# US 12,109,213 B2 · Fused heterotricyclic organic compounds, pharmaceutical compositions, and medical uses thereof

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- Number: US 12,109,213 B2
- Document ID: US12109213B2
- Status: Granted
- Kind: B2
- Application number: 17/858,712
- Filed: 2022-07-06
- Published: 2022-12-01
- Granted: 2024-10-08
- Earliest claimed: 2013-10-21
- Assignees: Alevere Medical Corporation
- Applicants: Alevere Medical Corporation
- Inventors: Tim Kamerzell
- Web page: https://patentgrep.com/patent/US12109213B2

## CPC

- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- A61K 8/4946: {Imidazoles or their condensed derivatives, e.g. benzimidazoles}
- A61K 8/4953: {containing pyrimidine ring derivatives, e.g. minoxidil}
- A61K 8/4966: {Triazines or their condensed derivatives}
- A61K 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)}
- A61K 31/496: Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
- A61K 31/4985: Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
- A61K 31/53: having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine (melarsoprol A61K31/555 {; with four nitrogen atoms A61K31/495})
- A61P 1/06: Anti-spasmodics, e.g. drugs for colics, esophagic dyskinesia
- A61P 3/04: Anorexiants; Antiobesity agents
- A61Q 19/00: Preparations for care of the skin
- A61Q 19/06: for countering cellulitis
- A61K 31/4162: condensed with heterocyclic ring systems
- C07D 487/14: Ortho-condensed systems
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61Q: SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

The invention provides fused heterocyclic organic compounds such as dihydropyrazolopyridotriazinones, compositions containing such compounds, medical kits, and methods for using such compounds and compositions for body contouring and/or reduction of fat in a subject.

## Claims

### Claim 1

A cosmetic method of modifying the contour of a subject's externally exposed body part containing fat, the method comprising administering to said body part an amount of a compound of Formula I effective to modify the contour of said body part, wherein Formula I is represented by:
or a pharmaceutically acceptable salt thereof, wherein:
R1 is phenyl, 5-6 membered heteroaryl, aralkyl, —(C1-C6)alkyl, —(C3-C6)cycloalkyl, —(C1-C6)alkylene-OH, or —(C1-C6)alkylene-O—(C1-C6)alkyl, wherein said phenyl, 5-6 membered heteroaryl, aralkyl, and cycloalkyl are optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, —(C1-C6)alkyl, —(C3-C6)cycloalkyl, hydroxyl, —(C1-C6)alkoxy, and —N(R5)R6;
R2 and R3 each represent independently for each occurrence hydrogen, —(C1-C6)alkyl, or halogen;
R4 is —C(O)N(R5)R6, —N(R5)C(O)R6, —CO2R6, —C(O)R6, —(C1-C6)alkylene-N(R5)R6, —(C1-C6)alkylene-OR6, or —(C1-C6)alkoxy;
R5 and R6 each represent independently for each occurrence hydrogen, —(C1-C6)alkyl, or —(C3-C6)cycloalkyl; or when R5 and R6 are attached to the same nitrogen atom, then R5 and R6 may be taken together with the nitrogen atom to which they are attached to form a 3-7 membered heterocycle; and
n and m each represent independently 1 or 2.

### Claim 2 (depends on 1)

The method of claim 1, wherein the body part is the subject's face, neck, chin, submental region, arm, thigh, knee, calf, buttocks, hips, or abdomen.

### Claim 3 (depends on 1)

The method of claim 1, wherein the body part is the subject's face.

### Claim 4 (depends on 1)

The method of claim 1, wherein the body part is the subject's neck or submental region.

### Claim 5 (depends on 1)

The method of claim 1, wherein the subject experiences at least a 5% by weight reduction in the amount of fat in the subject's body part exposed to said compound.

### Claim 6 (depends on 1)

The method of claim 1, wherein the subject experiences at least a 15% by weight reduction in the amount of fat in the subject's body part exposed to said compound.

