the case of a compound of the present invention which is sufficiently basic, a trifluoroacetate or formate salt, or, in the case of
a compound of the present invention, which is sufficiently acidic, an ammonium salt. A salt o
f this type can either be transformed into its free base or free acid form, respectively, by variou
s methods known to a person skilled in the art, or be used as salts in subsequent biological a
ssays. It is to be understood that the specific form of a compound of the present invention as isolated and as described herein is not necessarily the only form in which said compound can
be applied to a biological assay in order to quantify the specific biological activity. Chemical names were generated using the ChemDraw naming software (Version 17.0.0.206) by PerkinElmer Informatics, Inc.
In some cases, generally accepted names of commercially available reagents were used in place of names generated by the naming software. EXAMPLES General Methods 1H NMR (400 MHz) spectra were obtained in solution of deuterochloroform (CDCl 3 ), deuteromethanol (CD 3 OD) or dimethyl sulfoxide – D 6 (DMSO). HPLC retention times, purities, and mass spectra (LCMS) were obtained using Shimadzu LCMS 2010 (Shim
pack XR‐ ODS 3.0*30 mm 2.2 μm) operating in ES (+) ionizati
on mode. Flow Rate: 0.8 mL/min, Acquire Time: 3 min, Wavelength: UV220, Oven, Temp.: 50 °C.
The following additional abbreviations are used: ethyl acetate (EtOAc), N,N‐ diisopropylethylamine (DIEA), water (H 2 O), , hydrochloridric acid (HCl), methanol (MeOH), dimethyl sulfoxide (DMSO), silica gel (SiO 2 ), , trifluoroacetic acid (TFA), 1‐methyl‐2
pyrrolidinone (NMP), cesium fluoride (CsF), (2,2′‐bis(diphenylphosphino)‐1,1′‐binaphthyl) (BINAP), palladium(II) acetate (Pd(OAc) 2 ), [1,1′‐bis(diphenylphosphino)ferrocene]dichloropalladium(
II) (Pd(dppf)Cl 2 ), potassium carbonate (K 2 CO 3 ), sodium sulfate (Na 2 SO 4 ), cesium carbonate (Cs 2 CO 3 ), ammonia (NH 3 ),tetrahydrofuran (THF), dichloromethane (DCM), ac
etonitrile (MeCN or ACN), retention time (RT), molecular weight (MW), room temperature (rt), hour (h), volume/volume (v/v), proton nuclear magnetic resonance ( 1 HNMR), formic acid (FA), sodium hydride (NaH), formaldehyde (HCHO), acetic acid (AcOH), (2‐Dicyclohexylphosphino‐2′,4′,6′‐ triisopropyl‐1,1′‐biphenyl)[2‐(2′‐amino‐1,1′
‐biphenyl)]palladium(II) methanesulfonate (XPhosPdG3), degree Celsius (oC), milligram (mg), gram (g), millimole (mmol), milliliter (mL), polyethylene (PE), molar (M), sodium bicarbonate (NaHC
O 3 ), potential of hydrogen (pH), sodium cyanoborohydride (NaBH 3 CN), preparative high‐performance liquid chromatography (prep‐ HPLC), normal (N). EXAMPLE 1 INTERMEDIATE GENERAL SYNTHETIC ROUTE A General Scheme 1 Synthesis of 6‐chloro‐4‐methyl‐3‐(4‐(trifluoro
methyl)phenyl)pyridazine and 3‐chloro‐4‐methyl‐ 6‐(4‐(trifluoromethyl)phenyl)pyridazine To a solution of 3,6‐dichloro‐4‐methyl‐pyridazin
