# US 2018/0022756 A1 · Compounds and methods for preventing or treating sensory hair cell death

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- Number: US 2018/0022756 A1
- Document ID: US20180022756A1
- Status: Published application
- Kind: A1
- Application number: 15/547,438
- Filed: 2016-02-05
- Published: 2018-01-25
- Earliest claimed: 2015-02-06
- Assignees: University of Washington; Fred Hutchinson Cancer Research Center; Oricula Therapeutics LLC
- Applicants: University of Washington; Fred Hutchinson Cancer Research Center; Oricula Therapeutics LLC
- Inventors: Julian Simon; Graham Johnson; Edwin W. Rubel; David W. Raible; Mario D. Gonzalez; Peter C. Meltzer; Weishi Miao
- Web page: https://patentgrep.com/patent/US20180022756A1

## CPC

- C07D 495/18: Bridged systems
- A61K 31/439: the ring forming part of a bridged ring system, e.g. quinuclidine (8-azabicyclo [3.2.1] octanes A61K31/46)
- A61K 31/46: 8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
- A61K 31/7036: having at least one amino group directly attached to the carbocyclic ring, e.g. streptomycin, gentamycin, amikacin, validamycin, fortimicins
- A61K 33/243: Platinum; Compounds thereof
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 27/00: Drugs for disorders of the senses
- Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- 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
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

Disclosed herein are compounds, and pharmaceutical compositions that include such compounds, for preventing or treating hearing loss. The compounds and pharmaceutical compositions described herein prevent or treat hair cell death. In addition, the compounds and pharmaceutical compositions described herein protect against kidney damage in an individual receiving an aminoglycoside antibiotic. Methods of using the compounds, alone or in combination with other therapeutic agents, are also disclosed.

## Claims

### Claim 1

A compound having the structure of Formula (I):
wherein:
Z is a single bond, double bond, —CH2—, or —O—;
R1 is aryl or heteroaryl, wherein aryl and heteroaryl are optionally substituted with one or more R4;
R2 is H, C1-C6alkyl, C1-C6alkyl-OR6, C1-C6alkylC3-C6cycloalkyl, C1-C6alkylC2-C7heterocycloalkyl, C1-C6alkyl-CO2R6, optionally substituted C1-C6alkylaryl, or optionally substituted C1-C6alkylheteroaryl;
R3 and R5 are each independently H, or C1-C6alkyl; or
R3 and R5 together form an optionally substituted C3-C6cycloalkyl ring, optionally substituted C2-C7heterocycloalkyl ring, optionally substituted aryl ring, or an optionally substituted heteroaryl ring;
each R4 is independently selected from F, Cl, Br, I, —CN, —NO2, —CF3, —OR9, —OCF3, —NR8R9, —C(O)R10, —CO2R9, —C(O)NR8R9, —N(R8)C(O)R10, —N(R8)CO2R10, —NHS(O)2R10, —S(O)2NR8R9, C1-C6alkyl, C3-C6cycloalkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C2-C7heterocycloalkyl, aryl, and heteroaryl;
R6 is H, or C1-C6alkyl;
R8 is H, or C1-C6alkyl;
R9 is H, C1-C6alkyl, C3-C6cycloalkyl, C2-C7heterocycloalkyl, aryl, heteroaryl, C1-C6alkylaryl, or C1-C6alkylheteroaryl;
R10 is C1-C6alkyl, C3-C6cycloalkyl, C2-C7heterocycloalkyl, aryl, heteroaryl, C1-C6alkylaryl, or C1-C6alkylheteroaryl;
R11 is H, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, C2-C7heterocycloalkyl, aryl, heteroaryl, C1-C6alkylC3-C6cycloalkyl, C1-C6alkylaryl, or C1-C6alkylheteroaryl;
R12 is H, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, C2-C7heterocycloalkyl, aryl, heteroaryl, C1-C6alkylC3-C6cycloalkyl, C1-C6alkylaryl, or C1-C6alkylheteroaryl; or R11 and R12 together with the nitrogen to which they are attached form an optionally substituted C2-C7heterocycloalkyl ring; and
R13 and R14 are each independently H, or C1-C6alkyl;
or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate or hydrate, pharmaceutically acceptable salt hydrate, or pharmaceutically acceptable prodrug thereof.