### Claim 7 (depends on 1)

The method of claim 1, wherein the administering comprises injecting said compound into said body part.

### Claim 8

A method selected from:
(a) a method of reducing the amount of subcutaneous fat in a subject, comprising exposing subcutaneous fat in a subject to an effective amount of a compound of Formula I to reduce the amount of subcutaneous fat in said subject, wherein Formula I is represented by:
or a pharmaceutically acceptable salt thereof, wherein:
R1 is phenyl, 5-6 membered heteroaryl, aralkyl, —(C1-C6)alkyl, —(C3-C6)cycloalkyl, —(C1-C6)alkylene-OH, or —(C1-C6)alkylene-O—(C1-C6)alkyl, wherein said phenyl, 5-6 membered heteroaryl, aralkyl, and cycloalkyl are optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, —(C1-C6)alkyl, —(C3-C6)cycloalkyl, hydroxyl, —(C1-C6)alkoxy, and —N(R5)R6;
R2 and R3 each represent independently for each occurrence hydrogen, —(C1-C6)alkyl, or halogen;
R4 is —C(O)N(R5)R6, —N(R5)C(O)R6, —CO2R6, —C(O)R6, —(C1-C6)alkylene-N(R5)R6, —(C1-C6)alkylene-OR6, or —(C1-C6)alkoxy;
R5 and R6 each represent independently for each occurrence hydrogen, —(C1-C6)alkyl, or —(C3-C6)cycloalkyl; or when R5 and Re are attached to the same nitrogen atom, then R5 and R6 may be taken together with the nitrogen atom to which they are attached to form a 3-7 membered heterocycle; and
n and m each represent independently 1 or 2;
b) a method for inducing retraction of dermal tissue in a subject, comprising administering an effective amount of a compound of Formula I to dermal tissue of a subject to induce retraction of dermal tissue, wherein Formula I is represented by:
or a pharmaceutically acceptable salt thereof, wherein:
R1 is phenyl, 5-6 membered heteroaryl, aralkyl, —(C1-C6)alkyl, —(C3-C6)cycloalkyl, —(C1-C6)alkylene-OH, or —(C1-C6)alkylene-O—(C1-C6)alkyl, wherein said phenyl, 5-6 membered heteroaryl, aralkyl, and cycloalkyl are optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, —(C1-C6)alkyl, —(C3-C6)cycloalkyl, hydroxyl, —(C1-C6)alkoxy, and —N(R5)R6;
R2 and R3 each represent independently for each occurrence hydrogen, —(C1-C6)alkyl, or halogen;
R4 is —C(O)N(R5)R6, —N(R5)C(O)R6, —CO2R6, —C(O)R6, —(C1-C6)alkylene-N(R5)R6, —(C1-C6)alkylene-OR6, or —(C1-C6)alkoxy;
R5 and R6 each represent independently for each occurrence hydrogen, —(C1-C6)alkyl, or —(C3-C6)cycloalkyl; or when R5 and R6 are attached to the same nitrogen atom, then R5 and R6 may be taken together with the nitrogen atom to which they are attached to form a 3-7 membered heterocycle; and
n and m each represent independently 1 or 2;
(c) a method for inducing retraction of subcutaneous tissue in a subject, comprising administering an effective amount of a compound of Formula I to subcutaneous tissue of a subject to induce retraction of subcutaneous tissue, wherein Formula I is represented by:
or a pharmaceutically acceptable salt thereof, wherein:
R1 is phenyl, 5-6 membered heteroaryl, aralkyl, —(C1-C6)alkyl, —(C3-C6)cycloalkyl, —(C1-C6)alkylene-OH, or —(C1-C6)alkylene-O—(C1-C6)alkyl, wherein said phenyl, 5-6 membered heteroaryl, aralkyl, and cycloalkyl are optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, —(C1-C6)alkyl, —(C3-C6)cycloalkyl, hydroxyl, —(C1-C6)alkoxy, and —N(R5)R6;
R2 and R3 each represent independently for each occurrence hydrogen, —(C1-C6)alkyl, or halogen;
R4 is —C(O)N(R5)R6, —N(R5)C(O)R6, —CO2R6, —C(O)R6, —(C1-C6)alkylene-N(R5)R6, —(C1-C6)alkylene-OR6, or —(C1-C6)alkoxy;
R5 and R6 each represent independently for each occurrence hydrogen, —(C1-C6)alkyl, or —(C3-C6)cycloalkyl; or when R5 and R6 are attached to the same nitrogen atom, then R5 and R6 may be taken together with the nitrogen atom to which they are attached to form a 3-7 membered heterocycle; and
n and m each represent independently 1 or 2;