e (6000 mg, 36.8 mmol) and [4‐ (trifluoromethyl)phenyl]boronic acid (6996 mg, 36.8 mmol) in 1,4‐dioxane (72 mL) were added Pd(dppf)Cl 2 (1800 mg, 2.46 mmol), K 2 CO 3 (15.24 g, 110 mmol) and H 2 O (24 mL) under nitrogen atmosphere. The resulting mixture was stirred
at 80 °C for 2 h. The mixture was then diluted with water (80 mL) and extracted with EtOAc
(4 x 50 mL). The combined organic layer was washed with brine (50 mL), dried over Na 2 SO 4 and concentrated under reduced pressure to afford crude residue. The crude was purified by Combi‐flash (silica gel, 330 g, 0‐15% ethyl acetate in petrol ether) twice to afford desired products 6‐chloro‐4‐methyl‐3‐[4‐ (trifluoromethyl)phenyl]pyridazine (1800 mg, 17.94%) and 6‐chloro‐4‐methyl‐3‐[4‐ (trifluoromethyl)phenyl]pyridazine (660 mg, 6.58%) in a
~3:1 ratio. EXAMPLE 2 GENERAL SYNTHETIC ROUTE B General Scheme 2 more generally, Synthesis of (R)‐5‐methyl‐N‐(1‐methylpiperidin
3‐yl)‐6‐(4‐(trifluoromethyl)phenyl)‐pyridazin‐3
‐ amine Synthesis of (R)‐6‐chloro‐5‐methyl‐N‐(1‐meth
ylpiperidin‐3‐yl)pyridazin‐3‐amine To a solution of 3,6‐dichloro‐4‐methyl‐pyridazin
e (8.56 g, 52.5 mmol) in NMP (50 mL) were added (3R)‐1‐methylpiperidin‐3‐amin
e (5.0 g, 43.8 mmol) and DIEA (11 mL, 65.7 mmol). The resulting mixture was stirred at 110 °C
for 14 h under nitrogen atmosphere. The mixture was then poured into water (100 mL) and ext
racted with EtOAc (3 x 100 mL). The organic layers were combined, dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to afford crude residue. The crude was purified by silica gel column chromatography (4.6% MeOH in DCM) to afford desired product (R)‐6‐chloro‐5‐methyl‐N‐(1‐methylpiperidin‐3
‐ yl)pyridazin‐3‐amine (5.30 g) as yellow solid. Synthesis of (R)‐5‐methyl‐N‐(1‐methylpiperidin
3‐yl)‐6‐(4‐(trifluoromethyl)phenyl)‐pyridazin‐3
‐ amine (Compound No. 3) To a mixture of 4,4,5,5‐tetramethyl‐2‐[4‐(trifluoromethyl)phenyl]‐
1,3,2‐ dioxaborolane (1.70 g, 6.23 mmol) and (R)‐6‐chloro‐5‐methyl‐N‐(1‐methylpiperidin‐3
‐ yl)pyridazin‐3‐amine (1.0 g, 4.15 mmol) in 1,4‐d
ioxane (30 mL) were added Pd(dppf)Cl 2 (0.460 g, 0.623 mmol) and CsF (1.89 g, 12.5 mmol). The re
sulting mixture was stirred at 90 °C for 14 h under nitrogen atmosphere. The mixture was then filte
red over Celite, and the filtrate cake was washed with EtOAc (30 mL). The filtrate was poured
into water (30 mL) and was extracted with EtOAc (3 x 30 mL). The organic layers were combined
, washed with brine (30 mL), dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to aff
ord crude residue. The crude was purified by silica gel column chromatography (10%
MeOH in DCM) to afford impure desired product (R)‐5‐methyl‐N‐(1‐methylpiperidin‐3‐yl)‐6‐
(4‐(trifluoromethyl)phenyl)pyridazin‐3‐ amine (900 mg) as brown solid. The desired product
was further purified by prep‐HPLC (0.05% NH 3 .H 2 O as additive) to afford pure desired product
(R)‐5‐methyl‐N‐(1‐methylpiperidin‐3‐yl)‐6‐
(4‐(trifluoromethyl)phenyl)‐pyridazin‐3‐amine (339
mg, 23.2% yield) as a brown solid.