### Claim 2 (depends on 1)

The compound of claim 1 or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate or hydrate, pharmaceutically acceptable salt hydrate, or pharmaceutically acceptable prodrug thereof, having the structure of Formula (Ia):

### Claim 3 (depends on 1)

The compound of claim 1 or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate or hydrate, pharmaceutically acceptable salt hydrate, or pharmaceutically acceptable prodrug thereof, having the structure of Formula (Ib):

### Claim 4 (depends on 1, 2, 3)

The compound of any one of claims 1-3 wherein R1 is aryl optionally substituted with one or more R4.

### Claim 5 (depends on 4)

The compound of claim 4 wherein R1 is phenyl optionally substituted with one or more R4.

### Claim 6 (depends on 5)

The compound of claim 5 wherein R1 is phenyl substituted with one or more R4, wherein each R4 is independently selected from F, C, Br, I, —CN, —NO2, —CF3, —OR9, —OCF3, —NR8R9, —C(O)R10, —CO2R9, C1-C6alkyl, and C1-C6haloalkyl.

### Claim 7 (depends on 6)

The compound of claim 6 wherein R1 is phenyl substituted with one R4, wherein R4 is selected from F, C, Br, I, —CN, —CF3, —OR9, —OCF3, —C(O)R10, —CO2R9, and C1-C6alkyl.

### Claim 8 (depends on 7)

The compound of claim 7 wherein R1 is 4-chlorophenyl.

### Claim 9 (depends on 1, 2, 3, 4, 5, 6, 7, 8)

The compound of any one of claims 1-8 wherein R11 and R12 are each H.

### Claim 10 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9)

The compound of any one of claims 1-9 wherein R2 is H.

### Claim 11 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9)

The compound of any one of claims 1-9 wherein R2 is C1-C6alkyl.

### Claim 12 (depends on 11)

The compound of claim 11 wherein R2 is —CH3.

### Claim 13 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12)

The compound of any one of claims 1-12 wherein R13 and R14 are each H.

### Claim 14 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12)

The compound of any one of claims 1-12 wherein R13 and R14 are each —CH3.

### Claim 15 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14)

The compound of any one of claims 1-14 wherein R3 and R5 are each H.

### Claim 16 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15)

The compound of any one of claims 1-15 wherein Z is a single bond.

### Claim 17 (depends on 1)

The compound of claim 1 having the structure:
or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate or hydrate, pharmaceutically acceptable salt hydrate, or pharmaceutically acceptable prodrug thereof.

### Claim 18 (depends on 1)

The compound of claim 1 having the structure:
or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate or hydrate, pharmaceutically acceptable salt hydrate, or pharmaceutically acceptable prodrug thereof.

### Claim 19 (depends on 1)

The compound of claim 1 having the structure:
or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate or hydrate, pharmaceutically acceptable salt hydrate, or pharmaceutically acceptable prodrug thereof.