(d) a method of treating a disorder selected from the group consisting of an adipose tissue tumor, fat embolism, dyslipidemia, and or fatty liver disease due to alcohol-induced liver cirrhosis in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I to treat the disorder, wherein Formula I is represented by:
or a pharmaceutically acceptable salt thereof, wherein:
R1 is phenyl, 5-6 membered heteroaryl, aralkyl, —(C1-C6)alkyl, —(C3-C6)cycloalkyl, —(C1-C6)alkylene-OH, or —(C1-C6)alkylene-O—(C1-C6)alkyl, wherein said phenyl, 5-6 membered heteroaryl, aralkyl, and cycloalkyl are optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, —(C1-C6)alkyl, —(C3-C6)cycloalkyl, hydroxyl, —(C1-C6)alkoxy, and —N(R5)R6;
R2 and R3 each represent independently for each occurrence hydrogen, —(C1-C6)alkyl, or halogen;
R4 is —C(O)N(R5)R6, —N(R5)C(O)R6, —CO2R6, —C(O)R6, —(C1-C6)alkylene-N(R5)R6, —(C1-C6)alkylene-OR6, or —(C1-C6)alkoxy;
R5 and R6 each represent independently for each occurrence hydrogen, —(C1-C6)alkyl, or —(C3-C6)cycloalkyl; or when R5 and Re are attached to the same nitrogen atom, then R5 and R6 may be taken together with the nitrogen atom to which they are attached to form a 3-7 membered heterocycle; and
n and m each represent independently 1 or 2;
(e) a method of reducing the amount of fat or cholesterol in a subject, comprising administering to a subject in need thereof an effective amount of a compound of Formula I to reduce the amount of fat or cholesterol in the subject, wherein Formula I is represented by:
or a pharmaceutically acceptable salt thereof, wherein:
R1 is phenyl, 5-6 membered heteroaryl, aralkyl, —(C1-C6)alkyl, —(C3-C6)cycloalkyl, —(C1-C6)alkylene-OH, or —(C1-C6)alkylene-O—(C1-C6)alkyl, wherein said phenyl, 5-6 membered heteroaryl, aralkyl, and cycloalkyl are optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, —(C1-C6)alkyl, —(C3-C6)cycloalkyl, hydroxyl, —(C1-C6)alkoxy, and —N(R5)R6, R2 and R3 each represent independently for each occurrence hydrogen, —(C1-C6)alkyl, or halogen;
R4 is —C(O)N(R5)R6, —N(R5)C(O)R6, —CO2R6, —C(O)R6, —(C1-C6)alkylene-N(R5)R6, —(C1-C6)alkylene-OR6, or —(C1-C6)alkoxy;
R5 and R6 each represent independently for each occurrence hydrogen, —(C1-C6)alkyl, or —(C3-C6)cycloalkyl; or when R5 and Re are attached to the same nitrogen atom, then R5 and R6 may be taken together with the nitrogen atom to which they are attached to form a 3-7 membered heterocycle; and
n and m each represent independently 1 or 2; and
(f) a method of reducing the amount of mesenchymal pre-adipocyte stem cell precursors in a subject, comprising administering to a subject in need thereof an effective amount of a compound of Formula I to reduce the amount of mesenchymal pre-adipocyte stem cell precursors in the subject, wherein Formula I is represented by:
or a pharmaceutically acceptable salt thereof, wherein:
R1 is phenyl, 5-6 membered heteroaryl, aralkyl, —(C1-C6)alkyl, —(C3-C6)cycloalkyl, —(C1-C6)alkylene-OH, or —(C1-C6)alkylene-O—(C1-C6)alkyl, wherein said phenyl, 5-6 membered heteroaryl, aralkyl, and cycloalkyl are optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, —(C1-C6)alkyl, —(C3-C6)cycloalkyl, hydroxyl, —(C1-C6)alkoxy, and —N(R5)R6;
R2 and R3 each represent independently for each occurrence hydrogen, —(C1-C6)alkyl, or halogen;
R4 is —C(O)N(R5)R6, —N(R5)C(O)R6, —CO2R6, —C(O)R6, —(C1-C6)alkylene-N(R5)R6, —(C1-C6)alkylene-OR6, or —(C1-C6)alkoxy;
R5 and R6 each represent independently for each occurrence hydrogen, —(C1-C6)alkyl, or —(C3-C6)cycloalkyl; or when R5 and R6 are attached to the same nitrogen atom, then R5 and R6 may be taken together with the nitrogen atom to which they are attached to form a 3-7 membered heterocycle; and
n and m each represent independently 1 or 2.