EXAMPLE 3 GENERAL SYNTHETIC ROUTE C General Scheme 3 more generally, Synthesis of (R)‐2‐(3‐((5‐methyl‐6‐(4‐(trifl
uoromethyl)phenyl)pyridazin‐3‐yl)amino)‐piperidin‐ 1‐yl)ethan‐1‐ol Synthesis of tert‐butyl (3R)‐3‐[[5‐methyl‐6‐[
4‐(trifluoromethyl)phenyl]pyridazin‐3‐yl]‐ amino]piperidine‐1‐carboxylate To a mixture of tert‐butyl (3R)‐3‐aminopiperidine
‐1‐carboxylate (294 mg, 1.47 mmol) and 6‐chloro‐4‐methyl‐3‐[4‐(trifluoromet
hyl)phenyl]pyridazine (200 mg, 0.734 mmol) in toluene (2.6 mL) were added Cs 2 CO 3 (478 mg, 1.47 mmol, 2 eq), BINAP (64 mg, 0.
103 mmol, 0.14 eq) and Pd(OAc) 2 (12 mg, 0.0534 mmol, 0.07 eq). The resulting
mixture was stirred at 105 ^ for 16 h under nitrogen atmosphere. The mixture was
then diluted with water (8 mL) and extracted with EtOAc (4 x 8 mL). The combined organ
ic layer was dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to afford cru
de residue. The crude was purified by Combi‐flash (silica gel, 12 g, 10%‐100% ethyl ace
tate in petrol ether) to afford desired product tert‐butyl (3R)‐3‐[[5‐methyl‐6‐[4‐(trifluoromethyl)phenyl]p
yridazin‐3‐yl]amino]piperidine‐1‐ carboxylate (160 mg, 49.97%) as a yellow solid.
Synthesis of 5‐methyl‐N‐[(3R)‐3‐piperidyl]‐6
[4‐(trifluoromethyl)phenyl]pyridazin‐3‐amine To a solution of tert‐butyl (3R)‐3‐[[5‐methyl‐6‐[4‐(trifluoromethyl)phenyl]
pyridazin‐3‐yl]amino]piperidine‐1‐carboxylate (160
mg, 0.367 mmol) in 1,4‐dioxane (2 mL) was added HCl in dioxane (2.0 mL, 8.00 mmol, 4 M). The
resulting mixture was stirred at 25 ^ for 16 h. The mixture was then concentrated under reduced p
ressure and basified with NH 3 ∙H 2 O (27%) until pH~8. The mixture was concentrated under reduce
d pressure to afford crude residue. The crude was purified by prep‐HPLC (column: Phenomenex
C18 80 * 30 mm * 5 um; mobile phase: [water (ammonia hydroxide v/v)‐ACN]; B%: 5%‐95%, 10 min) to afford desired product 5‐ methyl‐N‐[(3R)‐3‐piperidyl]‐6‐[4‐(trifluoromet
hyl)phenyl]‐pyridazin‐3‐amine (26 mg, 21.48%) as
a white solid. Synthesis of 2‐[(3R)‐3‐[[5‐methyl‐6‐[4‐(trif
luoromethyl)phenyl]pyridazin‐3‐yl]amino]‐1‐ piperidyl]ethanol (Compound No. 15) To a mixture of 5‐methyl‐N‐[(3R)‐3‐piperidyl]‐6‐[4‐(trifluor
omethyl)‐ phenyl]pyridazin‐3‐amine (80 mg, 0.238 mmol) and 2‐bromoethanol (30 mg, 0.240 mmol) in MeCN (1 mL) was added K 2 CO 3 (65 mg, 0.471 mmol). The mixture was stirred
at 25 ^ for 16 h under nitrogen atmosphere. The resulting mixture was then diluted with water (4 mL) and extracted with EtOAc (6 x 4 mL). The combined organ
ic layer was concentrated under reduced pressure to afford crude residue. The crude was puri
fied by prep‐HPLC (column: Boston Prime C18 150 * 30 mm * 5 um; mobile phase: [water (amm
onia hydroxide v/v)‐ACN]; B%: 24%‐64%, 9 min) to afford desired product 2‐[(3R)‐3‐[[5
methyl‐6‐[4‐(trifluoromethyl)phenyl]pyridazin‐3‐ yl]amino]‐1‐piperidyl]ethanol (32 mg, 32.73%) as a
