(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 sicca, rhinitis medicamentosa, membranous rhinitis, seasonal rhinitis e.g. hay fever, and vasomotor rhinitis), 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 sclerosis, Hashimoto's thyroiditis, type I diabetes, idiopathic thrombocytopenia purpura, or Graves disease;

(h) an ocular condition such as uveitis, allergic conjunctivitis, or vernal conjunctivitis;

(i) a nervous system condition such as multiple sclerosis or 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 infection, meningitis, hepatitis (A, B or C, or other viral hepatitis), peritonitis, pneumonia, epiglottitis, malaria, dengue hemorrhagic fever, leishmaniasis, streptococcal myositis, Mycobacterium tuberculosis, Mycobacterium avium intracellulare, Pneumocystis carinii pneumonia, orchitis/epidydimitis, legionella, Lyme disease, influenza A, epstein-barr virus, viral encephalitis/aseptic meningitis, or pelvic inflammatory disease;

(k) a renal condition such as mesangial proliferative glomerulonephritis, nephrotic 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 lymphohistiocytosis, or graft versus host disease;

(n) a hepatic condition such as chronic active hepatitis, non-alcoholic steatohepatitis (NASH), alcohol-induced hepatitis, non-alcoholic fatty liver disease (NAFLD), alcoholic fatty liver disease (AFLD), alcoholic steatohepatitis (ASH) or primary 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;

(s) pain such as inflammatory hyperalgesia; and/or

(t) neurodegenerative disorders, such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, or amyotrophic lateral sclerosis.

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 (AOSD), 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, autoimmune diseases, such as acute disseminated encephalitis, Addison's disease, ankylosing spondylitis, antiphospholipid antibody syndrome (APS), anti-synthetase syndrome, aplastic anemia, autoimmune adrenalitis, autoimmune hepatitis, autoimmune oophoritis, autoimmune polyglandular failure, autoimmune thyroiditis, Coeliac disease, Crohn's disease, type 1 diabetes (TID), Goodpasture's syndrome, Graves' disease, Guillain-Barre syndrome (GBS), Hashimoto's disease, idiopathic thrombocytopeniarpura, 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 systemic 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, sarcoidosis, 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 and 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 trophoblastic 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 viral 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, Varicella-zoster virus, and KSHV), poxyiruses (such as vaccinia virus (Modified vaccinia virus Ankara) and Myxoma 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-related 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 processes.

As used herein the phrase “metabolic diseases” means for example, type 2 diabetes (T2D), atherosclerosis, obesity, gout, and pseudo-gout.

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 congestive 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 alcoholic 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) (dry and wet), uveitis, corneal infection, diabetic retinopathy, optic nerve damage, dry eye, and glaucoma.

As used herein the phrase “skin diseases” means for example, dermatitis such as contact dermatitis and atopic dermatitis, contact hypersensitivity, 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 administration are oral, parenteral (e.g., intravenous), or topical.

As used herein, the term “treatment” refers to an 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 of some or all clinical symptoms of the disease, a slower 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 prophylactic treatment is a treatment administered to a subject who 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 condition, 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 to be treated according to the present disclosure may have been subjected to standard tests or may have been identified, without examination, as one at risk due to the presence of one or more risk factors associated with the disease or condition. The term “patient” may be used interchangeably with the term “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, one embodiment a compound is provided having structure (I):

[Image Omitted]

or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, wherein:

- (1) when X is CR_aR_b;
- wherein R^aand R^bare each, independently, H or C_1-6alkyl;
- R¹is H, OH, CF₃, C_1-6alkyl, C_3-5cycloalkyl, CN, halo, OC_1-6alkyl or OCF₃;
- R²and R⁵are independently H, OH, CF₃, C_1-6alkyl, CN, halo, OCF₃or OC_1-6alkyl;
- one of R³or R⁴is OH and the other is H, OH, CF₃, C_1-6alkyl, CN, halo, OCF₃or OC_1-6alkyl;
- R⁸is H or halo;
- R⁹is H, C_3-5cycloalkyl, or C_1-6alkyl optionally substituted with one or more R^9′;
- R^9′ is OH, F or C_3-5cycloalkyl;
- R¹⁰and R¹³are independently H or halo;
- R¹¹and R¹²are each, independently, is H, halo, CF₃, C_1-6alkyl, CN or OC_1-6alkyl;
- n is 0, 1 or 2; or

(2) when X is NR_aor O;

- wherein R_aand R_bare each, independently, H or C_1-6alkyl;
- R¹is H, OH, CF₃, C_1-6alkyl, C_3-5cycloalkyl, CN, halo, OC_1-6alkyl or OCF₃;
- R²and R⁵are independently H, OH, CF₃, C_1-6alkyl, CN, halo, OCF₃or OC_1-6alkyl;

one of R³or R⁴is OH and the other is H, OH, CF₃, C_1-6alkyl, CN, halo, OCF₃or OC_1-6alkyl;

- R⁸is H or halo;
- R⁹is H, C_3-5cycloalkyl, or C_1-6alkyl optionally substituted with one or more R^9′;
- R^9′ is OH, F or C_3-5cycloalkyl;
- R¹⁰and R¹³are independently H or halo;
- R¹¹and R¹²are each, independently, is H, halo, CF₃, C_1-6alkyl, CN or OC_1-6alkyl;
- n is 0, 1 or 2; and
- wherein if X is NR_aor O and R¹is C₁, CH₃, CF₃, OCF₃, or methyl, then one of R²and R⁵is not H.

In another embodiment, a compound is provided having the following structure (I):

[Image Omitted]

or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, wherein:

- (1) when X is CR_aR_b;
- wherein R_aand R_bare each, independently, H or C_1-6alkyl;
- R¹is H, OH, CF₃, C_1-6alkyl, C_3-5cycloalkyl, CN, halo, OC_1-6alkyl or OCF₃;
- R²and R⁵are independently H, OH, CF₃, C_1-6alkyl, CN, halo, OCF₃or OC_1-6alkyl;
- one of R³or R⁴is OH and the other is H, OH, CF₃, C_1-6alkyl, CN, halo, OCF₃or OC_1-6alkyl;
- R⁸is H or halo;
- R⁹is H, C_3-5cycloalkyl, or C_1-6alkyl optionally substituted with one or more R^9′;
- R^9′ is OH, F or C_3-5cycloalkyl;
- R¹⁰and R¹³are independently H or halo;
- R¹¹and R¹²are each, independently, is H, halo, CF₃, C_1-6alkyl, CN or OC_1-6alkyl;
- n is 0, 1 or 2; or

(2) when X is NR_aor O;

- wherein R^aand R_bare each, independently, H or C_1-6alkyl; then
  - (A) R¹is H, OH, C_2-6alkyl, C_3-5cycloalkyl, CN, F, Br or OC_1-6alkyl;
  - R²and R⁵are independently H, OH, CF₃, C_1-6alkyl, CN, halo, OCF₃or OC_1-6alkyl;
  - one of R³or R⁴is OH and the other is H, OH, CF₃, C_1-6alkyl, CN, halo, OCF₃or OC_1-6alkyl;
  - R⁸is H or halo;
  - R⁹is H, C_3-5cycloalkyl, or C_1-6alkyl optionally substituted with one or more R^9′;
  - R^9′ is OH, F or C_3-5cycloalkyl;
  - R¹⁰and R¹³are independently H or halo;
  - R¹¹and R¹²are each, independently, is H, halo, CF₃, C_1-6alkyl, CN or OC_1-6alkyl; and
  - n is 0, 1 or 2; or
  - (B) R¹is CF₃, methyl, C₁or OCF₃;
  - one of R²and R⁵is OH, CF₃, C_1-6alkyl, CN, halo, OCF₃or OC_1-6alkyl and the other is H, OH, CF₃, C_1-6alkyl, CN, halo, OCF₃or OC_1-6alkyl;
  - one of R³or R⁴is OH and the other is H, OH, CF₃, C_1-6alkyl, CN, halo, OCF₃or OC_1-6alkyl;
  - R⁸is H or halo;
  - R⁹is H, C_3-5cycloalkyl, or C_1-6alkyl optionally substituted with one or more R^9′;
  - R^9′ is OH, F or C_3-5cycloalkyl;
  - R¹⁰and R¹³are independently H or halo;
  - R¹¹and R¹²are each, independently, is H, halo, CF₃, C_1-6alkyl, CN or OC_1-6alkyl; and
  - n is 0, 1 or 2.

In one embodiment, a compound is provided having the following structure (I′):

[Image Omitted]

or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, wherein:

- X is CR_aR_b, NR_aor O;
- wherein R_aand R_bare each, independently, H or C_1-6alkyl;
- R¹is H, OH, C_2-6alkyl, C_3-5cycloalkyl, CN, F, Br or OC_1-6alkyl;
- R²and R⁵are each, independently, H, OH, CF₃, C_1-6alkyl, CN, halo, OCF₃or OC_1-6alkyl;
- one of R³or R⁴is OH and the other is H, OH, CF₃, C_1-6alkyl, CN, halo, OCF₃or OC_1-6alkyl;
- R⁸is H or halo;
- R⁹is H, C_3-5cycloalkyl, or C_1-6alkyl optionally substituted with one or more R^9′;
- R^9′ is OH, F or C_3-5cycloalkyl;
- R¹⁰and R¹³are independently H or halo;
- R¹¹and R¹²are each, independently, is H, halo, CF₃, C_1-6alkyl, CN or OC_1-6alkyl; and
- n is 0, 1 or 2.