### Claim 9 (depends on 1)

The method of claim 1, wherein the subject is an adult human.

### Claim 10 (depends on 1)

The method of claim 1, wherein R4 is —C(O)NH2.

### Claim 11 (depends on 10)

The method of claim 10, wherein R1 is (i) phenyl substituted with a methoxy group and optionally 1 or 2 additional substituents independently selected from the group consisting of halogen and —(C1-C6)alkyl, or (ii) R1 is —(C1-C6)alkylene-OH.

### Claim 12 (depends on 1)

The method of claim 1, wherein the compound is represented by Formula I-A:
or a pharmaceutically acceptable salt thereof, wherein:
R1 is phenyl, —(C1-C6)alkylene-OH, or —(C1-C6)alkylene-O—(C1-C6)alkyl, wherein said phenyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, —(C1-C6)alkyl, —(C3-C6)cycloalkyl, hydroxyl, and —(C1-C6)alkoxy;
R2 and R3 each represent independently for each occurrence hydrogen and or methyl;
R4 is —C(O)N(R5)R6, —N(R5)C(O)R6, or —(C1-C2)alkylene-N(R5)R6; and
R5 and R6 each represent independently hydrogen, —(C1-C6)alkyl, or —(C3-C6)cycloalkyl; or
when R5 and R6 are attached to the same nitrogen atom, then R5 and R6 may be taken together with the nitrogen atom to which they are attached to form a 3-7 membered heterocycle.