white solid. EXAMPLE 4 GENERAL SYNTHETIC ROUTE D General Scheme 5 more generally, Synthesis of N‐((3S,4R)‐4‐fluoro‐1‐methylpiperid
in‐3‐yl)‐5‐methyl‐6‐(4‐(trifluoromethyl)‐ phenyl)pyridazin‐3‐amine (Compound No. 74) To a mixture of 6‐chloro‐4‐methyl‐3‐(4‐(trif
luoromethyl)phenyl)pyridazine (120 mg, 0.440 mmol) and (3S,4R)‐4‐fluoro‐1‐methyl‐
piperidin‐3‐amine;hydrochloride (96 mg, 0.569 mmol) in toluene (1.6 mL) were added BINAP (40 mg, 0.0642 mmol), Cs 2 CO 3 (288 mg, 0.884 mmol), Pd(OAc) 2 (12 mg, 0.0534 mmol) under nitrogen atmosphere
. The resulting mixture was stirred at 105 o C for 16 h. The mixture was then diluted with water (5 mL) and extracted with EtOAc (3 x 5 mL). The combined organic layer was dried over anhydrous Na 2 SO 4 and concentrated to afford crude residue. The crude was
purified by prep‐HPLC (Boston Prime C18 150*30mm*5um; mobile phase: water (0.05% ammonia hydroxide v/v)‐ACN; B%: 31‐71%, 9min) to afford desired product N‐[(3S,4R)‐4‐fluoro‐1‐methyl‐3‐piperidyl]‐5
methyl‐6‐[4‐ (trifluoromethyl)phenyl]pyridazin‐3‐amine (2.4 mg, 1.
45%) as a white solid. EXAMPLE 5 GENERAL SYNTHETIC ROUTE E General Scheme 6 more generally,
Synthesis of (R)‐N,5‐dimethyl‐N‐(1‐methylpiperid
in‐3‐yl)‐6‐(4‐ (trifluoromethyl)phenyl)pyridazin‐3‐amine Synthesis of tert‐butyl (R)‐3‐(methyl(5‐methyl‐
6‐(4‐(trifluoromethyl)phenyl)pyridazin‐3‐ yl)amino)piperidine‐1‐carboxylate To a solution of tert‐butyl (R)‐3‐((5‐methyl‐6‐(4‐ (trifluoromethyl)phenyl)pyridazin‐3‐yl)amino)piperidine
1‐carboxylate (73 mg, 0.167 mmol) in DMF (5 mL) was added NaH (6.0 mg, 0.251 mmol) at 0 °C under nitrogen atmosphere. The mixture was stirred for 20 min at 0 °C. Iodomethan
e (47 mg, 0.335 mmol) was then added and the resulting mixture was stirred at 25 o C for an additional 16 h. The mixture was con
centrated under reduced pressure to afford crude residue. The crude was purified by column chromatography (SiO 2 , Petroleum ether/Ethyl acetate, 2:1 to 1:1) to afford impure desired product tert‐butyl (R)‐3‐(methyl(5‐methyl‐6‐(4‐(trifluoromethyl)phe
nyl)pyridazin‐3‐ yl)amino)piperidine‐1‐carboxylate (425 mg) as yellow
liquid. Synthesis of (R)‐N,5‐dimethyl‐N‐(piperidin‐3‐y
l)‐6‐(4‐(trifluoromethyl)phenyl)pyridazin‐3‐amine
To a solution of tert‐butyl (R)‐3‐(methyl(5‐methyl‐6‐(4‐ (trifluoromethyl)phenyl)pyridazin‐3‐yl)amino)piperidine
1‐carboxylate (425 mg, 0.943 mmol) in DCM (2 mL) was added TFA (1.0 mL, 13.2 mmol). The
mixture was stirred at 25 o C for 1 h under nitrogen atmosphere. The mixture was concentrated unde
r reduced pressure to afford crude residue, (R)‐N,5‐dimethyl‐N‐(piperidin‐3‐yl)‐6‐(4‐(
trifluoromethyl)phenyl)pyridazin‐3‐amine, which was used without purification for the next ste
p. Synthesis of (R)‐N,5‐dimethyl‐N‐(1‐methylpiperidin‐3‐yl)‐
6‐(4‐ (trifluoromethyl)phenyl)pyridazin‐3‐amine (Compound No