In one embodiment, a compound is provided having the following structure (I″):

[Image Omitted]

or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, wherein:

- X is CR_aR_b, NR_aor O;
- wherein R_aand R_bare each, independently, H or C_1-6alkyl;
- R¹is H, F, CN, C_2-6alkyl or C_3-5cycloalkyl;
- R²and R⁵are each, independently, H or C_1-6alkyl;
- one of R³or R⁴is OH and the other is H, OH or C_1-6alkyl;
- R¹¹and R¹²are each, independently, H, F or C_1-6alkyl; and
- n is 0, 1 or 2.

In one embodiment, a compound is provided having the following structure (Ia):

[Image Omitted]

or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, wherein:

- R_ais H or C_1-6alkyl; and wherein
- (A) R¹is H, OH, C_2-6alkyl, C_3-5Cycloalkyl, CN, F, Br or OC_1-6alkyl;
- R²and R⁵are independently H, OH, CF₃, C_1-6alkyl, CN, halo, OCF₃or OC_1-6alkyl;
- one of R³or R⁴is OH and the other is H, OH, CF₃, C_1-6alkyl, CN, halo, OCF₃or OC_1-6alkyl;
- R⁸is H or halo;
- R⁹is H, C_3-5cycloalkyl, or C_1-6alkyl optionally substituted with one or more R^9′;
- R^9′ is OH, F or C_3-5cycloalkyl;
- R¹⁰and R¹³are independently H or halo;
- R¹¹and R¹²are each, independently, is H, halo, CF₃, C_1-6alkyl, CN or OC_1-6alkyl; and
- n is 0, 1 or 2; or

(B) R¹is CF₃, methyl, C₁or OCF₃;

- one of R²and R⁵is OH, CF₃, C_1-6alkyl, CN, halo, OCF₃or OC_1-6alkyl and the other is H, OH, CF₃, C_1-6alkyl, CN, halo, OCF₃or OC_1-6alkyl;
- one of R³or R⁴is OH and the other is H, OH, CF₃, C_1-6alkyl, CN, halo, OCF₃or OC_1-6alkyl;
- R⁸is H or halo;
- R⁹is H, C_3-5cycloalkyl, or C_1-6alkyl optionally substituted with one or more R^9′;
- R^9′ is OH, F or C_3-5cycloalkyl;
- R¹⁰and R¹³are independently H or halo;
- R¹¹and R¹²are each, independently, is H, halo, CF₃, C_1-6alkyl, CN or OC_1-6alkyl; and
- n is 0, 1 or 2.

In one embodiment, a compound is provided having the following structure (Ia):

[Image Omitted]

or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, wherein:

- R_ais H or C_1-6alkyl;
- R¹is H, OH, C_2-6alkyl, C_3-5cycloalkyl, CN, F, Br or OC_1-6alkyl;
- R²and R⁵are each, independently, H, OH, CF₃, C_1-6alkyl, CN, halo, OCF₃or OC_1-6alkyl;
- one of R³or R⁴is OH and the other is H, OH, CF₃, C_1-6alkyl, CN, halo, OCF₃or OC_1-6alkyl;
- R⁸is H or halo;
- R⁹is H, C_3-5cycloalkyl, or C_1-6alkyl optionally substituted with one or more R^9′;
- R^9′ is OH, F or C_3-5cycloalkyl;
- R¹⁰and R¹³are independently H or halo;
- R¹¹and R¹²are each, independently, is H, halo, CF₃, C_1-6alkyl, CN or OC_1-6alkyl; and
- n is 0, 1 or 2.

In one embodiment, a compound is provided having the following structure (Ia′):

[Image Omitted]

or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, wherein:

- R_ais H or C_1-6alkyl;
- R¹is H, F, CN, C_2-6alkyl or C_3-5cycloalkyl;
- R²and R⁵are each, independently, H or C_1-6alkyl;
- one of R³or R⁴is OH and the other is H, OH or C_1-6alkyl;
- R¹¹and R¹²are each, independently, H, F or C_1-6alkyl; and
- n is 0, 1 or 2.

In one embodiment, a compound is provided having the following structure (Ib):

[Image Omitted]

or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, wherein:

- (A) R¹is H, OH, C_2-6alkyl, C_3-5cycloalkyl, CN, F, Br or OC_1-6alkyl;
- R²and R⁵are independently H, OH, CF₃, C_1-6alkyl, CN, halo, OCF₃or OC_1-6alkyl;
- one of R³or R⁴is OH and the other is H, OH, CF₃, C_1-6alkyl, CN, halo, OCF₃or OC_1-6alkyl;
- R⁸is H or halo;
- R⁹is H, C_3-5cycloalkyl, or C_1-6alkyl optionally substituted with one or more R^9′;
- R^9′ is OH, F or C_3-5cycloalkyl;
- R¹⁰and R¹³are independently H or halo;
- R¹¹and R¹²are each, independently, is H, halo, CF₃, C_1-6alkyl, CN or OC_1-6alkyl; and
- n is 0, 1 or 2; or
- (B) R¹is CF₃, methyl, C₁or OCF₃;
- one of R²and R⁵is OH, CF₃, C_1-6alkyl, CN, halo, OCF₃or OC_1-6alkyl and the other is H, OH, CF₃, C_1-6alkyl, CN, halo, OCF₃or OC_1-6alkyl;
- one of R³or R⁴is OH and the other is H, OH, CF₃, C_1-6alkyl, CN, halo, OCF₃or OC_1-6alkyl;
- R⁸is H or halo;
- R⁹is H, C_3-5cycloalkyl, or C_1-6alkyl optionally substituted with one or more R^9′;
- R^9′ is OH, F or C_3-5cycloalkyl;
- R¹⁰and R₁₃are independently H or halo;
- R¹¹and R¹²are each, independently, is H, halo, CF₃, C_1-6alkyl, CN or OC_1-6alkyl; and
- n is 0, 1 or 2.

In one embodiment, a compound is provided having the following structure (Ib):

[Image Omitted]

or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, wherein:

- R¹is H, OH, C_2-6alkyl, C_3-5cycloalkyl, CN, F, Br or OC_1-6alkyl;
- R²and R⁵are each, independently, H, OH, CF₃, C_1-6alkyl, CN, halo, OCF₃or OC_1-6alkyl;
- one of R³or R⁴is OH and the other is H, OH, CF₃, C_1-6alkyl, CN, halo, OCF₃or OC_1-6alkyl;
- R⁸is H or halo;
- R⁹is H, C_3-5cycloalkyl, or C_1-6alkyl optionally substituted with one or more R^9′;
- R^9′ is OH, F or C_3-5cycloalkyl;
- R¹⁰and R¹³are independently H or halo;
- R¹¹and R¹²are each, independently, is H, halo, CF₃, C_1-6alkyl, CN or OC_1-6alkyl; and
- n is 0, 1 or 2.

In one embodiment, a compound is provided having the following structure (Ib′):

[Image Omitted]

or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, wherein:

- R¹is H, F, C_2-6alkyl or C_3-5cycloalkyl;
- R²and R⁵are each, independently, H or C_1-6alkyl;
- one of R³or R⁴is OH and the other is H, OH or C_1-6alkyl;
- R¹¹and R¹²are each, independently, H or C_1-6alkyl; and
- n is 0, 1 or 2.

In one embodiment, a compound is provided having the following structure (Ic):

[Image Omitted]

or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, wherein:

- R_aand R_bare each, independently, H or C_1-6alkyl;
- R¹is H, OH, CF₃, C_1-6alkyl, C_3-5cycloalkyl, CN, halo, OC_1-6alkyl or OCF₃;
- R²and R⁵are independently H, OH, CF₃, C_1-6alkyl, CN, halo, OCF₃or OC_1-6alkyl;
- one of R³or R⁴is OH and the other is H, OH, CF₃, C_1-6alkyl, CN, halo, OCF₃or OC_1-6alkyl;
- R⁸is H or halo;
- R⁹is H, C_3-5cycloalkyl, or C_1-6alkyl optionally substituted with one or more R^9′;
- R^9′ is OH, F or C_3-5cycloalkyl;
- R¹⁰and R¹³are independently H or halo;
- R¹¹and R¹²are each, independently, is H, halo, CF₃, C_1-6alkyl, CN or OC_1-6alkyl; and
- n is 0, 1 or 2.

In one embodiment, a compound is provided having the following structure (Ic):

[Image Omitted]

or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, wherein:

- R_aand R_bare each independently, H or C_1-6alkyl;
- R¹is H, OH, C_2-6alkyl, C_3-5cycloalkyl, CN, F, Br or OC_1-6alkyl;
- R²and R⁵are each, independently, H, OH, CF₃, C_1-6alkyl, CN, halo, OCF₃or OC_1-6alkyl;
- one of R³or R⁴is OH and the other is H, OH, CF₃, C_1-6alkyl, CN, halo, OCF₃or OC_1-6alkyl;
- R⁸is H or halo;
- R⁹is H, C_3-5cycloalkyl, or C_1-6alkyl optionally substituted with one or more R^9′;
- R^9′ is OH, F or C_3-5cycloalkyl;
- R¹⁰and R¹³are independently H or halo;
- R¹¹and R¹²are each, independently, is H, halo, CF₃, C_1-6alkyl, CN or OC_1-6alkyl; and
- n is 0, 1 or 2.