### Claim 13 (depends on 1)

The method of claim 1, wherein the compound is a compound in Table 4 below or a pharmaceutically acceptable salt thereof:
TABLE 4
Compound No.
R1
R2
R3
R4
I-1
2-methoxy-phenyl
H
H
—CONH2
I-2
3-methoxy-phenyl
H
H
—CONH2
I-3
4-methoxy-phenyl
H
H
—CONH2
I-4
H
H
—CONH2
I-5
H
H
—CONH2
I-6
H
H
—CONH2
I-7
benzyl
H
H
—CONH2
I-8
4-methoxy-benzyl
H
H
—CONH2
I-9
—(CH2)3-OH
H
H
—CONH2
I-10
—(CH2)2-OH
H
H
—CONH2
I-11
—CH2CH(CH3)-OH
H
H
—CONH2
I-12
H
H
—CONH2
I-13
H
H
—CONH2
I-14
H
H
—CONH2
I-15
H
H
—CONH2
I-16
H
H
—CONH2
I-17
H
H
—CONH2
I-18
—(CH2)3-OCH3
H
H
—CONH2
I-19
—(CH2)2-OCH3
H
H
—CONH2
I-20
H
H
—CONH2
I-21
2-methoxy-phenyl
CH3
H
—CONH2
I-22
3-methoxy-phenyl
H
CH3
—CONH2
I-23
4-methoxy-phenyl
CH3
CH3
—CONH2
I-24
H
CH3
—CONH2
I-25
H
CH3
—CONH2
I-26
CH3
CH3
—CONH2
I-27
benzyl
CH3
H
—CONH2
I-28
4-methoxy-benzyl
H
CH3
—CONH2
I-29
—(CH2)3-OH
CH3
CH3
—CONH2
I-30
—(CH2)2-OH
CH3
H
—CONH2
I-31
—CH2CH(CH3)-OH
H
CH3
—CONH2
I-32
CH3
CH3
—CONH2
I-33
CH3
H
—CONH2
I-34
H
CH3
—CONH2
I-35
CH3
F
—CONH2
I-36
F
H
—CONH2
I-37
H
F
—CONH2
I-38
—(CH2)3-OCH3
CH3
Cl
—CONH2
I-39
—(CH2)2-OCH3
Cl
H
—CONH2
I-40
H
Cl
—CONH2
I-41
2-methoxy-phenyl
H
H
—CON(H)CH3
I-42
3-methoxy-phenyl
H
H
—CON(H)CH3
I-43
4-methoxy-phenyl
H
H
—CON(H)CH3
I-44
H
H
—CON(H)CH3
I-45
H
H
—CON(H)CH3
I-46
H
H
—CON(H)CH2CH3
I-47
benzyl
H
H
—CON(H)CH2CH3
I-48
4-methoxy-benzyl
H
H
—CON(H)CH2CH3
I-49
—(CH2)3-OH
H
H
—CON(H)CH2CH3
I-50
—(CH2)2-OH
H
H
—CON(H)CH2CH3
I-51
2-methoxy-phenyl
H
H
—CO2H
I-52
3-methoxy-phenyl
H
H
—CO2H
I-53
4-methoxy-phenyl
H
H
—CO2H
I-54
H
—CO2H
I-55
H
H
—CO2H
I-56
H
H
—CO2H
I-57
benzyl
H
H
—CO2H
I-58
4-methoxy-benzyl
H
H
—CO2H
I-59
—(CH2)3-OH
H
H
—CO2H
I-60
—(CH2)2-OH
H
H
—CO2H
I-61
2-methoxy-phenyl
H
H
—CO2CH3
I-62
3-methoxy-phenyl
H
H
—CO2CH3
I-63
4-methoxy-phenyl
H
H
—CO2CH3
I-64
H
H
—CO2CH3
I-65
H
H
—CO2CH3
I-66
H
H
—CO2CH3
I-67
benzyl
H
H
—CO2CH3
I-68
4-methoxy-benzyl
H
H
—CO2CH3
I-69
—(CH2)3-OH
H
H
—CO2CH3
I-70
—(CH2)2-OH
H
H
—CO2CH3
I-71
2-methoxy-phenyl
H
H
—CH2NH2
I-72
3-methoxy-phenyl
H
H
—CH2NH2
I-73
4-methoxy-phenyl
H
H
—CH2NH2
I-74
H
H
—CH2NH2
I-75
H
H
—CH2NH2
I-76
H
H
—CH2NH2
I-77
benzyl
H
H
—CH2NH2
I-78
4-methoxy-benzyl
H
H
—CH2NH2
I-79
—(CH2)3-OH
H
H
—CH2NH2
I-80
—(CH2)2-OH
H
H
—CH2NH2.