. 142) To a solution of (R)‐N,5‐dimethyl‐N‐(piperidin‐3‐yl)‐6‐(4‐ (trifluoromethyl)phenyl)pyridazin‐3‐amine (425 mg, 1.21 mmol) ) in DCE (2 mL) was added formaldehyde (73 mg, 2.43 mmol). AcOH (7.3 mg, 0.121
mmol) was then added dropwise, and the resulting mixture was stirred at 25 o C for 2 h. Sodium cyanoborohydride (113 mg, 1.82 mmol) was added, and the mixture was stirred at 25
o C for an additional16 h. The mixture was concentrated under reduced pressure to afford crude r
esidue. The crude was purified by column chromatography (SiO2, dichloromethane/methanol= 5:1) to afford desired product (R)‐N,5‐ dimethyl‐N‐(1‐methylpiperidin‐3‐yl)‐6‐(4‐(tr
ifluoromethyl)phenyl)pyridazin‐3‐amine (291 mg, 53%) as yellow solid. EXAMPLE 6 GENERAL SYNTHETIC ROUTE F General Scheme 7 more generally,
Synthesis of (R)‐4‐methyl‐6‐((1‐methylpiperidin
3‐yl)oxy)‐3‐(4‐ (trifluoromethyl)phenyl)pyridazine Synthesis of tert‐butyl (R)‐3‐((6‐chloro‐5‐me
thylpyridazin‐3‐yl)oxy)piperidine‐1‐carboxylate To a mixture of (R)‐tert‐butyl 3‐hydroxypiperidin
e‐1‐carboxylate (1.00 g, 4.97 mmol) in THF (10 mL) was added NaH (230 mg, 5.85 mmol) (60%
in mineral oil) portionwise at 0 o C. The mixture was stirred at 20 o C for 2 h under nitrogen atmosphere. 3,6‐dich
loro‐4‐methylpyridazine (830 mg, 5.07 mmol) was then added and the resulting mixture was stirred at 20 o C for an additional 14 h. The mixture was poured into water
(30 mL) and was extracted with EtOAc (3 X 30 mL). The organic layers were combined, washed wit
h brine (30 mL), dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to aff
ord crude residue. The crude residue was purified by silica gel column chromatography (30%
EtOAc in PE) to afford desired product tert‐butyl (R)‐3‐((6‐chloro‐5‐methylpyridazin‐3‐yl)oxy)pi
peridine‐1‐carboxylate (1.27 g, 78% yield) as a yellow solid. Synthesis of (R)‐3‐chloro‐4‐methyl‐6‐(piperidi
n‐3‐yloxy)pyridazine To a mixture of tert‐butyl (R)‐3‐((6‐chloro‐5‐methylpyridazin‐3‐yl)oxy)pi
peridine‐1‐ carboxylate (11.6 g, 35.4 mmol) in DCM (110 mL) was
added 4 M HCl in dioxane (100 mL). The mixture was stirred at 20 °C for 2 h. Saturated a
queous NaHCO 3 was then added to adjust pH~8‐ 9. The resulting mixture was extracted with EtOAc (3 X 100 mL). The organic layers were combined, washed with brine (2 X 100 mL), dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to afford crude product (R)‐3‐chloro‐4‐methyl‐6‐(piperidin‐3‐ yloxy)pyridazine as an off‐white solid, which was u
sed without further purification. Synthesis of (R)‐3‐chloro‐4‐methyl‐6‐((1‐met
hylpiperidin‐3‐yl)oxy)pyridazine To a mixture of (R)‐3‐chloro‐4‐methyl‐6‐(pip
eridin‐3‐yloxy)pyridazine (6.95 g) in THF (50 mL) and water (5 mL) were added HCHO (2.48 g, 30.5
mmol) (37% in water), NaBH 3 CN (2.88 g, 45.8 mmol) and AcOH (1.83 g, 30.5 mmol). The mixture was stirred at 50 °C for 2 h under nitrogen atmosphere. The mixture was then poured into