### Claim 20

A compound having the structure of Formula (II):
wherein:
X− is a counterion;
Z is a single bond, double bond, —CH2—, or —O—;
R1 is aryl or heteroaryl, wherein aryl and heteroaryl are optionally substituted with one or more R4;
R2a is C1-C6alkyl, —C1-C6alkyl-OR5, or —C1-C6alkylC3-C6cycloalkyl;
R2 is C1-C6alkyl, —C1-C6alkyl-OR6, —C1-C6alkylC3-C6cycloalkyl, or —C1-C6alkyl-CO2R6;
R3 and R5 are each independently H, or C1-C6alkyl; or
R3 and R5 together form an optionally substituted C3-C6cycloalkyl ring, optionally substituted C2-C7heterocycloalkyl ring, optionally substituted aryl ring, or an optionally substituted heteroaryl ring;
each R4 is independently selected from F, Cl, Br, I, —CN, —NO2, —CF3, —OR9, —OCF3, —NR8R9, —C(O)R10, —CO2R9, —C(O)NR8R9, —N(R8)C(O)R10, —N(R8)CO2R10, —NHS(O)2R10, —S(O)2NR8R9, C1-C6alkyl, C3-C6cycloalkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C2-C7heterocycloalkyl, aryl, and heteroaryl;
R6 is H, or C1-C6alkyl;
R8 is H, or C1-C6alkyl;
R9 is H, C1-C6alkyl, C3-C6cycloalkyl, C2-C7heterocycloalkyl, aryl, heteroaryl, —C1-C6alkylaryl, or —C1-C6alkylheteroaryl;
R10 is C1-C6alkyl, C3-C6cycloalkyl, C2-C7heterocycloalkyl, aryl, heteroaryl, —C1-C6alkylaryl, or —C1-C6alkylheteroaryl;
R11 is H, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, C2-C7heterocycloalkyl, aryl, heteroaryl, —C1-C6alkylC3-C6cycloalkyl, —C1-C6alkylaryl, or —C1-C6alkylheteroaryl;
R12 is H, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, C2-C7heterocycloalkyl, aryl, heteroaryl, —C1-C6alkylC3-C6cycloalkyl, —C1-C6alkylaryl, or —C1-C6alkylheteroaryl; or R11 and R12 together with the nitrogen to which they are attached form an optionally substituted C2-C7heterocycloalkyl ring; and
R13 and R14 are each independently H, or C1-C6alkyl;
or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate or hydrate, pharmaceutically acceptable salt hydrate, or pharmaceutically acceptable prodrug thereof.

### Claim 21 (depends on 20)

The compound of claim 20 or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate or hydrate, pharmaceutically acceptable salt hydrate, or pharmaceutically acceptable prodrug thereof, having the structure of Formula (IIa).

### Claim 22 (depends on 20)

The compound of claim 20 or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate or hydrate, pharmaceutically acceptable salt hydrate, or pharmaceutically acceptable prodrug thereof, having the structure of Formula (IIb).

### Claim 23 (depends on 20, 21, 22)

The compound of any one of claims 20-22 wherein R1 is aryl.

### Claim 24 (depends on 23)

The compound of claim 23 wherein R1 is phenyl.

### Claim 25 (depends on 24)

The compound of claim 24 wherein R1 is substituted with one or more R4, wherein each R4 is independently selected from F, Cl, Br, I, —CN, —NO2, —CF3, —OR9, —OCF3, —NR8R9, —C(O)R10, —CO2R9, C1-C6alkyl, and C1-C6haloalkyl.

### Claim 26 (depends on 25)

The compound of claim 25 wherein R1 is substituted with one R4, wherein R4 is selected from F, Cl, Br, I, —CN, —CF3, —OR9, —OCF3, —C(O)R10, —CO2R9, and C1-C6alkyl.

### Claim 27 (depends on 26)

The compound of claim 26 wherein R1 is 4-chlorophenyl.

### Claim 28 (depends on 20, 21, 22, 23, 24, 25, 26, 27)

The compound of any one of claims 20-27 wherein R11 and R12 are each H.

### Claim 29 (depends on 20, 21, 22, 23, 24, 25, 26, 27, 28)

The compound of any one of claims 20-28 wherein R2 is —C1-C6alkyl.

### Claim 30 (depends on 20, 21, 22, 23, 24, 25, 26, 27, 28, 29)

The compound of any one of claims 20-29 wherein R2a is C1-C6alkyl.

### Claim 31 (depends on 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30)

The compound of any one of claims 20-30 wherein R13 and R14 are each H.

### Claim 32 (depends on 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30)

The compound of any one of claims 20-30 wherein R13 and R14 are each CH3.

### Claim 33 (depends on 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32)

The compound of any one of claims 20-32 wherein R3 and R5 are each H.

### Claim 34 (depends on 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33)

The compound of any one of claims 20-33 wherein Z is a single bond.

### Claim 35 (depends on 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)

A pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of claims 1-34, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate or hydrate, pharmaceutically acceptable salt hydrate, or pharmaceutically acceptable prodrug thereof, and a pharmaceutically acceptable excipient, and a pharmaceutically acceptable excipient.