In one embodiment, a compound is provided having the following structure (Ic′):

[Image Omitted]

or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, wherein:

- R_aand R_bare each, independently, H or C_1-6alkyl;
- R¹is H, F, C_2-6alkyl or C_3-5cycloalkyl;
- R²and R⁵are each, independently, H or C_1-6alkyl;
- one of R³or R⁴is OH and the other is H, OH or C_1-6alkyl;
- R¹¹and R¹²are each, independently, H or C_1-6alkyl; and
- n is 0, 1 or 2.

In more specific embodiments of each of Structures (I), (I′), (I″), (Ia), (Ia′), (Ib), (Ib′), (Ic), and (Ic′), as appropriate, such structures include the following more specific embodiments.

In one embodiment, X is CR_aR_b.

In another embodiment, X is NR_a.

In yet another embodiment, X is O.

In one embodiment, R¹¹and R¹²are not H.

In some embodiments, R¹¹is halo, CF₃, C_1-6alkyl, CN, or OC_1-6alkyl, and R¹²is H.

In other embodiments, R¹¹is H and R¹²is halo, CF₃, C_1-6alkyl, CN, or OC_1-6alkyl.

In yet other embodiments, both R¹¹and R¹²are H.

In some embodiments, both R¹¹and R¹²are not H.

In one embodiment, R¹is H.

In another embodiment, R¹is OH.

In other embodiments, R¹is CF₃.

In yet another embodiment, R¹is F.

In one embodiment, R¹is Cl.

In another embodiment, R¹is Br.

In another embodiment, R¹is I.

In some embodiments, R¹is OCF₃.

In one embodiment, R¹is CN.

In some embodiments, R¹is C_1-6alkyl.

In a certain embodiment, R¹is methyl.

In other embodiments, R¹is C_2-6alkyl.

In a certain embodiment, R¹is ethyl.

In a certain embodiment, R¹is isopropyl.

In one embodiment, R¹is OC_1-6alkyl.

In a certain embodiment, R¹is OCH₃.

In one embodiment, R¹is C_3-5cycloalkyl.

In a certain embodiment, R¹is cyclopropyl.

In a certain embodiment, R¹is cyclobutyl.

In one embodiment, R²and R⁵are independently H, C_1-6alkyl, F, Cl, CF₃or CN.

In another embodiment, R²is OH, CF₃, C_1-6alkyl, CN, halo, OCF₃or OC_1-6alkyl, and R⁵is H.

In some embodiments, R²is R²is H and R⁵is OH, CF₃, C_1-6alkyl, CN, halo, OCF₃or OC_1-6alkyl.

In one embodiment, R²is H.

In another embodiment, R²is OH.

In some embodiments, R²is CF₃.

In other embodiments, R²is C_1-6alkyl.

In certain embodiments, R²is methyl.

In other embodiments, R²is ethyl.

In yet other embodiments, R²is isopropyl.

In another embodiment, R²is CN.

In some embodiments, R²is F.

In yet another embodiment, R²is Cl.

In some embodiments, R²is Br.

In another embodiment, R²is I.

In one embodiment, R²is OCF₃.

In yet other embodiments, R²is OC_1-6alkyl.

In one embodiment, R²is OCH₃.

In some embodiments, R⁵is H.

In one embodiment, R⁵is OH.

In some embodiments, R⁵is CF₃.

In other embodiments, R⁵is C_1-6alkyl.

In yet other embodiments, R⁵is methyl.

In certain embodiments, R⁵is ethyl.

In other embodiments, R⁵is isopropyl.

In yet other embodiments, R⁵is CN.

In one embodiment, R⁵is F.

In some embodiments, R⁵is Cl.

In another embodiment, R⁵is Cl.

In other embodiments, R⁵is Br.

In another embodiment, R⁵is I.

In one embodiment, R⁵is OCF₃.

In yet other embodiments, R⁵is OC_1-6alkyl.

In one embodiment, R⁵is OCH₃.

In some embodiments, R³is OH and R⁴is H, OH, CF₃, C_1-6alkyl, CN, halo, OCF₃or OC_1-6alkyl.

In other embodiments, R⁴is OH and R³is H, OH, CF₃, C_1-6alkyl, CN, halo, OCF₃or OC_1-6alkyl.

In one embodiment, R³is OH and R⁴is H or C_1-6alkyl.

In another embodiment, R⁴is OH and R³is H or C_1-6alkyl.

In one embodiment, R³is OH.

In other embodiments, R³is H.

In another embodiment, R³is CF₃.

In some embodiments, R³is C_1-6alkyl.

In other embodiments, R³is methyl.

In certain embodiments, R³is ethyl.

In some embodiments, R³is isopropyl.

In other embodiments, R³is CN.

In yet other embodiments, R³is F.

In one embodiment, R³is Cl.

In some embodiments, R³is Br.

In another embodiment, R³is I.

In another embodiment, R³is OCF₃.

In yet other embodiments, R³is OC_1-6alkyl.

In one embodiment, R³is OCH₃.

In some embodiments, R⁴is OH.

In one embodiment, R⁴is H.

In another embodiment, R⁴is CF₃.

In yet another embodiment, R⁴is C_1-6alkyl.

In some embodiments, R⁴is methyl.

In other embodiments, R⁴is ethyl.

In some embodiments, R⁴is isopropyl.

In one embodiment, R⁴is CN.

In another embodiment, R⁴is F.

In yet another embodiment, R⁴is Cl.

In yet another embodiment, R⁴is Br.

In another embodiment, R⁴is I.

In another embodiment, R⁴is OCF₃.

In yet other embodiments, R⁴is OC_1-6alkyl.

In some embodiments, R⁴is OCH₃.

In one embodiment, R⁸is H.

In another embodiment, R⁸is F.

In yet another embodiment, R⁸is Cl.

In another embodiment, R⁸is Br.

In another embodiment, R⁸is I.

In some embodiments, R⁹is H.

In one embodiment, R⁹is not H.

In another embodiment, R⁹is C_1-6alkyl.

In some embodiments, R⁹is methyl.

In other embodiments, R⁹is ethyl.

In yet other embodiments, R⁹is isopropyl.

In one embodiment, R⁹is C_1-6alkyl optionally substituted with one or more F.

In certain embodiments, R⁹is —CH₂CH₂F.

In yet another embodiment, R⁹is —CH₂CHF₂.

In some embodiments, R⁹is —CH₂CF₃.

In one embodiment, R⁹is C_3-5cycloalkyl.

In certain embodiments, R⁹is cyclopropyl.

In one embodiment, R⁹is C_1-6alkyl optionally substituted with one or more C_3-5cycloalkyl.

In certain embodiments, R⁹is

[Image Omitted]

In some embodiments, R⁹is R⁹is C_1-6alkyl optionally substituted with one or more OH.

In other embodiments, R⁹is

[Image Omitted]

In another embodiment, R¹⁰and R¹³are both H.

In one embodiment, R¹⁰and R¹³are both halo.

In certain embodiments, R¹⁰and R¹³are both F.

In another embodiment, R¹⁰is H and R¹³is halo.

In yet another embodiment, R¹⁰is H and R¹³is F.

In one embodiment, R¹⁰is H.

In another embodiment, R¹⁰is F.

In certain embodiments, R¹⁰is Cl.

In other embodiments, R¹⁰is Br.

In another embodiment, R¹⁰is I.

In one embodiment, R¹³is H.

In some embodiments, R¹³is F.

In other embodiments, R¹³is Cl.

In yet other embodiments, R¹³is Br.

In another embodiment, R¹³is I.

In some embodiments, n is 0.

In other embodiments, n is 1.

In other embodiments, n is 2.

In one embodiment, a compound is selected from one of the compounds listed in Table 1, or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof.

TABLE 1

Representative compounds having Structure (I)

Cpd

Structure
No.

[Image Omitted]

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

In one embodiment, a compound is provided having structure (I″″):

[Image Omitted]

- or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof,
- wherein:
  - X is CR_aR_b, NR_aor O;
  - R_aand R_bare each, independently, H or C_1-6alkyl;
  - R¹is H, For CN;
  - R²and R⁵are each, independently, H, halo, OH, CN, C_1-6alkyl, C_1-6haloalkyl, OC_1-6alkyl or OC_1-6haloalkyl;
  - one of R³or R⁴is OH and the other is H, halo, OH, CN, C_1-6alkyl, C_1-6haloalkyl, OC_1-6alkyl or OC_1-6haloalkyl;
  - R⁸is H or halo;
  - R⁹is H, C_3-5cycloalkyl, or C_1-6alkyl optionally substituted with one or more R^9′;
  - R^9′ is OH, halo or C_3-5cycloalkyl;
  - R¹⁰and R¹³are each, independently, H or halo;
  - R¹¹and R¹²are each, independently, is H, halo, CN, C_1-6alkyl, C_1-6haloalkyl or OC_1-6alkyl;
  - R¹⁶is H or CO₂H; and
  - n is 0, 1 or 2.