water (100 mL) and was extracted with EtOAc (3 X 100 mL). The organic layers were combine
d, washed with brine (2 X 100 mL), dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to aff
ord crude product (R)‐ 3‐chloro‐4‐methyl‐6‐((1‐methylpiperidin‐3‐yl
)oxy)pyridazine as brown oil which was used without further purification. Synthesis of (R)‐4‐methyl‐6‐((1‐methylpiperidin
3‐yl)oxy)‐3‐(4‐ (trifluoromethyl)phenyl)pyridazine (Compound No. 177) To a mixture of (R)‐3‐chloro‐4‐methyl‐6‐((1‐methylpiperidin‐
3‐yl)oxy)pyridazine (300 mg) in dioxane (3 mL) and water (0.3 mL) were added 4,4,5,5‐tetramethyl‐2‐[4‐ (trifluoromethyl)phenyl]‐1,3,2‐dioxaborolane (405 mg,
1.49 mmol), XPhosPdG3 (105 mg, 0.124 mmol) and Cs 2 CO 3 (1.21 g, 3.72 mmol). The mixture was stirred
at 100 °C for 16 h under nitrogen atmosphere. The mixture was then poured into water (
20 mL) and was extracted with EtOAc (3 X 30 mL). The organic layers were combined, washed with brine (2 X 30 mL), dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to aff
ord crude residue. The crude residue was purified by silica gel column chromatography (10% MeOH in DCM) followed by prep‐HPLC (0.025% FA as additive) to afford desired product (R)‐4‐methyl‐6‐((1‐ methylpiperidin‐3‐yl)oxy)‐3‐(4‐(trifluoromethyl)ph
enyl)pyridazine (10 mg, 2% yield) as an off‐ white solid. EXAMPLE 7 SYNTHESIS OF REPRESENTATIVE COMPOUNDS The Compounds listed in Table 2 below were prepared
by procedures similar to the ones described in the representative schemes found in
the Examples with appropriate variations in reactants, quatitites of reagents, prote
ctions and deprotections, solvents and reaction conditions. The characterization data of the
compounds are also summarized herein in Table 2. Table 2
153 EXAMPLE 8 NLRP3 INFLAMMASOME ACTIVATION AND CELL VIABILITY ASSES
SMENT IN THP1 MACROPHAGES THP1 – Human acute monocytic leukemia cells were c
ultured (ATCC, cat # TIB‐ 202) in Gibco RPMI‐1640 medium (ThermoFisher cat #
72400054) supplemented with 10% Heat Inactivated FBS at density between 3‐8 x10^5 viable
cells/ml. The cells were then subcultured when the cell concentration reached 8 x10 5 cells/mL (every 2‐3 days). To determine the compounds’ IC 50 , 1.75x10 4 cells/well were plated in CELLSTAR 384 well plates (Greiner cat # 781091) in 50ul /wel
l DMEM (ThermoFisher, cat # 10393021), 10% FBS, 1x GlutaMax (ThermoFisher, cat # 35050038) +
20 nM PMA (Sigma, cat # P1585) and used in the inner 224 wells of a 384 well plate. The p
aremeter wells were filled with 50 ul PBS and incubated at 37 ^C, 5% CO 2 for 48 hrs. After 48 hrs incubation, the PMA containg media was removed, and
changed for 40 ul/well of fresh DMEM, 10% FBS, 1x GlutMax
and incubated at 37 ^C, 5% CO 2 for 24 hrs. The following day the cells were primed with LPS (E
.coli) (Sigma, cat # L3129) at 20 ng/ml in DMEM, 10%FBS, 1x GlutMax for 3 hrs at
