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1. WO2020014605 - INHIBITEURS DE L'HISTONE DÉSACÉTYLASE

Note: Texte fondé sur des processus automatiques de reconnaissance optique de caractères. Seule la version PDF a une valeur juridique

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Listing of Claims:

1. A compound of the Formula I:


or a pharmaceutically acceptable salt thereof, wherein

ring A is phenyl or thiophenyl;

X is (CRaRb)t, O, or NR5;

q and t are each independently 0, 1, 2, or 3;

R1 is phenyl or heteroaryl, each of which are optionally substituted with 1 to 3 groups selected from Rc;

R2 is hydrogen, halo, (Ci-C4)alkyl, (Ci-C4)alkoxy, or OH;

R is hydrogen or halo;

R4 is halo when ring A is phenyl and R4 is hydrogen when ring A is thiopheneyl;

R5 is hydrogen, (Ci-C4)alkyl, or (Ci-C4)alkylO(Ci-C4)alkyl;

Ra and Rb are each independently hydrogen, (Ci-C4)alkyl, halo(Ci-C4)alkyl, (Ci-C4)alkoxy, or halo; and

Rc is halo, (Ci-C4)alkyl, halo(Ci-C4)alkyl, (Ci-C4)alkoxy, halo(Ci-C4)alkoxy, (Ci-C4)alkylO(C1-C4)alkyl, (Ci-C4)alkylNH(Ci-C4)alkyl, (Ci-C4)alkylN((Ci-C4)alkyl)2, -( -C4)alkylheteroaryl, or -(Ci-C4)alkylheterocyclyl, wherein said heteroaryl and heterocyclyl are each optionally and independently substituted with 1 to 3 groups selected from (Ci-C4)alkyl, halo(Ci-C4)alkyl, (Ci-C4)alkoxy, and halo.

2. The compound of Claim 1, wherein the compound is of the Formula II:


or a pharmaceutically acceptable salt thereof.

3. The compound of Claim 1 or 2, wherein the compound is of the Formula III or Ilia:


(Ilia); or a pharmaceutically acceptable salt thereof.

2

4. The compound of any one of Claims 1 to 3, wherein q is 0 or 1; and R is halo when q is 1.

5. The compound of any one of Claims 1 to 4, wherein the compound is of the Formula

IV or IVa:


or a pharmaceutically acceptable salt thereof.

6. The compound of any one of Claims 1 to 5, wherein R is halo.

7. The compound of any one of Claims 1 to 6, wherein R3 is fluoro.

8. The compound of any one of Claims 1 to 5, wherein R is hydrogen.

9. The compound of any one of Claims 1 to 8, wherein R4 is fluoro.

10. The compound of any one of Claims to 9, wherein X is (CRaRb)t.

11. The compound of any one of Claims 1 to 10, wherein Ra and Rb are each hydrogen.

12. The compound of any one of Claims 1 to 9, wherein the compound is of the Formula

V or Va:


or a pharmaceutically acceptable salt thereof.

13. The compound of any one of Claims 1 to 10, wherein the compound is of the Formula

VI or Via:


or a pharmaceutically acceptable salt thereof.

14. The compound of any one of Claims 1 to 11, wherein the compound is of the Formula

VII or Vila:


(Vila);

or a pharmaceutically acceptable salt thereof.

15. The compound of any one of Claims 1 to 14, wherein R1 is phenyl or 5- to 6-membered monocyclic heteroaryl, each of which is optionally substituted with one or more groups selected from Rc.

16. The compound of any one of Claims 1 to 15, wherein R1 is phenyl, pyridinyl, pyrazinyl, pyridazinyl, or pyrimidinyl, each of which is optionally substituted with 1 to 2 groups selected from Rc.

17. The compound of any one of Claims 1 to 15, wherein R1 is thiazolyl, thiadiazolyl, imidazolyl, pyrazolyl, or oxazolyl, each of which is optionally substituted with 1 to 2 groups selected from Rc.