In another embodiment, a compound is provided having structure (Ia′″):

[Image Omitted]

- or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof,
- wherein:
  - R_ais H or C_1-6alkyl;
  - R¹is H, F or CN;
  - R²and R⁵are each, independently, H, halo, OH, CN, C_1-6alkyl, C_1-6haloalkyl, OC_1-6alkyl or OC_1-6haloalkyl;
  - one of R³or R⁴is OH and the other is H, halo, OH, CN, C_1-6alkyl, C_1-6haloalkyl, OC_1-6alkyl or OC_1-6haloalkyl;
  - R⁸is H or halo;
  - R⁹is H, C_3-5cycloalkyl, or C_1-6alkyl optionally substituted with one or more R^9′;
  - R^9′ is OH, halo or C_3-5cycloalkyl;
  - R¹⁰and R¹³are each, independently, H or halo;
  - R¹¹and R¹²are each, independently, is H, halo, CN, C_1-6alkyl, C_1-6haloalkyl or OC_1-6alkyl;
  - R¹⁶is H or CO₂H; and
  - n is 0, 1 or 2.

In another embodiment, a compound is provided having structure (Ia-1″″):

[Image Omitted]

- or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof,
- wherein:
  - R_ais H or C_1-6alkyl;
  - R¹is H, F or CN;
  - R²and R⁵are each, independently, H or C_1-6alkyl;
  - one of R³or R⁴is OH and the other is H or C_1-6alkyl;
  - R¹¹and R¹²are each, independently, H, F or C_1-6alkyl; and
  - n is 0, 1 or 2.

In another embodiment, a compound is provided having structure (Ib′″):

[Image Omitted]

- or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof,
- wherein:
  - R¹is H, For CN;
  - R²and R⁵are each, independently, H, halo, OH, CN, C_1-6alkyl, C_1-6haloalkyl, OC_1-6alkyl or OC_1-6haloalkyl;
  - one of R³or R⁴is OH and the other is H, halo, OH, CN, C_1-6alkyl, C_1-6haloalkyl, OC_1-6alkyl or OC_1-6haloalkyl;
  - R⁸is H or halo;
  - R⁹is H, C_3-5cycloalkyl, or C_1-6alkyl optionally substituted with one or more R^9′;
  - R^9′ is OH, halo or C_3-5cycloalkyl;
  - R¹⁰and R¹³are each, independently, H or halo;
  - R¹¹and R¹²are each, independently, is H, halo, CN, C_1-6alkyl, C_1-6haloalkyl or OC_1-6alkyl;
  - R¹⁶is H or CO₂H; and
  - n is 0, 1 or 2.

In another embodiment, a compound is provided having structure (Ib-1′″):

[Image Omitted]

- or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof,
- wherein:
  - R¹is H, F or CN;
  - R²and R⁵are each, independently, H or C_1-6alkyl;
  - one of R³or R⁴is OH and the other is H or C_1-6alkyl;
  - R¹¹and R¹²are each, independently, H or C_1-6alkyl; and
  - n is 0, 1 or 2.

In another embodiment, a compound is provided having structure (Ic′″):

[Image Omitted]

- or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof,
- wherein:
  - R_aand R_bare each, independently, H or C_1-6alkyl;
  - R¹is H, For CN;
  - R²and R⁵are each, independently, H, halo, OH, CN, C_1-6alkyl, C_1-6haloalkyl, OC_1-6alkyl or OC_1-6haloalkyl;
  - one of R³or R⁴is OH and the other is H, halo, OH, CN, C_1-6alkyl, C_1-6haloalkyl, OC_1-6alkyl or OC_1-6haloalkyl;
  - R⁸is H or halo;
  - R⁹is H, C_3-5cycloalkyl, or C_1-6alkyl optionally substituted with one or more R^9′;
  - R^9′ is OH, halo or C_3-5cycloalkyl;
  - R¹⁰and R¹³are each, independently, H or halo;
  - R¹¹and R¹²are each, independently, is H, halo, CN, C_1-6alkyl, C_1-6haloalkyl or OC_1-6alkyl;
  - R¹⁶is H or CO₂H; and
  - n is 0, 1 or 2.

In another embodiment, a compound is provided having structure (Ic-1′″):

[Image Omitted]

- or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof,
- wherein:
  - R_aand R_bare each, independently, H or C_1-6alkyl;
  - R¹is H, F or CN;
  - R²and R⁵are each, independently, H or C_1-6alkyl;
  - one of R³or R⁴is OH and the other is H or C_1-6alkyl;
  - R¹¹and R¹²are each, independently, H or C_1-6alkyl; and
  - n is 0, 1 or 2.

In more specific embodiments of each of Structures (I′″), (Ia′″), (Ia-1″″), (Ib′″), (Ib-1″″), (Ic′″), and (Ic-1′″), as appropriate, such structures include the following more specific embodiments.

In one embodiment, X is CR_aR_b. In another embodiment, X is NR_a. In yet another embodiment, X is O.

In one embodiment, one of R¹¹and R¹²is H. In another embodiment, R¹¹is C_1-6alkyl and R¹²is H. In another embodiment, R¹¹is H and R¹²is C_1-6alkyl. In another embodiment, both R¹¹and R¹²are H. In another embodiment, both R¹¹and R¹²are not H. In some embodiments, R¹¹is H, halo, CN, C_1-6alkyl, C_1-6haloalkyl or OC_1-6alkyl, and R¹²is H. In some embodiments, R¹¹is H, F, CN, methyl, CF₃or OCH₃, and R¹²is H. In other embodiments, R¹¹is H and R¹²is H, halo, CN, C_1-6alkyl, C_1-6haloalkyl or OC_1-6alkyl. In other embodiments, R¹¹is H and R¹²is H, F, CN, methyl, CF₃or OCH₃.

In one embodiment, wherein R¹is H. In another embodiment, wherein R¹is F. In another embodiment, R¹is CN.

In one embodiment, R²and R⁵are each, independently, H, C_1-6alkyl, F, Cl, CF₃, or CN. In another embodiment, R²is OH, CF₃, C_1-6alkyl, CN, halo, OCF₃or OC_1-6alkyl, and R⁵is H. In another embodiment, R²is H and R⁵is OH, CF₃, C_1-6alkyl, CN, halo, OCF₃or OC_1-6alkyl.

In one embodiment, R²is H. In another embodiment, R²is OH. In additional embodiments, R²is C_1-6haloalkyl. In some embodiments, R²is CF₃. In additional embodiments, R²is C_1-6alkyl. In a specific embodiment, R²is methyl. In another embodiment, R²is ethyl. In another embodiment, R²is isopropyl. In yet other embodiments, R²is CN. In one embodiment, R²is halo. In another embodiment, R²is F. In another embodiment, R²is Cl. In another embodiment, R²is Br. In another embodiment, R²is OC_1-6haloalkyl. In some embodiments, R²is OCF₃. In another embodiment, R²is OC_1-6alkyl. In a specific embodiment, R²is OCH₃.

In one embodiment, R⁵is H. In another embodiment, R⁵is OH. In another embodiment, R⁵is C_1-6haloalkyl. In another embodiment, R⁵is CF₃. In another embodiment, R⁵is C_1-6alkyl. In another embodiment, R⁵is methyl. In another embodiment, R⁵is ethyl. In another embodiment, R⁵is isopropyl. In another embodiment, R⁵is CN. In one embodiment, R⁵is halo. In another embodiment, R⁵is F. In another embodiment, R⁵is Cl. In another embodiment, R⁵is Br. In another embodiment, R⁵is OC_1-6haloalkyl. In another embodiment, R⁵is OCF₃. In another embodiment, R⁵is OC_1-6alkyl. In another embodiment, R⁵is OCH₃.

In one embodiment, R³is OH and R⁴is H, OH, CF₃, C_1-6alkyl, CN, halo, OCF₃or OC_1-6alkyl. In another embodiment, R⁴is OH and R³is H, OH, CF₃, C_1-6alkyl, CN, halo, OCF₃or OC_1-6alkyl. In yet other embodiments, R³is OH and R⁴is H or C_1-6alkyl. In another embodiment, R⁴is OH and R³is H or C_1-6alkyl.

In some embodiments, R³is OH. In another embodiment, R³is H. In another embodiment, R³is C_1-6haloalkyl. In one embodiment, R³is CF₃. In another embodiment, R³is C_1-6alkyl. In a specific embodiment, R³is methyl. In another embodiment, R³is ethyl. In certain embodiments, R³is isopropyl. In another embodiment, R³is CN. In one embodiment, R³is halo. In some embodiments, R³is F. In another embodiment, R³is Cl. In one embodiment, R³is Br. In another embodiment, R³is OC_1-6haloalkyl. In another embodiment, R³is OCF₃. In some embodiments, R³is OC_1-6alkyl. In certain embodiments, R³is OCH₃.

In one embodiment, R⁴is OH. In another embodiment, R⁴is H. In another embodiment, R⁴is C_1-6haloalkyl. In yet other embodiments, R⁴is CF₃. In another embodiment, R⁴is C_1-6alkyl. In specific embodiments, R⁴is methyl. In another embodiment, R⁴is ethyl. In certain embodiments, R⁴is isopropyl. In another embodiment, R⁴is CN. In one embodiment, R⁴is halo. In yet other embodiments, R⁴is F. In another embodiment, R⁴is Cl. In additional embodiments, R⁴is Br. In additional embodiments, R⁴is I. In another embodiment, R⁴is OC_1-6haloalkyl. In another embodiment, R⁴is OCF₃. In other embodiments, R⁴is OC_1-6alkyl. In certain embodiments, R⁴is OCH₃.