### Claim 36 (depends on 35)

The pharmaceutical composition of claim 35 further comprising an aminoglycoside antibiotic.

### Claim 37 (depends on 36)

The pharmaceutical composition of claim 36 wherein the aminoglycoside antibiotic is selected from streptomycin, neomycin, framycetin, paromomycin, paromomycin sulfate, ribostamycin, kanamycin, amikacin, arbekacin, bekanamycin, dibekacin, tobramycin, spectinomycin, hygromycin B, gentamicin, netilmicin, sisomicin, isepamicin, verdamicin, and astromicin.

### Claim 38 (depends on 36)

The pharmaceutical composition of claim 36 wherein the aminoglycoside antibiotic is streptomycin.

### Claim 39 (depends on 36)

The pharmaceutical composition of claim 36 wherein the aminoglycoside antibiotic is neomycin.

### Claim 40 (depends on 36)

The pharmaceutical composition of claim 36 wherein the aminoglycoside antibiotic is amikacin.

### Claim 41 (depends on 36)

The pharmaceutical composition of claim 36 wherein the aminoglycoside antibiotic is gentamicin.

### Claim 42 (depends on 36)

The pharmaceutical composition of claim 36 wherein the aminoglycoside antibiotic is kanamycin.

### Claim 43 (depends on 36)

The pharmaceutical composition of claim 36 wherein the aminoglycoside antibiotic is tobramycin.

### Claim 44 (depends on 35, 36, 37, 38, 39, 40, 41, 42, 43)

The pharmaceutical composition of any one of claims 35-43 formulated for oral, intravenous, intramuscular, or subcutaneous administration.

### Claim 45 (depends on 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)

A method for protecting against kidney damage in an individual receiving an aminoglycoside antibiotic comprising administering to the individual a therapeutically effective amount of a compound of any one of claims 1-34, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate or hydrate, pharmaceutically acceptable salt hydrate, or pharmaceutically acceptable prodrug thereof, and a pharmaceutically acceptable excipient.

### Claim 46 (depends on 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)

A method for preventing or treating hearing loss in an individual comprising administering to the individual a therapeutically effective amount of a compound of any one of claims 1-34, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate or hydrate, pharmaceutically acceptable salt hydrate, or pharmaceutically acceptable prodrug thereof, and a pharmaceutically acceptable excipient.

### Claim 47 (depends on 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)

A method for preventing or treating sensory hair cell death in an individual comprising administering to the individual a therapeutically effective amount of a compound of any one of claims 1-34, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate or hydrate, pharmaceutically acceptable salt hydrate, or pharmaceutically acceptable prodrug thereof, and a pharmaceutically acceptable excipient.

### Claim 48 (depends on 46)

The method of claim 46 wherein the hearing loss is associated with exposure to an ototoxic agent.

### Claim 49 (depends on 47)

The method of claim 47 wherein the sensory hair cell death is associated with exposure to an ototoxic agent.

### Claim 50 (depends on 48, 49)

The method of claim 48 or claim 49 wherein the ototoxic agent is an aminoglycoside antibiotic, chemotherapeutic agent, loop diuretic, antimalarial sesquiterpene lactone endoperoxide, antimalarial quinine, salicylate, or interferon polypeptide.

### Claim 51 (depends on 50)

The method of claim 50 wherein the ototoxic agent is an aminoglycoside antibiotic.

### Claim 52 (depends on 45, 51)

The method of claim 45 or claim 51, wherein the aminoglycoside antibiotic is selected from streptomycin, neomycin, framycetin, paromomycin, paromomycin sulfate, ribostamycin, kanamycin, amikacin, arbekacin, bekanamycin, dibekacin, tobramycin, spectinomycin, hygromycin B, gentamicin, netilmicin, sisomicin, isepamicin, verdamicin, and astromicin.

### Claim 53 (depends on 52)

The method of claim 52, wherein the aminoglycoside antibiotic is streptomycin.

### Claim 54 (depends on 52)

The method of claim 52, wherein the aminoglycoside antibiotic is neomycin.

### Claim 55 (depends on 52)

The method of claim 52, wherein the aminoglycoside antibiotic is amikacin.