18. The compound of any one of Claims 1 to 17, wherein Rc is halo, (Ci-C4)alkyl, or (Ci-C4)alkylO(C1-C4)alkyl.

19. The compound of any one of Claims 1 to 18, wherein Rc is fluoro, methyl, or CH2OCH3.

20. The compound of any one of Claims 1 to 17, wherein Rc is halo, halo(Ci-C4)alkyl, or (Ci-C4)alkyl.

21. The compound of any one of Claims 1 to 17 and 20, wherein Rc is fluoro, methyl, or CHF2.

22. The compound of Claim 1, wherein the compound is selected from

85

or a pharmaceutically acceptable salt thereof.

23. The compound of Claim 1, wherein the compound is selected from

87

88

or a pharmaceutically acceptable salt thereof.

24. A composition comprising a compound of any one of Claims 1 to 23, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

25. A method of inhibiting HD AC activity in a subject comprising the step of

administering to the subject in need thereof an effective amount of a compound of any one of Claims 1 to 23, or a pharmaceutically acceptable salt thereof, or the composition of Claim 24.

26. A method of treating a condition in a subject selected from a neurological disorder, memory or cognitive function disorder or impairment, extinction learning disorder, fungal disease or infection, inflammatory disease, hematological disease, psychiatric disorders, and neoplastic disease, comprising administering to the subject in need thereof an effective amount the compound of any one of Claims 1 to 23, or a pharmaceutically acceptable salt thereof, or the composition of Claim 24.

27. The method of Claim 26, wherein the condition is:

a. a cognitive function disorder or impairment associated with Alzheimer’s disease, posterior cortical atrophy, normal-pressure hydrocephalus, Huntington’s disease, seizure induced memory loss, schizophrenia, Rubinstein Taybi syndrome, Rett Syndrome, depression, Fragile X, Lewy body dementia, stroke, vascular dementia, vascular cognitive impairment (VCI), Binswanger’s Disease, fronto-temporal lobar degeneration (FTLD), ADHD, dyslexia, major depressive disorder, bipolar disorder and social, cognitive and learning disorders associated with autism, traumatic brain injury (TBI), chronic traumatic encephalopathy (CTE), multiple sclerosis (MS), attention deficit disorder, anxiety disorder, conditioned fear response, panic disorder, obsessive compulsive disorder, posttraumatic stress disorder (PTSD), phobia, social anxiety disorder, substance dependence recovery, Age Associated Memory Impairment (AAMI), Age Related Cognitive Decline (ARCD), ataxia, Parkinson’s disease, or Parkinson’s disease dementia; or

b. a hematological disease selected from acute myeloid leukemia, acute promyelocytic leukemia, acute lymphoblastic leukemia, chronic myelogenous leukemia, myelodysplastic syndromes, and sickle cell anemia; or

c. a neoplastic disease; or

d. a disorder of learning extinction selected from fear extinction and post-traumatic stress disorder; or

e. hearing loss or a hearing disorder; or

f. fibrotic diseases, such as pulmonary fibrosis, renal fibrosis, cardiac fibrosis, and scleroderma; or

g. bone pain in patients with cancer; or

h. neuropathic pain.

28. The method of Claim 27, wherein the condition is Alzheimer's disease, Huntington's disease, frontotemporal dementia, Friedreich's ataxia, post-traumatic stress disorder (PTSD), Parkinson’s disease, or substance dependence recovery.

29. The method of Claim 26, wherein the condition is selected from Alzheimer’s disease, Huntington’s disease, fronto-temporal lobar degeneration, Friedreich’s ataxia, post-traumatic stress disorder, Parkinson’s disease, Parkinson’s disease dementia, substance dependence recovery, memory or cognitive function disorder or impairment, neurological disorder with synaptic pathology, disorder of learning distinction, psychiatric disorders, cognitive function or impairment associated with Alzheimer’s disease, Lewy body dementia, schizophrenia, Rubinstein Taybi syndrome, Rett Syndrome, Fragile X, multiple sclerosis, age associated memory impairment, age related cognitive decline, and social, cognitive and learning disorders associated with autism.