In one embodiment, R⁸is H. In another embodiment, R⁸is F. In another embodiment, R⁸is Cl. In yet other embodiments, R⁸is Br. In yet other embodiments, R⁸is I.

In one embodiment, R⁹is H. In another embodiment, R⁹is not H. In some embodiments, R⁹is C_1-6alkyl. In a specific embodiment, R⁹is methyl. In some embodiments, R⁹is ethyl. In certain embodiments, R⁹is isopropyl. In some embodiments, R⁹is C_1-6alkyl optionally substituted with one or more F. In another embodiment, R⁹is —CH₂CH₂F. In certain embodiments, R⁹is —CH₂CHF₂. In another embodiment, R⁹is —CH₂CF₃. In one embodiment, R⁹is C_3-5cycloalkyl. In a specific embodiment, R⁹is cyclopropyl. In another embodiment, R⁹is C_1-6alkyl optionally substituted with one or more C_3-5cycloalkyl. In certain embodiments, R⁹is

[Image Omitted]

In another embodiment, R⁹is C_1-6alkyl optionally substituted with one or more OH. In some embodiments, R⁹is

[Image Omitted]

In one embodiment, R^9′ is OH. In one embodiment, R^9′ is halo. In yet other embodiments, R^9′ is F. In another embodiment, R^9′ is Cl. In additional embodiments, R^9′ is Br. In additional embodiments, R^9′ is I. In one embodiment, R^9′ is C_3-5cycloalkyl. In a specific embodiment, R^9′ is cyclopropyl.

In one embodiment, R¹⁰and R¹³are both H. In another embodiment, R¹⁰and R¹³are both halo. In yet other embodiments, R¹⁰is H and R¹³is halo. In other embodiments, R¹³is H and R¹⁰is halo.

In one embodiment, R¹⁰is H. In one embodiment, R¹⁰is F. In another embodiment, R¹⁰is Cl. In yet other embodiments, R¹⁰is Br.

In one embodiment, R¹³is H. In one embodiment, R¹³is F. In another embodiment, R¹³is Cl. In yet other embodiments, R¹³is Br.

In one embodiment, R¹⁶is H. In another embodiment, R¹⁶is CO₂H.

In one embodiment, Ra is H. In another embodiment, Ra is C_1-6alkyl. In certain embodiments, Ra is methyl.

In one embodiment, Rb is H. In another embodiment, Rb is C_1-6alkyl. In certain embodiments, Rb is methyl.

In one embodiment, n is 0-2. In one embodiment, n is 0 or 1. In other embodiments, n is 1 or 2. In yet other embodiments, n is 0 or 2. In some embodiments, n is 0. In other embodiments, n is 1. In other embodiments, n is 2.

In one embodiment, a compound is selected from one of the compounds listed in Table 2, or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof.

TABLE 2

Representative compounds having Structure (I′′′)

[Image Omitted]

1

2

4

5

6

7

8

9

10

11

17

18

19

20

21

22

23

24

25

26

30

31

32

33

34

35

36

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

77

78

79

80

81

84

85

86

87

88

90

91

94

95

99

100

101

102

103

105

106

In another embodiment, a compound is provided having structure (II):

[Image Omitted]

- or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof, wherein:
  - R_ais H or C_1-6alkyl;
  - each R¹⁵is, independently, halo, OH, CN, C_1-6alkyl, C_1-6haloalkyl, OC_1-6alkyl, OC_1-6haloalkyl or C_3-5cycloalkyl;
  - R⁹is H, C_3-5cycloalkyl, or C_1-6alkyl optionally substituted with one or more R^9′;
  - R^9′ is OH, halo or C_3-5cycloalkyl;
  - each R¹⁷is, independently, halo or CO₂H;
  - R¹¹and R¹²are each, independently, is H, halo, CN, C_1-6alkyl, C_1-6haloalkyl, or OC_1-6alkyl; and
  - n is 0-2;
  - m is 0-3; and
  - p is 0-9.

In more specific embodiments of Structure (II), as appropriate, such structures include the following more specific embodiments.

In one embodiment, one of R¹¹and R¹²is H. In another embodiment, R¹¹is C_1-6alkyl and R¹²is H. In another embodiment, R¹¹is H and R¹²is C_1-6alkyl. In another embodiment, both R¹¹and R¹²are H. In another embodiment, both R¹¹and R¹²are not H. In some embodiments, R¹¹is H, halo, CN, C_1-6alkyl, C_1-6haloalkyl or OC_1-6alkyl, and R¹²is H. In some embodiments, R¹¹is H, F, CN, methyl, CF₃or OCH₃, and R¹²is H. In other embodiments, R¹¹is H and R¹²is H, halo, CN, C_1-6alkyl, C_1-6haloalkyl or OC_1-6alkyl. In other embodiments, R¹¹is H and R¹²is H, F, CN, methyl, CF₃or OCH₃.

In one embodiment, R¹¹is H. In another embodiment, R¹¹is halo. In certain embodiments R¹¹is F. In other embodiments R¹¹is Cl. In certain embodiments R¹¹is Br. In specific embodiments R¹¹is I. In some embodiments, R¹¹is C_1-6alkyl. In one embodiment, R¹¹is methyl. In other embodiments, R¹¹is ethyl. In additional embodiments, R¹¹is propyl. In additional embodiments, R¹¹is propyl. In further embodiments, R¹¹is isopropyl. In other embodiments, R¹¹is n-butyl. In further embodiments, R¹¹is sec-butyl. In some embodiments, R¹¹is tert-butyl. In some embodiments, R¹¹is CN. In some embodiments, R¹¹is C_1-6haloalkyl. In specific embodiments, R¹¹is CF₃. In some embodiments, R¹¹is OC_1-6alkyl. In specific embodiments, R¹¹is OCH₃.

In one embodiment, R¹²is H. In another embodiment, R¹²is halo. In certain embodiments, R¹²is F. In other embodiments, R¹²is Cl. In certain embodiments, R¹²is Br. In specific embodiments, R¹²is I. In some embodiments, R¹²is C_1-6alkyl. In one embodiment, R¹²is methyl. In other embodiments, R¹²is ethyl. In additional embodiments, R¹²is propyl. In additional embodiments, R¹²is propyl. In further embodiments, R¹²is isopropyl. In other embodiments, R¹²is n-butyl. In further embodiments, R¹²is sec-butyl. In some embodiments, R¹²is tert-butyl. In some embodiments, R¹²is CN. In some embodiments, R¹²is C_1-6haloalkyl. In specific embodiments, R¹²is CF₃. In some embodiments, R¹²is OC_1-6alkyl. In specific embodiments, R¹²is OCH₃.

In one embodiment, R¹⁵is CN, halo, or C_1-6haloalkyl. In one embodiment, R¹⁵is CN, F, or CF₃. In one embodiment, R¹⁵is halo. In certain embodiments, R¹⁵is F. In other embodiments, R¹⁵is Cl. In certain embodiments R¹⁵is Br. In specific embodiments R¹⁵is I. In some embodiments, R¹⁵is CN. In other embodiments, R¹⁵is OH. In some embodiments, R¹⁵is C_1-6alkyl. In one embodiment, R¹⁵is methyl. In other embodiments, R¹⁵is ethyl. In additional embodiments, R¹⁵is propyl. In additional embodiments, R¹⁵is propyl. In further embodiments, R¹⁵is isopropyl. In other embodiments, R¹⁵is n-butyl. In further embodiments, R¹⁵is sec-butyl. In some embodiments, R¹⁵is tert-butyl. In some embodiments, R¹⁵is C_1-6haloalkyl. In specific embodiments, R¹⁵is CF₃. In some embodiments, R¹⁵is OC_1-6alkyl. In specific embodiments, R¹⁵is OCH₃. In some embodiments, R¹⁵is OC_1-6haloalkyl. In specific embodiments, R¹⁵is OCF₃. In some embodiments, R¹⁵is C_3-5cycloalkyl. In specific embodiments, R¹⁵is cyclopropyl.

In one embodiment, R⁹is H. In another embodiment, R⁹is not H. In some embodiments, R⁹is C_1-6alkyl. In a specific embodiment, R⁹is methyl. In some embodiments, R⁹is ethyl. In certain embodiments, R⁹is isopropyl. In some embodiments, R⁹is C_1-6alkyl optionally substituted with one or more F. In another embodiment, R⁹is —CH₂CH₂F. In certain embodiments, R⁹is —CH₂CHF₂. In another embodiment, R⁹is —CH₂CF₃. In one embodiment, R⁹is C_3-5cycloalkyl. In a specific embodiment, R⁹is cyclopropyl. In another embodiment, R⁹is C_1-6alkyl optionally substituted with one or more C_3-5cycloalkyl. In certain embodiments, R⁹is

[Image Omitted]

In another embodiment, R⁹is C_1-6alkyl optionally substituted with one or more OH. In some embodiments, R⁹is

[Image Omitted]

In one embodiment, R^9′ is OH. In one embodiment, R^9′ is halo. In yet other embodiments, R^9′ is F. In another embodiment, R^9′ is Cl. In additional embodiments, R^9′ is Br. In additional embodiments, R^9′ is I. In one embodiment, R^9′ is C_3-5cycloalkyl. In a specific embodiment, R^9′ is cyclopropyl.