### Claim 14 (depends on 1)

The method of claim 1, wherein the compound is one of the following or a pharmaceutically acceptable salt thereof:

### Claim 15 (depends on 2)

The method of claim 2, wherein the compound is represented by Formula I-A:
or a pharmaceutically acceptable salt thereof, wherein:
R1 is phenyl, —(C1-C6)alkylene-OH, or —(C1-C6)alkylene-O—(C1-C6)alkyl, wherein said phenyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, —(C1-C6)alkyl, —(C3-C6)cycloalkyl, hydroxyl, and —(C1-C6)alkoxy;
R2 and R3 each represent independently for each occurrence hydrogen and or methyl;
R4 is —C(O)N(R5)R6, —N(R5)C(O)R6, or —(C1-C2)alkylene-N(R5)R6; and
R5 and R6 each represent independently hydrogen, —(C1-C6)alkyl, or —(C3-C6)cycloalkyl; or
when R5 and R6 are attached to the same nitrogen atom, then R5 and R6 may be taken together with the nitrogen atom to which they are attached to form a 3-7 membered heterocycle.

### Claim 16 (depends on 2)

The method of claim 2, wherein the compound is a compound in Table 4 below or a pharmaceutically acceptable salt thereof:
TABLE 4
Compound No.
R1
R2
R3
R4
I-1
2-methoxy-phenyl
H
H
—CONH2
I-2
3-methoxy-phenyl
H
H
—CONH2
I-3
4-methoxy-phenyl
H
H
—CONH2
I-4
H
H
—CONH2
I-5
H
H
—CONH2
I-6
H
H
—CONH2
I-7
benzyl
H
H
—CONH2
I-8
4-methoxy-benzyl
H
H
—CONH2
I-9
—(CH2)3-OH
H
H
—CONH2
I-10
—(CH2)2-OH
H
H
—CONH2
I-11
—CH2CH(CH3)-OH
H
H
—CONH2
I-12
H
H
—CONH2
I-13
H
H
—CONH2
I-14
H
H
—CONH2
I-15
H
H
—CONH2
I-16
H
H
—CONH2
I-17
H
H
—CONH2
I-18
—(CH2)3-OCH3
H
H
—CONH2
I-19
—(CH2)2-OCH3
H
H
—CONH2
I-20
H
H
—CONH2
I-21
2-methoxy-phenyl
