Compounds for treatment of diseases of abnormal angiogenesis or aberrant growth factors and uses thereof

Patent metadata

Field	Value
Publication number	US-9988386-B2
Application number	US-201414894214-A
Country	US
Kind code	B2
Filing date	May 30, 2014
Priority date	May 30, 2013
Publication date	Jun 5, 2018
Grant date	Jun 5, 2018

Abstract

The present invention provides novel compounds of any one of Formulae (I)-(IV), and pharmaceutical compositions thereof. Also provided are particles (e.g., nanoparticles) comprising compounds of any one of Formulae (I)-(IV) and pharmaceutical compositions thereof that are mucus penetrating. The invention also provides methods and kits for using the inventive compounds, and pharmaceutical compositions thereof, for treating and/or preventing diseases associated with abnormal or pathological angiogenesis and/or aberrant signaling of a growth factor signaling pathway (e.g., vascular endothelial growth factor (VEGF)), such as proliferative diseases (e.g., cancers, benign neoplasms, inflammatory diseases, autoimmune diseases) and ocular diseases (e.g., macular degeneration, glaucoma, diabetic retinopathy, retinoblastoma, edema, uveitis, dry eye, blepharitis, and post-surgical inflammation) in a subject in need thereof.

First claim

What is claimed is:

1. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof;
wherein:
X is a bond, —C(═O)—, —S(═O)—, or —S(═O) 2 —;
Y is a bond, —C(═O)—, —S(═O)—, or —S(═O) 2 —;
Ring A is substituted or unsubstituted, 7-membered, monocyclic carbocyclyl, substituted or unsubstituted, 4-membered, monocyclic heterocyclyl, substituted or unsubstituted, 7-membered, monocyclic heterocyclyl, or substituted or unsubstituted, 7- to 10-membered, spiro bicyclic heterocyclyl, wherein one or two atoms in the heterocyclic ring are independently selected from the group consisting of oxygen and nitrogen;
Ring Y is substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
each instance of R A is independently hydrogen, halogen, substituted or unsubstituted alkyl, —OR A1 , —N(R A1 ) 2 , oxo, or a nitrogen protecting group when attached to a nitrogen atom;
each instance of R A1 is independently hydrogen, substituted or unsubstituted alkyl, a nitrogen protecting group when attached to a nitrogen atom, or an oxygen protecting group when attached to an oxygen atom, or two instances of R A1 are joined to form substituted or unsubstituted heterocyclyl;
a is 0, 1, 2, or 3;
R B is substituted or unsubstituted alkyl or of the formula:

Ring B is substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
each instance of R B1 is independently hydrogen, halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR B1a , N(R B1a ) 2 , —SR B1a , —CN, —SCN, —C(═NR B1a )R B1a , —C(═NR B1a )OR B1a , —C(═NR B1a )N(R B1a ) 2 , —C(═O)R B1a , —C(═O)OR B1a , —C(═O)N(R B1a ) 2 , —NO 2 , —NR B1a C(═O)R B1a , —NR B1a C(═O)OR B1a , —NR B1a C(═O)N(R B1a ) 2 , —OC(═O)R B1a , —OC(═O)OR B1a , —OC(═O)N(R B1a ) 2 , or a nitrogen protecting group when attached to a nitrogen atom, or two instances of R B1 are joined to form substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
each instance of R B1a is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of R B1a are joined to form substituted or unsubstituted heterocyclyl;
b is 0, 1, 2, 3, 4, or 5;
R C is hydrogen, substituted or unsubstituted C 1-6 alkyl, or a nitrogen protecting group;
R D is hydrogen, substituted or unsubstituted C 1-6 alkyl, or a nitrogen protecting group;
each instance of R L is independently hydrogen, halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —OR L1 , —N(R L1 ) 2 , —SR L1 , —CN, —SCN, —C(═NR L1 )R L1 , —C(═NR L1 )OR L1 , —C(═NR L1 )N(R L1 ) 2 , —C(═O)R L1 , —C(═O)OR L1 , —C(═O)N(R L1 ) 2 , —NO 2 , —NR L1 C(═O)R L1 , —NR L1 C(═O)OR L1 , —NR L1 C(═O)N(R L1 ) 2 , —OC(═O)R L1 , —OC(═O)OR L1 , or —OC(═O)N(R L1 ) 2 , or two instances of R L are joined to form substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
each instance of R L1 is independently hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two instances of R L1 are joined to form substituted or unsubstituted heterocyclyl;
l is 0, 1, 2, 3, or 4; and
m is 0, 1, 2, 3, 4, or 5.

2. The compound of claim 1 , wherein X is —C(═O)—.

3. The compound of claim 1 , wherein Y is a bond.

4. The compound of claim 1 , wherein Ring A is substituted or unsubstituted oxetanyl.

5. The compound of claim 1 , wherein Ring A is of the formula:

6. A The compound of claim 1 , wherein R B is of the formula

7. The compound of claim 6 , wherein Ring B is substituted or unsubstituted phenyl.

8. The compound of claim 6 , wherein Ring B is substituted or unsubstituted, 5- or 6-membered, monocyclic heteroaryl, wherein one, two, three, or four atoms in the heteroaryl ring is independently selected from the group consisting of nitrogen, oxygen, and sulfur.

9. The compound of claim 1 , wherein R B is of the formula:

10. The compound of claim 1 , wherein m is 1.

11. The compound of claim 1 , wherein m is 3.

12. A compound of Formula (II):

or a pharmaceutically acceptable salt thereof;
wherein:
U is a bond, —C(═O)—, —S(═O)—, —S(═O) 2 —, —N(R N )—S(═O)—, or —N(R N )—S(═O) 2 —;
V is a bond, CH, CH 2 , —C(═O)—, —S(═O)—, or —S(═O) 2 —;
W is a bond, CH 2 , —S(═O) 2 —, —S(═O) 2 —N(R K )—, or

Ring Z is substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R N is hydrogen, substituted or unsubstituted C 1-6 alkyl, or a nitrogen protecting group;
R K is hydrogen, substituted or unsubstituted C 1-6 alkyl, or a nitrogen protecting group;
R E is substituted or unsubstituted alkyl or of the formula:

Ring E is substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
each instance of R E1 is independently hydrogen, halogen, substituted or unsubstituted acyl

Assignees

• Kala Pharmaceuticals Inc
• Kata Pharmaceuticals Inc

Inventors

• Ong Winston Zapanta
• Nowak Pawel Wojciech
• Askew Ben C
• Good Andrew

Classifications

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P7/10

  Antioedematous agents; Diuretics · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title