In one embodiment, R¹⁷is halo. In certain embodiments, R¹⁷is F. In other embodiments, R¹⁷is Cl. In certain embodiments R¹⁷is Br. In specific embodiments R¹⁷is I. In some embodiments, R¹⁷is CO₂H.

In one embodiment, Ra is H. In another embodiment, Ra is C_1-6alkyl. In certain embodiments, Ra is methyl.

In one embodiment, n is 0-2. In one embodiment, n is 0 or 1. In other embodiments, n is 1 or 2. In yet other embodiments, n is 0 or 2. In some embodiments, n is 0. In other embodiments, n is 1. In other embodiments, n is 2.

In one embodiment, m is 0-3. In one embodiment, m is 0 or 1. In other embodiments, m is 1 or 2. In yet other embodiments, m is 0 or 2. In some embodiments, m is 0. In other embodiments, m is 1. In other embodiments, m is 2. In other embodiments, m is 3.

In one embodiment, p is 0-9. In one embodiment, p is 0-3. In one embodiment, p is 0 or 1. In other embodiments, p is 1 or 2. In yet other embodiments, p is 0 or 2. In some embodiments, p is 0. In other embodiments, p is 1. In other embodiments, p is 2. In other embodiments, p is 3.

In one embodiment, a compound is selected from one of the compounds listed in Table 3, or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof.

TABLE 3

Representative compounds having Structure (II)

[Image Omitted]

107

108

109

110

In another embodiment, a compound is provided having structure (III):

[Image Omitted]

- or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof,
- wherein:
  - R¹is H, halo, OH, CN, C_1-6alkyl, C_1-6haloalkyl, OC_1-6alkyl, OC_1-6haloalkyl or C_3-5cycloalkyl;
  - R²and R⁵are each, independently, H, halo, OH, CN, C_1-6alkyl, C_1-6haloalkyl, OC_1-6alkyl or OC_1-6haloalkyl;
  - one of R³or R⁴is OH and the other is H, halo, OH, CN, C_1-6alkyl, C_1-6haloalkyl, OC_1-6alkyl or OC_1-6haloalkyl;
  - R¹¹and R¹²are each, independently, is H, halo, CN, C_1-6alkyl, C_1-6haloalkyl or OC_1-6alkyl;
  - each R¹⁸is halo, CO₂H, aminyl, C_3-5cycloalkyl, or C_1-6alkyl, wherein the C_1-6alkyl is optionally substituted with one or more R^9′;
  - R^9′ is OH, halo or C_3-5cycloalkyl;
  - n is 1 or 2; and
  - p is 1-9.

In more specific embodiments of Structure (III), as appropriate, such structures include the following more specific embodiments.

In one embodiment, one of R¹¹and R¹²is H. In another embodiment, R¹¹is C_1-6alkyl and R¹²is H. In another embodiment, R¹¹is H and R¹²is C_1-6alkyl. In another embodiment, both R¹¹and R¹²are H. In another embodiment, both R¹¹and R¹²are not H. In some embodiments, R¹¹is H, halo, CN, C_1-6alkyl, C_1-6haloalkyl or OC_1-6alkyl, and R¹²is H. In some embodiments, R¹¹is H, F, CN, methyl, CF₃or OCH₃, and R¹²is H. In other embodiments, R¹¹is H and R¹²is H, halo, CN, C_1-6alkyl, C_1-6haloalkyl or OC_1-6alkyl. In other embodiments, R¹¹is H and R¹²is H, F, CN, methyl, CF₃or OCH₃.

In one embodiment, R¹¹is H. In another embodiment, R¹¹is halo. In certain embodiments R¹¹is F. In other embodiments R¹¹is Cl. In certain embodiments R¹¹is Br. In specific embodiments R¹¹is I. In some embodiments, R¹¹is C_1-6alkyl. In one embodiment, R¹¹is methyl. In other embodiments, R¹¹is ethyl. In additional embodiments, R¹¹is propyl. In additional embodiments, R¹¹is propyl. In further embodiments, R¹¹is isopropyl. In other embodiments, R¹¹is n-butyl. In further embodiments, R¹¹is sec-butyl. In some embodiments, R¹¹is tert-butyl. In some embodiments, R¹¹is CN. In some embodiments, R¹¹is C_1-6haloalkyl. In specific embodiments, R¹¹is CF₃. In some embodiments, R¹¹is OC_1-6alkyl. In specific embodiments, R¹¹is OCH₃.

In one embodiment, R¹²is H. In another embodiment, R¹²is halo. In certain embodiments, R¹²is F. In other embodiments, R¹²is Cl. In certain embodiments, R¹²is Br. In specific embodiments, R¹²is I. In some embodiments, R¹²is C_1-6alkyl. In one embodiment, R¹²is methyl. In other embodiments, R¹²is ethyl. In additional embodiments, R¹²is propyl. In additional embodiments, R¹²is propyl. In further embodiments, R¹²is isopropyl. In other embodiments, R¹²is n-butyl. In further embodiments, R¹²is sec-butyl. In some embodiments, R¹²is tert-butyl. In some embodiments, R¹²is CN. In some embodiments, R¹²is C_1-6haloalkyl. In specific embodiments, R¹²is CF₃. In some embodiments, R¹²is OC_1-6alkyl. In specific embodiments, R¹²is OCH₃.

In one embodiment, R¹is H or CN. In one embodiment, R¹is H. In one embodiment, R¹is halo. In certain embodiments, R¹is F. In other embodiments, R¹is Cl. In certain embodiments R¹is Br. In specific embodiments R¹is I. In some embodiments, R¹is CN. In other embodiments, R¹is OH. In some embodiments, R¹is C_1-6alkyl. In one embodiment, R¹is methyl. In other embodiments, R¹is ethyl. In additional embodiments, R¹is propyl. In additional embodiments, R¹is propyl. In further embodiments, R¹is isopropyl. In other embodiments, R¹is n-butyl. In further embodiments, R¹is sec-butyl. In some embodiments, R¹is tert-butyl. In some embodiments, R¹is C_1-6haloalkyl. In specific embodiments, R¹is CF₃. In some embodiments, R¹is OC_1-6alkyl. In specific embodiments, R¹is OCH₃. In some embodiments, R¹is OC_1-6haloalkyl. In specific embodiments, R¹is OCF₃. In some embodiments, R¹is C_3-5cycloalkyl. In specific embodiments, R¹is cyclopropyl.

In one embodiment, R²and R⁵are each, independently, H, C_1-6alkyl, F, Cl, CF₃, or CN. In another embodiment, R²is OH, CF₃, C_1-6alkyl, CN, halo, OCF₃or OC_1-6alkyl, and R⁵is H. In another embodiment, R²is H and R⁵is OH, CF₃, C_1-6alkyl, CN, halo, OCF₃or OC_1-6alkyl.

In one embodiment, R²is H. In another embodiment, R²is OH. In additional embodiments, R²is C_1-6haloalkyl. In some embodiments, R²is CF₃. In additional embodiments, R²is C_1-6alkyl. In a specific embodiment, R²is methyl. In another embodiment, R²is ethyl. In another embodiment, R²is isopropyl. In yet other embodiments, R²is CN. In one embodiment, R²is halo. In another embodiment, R²is F. In another embodiment, R²is Cl. In another embodiment, R²is Br. In another embodiment, R²is OC_1-6haloalkyl. In some embodiments, R²is OCF₃. In another embodiment, R²is OC_1-6alkyl. In a specific embodiment, R²is OCH₃.

In one embodiment, R⁵is H. In another embodiment, R⁵is OH. In another embodiment, R⁵is C_1-6haloalkyl. In another embodiment, R⁵is CF₃. In another embodiment, R⁵is C_1-6alkyl. In another embodiment, R⁵is methyl. In another embodiment, R⁵is ethyl. In another embodiment, R⁵is isopropyl. In another embodiment, R⁵is CN. In one embodiment, R⁵is halo. In another embodiment, R⁵is F. In another embodiment, R⁵is Cl. In another embodiment, R⁵is Br. In another embodiment, R⁵is OC_1-6haloalkyl. In another embodiment, R⁵is OCF₃. In another embodiment, R⁵is OC_1-6alkyl. In another embodiment, R⁵is OCH₃.

In one embodiment, R³is OH and R⁴is H, OH, CF₃, C_1-6alkyl, CN, halo, OCF₃or OC_1-6alkyl. In another embodiment, R⁴is OH and R³is H, OH, CF₃, C_1-6alkyl, CN, halo, OCF₃or OC_1-6alkyl. In yet other embodiments, R³is OH and R⁴is H or C_1-6alkyl. In another embodiment, R⁴is OH and R³is H or C_1-6alkyl.