CH3
H
—CONH2
I-22
3-methoxy-phenyl
H
CH3
—CONH2
I-23
4-methoxy-phenyl
CH3
CH3
—CONH2
I-24
H
CH3
—CONH2
I-25
H
CH3
—CONH2
I-26
CH3
CH3
—CONH2
I-27
benzyl
CH3
H
—CONH2
I-28
4-methoxy-benzyl
H
CH3
—CONH2
I-29
—(CH2)3-OH
CH3
CH3
—CONH2
I-30
—(CH2)2-OH
CH3
H
—CONH2
I-31
—CH2CH(CH3)-OH
H
CH3
—CONH2
I-32
CH3
CH3
—CONH2
I-33
CH3
H
—CONH2
I-34
H
CH3
—CONH2
I-35
CH3
F
—CONH2
I-36
F
H
—CONH2
I-37
H
F
—CONH2
I-38
—(CH2)3-OCH3
CH3
Cl
—CONH2
I-39
—(CH2)2-OCH3
Cl
H
—CONH2
I-40
H
Cl
—CONH2
I-41
2-methoxy-phenyl
H
H
—CON(H)CH3
I-42
3-methoxy-phenyl
H
H
—CON(H)CH3
I-43
4-methoxy-phenyl
H
H
—CON(H)CH3
I-44
H
H
—CON(H)CH3
I-45
H
H
—CON(H)CH3
I-46
H
H
—CON(H)CH2CH3
I-47
benzyl
H
H
—CON(H)CH2CH3
I-48
4-methoxy-benzyl
H
H
—CON(H)CH2CH3
I-49
—(CH2)3-OH
H
H
—CON(H)CH2CH3
I-50
—(CH2)2-OH
H
H
—CON(H)CH2CH3
I-51
2-methoxy-phenyl
H
H
—CO2H
I-52
3-methoxy-phenyl
H
H
—CO2H
I-53
4-methoxy-phenyl
H
H
—CO2H
I-54
H
—CO2H
I-55
H
H
—CO2H
I-56
H
H
—CO2H
I-57
benzyl
H
H
—CO2H
I-58
4-methoxy-benzyl
H
H
—CO2H
I-59
—(CH2)3-OH
H
H
—CO2H
I-60
—(CH2)2-OH
H
H
—CO2H
I-61
2-methoxy-phenyl
H
H
—CO2CH3
I-62
3-methoxy-phenyl
H
H
—CO2CH3
I-63
4-methoxy-phenyl
H
H
—CO2CH3
I-64
H
H
—CO2CH3
I-65
H
H
—CO2CH3
I-66
H
H
—CO2CH3
I-67
benzyl
H
H
—CO2CH3
I-68
4-methoxy-benzyl
H
H
—CO2CH3
I-69
—(CH2)3-OH
H
H
—CO2CH3
I-70
—(CH2)2-OH
H
H
—CO2CH3
I-71
2-methoxy-phenyl
H
H
—CH2NH2
I-72
3-methoxy-phenyl
H
H
—CH2NH2
I-73
4-methoxy-phenyl
H
H
—CH2NH2
I-74
H
H
—CH2NH2
I-75
H
H
—CH2NH2
I-76
H
H
—CH2NH2
I-77
benzyl
H
H
—CH2NH2
I-78
4-methoxy-benzyl
H
H
—CH2NH2
I-79
—(CH2)3-OH
H
H
—CH2NH2
I-80
—(CH2)2-OH
H
H
—CH2NH2.