### Claim 56 (depends on 52)

The method of claim 52, wherein the aminoglycoside antibiotic is gentamicin.

### Claim 57 (depends on 52)

The method of claim 52, wherein the aminoglycoside antibiotic is kanamycin.

### Claim 58 (depends on 52)

The method of claim 52, wherein the aminoglycoside antibiotic is tobramycin.

### Claim 59 (depends on 50)

The method of claim 50, wherein the ototoxic agent is a chemotherapeutic agent.

### Claim 60 (depends on 59)

The method of claim 59, wherein the chemotherapeutic agent is cisplatin or carboplatin.

### Claim 61 (depends on 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)

A compound of any one of claims 1-34, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate or hydrate, pharmaceutically acceptable salt hydrate, or pharmaceutically acceptable prodrug thereof, with a maximum hair cell protection of greater than 50% in the assay described in Example 12.

### Claim 62 (depends on 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)

Use of the assay described in Example 12 for the testing of a compound of any one of claims 1-34, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate or hydrate, pharmaceutically acceptable salt hydrate, or pharmaceutically acceptable prodrug thereof.

### Claim 63

A process for the preparation of (4R,7S)-2-(3-(4-chlorophenyl)ureido)-9-methyl-5,6,7,8-tetrahydro-4H-4,7-epiminocyclohepta[b]thiophene-3-carboxamide hydrochloride, comprising:
A) the reaction of a compound with the structure
with sodium borohydride in the presence of a solvent to produce a compound with the structure
B) followed by the reaction of the compound with the structure
with pyridine and methanesulfonyl chloride in the presence of a solvent, followed by treatment with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) to produce a compound with the structure
C) followed by the reaction of the compound with the structure
with an aqueous base and then an acid to produce a compound with the structure
D) followed by the reaction of the compound with the structure
with sodium carbonate, 4-dimethylaminopyridine (DMAP), and diphenyl phosphoryl azide (DPPA) in the presence of a solvent followed by treatment with an acid to produce a compound with the structure
E) followed by the reaction of the compound with the structure
with malononitrile, sulfur, and morpholine to produce a compound with the structure
F) followed by the reaction of the compound with the structure
with concentrated sulfuric acid to produce a compound with the structure
G) followed by the reaction of the compound with the structure
with 4-chlorophenyl isocyanate in the presence of a solvent to produce a compound with the structure
H) followed by the reaction of the compound with the structure
with hydrochloric acid in the presence of a solvent produce (4R,7S)-2-(3-(4-chlorophenyl)ureido)-9-methyl-5,6,7,8-tetrahydro-4H-4,7-epiminocyclohepta[b]thiophene-3-carboxamide hydrochloride having the structure

### Claim 64

A process for the preparation of (4R,7S)-2-(3-(4-chlorophenyl)ureido)-9-methyl-5,6,7,8-tetrahydro-4H-4,7-epiminocyclohepta[b]thiophene-3-carboxamide hydrochloride, comprising:
A) the reaction of a compound with the structure
with sodium borohydride in the presence of a solvent to produce a compound with the structure
B) followed by the reaction of the compound with the structure
with pyridine and methanesulfonyl chloride in the presence of a solvent, followed by treatment with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) to produce a compound with the structure
C) followed by the reaction of the compound with the structure
with an aqueous base and then an acid to produce a compound with the structure
D) followed by the reaction of the compound with the structure
with sodium carbonate, 4-dimethylaminopyridine (DMAP), and diphenyl phosphoryl azide (DPPA) in the presence of a solvent followed by treatment with an acid to produce a compound with the structure
E) followed by the reaction of the compound with the structure
with NCCH2C(O)NH2, sulfur, and morpholine to produce a compound with the structure
F) followed by the reaction of the compound with the structure
with 4-chlorophenyl isocyanate in the presence of a solvent to produce a compound with the structure
G) followed by the reaction of the compound with the structure
with hydrochloric acid in the presence of a solvent produce (4R,7S)-2-(3-(4-chlorophenyl)ureido)-9-methyl-5,6,7,8-tetrahydro-4H-4,7-epiminocyclohepta[b]thiophene-3-carboxamide hydrochloride having the structure