In some embodiments, R³is OH. In another embodiment, R³is H. In another embodiment, R³is C_1-6haloalkyl. In one embodiment, R³is CF₃. In another embodiment, R³is C_1-6alkyl. In a specific embodiment, R³is methyl. In another embodiment, R³is ethyl. In certain embodiments, R³is isopropyl. In another embodiment, R³is CN. In one embodiment, R³is halo. In some embodiments, R³is F. In another embodiment, R³is Cl. In one embodiment, R³is Br. In another embodiment, R³is OC_1-6haloalkyl. In another embodiment, R³is OCF₃. In some embodiments, R³is OC_1-6alkyl. In certain embodiments, R³is OCH₃.

In one embodiment, R⁴is OH. In another embodiment, R⁴is H. In another embodiment, R⁴is C_1-6haloalkyl. In yet other embodiments, R⁴is CF₃. In another embodiment, R⁴is C_1-6alkyl. In specific embodiments, R⁴is methyl. In another embodiment, R⁴is ethyl. In certain embodiments, R⁴is isopropyl. In another embodiment, R⁴is CN. In one embodiment, R⁴is halo. In yet other embodiments, R⁴is F. In another embodiment, R⁴is Cl. In additional embodiments, R⁴is Br. In another embodiment, R⁴is OC_1-6haloalkyl. In another embodiment, R⁴is OCF₃. In other embodiments, R⁴is OC_1-6alkyl. In certain embodiments, R⁴is OCH₃.

In one embodiment, R¹⁸is halo. In certain embodiments, R¹⁸is F. In other embodiments, R¹⁸is Cl. In certain embodiments R¹⁸is Br. In specific embodiments R¹⁸is I. In some embodiments, R¹⁸is CO₂H. In other embodiments, R¹⁸is aminyl. In certain embodiments, R¹⁸is N(CH₃) 2. In certain embodiments, R¹⁸is NH(CH₃). In some embodiments, R¹⁸is C_3-5cycloalkyl. In specific embodiments, R¹⁸is cyclopropyl. In some embodiments, R¹⁸is C_1-6alkyl. In one embodiment, R¹⁸is methyl. In other embodiments, R¹⁸is ethyl. In additional embodiments, R¹⁸is propyl. In additional embodiments, R¹⁸is propyl. In further embodiments, R¹⁸is isopropyl. In other embodiments, R¹⁸is n-butyl. In further embodiments, R¹⁸is sec-butyl. In some embodiments, R¹⁸is tert-butyl. In some embodiments, R¹⁸is C_1-6alkyl optionally substituted with one or more F. In another embodiment, R¹⁸is —CH₂CH₂F. In certain embodiments, R¹⁸is —CH₂CHF₂. In another embodiment, R¹⁸is —CH₂CF₃. In one embodiment, R¹⁸is C_3-5cycloalkyl. In a specific embodiment, R¹⁸is cyclopropyl. In another embodiment, R¹⁸is C_1-6alkyl optionally substituted with one or more C_3-5cycloalkyl. In certain embodiments, R¹⁸is

[Image Omitted]

In another embodiment, R¹⁸is C_1-6alkyl optionally substituted with one or more OH. In some embodiments, R¹⁸is

[Image Omitted]

In one embodiment, R^9′ is OH. In one embodiment, R^9′ is halo. In yet other embodiments, R^9′ is F. In another embodiment, R^9′ is Cl. In additional embodiments, R^9′ is Br. In additional embodiments, R^9′ is I. In one embodiment, R^9′ is C_3-5cycloalkyl. In a specific embodiment, R^9′ is cyclopropyl.

In one embodiment, n is 1 or 2. In other embodiments, n is 1. In other embodiments, n is 2.

In one embodiment, p is 1-9. In one embodiment, p is 1-3. In other embodiments, p is 1 or 2. In yet other embodiments, p is 2 or 3. In yet other embodiments, p is 1 or 3. In other embodiments, p is 1. In other embodiments, p is 2. In other embodiments, p is 3.

In one embodiment, a compound is selected from one of the compounds listed in Table 4, or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof.

TABLE 4

Representative compounds having Structure (III)

[Image Omitted]

111

112

In another embodiment, a compound is provided having structure (IV):

[Image Omitted]

- or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof,
- wherein:
  - ring A is C_3-8cycloalkyl,

[Image Omitted]

- - or a saturated heterocyclic ring wherein the heteroatoms consist of 1-2 oxygen atoms;
  - each R_aand R_bare each, independently, H or C_1-6alkyl;
  - R¹is H, halo, OH, CN, C_1-6alkyl, OC_1-6alkyl, OC_1-6haloalkyl or C_3-5cycloalkyl;
  - R²and R⁵are each, independently, H, halo, OH, CN, C_1-6alkyl, C_1-6haloalkyl, OC_1-6alkyl or OC_1-6haloalkyl;
  - one of R³or R⁴is OH and the other is H, halo, OH, CN, C_1-6alkyl, C_1-6haloalkyl, OC_1-6alkyl or OC_1-6haloalkyl;
  - R⁹is H, C_3-5cycloalkyl, or C_1-6alkyl optionally substituted with one or more R^9′;
  - R¹¹and R¹²are each, independently, is H, halo, CN, C_1-6alkyl, C_1-6haloalkyl or OC_1-6alkyl;
  - R¹⁸is halo, CO₂H, aminyl, C_3-5cycloalkyl, or C_1-6alkyl, wherein the C_1-6alkyl is optionally substituted with one or more R^9′;
  - R^9′ is OH, halo or C_3-5cycloalkyl;
  - n is 0, 1 or 2;
  - p is 0-9; and
  - q is 1-3.
  - provided that when R¹is H and A is

[Image Omitted]

- - then R⁹is not unsubstituted ethyl.

In more specific embodiments of Structure (IV), as appropriate, such structures include the following more specific embodiments.

In one embodiment, one of R¹¹and R¹²is H. In another embodiment, R¹¹is C_1-6alkyl and R¹²is H. In another embodiment, R¹¹is H and R¹²is C_1-6alkyl. In another embodiment, both R¹¹and R¹²are H. In another embodiment, both R¹¹and R¹²are not H. In some embodiments, R¹¹is H, halo, CN, C_1-6alkyl, C_1-6haloalkyl or OC_1-6alkyl, and R¹²is H. In some embodiments, R¹¹is H, F, CN, methyl, CF₃or OCH₃, and R¹²is H. In other embodiments, R¹¹is H and R¹²is H, halo, CN, C_1-6alkyl, C_1-6haloalkyl or OC_1-6alkyl. In other embodiments, R¹¹is H and R¹²is H, F, CN, methyl, CF₃or OCH₃.

In one embodiment, R¹¹is H. In another embodiment, R¹¹is halo. In certain embodiments R¹¹is F. In other embodiments R¹¹is Cl. In certain embodiments R¹¹is Br. In specific embodiments R¹¹is I. In some embodiments, R¹¹is C_1-6alkyl. In one embodiment, R¹¹is methyl. In other embodiments, R¹¹is ethyl. In additional embodiments, R¹¹is propyl. In additional embodiments, R¹¹is propyl. In further embodiments, R¹¹is isopropyl. In other embodiments, R¹¹is n-butyl. In further embodiments, R¹¹is sec-butyl. In some embodiments, R¹¹is tert-butyl. In some embodiments, R¹¹is CN. In some embodiments, R¹¹is C_1-6haloalkyl. In specific embodiments, R¹¹is CF₃. In some embodiments, R¹¹is OC_1-6alkyl. In specific embodiments, R¹¹is OCH₃.

In one embodiment, R¹²is H. In another embodiment, R¹²is halo. In certain embodiments, R¹²is F. In other embodiments, R¹²is Cl. In certain embodiments, R¹²is Br. In specific embodiments, R¹²is I. In some embodiments, R¹²is C_1-6alkyl. In one embodiment, R¹²is methyl. In other embodiments, R¹²is ethyl. In additional embodiments, R¹²is propyl. In additional embodiments, R¹²is propyl. In further embodiments, R¹²is isopropyl. In other embodiments, R¹²is n-butyl. In further embodiments, R¹²is sec-butyl. In some embodiments, R¹²is tert-butyl. In some embodiments, R¹²is CN. In some embodiments, R¹²is C_1-6haloalkyl. In specific embodiments, R¹²is CF₃. In some embodiments, R¹²is OC_1-6alkyl. In specific embodiments, R¹²is OCH₃.

In one embodiment, R¹is H. In one embodiment, R¹is halo. In certain embodiments, R¹is F. In other embodiments, R¹is Cl. In certain embodiments R¹is Br. In specific embodiments R¹is I. In some embodiments, R¹is CN. In other embodiments, R¹is OH. In some embodiments, R¹is C_1-6alkyl. In one embodiment, R¹is methyl. In other embodiments, R¹is ethyl. In additional embodiments, R¹is propyl. In additional embodiments, R¹is propyl. In further embodiments, R¹is isopropyl. In other embodiments, R¹is n-butyl. In further embodiments, R¹is sec-butyl. In some embodiments, R¹is tert-butyl. In some embodiments, R¹is OC_1-6alkyl. In specific embodiments, R¹is OCH₃. In some embodiments, R¹is OC_1-6haloalkyl. In specific embodiments, R¹is OCF₃. In some embodiments, R¹is C_3-5cycloalkyl. In specific embodiments, R¹is cyclopropyl.