### Claim 17 (depends on 2)

The method of claim 2, wherein the compound is one of the following or a pharmaceutically acceptable salt thereof:

### Claim 18 (depends on 8)

The method of claim 8, wherein the compound is represented by Formula I-A:
or a pharmaceutically acceptable salt thereof, wherein:
R1 is phenyl, —(C1-C6)alkylene-OH, or —(C1-C6)alkylene-O—(C1-C6)alkyl, wherein said phenyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, —(C1-C6)alkyl, —(C3-C6)cycloalkyl, hydroxyl, and —(C1-C6)alkoxy;
R2 and R3 each represent independently for each occurrence hydrogen and or methyl;
R4 is —C(O)N(R5)R6, —N(R5)C(O)R6, or —(C1-C2)alkylene-N(R5)R6; and
R5 and R6 each represent independently hydrogen, —(C1-C6)alkyl, or —(C3-C6)cycloalkyl; or
when R5 and R6 are attached to the same nitrogen atom, then R5 and R6 may be taken together with the nitrogen atom to which they are attached to form a 3-7 membered heterocycle.

### Claim 19 (depends on 8)

The method of claim 8, wherein the compound is a compound in Table 4 below or a pharmaceutically acceptable salt thereof:
TABLE 4
Compound No.
R1
R2
R3
R4
I-1
2-methoxy-phenyl
H
H
—CONH2
I-2
3-methoxy-phenyl
H
H
—CONH2
I-3
4-methoxy-phenyl
H
H
—CONH2
I-4
H
H
—CONH2
I-5
H
H
—CONH2
I-6
H
H
—CONH2
I-7
benzyl
H
H
—CONH2
I-8
4-methoxy-benzyl
H
H
—CONH2
I-9
—(CH2)3-OH
H
H
—CONH2
I-10
—(CH2)2-OH
H
H
—CONH2
I-11
—CH2CH(CH3)-OH
H
H
—CONH2
I-12
H
H
—CONH2
I-13
H
H
—CONH2
I-14
H
H
—CONH2
I-15
H
H
—CONH2
I-16
H
H
—CONH2
I-17
H
H
—CONH2
I-18
—(CH2)3-OCH3
H
H
—CONH2
I-19
—(CH2)2-OCH3
H
H
—CONH2
I-20
H
H
—CONH2
I-21
2-methoxy-phenyl
CH3
H
—CONH2
I-22
3-methoxy-phenyl
H
CH3
—CONH2
I-23
4-methoxy-phenyl
CH3
CH3
—CONH2
I-24
H
CH3
—CONH2
I-25
H
CH3
—CONH2
I-26
CH3
CH3
—CONH2
I-27
benzyl
CH3
H
—CONH2
I-28
4-methoxy-benzyl
H
CH3
—CONH2
I-29
—(CH2)3-OH
CH3
CH3
—CONH2
I-30
—(CH2)2-OH
CH3
H
—CONH2
I-31
—CH2CH(CH3)-OH
H
CH3
—CONH2
I-32
CH3
CH3
—CONH2
I-33
CH3
H
—CONH2
I-34
H
CH3
—CONH2
I-35
CH3
F
—CONH2
I-36
F
H
—CONH2
I-37
H
F
—CONH2
I-38
—(CH2)3-OCH3
CH3
Cl
—CONH2
I-39
—(CH2)2-OCH3
Cl
H
—CONH2
I-40
H
Cl
—CONH2
I-41
2-methoxy-phenyl
H
H
—CON(H)CH3
I-42
3-methoxy-phenyl
H
H
—CON(H)CH3
I-43
4-methoxy-phenyl
H
H
—CON(H)CH3
I-44
H
H
—CON(H)CH3
I-45
H
H
—CON(H)CH3
I-46
H
H
—CON(H)CH2CH3
I-47
benzyl
H
H
—CON(H)CH2CH3
I-48
4-methoxy-benzyl
H
H
—CON(H)CH2CH3
I-49
—(CH2)3-OH
H
H
—CON(H)CH2CH3
I-50
—(CH2)2-OH
H
H
—CON(H)CH2CH3
I-51
2-methoxy-phenyl
H
H
—CO2H
I-52
3-methoxy-phenyl
H
H
—CO2H
I-53
4-methoxy-phenyl
H
H
—CO2H
I-54
H
—CO2H
I-55
H
H
—CO2H
I-56
H
H
—CO2H
I-57
benzyl
H
H
—CO2H
I-58
4-methoxy-benzyl
H
H
—CO2H
I-59
—(CH2)3-OH
H
H
—CO2H
I-60
—(CH2)2-OH
H
H
—CO2H
I-61
2-methoxy-phenyl
H
H
—CO2CH3
I-62
3-methoxy-phenyl
H
H
—CO2CH3
I-63
4-methoxy-phenyl
H
H
—CO2CH3
I-64
H
H
—CO2CH3
I-65
H
H
—CO2CH3
I-66
H
H
—CO2CH3
I-67
benzyl
H
H
—CO2CH3
I-68
4-methoxy-benzyl
H
H
—CO2CH3
I-69
—(CH2)3-OH
H
H
—CO2CH3
I-70
—(CH2)2-OH
H
H
—CO2CH3
I-71
2-methoxy-phenyl
H
H
—CH2NH2
I-72
3-methoxy-phenyl
H
H
—CH2NH2
I-73
4-methoxy-phenyl
H
H
—CH2NH2
I-74
H
H
—CH2NH2
I-75
H
H
—CH2NH2
I-76
H
H
—CH2NH2
I-77
benzyl
H
H
—CH2NH2
I-78
4-methoxy-benzyl
H
H
—CH2NH2
I-79
—(CH2)3-OH
H
H
—CH2NH2
I-80
—(CH2)2-OH
H
H
—CH2NH2.