37 ^C, 5% CO 2. Following the LPS priming step, the cells were treat
ed with compounds at 10 uM top final concentration, 1:4 dilution, 8 times: (
10 uM, 2.5 uM, 0.625 uM, 0.156 uM, 0.039 uM, 0.0097 uM, 0.0024 uM, 0.0006 uM). DMSO was used
as a vehicle control, and MCC950 (InvivGen, cat # inh‐mcc) was used at 1 uM as a
postive control, and incubated for 1 hrs at 37 ^C, 5% CO 2. Following the 1 hr compound incubation, the NLRP3 in
flammasome activation step was conducted by treateing cells with Nigericin
(InvivoGen, cat # tlrl‐nig) at 6.7 uM final concentration for 3 hrs at 37 ^C, 5% CO 2. Thereafter, 30 ul samples of cells’ supernatants were collected for cytokine analysis which was conducted on Hu IL‐1 ^ AlphaLISA (Perkin Elemer, cat # AL220C) and Hu IL
‐6 AlphaLISA (Perkin Elemer, cat # AL220C). The cells’
viability was assessed by perfoming CellTiter‐ Glo Luminescent Assay (Promega, cat #G7572) according
to the manufacturer’s protocol. Cell viability assessment for select NLRP3 inflammasome modulators is displayed in Tables 3 and 4. For Table 3 ‐ The activity ranges are as follows:
“++++++” denotes IL‐1β activity ≤ 10 nM; “+++++” denotes IL‐1β activity >
10 nM and ≤ 50 nM; “++++” denotes IL‐1β
activity > 50 nM and ≤ 100 nM; “+++” denotes IL‐1β ac
tivity > 100 nM and ≤ 500 nM; and “++” de
notes IL‐ 1β activity > 500 nM and ≤ 1,000 nM; “+”
denotes IL‐1β activity > 1,000 nM. “*” den
otes not yet tested. For Table 4 – The activity ranges are as follows:
“++++” denotes IL‐6 activity ≤ 1 μM; “+++” denotes IL‐6 activity > 1 μM an
d ≤ 5 μM; “++” denotes IL‐6 activity >
5 μM and ≤ 10 μM; and “+” denotes IL‐6 activity of > 10
μM. “*” denotes not yet tested. Table 3 Attorney Docket No.: 151123.402P2 Table 4 The various embodiments described above can be combin
ed to provide further embodiments. All of the U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applicati
ons and non‐patent publications referred to in this specification and/or listed in the Application Data Sheet, including U.S. Provisional Application No. 63/294,619, filed December 29, 2021,
and U.S. Provisional Patent Application No. 63/341,955, filed on May 13, 2022, are incorpora
ted herein by reference, in their entirety. Aspects of the embodiments can be modified, if neces
sary, to employ concepts of the various patents, applications and publications to provide yet
further embodiments. These and other changes can be made to the embodime
nts in light of the above‐ detailed description. In general, in the following
claims, the terms used should not be construed to limit the claims to the specific embodiments disc
losed in the specification and the claims, but should be construed to include all possible embodimen
ts along with the full scope of equivalents to which such claims are entitled. Accordingly, the
claims are not limited by the disclosure.