In one embodiment, R²and R⁵are each, independently, H, C_1-6alkyl, F, Cl, CF₃, or CN. In another embodiment, R²is OH, CF₃, C_1-6alkyl, CN, halo, OCF₃or OC_1-6alkyl, and R⁵is H. In another embodiment, R²is H and R⁵is OH, CF₃, C_1-6alkyl, CN, halo, OCF₃or OC_1-6alkyl.

In one embodiment, R²is H. In another embodiment, R²is OH. In additional embodiments, R²is C_1-6haloalkyl. In some embodiments, R²is CF₃. In additional embodiments, R²is C_1-6alkyl. In a specific embodiment, R²is methyl. In another embodiment, R²is ethyl. In another embodiment, R²is isopropyl. In yet other embodiments, R²is CN. In one embodiment, R²is halo. In another embodiment, R²is F. In another embodiment, R²is Cl. In another embodiment, R²is Br. In another embodiment, R²is OC_1-6haloalkyl. In some embodiments, R²is OCF₃. In another embodiment, R²is OC_1-6alkyl. In a specific embodiment, R²is OCH₃.

In one embodiment, R⁵is H. In another embodiment, R⁵is OH. In another embodiment, R⁵is C_1-6haloalkyl. In another embodiment, R⁵is CF₃. In another embodiment, R⁵is C_1-6alkyl. In another embodiment, R⁵is methyl. In another embodiment, R⁵is ethyl. In another embodiment, R⁵is isopropyl. In another embodiment, R⁵is CN. In one embodiment, R⁵is halo. In another embodiment, R⁵is F. In another embodiment, R⁵is Cl. In another embodiment, R⁵is Br. In another embodiment, R⁵is OC_1-6haloalkyl. In another embodiment, R⁵is OCF₃. In another embodiment, R⁵is OC_1-6alkyl. In another embodiment, R⁵is OCH₃.

In one embodiment, R³is OH and R⁴is H, OH, CF₃, C_1-6alkyl, CN, halo, OCF₃or OC_1-6alkyl. In another embodiment, R⁴is OH and R³is H, OH, CF₃, C_1-6alkyl, CN, halo, OCF₃or OC_1-6alkyl. In yet other embodiments, R³is OH and R⁴is H or C_1-6alkyl. In another embodiment, R⁴is OH and R³is H or C_1-6alkyl.

In some embodiments, R³is OH. In another embodiment, R³is H. In another embodiment, R³is C_1-6haloalkyl. In one embodiment, R³is CF₃. In another embodiment, R³is C_1-6alkyl. In a specific embodiment, R³is methyl. In another embodiment, R³is ethyl. In certain embodiments, R³is isopropyl. In another embodiment, R³is CN. In one embodiment, R³is halo. In some embodiments, R³is F. In another embodiment, R³is Cl. In one embodiment, R³is Br. In another embodiment, R³is OC_1-6haloalkyl. In another embodiment, R³is OCF₃. In some embodiments, R³is OC_1-6alkyl. In certain embodiments, R³is OCH₃.

In one embodiment, R⁴is OH. In another embodiment, R⁴is H. In another embodiment, R⁴is C_1-6haloalkyl. In yet other embodiments, R⁴is CF₃. In another embodiment, R⁴is C_1-6alkyl. In specific embodiments, R⁴is methyl. In another embodiment, R⁴is ethyl. In certain embodiments, R⁴is isopropyl. In another embodiment, R⁴is CN. In one embodiment, R⁴is halo. In yet other embodiments, R⁴is F. In another embodiment, R⁴is Cl. In additional embodiments, R⁴is Br. In another embodiment, R⁴is OC_1-6haloalkyl. In another embodiment, R⁴is OCF₃. In other embodiments, R⁴is OC_1-6alkyl. In certain embodiments, R⁴is OCH₃.

In one embodiment, R⁹is H. In another embodiment, R⁹is not H. In some embodiments, R⁹is C_1-6alkyl. In a specific embodiment, R⁹is methyl. In some embodiments, R⁹is ethyl. In certain embodiments, R⁹is isopropyl. In some embodiments, R⁹is C_1-6alkyl optionally substituted with one or more F. In another embodiment, R⁹is —CH₂CH₂F. In certain embodiments, R⁹is —CH₂CHF₂. In another embodiment, R⁹is —CH₂CF₃. In one embodiment, R⁹is C_3-5cycloalkyl. In a specific embodiment, R⁹is cyclopropyl. In another embodiment, R⁹is C_1-6alkyl optionally substituted with one or more C_3-5cycloalkyl. In certain embodiments, R⁹is

[Image Omitted]

In another embodiment, R⁹is C_1-6alkyl optionally substituted with one or more OH. In some embodiments, R⁹is

[Image Omitted]

In one embodiment, R^9′ is OH. In one embodiment, R^9′ is halo. In yet other embodiments, R^9′ is F. In another embodiment, R^9′ is Cl. In additional embodiments, R^9′ is Br. In additional embodiments, R^9′ is I. In one embodiment, R^9′ is C_3-5cycloalkyl. In a specific embodiment, R^9′ is cyclopropyl.

In one embodiment, R¹⁸is halo. In certain embodiments, R¹⁸is F. In other embodiments, R¹⁸is Cl. In certain embodiments R¹⁸is Br. In specific embodiments R¹⁸is I. In some embodiments, R¹⁸is CO₂H. In other embodiments, R¹⁸is aminyl. In certain embodiments, R¹⁸is N(CH₃) 2. In certain embodiments, R¹⁸is NH(CH₃). In some embodiments, R¹⁸is C_3-5cycloalkyl. In specific embodiments, R¹⁸is cyclopropyl. In some embodiments, R¹⁸is C_1-6alkyl. In one embodiment, R¹⁸is methyl. In other embodiments, R¹⁸is ethyl. In additional embodiments, R¹⁸is propyl. In additional embodiments, R¹⁸is propyl. In further embodiments, R¹⁸is isopropyl. In other embodiments, R¹⁸is n-butyl. In further embodiments, R¹⁸is sec-butyl. In some embodiments, R¹⁸is tert-butyl. In some embodiments, R¹⁸is C_1-6alkyl optionally substituted with one or more F. In another embodiment, R¹⁸is —CH₂CH₂F. In certain embodiments, R¹⁸is —CH₂CHF₂. In another embodiment, R¹⁸is —CH₂CF₃. In one embodiment, R¹⁸is C_3-5cycloalkyl. In a specific embodiment, R¹⁸is cyclopropyl. In another embodiment, R¹⁸is C_1-6alkyl optionally substituted with one or more C_3-5cycloalkyl. In certain embodiments, R¹⁸is

[Image Omitted]

In another embodiment, R¹⁸is C_1-6alkyl optionally substituted with one or more OH. In some embodiments, R¹⁸is

[Image Omitted]

In one embodiment, Ra is H. In another embodiment, Ra is C_1-6alkyl. In certain embodiments, Ra is methyl.

In one embodiment, R_bis H. In another embodiment, R_bis C_1-6alkyl. In certain embodiments, R_bis methyl.

In one embodiment, n is 0-2. In one embodiment, n is 0 or 1. In other embodiments, n is 1 or 2. In yet other embodiments, n is 0 or 2. In some embodiments, n is 0. In other embodiments, n is 1. In other embodiments, n is 2.

In one embodiment, p is 0-9. In one embodiment, p is 0-3. In one embodiment, p is 0 or 1. In other embodiments, p is 1 or 2. In yet other embodiments, p is 0 or 2. In some embodiments, p is 0. In other embodiments, p is 1. In other embodiments, p is 2. In other embodiments, p is 3.

In one embodiment, q is 1-3. In other embodiments, q is 1 or 2. In yet other embodiments, q is 1 or 3. In some embodiments, q is 2 or 3. In other embodiments, q is 1. In other embodiments, q is 2. In other embodiments, q is 3.

In one embodiment, a compound is selected from one of the compounds listed in Table 5, or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof.

TABLE 5

Representative compounds having Structure (IV)

[Image Omitted]

113

114

115

116

117

118

119

120

121

122

In another embodiment, a compound is provided having structure (V):

[Image Omitted]

- or a pharmaceutically acceptable salt, isomer, hydrate, solvate or isotope thereof,
- wherein:
  - R_ais H or C_1-6alkyl;
  - each R_cand R_dare each, independently, H or C_1-6alkyl, or R_cand R_djoin together to form oxo;
  - R¹is H, halo, OH, CN, C_1-6alkyl, OC_1-6alkyl, OC_1-6haloalkyl or C_3-5cycloalkyl;
  - R²and R⁵are each, independently, H, halo, OH, CN, C_1-6alkyl, C_1-6haloalkyl, OC_1-6alkyl or OC_1-6haloalkyl;
  - one of R³or R⁴is OH and the other is H, halo, OH, CN, C_1-6alkyl, C_1-6haloalkyl, OC_1-6alkyl or OC_1-6haloalkyl;
  - R¹¹and R¹²are each, independently, is H, halo, CN, C_1-6alkyl, C_1-6haloalkyl or OC_1-6alkyl;
  - R¹⁸is C_1-3alkyl, wherein the C_1-3alkyl is optionally substituted with one or more R^9′;
  - R^9′ is OH, halo or C_3-5cycloalkyl; and
  - q is 1-3.

In more specific embodiments of Structure (V), as appropriate, such structures include the following more specific embodiments.